CA2685134A1 - Use of cyclically substituted furopyrimidine derivatives for treating pulmonary arterial hypertonia - Google Patents

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

BHC 07 1 039-Foreign countries CR/XP/2008-01-08 Use of cyclically substituted furopyrimidine derivatives for treatinp_ pulmonary arterial hypertonia 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 types of pulmonary hypertension, and to the use thereof for the preparation of medicaments for the treatment and/or propylaxis of pulmonary arterial hypertension and other types of pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive lung disorder which, untreated, leads to death on average within 2.8 years after being diagnosed. An increasing constriction of the pulmonary circulation leads to increased stress on the right heart, which may develop into right heart failure. By definition, the mean pulmonary arterial pressure (mPAP) in a case of chronic pulmonary hypertension is > 25 mmHg at rest or > 30 mmHg during exertion (normal value < 20 mmHg). The pathophysiology of pulmonary arterial hypertension is characterized by vasoconstriction and remodeling of the pulmonary vessels. In chronic PAH there is neomuscularization of initially unmuscularized pulmonary vessels, and the vascular muscles of the already muscularized vessels increase in circumference. This increasing obliteration of the pulmonary circulation results in progressive stress on the right heart, which leads to a reduced output from the right heart and eventually ends in right heart failure [M.
Humbert et al., J. Am.
Coll. Cardiol. 2004, 43, 13S-24S]. PAH is an extremely rare disorder, with a prevalence of 1-2 per million. The average age of the patients has been estimated to be 36 years, and only 10% of the patients were over 60 years of age. Distinctly more women than men are affected [G.E. D'Alonzo et al., Ann. Intern. Med. 1991, 115, 343-349].

Despite all the advances in the therapy of pulmonary arterial hypertension there is as yet no prospect of cure of this serious disorder. Standard therapies available on the market (e.g.
prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase inhibitors) are able to improve the quality of life, the exercise tolerance and the prognosis of the patients. However, the possibility of using these medicaments is restricted through the sometimes serious side effects and/or complicated types of administration. The period over which the clinical situation of the patients can be improved or stabilized by specific monotherapy is limited.
Eventually the therapy escalates and thus a combination therapy is applied, where a plurality of medicaments must be given concurrently.

Accordingly there is a great need for novel active compounds and noel pharmaceutical therapeutic options for the treatment of pulmonary arterial hypertension, which novel therapies should be compatible with those already known. [Ghofrani et al., Herz 2005, 30, 296-302;
E.B. Rosenzweig, BHC 07 1 039-Foreign countries Expert Opin. 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 medicament-medicament interactions in such a combination therapy, these novel active ingredients ought to inhibit metabolizing P450 CYP
enzymes to only a very small extent or not at all.

The term " pulmonary arterial hypertension" includes particular types of pulmonary hypertension as have been specified for example by the World Health Organization (WHO) [Clinical Classifi-cation of Pulmonary Hypertension, Venice 2003; G. Simonneau et al., J. Am.
Coll. Cardiol. 2004, 43, 5S-12S].

According to this classification, pulmonary arterial hypertension includes idiopathic pulmonary arterial hypertension (IPAH, formerly also called primary pulmonary hypertension), familial pulmonary arterial hypertension (FPAH) and associated pulmonary arterial hypertension (APAH) which is associated with collagenoses, congenital systemic-pulmonary shunts, portal hypertension, HIV infections, intake of particular drugs and medicaments, with other disorders (thyroid disorders, glycogen storage diseases, Gaucher's disease, hereditary teleangiactasia, hemoglobino-pathies, myeloproliferative disorders, splenectomy), with disorders with a significant venous/capillary involvement such as pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis, and persistent pulmonary hypertension of neonates.

Other types of pulmonary hypertension include for example the pulmonary hypertension associated with left heart disorders, e.g. with ventricular or valvular disorders, the pulmonary hypertension associated with disorders of the respiratory tract and/or of the lungs, e.g. with chronic obstructive lung disease, interstitial lung disease or pulmonary fibrosis, the pulmonary hypertension attributable to chronic thrombotic and/or embolic disorders, e.g.
associated with thromboembolic obstruction of pulmonary arteries, and the pulmonary hypertension caused by generally inflammatory disease processes or by special causes (e.g. associated with schistosomiasis, sarcoidosis, neoplastic diseases).

Prostacyclin (PGIZ) belongs to the class of bioactive prostaglandins, which are derivatives of arachidonic acid. PGIZ is the main product of arachidonic acid metabolism in endothelial cells and is a potent vasodilator and inhibitor of platelet aggregation. PGI2 is the physiological antagonist of thromboxane A2 (TxA2), a strong vasoconstrictor and stimulator of thrombocyte aggregation, and thus contributes to the maintenance of vascular homeostasis. A drop in PGI, levels is presumed to be partly responsible for the development of various cardiovascular diseases [Dusting, G.J. et al., Pharmac. Ther. 1990, 48: 323-344; Vane, J. et al., Eur. J. Vasc. Endovasc.
Surg. 2003, 26: 571-578].

BHC 07 1 039-Foreign countries After release of arachidonic acid from phospholipids via phospholipases A2, PGIZ is synthesized by cyclooxygenases and then by PGI2-synthase. PGI2 is not stored, but is released immediately after synthesis, exerting its effects locally. PGIZ is an unstable molecule, which is transformed rapidly (half-life approx. 3 minutes) and non-enzymatically, to an inactive metabolite, 6-keto-prostaglandin-Flalpha [Dusting, G.J. et a]., Pharmac. Ther. 1990, 48: 323-344].

The biological effects of PGI2 occur through binding to a membrane-bound receptor, called the prostacyclin receptor or IP receptor [Narumiya, S. et al., Physiol. Rev. 1999, 79: 1193-1226]. The IP receptor is one of the G-protein-coupled receptors, which are characterized by seven transmembrane domains. In addition to the human IP receptor, prostacyclin receptors have also been cloned from rat and mouse [Vane, J. et al., Eur. J. Vasc. Endovasc. Surg.
2003, 26: 571-578].
In smooth muscle cells, activation of the IP receptor leads to stimulation of adenylate cyclase, which catalyses the formation of cAMP from ATP. Increase in the intracellular cAMP
concentration is responsible for prostacyclin-induced vasodilation and for inhibition of platelet aggregation. In addition to the vasoactive properties, anti-proliferative effects [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 Sci. 1995, 57: 1233-1240] and anti-arteriosclerotic effects [Rudic, R.D. et al., Circ. Res. 2005, 96: 1240-1247; Egan K.M. et al., Science 2004, 114: 784-794] have also been described for PGIZ. Furthermore, PGIZ also inhibits the formation of metastases [Schneider, M.R.
et al., Cancer Metastasis Rev. 1994, 13: 349-64]. It is unclear whether these effects are due to stimulation of cAMP formation or to 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 of potassium channels.

Although the effects of PGI2 are on the whole of benefit therapeutically, clinical application of PGI2 is severely restricted by its chemical and metabolic instability. PGIZ
analogues that are more stable, for example iloprost [Badesch, D.B. et al., J. Am. Coll. Cardiol.
2004, 43: 56S-61 S] and treprostinil [Chattaraj, S.C., Curr. Opion. Invest. Drugs 2002, 3: 582-586]
have been made available, but these compounds still have a very short time of action.
Moreover, the substances can only be administered to the patient via complicated routes of administration, e.g. by continuous infusion, subcutaneously or via repeated inhalations. These routes of administration can also have additional side-effects, for example infections or pains at the site of injection. The use of beraprost, which to date is the only PGIz derivative available for oral administration to the patient [Barst, R.J. et al., J. Am. Coll. Cardiol. 2003, 41: 2119-2125], is once again limited by its short time of action.

The compounds described in the present application are, compared with PGIZ, chemically and metabolically stable, non-prostanoid activators of the IP receptor, which imitate the biological BHC 07 1 039-Foreign countries action of PG12 and, in addition, have sufficiently high bioavailability after oral administration and/or good solubility for parental administration. Accordingly, they are highly promising starting points for novel medicaments for the treatment of pulmonary arterial hypertension as a monotherapy or in combination with other active compounds.

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 describe various 4-oxy-, 4-thio- and/or 4-aminofuro[2,3-d]pyrimidine derivatives and their use for the treatment of diseases. WO
03/018589 discloses 4-aminofuropyrimidines as adenosine kinase inhibitors for the treatment of cardiovascular diseases.
The production of certain 4-aminofuropyrimidine derivatives was announced in Chemica Scripta 1986, 26 (2): 337-342, Yakugaku Zasshi 1969, 89 (10): 1434-1439 and Yakugaku Zasshi 1977, 97 (9): 1022-1033. Compounds with a bicyclic heteroaryl nuclear structure are claimed as inhibitors of cellular adhesion in WO 00/75145.

The compounds claimed within the framework of the present application are characterized, in contrast to the compounds from the state of the art, by a 5,6-diphenylfuro[2,3-d]pyrimidine nuclear structure, which is coupled via position 4, at a certain spatial distance, to a carboxylic acid or carboxylic acid-like functionality.

The present invention provides the use of compounds of the general formula (I) A~L' L? Z

N
õ - O I N~ R 3 (1), (R ) in which A represents 0, S or N-R4, where R4 represents hydrogen, (Ci-C6)-alkyl, (C3-C+cycloalkyl or (C4-C+cycloalkenyl, Ll represents a bond or represents (CI-C4)-alkanediyl, the ring Q represents (C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-meinbered heteroaryl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (CI-C4)-alkyl, trifluoromethyl, hydroxy, (CI-Cq)-alkoxy, trifluoromethoxy, amino, BHC 07 1 039-Foreign countries mono-(CI-C4)-alkylamino and/or di-(CI-C4)-alkylamino, where (CI-C4)-alkyl for its part may be substituted by hydroxy, (CI-C4)-alkoxy, amino, mono- or di-(Ci-C4)-alkylamino, L2 represents (CI-C4)-alkanediyl which is mono- or disubstituted by fluorine and in which one methylene group may be replaced by 0 or N-R5, where R5 represents hydrogen, (Q-C6)-alkyl or (C3-C+cycloalkyl, or represents (C2-C4)-alkenediyl, Z represents a group of the formula O N-- N
#-~ # R6 #-<~ II
~N

O

~ ~NH
or #~
O--~O
in which # represents the point of attachment to the group L 2 and R6 represents hydrogen or (CI-C4)-alkyl, R' and R 2 independently of one another represent a substituent selected from the group consisting of halogen, cyano, nitro, (Ci-C6)-alkyl, (CZ-W-alkenyl, (C2-C4)-alkynyl, (C3-C7)-cycloalkyl, (C4-C+cycloalkenyl, (CX6)-alkoxy, trifluoromethyl, trifluoromethoxy, (Cl-C6)-alkylthio, (Q-C6)-acyl, amino, mono-(CI-C6)-alkylamino, di-(CI-C6)-alkylamino and (CI -C6)-acylamino, where (CI-C6)-alkyl and (CI-C6)-alkoxy for their part may each be substituted by cyano, hydroxy, (CI-C4)-alkoxy, (CI-C4)-alkylthio, amino, mono- or di-(CI-C4)-alkylamino, or two radicals R' and/or R 2 attached to adjacent carbon atoms of the respective phenyl ring BHC 07 1 039-Foreign countries together form a group of the formula -O-CHZ-O-, -O-CHF-O-, -O-CF2-O-, -O-CH2-or -O-CFZ-CFz-O-, n and o independently of one another represent the number 0, 1, 2 or 3, where, if R' or R 2 is present more than once, their meanings may in each case be identical or different, and R3 represents hydrogen, (CI-C4)-alkyl or cyclopropyl, and its salts, solvates and solvates of the salts for preparing 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, also referred to hereinafter comprehensively as compounds of the invention, are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, the compounds which are encompassed by formula (I) and are of the formulae mentioned hereinafter, and the salts, solvates and solvates of the salts thereof, and the compounds which are encompassed by formula (I) and are mentioned hereinafter as exemplary embodiments, and the salts, solvates and solvates of the salts thereof, insofar as the compounds encompassed by formula (I) and mentioned hereinafter are not already salts, solvates and solvates of the salts.

The compounds of the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The present invention therefore relates to the enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically pure constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers.

If the compounds of the invention may occur in tautomeric forms, the present invention encompasses all tautomeric forms.

Salts which are preferred for the purposes of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed are salts which are themselves unsuitable for pharmaceutical uses but can be used for example for isolating or purifying the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic BHC 07 1 039-Foreign countries acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, maleic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
Physiologically acceptable salts of the compounds of the invention include salts of conventional bases such as, by way of example and preferably, alkali metal salts (e.g.
sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having I to 16 C atoms, such as, by way of example and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Solvates refers for the purposes of the invention to those forms of the compounds of the invention which form, in the solid or liquid state, a complex by coordination with solvent molecules.
Hydrates are a specific form of solvates in which the coordination takes place with water. Hydrates are preferred solvates in the context of the present invention.

The present invention additionally encompasses the use of prodrugs of the compounds of the invention. The term "prodrugs" encompasses compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body into compounds of the invention (for example by metabolism or hydrolysis).

In particular, for the compounds of the formula (I) in which Z represents a group of the formula O O
#-`( or #
\O H O H

the present invention also includes hydrolysable ester derivatives of these compounds. These are to be understood as meaning esters which can be hydrolyzed to the free carboxylic acids, as the compounds that are mainly active biologically, in physiologically media, under the conditions of the biological tests described later and in particular in vivo by enzymatic or chemical routes. (Cl-C4)-alkyl esters, in which the alkyl group can be straight-chain or branched, are preferred as such esters. Particular preference is given to methyl or ethyl esters (see also the corresponding definitions of the radical R6).

In the context of the present invention, the substituents have the following meaning, unless specified otherwise:

BHC 07 1 039-Foreign countries LC&-al) kyl,_(Cj-Cs -al~Y_l, (CI-C4)-alkyl and (CiC -a 1kyl stand in the context of the invention for a straight-chain or branched alkyl radical having respectively I to 6, 1 to 5, 1 to 4 and I to 3 carbon atoms. A straight-chain or branched alkyl radical having I to 4, in particular I to 3, carbon atoms is preferred. Examples which may be preferably mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

(C -C6)-alkenyl and (C,-CS -alken l stand in the context of the invention for a straight-chain or branched alkenyl radical having respectively 2 to 6 and 2 to 5 carbon atoms and 1 or 2 double bonds. A straight-chain or branched alkenyl radical having 2 to 5 carbon atoms and one double bond is preferred. Examples which may be preferably mentioned are: vinyl, allyl, isopropenyl and n-but-2-en-l-yl.

CC2-C4 -alk n 1 stands in the context of the invention for a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms and one triple bond. A straight-chain alkynyl radical having 2 to 4 carbon atoms is preferred. Examples which may be preferably mentioned are:
ethynyl, n-prop-l-in-l-yl, n-prop-2-in-1-yl, n-but-2-in-1-yl and n-but-3-in-l-yl.

LC,-C4)-alkanediyl and(Cj-C3 -alkanediyl stand in the context of the invention for a straight-chain or branched divalent alkyl radical having respectively I to 4 and I to 3 carbon atoms. In each case, a straight-chain alkanediyl radical having respectively I to 4 and I to 3 carbon atoms is preferred.
Examples which may be preferably mentioned are: methylene, 1,2-ethylene, ethane-l,l-diyl, 1,3-propylene, propane-l,l -diyl, propane-l,2-diyl, propane-2,2-diyl, 1,4-butylene, butane-l,2-diyl, butane-1,3-diyl and butane-2,3-diyl.

LC~,-C&alkenediyl and Lz-C3)-alkenediyl stand in the context of the invention for a straight-chain or branched divalent alkenyl radical having respectively 2 to 4 and 2 to 3 carbon atoms and up to 2 double bonds. In each case, a straight-chain alkenediyl radical having respectively 2 to 4 and 2 to 3 carbon atoms and one double bond is preferred. Examples which may be preferably mentioned are:
ethene-1,1-diyl, ethene-1,2-diyl, propene-l,l-diyl, propene-1,2-diyl, propene-1,3-diyl, but-l-ene-1,4-diyl, but-l-ene-1,3-diyl, but-2-ene-1,4-diyl and buta-1,3-diene-1,4-diyl.

(Ci-C6 -alkoxy and (Ci-C4 -alkox stand in the context of the invention for a straight-chain or branched alkoxy radical having respectively I to 6 and 1 to 4 carbon atoms. A
straight-chain or branched alkoxy radical having I to 4 carbon atoms is preferred. Examples which may be preferably mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

LCI-C6 -Llkylthio and (C -C4 -alk lthio stand in the context of the invention for a straight-chain or branched alkylthio radical having respectively I to 6 and I to 4 carbon atoms.
A straight-chain or BHC 07 1 039-Foreign countries = -9-branched alkylthio radical having 1 to 4 carbon atoms is preferred. Examples which may be preferably mentioned are: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

LCI-C6 -ac 1 [(Ci-C6)-alkanoyl], (CI-Cs -ac 1 [(CI-CS)-alkanoyl] and Ci-C4 -ac l [(CI-C4)-alkanoyl] stand in the context of the invention for a straight-chain or branched alkyl radical having respectively I to 6, 1 to 5 and I to 4 carbon atoms which carries a doubly attached oxygen atom in the 1-position and is attached via the l-position. A straight-chain or branched acyl radical having 1 to 4 carbon atom is preferred. Examples which may be preferably mentioned are:
formyl, acetyl, propionyl, n-butyryl, isobutyryl and pivaloyl.

Mono- C&6)-alkylamino and mono-(CI-C4, -Lalkylamino stand in the context of the invention for an amino group having a straight-chain or branched alkyl substituent which has respectively I to 6 and I to 4 carbon atoms. A straight-chain or branched monoalkylamino radical having I to 4 carbon atoms is preferred. Examples which may be preferably mentioned are:
methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di- C~ C~ -~ylamino and di (Ci-C4)-alk~amino stand in the context of the invention for an amino group having two identical or different straight-chain or branched alkyl substituents having respectively I to 6 and 1 to 4 carbon atoms. Straight-chain or branched dialkylamino radicals having in each case I to 4 carbon atoms are preferred. Examples which may be preferably mentioned are: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

~CI-C-acylamino and (CI-C4 -acylamino stand in the context of the invention for an amino group having a straight-chain or branched acyl substituent which has respectively I
to 6 and 1 to 4 carbon atoms and is attached via the carbonyl group. An acylamino radical having I to 4 carbon atoms is preferred. Examples which may be preferably mentioned are: formamido, acetamido, propion-amido, n-butyramido and pivaloylamido.

LC3-C7)-cycloalkyl and (C3-C&c c~loalkyl stand in the context of the invention for a monocyclic saturated cycloalkyl group having respectively 3 to 7 and 3 to 6 carbon atoms.
A cycloalkyl radical having 3 to 6 carbon atoms is preferred. Examples which may be preferably mentioned are: cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

T4-C7)-cycloalkenyl, (C4-C~)-cycloalkenyl and (CS-C6)-c_ycloalkenyi stand in the context of the invention for a monocyclic cycloalkyl group having respectively 4 to 7, 4 to 6 and 5 or 6 carbon atoms and one double bond. A cycloalkenyl radical having 4 to 6, particularly preferably 5 or 6, BHC 07 1 039-Foreign countries carbon atoms is preferred. Examples which may be preferably mentioned are:
cyclobutenyl, cyclo-pentenyl, cyclohexenyl and cycloheptenyl.

A 5- to 7-membered heterocycle stands in the context of the invention for a saturated or partially unsaturated heterocycle having 5 to 7 ring atoms which contains one or two ring heteratoms from the group consisting of N and 0 and is attached via ring carbon atoms and/or, if appropriate, ring nitrogen atoms. A 5- or 6-membered saturated heterocycle having one or two ring heteroatoms from the group consisting of N and 0 is preferred. Examples which may be mentioned are: pyrro-lidinyl, 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 stands in the context of the invention for an aromatic heterocycle (heteroaromatic) having 5 or 6 ring atoms which contains one or two ring heteroatoms from the group consisting of N, 0 and S and is attached via ring carbon atoms and/or, if appropriate, a ring nitrogen atom. 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 includes in the context of the invention fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

If radicals in the compounds according to the invention are substituted, the radicals, unless specified otherwise, maybe mono- or polysubstituted. In the context of the present invention, for all radicals that occur more than once, their meanings are independent of one another. Substitution by 1, 2 or 3 identical or different substituents is preferred. Very particular preference is given to substitution by one substituent.

In the context of the present invention, preference is given to using compounds of the formula (1) in which A represents 0, S or N-R4, where R4 represents hydrogen, (C]-C6)-alkyl, (C3-C7)-cycloalkyl or (C4-C,)-cycloalkenyl, L' represents a bond or represents (CI-C4)-alkanediyl, the ring Q represents (C3-C+cycloalkyl, (C4-C7)-cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be substituted up to two times BHC 07 1 039-Foreign countries by identical or different substituents from the group consisting of fluorine, chlorine, (Cl-C4)-alkyl, trifluoromethyl, hydroxy, (CI-C4)-alkoxy, trifluoromethoxy, amino, mono-(Cl-C4)-alkylamino and/or di-(Ci-C4)-alkylamino, where (CI-C4)-alkyl for its part may be substituted by hydroxy, (CI-C4)-alkoxy, amino, mono- or di-(CI-C4)-alkylamino, L 2 represents (CI-C4)-alkanediyl which is mono- or disubstituted by fluorine and in which one methylene group may be replaced by 0 or N-R5, where R5 represents hydrogen, (CI-C6)-alkyl or (C3-C7)-cycloalkyl, or represents (C2-C4)-alkenediyl, Z represents a group of the formula O O N-- N
#4 # /R6 #---C~ II

H
O

j ~NH
or #~
O--~O
in which # represents the point of attachment to the group L2 and R6 represents hydrogen or (CI-C4)-alkyl, R' and R2 independently of one another represent a substituent selected from the group consisting of halogen, cyano, nitro, (CI-C6)-alkyl, (C2-C6)-alkenyl, (C2-C4)-alkynyl, (C3-C+
cycloalkyl, (C4-C7)-cycloalkenyl, (CI-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, (Cl-C6)-alkylthio, (CI-C6)-acyl, amino, mono-(CI-C6)-alkylamino, di-(CI-C6)-alkylamino and (CI-C6)-acylamino, where (CI-C6)-alkyl and (CI-C6)-alkoxy for their part may each be substituted by hydroxy, (Cf-C4)-alkoxy, amino, mono- or di-(CI-C4)-alkylamino, BHC 07 1 039-Foreign countries or two radicals R' and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CHZ-O-, -O-CHF-O-, -O-CF2-O-, -O-CH2-or -O-CF2-CFZ-O-, n and o independently of one another represent the number 0, 1, 2 or 3, where, if R' or R2 is present more than once, their meanings may in each case be identical or different, and R3 represents hydrogen, (CI-C4)-alkyl or cyclopropyl, and its salts, solvates and solvates of the salts.

In the context of the present invention, particular preference is given to using compounds of the formula (I) in which A represents 0 or N-R4, where R4 represents hydrogen, (CI-C4)-alkyl or (C3-W-cycloalkyl, L' represents a bond or represents (C,-C3)-alkanediyl, the ring Q represents (C3-W-cycloalkyl, (C4-W-cycloalkenyl, a 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (Cl-C3)-alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and/or diethylamino, where (Ci-C3)-alkyl for its part may be substituted by hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino or diethylamino, L 2 represents (C,-C3)-alkanediyl which may be mono- or disubstituted by fluorine, represents (C2-C3)-alkenediyl or represents a group of the formula *-M-CR'R8-, *-M-CHZ-CR'R8- or *-CHZ-M-CR'R8-, where * represents the point of attachment to the ring Q, M represents 0 or N-R5, where BHC 07 1 039-Foreign countries R5 represents hydrogen, (CI-C3)-alkyl or cyclopropyl, and R7 and R8 independently of one another represent hydrogen or fluorine, Z represents a group of the formula O N-- N N-- NH
#4 6 ,N or #
O-R N O
H O

in which # represents the point of attachment to group L 2 and R6 represents hydrogen, methyl or ethyl, R' and R2 independently of one another represent a substituent selected from the group consisting of fluorine, chlorine, cyano, (Q-CS)-alkyl, (C2-C5)-alkenyl, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, (Ci-C4)-alkoxy, trifluoromethyl, trifluoromethoxy, (CI-C4)-alkylthio, (CI-Cs)-acyl, amino, mono-(CI-Cq)-alkylamino, di-(Ci-Cq)-alkylamino and (CI-C4)-acylamino, or two radicals R' and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O- or -O-CF2-O-, n and o independently of one another represent the number 0, 1, 2 or 3, where, if R' or R2 is present more than once, their meanings may in each case be identical or different, and R3 represents hydrogen or (CI -C3)-alkyl, and its salts, solvates and solvates of the salts.

In the context of the present invention, very particular preference is given to using compounds of the formula (I) in which BHC 07 1 039-Foreign countries A represents 0 or N-R4, where R4 represents hydrogen or (CI -C4)-alkyl, L' represents a bond or represents (CI-C3)-alkanediyl, the ring Q represents (C4-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, a 5- or 6-membered heterocycle or phenyl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (Cl-C3)-alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethyl-amino and diethylamino, L 2 represents (CI-C3)-alkanediyl which may be mono- or disubstituted by fluorine, represents (C2-C3)-alkenediyl or represents a group of the formula *-M-CR'Rg-, *-M-CHZ-CR'R8- or *-CHZ-M-CR'Rg-, where * represents the point of attachment to the ring Q, M represents 0 or N-R5, where R5 represents hydrogen or (CI-C3)-alkyl, and R' and R8 independently of one another represent hydrogen or fluorine, Z represents a group of the formula N-- N N~NH
#- #~j or ~
O-R 6 H~ O O
in which # represents the point of attachment to the group L2 and R6 represents hydrogen, methyl or ethyl, R' and R2 independently of one another represent a substituent selected from the group consisting of fluorine, chlorine, cyano, (CI-Cs)-alkyl, (C2-C5)-alkenyl, (C3-C6)-cycloalkyl, (C4-C6)-BHC 07 1 039-Foreign countries cycloalkenyl, (Ci-C4)-alkoxy, trifluoromethyl, trifluoromethoxy, (CI-C4)-alkylthio, (CI-CS)-acyl, amino, mono-(CI-C4)-alkylamino, di-(CI-C4)-alkylamino and (Ci -C4)-acylamino, or two radicals R' and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CHZ-O-, -O-CHF-O- or -O-CF2-O-, n and o independently of one another represent the number 0, 1 or 2, where if R' or R 2 is present twice, their meanings may in each case be identical or different, and R3 represents hydrogen or (CI -C3)-alkyl, and its 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 represents 0 or NH, L' represents a bond, methylene, ethane-l,l -diyl or ethane-1,2-diyl, the ring Q represents cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino, L 2 represents (CI-C3)-alkanediyl, (CZ-C3)-alkenediyl or a group of the formula *-M-CH2- or *-M-CHZ-CH2-, where * represents the point of attachment to the ring Q
and M represents 0 or N-R5, where R 5 represents hydrogen or (Ci-C3)-alkyl, BHC 07 1 039-Foreign countries . =

Z represents a group of the formula O N--#- ( or #~ 11 \ \ ~N

in which # represents the point of attachment to the group L2 and R6 represents hydrogen, methyl or ethyl, R' and R 2 independently of one another represent a substituent selected from the group consisting of fluorine, chlorine, cyano, (C)-CS)-alkyl, (C2-C5)-alkenyl, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, (CI-C4)-alkoxy, trifluoromethyl, trifluoromethoxy, (CI-C4)-alkylthio, (CI-Cs)-acyl, amino, mono-(CI-C4)-alkylamino, di-(CI-C4)-alkylamino and (CI-C4)-acylamino, or two radicals R' and/or R 2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O- or -O-CF2-O-, n and o independently of one another represent the number 0, 1 or 2, where, if R' or R2 is present twice, their meanings may in each case be identical or different, and R3 represents hydrogen, and its salts, solvates and solvates of the salts.

Of very particular importance in the context of the present invention is the use of compounds of the formula (1) in which A represents 0 or NH, L' represents a bond, methylene or ethane-l,1-diyl, the ring Q represents cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl BHC 07 1 039-Foreign countries or phenyl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, methyl, hydroxy and methoxy, L2 represents (Ci-C3)-alkanediyl, (C2-C3)-alkenediyl or a group of the formula *-M-CHz- or *-M-CH2-CHZ-, where * represents the point of attachment to the ring Q
and M represents 0 or NH, Z represents a group of the formula //O N~
#~( or #
\ \ ~N

in which # represents the point of attachment to the group L2 and R 6 represents hydrogen, methyl or ethyl, R' represents a substituent selected from the group consisting of fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl and methoxy, R2 represents a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methyl-thio, ethylthio, amino, methylainino and ethylamino, n and o independently of one another represent the number 0, 1 or 2, where, if R' or R 2 is present twice, their meanings can in each case be identical or different, and R3 represents hydrogen, and its salts, solvates and solvates of the salts.

BHC 07 1 039-Foreign countries The individual definitions of radicals given in the respective combinations and preferred combinations of radicals are, independently of the given combination of radicals in question, also replaced by radical definitions of other combinations.

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

The compounds, which can be used according to the invention, of the formula (I) in which Z
represents -COOH or -C(=0)-COOH can be prepared by either [A] reacting compounds of the formula (II) X

N
1 - o ~ ~ (II)~
(R )~ N R3 in which R', RZ, R3, n and o each have the meanings given above and X' represents a leaving group, such as, for example, halogen, in particular chlorine, in the presence of a base, if appropriate in an inert solvent, with a compound of the formula (III) HAI-, L' &L2 Z' (I11), in which A, L', LZ and Q each have the meanings given above and Z' represents cyano or a group of the formula -[C(O)]y COOR~", in which y represents the number 0 or 1 and R6A represents (C,-C4)-alkyl, BHC 07 1 039-Foreign countries to give compounds of the formula (IV) (R2)o LL &QL2 Z' N
~ - 0 %\ 3 (IV), (R )n N R

in which A, L', LZ, Q, Z', R', R2, R3, n and o each have the meanings given above, or [B] reacting compounds of the formula (V- I) x N
1 /1 (V-1), (R )n O Nj\Rs in which R', R3, 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-1) ,L' Q L? Z' A

~ O
--- N
(R )n R3 in which A, L', L2, Q, Z', R', R3 and n each have the meanings given above, then brominating in an inert solvent using, for example, N-bromosuccinimide, to give compounds of the formula (VII-1) BHC 07 1 039-Foreign countries ,-L' Q L? Z' Br A

N
R~ O I ~ (VII-1), ~ )n N R3 in which A, L', LZ, Q, Z', R', R3 and n each have the meanings given above, and then coupling these in an inert solvent in the presence of a base and a suitable palladium catalyst with a phenylboronic acid of the formula (VIII-1) (R2)o \ OH

B (VIII-l ), - OH

in which R2 and o have the meanings given above, to give compounds of the formula (IV), or [C] reacting compounds of the formula (V-2) (R2)o x N

in which R2, R3, Xl 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) BHC 07 1 039-Foreign countries (R2)o L' Q L? Z' III:I3 in which A, L', L', Q, Z', R2, R3 and o each have the meanings given above, then brominating in an inert solvent using, for example, N-bromosuccinimide, to give compounds of the formula (VII-2) (R2)o L' L? Z' A

Br I (VII-2), O ~

in which A, L', L2, Q, Z', R2, R3 and o each have the meanings given above, and then coupling these in an inert solvent in the presence of a base and a suitable palladium catalyst with a phenylboronic acid of the formula (VIII-2) OH

B (VIII-2), (R')n OH

in which R' and n have the meanings given above, to give compounds of the formula (IV), and subsequently converting the respective resulting compounds of the formula (IV) by hydrolysis of the ester or cyano group Z' into the carboxylic acids of the formula (I-A) BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 (R2)o L' Q L? [C(O)]Y COOH
N
1 ~/ \ 3 (I-A), (R )n 0 N R

in which A, L', L2, Q, R', R2, R3, n, o and y each have the meanings given above, and then converting these, if appropriate, with the appropriate (i) solvents and/or (ii) bases or acids into their solvates, salts and/or solvates of the salts.

Inert solvents for process steps (II) + (III) -> (IV), (V-1) + (111) -> (VI-1) and (V-2) + (III) -~
(VI-2) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydro-furan, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichioroethylene, chlorobenzene or chlorotoluene, or other solvents, such as di-methylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. It is also possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or mixtures of these.

However, if appropriate, the process steps (lI) + (1I1) -> (IV), (V-1) + (III) -> (VI-1) and (V-2) +
(III) --> (VI-2) can also be carried out in the absence of a solvent.

Suitable bases for process steps (II) + (I1I) -> (IV), (V-1) + (III) -> (VI-1) and (V-2) + (III) ~
(VI-2) are customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide, or potassium hydroxide, alkali metal or alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, alkali metal alkoxides, such as sodium tert-butoxide or potassium tert-butoxide, alkali metal hydrides, such as sodium hydride or potassium hydride, amides, such as lithium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide or lithium diisopropylamide, organic metallic compounds, such as butyllithium or phenyllithium, or organic amines, such as triethylamine, N-methylmorpholine, N-methylpiperidine, N,N-diisopropyl-ethylamine or pyridine.

In the case of the reaction with alcohol derivatives [A in (III) = 0], phosphazene bases (so-called "schwesinger-bases"), such as, for example, P2-t-Bu or P4-t-Bu are likewise expedient [cf., for BHC 07 1 039-Foreign countries example, R. Schwesinger, H. Schlemper, Angew. Chetn. Int. Ed. Engl. 26, 1167 (1987);
T. Pietzonka, D. Seebach, Chem. Ber. 124, 1837 (1991)].

In the reaction with amine derivatives [A in (III) = N], the base used is preferably a tertiary amine, such as, in particular, N,N-diisopropylethylamine. However, if appropriate, these reactions can - if an excess of the amine component (III) is used - also be carried out without the addition of an auxiliary base. In the reaction with alcohol derivatives [A in (III) = 0], preference is given to potassium carbonate or cesium carbonate or the phosphazene bases P2-t-Bu and P4-t-Bu.

If appropriate, the process steps (II) + (III) -a (IV), (V-1) + (III) -> (VI-1) and (V-2) + (III) ~
(VI-2) can advantageously be carried out with addition of a crown ether.

In one process variant, the reactions (II) + (I11) --> (IV), (V-1) + (III) ->
(VI-I) and (V-2) + (III) ~
(VI-2) can also be carried out in a two-phase mixture consisting of an aqueous alkali metal hydroxide solution as base and one of the hydrocarbons or halogenated hydrocarbons mentioned above as further solvent, using a phase-transfer catalyst, such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide.

The process steps (II) + (III) -> (IV), (V-1) + (III) -> (VI-1) and (V-2) +
(111) -> (VI-2) are, in the reaction with amine derivatives [A in (III) = N], generally carried out in a temperature range of from +50 C to +150 C. In the reaction with alcohol derivatives [A in (III) =
0], the reactions are generally carried out in a temperature range of from -20 C to +120 C, preferably at from 0 C to +60 C.

The bromination in process steps (VI-1) -> (VII-1) and (VI-2) -> (VII-2) is preferably carried out in a halogenated hydrocarbon as solvent, in particular in carbon tetrachloride, in a temperature range of from +50 C to +100 C. Suitable brominating agents are elemental bromine and also, in particular, N-bromosuccinimide (NBS), if appropriate with addition of a,a'-azobis-(isobutyronitrile) (AIBN) as initiator.

Inert solvents for process steps (VII-1) +(VIII-1) -> (IV) and (VII-2) +(VIII-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 mineral oil fractions, or other solvents, such as dimethylformamide, dimethyl sulfoxide, NN'-dimethyl-propyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or else water. It is also possible to use mixtures of the solvents mentioned. Preference is given to a mixture of dimethyl sulfoxide and water.

BHC 07 1 039-Foreign countries Suitable bases for the process steps (VII-1) + (VIII-l) -> (IV) and (VII-2) +
(VIII-2) -> (IV) are customary inorganic bases. These include in particular alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal bicarbonates, such as sodium bicarbonate or potassium bicarbonate, alkali metal carbonate and alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, or alkali metal hydrogenphosphates, such as disodium hydrogenphosphate or dipotassium hydrogenphosphate. Preference is given to using sodium carbonate or potassium carbonate.

Suitable palladium catalysts for the process steps (VII-1) +(VIII-1) -> (IV) and (VII-2) +(VIII-2) -> (IV) ["Suzuki coupling"] are, for example, palladium on activated carbon, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis-(acetonitrile)palladium(II) chloride and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-(11)/dichloromethane complex [c.f., for example, J. Hassan et al., Chem. Rev.
102, 1359-1469 (2002)].

The reactions (VII-1) +(VIII-l) --> (IV) and (VII-2) +(VI1I-2) -> (IV) are generally carried out in a temperature range of from +20 C to +150 C, preferably at from +50 C to +100 C.

The hydrolysis of the ester or nitrile group Z' 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, where in the latter case the salts initially formed are converted by treatment with acid into the free carboxylic acids. In the case of the tert-butyl esters, the ester cleavage is preferably carried out using 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, dimethylforma-nide or dime-thyl sulfoxide. It is also possible to use mixtures of the solvents mentioned.
In the case of a basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and/or ethanol, and for nitrile hydrolysis, preference is given to using water and/or n-propanol. 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, preference is given to using tetrahydrofuran, diethyl ether, dioxane or water.

Suitable bases are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides, such as, for example, sodium hydroxide, lithium hydroxide, BHC 07 1 039-Foreign countries , =

potassium hydroxide or barium hydroxide, or alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate or calcium carbonate. Particular preference is given to sodium hydroxide or lithium hydroxide.

Acids suitable for the ester cleavage are, in general, sulfuric acid, hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid, or mixtures thereof, if appropriate with added water. Preference is given to hydrogen chloride or trifluoroacetic acid in the case of the tert-butyl esters and to hydrochloric acid in the case of the methyl esters.

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

Reactions mentioned can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, reactions are carried out at atmospheric pressure.

The compounds, which can be used according to the invention, of the formula (I) in which Z
represents a group of the formula N, N
#---/ I I
N`-N
H

can be prepared by reacting compounds of the formula (IV) in which Z' represents cyano in an inert solvent with an alkali metal azide in the presence of ammonium chloride or with trimethylsily] azide, if appropriate in the presence of a catalyst.

Inert solvents for this reaction are, for example, ethers, such as diethyl ether, dioxane, tetra-hydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethyl sulfoxide, dim ethyl formam ide, N,N'-dimethylpropyleneurea (DMPU) or N-methyl-pyrrolidone (NMP). It is also possible to use mixtures of the solvents mentioned. Preference is given to using toluene.

A suitable azide reagent is in particular sodium azide in the presence of amrnonium chloride or trimethylsilyl azide. The latter reaction can advantageously be carried out in the presence of a catalyst. Suitable for this purpose are in particular compounds such as di-n-butyltin oxide, trimethylaluminum or zinc bromide. Preference is given to using trimethylsilyl azide in BHC 07 1 039-Foreign countries combination with di-n-butyltin oxide.

The reaction is generally carried out in a temperature range of from +50 C to +150 C, preferably at from +60 C to +110 C. The reaction can be carried out at atmospheric, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.

The compounds, which can be used according to the invention, of the formula (1) in which Z
represents a group of the formula j -- NH
#-~
O
O
can be prepared by converting compounds of the formula (IV) in which Z' represents methoxycarbonyl or ethoxycarbonyl initially in an inert solvent with hydrazine into compounds of the formula (IX) O

H-NHz N
~ - O I %\ s (IX), ~R)~ N R

in which A, L', L 2, Q, R', RZ, R3, n and o each have the meanings given above, and then in an inert solvent with phosgene or a phosgene equivalent, such as, for example, N,N'-carbonyl diimidazole.

Suitable inert solvents for the first step of this reaction sequence are in particular 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. It is also possible to use mixtures of these solvents. Preference is given to using a mixture of methanol and tetrahydrofuran. The second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran. The reactions are generally carried out in a temperature range of from 0 C to +70 C, under atmospheric pressure.

The compounds of the formula (I) according to the invention in which L 2 represents a group of the formula *-M-CR7 R8- or *-M-CHZ-CR'R$- in which M, R' and R8 have the meanings given above BHC 07 1 039-Foreign countries can alternatively also be prepared by converting compounds of the formula (X) (R2)o ~ A1-1 L' Q MH
N
R, - o ~ ~ 3 (X), ( )~ N R

in which A, L', M, Q, R', R2, R3, n 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 (XI) X? (CHZ)m CR7 RB Z' (XI), in which R', R8 and Z' each have the meanings given above, m represents the number 0 or I

and Xz represents a leaving group, such as, for example, halogen, mesylate or tosylate, or, in the case that L2 represents *-M-CHzCHz- with a compound of the formula (XII) HZC-;:::~~Z' (XII), in which Z' has the meaning given above, into compounds of the formula (IV-A) (R2)o AL' M-(CHZ)m CR'R8 Z' kN
~
(R )n 0 N_5~k R3 in which A, L', M, Q, Z', R', R2, R3, R', R8, m, n and o each have the meanings given above, BHC 07 l 039-Foreign countries and then reacting these further, in a manner corresponding to the process described above.

The compounds of the formula (X) can be obtained from a compound of the formula (II), (V-1) or (V-2) by base-catalyzed reaction with a compound of the formula (XIII) HAL' Q M-T (XIII), in which A, L', M and Q each have the meanings given above and T represents hydrogen or a temporary 0- or N-protective group, and appropriate further reaction analogously to the process variants [B] and [C] described above, where in the case of the reaction sequence (V-1) or (V-2) ---> (IV-A) the sequence of the individual process steps, if expedient, may also be varied (cf. also the reaction schemes 2-9 below).

For the process steps (X) + (XI) or (XII) -> (IV-A) and (II) + (XIII) -~ (X), the reaction parameters described above for the reactions (II) + (III) -> (IV), (V-l ) +
(III) --~ (VI-1) and (V-2) +
(III) --> (VI-2), such as solvents, bases and reaction temperatures, are used in an analogous manner.
The compounds of the formulae (II), (III), (V-1), (VIII-1), (V-2), (VIII-2), (XI), (XII) and (XIII) are commercially available, known from the literature or can be prepared analogously to processes known from the literature (cf., for example, WO 03/018589; see also reaction scheme 1).

The preparation of the compounds according to the invention can be illustrated by the synthesis schemes below:

BHC 07 1 039-Foreign countries Scheme I

H3c-p H3c-O H3c-O

NCCN AczO O

p Et2NH CN NH
pH p NH2 p N

p J
cxLN
N

~ Br NCCN CN AcZNH
base 0 NH2 0 N/
CI

POCI3 / \ N
- p I N

HCOZH
NCCN Ac20 O
CN
0 base NH
O N

N
) BHC 07 1 039-Foreign countries Scheme 2 CI HN OH
N HzN OH N

O J base O
N

O
Br-"'Y *CH3 HN O CH3 base I J
O N

OH
I
B.
CH3 ~y Br HN O~OCH3 OH

N
base / Pd-catalyst O N-) HN O"'fO--~CH3 TFA

\N
- o J
N
~ HN OH
O
\N
- o N

BHC 07 1 039-Foreign countriescA 02685134 2009-10-23 Scheme 3 CI ~ O OH
HO OH

O I N base 0 N"

Br~
0 O+CH3 O OO~CH3 NBS

base ~
O ~
N

OH

O OO~CH3 OH

Br tj base / Pd-catalyst N

O O'-~O-f-CH3 TFA

N
o J
N
O O~OH
N O

-) BHC 07 ] 039 Forei countries Sch_e 4 H3C--O _ \ j HN Nci Hz NaNHBoC

N base /
N
O N

HN
TFA NaB(OAc)3H

O NJ

H3C-'p r`COOH
HN
~'COOCH3 NaOH
HN H \ / I N
N O N"
I ~
O N

BHC 07 1 039-Foreign countriescA 02685134 2009-10-23 Scheme 5 CI HzN O~ +CH3 / \ / \N
~ base O N

HN -'-"a O+O C

c$III1O( o N

HN O-*"Y OH
O
N

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Scheme 6 ~
I
CI HO ~ INH O \ NHz z l ~ ~ \ N base NI
- O NJ N

- r ~
Br^COOCH3 H COOCH3 NaOH
I
base N
O NJ

/ I

O \ N'-"COOH
H
O
N
Scheme 7 ~
a~--Iy `
CI HzN COOCH3 HN ~ I Y"^COOCH3 O N base O N
NJ NJ

~ I

NaOH HN \ YCOOH
! ~ ~ I N

O N
[Y = 0, NH or CHZ].

