HK1130054B

HK1130054B - Novel, acyclic substituted furopyrimidine derivatives and use thereof

Info

Publication number: HK1130054B
Application number: HK09108053.8A
Authority: HK
Inventors: Thomas Lampe; Eva-Maria Becker; Raimund Kast; Hartmut Beck; Mario Jeske; Joachim Schuhmacher; Friederike Stoll; Martina Klein; Metin Akbaba; Andreas Knorr; Johannes-Peter Stasch; Lars BÄRFACKER; Alexander Hillisch; Gunter Karig; Mark Meininghaus; Karl-Heinz Schlemmer; Rudolf Schohe-Loop
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2005-12-21
Filing date: 2006-12-08
Publication date: 2013-07-12

Description

Novel, acyclic substituted furopyrimidine derivatives and their use

The present application relates to novel, acyclic substituted furan (furo) pyrimidine derivatives, to a process for their production, and to their use for the treatment and/or prophylaxis of diseases and to their use for the production of pharmaceutical products for the treatment and/or prophylaxis of diseases.

Prostacyclin (PGI)₂) Belongs to a class of physiologically active prostatesA hormone which is a derivative of arachidonic acid. PGI₂Is a major product of arachidonic acid metabolism in endothelial cells and is a potent vasodilator and an inhibitor of platelet aggregation. PGI₂Is thromboxane A₂(TxA₂) And a strong vasoconstrictor and a stimulator of platelet aggregation, and thus helps maintain vascular homeostasis. Presumably due in part to PGI₂The decrease in levels has led to 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]。

By phospholipase A₂PGI after removal of arachidonic acid from phospholipids₂Passage through cyclooxygenase followed by PGI₂The synthase is synthesized synthetically. PGI₂It is not stored, but is released immediately after synthesis, exerting its effect in situ. PGI₂Is an unstable molecule that is rapidly (half-life of about 3 minutes) not enzymatically converted to the inactive metabolite, 6-oxoprostaglandin-F1 α [ Dusting, g.j. et al, pharmac. ther.1990, 48: 323-344]。

PGI₂The biological effects of (a) occur through binding to membrane-bound receptors, called prostacyclin receptors or IP receptors [ Narumiya, s. et al, physiol.rev.1999, 79: 1193-1226]. The IP receptor is a G protein-linked receptor characterized by a seven transmembrane domain. In addition to the human IP receptor, the prostacyclin receptor has also been cloned from mice and mice [ Vane, j, et al, eur.j.vasc.endovasc.surg.2003, 26: 571-578]. In smooth muscle cells, activation of IP receptors results in stimulation of adenylate cyclase, which catalyzes the formation of cAMP from ATP. The increase in intracellular cAMP concentration is responsible for prostacyclin-induced vasodilation and inhibition of platelet aggregation. In addition to vascular activity, for PGI₂Anti-proliferative effects are also described [ 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]. Moreover, PGI₂Inhibition of Metastasis formation [ 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 in the respective target cells [ Wise, h. et al TIPS 1996, 17: 17-21]Other signal transduction pathways, such as phosphoinositide cascades, and IP receptor-mediated activation of potassium channels.

Despite PGI₂Is generally therapeutically beneficial, PGI₂Still severely limited by its chemical and metabolic instability. More stable PGI's have been available₂Analogs, such as iloprost [ badisch, d.b. et al, j.am.col.cardiol.2004, 43: 56S-61S]And treprostinil [ Chattaraj, s.c., curr. opinion. invest. drugs 2002, 3: 582-586]However, these compounds still have a very short-term effect. Moreover, the substance can only be administered to the patient by a complex route of administration, for example by continuous infusion, subcutaneously or by repeated inhalation. These routes of administration may also have additional side effects, such as infection or pain at the injection site. Beraprost, which is by far the only PGI2 derivative available for oral administration to patients [ Barst, r.j. et al, j.am.col.cardiol.2003, 41: 2119-2125]Its use is once again limited by its transient effect.

Compounds described in the present application, with PGI₂By comparison, chemically and metabolically stable, non-prostanoid activators of IP receptors which mimic PGI₂And thus can be used in the treatment of diseases, in particular cardiovascular diseases.

DE 1817146, EP 1018514, EP 1132093, WO 02/092603, WO03/022852, WO 2005/092896, WO 2005/121149 and WO 2006/004658 describe various 4-oxy-, 4-thio-and/or 4-aminofuran [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. In Chemica script 1986, 26 (2): 337-: 1434-: 1022-1033 discloses the production of certain 4-aminofuran pyrimidine derivatives. In WO 00/75145 compounds having a bicyclic heteroaromatic nucleus structure are claimed to be protected as inhibitors of cell adhesion.

The compounds claimed in the context of this application are distinguished, unlike the compounds from the state of the art, by a 5, 6-diphenylfuro [2, 3-d ] pyrimidine core structure which is attached at a certain spatial distance via position 4 to a carboxylic acid or a carboxylic acid-like function.

The invention relates to compounds having the following general formula (I)

Wherein

A represents O, S or N-R⁵Wherein

R⁵Represents hydrogen, (C)₁-C₆) Alkyl radical (C)₃-C₇) Cycloalkyl or (C)₄-C₇) Cycloalkenyl, L represents (C)₁-C₇) Alkanediyl or C₂-C₇) Alkenediyl which may be mono-or doubly substituted by fluorine, or represents a compound of formula¹-Q-L²The group of (a), wherein,

is represented by and CHR³The point of attachment of the group,

L¹is represented by (C)₁-C₅) Alkanediyl which may be (C)₁-C₄) Alkyl or (C)₁-C₄) The substitution of alkoxy groups is carried out,

L²represents a bond or (C)₁-C₃) Alkanediyl, which may be singly or doubly substituted by fluorine,

and

q represents O orN-R⁶Wherein

R⁶Represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

z represents a group of the formula

Or

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

R¹and R²Independently of one another, represents a radical selected from halogen, cyano, nitro, (C)₁-C₆) Alkyl radical (C)₂-C₆) Alkenyl (C)₂-C₄) Alkynyl (C)₃-C₇) Cycloalkyl group, (C)₄-C₇) Cycloalkenyl radical, (C)₁-C₆) Alkoxy, trifluoromethyl, trifluoromethoxy, (C)₁-C₆) Alkylthio (C)₁-C₆) Acyl, amino, mono- (C)₁-C₆) Alkylamino, di- (C)₁-C₆) Alkylamino and (C)₁-C₆) A substituent of the acylamino group,

wherein (C)₁-C₆) Alkyl and (C)₁-C₆) The alkoxy radicals may themselves be substituted by cyano, hydroxy, (C)₁-C₄) Alkoxy group, (C)₁-C₄) Alkylthio, amino, mono-or di- (C)₁-C₄) The alkyl amino group is substituted by the alkyl amino group,

or

With respective benzene ringTwo radicals R bound to adjacent carbon atoms¹And/or R²Together form a compound having the formula-O-CH₂-O-，-O-CHF-O-，-O-CF₂-O-，-O-CH₂-CH₂-O-or-O-CF₂-CF₂-a group of-O-,

n and o, independently of one another, represent the numbers 0, 1, 2 or 3,

wherein for when R¹Or R²Where they are present in multiple instances, they may have the same or different meanings,

R³represents hydrogen or (C)₁-C₄) An alkyl group which may be substituted with a hydroxyl group or an amino group,

and

R⁴represents hydrogen, (C)₁-C₄) An alkyl group or a cyclopropyl group, or a salt thereof,

and their salts, solvates and solvates of such salts.

The compounds according to the invention are compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds covered by formula (I) and their salts, solvates and solvates of the salts having the formula and the compounds listed below as application examples and their salts, solvates and solvates of the salts covered by formula (I) as long as the compounds listed below covered by formula (I) are not also salts, solvates and solvates of the salts.

The compounds according to the invention may, depending on their structure, exist in stereoisomeric forms (enantiomers, diastereomers). The present invention thus includes enantiomers or diastereomers and their respective mixtures. Stereoisomerically identical components can be separated from such mixtures of enantiomers and/or diastereomers in a known manner.

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

Salts within the scope of the invention are preferably physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not suitable per se for pharmaceutical use, but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include the acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

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

Within the scope of the present invention, this form of the compound according to the invention, which forms a complex in the solid or liquid state by coordination with solvent molecules, is referred to asSolvates. Hydrates are a special form of solvates in which coordination is accomplished with water. Hydrates are preferred as solvates within the scope of the present invention.

In addition, the invention also includes prodrugs of the compounds according to the invention. The term "prodrug" includes compounds which may be biologically active or inactive per se, but which are converted (e.g. metabolised or by hydrolysis) to the compounds according to the invention when they reside in the body.

In particular, for compounds having formula (I), the invention includes, wherein

Z represents a group of the formula

Or

The invention also includes hydrolyzable ester derivatives of these compounds. Esters are understood hereinafter to include esters which, in physiological media, under the conditions of the biological tests described subsequently and in particular in vivo, can be hydrolyzed by enzymatic or chemical pathways to the free carboxylic acid as the main biologically active compound. Such esters are preferably (C)₁-C₄) Alkyl esters, wherein the alkyl group may be linear or branched. Particular preference is given to methyl or ethyl esters (see the radical R)₇Corresponding definition of (d).

Within the scope of the present invention, unless otherwise indicated, the substituents have the following meanings:

within the scope of the present invention is,(C ₁ -C ₆ ) Alkyl radical (C) ₁ -C ₅ ) Alkyl radical (C) ₁ -C ₄ ) Alkyl radical And (C) ₁ -C ₃ )Alkyl represents a linear or branched alkyl group having 1 to 6, 1 to 5, 1 to 4 or 1 to 3 carbon atoms. Preference is given to linear or branched alkyl groups having from 1 to 4 carbon atoms, particularly preferably from 1 to 3 carbon atoms. The following may be mentioned as preferred examples: methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

Within the scope of the present invention is,(C ₂ -C ₆ ) Alkenyl and (C) ₂ -C ₅ ) Alkenyl radicalRepresents a compound having 2 to 6 or 2 to 5 carbon atoms and one or two double bondsLinear or branched alkenyl groups of (a). Linear or branched alkenyl groups having 2 to 5 carbon atoms and one double bond are preferred. The following may be mentioned as preferred examples: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

Within the scope of the present invention is,(C ₂ -C ₄ )alkynyl represents a linear or branched alkynyl group having 2 to 4 carbon atoms and a triple bond. Linear alkynyl groups having 2 to 4 carbon atoms are preferred. The following may be mentioned as preferred examples: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl.

Within the scope of the present invention is,(C ₁ -C ₇ ) Alkanediyl group(alkanediyl)，(C ₁ -C ₅ ) Alkanedioic acid Base of，(C ₁ -C ₃ ) Alkanediyl and (C) ₃ -C ₇ ) Alkanediyl groupRepresents a linear or branched divalent alkyl radical having 1 to 7, 1 to 5, 1 to 3 or 3 to 7 carbon atoms. Linear or branched alkanediyl radicals having 1 to 5, 1 to 3 or 3 to 7 carbon atoms are preferred. The following may be mentioned as preferred examples: methylene, 1, 2-ethylene, ethane-1, 1-diyl, 1, 3-propylene, propane-1, 1-diyl, propane-1, 2-diyl, propane-2, 2-diyl, 1, 4-butylene, butane-1, 2-diyl, butane-1, 3-diyl, butane-2, 3-diyl, pentane-1, 5-diyl, pentane-2, 4-diyl, 3-methylpentane-2, 4-diyl and hexane-1, 6-diyl.

Within the scope of the present invention, (C)₂-C₇) Alkenediyl and (C)₃-C₇) Alkenediyl represents a linear or branched divalent alkenediyl radical having 2 to 7 or 3 to 7 carbon atoms and up to 3 double bonds. Linear or branched alkenediyl radicals having 3 to 7 carbon atoms and one double bond are preferred. The following may be mentioned as preferred examples: ethylene-1, 1-diyl, ethylene-1, 2-diylPropylene-1, 1-diyl, propylene-1, 2-diyl, propylene-1, 3-diyl, but-1-en-1, 4-diyl, but-1-en-1, 3-diyl, but-2-en-1, 4-diyl, but-1, 3-diene-1, 4-diyl, pent-2-en-1, 5-diyl, hex-3-en-1, 6-diyl and hex-2, 4-diene-1, 6-diyl.

Within the scope of the present invention is,(C ₁ -C ₆ ) Alkoxy and (C) ₁ -C ₄ ) Alkoxy radicalRepresents a linear or branched alkoxy group having 1 to 6 or 1 to 4 carbon atoms. Linear or branched alkoxy groups having 1 to 4 carbon atoms are preferred. The following may be mentioned as preferred examples: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Within the scope of the present invention is,(C ₁ -C ₆ ) Alkylthio and (C) ₁ -C ₄ ) Alkylthio groupRepresents a linear or branched alkylthio group having 1 to 6 or 1 to 4 carbon atoms. Linear or branched alkylthio groups having 1 to 4 carbon atoms are preferred. The following may be mentioned as preferred examples: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Within the scope of the present invention is,(C ₁ -C ₆ ) Acyl radical[(C₁-C₆) Alkanoyl radical]，(C ₁ -C ₅ ) Acyl radical[(C₁-C₅) -alkanoyl radical]And (C) ₁ -C ₄ ) Acyl radical[(C₁-C₄) Alkanoyl radical]Represents a linear or branched alkyl group having 1 to 6, 1 to 5 or 1 to 4 carbon atoms, which has a double-bonded oxygen atom in position 1 and is bonded via position 1. Linear or branched acyl groups having 1 to 4 carbon atoms are preferred. The following may be mentioned as preferred examples: formyl, acetyl, propionylN-butyryl, iso-butyryl and pivaloyl.

Within the scope of the present invention is,a- (C) ₁ -C ₆ ) Alkylamino and mono- (C) ₁ -C ₄ ) Alkylamino radicalRepresents an amino group having a linear or branched alkyl substituent having 1 to 6 or 1 to 4 carbon atoms. Linear or branched monoalkylamino groups having 1 to 4 carbon atoms are preferred. The following may be mentioned as preferred examples: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Within the scope of the present invention is,di- (C) ₁ -C ₆ ) Alkylamino and di- (C) ₁ -C ₄ ) Alkylamino radicalRepresents an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 or 1 to 4 carbon atoms. Preference is given to linear or branched dialkylamino radicals having in each case 1 to 4 carbon atoms. The following may be mentioned as preferred examples: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-pentylamino and N-hexyl-N-methylamino.

Within the scope of the present invention, (C)₁-C₆) Acylamino group and (C)₁-C₄) Acylamino represents amino having a linear or branched acyl substituent having 1 to 6 or 1 to 4 carbon atoms and being linked via a carbonyl group. Preference is given to acylamino groups having 1 to 4 carbon atoms. The following may be mentioned as preferred examples: carboxamido, acetamido, propionamido, n-butyramido and pivaloyl.

Within the scope of the present invention is,(C ₃ -C ₇ ) Cycloalkyl and (C) ₃ -C ₆ ) Cycloalkyl radicalsRepresents a compound having 3 to 7 or 3 to 6 carbon atomsA monocyclic saturated cycloalkyl group. Cycloalkyl groups having 3 to 6 carbon atoms are preferred. The following may be mentioned as preferred examples: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Within the scope of the present invention is,(C ₄ -C ₇ ) Cycloalkenyl and (C) ₄ -C ₆ ) Cycloalkenyl groupRepresents a monocyclic cycloalkyl group having 4 to 7 or 4 to 6 carbon atoms and a double bond. Cycloalkenyl groups having from 4 to 6 carbon atoms are preferred. The following may be mentioned as preferred examples: cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

Within the scope of the present invention is,halogen elementIncluding fluorine, chlorine, bromine and iodine. Chlorine or fluorine are preferred.

If a group is substituted in a compound of the present invention, the group may be mono-or polysubstituted unless otherwise specified. Within the scope of the present invention, for all the radicals which are present in a plurality, their meanings are independent of one another. Preference is given to substitution with one, two or three identical or different substituents. Very particular preference is given to substitution with one substituent.

Within the scope of the present invention, preference is given to compounds of the formula (I), in which

A represents O, S or N-R⁵Wherein

R⁵Represents hydrogen, (C)₁-C₆) Alkyl radical (C)₃-C₇) Cycloalkyl or (C)₄-C₇) A cycloalkenyl group, a cycloalkyl group,

l represents (C)₁-C₇) Alkanediyl or (C)₂-C₇) Alkenediyl which may be substituted once or twice by fluorine, or represents a compound of formula¹-Q-L²A group of (1), wherein

Is represented by and CHR³The point of attachment of the group,

L¹is represented by (C)₁-C₅) Alkanedioic acidThe base group is a group of a compound,

L²represents a bond or (C)₁-C₃) Alkanediyl, which may be substituted once or twice by fluorine,

and

q represents O or N-R⁶Wherein

R⁶Represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

z represents a group of the formula

Or

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

wherein (C)₁-C₆) Alkyl and (C)₁-C₆) The alkoxy radicals may themselves each be substituted by hydroxy groups (a)C₁-C₄) Alkoxy, amino, mono-or di- (C)₁-C₄) The alkyl amino group is substituted by the alkyl amino group,

or

Two radicals R bound to adjacent carbon atoms of the respective phenyl rings¹And/or R²Together form a compound having the formula-O-CH₂-O-，-O-CHF-O-，-O-CF₂-O-，-O-CH₂-CH₂-O-or-O-CF₂-CF₂-a group of-O-,

n and o represent, independently of one another, the numbers 0, 1, 2 or 3,

wherein for when R¹Or R²Where they are present in a plurality of instances, their meanings may each be the same or different,

and

and their salts, solvates and solvates of such salts.

Within the scope of the present invention, particular preference is given to compounds of the formula (I), in which

A represents O or N-R⁵Wherein

R⁵Represents hydrogen, (C)₁-C₄) Alkyl or (C)₃-C₆) A cycloalkyl group,

l represents (C)₃-C₇) Alkanediyl or (C)₃-C₇) Alkenediyl which may be substituted once or twice by fluorine, or represents a compound of formula¹-Q-L²A group of (1), wherein

Is represented by and CHR³The point of attachment of the group,

L¹is represented by (C)₁-C₃) An alkanediyl group, which is a cyclic alkyl group,

L²is represented by (C)₁-C₃) Alkanediyl, which may be substituted once or twice by fluorine,

and

q represents O or N-R⁶Wherein

R⁶Represents hydrogen, (C)₁-C₃) An alkyl group or a cyclopropyl group, or a salt thereof,

z represents a group of the formula

Or

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

R¹and R²Independently of one another, represents a radical selected from fluorine, chlorine, cyano, (C)₁-C₅) Alkyl radical (C)₂-C₅) Alkenyl (C)₃-C₆) Cycloalkyl group, (C)₄-C₆) Cycloalkenyl radical, (C)₁-C₄) Alkoxy, trifluoromethyl, trifluoromethoxy, (C)₁-C₄) Alkylthio (C)₁-C₅) Acyl, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino and (C)₁-C₄) A substituent of the acylamino group,

or

Two radicals R bound to adjacent carbon atoms of the respective phenyl rings¹And/or R²Together form a compound having the formula-O-CH₂-O-，-O-CHF-O-，-O-CF₂-a group of-O-,

n and o, independently of one another, represent the numbers 0, 1, 2 or 3,

R³represents hydrogen or (C)₁-C₃) An alkyl group which may be substituted with a hydroxyl group or an amino group,

and

R⁴represents hydrogen or (C)₁-C₃) An alkyl group, a carboxyl group,

and their salts, solvates and solvates of such salts.

Within the scope of the present invention, very particular preference is given to compounds of the formula (I) in which

A represents O or NH, and the compound is selected from the group consisting of,

l represents (C)₃-C₇) Alkanediyl (C)₃-C₇) Alkenediyl radical or represents a radical of formula¹-O-L²A group of (1), wherein

Is represented by and CHR³The point of attachment of the group,

and

L¹and L²Independently of each other represent (C)₁-C₃) An alkanediyl group, which is a cyclic alkyl group,

z represents a group of the formula

Or

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

or

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

wherein for when R¹Or R²There are two instances, each of which may be the same or different in meaning,

R³represents hydrogen, methyl or ethyl

And

R⁴represents hydrogen, and is selected from the group consisting of,

and their salts, solvates and solvates of such salts.

Within the scope of the present invention, very particular preference is also given to compounds of the formula (I) in which

l represents a compound having the formula¹-N(CH₃)-L²A group of (1), wherein

Is represented by and CHR³The point of attachment of the group,

and

z represents a group of the formula

Or

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

R¹and R²Independently of one another, represents a radical selected from fluorine, chlorine, cyano, (C)₁-C₅) Alkyl radical (C)₂-C₅) Alkenyl (C)₃-C₆) Cycloalkyl group, (C)₄-C₆) Cycloalkenyl radical, (C)₁C₄) Alkoxy, trifluoromethyl, trifluoromethoxy, (C)₁-C₄) Alkylthio (C)₁-C₅) Acyl, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino and (C)₁-C₄) A substituent of the acylamino group,

or

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

R³represents hydrogen, methyl or ethyl

And

R⁴represents hydrogen, and is selected from the group consisting of,

and their salts, solvates and solvates of such salts.

Within the scope of the present invention, particular preference is given, above all, to compounds of the formula (I) in which

l represents (C)₃-C₇) Alkanediyl (C)₃-C₇) Alkenediyl radical or represents a radical of formula¹-Q-L²A group of (1), wherein

Is represented by and CHR³The point of attachment of the group,

and

q represents O or N (CH)₃) Wherein

Z represents a group of the formula

Or

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

R¹represents a substituent selected from fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl and methoxy,

R²represents a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, amino, methylamino and ethylamino,

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

R³represents hydrogen, methyl or ethyl

And

R⁴represents hydrogen, and is selected from the group consisting of,

and their salts, solvates and solvates of such salts.

Of particular interest within the scope of the present invention are compounds of formula (I), wherein

A represents O, and the compound A represents O,

and their salts, solvates and solvates of such salts.

Of particular importance within the scope of the present invention are also compounds of the formula (I), in which

L represents a compound having the formula¹-Q-L²A group of (1), wherein

Is represented by and CHR³The point of attachment of the group,

L¹is represented by (C)₁-C₅) An alkanediyl group, which is a cyclic alkyl group,

and

q represents O or N-R⁶Wherein

R⁶Represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group,

and their salts, solvates and solvates of such salts.

The detailed definitions of the radicals given in the respective combinations and/or preferred combinations of radicals can also be replaced by the definitions of the radicals of any other combination, irrespective of the combination of the respective radicals mentioned.

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

The invention also relates to a method for producing compounds of formula (I) according to the invention, characterized in that

[A] A compound having the following formula (II)

Wherein R is¹，R²，R⁴N and o each have the meanings given above

And

X¹represents a leaving group, such as halogen, and in particular chlorine,

neutralizing a compound having the following formula (III) in the presence of a base and optionally in an inert solvent

Wherein A, L and R³Each having the meaning given above

And

Z¹represents cyano or has the formula- [ C (O)]y-COOR^7AA group of (1), wherein

y represents the number 0 or 1

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

reacted to a compound having the following formula (IV)

Wherein A, L, Z¹，R¹，R²，R⁴N and o each have the meanings given above, or

[B] A compound having the following formula (V-1)

Wherein R is¹，R⁴，X¹And n each have the meaning given above,

with a compound of formula (III) in the presence of a base and optionally in an inert solvent to form a compound of formula (VI-1)

Wherein A, L, Z¹，R¹，R³，R⁴And n each have the meaning given above,

and subsequent bromination in an inert solvent, e.g., with N-bromosuccinimide, to a compound having the formula (VII-1)

Wherein A, L, Z¹，R¹，R³，R⁴And n each have the meaning given above,

and these are then coupled in an inert solvent in the presence of a base and of a suitable palladium catalyst with a phenylboronic acid of the formula (VIII-1)

Wherein R is²And o has the meaning given above,

to a compound having formula (IV)

Or

[C] A compound having the following formula (V-2)

Wherein R is²，R⁴，X¹And o each have the meaning given above,

with a compound of formula (III) in the presence of a base and optionally in an inert solvent to form a compound of formula (VI-2)

Wherein A, L, Z¹，R²，R³，R⁴And o each haveHaving the significance given above, the method has the advantages that,

followed by bromination in an inert solvent, e.g. with N-bromosuccinimide, to give the compound of formula (VII-2)

Wherein A, L, Z¹，R²，R³，R⁴And o each have the meaning given above,

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

Wherein R is¹And n has the meaning given above,

to a compound having formula (IV)

And the respective resulting compound of the formula (IV) are then converted by hydrolysis of the ester-or cyano group Z1 into the carboxylic acid of the formula (I-A)

Wherein A, L, R¹，R²，R³，R⁴N, o and y each have the meanings given above,

and if necessary these are converted into their solvates, salts and/or solvates of the salts with the corresponding (i) solvents and/or (ii) bases or acids.

Inert solvents for steps (II) + (III) → (IV), (V-1) + (III) → (VI) and (V-2) + (III) → (VI-2) are, for example, ethers such as diethyl ether, methyl-tert-butyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum components, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1, 2-dichloroethane, trichloroethane, tetrachloroethane, trichloroethylene, chlorobenzene or chlorotoluene, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP) or acetonitrile. Mixtures of the above-mentioned solvents may also be used. Tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or mixtures thereof are preferably used.

However, steps (II) + (III) → (IV), (V-1) + (III) → (VI-1) and (V-2) + (III) → (VI-2) can be carried out without solvent if necessary.

Inorganic or organic bases which are customary for steps (II) + (III) → (IV), (V-1) + (III) → (VI-1) and (V-2) + (III) → (VI-2) are suitable as bases. Preferably these include alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonates, alkali metal-alcoholates, such as sodium or potassium tert-butoxide, alkali metal hydrides, such as sodium or potassium hydride, amides, such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds, such as butyllithium or phenyllithium, or organic amines, such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine or pyridine.