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Scheme 8 _ / I

HN \ O~-\COOCH3 N

O Nj ~ I / ~ cyanuric ~ I /~
HN O CONH2 chloride HN O CN
N N
O N/ - O N) / I

Me3SiN3 HN \ ON\ N
--> N ~ //
Bu2SnO N H N

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Scheme 9 CI HAN, Boc N~Boc O N base O N
NJ NJ

NH Br CH COOCH
TFA A ( z)x s ~
N base o NJ

A N'(CHz)X COOCH3 NaOH
o N

A N-(CHz)X COOH
N
o NJ

[A=OorNH;x1-3].
The compounds according to the invention are chemically and metabolically stable, non-prostanoid activators of the IP receptor and have good physicochemical and pharmacokinetic properties. In particular, their bioavailability after oral administration is sufficiently high and/or their solubility is satisfactory for parenteral administration.

The compounds of the invention are therefore particularly suitable for the treatment and/or prophylaxis of pulmonary arterial hypertension including its subtypes such as idiopathic and familial pulmonary arterial hypertension, and the pulmonary arterial hypertension which is associated for example with portal hypertension, fibrotic disorders, HIV
infection or inappropriate medications or toxins.

BHC 07 1 039-Foreign countries The compounds of the invention can also be used for the treatment and/or prophylaxis of other types of pulmonary hypertension. Thus, for example, they can be employed for the treatment and/or prophylaxis of pulmonary hypertension associated with left atrial or left ventricular disorders and with left heart valve disorders. ln addition, the compounds of the invention are suitable for the treatment and/or prophylaxis of pulmonary hypertension associated with chronic obstructive pulmonary disease, interstitial pulmonary disease, pulmonary fibrosis, sleep apnoea syndrome, disorders with alveolar hypoventilation, altitude sickness and pulmonary development impairments.

The compounds of the invention are furthermore suitable for the treatment and/or prophylaxis of pulmonary hypertension based on chronic thrombotic and/or embolic disorders such as, for example, thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism. The compounds of the invention can further be used for the treatment and/or prophylaxis of pulmonary hypertension connected with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis, and where the pulmonary hypertension is caused by external compression of vessels (lymph nodes, tumor, fibrosing mediastinitis).

Owing to their pharmacological profile of action, the compounds of the invention are particularly suitable for the treatment and/or prophylaxis of pulmonary arterial hypertension and of pulmonary hypertension associated with chronic obstructive and/or fibrotic pulmonary disorders, and the pulmonary hypertension attributable to chronic thrombotic and/or embolic disorders.

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

The compounds of the invention can be employed alone or in combination with other active ingredients. The present invention further relates to medicaments comprising at least one of the compounds of the invention and one or more further active ingredients, especially for the treatment and/or prophylaxis of the aforementioned disorders. Suitable active ingredients for combinations are by way of example and preferably:

= organic nitrates and NO donors such as, for example, sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

= compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as, for example, inhibitors of phospho-diesterases (PDE) 1, 2, 3, 4 and/or 5, especially PDE 5 inhibitors such as sildenafil, vardenafil and tadalafil;

BHC 07 1 039-Foreign countries = NO-independent but heme-dependent stimulators of guanylate cyclase such as in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

= NO- and heme-independent activators of guanylate cyclase, such as in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO
02/070462 and WO 02/0705 10;

= compounds which inhibit human neutrophile elastase (HNE), such as, for example, sivelestat, DX-890 (Reltran), elafin or in particular the compounds 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;

= compounds which inhibit the signal transduction cascade, 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 soluble epoxide hydrolase (sEH), such as, for example, N,N'-dicyclohexylurea, 12-(3-adamantan-1-yl-ureido)dodecanoic acid or 1 -adamantan-l-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy] pentyl } urea;

= compounds which influence 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 vasocactive intestinal polypeptide (VIP);

= agents having an antithrombotic effect, for example and preferably from the group of platelet aggregation inhibitors, of anticoagulants or of profibrinolytic substances;

= active ingredients which lower blood pressure, for example and preferably from the group of calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, Rho kinase inhibitors and diurectics; and/or = active ingredients which alter lipid metabolism, for example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT
inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile adsorbents, bile BHC 07 1 039-Foreign countries acid reabsorption inhibitors and lipoprotein(a) antagonists.

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

Agents having an antithrombotic effect preferably mean compounds from the group of platelet aggregation inhibitors, of anticoagulants or of profibrinolytic substances.

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

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

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a factor Xa inhibitor such as by way of example and preferably rivaroxaban, 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 of 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 of the invention are administered in combination with a vitamin K antagonist such as by way of example and preferably coumarin.
Agents which lower blood pressure preferably mean compounds from the group of calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, Rho kinase inhibitors, and diuretics.

BHC 07 1 039-Foreign countries In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist such as by way of example and preferably nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-I receptor blocker such as by way of example and preferably prazosin.
In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-receptor blocker such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

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

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

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist such as by way of example and preferably 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 of 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 of the invention are administered in combination with a Rho kinase inhibitor such as by way of 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 of the invention are administered in combination with a diuretic such as by way of example and preferably furosemide.

BHC 07 1 039-Foreign countries Agents which alter lipid metabolism preferably mean compounds from the group of CETP
inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT inhibitors, MTP
inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and lipoprotein(a) antagonists.

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

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

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

In a preferred embodiment of the invention, the compounds of 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 conipounds of 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 of the invention are administered in BHC 07 1 039-Foreign countries 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 of the invention are administered in combination with a lipase inhibitor such as by way of example and preferably orlistat.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as by way of example and preferably cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

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

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

The present invention further relates to 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 or familial pulmonary arterial hypertension, or pulmonary arterial hypertension associated with medicaments, toxins or other disorders, for the treatment and/or prophylaxis of pulmonary hypertension associated with left atrial or left ventricular disorders, left heart valve disorders, chronic obstructive pulmonary disease, interstitial pulmonary disease, pulmonary fibrosis, sleep apnoea syndrome, disorders with alveolar hypoventilation, altitude sickness, pulmonary development impairments, chronic thrombotic and/or embolic disorders such as, for example, thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism, or in conjunction with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis, and for the treatment and/or prophylaxis of pulmonary hypertension caused by external compression of vessels.

The present invention further relates to a method for the treatment and/or prophylaxis of pulmonary arterial hypertension and other types of pulmonary hypertension in humans and animals by administering an effective amount of at least one of the compounds of the invention or of a medicament comprising at least one of the compounds of the invention.

The medicaments to be manufactured in accordance with the use according to the invention or to be used according to the invention comprise at least one of the compounds of the invention, BHC 07 I 039-Foreign countries normally together with one or more inert, non-toxic, pharmaceutically suitable excipients.

The present invention further relates to medicaments comprising 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 disorders.

The compounds of the invention may have systemic and/or local effects. For this purpose, they can be administered in a suitable way such as, for example, by the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route or as implant or stent.

The compounds of the invention can be administered in administration forms suitable for these administration routes.

Suitable for oral administration are administration forms which function according to the prior art and deliver the compounds of the invention rapidly and/or in ainodified manner, and which contain the compounds of the invention in crystalline and/or amorphized and/or dissolved form, such as, for example, tablets (uncoated and coated tablets, for example having coatings which are resistant to gastric juice or are insoluble or dissolve with a delay and control the release of the compound of the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorption step (e.g. intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with inclusion of an absorption (e.g. by inhalation, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal).
Administration forms suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.

Suitable for the other routes of administration are, for example, pharmaceutical forms for inhalation (inter alia powder inhalers, nebulizers), nasal drops, solutions or sprays; tablets for lingual, sublingual or buccal administration, films/wafers or capsules, suppositories, preparations for the ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example patches), milk, pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration are preferred, especially oral and intravenous administration and BHC 07 1 039-Foreign countries A 02685134 2009-10-23 administration by inhalation.

The compounds of the invention can be converted into the stated administration forms. This can take place in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable excipients. These excipients include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g.
antioxidants such as, for example, ascorbic acid), colorings (e.g. inorganic pigments such as, for example, iron oxides) and masking flavors and/or odors.

It has generally proved to be advantageous on parenteral administration to administer amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight to achieve effective results. On oral administration, the dosage is about 0.01 to 100 mg/kg, preferably about 0.01 to mg/kg, and very particularly preferably 0.1 to 10 mg/kg of body weight.

It may nevertheless be necessary where appropriate to deviate from the stated amounts, in 15 particular as a function of body weight, administration route, individual response to the active ingredient, type of preparation and time or interval over which administration takes place. Thus, in some cases it may be sufficient to make do with less than the aforementioned minimum amount, whereas in other cases the upper limit mentioned must be exceeded. Where relatively large amounts are administered, it may be advisable to distribute these in a plurality of single doses over 20 the day.

The following exemplary embodiments illustrate the invention. The invention is not restricted to the examples.

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

BHC 07 l 039-Foreign countries A. Examples Abbreviations:
abs. absolute Ac acetyl Ac20 acetic anhydride Boc tert-butoxycarbonyl Bu butyl c concentration DCI direct chemical ionization (in MS) DIEA diisopropylethylamine ("Hunig base") DMF N,N-dimethylformamide DMSO dimethyl sulfoxide El electron impact ionization (in MS) eq equivalent(s) ESI electrospray ionization (in MS) Et ethyl M.P. melting point GC-MS gas chromatography-coupled mass spectrometry sat. saturated h hour(s) HPLC high pressure liquid chromatography conc. concentrate LC-MS liquid chromatography-coupled mass spectrometry Me methyl min minute(s) Ms methanesulfonyl (mesyl) MS mass spectrometry NBS N-bromosuccinimide NMR locally magnetic resonance spectrometry Pd/C palladium on activated carbon rac. racemic RP reversed phase (in HPLC) RT room temperature Rt retention time (in HPLC) TFA trifluoroacetic acid BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 THF tetrahydrofuran LC-MS, GC-MS and HPLC methods:
Method 1 (HPLC):

Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 m; mobile phase A: 5 ml of HC1O4 (70% strength)/l of water, mobile phase B:
acetonitrile;
gradient: 0 min 2% B -> 0.5min2%B-> 4.5min90%B-> 9min90%B-> 9.2min2%B--> 10 min 2% B; flow rate: 0.75 ml/min; column temperature: 30 C; UV detection: 210 nm.

Method 2 (HPLC):

Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 m; mobile phase A: 5 ml HC1O4 (70% strength)/1 of water, mobile phase B:
acetonitrile; gradient:
0min2%B-> 0.5min2%B-* 4.5min90%B-> 6.5min90%B-> 6.7min2%B-> 7.5min 2% B; flow rate: 0.75 ml/min; column temperature: 30 C; UV detection: 210 nm.

Method 3 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795;
column:
Phenomenex Synergi 2 Hydro-RP Mercury 20 mm x 4 mm; mobile phase A: I I of water + 0.5 ml of 50% strength formic acid, mobile phase B: I I of acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A--> 2.5 min 30% A-> 3.0 min 5% A -> 4.5 min 5% A;
flow rate:
0.0 min I ml/min -> 2.5 min/3.0 min/4.5 min 2 ml/min; oven: 50 C; UV
detection: 210 nm.

Method 4 (LC-MS):

Instrument: Micromass Plattform LCZ with HPLC Agilent Series 1100; column:
Thermo Hypersil GOLD 3 20 mm x 4 mm; mobile phase A: 1 1 of water + 0.5 ml of 50% strength formic acid, mobile phase B: I I of acetonitrile + 0.5 ml of 50% strength 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 rate: 0.8 ml/min; UV detection: 210 nm.

Method 5 (LC-MS):

MS instrument type: Micromass ZQ; HPLC instrument type: HP l 100 Series; UV
DAD; column:
Phenomenex Synergi 2 Hydro-RP Mercury 20 mm x 4 mm; mobile phase A: 1 1 of water + 0.5 ml of 50% strength formic acid, mobile phase B: I I of acetonitrile + 0.5 ml of 50% strength formic BHC 07 1 039-Foreign countries acid; gradient: 0.0 min 90% A-> 2.5 min 30% A -> 3.0 min 5% A-> 4.5 min 5% A;
flow rate:
0.0 min I 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 2 Hydro-RP Mercury 20 mm x 4 mm; mobile phase A: 1 1 of water + 0.5 ml of 50%
strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.5 ml of 50%
strength formic acid;
gradient: 0.0 min 90% A--> 2.5 min 30% A-> 3.0 min 5% A-> 4.5 min 5% A; flow rate: 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):

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795;
column:
Merck Chromolith SpeedROD RP-18e 100 x 4.6 mm; mobile phase A: water + 500 l of 50%
strength formic acid/1, mobile phase B: acetonitrile + 500 l of 50% strength formic acid/I;
gradient: 0.0 min 10% B-> 7.0 min 95% B -> 9.0 min 95% B; oven: 35 C; flow rate: 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):

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series; UV
DAD; column:
Phenomenex Gemini 31t 30 mm x 3.00 mm; mobile phase A: 1 I of water + 0.5 ml of 50% strength formic acid, mobile phase B: 1 I acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A-> 2.5 min 30% A-> 3.0 min 5% A--> 4.5 min 5% A; flow rate: 0.0 min I
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 x 200 m x 0.33 m;
constant helium flow: 0.88 ml/min; oven: 70 C; inlet: 250 C; gradient: 70 C, 30 C/min -> 310 C
(maintained for 3 min).

Method 10 (GC-MS):

Instrument: Micromass GCT, GC6890; column: Restek RTX-35MS, 30 m x 250 m x 0.25 m;
constant helium flow: 0.88 ml/min; oven: 60 C; inlet: 250 C; gradient: 60 C
(maintained for 0.30 min), 50 C/min -> 120 C, 16 C/min -> 250 C, 30 C/min --> 300 C
(maintained for 1.7 min).

BHC 07 1 039-Foreign countries Method I1 (GC-MS):

Instrument: Micromass GCT, GC6890; column: Restek RTX-35, 15 mx 200 pm x 0.33 m;
constant helium flow: 0.88 ml/min; oven: 70 C; inlet: 250 C; gradient: 70 C, 30 C/min -> 310 C
(maintained for 12 min).

Method 12 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:
Phenomenex Gemini 3 30 mm x 3.00 mm; mobile phase A: 1 1 water + 0.5 ml of 50% strength formic acid, mobile phase B: 1 1 of acetonitrile + 0.5 ml of 50% strength formic acid;
gradient: 0.0 min 90% A
-> 2.5 min 30% A-> 3.0 min 5% A-> 4.5 min 5% A; flow rate: 0.0 min I 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; mobile phase A: 1 1 of water + 0.5 ml of 50%
strength formic acid, mobile phase B: I I of acetonitrile + 0.5 ml of 50% strength formic acid; gradient: 0.0 min 90% A--> 2 min 65% A -> 4.5 min 5% A-> 6 min 5% A; flow rate: 2 ml/min; oven:
40 C; UV
detection: 208-400 nm.

BHC 07 1 039-Foreign countries Startin2 materials and intermediates:

Example 1A

Methyl 3-nitrophenoxyacetate I :~CH O2N LO ~ O3 O
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 71.5 g (467.3 mmol) of methyl bromoacetate are added. The mixture is stirred at 50 C for 1 h and, after cooling, poured into 7.5 liters of water. The suspension is stirred for 30 min and then filtered off with suction, and the filter residue is washed with water.
The solid is dried in a drying cabinet 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+NH4)+

'H-NMR (300 MHz, CDC13): S= 7.90 (dd, IH), 7.43 (t, IH), 7.48 (t, IH), 7.28 (dd, 1H), 4.75 (s, 2H), 3.86 (s, 3H).

Example 2A

Methyl 3-aminophenoxyacetate i a O
HzN O *11 CH3 O
Under argon, 1.3 g of palladium on activated carbon (10%) are added to 13 g (61.6 mmol) of methyl 3-nitrophenoxyacetate in 150 ml of methanol. The mixture is stirred at RT under a hydrogen atmosphere (atmospheric pressure) for 18 h. The catalyst is filtered off through kieselguhr, and the filtrate is concentrated under reduced pressure. This gives, after drying under high vacuum, 10.7 g (95.9% of theory) of the target compound.

HPLC (Method 2): R, = 2.81 min BHC 07 1 039-Foreign countries MS (DCI): m/z = 199 (M+NH4)+, 182 (M+H)+

'H-NMR (400 MHz, CDC13): b= 7.10-7.02 (m, 1H), 6.35-6.23 (m, 2H), 4.58 (s, 2H), 3.79 (s, 3H), 3.65 (br. s, 2H).

Example 3A

2-Amino-4,5-diphenyl-3-furonitrile CN

At RT, 100 g (470 mmol) of benzoin, 62.25 g (940 mmol) of malononitrile and 47.68 g (470 mmol) of triethylamine are stirred in 1345 ml of DMF overnight. A further 41 g (620 mmol) of malononitrile are added, and the mixture is once more stirred at RT for 24 h.
Ethyl acetate and water are then added, and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure.
Column chromatography on silica gel (mobile phase: dichloromethane -> dichloro-methane/methanol 98:2) gives 120 g (97.9% of theory) of the target product as a yellowish solid.
HPLC (Method 2): R, = 4.68 min MS (DCI): m/z = 278 (M+NH4)+, 261 (M+H)+.
Example 4A

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

NH
O N i At 0 C, 28.5 ml of formic acid are added dropwise to 57 ml of acetic anhydride. The mixture is stirred at 0 C for 30 min, and 10.0 g (40 mmol) of 2-amino-4,5-diphenyl-3-furonitrile are then BHC 07 1 039-Foreign countries added. Cooling is removed, and the mixture is heated under reflux 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): Rt = 4.40 min MS (DCI): m/z = 306 (M+NH4)+, 289 (M+H)+.
Example 5A

4-Chloro-5,6-diphenylfuro[2,3-d]pyrimidine c~?1 N
/J
0 Nj 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 under reflux for 3 h and then cooled and concentrated under reduced pressure. The residue is stirred with ice-water for 30 min, and dichloromethane is then added. The resulting organic phase is washed three times with water, dried over sodium sulfate and concentrated under reduced pressure. This gives 58 g (93.2% of theory) of the target product.

HPLC (Method 1): R, = 5.26 min MS (DCI): m/z = 324 (M+NH4)+, 307 (M+H)' 'H-NMR (400 MHz, CDC13): 8= 8.78 (s, IH), 7.62-7.58 (m, 2H), 7.55-7.42 (m, 5H), 7.38-7.30 (m, 3 H).

Example 6A
(4-Methoxyphenyl)[(trimethylsilyl)oxy]acetonitri 1e H3) H3C NC ~ ~ o BHC 07 1 039-Foreijzn countries Analogously to the literature procedure [J. Chem. Soc. Perkin Trans. I, 1992, 2409-2417], a solution of 221.88 g (2236 mol) of trimethylsilyl cyanide in 25 liters of benzene is added at RT
with cooling and over a period of about 5 min to a mixture of 290.0 g (2130 mmol) of 4-methoxybenzaldehyde and 1.156 g (3.622 mmol) of zinc iodide in 37.5 liters of benzene. The mixture is stirred at RT for 90 min and then concentrated under reduced pressure. T'he residue is purified by column filtration on silica gel (mobile phase:
cyclohexane/ethylacetate 4:1). This gives 442.4 g (88.3% of theory) of the target compound.

HPLC (Method 2): R, = 3.76 min MS (DCI): m/z = 253 (M+NH4)+

'H-NMR (400 MHz, CDCl3): b= 7.49 (d, 2H), 6.92 (d, 2H), 5.42 (s, IH) 3.81 (s, 3H).
Example 7A

2-Hydroxy-l-(4-methoxyphenyl)-2-phenylethanone O - CFi3 OH

According to the literature procedure [J. Cheni. 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. At below -60 C, 826 ml of n-butyllithium solution (2.5 M in n-hexane, 2.066 mol) are metered in. The mixture is stirred at <-60 C for 15 min, and a solution of 442 g (1.877 mol) of (4-methoxyphenyl)[(trimethylsilyl)oxy]acetonitrile and 1.41 liters of 1,2-dimethoxyethane is then added dropwise at <-60 C. After 30 min of further stirring at -60 C, a solution of 199.3 g (1.878 mol) of benzaldehyde in 1.4 liters of 1,2-dimethoxyethane is added at -60 C over a period of 20 min. The reaction mixture is then slowly warmed to RT over a period of 4 h. 7 liters of saturated ammonium chloride solution are added, and the mixture is extracted with ethyl acetate.
The organic phase is washed with saturated ammonium chloride solution, dried and concentrated under reduced pressure. The residue is taken up in 7 liters of dioxane and 5 liters of methanol, and 6 liters of I N hydrochloric acid are added. The mixture is stirred at RT for 3 h, 3 liters of saturated sodium chloride solution are then added and the mixture is extracted with 6.5 liters of ethyl acetate. The organic phase is washed with 1.0 liter of I N aqueous sodium hydroxide solution and with saturated sodium chloride solution and concentrated under reduced pressure. The residue is taken up in 2 liters of diisopropyl ether, insoluble components are removed by decantation and BHC 07 1 039-Foreign countries the solution is seeded with crystals. The suspension formed is stirred at RT
for 2 h, and the crystals are then filtered off with suction. The crystals are washed with 300 ml of diisopropyl ether and petroleum ether and dried under reduced pressure. This gives 236.8 g (47.8% of theory) of the target compound.

HPLC (Method 2): R, = 4.23 min MS (DCI): m/z = 260 (M+NH4)+, 243 (M+H)+

'H-NMR (400 MHz, CDC13): b= 7.92 (d, 2H), 7.38-7.28 (m, 5H), 6.88 (d, 2H), 5.90 (d, IH), 4.64 (d, 1H), 3.82 (s, 3H).

Example 8A

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

236 g (974 mmol) of 2-hydroxy-l-(4-1 nethoxyphenyl)-2-phenylethanone and 83.66 g(1266 mmol) of malononitrile are dissolved in 470 ml of DMF, and 86.6 ml (836.7 mmol) of diethylamine are added with ice-bath cooling. After I h, the mixture is warmed to RT and stirred at RT for another 4 h, and 2.5 liters of water and a few seed crystals are then added. After 30 min, supernatant water is decanted and replaced by 1.25 liters of fresh water. The suspension is mixed, and supernatant water is again removed by decantation. The sticky/crystalline residue is taken up in ethyl acetate and then concentrated almost completely under reduced pressure. The residue is stirred with 730 ml of diisopropyl ether, and the suspension is allowed to stand at RT
overnight. The solid is then filtered off with suction and dried under reduced pressure. This gives 211.5 g (57.6% of theory) of the title compound.

HPLC (Method 2): Rt = 4.60 min MS (DCI): m/z = 308 (M+NH4)+, 291 (M+H)+

'H-NMR (400 MHz, CDC13): b= 7.39-7.33 (m, 5H), 7.28-7.18 (m, 3H), 6.93 (d, 2H), 5.02 (s, 2H), 3.85 (s, 3H).

BHC 07 1 039-Foreiv-n countries . =

Example 9A

5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4(3H)-one O

NH
NJ

At 0 C, 800 ml (21.21 mol) of formic acid are added dropwise to 1600 ml (16.96 mol) of acetic anhydride. The mixture is stirred at 0 C for 30 min, and 211 g (727 mmol) of 2-amino-4-(4-methoxyphenyl)-5-phenyl-3-furonitrile are then added. Cooling is removed and the mixture is heated; at about 80 C gas starts to evolve, which lasts for about 3 h. The mixture is stirred under reflux (bath temperature about 130 C) for a total of 24 h. After cooling to RT, the mixture is stirred at 10 C for 2 h, and the solid formed is filtered off. The residue is washed with diethyl ether and dried under high vacuum. This gives 135.6 g (58.6% of theory) of the title compound.

HPLC (Method 2): Rt = 4.38 min MS (DCI): m/z = 336 (M+NH4)+, 319 (M+H)+

'H-NMR (400 MHz, CDC13): b= 10.3 (br. s, 1 H), 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 l0A
4-Chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine CI

N
N) At RT, 135 g (424 mmol) of 5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4(3H)-one are suspended in 675 ml (7241 mmol) of phosphorus oxychloride, and the mixture is then heated at BHC 07 1 039-Foreign countries . ' boiling point (evolution of HCI). After I h, the dark solution is cooled to RT
and added dropwise to a vigorously stirred mixture of 2.25 liters of water and 4.05 liters of conc. ammonia solution (25% by weight) (temperature increased to 55-75 C, pH > 9). After the addition is ended, the mixture is cooled to RT and extracted three times with in each case 1.0 liter of dichloromethane.
The combined organic phases are dried and concentrated under reduced pressure.
The residue is titrated with diethyl ether, filtered off with suction and dried under high vacuum. This gives 134.4 g(94.1 % of theory) of the title compound.

HPLC (Method 2): R, = 4.96 min MS (DCI): m/z = 354 (M+NH4)+, 337 (M+H)+

'H-NMR (400 MHz, CDC13): 8= 8.76 (s, 1H), 7.62 (d, 2H), 7.40-7.30 (m, 5H), 7.03 (d, 2H), 3.90 (s, 3H).

Example IlA
2-Amino-5-phenyl-3-furonitrile 0_/O CN

At RT, 68.6 ml (663 mmol) of diethylamine are added dropwise 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 required to maintain the temperature). Toward the end of the addition, cooling is removed, and the mixture is stirred at RT for I h and then added to 385 ml of water. The mixture is diluted with a further 125 ml of water and stirred at RT for 20 min. The precipitated solid is filtered off suction, washed twice with in each case 125 ml of water, sucked dry and washed with petroleum ether. The residue is dried under high vacuum. This gives 33.3 g (50.1% of theory) of the target compound as yellow-brown crystals.

HPLC (Method 2): R, = 4.27 min MS (DCI): m/z = 202 (M+NH4)+, 185 (M+H)+

'H-NMR (400 MHz, CDC13): b= 7.51-7.45 (m, 2H), 7.39-7.32 (m, 3H), 6.54 (s, 1H), 4.89 (br. s, I H).

BHC 07 1 039-Foreign countriescA 02685134 2009-10-23 Example 12A

6-Phenylfuro[2,3-d]pyrimidin-4(3H)-one O
ÃIXNH
o NJ

At 0 C, 424.5 ml (11.25 mol) of formic acid are added dropwise to 884.9 ml (9.378 mol) of acetic anhydride. The mixture is stirred at 0 C for 30 min, and 69.1 g (0.375 mol) of 2-amino-5-phenyl-3-furonitrile are then added. Cooling is removed and the mixture is heated; at about 80 C, gas begins to evolve, which lasts for about 3 h. The mixture is stirred under reflux for a total of 24 h (bath temperature about 130 C). After cooling of the suspension to RT, 750 ml of diisopropyl ether are added, and the mixture is cooled to 0 C and filtered off. The residue is washed with diisopropyl ether and dried under high vacuum. This gives 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)+

'H-NMR (400 MHz, DMSO-d6): b= 12.68 (br. s, 1 H), 8.17 (s, 1H), 7.88 (d, 2H), 7.52-7.48 (m, 3H), 7.42-7.38 (m, 1H).

Example 13A
4-Chloro-6-phenylfuro[2,3-d]pyrimidine CI

N

O N//

At RT, 50 g (235.6 mmol) of 6-phenylfuro[2,3-d]pyrimidin-4(3H)-one are suspended in 375 ml (4023 mmol) of phosphorus oxychloride, and the mixture is heated at boiling point (evolution of HCI). After I h, the dark solution is cooled to RT and added dropwise to a vigorously stirred mixture of 1.25 liters of water and 2.25 liters of conc. ammonia solution (25%
by weight) (temperature increased to 55-75 C, pH > 9). After the addition has ended, the mixture is cooled to RT and extracted three times with in each case 1.6liters of dichloromethane.
The combined BHC 07 1 039-Foreign countries organic phases are dried and concentrated under reduced pressure. The residue is titrated with diethyl ether, filtered off with suction and dried under high vacuum. This gives 47.3 g (87% of theory) of the target compound.

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

'H-NMR (300 MHz, DMSO-d6): S= 8.84 (s, l H), 8.05 (m, 2H), 7.77 (s, 1 H), 7.61-7.50 (m, 3H).
Example 14A

2-Amino-4-phenyl-3-furonitrile CN
~

~ NH2 With cooling at RT, 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) malononitrile in 24 ml of DMF.
The dark mixture is stirred at RT for 2 h and then, with stirring and cooling, added slowly to water (200 ml). The resulting precipitate is stirred at about 10 C for another 30 min, filtered off with suction and twice resuspended in water and again filtered off with suction.
The residue is dried under high vacuum until the weight remains constant. This gives 10.99 g(81.2%
of theory) of the target compound as a yellow-brown solid.

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

'H-NMR (400 MHz, DMSO-d6): d= 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 BHC 07 1 039-Foreign countries ~ ~O O
~ (NH

108.5 ml (1154 mmol) of acetic anhydride are cooled to 0 C, and 52.2 ml (1384 mmol) of formic acid are added under argon. The mixture is stirred at 0 C for about 45 min, and 8.5 g (46.2 mmol) of 2-amino-4-phenyl-3-furonitrile are then added a little at a time. A dark mixture is formed, the color of which, after 15 mins at 0 C, changes to violet. Cooling is removed, and the suspension, which is now blue, is warmed to RT. After 15 min, the mixture is heated to reflux (bath temperature 125-130 C), whereupon gas evolves. The mixture is stirred under reflux overnight.
After cooling, the mixture is concentrated under reduced pressure and the residue is dried under high vacuum. The crude product gives, by column filtration on silica gel (mobile phase gradient:

dichloromethane -> dichloromethane/methanol 50:1), about 3 g of a deep dark-red to black solid.
This solid is dissolved in about 8 ml of dichloromethane, precipitated with diisopropyl ether, filtered off with suction and dried under high vacuum. This gives 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, = 3.2 min.; m/z = 211 (M-H)+

'H-NMR (400 MHz, DMSO-d6): 6= 12.7 (s, 1 H), 8.26 (s, 1H), 8.19 (s, 1 H), 7.98 (d, 2H), 7.50-7.30 (m, 3H).

Example 16A
4-Chloro-5-phenylfuro[2,3-d]pyrimidine CI

N
O NJ

At RT, 9.5 ml (101.8 mmol) of phosphorus oxychloride are added to 1.8 g (about 6.8 mmol) of 5-phenylfuro[2,3-d]pyrimidin-4(3H)-one, and the mixture is heated under reflux for I h. The resulting black mixture is cooled to RT and, at < 10 C, carefully added dropwise to an efficiently stirred solution, cooled to 0 C, of 70 ml of conc. ammonia solution and 50 ml of water (pH > 9).

BHC 07 1 039-Foreign countries After the addition has ended, the black suspension is warmed to RT and stirred for another 15 min.
The black solid is filtered off with suction, three times resuspended in water and again filtered off with suction, and dried under high vacuum. The solid is dissolved in dichloromethane and subjected to column filtration on silica gel (mobile phase: dichloromethane).
This gives 1371 mg (80.6% of theory) of the target compound as a yellow solid.
LC-MS (Method 5): R, = 2.47 min.; m/z = 231(M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.90 (s, 1H), 8.49 (s, 1H), 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 H3C-0 ~ I

O \ OH
N
o NJ

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 are heated at 120 C for 2 h. After cooling, the mixture is filtered off and the filtrate is purified directly by preparative HPLC. The product obtained is titrated with dichloromethane, filtered off with suction, washed with dichloromethane and dried under reduced pressure. This gives 171.4 mg (27% of theory) of the target product 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 BHC 07 1 039-Foreign countries _ / I

O \ NH2 I \N
o J
N
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 of DMF are stirred at 80 C for 8 h. After cooling, the mixture is concentrated under reduced pressure and the residue is taken up in water. The precipitated solid is filtered off, the filter residue is washed repeatedly with water and the solid is dried at 50 C under high vacuum.
This gives 1195 mg (98.3% of theory) of the target product as a brownish solid.

LC-MS (Method 3): Rt = 2.53 min.; m/z = 410 (M+H)+

'H-NMR (300 MHz, DMSO-d6): 6= 8.53 (s, IH), 7.60-7.40 (m, 7H), 7.06-6.99 (m, 3H), 6.45 (dd, 1H), 6.34-6.27 (m, 2H), 6.25 (br. s, 2H), 3.80 (s, 3H).

Example 19A

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

HN ~ ONHZ
O
O-KJfT) At RT, ammonia in methanol (14.2 ml of an about 7 M solution) is added to 800 mg (1.66 mmol) of methyl 3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}
phenoxyacetate (example 9), and the mixture is stirred overnight. The mixture is concentrated under reduced pressure, titrated with a little methanol and filtered off with suction. The filter residue is washed with diisopropyl ether and dried at 50 C under high vacuum overnight. This gives 663 mg (86.5%
of theory) of the target product as an almost white solid.

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

BHC 07 1 039-Foreign countries 'H-NMR (300 MHz, DMSO-d6): b= 8.54 (s, IH), 7.63-7.50 (m, 5H), 7.45-7.20 (m, 9H), 6.90 (s, 1H), 6.81 (dd, 1H), 6.64 (dd, 1H), 4.41 (s, 2H), 3.90 (s, 3H).

Example 20A

(3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}
phenoxy)acetonitrile H3li-O
/ I

HN \ OCN
O-) 800 mg (1.72 mmol) of 2-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-phenoxy)acetamide are dissolved in 5 ml of DMF, the mixture is cooled to 0 C
and 316 mg (1.72 mmol) of cyanuric chloride are added. The mixture is stirred 0 C for 2 h.
Water and ethyl acetate are then 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 under reduced pressure. The crude product is purified by chromatography on silica gel (mobile phase: dichloromethane/ethyl acetate 20:1). This gives 179 mg (22.3% of theory) of the target product as a white solid.

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

'H-NMR (300 MHz, DMSO-d6): 6= 8.57 (s, 1H), 7.63-7.51 (m, 4H), 7.45-7.20 (m, 7H), 6.99 (s, 1 H), 6.89 (dd, 1 H), 6.28 (dd, 1 H), 5.65 (s, 2H), 3.90 (s, 3 H).

Example 21A

Methyl 3-(3-aminophenyl)propionate hydrochloride H 2 N O ~CH3 O
x HCI

2000 mg (12.1 mmol) of 3-(3-aminophenyl)propanoic acid are dissolved in 30 ml of methanol, the mixture is cooled to 0 C and 0.93 ml (12.7 mmol) of thionyl chloride is added dropwise. The BHC 07 1 039-Foreign countries mixture is slowly warmed to RT and stirred overnight. After concentration under reduced pressure, the residue is taken up in a little methanol. Following addition of diisopropyl ether, the precipitated solid is filtered off with suction. This gives 2450 mg (93.8% of theory) of the target product as a white solid.

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

'H-NMR (300 MHz, DMSO-d6): b= 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 dichloro-methane with saturated sodium bicarbonate solution and concentration under reduced pressure.

Example 22A

Methyl 4-(4-aminophenyl)butanoate hydrochloride ~ CH3 ~ I O
HZN
x HCI

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

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

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

Example 23A

Methyl 4-(2-nitrophenyl)butanoate BHC 07 1 039-Foreign countries O

705 mg (3.37 mmol) of 4-(2-nitrophenyl)butanoic acid are initially charged in 7 ml of methanol, the mixture is cooled to 0 C and 0.26 ml (3.54 mmol) of thionyl chloride is added dropwise. The mixture is slowly warmed to RT and stirred overnight. To bring the reaction to completion, about 20% excess of thionyl chloride are added, and the mixture is stirred at RT for a further 5 h. After concentration under reduced pressure, the residue is titrated with a little methanol, and the resulting solid is filtered off with suction. This gives 700 mg (95.5% of theory) of the target product as a white solid.

LC-MS (Method 5): R, = 2.34 min.; m/z = 224 (M+H)+.
Example 24A

Methyl 4-(2-aminophenyl)butanoate HZN

O
715 mg (3.2 mmol) of methyl 4-(2-nitrophenyl)butanoate are initially charged in 1.5 ml of ethanol, 34 mg of palladium on activated carbon (10%) are added under argon and the mixture is stirred at RT under an atmosphere of hydrogen (atmospheric pressure) overnight. To bring the reaction to completion, more palladium on activated carbon is added and the mixture is stirred under an atmosphere of hydrogen at RT for a further 24 h. The catalyst is filtered off and the solution is concentrated under reduced pressure. 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 BHC 07 1 039-Foreign countries hydrazide H
N
NJ

At RT, 215 mg (4.3 mmol) of hydrazine hydrate are added 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 of THF and 2 ml of methanol. The mixture is stirred at 65 C for I h and at RT
overnight and then concentrated under reduced pressure. After titration with diisopropyl ether, the solid is filtered off with suction and dried under reduced pressure. This gives 89.3 mg (89.3% of theory) of the target product.

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

'H-NMR (400 MHz, DMSO-d6): 8= 9.20 (s, 1 H), 8.51 (s, 1 H), 7.62-7.51 (m, 4H), 7.43-7.36 (m, 3H), 7.30-7.20 (m, 5H), 6.95 (d, 1 H), 6.89 (s, 1 H), 4.24 (br. s, 2H), 3.89 (s, 3H).

General Procedure A: reaction of amines with 4-chlorofuro[2,3-d]pyrimidine derivatives A mixture of 1.0 eq. of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, 1.0 to 1.4 eq. of amine component and 1.5 to 3.0 eq. of DIEA in DMF (concentration 0.5 to 1.5 mol/1) is stirred at 80-140 C for 1-24 h. After cooling, the DMF is removed under reduced pressure and the residue is treated with water. The mixture is extracted with dichloromethane, and the organic phase is washed with saturated sodium bicarbonate solution and sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The target compound can be isolated and purified from the crude product by crystallization from alcoholic solvents (for example methanol), by chromatography on silica gel (preferred mobile phase systems are dichloromethane/methanol and cyclohexane/ethyl acetate), by preparative RP-HPLC (mobile phase: water/acetonitrile) or by a combination of these methods.

General Procedure B: reaction of alcohols with 4-chlorofuro[2,3-d]pyrimidine derivatives At from 0 C to RT, a solution of from 1.0 to 1.5 eq. of phosphazene base P2-t-Bu in THF (about 2 mol/l) [from Fluka, Art. No. 79416] or phosphazene P4-t-Bu in cyclohexane (about I mol/1) [from Fluka, Art. No. 79421 ] is added dropwise to a mixture of 1.0 eq. of 4-chloro-5-(4-BHC 07 1 039-Foreign countries methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and from 1.0 to 1.5 eq. of alcohol component in THF or DMF (or mixtures thereof; concentration from 0.2 to 1.0 mol/1). The mixture is stirred at RT for 30 min to 6 h. The mixture is then diluted with dichloromethane or ethyl acetate and subjected to aqueous work-up. 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 under reduced pressure. The target compound can be isolated and purified from the crude product by crystallization from alcoholic solvents (for example methanol), by chromatography on silica gel (preferred mobile phase systems are dichloromethane/methanol and cyclohexane/ethyl acetate), by preparative RP-HPLC (mobile phase:
water/acetonitrile) or by a combination of these methods.

The following compounds are prepared according to General Procedure A or B
starting with 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and the appropriate amines or alcohols:

Example Structure Analytical data 26A H3C-O LC-MS (Method 6): R, = 3.10 O CFi3 ~-CH3 min.; m/z = 515 (M+H)+.

N
o NJ

(+/-)-cis/trans 27A H3C-O LC-MS (Method 6): R, = 3.22 CH3 min.; m/z = 502 (M+H)+
p N~~~CH3 0 CH3 'H-NMR (400 MHz, DMSO-db):
~~ b= 8.61 (s, 1 H), 7.52 (d, 2H), 7.45-7.31 (m, 5H), 7.0 (d, 2H), (rac.) 5.20 (br. s, 1 H), 4.34 (br. d, 1 H), 3.90-3.80 (m, 4H), 3.14 (br. d, 1 H), 2.28 (br. t, 1 H), 1.85-1.68 (m, 2H), 1.45-1.25 (m, 5H), 0.97 (s, 9H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 28A H3C-0 LC-MS (Method 6): Rt = 3.27 min.; m/z = 502 (M+H)+
o ~-C CH3 o ~CH3 'H-NMR (400 MHz, DMSO-d6):
N
) CH3 b= 8.58 (s, IH), 7.52 (d, 2H), N
7.42-7.37 (m, 5H), 7.03 (d, 2H), (rac.) 4.58-4.40 (m, 2H), 3.90-3.81 (m, 4H), 3.22-3.13 (m, 1H), 2.95-2.80 (m, IH), 1.88-1.75 (m, IH), 1.64-1.45 (m, 3H), 1.35 (s, 9H).

29A H3C-0 LC-MS (Method 6): Rt = 3.06 /CH3 min.; m/z = 501 (M+H)+
\
~ `f---CH3 HN NY
O ICH3 'H-NMR (400 MHz, DMSO-d6):
J N 8= 8.39 (s, 1 H), 7.49 (d, 2H), 7.47-7.33 (m, 5H), 7.15 (d, 2H), (rac.) 4.92 (d, 1H), 4.05 (br. s, 1H), 3.86 (s, 3H), 3.60 (br. s, l H), 3.17 (br. s, 1 H), 2.89 (br. s, I H), 1.75 (br. t, IH), 1.45-1.0 (m, 12H).

30A H3C-0 LC-MS (Method 6): R, = 3.32 N13 min.; m/z = 502 (M+H)+
0 ~-p CH3 o ~CH3 'H NMR (400 MHz, DMSO-d6):
N
CH3 S= 8.58 (s, 1 H), 7.52 (d, 2H), 7.42-7.37 (m, 5H), 7.03 (d, 2H), (R-enantiomer) 4.59-4.40 (m, 2H), 3.87 (m, 1 H), 3.81 (s, 3H), 3.22-3.13 (m, 1H), 2.95-2.80 (m, 1H), 1.88-1.75 (m, 1H), 1.64-1.45 (m, 3H), 1.35 (s, 9H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 31A H3C-O LC-MS (Method 3): Rt = 3.14 f""' 0 min.; m/z = 502 (M+H)+
O /~-O CH3 ~ ~~H3 'H NMR (400 MHz, DMSO-d6):
N
_ ) CH3 b= 8.58 (s, 1H), 7.52 (d, 2H), N
7.42-7.37 (m, 5H), 7.03 (d, 2H), (S-enantiomer) 4.59-4.40 (m, 21-1), 3.87 (m, 1 H), 3.81 (s, 3H), 3.22-3.13 (m, 1H), 2.95-2.80 (m, 1H), 1.88-1.75 (m, 1H), 1.64-1.45 (m, 3H), 1.35 (s, 9H).

Example 32A

(+/-)-cis/trans-3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyclohexanol O OH
N
N/
1.552 g (13.36 mmol) of 1,3-cyclohexanediol (cis/trans mixture) are dissolved in 12 ml of absolute THF, the mixture is cooled to 0 C and 13.36 ml of phosphazene base P2-t-Bu in THF (about 2 M
solution) are added. After the addition has ended, stirring at RT is continued for about 10 min, the mixture is then once more cooled to 0 C and 3.0 g (8.91 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine are added a little at a time. The reaction mixture is stirred at RT for 1 h, 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 under reduced pressure. The residue is purified by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 5:1 -> 1:1). This gives 3.02 g(81 % of theory) of the target compound.
LC-MS (Method 3):
Isomer I R, = 2.52 min.; m/z = 417 (M+H)+, Isomer 2 R, = 2.55 min.; m/z = 417 (M+H)+.

BHC 07 1 039-Foreign countries The cis/trans isomer mixture obtained in this manner is separated by HPLC
[mobile phase:
water/acetonitrile 1:1; Kromasil column 100 C 18, 250 mm x 20 mm; flow rate:
25 ml/min; UV
detection: 210 nm; temperature: 30 C]. 2.0 g of isomer mixture, dissolved in 35 ml of THF and about 15 mi of water, are applied in a plurality of injections (injection volume about I ml). This gives 750 mg of (+/-)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]oxy}cyclohexanol (example 33A) and 640 mg of (+/-)-trans-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol (example 34A).

Example 33A

(+I-)-cis-3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
cyclohexanol O OH
N
/
N

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

'H-NMR (400 MHz, DMSO-d6): b= 8.57 (s, 1 H), 7.53 (m, 2H), 7.42-7.37 (m, 5H), 7.0 (d, 2H), 5.11 (m, IH), 4.69 (d, 1 H), 3.83 (s, 3H), 2.27 (d, 1 H), 2.01 (d, l H), 1.79 (d, 1 H), 1.62-1.68 (m, IH), 1.30-1.05 (m, 4H).

Example 34A

(+/-)-trans-3-{ [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
cyclohexanol O ""' OH
N
O N) LC-MS (Method 5): R, = 2.88 min.; m/z = 417 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6 = 8.58 (s, IH), 7.54 (d, 2H), 7.42-7.39 (m, 5H), 7.04 (d, 2H), BHC 07 1 039-Foreign countries 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 OH

O OH
N
O N) Dehydration of all-cis-1,3,5-cyclohexanetriol dihydrate: all-cis-1,3,5-cyclohexanetriol dihydrate is dissolved in DMF at 70 C. The volatile components are removed under reduced pressure, and the residue is dried under high vacuum.

0.81 g (6.12 mmol) of all-cis-1,3,5-cyclohexanetriol are dissolved in 15 ml of DMF, the mixture is cooled to 0 C and 245 mg of sodium hydride (about 60% strength dispersion in oil, about 6.12 mol) are added a little at a time. The suspension is stirred at RT for I
h and at 40-50 C for about 2.5 h. 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. The reaction mixture is carefully poured into water. After saturation with sodium chloride, the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel (mobile phase: dichloromethane/methanol 30:1 -> 4:1). This gives 1.38 g (77.8%
of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): S= 8.59 (s, IH), 7.55 (m, 2H), 7.46-7.40 (m, 5H), 7.02 (d, 2H), 5.61 (m, l H), 4.74 (d, 2H), 3.84 (s, 3H), 3.58-3.49 (m, 2H), 2.27-2.20 (m, 2H), 2.05 (d, 1 H), 1.06 (q, 3H).

General Procedure C: Removal of Boc protective groups At from 0 C to RT, 0.5-1.0 parts by volume of TFA are added dropwise to a solution of Boc-BHC 07 1 039-Foreign countries protected amine in dichloromethane (concentration froin 0.1 to 1.5 mol/1, if appropriate with a few drops of water) (resulting in a dichloromethane/TFA ratio of from about 2:1 to 1:1). The mixture is stirred at RT for a period of from 30 min to 18 h. After dilution with dichloromethane, the mixture is washed with saturated sodium carbonate solution or sodium bicarbonate solution. The organic phase is dried over magnesium sulfate or sodium sulfate and concentrated under reduced pressure.
If appropriate, the amine can be purified further by preparative HPLC or chronlatography on silica gel (mobile phase: dichloromethane/methanol).

The following compounds are prepared in accordance with the General Procedure C starting with compounds 26A - 31 A:

Example Structure Analytical data 36A H3C-O LC-MS (Method 3): R, = 1.56 min.; m/z = 415 (M+H)+. -'-"a HN NH2 (+/-)-cis/trans 37A H3C-O LC-MS (Method 5): Rt = 1.81 NH min.; m/z = 402 (M+H)+
O
'H-NMR (400 MHz, DMSO-d6):
6= 8.68 (s, IH), 7.56 (d, 2H), O N 7.49-7.39 (m, 5H), 7.03 (d, 2H), (rac.) 5.15 (m, 1H), 3.83 (s, 3H), 3.02 (dd, 1H), 2.72-2.55 (m, 3H), 1.97-1.90 (m, 1H), 1.56-1.32 (m, 3H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 38A H3C-O LC-MS (Method 3): R, = 1.54 NN min.; m/z = 402 (M+H)+

'H-NMR (400 MHz, DMSO-d6):
6= 8.59 (s, 1 H), 7.55 (d, 2H), - o J
N 7.46-7.39 (m, 5H), 7.03 (d, 2H), (rac.) 4.31 (q, 2H), 3.82 (s, 3H), 3.5-3.30 (m, 2H), 2.80-2.72 (m, 1 H), 2.20-2.12 (m, 1H), 1.78-1.70 (m, IH), 1.60-1.55 (m, 2H), 1.40-1.30 (m, 1 H).

39A H3C-O LC-MS (Method 3): R, = 1.52 NH min.; m/z = 401 (M+H)+
HN
'H-NMR (400 MHz, DMSO-d6):
N
S= 8.35 (s, lH), 7.50-7.47 (m, 0 N 4H), 7.40-7.31 (m, 4H), 7.15 (d, (rac.) 2H), 5.29 (d, I H), 4.19 (m, 1 H), 3.86 (s, 3H), 2.95 (d, 1 H), 2.75-2.69 (m, 1H), 2.62-2.58 (m, 1 H), 2.50-2.47 (m, 2H), 1.73-1.68 (m, 1 H), 1.47-1.32 (m, 3H).

40A H3C-O LC-MS (Method 6): R, = 1.66 N min.; m/z = 402 (M+H)+
p H
'H-NMR (400 MHz, DMSO-d6):
N 8 = 8.58 (s, 1H), 7.55 (d, 2H), 0 7.46-7.39 (m, 5H), 7.03 (d, 2H), (R-enantiomer) 4.30 (dd, 1 H), 4.20 (dd, 1 H), 3.82 (s, 3H), 3.20 (m, l H), 2.70 (m, 2H), 1.69-1.52 (m, 3H), 1.30-1.20 (m, 2H).

BHC 07 1 039-Forei gn countries Example Structure Analytical data 41A H3C-O LC-MS (Method 6): Rt = 1.66 ..."'N min.; m/z = 402 (M+H)+
O H
'H-NMR (400 MHz, DMSO-d6):
8= 8.58 (s, 1H), 7.55 (d, 2H), O N_)_ 7.46-7.39 (m, 5H), 7.03 (d, 2H), (S-enantiomer) 4.30 (dd, 1 H), 4.20 (dd, 1 H), 3.82 (s, 3H), 3.20 (m, 1H), 2.70 (m, 2H), 1.69-1.52 (m, 3H), 1.30-1.20 (m, 2H).

Example 42A

tert-Butyl (+I-)-cis- [3-hydroxycyclohexyl]oxy} acetate "", =,O CH
HO O ~ )<CH, 5.0 g (43 mmol) of cis/trans-1,3-cyclohexanediol (about 1.2:1 cis/trans mixture) are dissolved in 20 ml of absolute THF, and 24.8 ml (about 49.5 mmol) of phosphazene base P2-t-Bu in THF
(about 2 M solution) are added dropwise at RT. The solution is stirred at RT
for 30 min and then added dropwise to a mixture of 9.5 ml (64.6 mmol) of tert-butyl bromoacetate and 10 ml of THF.
The mixture is stirred at RT overnight and then diluted with dichloromethane, and the organic phase is washed successively with I N hydrochloric acid, buffer solution (pH
7) and sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product is separated by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 5:1 -> 1:1). 2.73 g (27.6% of theory) of the cis-configured target compound are isolated as a pure fraction.

MS (DCI): m/z = 248 (M+NH4)+

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

BHC 07 1 039-Foreign countries Example 43A

tert-Butyl (+/-)-trans-{[3-aminocyclohexyl]oxy}acetate ,,, O CH3 H2N O~ )<CH3 Step a :

500 mg (2.17 mmol) of tert-butyl (+/-)-cis-{[3-hydroxycyclohexyl]oxy}acetate and 0.907 ml (6.51 mmol) of triethylamine are dissolved in 2 ml of dichloromethane, and the mixture is cooled to 0 C. 0.20 ml (2.61 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 0 C for I h and then added to water. The organic phase is separated off, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure.
This gives 690 mg of the mesylate, which is directly reacted further.

Step b :

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

Step c :

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

Example 44A

(+/-)-cis/trans-3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} cyclohexanol BHC 07 1 039-Foreign countries HN OH
N
O NJ

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) of (+/-)-cis/trans-3-aminocyclohexanol (about 3:1 cis/trans mixture; prepared according to J. Chem. Soc. Perkin Trans. I, 1994, 537) are initially charged in 2.7 ml of DMF.
After addition of 1.03 ml (5.94 mmol) of DIEA, the mixture is heated at 120 C
for 2 h. After cooling, the mixture is added to ice-water. The precipitated solid is filtered with suction, washed with water and dried under reduced pressure. The crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1 -> 1:2). This gives 1.05 g(85.1% of theory) of the target product as a cis/trans mixture.

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

(+/-)-cis-3-[(6-Phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexanol HN OH
\N
o J

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 of (+/-)-cis/trans-3-aminocyclohexanol (about 85% pure, 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 heated at 120 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 under reduced pressure.
By repeatedly stirring the crude product with a mixture of methyl tert-butyl ether and dichloromethane, the product is enriched in the mother liquor. After concentration of the mother liquor, the product is, after crystallization from dichloromethane/methanol (10:1), filtered off with BHC 07 1 039-Foreigii countries suction and dried under reduced pressure. 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)+

'H-NMR (400 MHz, DMSO-d6): b= 8.25 (s, 1H), 7.88-7.72 (m, 3H), 7.55-7.47 (m, 2H), 7.46-7.38 (m, 2H), 4.71 (d, 1H), 4.11-4.01 (m, 1H), 3.59-3.47 (m, 1H), 2.19 (d, 1H), 1.96-1.19 (m, 3H), 1.36-1.05 (m, 4H).

Example 46A

tert-Butyl (+/-)-cis-({3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}oxy)acetate ~CH
C! CH3 O~JfIJ

At 40 C, about 0.06 mmol of tetrabutylammonium hydrogensulfate and a solution of 200 mg (0.646 mmol) of (+/-)-cis-3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexanol in 0.5 ml of toluene and 0.1 ml of THF are added to a mixture of 517 mg of 50% strength aqueous sodium hydroxide solution (6.5 mmol) and 0.5 ml of toluene. With vigorous stirring, 0.19 ml (1.29 mmol) of tert-butyl bromoacetate are added to the resulting mixture, and the mixture is heated at 70 C.
After 2 h, the mixture is cooled and added to water. The mixture is extracted three times with dichloromethane, and the combined organic phases are washed with saturated sodium chloride solution and concentrated under reduced pressure. The crude product gives, after preparative RP-HPLC (mobile phase: acetonitrile/water) 152 mg (55.5% of theory) of the target product.

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

'H-NMR (400 MHz, DMSO-d6): b= 8.26 (s, 1H), 7.89-7.78 (m, 3H), 7.51 (t, 2H), 7.45-7.39 (m, 2H), 4.17-4.05 (m, 1 H), 4.01 (s, 2H), 3.49-3.40 (m, I H), 2.33 (br. d, 1 H), 2.01 (br. d, 1 H), 1.91 (br.
d, 1 H), 1.81-1.75 (m, 1 H), 1.42 (s, 9H), 1.34-1.10 (m, 4H).

Example 47A

tert-Butyl (+/-)-cis-({3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}oxy)acetate BHC 07 1 039-Foreign countries Br HN O )<CH 3 N

O Ni 132 mg (0.312 mmol) of tert-butyl (+/-)-cis-({3-[(6-phenylfuro[2,3-d]pyrimidin-yl)amino]cyclohexyl}oxy)acetate are suspended in 0.3 ml of carbon tetrachloride, 61 mg (0.343 mmol) of NBS are added and the mixture is heated at reflux. After complete conversion (about I h), the reaction mixture is cooled and the product is isolated directly by preparative RP-HPLC. This gives 104 mg (66.4% of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.34 (s, IH), 8.01 (d, 2H), 7.60-7.49 (m, 3H), 7.08 (br. d, 1H), 4.42-4.25 (m, IH), 4.09 (s, 2H), 3.65-3.58 (m, IH), 2.11 (br. d, 1H), 1.81-1.68 (m, 4H), 1.65-1.47 (m, 2H), 1.43 (s, 9H), 1.41-1.30 (m, 1H).

Example 48A

tert-Butyl (+/-)-cis-({3-[(5-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate ~ I N
O Ni 500 mg (2.17 mmol) of tert-butyl (+/-)-cis-{[3-hydroxycyclohexyl]oxy}acetate are dissolved in 2.0 ml of dry THF, the mixture is cooled to 0 C and 1.24 ml (about 2.5 mmol) of a 2 N solution of phosphazene base P2-t-Bu in THF are added. Cooling is removed, and the mixture is then stirred at RT for 30 min, followed by the addition of 500.7 mg (2.17 mmol) of 4-chloro-5-phenylfuro[2,3-d]pyrimidine at RT. The mixture is stirred at RT overnight and then concentrated under reduced pressure. 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 RP-HPLC
(mobile phase: acetonitrile/water). This gives 380 mg (41.2% of theory).

BHC 07 1 039-Foreign countries LC-MS (Method 3): R, = 2.89 min.; m/z = 425 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.61 (s, 1H), 8.35 (s, IH), 7.27 (d, 2H), 7.49-7.39 (m, 3H), 5.25 (m, l H), 3.99 (s, 2H), 3.47 (m, 1 H), 2.12 (br. s, IH), 1.99 (br. d, 1 H), 1.32-1.26 (m, IH), 1.41 (s, 9H), 1.40-1.12 (m, 5H).

Example 49A

tert-Butyl (+/-)-cis-({3-[(6-bromo-5-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate Q O O~ O C H 3 )<CH

I
N
100 mg (0.236 mmol) of tert-butyl (+/-)-cis-({3-[(5-phenylfuro[2,3-d]pyrimidin-yl)oxy]cyclohexyl}oxy)acetate are suspended in 0.2 ml of carbon tetrachloride, and 46.1 g (0.259 mmol) of NBS are added. The reaction mixture is stirred at 60 C for a total of 2 h, with a further 23 mg of NBS being added after I h. After cooling, the carbon tetrachloride is removed under reduced pressure and the residue is purified by preparative RP-HPLC
(mobile phase:
acetonitrile/water). This gives 43.6 mg (36.8% of theory) of the target product.

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

'H-NMR (400 MHz, DMSO-d6): b= 8.59 (s, 1H), 7.62 (d, 2H), 7.53-7.43 (m, 3H), 5.15 (m, 1H), 3.98 (s, 2H), 3.41 (m, 1 H), 2.45 (br. d, 1 H), 2.04 (br. d, l H), 1.95 (br.
d, 1 H), 1.41 (s, 9H), 1.30-1.06 (m, 5H).

Example 50A
(4-Ethylphenyl)[(trimethylsilyl)oxy]acetonitrile ~ H3 NC

In 5.3 liters of toluene, 600 g (4.47 mol) of 4-ethylbenzaldehyde are mixed with 2.4 g (7.5 mmol) of zinc iodide. At RT and with gentle cooling, 587.4 ml (4.7 mol) of trimethylsilyl cyanide, BHC 07 1 039-Foreign countries dissolved in 3.6 liters of toluene, are added over a period of about 5 min.
The mixture is stirred at RT for 90 min, after which volatile components are removed under reduced pressure and the residue is subjected to flash chromatography on silica gel (mobile phase:
petroleum ether/ethyl acetate 9:1). This gives 990 g (94.9% of theory) of the title compound as a colorless oil.

'H-NMR (400 MHz, CDC13): S= 7.38 (d, 2H), 7.23 (d, 2H), 4.97 (s, 1H), 2.68 (q, 2H), 1.25 (t, 3H), 0.23 (s, 9H).

Example 51A
1-(4-Ethylphenyl)-2-hydroxy-2-phenylethanone OH
290 ml (2.069 mol) of diisopropylamine are dissolved in 3.6 liters of DME and pre-cooled to -78 C. Over a period of about 20 min, 820 ml (2.05 mol) of n-butyllithium (2.5 M solution in hexane) are added dropwise (temperature <-60 C). After 15 min at -60 C, a solution of 435 g (1.864 mol) of (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.4 liters of DME is added dropwise (temperature <-60 C). The mixture is stirred at -60 C for 30 min, after which a solution of 189.5 ml (1.864 mol) of benzaldehyde in 1.4 liters of DME is added (over a period of about min, temperature -60 C). Over a period of 4 h, the mixture is warmed to RT, and 7 liters of sat.
ammonium chloride solution are then added. The reaction mixture is extracted with ethyl acetate.
After phase separation, the organic phase is washed with sat. ammonium chloride solution, dried and concentrated under reduced pressure. The residue is dissolved in 7 liters of dioxane and 20 5 liters of methanol, and 6 liters of I N hydrochloric acid are added. The mixture is stirred at RT
overnight and then, after addition of 11 liters of sat. sodium chloride solution, extracted with 6.5 liters of ethyl acetate. The organic phase is washed with water and sat.
sodium chloride solution, dried and concentrated under reduced pressure. The residue is dissolved in 2 liters of diisopropyl ether, seed crystals are added and the mixture is stirred for 2 h.
The precipitated solid is filtered off with suction, washed with 300 ml of diisopropyl ether and petroleum ether and dried under reduced pressure. The mother liquor is concentrated and, after 2 days of storage at 4 C, precipitated solid is once more filtered off with suction, washed with about 100 ml of diisopropyl ether and petroleum ether and dried under reduced pressure. Both solids are combined, giving 154.9 g (34% of theory) of the target product.

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

BHC 07 1 039-Foreign countries MS (DCI): m/z = 258 (M+NH4)+

'H-NMR (400 MHz, CDC13): 6= 7.85 (d, 2H), 7.48-7.35 (m, 5H), 7.21 (d, 2H), 5.92 (d, 1H), 4.59 (d, 1 H), 2.65 (q, 2H), 1.20 (t, 3H).

Example 52A

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

A mixture of 145 g (603 mmol) of 1-(4-ethylphenyl)-2-hydroxy-2-phenylethanone and 51.8 g (784.4 mmol) of malononitrile in 2.23 liters of DMF is cooled to 0 C, and 53.7 ml (518 mmol) of diethylamine are added with cooling. After I h, the reaction mixture is warmed to RT and stirred for a further 4 h, followed by the addition of 1.5 liters of water. After 30 min, most of the water is decanted off and replaced by 750 ml of fresh water. The mixture is stirred vigorously and then decanted from the sticky organic residue. The residue is dissolved in ethyl acetate, dried and concentrated under reduced pressure until the product begins to crystallize out. 450 ml of diisopropyl ether are added, and the mixture is stirred and then allowed to stand overnight. The crystalline precipitate is fittered off with suction, washed twice with 50 ml of diisopropyl ether and dried under reduced pressure. This gives 98.5 g (56.6% of theory) of the target product.

HPLC (Method 1): R, = 5.10 min.
MS (DCI): m/z = 306 (M+NH4)+

'H-NMR (400 MHz, CDC13): 6 = 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-phenylfuro[2,3-d]pyrimidin-4(3H)-one BHC 07 1 039-Foreign countriescA 02685134 2009-10-23 H3c NH

0 N"

770 ml (8.16 mol) of acetic anhydride are cooled to 0 C, and 372 ml (10.4 mol) of formic acid are added with cooling. The mixture is stirred at 0 C for 30 min, and 98 g (340 mmol) of 2-amino-4-(4-ethylphenyl)-5-phenyl-3-furonitrile are then added. The mixture is heated to reflux (with increasingly vigorous evolution of gas) and stirred at reflux for 24 h. After cooling, the mixture is stirred at 10 C for about 2 h, and the precipitated solid is then filtered off with suction, washed with diisopropyl ether and dried under high vacuum. This gives 69.3 g (64.5%
of theory) of the target product.

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

MS (DCI): m/z = 334 (M+NH4)+, 317 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 12.63 (br. s, 1H), 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 CI

N
- o ~
NJ

72 g (227.6 mmol) of 5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4(3H)-one are initially charged in 360 ml (4.6 mol) of phosphorus oxychloride and heated to reflux.
The mixture is stirred at 120 C for about 1 h and then, after cooling to RT, metered dropwise with vigorous stirring into a mixture of 2.2 liters of 25% strength ammonia solution and 1.2 liters of water (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 under reduced pressure.

BHC 07 1 039-Foreign countries , ' .

The residue is washed with a little diisopropyl ether, giving, after filtration and drying under high vacuum, 66.1 g (85.2% of theory) of the target product.

HPLC (Method 1): R, = 5.68 min.
MS (DCI): m/z = 335 (M+H)+

'H-NMR (400 MHz, CDC13): 8= 8.76 (s, IH), 7.61 (d, 2H), 7.48-7.30 (m, 7H), 2.78 (q, 2H), 1.36 (t, 3H).

Example 55A
6-Phenylfuro[2,3-d]pyrimidin-4-amine \N
u N"

110 g (597 mmol) of 2-amino-5-phenyl-3-furonitrile are suspended in 355 ml (9 mol) of formamide, and the mixture is heated for 1.5 h (bath temperature about 210 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 product, still moist, is stirred into dichloromethane, once more filtered off with suction and dried under reduced pressure. 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): Rt = 3.63 min.

'H-NMR (400 MHz, DMSO-d6): 8= 8.20 (s, 1H), 7.8 (d, 2H), 7.55-7.32 (m, 6H).
Example 56A

5-Bromo-6-phenylfuro[2,3-d]pyrimidin-4-amine Br NH2 ~N
~
~ N~

BHC 07 1 039-Foreign countries 80 g (378.7 mmol) of 6-phenylfuro[2,3-d]pyrimidin-4-amine in 770 ml of carbon tetrachloride are heated at 60 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, and the filtercake is titrated successively with dichloromethane and acetonitrile and again filtered off. The filtercake is then dried under reduced pressure. This gives 86 g of the target product (78.2% of theory).
MS (DCI): m/z = 290/292 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 8.28 (s, 1H), 8.03 (d, 2H), 7.60-7.50 (m, 5H).
Example 57A

5-Bromo-4-chloro-6-phenylfuro[2,3-d]pyrimidine Br CI

N

NJ

54 g (186 mmol) of 5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-amine are initially charged in 135 ml of chloroform, 70 ml of 4 N hydrogen chloride in dioxane (280 mmol) are added and the mixture is heated at reflux. Dropwise, with evolution of gas, 50 ml (372 mmol) of isoamyl nitride are added. After the addition has ended, the mixture is stirred at reflux for 3 h, and the cooled reaction mixture is then added to water and extracted with dichloromethane. The organic phase is washed with sat. sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (mobile phase:
dichloromethane). For further purification, the product is titrated with methanol, filtered off with suction and dried under high vacuum. This gives 32 g of the target product (55.5% of theory).

LC-MS (Method 3): Rt = 2.54 min.; m/z = 309/310 (M+H)+
HPLC (Method 1): R, = 5.08 min.

'H-NMR (400 MHz, CDC13): b= 8.79 (s, 1 H), 8.23-8.20 (m, 2H), 7.58-7.51 (m, 3H).
Example 58A and example 59A

(+/-)-trans- and (+/-)-cis-3-{ [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}-cyclohexanol BHC 07 1 039-Foreign countries HN "//OH HN OH

N N

By preparative HPLC [column: Phenomenex Gemini, C-18, 5 [tm, 250 mm x 21.2 mm;
flow rate:
20 ml/min; temperature: 25 C; mobile phase: water/THF 60:40], 300 mg (0.72 mmol) of (+/-)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexanol (cisltrans mixture) are separated into the pure cis- and trans-isomers. This gives 43 mg (14.3% of theory) of (+/-)-trans-3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}
cyclohexanol (example 58A) and 150 mg (50.0% of theory) of (+/-)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro-[2,3-d]pyrimidin-4-yl]amino}cyclohexanol (example 59A).

Example 58A:

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

'H-NMR (400 MHz, DMSO-d6): 6= 8.32 (s, 1H), 7.50 (d, 4H), 7.40-7.30 (m, 3H), 7.19 (d, 2H), 4.75 (d, 1 H), 4.49 (s, 1 H), 4.40-4.30 (m, 1 H), 3.86 (s, 3H), 3.48 (s, 1 H), 1.67-1.01 (m, 8H).
Example 59A:

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

'H-NMR (400 MHz, DMSO-d6): 6= 8.32 (s, IH), 7.49-7.41 (m, 4H), 7.40-7.30 (m, 3H), 7.13 (d, 2H), 5.15 (s, I H), 4.52 (s, 1 H), 4.10-4.00 (m, l H), 3.88 (s, 3H), 3.53-3.48 (m, l H), 1.80-0.89 (m, 8H).

Example 60A

(+/-)- 4-(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl)butanenitrile BHC 07 1 039-Foreign countries O N~CN
N
O N/

At RT, 147.5 mg (0.996 mmol) of 4-bromobutyronitrile are added 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) diisopropylethylamine and 8.3 mg of potassium iodide in 2 ml of THF. The mixture is stirred under reflux for 10 h. After addition of a further 0.25 ml (1.5 mmol) of diisopropylethylamine and 147.5 mg (0.996 mmol) of 4-bromobutyronitrile, the mixture is once more stirred under reflux overnight. After cooling to RT, the mixture is diluted with dichloromethane and washed with sat. sodium bicarbonate solution, and the organic phase is separated off, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparative RP-HPLC (mobile phase: acetonitrile/water gradient) gives 189 mg of the target product (81.1 % of theory).

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.59 (s, IH), 7.55 (d, 2H), 7.45-7.35 (m, 5H), 7.00 (d, 2H), 5.31-5.23 (m, 1 H), 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, 1H), 1.67 (t, 3H), 1.50-1.30 (m, 2H).

Example 61A

(+/-)-cis-3- { [3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyc lohexyl ] oxy } -propanenitrile O ao,,,^~CN
N
/l O Ni A solution of 10 mg of potassium tert-butoxide in 0.5 ml of THF is added dropwise to a solution of 150 mg (0.36 mmol) of (+/-)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-BHC 07 1 039-Foreign countries , ~ -yl]oxy}cyclohexanol in 1 ml of acrylonitrile. With exclusion of light, the reaction mixture is stirred at RT for about 2 h. After dilution with dichioromethane, the mixture is washed successively with I N hydrochloric acid, sat. sodium bicarbonate solution and sat. sodium chloride solution and the organic phase is concentrated under reduced pressure.
Purification of the residue by preparative RP-HPLC (mobile phase: acetonitrile/water gradient) gives 136.9 mg of the target product (81 % of theory).

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

'H-NMR (400 MHz, DMSO-d6): b= 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

(+/-)-trans-3- { [3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} cyclohexyl]-oxy}propanenitrile HN ",/ O,,-,,,,,,CN
N
- o ~
NJ

A solution of about 2 mg of potassium tert-butoxide in 0.2 ml of THF is added dropwise to a solution of 34.4 mg (0.059 mmol) of (+/-)-trans-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexanol in 0.23 ml of acrylonitrile. With exclusion of light, the reaction mixture is stirred at RT for about 2 h. After dilution with dichloromethane, the mixture is washed successively with I N hydrochloric acid, sat. sodium bicarbonate solution and sat. sodium chloride solution, and the organic phase is concentrated under reduced pressure. Purification of the residue by preparative RP-HPLC (mobile phase: acetonitrile/water gradient) gives 33.6 mg of the target product (86.6% of theory).

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

'H-NMR (400 MHz, DMSO-d6): 6= 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).

BHC 07 1 039-Foreign countries Example 63A

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

At RT, 221.2 mg (0.996 mmol) of 4-bromobutyronitrile are added 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. The mixture is stirred under reflux for 6 h. After cooling to RT, the mixture is diluted with dichloromethane and washed with sat. sodium bicarbonate solution, and the organic phase is separated off, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparation RP-HPLC (mobile phase: 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)+

'H-NMR (400 MHz, DMSO-d6): b= 8.49 (s, I H), 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, 1H), 2.69-2.60 (m, 2H), 2.41-2.01 (m, 4H), 1.79-1.70 (m, 1H), 1.61-1.40 (m, 5H).

Example 64A

(+/-)-3-(3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyri midin-4-yl]oxy}
piperidin-1-yl)propane-nitrile O N-~CN
N

O N

BHC 07 1 039-Foreign countries Y =

A mixture of 900 mg (2.24 mmol) of (+/-)-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. This gives 1000 mg (98.1% of theory) of the target compound.

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

By chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 m, 250 mm x 20 mm;
flow rate: 15 ml/min; temperature: 30 C; mobile phase: isohexane/THF 50:50], 1.0 g (2.2 mmol) of the (+/-)-3-(3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} piperidin-l-yl)propanenitrile obtained is separated into the enantiomers (see examples 65A
and 66A).

Example 65A

(-)-3-(3-{ [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl)propane-nitrile (enantiomer 1) Yield: 459 mg (45.1 % of theory) [a]D20 = -60.5 , c = 0.545, CHC13 LC-MS (Method 6): R, = 2.05 min.; m/z = 455 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.60 (s, 1H), 7.54 (d, 2H), 7.48-7.37 (m, 5H), 7.01 (d, 2H), 5.31-5.23 (m, 1H), 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, 1H), 1.50-1.29 (m, 2H).

Example 66A

(+)-3-(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl)propane-nitrile (enantiomer 2) Yield: 479 mg (47.0% of theory) [a]D 20 = +59.1 , c = 0.545, CHC13 LC-MS (Method 6): R, = 2.05 min.; m/z = 455 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.60 (s, IH), 7.54 (d, 2H), 7.48-7.37 (m, 5H), 7.01 (d, 2H), 5.31-5.23 (m, 1H), 3.81 (s, 3H), 2.91-2.82 (m, lH), 2.68-2.58 (m, 3H), 2.55 (s, 2H), 2.38-2.22 (m, 2H), 1.93-1.82 (m, I H), 1.69-1.58 (m, 1 H), 1.50-1.29 (m, 2H).

BHC 07 1 039-Foreign countries Example 67A

Methyl (2E)-3-{(2S,4R)-4-hydroxy-l-[(1R)-1-phenylethyl]piperidin-2-yl}acrylate HO~~~` CH

O

2.0 g (8.647 mmol) of (1S,5R)-2-[(IR)-I-phenylethyl]-6-oxa-2-azabicyclo[3.2.1]octan-7-one [prepared from N-[(1R)-1-phenylethyl]but-3-en-l-amine according to Bioorg.
Med. Chem. Lett. 6 (8), 964 (1996)] are dissolved in 8 ml of abs. THF, the mixture is cooled to -78 C and 9.5 ml (9.5 mmol) of a 1 M solution of L-selectride in THF are added. After the addition has ended, the mixture is stirred at -78 C for I h and then warmed to -20 C, and 2.1 ml (13 mmol) of trimethyl phosphonoacetate are added. The reaction mixture is then warmed to 0 C and stirred for 1 h.
Water is then added, and the pH is adjusted to about 7-8 using 1 N
hydrochloric acid. The mixture is extracted three times with dichloromethane, and the organic phases are combined, dried over magnesium sulfate and concentrated under reduced pressure. This gives 4.32 g of crude product which is used without further purification for the subsequent step.

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

tert-Butyl (2R,4R)-4-hydroxy-2-(3-methoxy-3-oxopropyl)piperidine-l -carboxylate HO"''/'YO'~CH

O

3.8 g of methyl (2E)-3-{(2S,4R)-4-hydroxy-l-[(lR)-1-phenylethyl]piperidin-2-yl}acrylate (as crude product) are dissolved in 50 ml of isopropanol, and 4.3 g of di-tert-butyl dicarbonate and a catalytic amount of 10% Pd/C are added. At RT and under an atmosphere of hydrogen at atmospheric pressure, the mixture is stirred overnight. The mixture is filtered through kieselguhr BHC 07 1 039-Foreign countries and the filtrate is concentrated under reduced pressure. The residue gives, after purification by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1 ->
1:1) 0.98 g of the target product.

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

'H-NMR (400 MHz, DMSO-d6): 8= 4.64 (d, 1H), 4.08-3.99 (m, 1H), 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

tert-Butyl (+/-)-({3-[(6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}oxy)acetate HN "' O~ 111~ CH3 NJ

1.61 g (6.98 mmol) of 4-chloro-6-phenylfuro[2,3-d]pyridine and 1.60 g (6.98 mmol) of tert-butyl (+/-)-trans-{[3-aminocyclohexyl]oxy}acetate are initially charged in 6.0 ml of DMF, and 1.8 ml (10.5 mmol) of N,N-diisopropylethylamine are added. The reaction mixture is heated at 120 C for 3 h and then cooled to RT and poured into water. The mixture is extracted three times with ethyl acetate, and the organic phases are combined, washed with sat. sodium chloride solution and concentrated under reduced pressure. The residue gives, after purification by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1 ---> 2:1), 1.67 g of the target product (56.5% of theory).

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

'H-NMR (400 MHz, DMSO-d6): b= 8.27 (s, 1H), 7.88-7.68 (m, 3H), 7.50 (t, 2H), 7.47-7.39 (m, 1 H), 4.40 (s, 1 H), 4.03 (s, 2H), 3.80 (s, l H), 2.15-1.50 (m, 8H), 1.50-1.30 (m, 9H).

Example 70A

tert-Butyl (+/-)-( {3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl } oxy)acetate BHC 07 1 039-Foreign countries HN "~~ O~ "'~CH3 Br O NJ

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

LC-MS (Method 3): Rt = 3.09 min.; miz = 502 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.38 (s, IH), 8.00 (d, 2H), 7.61-7.49 (m, 3H), 6.39 (d, IH), 4.53-4.42 (m, 1H), 4.03 (s, 2H), 3.78 (s, 1H), 2.09-1.42 (m, 8H), 1.40 (s, 9H).

Example 71A and example 72A

tert-Butyl (+)-cis-{[3-hydroxycyclohexyl]oxy}acetate (enantiomer 1) and tert-butyl (-)-cis-{[3-hydroxycyclohexyl]oxy}acetate (enantiomer 2) HO ***a O~ ~CH3 HO\\\'01'// O ~CH 3 By chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 m, 250 mm x 20 mm;
flow rate: 15 ml/min; temperature: 30 C; mobile phase: isohexane/ethanol 75:25], 500 mg (2.17 mmol) of tert-butyl (+/-)-cis-{[3-hydroxycyclohexyl]oxy}acetate are separated into the enantiomers.

Enantiomer 1:

Yield: 124 mg (24.8% of theory) BHC 07 1 039-Foreign countries [a]o = +2.4 , c = 0.50, CHC13 'H-NMR (400 MHz, DMSO-d6): b= 4.60 (d, 1H), 3.97 (s, 2H), 3.39-3.29 (m, 1H), 3.28-3.19 (m, 1H), 2.20-2.12 (m, IH), 1.90 (d, 1H), 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) [a]D20 = -3.4 , c = 0.50, CHC13 'H-NMR (400 MHz, DMSO-d6): S= 4.60 (d, 1H), 3.97 (s, 2H), 3.39-3.29 (m, 1H), 3.28-3.19 (m, 1 H), 2.20-2.12 (m, 1 H), 1.90 (d, 1 H), 1.74 (d, 1 H), 1.69-1.59 (m, l H), 1.41 (s, 9H), 1.17-0.90 (m, 4H).

Example 73A

tert-Butyl (+/-)-3-(benzyloxy)piperidinecarbamate 0\\', N~O~CH3 g (74.5 mmol)of tert-butyl (+/-)-3-hydroxypiperidinecarbamate are dissolved in 86.5 ml of hot 15 toluene, and 11.9 ml of 50% strength aqueous sodium hydroxide solution (447 mmol), 2.53 g (7.5 mmol) of tetra-n-butylammonium hydrogensulfate and 11.5 ml (96.9 mmol) of benzyl bromide are added in succession. The two-phase reaction mixture is stirred vigorously at 70 C for 4 h. After cooling, water is added and the mixture is neutralized using conc.
hydrochloric acid. The organic phase is separated off, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 30:1 -> 10:1). This gives 16.21 g of the target product (74.6% of theory).

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

'H-NMR (400 MHz, DMSO-d6): 8= 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, l H), 1.71-1.48 (m, 4H), 1.36 (s, 9H).

BHC 07 1 039-Foreign countries Example 74A and example 75A

tert-Butyl (-)-(3R)-3-(benzyloxy)piperidinecarbamate (enantiomer 1) and tert-butyl (+)-(3S)-3-(benzyloxy)piperidinecarbamate (enantiomer 2) O\``, y ~CH3 O y 11-~ CH3 By chromatography on chiral phase [column: Daicel Chiralpak AS-H, 5 m, 250 mm x 20 mm;
flow rate: 15 ml/min; temperature: 28 C; mobile phase: isohexane/2-propanol 95:5], 16.0 g (54.9 mmol) of tert-butyl (+/-)-3-(benzyloxy)piperidinecarbamate are separated into the enantiomers.

Enantiomer 1:

Yield: 7.40 g (49.3% of theory) [a]D20 = -5.8 , c = 0.635, CHC13 LC-MS (Method 3): R, = 2.65 min.; m/z = 292 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 7.49-7.23 (m, 5H), 4.60-4.45 (m, 2H), 3.42-3.38 (m, 2H), 1.82 (br. s, 1 H), 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) [a]D20 = +6.0 , c = 1.045, CHC13 LC-MS (Method 3): R, = 2.65 min.; m/z = 292 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 7.49-7.23 (m, 5H), 4.60-4.45 (m, 2H), 3.42-3.38 (m, 2H), 1.82 (br. s, 1 H), 1.70-1.48 (m, 2H), 1.34 (s, 9H), 1.40-1.26 (m, 4H).

Example 76A

Methyl (+)-4-[(3R)-3-(benzyloxy)piperidin-l-yl]butanoate BHC 07 1 039-Foreign countries O
O ~,. N O~CH3 At RT, one drop of water and 7.7 ml of trifluoroacetic acid are added to a solution of 3.025 g (10.38 mmol) of tert-butyl (+)-(3S)-3-(benzyloxy)piperidinecarbamate in 14.4 ml of dichloromethane. 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.
sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure.
This gives 2.12 g of crude product which is dissolved without further purification in 37 ml of THF, and 5.7 ml (32.9 mmol) of N,N-diisopropylethylamine, 182 mg (1. I mmol) of potassium iodide and 3.98 g (22 mmol) of methyl 4-bromobutyrate are added successively to the solution. The mixture is then stirred under reflux for 3 h. After cooling, the mixture is diluted with dichloromethane, washed successively with water, sat. ammonium chloride solution and sat.
sodium chloride solution, and the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue gives, after purification by preparative RP-HPLC (mobile phase:
acetonitrile/water), 2.0 g of the target product (62.6% of theory over the two steps).

[a]DZO = +1.3 , c = 0.51, CHC13 LC-MS (Method 8): R, = 0.89 min.; m/z = 292 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 7.38-7.23 (m, 5H), 4.51 (s, 2H), 3.59 (s, 2H), 3.45-3.31 (in, 1H), 3.00-2.90 (m, 1H), 2.69-2.56 (m, 1H), 2.37-2.19 (m, 5H), 1.99-1.80 (m, 3H), 1.70-1.60 (m, 3H), 1.44-1.30 (m, lH), 1.22-1.10 (m, IH).

Example 77A

Methyl (-)-4-[(3R)-3-hydroxypiperidin-1-yl]butanoate HO~,,, N O~CH3 At RT, about 200 mg of 10% Pd/C are added to a solution of 2.0 g (6.86 mmol) of methyl (+)-4-[(3R)-3-(benzyloxy)piperidin-l-yl]butanoate in 15 ml of acetic acid. The suspension is, at RT, stirred vigorously under an atmosphere of hydrogen (atmospheric pressure) overnight. The reaction mixture is then filtered through Celite, the filter residue is washed with dichloromethane BHC 07 1 039-Foreign countriesA 02685134 2009-10-23 and the filtrate is concentrated under reduced pressure. The residue is taken up in dichloromethane, washed with sat. sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. 'This gives 833.9 mg (60.4% of theory) of the target compound.

[a]D20 = +6.9 , c = 0.57, CHC13 GC-MS (Method 9): Rt = 5.20 min.; m/z = 202 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 4.54 (br. s, IH), 3.60 (s, 3H), 3.48-3.38 (m, 1H), 2.81-2.71 (m, IH), 2.65-2.56 (m, 1H), 2.32-2.15 (m, 4H), 1.81-1.70 (m, 2H), 1.70-1.52 (m, 4H), 1.42-1.30 (m, I H), 1.10-0.98 (m, I H).

Example 78A

1-tert-Butyl rac-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidinecarbamate Br O Yo~CH 3 NJ

At 70 C, 1.1 g (3.55 mmol) of 5-bromo-4-chloro-6-phenylfuro[2,3-d]pyrimidine are dissolved in ml of toluene and 10 ml of 1,2-dimethoxyethane. 2.84 g of 50% strength aqueous sodium hydroxide solution (35.5 mmol), 120.6 mg (0.26 mmol) of tetra-n-butylammonium hydrogensulfate 15 and 1.79 g (8.88 mmol) of 1-tert-butoxycarbonyl-3-hydroxypiperidine are added, and the reaction mixture is then stirred vigorously at 70 C for I h. After cooling, the mixture is added to water and adjusted to a pH of about 7 using conc. hydrochloric acid. 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 under reduced pressure. The residue 20 gives, after purification by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 5:1), 1.06 g of the target compound (62.9% of theory).

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

'H-NMR (400 MHz, DMSO-d6): S= 8.66 (s, 1 H), 8.07 (d, 2H), 7.63-7.51 (m, 3H), 5.33 (br. s, IH), 4.30 (br. d, 1 H), 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).

BHC 07 1 039-Foreig,n countries Example 79A

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

I \N
o At RT, a total of 3.4 ml of TFA is added in a plurality of portions to a solution of 1.05 g (2.21 mmol) of 1-tert-butyl rac-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]-piperidinecarbamate in 2 ml of dichloromethane, and the mixture is stirred at RT for 2 h. The mixture is then diluted with dichloromethane, sat. sodium bicarbonate solution is added carefully to the solution and the mixture is then washed twice with sat. sodium bicarbonate solution. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The oily residue is titrated with methanol, and the precipitated solid is filtered off with suction and washed with methanol. Mother liquor and wash solution are combined, concentrated under reduced pressure and again titrated with a little methanol. The crystals obtained are filtered off with suction, washed with methanol and combined with the first crystal fraction.
This gives a total of 550 mg (66.4% of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): b= 8.60 (s, 1H), 8.09 (d, 2H), 7.64-7.51 (m, 3H), 5.29-5.20 (m, IH), 3.15 (dd, 1H), 2.80-2.70 (m, 2H), 2.65-2.57 (m, lH), 2.21-2.08 (m, 2H), 1.82-1.68 (m, 2H), 1.56-1.43 (m, IH).

Example 80A

Methyl (+/-)-4-{3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-l-yl}butanoate O
O N O,,CH3 Br N
- o ~ J
N

BHC 07 1 039-Foreign countries 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 methyl 4-bromobutyrate, 24.4 mg (0.147 mmol) of potassium iodide and 0.77 ml (4.41 mmol) of N,N-diisopropylethylamine in 1.5 ml of THF
is heated under reflux for 2 h. After cooling, the mixture is diluted with dichloromethane and added to water. After phase separation, the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with sat. sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue gives, after purification by preparative RP-HPLC (mobile phase: acetonitrile/water), 780 mg of the target product which are used without further purification.

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.61 (s, 1H), 8.09 (d, 2H), 7.62-7.51 (m, 3H), 5.39-5.30 (m, 1H), 3.52 (s, 3H), 2.90 (d, IH), 2.60-2.52 (m, IH), 2.47-2.39 (m, 1H), 2.38-2.28 (m, 4H), 2.26-2.19 (m, IH), 2.19-2.00 (m, 1 H), 1.90-1.80 (m, 1 H), 1.70-1.51 (m, 4H).

Example 81A and example 82A

Methyl (-)-4-{(3R)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-l-yl}butanoate (enantiomer 1) and methyl (+)-4-{(3S)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-l-yl} butanoate (enantiomer 2) O ~,.= N O~CH3 Br N
O N"

O
O N O~oCH3 Br N
- ~ N~

BHC 07 1 039-Foreign countries By chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 [im, 250 mm x 20 mm;
flow rate: 15 ml/min; temperature: 28 C; mobile phase: isohexane/2-propanol (+
0.2%
diethylamine) 80:20], 780 mg (1.64 mmol) of methyl (+/-)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-l-yl}butanoate are separated into the enantiomers.

Enantiomer 1:

Yield: 350 mg (44.8% of theory) [a]D20 = -43.1 , c = 0.505, CHC13 LC-MS (Method 3): R, = 1.59 min.; m/z = 475 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.62 (s, 1H), 8.08 (d, 2H), 7.64-7.51 (m, 3H), 5.38-5.30 (m, 1H), 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, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.70-1.52 (m, 4H), 0.90-0.79 (m, 1H).