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

For the reaction with the amine derivative [ a ═ N in (III) ], tertiary amines, such as in particular N, N-diisopropylethylamine, are preferably used as bases. However, if necessary, these reactions can also be carried out using an excess of amine component (III) without addition of a promoter base. For the reaction with the alcohol derivative [ a ═ O in (III) ], potassium or cesium carbonate or phosphazene bases P2-t-Bu and P4-t-Bu are preferred.

It may be advantageous to carry out steps (II) + (III) → (IV), (V-1) + (III) → (VI-1) and (V-2) + (III) → (VI-2) with the addition of crown ethers if necessary.

In a variant of the process, the reactions (II) + (III) → (IV), (V-1) + (III) → (VI-1) and (V-2) + (III) → (VI-2) can also be carried out in a two-phase mixture comprising an aqueous solution of an alkali metal hydroxide as base and one of the abovementioned hydrocarbons or halogenated hydrocarbons as further solvent, using a phase transfer catalyst, for example tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide.

Steps (II) + (III) → (IV), (V-1) + (III) → (VI-1) and (V-2) + (III) → (VI-2) are carried out, in the case of reaction with the amine derivative [ a ═ N in (III) ], typically in the temperature range of +50 ° to +150 ℃. For the reaction with the alcohol derivative [ a ═ O in (III) ], the reaction is generally at a temperature range of-20 ℃ to +120 ℃, and preferably at 0 ℃ to +60 ℃.

The bromination in step (VI-1) → (VII-1) or (VI-2) → (VII-2) is preferably carried out in a halogenated hydrocarbon as solvent, in particular in tetrachloromethane, at a temperature in the range from +50 ℃ to +100 ℃. Suitable brominating agents are elemental bromine and in particular N-bromosuccinimide (NBS), if necessary with addition of alpha, alpha' -azobis (isobutyronitrile) (AIBN) as initiator.

Inert solvents for steps (VII-1) + (VIII-1) → (IV) and (VII-2) + (VIII-2) → (IV) such as alcohols, e.g. methanol, ethanol, N-propanol, isopropanol, N-butanol or tert-butanol, ethers, e.g. diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl alcohol or diethylene glycol dimethyl ether, hydrocarbons, e.g. benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, e.g. dimethylformamide, dimethyl sulfoxide, N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile and water. It is also possible to use mixtures of the above-mentioned solvents. A mixture of dimethyl sulfoxide and water is preferred.

Inorganic bases which are customary for steps (VII-1) + (VIII-1) → (IV) and (VII-2) + (VIII-2) → (IV) are suitable as bases. These include in particular the alkali metal hydroxides, such as lithium, sodium or potassium hydroxide, the alkali metal bicarbonates, such as sodium or potassium bicarbonate, the alkali metal or alkaline earth metal carbonates, such as lithium, sodium, potassium, calcium or cesium carbonate, or the alkali metal hydrogenphosphates, such as disodium or dipotassium hydrogen phosphate. Preferably sodium or potassium carbonate is used.

For steps (VII-1) + (VIII-1) → (IV) and (VII-2) + (VIII-2) → (IV) [ "Suzuki coupling"]Suitable palladium catalysts are, for example, palladium on activated carbon, palladium (II) acetate, tetrakis- (triphenylphosphine) -palladium (0), bis- (triphenylphosphine) -palladium (II) dichloride, bis- (acetonitrile) -palladium (II) dichloride and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride-dichloromethane complex [ see, e.g., j.hassan et al, chem.rev.102，1359-1469(2002)]。

The reactions (VII-1) + ((VIII-1) → (IV) and (VII-2) + (VIII-2) → (IV) are usually carried out in a temperature range of +20 ℃ to +150 ℃, preferably in a temperature range of +50 ℃ to +100 ℃.

The hydrolysis of the ester or cyano group Z' in step (IV) → (I-a) is carried out by a usual method in which the ester or nitrile is treated with an acid or a base in an inert solvent, and in the latter case the initially formed salt is converted into the free carboxylic acid by treatment with an acid. In the case of tert-butyl esters, the ester cleavage is preferably carried out with an acid.

For these reactions, water or organic solvents customary for ester dissociation are suitable as inert solvents. 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 ethylene glycol dimethyl ether, or other solvents, such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. Mixtures of the above-mentioned solvents may also be used. In the case of basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and/or ethanol, and for nitrile hydrolysis preferably water and/or n-propanol. Dichloromethane is preferably used in the case of reaction with trifluoroacetic acid, and tetrahydrofuran, diethyl ether, dioxane or water is preferably used in the case of reaction with hydrogen chloride.

Customary inorganic bases are suitable as bases. These preferably include alkali metal or alkaline earth metal hydroxides, such as sodium, lithium, potassium or barium hydroxides, or alkali metal or alkaline earth metal carbonates, such as sodium, potassium or calcium carbonates. Sodium or lithium hydroxide is particularly preferred.

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 are generally suitable as the acid for ester cleavage, water being added if necessary. Preference is given in the case of tert-butyl esters to hydrogen chloride or trifluoroacetic acid and in the case of methyl esters to hydrochloric acid.

The ester dissociation is generally carried out at a temperature in the range from 0 ℃ to +100 ℃, preferably from +0 ℃ to +50 ℃. Nitrile hydrolysis is generally carried out at a temperature in the range from +50 ℃ to +150 ℃ and preferably from +80 ℃ to +120 ℃.

The above-mentioned reaction can be carried out under normal pressure, under increased pressure or under reduced pressure (e.g. 0.5-5 bar). In each case atmospheric pressure is generally used.

The compounds according to the invention having formula (I), wherein Z represents a group having the formula

Can be prepared by reacting a compound of formula (IV) with an alkali metal azide in the presence of ammonium chloride in an inert solvent or optionally in the presence of a catalystIn the presence of a trimethylsilyl azide, wherein Z¹Represents cyano.

Inert solvents for the reaction are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethyl sulfoxide, dimethylformamide, N' -Dimethylpropyleneurea (DMPU) or N-methylpyrrolidone (NMP). Mixtures of the above-mentioned solvents may also be used. Toluene is preferably used.

Sodium azide is suitable as azide reagent, particularly in the presence of ammonium chloride or trimethylsilyl azide. The latter reaction may be more advantageously carried out in the presence of a catalyst. Compounds such as di-n-butyltin oxide, trimethylaluminum bromide or zinc bromide are particularly suitable for this. Preferably, trimethylsilyl azide mixed with di-n-butyltin oxide is used.

The reaction is generally carried out at a temperature ranging from +50 ℃ to +150 ℃ and preferably from +60 ℃ to +110 ℃. The reaction can be carried out at normal pressure, under increased pressure or under reduced pressure (e.g. 0.5-5 bar). Usually at atmospheric pressure.

Can be prepared by first converting a compound having the formula (IV) with hydrazine in an inert solvent to a compound having the formula (IX) wherein Z¹Represents a methoxycarbonyl group or an ethoxycarbonyl group,

wherein A, L, R¹，R²，R³，R⁴N and o each have the meanings given above,

and then they are reacted in an inert solvent with phosgene or a phosgene equivalent, for example N, N' -carbonyldiimidazole.

Suitable inert solvents for the first step of the 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, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether. Mixtures of these solvents may also be used. Preferably, a mixture of methanol and tetrahydrofuran is used. The second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran. The reaction is generally carried out at a temperature ranging from 0 ℃ to +70 ℃ under normal pressure.

Alternatively, the compounds of the formula (I) according to the invention can also be prepared by reacting a compound of the formula (XI) with a compound of the formula (XI)

X²-L²-Z¹ (XI)，

Wherein L is²And Z¹Having the meanings given above

And

X²represents a leaving group, for example halogen, methanesulfonate or toluenesulfonate,

converting a compound of formula (X) to produce a compound of formula (X), wherein L represents a compound of formula¹-Q-L²Group of (A), L¹，L²And Q has the meaning given above,

wherein A, L¹，Q，R¹，R²，R³，R⁴N and o each have the meanings given above,

or in L²represents-CH₂CH₂In the case of (II), a compound having the following formula (XII)

Wherein Z¹Having the significance given above in respect of the properties,

conversion to a compound having the following formula (IV-A) to produce

Wherein A, L¹，L²，Q，Z¹，R¹，R²，R³，R⁴N and o each have the meanings given above,

and these are then further reacted according to the previously described methods.

The compounds of the formula (X) can be obtained starting from compounds of the formula (II), (V-1) or (V-2) by base-catalyzed reaction with compounds of the formula (XIII) and correspondingly by further reaction analogously to the previously described transformation methods [ B ] or [ C ]

Wherein A, L¹Q and R³Each having the meaning given above

And

t represents hydrogen or a temporary O-or N-protecting group,

wherein the sequence of the individual process steps can also be varied if appropriate with regard to the reaction sequence (V-1) or (V-2) → (IV-A) (see also reaction schemes 2 to 8 given below).

For steps (X) + (XI) or (XII) → (IV-a) and (II) + (XIII) → (X), reaction parameters described for reactions (II) + (III) → (IV), (V-1) + (III) → (VI-1) or (V-2) + (III) → (VI-2), such as solvent, base and reaction temperature, are similarly used.

Compounds of the formulae (II), (III), (V-1), (VIII-1), (V-2), (VIII-2), (XI), (XII) and (XIII) are commercially available, are known from the literature or can be produced by methods analogous to those known in the literature (see, for example, WO 03/018589; see also reaction scheme 1).

The production of the compounds according to the invention is illustrated by the following synthetic diagrams:

FIG. 1 shows a schematic view of a

FIG. 2

[x＝2-8]

FIG. 3

[ x ] 2 to 8; R-COOMe, COOEt or CN ]

FIG. 4

[ x ] 2 to 8; R-COOMe, COOEt or CN ]

FIG. 5

FIG. 6

FIG. 7

FIG. 8

The compounds according to the invention have valuable pharmacological properties and can be used for the prophylaxis and treatment of diseases in humans and animals.

They are particularly suitable for the prophylaxis and/or treatment of cardiovascular diseases, such as stable and unstable angina pectoris, peripheral and cardiovascular diseases, hypertension and heart failure, pulmonary hypertension, peripheral circulatory disorders, for the prophylaxis and/or treatment of thromboembolic diseases and ischaemias, such as myocardial infarction, stroke, transient and ischemic attacks and subarachnoid haemorrhages, and for the inhibition of restenosis after, for example, thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), coronary angioplasty (PTCA) and bypass surgery.

Furthermore, the compounds according to the invention may be used for the treatment of arteriosclerosis, hepatitis, asthma, Chronic Obstructive Pulmonary Disease (COPD), fibrotic pulmonary diseases, such as Idiopathic Pulmonary Fibrosis (IPF) and ARDS, inflammatory vascular diseases, such as scleroderma and lupus erythematosus, renal failure, arthritis and osteoporosis.

Furthermore, the compounds according to the invention can be used for the prevention and/or treatment of cancer, in particular metastatic tumors.

Furthermore, the compounds according to the invention can also be used as additives for preservation media for organ transplants, such as kidney, lung, heart or islet cells.

The invention also relates to the use of the compounds according to the invention for the treatment and/or prophylaxis of diseases, and in particular of the diseases mentioned above.

The invention also relates to the use of the compounds according to the invention for the production of pharmaceutical products for the treatment and/or prophylaxis of diseases, and in particular of the diseases mentioned above.

The invention also relates to a method for the treatment and/or prophylaxis of diseases, in particular the above-mentioned diseases, using an effective amount of at least one compound according to the invention.

The compounds according to the invention can be used alone or, if desired, in combination with other active substances. The invention also relates to pharmaceutical products which comprise at least one compound according to the invention and one or more additional active substances, in particular for the treatment and/or prevention of the abovementioned diseases. The following may be mentioned as preferred examples of suitable combined active substances:

organic nitrates and NO-donors, such as 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), for example Phosphodiesterase (PDE)1, 2, 3, 4 and/or 5 inhibitors, in particular PDE 5 inhibitors, for example sildenafil, vardenafil and tadalafil;

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

activators of NO-and heme-independent guanylate cyclases, such as, inter alia, the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO02/070462 and WO 02/070510;

compounds which inhibit human neutrophilic trypsin E, such as sevelamer (sevlestat) or DX-890 (Reltran);

compounds which inhibit signal transduction cascades, such as tyrosine kinase and/or serine/threonine kinase inhibitors, in particular imatinib, gefitinib (gefitinib), erloti-nib, sorafenib (sorafenib) and sunitinib (sunitinib);

compounds which influence the metabolism of cardiac energy, such as and preferably etolimus (etomoxir), dichloroacetate, ranolazine (ranolazine) or trimethoprim;

antithrombotic agents, for example and preferably from platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;

hypotensive active substances, such as and preferably from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists, rho kinase inhibitors and diuretics; and/or

Active substances which alter lipid metabolism, for example and preferably from thyroid receptor agonists, inhibitors of cholesterol synthesis, for example and preferably HMG-CoA reductase inhibitors or inhibitors of squalene synthesis, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid resorption inhibitors and lipoprotein (a) antagonists.

By "antithrombotic agent" is preferably meant a compound derived from a platelet aggregation inhibitor, anticoagulant or profibrinolytic substance.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with platelet aggregation inhibitors, such as and preferably aspirin, clopidogrel, ticlopidine or dipyridamole.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a coagulation inhibiting factor, for example and preferably ximela-gatran, melagatran, bivalirudin or cremains (clexane).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist, for example and preferably either ticalor or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, and preferably, BAY 59-7939, DU-176b, Fidexaban, Razaaban, Fondaparinux, Idra-pa-rinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with heparin or a Low Molecular Weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a vitamin K antagonist, for example and preferably with coumarins.

By "hypotensive agent" is preferably understood a compound derived from calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-blockers, beta-blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and diuretics.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1 receptor blocker, for example and preferably Prazosin (Prazosin).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a beta blocker, such as and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, blanalol, metipranolol, nadolol, caraprolol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, eparnolol or bucindolol.

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

In a preferred embodiment of the present invention, the compounds according to the present invention are administered in combination with an ACE inhibitor, such as and preferably enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinapril (quinopril), perindopril or trandolapril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist, such as and preferably bosentan, daruesentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an renin inhibitor, for example and preferably alipkiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a mineralocorticoid receptor antagonist, for example and preferably with a steroid spironolactone or eplerenone (eplerenone).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with rho-kinase inhibitors, such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, for example and preferably also with paracetamol.

"agent which alters lipid metabolism" is preferably understood to mean compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors, such as HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPA-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polybile acid adsorbents, bile acid resorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, for example and preferably torcetrapib (CP-529414), JJT-705 or CETP-vaccine (Avant).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist, for example and preferably with dextrothyroxine, 3, 5, 3' -triiodothyronine (T3), CGS23425 or axitirome (CGS 26214).

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

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

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example and preferably pioglitazone (pioglitazone) or rosiglitazone (rosiglitazone).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a PPAR- Δ agonist, for example with preferably GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe, tiquinamine or pamaquine.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, e.g. and preferably orlistat.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a polybile acid adsorbent, such as and preferably cholestyramine, lipid lowering resin No. II, Colesolvam, CholestaGel or Colestimid.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid resorption inhibitor, such as, and preferably, an ASBT (═ IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, baii-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, for example and preferably Gemcabene calcium (CI-1027) or niacin.

The invention also relates to a pharmaceutical product comprising at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmacologically acceptable excipients, and to the use thereof for the purposes mentioned before.

The compounds according to the invention may have a systemic and/or topical effect. They can be applied for this purpose by suitable routes, for example oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, epidermal, transdermal, conjunctival, otic or as implants or stents (stents).

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

Dosage forms suitable for oral administration are those which function according to the prior art, which provide a rapid and/or modified release of the compound according to the invention and which comprise the compound according to the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated tablets or tablets coated, for example, with enteric coatings or with insoluble coatings or coatings with delayed dissolution, the release of which is controlled according to the compound of the invention), tablets which disintegrate rapidly in the oral cavity or films/films, films/lyophilisates, capsules (for example hard-or soft-gel capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out without an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraabdominal). Suitable dosage forms for parenteral administration include injectable and infusible preparations in the form of solutions, suspensions, emulsions as lyophilized products or as sterile powders.

The following are examples of forms suitable for other routes of administration: for inhaled pharmaceutical forms (including powder inhalants, sprays), nasal drops, solutions or sprays, for tablets for lingual, sublingual or buccal application, films/membranes or capsules, suppositories, otic or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal dosage forms (e.g. patches), emulsions, pastes, foams, dusting powders, implants or stents (stents).

Oral or parenteral administration is preferred, and oral administration is particularly preferred.

The compounds according to the invention can be converted into the above-mentioned dosage forms. This can be done in a manner known per se by mixing with inert, non-toxic, pharmacologically acceptable excipients. These excipients include, inter alia: excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium lauryl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants, for example ascorbic acid), colorants (for example inorganic pigments, for example iron oxides) and agents for correcting taste and/or odor.

In general, it has proven advantageous to administer an amount of about 0.001-1mg/kg, preferably about 0.01-0.5mg/kg, of body weight in order to obtain effective results in the case of parenteral administration. For oral administration, the dosage is about 0.01 to 100mg/kg, preferably about 0.01 to 20mg/kg and very particularly preferably 0.1 to 10mg/kg of body weight.

However, in some cases it may be necessary to deviate from the stated amounts, depending on the body weight, the route of administration, the individual's response to the active substance, the type of formulation and the point or time interval of administration. Thus, in some cases smaller amounts than the minimum amounts mentioned above may prove sufficient, while in other cases the upper limit must be exceeded. If larger amounts are taken, it may be reasonable to dispense these in several divided doses during the day.

The following application examples illustrate the invention. The invention is not limited by this example.

Unless otherwise indicated, percentages in the following tests and examples are weight percentages; parts are parts by weight. For liquid/liquid solution solvent ratios, dilution ratio and concentration data are each based on volume.

A.Examples

Abbreviations

abs absolute

Ac acyl group

Ac₂O acid anhydride

Boc tert-butoxycarbonyl

Bu butyl

c concentration

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DIBAH diisobutylaluminum hydride

DIEA diisopropylethylamine ("Hunig's base")

DMAP 4-N, N-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

of the or. theoretical (yield)

ee enantiomeric excess

EI Electron impact ionization (in MS)

ESI electrospray ionization (in MS)

Et Ethyl group

m.p. melting Point

GC gas chromatography

saturated in satd

h hours

HPLC high performance liquid chromatography

conc. concentrated

LC-MS liquid chromatography-mass spectrometry combination

Me methyl group

min for

Ms methanesulfonyl (mesyl)

MS Mass Spectrometry

NBS N-bromosuccinimide

NMR nuclear magnetic resonance spectrometry

Pd/C on activated carbon

rac

RP reversed phase (in high Performance liquid chromatography)

RT Room temperature

R_tRetention time (in high performance liquid chromatography)

TFA trifluoroacetic acid

THF tetrahydrofuran

LC-MS, HPLC and GC methods:

method 1 (HPLC):

the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml HClO₄(70%)/liter water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 6.5min 90% B → 6.7min 2% B → 7.5min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

Method 2 (LC-MS):

device type MS: micromass ZQ; equipment type HPLC: waters Alliance 2795; column: phenomenex Syn-ergi 2 μ Hydro-RP Mercury20mm × 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 3 (LC-MS):

the instrument comprises the following steps: micromass platform LCZ with HPLC Agilent Series 1100; column: thermo Hypersil GOLD 3 μ 20mm × 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 5.5min 10% A; furnace: 50 ℃; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

Method 4 (LC-MS):

device type MS: micromass ZQ; equipment type HPLC: HP 1100 Series; UV DAD; column: phenomenex Synergi 2. mu. Hydro-RP Mercury20mm X4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 5 (LC-MS):

the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Synergi 2. mu. Hydro-RP Mercury20 mm. times.4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 208-400 nm.

Method 6 (HPLC):

the instrument comprises the following steps: HP 1100 with DAD detection; column: kromasil 100RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml HClO₄(70%)/liter water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 9min 90% B → 9.2min 2% B → 10min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

Method 7 (LC-MS):

the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Onyx Mono-lithic C18, 100 mm. times.3 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2min 65% A → 4.5min 5% A → 6min 5% A; flow rate: 2 ml/min; furnace: 40 ℃; and (4) UV detection: 208-400 nm.

Method 8 (LC-MS):

device type MS: micromass ZQ; equipment type HPLC: HP 1100 series; UV DAD; column: phenomenex Gemini 3 mu 30mm x 3.00 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

Method 9 (LC-MS):

device type MS: waters ZQ; equipment type HPLC: waters Alliance 2795; column: merck Chromolith RP18e, 100 mm. times.3 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2min 65% A → 4.5min 5% A → 6min 5% A; flow rate: 2ml min; furnace: 40 ℃; and (4) UV detection: 210 nm.

Method 10 (LC-MS):

the instrument comprises the following steps: micromass Quattro LCZ with HPLC Agilent Series 1100; column: phenomenex Gemini 3 mu 30mm x 3.00 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min2 ml/min; furnace: 50 ℃; and (4) UV detection: 208-400 nm.

Method 11 (LC-MS):

device type MS: micromass ZQ; equipment type HPLC: waters Alliance 2795; column: merck Chromolith speedROD RP-18e 100 mm. times.4.6 mm; eluent A: water +500 μ l 50% formic acid/l, eluent B: acetonitrile + 500. mu.l 50% formic acid/l; gradient: 0.0min 10% B → 7.0min 95% B → 9.0min 95% B; flow rate: 0.0min1.0ml/min → 7.0min 2.0ml/min → 9.0min 2.0 ml/min; furnace: 35 ℃; and (4) UV detection: 210 nm.

Method 12 (GC):

the instrument comprises the following steps: micromass GCT, GC 6890; column: restek RTX-35, 15 m.times.200. mu.m.times.0.33. mu.m; with a constant flow rate of helium: 0.88 ml/min; furnace: 70 ℃; an inlet: 250 ℃; gradient: 70 ℃, 30 ℃/min → 310 ℃ (hold for 3 min).

Starting compounds and intermediates:

example 1A

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

A solution of 221.88g (2236mmol) of trimethylsilyl cyanide in 25 l of benzene was added to a mixture of 290.0g (2130mmol) of 4-methoxybenzaldehyde and 1.156g (3.622mmol) of zinc iodide in 37.5 l of benzene as described in the literature procedure [ J.chem.Soc.Perkin Trans.I, 1992, 2409-2417] in about 5min at RT with cooling. The mixture was stirred at RT for 90min and then concentrated by evaporation in vacuo. The residue is purified by column filtration over silica gel (flow agent: cyclohexane/ethyl acetate 4: 1). 442.4g (88.3% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝3.76min

MS(DCI)：m/z＝253(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.49(d，2H)，6.92(d，2H)，5.42(s，1H)，3.81(s，3H).

Example 2A

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

292ml (2.08mol) of diisopropylamine were dissolved in 3.6 l of 1, 2-dimethoxyethane and cooled to-78 ℃ according to the procedure in the literature [ J.chem.Soc.Perkin Trans.I, 1992, 2409-2417 ]. 826ml of n-butyllithium solution (2.5M in n-hexane, 2.066mol) were added at a temperature below 60 ℃. The mixture is stirred for a further 15min at < -60 ℃ and then a solution of 442g (1.877mol) (4-methoxyphenyl) [ (trimethylsilyl) oxy ] acetonitrile in 1.41 l1, 2-dimethoxyethane is added dropwise at < -60 ℃. After stirring at-60 ℃ for a further 30min, a solution of 199.3g (1.878mol) of benzaldehyde in 1.4 l of 1, 2-dimethoxyethane is added at-60 ℃ over a period of 20 min. Subsequently, the reaction mixture was slowly heated to RT over 4 h. 7 l of saturated ammonium chloride solution were added and extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride solution, dried and concentrated under vacuum. The residue was taken up in 7 l dioxane and 5 l methanol and 6 l1N hydrochloric acid was added. The mixture was stirred at RT for 3h, after which 3 l of saturated sodium chloride solution were added and the mixture was extracted with 6.5 l of ethyl acetate. The organic phase is washed with 1.0 l of 1N sodium hydroxide solution and with saturated sodium chloride solution, dried and concentrated in vacuo. The residue is taken up in2 l of diisopropyl ether, decanted from insoluble material and seeded with crystals. The resulting suspension was stirred at RT for 2h and then the crystals were suction filtered. Washed with 300ml diisopropyl ether and petroleum ether and dried under vacuum. 236.8g (47.8% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.23min

MS(DCI)：m/z＝260(M+NH₄)⁺，243(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.92(d，2H)，7.38-7.28(m，5H)，6.88(d，2H)，5.90(d，1H)，4.64(d，1H)，3.82(s，3H).

Example 3A

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

236g (974mmol) of 2-hydroxy-1- (4-methoxyphenyl) -2-phenylethanone and 83.66g (1266mmol) of malononitrile were dissolved in 470ml of DMF, and 86.6ml (836.7mmol) of diethylamine were added with cooling on an ice bath. After 1h, the mixture was heated to RT and stirring at RT was continued for 4h, then 2.5 l of water and some seed crystals (Impfkristalle) were added. After 30min, the supernatant water was decanted and replaced with 1.25 liters of fresh water. The suspension was stirred thoroughly and the supernatant water was decanted again. The viscous crystalline residue was taken up in ethyl acetate and then concentrated under almost complete vacuum. The residue was stirred with 730ml diisopropyl ether and the suspension was allowed to stand overnight at RT. The solid material is then filtered off with suction and dried under vacuum. 211.5g (57.6% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.60min

MS(DCI)：m/z＝308(M+NH₄)⁺，291(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.39-7.33(m，5H)，7.28-7.18(m，3H)，6.93(d，2H)，5.02(s，2H)，3.85(s，3H).