Enantiomer 2:

Yield: 320 mg (41.0% of theory) [a]D20 = +42.2 , c = 0.53, CHC13 LC-MS (Method 3): R, = 1.59 min.; m/z = 475 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.62 (s, 1 H), 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, 1 H), 1.90-1.80 (m, 1 H), 1.70-1.52 (m, 4H), 0.90-0.79 (m, 1 H).

Example 83A

cis/trans-3-[(5-Bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexanol Br O OH
N
O NJ

At 70 C, 1.1 g (8.88 mmol) of cis/trans-cyclohexanediol are dissolved in 10 ml of toluene and BHC 07 1 039-Foreign countries ml of 1,2-dimethoxyethane, and 2.84 g of 50% strength aqueous sodium hydroxide solution (35.5 mmol) are added. Water is added until a two-phase reaction mixture is formed. 120.6 mg (3.55 mmol) of tetra-n-butylammonium hydrogensulfate and 1.10 g (3.55 mmol) of 5-bromo-4-chloro-6-phenylfuro[2,3-d]pyrimidine are added, and the mixture is stirred vigorously at 70 C for 5 1 h. After cooling, the reaction mixture is added to water and neutralized with conc. hydrochloric acid. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined, washed with sat. sodium hydrogensulfate solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1 -> 3:1). This gives 0.63 g of the target compound (45.6% of theory).

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

1H-NMR (400 MHz, DMSO-d6): 8= 8.61 (s, 1 H), 8.03 (d, 2H), 7.63-7.51 (m, 3H), 5.30-5.20 (m, 1H), 4.79 (d, 1H), 3.62-3.52 (m, IH), 2.46-2.38 (m, IH), 2.20-2.10 (m, 1H), 1.90-1.66 (m, 3H), 1.47-1.29 (m, 2H), 1.20-1.09 (m, IH).

Example 84A

tert-Butyl cis/trans-({3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate o CH3 Br O o"'Y ~CH 3 O N"

A solution of 625 mg (1.606 mmol) of cis/trans-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexanol in 3 ml of toluene is added to a mixture of 2 ml of toluene and 1.28 g of 50%
strength aqueous sodium hydroxide solution (16.05 minol). 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 h. The mixture is then added to water and neutralized with conc. hydrochloric acid.
The aqueous phase is extracted three times with ethyl acetate, and the organic phases are combined and dried over magnesium sulfate. The residue is purified by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 10:1 -> 8:1). This gives 592 mg of the target compound (73.2% of theory).

BHC 07 1 039-Foreign countries LC-MS (Method 8): R, = 3.36 min.; m/z = 503 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.61 (s, 1H), 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, 1 H), 1.88-1.78 (m, IH), 1.50-1.12 (m, 14H).

Example 85A and example 86A

tert-Butyl (+)-({3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate (enantiomer 1) and tert-butyl (-)-({3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate (enantiomer 2) Br Oe o a"~O *'-~CH3 0 N"

0 ' O CH3 Br 0 X''~ ~Y ~-~CH3 p N) By chromatography on a chiral phase [column: Daicel Chiralpak AS-H, 5 [tm, 250 mm x 20 mm;
flow rate: 15 ml/min; temperature: 28 C; mobile phase: isohexane/2-propanol (+
0.2%
diethylamine) 80:20], 780 mg (1.64 mmol) of tert-butyl (+/-)-({3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate are separated into the enantiomers.

Enantiomer 1:

Yield: 159 mg (20.4% of theory) [a]D20 = +64.5 , c = 0.495, CHC13 BHC 07 1 039-Foreign countries LC-MS (Method 8): R, = 3.37 min.; m/z = 503 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.61 (s, IH), 8.10 (d, 2H), 7.65-7.50 (m, 3H), 5.30-5.20 (m, 1H), 4.01 (s, 2H), 3.53-3.42 (m, IH), 2.20-2.10 (m, IH), 2.06-1.98 (m, 1H), 1.88-1.80 (m, 1H), 1.41 (s, 9H), 1.50-1.23 (m, 5H).

Enantiomer 2:

Yield: 320 mg (41.0% of theory) [a]D20 = -68.9 , c = 0.54, CHC13 LC-MS (Method 8): R, = 3.37 min.; m/z = 503 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.61 (s, lH), 8.10 (d, 2H), 7.65-7.50 (m, 3H), 5.30-5.20 (m, 1H), 4.01 (s, 2H), 3.53-3.42 (m, 1H), 2.20-2.10 (m, IH), 2.06-1.98 (m, IH), 1.88-1.80 (m, 1H), 1.41 (s, 9H), 1.50-1.23 (m, 5H).

Example 87A

(+/-)-cis/trans-3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyclopentanol O OH
O

1,2-dimethoxyethane is added to 10 g (29.7 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 150 ml of toluene of a temperature of 70 C
until a homogenous solution is formed. 23.75 g (296.9 mmol) of 50% strength aqueous 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) of (+/-)-cis/trans-1,3-cyclopentanediol are then added, and the reaction mixture is stirred at 70 C for 4 h. After cooling, the mixture is added to water and neutralized with conc. hydrochloric acid. The mixture is extracted three times with dichloromethane, and the combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue gives, by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1 --->
2:1), an impure product. This crude product is crystallized by titration with methanol. The crystals obtained are BHC 07 1 039-Foreign countries filtered off and dried (yield: 690 mg). The mother liquor is concentrated under reduced pressure and purified further by preparative RP-HPLC. In this manner, a further 1230 mg of the target product are obtained. In total, 1920 mg of the target compound (16.1% of theory) are obtained.
LC-MS (Method 8): R, = 2.64 min.; m/z = 403 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.59 (s, 1H), 7.57 (d, 2H), 7.42-7.33 (m, 5H), 7.00 (d, 2H), 5.64-5.59 (m, I H), 4.60 (d, 1 H), 4.15-4.09 (m, I H), 3.82 (s, 3H), 2.15-2.03 (m, 1 H), 1.92-1.84 (m, 1H), 1.83-1.74 (m, 1H), 1.73-1.62 (m, 1H), 1.61-1.51 (m, 1H), 1.50-0.91 (m, 1H).

Example 88A

tert-Butyl (+/-)-cis/trans-[(3-hydroxycyclopentyl)oxy]acetate HO O~ _~CH3 2.5 g (24.5 mmol) of cis/trans-cyclopentanediol are dissolved in 5 ml of THF, and 16.3 ml (16.3 mmol) of the phosphazene base P4-t-Bu (about I M solution in hexane) are added at 0 C.
After 10 min, the resulting solution is added dropwise to an ice-cooled solution of 4.77 g (24.5 mmol) of tert-butyl bromoacetate. After the addition is ended, the mixture is warmed to RT
and stirred overnight. Some of the THF is removed under reduced pressure, and the mixture is 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 under reduced pressure. The residue gives, by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 10:1 -> 2:1), the product. What is obtained are 631.4 mg (10.7% of theory) of the target compound as a cis/trans mixture.

GC-MS (Method 10): Rr = 7.35 min (cis), 7.21 min (trans); m/z = 217 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 4.52 (d, 0.25H, trans), 4.48 (d, 0.75H, cis), 4.20-4.13 (m, 1 H), 4.07-3.98 (m, I H), 3.90 (d, 2H), 2.14-1.49 (m, 5H), 1.41 (s, 9H).

Example 89A

tert-Butyl (+/-)-cis/trans-[(3-aminocyclopentyl)oxy]acetate BHC 07 1 039-Foreign countries H 2 N O~ *'-~CH3 Step a :

620 mg (2.87 mmol) of tert-butyl (+/-)-cis/trans-[(3-hydroxycyclopentyl)oxy]acetate and 1.2 ml (8.6 mmol) of triethylamine are dissolved in 6.5 ml of dichloromethane, and the mixture is cooled to 0 C. 0.28 ml (3.58 mmol) of methanesulfonic chloride are added dropwise.
The mixture is warmed to RT over a period of 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 under reduced pressure.
This gives 849 mg of the mesylate which is directly reacted further.

Ste b :

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

Step c):

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

Example 90A

tert-Butyl cis-(+/-)-{[(4-hydroxycyclopent-2-en-l-yl]oxy}acetate HO~~~ CH3 BHC 07 1 039-Foreign countries 2.0 g (20 mmol) of cis-4-cyclopentene-1,3-diol are dissolved in 1.5 ml of DMF
and 15 ml of THF, and 799 mg (60% pure, about 20 mmol) of sodium hydride are added a little at a time at 0 C. After the addition has ended, the mixture is warmed to RT and stirred at RT for 1 h, and 2.7 ml (18.2 mmol) of tert-butyl bromoacetate are then added. The mixture is then stirred at RT
overnight. Water is then added, the mixture is extracted with dichloromethane, the organic phase is washed with sat. sodium chloride solution and concentrated under reduced pressure and the residue is dried under high vacuum. The product is isolated by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1 -> 2:1). This gives 1.10 g (25.6%
of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): b= 5.90 (dt, 2H), 5.00 (d, 1H), 4.44 (q, 1H), 4.35 (t, 1H), 3.99 (s, 2H), 2.60 (dd, 1 H), 1.62 (s, 9H), 1.37 (dd, 1 H).

Example 91A

tert-butyl cis-(-)-{[(1R,4S)-4-acetoxycyclopent-2-en-l-yl]oxy}acetate H3C 0~~~ O~ CH3 1.0 g(7.04 mmol) of (1R,4S)-cis-4-acetoxy-2-cyclopenten-l-ol is initially charged in 5 ml of dichloromethane, and 155 mg (0.25 mmol) of rhodium(II) acetate (as dimer) are added under argon. At RT, 1.56 g (90% pure, about 9.84 mmol) of tert-butyl diazoacetate are then added dropwise to the vigorously stirred suspension. After 30 min, a further 0.3 eq.
of tert-butyl diazoacetate are added dropwise, and a reaction mixture is stirred at RT for a further 30 min. The mixture is then diluted with dichloromethane and washed three times with water and with sat.
sodium chloride solution. The mixture is dried over magnesium sulfate and concentrated under reduced pressure. The product is isolated from the residue by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1). This gives 1.33 g of the target compound (73.7% of theory).
[a]D20 = -23 , c = 0.55, CHC13 GC-MS (Method 9): R, = 5.49 min.; m/z = 257 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 6.18 (dd, IH), 5.97 (dd, 1 H), 5.41-5.36 (m, 1 H), 4.48-4.41 (m, IH), 4.01 (s, 2H), 2.72 (dt, 1H), 2.10-1.98 (m, 3H), 1.55 (td, 1H), 1.43 (s, 9H).

BHC 07 1 039-Foreign countries - l 04 -Example 92A

tert-Butyl cis-(+)-{[(4-hydroxycyclopent-2-en-l-yl]oxy}acetate HO~~~ ~CH 3 1.30 g (5.07 mmol) of tert-butyl cis-(-)-{[(1R,4S)-4-acetoxycyclopent-2-en-l-yl]oxy}acetate are dissolved in 3 ml of THF and 2 ml of methanol, and 5.6 ml of I N aqueous sodium hydroxide solution are added dropwise at RT. After 10 min, the mixture is diluted with water and extracted three times with dichloromethane. The organic phases are combined, washed with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. This gives 780 mg of the target compound (71.8% of theory).
[a]D20 = +6.5 , c = 0.515, CHC13 GC-MS (Method 9): R, = 4.93 min.; m/z = 232 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): b= 5.93-5.89 (m, 2H), 5.00 (d, l H), 4.45 (q, IH), 4.36 (t, l H), 3.99 (s, 2H), 2.65-2.56 (m, 1 H), 1.42 (s, 9H), 1.40-1.31 (m, I H).

Example 93A

tert-Butyl cis-(+)-{[(1S,3R)-3-hydroxycyclopentyl]oxy}acetate HO~~~ ~CHs 350 mg (1.63 mmol) of tert-butyl cis-(+)-{[(4-hydroxycyclopent-2-en-l-yl]oxy}acetate are dissolved in 7 ml of ethanol, and 35 mg (0.163 mmol) of platinum (IV) oxide are added. At RT, the suspension is stirred vigorously under an atmosphere of hydrogen (atmospheric pressure) for 4 h.
The reaction mixture is then filtered through kieselguhr. The filtercake is washed with ethanol, and all filtrates are combined and concentrated under reduced pressure. This gives 278.8 of the target compound (81.5% of theory).

[a]D20 = +6.8 , c = 0.51, CHC13 GC-MS (Method 9): Rt = 4.93 min.; m/z = 234 (M+NH4)+

BHC 07 1 039-Foreign countries ' H-NMR (400 MHz, DMSO-d6): b= 4.50 (d, I H), 4.01-3.96 (m, I H), 3.90 (s, 2H), 3.88-3.81 (m, 1H), 2.14-2.05 (m, 2H), 1.71-0.96 (m, 4H), 1.40 (s, 9H).

Example 94A

tert-Butyl cis-(+)-{[(1S,4R)-4-acetoxycyclopent-2-en-l-yl]oxy}acetate O CH3 H 3 C~O CH3 ~

248.7 mg (0.56 mmol) of rhodium(II) acetate (as dimer) are added to a solution of 1.6 g (11.26 mmol) of (1R,3S)-(+)-cis-4-cyclopentene-l,3-diol 1-acetate in 9.6 ml of dichloromethane.
The resulting suspension is stirred vigorously, and 2.49 g (90% pure, about 15.8 mmol) of tert-butyl diazoacetate are added dropwise. After the addition has ended, the mixture is stirred at RT
for 2 h. A further 0.5 eq. of tert-butyl diazoacetate is then added, and the mixture is stirred at RT
for a further hour. After concentration under reduced pressure, the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1).
This gives 1.96 g of the target compound (68% of theory).

[a]p = +27.2 , c = 0.59, CHC13 LC-MS (Method 12): R, = 2.06 min.; m/z = 257 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 6.20-6.15 (m, 1 H), 6.00-5.94 (m, IH), 5.41-5.37 (m, IH), 4.47-4.41 (m, 1 H), 4.00 (s, 2H), 2.79-2.70 (m, 1 H), 2.00 (s, 3H), 1.58-1.50 (td, 1 H), 1.42 (s, 9H).
Example 95A

tert-Butyl cis-(-)-{[(IS,4R)-4-hydroxycyclopent-2-en-1-yl]oxy}acetate HO \
O~ `~-CH3 1000 mg (3.9 mmol) of tert-butyl cis-(+)-{[(lS,4R)-4-acetoxycyclopent-2-en-l-yl]oxy}acetate are dissolved in 3 ml of THF and 2 ml of methanol, and 4.7 ml of 1 N aqueous sodium hydroxide solution are added dropwise at RT. After 10 min, the mixture is diluted with water and extracted three times with dichloromethane. The organic phases are combined, washed with sat. sodium BHC 07 1 039-Foreign countries bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. This gives 570 mg of the target compound (68.2% of theory).
[a]D20 = -9.3 , c = 0.515, CHC13 GC-MS (Method 9): R~ = 4.93 min.; m/z = 232 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): b= 6.39-5.92 (m, 2H), 5.00 (d, 1H), 4.45 (q, 1H), 4.35 (t, 1H), 3.99 (s, 2H), 2.64-2.56 (m, 1H), 1.42 (s, 9H), 1.40-1.31 (m, 1 H).

Example 96A

tert-Butyl cis-(-)- { [(1 R,3S)-3-hydroxycyclopentyl]oxy} acetate HO O~ ~CH3 1170 mg (5.46 mmol) of tert-butyl cis-(-)-{[(1S,4R)-4-hydroxycyclopent-2-en-l-yl]oxy}acetate are dissolved in 10 ml of ethanol, and 25 mg of platinum(IV) oxide are added. At RT, the suspension is stirred vigorously under an atmosphere of hydrogen (atmospheric pressure) for 4 h. The reaction mixture is then filtered through kieselguhr. The filter residue is washed twice with a mixture of ethanol and water, and all filtrates are combined and concentrated under reduced pressure. This l 5 gives 940 mg of the target compound (79.9% of theory).

[a]~20 = -7.4 , c = 0.475, CHCI3 GC-MS (Method 9): R, = 3.88 min.; m/z = 234 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): 6= 4.50 (d, l H), 4.00-3.91 (m, 2H), 3.90 (s, 2H), 3.89-3.80 (m, 2H), l.7l -1.45 (m, 6H), 1.40 (s, 9H).

Example 97A

trans-(-)-4-(2-tert-Butoxy-2-oxoethoxy)cyclopent-2-en-l-yl 4-n itrobenzoate O .._-\ O\``` O~ ~CH3 BHC 07 1 039-Foreign countries Under argon and at RT, 881.4 mg (3.36 mmol) of triphenylphosphine, 561.6 mg (3.36 mmol) 4-nitrobenzoic acid and, dropwise, 1.46 g (about 3.36 mmol) of a 40% strength solution of diethyl azodicarboxylate in toluene are added to a solution of 400 mg (1.87 mmol) of tert-butyl cis-(-)-{[(1R,3,S)-3-hydroxycyclopentyl]oxy}acetate in 1.8 ml of THF. After 3 h, a further 0.5 eq. of triphenylphosphine and 0.5 eq. of diethyl azodicarboxylate in toluene are added, and the reaction mixture is stirred at RT for a further 2 h. The reaction mixture is then added to water and extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is isolated from the residue by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1 ->
3:1). This gives 555 mg (81.8% of theory) of the target compound.

[a]D20 = -169.8 , c = 0.48, CHC13 LC-MS (Method 12): R, = 2.71 min.; m/z = 381 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): b= 8.35 (d, 2H), 8.19 (d, 2H), 6.39-6.34 (m, IH), 6.20-6.17 (m, 1 H), 6.00-5.95 (m, IH), 4.88-4.81 (m, 1H), 4.04 (s, 2H), 2.32-2.19 (m, 2H), 1.43 (s, 9H).

Example 98A

tert-Butyl trans-(-)-{[(4-hydroxycyclopent-2-en-l-yl]oxy}acetate HO~~~ O~ ~CH3 300 mg (0.83 mmol) of trans-(-)-4-(2-tert-butoxy-2-oxoethoxy)cyclopent-2-en-1-y14-nitrobenzoate are dissolved in 2.4 ml of THF and 0.6 ml of methanol, and 0.9 ml of I N
aqueous sodium hydroxide solution is added at RT. After 30 min, the reaction mixture is added to water and extracted three times with dichloromethane. The organic phases are combined and washed successively with sat. sodium carbonate solution, sodium bicarbonate solution and sodium chloride solution. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. This gives 137.3 mg (77.6% of theory) of the target compound.

[a]D 20 = -83.1 , c = 0.525, CHCI3 GC-MS (Method 9): R, = 5.03 min.; m/z = 157 (M-C4H9)+

'H-NMR (400 MHz, DMSO-d6): 6 = 5.97 (s, 2H), 4.81 (d, 1H), 4.79-4.71 (m, 1H), 4.68-4.62 (m, BHC 07 1 039-Foreign countries 1 H), 3.93 (s, 2H), 2.00-1.93 (m, I H), 1.80-1.73 (m, 1 H), 1.40 (s, 9H).
Example 99A

tert-Butyl trans-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopent-2-en-l-yl]oxy}acetate NO~ ~CH 3 O

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

[a]D20 = -256.6 , c = 0.545, CHC13 LC-MS (Method 3): R, = 2.29 min.; m/z = 361 (M+NH4)+

'H-NMR (400 MHz, DMSO-d6): b= 7.83 (s, 4H), 6.20-6.15 (m, 1H), 5.97-5.90 (m, IH), 5.38-5.30 (m, 1 H), 4.92-4.88 (m, I H), 4.03 (s, 2H), 2.40-2.30 (m, I H), 2.19-2.19 (m, 1 H), 1.46 (s, 9H).
Example 100A

tert-Butyl trans-{[(4-aininocyclopent-2-en-l-yl]oxy}acetate H2N\``` O~ "~CH3 In 0.3 ml of ethanol, 22 l (0.545 mmol) of hydrazine monohydrate are added to 120 mg (0.349 mmol) of tert-butyl trans-{[4-(1,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)cyclopent-2-en-l-BHC 07 1 039-Foreign countries yl]oxy}acetate. The mixture is heated under reflux for 15 min. A bulky precipitate is formed which, after cooling, is removed by filtration and washed with a little ethanol. The filtrate is concentrated under reduced pressure, and the product obtained (74 mg) is used without further purification.

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

'H-NMR (400 MHz, DMSO-d6): 8= 5.96-5.90 (m, IH), 5.89-5.83 (m, 1H), 4.68-4.60 (m, 1H), 4.04-3.85 (m, 4H), 2.07-1.98 (m, IH), 1.97-1.79 (m, 1H), 1.68-1.57 (m, 1H), 1.41 (s, 9H).
Example lOlA

2-(2-Fluorophenyl)-2-hydroxy-l-(4-methoxyphenyl)ethanone H3C"0 OH F
O

At -78 C, 441 ml (1.10 mol) of a 2.5 M solution of n-butyllithium in n-hexane are added dropwise to a solution of 156 ml (1.11 mol) of N,N-diisopropylamine in 1937 ml of 1,2-dimethoxyethane such that the temperature does not exceed -60 C. After 15 min of stirring at this temperature, a solution of 236 g (1.00 mol) of (4-methoxyphenyl)[(trimethylsilyl)oxy]acetonitrile [N. Kurono, J.
Org. Chenz 2005, 16, 6530-6532] in 753 ml of 1,2-dimethoxyethane is added dropwise over a period of 30 inin. After 30 min of stirring at this temperature, a solution of 128 g (1.00 mol) of 2-fluorobenzaldehyde in 753 ml of 1,2-dimethoxyethane is added dropwise over a period of min. Over a period of 4 h, the reaction mixture is allowed to warin to room temperature. After addition of 3800 ml of sat. aqueous ammonium chloride solution, the mixture is extracted with 20 ethyl acetate. The organic phase is washed with sat. ammonium chloride solution, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. 3800 ml of dioxane, 2700 ml of methanol and 3120 ml of I M hydrochloric acid are added to the residue, and the mixture is stirred at room temperature for 16 h. After addition of 8000 ml of sat. aqueous sodium chloride solution, the mixture is extracted with 4000 ml of ethyl acetate. The aqueous phase is re-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 and filtered, and the filtrate is concentrated under reduced pressure. The residue is titrated with 600 ml of diisopropyl ether and filtered. The mother liquor is concentrated under reduced pressure. The residue is taken up in dichloromethane and purified by flash chromatography on silica gel (mobile BHC 07 1 039-Foreign countries phase: cyclohexane/ethyl acetate 4: 1). The product fraction obtained in this manner is titrated with diisopropyl ether/petroleum ether (1:1), filtered and dried under reduced pressure. This gives 94 g (purity 80%, 29% of theory) of the title compound.

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

'H-NMR (400 MHz, CDC13): 6= 7.93-7.91 (m, 2H), 7.28-7.18 (m, 2H), 7.10-7.04 (m, 2H), 6.89-6.86 (m, 2H), 6.19 (d, I H), 4.69 (s, 1 H), 3.82 (s, 3H).

Example 102A
2-Amino-5-(2-fluorophenyl)-4-(4-methoxyphenyl)-3-furon itri le CN
NH
p 2 F

84 g (0.32 mol) of 2-(2-fluorophenyl)-2-hydroxy-l-(4-methoxyphenyl)ethanone and 32 g (0.48 mol) of malononitrile are initially charged in 153 ml of THF. After 5 minutes of stirring, 49 ml (36 g, 0.36 mol) of triethylamine are added with ice-cooling. The reaction mixture is stirred with ice-cooling for 1 h. The reaction mixture is then allowed to warm to room temperature and stirred at this temperature for 4 h. 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 under reduced pressure. The residue is taken up in dichloromethane and purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 70:1, then cyclo-hexane/ethyl acetate 2:1). 37 g (0.11 mol) of the 2-(2-fluorophenyl)-2-hydroxy-l-(4-methoxyphenyl)ethanone recovered during the flash chromatography are reacted again according to the above procedure with 14 g (0.03 mol) of malononitrile and 21 ml (15 g, 0.15 mol) of triethylamine and 67 ml of THF. This gives a total of 70 g (purity 52%, 36% of theory) of the target compound.

'H-NMR (400 MHz, CDC13): b= 7.23-7.11 (m, 4H), 7.03-6.95 (m, 2H), 6.82-6.79 (m, 2H), 4.86 (s, NHz), 3.74 (s, 3H).

BHC 07 1 039-Foreign countries Example 103A

6-(2-Fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-one H 3 c ~o O

NH
N
CPO
F
At 0 C, 268 ml of formic acid are added dropwise to 436 ml of acetic anhydride, and the mixture is stirred at this temperature for 30 min. A solution of 70 g(0.12 mol) of 2-amino-5-(2-fluorophenyl)-4-(4-methoxyphenyl)-3-furonitrile in 100 ml of acetic anhydride is then added, and the mixture is stirred at 130 C for 24 h. After cooling to room temperature, the mixture is concentrated under oii pump vacuum at 50 C. The residue is, with ice-cooling, titrated with 250 ml of diisopropyl ether, and is filtered, washed with 70 ml of diisopropyl ether and dried under reduced pressure. This gives 23.7 g (60% of theory) of the title compound.

HPLC (Method 1): Rt = 4.27 min.
MS (DCI): m/z = 354 (M+NH4)' 'H-NMR (400 MHz, CDC13): 6= 12.68 (br. s, NH), 8.19 (d, 1H), 7.53-7.45 (m, 2H), 7.34-7.25 (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 H3C~0 CI
CAO N
Nj F

BHC 07 1 039-Foreign countries 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 of sulfolane and 11 ml (18 g, 0.12 mol) of phosphoryl chloride is stirred at 120 C for I h. After cooling to room temperature, the reaction solution is, with vigorous stirring and ice-cooling, added dropwise to a mixture of 1000 ml of water and 100 ml of 25% strength aqueous ammonia solution. The solid which precipitates at 10 C is filtered off and washed repeatedly with water. The solid is re-dissolved in 700 ml of ethyl acetate, and the solution is washed twice with in each case 500 ml of water. The organic phase is dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The residue is titrated with 60 ml of diisopropyl ether, filtered and dried under reduced pressure. This gives 18 g (81% of theory) of the title compound.

HPLC (Method 1): Rt = 5.03 min.

'H-NMR (400 MHz, DMSO-d6): b= 8.90 (s, 1H), 7.58-7.50 (m, 2H), 7.36-7.27 (m, 4H), 7.01-6.97 (m, 2H), 3.79 (s, 3H).

Example 105A

1 -(4 -Ethyl ph enyl)-2 -(2 -fl uoroph enyl)-2 -hydroxyethanone O
At -78 C, 217 ml (0.54 mol) of a 2.5 M solution of n-butyllithium in hexane are added dropwise to a solution of 77 ml (56 g, 0.55 mol) of N,N-diisopropylamine in 960 ml of 1,2-dimethoxyethane such that the temperature does not exceed -60 C. After 15 min of stirring at this temperature, a solution of 116 g (0.50 mol) of (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile [D.S. Dhanoa, J.
Med. Chem. 1993, 36 (23), 3738-3742] in 373 ml of 1,2-dimethoxyethane is added dropwise over a period of 30 min. After 30 min of stirring at this temperature, a solution of 64 g (0.50 mol) of 2-fluorobenzaldehyde in 373 inl of 1,2-dimethoxyethane is then added dropwise over a period of 20 min. Over a period of 4 h, the reaction mixture is allowed to warm to room temperature. After addition of 1900 ml of sat. aqueous ammonium chloride solution, the mixture is extracted with ethyl acetate. The organic phase is washed with sat. ammonium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. 1900 ml of dioxane, 1350 ml of methanol and 1560 ml of I M hydrochloric acid are added to the residue, and the mixture is stirred at room temperature for 16 h. After addition of 4000 ml of sat. aqueous BHC 07 1 039-Foreign countries sodium chloride solution, the mixture is extracted with 2000 ml of ethyl acetate. The organic phase is washed with 1000 ml of water and 1000 ml sat. sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1). The product fraction obtained in this manner is titrated with 80 ml of diisopropyl ether and 240 ml of petroleum ether, filtered, washed with petroleum ether and dried under reduced pressure.
This gives 50 g (purity 85%, 33% of theory) of the title compound.

HPLC (Method 1): R, = 4.50 min.
MS (DCI): m/z = 276 (M+NH4)+

'H-NMR (400 MHz, CDC13): S= 7.87-7.85 (m, 2H), 7.28-7.19 (m, 4H), 7.11-7.04 (m, 2H), 6.22 (d, 1 H), 4.64 (d, 1 H), 2.65 (q, 2H), 1.21 (t, 3H).

Example 106A
2-Amino-4-(4-ethylphenyl)-5-(2-fluorophenyl)-3-furonitrile CN

F

50 g(0.19 mol) of 1-(4-ethylphenyl)-2-(2-fluorophenyl)-2-hydroxyethanone and 17 g (0.25 mol) of malononitrile are initially charged in 93 ml of DMF. After five minutes of stirring, 17 ml (12 g, 0.12 mol) of diethylamine are added with ice-cooling. The reaction mixture is stirred with ice-cooling for I h. The mixture is then allowed to warm to room temperature and stirred at this temperature for 4 h. After addition of 500 ml of water and after 30 min of stirring, the aqueous phase is decanted off. By adding another 500 ml of water and decanting again, an oily residue is obtained which is dissolved in ethyl acetate, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. According to DC analysis (mobile phase:
cyclohexane/ethyl acetate 4:1), the residue still contains 1-(4-ethylphenyl)-2-(2-fluorophenyl)-2-hydroxyethanone.
Accordingly, according to the above procedure, the residue in 90 ml of DMF is again reacted with 5.5 g (0.08 mol) of malononitrile and 10 ml (7 g, 0.10 mol) of diethylamine.
The reaction mixture is added to 500 ml of ethyl acetate and washed three times with in each case 300 ml of water and BHC 07 1 039-Foreign countries once with 300 ml of sat. sodium chloride solution. The organic phase is dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1).
This gives 36 g (61%
of theory) of the title compound which is reacted without further characterization.

Example 107A
5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4(3H)-one 71?
NH
O Ni F
At 0 C, 140 ml (3.71 mol) of formic acid are added dropwise to 280 mi (2.97 mol) of acetic anhydride, and the mixture is stirred at this temperature for 30 min. 36.0 g (0.12 mol) of 2-amino-4-(4-ethylphenyl)-5-(2-fluorophenyl)-3-furonitrile are then added, and the mixture is stirred at 130 C for 24 h. After cooling to room temperature, the mixture is concentrated at 50 C under oil pump vacuum. At -10 C, the residue is stirred with 150 ml of diisopropyl ether for 30 min, filtered off, washed with 50 ml of ice-cooled diisopropyl ether and dried under reduced pressure. This gives 20.6 g (purity 86%, 45% of theory) of the title compound.

HPLC (Method 1): R, = 4.65 min.
MS (ESIpos): m/z = 335 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 12.68 (br. s, NH), 8.20 (s, 1H), 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 BHC 07 1 039-Foreign countries CI

N
O Ni F
A suspension of 20.0 g (0.06 mol) of 5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4(3H)-one in 100 ml (165 g, 1.07 mol) of phosphoryl chloride is stirred at 120 C for I h. After cooling to room temperature, the reaction solution is, with vigorous stirring, added dropwise to a mixture of 330 ml of water and 610 ml of 25% strength aqueous ammonia solution, resulting in a temperature increase to 55-65 C. The reaction mixture is allowed to cool to room temperature.
After two extractions with in each case 500 ml of dichoromethane, the organic phase is washed with sat. aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is titrated with 150 ml of petroleum ether, filtered off, washed with ice-cooled petroleum ether and dried under reduced pressure. This gives 18.7 g (purity 90%, 80% of theory) of the title compound.

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

'H-NMR (400 MHz, DMSO-dO: 6 = 8.91 (s, 1H), 7.58-7.49 (m, 2H), 7.36-7.24 (m, 6H), 2.66 (q, 2H), 1.21 (t, 3H).

Example 109A
1-[(Z)-2-Chloro-2-nitrovinyl]-4-ethylbenzene CI

~ ~

Analogously to the literature procedure [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 dimethylammonium chloride and 0.6 g (11.2 mmol) of potassium fluoride in 150 ml of xylene is stirred on a water separator at 160 C for 15 hours and then at 175 C for seven hours. After addition of 25 ml of water and 100 ml of dichloromethane, the organic phase is separated off and the aqueous phase is extracted three times with in each case 100 ml of BHC 07 1 039-Foreign countries dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel (mobile phase:
cyclohexane/dichloromethane 1:1). This gives 11.9 g (purity 85%, 64% of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): 6= 8.60 (s, 1 H), 7.94 (d, 2H), 7.42 (d, 2H), 2.68 (q, 2H), 1.21 (t, 3H).

Example 110A
5-(4-Ethylphenyl)furo[2,3-d]pyrimidin-4(3H)-one O

NH
Ni Analogously to the literature procedure [D. Dauzonne, Tetrahedron, 1992, 3069-3080], a suspension of 11.9 g (purity 85%, 47.6 mmol) of 1-[(Z)-2-chloro-2-nitrovinyl]-4-ethylbenzene and 5.9 g(52.3 mmol) of 4,6-dihydroxypyrimidine in 200 ml of ethanol is stirred at 60-70 C for 30 minutes. 14.4 ml (14.6 g, 96.1 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene are then added slowly. The resulting reaction solution is stirred under reflux for 6 hours and then at 60 C for 15 hours. After concentration under reduced pressure, the residue is taken up in dichloromethane and chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1 --> 1:5). The residue obtained is titrated with diethyl ether and filtered. This gives 5.0 g (44% of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): b= 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 111A
5-(4-Ethylphenyl)-6-iodofuro[2,3-d]pyrimidin-4(3H)-one BHC 07 1 039-Foreign countries O
I NH
' J
O N-7.0 g (31.3 mmol) of N-iodosuccinimide are added to a solution of 5.0 g (20.9 mmol) of 5-(4-ethylphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 250 ml of acetonitrile/carbon tetrachloride (1:1).
The resulting suspension is stirred under reflux for 2 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure. The residue is stirred in ethyl acetate and filtered. Water is added to the filtrate. The organic phase is separated off, and the aqueous phase is then extracted repeatedly with ethyl acetate. The combined organic phases are concentrated under reduced pressure. The residue is taken up in ethyl acetate and chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1 -> 1:2). The solid obtained is titrated with diethyl ether/n-pentane and filtered. This gives 1.4 g(purity 85%, 16% of theory) of the target compound.
LC-MS (Method 8): Rt = 2.34 min.; m/z = 367 (M+H)+

'H-NMR (400 MHz, DMSO-db): S= 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 112A

4-Chloro-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine Cl N
O N%

A suspension of 1.4 g (purity 85%, 3.3 mmol) of 5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidin-4(3H)-one in 20 ml (32.9 g, 214.6 mmol) of phosphoryl chloride is stirred under reflux for one hour. After concentration under reduced pressure, ice-cold water and dichloromethane are added to the residue. The organic phase is dried over sodium sulfate and filtered. The filtrate is concentrated BHC 07 1 039-Foreign countries under reduced pressure and dried. This gives 1.0 g (purity 70%, 57% of theory) of the target compound.

LC-MS (Method 6): Rt = 2.97 min.; m/z = 385 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.80 (s, 1H), 7.43-7.36 (m, 4H), 2.70 (q, 2H), 1.26 (t, 3H).
Example 113A

4-{ [(3R)-1-Benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine 0~.~`' N
O
NJ

106 mg (2.65 mmol) of sodium hydride (60% dispersion in mineral oil) are added to a solution of 483 mg (2.53 mmol) of (3R)-1-benzylpiperidin-3-ol [H. Tomori, Bull. Chem. Soc.
Jpn. 69, 1, 207-216 (1996)] in 5 ml of THF. After 10 minutes of stirring, a solution of 1020 mg (purity 70%, 1.86 mmol) of 4-chloro-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine in 5 ml of THF and 47 mg (0.13 mmol) of tetra-n-butylammonium iodide are added. The reaction mixture is stirred at room temperature for 5 hours. After addition of water and ethyl acetate, the organic phase is separated off, washed with I N hydrochloric acid and sat. sodium chloride solution and then concentrated under reduced pressure. The residue is taken up acetonitrile and purified by preparative RP-HPLC
(gradient: water/acetonitrile). This gives 266 mg (20% of theory) of the desired product.

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

'H-NMR (400 MHz, DMSO-d6): b= 8.46 (s, 1 H), 7.58-7.56 (m, 2H), 7.32-7.29 (m, 2H), 7.24-7.17 (m, 5H), 5.34-5.29 (m, 1 H), 3.45 (d, 2H), 2.71-2.63 (m, 3H), 2.39-2.33 (m, 214), 2.30-2.24 (m, 1 H), 1.89-1.84 (m, 1 H), 1.66-1.60 (m, 1 H), 1.47-1.39 (m, 2H), 1.21 (t, 3H).

Example 114A

4-{ [(3R)-1-Benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidine BHC 07 1 039-Foreign countries O

N
O
F
0.68 ml of a 2 M aqueous sodium carbonate solution is added to a mixture of 365 mg (0.68 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-iodofuro[2,3-d]pyrimidine and 24 mg (0.03 mmol) of bis(triphenylphosphine)palladium(II) chloride in 15 ml of DMSO.
118 mg (0.85 mmol) of (2-fluorophenyl)boronic acid are then added, and the mixture is stirred at 80 C for hours. The reaction mixture is then filtered and purified directly by preparative RP-HPLC
(gradient: water/acetonitrile). This gives 291 mg (84% of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): b= 8.57 (s, l H), 7.57-7.53 (m, 2H), 7.39-7.29 (m, 4H), 7.24-7.18 10 (m, 7H), 5.40-5.34 (m, 1 H), 3.49-3.46 (m, 2H), 2.74-2.69 (m, 1 H), 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

(3R)-3-{[5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-y1]oxy}piperidinium formate \\,,-NH x HCO2H
N
O NJ
F

15 30 mg of 10% palladium on activated carbon are added to a solution, covered with argon, of 275 mg (0.54 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidine in 5 ml of methanol/ethanol (1:2), and the mixture is stirred under a hydrogen atmosphere (atmospheric pressure) at room temperature for 3 hours. After BHC 07 1 039-Foreign countries addition of a further 70 mg of 10% palladium on activated carbon, the reaction mixture is again stirred under a hydrogen atmosphere (atmospheric pressure) at room temperature for 19 hours. A
further 175 mg of 10% palladium on activated carbon and 0.2 ml of formic acid are added, and the reaction mixture is again stirred under an atmosphere of hydrogen (atmospheric pressure) at room temperature for 15 hours. The catalyst is filtered off, and the catalyst residue is then washed with methanol/water. The filtrate is concentrated under reduced pressure, and the residue is taken in acetonitrile/DMSO and purified by preparative RP-HPLC (gradient:
water/acetonitrile/formic acid). This gives 137 mg (54% of theory) of the desired product.

LC-MS (Method 8): R, = 1.74 min.; m/z = 418 (M-HCOZH+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 8.57 (s, 1 H), 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, 1H), 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, lH), 1.50-1.44 (m, 2H), 1.17 (t, 3H).
Example 116A

3-{[5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol O OH
N
O NJ
F

At 70 C, 4.5 ml of a 12.5 N aqueous sodium hydroxide solution are added to a mixture of 1.65 g (14.17 mmol) of cyclohexane-l,3-diol in 45 ml of toluene, 15 ml of 1,2-dimethoxyethane and 15 ml of water. 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-fluorophenyl)furo[2,3-d]pyrimidine, the reaction mixture is stirred at 70 C for 17 hours. After cooling to room temperature, the mixture is adjusted to pH 7 using conc. hydrochloric acid. The mixture is extracted with dichloromethane.
The organic phase is washed with sat. sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). This gives 0.60 g (24% of theory) of the desired product as a racemic mixture of diasteromers.

BHC 07 1 039-Foreign countries LC-MS (Method 8): R, = 2.96 min.; m/z = 433 (M+H)+

'H-NMR (400 MHz, DMSO-d6): [Minor stereoisomer in brackets] 8= 8.62 (s, 1H), [8.61, s, 1H], 7.57-7.52 (m, 2H), 7.34-7.28 (m, 4H), 7.20-7.18 (m, 2H), [5.68-5.64, m, 1H], 5.21-5.14 (m, 1H), 4.75 (d, OH), [4.45, d, OH], 3.57-3.48 (m, 1H), 2.63 (q, 2H), 2.37-2.31 (m, 1H), 2.08-2.03 (m, 1H), 1.82-1.77 (m, 1H), 1.74-1.69 (m, 1H), 1.34-1.02 (m, 4H), 1.20 (t, 3H).

Example 117A

4- { [(3R)-1-Benzylpiperidin-3-yl]oxy} -6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimi-dine O ~,,= N
\1 N
O
F

1037 mg (5.37 mmol) of (3R)-1-benzylpiperidin-3-ol [H. Tomori, Bull. Chem.
Soc. Jpn. 69, 1, 207-216 (1996)] are dissolved in 10 ml of THF, and 268 mg (6.71 mmol) of sodium hydride (60% in mineral oil) are added. 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 are added. The reaction mixture is heated under reflux for 16 hours. 100 ml of water and 100 ml of ethyl acetate are then added. The organic phase is separated off and washed with 50 ml of l N hydrochloric acid and 100 ml of sat. sodium chloride solution. The aqueous phase is re-extracted with 50 ml of ethyl acetate, and the combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure. This gives 2645 mg (89% of theory, purity 92%) of the desired product.

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

'H-NMR (400 MHz, DMSO-d6): S= 8.63 (s, 1H), 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, l H), 3.77 (s, 3 H), 3.68-3.66 (m, 1 H), 2.89-2.83 (m, 1 H), 2.36-2.27 (m, 2H), 1.91-1.81 (m, 3H), 1.51-1.45 (m, 1H).

BHC 07 1 039-Foreign countries Example 118A

6-(2-Fluorophenyl)-5-(4-methoxyphenyl)-4-[(3R)-piperidin-3-yloxy]furo[2,3-d]pyrimidine formate , NH x HCO2HCN
F

400 mg of palladium black are added to a solution, covered with argon, of 510 mg (1.00 mmol) of 4-{[(3R)-1-benzylpiperidin-3-yl]oxy}-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 5 ml of a 4.4% strength solution of formic acid in methanol, and the mixture is stirred at room temperature for two days. The catalyst is filtered off, and the catalyst residue is then washed with methanol/water. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative RP-HPLC (mobile phase: water/acetonitrile gradient with 0.1%
formic acid). This gives 70 mg (12% of theory, purity 80%) of the desired product.
LC-MS (Method 8): Rt = 1.66 min.; m/z = 420 (M-HCOzH+H)+.

Example 119A

6-(2-Fluorophenyl)-5-(4-methoxyphenyl)-4-[(3R)-piperid in-3-yloxy] furo[2,3-d]pyrimidine O\\,, NH
\1 ~N

O N
F

300 mg of palladium black are added to a solution, covered with argon, of 2600 mg (4.69 mmol) of 4-{[(3R)-I-benzylpiperidin-3-yl]oxy}-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 25 ml of a 4.4% strength solution of formic acid in methanol, and the mixture is stirred at room temperature for 5 hours. Another 300 mg of palladium black and 0.9 ml of formic BHC 07 1 039-Foreign countries acid are then added, and the mixture is stirred at room temperature for a further 16 hours. The catalyst is filtered off, and the catalyst residue is then washed with methanol/water. The filtrate is concentrated under reduced pressure, and the residue is titrated with acetonitrile, filtered off and dried under reduced pressure. This gives 1376 mg (68% of theory) of the desired product.

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

'H-NMR (400 MHz, DMSO-d6): b= 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, 1H), 1.78-1.71 (m, 3H).

Example 120A

Methyl 3-[(2R,4R)-1-(tert-butoxycarbonyl)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} piperidin-2-yl]propanoate O HC
H3C-O ~/CH3 NO/3\CH3 O ''/~O~CH

O
N
NJ
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-I-carboxylate are dissolved in 1 ml of DMF, the mixture is cooled to -l0 C and 1.02 ml (2.05 mmol) of the phosphazene base P2-t-Bu (about 2 M solution in THF) are added. The reaction mixture is stirred at 0 C for I h and then added to water. The mixture is extracted three times with dichloromethane, and the organic phases are combined, washed with sat. sodium chloride solution and dried over magnesium sulfate. After concentration under reduced pressure, the product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1 -> 3:1).
This gives 420 mg (38.1 % of theory) of the target compound.

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.60 (s, I H), 7.55 (d, 2H), 7.43-7.32 (m, 5H), 7.02 (d, 2H), 5.58 (s, IH), 4.02-3.93 (m, 1 H), 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, 1 H), 1.36 (s, 9H), 1.16-1.05 (m, 2H).

BHC 07 1 039-Foreign countries Example 121A

3-[(2R,4R)-1-(tert-Butoxycarbonyl)-4-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]-oxy}piperidin-2-yl]propanoic acid H3C-O ~CH3 O

N O
O NJ

35 mg (0.06 mmol) of methyl 3-[(2R,4R)-1-(tert-butoxycarbonyl)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-2-yl]propanoate are dissolved in 0.1 ml of methanol, the mixture is cooled to 0 C and about 240 mg of 10% strength aqueous sodium hydroxide solution are added. The mixture is stirred at about 40 C for a number of hours and then at RT overnight. The reaction mixture is then made slightly acidic (pH about 3) using I N
hydrochloric acid and extracted repeatedly with dichloromethane. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The target compound is obtained in quantitative yield (34 mg) and not purified any further.

Example 122A

[1-({[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)cyclobutyl]methanol O OH
N
o J
N
At 70 C, 2.6 ml of an 11.25 N aqueous sodium hydroxide solution are added to a solution of 1.72 g (14.85 mmol) of cyclobutane-l,l-diyldimethanol [F.X. Tavares, J. Med. Chem.
2004, 47 (21), 5057-5068] in 20 ml of toluene, 8 ml of 1,2-dimethoxyethane and 8 ml of water.
After addition of 0.10 g (0.30 mmol) of tetra-n-butylammonium hydrogensulfate and 1.00 g (2.97 mmol) of 4-BHC 07 1 039-Foreign countries chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine, the reaction mixture is stirred at 70 C
for 17 h. After cooling to room temperature, the pH is adjusted to 7 using concentrated hydrochloric acid. The mixture is extracted three times with in each case 50 ml of dichloromethane. The combined organic extracts are washed with sat. sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is stirred with acetonitrile and filtered, and the filtrate is purified by preparative RP-HPLC
(gradient: water/acetonitrile). This gives 0.30 g (24% of theory) of the desired product.

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.58 (s, 1H), 7.56-7.54 (m, 2H), 7.42-7.37 (m, 5H), 7.04-6.99 (m, 2H), 4.56 (t, 1 H), 4.30 (s, 2H), 3.81 (s, 3H), 3.21 (d, 2H), 1.77-1.58 (m, 6H).

BHC 07 1 039-Foreign countries Exemplary embodiments:

Example 1 Methyl 3-{[6-(4-bromophenyl)-5-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate _ /

N
Br N
In an oil bath, 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-aminophenoxy acetate are heated at 150 C for 1.5 h. After cooling, the residue is taken up in DMSO and filtered through silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). This gives 140 mg (25.5% of theory) of the target compound as a yellowish solid.

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

'H-NMR (400 MHz, DMSO-d6): b= 8.57 (s, l H), 7.19 (s, 5H), 7.61 (d, 2H), 7.44 (d, 2H), 7.22-7.18 (m, 2H), 6.82 (s, l H), 6.86 (dd, I H), 6.61 (dd, I H), 4.77 (s, 2H), 3.71 (s, 3H).

Example 2 Methyl 3-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]phenoxy acetate _ ja HN OO~CH3 200 mg (0.377 mmol) of methyl 3-{[6-(4-bromophenyl)-5-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate are dissolved in 5 ml of dichloromethane and 2 ml of THF, and 40 mg of 10% palladium on activated carbon are added under argon. The mixture is stirred under a hydrogen atmosphere of 3 bar excess pressure at RT for 3 h, and the catalyst is then filtered off.
The catalyst residue is washed with dichloromethane and methanol, the combined filtrates are BHC 07 1 039-Foreign countries concentrated under reduced pressure and the residue is chromatographed on silica gel (mobile phase: dichloromethane/ethyl acetate 10:1). This gives 79.1 mg (45.5% of theory) of the target compound as a colorless solid.

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

'H-NMR (300 MHz, DMSO-d6): S= 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, 1 H), 6.78 (dd, I H), 6.61 (dd, 1 H), 4.78 (s, 2H), 3.72 (s, 3H).
Example 3 3-[(5,6-Diphenylfuro[2,3-d]pyrimidin-4-yl)amino]phenoxy acetic acid _ jao-*' HN OH

N O
O N

50 mg (0.111 mmol) of methyl 3-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]phenoxy acetate are dissolved in 2 ml of THF, 0.33 ml of 1 N aqueous sodium hydroxide solution is added at RT
and the mixture is stirred at 50 C for 1 h. The mixture is cooled to RT and the THF is removed under reduced pressure. Water and then, with ice-cooling, I N hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed repeatedly with water and dried under reduced pressure. This gives 39.4 mg (81.3% of theory) of the target compound as a white solid.
LC-MS (Method 3): R, = 2.52 min.; m/z = 438 (M+H)+

'H-NMR (300 MHz, DMSO-db): d= 13.04 (br. s, l H), 8.58 (s, 1 H), 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, I H), 4.62 (s, 2H).
Example 4 Methyl 3-{ [6-(4-bromophenyl)-5-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino} phenoxy acetate BHC 07 1 039-Foreign countries F
_ / I

HN \ O11~y 0 CH3 O
N
Br j O N

In an oil bath, 400 mg (0.991 mmol) of 6-(4-bromophenyl)-4-chloro-5-(4-fluorophenyl)furo[2,3-d]pyrimidine (preparation see W003/018589) and 215.5 mg (1.19 mmol) of methyl aminophenoxy acetate are heated at 150 C for 1.5 h. After cooling, the residue is taken up in DMSO and filtered through silica gel (mobile phase: dichloromethane/ethyl acetate 10:1). 242 mg of a mixture which is purified further by preparative HPLC are isolated. This gives 120 mg (15%
of theory) of the target compound as a colorless solid.

LC-MS (Method 6): Rt = 3.2 min.; m/z = 548, 550 (M+H)+.
Example 5 Methyl 3-{[5-(4-fluorophenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate F
/ I

HN \ O-"-y Oll CH3 O
N

N
115 mg (0.21 mmol) of methyl 3-{[6-(4-bromophenyl)-5-(4-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate are dissolved in 5 ml dichloromethane and 5 ml of ethyl acetate, and 22 mg of 10% palladium on activated carbon are added under argon. The mixture is stirred under a hydrogen atmosphere of 3 bar excess pressure at RT until all the starting material has been converted. The catalyst is filtered off, the filtrate obtained is concentrated under reduced pressure and the residue is chromatographed on silica gel (mobile phase:
dichloromethane/ethyl acetate 10:1). This gives 27.9 mg (28.3% of theory) of the target compound as a colorless solid.

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

'H-NMR (300 MHz, DMSO-d6): S= 8.55 (s, 1 H), 7.74-7.68 (m, 2H), 7.55-7.39 (m, 6H), 7.26-7.20 (m, 2H), 7.02 (s, 1 H), 6.86 (d, 1 H), 6.63 (dd, 1 H), 4.78 (s, 2H), 3.71 (s, 3H).

BHC 07 1 039-Foreign countries Example 6 3-{ [5-(4-Fluorophenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} phenoxy acetic acid F

<),,,O,,-,yOH
HN 21.1 mg (0.045 mmol) of methyl 3-{[5-(4-fluorophenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate are dissolved in 1 ml of THF, 0.135 ml of I N aqueous sodium hydroxide solution are added at RT and the mixture is stirred at 50 C for 1 h.
The mixture is cooled to RT and the THF is removed under reduced pressure. Water and then, with ice-cooling, I N hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed repeatedly with water and dried at 40 C under reduced pressure. This gives 11.5 mg (56.2% of theory) of the target compound as a white solid.

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

'H-NMR (300 MHz, DMSO-d6): b= 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, 1 H), 6.83 (dd, 1 H), 6.61 (dd, 1H), 4.65 (s, 3 H).

Example 7 Methyl 3-{[5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate / I

HN \ O~O~CH3 _ O NJ

In an oil bath, 400 mg (1.091 mmol) of 4-chloro-5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidine (preparation see WO 03/0 1 85 89) and 237.1 mg (1.309 mmol) of methyl 3-aminophenoxy acetate are heated at 150 C for 1.5 h. After cooling, dichloromethane is added to the residue, and the product is purified on silica gel (mobile phase: dichloromethane/ethyl acetate 10:1). This gives BHC 07 1 039-Foreign countries 139.3 mg (25% of theory) of the target compound as a light-yellow solid.
LC-MS (Method 6): R, = 3.02 min.; m/z = 512 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.51 (s, 1H), 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, 1H), 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 Jao~OH

O N) 107 mg (0.209 mmol) of methyl 3-{[5,6-bis(4-methoxyphenyl)furo[2,3-d]pyrimidin-yl]amino}phenoxy acetate are dissolved in 2 ml of THF, 0.628 ml of 1 N aqueous sodium hydroxide solution is added at RT and the mixture is stirred at 50 C for I h.
The mixture is cooled to RT and the THF is removed under reduced pressure. Water and then, with ice-cooling, I N
hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed repeatedly with water and dried at 40 C under reduced pressure. This gives 92.5 mg (88.9%
of theory) of the target compound as a white solid.

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

'H-NMR (300 MHz, DMSO-d6): b= 13.04 (br. s, 1 H), 8.51 (s, 1 H), 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, 1 H), 6.59 (dd, l H), 4.65 (s, 2H), 3.90 (s, 3H), 3.78 (s, 3H).

Example 9 Methyl3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate BHC 07 1 039-Foreign countries ~ ~ HN \ O~O~CH3 O
N
NJ

In an oil bath, 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-aminophenoxy acetate are heated at 150 C
for 1.5 h. After cooling, dichloromethane is added to the residue and the product is purified on silica gel (mobile phase: cyclohexane/ethyl acetate 2:1). This gives 2.29 g(34.1% of theory) of the target compound as a light-yellowish solid.

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

'H-NMR (300 MHz, DMSO-d6): b= 8.56 (s, 1H), 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 Jao~OH
HN O
N
- o ~
NJ

1000 mg (2.08 mmol) of inetliyl 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetate are dissolved in 10 ml of THF, 4.2 ml of 1 N aqueous sodium hydroxide solution are added at RT and the mixture is stirred at 50 C for 1 h. The mixture is cooled to RT
and the THF is removed under reduced pressure. Water and then, with ice-cooling, l N
hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed repeatedly with water and dried at 40 C under reduced pressure. This gives 913.7 mg (92.5% of theory) of the target compound as a white solid.

LC-MS (Method 5): R, = 2.75 min.; m/z = 468 (M+H)+

BHC 07 1 039-Foreign countries 'H-NMR (300 MHz, DMSO-d6): b= 12.90 (br. s, 1H), 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, 1H), 6.78 (d, 1H), 6.59 (dd, 1H), 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 H OHN / I \ O O

::;
IOI N ~ ~ ~ I \ N H

- O N) 50 mg (0.107 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phen-oxy acetic acid are initially charged in 2 ml of a 1:1 mixture of methanol and dichloromethane, 13 mg (0.107 mmol) of 2-amino-2-hydroxymethyl-1,3-propanediol (trisethanolamine) are added and the mixture is stirred at RT overnight. The mixture is then concentrated under reduced pressure.
This gives 60.3 mg of the target compound as a colorless glass.

LC-MS (Method 5): R, = 2.53 min.; m/z = 468 (C27HZ1N3O5)+

'H-NMR (300 MHz, CD3OD): b= 8.45 (s, 1 H), 7.60-7.51 (m, 4H), 7.36-7.11 (m, 7H), 6.81 (dd, 1H), 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}phenoxy acetic acid sodium salt / I -HN \ O'-~r O
Na+
O
N
- o ~
NJ

BHC 07 1 039-Foreign countries At RT, 2.52 g(5.39 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy acetic acid are suspended in a mixture of 10 ml of THF, 10 ml of methanol and 1 ml of water. 5.39 ml of 1 N aqueous sodium hydroxide solution are added dropwise, and the resulting solution is stirred at RT for 10 min and then filtered off with suction through a fine frit (removal of suspended particles). The solution is concentrated under reduced pressure and the residue is treated with ethanol. The insoluble solid is filtered off with suction, washed with a little ethanol and dried under reduced pressure and then under high vacuum. The filtrate is concentrated and the residue is again titrated with a little ethanol giving, after filtration with suction, a second product batch. The two fractions are combined, giving a total of 2.32 g (87.9%
of theory) of the target compound as a colorless solid.

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.54 (s, 1H), 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, 1H), 4.03 (s, 2H), 3.91 (s, 3H).
Example 13 Ethyl 3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}phenoxy)acetate N O
N) 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 repeatedly with water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. This gives 331.4 mg (91.3% of theory) of the target compound as a yellowish solid.

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

'H-NMR (300 MHz, DMSO-d6): b= 8.51 (s, 1H), 7.60-7.51 (m, 4H), 7.46-7.41 (m, 3H), 7.33 (t, 1H), 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).

BHC 07 1 039-Foreign countries Example 14 Methyl 3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
phenoxy)acetate O O""-)r 0~1 CH3 O
N
o NJ

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) of cesium carbonate are stirred under reflux for 45 min. After cooling, the mixture is concentrated and the crude product is used without further purification for the next reaction.

Example 15 3- { [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
phenoxy)acetic acid ao,,-~OH
O O
N

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

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

'H-NMR (400 MHz, DMSO-d6): b= 13.00 (br. s, 1H), 8.54 (s, 1H), 7.61-7.51 (m, 4H), 7.47-7.40 (m, 3H), 7.32 (t, 1H), 7.03 (d, 2H), 6.88-6.78 (m, 3H), 4.68 (s, 2H), 3.80 (s, 3H).

BHC 07 1 039-Foreign countries Example 16 Methyl N-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}phenyl)glycinate O H~O~CH3 O
N

Ni 450 mg (1.1 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}aniline, 202 mg (1.32 mmol) of methyl bromoacetate and 465.5 mg (1.43 mmol) of cesium carbonate in ml of acetone are stirred under reflux overnight. The acetone is removed under reduced pressure and the residue is taken up in water and extracted repeatedly with dichloromethane/ethyl acetate (1:1). The combined organic phases are dried over magnesium sulfate and concentrated.
The residue is chromatographed twice on silica gel (mobile phase:
dichloromethane/ethyl acetate 10 1:1). This gives 75.4 mg (13.8% of theory) of the target compound as a white foam.

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

'H-NMR (400 MHz, DMSO-d6): 8= 8.53 (s, 1H), 7.59-7.40 (m, 7H), 7.09 (t, IH), 7.02 (d, 2H), 6.45-6.39 (m, 3H), 6.20 (t, 1H), 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 O HOH
aN
O
N
O N) 65 mg (0.135 mmol) of methyl N-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}phenyl)glycinate, 0.27 ml of I N aqueous sodium hydroxide solution and 2 ml of dioxane are stirred at RT overnight. The mixture is acidified with I N hydrochloric acid and extracted repeatedly with ethyl acetate/dichloromethane (1:1). The combined organic phases are dried over BHC 07 1 039-Foreign countries magnesium sulfate and concentrated. The residue is chromatographed on silica gel (mobile phase:
dichloromethane/methanol 100:1 -> 50:1). This gives 16.8 mg (13.8% of theory) of the target compound as a yellowish, highly viscous oil.

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

'H-NMR (300 MHz, DMSO-d6): b= 12.30 (br. s, 1H), 8.52 (s, 1H), 7.59-7.40 (m, 8H), 7.09 (t, 1H), 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-(1 H-tetrazol-5-ylmethoxy)phenyl]furo[2,3-d]pyrimidine-4-amine / I

HN \ O-**'~ N\ N
N
N H N

A mixture of 100 mg (0.223 mmol) of (3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-y1]amino}phenoxy)acetonitrile, 383 mg (3.345 mmol) of trimethylsilyl azide and 83.32 mg (0.334 mmol) of di-n-butyltin oxide in 5 ml of toluene is stirred at 80 C
overnight. After cooling, the precipitated solid is filtered off with suction, washed with toluene and dried at 50 C under high vacuum overnight. This gives 80.1 mg (73.1 % of theory) of the target compound as a whitish solid.
LC-MS (Method 6): R, = 2.70 min.; m/z = 492 (M+H)+

'H-NMR (300 MHz, DMSO-d6): 8= 8.55 (s, 1H), 7.62-7.50 (m, 4H), 7.45-7.35 (m, 4H), 7.29-7.21 (m, 3H), 6.93 (s, 1H), 6.81-6.73 (m, 2H).

Example 19 (3-{[5-(4-Hydroxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxy)acetic acid BHC 07 1 039-Foreign countries HO
/ I

HN \ O-,-*,y OH
O

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

LC-MS (Method 6): Rt = 2.41 min.; m/z = 454 (M+H)+.
Example 20 Ethyl (2E)-3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acrylate O~~CH3 HN
O
N
O NJ

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-trans-cinnamate are heated at 150 C for 1.5 h.
After cooling, dichloromethane is added and the crude product is purified by chromatography on silica gel (mobile phase: dichloromethane/ethyl acetate 20:1). This gives 539.5 mg (73.9%
of theory) of the target product as a yellowish solid.

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

'H-NMR (300 MHz, DMSO-d6): b= 8.53 (s, 1H), 7.71 (s, 1H), 7.62-7.51 (m, 5H), 7.46-7.35 (m, 6H), 7.23 (d, 2H), 7.05 (s, 1H), 6.54 (d, 1H), 4.21 (q, 2H), 3.90 (s, 3H), 1.27 (t, 3H).

BHC 07 1 039-Foreign countries Exampl:e 21 (2E)-3-(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acrylic acid OH
P--- H
O
NJ

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

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

'H-NMR (400 MHz, DMSO-d6): 8= 12.47 (br. s, IH), 8.55 (s, 1 H), 7.71 (s, IH), 7.62-7.50 (m, 5H), 7.45-7.31 (m, 6H), 7.23 (d, 2H), 7.04 (s, 1 H), 6.44 (d, 1 H), 3.39 (s, 3H).

Example 22 (2E)-3-(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acrylic acid sodium salt HN O
O Na N
NJ
76 mg (0.164 mmol) of (2E)-3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)acrylic acid are additionally charged in 1.5 ml of a 1:1 mixture of methanol and THF, and 0.164 ml of 1 N aqueous sodium hydroxide solution is added at RT. The mixture is stirred at RT for 2 h and then concentrated under reduced pressure, and the residue is dried under BHC 07 1 039-Foreign countries high vacuum overnight. This gives 79.6 mg (99.9% of theory) of the target compound as a yellowish solid.

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

'H-NMR (400 MHz, DMSO-d6): S= 8.54 (s, 1H), 7.65-7.48 (m, 5H), 7.43-7.34 (m, 3H), 7.31-7.21 (m, 4H), 7.15 (br. s, 1 H), 6.97 (d, l H), 6.92 (s, I H), 6.71 (d, 1 H), 3.91 (s, 3H).

Example 23 Methyl 3-(4-{ [5-(4-methoxyphenyl)-6-phenylfuro [2,3-d] pyrimidin-4-yl]oxy}
phenyl)propanoate O
H3C-O JJJlCH3 \ / Q

N
- Q ~
NJ

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) of cesium carbonate are heated at 120 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 is washed twice with buffer solution (pH 7), dried over magnesium sulfate and re-concentrated. The residue is treated with methanol, resulting in the precipitation of a solid which is filtered off, washed with a little methanol and dried under reduced pressure. This gives 160 mg (36.3% of theory) of the target compound as a colorless solid.

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

'H-NMR (300 MHz, DMSO-d6): 8= 8.52 (s, 1H), 7.60-7.50 (m, 4H), 7.45-7.38 (m, 3H), 7.28 (d, 2H), 7.12 (d, 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 BHC 07 1 039-Foreign countries O

OH
O \

N
O N/

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

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

'H-NMR (400 MHz, DMSO-d6): 8= 12.16 (s, 1H), 8.52 (s, 1H), 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 Methyl 3-(3- {[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrim idin-4-yl]am ino}
phenyl)propanoate N O
N) 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 heated at 150 C
for 1.5 h. After cooling, dichloromethane is added and the crude product is purified by chromatography on silica gel (mobile phase: dichloromethane/ethyl acetate 20:1). The product obtained in this manner is titrated with diisopropyl ether, and the resulting solid is filtered off with suction and washed with a little diisopropyl ether. This gives 1367 mg (45.7% of theory) of the target product as a colorless solid.

BHC 07 1 039-Foreign countries LC-MS (Method 5): Rt = 3.19 min.; m/z = 480 (M+H)+.
Example 26 3-(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)propanoic acid I
OH
HN
O
N

N
1000 mg (2.085 mmol) of methyl 3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)propanoate are initially charged in 30 ml of THF, and 6.3 ml of 1 N aqueous sodium hvdroxide solution are added at RT. The mixture is stirred at 50 C for I h and then, after cooling, acidified slightly with I N hydrochloric acid. The precipitated solid is filtered off with suction, washed repeatedly with water and dried at 40 C under high vacuum overnight. This gives 934.5 mg (96.3% of theory) of the target product as a colorless solid.
LC-MS (Method 3): R, = 2.62 min.; m/z = 465 (M+H)+

' H-NMR (300 MHz, DMSO-d6): S= 12.15 (br. s, 1 H), 8.52 (s, l H), 7.62-7.51 (m, 4H), 7.45-7.36 (m, 3H), 7.27-7.20 (m, 5H), 6.95-6.90 (m, I H), 6.88 (s, I H), 3.89 (s, 3H), 2.78 (t, 2H), 2.51 (t, 2H).
Example 27 3-(3-{ [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)propanoic acid sodium salt HN O

N a O +
N
o NJ

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 0.322 ml of 1 N
aqueous sodium BHC 07 1 039-Foreign countries hydroxide solution is added. The mixture is stirred at RT for 1 h and then concentrated under reduced pressure, and the residue is dried under high vacuum overnight. This gives 155.7 mg (99.1% of theory) of the target product as a colorless solid.

LC-MS (Method 5): R, = 2.95 min.; m/z = 466 (M-Na+2H)+

'H-NMR (400 MHz, DMSO-d6): 8= 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 Methyl3- { [5-(4-methoxyphenyl)-6-phenylfuro [2,3-d]pyrimidin-4-yl]amino}
phenylacetate _ ~ I O
HN ~ O."CH3 o-) 300 mg (0.89 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 191.3 mg (1.16 mmol) of 3-aminophenylacetate are heated at 150 C for 1.5 h.
After cooling, dichloromethane is added and the resulting solid is filtered off with suction, washed with dichloromethane and dried at 50 C under high vacuum overnight. The crude product is purified by chromatography on silica gel (mobile phase: dichloromethane/ethyl acetate 10:1). This gives 273.2 mg (65.9% of theory) of the target product as a yellowish solid.

LC-MS (Method 3): R, = 2.88 min.; m/z = 466 (M+H)+

'H-NMR (400 MHz, DMSO-db): 8= 8.52 (s, 1H), 7.59 (d, 2H), 7.53 (d, 2H), 7.44-7.37 (m, 3H), 7.32-7.21 (m, 5H), 6.95 (d, 1 H), 6.90 (s, 1 H), 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}phenylacetic acid BHC 07 1 039-Foreign countries - ~ I O
HN OH
N
O N) 50 mg (0.107 mmol) of methyl 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenylacetate are dissolved in 2 ml of THF, 0.322 ml of I N aqueous sodium hydroxide solution is added at RT and the mixture is stirred at 50 C for 4 h. The mixture is cooled to RT and the THF is removed under reduced pressure. Water and then 1 N hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed with water and dried at 50 C under reduced pressure. This gives 41.7 mg (86% of theory) of the target compound as a white solid.
LC-MS (Method 5): R, = 2.85 min.; m/z = 452 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 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 Methyl4-(4- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yi]amino}
phenyl)butanoate - ~ I ~1 CH3 HN ~ O
N
o NJ

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 heated at 150 C
for 1.5 h. After cooling, the mixture is concentrated under reduced pressure, dichloromethane is added to the residue and the crude product is purified by chromatography on silica gel (mobile phase: dichloro-methane/ethyl acetate 20:1). The product obtained in this manner is titrated with diisopropyl ether, and the resulting solid is filtered off with suction and washed with a little diisopropyl ether. This gives 236.7 mg (80.4% of theory) of the target product as a slightly pink solid.

LC-MS (Method 3): R, = 3.08 min.; m/z = 494 (M+H)+

BHC 07 1 039-Foreign countries 'H-NMR (400 MHz, DMSO-d6): b= 8.49 (s, 1H), 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, 1H), 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 HN O
Jo ~~~~N

- o ~
NJ

175.6 mg (0.356 mmol) of methyl 4-(4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenyl)butanoate are dissolved in 3.5 ml of THF, 1.07 ml of I N
aqueous sodium hydroxide solution are added at RT and the mixture is stirred at 50 C for 1 h.
The mixture is cooled to RT and the THF is removed under reduced pressure. Water and then I N
hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed repeatedly with water and dried at 40 C under reduced pressure overnight. 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)+

'H-NMR (400 MHz, CDC13): b= 8.54 (s, 1H), 7.59 (d, 2H), 7.49 (d, 2H), 7.38-7.25 (m, 5H), 7.18-7.10 (m, 4H), 6.60 (s, 1 H), 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 HN
O
~ N CH3 J O
N

BHC 07 1 039-Foreign countries 259.8 mg (0.771 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 228 mg of methyl 4-(2-aminophenyl)butanoate (85% pure, about 1.0 mmol) are heated at 150 C
overnight. After cooling, the mixture is concentrated under reduced pressure, 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 obtained in this manner is purified further by preparative RP-HPLC. This gives 33.1 mg (8.7% of theory) of the target product.

LC-MS (Method 3): R, = 3.08 min.; m/z = 494 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 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 HN
OH
N

O NJ O

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, 0.176 ml of I N
aqueous sodium hydroxide solution is added at RT and the mixture is stirred at 50 C for I h.
The mixture is cooled to RT and the THF is removed under reduced pressure. Water and then 1 N
hydrochloric acid are added to the residue. The precipitated solid is filtered off, washed repeatedly with water and dried at 40 C under reduced pressure overnight. This gives 16.9 mg (60.2% of theory) of the target compound as a white solid.

LC-MS (Method 6): R, = 2.89 min.; m/z = 480 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.02 (br. s, 1 H), 8.50 (s, IH), 7.60 (d, 2H), 7.52 (d, 2H), 7.43-7.12 (m, 9H), 6.84 (s, 1 H), 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-BHC 07 1 039-Foreign countries 2(3H)-one N~N
- ~ ~ I ~=O
HN O
o-) 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) of N,N'-carbonyldiimidazole in 3 ml of THF are heated under reflux for 2 h. After cooling to RT, the mixture is added to water and extracted repeatedly with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. This gives 79.9 mg (89% of theory) of the target product as a beige solid.

LC-MS (Method 3): R, = 2.55 min.; m/z = 492 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.51 (s, 1 H), 7.68 (s, 1 H), 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 Methyl (+/-)-cis-N-(3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} cyclohexyl)glycate and methyl (+/-)-trans-N-(3-{ [5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)glycate HN N'-~YOll, CH3 H
O
N
NJ
132 mg (0.318 mmol) of (+/-)-cis/trans-N-[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-BHC 07 1 039-Foreign countries yl]cyclohexane-1,3-diamine (example 36A) are dissolved in 1.5 ml of dichloromethane, and 18.7 l of acetic acid are added at RT. 28 mg (0.318 mmol) of inethyl oxoacetate are added, followed after 5 min by 101 mg (0.478 mmol) of sodium triacetoxyborohydride.
The mixture is stirred at RT for 2 h and then diluted with water and dichloromethane. The organic phase is washed with saturated sodium carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product is purified by preparative RP-HPLC
(mobile phase:
acetonitrile/water gradient) and in the process separated into the cis/trans isomers:

Methyl (+/-)-cis-N-(3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexyl)glycinate (example 35) Yield: 26.5 mg (17.1% of theory) LC-MS (Method 3): Rt = 1.70 min.; m/z = 487 (M+H)+;

Methyl (+/-)-trans-N-(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)glycinate (example 36) Yield: 22.1 mg (14.3% of theory) LC-MS (Method 3): R, = 1.61 min.; m/z = 487 (M+H)+.
Example 37 tert-Butyl (+/-)-cis-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclo-hexyl)oxy]acetate )<CH

- 0 N) 350 mg (0.84 mmol) of (+/-)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol are dissolved in 1 ml of absolute THF, the mixture is cooled to 0 C and 0.48 ml (about 0.97 mmol) of the phosphazene base P2-t-Bu (2 M solution in THF) is added. Cooling is removed and the solution is stirred at RT for 10 min and then, at RT, added dropwise to a solution of 295 mg (1.51 mmol) of tert-butyl bromoacetate in 2 ml of THF. After 2 h at RT, the reaction mixture is concentrated under reduced pressure and purified directly by chromatography on silica BHC 07 1 039-Foreign countries gel (Biotage, mobile phase: cyclohexane/ethyl acetate 10:1 -> 1:1). This gives, in addition to 180 mg of starting material, 207 mg (46.4% of theory) of the target product.

LC-MS (Method 6): R, = 3.38 min.; m/z = 531 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 8.58 (s, 1H), 7.54 (dd, 2H), 7.43-7.39 (m, 5H), 7.0 (d, 2H), 5.13 (m, 1H), 3.98 (s, 2H), 3.82 (s, 3H), 3.42 (m, 1H), 2.41 (br. d, 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 of tert-butyl (+/-)-cis-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate are dissolved in 4 ml of ethanol and 16 ml of isohexane. The racemate is separated into the enantiomers (see examples 38 and 39) by preparative HPLC on a chiral phase [column: Daicel Chiralcel OJ-H, 5 [tm, 250 mm x 20 mm; flow rate:
15 ml/min;
detection: 220 nm; injection volume 0.5 ml; temperature: 45 C; mobile phase: t = 0 min 90%
isohexane / 10% ethanol -> t = 7 min 90% isohexane / 10% ethanol].

Example 38 tert-Butyl cis-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]-acetate (enantiomer 1) LC-MS (Method 3): Rr = 3.22 min.; m/z = 531 (M+H)+
[0,]o = -59 , c = 0.525, CHC13.

Example 39 tert-Butyl cis-[(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate (enantionier 2) LC-MS (Method 3): R, = 3.22 min.; m/z = 531 (M+H)+
[a]p = +55.5 , c = 0.51, CHC13.

Example 40 tert-Butyl (+/-)-trans-[(3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclo-hexyl)oxy]acetate BHC 07 1 039-Foreign countries p 00 ''~ 0,,,,YO)<CH

p N) 920 mg (11.53 mmol) of 50% strength aqueous sodium hydroxide solution and about 5 ml of toluene are warmed to 40 C, and 65.2 mg (0.192 mmol) of tetrabutylammonium hydrogensulfate and 800 mg (1.91 mmol) of (+/-)-trans-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol are added. The suspension is diluted with a little THF, some of the solid going into solution. After addition of 749 mg (3.84 mmol) of tert-butyl bromoacetate, the suspension is heated at 60 C with vigorous stirring. After a total of 3 h at 60 C, with intermittent addition of a further 920 mg of 50% strength aqueous sodium hydroxide solution and about 1500 mg of tert-butyl bromoacetate, the reaction mixture is cooled and added to water. The mixture is extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. 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. l% of theory) of the target compound are isolated.

LC-MS (Method 6): R, = 3.36 min.; m/z = 531 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.58 (s, 1H), 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, 1H), 1.99-1.92 (m, 1H), 1.78-1.70 (m, 1H), 1.61-1.53 (m, 3H), 1.49-1.40 (m, 1H), 1.38 (s, 9H), 1.27-1.17 (m, 2H).

Separation of the enantiomers:

0.3 g of tert-butyl (+/-)-trans-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate is dissolved in 2 ml of ethanol and 8 ml of isohexane. The racemate is separated into the enantiomers (see examples 41 and 42) by preparative HPLC
on a chiral phase [column: Daicel Chiralcel OJ-H, 5 [tm, 250 mm x 20 mm; flow rate: 15 ml/min;
detection: 220 nm; injection volume 0.5 ml; temperature: 40 C; mobile phase: t= 0 min 90%
isohexane / 10%
ethanol --> t = 10 min 90% isohexane / 10% ethanol].

Example 41 tert-Butyl (+)-trans-[(3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyclo-BHC 07 1 039-Foreign countries hexyl)oxy]acetate (enantiomer 1) [a]D20 = +60.6 , c = 0.50, CHCI3 'H-NMR (400 MHz, DMSO-d6): 8= 8.58 (s, 1H), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.05 (d, 2H), 5.58 (br. s, 1H), 3.88 (d, 2H), 3.82 (s, 3H), 3.21 (m, IH), 1.99-1.92 (m, IH), 1.78-1.70 (m, 1H), 1.61-1.53 (m, 3H), 1.49-1.40 (m, IH), 1.38 (s, 9H), 1.27-1.17 (m, 2H).

Example 42 tert-Butyl (-)-trans-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclo-hexyl)oxy]acetate (enantiomer 2) [a]D20 = -70.4 , c = 0.525, CHC13 'H-NMR (400 MHz, DMSO-d6): 8= 8.58 (s, 1H), 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, 1H), 1.99-1.92 (m, IH), 1.78-1.70 (m, 1H), 1.61-1.53 (m, 3H), 1.49-1.40 (m, 1H), 1.38 (s, 9H), 1.27-1.17 (m, 2H).

Example 43 tert-Butyl (+/-)-all-cis-[(3-hydroxy-5-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate OH

O 0_,-yO)<CH3 ~ ~ ~ I \N
O N) 0.69 ml (about 1.39 mmol) of the phosphazene base Pt-t-Bu (about 2 M solution in THF) is added to a solution, cooled to 0 C, of 600 mg (1.39 mmol) of (+/-)-all-cis-5-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexane-l,3-diol in 1.2 ml of DMF. The resulting solution is stirred at 0 C for 5 min, and 0.25 ml (1.67 mmol) of tert-butyl bromoacetate are then added. Cooling is removed, and the mixture is stirred at RT for 15 min. The mixture is then added to water and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient) gives 207 mg (27.3% of theory) of the target product.

BHC 07 1 039-Foreign countries LC-MS (Method 6): Rt = 2.90 min.; -n/z = 547 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.60 (s, 1H), 7.56 (dd, 2H), 7.43-7.38 (m, 5H), 7.02 (d, 2H), 5.13 (m, 1H), 4.85 (d, 1H), 3.98 (s, 2H), 3.83 (s, 3H), 3.59-3.49 (m, 2H), 2.96-2.90 (m, IH), 2.30-2.18 (m, 2H), 1.42 (s, 9H), 1.13-1.02 (m, 3fl).

Example 44 Methyl (+/-)-3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl)propanoate O N~/~ON, CH3 IOI
N
NJ
200 mg (0.5 mmol) of (+/-)-5-(4-methoxyphenyl)-6-phenyl-4-(piperidin-3-yloxy)furo[2,3-d]-pyrimidine (example 37A) are dissolved in I ml of THF, and 69 gl (0.5 mmol) of triethylamine are added. After the addition of 54 l (0.5 mmol) of methyl 3-bromopropionate, the mixture is stirred at 20-40 C for about 8 h. Intermittently, two more portions of triethylamine (about 1.2 mmol in total) and methyl 3-bromopropionate (about 1.2 mmol in total) are added. After dilution with dichloromethane, the mixture is washed with saturated sodium bicarbonate solution and concentrated under reduced pressure. The crude product is purified by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient). This gives 118 mg (45.7% of theory) of the target product.

LC-MS (Method 5): R, = 1.91 min.; m/z = 488 (M+H)+

'H-NMR (400 MHz, DMSO-db): S= 8.59 (s, 1 H), 7.58-7.52 (m, 2H), 7.43-7.39 (m, 5H), 7.01 (d, 2H), 5.26 (m, 1H), 3.82 (s, 3H), 3.50 (s, 3H), 2.80-2.75 (m, 1H), 2.60-2.50 (m, 2H), 2.46-2.22 (m, 5H), 1.89-1.81 (m, 1H), 1.68-1.59 (m, 1H), 1.45-1.32 (m, 2H).

Example 45 Methyl (+/-)-4-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl)butanoate BHC 07 1 039-Foreign countries O
O N O'CH3 N
O NJ

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 methyl 4-bromobutyrate are added successively to 500 mg (1.25 mmol) of (+/-)-5-(4-methoxyphenyl)-6-phenyl-4-(piperidin-3-yloxy)furo[2,3-d]pyrimidine (example 37A) in 1 ml of THF. The mixture is heated under reflux for 4 h and then cooled, diluted with dichloromethane, washed with saturated sodium bicarbonate solution and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel (mobile phase:
cyclohexane/ethyl acetate 4:1 -> 1:1). This gives 662 mg (100% of theory) of the target compound.

LC-MS (Method 5): R, = 1.89 min.; m/z = 502 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.58 (s, 1H), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.00 (d, 2H), 5.24 (m, 1H), 3.81 (s, 3H), 3.52 (s, 3H), 2.79-2.74 (m, IH), 2.48-2.41 (m, 1H), 2.28-2.21 (m, 5H), 2.14 (m, 1H), 1.92-1.85 (m, IH), 1.68-1.58 (m, 3H), 1.47-1.30 (m, 2H).

Separation of the enantiomers:

Racemic methyl (+/-)-4-(3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]oxy}piperidin-1-yl)butanoate is dissolved in a 1:4 mixture of ethanol and isohexane and separated into the enantiomers (see examples 46 and 47) by preparative HPLC on a chiral phase [column: Daicel Chiralpak AS-H, 5 [tm, 250 mm x 20 mm; flow rate: 15 ml/min;
detection: 220 nm; injection volume 0.5 ml; temperature: 28 C; mobile phase: t = 0 min 90%
isohexane / 10%
ethanol --> t = 8 min 90% isohexane / 10% ethanol].

Example 46 Methyl 4-(3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
piperidin-l-yl)butanoate (enantiomer 1) LC-MS (Method 6): Rr = 1.84 min.; m/z = 502 (M+H)+

Rt = 7.26 min [column: Daicel Chiralpak AS-H, 5 m, 250 mm x 4.6 mm; flow rate: 1.0 ml/min;
detection: 230 nm; temperature: 25 C; mobile phase: 90% isohexane / 10%
ethanol with 0.2%

BHC 07 1 039-Foreign countries diethylamine];

'H-NMR (400 MHz, DMSO-d6): b= 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.00 (d, 2H), 5.24 (m, 1H), 3.81 (s, 3H), 3.52 (s, 3H), 2.79-2.74 (m, 1H), 2.48-2.41 (m, 1H), 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 Methyl 4-(3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
piperidin-l-yl)butanoate (enantiomer 2) LC-MS (Method 3): R, = 1.67 min.; m/z = 502 (M+H)+

Rt = 7.63 min [column: Daicel Chiralpak AS-H, 5 m, 250 mm x 4.6 mm; flow rate: 1.0 ml/min;
detection: 230 nm; temperature: 25 C; mobile phase: 90% isohexane / 10%
ethanol with 0.2%
diethylamine];

'H-NMR (400 MHz, DMSO-d6): 6= 8.58 (s, IH), 7.54 (d, 2H), 7.43-7.39 (m, 5H), 7.00 (d, 2H), 5.24 (m, 1H), 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, 1H), 1.92-1.85 (m, lH), 1.68-1.58 (m, 3H), 1.47-1.30 (m, 2H).

Example 48 Methyl (+/-)-3-[2-({[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}meth-yl)pyrrolidin-1-yl]propanoate p N 0 O ~,CH3 O N"

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 ml of THF, and 110 l (0.8 mmol) of triethylamine and 87 l (0.8 mmol) of methyl 3-bromopropionate are added. The mixture is stirred at 20-40 C
overnight and then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The solution is concentrated under reduced pressure and the resulting oil is purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gives 90 mg (44% of theory) of the target product.

BHC 07 1 039-Foreign countries LC-MS (Method 6): R, = 1.79 min.; m/z = 488 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.58 (s, IH), 7.53 (d, 2H), 7.42-7.36 (m, 5H), 7.01 (d, 2H), 4.39 (dd, 1H), 4.18 (dd, IH), 3.81 (s, 3H), 3.51 (s, 3H), 2.96-2.89 (m, 2H), 2.64 (m, 1H), 2.41-2.30 (m, 3H), 2.12 (q, 1H), 1.75-1.35 (m, 4H).

The following enantiomerically pure compounds are prepared in an analogous manner (4 h reaction time at about 40 C, altogether greater excesses of DIEA and methyl 3-bromopropionate) from the enantiomerically pure pyrrolidine derivatives examples 40A and 41A, respectively:

Example Structure Analytical data 49 H3C-O LC-MS (Method 5): Rt = 1.91 No 0 min.; m/z = 488 (M+H)+
O
"OH3 'H-NMR (400 MHz, DMSO-d6):
J 8= 8.58 (s, IH), 7.52 (d, 2H), N
7.42-7.36 (m, 5H), 7.01 (d, 2H), 4.38 (dd, 1H), 4.18 (dd, 1H), 3.81 (s, 3H), 3.52 (s, 3H), 2.97-2.89 (m, 2H), 2.69-2.61 (m, 1 H), 2.41-2.30 (m, 3H), 2.12 (q, 1H), 1.75-1.35 (m, 4H).

50 H3C-O LC-MS (Method 6): R, = 1.80 N 0 min.; m/z = 488 (M+H)+
~ ]~

~/ ~O~~H3 'H-NMR (400 MHz, DMSO-d6):
J 8= 8.58 (s, 1H), 7.52 (d, 2H), N
7.42-7.36 (m, 5H), 7.01 (d, 2H), 4.39 (dd, 1 H), 4.18 (dd, 1 H), 3.81 (s, 3H), 3.52 (s, 3H), 2.97-2.89 (m, 2H), 2.69-2.61 (m, 1H), 2.41-2.30 (m, 3H), 2.12 (q, 1H), 1.75-1.35 (m, 4H).

Example 51 Methyl (+/-)-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}piperidin-1-yl)-propanoate BHC 07 1 039-Foreign countries O
N

N) 82 l (0.749 mmol) of methyl 3-bromopropanoate and 104 l (0.749 mmol) of triethylamine are added to 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, and the mixture is stirred at 20-40 C overnight. The mixture is diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After concentration under reduced pressure, the residue is stirred with methanol, and the precipitated product is filtered off with suction and dried under high vacuum.
From the filtrate, a second product charge is isolated after concentration by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient). This gives a total of 124 mg (67.1% of theory) of the target product.

LC-MS (5): R, = 1.83 min.; m/z = 487 (M+H)' 'H-NMR (400 MHz, DMSO-d6): S= 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, 1H), 1.62-1.55 (m, 1H), 1.40 (br. s, 2H).

Example 52 Methyl (+/-)-4-[2-( { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} meth-yl)pyrrolidin- l -yl]butanoate O N
O
N ~1 CH3 O
O -) N
100 mg (0.25 mmol) of (+/-)-5-(4-methoxyphenyl)-6-phenyl-4-(pyrrolidin-2-ylmethoxy)furo[2,3-d]-pyrimidine (example 38A) are dissolved in 2 ml of THF, and 65 l (0.374 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of methyl 4-bromobutyrate are BHC 07 1 039-Foreign countries added in succession. The mixture is heated under reflux for I h and then, after cooling, added to water. The mixture 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 under reduced pressure. The crude product is purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gives 47 mg (37.6% of theory) of the target product.

LC-MS (Method 3): Rt = 1.73 min.; m/z = 502 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 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, 1H), 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, 1H), 1.60-1.37 (m, 5H).

The following enantomerically pure compounds are prepared in an analogous manner from the enantiomerically pure pyrrolidine derivatives examples 40A and 41A, respectively:

BHC 07 1 039-Foreign countries Example Structure Analytical data 53 H3C-O LC-MS (Method 3): R, = 1.72 N min.; m/z = 502 (M+H)+

N 0, CH3 'H-NMR (400 MHz, DMSO-d6):
NJ 0 6= 8.60 (s, 1H), 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, 1H), 2.62-2.50 (m, 2H), 2.20-2.02 (m, 4H), 1.74-1.67 (m, 1H), 1.60-1.37 (m, 5H).