Example 4A

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

To 1600ml (16.96mol) of acetic anhydride, 800ml (21.21mol) of formic acid are added dropwise at 0 ℃. The mixture was stirred at 0 ℃ for 30min and then 211g (727mmol) 2-amino-4- (4-methoxyphenyl) -5-phenyl-3-furonitrile were added. Removing the cooling and heating the mixture; the gas evolution started at about 80 ℃ and was stopped after about 3 h. Stirring was carried out at reflux (bath temperature about 130 ℃ C.) for a total of 24 h. After cooling to RT, stirring was carried out at 10 ℃ for 2h and the solid material formed was filtered off. The residue was washed with diethyl ether and dried under high vacuum. 135.6g (58.6% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.38min

MS(DCI)：m/z＝336(M+NH₄)⁺，319(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝10.3(br.s，1H)，7.95(s，1H)，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 5A

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

135g (424mmol) of 5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4 (3H) -one are suspended in 675ml (7241mmol) of phosphorus oxychloride at RT and the mixture is heated to boiling (evolution of HCl). After 1h, the dark solution was cooled to RT and added dropwise (heated to 55-75 ℃ pH > 9) to a vigorously stirred mixture of 2.25 l water and 4.05 l concentrated ammonia solution (25 wt.%). At the end of the addition, it is cooled to RT and the mixture is extracted three times with 1.0 l of dichloromethane each time. The combined organic phases were dried and concentrated by evaporation in vacuo. The residue is stirred with diethyl ether, filtered off with suction and dried under high vacuum. 134.4g (94.1% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.96min

MS(DCI)：m/z＝354(M+NH₄)⁺，337(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.76(s，1H)，7.62(d，2H)，7.40-7.30(m，5H)，7.03(d，2H)，3.90(s，3H).

Example 6A

2-amino-5-phenyl-3-furonitrile

To a mixture of 60.0g (301mmol) bromoacetophenone and 25.89g (391.86mmol) malononitrile in 130ml DMF at RT was added dropwise 68.6ml (663mmol) diethylamine (cooling was required to maintain the temperature). At the end of the addition, the cooling was removed, the mixture was stirred at RT for 1h and then water was added to 385 ml. It was then diluted with 125ml of water and stirred at RT for 20 min. The precipitated solid is filtered off with suction, washed twice with 125ml of water each time, dried with suction and washed with petroleum ether. The residue was dried under high vacuum. 33.3g (50.1% of theory) of the title compound are obtained as yellow brown crystals.

HPLC (method 1): r_t＝4.27min

MS(DCI)：m/z＝202(M+NH₄)⁺，185(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.51-7.45(m，2H)，7.39-7.32(m，3H)，6.54(s，1H)，4.89(br.s，1H).

Example 7A

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

424.5ml (11.25mol) of formic acid are added dropwise at 0 ℃ to 884.9ml (9.378mol) of acetic anhydride. The mixture is stirred at 0 ℃ for 30min and then 69.1g (0.375mol) of 2-amino-5-phenyl-3-furonitrile are added. Removing the cooling and heating the mixture; the gas evolution started at about 80 ℃ and was stopped after about 3 h. Stirring was carried out at reflux for a total of 24h (bath temperature approx. 130 ℃). After cooling the suspension to RT, 750ml diisopropyl ether were added, cooled to 0 ℃ and filtered. The residue was washed with diisopropyl ether and dried under high vacuum. 50.83g (58.7% of theory) of the title compound are obtained as a brown solid.

HPLC (method 1): r_t＝3.92min

MS：m/z＝213(M+H)⁺

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

Example 8A

4-chloro-6-phenyl-furan [2, 3-d ] pyrimidine

50g (235.6mmol) of 6-phenylfuran [2, 3-d ] pyrimidin-4 (3H) -one are suspended in 375ml (4023mmol) of phosphorus oxychloride at RT and the mixture is heated to boiling (evolution of HCl). After 1h, the dark solution is cooled to RT and 47.3g (87% of theory) of the title compound are obtained by adding vigorously stirred 1.25 l of water and 2.25 l of concentrated ammonia solution (25 wt.%) (heated to 55-75 ℃, dropwise at pH > 9. after the end of the addition, cooling to RT and extracting the mixture three times with 1.6 l of dichloromethane each time.

HPLC (method 1): r_t＝4.67min

MS：m/z＝231(M+H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.84(s，1H)，8.05(m，2H)，7.77(s，1H)，7.61-7.50(m，3H).

Example 9A

2-amino-4-phenyl-3-furonitrile

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

LC-MS (method 2): r_t＝1.81min；m/z＝185(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.54(d，2H)，7.50(s，2H)，7.45-7.32(m，4H).

Example 10A

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

108.5ml (1154mmol) of acetic anhydride are cooled to 0 ℃ and 52.2ml (1384mmol) of formic acid are added under argon. The mixture is stirred at 0 ℃ for approximately 45min and then 8.5g (46.2mmol) of 2-amino-4-phenyl-3-furonitrile are added in portions. A dark mixture formed and became violet after 15min at 0 ℃. The cooling was removed and the suspension was heated to RT, which is now blue. After 15min, the mixture was heated to reflux (bath temperature 125-. The mixture was stirred at reflux overnight. After cooling, it was concentrated under vacuum and the residue was dried under high vacuum. About 3g of dark red to black solid are obtained from the crude product by column filtration on silica gel (solvent gradient: dichloromethane → dichloromethane/methanol 50: 1). It is dissolved in about 8ml of dichloromethane, precipitated with diisopropyl ether, filtered off with suction and dried under high vacuum. 1.81g (purity about 84%, yield about 15% of theory) of the title compound are obtained as a dark red solid.

LC-MS (method 3): r_t＝3.2min；m/z＝211(M-H)⁺

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

Example 11A

4-chloro-5-phenyl-furo [2, 3-d ] pyrimidine

To 1.8g (ca. 6.8mmol) of 5-phenyl-furan [2, 3-d ] pyrimidin-4 (3H) -one at RT was added 9.5ml (101.8mmol) of phosphorus oxychloride and the mixture was heated at reflux for 1H. The resulting black mixture was cooled to RT and carefully added dropwise at < 10 ℃ to a well stirred solution of 70ml of concentrated ammonia solution cooled to 0 ℃ and 50ml of water (pH > 9). At the end of the addition, the black suspension was heated to RT and stirred for a further 15 min. The black solid was filtered off with suction, reslurried three times with water, filtered with suction and dried under high vacuum. The solid was dissolved in dichloromethane and filtered on a column of silica gel (flow agent: dichloromethane). 1371mg (80.6% of theory) of the title compound are obtained as a yellow solid.

LC-MS (method 4): r_t＝2.47min；m/z＝231(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.90(s，1H)，8.49(s，1H)，7.64-7.58(m，2H)，7.52-7.45(m，3H).

Example 12A

N- (4, 4-diethoxybutyl) -5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-amine

600mg (1.78mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, 344.7mg (2.14mmol) 4-aminobutanal-diethylacetal and 0.465ml (2.67mmol) DIEA were stirred in 5ml DMF at 80 ℃ overnight. After cooling, the mixture was purified directly by preparative RP-HPLC (gradient acetonitrile/water). 746mg (90.7% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.87min；m/z＝462(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.34(s，1H)，7.48-7.41(m，4H)，7.38-7.30(m，3H)，7.13(d，2H)，5.12(t，1H)，4.40(t，1H)，3.35(s，3H)，3.55-3.47(m，2H)，3.42-3.35(m，4H)，1.49-1.38(m，4H)，1.09(t，6H).

Example 13A

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

640mg (1.39mmol) of N- (4, 4-diethoxybutyl) -5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-amine are dissolved in 5ml of acetone and 1ml of 1N hydrochloric acid are added at RT. After 1h, the reaction mixture was added to water and extracted three times with dichloromethane. The organic phases are combined and washed with buffer solution (pH 7) and saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (flow agent: dichloromethane/ethyl acetate 2: 1). 191mg (35.6% of theory) of the title compound are obtained.

LC-MS (method 5): r_t＝2.57min；m/z＝388(M+H)⁺。

Example 14A

6- [ (6-Phenylfuro [2, 3-d ] pyrimidin-4-yl) amino ] hexanoic acid methyl ester

2.0g (8.67mmol) of 4-chloro-6-phenylfuran [2, 3-d ] pyrimidine in 5ml of DMF and 6.04ml (34.7mmol) of DIEA were heated to 160 ℃. 3.15g (17.34mmol) of methyl 6-aminocaproate hydrochloride were added and stirred at 160 ℃ for 4 h. After cooling, the mixture was added to ice water and extracted three times with ethyl acetate. The organic phases are combined and washed with saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Methanol was added to the resid. The precipitated solid is filtered off with suction, washed with methanol and dried under high vacuum. 1.85g (57.2% of theory) of the title compound are obtained.

LC-MS (method 5): r_t＝2.38min；m/z＝340(M+H)⁺。

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.24(s，1H)，7.98(br.s，1H)，7.79(d，2H)，7.51(t，2H)，7.43-7.37(m，2H)，3.59(s，3H)，3.49(q，2H)，2.32(t，2H)，1.65-1.56(m，4H)，1.41-1.35(m，2H).

Example 15A

6- [ (5-bromo-6-phenylfuro [2, 3-d ] pyrimidin-4-yl) amino ] hexanoic acid methyl ester

1.75g (5.15mmol) of methyl 6- [ (6-phenylfuran [2, 3-d ] pyrimidin-4-yl) amino ] hexanoate was placed in 5.2ml of tetrachloromethane. At RT, 1.054g (5.92mmol) of N-bromosuccinimide are added and the mixture is then heated at reflux for about 1 h. After cooling, the residue is concentrated by evaporation in vacuo and chromatographed on silica gel (flow agent: cyclohexane/ethyl acetate 4: 1). 0.89g (41.2% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.64min；m/z＝420(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.33(s，1H)，8.02(d，2H)，7.61-7.49(m，3H)，7.04(t，1H)，3.59(s，3H)，3.59-3.52(m，2H)，2.31(t，2H)，1.68-1.54(m，4H)，1.40-1.31(m，2H).

Example 16A

6- [ (5-Phenylfuro [2, 3-d ] pyrimidin-4-yl) amino ] hexanoic acid methyl ester

500mg (2.19mmol) of 4-chloro-5-phenylfuran [2, 3-d ] pyrimidine, 1.51ml (8.67mmol) of DIEA and 1ml of DMF are heated to 160 ℃ and 787.6mg (4.34mmol) of methyl 6-aminocaproate hydrochloride are added. After 4h at 160 ℃ the reaction mixture was cooled, added to ice water and extracted three times with ethyl acetate. The organic phases are combined and washed with saturated ammonium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 10: 1 → 3: 1). 470mg (63.9% of theory) of the title compound are obtained.

LC-MS (method 5): r_t＝2.43min；m/z＝340(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.35(s，1H)，7.48(s，1H)，7.55-7.45(m，5H)，5.82(t，1H)，3.49(s，3H)，3.44(q，2H)，2.31(t，2H)，1.60-1.50(m，4H)，1.33-1.25(m，2H).

Example 17A

6- [ (6-bromo-5-phenylfuro [2, 3-d ] pyrimidin-4-yl) amino ] hexanoic acid methyl ester

To a mixture of 100mg (0.295mmol) 4-chloro-5-phenyl-furo [2, 3-d ] pyrimidine and 0.3ml tetrachloromethane at RT was added 57.7mg (0.324mmol) N-bromosuccinimide. After 1h at RT, the reaction mixture was concentrated by evaporation in vacuo and the residue was purified by preparative RP-HPLC (gradient acetonitrile/water). 72mg (58.4% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.52min；m/z＝418/420(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.61-7.50(m，5H)，5.07(t，1H)，3.57(s，3H)，3.49(q，2H)，2.29(t，2H)，1.52-1.42(m，4H)，1.28-1.20(m，2H).

Example 18A

6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl) amino } hexanenitrile

To 1.0g (3.0mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in10 ml DMF are added 1.15g (8.9mmol) DIEA and 0.67g (5.9mmol) 6-aminocapronitrile and heated 2h to 120 ℃. After cooling, water was added to the mixture and extracted three times with ethyl acetate. The organic phase is washed with water, with dilute hydrochloric acid and with saturated sodium chloride solution, dried and concentrated by evaporation. 1.2g (98% of theory) of a yellow oil are obtained and used as starting material in further reactions.

LC-MS (method 5): r_t＝2.87min；m/z＝412(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.4(s，1H)，7.55(m，2H)，7.4(m，2H)，7.25(m，3H)，7.15(m，2H)，4.4(br.s，1H)，3.9(s，3H)，3.5(m，2H)，2.35(t，2H)，1.65(m，2H)，1.5(m，2H)，1.4(m，2H).

Example 19A

7- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl) amino } heptanenitrile

The title compound can be obtained from 4-chloro-5- (4-methoxyphenyl) -6-phenyl-furan [2, 3-d ] pyrimidine in three stages:

stage 1:

to 1.0g (3.0mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine and 0.70g (5.9mmol) 6-aminohexanol in10 ml DMF was added 1.15g (8.9mmol) DIEA and heated 4h to 120 ℃. The mixture was then diluted with ethyl acetate, washed with water and dilute hydrochloric acid, dried, and concentrated by evaporation. The residue was purified by RP-HPLC (column: Grossil 250 mm. times.40 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile). 364mg (29% of theory) of 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hex-1-ol are obtained as a yellow oil which solidifies after 2 days of rest.

And (2) stage:

333mg (0.80mmol) of 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hex-1-ol and 122. mu.l (0.88mmol) of triethylamine were dissolved in dichloromethane and 62. mu.l (0.80mmol) of methanesulfonyl chloride dissolved in dichloromethane (the total amount of dichloromethane was 20ml) were added at 0 ℃. After stirring overnight at RT, the mixture was washed with water and with saturated sodium chloride solution and dried over magnesium sulfate. Concentration by evaporation gave 400mg (amount) of 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexyl-methanesulfonate, which was used as starting material in the further reaction.

And (3) stage:

a mixture of 400mg (approx. 0.80mmol) of 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexyl-methanesulfonate and 526mg (8.1mmol) of potassium cyanide in 20ml of DMF was stirred at 80 ℃ overnight. After cooling, it was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated by evaporation. The crude product was purified by RP-HPLC (column: Grossil 250 mm. times.40 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). 249mg (72% of theory) of the title compound are obtained as a pale yellow oil.

LC-MS (method 4): r_t＝2.90min；m/z＝426(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.35(s，1H)，7.55(m，4H)，7.35(m，3H)，7.15(m，2H)，5.0(t，1H)，3.85(s，3H)，3.45(m，2H)，2.45(t，2H)，1.55(m，2H)，1.4(m，2H)，1.3(m，2H)，1.15(m，2H).

Example 20A

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

850mg (3.8mmol) of 6-hydroxyhexanenitrile obtained according to Eur.J.Med.chem.36(4), 303-311(2001) is dissolved in 15ml of DMF, 180mg of 60% sodium hydride (dispersed in mineral oil; approx. 4.5mmol) are added at 0 ℃ and the mixture is stirred at room temperature for 1 h. Next, 1.26g (3.8mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine were added and the mixture was stirred at 120 ℃ overnight. After cooling, water was added to the mixture and extracted with ethyl acetate. The organic phase was dried and concentrated by evaporation. The residue is purified by flash chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 2: 1 → cyclohexane/ethyl acetate 1: 2). 1.05g (68% of theory) of an orange oil are obtained, which are used as starting material in further reactions.

LC-MS (method 5): r_t＝2.97min；m/z＝413(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，7.55(m，2H)，7.25-7.45(m，5H)，7.0-7.1(m，2H)，4.4(t，2H)，3.85(s，3H)，2.4(t，2H)，1.6(m，2H)，1.5(m，2H)，1.25(m，2H).

Example 21A

5- (4-methoxyphenyl) -6-phenyl-N- {3- [ 2-cyanoethoxy ] propyl } furan [2, 3-d ] pyrimidin-4-amine

Stage 1:

1.00g (3.0mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine are dissolved in10 ml of DMF and 1.15g (8.9mmol) of DIEA are added. 0.45g (5.9mmol) of 3-aminopropanol was added and then heated to 120 ℃ over a period of 2 h. After cooling, the mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid followed by saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated by evaporation. Purification by RP-HPLC (column: Grossil 250mm X30mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). 671mg (60% of theory) of 3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } propan-1-ol are obtained in the form of light brown crystals.

LC-MS (method 2): r_t＝2.13min；m/z＝376(M+H)⁺

And (2) stage:

to 300mg (0.80mmol) of the compound from stage 1 were added 47mg (0.89mmol) of acrylonitrile and 57mg (0.83mmol) of sodium ethoxide. The mixture was stirred at 80 ℃ overnight. After cooling, the mixture was taken up in DMSO and purified directly by RP-HPLC (column: Grossil 250mm X30mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). 160mg (47% of theory) of the title compound are obtained as a yellow oil.

LC-MS (method 2): r_t＝2.43min；m/z＝429(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 8.3(s, 1H), 7.1-7.45(m, 9H), 5.2(m, 1H), 3.85(s, 3H), 3.5(m, 4H), aprex.3.3 (m, 2H, nh, H)₂Partial O occlusion), 2.7(t, 2H), 1.7(quin, 2H).

Example 22A

5- (4-methoxyphenyl) -6-phenyl-N- (5-aminopentyl) -furan [2, 3-d ] pyrimidin-4-amine

Stage 1:

in 5ml DMF 1.00g (3.0mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenyl-furan [2, 3-d ] pyrimidine was dissolved and 1.15g (8.9mmol) DIEA was added. 1.20g (5.9mmol) of 5- [ (tert-butyloxycarbonyl) amino ] -1-pentylamine [ obtainable from 1, 5-diaminopentane according to J.Med.chem.47(20), 4933-4940(2004) ] and the mixture was then heated to 80 ℃ for 3 h. After cooling, the mixture was diluted with dichloromethane and washed with water and then with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated by evaporation. The residue was purified by RP-HPLC (column: Grossil 250mmx30mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). A total of 1.07g (67% of theory) of tert-butyl- (5- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } pentyl) carbamate in the form of light brown crystals were obtained.

LC-MS (method 2): r_t＝2.85min；m/z＝503(M+H)⁺

And (2) stage:

380mg (0.76mmol) of the compound from stage 1 are dissolved in 5ml of dichloromethane and 0.4ml of anisole and then 5.5ml of trifluoroacetic acid are added. Stir at room temperature for 2 h. The mixture was diluted with dichloromethane and washed with sodium bicarbonate solution until neutral. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The residue remaining after concentration by evaporation is dissolved in ethanol and concentrated by evaporation; this operation was repeated three times. 349mg (82% of theory) of the title compound are obtained as pale yellow foam.

LC-MS (method 2): r_t＝2.43min；m/z＝429(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 8.3(s, 1H), 7.1-7.45(m, 9H), 5.4(br.m, 1H), 5.1(m, 1H), 3.85(s, 3H), about 3.3(m, 2H, H-coated), and₂partial O-masking), 2.6(t, 2H), 1.1-1.57(m, 6H).

Example 23A

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

Stage 1:

to a solution of 461mg (7.4mmol) of ethylene glycol in10 ml of DMF at 0 ℃ are added 59mg (1.5mmol) of 60% sodium hydride. After warming to room temperature, stirring was continued for 1 h. Thereafter 0.50g (1.5mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine are added and the mixture is stirred at room temperature for 3 h. Next, diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The crude product thus obtained is purified by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). In this way 412mg (77% of theory) of 2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } ethanol are obtained.

And (2) stage:

as in example 21A, stage 2, 245mg (61% of theory) of the title compound are obtained from 350mg (0.97mmol) of the compound from stage 1 in the form of yellow crystals.

m.p.：103-104℃

LC-MS (method 2): r_t＝2.84min；m/z＝416(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.6(s，1H)，7.35-7.55(m，7H)，7.05(m，2H)，4.55(m，2H)，3.85(s，3H)，3.7(m，2H)，3.45(t，2H)，2.7(t，2H).

Example 24A

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

The title compound was obtained from 1, 3-propanediol and 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in two stages as in example 23A.

Yield: 304mg (89% of theory)

m.p.：88-89℃

LC-MS (method 4): r_t＝2.94min；m/z＝430(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.6(s，1H)，7.35-7.55(m，7H)，7.05(m，2H)，4.45(m，2H)，3.85(s，3H)，3.7(m，2H)，3.5(t，2H)，2.7(t，2H)，1.7(quin，2H).

Example 25A

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

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

¹H-NMR(400MHz，CDCl₃)：δ＝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 26A

1- (4-ethylphenyl) -2-hydroxy-2-phenylethanones

290ml (2.069mol) of diisopropylamine were dissolved in 3.6 l of DME and precooled to-78 ℃. 820ml (2.05mol) of n-butyllithium (2.5M solution in hexane) are added over a period of about 20min (temperature < -60 ℃). After 15min at-60 ℃ a solution of 435g (1.864mol) (4-ethylphenyl) [ (trimethylsilyl) oxy ] acetonitrile in 1.4 l DME was added dropwise. The mixture was stirred at-60 ℃ for a further 30min before addition of 189.5ml (1.864mol) of a solution of benzaldehyde in 1.4 l of DME (time approx. 20min, temperature-60 ℃). The mixture was heated to RT over a period of 4h before 7 l of saturated ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate. After phase separation, the organic phase is washed with saturated ammonium chloride solution, dried and concentrated by evaporation in vacuo. The residue was dissolved in 7 liters of dioxane and 5 liters of methanol, and 6 liters of 1N hydrochloric acid was added. The mixture is stirred at RT overnight, after which 11 l of saturated sodium chloride solution are added and extracted with 6.5 l of ethyl acetate. The organic phase is washed with water and with saturated sodium chloride solution, dried and concentrated by evaporation in vacuo. The residue is dissolved in2 l diisopropyl ether, seeded crystals are added and stirred for 2 h. The precipitated solid is filtered off with suction, washed with 300ml of diisopropyl ether and petroleum ether and dried under vacuum. After concentration of the mother liquor and storage at 4 ℃ for 2 days, the precipitated solid is filtered off again with suction, washed with approximately 100ml of diisopropyl ether and petroleum ether and dried under vacuum. When the two solids are combined, 154.9g (34% of theory) of the target product are obtained.

HPLC (method 1): r_t＝4.55min

MS(DCI)：m/z＝258(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.85(d，2H)，7.48-7.35(m，5H)，7.21(d，2H)，5.92(d，1H)，4.59(d，1H)，2.65(q，2H)，1.20(t，3H).

Example 27A

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

A mixture of 145g (603mmol) of 1- (4-ethylphenyl) -2-hydroxy-2-phenylethanone and 51.8g (784.4mmol) of malononitrile in 2.23 l of DMF is cooled to 0 ℃ and 53.7ml (518mmol) of diethylamine are added with cooling. After 1h, the reaction mixture was heated to RT and stirred at RT for a further 4h, after which 1.5 l of water were added. After 30min, most of the water was decanted and replaced with 750ml of fresh water. The mixture was stirred vigorously and then decanted from a sticky organic residue. The residue was dissolved in ethyl acetate, dried, and concentrated under vacuum until the product started to crystallize. 450ml of diisopropyl ether was added, stirred and then allowed to stand overnight. The crystals are filtered off with suction, washed twice with 50ml of diisopropyl ether and dried under vacuum. 98.5g (56.6% of theory) of the title product are obtained.

HPLC (method 1): r_t＝5.10min

MS(DCI)：m/z＝306(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.90-7.82(m，4H)，7.28-7.18(m，5H)，4.98(s，2H)，2.69(q，2H)，1.28(t，3H).

Example 28A

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

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

HPLC (method 1): r_t＝4.77min

MS(DCI)：m/z＝334(M+NH₄)⁺，317(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.63(br.s，1H)，8.19(s，1H)，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 29A

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

To 360ml (4.6mmol) of phosphorus oxychloride were placed in a pre-charge of 72g (227.6mmol) of 5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4 (3H) -one and heated to reflux. The mixture is stirred at 120 ℃ for about 1h, after which, after cooling to RT, the reaction mixture is added dropwise (pH > 9, temperature 55-75 ℃) to a mixture of 2.2 l of a 25% ammonia solution and 1.2 l of water, under controlled dosage and with vigorous stirring. The aqueous mixture was extracted three times with dichloromethane, the organic phases were combined, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is washed with a small amount of diisopropyl ether and, after filtration and drying under high vacuum, 66.1g (85.2% of theory) of the title product are obtained.

HPLC (method 6): r_t＝5.68min

MS(DCI)：m/z＝335(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.76(s，1H)，7.61(d，2H)，7.48-7.30(m，7H)，2.78(q，2H)，1.36(t，3H).

Example 30A

6-phenyl-furan [2, 3-d ] pyrimidin-4-amine

110g (597mmol) of 2-amino-5-phenyl-3-furonitrile are suspended in 355ml (9mol) of formamide and heated for 1.5h (bath temperature approx. 210 ℃). After which the mixture was cooled to RT and stirred into water. The precipitated solid was filtered off with suction and washed with water. The still moist product is stirred in dichloromethane, filtered once more with suction and dried under vacuum. 106g (80% of theory) of the title compound are obtained.

LC-MS (method 3): r_t＝3.1min；m/z＝212(M+H)⁺

HPLC (method 1): r_t3.63minHPLC (method 1): r_t＝3.63min

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.20(s，1H)，7.8(d，2H)，7.55-7.32(m，6H).

Example 31A

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

80g (378.7mmol) of 6-phenyl-furan [2, 3-d ] pyrimidin-4-amine in 770ml of carbon tetrachloride were heated to 60 ℃. 84.3g (473.4mmol) of N-bromosuccinimide are added and the mixture is stirred at reflux overnight. After cooling, filtration, the filter cake is stirred with dichloromethane and then acetonitrile and filtered again. The filter cake was then dried under vacuum. 86g of the expected product (78.2% of theory) are obtained.

MS(DCI)：m/z＝290/292(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.28(s，1H)，8.03(d，2H)，7.60-7.50(m，5H).