54 H3C-O LC-MS (Method 3): Rt = 1.70 N/ min.; m/z = 502 (M+H)+

N H(CH3 'H-NMR (400 MHz, DMSO-d6):
0 b= 8.60 (s, 1H), 7.55-7.52 (m, 2H), 7.42-7.37 (m, 5H), 7.01 (d, 2H), 4.32 (dd, 1 H), 4.19 (dd, I H), 3.80 (s, 3H), 3.49 (s, 3H), 2.93 (t, 1 H), 2.62-2.50 (m, 2H), 2.20-2.02 (m, 4H), 1.74-1.67 (m, IH), 1.60-1.37 (m, 5H).

Example 55 Methyl (+/-)-4-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}piperidin-l-yl)butanoate O

o-) A mixture of 100 mg (0.25 mmol) of (+/-)-5-(4-methoxyphenyl)-6-phenyl-N-piperidin-3-ylfuro-BHC 07 1 039-Foreign countries - l58 -[2,3-d]pyrimidine-4-amine (example 39A), 65 l (0.375 mmol) of DIEA, 4.1 mg (0.025 mmol) of potassium iodide and 45 mg (0.25 mmol) of methyl 4-bromobutyrate in 2 ml of THF is heated under reflux for I 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 under reduced pressure. The crude product is purified by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient), followed by chromatography on silica gel (mobile phase: dichloro-methane -> dichloromethane/methanol 50:1). The product obtained is titrated with methanol, and the precipitate is then filtered off with suction, washed with a little methanol and dried under high vacuum. This gives 58 mg (46.4% of theory) of the target product.

LC-MS (Method 6): Rr = 1.85 min.; m/z = 501 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 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, 1H), 3.83 (s, 3H), 3.59 (s, 3H), 2.50-2.42 (m, IH), 2.38-2.31 (m, 1 H), 2.22-2.15 (m, 3H), 2.12 (t, 1 H), 2.02 (br. s, 1 H), 1.58-1.40 (m, 6H).

Example 56 tert-Butyl (+/-)-trans-[(3-{[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)oxy]acetate HN ''I O"'~ O)<CH

p N) A mixture of 549 mg (1.63 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyri-midine, 0.43 ml (2.45 mmol) of DIEA and 456 mg of tert-butyl (+/-)-trans-{[3-aminocyclohexyl]oxy}acetate (example 43A / crude product, about 1.63 mmol) in 1.5 ml of DMF
is stirred at 120 C for 2 h. 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 under reduced pressure. The crude product is purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gives 434 mg (50.3%
of theory) of the target product.

LC-MS (Method 5): R, = 3.29 min.; m/z = 530 (M+H)+

BHC 07 1 039-Foreign countries 'H-NMR (400 MHz, DMSO-d6): 6= 8.35 (s, IH), 7.50-7.45 (m, 4H), 7.40-7.31 (m, 3H), 7.18 (d, 2H), 4.71 (d, 1H), 4.31 (m, 1H), 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 of tert-butyl (+/-)-trans-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexyl)oxy]acetate is dissolved in 4 ml of 2-propanol and 13 ml of isohexane. The racemate is separated into the enantiomers (see examples 57 and 58) by preparative HPLC on a chiral phase [column: Daicel Chiralpak AD-H, 5 [tm, 250 mm x 20 mm; flow rate:
15 ml/min;
detection: 215 nm; injection volume 1.0 ml; temperature: 30 C; mobile phase: t = 0 min 80%
isohexane / 20% 2-propanol -> t = 9.5 min 80% isohexane / 20% 2-propanol].

Example 57 tert-Butyl (+)-trans-[(3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)oxy]acetate (enantiomer 1) [a]D20 = +43.3 , c = 0.51, CHC13 'H-NMR (400 MHz, DMSO-d6): 6 = 8.34 (s, lH), 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, 1H), 3.93 (s, 2H), 3.87 (s, 3H), 3.38-3.30 (m, 1H), 1.77-1.67 (m, 2H), 1.55-1.42 (m, 4H), 1.40 (s, 9H), 1.18-1.10 (m, 2H).

Example 58 tert-Butyl (-)-trans-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)oxy] acetate (enantion2er 2) [a]D 20 = -49.1 , c = 0.49, CHC13 'H-NMR (400 MHz, DMSO-d6): b= 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, lH), 3.93 (s, 2H), 3.87 (s, 3H), 3.38-3.30 (m, 1H), 1.77-1.67 (m, 2H), 1.55-1.42 (m, 4H), 1.40 (s, 9H), 1.19-1.10 (m, 2H).

Example 59 tert-Butyl (+/-)-cis-[(-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)oxy]acetate BHC 07 1 039-Foreign countries , .

HNOOO O~O)<CH3 N

O Ni At 40 C, 1.05 g (2.53 mmol) of (+/-)-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 tert-butyl bromoacetate are added to a mixture of 2.02 g of 50% strength aqueous sodium hydroxide solution (25.3 mmol), 2.5 ml of toluene and 85.8 mg (0.25 mmol) of tetrabutylammonium hydrogensulfate. At 70 C, the heterogeneous mixture is stirred vigorously for 2 h. 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 under reduced pressure. The crude product gives, by chromatography on silica gel (Biotage, mobile phase: dichloromethane/methanol 500:1 --> 100:1) 671 mg (50.2% of theory) of the target compound.

LC-MS (Method 5): Rr = 3.33 min.; m/z = 530 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 8.34 (s, 1H), 7.48-7.41 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.13 (br. d, 1 H), 4.14-4.08 (m, IH), 3.85 (s, 3H), 3.82 (d, 2H), 3.43-3.35 (m, IH), 2.09 (br. d, 1H), 1.81-1.60 (m, 3H), 1.41 (s, 9H), 1.30-1.04 (m, 4H).

Separation of the enantiomers:

tert-Butyl (+/-)-cis-[(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclo-hexyl)oxy]acetate is dissolved in equal amounts of ethanol and isohexane. The racemate is separated into the enantiomers (see examples 60 and 61) by preparative HPLC on a chiral phase [column: Daicel Chiralcel OJ-H, 5 pm, 250 mm x 20 mm; flow rate: 15 ml/min;
detection: 220 nm; injection volume 0.5 ml; temperature: 29 C; mobile phase: t = 0 min 80%
isohexane / 20%
ethanol -> t = 12 min 80% isohexane / 20% ethanol].

Example 60 tert-Butyl (+)-cis-[(-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexyl)oxy]acetate (enantiomer 1) [a]D20 = +77.4 , c = 0.53, CHC13 BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 LC-MS (Method 3): R, = 3.10 min.; in/z = 530 (M+H)+

'H-NMR (400 MHz, DMSO-db): 6 = 8.34 (s, 1 H), 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, 1H), 1.41 (s, 9H), 1.30-1.04 (m, 4H).

Example 61 tert-Butyl (-)-trans-[(-3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]amino}cyclohexyl)oxy]acetate (enantiomer 2) [a]D20 = -71.4 , c = 0.54, CHC13 LC-MS (Method 3): R, = 3.09 min.; m/z = 530 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6 = 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, 1H), 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 tert-Butyl (+/-)-cis-({-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}oxy)acetate ~ ~ HN O~O)<CH CH3 N-50 mg (0.10 mmol) of tert-butyl (+/-)-cis-({[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}oxy)acetate (example 47A) are dissolved in 0.33 ml of DMSO, and 3.5 mg of bis(triphenylphosphine)palladium(II) chloride are added. Under argon, 0.1 ml of 2 N sodium carbonate solution and 15.2 mg (0.124 mmol) of phenylboronic acid are added successively at RT.
At 80 C, the heterogeneous mixture is stirred vigorously for 4 h. After cooling, the product is isolated directly by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gives 43.9 mg (88.3% of theory) of the target compound.

LC-MS (Method 5): R, = 3.38 min.; m/z = 500 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6 = 8.35 (s, 1 H), 7.64-7.53 (m, 5H), 7.46-7.40 (m, 2H), 7.38-7.31 BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 , (m, 3H), 5.03 (d, 1H), 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, 1H), 1.41 (s, 9H), 1.30-1.12 (m, 2H), 1.08-0.95 (m, 2H).

Example 63 tert-Butyl (+/-)-cis-({3-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate O O,,,YO)<CH

3, 0 CH3 O N/J

36 mg (0.072 mmol) of tert-butyl (+/-)-cis-({[(6-bromo-5-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]cyclohexyl}oxy)acetate (example 49A) are dissolved in 0.15 ml of DMSO, and 2.5 mg of bis(triphenylphosphine)palladium(II) chloride are added. 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.
At 80 C, the heterogeneous mixture is stirred vigorously for 4 h. After cooling, the product is isolated directly by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gives 19.8 mg (55.3% of theory) of the target compound.

LC-MS (Method 6): R, = 3.41 min.; m/z = 501 (M+H)+

'H-NMR (400 MHz, DMSO-d6): d= 8.59 (s, 1 H), 7.56-7.39 (m, l OH), 5.11 (m, 1 H), 3.98 (s, 2H), 3.40 (m, 1H), 2.39 (br. d, 1 H), 2.03-1.92 (m, 2H), 1.75-1.67 (m, I H), 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 At RT, 1.5 to 10 eq. of sodium hydroxide, as a I N aqueous solution, are added to a solution of the methyl or ethyl ester in THF or THF/methanol (1:1) (concentration about 0.05 to 0.5 mol/I). The mixture is stirred at RT for a period of 0.5-18 h and then neutralized or acidified slightly with I N
hydrochloric acid. If a solid precipitates out, the product can be isolated by filtration, washing with water and drying under high vacuum. Alternatively, the target compound is isolated directly from the crude product, if appropriate after extractive work-up with dichloromethane, by preparative RP-HPLC (mobile phase: water/acetonitrile gradient).

BHC 07 1 039-Foreign countries General Procedure E: cleavage of tert-butyl esters to the correspondin carboxylic arboxYlic acid derivatives At from 0 C to RT, TFA is added dropwise to a solution of the tert-butyl ester in dichloromethane (concentration from 0.05 to 1.0 mol/1; additionally one drop of water), until a dichloromethane/TFA ratio of about 2:1 to 1:1 is reached. The mixture is stirred at RT for 1-18 h and then concentrated under reduced pressure. The residue is purified by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient).

The following examples are prepared in accordance with the General Procedure D
or E from the compounds described above:

Example Starting Structure Analytical data material (Method) 64 Example H3C-o LC-MS (Method 6): Rt =
36 (D) oH 1.90 min.; m/z = 473 HN~~ H~ (M+H)+
O N
N O
(+/-)-trans 65 Example H3C-0 LC-MS (Method 6): Rt _ 35 (D) ^ /oH 1.94 min.; m/z = 473 HN 0 ~~H Tf (M~-H)+
N O
O N) (+/-)-CZS

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example Starting Structure Analytical data material (Method) 66 Example H3C-O LC-MS (Method 3): R, _ 37 (E) o o,,-YH 2.57 min.; m/z = 475 01, 0 (M+H) +
J 'H-NMR (400 MHz, N
DMSO-d6): b = 8.59 (s, (+I-)-cis 1 H), 7.58-7.53 (m, 2H), 7.44-7.39 (m, 5H), 7.01 (d, 2H), 5.13 (m, 1 H), 4.03 (s, 2H), 3.83 (s, 3H), 3.49-3.35 (m, 2H), 2.46-2.40 (m, 1H), 2.06-1.93 (m, 2H), 1.78-1.70(m, 1H), 1.37-1.05 (m, 4H).

67 Example H3C-O LC-MS (Method 5): R, _ 38 (E) OH 2.84 min.; m/z = 475 o o'~ (M+H)+

N
~ [a.]p =-64.2 ,c=0.55, (-)-enantiomer 'H-NMR (400 MHz, DMSO-d6): 8 = 8.59 (s, 1H), 7.58-7.53 (m, 2H), 7.44-7.39 (m, 5H), 7.01 (d, 2H), 5.15-5.08 (m, 1 H), 4.03 (s, 2H), 3.83 (s, 3H), 3.49-3.35 (m, 1H), 2.46-2.40 (m, 1H), 2.06-1.93 (m, 2H), 1.78-1.70 (m, IH), 1.37-1.05 (m, 4H).

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example Starting Structure Analytical data material (Method) 68 Example H3C-o LC-MS (Method 5): Ri =
39 (E) o o oH 2.84 min.; m/z = 475 00 o (M+H)+

N
J [a]D20 =+62.8 , c= 0.5 5, - o N

(+)-enantiomer 'H-NMR (400 MHz, DMSO-d6): 8 = 8.59 (s, 1H), 7.58-7.53 (m, 2H), 7.44-7.39 (m, 5H), 7.01 (d, 2H), 5.17-5.08 (m, 1H), 4.03 (s, 2H), 3.83 (s, 3H), 3.49-3.35 (m, 1H), 2.46-2.40 (m, 1 H), 2.06-1.93 (m, 2H), 1.78-1.70 (m, 1H), 1.37-1.05 (m, 4H).

69 Example H3C-o LC-MS (Method 3): R, 40 (E) aH 2.53 min.; mlz = 475 ~"' o~ (M+H)+

~ J 'H-NMR (400 MHz, N
DMSO-d6): b = 12.54 (br.
(+I-)-trans s, 1 H), 8.56 (s, 1 H), 7.54 (d, 2H), 7.43-7.35 (m, 5H), 7.05 (d, 2H), 5.63-5.59 (m, l H), 3.90 (d, 2H), 3.81 (s, 3H), 3.30-3.20 (m, I H), 1.96-1.90 (m, 1 H), 1.79-1.43 (m, 5 H), 1.30-1.13 (m, 2H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 70 Example H3C-o LC-MS (Method 3): R, _ 2.53 min.; m/z = 475 41 (E) oH
o ~ (M+H)+
o ~ J 'H-NMR (400 MHz, N
DMSO-d6): b = 12.55 (br.
(+)-enantiomer s, 1H), 8.56 (s, 1H), 7.54 (d, 2H), 7.43-7.35 (m, 5H), 7.05 (d, 2H), 5.63-5.59 (m, IH), 3.90 (d, 2H), 3.81 (s, 3H), 3.30-3.20 (m, 1H), 1.96-1.90 (m, IH), 1.76-1.69 (m, IH), 1.65-1.54 (m, 3H), 1.51-1.43 (m, 1H), 1.30-1.13 (m, 2H).
[a]p20 = +62.4 , c = 0.48, BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 = -167-Example Starting Structure Analytical data material (Method) 71 Example H3o-o LC-MS (Method 5): R, _ 42 (E) OH 2.80 min.; m/z = 475 o (M+)+
' H-NMR (400 MHz, DMSO-d6): b = 12.54 (br.
(-)-enantiomer s, 1H), 8.56 (s, 1H), 7.54 (d, 2H), 7.43-7.35 (m, 5H), 7.05 (d, 2H), 5.63-5.59 (m, 1 H), 3.90 (d, 2H), 3.81 (s, 3H), 3.30-3.20 (m, IH), 1.96-1.90 (m, 1H), 1.76-1.69 (m, lH), 1.65-1.54 (m, 3H), 1.51-1.43 (m, 1 H), 1.30-1.13 (m, 2H).
[a]D2 = -74.0 , c = 0.50, 72 Example OH LC-MS (Method 5): Rt _ H3C-o 43 (E) 2.42 min.; m/z = 491 o poH (M+H)+

N o 'H-NMR (400 MHz, o NJ DMSO-d6): 8= 8.60 (s, (+l-)-cis 1 H), 7.57 (d, 2H), 7.45-7.38 (m, 5H), 7.02 (d, 2H), 5.15 (m, 1 H), 4.80 (br. s, 1 H), 4.02 (s, 2H), 3.82 (s, 3H), 3.58-3.35 (m, 2H), 2.45-2.38 (m, 1H), 2.20-2.10 (m, 2H), 1.18-1.02 (m, 3H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 73 Example H3C-o LC-MS (Method 3): R, _ 44 (D) \/ o N~oH 1.68 min.; m/z = 474 0 (M+H) J 'H-NMR (400 MHz, O N
DMSO-d6): 8 = 8.59 (s, (rac.) IH), 7.55 (d, 2H), 7.45-7.40 (m, 5H), 7.01 (d, 2H), 5.26 (m, IH), 3.82 (s, 3H), 3.45-3.25 (m, 2H), 2.83 (d, 1 H), 2.60-2.45 (m, 2H), 2.39-2.27 (m, 4H), 1.90-1.82 (m, 1H), 1.65-1.55 (m, 1 H), 1.48-1.31 (m, 2H).

74 Example H 3C-0 LC-MS (Method 6): Rr =
48 (D) r-~N3 0 1.76 min.; m/z = 464 o (M+H)+
OH
~ 'H-NMR (400 MHz, O N
DMSO-d6): S = 8.59 (s, (rac.) 1H), 7.54 (dd, 2H), 7.43-7.35 (m, 5H), 7.02 (d, 2H), 4.41 (dd, 1 H), 4.22 (dd, 1 H), 3.82 (s, 3H), 2.99-2.88 (m, 2H), 2.72-2.65 (m, l H), 2.42-2.38 (m, 1H), 2.30-2.22 (m, 2H), 2.22-2.12 (m, 1 H), 1.76-1.68 (m, 1H), 1.65-1.55 (m, IH), 1.50-1.40 (m, 2H).

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example Starting Structure Analytical data material (Method) 75 Example H3C-O LC-MS (Method 5): Rt =
49 (D) N 0 1.85 min.; m/z = 474 o ~'KOH (M+H)+

J 'H-NMR (400 MHz, O N
DMSO-d6): 8 = 8.56 (s, (R-enantiomer) 1 H), 7.53 (d, 2H), 7.43-7.36 (m, 5H), 7.01 (d, 2H), 4.42 (dd, 1 H), 4.15 (dd, 1H), 3.81 (s, 3H), 2.96-2.88 (m, 2H), 2.67-2.60 (m, 1H), 2.42-2.35 (m, 1 H), 2.21-2.10 (m, 3 H), 1.73-1.35 (m, 4H).

76 Example H3C-O LC-MS (Method 5): R, 50 (D) N 0 1.83 min.; m/z = 474 o ~'AOH (M+H)+
N
J 'H-NMR (400 MHz, O N
DMSO-d6): b = 8.56 (s, (S-enantiomer) IH), 7.53 (d, 2H), 7.43-7.36 (m, 5H), 7.01 (d, 2H), 4.42 (dd, 1 H), 4.15 (dd, 1H), 3.81 (s, 3H), 2.96-2.88 (m, 2H), 2.67-2.60 (m, 1H), 2.42-2.35 (m, 1H), 2.21-2.10 (m, 3H), 1.73-1.35 (m, 4H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 77 Example HC-o LC-MS (Method 6): Rt =
51 (D) HN N~oH 1.80 min.; m/z = 473 (M+H)+
O
N
_ ( J 'H-NMR (400 MHz, O N
DMSO-d6): 8 = 8.32 (s, (rac.) 1H), 7.50-7.45 (m, 4H), 7.40-7.30 (m, 3H), 7.14 (d, 2H), 5.59 (br. d, I H), 4.25 (br. s, 1 H), 3.84 (s, 2H), 2.48-2.35 (m, 2H), 2.27-1.98 (m, 3H), 1.55 (br. s, 1H), 1.48 (br. s, 2H).

78 Example H3C-o O LC-MS (Method 5): Rt =
55 (D) N~ 1.87 min.; m/z = 487 HN OH
(M+H)+
o N J 'H-NMR (400 MHz, DMSO-d6): 8 = 8.32 (s, (rac.) 1 H), 7.49-7.45 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.58 (br. d, IH), 4.27 (br. s, 1H), 3.85 (s, 3H), 2.50-2.42 (m, 1H), 2.39-2.32 (m, 1 H), 2.27-2.19 (m, 1 H), 2.16-2.02 (m, 4H), 1.55-1.26 (m, 5H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 79 Example H3C-O LC-MS (Method 3): R, _ 52 (D) 1.61 min.; m/z = 488 O
OH (M+H)+

TJj 0 'H-NMR (400 MHz, O N
DMSO-d6): 8 = 8.58 (s, (rac.) 1H), 7.53 (dd, 2H), 7.42-7.37 (m, 5H), 7.02 (d, 2H), 4.38 (dd, 1H), 4.16 (dd, 1 H), 3.81 (s, 3H), 2.95 (br.
t, 1 H), 2.62-2.50 (m, 1 H), 2.18-1.92 (m, 4H), 1.74-1.65 (m, IH), 1.60-1.37 (m, 6H).

80 Example H3C-O LC-MS (Method 3): R, _ 53 (D) ~ 1.59 min.; m/z = 488 o OH (M+H)+

) 0 'H-NMR (400 MHz, N
DMSO-d6): b = 8.58 (s, (R-enantiomer) I H), 7.53 (dd, 2H), 7.42-7.37 (m, 5H), 7.02 (d, 2H), 4.38 (dd, 1 H), 4.16 (dd, 1 H), 3.81 (s, 3H), 2.95 (br.
t, I H), 2.62-2.50 (m, l H), 2.18-1.92 (m, 4H), 1.74-1.65 (m, l H), 1.60-1.37 (m, 6H).

[a]D20 = -124.4 , c = 0.50, BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 . .

Example Starting Structure Analytical data material (Method) 81 Example H3C-o LC-MS (Method 5): R, _ 54 (D) """N 1.86 min.; m/z = 488 o +
oH (M+H) 0 ' H-NMR (400 MHz, N) DMSO-d6): 8 = 8.58 (s, (S-enantiomer) IH), 7.53 (dd, 2H), 7.42-7.37 (m, 5H), 7.02 (d, 2H), 4.3 8 (dd, 1 H), 4.16 (dd, IH), 3.81 (s, 3H), 2.95 (br.
t, 1 H), 2.62-2. 50 (m, 1 H), 2.18-1.92 (m, 4H), 1.74-1.65 (m, 1H), 1.60-1.37 (m, 6H).

[a]D20 = +81.0 , c = 0.50, 82 Example H3C-o o LC-MS (Method 5): Rt =
45 (D) `"-~oH 1.88 min.; m/z = 488 \ / o (M+H)+
a J 'H-NMR (400 MHz, N
DMSO-d6): 8 = 8.57 (s, (rac.) 1 H), 7.54 (dd, 2H), 7.45-7.38 (m, 5H), 7.00 (d, 2H), 5.24 (m, 1H), 3.82 (s, 3H), 2.84 (br. d, l H), 2.53-2.45 (m, I H), 2.29-2.22 (m, 2H), 2.18-1.99 (m, 4H), 1.93-1.86 (m, 1 H), 1.64-1.52 (m, 2H), 1.49-1.36 (m, 1H), 1.34-1.25 (m, l H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 83 Example H3C-o o LC-MS (Method 5): R, _ 48 (D) OJN\~~OH 1.87 min.; m/z = 488 (M+H)+
~ N J [a]D20 =+84.0 , c = 0.50, - o (+)-enantiomer 84 Example H3C-o o LC-MS (Method 5): Rt =
47 (D) O N OH 1.88 min.; m/z = 488 (M+H)+

o( N J [aID20 =-85.7 , C= 0.50, (-)-enantiomer 85 Example H3C-o LC-MS (Method 3): Rt =
56 (E) oH 2.39 min.; m/z = 474 HN 'o~ (M+H)+
o ~ J ' H-NMR (400 MHz, O N
DMSO-d6): b = 8.35 (s, (+/-)-trans 1H), 7.52-7.47 (m, 2H), 7.39-7.30 (m, 3H), 7.18 (d, 2H), 4.73 (d, 1 H), 4.34 (br.
s, l H), 3.95 (br. s, 2H), 3.87 (s, 3H), 3.40-3.25 (m, 1H), 1.80-1.63 (m, 2H), 1.60-1.40 (m, 4H), 1.20-1.10 (m, 2H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 86 Example H3C-O LC-MS (Method 6): R, _ 58 (E) OH 2.55 min.; m/z = 474 HN (M+H) +

N
_ J [a]D20 = -72.2 , c = 0.50, ~ N
CHCl3 (-)-enantiomer 'H-NMR (400 MHz, DMSO-d6): 8 = 12.66 (br.
s, 1H), 8.35 (s, 1H), 7.52-7.45 (m, 5H), 7.39-7.30 (m, 3H), 7.18 (d, 2H), 4.74 (d, 1 H), 4.40-4.30 (m, 1 H), 3.96 (s, 2H), 3.88 (s, 3H), 3.40-3.25 (m, 1 H), 1.80-1.62 (m, 2H), 1.60-1.40 (m, 4H), 1.20-1.08 (m, 2H).

BHC 07 1 039-Foreign countries Example Starting Structure Analytical data material (Method) 87 Example H3C-O LC-MS (Method 6): R, _ 57 (E) oH 2.55 min.; m/z = 474 HN ~~ o~ (M+H)+
o I N
~ [a]D 20 = +63 , c = 0.50, (+)-enantiomer 'H-NMR (400 MHz, DMSO-d6): 8 = 12.66 (br.
s, 1 H), 8.35 (s, 1 H), 7.52-7.45 (m, 5H), 7.39-7.30 (m, 3H), 7.18 (d, 2H), 4.74 (d, 1H), 4.40-4.30 (m, 1H), 3.96 (s, 2H), 3.88 (s, 3H), 3.40-3.25 (m, IH), 1.80-1.62 (m, 2H), 1.60-1.40 (m, 4H), 1.20-1.08 (m, 2H).

88 Example H3C-o LC-MS (Method 3): R, _ 59 (E) oH 2.39 miii.; m/z = 474 HN O~ (M+H)+
O
N
'H-NMR (400 MHz, DMSO-d6): b = 12.40 (br.
(+I-)-cis s, I H), 8.35 (s, 1 H), 7.48-7.42 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.15 (br. d, 1 H), 4.15-4.07 (m, 1H), 3.35 (2 s, 5H), 3.45-3.3 8 (m, 1 H), 2.10 (br. d, 1 H), 1.82-1.72 (m, 2H), 1.66-1.55 (m, IH), 1.28-1.18 (m, 2H), 1.12-1.02 (m, 2H).

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example Starting Structure Analytical data material (Method) 89 Example H3C-O LC-MS (Method 6): Rt _ 60 (E) oH 2.54 min.; m/z = 474 HN ~ (M+H)+

[a]DZ = +69.5 , c = 0.5, CHCl3 (+)-enantiomer 1H-NMR (400 MHz, DMSO-d6): b = 12.57 (br.
s, 1 H), 8.35 (s, I H), 7.48-7.42 (m, 4H), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.18-5.11 (m, 1 H), 4.15-4.07 (m, IH), 3.35 (2 s, 5H), 3.45-3.36 (m, 1H), 2.10 (br. d, 1 H), 1.82-1.72 (m, 2H), 1.66-1.55 (m, 1H), 1.28-1.18 (m, 2H), 1.12-1.02 (m, 2H).

r BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example Starting Structure Analytical data material (Method) 90 Example H3C-O LC-MS (Method 6): R, _ 61 (E) OH 2.54 min.; m1z = 474 HN ~ao(M+H)+

LaID20 = -85.4 , c = 0.54, (-)-enantiomer 'H-NMR (400 MHz, DMSO-d6): 6 = 12.57 (br.
s, 1H), 8.35 (s, lH), 7.48-7.42 (m, 414), 7.39-7.30 (m, 3H), 7.14 (d, 2H), 5.18-5.11 (m, 1 H), 4.15-4.07 (m, IH), 3.35 (2 s, 5H), 3.45-3.36 (m, IH), 2.10 (br. d, 1 H), 1.82-1.72 (m, 2H), 1.66-1.55 (m, 1 H), 1.28-1.18 (m, 2H), 1.12-1.02 (m, 2H).

91 Example LC-MS (Method 3): Rt =
63 (E) oY OH 2 .59 mi.; mlz = 445 o (M+H)KIIEE:TIICccIIIIIIir o N~ 'H-NMR (400 MHz, DMSO-d6): b = 12.35 (br.
(+l-)-cis s, 1H), 8.61 (s, IH), 7.56-7.37 (m, 10H), 5.15-5.06 (m, 1 H), 4.00 (s, 2H), 3.46-3.25 (m, IH), 2.41 (br. d, 1H), 2.05-1.95 (m, 2H), 1.71 (br. d, 1 H), 1.30-1.02 (m, 4H).

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example Starting Structure Analytical data material (Method) 92 Example LC-MS (Method 5): R, _ 62 (E) a0I HN N oH 2.70 min.; m/z = 444 o (M+H)+. N

(+l-)-cis Example 93 (+/-)-(5-cis,3-trans)-[(3-Fluoro-5- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} -cyclohexyl)oxy]acetic acid O =
O O OH

N O
O Ni 150 mg (0.27 mmol) of tert-Butyl (+/-)-all-cis-[(3-hydroxy-5-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate are initially charged in 2.5 ml of dichloromethane and cooled to 0 C. 53 mg (0.33 mmol) of diethylaminosulfur trifluoroide (DAST) are added, and the mixture is allowed to warm to RT. The mixture is then diluted with water and dichloromethane, and the phases are separated. The aqueous phase is extracted twice with dichloromethane, and the combined organic phases are washed once with sat.
sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is dissolved in 5 ml of dichloromethane, I ml of trifluoroacetic acid is added and the mixture is stirred at RT for 30 min.
Sat. sodium bicarbonate solution is then added, and the aqueous phase is separated off and washed once with diethyl ether. The aqueous phase is then acidified with I N
hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is purified chromatographically on a silica gel thick-layer plate (mobile phase:
dichloromethane/methanol BHC 07 l 039-Foreign countries 9:1). The product zone is extracted with dichloromethane/methanol 9:1. The product is subsequently purified once more by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient), giving 46 mg (34.0% of theory) of the target compound.

LC-MS (Method 8): R, = 2.76 min.; m/z = 493 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.55 (s, 1H), 8.61 (s, 1H), 7.55 (d, 2H), 7.44-7.35 (m, 5H), 7.01 (d, 2H), 5.45-5.35 (m, 1H), 5.15-4.96 (d, IH), 4.05 (s, 2H), 3.81 (s, 3H), 3.78-3.69 (m, 1H), 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 At RT, about 15 eq. of trimethylsilyl azide and about 1.5 eq. of di-n-butyltin oxide are added to a solution of the nitrile in toluene (concentration about 100 mg/ml). The mixture is stirred in a temperature range of from 70 C to reflux for a number of hours, preferably overnight. After the reaction has ended, a relatively large excess of ethvlene glycol is added and the mixture is stirred at reflux for about I h. After cooling, the mixture is diluted with ethyl acetate, washed with sat.
sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution and concentrated under reduced pressure. The product is obtained after purification by preparative RP-HPLC (mobile phase: water/acetonitrile gradient) or by chromatography on silica gel.

The following examples are obtained in accordance with the General Procedure F:
Example Structure Analytical data 94 H 3C-0 N-N LC-MS (Method 5): R, = 1.88 N min.; m/z = 512 (M+H)+
H
J:N

'H-NMR (400 MHz, DMSO-d6):
_ ~ 8= 8.59 (s, 1 H), 7.53 (d, 2H), 7.46-7.35 (m, 5H), 7.00 (d, 2H), (+l-)-trans 5.78 (s, 0.3H), 5.79-5.71 (m, 1H), 3.81 (s, 3H), 2.90-2.85 (m, 1 H), 2.61-2.56 (m, l H), 2.30 (t, 2H), 2.19-2.04 (m, 2H), 1.95-1.86 (m, I H), 1.79-1.65 (m, 2H), 1.69-1.57 (m, 1 H), 1.50-1.40 (m, I H), 1.32-1.21 (m, 1 H).

BHC 07 1 039-Forei pn countries Example Structure Analytical data 95 H3C-O N-N LC-MS (Method 6): Rt = 2.69 lI NN min.; m/z = 513 (M+H)+

'H-NMR (400 MHz, DMSO-d6):
J S= 8.60 (s, 1H), 8.00-7.71 (m, N
111), 7.59-7.50 (m, 2H), 7.44-7.3 8 (+/-)-cis (m, 5H), 7.01 (d, 2H), 5.19-5.09 (m, 1H), 3.81 (s, 3H), 3.71-3.62 (m, 2H), 2.82 (t, 2H), 2.47-2.39 (m, 1 H), 2.07-1.90 (m, 2H), 1.79-1.68 (m, 1 H), 1.32-1.00 (m, 5H).

96 H3C-O LC-MS (Method 3): Rt = 2.42 '0'0 mi.; m/z = 512 (M+H)H-NMR (400 MHz, DMSO-d6):
J S= 8.60 (s, 1 H), 7.60-7.52 (m, c$OJcN
N
2H), 7.41 (d, 2H), 7.31-7.22 (m, (+/-)-trans 4H), 7.09 (d, 2H), 4.71 (d, 1H), 4.35-4.23 (m, 1H), 3.90 (s, 3H), 3.82-3.78 (m, 1H), 3.70 (s, 1H), 3.40-3.29 (m, 2H), 2.50-2.41 (m, 1 H), 1.85-0.81 (m, 9H).

97 N-N N LC-MS (Method 8): R, = 1.82 H3C-O N min.; m/z = 512 (M+H)+

p 'H-NMR (400 MHz, DMSO-d6):
N 8= 8.60 (s, 1 H), 7.52 (d, 2H), 0 NJ 7.44-7.32 (m, 5H), 7.00 (d, 2H), 4.43-4.35 (m, l H), 4.23-4.15 (m, (+/-) 1 H), 3.81 (s, 3 H), 3.01-2.94 (m, 1 H), 2.72-2.45 (m, 7H), 2.28-2.19 (m, 1 H), 2.18-2.07 (m, 1 H), 1.79-1.39 (m, 4H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 98 H3C-O LC-MS (Method 3): Rt = 1.70 min.; m/z = 498 (M+H)+
O N~NN
N_ 'H-NMR (400 MHz, DMSO-d6):
~ ~ ~ \N H
J 8= 8.59 (s, 1 H), 7.54 (d, 2H), O N
7.45-7.32 (m, 5H), 6.98 (d, 2H), (+/-) 5.76 (s, 0.3 H), 5.30-5.21 (m, IH), 3.80 (s, 3H), 3.01 (t, 2H), 2.88 (d, 1 H), 2.73 (t, 2H), 2.42-2.28 (m, 2H), 1.90-1.82 (m, IH), 1.64-1.53 (m, 1H), 1.50-1.20 (m, 3H).

99 H3C-O LC-MS (Method 3): Rt = 1.71 min.; m/z = 498 (M+H)+
O~ NN~N
N_ 'H-NMR (400 MHz, DMSO-d6):
~ ~ ~ \N H
8= 8.59 (s, 1H), 7.53 (d, 2H), O N
7.45-7.32 (m, 5H), 6.98 (d, 2H), (-)-enantiomer 5.31-5.22 (m, IH), 3.81 (s, 3H), 3.08 (s, 2H), 2.93 (d, 1H), 2.80 (t, 2H), 2.65-2.36 (m, 4H), 1.92-1.82 (m, 1 H), 1.68-1.55 (m, 1 H), 1.51-1.30 (in, 2H).

100 H3C-0 LC-MS (Method 6): R, = 1.81 O min.; m/z = 498 (M+H)+
N ~ N N
N_ 'H-NMR (400 MHz, DMSO-d6):
~ ~ ~ \N H
J 8= 8.59 (s, I H), 7.53 (d, 2H), N
7.45-7.32 (m, 5H), 6.98 (d, 2H), (+)-enantiomer 5.31-5.22 (m, 1H), 3.81 (s, 3H), 3.08 (s, 2H), 2.93 (d, l H), 2.80 (t, 2H), 2.65-2.36 (m, 4H), 1.92-1.82 (m, l H), 1.68-1.55 (m, 1 H), 1.51-1.30 (m, 2H).

= BHC 07 1 039-Foreign countries Example 101 (+)-3-[(3S)-3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl]-propanoic acid O N~~ OH
Olf N
NJ

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 suspended in 0.5 ml of conc. hydrochloric acid, and the mixture is heated under reflux for 30 min. After cooling, the mixture is concentrated under high vacuum and the residue is adjusted to pH 7 using 1 N aqueous sodium hydroxide solution.
The mixture is purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient).
This gives 29.8 mg (57.2% of theory) of the target compound.

[a]o20 = +76.1 , c = 0.49, CHC13 LC-MS (Method 8): R, = 1.94 min.; m/z = 474 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.59 (s, 1H), 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, 1H), 2.28-2.09 (m, 4H), 1.92-1.81 (m, 1 H), 1.64-1.51 (m, 1H), 1.49-1.37 (m, 1H), 1.36-1.21 (m, 1H).

Example 102 (-)-3-[(3R)-3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l -yl]-propanoic acid H3C';-O

,.= N~\ OH
IOI
N

N-) BHC 07 1 039-Foreign countries 55 mg (0.121 mmol) of (-)-3-(3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-piperidin-1-yl)propanenitrile are suspended in 0.55 ml of conc. hydrochloric acid, and the mixture is heated under reflux for 30 min. After cooling, the mixture is concentrated under high vacuum and the residue is adjusted to pH 7 using I N aqueous sodium hydroxide solution. The mixture is purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient).
This gives 38.4 mg (67.0% of theory) of the target compound.

[a]D 20 = -87.9 , c = 0.565, CHC13 LC-MS (Method 3): R, = 1.68 min.; m/z = 474 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 12.60 (br, 1H), 8.60 (s, 1H), 7.55 (d, 2H), 7.46-7.35 (m, 5H), 7.00 (d, 2H), 5.29-5.20 (m, 1H), 3.80 (s, 3H), 2.82 (d, lH), 2.61-2.54 (m, 1H), 2.40-2.21 (m, 4H), 2.19 (s, 2H), 1.91-1.81 (m, 1 H), 1.65-1.52 (m, 1 H), 1.49-1.29 (m, 2H).

Example 103 3-[(2R,4R)-4-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
piperidin-2-yl]-propanoic acid NH
O OH
IOI
N

NJ
34 mg of 3-[(2R,4R)-1-(tert-butoxycarbonyl)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimi-din-4-yl]oxy}piperidin-2-yl]propanoic acid are stirred at RT in about 0.1 ml of a 3:2 mixture of trifluoroacetic acid and dichloromethane for 30 min. The volatile components are then removed under reduced pressure, and the residue is dried under high vacuum. The residue is taken up in acetonitrile/water and neutralized using 1 N aqueous sodium hydroxide solution (pH about 7). The precipitated colorless solid is filtered off with suction, washed twice with water and twice with acetonitrile and dried under high vacuum. This gives 20 mg (71.3% of theory) of the target compound.

LC-MS (Method 4): Rr = 3.12 min.; m/z = 474 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6= 8.59 (s, IH), 7.55 (d, 2H), 7.45-7.38 (m, 5H), 7.00 (d, 2H), BHC 07 1 039-Foreign countries 5.30-5.20 (m, 1H), 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, 1 H).

Example 104 3-[(2R,4R)-4-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-1-methylpiperidin-2-yl] propanoic acid N~ 3 O
-,Y OH
N O

O
Ni 8 mg (17 mol) of 3-[(2R,4R)-4-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}-piperidin-2-yl]propanoic acid are dissolved in 50 l of acetic acid, and 13 1 of conc. (about 37%) formalin solution and 53.7 g (253 mol) of sodium triacetoxyborohydride are successively added.
The mixture is stirred at RT for 4 h. Another 13 l of conc. formalin solution and 53.7 g (253 mol) of sodium triacetoxyborohydride are then added, and the mixture is stirred further overnight. The mixture is then purified directly by preparative RP-HPLC
(mobile phase:
acetonitrile/water gradient). This gives 5 mg of the target product (60.7% of theory).

LC-MS (Method 8): R, = 1.69 min.; m/z = 488 (M+H)}

1 H-NMR (400 MHz, DMSO-d6): b= 8.59 (s, 1H), 7.55 (d, 2H), 7.43-7.36 (m, 5H), 7.01 (d, 2H), 5.19-5.10 (m, 1H), 3.81 (s, 3H), 2.84-2.79 (m, 1 H), 2.66-2.57 (m, 6H), 2.13-1.93 (m, 2H), 1.72-1.58 (m, 2H), 1.48-1.38 (m, 1 H), 1.21 (s, 3H).

General Procedure G: palladium-catalyzed arylation of 5-bromo-6-phen ly furo[2,3-d]pyrimidine derivatives At RT, 1.2 to 1.5 eq. of the appropriate arylboronic acid and, as base, either about 2.0 eq. of sodium carbonate (as a 2 M aqueous solution) or about 1.5 to 2.5 eq. of solid potassium carbonate and methanol (about 10% by volume) are added successively to a solution of 1.0 eq. of the 5-bromo-6-phenylfuro[2,3-d]pyrimidine derivative in DMSO (about 0.1 to 0.5 mol/1). About 5 mol%
of bis(triphenylphosphine)palladium(II) chloride are then added under argon.
The mixture is stirred at temperatures of 70-100 C for a period of 3-18 h. After cooling, the target product is isolated directly from the reaction solution by RP-HPLC (mobile phase:
acetonitrile/water BHC 07 1 039-Foreign countries gradient). If required, further purification may be carried out by chromatography on silica gel (mobile phase: dichloromethane/methanol or cyclohexane/ethyl acetate mixtures).

The following examples are obtained according to the General Procedure G:

BHC 07 1 039-Foreign countries Example Structure Analytical data 105 H3C-o F LC-MS (Method 6): R, = 3.16 ` /CH33 min.; m/z = 548 (M+H)+
HN "/ o~C`~-CH
o CI H3 'H-NMR (400 MHz, CDC13):
J b= 8.41 (s, 1 H), 7.58-7.51 (m, N
2H), 7.32-7.19 (m, 5H), 7.18-7.10 (+/-)-trans (m, 1 H), 4.59 (d, 1 H), 4.50-4.40 (m, l H), 4.01 (s, 3H), 3.98 (d, 1 H), 3.50 (br. s, 1 H), 2.01-1.91 (m, 1 H), 1.89-1.60 (m, 3H), 1.59 (s, 2H), 1.47 (s, 9H), 1.30-1.17 (m, 3H).

106 ci LC-MS (Method 8): Rt = 3.40 CH3 min.; m/z = 534 (M+H)+
HN "/CH3 N o CH3 'H-NMR (400 MHz, CDC13):
8= 8.40 (s, lH), 7.58-7.49 (m, ~ N
4H), 7.44 (d, 2H), 7.31-7.24 (m, (+I-)-trans 3H), 4.50-4.40 (m, 2H), 3.99 (d, 2H), 3.48 (br. s, 1H), 2.01-1.91 (m, 1 H), 1.88-1.60 (m, 2H), 1.49 (s, 9H), 1.26 (s, 4H), 0.91-0.85 (in, I H).

107 H2N LC-MS (Method 8): R, = 3.01 CH3 min.; m/z = 515 (M+H)+
HN ~~ o~C~CH3 N o CH3 'H-NMR (400 MHz, CDC13):
S= 8.39 (s, 1 H), 7.60 (d, 2H), 7.30-7.20 (m, 5H), 6.85 (d, 2H), (+/-)-trans 4.78 (d, IH), 4.50-4.40 (m, 1H), 4.05-3.88 (m, 3H), 3.40 (br. s, 1 H), 1.93-1.82 (m, 1 H), 1.80-1.67 (m, 2H), 1.65-1.50 (m, 3H), 1.48 (s, 9H), 1.31-1.19 (m, 3H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 108 F3C LC-MS (Method 8): Rt = 3.38 - cH3 min.; m/z = 568 (M+H)+
~ ~ HN o~C~CH3 N o CH3 'H-NMR (400 MHz, CDC13):

b= 8.43 (s, 1 H), 7.72 (d, 2H), 7.68 (d, 2H), 7.53-6.97 (m, 2H), 7.37-7.29 (m, 3H), 4.50-4.40 (m, I H), (+/-)-trans 4.38 (d, IH), 3.97 (s, 2H), 3.46 (br.
s, 1 H), 2.00-1.90 (m, 1 H), 1.88-1.69 (m, 3H), 1.68-1.51 (m, 2H), 1.48 (s, 9H), 1.20-1.09 (m, 2H).