Example 32A

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

54g (186mmol) of 5-bromo-6-phenyl-furan [2, 3-d ] pyrimidin-4-amine are placed in 135ml of chloroform, 70ml of 4N hydrogen chloride in dioxane (280mmol) are added and heated to reflux. 50ml (372mmol) of isoamyl nitrite (release gas) are added dropwise. At the end of the addition, it was stirred at reflux for 3h, after which the cooled reaction mixture was added to water and it was extracted with dichloromethane. The organic phase is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product is purified by chromatography on silica gel (eluent: dichloromethane). For further purification, the product is mixed in methanol, filtered with suction, and dried under high vacuum. 32g of the expected product are obtained (55.5% of theory).

LC-MS (method 2): r_t＝2.54min；m/z＝309/310(M+H)⁺

HPLC (method 1): r_t＝5.08min

¹H-NMR(400MHz，CDCl₃)：δ＝8.79(s，1H)，8.23-8.20(m，2H)，7.58-7.51(m，3H).

Example 33A

[ (5-bromo-6-phenylfuran [2, 3-d ] pyrimidin-4-yl) (methyl) amino ] hexanoic acid methyl ester

To a mixture of 500mg (1.2mmol) of methyl 6- [ (5-bromo-6-phenylfuran [2, 3-d ] pyrimidin-4-yl) amino ] hexanoate and 112. mu.l (1.79mmol) of methyl iodide in 1ml of DMF at 0 ℃ were added 52.5mg (1.32mmol) of 60% sodium hydride in portions. The ice-cold was removed and the mixture was heated to RT. After 1h, dilute with water and dichloromethane and extract the separated aqueous phase with dichloromethane. The organic phases are combined and washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. 472.6mg (91.2% of theory) of oil are obtained.

LC-MS (method 7): r_t＝4.24min；m/z＝432/434(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.38(s，1H)，8.0(d，2H)，7.60-7.50(m，3H)，3.70(t，2H)，3.29(s，3H)，2.29(t，2H)，1.72-1.65(m，2H)，1.60-1.52(m，2H)，1.31-1.26(m，2H).

Example 34A

(-) - (2R) -2-methyl-3- (trityloxy) propionic acid methyl ester

In 13ml of dichloromethane and 2.5ml (17.8mmol) of triethylamine 1.5g (12.7mmol) (-) -methyl-D-. beta. -hydroxyisobutyrate are placed in a pre-reaction, cooled to 0 ℃ and 4.43g (15.9mmol) of triphenylmethyl chloride dissolved in dichloromethane are added. The cooling was removed and the mixture was stirred for 2h, after which it was diluted with dichloromethane, washed several times with water and with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated by evaporation in vacuo. The product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20: 1). 2.81g of the expected product are obtained (61.4% of theory).

LC-MS (method 2): r_t＝2.98min；m/z＝243

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.38-7.20(m，approx.15H)，3.63(s，3H)，3.17-3.09(m，2H)，2.72(q，1H)，1.05(d，3H).

[α]_D ²⁰-15.5 °, c-0.545, chloroform.

Example 35A

(-) - (2S) -2-methyl-3- (trityloxy) propan-1-ol

1.4g (3.88mmol) of methyl (-) -2R-2-methyl-3- (trityloxy) propionate were dissolved in 5ml of anhydrous THF and 1.94ml (1.94mmol) of a 1M solution of lithium aluminum hydride in THF were added dropwise. The mixture was stirred at-10 ℃ for 1h, after which it was diluted with a mixture of acetone and dichloromethane and water was added. The aqueous phase was extracted twice with dichloromethane. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. After chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8: 1 → 4: 1), 0.98g (75.5% of theory) of the expected product is obtained.

LC-MS (method 8): r_t＝2.85min；m/z＝243，355(M+H)⁺

MS(DCI)：m/z＝243，350(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆): δ 7.40-7.24(m, about 15H), 4.38(t, 1H), 3.43-3.37(m, 1H), 3.32-3.28(m, 1H), 3.01(dd, 1H), 2.83(dd, 1H), 1.84(m, 1H), 0.88(d, 3H).

[α]_D ²⁰-30 °, c-0.49, chloroform.

Example 36A

(-) - { [ (2S) -2-methyl-3- (trityloxy) propyl ] oxy } acetic acid tert-butyl ester

To 800mg (2.41mmol) of (-) -2S-2-methyl-3- (trityloxy) propan-1-ol in2ml of dichloroTo the solution in methane was added 53.2mg (0.12mmol) of rhodium diacetate [ as dimer Rh ]₂(OAc)₄]. To the vigorously stirred suspension, an excess of tert-butyl diazoacetate (approx.2 equivalents) is slowly added dropwise with N₂Is discharged (time about 1 h). The reaction mixture was then diluted with dichloromethane, washed three times with water and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10: 1). Approximately 1000mg of the title product are obtained with slight contamination.

MS(DCI)：m/z＝464(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.40-7.25(m，15H)，3.91(s，2H)，3.48(dd，1H)，3.35(dd，1H)，2.98(dd，1H)，2.88(dd，1H)，1.98(m，1H)，1.41(s，9H)，0.89(d，3H).

[α]_D ²⁰-6.6 °, c-0.505, chloroform.

Example 37A

(+) - { [ (2R) -3-hydroxy-2-methylpropyl ] oxy } acetic acid tert-butyl ester

900mg (approx.2.02 mmol) of tert-butyl (-) - { [ (2S) -2-methyl-3- (trityloxy) propyl ] oxy } acetate are dissolved in2ml of dichloromethane and 0.5ml of methanol and then firstly at 0 ℃ and then at RT excess (approx.3 equiv.) of anhydrous zinc bromide are added portionwise. The mixture was stirred at RT for 2-3h, after which it was diluted with dichloromethane and washed twice with water and with saturated sodium chloride solution. Dried over magnesium sulfate and concentrated by evaporation in vacuo. 257mg (approximately 62% of theory) of the title product are isolated by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10: 1 → 2: 1).

MS(DCI)：m/z＝222(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.40(t，1H)，3.95(s，2H)，3.42-3.36(m，2H)，3.28-3.22(m，2H)，1.77(m，1H)，1.44(s，9H)，0.85(d，3H).

[α]_D ²⁰+10.5 °, c-0.525, chloroform.

Example 38A

(+) - (2S) -2-methyl-3- (trityloxy) propionic acid methyl ester

10.33g (87.5mmol) (+) -methyl-L-. beta. -hydroxyisobutyrate was placed in10 ml of dichloromethane and 14.2ml (174.9mmol) of pyridine beforehand, cooled to 0 ℃ and 1.07g (8.7mmol) of DMAP was added, and then 30.5g (109mmol) of trityl chloride dissolved in dichloromethane was added with ice cooling. The cooling was removed and the mixture was stirred for 5h, after which it was diluted with enough dichloromethane and washed with water, 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated by evaporation in vacuo. The precipitated crystals were mixed with methanol, filtered, and dried under vacuum. 25.36g (41.4% of theory) of the title compound are obtained.

MS(DCI)：m/z＝378(M+NH₄)⁺

[α]_D ²⁰+6.4 °, c-0.555, chloroform.

Examples39A

(+) - (2R) -2-methyl-3- (trityloxy) propan-1-ol

23g (63.8mmol) (+) - (2S) -2-methyl-3- (trityloxy) propionic acid methyl ester were dissolved in100 ml dry THF, cooled to-20 ℃ and 31.9ml (31.9mmol) of a 1M solution of lithium aluminium hydride in THF were added dropwise. At the end of the addition, stirring was continued for a further 10min at-10 ℃ before dilution with dichloromethane and, at about 0 ℃, a saturated ammonium chloride solution was added carefully. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 5: 1). 11.16g of the title compound (52.6% of theory) are obtained.

¹H-NMR(400MHz，DMSO-d₆): δ ═ 7.40-7.25(m, about 15H), 4.39(t, 1H), 3.43-3.38(m, 1H), 3.32-3.28(m, 1H), 3.02(dd, 1H), 2.82(dd, 1H), 1.84(m, 1H), 0.88(d, 3H).

[α]_D ²⁰25.1 °, c 0.575, chloroform.

Example 40A

(-) - { [ (2R) -2-methyl-3- (trityloxy) propyl ] oxy } acetic acid ethyl ester

To a suspension of 5.0g (15.0mmol) (+) - (2R) -2-methyl-3- (trityloxy) propan-1-ol and 0.332g (0.75mmol) rhodium (II) acetate dimer in 25ml anhydrous dichloromethane was added 3.4ml (33.1mmol) ethyl diazoacetate with vigorous stirring at 0 ℃. At the end of the addition, stirring was continued for a further 5min at 0 ℃ before heating to RT and stirring continued for 2.5h at RT. After dilution with dichloromethane, washing with saturated sodium chloride solution, drying over sodium sulfate and concentration by evaporation in vacuo. The crude product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20: 1). 5.18g of the title compound (79.7% of theory) are obtained.

MS(DCI)：m/z＝436(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.40-7.25(m，15H)，4.10(q，2H)，4.03(s，2H)，3.48(dd，1H)，3.38(dd，1H)，2.98(dd，1H)，2.40(dd，1H)，1.98(m，1H)，1.18(t，3H)，0.90(d，3H).

[α]_D ²⁰-0.9 °, c-0.47, chloroform.

Example 41A

(-) - { [ (2S) -3-hydroxy-2-methylpropyl ] oxy } acetic acid ethyl ester

2.75g (6.58mmol) ethyl (-) - { [ (2R) -2-methyl-3- (trityloxy) propyl ] oxy } acetate are dissolved in 25ml ethanol, 300mg of 10% Pd/C are added and the mixture is stirred at RT under a hydrogen atmosphere (atmospheric pressure) for 3 h. Filter over Celite and concentrate the filtrate under vacuum. The crude product is purified by filtration over silica gel (eluent: ethyl/ethyl acetate 7: 1 → 4: 1). 1.05g of the title compound (90.6% of theory) are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.40(t，1H)，4.12(q，2H)，4.05(s，2H)，3.41(dd，1H)，3.38-3.32(m，1H)，3.30-3.23(m，2H)，1.78(m，1H)，1.20(t，3H)，0.85(d，3H).

[α]_D ²⁰-12.4 °, c-0.50, chloroform.

Example 42A

3- [ (1S) -2-benzyloxy-1-methylethoxy ] propionic acid tert-butyl ester

A mixture of 20g (120.3mmol) (+) - (S) -1-benzyloxy-2-propanol and 123g (962mmol) tert-butyl acrylate was cooled to 0 ℃ and 962mg (24mmol, 60%) sodium hydride were added in portions. The mixture was stirred at 0 ℃ for 10min, after which saturated ammonium chloride solution was carefully added. After phase separation, the aqueous phase was extracted twice with dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated under vacuum, then under high vacuum. The crude product is purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 30: 1). 18.4g of the title compound (51.9% of theory) are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.38-7.25(m，5H)，4.49(s，2H)，3.64(t，2H)，3.61-3.58(m，1H)，3.40(dd，1H)，3.32(dd，1H)，2.39(t，2H)，1.39(s，9H)，1.05(d，3H).

Example 43A

(+) -3- [ (1S) -2-hydroxy-1-methylethoxy ] propionic acid tert-butyl ester

18.1g (61.5mmol) tert-butyl 3- [ (1S) -2-benzyloxy-1-methylethoxy ] propionate was dissolved in100 ml ethanol, 1.96g 10% Pd/C was added and stirred at RT under hydrogen atmosphere (atmospheric pressure) for 2 h. Filter over Celite and concentrate the filtrate under vacuum. 13.8g of the title compound are obtained as crude product which is not further purified (about 92% of theory).

MS(DCI)：m/z＝222(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.50(t，1H)，3.67-3.60(m，2H)，3.40-3.34(m，approx.2H)，3.27-3.21(m，1H)，2.39(t，2H)，1.39(s，9H)，1.02(d，3H).

[α]_D ²⁰+15.0 °, c-0.49, chloroform.

Example 44A

6-oxo-heptanoic acid methyl ester

10g of 6-oxoheptanoic acid (69.4mmol) was dissolved in100 ml of methanol. A few drops of concentrated sulfuric acid were added and stirred under reflux for 1.5 h. And then concentrated by evaporation. Taken up in dichloromethane and washed once with saturated sodium bicarbonate solution. The phases were separated, the organic phase was dried and concentrated by evaporation. 10.1g of the title compound (91.1% of theory) are obtained.

¹H-NMR(400MHz，CDCl₃)：δ＝3.67(s，3H)，2.44(t，2H)，2.32(t，2H)，2.13(s，3H)，1.67-1.55(m，4H).

Example 45A

(+/-) -6-hydroxy-heptanoic acid methyl ester

To 50ml of methanol was placed 10g (63.2mmol) of 6-oxo-heptanoic acid methyl ester. 1.196g (31.6mmol) of sodium borohydride were added in portions. After the exothermic reaction subsided, it was stirred under reflux for another 30 min. And then concentrated by evaporation. The residue was taken up in water, acidified with 1M hydrochloric acid and extracted twice with dichloromethane. The organic phase was dried and concentrated by evaporation. 7.9g (78.0% of theory) of the title compound are obtained.

¹H-NMR(400MHz，CDCl₃)：δ＝3.83-3.75(m，1H)，3.67(s，3H)，2.32(t，2H)，1.69-1.58(m，2H)，1.53-1.30(m，4H)，1.19(d，3H).

Example 46A

[ (3R) -3-hydroxybutyl ] oxy-acetic acid tert-butyl ester

1.0g (11.1mmol) of (3R) -butane-1, 3-diol are placed in 20ml of THF at 0 ℃. 5.55ml (11.1mmol) of a 2M solution of the phosphazene base P2-tert-butyl in THF are added dropwise and stirred at 0 ℃ for 30 min. Thereafter, 2.27g (11.65mmol) of tert-butyl bromoacetate were added. After stirring at 0 ℃ for 30min, it was allowed to return to RT and stirred for a further 1 h. After this time, it was diluted with ethyl acetate, water was added and acidified with 10% citric acid solution. Extracted once more with ethyl acetate and the combined organic phases are washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Purification is carried out by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 8: 2). 730mg (32.2% of theory) of the title compound are obtained, whichAccording to¹H-NMR (bimodal at 1.18 ppm) contained about 10% of the regioisomer [ (1R) -3-hydroxy-1-methylpropyl ]]Oxy } acetic acid tert-butyl ester.

¹H-NMR(400MHz，CDCl₃)：δ＝4.11-4.02(m，1H)，3.96(d，2H)，3.76-3.62(m，2H)，1.79-1.62(m，2H)，1.48(s，9H)，1.21(d，3H).

Example 47A

(2R) -1- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-2-ol

And

(2R) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-1-ol

5.648g (74.23mmol) of (2R) -propane-1, 2-diol are placed in 30ml of THF. 4.165g (37.11mmol) potassium tert-butoxide are added and stirring is continued at RT for a further 15 min. Then cooled to 0 ℃ and 5.00g (14.85mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] are added dropwise over a period of 30min]Solutions of pyrimidine in 15ml THF. After which it was allowed to return to RT and stirred for a further 3 h. After this time, it was diluted with dichloromethane, water was added and acidified with 10% citric acid solution. The phases were separated, the aqueous phase was extracted once with dichloromethane, the organic phases were combined, washed once with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. Purification was carried out by chromatography on silica gel (solvent: cyclohexane/ethyl acetate 7: 3). According to¹H-NMR, the isolate was a mixture of the two title compounds. ObtainA total of 3.56g (63.7% of theory) are obtained.

LC-MS (method 8): r_t2.71min (singlet); m/z 377(M + H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.50(2x s，2x 1H)，7.62(m，2x 2H)，7.42(m，2x 2H)，7.31(m，2x 3H)，6.97(m，2x 2H)，5.31(m，1x 1H)，4.48(dd，1x 1H)，4.14(dd，1x 1H)，4.01(m，1x 1H)，3.39(2x s，2x 3H)，3.72(m，1x 1H)，3.55(m，1x 1H)，1.31(d，1x 3H)，1.15(d，1x 3H).

The production of the compounds listed in the following table is analogous to the synthesis described above. It correspondingly starts from 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidine or from 4-chloro-5- (4-ethylphenyl) -6-phenylfuro [2, 3-d ] pyrimidine and uses (2S) -propane-1, 2-diol or (2R) -propane-1, 2-diol, respectively:

example 51A

1- [ benzyl (methyl) amino ] propanone

In100 ml of toluene were placed 12.118g (100mmol) of N-methylbenzylamine and 16.584g (120mmol) of potassium carbonate. 11.103g (120mmol) of chloroacetone were added dropwise and stirred at reflux overnight. After cooling to RT, filtration to remove salts and concentration by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 8: 2) to yield 9.0g (50.8% of theory) of the title compound.

¹H-NMR(400MHz，CDCl₃)：δ＝7.36-7.22(m，5H)，3.57(s，2H)，3.13(s，2H)，2.29(s，3H)，2.13(s，3H).

Example 52A

(+/-) -1- [ benzyl (methyl) amino ] propan-2-ol

To 40ml of methanol was added 8.00g (45.13mmol) of 1- [ benzyl (methyl) amino ] acetone. 854mg (22.57mmol) of sodium borohydride are added in portions with stirring at RT. Stirring was carried out at RT for 30min and then at reflux for a further 30 min. Concentrate by evaporation and absorb the residue in water. Extracted twice with ethyl acetate, the combined organic phases washed once with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated by evaporation. 7.80g (81.9% of theory) of the title compound are obtained without further purification.

¹H-NMR(400MHz，CDCl₃)：δ＝7.36-7.22(m，5H)，3.90-3.80(m，1H)，3.66(d，1H)，3.43(d，1H)，2.33(dd，1H)，2.31(dd，1H)，2.21(s，3H)，1.11(d，3H).

Example 53A

(+/-) -N-benzyl-2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropan-1-amine

1.878g (8.91mmol) (+/-) -1- [ benzyl (methyl) amino ] propan-2-ol are placed in 20ml THF under argon and cooled to 0 ℃. 4.5ml (8.91mmol) of a 2M solution of the phosphazene base P2-tert-butyl in THF are added and stirred for a further 10min at RT. Then cooled to 0 ℃ again. 2.00g (5.94mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine were added and stirred at RT for 1 h. After which it was diluted with ethyl acetate and washed with water. The aqueous phase was extracted once more with ethyl acetate. The organic phases are combined and washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Purification by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 85: 15) gives 1.71g (60.0% of theory) of the title compound.

LC-MS (method 8): r_t＝1.88min；m/z＝480(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.50(s，1H)，7.62(m，2H)，7.36(d，2H)，7.32-7.15(m，8H)，6.86(d，2H)，5.65-5.57(m，1H)，3.81(s，3H)，3.41(dd，2H)，2.62(dd，1H)，2.43(dd，1H)，2.10(s，3H)，1.29(d，3H).

Example 54A

(+/-) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropan-1-amine

500mg of palladium on charcoal (10%) are placed in100 ml of methanol under argon. 1.7g (3.55mmol) (+/-) -N-benzyl-2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropan-1-amine and 2.5ml acetic acid were added and hydrogenated at RT and normal pressure. After 2h, it was filtered through a celite filter and concentrated by evaporation. The residue was dissolved in water and washed twice with ethyl acetate. The ethyl acetate phase was discarded. The aqueous phase was made alkaline with solid sodium bicarbonate and extracted twice with ethyl acetate. The combined ethyl acetate phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. 900mg (65.2% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝1.57min；m/z＝390(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.50(s，1H)，7.63(m，2H)，7.38(d，2H)，7.34-7.25(m，3H)，6.96(d，2H)，5.45-5.35(m，1H)，3.88(s，3H)，2.64(m，2H)，2.30(s，3H)，1.35(d，3H).

Example 55A

(+) -tert-butyl { [1, 5-dimethylhex-4-en-1-yl ] oxy } diphenylsilane

50g (390.0mmol) of (6R) -6-methyl-5-heptan-2-ol are placed in 500ml of dichloromethane. 53.10g (779.9mmol) of imidazole and 2.382g (19.50mmol) of 4-dimethylaminopyridine are added. It is cooled to 0 ℃ and 117.91g (429.0mmol) of tert-butyldiphenylchlorosilane are added dropwise. The cooling was removed, allowed to return to RT and stirred at RT for an additional 1 h. 250ml of dichloromethane are added and washed twice with 500ml of water each time. The organic phase was dried over magnesium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: petroleum ether/ethyl acetate 95: 5). 135.0g (94.4% of theory) of the title compound are obtained.

¹H-NMR(400MHz，CDCl₃)：δ＝7.69(m，4H)，7.42-7.32(m，6H)，5.00-4.95(t，1H)，3.88-3.80(m，1H)，2.02-1.88(m，2H)，1.62(s，3H)，1.52(s，3H)，1.52-1.48(m，2H)，1.06(s，3H)，1.05(s，9H).

[α]_D ²⁰+20.2 °, c-0.689, methanol.

Example 56A

(+) - (2E) -6- { [ tert-butyl (diphenyl) silyl ] oxy } hept-2-enoic acid tert-butyl ester

22.20g (60.55mmol) (+) -tert-butyl { [1, 5-Dimethylhexan-4-en-1-yl ] are placed in 240ml of dichloromethane]Oxy diphenylsilane and 165mg (1.96mmol) of sodium bicarbonate and cooled to-78 ℃. Ozone gas was added at-78 ℃ until the solution had a light blue color. Thereafter 47.376g (762mmol) of dimethylsulfide were added, allowed to return to RT and stirred at RT for a further 1 h. Thereafter 27.352g (72.66mmol) triphenylphosphine ylidene (phosphoranylidene) -tert-butyl acetate were added and the mixture was stirred at RT overnight. The mixture was then concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 95: 5) to yield 25.1g (95.4% of theory) of the title compound. According to¹H-NMR, the E/Z ratio being > 10: 1.

MS(DCI)：m/z＝456(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.67(d，4H)，7.43-7.33(m，6H)，6.82-6.73(dt，1H)，5.65(d，1H)，3.91-3.82(m，1H)，2.28-2.10(m，2H)，1.65-1.42(m，2H)，1.48(s，9H)，1.06(d，3H)，1.05(s，9H).

[α]_D ²⁰+22.5 °, c-0.520, methanol.

Example 57A

(2E, 6R) -6-hydroxyhept-2-enoic acid tert-butyl ester

Solution A: 10.71g (267.7mmol) of 60% sodium hydride are suspended in 150ml of anhydrous THF and 43.3ml (276.7mmol) of tert-butyl P, P-dimethylphosphonoacetate are added dropwise with cooling. The mixture was stirred at RT and after about 30min a solution was obtained.

To a solution of 17.87g (178.5mmol) (R) - (γ -valerolactone [ (5R) -5-methyldihydrofuran-2 (3H) -one ] (5R) -5-methyldihydrofuran-2 (3H) -one) in 200ml anhydrous THF cooled to-78 ℃ are added dropwise 187.4ml (187.4mmol) of a 1M DIBAH solution in THF at-78 ℃ and after further stirring for 1H and addition of the solution A prepared above, the addition is ended, the mixture is heated slowly to RT and stirred overnight at RT, the reaction mixture is added to 300ml ethyl acetate and concentrated with 50ml potassium sodium tartrate, after phase separation the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum, the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 5: 1), 32.2g (90.1% of theory) of the title product are obtained, it contains a small amount of cis-isomer.

MS(DCI)：m/z＝218(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝6.70(dt，1H)，5.73(d，1H)，4.44(d，1H)，3.58(m，1H)，2.28-2.13(m，2H)，1.47-1.40(m，2H)，1.45(s，9H)，1.04(d，3H).

Example 58A

(+) -6- { [ tert-butyl (diphenyl) silyl ] oxy } heptic acid tert-butyl ester

149.0g (339.64mmol) (+) - (2E) -6- { [ tert-butyl (diphenyl) silyl ] oxy } hept-2-enoic acid tert-butyl ester were placed in 1000ml ethanol under argon at RT. 15.0g palladium on charcoal (20%, wet with water) was added and hydrogenated at RT under normal pressure. The hydrogen uptake was complete and the mixture was filtered over celite and concentrated by evaporation. 142.0g (95.0% of theory) of the title compound are obtained.

MS(DCI)：m/z＝458(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.68(d，4H)，7.43-7.33(m，6H)，3.87-3.80(m，1H)，2.12(t，2H)，1.53-1.20(m，6H)，1.45(s，9H)，1.05(d，3H)，1.05(s，9H).

[α]_D ²⁰+14.7 °, c-0.7925, methanol.

Example 59A

(-) -6-Hydroxyheptoic acid tert-butyl ester

The method comprises the following steps:

141.0g (319.94mmol) of tert-butyl (+) -6- { [ tert-butyl (diphenyl) silyl ] oxy } heptanoate are placed in 280ml of THF. 479.90ml (479.90mmol) of a 1M solution of tetrabutylammonium fluoride in THF are added dropwise and stirred overnight at RT. Thereafter 4000ml of 10% aqueous sodium chloride solution were added and the pH was adjusted to about 3-4 with citric acid. The extraction was carried out twice with 2000ml of ethyl acetate each time and the combined ethyl acetate phases were washed once with 2000ml of saturated sodium chloride solution. Drying over magnesium sulfate, concentration by evaporation and purification of the residue by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 7: 3). 50.2g (77.5% of theory) of the title product are obtained.

MS(DCI)：m/z＝220(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝3.85-3.75(m，1H)，2.22(t，2H)，1.68-1.54(m，2H)，1.53-1.30(m，4H)，1.45(s，9H)，1.18(d，3H).

[α]_D ²⁰-6.8 °, c 1.073, methanol.

The method 2 comprises the following steps:

32.2g (160.8mmol) of tert-butyl (2E, 6R) -6-hydroxyhept-2-enoate are dissolved in 200ml of ethanol and 1.7g of 10% palladium on charcoal are added. The mixture was stirred at RT under a hydrogen atmosphere (atmospheric pressure) for 2h and then filtered over Celite. The filtrate was concentrated by evaporation in vacuo. After chromatography on silica gel (eluent: cyclohexane/ethyl acetate 10: 1 → 6: 1), 15.66g of the title product (48.1% of theory) are obtained from the residue.

[α]_D ²⁰-21 °, c-0.118, chloroform.

Example 60A

(+) -1- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } propan-2-ol

To 500mg (1.49mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidine are added 2ml of DMF, 223mg (2.97mmol) of (S) - (+) -1-amino-2-propanol and 768mg (5.94mmol) of N, N-diisopropylethylamine. Heated to 100 ℃ for 2h and then allowed to cool to RT. The mixture was separated directly by preparative RP-HPLC (flow agent: acetonitrile/water gradient) without further work-up. 230mg (41.3% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.25min；m/z＝376(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.36(s，1H)，7.53(m，2H)，7.40(d，2H)，7.27(m，3H)，7.07(d，2H)，5.13(m，1H)，3.92(m，4H)，3.56(m，1H)，3.32(m，1H)，1.15(d，2H).

[α]_D ²⁰+3.0 °, c-0.298, methanol.

Example 61A

(-) -1- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } propan-2-ol

To 1.00g (2.97mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine were added 5ml of DMSO, 446mg (5.94mmol) of (R) - (-) -1-amino-2-propanol and 2.07ml (11.88mmol) of N, N-diisopropylethylamine. Heated to 100 ℃ for 2h and then allowed to cool to RT. Then poured onto the ice-water mixture and awaited ice melting. The aqueous phase is decanted, the organic phase is diluted with dichloromethane and washed with water. The aqueous phase was extracted once more with dichloromethane. The organic phases are combined and washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. 1.10g (98.7% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.25min；m/z＝376(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.36(s，1H)，7.53(m，2H)，7.40(d，2H)，7.27(m，3H)，7.07(d，2H)，5.13(t，1H)，3.92(m，4H)，3.56(m，1H)，3.32(m，1H)，1.15(d，2H).

[α]_D ²⁰-3.1 °, c-0.455, methanol.

Example 62A

3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2, 2-dimethylpropan-1-ol

1.546g (14.85mmol) of 2, 2-dimethylpropane-1, 3-diol are placed in 30ml of THF. 833mg (7.42mmol) of potassium tert-butoxide are added and stirring is continued at RT for a further 15 min. After this time, it was cooled to 0 ℃ and a solution of 1.00g (2.97mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in 15ml of THF was added dropwise over a period of 30 min. Let it return to RT and stir at RT for another 30 min. After which dichloromethane and water were added, acidified with 10% citric acid solution and the phases were separated. The aqueous phase was extracted once with dichloromethane. The organic phases are combined and washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. 1.20g (99.9% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝3.99min；m/z＝405(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.53(d，2H)，7.42-7.33(m，5H)，7.02(d，2H)，4.52(t，1H)，4.11(s，2H)，3.81(s，3H)，3.01(d，2H)，0.69(s，6H).

Example 63A

(+) -4- (trityloxy) butan-2-ol

18.560g (205.94mmol) of (R) - (-) -1, 3-butanediol were placed in 260ml of dichloromethane and 27.092g (267.72mmol) of triethylamine were added. Cooled to 0 ℃ and 57.987g (208.00mmol) of chlorotriphenylmethane were slowly added. It was allowed to return to RT and stirred at RT overnight. Thereafter 12.9ml of methanol were added and stirred for 30 min. Washed twice with water, twice with saturated ammonium chloride solution and once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 10: 1 → 2: 1). 60.990g (89.1% of theory) of the title compound are obtained.

MS(DCI)：m/z＝350(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.40-7.30(m，12H)，7.38-7.23(m，3H)，4.32(d，1H)，3.80-3.70(m，1H)，3.10-2.97(m，2H)，1.70-1.55(m，2H)，1.00(d，3H).

[α]_D ²⁰+24.2 °, c-0.520, chloroform.

Example 64A

(-) - [ { [3- (benzyloxy) butyl ] oxy } (diphenyl) methyl ] benzene

10.997g (274.95mmol) of sodium hydride are placed in 150ml of DMF at RT. 60.937g (183.29mmol) (+) -4- (trityloxy) butan-2-ol were added and stirred at RT for a further 15 min. It was cooled to 0 ℃ and 62.704g (366.59mmol) of benzyl bromide were added. After this time 50ml of DMF was added and allowed to return to RT and stirred overnight. Carefully add water and extract twice with ethyl acetate. The organic phases are combined and washed twice with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/dichloromethane 5: 1 → 1: 1). 71.750g (92.6% of theory) of the title compound are obtained.

MS(DCI)：m/z＝440(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.40-7.23(m，18H)，7.16(d，2H)，4.48(d，1H)，4.31(d，1H)，3.73-3.66(m，1H)，3.13-3.02(m，2H)，1.81-1.68(m，2H)，1.10(d，3H).

[α]_D ²⁰-10.8 °, c-0.500, chloroform.

Example 65A

(-) -3- (benzyloxy) butan-1-ol

To 71.750g (169.79mmol) of (-) - [ { [3- (benzyloxy) butyl ] oxy } (diphenyl) methyl ] benzene was added a mixture of water/acetic acid/methanol (3: 4: 3) and after stirring overnight at 50 ℃ water was added and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated by evaporation. The residue was mixed with cyclohexane. The solid was filtered off on a frit, washed three times with cyclohexane, the solid discarded and the filtrate concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 10: 1 → 4: 1). 21.97g (71.8% of theory) of the title compound are obtained.

MS(DCI)：m/z＝190(M+NH₄)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.35-7.24(m，5H)，4.52(d，1H)，4.39(d，1H)，4.33(t，1H)，3.65-3.58(m，1H)，3.52-3.45(m，2H)，1.74-1.65(m，1H)，1.57-1.48(m，1H)，1.13(d，3H).

[α]_D ²⁰-65.7 °, c-0.530, chloroform.

Example 66A

(-) -4- { [3- (benzyloxy) butyl ] oxy } -5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine

802mg (4.45mmol) of (3R) -3- (benzyloxy) butan-1-ol are placed in10 ml of THF under argon and cooled to 0 ℃. 2.30ml (4.45mmol) of a 2M phosphazene base P2-tert-butyl solution in THF were added and stirred at RT for 10 min. After which it is cooled again to 0 c. 1.0g (2.97mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidine are added and stirred at RT overnight. After this time, it was diluted with ethyl acetate, water was added and acidified with 10% citric acid solution. The aqueous phase was extracted once with ethyl acetate. The combined ethyl acetate phases were washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. Purification by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 9: 1) gives 1.16g (81.3% of theory) of the title compound.

LC-MS (method 7): r_t＝4.70min；m/z＝481(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.52(s，1H)，7.62(m，2H)，7.31(m，5H)，7.25-7.12(m，5H)，6.91(d，2H)，4.55-4.44(m，3H)，4.22(d，1H)，3.82(s，3H)，3.40-3.31(m，1H)，1.88-1.82(m，1H)，1.79-1.71(m，1H)，1.12(d，3H).

[α]_D ²⁰-79.0 °, c-0.455, methanol.

Example 67A

(-) -4- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butan-2-ol

In 20ml dioxane was dissolved 1.0g (2.08mmol) (-) -4- { [3- (benzyloxy) butyl ] oxy } -5- (4-methoxyphenyl) -6-phenyl-furan [2, 3-d ] pyrimidine and 100mg palladium on charcoal (10%) was added. Hydrogenation was carried out at atmospheric pressure and RT for about 5h until hydrogen uptake ceased. The catalyst was then filtered over Celite and the filtrate was concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 7: 3 → 1: 1). 675mg (83.1% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝3.78min；m/z＝391(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.51(s，1H)，7.62(m，2H)，7.38(d，2H)，7.31(m，3H)，6.95(d，2H)，4.73-4.67(m，1H)，4.46-4.40(m，1H)，3.88(s，3H)，3.75-3.65(m，1H)，2.20(br.s，1H)，1.83-1.76(m，1H)，1.75-1.68(m，1H)，1.16(d，3H).

[α]_D ²⁰-60.0 °, c-0.5305, methanol.

Example 68A

3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-1-ol

1.13g (14.85mmol) of 1, 3-propanediol are placed in 30ml of THF. 833mg (7.42mmol) of potassium tert-butoxide are added and stirring is carried out at RT for 15 min. After this time, it was cooled to 0 ℃ and a solution of 1.0g (2.97mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in 15ml of THF was added dropwise over a period of 30 min. After which it was allowed to return to RT and stirred for a further 2 h. Diluted with dichloromethane and water, acidified with 10% citric acid solution and the phases separated. The aqueous phase was extracted once with dichloromethane. The organic phases were combined and washed once with saturated sodium chloride solution. Drying over magnesium sulfate, concentration by evaporation and purification of the residue by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 7: 3 → 1: 1). 772mg (69.0% of theory) of the title compound are obtained.

LC-MS (method 9): r_t＝3.47min；m/z＝377(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.52(s，1H)，7.62(m，2H)，7.39(d，2H)，7.31(m，3H)，6.96(d，2H)，4.58(t，2H)，3.89(s，3H)，3.58(t，2H)，1.90(quin，2H).

Example 69A

1- [ (Z) -2-chloro-2-nitrovinyl ] -4-methoxybenzene

A mixture of 10.0g (73.5mmol) of 4-methoxybenzaldehyde, 9.0ml (13.5g, 96.2mmol) of bromonitromethane, 53.9g (661.0mmol) of dimethylammonium chloride and 0.6g (11.0mmol) of potassium fluoride in 150ml of xylene is stirred on a water separator for 15 hours at 160 ℃ as in the procedure described in document [ D.Dauzonne, Synthesis, 1990, 66-70 ]. After addition of 25ml of water and 100ml of dichloromethane, the organic phase is separated and the aqueous phase is extracted three times with 100ml of dichloromethane each time. The combined organic extracts were dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel (flow agent: cyclohexane/dichloromethane 1: 1). 9.6g (59% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.52min

¹H-NMR(400MHz，CDCl₃)：δ＝8.60(s，1H)，8.03(d，2H)，7.15(d，2H)，3.86(s，3H).

Example 70A

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

A suspension of 10.1g (47.4mmol) of 1- [ (Z) -2-chloro-2-nitrovinyl ] -4-methoxybenzene and 5.8g (52.2mmol) of 4, 6-dihydroxypyrimidine in 200ml of ethanol is stirred at 85 ℃ for ten minutes in a procedure described in the document [ D.Dauzonne, Tetrahedron, 1992, 3069-3080 ]. Next, 15.6ml (15.9g, 104.3mmol) of 1, 8-diazabicyclo [5.4.0] undec-7-ene were slowly added. Stirred at this temperature for 15h and then concentrated by evaporation in vacuo. The residue is taken up in dichloromethane and chromatographed on silica gel (flow agent: dichloromethane/methanol 95: 5). The obtained solid was mixed with acetonitrile with stirring and then filtered. 2.3g (20% of theory) of the title product are obtained.

LC-MS (method 2): r_t＝1.57min；m/z＝290(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝12.66(s，NH)，8.15(s，1H)，8.14(s，1H)，7.92(d，2H)，6.98(d，2H)，3.79(s，3H).

Example 71A

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

To a suspension of 10.0g (41.3mmol) of 5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4 (3H) -one in 250ml of toluene was added 14.5ml (13.6g, 90.8mmol) of N, N-diethylaniline and heated to 100 ℃. At this temperature, 4.2ml (7.0g, 45.4mmol) of phosphorus oxychloride are added dropwise and the reaction mixture is stirred at 100 ℃ for 15 h. Thereafter, 1.2ml (2.0g, 13mmol) of phosphorus oxychloride were added and the reaction mixture was stirred for a further 22h at 100 ℃. After cooling to room temperature, the reaction solution is washed rapidly with 250ml of ice-water, in succession twice with 250ml of cold 20% sodium hydroxide solution and then with 250ml of ice-water, 250ml of saturated sodium chloride solution, 1N hydrochloric acid and 250ml of ice-water. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. 6.3g (59% of theory) of the title compound are obtained.

LC-MS (method 10): r_t＝2.28min；m/z＝261(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.86(s，1H)，8.40(s，1H)，7.52(d，2H)，7.08(d，2H)，3.82(s，3H).

Example 72A

6- { [5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

7.1g (27.2mol) of 4-chloro-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidine are dissolved in 250ml of acetonitrile, and 5.9g (32.7mmol) of methyl 6-aminocaproate hydrochloride and 9.4g (68.1mmol) of potassium carbonate are added. The mixture was heated at reflux for 18 hours and then cooled to room temperature before filtration. The residue is mixed three times in 50ml of water each time, filtered and dried under vacuum. 4.1g (41% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.47min；m/z＝370(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.31(s，1H)，7.88(s，1H)，7.42(d，2H)，7.10(d，2H)，5.79(t，NH)，3.82(s，3H)，3.57(s，3H)，3.43(q，2H)，2.30(t，2H)，1.57-1.48(m，4H)，1.31-1.24(m，2H).

Example 73A

6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

4.1g (11.1mmol) methyl 6- { [5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate were dissolved in 150ml of carbon tetrachloride at room temperature and 2.2g (12.2mmol) N-bromosuccinimide were added. The mixture was stirred at reflux for three hours, then cooled to room temperature, filtered and the filtrate concentrated by evaporation in vacuo. 4.8g (96% of theory) of the title compound are obtained.

LC-MS (method 10): r_t＝2.65min；m/z＝448(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.29(s，1H)，7.41(d，2H)，7.12(d，2H)，5.61(t，NH)，3.82(s，3H)，3.57(s，3H)，3.38(q，2H)，2.28(t，2H)，1.54-1.42(m，4H)，1.26-1.18(m，2H).

Example 74A

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

To a solution of 156ml (1.11mol) of N, N-diisopropylamine in 1937ml of 1, 2-dimethoxyethane was added 441ml (1.10mol) of a 2.5M solution of N-butyllithium in N-hexane at-78 ℃ at a temperature not exceeding-60 ℃. After stirring at this temperature for 15min, a solution of 236g (1.00mol) of (4-methoxyphenyl) [ (trimethylsilyl) oxy ] acetonitrile [ N.Kurono, J.org.chem.2005, 16, 6530-propanoic acid 6532] in 753ml of 1, 2-dimethoxyethane was added dropwise at 30min intervals. Next, after stirring at this temperature for 30min, a solution of 128g (1.00mol) of 2-fluorobenzaldehyde in 753ml of 1, 2-dimethoxyethane was added dropwise over a 20min interval. The reaction mixture was allowed to warm to room temperature over 4 h. After adding 3800ml of a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate. The organic phase is washed with saturated ammonium chloride solution, dried over sodium sulfate, filtered and the filtrate is concentrated by evaporation in vacuo. To the residue was added 3800ml dioxane, 2700ml methanol and 3120ml 1M hydrochloric acid and stirred at room temperature for 16 h. 8000ml of a saturated aqueous solution of sodium chloride was added thereto, followed by extraction with 4000ml of ethyl acetate. The aqueous phase is re-extracted with 2000ml of ethyl acetate. The organic phases are combined and washed with 2000ml of water and 2000ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate is concentrated by evaporation in vacuo. The residue is stirred with 600ml of diisopropyl ether and filtered. The mother liquor was concentrated by vacuum evaporation. The residue is taken up in dichloromethane and purified by flash chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 4: 1). The product fractions thus obtained were mixed with stirring in diisopropyl ether/petroleum ether (1: 1), filtered and dried under vacuum. 94g (80% purity, 29% of theory) of the title compound are obtained.

LC-MS (method 11): r_t＝4.59min；m/z＝261(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝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，1H)，4.69(s，1H)，3.82(s，3H).

Example 75A

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

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

¹H-NMR(400MHz，CDCl₃)：δ＝7.23-7.11(m，4H)，7.03-6.95(m，2H)，6.82-6.79(m，2H)，4.86(s，NH₂)，3.74(s，3H).

Example 76A

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

268ml of formic acid are added dropwise to 436ml of acetic anhydride at 0 ℃ and stirred at this temperature for 30 min. Thereafter a solution of 70g (0.12mol) 2-amino-5- (2-fluorophenyl) -4- (4-methoxyphenyl) -3-furfurylnitrile in100 ml acetic anhydride and the mixture are added and stirred at 130 ℃ for 24 h. After cooling to room temperature, the mixture was concentrated by evaporation at 50 ℃ in an oil pump vacuum. The residue is mixed with 250ml of diisopropyl ether with ice cooling for 30min, filtered, washed with 70ml of diisopropyl ether and dried under vacuum. 23.7g (60% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.27min

MS(DCI)：m/z＝354(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝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 77A

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

A mixture of 20g (0.06mol)6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4 (3H) -one in 78ml sulfolane and 11ml (18g, 0.12mol) phosphorus oxychloride was stirred at 120 ℃ for 1H. After cooling to room temperature, the reaction solution was added dropwise to a mixture of 1000ml of water and 100ml of a 25% aqueous ammonia solution with vigorous stirring and ice-cooling. The precipitated solid was filtered off at 10 ℃ and washed several times with water. The solid was redissolved in 700ml of ethyl acetate and the solution was washed twice with 500ml of water each time. The organic phase was dried over sodium sulfate, filtered and the filtrate was concentrated by evaporation in vacuo. The residue is mixed with 60ml of diisopropyl ether, stirred, filtered and dried under vacuum. 18g (81% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝5.03min

¹H-NMR(400MHz，DMSO-d₆)：δ＝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 78A

1- (4-ethylphenyl) -2- (2-fluorophenyl) -2-hydroxyacetophenone

To a solution of 77ml (56g, 0.55mol) of N, N-diisopropylamine in 960ml of 1, 2-dimethoxyethane was added dropwise 217ml (0.54mol) of a 2.5 molar solution of N-butyllithium in hexane at-78 ℃ at a temperature not exceeding-60 ℃. After stirring at this temperature for 15min, a solution of 116g (0.50mol) of (4-ethylphenyl) [ (trimethylsilyl) oxy ] acetonitrile [ D.S.Dhanoa, J.Med.chem.1993, 36(23), 3738-propanoic 3742] in 373ml of 1, 2-dimethoxyethane was added dropwise in 30min intervals. Next, after stirring at this temperature for 30min, a solution of 64g (0.50mol) of 2-fluorobenzaldehyde in 373ml of 1, 2-dimethoxyethane was added dropwise at 20-min intervals. The reaction mixture was allowed to warm to room temperature over 4 h. 1900ml of a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with saturated ammonium chloride solution, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. To the residue was added 1900ml dioxane, 1350ml methanol and 1560ml 1M hydrochloric acid and stirred at room temperature for 16 h. 4000ml of a saturated aqueous solution of sodium chloride was added thereto, followed by extraction with 2000ml of ethyl acetate. The organic phase is washed with 1000ml of water and 1000ml of saturated sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The residue was purified by flash chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 5: 1). The product fractions thus obtained were mixed with stirring in 80ml of diisopropyl ether and 240ml of petroleum ether, filtered, washed with petroleum ether and dried under vacuum. 50g (85% purity, 33% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.50min

MS(DCI)：m/z＝276(M+NH₄)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝7.87-7.85(m，2H)，7.28-7.19(m，4H)，7.11-7.04(m，2H)，6.22(d，1H)，4.64(d，1H)，2.65(q，2H)，1.21(t，3H).

Example 79A

2-amino-4- (4-ethylphenyl) -5- (2-fluorophenyl) -3-furonitrile

50g (0.19mol) of 1- (4-ethylphenyl) -2- (2-fluorophenyl) -2-hydroxyacetophenone and 17g (0.25mol) of malononitrile were placed in 93ml of DMF. After stirring for five minutes, 17ml (12g, 0.12) diethylamine was added with ice cooling. The reaction mixture was stirred for 1h with ice cooling. The reaction mixture was then allowed to warm to room temperature and stirred at this temperature for 4 h. After addition of 500ml of water and stirring for 30min, the aqueous phase is decanted. An additional 500ml of water was added and decanted again to give an oily residue which was dissolved in ethyl acetate, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. According to DC analysis (flow agent: cyclohexane/ethyl acetate 4: 1), the residue still contained 1- (4-ethylphenyl) -2- (2-fluorophenyl) -2-hydroxyacetophenone. The residue is therefore reacted according to the above procedure with 5.5g (0.08mol) of malononitrile and 10ml (7g, 0.10mol) of diethylamine again in90 ml of DMF. The reaction mixture is added to 500ml of ethyl acetate and washed three times with 300ml of water each time and once with 300ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The residue was purified by flash chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 3: 1). 36g (61% of theory) of the title compound are obtained without further reaction characteristics.

Example 80A

6- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4 (3H) -one

To 280ml (2.97mol) of acetic anhydride 140ml (3.71mol) of formic acid are added dropwise at 0 ℃ and stirred at this temperature for 30 min. Thereafter 36.0g (0.12mol) 2-amino-4- (4-ethylphenyl) -5- (2-fluorophenyl) -3-furonitrile are added and the mixture is stirred at 130 ℃ for 24 h. After cooling to room temperature, the mixture was concentrated by evaporation at 50 ℃ under oil pump vacuum. The residue is mixed for 30min at-10 ℃ in 150ml of diisopropyl ether, filtered, washed with 50ml of ice-cooled diisopropyl ether and dried under vacuum. 20.6g (86% purity, 45% of theory) of the title compound are obtained.

HPLC (method 1): r_t＝4.65min

MS(ESIpos)：m/z＝335(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝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 81A

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

A suspension of 20.0g (0.06mol)5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4 (3H) -one in100 ml (165g, 1.07mol) of phosphorus oxychloride at 120 ℃ is stirred for 1H. After cooling to room temperature, a mixture of the reaction solution was added dropwise to 330ml of water and 610ml of a 25% aqueous ammonia solution with vigorous stirring; the temperature was observed to rise to 55-65 ℃. The reaction mixture was allowed to cool to room temperature. After two extractions with 500ml of dichloromethane each time, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The residue is mixed with 150ml of petroleum ether, filtered, washed with ice-cold petroleum ether and dried under vacuum. 18.7g (90% purity, 80% of theory) of the title compound are obtained.

LC-MS (method 5): r_t＝3.14min；m/z＝353(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝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 82A

3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropan-1-ol

To a solution of 2.68g (29.7mmol) of 2-methylpropane-1, 3-diol in 45ml of toluene, 15ml of 1, 2-dimethoxyethane and 15ml of water at 70 ℃ are added 4.8ml of 12.5N sodium hydroxide solution. After addition of 202mg (0.59mmol) tetrabutylammonium hydrogen sulfate and 2.0g (5.94mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, the reaction mixture is stirred at 70 ℃ for 17 h. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid. Extracted three times with 50ml of dichloromethane each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The crude product is stirred with methanol, filtered and the filtrate is purified by preparative RP-HPLC (gradient: water/acetonitrile). 1.26g (54% of theory) of the desired product (racemate) are obtained.

LC-MS (method 8): r_t＝2.73min；m/z＝391(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.58(s，1H)，7.55(d，2H)，7.48-7.35(m，5H)，7.00(d，2H)，4.48(t，OH)，4.34(dd，1H)，4.24(dd，1H)，3.81(s，3H)，3.23-3.14(m，2H)，1.86-1.78(m，1H)，0.72(d，3H).

Example 83A

(2R, 3R) -3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butan-2-ol

To a solution of 1.34g (14.8mmol) of (2R, 3R) -butane-2, 3-diol in 20ml of toluene, 7ml of 1, 2-dimethoxyethane and 7ml of water at 70 ℃ was added 2.4ml of a 12.5N sodium hydroxide solution. 101mg (0.30mmol) of tetra-n-butylammonium hydrogen sulfate and 1.00g (2.97mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine are added and the reaction mixture is stirred at 70 ℃ for 17 h. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid. Extracted three times with 50ml of dichloromethane each time. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The crude product is stirred with methanol, filtered and the filtrate is purified by preparative RP-HPLC (gradient: water/acetonitrile). 0.60g (50% of theory) of the desired product is obtained.

LC-MS (method 7): r_t＝3.95min；m/z＝391(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.56(s，1H)，7.55(d，2H)，7.48-7.35(m，5H)，7.00(d，2H)，5.29(dt，1H)，4.71(d，OH)，3.81(s，3H)，3.73-3.62(m，1H)，1.13(d，3H)，0.85(d，3H).

Example 84A

(2R) -1- [ benzyl (methyl) amino ] propan-2-ol

A mixture of 3.5g (21.2mmol) of (2R) -1- (benzylamino) propan-2-ol [ F.L.Delft, Synthesis 1997, 4, 450-propan-454 ], 1.85ml (2.0g, 23.3mmol) of 35% aqueous formaldehyde and 3.6ml (4.4g, 95.3mmol) of formic acid was stirred at reflux for 16 h. After cooling to room temperature, the pH was first neutralized with 45% sodium hydroxide solution and then adjusted to 9. Extracting with ethyl acetate. The organic phase is washed three times with 10ml of water each time, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo and dried. 3.08g (78% of theory) of the desired product are obtained.

LC-MS (method 3): r_t＝1.85min；m/z＝180(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.31-7.21(m，5H)，4.28(d，1H)，3.81-3.72(m，1H)，3.48(q，2H)，2.24(dq，2H)，2.13(s，3H)，1.04(d，3H).

Example 85A

(2R) -N-benzyl-2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropan-1-amine

To a solution of 600mg (3.35mmol) of (2R) -1- [ benzyl (methyl) amino ] propan-2-ol in 7ml of THF at room temperature was added 167mg (4.18mmol) of sodium hydride (as a 60% dispersion in mineral oil). After stirring for ten minutes, 1177mg (3.51mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in 8ml of THF and 62mg (0.17mmol) of tetra-n-butylammonium iodide were added. The reaction mixture was stirred at reflux for 16 h. After addition of water and ethyl acetate, the organic phase is washed with 1N hydrochloric acid and saturated sodium chloride solution. The aqueous phase was re-extracted with ethyl acetate. The organic phases were combined and dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The residue is taken up in cyclohexane/ethyl acetate/dichloromethane and chromatographed on silica gel (flow agent: cyclohexane/ethyl acetate 5: 1, 2: 1, 1: 1, then ethyl acetate). 1366mg (83% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝2.08min；m/z＝478(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.55-7.53(m，2H)，7.42-7.34(m，5H)，7.26-7.17(m，5H)，7.13-7.11(m，2H)，5.57-5.49(m，1H)，3.36(d，2H)，2.63(q，2H)，2.48-2.39(m，2H)，1.98(s，3H)，1.23-1.17(m，6H).