109 H3C LC-MS (Method 3): Rt = 3.27 C` `~-C /~H,H3 min.; m/z = 528 (M+H)+

0 CI H3 'H-NMR (400 MHz, CDC13):
N
b= 8.39 (s, 1H), 7.59 (d, 2H), J

N
7.42-7.35 (m, 3H), 7.30-7.21 (m, 4H), 4.61 (d, 1 H), 4.50-4.40 (m, (+/-)-trans 1H), 3.95 (d, 2H), 3.42-3.34 (m, IH), 2.79 (q, 2H), 1.88-1.79 (m, 1H), 1.78-1.62 (m, 2H), 1.60-1.51 (m, 2H), 1.48 (s, 9H), 1.32 (t, 3H), 1.22-1.03 (m, 3H).

110 /-o LC-MS (Method 6): Rt = 3.31 H3C HN /~/,,, O o CH3 min.; m/z = 544 (M+H)+
)<
o CH~H3 ' N H-NMR (400 MHz, CDC13):
_ o N) b= 8.40 (s, 1H), 7.58 (d, 2H), 7.39 (d, 2H), 7.30-7.22 (m, 3H), 7.05 (d, (+/-)-trans 2H), 4.65 (d, 1H), 4.49-4.39 (m, 1 H), 4.13 (q, 2H), 3.97 (d, 2H), 3.40 (br. s, 1 H), 2.19 (s, 1 H), 1.94-1.87 (m, 1H), 1.82-1.66 (m, 2H), 1.62-1.53 (m, 4H), 1.48 (s, 9H), 1.29-1.13 (m, 3H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 111 H3C LC-MS (Method 3): R, = 3.19 CH3 min.; m/z = 514 (M+H)+
HN 'O~O'_~CH3 O CH3 'H-NMR (400 MHz, CDC13):
J 8= 8.40 (s, 1 H), 7.60-7.52 (m, N
3H), 7.40-7.32 (m, 4H), 7.30-7.21 (+/-)-trans (m, 2H), 4.61 (d, 1 H), 4.48-4.39 (m, 1H), 3.94 (d, 2H), 3.39 (br. s, 1H), 2.50 (s, 3H), 1.90-1.81 (m, 1H), 1.80-1.64 (m, 2H), 1.59 (s, 1H), 1.48 (s, 9H), 1.30-1.11 (m, 4H).

112 H2C- LC-MS (Method 6): Rt = 3.35 CH3 min.; m/z = 526 (M+H)+

N O CH3 'H-NMR (400 MHz, CDC13):
NJ 8= 8.43 (s, 1H), 7.88-7.78 (m, 2H), 7.50-7.40 (m, 3H), 7.40-7.30 (m, 1 H), 6.97-6.86 (m, 3H), 5.70 (+/-)-trans (br. s, I H), 5.52 (d, I H), 4.64-4.53 (m, I H), 3.90 (s, 2H), 3.60 (br. s, I H), 2.12-2.03 (m, 1H), 1.98-1.88 (m, 1 H), 1.82-1.71 (m, 1 H), 1.64 (s, 4H), 1.50 (s, 9H), 1.26 (s, 2H), 0.91-0.80 (m, l H).

113 LC-MS (Method 3): R, = 3.11 HN O~o~CH3 CH min.; m/z = 500 (M+H)+

N o CH3 'H-NMR (400 MHz, CDC13):
N~ 8= 8.40 (s, I H), 7.60-7.48 (m, - o 7H), 7.31-7.22 (m, 3H), 4.54 (d, (+/-)-trans 1 H), 4.48-4.39 (m, 1 H), 3.96 (d, 2H), 3.40 (br. s, 1H), 1.92-1.83 (m, 1 H), 1.80-1.64 (m, 2H), 1.58 (s, 3H), 1.47 (s, 9H), 1.23-1.10 (m, 2H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 114 F3C-O LC-MS (Method 6): Rt = 3.35 ` /CH, min.; m/z = 584 (M+H)+
HN 0"" o~C `f-CH3 o ICH3 'H-NMR (400 MHz, CDC13):
N
6= 8.41 (s, 1H), 7.5 8-7.49 (m, 4H), 7.42 (d, 2H), 7.31-7.29 (m, 3H), 4.50-4.38 (m, 2H), 3.96 (d, (+/-)-trans 2H), 3.49 (br. s, 1H), 1.98-1.90 (m, 111), 1.86-1.69 (m, 2H), 1.68-1.60 (m, IH), 1.55 (s, 2H), 1.48 (s, 9H), 1.21-1.09 (m, 2H).

115 Ci LC-MS (Method 3): Rt = 3.35 CH3 min.; m/z = 535 (M+H)+
O O~~~CH3 o CH3 'H-NMR (400 MHz, DMSO-d6):
J 6= 8.61 (s, 1H), 7.55-7.49 (m, 6H), 7.48-7.40 (m, 3H), 5.18-5.08 (m, 1H), 3.99 (s, 2H), 3.48-3.38 (m, 1 H), 2.45-2.3 8 (m, l H), 2.04-1.90 (m, 2H), 1.78-1.69 (m, 1H), 1.40 (s, 9H), 1.29-1.04 (m, 4H).

116 H3C-o F LC-MS (Method 3): Rt = 3.40 CH3 min.; m/z = 547 (M+H)+

N o CH3 'H-NMR (400 MHz, DMSO-d6):
6= 8.61 (s, 1H), 7.59-7.51 (m, 2H), 7.48-7.40 (m, 3H), 7.39-7.29 (m, 2H), 7.22-7.19 (m, 1 H), 5.18-5.07 (m, 1H), 3.98 (s, 2H), 3.47-3.38 (m, 1H), 2.71 (q, 2H), 2.45-2.37 (m, 1H), 2.06-1.89 (m, 2H), 1.78-1.69 (m, 1H), 1.39 (s, 9H), 1.29-1.01 (m, 7H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 117 H3C-O F LC-MS (Method 8): Rt = 1.86 p o "CH3 min.; m/z = 520 (M+H)+
~ `"= N
'H-NMR (400 MHz, DMSO-d6):
J b= 8.60 (s, 1 H), 7.59-7.51 (m, N
2H), 7.47-7.39 (m, 5H), 7.24-7.18 (m, 2H), 7.30-7.20 (m, 1H), 3.90 (s, 3H), 3.52 (s, 2H), 2.80-2.70 (m, IH), 2.31-2.20 (m, 5H), 2.19-2.11 (m, IH), 1.93-1.81 (m, 1 H), 1.68-1.53 (m, 2H), 1.50-1.30 (m, 2H).

118 H3C F LC-MS (Method 8): Rt = 2.01 min.; m/z = 518 (M+H)+
.= N ICH3 p 'H-NMR (400 MHz, DMSO-d6):
J 8= 8.60 (s, 1H), 7.59-7.51 (m, 2H), 7.48-7.39 (m, 3H), 7.38-7.30 (m, 2H), 7.20 (d, l H), 5.29-5.20 (m, 1 H), 3.50 (s, 3H), 2.75-2.61 (m, 3H), 2.42-2.35 (m, l H), 2.35-2.12 (m, 5H), 1.90-1.80 (m, 1H), 1.66-1.49 (m, 3H), 1.48-1.30 (m, 2H), 1.29-1.15 (m, 4H).

119 cl LC-MS (Method 8): R, = 1.88 o o,= N-'~OICH3 min.; m/z = 506 (M+H)+

N 'H-NMR (400 MHz, DMSO-d6):
NJ 8= 8.60 (s, 1H), 7.56-7.47 (m, 6H), 7.48-7.39 (m, 3H), 5.30-5.20 (m, 1 H), 3.52 (s, 3H), 2.78-2.69 (m, IH), 2.48-2.39 (m, 1H), 2.30-2.20 (m, 5H), 2.20-2.11 (m, IH), 1.90-1.81 (in, 1 H), 1.66-1.50 (m, 3H), 1.49-1.29 (m, 2H).

BHC 07 1 039-Foreign countries Example 120 tert-Butyl (-)-{ [(3-{ [5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyclohexyl]oxy} acetate O O~O\ CH3 - O N"

With cooling, 0.104 ml (0.208 mmol) of the phosphazene base P2-t-Bu (2 M
solution in THF) is added to a mixture of 40 mg (0.174 mmol) of tert-butyl (-)-cis-{[3-hydroxycyclohexyl]oxy}acetate and 58.15 mg (0.174 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine in 0.3 ml of DMF. The mixture is stirred at RT for I h. Water is then added, and the mixture is extracted with dichloromethane. The organic phase is washed with pH 7 buffer solution and with sat. sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. 45.6 mg (49.7% of theory) of the target compound are isolated from the residue by preparative RP-HPLC
(mobile phase: acetonitrile/water).

[a]D20 = -56.7 , c = 0.485, CHC13 LC-MS (Method 3): R, = 3.41 min.; m/z = 529 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.60 (s, 1H), 7.58-7.50 (m, 2H), 7.43-7.35 (m, 5H), 7.29 (d, 2H), 5.18-5.07 (m, 1H), 3.90 (s, 2H), 3.46-3.36 (m, 1 H), 2.70 (q, 2H), 2.44-2.36 (m, 1 H), 2.05-1.90 (m, 2H), 1.78-1.69 (m, 1 H), 1.41 (s, 9H), 1.25 (t, 3H), 1.20-1.01 (m, 4H).

Example 121 tert-Butyl (+)-{[(3-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl]oxy}acetate BHC 07 1 039-Foreign countries - l 92 -O
000 O~O `~-CH3 O N) The title compound is obtained analogously to example 120 by reacting tert-butyl (+)-cis-{[3-hydroxycyclohexyl]oxy} acetate with 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine.
[a]p20 = +54.7 , c = 0.505, CHC13 LC-MS (Method 3): R, = 3.41 min.; m/z = 529 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.60 (s, 1H), 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, 1H), 2.70 (q, 2H), 2.44-2.36 (m, IH), 2.05-1.90 (m, 2H), 1.78-1.69 (m, 1H), 1.41 (s, 9H), 1.25 (t, 3H), 1.20-1.01 (m, 4H).

Example 122 Methyl (-)-4-[(3R)-3-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl]butanoate p \\ N O~CH3 N

O N~

With ice-cooling, 1.55 ml (3.10 mmol) of the phosphazene base P4-t-Bu (1 M
solution in hexane) are added 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 methyl (-)-4-[(3R)-3-hydroxypiperidin-1-yl]butanoate in 2 ml of DMF. After 2 h at RT, a further 220 mg of methyl (-)-4-[(3R)-3-hydroxypiperidin-l-yl]butanoate and 0.57 ml of the phosphazene base P4-t-Bu (1 M solution in hexane) are added, and the mixture is stirred at RT for a further 2 h. For work-up, the mixture is diluted with dichloromethane, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient) gives 548.4 mg of the target product (46.0% of theory).

BHC 07 1 039-Foreign countries [a]D20 = -40.6 , c = 0.505, CHC13 LC-MS (Method 8): R, = 1.95 min.; m/z = 500 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.59 (s, 1H), 7.59-7.52 (m, 2H), 7.46-7.38 (m, 5H), 7.30-7.21 (m, 2H), 5.25-5.19 (m, lH), 3.52 (s, 3H), 2.73-2.65 (m, 3H), 2.44-2.38 (m, 1H), 2.30-2.20 (m, 5H), 2.19-2.05 (m, 1H), 1.90-1.80 (m, 1H), 1.64-1.50 (m, 3H), 1.44-1.39 (m, 2H), 1.23 (t, 3H).
Example 123 Methyl4-[(3S)-3-{ [5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}
piperidin-l-yl]butanoate O
O O~CH3 \N
O N) Under argon, 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) of 4-ethylbenzeneboronic acid are added successively to a solution of 70 mg (0.148 mmol) of methyl (+)-4-{(3S)-3-[(5-bromo-6-phenylfuro[2,3-d]pyrimidin-4-yl)oxy]piperidin-l-yl}butanoate in 0.4 ml of DMSO. The mixture is stirred at 80 C for a total of 3.5 h. After cooling, the reaction mixture is purified directly by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gives 37.3 mg (50.6% of theory) of the target compound.

LC-MS (Method 8): R, = 1.86 min.; m/z = 500 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.59 (s, 1 H), 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 (in, 1 H), 1.90-1.80 (m, 1 H), 1.64-1.50 (m, 3H), 1.44-1.39 (m, 2H), 1.23 (t, 3H).

Example 124 tert-Butyl rac-(cis/trans)-{[3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopentyl]oxy}acetate BHC 07 1 039-Foreign countries O O~ CH3 N
o N
At 40 C, a solution of 2.5 g (6.2 mmol) of rac-(cis/trans)-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 tert-butyl bromoacetate are added successively to 4.97 g (62.1 mmol) of 50%
strength aqueous sodium hydroxide solution and 10 ml of toluene. The two-phase reaction mixture is stirred vigorously at 60 C for a total of 3 h. After cooling, the reaction mixture is added to water and neutralized using conc. hydrochloric acid. The mixture is extracted three times with ethyl acetate, and the organic phases are combined, dried over magnesium sulfate and concentrated under reduced pressure. 300 mg (9.4% of theory) of the target compound are isolated from the residue by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1 --> 1:1).
LC-MS (Method 3): R, = 3.17 min.; m/z = 517 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.60 (s, 1H), 7.59-7.52 (m, 2H), 7.45-7.36 (m, 5H), 7.08-6.99 (m, 2H), 5.62-5.40 (m, 1 H), 3.89 (d, I H), 3.81 (s, 3H), 2.10-1.60 (m, 6H), 1.40 (d, 9H), 1.10-1.00 (m, I H), 0.90-0.79 (m, I H).

Separation of the cis/trans-isomers and enantiomers:

300 mg (0.581 mmol) of tert-butyl rac-(cis/trans)-{[3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopentyl]oxy}acetate are separated into the isomers/enantiomers (see examples 125-128) by chromatography on a chiral phase [column: Daicel Chiralpak AD-H 5 m, 250 mm x 20 mm; flow rate: 15 ml/min; detection: 220 nm; temperature: 25 C;
mobile phase:
isohexane/2-propanol 90:10].

Example 125 tert-Butyl (-)-cis-{ [3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyclopentyl]oxy} acetate BHC 07 1 039-Foreign countries O 11. O CH3 O] CH3 N
- o NJ
Yield: 75 mg (25.0% of theory) [a]D20 = -24.7 , c = 0.455, CHC13 LC-MS (Method 3): R, = 3.17 min.; m/z = 517 (M+H)+

'H-NMR (400 MHz, DMSO-db): b= 8.59 (s, 1H), 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, 1H), 3.88 (d, 2H), 3.80 (s, 3H), 2.37-2.26 (m, 1H), 1.96-1.61 (m, 5H), 1.40 (s, 9H).

Example 126 tert-Butyl (+)-cis- {[3- {[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopentyl]oxy}acetate O O~ ~CH3 N
O N) Yield: 57 mg (19.0% of theory) [a]D20 = +24.2 , c = 0.48, CHC13.
Example 127 tert-Butyl (+)-trans-{ [3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]oxy} cyclopentyl]oxy} acetate BHC 07 1 039-Foreign countries N
- O N) Yield: 23 mg (7.7% of theory) [a]D20 = +32.6 , c = 0.48, CHC13 LC-MS (Method 6): R, = 3.31 min.; m/z = 517 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.59 (s, 1H), 7.56 (d, 2H), 7.45-7.36 (m, 5H), 7.01 (d, 2H), 5.63-5.58 (m, 1H), 3.97-3.90 (m, 1H), 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 tert-Butyl (-)-trans- {[3- {[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]oxy}cyclopentyl]oxy}acetate O O~ ~CH3 N
O N) Yield: 39 mg (13.0% of theory) [a]D20 = -30.1 , c = 0.54, CHC13.
Example 129 tert-Butyl (+)-cis-{[(1R,3S')-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopentyl]oxy}acetate BHC 07 1 039-Foreign countries ~ CH3 000 O~ --~CH3 N
O
Ni 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 tert-butyl cis-(-)-{[(1R,3S)-3-hydroxycyclopentyl]oxy}acetate are dissolved in 0.35 ml of DMF, the mixture is cooled to 0 C and 0.69 ml (0.69 mmol) of the phosphazene base P4-t-Bu (1 M solution in hexane) is added. 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 combined, washed with sat.
sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative RP-HPLC (mobile phase: acetonitrile/water gradient) gives 27.2 mg (7.6% of theory) of the target compound.

[a]D20 = +28.4 , c = 0.48, CHC13 LC-MS (Method 3): R, = 3.18 min.; m/z = 517 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.59 (s, 1H), 7.56 (d, 2H), 7.47-7.35 (m, 5H), 7.00 (d, 2H), 5.47-5.40 (m, 1 H), 4.00-3.92 (m, l H), 3.88 (d, 2H), 3.80 (s, 3H), 2.37-2.26 (m, 1 H), 1.96-1.61 (m, 5H), 1.40 (s, 9H).

Example 130 and example 131 tert-Butyl rac-trans-{ [3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]amino} cyclopentyl]oxy} acetate and tert-butyl rac-cis-{[3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} cyclopentyl]oxy} acetate BHC 07 1 039-Foreign countries HN\~~` O~ ~CH3 N
O NJ

HN\\\, , O CH3 N
O N) 0.86 ml (5.2 mmol) of diisopropylethylamine is added to a mixture of 560.4 mg of tert-butyl cis/trans-[(3-aminocyclopentyl)oxy]acetate (crude product, about 2.60 mmol) and 964.3 mg (2.86 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 2.0 ml of DMF.
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 bicarbonate solution and sat. sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. After drying under high vacuum, the product mixture is purified and separated into the cis/trans-isomers by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient).

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)+

'H-NMR (400 MHz, DMSO-d6): S= 8.32 (s, 1H), 7.47-7.39 (m, 4H), 7.38-7.29 (m, 3H), 7.10 (d, 2H), 5.31 (d, l H), 4.61-4.52 (m, 1 H), 3.92 (br. s, 1 H), 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-cis-isomer (example 131 ):
Yield: 404.1 mg (30.1% of theory) LC-MS (Method 3): Rt = 3.05 min.; m/z = 516 (M+H)+

BHC 07 1 039-Foreign countries 'H-NMR (400 MHz, DMSO-d6): S= 8.35 (s, 1H), 7.51-7.45 (m, 4H), 7.40-7.30 (m, 3H), 7.15 (d, 2H), 4.81 (d, 1H), 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 tert-butyl rac-cis-{[3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclopenty l]oxy}acetate and 119 mg (0.231 mmol) of tert-butyl rac-trans- {[3- { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclopentyl]oxy}acetate are each separated into the enantiomers (see examples 132 to 135) by chromatography on a chiral phase [column: Sepapak-2 5 [tm, 250 mm x 20 mm; flow rate:
15 ml/min; detection: 220 nm; temperature: 40 C; mobile phase: isohexane/2-propanol 50:50].
Example 132 tert-Butyl cis-(-)-{[3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} cyclopentyl]oxy}acetate HNO~ CH3 N
- o ~
NJ
Yield: 165 mg (47.1 % of theory) [a]D20 = -12.2 , c = 0.455, CHC13 LC-MS (Method 6): R, = 3.20 min.; m/z = 516 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.35 (s, 1H), 7.48-7.40 (m, 4H), 7.39-7.29 (m, 3H), 7.11 (d, 2H), 5.32 (d, 1 H), 4.62-4.52 (m, 1 H), 3.97-3.90 (m, 1 H), 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 tert-Butyl cis-(+)- { [3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino} cyclopentyl]oxy} acetate BHC 07 1 039-Foreign countries HN Oooe) ~ O ___~CH3 N
I '1 O N
Yield: 163 mg (46.6% of theory) [a]D20 = +8.4 , c = 0.51, CHC13 LC-MS (Method 6): R, = 3.20 min.; m/z = 516 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.34 (s, 1H), 7.47-7.39 (m, 4H), 7.38-7.29 (m, 3H), 7.10 (d, 2H), 5.32 (d, 1H), 4.61-4.51 (m, 1H), 3.97-3.90 (m, 1H), 3.83 (s, 3H), 3.66 (s, 2H), 2.00-1.89 (m, 2H), 1.70-1.60 (ni, 2H), 1.53-1.47 (m, l H), 1.40 (s, 9H), 0.90-0.79 (m, 1H).

Example 134 tert-Butyl trans-(+)-{ [3-{ [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-yl]amino}cyclopentyl]oxy}acetate HN ~ O CH3 N
o N
Yield: 54 mg (45.4% of theory) [a]D 20 = +29.5 , c = 0.46, CHC13 'H-NMR (400 MHz, DMSO-d6): 6 8.35 (s, 1H), 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, 1H), 1.63-1.54 (m, 1H), 1.42 (s, 9H), 1.40-1.32 (m, lH), 1.21-1.10 (m, 1H).

Example 135 tert-Butyl trans-(-)-{[3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-BHC 07 1 039-Foreign countries yl]amino} cyclopentyl]oxy } acetate HN~~~, ~CH 3 N

O N) Yield: 50 mg (42.0% of theory) [a]D20 = -30.3 , c = 0.52, CHC13 'H-NMR (400 MHz, DMSO-d6): 8= 8.36 (s, 1H), 7.51-7.44 (m, 4H), 7.40-7.30 (m, 3H), 7.17 (d, 2H), 4.81 (d, 1H), 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, 1H), 1.42 (s, 9H), 1.40-1.35 (m, 1H), 1.21-1.11 (m, IH).

Example 136 tert-Butyl cis-(+/-)-{ [4- [5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} cyclopent-2-en-l -yl]oxy}acetate N
- o J
N
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 tert-butyl cis-(+/-)-{[(4-hydroxycyclopent-2-en-I-yl]oxy}acetate are dissolved in 0.95 ml of DMF, the mixture is cooled to 0 C and 0.58 ml (1.17 mmol) of the phosphazene base P2-t-Bu (2 M solution in THF) is added. After the addition has ended, the mixture is warmed to RT and stirred for another I h. The reaction mixture is then added to water, adjusted to pH 7 using I 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 under reduced pressure. The crude product is isolated by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1 --> 5:1). This gives 510 mg (85.3% of theory) of BHC 07 1 039-Foreign countries the target compound.

LC-MS (Method 8): R, = 3.47 min.; m/z = 513 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.61 (s, 1H), 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, 1 H), 4.53-4.48 (m, 1 H), 3.93 (s, 2H), 2.88-2.79 (m, IH), 2.68 (q, 2H), 1.52 (td, 1H), 1.40 (s, 9H), 1.23 (t, 3H).

Example 137 tert-Butyl cis-(-)-{[4-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopent-2-en-1-yl]oxy} acetate - ~ O CH3 p ` OY CH3 N

N) 125 mg (0.373 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 80 mg (0.373 mmol) of tert-butyl cis-(+)-{[(4-hydroxycyclopent-2-en-l-yl]oxy}acetate are dissolved in 0.19 ml of DMF, the mixture is cooled to 0 C and 0.19 ml (0.373 mmol) of the phosphazene base P2-t-Bu (2 M solution in THF) is added. After the addition has ended, the mixture is warmed to RT and stirred for another I h. The reaction mixture is then added to water, adjusted to pH 7 using 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 under reduced pressure. The crude product is purified by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient). This gives 140.5 mg (73.4% of theory) of the target compound.

[a]D20 = -92.2 , c = 0.515, CHC13 LC-MS (Method 12): R, = 3.37 min.; m/z = 513 (M+H)+

'H-NMR (400 MHz, DMSO-db): b= 8.61 (s, 1H), 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, 1 H), 4.53-4.49 (m, 1 H), 3.92 (s, 2H), 2.88-2.79 (m, 1 H), 2.69 (q, 2H), 1.53 (td, IH), 1.40 (s, 9H), 1.23 (t, 3H).

BHC 07 1 039-Foreign countries Example 138 tert-Butyl cis-(-)-{[4-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopent-2-en-1-yl]oxy} acetate O O CHs N
O i N
218 mg (0.652 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 141 mg (0.652 mmol) of tert-butyl cis-(+)- { [(1 S,3R)-3-hydroxycyclopentyl]oxy}
acetate are dissolved in 0.19 ml of DMF, the mixture is cooled to 0 C and 0.65 ml (0.65 mmol) of the phosphazene base P4-t-Bu (1 M solution in hexane) is added. After the addition has ended, the mixture is warmed to RT and stirred for another I h. The reaction mixture is then added to water, adjusted to pH 7 using 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 under reduced pressure. The crude product is purified by preparative RP-HPLC
(mobile phase: acetonitrile/water gradient). This gives 92.1 mg (27.5% of theory) of the target compound.

[a]D20 = -36.2 , c = 0.490, CHC13 LC-MS (Method 12): R, = 3.40 min.; m/z = 515 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 6 = 8.60 (s, 1 H), 7.54 (d, 2H), 7.45-7.37 (m, SH), 7.29 (d, 2H), 5.45-5.39 (in, 1 H), 4.00-3.94 (m, 1 H), 3.81 (d, 2H), 2.69 (q, 2H), 2.34-2.22 (m, 1 H), 1.94-1.83 (m, 1H), 1.81-1.71 (m, 1H), 1.70-1.56 (m, 3H), 1.40 (s, 9H), 1.22 (t, 3H).

Example 139 tert-Butyl trans-(-)-{[4-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopent-2-en-l-yl]oxy}acetate BHC 07 1 039-Foreign countries - ~ O CH3 O 11~ ~CH3 N
O J
N
393.9 mg (1.18 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 274 mg (purity 80%, about 1.02 mmol) of tert-butyl trans-(-)-{[(4-hydroxycyclopent-2-en-l-yl]oxy}acetate are dissolved in 0.59 ml of THF, the mixture is cooled to 0 C and 1.02 ml (1.02 mmol) of the phosphazene base P4-t-Bu (1 M solution in hexane) are added slowly. After 1 h of stirring at 0 C, the reaction mixture is added to water. The mixture is adjusted to pH 7 using I 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 under reduced pressure. The crude product is purified by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient). This gives 258.3 mg (42.8% of theory) of the target compound.

[a]D 20 = -102.7 , c = 0.58, CHC13 LC-MS (Method 8): Rt = 3.49 min.; m/z = 513 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 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, 1 H), 6.19-6.09 (m, 2H), 4.67-4.60 (m, 1 H), 4.00 (s, 2H), 2.69 (q, 2H), 2.65-2.57 (m, 1 H), 2.20-2.10 (m, 1 H), 2.05-1.95 (m, 1 H), 1.46 (s, 9H), 1.29-1.20 (m, 2H).

Example 140 tert-Butyl tNans-(-)-{[4-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclopent-2-en-l-yl]oxy}acetate HN" ~, CH3 N
O J
N

87 l (0.524 mmol) of diisopropylethylamine are added to a mixture of 128.6 mg (0.384 mmol) of BHC 07 1 039-Foreign countries 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 74.5 mg tert-butyl trans-{[(4-aminocyclopent-2-en-l-yl]oxy}acetate (crude product) in 0.5 ml of DMF. The reaction mixture is heated at 100 C for 4.5. 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 under reduced pressure. The crude product is purified by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient).
This gives 70.5 mg (39.5% of theory) of the target compound.

[a]D20 = -195.3 , c = 0.50, CHC13 LC-MS (Method 3): Rt = 3.20 min.; m/z = 512 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.39 (s, 1H), 7.52-7.48 (m, 2H), 7.47-7.30 (m, 7H), 6.07-6.01 (m, 1H), 5.90 (d, 1H), 5.24-5.16 (m, 1H), 4.65 (d, 1H), 4.59-4.51 (m, 1H), 3.98 (s, 2H), 2.72 (q, 2H), 2.20-2.10 (m, 1H), 1.67-1.58 (m, 1 H), 1.42 (s, 9H), 1.27 (t, 3H).

Example 141 tert-Butyl cis-(+)-{[4-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclopent-2-en-1-yl]oxy} acetate ~ CH3 O O~ ~CH3 N
o NJ

233.6 mg (0.698 mmol) of 4-chloro-5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidine and 150.9mg (0.698 mmol) of tert-butyl cis-(-)-{[(1R,3S)-3-hydroxycyclopentyl]oxy}acetate are dissolved in 0.35 ml of DMF, the mixture is cooled to 0 C and 0.7 ml (0.7 mmol) of the phosphazene base P4-t-Bu (1 M solution in hexane) is added. After 2 h of stirring at 0 C, the reaction mixture is added to water. The mixture is adjusted to pH 7 using 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 under reduced pressure. The crude product is purified by preparative RP-HPLC (mobile phase:
acetonitrile/water gradient). This gives 60.9 mg (17.0% of theory) of the target compound.

[a]D20 = +26.7 , c = 0.475, CHC13 BHC 07 1 039-Foreign countries LC-MS (Method 12): R, = 3.39 min.; m/z = 515 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.60 (s, 1 H), 7.56 (d, 2H), 7.44-7.38 (m, 5H), 7.29 (d, 2H), 5.45-5.40 (m, I H), 4.00-3.92 (m, 1 H), 3.82 (d, 2H), 2.69 (q, 2H), 2.32-2.25 (m, 1 H), 1.92-1.85 (m, IH), 1.81-1.74 (m, 1H), 1.70-1.58 (m, 3H), 1.40 (s, 9H), 1.22 (t, 3H).

The following examples are prepared in accordance with the General Procedure D
or E (see above) from the compounds described above:

Example Structure Analytical data 142 H3C-o F LC-MS (Method 6): Rt = 2.50 min.;
HN "I 0 oH m/z = 492 (M+H)+
~
o 'H-NMR (400 MHz, CDCl3):
N
1 ) b= 8.40 (s, 1H), 7.59-7.50 (m, 3H), O N
7.34-7.10 (m, 5H), 4.60-4.53 (m, (+/-)-trans 1 H), 4.49-4.39 (m, 1 H), 4.18-4.05 (m, 1H), 4.00 (s, 3H), 3.64-3.50 (m, 1H), 2.11-2.00 (m, 2H), 1.88-1.53 (m, 2H), 1.28 (s, 4H), 0.93-0.80 (m, 2H).

143 ci LC-MS (Method 6): R, = 2.69 min.;
m/z = 478 (M+H)+
HN "" 0,-,,rOH
o 'H-NMR (400 MHz, CDC13):

J 6= 8.40 (s, 1 H), 7.59-7.49 (m, 4H), O N
7.46 (d, 2H), 7.33-7.29 (m, 3H), (+/-)-trans 4.50-4.38 (m, 2H), 4.20-4.05 (m, 2H), 3.55 (br. s, 1 H), 2.10-2.00 (m, 1H), 1.88-1.79 (in, IH), 1.78-1.62 (m, 2H), 1.61-1.50 (m, IH), 1.49-1.11 (m, 4H).

BHC 07 1 039-Foreiv-n countries Example Structure Analytical data 144 H2N LC-MS (Method 6): Rt = 2.19 min.;
m/z = 459 (M+H)+
O~OH
o 'H-NMR (400 MHz, CDC13):

J S= 8.40 (s, IH), 7.57 (d, 2H), 7.33-7.21 (m, 5H), 6.90 (d, 2H), 4.80 (d, (+/-)-trans l H), 4.49 (br. s, 1 H), 4.10 (dd, 2H), 3.20 (br. s, 1H), 1.88-1.73 (m, 2H), 1.72-1.53 (m, 5H), 1.49-1.38 (m, IH), 1.36-1.20 (m, 3H).

145 F3C LC-MS (Method 6): Rt = 2.74 min.;
HN " 0,-,IoH m/z = 512 (M+H)+

o 'H-NMR (400 MHz, CDCl3):

o 1 N J b= 8.43 (s, 1H), 7.83 (d, 2H), 7.65 -(d, 2H), 7.51-7.44 (m, 2H), 7.34-(+I-)-trans 7.29 (m, 3H), 4.48-4.38 (m, 1H), 7.34 (d, 1H), 4.01 (dd, 2H), 3.58 (br.
s, 1H), 2.11-2.00 (m, 1H), 1.88-1.79 (m, 1 H), 1.77-1.63 (m, 2H), 1.58-1.47 (in, 1H), 1.45-1.35 (m, 1H), 1.28 (s, 2H), 1.18-1.04 (m, 1H).

146 H3C LC-MS (Method 6): R, = 2.81 min.;
m/z = 472 (M+H)+
HN ",,O~OH
o 'H-NMR (400 MHz, CDC13):

N J b= 8.40 (s, 1 H), 7.60-7.53 (m, 2H), - o 7.43-7.35 (m, 4H), 7.30-7.22 (m, (+/-)-trans 3H), 4.60 (d, IH), 4.48-4.38 (m, 1H), 4.10 (dd, 2H), 3.50 (br. s, 1H), 2.80 (q, 2H), 2.00-1.90 (m, 1H), 1.80-1.45 (m, 5H), 1.32 (t, 3H), 1.29-1.10 (m, 3H).

BHC 07 1 039-Foreign countries 02685134 2009-10-23 Example Structure Analytical data 147 /-0 LC-MS (Method 8): Rt = 2.87 min.;
H3C oH m/z = 488 (M+H)+
HN ~~ O~
o 'H-NMR (400 MHz, CDC13):
N
O 1 ) b= 8.40 (s, 1H), 7.57 (d, 2H), 7.40 N
(d, 2H), 7.32-7.22 (m, 3H), 7.07 (d, (+/-)-trans 2H), 4.64 (d, 1H), 4.48-4.3 7 (m, 1 H), 4.19-4.02 (m, 4H), 3.49 (br. s, 1H), 2.03-1.94 (m, 1H), 1.80-1.68 (m, 2H), 1.60 (br. s, 2H), 1.51 (t, 3H), 1.39-1.20 (m, 4H).

148 H3c LC-MS (Method 6): Rt = 2.68 min.;
m/z = 458 (M+H)+
HN "" 0,,,,rOH
k o ~H-NMR (400 MHz, CDC13):
N
o 1 N) 6= 8.40 (s, 1H), 7.59-7.50 (m, 2H), -7.40-7.34 (m, 5H), 7.31-7.21 (m, (+/-)-trans 2H), 4.60 (d, l H), 4.48-4.36 (br. m, 1 H), 4.19-4.00 (br. m, 2H), 3.50 (br.
s, 1 H), 2.50 (s, 3H), 2.05-1.92 (m, lH), 1.81-1.40 (m, 5H), 1.35-1.12 (m, 3H).

149 HzC- LC-MS (Method 3): Rt = 2.57 min.;
m/z = 470 (M+H)+
HN "' O,-,,,rOH
o 'H-NMR (400 MHz, CDCI3):

O ~) b= 8.49 (s, I H), 7.62 (d, 2H), 7.55 N
(s, 2H), 7.49 (d, 2H), 7.29 (d, 2H), (+/-)-trans 6.82 (dd, 1 H), 5.91 (d, 1 H), 5.42 (d, 1 H), 4.90-4.78 (br. m, 1 H), 4.51-4.40 (br. m, 1 H), 4.09 (dt, 2H), 3.50 (s, 1 H), 2.09-1.90 (m, 1 H), 1.89-1.78 (m, IH), 1.77-1.61 (m, 2H), 1.54-1.42 (m, 1 H), 1.41-1.30 (m, 2H), 1.20-1.10 (m, I H), 0.92-0.80 (m, l H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 150 LC-MS (Method 6): Rt = 2.55 min.;
HN Pe' 0 0 OH m/z = 444 (M+H)+

0 'H-NMR (400 MHz, CDC13):
N
o N J b= 8.42 (s, 1 H), 7.60-7.49 (m, 7H), 7.29 (s, 1H), 5.31 (s, 2H), 4.55 (d, (+/-)-trans 1 H), 4.48-4.36 (br. m, 1 H), 4.10 (dd, 2H), 3.48 (br. s, 1 H), 2.02-1.92 (m, 1H), 1.81-1.50 (m, 3H), 1.49-1.39 (m, 1H), 1.38-1.12 (m, 3H).

151 F3C-o LC-MS (Method 3): R, = 2.67 min.;
m/z = 528 (M+H)+
HN "/ O~OH
o 'H-NMR (400 MHz, CDC13):

J 8= 8.42 (s, 1 H), 7.56 (d, 2H), 7.52-7.49 (m, 2H), 7.42 (d, 2H), 7.33-(+I-)-trans 7.29 (m, 3H), 4.50-4.38 (m, 2H), 4.11 (dd, 2H), 3.60 (br. s, l H), 2.11-2.01 (m, 1 H), 1.91-1.80 (m, 1 H), 1.79-1.62 (m, 2H), 1.58-1.48 (m, 1 H), 1.47-1.38 (m, l H), 1.37-1.22 (m, 1 H), 1.17-1.04 (m, 1 H).

152 H3C LC-MS (Method 3): R, = 2.90 min.;
m/z = 473 (M+H)+
O`',= O^ /OH

~XOI 'H-NMR (400 MHz, DMSO-d6):
~) b= 12.51 (s, 1 H), 8.60 (s, 1 H), 7.58-N
7.51 (m, 2H), 7.43-7.35 (m, 5H), 7.29 (d, 2H), 5.18-5.09 (m, 1H), 4.01 (s, 2H), 3.15-3.08 (m, 1H), 2.74-2.65 (m, 3H), 2.05-1.92 (m, 2H), 1.79-1.69 (m, 1H), 1.24 (t, 3H), 1.20-1.00 (m, 4H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 153 H3C LC-MS (Method 3): R, = 2.89 min.;
o o ""'( OH m/z = 473 (M+H)+

O 'H-NMR (400 MHz, DMSO-d6):

J 6 = 12.51 (s, 1 H), 8.60 (s, 1 H), 7.59-N
7.51 (m, 2H), 7.43-7.36 (m, 5H), 7.29 (d, 2H), 5.18-5.08 (m, 1H), 4.01 (s, 2H), 3.49-3.39 (m, 1H), 2.70 (q, 2H), 2.05-1.91 (m, 2H), 1.79-1.69 (m, 1H), 1.24 (t, 3H), 1.20-1.00 (m, 5H).

154 H3C LC-MS (Method 6): R, = 1.99 min.;
O
m/z = 486 (M+H)+
O,, N OH
'H-NMR (400 MHz, DMSO-d6):
~N
J S= 8.60 (s, 1 H), 7.59-7.51 (m, 2H), N
7.43-7.38 (m, 5H), 7.28 (d, 2H), (-)-enantiomer 5.25-5.18 (m, 1 H), 3.63-3.59 (m, 1 H), 2.80 (d, 1 H), 2.70 (q, 2H), 2.25-2.18 (m, 2H), 2.14-2.02 (m, 2H), 1.92-1.72 (m, 4H), 1.61-1.49 (m, 3H), 1.48-1.35 (m, 2H), 1.25 (t, 3 H).

155 H3C LC-MS (Method 8): R, = 1.87 min.;
O o OH m/z = 486 (M+H)+
N
'H-NMR (400 MHz, DMSO-d6):
N
N J b= 8.60 (s, 1 H), 7.59-7.51 (m, 2H), 7.43-7.38 (m, 5H), 7.28 (d, 2H), (+)-enantiomer 5.25-5.18 (m, 1 H), 3.63-3.59 (m, l H), 2.80 (d, 1 H), 2.70 (q, 2H), 2.25-2.18 (m, 2H), 2.14-2.02 (m, 2H), 1.92-1.72 (m, 4H), 1.61-1.49 (m, 3H), 1.48-1.35 (m, 2H), 1.25 (t, 3H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 156 ci LC-MS (Method 3): R, = 2.78 min.;
o o~oH m/z = 479 (M+H)+

o 'H-NMR (400 MHz, DMSO-d6):
J S= 8.60 (s, 1H), 7.55-7.49 (m, 6H), O N
7.56-7.39 (m, 3H), 5.15-5.04 (m, 1 H), 3.55 (s, 2H), 2.14 (d, l H), 2.02-1.90 (m, 2H), 1.75-1.67 (m, 1H), 1.30-1.15 (m, 4H), 1.14-0.95 (m, 2H).

157 HC-o F LC-MS (Method 8): Rt = 3.19 min.;
)ao~OH m/z = 491 (M+H)+.

O N I
O
N

158 H3c-O F LC-MS (Method 3): Rt = 1.68 min.;
O
m/z = 506 (M+H)+
ON OH
'H-NMR (400 MHz, DMSO-d6):
~ 6=8.60(s, 1H),7.71-7.68(m, 1H), N
7.66-7.60 (m, 1 H), 7.59-7.51 (m, enantiomer I 1H), 7.50-7.35 (m, 4H), 7.23-7.17 (m, 1 H), 5.95-5.86 (m, 1H), 5.32-5.21 (m, 1 H), 4.70-4.67 (m, 1 H), 3.90 (s, 2H), 2.86-2.78 (m, 1 H), 2.30-2.07 (m, 3H), 2.00 (s, 1 H), 1.95-1.86 (m, IH), 1.65-1.51 (m, 2H), 1.50-1.40 (m, 111), 1.40-1.29 (m, 2H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 159 H3C F LC-MS (Method 8): R, = 1.88 min.;
m/z = 504 (M+H)+
ON OH
'H-NMR (400 MHz, CDC13):

J b= 8.51 (s, 1H), 7.65-7.59 (m, 2H), N
7.36-7.31 (m, 3H), 7.30-7.18 (m, enantiomer 1 3H), 5.40-5.31 (m, 1H), 3.12 (br. s, IH), 2.86-2.73 (m, 1 H), 2.77 (q, 2H), 2.68-2.53 (m, 3H), 2.47 (br. s, 1H), 2.09 (br. s, IH), 1.83-1.68 (m, 4H), 1.51-1.40 (m, 2H), 1.30 (t, 3H), 1.25 (s, IH), 0.90-0.81 (m, IH).

160 ci LC-MS (Method 8): Rt = 1.81 min.;
_ O
m/z = 492 (M+H)+
ON OH
'H-NMR (400 MHz, CDC13):

J 6= 8.54 (s, 1H), 7.61-7.53 (m, 2H), O N
7.48 (d, 2H), 7.40 (d, 2H), 7.37-7.30 enantiomer I (m, 3H), 5.41-5.32 (m, 1H), 3.08 (br. s, 1 H), 2.76 (br. s, 1 H), 2.70-2.48 (m, 6H), 2.01 (br. s, 1 H), 1.85-1.68 (m, 4H), 1.46 (br. s, 1H), 1.26 (s, 1 H).

161 H3C-O LC-MS (Method 8): R, = 2.74 min.;
m/z = 461 (M+H)+
v _o kIN 0 'H-NMR (400 MHz, DMSO-d6):

1 ) b= 8.59 (s, I H), 7.59-7.51 (m, 2H), O N
7.44-7.32 (m, 5H), 7.05-6.98 (m, 2H), 5.62-5.55 (m, l H), 4.11 (s, I H), 3.71 (d, 2H), 2.14 (d, l H), 2.05-1.55 (m, 2H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 162 H3C-O LC-MS (Method 8): R, = 2.71 min.;
o oH m/z = 461 (M+H)+

~ 'H-NMR (400 MHz, CDC13):

NJ b= 8.50 (s, 1 H), 7.67-7.60 (m, 2H), 7.40-7.33 (m, 2H), 7.32-7.28 (m, 3H), 6.99-6.81 (m, 2H), 5.72-5.65 (m, 2H), 5.31 (s, 2H), 4.16 (br. s, 1H), 3.90 (s, 3H), 2.40-2.21 (m, 2H), 2.21-2.10 (m, 1H), 2.06-1.98 (m, 1H), 1.88-1.63 (m, 2H).

163 H3C-o LC-MS (Method 8): Rt = 2.72 min.;
'0' o/,,roH m/z = 461 (M+H)+

O 'H-NMR (400 MHz, DMSO-d6):
N
J 8= 8.58 (s, 1H), 7.59-7.51 (m, 2H), N
7.45-7.33 (m, 5H), 7.04-6.95 (m, 2H), 5.45-5.38 (m, 1H), 4.06-3.96 (m, 2H), 3.82 (s, 3H), 3.62 (s, IH), 2.15 (d, 1 H), 1.79-1.60 (m, 2H), 1.28 (s, 4H).