Example 86A

(2R) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropane-1-ammonium formate

To a solution of 1.45g (3.04mmol) of (2R) -N-benzyl-2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropan-1-amine in 20ml of 4.4% formic acid in methanol under argon was added 0.50g (4.70mmol) of palladium black and stirred at room temperature for 14 h. After filtration through a Millipore filter and washing several times with methanol/water, the filtrate was concentrated by evaporation in vacuo. The residue is taken up in acetonitrile/methanol and purified by preparative RP-HPLC (gradient: water/acetonitrile). 1.03g (77% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝1.79min；m/z＝388(M-HCO₂H+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，8.18(s，HCOO)，7.56-7.52(m，2H)，7.46-7.35(m，5H)，7.34-7.28(m，2H)，5.48-5.40(m，1H)，4.22-2.93(br.s，H₂N⁺)，2.86-2.82(m，1H)，2.72-2.62(m，3H)，2.24(s，3H)，1.27-1.23(m，6H).

Example 87A

Tert-butyl 4- { [ (2S) -2-hydroxypropyl ] amino } butanoate

To a solution of 936mg (12.46mmol) of (2S) -1-aminopropan-2-ol in10 ml THF were added 2583mg (18.69mmol) of potassium carbonate, 2780mg (12.46mmol) of tert-butyl 4-bromobutyrate and 184mg (0.50mmol) of tetra-n-butylammonium iodide. The reaction mixture was stirred at room temperature for 48 h. After filtering off the inorganic salts, the filtrate was concentrated by evaporation in vacuo. The residue is taken up in dichloromethane and chromatographed on silica gel (flow agent: dichloromethane/methanol/35% aqueous ammonia solution 9: 1: 0.1). 810mg (30% of theory) of the desired product are obtained.

GC-MS (method 12): r_t＝4.73min；m/z＝712(M-CH₃CHOH)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.39(br.s，OH)，3.67-3.59(m，1H)，3.38-3.20(br.s，NH)，2.51-2.47(m，2H)，2.39-2.37(m，2H)，2.21(t，2H)，1.60(quin，2H)，1.39(s，9H)，1.02(d，3H).

Example 88A

Tert-butyl 4- { [ (2S) -2-hydroxypropyl ] (methyl) amino } butanoate

To a solution of 350mg (1.61mmol) tert-butyl 4- { [ (2S) -2-hydroxypropyl ] amino } butyrate in10 ml methanol were added 0.62ml (670mg, 7.81mmol) of 35% aqueous formaldehyde and 101mg (1.61mmol) of sodium cyanoborohydride. The reaction mixture was stirred at room temperature for 16 h. After addition of 30ml of water and 40ml of dichloromethane, the organic phase is dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo and dried. 323mg (81% of theory) of the desired product are obtained.

GC-MS (method 12): r_t＝4.57min；m/z＝186(M-CH₃CHOH)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝4.16(d，1H)，3.71-3.62(m，1H)，2.29(t，2H)，2.23-2.18(m，3H)，2.16-2.10(m，4H)，1.63-1.55(m，2H)，1.39(s，9H)，1.02(d，3H).

Example 89A

4- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } pent-2-ol

To a solution of 4.64g (44.54mmol) of pentane-2, 4-diol in 75ml of toluene, 27ml of 1, 2-dimethoxyethane and 25ml of water at 70 ℃ is added 7.9ml of 11.25N sodium hydroxide solution. After addition of 302mg (0.89mmol) of tetra-n-butylammonium hydrogen sulfate and 3.00g (8.91mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, the reaction mixture is stirred at 70 ℃ for 17 h. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid. Extracted three times with 150ml of dichloromethane each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated by evaporation in vacuo. The residue is mixed with acetonitrile, filtered and the filtrate is chromatographed on silica gel (flow agent: dichloromethane/methanol). 2.37g (65% of theory) of the desired product are obtained as a racemic diastereoisomeric mixture.

LC-MS (method 8): r_t＝2.81min；m/z＝405(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): [ minor stereoisomers in brackets ]]δ＝[8.57，s，1H]，8.56(s，1H)，7.56-7.52(m，2H)，7.42-7.37(m，5H)，7.02-6.99(m，2H)，5.54-5.46(m，1H)，[5.38-5.30，m，1H]，4.46(d，OH)，[4.39，d，OH]，3.82(s，3H)，[3.81，s，3H]，3.69-3.60(m，1H)，[3.46-3.37，m，1H]，1.77-1.70(m，1H)，1.47-1.41(m，1H)，[1.28，d，3H]，1.26(d，3H)，1.00(d，3H)，[0.93，d，3H].

Example 90A

2- ({ [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } methyl) -3, 3-dimethylbut-1-ol

To a solution of 1974mg (14.93mmol) of 2-tert-butylpropan-1, 3-diol in 25ml toluene, 8ml 1, 2-dimethoxyethane and 8ml water at 70 ℃ was added 2.7ml of 11.25N sodium hydroxide solution. After addition of 101mg (0.30mmol) of tetra-n-butylammonium hydrogen sulfate and 1000mg (2.99mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, the reaction mixture is stirred at 70 ℃ for 17 h. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid. Extracting with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The residue was mixed with methanol, filtered and washed with diethyl ether. The filtrate was purified by preparative RP-HPLC (gradient: water/acetonitrile). 275mg (21% of theory) of the desired product are obtained.

LC-MS (method 9): r_t＝4.55min；m/z＝431(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，7.53-7.51(m，2H)，7.39-7.36(m，5H)，7.30-7.28(m，2H)，4.53(dd，1H)，4.45(dd，1H)，4.40(t，1H)，3.45-3.41(m，1H)，3.30-3.25(m，1H)，2.68(q，2H)，1.39-1.34(m，1H)，1.29(t，3H)，0.67(s，9H).

Example 91A

3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butan-2-ol

To a mixture of 2.68g (29.70mmol) (2R, 3S) -butane-2, 3-diol in 45ml toluene, 15ml 1, 2-dimethoxyethane and 15ml water at 70 ℃ was added 4.8ml of 12.5N sodium hydroxide solution. After addition of 0.20g (0.60mmol) of tetra-n-butylammonium hydrogen sulfate and 2.00g (5.94mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, the reaction mixture is stirred at 70 ℃ for 17 h. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid. Extracted three times with 100ml of dichloromethane each time. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The crude product was purified by preparative RP-HPLC (gradient: water/acetonitrile). 1.26g (54% of theory) of the desired product are obtained as (R, S/S, R) racemate.

LC-MS (method 8): r_t＝2.81min；m/z＝391(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.55-7.53(m，2H)，7.43-7.36(m，5H)，7.01-7.00(m，2H)，5.21-5.16(m，1H)，4.68(d，OH)，3.81(s，3H)，3.61-3.55(m，1H)，1.19(d，3H)，0.86(d，3H).

Example 92A

(+/-) -2-methoxy-3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-1-ol

1.014g (9.65mmol) of 2-methoxypropane-1, 3-diol was placed in 20ml of THF. 542mg (4.825mmol) of potassium tert-butoxide are added and stirring is carried out at RT for 15 min. After this time, it is cooled to 0 ℃ and a solution of 650mg (1.93mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in10 ml of THF is added dropwise over the course of 30 min. It was then allowed to return to RT and stirred at RT overnight. Next, it was diluted with tert-butyl methyl ether and water. Acidified with 10% citric acid solution and the phases separated. The aqueous phase was extracted once more with tert-butyl methyl ether. The organic phases were combined and washed once with saturated sodium chloride solution. After which it is dried over magnesium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 7: 3); 587mg (74.8% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.53min；m/z＝407(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.53(s，1H)，7.62(m，2H)，7.39(m，2H)，7.32(m，3H)，6.97(d，2H)，4.53(d，2H)，3.88(s，3H)，3.62-3.52(m，1H)，3.52-3.43(m，2H)，3.32(s，3H).

Example 93A

6- { [ (1R) -1-phenylethyl ] amino } heptanoic acid methyl ester

8.80g (55.63mmol) of 6-oxoheptanoic acid and 6.741g (55.63mmol) of (R) - (+) -1-phenylethylamine are taken together in100 ml of toluene at RT. A catalytic amount (about 50mg) of p-toluenesulfonic acid was added and heated overnight on a water trap with stirring. After which it was partially concentrated by evaporation, any solids were filtered off using a paper filter, and the filtrate was completely concentrated by evaporation. The residue was dissolved in 170ml of methanol. About 1.7g of Raney nickel (wetted with water) are added and hydrogenated at 4bar for 48 h. Next, filter over celite and concentrate the filtrate by evaporation. The residue is purified by column chromatography on silica gel (flow agent: dichloromethane/methanol 95: 5) to yield 4.15g (48.5% of theory) of the title compound, which is free of further reaction features.

The application example is as follows:

example 1

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

1.0g (3.0mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, 0.78g (5.94mmol) 6-aminocaproic acid and 1.5ml DIEA in10 ml DMF were stirred at 120 ℃ overnight. The reaction mixture was added to water and extracted three times with ethyl acetate. The organic phases are combined and washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel (flow agent: cyclohexane/ethyl acetate 2: 1 → 1: 2). 560mg (43.7% of theory) of the title compound are obtained.

LC-MS (method 4): r_t＝2.62min；m/z＝432(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.0(br.s，1H)，8.31(s，1H)，7.47-7.42(m，4H)，7.40-7.30(m，3H)，7.15(d，2H)，5.08(t，1H)，3.87(s，3H)，2.08(t，2H)，1.50-1.35(m，4H)，1.25-1.10(m，4H).

Example 2

7- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } heptanoic acid

The title compound was obtained in analogy to example 1 in 55.1% yield of theory.

LC-MS (method 4): r_t＝2.72min；m/z＝446(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.33(s，1H)，7.48-7.43(m，4H)，7.40-7.30(m，3H)，7.15(d，2H)，5.04(t，1H)，3.85(s，3H)，2.08(t，2H)，1.50-1.38(m，4H)，1.20-1.11(m，2H).

Example 3

Sodium salt of 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

200mg (0.464mmol) of 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid are dissolved in 0.75ml of methanol, 0.5ml of THF and a few drops of water at RT and 0.464ml of 1N sodium hydroxide solution are added. The mixture was stirred for 5min, then concentrated by vacuum evaporation and the residue was dried under high vacuum. 221mg of the title compound were obtained.

LC-MS (method 2): r_t＝2.34min；m/z＝432(M-Na+2H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.48-7.43(m，4H)，7.39-7.30(m，3H)，7.17(d，2H)，5.04(t，1H)，3.88(s，3H)，1.72(t，2H)，1.40-1.32(m，4H)，1.15-1.08(m，2H).

Example 4

5- (4-methoxyphenyl) -6-phenyl-N- {5- (1H-tetrazol-5-yl) pentyl ] furan [2, 3-d ] pyrimidin-4-amine

1.00g (2.4mmol)6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexanenitrile, 4.19g (26.3mmol) trimethylsilyl azide and 0.91g (3.6mmol) di-n-butyltin oxide in 50ml toluene are stirred at 80 ℃ overnight. After concentration by evaporation, the residue is taken up in water, acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The crude product was purified by RP-HPLC (column: Grossil 250 mm. times.40 mm, 10 μm; acetonitrile/water gradient: 0-3min 10% acetonitrile, 3-50min 10% → 98% acetonitrile, 50-55min 98% acetonitrile). The combined product fractions were crystallized from diethyl ether and dried overnight in a vacuum oven at 50 ℃. 598mg (54% of theory) of the title compound are obtained as almost white crystals.

LC-MS (method 2): r_t＝2.22min；m/z＝455(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 16(br.s, 1H), 8.3(s, 1H), 7.5-7.25(m, 7H), 7.1(m, 2H), 5.1(m, 1H), 3.85(s, 3H), approximately 3.5(m, masked by the DMSO signal), 2.75(t, 2H), 1.65(m, 2H), 1.45(m, 2H), 1.2(m, 2H).

Example 5

(2E) -6- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] amino } -hex-2-enoic acid methyl ester

To a suspension of 21.6mg of sodium hydride (60% dispersion in oil, approx. 0.539mmol) in2ml of THF are added dropwise at RT 0.095ml (0.588mmol) of trimethyl phosphonoacetate. The mixture is stirred for a further 1h and then 190mg (0.49mmol) of 4- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } butanal are added. Stir at RT overnight and then dilute the mixture with dichloromethane and water. The organic phase was washed with saturated sodium chloride solution, dried and concentrated under vacuum. The title compound was isolated from the crude product by preparative RP-HPLC (twice) (gradient: water/acetonitrile). 23.4mg (10.8% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.65min；m/z＝444(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.33(s，1H)，7.47-7.43(m，4H)，7.40-7.31(m，3H)，7.14(d，2H)，6.85(dd，1H)，5.84-5.78(m，1H)，5.68(t，1H)，3.85(s，3H)，3.63(s，3H)，3.49(q，2H)，2.17-2.10(m，2H)，1.63-1.57(m，2H).

Example 6

(2E) -6- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] amino } -hex-2-enoic acid sodium salt

In 0.5ml THF were placed 19mg (0.043mmol) methyl (2E) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] amino } hex-2-enoate and, at RT, 0.43ml 1N sodium hydroxide solution was added. The mixture was stirred at RT for 24h, then neutralized with 1N hydrochloric acid and concentrated by evaporation in vacuo. Some 1N sodium hydroxide solution was added to the residue and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 9mg (46.5% of theory) of the title compound are isolated.

LC-MS (method 5): r_t＝2.51min；m/z＝429(M-Na+2H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.3(s，1H)，7.48-7.3(m，7H)，7.12(d，2H)，6.20(dd，1H)，5.58(d，2H)，5.60(t，1H)，3.85(s，3H)，1.95(q，2H)，1.52(m，2H).

Example 7

5- (4-methoxyphenyl) -6-phenyl-N- [6- (1H-tetrazol-5-yl) hexyl ] furan [2, 3-d ] pyrimidin-4-amine

0.098g (0.23mmol) of 7- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } heptanenitrile, 0.41g (3.5mmol) of trimethylsilyl azide and 86mg (0.25mmol) of di-n-butyltin oxide in 5ml of toluene are stirred at 80 ℃ overnight. After concentration by evaporation, the residue is taken up in water, acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The crude product was purified by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile). 61mg (55% of theory) of the title compound are obtained as white crystals.

LC-MS (method 2): r_t＝2.30min；m/z＝469(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 16(br.s, 1H), 8.3(s, 1H), 7.5-7.25(m, 7H), 7.15(m, 2H), 5.1(m, 1H), 3.85(s, 3H), approximately 3.5(m, masked by the DMSO signal), 2.85(t, 2H), 1.65(m, 2H), 1.35(m, 2H), 1.1-1.3(m, 4H).

Example 8

6- [ (5, 6-Diphenylfuran [2, 3-d ] pyrimidin-4-yl) amino ] hexanoic acid methyl ester

55mg (0.131mmol) of methyl 6- [ (6-bromo-5-phenyl-furo [2, 3-d ] pyrimidin-4-yl) amino ] hexanoate, 0.131ml of 2M aqueous sodium carbonate (0.26mmol), 4.6mg (0.006mmol) of bis (triphenylphosphine) palladium (II) chloride and 20mg (0.164mmol) of phenylboronic acid are stirred at 80 ℃ under argon in 0.4ml of DMSO. After cooling, the mixture is purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 35mg (64.1% of theory) of the title compound are obtained.

LC-MS (method 4): r_t＝3.01min；m/z＝416(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.34(s，1H)，7.62-7.53(m，5H)，7.47-7.42(m，2H)，7.39-7.30(m，3H)，4.97(t，1H)，3.60(s，3H)，3.35(q，2H)，2.17(t，2H)，1.50-1.35(m，4H)，1.18-1.10(m，2H).

Example 9

6- { [5- (4-Methylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

50mg (0.12mmol) methyl 6- [ (5-bromo-6-phenyl-furan [2, 3-d ] pyrimidin-4-yl) amino ] hexanoate, 0.12ml 2M aqueous sodium carbonate solution (0.24mmol), 4.2mg (0.006mmol) bis (triphenylphosphine) palladium (II) chloride and 20.3mg (0.149mmol) p-tolueneboronic acid l h in 0.4ml DMSO, stirring at 80 ℃ under argon. After cooling, the mixture is purified directly by preparative RP-HPLC (gradient: water/acetonitrile) followed by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate). 38.1mg (74.2% of theory) of the title compound are obtained.

LC-MS (method 4): r_t＝3.15min；m/z＝430(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.48-7.30(m，10H)，5.01(t，1H)，3.58(s，3H)，3.38(q，2H)，2.43(s，3H)，2.27(t，2H)，1.50-1.35(m，4H)，1.17-1.10(m，2H).

Example 10

6- [ (5, 6-Diphenylfuran [2, 3-d ] pyrimidin-4-yl) amino ] hexanoic acid

In 0.1ml of methanol, 0.05ml of THF and one drop of water were dissolved 27.5mg (0.066mmol) of methyl 6- [ (5, 6-diphenylfuran [2, 3-d ] pyrimidin-4-yl) amino ] hexanoate and 0.09ml of 2.5M sodium hydroxide solution were added. The mixture was stirred at RT for 1h and then slightly acidified with 1N hydrochloric acid. The aqueous phase was extracted three times with dichloromethane. The organic phases are combined and dried over magnesium sulfate, concentrated by evaporation in vacuo and the residue is dried under high vacuum. 25mg (96.1% of theory) of the title compound are obtained.

LC-MS (method 5): r_t＝2.51min；m/z＝402(M+H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ＝12.0(br.s，1H)，8.35(s，1H)，7.62-7.51(m，5H)，7.46-7.41(m，2H)，7.39-7.30(m，3H)，4.97(t，1H)，3.39(q，2H)，2.18(t，2H)，1.45-1.35(m，4H)，1.18-1.10(m，2H).

Example 11

6- { [5- (4-methylphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

In 0.1ml of methanol, 0.05ml of THF and one drop of water were dissolved 30mg (0.07mmol) of methyl 6- { [5- (4-methylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate, and 0.1ml of 2.5M sodium hydroxide solution was added. The mixture was stirred at RT for 1h and then slightly acidified with 1N hydrochloric acid. The precipitate is filtered off with suction, washed several times with water and dried under high vacuum. 28mg (96.5% of theory) of the title compound are obtained.

LC-MS (method 4): r_t＝2.70min；m/z＝416(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.0(br.s，1H)，8.33(s，1H)，7.48-7.30(m，10H)，4.99(t，1H)，3.38(q，2H)，2.45(s，3H)，2.18(t，2H)，1.46-1.37(m，4H)，1.18-1.10(m，2H).

Example 12

Ethyl 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } hexanoate

To a mixture of 300mg (0.89mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine and 214mg (1.34mmol) ethyl 6-hydroxyhexanoate in1.0ml THF and 0.7ml DMF at RT was added in portions 42.8mg sodium hydride (60% dispersion in oil, ca. 1.07 mmol). The mixture was stirred at RT for 1h, after which dichloromethane and water were added. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. After preparative RP-HPLC 120.9mg (29.5% of theory) of the title compound are isolated from the residue.

LC-MS (method 5): r_t＝3.25min；m/z＝461(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.56(m，2H)，7.44-7.39(m，5H)，7.03(d，2H)，4.37(t，2H)，4.04(q，2H)，3.81(s，3H)，2.21(t，2H)，1.61-1.55(m，2H)，1.50-1.42(m，2H)，1.18(m，5H).

Example 13

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

103mg (0.224mmol) of ethyl 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } hexanoate are dissolved in2ml of THF and 2.2ml of 1N sodium hydroxide solution are added at RT. The mixture was stirred overnight, then neutralized with 1N hydrochloric acid and concentrated by evaporation in vacuo. The residue was purified by preparative RP-HPLC. 23.2mg (24% of theory) of the title compound are obtained.

LC-MS (method 5): r_t＝2.73min；m/z＝433(M+H)⁺。

Example 14

5- (4-methoxyphenyl) -6-phenyl-4- { [5- (1H-tetrazol-5-yl) pentyl ] oxy } -furan [2, 3-d ] pyrimidine

1.00g (2.1mmol)6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } hexanenitrile, 0.79g (3.2mmol) di-n-butyltin oxide and 3.68g (32mmol) trimethylsilyl azide in 44ml toluene are stirred at 80 ℃ overnight. After this time, 1ml of ethylene glycol was added, stirred under reflux for 1h and then concentrated by evaporation. The residue is taken up in ethyl acetate, washed with dilute hydrochloric acid and with sodium chloride solution, dried and concentrated by evaporation. The crude product was purified by RP-HPLC (column: Grossil 250 mm. times.40 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). The combined product fractions were crystallized from diethyl ether. 372mg (38% of theory) of the title compound are obtained as light-brown crystals.

LC-MS (method 5): r_t＝2.39min；m/z＝456(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is about 16-14 (width, 1H), 8.6(s, 1H), 7.55(m, 2H), 7.4(m, 5H), 7.0(m, 2H), 4.35(t, 2H), 3.8(s, 3H), 2.3(t, 2H), 1.6(m, 4H), 1.2(m, 2H).

Example 15

5- (4-methoxyphenyl) -6-phenyl-N- {3- [2- (1H-tetrazol-5-yl) ethoxy ] propyl } furan [2, 3-d ] pyrimidin-4-amine

137mg (0.32mmol) of 5- (4-methoxyphenyl) -6-phenyl-N- {3- [ 2-cyanoethoxy ] propyl } furan [2, 3-d ] pyrimidin-4-amine, 552mg (4.8mmol) of trimethylsilyl azide and 119mg (0.48mmol) of di-N-butyltin oxide in10 ml of toluene are stirred at 80 ℃ overnight. The mixture was then cooled and concentrated by evaporation. The remaining residue was dissolved in dichloromethane and washed with water and sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure in a rotary evaporator. The residue was purified by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile). 48.6mg (32% of theory) of the title compound are obtained as a colorless solid.

LC-MS (method 4): r_t＝2.44min；m/z＝472(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝16.0(br.s，1H)，8.35(s，1H)，71-7.45(m, 9H), 5.2(m, 1H), 3.85(s, 3H), 3.65(t, 2H), about 3.3(m, 2H, H)₂Partial O masking), 3.05(t, 2H), 1.65(quin, 2H).

Example 16

3- (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } propoxy) propionic acid

160mg (0.37mmol) of 5- (4-methoxyphenyl) -6-phenyl-N- {3- [ 2-cyanoethoxy ] propyl } furan [2, 3-d ] pyrimidin-4-amine in 6ml of concentrated hydrochloric acid were heated to boiling and stirred for 7 h. After cooling to room temperature, it was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated by evaporation. Purification of the residue by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile) and flash chromatography on silica gel (flow agent gradient: ethyl acetate → ethyl acetate/methanol 5: 1) several times yielded an oil which was then dissolved in hot ethyl acetate. When hot, diisopropyl ether was added until cloudiness occurred. After standing overnight in the freezer, a pale yellow solid was obtained, which was taken up in dichloromethane. After further concentration by evaporation, the residue was mixed with diethyl ether. In this way, 7.1mg (4.3% of theory) of the title compound are obtained as a grey powder, which after a certain time again becomes oily.

LC-MS (method 4): r_t＝2.42min；m/z＝448(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ -8.35 (s, 1H), 7.1-7.45(m, 9H), 5.2(m, 1H), 3.85(s, 3H), 3.65(t, 2H), about 3.3(m, 4H, H-coated H)₂Partial O masking), 2.1(t, 2H), 1.6(m, 2H).

Example 17

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

In10 ml dichloromethane 150mg (0.37mmol)5- (4-methoxyphenyl) -6-phenyl-N- (5-aminopentyl) furan [2, 3-d ] pyrimidin-4-amine are dissolved. 50mg (0.41mmol) of oxalic acid methyl ester chloride and 72mg (0.56mmol) of DIEA were slowly added dropwise at 0 ℃ simultaneously. Stirring is continued for a further 1h at room temperature. The mixture was diluted with dichloromethane and washed with water and sodium chloride solution. The organic phases are combined and dried over magnesium sulfate and concentrated in a rotary evaporator. The residue was purified by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile). After concentration of the product fractions by evaporation, the residue is chromatographed on silica gel (Analogix cartridge F12M, eluent: cyclohexane/ethyl acetate 1: 1). 47.8mg (26% of theory) of the title compound are obtained as a colorless foam.

LC-MS (method 4): r_t＝2.60min；m/z＝489(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 8.9(m, 1H), 8.30(s, 1H), 7.1-7.45(m, 9H), 5.1(m, 1H), 3.85(s, 3H), 3.75(s, 3H), about 3.4(m, 2H, H)₂Partial masking of O), 3.1(q, 2H), 1.6-1.1(m, 6H).

Example 18

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

30mg (0.06mmol) of (5- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } pentyl) amino (oxo) methyl acetate are dissolved in 3ml of dioxane and 0.12ml of 1N sodium hydroxide solution are added. Next, the mixture was stirred at 50 ℃ for 1 hour. The mixture was concentrated by evaporation, the residue was taken up in water and washed with dichloromethane. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is separated, dried over magnesium sulfate and concentrated by evaporation. 26.5mg (91% of theory) of the title compound are obtained as a white foam.

LC-MS (method 4): r_t＝2.10min；m/z＝475(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 8.75(m, 1H), 8.30(s, 1H), 7.1-7.45(m, 9H), 5.05(m, 1H), 3.85(s, 3H), about 3.4(m, 2H, H-coated with H)₂Partial O masking), 3.05(q, 2H), 1.6-1.1(m, 6H).

Example 19

5- (4-methoxyphenyl) -6-phenyl-4- {2- [2- (1H-tetrazol-5-yl) ethoxy ] ethoxy } furan [2, 3-d ] pyrimidine

180mg (0.43mmol) of 4- [3- (2-cyanoethoxy) ethoxy ] -5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, 749mg (6.5mmol) of trimethylsilyl azide and 161mg (0.65mmol) of di-n-butyltin oxide in10 ml of toluene are stirred at 80 ℃ overnight. The mixture was concentrated by evaporation, the residue was taken up in water and acidified with dilute hydrochloric acid. Next, extraction with dichloromethane was performed. The organic extract was washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The remaining residue was purified by RP-HPLC (column: Grossil 250mm X30mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). To remove the organotin compounds, the light brown foam obtained was dissolved in10 ml of toluene and 1ml of ethylene glycol was added. After heating at reflux for 1h, the solvent was removed under vacuum. The residue is dissolved in dichloromethane, washed with dilute hydrochloric acid and with sodium chloride solution, dried and concentrated by evaporation. Purification of the residue by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile) gives 82.6mg (42% of theory) of the title compound as a light brown foam.

LC-MS (method 5): r_t＝2.38min；m/z＝459(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.55(s，1H)，7.3-7.55(m，7H)，6.9(m，2H)，4.5(m，2H)，3.8(s，3H)，3.6(m，4H)，3.0(t，2H).

Example 20

5- (4-methoxyphenyl) -6-phenyl-4- {3- [2- (1H-tetrazol-5-yl) ethoxy ] propoxy } furan [2, 3-d ] pyrimidine

200mg (0.47mmol) of 4- [3- (2-cyanoethoxy) propoxy ] -5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine, 804mg (7.0mmol) of trimethylsilyl azide and 174mg (0.70mmol) of di-n-butyltin oxide in10 ml of toluene are stirred at 80 ℃ overnight. The mixture was concentrated by evaporation, the residue was taken up in water and acidified with dilute hydrochloric acid. Next, extraction with dichloromethane was performed. The organic extract was washed with sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The remaining residue was purified by RP-HPLC (column: Grossil 250mm X30mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-50min 5% → 98% acetonitrile, 50-55min 98% acetonitrile). To remove the organotin compounds, the light brown foam obtained was dissolved in10 ml of toluene and 1ml of ethylene glycol was added. After heating at reflux for 1h, the solvent was removed under vacuum. The residue is dissolved in dichloromethane, washed with dilute hydrochloric acid and with sodium chloride solution, dried and concentrated by evaporation. Purification of the residue by RP-HPLC (column: Grossil 250 mm. times.30 mm, 10 μm; acetonitrile/water gradient: 0-3min 5% acetonitrile, 3-34min 5% → 98% acetonitrile, 34-38min 98% acetonitrile) gave 46mg (21% of theory) of the title compound as a light brown foam.

LC-MS (method 4): r_t＝2.62min；m/z＝473(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ ═ 16.0(br.s, 1H), 8.55(s, 1H), 7.3-7.55(m, 7H), 6.9(m, 2H), 4.35(m, 2H), 3.8(s, 3H), 3.65(t, 2H), approximately 3.4(m, 2H, H-coated glass fiber), and₂partial O masking), 3.05(t, 2H), 1.65(quin, 2H).

General procedure a: 5-bromo-6-phenylfuran [2, 3-d ]]Palladium-catalyzed arylation of pyrimidine derivatives

To a solution of 1.0 equivalent of 6- [ (5-bromo-6-phenylfuran [2, 3-d ] pyrimidin-4-yl) amino ] -hexanoic acid methyl ester in DMSO (ca 3mol/l) were added at RT, 1.2 to 1.5 equivalents of the corresponding arylboronic acid, approximately 2.0 equivalents of sodium carbonate (as a 2M aqueous solution) and approximately 5 mol-% bis (triphenylphosphine) palladium (II) chloride in succession. The mixture is stirred at a temperature of 70-90 ℃ for a period of 3-18 h. After cooling, the title product is isolated directly from the reaction solution by RP-HPLC (eluent: acetonitrile/water gradient). If necessary, it can be further purified by chromatography on silica gel (flow agent: dichloromethane/methanol or cyclohexane/ethyl acetate mixture).

The following examples were prepared according to general procedure a:

general procedure B: hydrolysis of methyl esters to the corresponding carboxylic acid derivatives

To a solution of the methyl ester in THF or THF/methanol (1: 1) (concentration approximately 0.05-0.5mol/l) at RT is added 1.5-10 equivalents of sodium hydroxide as 1N aqueous solution. The mixture is stirred at RT for a period of 0.5 to 18h and then neutralized with 1N hydrochloric acid or slightly acidified. If solid precipitation occurs, the product can be isolated by filtration, washed with water and dried under high vacuum. Alternatively, the title compound is isolated directly from the crude product, after workup by extraction with dichloromethane if necessary, by preparative RP-HPLC (eluent: water/acetonitrile gradient).

The following examples were prepared according to general procedure B:

the following examples were prepared according to general procedure a (see above for description) from the corresponding 5-bromo-6-phenyl-furan [2, 3-d ] pyrimidine derivatives and phenylboronic acid derivatives:

example 45

6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] (methyl) amino } hexanoic acid methyl ester

200mg (0.463mmol) of methyl [ (5-bromo-6-phenyl-furan [2, 3-d ] pyrimidin-4-yl) (methyl) amino ] hexanoate are dissolved in 1.25ml of dimethyl sulfoxide and 0.125ml of methanol. 16.2mg (0.023mmol) of bis (triphenylphosphine) palladium (II) chloride, 127mg (0.925mmol) of potassium carbonate and 105.4mg (0.694mmol) of 4-methoxyphenylboronic acid are added successively at RT under argon. The mixture was heated to 80 ℃ for about 3h with vigorous stirring. After cooling, the reaction mixture is purified directly by preparative RP-HPLC (gradient: acetonitrile/water). 133.9mg (63% of theory) of the title product are obtained.

LC-MS (method 2): r_t＝2.85min；m/z＝460(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 8.33(s, 1H), 7.40-7.30(m, 7H), 7.07(d, 2H), 3.83(s, 3H), 3.58(s, 3H), 3.30(m, about 2H), 2.58(s, 3H), 2.25(t, 2H), 1.50-1.33(m, 4H), 1.12-1.03(m, 2H).

Example 46

6- ({5-4- (ethylamino) phenyl ] -6-phenylfuran [2, 3-d ] pyrimidin-4-yl } amino) hexanoic acid methyl ester

29.2mg (0.068mmol) methyl 6- ({5- [ 4-aminophenyl ] -6-phenylfuran [2, 3-d ] pyrimidin-4-yl } amino) hexanoate and 14. mu.l (0.102mmol) triethylamine in 0.5ml acetonitrile were placed and excess ethyl iodide was added in portions over 12h at 45 ℃ in a closed apparatus. After cooling, the reaction mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate solution and then saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. After preparation of RP-HPLC (gradient: acetonitrile/water), 6.2mg of the title compound (19.9% of theory) are isolated from the crude product mixture.

LC-MS (method 5): r_t＝2.96min；m/z＝459(M+H)⁺

¹H-NMR(400MHz，CDCl₃): δ is 8.39(s, 1H), 7.61(d, 2H), 7.30-7.21(m, about 5H), 6.73(d, 2H), 4.83(t, 1H), 3.88(br.s, 1H)3.68(s, 3H), 3.43(q, 2H), 3.25(q, 2H), 2.29(t, 2H), 1.66-1.60(m, 2H), 1.52-1.45(m, 2H), 1.35(t, 3H), 1.29-1.21(m, 2H).

Example 47

(+) - { [ (2S) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } -acetic acid tert-butyl ester

85mg (0.416mmol) of tert-butyl (+) - { [ (2R) -3-hydroxy-2-methylpropyl ] oxy } acetate are dissolved in2ml of anhydrous THF, cooled to 0 ℃ and 0.21ml (0.416mmol) of the phosphazene base P2-t-Bu (2M solution in THF) are added. After 10min at 0 ℃ 126.7mg (0.378mmol) 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine are added and the mixture is stirred at 0 ℃ for 10min and at RT for a further 2 h. Thereafter water was added, the pH was adjusted to about 7 with 1N hydrochloric acid and extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. 125.1mg (65.8% of theory) of the title product are isolated from the crude product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1: 1).

LC-MS (method 9): r_t＝4.88min；m/z＝503(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.59(s，1H)，7.54(d，2H)，7.43-7.38(m，5H)，7.32(d，2H)，4.30(m，2H)，3.84(s，2H)，3.13(d，2H)，2.69(q，2H)，1.98(m，1H)，1.40(s，9H)，1.24(t，3H)，0.72(d，3H).

[α]_D ²⁰+11 °, c-0.255, chloroform.

Example 48

Ethyl (-) - { [ (2R) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate

A solution of 670.3mg (2.0mmol) 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine and 441mg (2.5mmol) ethyl (-) - { [ (2S) -3-hydroxy-2-methylpropyl ] oxy } acetate in 5.5ml dry THF was cooled to 0 ℃ and 2.4ml (2.4mmol) phosphazene base P4-t-Bu (1M solution in hexane) was added. At the end of the addition, it was heated to RT and stirred at RT for 2h, after which water was added to the reaction mixture and neutralized with 1N hydrochloric acid. Extracted with dichloromethane, the organic phase dried over sodium sulfate and concentrated in vacuo. After preparation of RP-HPLC (gradient: water/acetonitrile), 107.6mg of the title compound (65.8% of theory) are obtained from the crude product.

LC-MS (method 8): r_t＝3.36min；m/z＝475(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.59(s，1H)，7.54(d，2H)，7.43-7.37(m，5H)，7.31(d，2H)，4.35-4.27(m，2H)，4.09(q，2H)，3.97(s，2H)，3.19-3.11(m，2H)，2.68(q，2H)，1.98(m，1H)，1.22(t，3H)，1.17(t，3H)，0.71(d，3H).

[α]_D ²⁰-17.1 °, c-0.52, chloroform.

The following examples were prepared according to general procedure B (hydrolysis of methyl or ethyl ester-like) from the corresponding carboxylic acid esters:

example 61

(+) - { [ (2S) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } -acetic acid

120mg (0.239mmol) of tert-butyl { [ (2S) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate are first treated with 0.46ml of TFA in 2.0ml of dichloromethane at RT. The mixture was stirred at RT for about 4h and more TFA was added in portions. The reaction mixture is then concentrated by evaporation in vacuo and the title product is isolated after preparation of RP-HPLC (gradient: acetonitrile/water). 106.8mg (96.1% of theory) are obtained.

LC-MS (method 8): r_t＝2.98min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): δ is 8.58(s, 1H), 7.55(d, 2H), 7.42-7.37(m, 5H), 7.30(d, 2H), 4.30(m, about 2H), 3.89(s, 2H), 3.20-3.10(m, 2H), 2.69(q, 2H), 1.95(m, 1H), 1.24(t, 3H), 0.71(d, 3H).

[α]_D ²⁰+12.8 °, c-0.41, chloroform.

Example 62

(-) - { [ (2R) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetic acid

85.3mg (0.18mmol) of ethyl (-) - { [ (2R) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate are dissolved in 1ml of THF and 0.9ml of 1N sodium hydroxide solution are added. The mixture was stirred at RT for 3.5h, then neutralized with 1N hydrochloric acid and extracted with dichloromethane. The organic phase was concentrated by vacuum evaporation. After preparation of RP-HPLC (gradient: acetonitrile/water), 18.3mg of the title product (22.8% of theory) are isolated from the residue.

LC-MS (method 9): r_t＝4.02min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.59(s，1H)，7.54(d，2H)，7.42-7.36(m，5H)，7.32(d，2H)，4.30(m，2H)，3.85(s，2H)，3.20-3.10(m，2H)，2.69(q，2H)，1.98(m，1H)，1.21(t，3H)，0.70(d，3H).

[α]_D ²⁰-18.5 °, c-0.585, chloroform.

Example 63

(+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid methyl ester

1.902g (11.9mmol) (+/-) -6-hydroxyheptanoic acid methyl ester were placed in 20ml THF under argon and cooled to 0 ℃.6ml (11.9mmol) of a 2M solution of the phosphazene base P2-tert-butyl in THF are added and stirred for a further 10min at RT. After which it is cooled again to 0 c. 2.00g (5.94mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidine are added and then stirred for a further 1h at RT. Diluted with water, acidified with 10% aqueous citric acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined and washed once with saturated sodium chloride solution. Drying over magnesium sulfate, concentration by evaporation and purification of the residue by column chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 9: 1). 1.38g (78.0% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝3.12min；m/z＝461(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.50(s，1H)，7.62(m，2H)，7.36(d，2H)，7.30(m，3H)，6.94(d，2H)，5.35-5.26(m，1H)，3.88(s，3H)，3.64(s，3H)，2.22(m，2H)，1.61-1.47(m，4H)，1.28(d，3H)，1.28-1.15(m，2H).

Example 64

(+/-) -tert-butyl 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate

9.010g (44.54mmol) (+/-) -tert-butyl 6-hydroxyheptanoate were placed in100 ml THF under argon and cooled to 0 ℃. 15.117g (44.54mmol) of the phosphazene base P2-ethyl were added and stirred for a further 10min at RT. After which it is cooled again to 0 c. 10.00g (29.69mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine were added and then stirred at RT overnight. Then diluted with water, acidified with 10% aqueous citric acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined and washed once with saturated sodium chloride solution. Drying over magnesium sulfate, concentration by evaporation and purification of the residue by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 9: 1). 11.4g (76.4% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝3.53min；m/z＝503(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.49(s，1H)，7.62(m，2H)，7.36(d，2H)，7.30(m，3H)，6.94(d，2H)，5.36-5.27(m，1H)，3.89(s，3H)，2.12(t，2H)，1.64-1.45(m，4H)，1.42(s，9H)，1.28(d，3H)，1.28-1.12(m，2H).

Separation of enantiomers:

the racemate pair enantiomers obtained above were separated by preparative chiral-phase HPLC [ column: daicel Chiralpak AD-H, 250mm × 20 mm; flow rate: 25 ml/min; and (3) detection: 260 nm; injection volume: 1500 mul; temperature: 24 ℃; eluent: 98% iso-hexane/2% 2-propanol ]. 3.9g (7.76mmol) of tert-butyl (+) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate (example 65) and 4.8g (9.45mmol) of tert-butyl (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate (example 66) are obtained from 11.4g of the racemate in this way.

Example 65

T-butyl (+) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate (enantiomer 1)

HPLC：R_t11.76 min; ee > 99.5% [ column: daicel AD-H, 250mm × 4 mm; eluent: isopropanol/isohexane 3: 97; flow rate: 1 ml/min; and (4) UV detection: 250nm]。

Example 66

Tert-butyl (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate (enantiomer 2)

HPLC：R_t14.00 min; ee > 98.9% [ column: daicel AD-H, 250mm × 4 mm; eluent: isopropanol/isohexane 3: 97; flow rate: 1 ml/min; and (4) UV detection: 250nm]。

Alternatively, (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid tert-butyl ester can be produced by the reaction of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine with (-) -6-hydroxyheptanoic acid tert-butyl ester:

a solution of 5.50g (27.19mmol) tert-butyl (-) -6-hydroxyheptanoate in10 ml DMF was cooled under argon to 0 ℃ and 1.054g (26.36mmol, 60%) sodium hydride was added with ice cooling. The mixture was stirred at 0 deg.C-RT for about 20 min. After cooling to 0 ℃ again, 5.549g (16.47mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine were added. At the end of the addition, the mixture was slowly heated to RT and stirred overnight at RT, after which water was added and neutralized with 1N hydrochloric acid. The mixture was extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 10: 1). 4.68g of the title compound (56.5% of theory) are obtained.

LC-MS (method 2): r_t＝3.33min；m/z＝503(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.56(s，1H)，7.53(d，2H)，7.43-7.35(m，5H)，7.02(d，2H)，5.29(m，1H)，3.83(s，3H)，2.10(t，2H)，1.54-1.36(m，4H)，1.36(s，9H)，1.22(d，3H)，1.21-1.09(m，2H).

[α]_D ²⁰-61.4 °, c-0.55, chloroform.

Example 67

(+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid

The method comprises the following steps:

preparation starting from methyl (+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate:

1.38g (3.0mmol) of methyl (+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate are placed in 40ml of THF. 30ml of 1N sodium hydroxide solution are added and stirred at RT overnight. Then about 40ml of 1M hydrochloric acid was added to pH about 2, diluted with a little water and extracted twice with ethyl acetate. The ethyl acetate phases were combined and washed once with saturated sodium chloride solution. Dried over magnesium sulfate and concentrated by evaporation. 1.34g (78.0% of theory) of the title compound are obtained.

The method 2 comprises the following steps:

preparation starting from tert-butyl (+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate:

800mg (1.59mmol) of tert-butyl (+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate are dissolved in10 ml of dichloromethane. 2.5ml of trifluoroacetic acid were added and stirred at RT for 2 h. After concentration by evaporation, petroleum ether was added to the residue and the product was allowed to crystallize. After which some more tert-butyl methyl ether was added, stirred for a few minutes and then filtered with suction on a frit. 640mg (89.9% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.71min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.55(s，1H)，7.55(d，2H)，7.45-7.35(m，5H)，7.02(d，2H)，5.31-5.25(m，1H)，3.81(s，3H)，2.21(m，2H)，1.55-1.35(m，4H)，1.22(d，3H)，1.22-1.05(m，2H).

Separation of enantiomers:

1.330g (+/-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid were dissolved in 240ml of warm ethanol. Separation of the racemate enantiomers by preparative chiral-phase HPLC [ column: daicel Chiralpak AS-H, 5 μm, 250mm × 20 mm; flow rate: 15 ml/min; and (3) detection: 220 nm; injection volume: 1000 μ l; temperature: 30 ℃; eluent: 50% iso-hexane/50% ethanol + 0.2% glacial acetic acid + 1% water ] (see examples 68 and 69).

Example 68

(+) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid (enantiomer 1)

[ α ] D20 ═ 86.2 °, c ═ 0.630, methanol.

LC-MS (method 2): r_t＝2.68min；m/z＝447(M+H)⁺

Example 69

(-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid (enantiomer 2)

[α]_D ²⁰-79.5 °, c-0.520, methanol.

LC-MS (method 8): r_t＝2.93min；m/z＝447(M+H)⁺

Alternatively, (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid can be prepared by ester dissociation of (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid tert-butyl ester:

9.24g (18.38mmol) tert-butyl (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate are dissolved in100 ml dichloromethane at RT and 25ml TFA are added. After 2h at RT, the mixture was diluted with dichloromethane, washed several times with water and once with saturated sodium chloride solution, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue was purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 5: 1 → 2: 1, followed by cyclohexane/ethyl acetate 2: 1+ 0.5% acetic acid). The fractions containing the product were concentrated by evaporation in vacuo, the residue was taken up again in dichloromethane and washed several times with water and saturated sodium chloride solution. The organic phase is dried over sodium sulfate, concentrated by evaporation and dried under high vacuum. 6.89g of the title compound (83.9% of theory) are obtained.

LC-MS (method 7): r_t＝4.10min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.98(br.s，1H)，8.57(s，1H)，7.55(d，2H)，7.45-7.36(m，5H)，7.02(d，2H)，5.29(m，1H)，3.72(s，3H)，2.12(t，2H)，1.54-1.37(m，4H)，1.22(d，3H)，1.21-1.08(m，2H).

[α]_D ²⁰-70.8 °, c-0.685, chloroform.

Example 70

(-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid sodium salt

To 893mg (2.0mmol) (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid was added 5.0ml demineralized water (Millipore ion exchanger). 2.0ml (2.0mmol) of 1N sodium hydroxide solution are added and stirred at RT for 30 min. Next, the treatment was carried out in an ultrasonic bath for several minutes. 50ml of demineralized water are added, filtered once through a paper filter and the filter is washed once more with 10ml of demineralized water. To the filtrate was added 200ml more demineralized water and lyophilized overnight. 935mg (99.7% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.93min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.55(s，1H)，7.54(d，2H)，7.42-7.35(m，5H)，7.01(d，2H)，5.31-5.24(m，1H)，3.82(s，3H)，1.79(t，2H)，1.52-1.40(m，2H)，1.39-1.31(m，2H)，1.21(d，3H)，1.21-1.06(m，2H).

[α]_D ²⁰-32.0 °, c-0.145, dimethylsulfoxide.

Example 71

Bis ethanolamine (bisethaneamine) 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate

To 26.8mg (0.060mmol) (-) -6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid was added 250. mu.l of demineralized water (Millipore ion exchanger). 6.3mg (0.060mmol)2, 2' -iminodiethanol were added and stirred at RT for 30 min. Next, the treatment was carried out in an ultrasonic bath for several minutes. A few drops of dioxane were added, followed by lyophilization overnight. 33.0mg (99.7% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.93min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.55(s，1H)，7.53(d，2H)，7.42-7.35(m，5H)，7.01(d，2H)，5.31-5.24(m，1H)，3.82(s，3H)，3.44(t，4H)，2.61(t，3H)，2.10(t，2H)，1.52-1.45(m，2H)，1.45-1.35(m，2H)，1.22(d，3H)，1.22-1.06(m，2H).

[α]_D ²⁰-36.0 °, c-0.325, dimethylsulfoxide.

Example 72

(+/-) -6- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid methyl ester

In10 ml of THF under argon 717mg (4.48mmol) (+/-) -6-hydroxyheptanoic acid methyl ester are placed and cooled to 0 ℃. 2.25ml (4.48mmol) of a 2M solution of the phosphazene base P2-tert-butyl in THF are added and stirred for a further 10min at RT. After which it is cooled again to 0 c. 1.0g (2.99mmol) 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine was added and stirring was continued at RT overnight. Diluted with water, acidified with 10% aqueous citric acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined and washed once with saturated sodium chloride solution. Drying over magnesium sulfate, concentration by evaporation and purification of the residue by column chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 9: 1). 640mg (46.7% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝3.44min；m/z＝459(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.50(s，1H)，7.64(m，2H)，7.38(d，2H)，7.31(m，3H)，7.24(d，2H)，5.35-5.26(m，1H)，3.63(s，3H)，2.76-2.67(q，2H)，2.21(dd，2H)，1.60-1.41(m，4H)，1.32-1.22(m，6H)，1.22-1.10(m，2H).

Example 73

(+/-) -6- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid

1.38g (3.0mmol) of methyl (+/-) -6- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate are placed in 25ml of THF. 13.8ml of 1N sodium hydroxide solution are added and stirred at RT overnight. Diluted with water and ethyl acetate and then 1M hydrochloric acid was added to a pH of about 2. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The ethyl acetate phases were combined and washed once with saturated sodium chloride solution. Dried over magnesium sulfate and concentrated by evaporation. 600mg (98.2% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝3.32min；m/z＝445(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.51(s，1H)，7.62(m，2H)，7.37(d，2H)，7.30(m，3H)，7.23(m，2H)，5.34-5.25(m，1H)，2.76-2.58(q，2H)，2.24(dd，2H)，1.59-1.49(m，4H)，1.32-1.23(m，6H)，1.23-1.12(m，2H).

Separation of enantiomers:

600mg of (+/-) -6- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid were dissolved in 20ml of 2-propanol/20 ml of iso-hexane and separated into the enantiomers by preparative chiral-phase HPLC [ column: daicel Chiralpak AS-H, 5 μm, 250mm × 20 mm; flow rate: 15 ml/min; and (3) detection: 220 nm; injection volume: 400 mul; temperature: 40 ℃; eluent: 80% iso-hexane/20% 2-propanol + 0.2% TFA + 1% water ] (see examples 74 and 75).

Example 74

(+) -6- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid (enantiomer 1)

[α]_D ²⁰+83.4 °, c-0.580, methanol.

LC-MS (method 8): r_t＝3.28min；m/z＝445(M+H)⁺。

Example 75

(-) -6- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid (enantiomer 2)

[α]_D ²⁰-81.3 °, c-0.520, methanol.

LC-MS (method 8): r_t＝3.17min；m/z＝445(M+H)⁺。

Example 76

{ [ (3R) -3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butyl ] oxy } acetic acid tert-butyl ester

455mg (2.23mmol) of tert-butyl { [ (3R) -3-hydroxybutyl ] oxy } acetate, which comprises approximately 10% tert-butyl { [ (1R) -3-hydroxy-1-methylpropyl ] oxy } acetate, are placed in 5ml of THF under argon and cooled to 0 ℃. 1.15ml (2.23mmol) of a 2M solution of the phosphazene base P2-tert-butyl in THF are added and stirred for a further 10min at RT. After which it is cooled again to 0 c. 500mg (1.49mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine are added and stirred at RT overnight. Then diluted with water, acidified with 10% aqueous citric acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined and washed once with saturated sodium chloride solution. Dried over magnesium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 9: 1). 450mg (60.1% of theory) of the title compound are obtained. 75mg (9.0% of theory) of tert-butyl (-) - { [ (1R) -3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } acetate are isolated as by-product (cf. example 77).

LC-MS (method 2): r_t＝3.15min；m/z＝405(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.51(s，1H)，7.62(m，2H)，7.37(d，2H)，7.31(m，3H)，6.94(d，2H)，5.53-5.45(m，1H)，3.72(s，2H)，3.47-3.32(m，2H)，1.86(m，2H)，1.43(s，9H)，1.32(d，3H).

Example 77

(-) - { [ (1R) -3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } acetic acid tert-butyl ester

The title compound was obtained as a by-product in the preparation of example 76.