164 H3C-o LC-MS (Method 3): R, = 2.45 min.;
o o oH m/z = 461 (M+H)+
'~
o 'H-NMR (400 MHz, DMSO-d6):

0 ) s= 8.59 (s, 1 H), 7.59-7.52 (m, 2H), N
7.46-7.35 (m, 5H), 7.00 (d, 2H), 5.48-5.40 (m, 1 H), 4.04-3.97 (m, 1H), 3.91 (s, 2H), 3.82 (s, 2H), 2.39-2.28 (m, 2H), 1.98-1.89 (m, 2H), 1.84-1.76 (m, 1H), 1.75-1.62 (m, 3H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 165 H3C-o LC-MS (Method 3): Rt = 2.27 min.;
oH m/z = 460 (M+H)+
HN ~
0 'H-NMR (400 MHz, CDC13):
N
6=8.42(s, 1H),7.55(d,2H),7.40 (d, 2H), 7.31-7.26 (m, 3H), 7.08 (d, (+/-)-trans 2H), 4.66 (d, 1H), 4.61-4.53 (m, 1H), 4.10-4.00 (m, 3H), 3.91 (s, 3H), 2.29-2.17 (m, 2H), 1.95-1.85 (m, IH), 1.81-1.71 (m, 1H), 1.50-1.41 (m, 1H), 1.30-1.18 (m, 2H).

166 H3C-0 LC-MS (Method 3): R, = 2.25 min.;
oH m/z = 460 (M+H)+
HNO
o 'H-NMR (400 MHz, DMSO-d6):

0 N J b= 8.41 (s, 1 H), 7.52 (d, 2H), 7.39 -(d, 2H), 7.30-7.24 (m, 3H), 7.05 (d, (+/-)-cis 2H), 5.07 (d, 1 H), 4.69-4.60 (m, I H), 4.09-4.03 (m, 1 H), 3.90 (s, 3H), 3.88 (d, 2H), 2.20-2.04 (m, 2H), 1.81-1.74 (m, 2H), 1.62-1.48 (m, 3H).

167 H3C-o LC-MS (Method 6): R, = 2.42 min.;
HN ~ ~o oH m/z = 460 (M+H)+

0 'H-NMR (400 MHz, DMSO-d6):
N
) b= 12.62 (br. s, 1 H), 8.32 (s, 1H), 7.48-7.40 (m, 4H), 7.39-7.29 (m, (-)-enantiomer 3H), 7.11 (d, 2H), 5.31 (d, 1H), 4.61-4.52 (m, 1 H), 4.00-3.94 (m, 1H), 3.83 (s, 3H), 3.69 (s, 2H), 2.00-1.88 (m, 2H), 1.70-1.61 (m, 2H), 1.54-1.35 (m, 2H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 168 H3C-O LC-MS (Method 6): Rt = 2.42 min.;
oH m/z = 460 (M+H)+
HN O
0 'H-NMR (400 MHz, DMSO-d6):
~ b= 12.62 (br. s, 1 H), 8.32 (s, 1 H), 7.48-7.40 (m, 4H), 7.39-7.29 (m, (+)-enantiomer 3H), 7.11 (d, 2H), 5.31 (d, IH), 4.61-4.52 (m, IH), 4.00-3.94 (m, 1 H), 3.83 (s, 3H), 3.69 (s, 2H), 2.00-1.88 (m, 2H), 1.70-1.61 (m, 2H), 1.54-1.35 (m, 2H).

169 H3C-o LC-MS (Method 8): R, = 2.55 min.;
HNe 0 oH m/z = 460 (M+H)+

0 'H-NMR (400 MHz, DMSO-d6):
N
S= 12.60 (br. s, 1H), 8.38 (s, 1H), N
7.51-7.45 (m, 4H), 7.40-7.30 (m, (+)-enantiomer 3H), 7.27 (d, 2H), 4.81 (d, 1 H), 4.52-3.90 (m, 1H), 3.98-3.90 (m, 3H), 3.88 (s, 3H), 2.09-1.99 (m, 2H), 1.82-1.71 (m, IH), 1.67-1.55 (m, IH), 1.45-1.35 (m, 1H), 1.21-1.11 (m, IH).

170 H3C-o LC-MS (Method 8): R, = 2.55 min.;
~ oH m/z = 460 (M+H)+
HN"' O
0 'H-NMR (400 MHz, DMSO-d6):
N
~ 8= 12.60 (br. s, 1 H), 8.3 8 (s, l H), 7.51-7.45 (m, 4H), 7.40-7.30 (m, (-)-enantiomer 3H), 7.27 (d, 2H), 4.81 (d, 1 H), 4.52-3.90 (m, 1H), 3.98-3.90 (m, 3H), 3.88 (s, 3H), 2.09-1.99 (m, 2H), 1.82-1.71 (m, IH), 1.67-1.55 (m, IH), 1.45-1.35 (m, 1H), 1.21-1.11 (m, 1 H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 171 H3C LC-MS (Method 3): R, = 2.66 min.;
oH m/z = 457 (M+H)+
o 0 'H-NMR (400 MHz, DMSO-d6):
~~ b= 12.65 (s, IH), 8.62 (s, 1H), 7.56 o N (d, 2H), 7.48-7.31 (m, 5H), 7.28 (d, (+I-)-cis 2H), 6.14 (dd, 2H), 5.89-5.80 (m, 1H), 4.55-4.50 (m, IH), 3.97 (s, 2H), 2.83 (q, 2H), 1.96-1.88 (m, IH), 1.53 (td, IH), 1.22 (t, 3H).

172 H3C LC-MS (Method 8): Rt = 2.92 min.;
''~ oH m/z = 457 (M+H)+

o o 'H-NMR (400 MHz, DMSO-d6):
~~ S= 8.60 (s, 1 H), 7.54 (d, 2H), 7.43-0 N 7.38 (m, 5H), 7.28 (d, 2H), 6.20 (d, (-)-enantiomer 1 H), 6.00 (d, 1 H), 5.82-5.78 (m, 1 H), 4.59-4.51 (m, 1 H), 3.51 (d, 2H), 2.82-2.71 (m, 1 H), 2.69 (q, 2H), 1.52-1.44 (m, 1H), 1.22 (t, 3H), 1.06 (t, 1 H).

173 H3C LC-MS (Method 3): R, = 2.72 min.;
~ pH m/z = 459 (M+H)+

0 'H-NMR (400 MHz, DMSO-d6):
"Z N
~ s= 8.59 (s, 1 H), 7.55 (d, 2H), 7.45-7.36 (m, 5H), 7.29 (d, 2H), 5.46-(-)-enantiomer 5.39 (m, 1H), 4.03-3.96 (m, 1H), 3.50 (d, 2H), 2.70 (q, 2H), 2.38-2.25 (m, 1 H), 2.22-2.12 (m, 1 H), 1.95-1.74 (m, 2H), 1.71-1.58 (m, 3H), 1.25 (t, 3H).

BHC 07 1 039-Foreign countries Example Structure Analytical data 174 H3c 'H-NMR (400 MHz, DMSO-d6):
ooe~o oH S= 12.55 (s, 1H), 8.59 (s, 1H), 7.55 ~ (d, 2H), 7.45-7.36 (m, 5H), 7.29 (d, N
I~ 2H), 5.46-5.39 (m, 1H), 4.03-3.96 o N (m, 1H), 3.88 (d, 2H), 2.70 (q, 2H), (+)-enantiomer 2.38-2.25 (m, 1H), 1.95-1.74 (m, 2H), 1.71-1.58 (m, 3H), 1.25 (t, 3H).
175 H3c LC-MS (Method 8): R, = 3.13 min.;
'.ao,,,yoH m/z = 457 (M+H)+

o 'H-NMR (400 MHz, DMSO-d6):
N
N) 8= 12.65 (s, 1 H), 8.61 (s, 1 H), 7.60-7.52 (m, 2H), 7.47-7.30 (m, 5H), (-)-enantiomer 7.27 (d, 2H), 6.28 (d, 1 H), 6.15 (d, 1 H), 6.11 (d, 1 H), 4.70-4.63 (m, I H), 4.02 (s, 2H), 2.70 (q, 2H), 2.20-2.10 (m, l H), 2.05-1.98 (m, 1H), 1.24 (t, 3H).

176 H3c LC-MS (Method 12): R, = 2.66 HN min.; m/z = 456 (M+H)+
a oH

o 'H-NMR (400 MHz, DMSO-d6):
N
N) 8= 12.60 (s, 1 H), 8.39 (s, 1 H), 7.50 (d, 2H), 7.47-7.30 (m, 7H), 6.06 (d, (-)-enantiomer 1 H), 5.90 (d, I H), 5.22-5.16 (m, 1 H), 4.65 (d, 1 H), 4.60-4.54 (m, 1H), 4.00 (s, 2H), 2.71 (q, 2H), 2.20-2.11 (m, 1 H), 1.67-1.58 (m, 1 H), 1.23 (t, 3H).

Example 177 tert-Butyl [(3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate (rac. mixture of diastereomers) BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 0,- ao~ )<CH3 o NJ
F
At 70 C, 1.4 ml of an 11.25 N aqueous sodium hydroxide solution are added to a solution of 700 mg (1.62 mmol) of 3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol in 15 ml of toluene. After addition of 55 mg (0.16 mmol) of tetra-n-butylammonium hydrogensulfate and 631 mg (3.24 mmol) of tert-butyl bromoacetate, the reaction mixture is stirred at 70 C for 30 hours. A further 330 mg (1.69 mmol) of tert-butyl bromoacetate are then added, and the reaction mixture is stirred at 70 C for another 14 hours. After cooling to room temperature, the mixture is adjusted to pH 7 using conc. hydrochloric acid. The mixture is extracted with dichloromethane. The organic phase is washed with sat. sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure.
The residue is purified by preparative RP-HPLC (mobile phase: water/acetonitrile gradient).
This gives 632 mg (69% of theory) of the desired product as a racemic mixture of diastereomers.

LC-MS (Method 8): R, = 3.47 min.; m/z = 547 (M+H)+

'H-NMR (400 MHz, DMSO-d6): [Minor stereoisomer in brackets] 8= 8.62 (s, 1 H), 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, 1 H), 3.99 (d, 2H), [3.89, d, 2H], 3.47-3.40 (m, 1 H), 2.64 (q, 2H), 2.46-2.42 (m, 1 H), 2.09-2.05 (m, 1 H), 1.99-1.93 (m, 1 H), 1.78-1.73 (m, 1 H), 1.41 (s, 9H), 1.30-1.12 (m, 4H), 1.20 (t, 3H).

Example 178 tert-Butyl [(3-{ [5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate (cis-enantiomer 1) BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 O C H O O~ )<CH3 o F
600 mg (1.10 mmol) of tert-butyl [(3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate (rac. mixture of diastereomers) give, after chromatographic separation of the enantiomers on a chiral phase [column: Daicel Chiralpak AD-H, 5 [im, 250 mm x 20 mm; flow rate: 15 ml/min; detection: 220 nm; temperature: 30 C; mobile phase: 93% isohexane / 7% ethanol], 236 mg (39% of theory) of the pure cis-enantiomer 1.

HPLC [column: Daicel Chiralpak AD-H, 5 m, 250 mm x 4.6 mm; flow rate: 1 ml/min; detection:
215 nm; temperature: 35 C; mobile phase: 93% isohexane / 7% ethanol]: Rt =
6.64 min.

'H-NMR (400 MHz, DMSO-d6): 8= 8.62 (s, 1 H), 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, 1 H), 2.64 (q, 2H), 2.48-2.44 (m, 1 H), 2.09-2.05 (m, l H), 1.98-1.94 (m, 1 H), 1.78-1.73 (m, 1 H), 1.41 (s, 9H), 1.30-1.10 (m, 4H), 1.20 (t, 3H).
Example 179 tert-Butyl [(3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate (cis-enantiomer 2) ~ )<CH3 _ o F

600 mg (1.10 mmol) of tert-butyl [(3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}cyclohexyl)oxy]acetate (rac. mixture of diastereomers) give, after chromatographic separation of the enantiomers on a chiral phase [column: Daicel Chiralpak AD-H, 5 m, 250 mm x BHC 07 1 039-Foreign countries 20 mm; flow rate: 15 ml/min; detection: 220 nm; temperature: 30 C; mobile phase: 93% isohexane / 7% ethanol], 263 mg (43% of theory) of the pure cis-enantiomer 2.

HPLC [column: Daicel Chiralpak AD-H, 5 [tm, 250 mm x 4.6 mm; flow rate: 1 ml/min; detection:
215 nm; temperature: 35 C; mobile phase: 93% isohexane / 7% ethanol]: R, =
8.06 min.

iH-NMR (400 MHz, DMSO-d6): 8= 8.62 (s, 1H), 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, 1 H), 2.64 (q, 2H), 2.48-2.44 (m, 1 H), 2.09-2.05 (m, 1 H), 1.98-1.94 (m, 1 H), 1.78-1.73 (m, 1 H), 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-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy} piperidin-1-yl]butyrate H 3 c 0~~~'' N 0I-ICH3 N

F

1677 mg (12.1 mmol) of potassium carbonate are added to a solution of 2250 mg (4.9 mmol) of 5-(4-ethylphenyl)-6-(2-fluorophenyl)-4-[(3R)-piperidin-3-yloxy]furo[2,3-d]pyrimidine in 100 ml of THF and 10 ml of acetonitrile. 0.74 ml (1054 mg, 5.8 mmol) of methyl 4-bromobutyrate and 72 mg (0.19 mmol) of tetra-n-butylammonium iodide are then added. The reaction mixture is stirred at 80 C for 13 hours. After cooling to room temperature, the residue is filtered off and washed with THF, the filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:2).
This gives 2005 mg (75% of theory) of the target compound.

LC-MS (Method 12): Rt = 1.82 min.; m/z = 518 (M+H)+

'H-NMR (300 MHz, DMSO-d6): b= 8.63 (s, 1 H), 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, 1H), 1.67-1.59 (m, 3H), 1.44-1.42 (m, 2H), 1.19 (t, 3H).

BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 Example 181 4-[(3R)-3- { [5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy} piperidin-1-yl]-butyric acid H 3 c O
0\\\ N OH
N
o NJ
F

500 mg (0.97 mmol) of methyl 4-[(3R)-3-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl]butyrate are dissolved in 10 ml of dioxane, and 2.9 ml of a I N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 16 hours.
2.9 ml of I N hydrochloric acid are then added, and the mixture is extracted with 20 ml of ethyl acetate. The organic phase is separated off, dried over sodium sulfate, filtered and concentrated.
The residue is purified by preparative RP-HPLC (mobile phase:
water/acetonitrile gradient with 0.1% formic acid). The product obtained is taken up in 10 ml of ethyl acetate and washed twice with in each case 10 ml of a I M aqueous sodium bicarbonate solution. The organic phase is separated off, dried over sodium sulfate, filtered and concentrated. This gives 309 mg (62% of theory) of the target compound.

LC-MS (Method 3): R, = 1.74 min.; m/z = 504 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 12.12 (s, 1H), 8.62 (s, 1H), 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, 1 H), 2.63 (q, 2H), 2.49-2.47 (m, 1 H), 2.33-2.25 (m, 4H), 2.19 (t, 2H), 1.94-1.91 (m, 1H), 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-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl]-butyric acid formate BHC 07 1 039-Foreign countries O
O\\\, N ""'~OH
N x HC02H
O ~ N.) F

500 mg (0.97 mmol) of methyl 4-[(3R)-3-{[5-(4-ethylphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}piperidin-1-yl]butyrate are dissolved in 10 ml of dioxane, and 2.9 ml of a I N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 16 hours.
2.9 ml of 1 N hydrochloric acid are then added, and the mixture is extracted with 20 ml of ethyl acetate. The organic phase is separated off, dried over sodium sulfate, filtered and concentrated.
The residue is purified by preparative RP-HPLC (mobile phase:
water/acetonitrile gradient with 0.1 % formic acid). This gives 411 mg (77% of theory) of the target compound.

LC-MS (Method 8): R, = 1.88 min.; m/z = 504 (M-HCO2H+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.62 (s, IH), 8.14 (s, 1H), 7.56-7.51 (m, 2H), 7.36-7.29 (m, 4H), 7.19 (d, 2H), 5.33 (t, 1H), 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, I H), 1.66-1.58 (m, 3H), 1.48-1.34 (m, 2H), 1.19 (t, 3H).

Example 183 Methyl 4-[(3R)-3-{ [6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-yl]oxy}piperidin-l-yl]butyrate H3C~0 O
,' N O~CH3 ~ J

F
411 mg (3.0 mmol) of potassium carbonate are added to a suspension of 500 mg (1.2 mmol) of 6-(2-fluorophenyl)-5-(4-methoxyphenyl)-4-[(3R)-piperidin-3-yloxy]furo[2,3-d]pyrimidine in 10 ml BHC 07 1 039-Foreign countries of THF. 0.18 ml (259 mg, 1.4 mmol) of inethyl4-bromobutyrate and 17 mg (0.05 mmol) of tetra-n-butylammonium iodide are then added. The reaction mixture is stirred at 80 C
for 13 hours. 10 ml of DMF are then added, and the mixture is stirred at 70 C for another 13 hours. After addition of in each case 10 ml of water, I N hydrochloric acid and ethyl acetate, the organic phase is separated off and concentrated under reduced pressure and the residue is purified by preparative RP-HPLC
(mobile phase: water/acetonitrile gradient). This gives 146 mg (22% of theory) of the target compound.

LC-MS (Method 13): R, = 2.77 min.; m/z = 520 (M+H)+

'H-NMR (400 MHz, DMSO-d6): b= 8.61 (s, 1 H), 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, 1H), 3.53 (s, 3H), 2.81-2.79 (m, 1H), 2.48-2.42 (m, 1 H), 2.32-2.18 (m, 6H), 2.00-1.92 (m, l H), 1.67-1.60 (m, 3H), 1.45-1.41 (m, 2H).

Example 184 Methyl 4-[(3R)-3- { [6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]oxy}piperidin-l-yl]butyrate formate H3C~0 ~ O
~ ~ 0N O,CH3 ~ ~ ~
x HCO2H
O N%

F

52 mg (0.38 mmol) of potassium carbonate are added to 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. 0.02 ml (33 mg, 0.18 mmol) of methyl 4-bromobutyrate and 2 mg (0.01 mmol) of tetra-n-butylammonium iodide are then 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 (mobile phase: water/acetonitrile gradient with 0.1%
formic acid). This gives 40 mg (42% of theory) of the target compound.

LC-MS (Method 3): R, = 1.75 min.; m/z = 520 (M+H)+

'H-NMR (300 MHz, DMSO-d6): b= 8.62 (s, IH), 8.15 (s, 1 H), 7.53-7.51 (m, 2H), 7.35 (d, 2H), 7.32-7.28 (m, 2H), 6.90 (d, 2H), 5.5-5.30 (rn, IH), 3.76 (s, 3H), 3.52 (s, 3H), 2.82-2.79 (m, IH), BHC 07 1 039-Foreign countries 2.36-2.24 (m, 5H), 1.94-1.88 (m, 1H), 1.67-1.60 (m, 2H), 1.45-1.41 (m, 2H).
Example 185 4-[(3R)-3- { [6-(2-Fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]oxy} piperidin-l-yl]butyric acid H3C'O

O
0~~~ N OH
N
o F

113 mg (0.20 mmol) of methyl 4-[(3R)-3-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]oxy}piperidin-1-yl]butyrate are dissolved in 3 ml of dioxane, and 0.8 ml of a 1 N
aqueous sodium hydroxide solution is added. The mixture is stirred at room temperature for 16 hours, 0.8 ml of I N hydrochloric acid are then added, and 10 ml of ethyl acetate are added. The organic phase is separated off, dried over sodium sulfate, filtered and concentrated. This gives 95 mg (90% of theory) of the target compound.

LC-MS (Method 8): R, = 1.70 min.; m/z = 504 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 12.20 (br. s, 1 H), 8.63 (s, 1 H), 7.56-7.51 (m, 2H), 7.37-7.29 (m, 4H), 6.91 (d, 2H), 5.35 (t, lH), 3.76 (s, lH), 2.99-2.94 (m, 1H), 2.64-2.62 (m, 1H), 2.40-2.32 (m, 4H), 2.20 (t, 2H), 2.02-1.98 (m, l H), 1.67-1.63 (m, 3H), 1.43-1.39 (m, 2H).

Example 186 { [(1 S,3R)-3- { [5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy} cyclohexyl]-oxy}acetic acid BHC 07 1 039-Foreign countries CA 02685134 2009-10-23 0 0.,~ O,,,-~OH
N O
o NJ
F

ml of 4 N hydrogen chloride in dioxane are added to 237 mg (0.43 mmol) of tert-butyl { [(1 S,3R)-3- { [5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-oxy}cyclohexyl]oxy}acetate, and the mixture is stirred at room temperature for 16 hours. The 5 solvent is removed under reduced pressure, and the residue is then purified by preparative RP-HPLC (mobile phase: water/acetonitrile gradient). This gives 132 mg (62% of theory) of the target compound.

LC-MS (Method 8): R, = 3.10 min.; m/z = 491 (M+H)+

'H-NMR (400 MHz, DMSO-d6): S= 12.54 (s, 1H), 8.63 (s, 1H), 7.56-7.52 (m, 2H), 7.34-7.28 (m, 10 4H), 7.20 (d, 2H), 5.22-5.16 (m, 1H), 4.03 (s, 2H), 3.48-3.43 (m, lH), 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, 3 H).

[U]p20 = +62 , c = 0.525, CHC13.
Example 187 { [(1 R,3S)-3-{ [5-(4-Ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]oxy} cyclohexyl]-oxy}acetic acid O O OH
O
N
O
N~
F

10 m] of 4N hydrogen chloride in dioxane are added to 215 mg (0.39 mmol) of tert-butyl {[(1R,3S)-3-{[5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4-yl]-BHC 07 1 039-Foreign countries oxy}cyclohexyl]oxy}acetate, and the mixture is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure, and the residue is then purified by preparative RP-HPLC (mobile phase: water/acetonitrile gradient). This gives 128 mg (66% of theory) of the target compound.

LC-MS (Method 8): R, = 3.11 min.; m/z = 491 (M+H)+

'H-NMR (300 MHz, DMSO-d6): 8= 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, 1 H), 4.03 (s, 2H), 3.48-3.43 (m, 1 H), 2.63 (q, 2H), 2.12-2.06 (m, 1 H), 2.00-1.96 (m, 1 H), 1.77-1.74 (m, 1 H), 1.29-1.08 (m, 4H), 1.18 (t, 3H).

[a]D20 = -57 , c = 0.660, CHC13.
Example 188 tert-Butyl { [ 1-( { [5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy} methyl)cyclobutyl]methoxy} acetate H3C~0 O OY )<CH

o J

0.6 ml of an 11.25 N aqueous sodium hydroxide solution is added to a solution of 285 mg (0.68 mmol) of [1-({[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)cyclo-butyl]methanol in 5 ml of toluene. After addition of 23 mg (0.07 mmol) of tetra-n-butylammonium hydrogensulfate and 267 mg (1.37 mmol) of tert-butyl bromoacetate, the reaction mixture is stirred at 70 C for 20 h. After cooling to room temperature, the pH is adjusted to 7 using conc.
hydrochloric acid. The mixture is extracted three times with in each case 20 ml of dichloromethane. The combined organic extracts are washed with sat. aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The crude product is purified by preparative RP-HPLC (gradient:
water/acetonitrile).
This gives 260 mg (72% of theory) of the desired product.

LC-MS (Method 8): R, = 3.38 min.; m/z = 531 (M+H)+

'H-NMR (400 MHz, DMSO-d6): 8= 8.58 (s, 1H), 7.56-7.54 (m, 2H), 7.42-7.37 (m, 5H), 7.04-7.00 BHC 07 1 039-Foreign countries (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 {[1-({[5-(4-Methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)cyclobutyl]methoxy}-acetic acid OH
O O~

O
N

O N/

237 mg (0.45 mmol) of tert-butyl {[1-({[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}methyl)cyclobutyl]methoxy}acetate are dissolved in I ml of dioxane, 2 ml of 4 N hydrogen chloride in dioxane are added and the mixture is stirred at RT for 16 h. The reaction solution is concentrated under reduced pressure, and the residue is then purified by preparative RP-HPLC
(gradient: water/acetonitrile). This gives 180 mg (85% of theory) of the desired product.

LC-MS (Method 8): R, = 2.84 min.; m/z = 475 (M+H)+

' H-NMR (400 MHz, DMSO-d6): b= 12.49 (br. s, 1 H), 8.57 (s, I H), 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).

BHC 07 1 039-Foreign countries B. Assessment of pharmacological efficacy The pharmacological action of the compounds according to the invention can be demonstrated in the following assays:

B-1. Studies of binding to prostacyclin receptors (IP receptors) of human thromboc~te membranes Thrombocyte membranes are obtained by centrifuging 50 ml human blood (Buffy coats with CDP
Stabilizer, from Maco Pharma, Langen) for 20 min at 160 x g. Remove the supernatant (platelet-rich plasma, PRP) and then centrifuge again at 2000 x g for 10 min at room temperature.
Resuspend the sediment in 50 mM tris(hydroxymethyl)aminomethane, which has been adjusted to a pH of 7.4 with 1 N hydrochloric acid, and store at -20 C overnight. On the next day, centrifuge the suspension at 80 000 x g and 4 C for 30 min. Discard the supernatant.
Resuspend the sediment in 50 mM tris(hydroxymethyl)aminomethane/hydrochloric acid, 0.25 mM ethylene diamine tetraacetic acid (EDTA), pH 7.4, and then centrifuge once again at 80 000 x g and 4 C for 30 min.
Take up the membrane sediment in binding buffer (50 mM tris(hydroxymethyl)-aminomethane/hydrochloric acid, 5 mM magnesium chloride, pH 7.4) and store at -70 C until the binding test.

For the binding test, incubate 3 nM 3H-Iloprost (592 GBq/mmol, from AmershamBioscience) for 60 min with 300-1000 g/ml human thrombocyte membranes per charge (max. 0.2 ml) in the presence of the test substances at room temperature. After stopping, add cold binding buffer to the membranes and wash with 0.1% bovine serum albumin. After adding Ultima Gold Scintillator, quantify the radioactivity bound to the membranes using a scintillation counter. The nonspecific binding is defined as radioactivity in the presence of I p.M Iloprost (from Cayman Chemical, Ann Arbor) and is as a rule < 25% of the bound total radioactivity. The binding data (IC50 values) are determined using the program GraphPad Prism Version 3.02.

Representative results for the compounds according to the invention are shown in Table 1:

BHC 07 1 039-Foreign countriescA 02685134 2009-10-23 Table I

Example No. IC50 [nM]

B-2. IP-receptor stimulation on whole cells The IP-agonistic action of test substances is determined by means of the human erythroleukaemia BHC 07 1 039-Foreign countries line (HEL), which expresses the IP-receptor endogenously [Murray, R., FEBS
Letters 1989, 1:
172-174]. For this, the suspension cells (4 x 107 cells/mi) are incubated with the particular test substance for 5 minutes at 30 C in buffer [10 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid) / PBS (phosphate-buffered saline, from Oxoid, UK)], 1 mM
calcium chloride, 1 mM magnesium chloride, 1 mM IBMX (3-isobutyl-l-methylxanthine), pH 7.4.
Next, the reaction is stopped by addition of 4 C cold ethanol and the charges are stored for a further 30 minutes at 4 C. Then the samples are centrifuged at 10 000 x g and 4 C. The resultant supernatant is discarded and the sediment is used for determination of the concentration of cyclic adenosine monophosphate (cAMP) in a commercially available cAMP-radioimmunoassay (from IBL, Hamburg). In this test, IP agonists lead to an increase in cAMP
concentration, but IP
antagonists have no effect. The effective concentration (EC50 value) is determined using the program GraphPad Prism Version 3.02.

B-3. Inhibition of thrombocyte aggregation in vitro Inhibition of thrombocyte aggregation is determined using blood from healthy test subjects of both sexes. Mix 9 parts blood with one part 3.8% sodium citrate solution as coagulant. Centrifuge the blood at 900 rev/min for 20 min. Adjust the pH value of the platelet-rich plasma obtained to pH
6.5 with ACD solution (sodium citrate/citric acid/glucose). Then remove the thrombocytes by centrifugation, take up in buffer and centrifuge again. Take up the thrombocyte deposit in buffer and additionally resuspend with 2 mmol/I calcium chloride.

For the measurements of aggregation, incubate aliquots of the thrombocyte suspension with the test substance for 10 min at 37 C. Next, aggregation is induced by adding ADP
and is 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. Measurement of blood pressure of anaesthetized rats Anaesthetize male Wistar rats with a body weight of 300-350 g with thiopental (100 mg/kg i.p.).
After tracheotomy, catheterize the arteria femoralis for blood pressure measurement. Administer the test substances as solution, orally by oesophageal tube or intravenously via the femoral vein in a suitable vehicle.

B-5. PAH model in the anaesthetized dog In this animal model of pulmonary arterial hypertension (PAH), mongrel dogs having a body weight of about 25 kg are used. Narcosis is induced by slow i.v.
administration of 25 mg/kg of sodium thiopental (Trapanal ) and 0.15 mg/kg of alcuronium chloride (Alloferin ) and maintained BHC 07 1 039-Foreign countries during the experiment by continuous infusion of 0.04 mg/kg/h of Fentanyl , 0.25 mg/kg/h of droperidol (Dehydrobenzperidol ) and 15 g/kg/h of alcuronium chloride (Alloferin ). Reflectory effects on the pulse by lowering of the blood pressure are kept to a minimum by autonomous blockage [continuous infusion of atropin (about 10 g/kg/h) and propranolol (about 20 g/kg/h)].
After intubation, the animals are ventilated using a ventilator with constant tidal volume such that an end-tidal COZ concentration of about 5% is reached. Ventilation takes place with ambient air enriched with about 30% oxygen (normoxa). For measuring the hemodynamic parameters, a liquid-filled catheter is implanted into the femoralis artery for measuring the blood pressure. A
double-lumiger Swan-Ganz catheter is introduced via the jugulara vein into the pulmonary artery (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venus pressure). The left-ventricular pressure is measured following introduction of a micro-tip catheter (Millar Instruments) via the carotis artery into the left ventricle, and from this, the dP/dt value is derived as a measure for the contractility. Substances are administered i.v. via the femoralis vein. The hemodynamic signals are recorded and evaluated using pressure sensors/amplifiers and PONEMAH as data acquisition software.

To induce acute pulmonary hypertension, the stimulus used is either hypoxia or continuous infusion of thromboxan A2 or a thromboxan A2 analog. Acute hypoxia is induced by gradually reducing the oxygen in the ventilation air to about 14%, such that the mPAP
increases to values of > 25 mm Hg. If the stimulus used is a thromboxan A2 analog, 0.21-0.32 g/kg/min of U-46619 [9,11-dideoxy-9a,11 a-epoxymethanoprostaglandin FZa (from Sigma)] are infused to increase the mPAP to > 25 mm Hg.

B-6. PAH model in anaesthetized Gottingen Minipig In this animal model of pulmonary arterial hypertension (PAH), gottingen minipigs having a body weight of about 25 kg are used. Narcosis is induced by 30 mg/kg of ketamine (Ketavet ) i.m., followed by i.v. administration of 10 mg/kg of sodium thiopental (Trapanal );
during the experiment, it is maintained by inhalation narcosis using enfluran (2-2.5%) in a mixture of ambient air enriched with about 30-35% oxygen / N20 (1:1.5). For measuring the hemodynamic parameters, a liquid-filled catheter is implanted into the femoralis artery for measuring the blood pressure. A double-lumiger Swan-Ganz catheter is introduced via the jugulara vein into the pulmonary artery (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venus pressure). The left-ventricular pressure is measured following introduction of a micro-tip catheter (Millar Instruments) via the carotis artery into the left ventricle, and from this, the dP/dt value is derived as a measure for the contractility. Substances are administered i.v. via the femoralis vein. The hemodynamic signals are recorded and evaluated using pressure sensors/amplifiers and PONEMAH as data acquisition software.

BHC 07 1 039-Foreign countries To induce acute pulmonary hypertension, the stimulus used is continuous infusion of a thromboxan A2 analog. Here, 0.12-0.14 g/kg/min of U-46619 [9,11-dideoxy-9a,11 a-epoxy-methanoprostaglandin Fza (from Sigma)] are infused to increase the mPAP to >
25 mm Hg.

BHC 07 1 039-Foreign countries C. Exemplary embodiments of pharmaceutical compositions The compounds of the invention can be converted into pharmaceutical preparations in the following ways:

Tablet:
Composition:

100 mg of the compound of the invention, 50 mg of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (from 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% strength solution (m/m) of the PVP in water. The granules are mixed with the magnesium stearate for 5 minutes after drying. This mixture is compressed with a conventional tablet press (see above for format of the tablet). A guideline compressive force for the compression is 15 kN.

Suspension which can be administered orally:
Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of the compound of the invention.
Production:

The Rhodigel is suspended in ethanol, and the compound of the invention is added to the suspension. The water is added while stirring. The mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.

BHC 07 1 039-Foreign countries Solution which can be administered orally:

Composition:
500 mg of the compound of the invention, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. 20 g of oral solution correspond to a single dose of 100 mg of the compound according to the invention.

Production:
The compound of the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process is continued until the compound according to the invention has completely dissolved.

i.v. Solution:

The compound of the invention is dissolved in a concentration below the saturation solubility in a physiologically tolerated solvent (e.g. isotonic saline solution, 5% glucose solution and/or 30%
PEG 400 solution). The solution is sterilized by filtration and used to fill sterile and pyrogen-free injection containers.

Claims (12)

1. The use of a compound of the formula (I) in which A represents O, S or N-R4, where R4 represents hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl or (C4-C7)-cycloalkenyl, L1 represents a bond or represents (C1-C4)-alkanediyl, the ring Q represents (C3-C7)cycloalkyl, (C4-C7)-cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (C1-C4)-alkyl, trifluoromethyl, hydroxy, (C1-C4)-alkoxy, trifluoromethoxy, amino, mono-(C1-C4)-alkylamino and/or di-(C1-C4)-alkylamino, where (C1-C4)-alkyl for its part may be substituted by hydroxy, (C1-C4)-alkoxy, amino, mono- or di-(C1-C4)-alkylamino, L2 represents (C1-C4)-alkanediyl which is mono- or disubstituted by fluorine and in which one methylene group may be replaced by O or N-R5, where R5 represents hydrogen, (C1-C6)-alkyl or (C3-C7)-cycloalkyl, or represents (C2-C4)-alkenediyl, Z represents a group of the formula in which # represents the point of attachment to the group L2 and R6 represents hydrogen or (C1-C4)-alkyl, R1 and R2 independently of one another represent a substituent selected from the group consisting of halogen, cyano, nitro, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C4)-alkynyl, (C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, (C1-C6)-alkylthio, (C1-C6)-acyl, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino and (C1-C6)-acylamino, where (C1-C6)-alkyl and (C1-C6)-alkoxy for their part may each be substituted by cyano, hydroxy, (C1-C4)-alkoxy, (C1-C4)-alkylthio, amino, mono- or di-(C1-C4)-alkylamino, or two radicals R1 and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O-, -O-CF2-O-, -O-CH2-CH2-O- or -O-CF2-CF2-O-, n and o independently of one another represent the number 0, 1, 2 or 3, where, if R1 or R2 is present more than once, their meanings may in each case be identical or different, and R3 represents hydrogen, (C1-C4)-alkyl or cyclopropyl, or one of its salts, solvates or solvates of the salts for preparing a medicament for the treatment and/or prophylaxis of pulmonary arterial hypertension and other forms of pulmonary hypertension.

2. The use as claimed in claim 1 of a compound of the formula (I) as defined in claim 1, in which A represents O, S or N-R4, where R4 represents hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl or (C4-C7)-cycloalkenyl, L1 represents a bond or represents (C1-C4)-alkanediyl, the ring Q represents (C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (C1-C4)-alkyl, trifluoromethyl, hydroxy, (C1-C4)-alkoxy, trifluoromethoxy, amino, mono-(C1-C4)-alkylamino and/or di-(C1-C4)-alkylamino, where (C1-C4)-alkyl for its part may be substituted by hydroxy, (C1-C4)-alkoxy, amino, mono- or di-(C1-C4)-alkylamino, L2 represents (C1-C4)-alkanediyl which is mono- or disubstituted by fluorine and in which one methylene group may be replaced by O or N-R5, where R5 represents hydrogen, (C1-C6)-alkyl or (C3-C7)-cycloalkyl, or represents (C2-C4)-alkenediyl, Z represents a group of the formula in which # represents the point of attachment to the group L2 and R6 represents hydrogen or (C1-C4)-alkyl, R1 and R2 independently of one another represent a substituent selected from the group consisting of halogen, cyano, nitro, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C4)-alkynyl, (C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C6)-alkoxy, trifluoromethyl, trifluoromethoxy, (C1-C6)-alkylthio, (C1-C6)-acyl, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino and (C1-C6)-acylamino, where (C1-C6)-alkyl and (C1-C6)-alkoxy for their part may each be substituted by hydroxy, (C1-C4)-alkoxy, amino, mono- or di-(C1-C4)-alkylamino, or two radicals R1 and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O-, -O-CF2-O-, -O-CH2-CH2-O- or -O-CF2-CF2-O-, n and o independently of one another represent the number 0, 1, 2 or 3, where, if R1 or R2 is present more than once, their meanings may in each case be identical or different, and R3 represents hydrogen, (C1-C4)-alkyl or cyclopropyl, or one of its salts, solvates or solvates of the salts.

3. The use as claimed in claim 1 of a compound of the formula (I) as defined in claim 1 or 2, in which A represents O or N-R4, where R4 represents hydrogen, (C1-C4)-alkyl or (C3-C6)-cycloalkyl, L1 represents a bond or represents (C1-C3)-alkanediyl, the ring Q represents (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, a 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (C1-C3)-alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and/or diethylamino, where (C1-C3)-alkyl for its part may be substituted by hydroxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino or diethylamino, L2 represents (C1-C3)-alkanediyl which may be mono- or disubstituted by fluorine, represents (C2-C3)-alkenediyl or represents a group of the formula *-M-CR7R8-, *-M-CH2-CR7R8- or *-CH2-M-CR7R8-, where * represents the point of attachment to the ring Q, M represents O or N-R5, where R5 represents hydrogen, (C1-C3)-alkyl or cyclopropyl, and R7 and R8 independently of one another represent hydrogen or fluorine, Z represents a group of the formula in which # represents the point of attachment to the group L2 and R6 represents hydrogen, methyl or ethyl, R1 and R2 independently of one another represent a substituent selected from the group consisting of fluorine, chlorine, cyano, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, (C1-C4)-alkoxy, trifluoromethyl, trifluorometh-oxy, (C1-C4)-alkylthio, (C1-C5)-acyl, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino and (C1-C4)-acylamino, or two radicals R1 and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O- or -O-CF2-O-, n and o independently of one another represent the number 0, 1, 2 or 3, where, if R1 or R2 is present more than once, their meanings may in each case be identical or different, and R3 represents hydrogen or (C1-C3)-alkyl, or one of its salts, solvates or solvates of the salts.

4. The use as claimed in claim 1 of a compound of the formula (1) as defined in claim 1, 2 or 3, in which A represents O or N-R4, where R4 represents hydrogen or (C1-C4)-alkyl, L1 represents a bond or represents (C1-C3)-alkanediyl, the ring Q represents (C4-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, a 5- or 6-membered heterocycle or phenyl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, chlorine, (C1-C3)-alkyl, trifluoromethyl, hydroxy, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and diethylamino, L2 represents (C1-C3)-alkanediyl which may be mono- or disubstituted by fluorine, represents (C2-C3)-alkenediyl or represents a group of the formula *-M-CR7R8-, *-M-CH2-CR7R8- or *-CH2-M-CR7R8-, where * represents the point of attachment to the ring Q, M represents O or N-R5, where R5 represents hydrogen or (C1-C3)-alkyl, and R7 and R8 independently of one another represent hydrogen or fluorine, Z represents a group of the formula in which # represents the point of attachment to the group L2 and R6 represents hydrogen, methyl or ethyl, R1 and R2 independently of one another represent a substituent selected from the group consisting of fluorine, chlorine, cyano, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, (C1-C4)-alkoxy, trifluoromethyl, trifluorometh-oxy, (C1-C4)-alkylthio, (C1-C5)-acyl, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino and (C1-C4)-acylamino, or two radicals R1 and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O- or -O-CF2-O-, n and o independently of one another represent the number 0, 1 or 2, where if R1 or R2 is present twice, their meanings may in each case be identical or different, and R3 represents hydrogen or (C1-C3)-alkyl, or one of its salts, solvates or solvates of the salts.

5. The use as claimed in claim 1 of a compound of the formula (I) as defined in any of claims 1 to 4, in which A represents O or NH, L1 represents a bond, methylene, ethane-1,1-diyl or ethane-1,2-diyl, the ring Q represents cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, ethoxy, amino, methylamino and dimethylamino, L2 represents (C1-C3)-alkanediyl, (C2-C3)-alkenediyl or a group of the formula *-M-CH2- or *-M-CH2-CH2-, where * represents the point of attachment to the ring Q
and M represents O or N-R5, where R5 represents hydrogen or (C1-C3)-alkyl, Z represents a group of the formula in which # represents the point of attachment to the group L2 and R6 represents hydrogen, methyl or ethyl, R1 and R2 independently of one another represent a substituent selected from the group consisting of fluorine, chlorine, cyano, (C1-C5)-alkyl, (C2-C5)-alkenyl, (C3-C6)-cycloalkyl, (C4-C6)-cycloalkenyl, (C1-C4)-alkoxy, trifluoromethyl, trifluorometh-oxy, (C1-C4)-alkylthio, (C1-C5)-acyl, amino, mono-(C1-C4)-alkylamino, di-(C1-C4)-alkylamino and (C1-C4)-acylamino, or two radicals R1 and/or R2 attached to adjacent carbon atoms of the respective phenyl ring together form a group of the formula -O-CH2-O-, -O-CHF-O- or -O-CF2-O-, n and o independently of one another represent the number 0, 1 or 2, where, if R1 or R2 is present twice, their meanings may in each case be identical or different, and R3 represents hydrogen, or one of its salts, solvates or solvates of the salts.

6. The use as claimed in claim 1 of a compound of the formula (I) as defined in any of claims 1 to 5, in which A represents O or NH, L1 represents a bond, methylene or ethane-1,1-diyl, the ring Q represents cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl or phenyl, each of which may be substituted up to two times by identical or different substituents from the group consisting of fluorine, methyl, hydroxy and methoxy, L2 represents (C1-C3)-alkanediyl, (C2-C3)-alkenediyl or a group of the formula *-M-CH2- or *-M-CH2-CH2-, where * represents the point of attachment to the ring Q

and M represents O or NH, Z represents a group of the formula in which # represents the point of attachment to the group L2 and R6 represents hydrogen, methyl or ethyl, R1 represents a substituent selected from the group consisting of fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl and methoxy, R2 represents a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, trifluoromethyl, methoxy, ethoxy, trifluoro-methoxy, methylthio, ethylthio, amino, methylamino and ethylamino, n and o independently of one another represent the number 0, 1 or 2, where, if R1 or R2 is present twice, their meanings can in each case be identical or different, and R3 represents 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 of claims 1 to 6, and one or more further active compounds selected from the group consisting of kinase inhibitors, stimulators and activators of soluble guanylate cyclase, elastase inhibitors, endotheline receptor antagonists and phosphodiesterase inhibitors.

8. The use of the combination as claimed in claim 7 for preparing a medicament for the treatment and/or prophylaxis of pulmonary arterial hypertension and other types of pulmonary hypertension.

9. The use of a compound of the formula (I) as defined in any of claims 1 to 6 or of a combination as defined in claim 7 for the preparation of a medicament for the treatment and/or prophylaxis of idiopathic or familiar pulmonary arterial hypertension, or pulmonary arterial hypertension associated with medicaments, toxins or other disorders, for the treatment and/or prophylaxis of pulmonary hypertension associated with left atrial or left ventricular disorders, left heart valve disorders, chronic obstructive pulmonary disease, interstitial pulmonary disease, pulmonary fibrosis, sleep apnoea syndrome, disorders with alveolar hypoventilation, altitude sickness, pulmonary development impairments, chronic thrombotic and/or embolic disorders or in conjunction with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis, and for the treatment and/or prophylaxis of pulmonary hypertension caused by external compression of vessels.

10. A medicament comprising a combination as defined in claim 7, where appropriate combined with one or more inert, non-toxic, pharmaceutically suitable excipients.

11. A medicament as claimed in 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 types of pulmonary hypertension in humans and animals by administering an effective amount of at least one compound of the formula (I) as defined in any of claims 1 to 6, of a combination as defined in claim 7, or of a medicament comprising at least one compound of the formula (I) as defined in any of claims 1 to 6.