LC-MS (method 5): r_t＝3.26min；m/z＝405(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.52(s，1H)，7.62(m，2H)，7.37(d，2H)，7.31(m，3H)，6.94(d，2H)，4.54(m，2H)，3.82(m，2H)，3.36-3.27(m，1H)，1.95-1.83(m，1H)，1.79-1.69(m，1H)，1.42(s，9H)，1.099(d，3H).

[α]_D ²⁰-96.8 °, c 0.380, methanol.

Example 78

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

350mg (0.69mmol) of tert-butyl { [ (3R) -3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butyl ] oxy } acetate are placed in 7ml of dichloromethane. 1.75ml TFA was added and stirred at RT overnight. The residue is then concentrated by evaporation and purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 1: 1). 110mg (35.4% of theory) of the title compound are obtained.

LC-MS (method 10): r_t＝2.67min；m/z＝449(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.50(s，1H)，7.61(m，2H)，7.36(m，2H)，7.31(m，3H)，6.93(d，2H)，5.52(m，1H)，3.96(d，2H)，3.47-3.36(m，2H)，1.92-1.80(m，2H)，1.34(d，3H).

[α]_D ²⁰-79.6 °, c-0.42, acetonitrile.

Example 79

(-) - { [3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } acetic acid

To 1ml of methylene chloride was added 45mg (0.089mmol) of tert-butyl (-) - { [3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } acetate. Add 250. mu.l TFA and stir at RT overnight. The residue is then concentrated by evaporation and purified by chromatography on a thick-layer silica gel plate (flow agent: cyclohexane/ethyl acetate 1: 1). The product was extracted with dichloromethane/methanol 95: 5.8 mg (21.5% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.65min；m/z＝449(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.49(s，1H)，7.58(m，2H)，7.34(m，2H)，7.27(m，3H)，6.94(d，2H)，5.58-4.45(m，2H)，3.75(s，2H)，3.36-3.24(m，1H)，1.92-1.81(m，1H)，1.81-1.71(m，1H)，1.11(d，3H).

[α]_D ²⁰-77.1 °, c 0.370, methanol.

The following two compounds were obtained analogously:

example 80

(-) - { [3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butyl ] oxy } ethanoic acid

In analogy to the synthesis procedure described above 500mg (0.99mmol) tert-butyl { [ (3R) -3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butyl ] oxy } acetate were reacted with TFA. 447mg (92.3% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝3.00min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.49(s，1H)，7.60(m，2H)，7.33(d，2H)，7.27(m，3H)，7.22(d，2H)，5.52-5.43(m，1H)，3.97-3.87(dd，2H)，3.45-3.32(m，2H)，2.75-2.68(q，2H)，1.90-1.75(m，2H)，1.32(t，3H)，1.28(d，3H).

[α]_D ²⁰-94 °, c-0.530, methanol.

Example 81

(-) - { [3- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butyl ] oxy } acetic acid tert-butyl ester

In analogy to the synthesis procedure described above 800mg (2.39mmol) tert-butyl { [ (3R) -3-hydroxybutyl ] oxy } acetate, which comprises approximately 10% tert-butyl { [ (1R) -3-hydroxy-1-methylpropyl ] oxy } acetate, were reacted with 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine. 690mg (57.4% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝3.35min；m/z＝503(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.50(s，1H)，7.62(m，2H)，7.37(d，2H)，7.31(m，3H)，7.22(d，2H)，5.50-5.41(m，1H)，3.71(s，2H)，3.42-3.28(m，2H)，2.75-2.68(q，2H)，1.82(m，2H)，1.43(s，9H)，1.33(t，3H)，1.30(d，3H).

[α]_D ²⁰-90.7 °, c-0.370, acetonitrile.

Example 82

(+) -tert-butyl 3- [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propionate

A suspension of 2.548g (7.57mmol) 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine and 1.70g (8.32mmol) (+) -3- [ (1S) -2-hydroxy-1-methylethoxy ] propionic acid tert-butyl ester in 8ml DMF was cooled to 0 ℃ and over 30min, 272mg (6.81mmol, 60%) sodium hydride were added in portions. Thereafter 0.5ml of anhydrous THF was added and the mixture was stirred at 0 ℃ for 10min, after which some acetic acid was added and after which the mixture was added to water. The aqueous phase was extracted three times with dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified either by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 10: 1 → 8: 1) or by preparative RP-HPLC (gradient: acetonitrile/water). 2.27g (59.5% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝3.27min；m/z＝505(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，7.54(d，2H)，7.45-7.39(m，5H)，7.03(d，2H)，4.38-4.32(m，2H)，3.81(s，3H)，3.65-3.59(m，1H)，3.50-3.40(m，2H)，2.28(t，2H)，1.35(s，9H)，1.00(d，3H).

[α]_D ²⁰22.4 °, c 0.515, chloroform.

Example 83

(+) -3- { [ (2S) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] oxy } propanoic acid

3.17g (6.28mmol) (+) -tert-butyl 3- [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propanoate were dissolved in 21ml dichloromethane and 12.1ml TFA were added at RT. The reaction mixture was stirred at RT for 2.5h and then concentrated carefully by evaporation in vacuo. The residue is taken up in dichloromethane, washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is purified by chromatography on silica gel (flow agent: dichloromethane/acetone 10: 1 → 3: 1). The product-containing fractions were combined and concentrated under vacuum. The resulting residue was mixed with petroleum ether. After filtration and drying under high vacuum, 1.77g (62.8% of theory) of the title product are obtained.

LC-MS (method 8): r_t＝2.63min；m/z＝449(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.1(s，1H)，8.60(s，1H)，7.54(d，2H)，7.43-7.37(m，5H)，7.03(d，2H)，4.38-4.30(m，2H)，3.82(s，3H)，3.67-3.60(m，1H)，3.53-3.44(m，2H)，2.31(t，2H)，1.00(d，3H).

[α]_D ²⁰+30.6 °, c ═ 0.495, chloroform.

Example 84

(+) -3- [2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propionic acid

A mixture of 1.14g (3.05mmol) of (2S) -1- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-2-ol and (2S) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-1-ol and 1.951g (15.22mmol) of tert-butyl acrylate and 207mg (0.609mmol) of tetra-n-butylammonium hydrogen sulfate are placed in10 ml of dichloromethane and cooled to 0 ℃. 2.5ml of 50% sodium hydroxide solution are added and stirred vigorously at 0 ℃ for 1 h. After which it was diluted with dichloromethane and slightly acidified with 10% citric acid solution. The phases were separated, the aqueous phase was extracted once with dichloromethane, the organic phases were combined, dried over magnesium sulphate and concentrated by evaporation. The residue obtained was dissolved in 30ml of dichloromethane. 7.5ml TFA was added and stirred at RT for 1 h. The mixture was then concentrated by evaporation and the residue was dried under high vacuum. First, purification by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 1: 1) gives 1.15g of a mixture of regioisomers.

The obtained mixture of regioisomers (1.15g) was dissolved in a mixture of 5ml of isohexane and 5ml of ethyl acetate and separated by chiral-phase chromatography [ column: a chiral silica phase based on the selector poly (N-methacryloyl-L-leucine-tert-butylamide), 500mm x30 mm; flow rate: 50 ml/min; and (3) detection: 260 nm; injection volume: 300 mu l; temperature: 24 ℃; eluent: isohexane/ethyl acetate 1: 1] separated into isomers.

[α]_D ²⁰+50.1, c-0.500, methanol.

LC-MS (method 8): r_t＝2.82min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.12(br.s，1H)，8.49(s，1H)，7.52(d，2H)，7.39(m，5H)，7.30(d，2H)，4.31(m，2H)，3.63-3.55(m，1H)，3.53-3.38(m，2H)，2.72-2.65(q，2H)，2.30(t，2H)，1.22(t，3H)，0.93(d，3H).

Example 85

(+) -3- { [2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] oxy } propanoic acid

See above for preparation, example 84.

LC-MS (method 8): r_t＝2.85min；m/z＝447(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.12(br.s，1H)，8.49(s，1H)，7.53(d，2H)，7.39(m，5H)，7.29(d，2H)，5.45-5.36(m，1H)，3.52-3.32(m，4H)，2.72-2.65(q，2H)，2.30(t，2H)，1.22(t，3H)，1.20(d，3H).

[α]_D ²⁰+46.0 °, c-0.590, methanol.

The compounds provided in the following table were prepared analogously to the syntheses described above. The details of regioisomer separation are as follows:

example 86 and example 87:

in a mixture of 5ml of isohexane and 5ml of ethyl acetate, 1.00g (1.99mmol) of a mixture of (-) -3- [2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propanoic acid (example 86) and (-) -3- [2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] oxy } propanoic acid (example 87) were dissolved and separated into isomers by chiral-phase chromatography; column: 680mm x 40mm based on the chiral silica phase of the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); flow rate: 50 ml/min; and (3) detection: 260 nm; injection volume: 1700 ul; temperature: 24 ℃; eluent: 50% isohexane/50% ethyl acetate.

Example 83 and example 88:

dissolving a mixture of 7.80g (15.45mmol) (+) -3- [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propanoic acid (example 83) and (+) -3- { [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] oxy } propanoic acid (example 88) in a mixture of 50ml isohexane and 50ml ethyl acetate and separating into isomers by chiral-phase chromatography; column: a chiral silica gel phase based on the selector poly (N-methacryloyl-L-leucine-1-methylamide), 250mm × 30 mm; flow rate: 50 ml/min; and (3) detection: 260 nm; injection volume: 400 mul; temperature: 24 ℃; eluent: 50% isohexane/50% ethyl acetate.

Example 83 can also be prepared in another manner (see above for description).

Example 89 and example 90:

dissolving a mixture of 250mg (0.56mmol) of (-) -3- [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propionic acid (example 89) and (-) -3- { [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] oxy } propionic acid (example 90) in a mixture of 2ml of isohexane and 2ml of ethyl acetate and separating into isomers by chiral-phase chromatography; column: based on the selection agent poly (chiral silica gel phase of N-methacryloyl-L-leucine-dicyclopropylmethylamide, 680mm × 40 mm; flow rate: 50 ml/min; detection: 260 nm; injection volume: 4000 μ L; temperature: 24 ℃; eluent t ═ 0min 60% isohexane/40% ethyl acetate → t ═ 13min 45% isohexane/55% ethyl acetate.

Example 91

(+/-) -4- [ (2- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] oxy } propyl) (methyl) amino ] butanoic acid methyl ester

25mg (0.064mmol) (+/-) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropan-1-amine and 13mg (0.128mmol) triethylamine were placed in 250. mu.l dichloromethane. 23.2mg (0.128mmol) of methyl 4-bromobutyrate are added and stirred at RT overnight. The same amounts of triethylamine and 4-bromobutyric acid methyl ester were added once more and stirred for a further 24h at RT. The residue is then concentrated by evaporation and purified by thick-layer chromatography on silica gel (flow agent: dichloromethane/methanol 95: 5). The product-containing zone was extracted with dichloromethane/methanol 9: 1. 22.4mg of the title compound are obtained as crude product.

LC-MS (method 8): r_t＝1.84min；m/z＝490(M+H)⁺。

Example 92

(+/-) -4- [ (2- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] oxy } propyl) (methyl) amino ] butanoic acid

20mg (0.027mmol) (+/-) -4- [ (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl) (methyl) amino ] butanoic acid methyl ester were placed in 0.8ml THF. 0.27ml (0.27mmol) of 1N sodium hydroxide solution are added and stirred at RT overnight. The residue is then concentrated by evaporation and purified by thick-layer chromatography on silica gel (flow agent: dichloromethane/methanol 9: 1). The product region was extracted with dichloromethane/methanol 7: 3. 8.5mg (66.3% of theory) of the title compound are obtained.

LC-MS (method 10): r_t＝1.70min；m/z＝476(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.52(m，2H)，7.43-7.35(m，5H)，7.02(d，2H)，5.57-5.48(m，1H)，3.81(s，3H)，3.6-3.4(br.s，2H)，2.36-2.25(br.s，2H)，2.14-2.06(m，5H)，1.57-1.45(m，2H)，1.22(d，3H).

Example 93

3- [2- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] amino } -1-methylethoxy ] propionic acid

100mg (0.27mmol) (+) -1- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } propan-2-ol and 170mg (1.33mmol) tert-butyl acrylate and 18.1mg (0.053mmol) tetra-n-butylammonium hydrogen sulfate are placed in2ml dichloromethane and cooled to 0 ℃. After which 250. mu.l of 50% sodium hydroxide solution were added and the mixture was stirred vigorously at 0 ℃ for 1 h. Let it return to RT and continue stirring at RT overnight. And then diluted with dichloromethane and water. Acidified with 10% citric acid solution and the phases separated. The aqueous phase was extracted once more with dichloromethane. The organic phases are combined, washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue thus obtained is dissolved in 2.5ml of dichloromethane, 600. mu.l of trifluoroacetic acid are added and stirring is carried out for a further 2h at RT. The residue is then concentrated by evaporation and purified twice by chromatography on thick-layer silica gel plates (flow agent: dichloromethane/methanol 9: 1). The product region was extracted with dichloromethane/methanol 9: 1. After concentration by evaporation and drying, 38mg (42.8% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.41min；m/z＝448(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.32(s，1H)，7.44(m，4H)，7.38-7.30(m，3H)，7.13(d，2H)，5.18(t，1H)，3.84(s，3H)，3.66-3.45(m，3H)，3.39-3.15(m，2H)，2.26(m，2H)，1.01(d，3H).

Example 94

(3- { [5- (2, 2-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2, 2-dimethylpropoxy) acetic acid tert-butyl ester

300mg (0.742mmol) of 3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2, 2-dimethylpropan-1-ol and 723mg (3.71mmol) of tert-butyl bromoacetate and 50mg (0.148mmol) of tetra-n-butylammonium hydrogen sulfate are placed in 6ml of dichloromethane. Cooled to 0 ℃. After which 750. mu.l of 50% sodium hydroxide solution are added and stirred vigorously for a few minutes at 0 ℃. Vigorous stirring was allowed to return to RT and continued overnight. After which it was diluted with dichloromethane and slightly acidified with 10% citric acid solution. The phases were separated and the aqueous phase was extracted once with dichloromethane. The organic phases are combined and washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 9: 1). 295mg (76.7% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝3.33min；m/z＝419(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.51(s，1H)，7.61(m，2H)，7.49(d，2H)，7.30(m，3H)，6.98(d，2H)，4.21(s，2H)，3.87(s，3H)，3.77(s，2H)，3.02(s，2H)，1.44(s，9H)，0.82(s，6H).

Example 95

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

280mg (0.54mmol) of tert-butyl (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2, 2-dimethylpropoxy) acetate are placed in 8ml of dichloromethane. 2ml of trifluoroacetic acid were added and stirred at RT for 1 h. After which it is concentrated by evaporation and the residue is mixed with petroleum ether. The solid was filtered with suction on a frit and dried under high vacuum. 220mg (88.1% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝4.03min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.56(s，1H)，7.54(d，2H)，7.42-7.35(m，5H)，7.02(d，2H)，4.12(s，2H)，3.86(s，2H)，3.81(s，3H)，3.01(s，2H)，0.72(s，6H).

Example 96

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

200mg (0.53mmol) of 3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propan-1-ol and 518mg (2.66mmol) of tert-butyl bromoacetate and 36mg (0.106mmol) of tetra-n-butylammonium hydrogen sulfate are placed in 5ml of dichloromethane and cooled to 0 ℃. 1.0ml of 50% sodium hydroxide solution was added and stirred vigorously at 0 ℃. It was then allowed to return to RT and stirring was continued overnight. After which it was diluted with dichloromethane and water, acidified with a 10% citric acid solution and the phases separated. The aqueous phase was extracted once more with dichloromethane. The organic phases are combined, washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue was dissolved in 5ml of dichloromethane. 1.25ml TFA was added and stirred at RT for 2 h. After which it is concentrated by evaporation and dried under high vacuum. The residue is purified by chromatography on a thick-layer silica gel plate (flow agent: dichloromethane/methanol 95: 5). The product region was extracted with dichloromethane/methanol 9: 1.50 mg (23.0% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝3.68min；m/z＝435(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝12.58(br.s，1H)，8.59(s，1H)，7.54(d，2H)，7.42-7.35(m，5H)，7.02(d，2H)，4.43(t，2H)，3.82(s，3H)，3.39-3.31(m，4H)，1.84-1.78(m，2H).

Example 97

(-) -4- [2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } -1-methylethoxy ] butyric acid

110mg (0.29mmol) (+) -1- { [5- (4-methoxyphenyl) -6-phenyl [2, 3-d ] pyrimidin-4-yl ] amino } propan-2-ol and 327mg (1.47mmol) tert-butyl 4-bromobutyrate and 20mg (0.059mmol) tetra-n-butylammonium hydrogen sulfate were placed in2ml dichloromethane and cooled to 0 ℃. After which 500. mu.l of 50% sodium hydroxide solution were added and stirred at RT for two days. Again, the same amounts of tert-butyl 4-bromobutyrate, tetra-n-butylammonium hydrogen sulfate and 50% sodium hydroxide solution were added and stirred at RT for a further 24 h. Then heated under reflux for 24 h. It was allowed to cool and diluted with dichloromethane and water. Acidified with 10% citric acid solution and the phases separated. The aqueous phase was extracted once more with dichloromethane. The organic phases are combined, washed once with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. The residue was purified by preparative HPLC. The product thus obtained (30mg) was dissolved in 1ml of dichloromethane. Add 250 μ l trifluoroacetic acid and stir at RT overnight. The residue is then concentrated by evaporation and chromatographed on a thick-layer silica gel plate (flow agent: dichloromethane/methanol 95: 5). The product region was extracted with dichloromethane/methanol 9: 1.25 mg (21.2% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝3.64min；m/z＝462(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.39(s，1H)，7.51(m，2H)，7.41(d，2H)，7.26(m，3H)，7.06(d，2H)，5.12(t，1H)，3.89(s，3H)，3.77-3.70(m，1H)，3.55-3.47(m，1H)，3.42-3.38(m，1H)，3.28-3.20(m，2H)，2.31(t，2H)，1.76-1.67(m，2H)，1.09(d，3H).

[α]_D ²⁰-20.0 °, c-0.077, acetonitrile.

Example 98

Tert-butyl 3- { [ (1R, 2R) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } propanoate

To a solution of 535mg (1.37mmol) of (2R, 3R) -3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butan-2-ol in 5ml of THF were added 157mg (1.37mmol) of potassium tert-butoxide. After stirring at RT for 15min, 1.0ml (878mg, 6.65mmol) tert-butyl acrylate was added. After three hours, 10ml of water were added and the reaction mixture was concentrated by evaporation in vacuo. The residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 346mg (47% of theory) of the desired product are obtained.

LC-MS (method 7): r_t＝4.83min；m/z＝519(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.56(s，1H)，7.55(d，2H)，7.40-7.35(m，5H)，7.01(d，2H)，5.29(dt，1H)，3.81(s，3H)，3.63-3.40(m，3H)，2.26(t，2H)，1.33(s，9H)，1.15(d，3H)，0.88(d，3H).

Example 99

4- { [ (2R) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butanoic acid methyl ester

To a solution of 1000mg (2.31mmol) of (2R) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -N-methylpropane-1-ammonium formate in 20ml of THF were added 797mg (5.77mmol) of potassium carbonate. After addition of 0.35ml (501mg, 2.77mmol) of methyl 4-bromobutyrate and 34mg (0.09mmol) of n-butylammonium iodide, the reaction mixture is stirred at 80 ℃ for 16 h. After cooling to room temperature, the inorganic salts were filtered off and washed with THF. The filtrate was concentrated by evaporation in vacuo. The residue is taken up in acetonitrile and purified by preparative RP-HPLC (gradient: water/acetonitrile/ammonia). 308mg (73% purity, 20% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝1.91min；m/z＝488(M+H)⁺。

Example 100

Tert-butyl (6R) -6- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate

To a solution of 350mg (1.73mmol) of tert-butyl (6R) -6-hydroxyheptanoate in 5ml of THF were added 87mg (2.16mmol) of sodium hydride (60% dispersion in mineral oil) with ice cooling. After stirring for ten minutes with ice-cooling, 644mg (1.82mmol) of 4-chloro-6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidine in 5ml of THF and 32mg (0.09mmol) of tetra-n-butylammonium iodide were added. The reaction mixture was stirred at RT for 48 h. After addition of water and ethyl acetate, the separated organic phase is washed with 1N hydrochloric acid and concentrated by evaporation in vacuo. The residue is taken up in acetonitrile/DMSO and purified by preparative RP-HPLC (gradient: water/acetonitrile). 425mg (47% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝3.37min；m/z＝521(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，7.55-7.50(m，2H)，7.34-7.28(m，4H)，6.93-6.91(m，2H)，5.41-5.34(m，1H)，3.77(s，3H)，2.10(t，2H)，1.60-1.55(m，2H)，1.46-1.39(m，2H)，1.34(s，9H)，1.28(d，3H)，1.25-1.15(m，2H).

Example 101

Tert-butyl 4- { [ (2S) -2- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butanoate

To a solution of 100mg (0.43mmol) tert-butyl 4- { [ (2S) -2-hydroxypropyl ] (methyl) amino } butyrate in 1ml THF were added 22mg (0.54mmol) of sodium hydride (60% dispersion in mineral oil) with ice cooling. After stirring for ten minutes with ice-cooling, a solution of 161mg (0.45mmol) of 4-chloro-6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidine in2ml of THF and 8mg (0.02mmol) of tetra-n-butylammonium iodide were added. The reaction mixture was stirred at room temperature for 16 h. After addition of water and ethyl acetate, the separated organic phase is washed with 1N hydrochloric acid and concentrated by evaporation in vacuo. The residue is taken up in acetonitrile/DMSO and purified by preparative RP-HPLC (gradient: water/acetonitrile). 114mg (93% purity, 45% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝1.90min；m/z＝550(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，7.55-7.51(m，2H)，7.33-7.28(m，4H)，6.93-6.91(m，2H)，5.59-5.51(m，1H)，3.77(s，3H)，2.40-2.29(m，2H)，2.25-2.22(m，2H)，2.08(s，3H)，2.05-2.00(m，2H)，1.53-1.42(m，2H)，1.32(s，9H)，1.27(d，3H).

Example 102

Tert-butyl 6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate

To a solution of 200mg (0.99mmol) tert-butyl 6-hydroxyheptanoate in 5ml THF were added 49mg (1.24mmol) sodium hydride (60% dispersion in mineral oil). After stirring for ten minutes, 407mg (90% purity, 1.04mmol)) of 4-chloro-5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidine in 5ml THF and 18mg (0.05mmol) of tetra-n-butylammonium iodide were added. The reaction mixture was stirred at 75 ℃ for 40 h. After addition of water and ethyl acetate, the separated organic phase is washed with 1N hydrochloric acid and concentrated by evaporation in vacuo. The residue is taken up in acetonitrile/DMSO and purified by preparative RP-HPLC (gradient: water/acetonitrile). 104mg (19% of theory) of the desired product (racemate) are obtained.

LC-MS (method 8): r_t＝3.59min；m/z＝519(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.61(s，1H)，7.55-7.51(m，2H)，7.33-7.27(m，4H)，7.20-7.18(m，2H)，5.39-5.31(m，1H)，2.63(q，2H)，2.08(t，2H)，1.60-1.50(m，2H)，1.45-1.37(m，2H)，1.34(s，9H)，1.28(d，3H)，1.24-1.16(m，5H).

Example 103

Tert-butyl (6R) -6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate

To a solution of 350mg (1.73mmol) of tert-butyl (6R) -6-hydroxyheptanoate in 5ml of THF were added 87mg (2.16mmol) of sodium hydride (60% dispersion in mineral oil) with ice cooling. After stirring for ten minutes with ice-cooling, 712mg (90% purity, 1.82mmol) of 4-chloro-5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidine in 5ml of THF and 32mg (0.09mmol) of tetra-n-butylammonium iodide were added. The reaction mixture was stirred at room temperature for 48 h. After addition of water and ethyl acetate, the separated organic phase is washed with 1N hydrochloric acid and concentrated by evaporation in vacuo. The residue is taken up in acetonitrile/DMSO and purified by preparative RP-HPLC (gradient: water/acetonitrile). 459mg (51% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝3.51min；m/z＝519(M+H)⁺

Example 104

(3- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylbutoxy) acetic acid tert-butyl ester

To a solution of 2.19g (5.41mmol) of 4- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } pentan-2-ol in 20ml of toluene was added 4.8ml of 11.25N sodium hydroxide solution. After addition of 184mg (0.54mmol) of tetra-n-butylammonium hydrogen sulfate and 2.11g (10.83mmol) of tert-butyl bromoacetate, the reaction mixture is stirred at 70 ℃ for 15 h. After cooling to room temperature, the pH was adjusted to 7 with concentrated hydrochloric acid. Extracted three times with 50ml of dichloromethane each time. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated by evaporation in vacuo. The residue is taken up in ethyl acetate and purified by flash chromatography on silica gel (flow agent: ethyl acetate/methanol 1: 0, 5: 1). 0.08g (92% purity, 3% of theory) of the desired product is obtained as a racemic mixture of non-corresponding isomers.

LC-MS (method 8): r_t＝3.33min；m/z＝519(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): [ minor stereoisomers in brackets ]]δ＝8.57(s，1H)，[8.56，s，1H]，7.55-7.51(m，2H)，7.43-7.37(m，5H)，7.04-7.01(m，2H)，5.54-5.46(m，1H)，[5.39-5.30，m，1H]，3.83-3.81(m，5H)，3.42-3.36(m，1H)，1.87-1.80(m，1H)，1.56-1.49(m，1H)，1.39(s，9H)，[1.34，d，3H]，1.27(d，3H)，1.00(d，3H)，[0.89，d，3H].

Example 105

[2- ({ [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } methyl) -3, 3-dimethylbutoxy ] acetic acid tert-butyl ester

To a solution of 265mg (0.62mmol)2- ({ [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } methyl) -3, 3-dimethylbut-1-ol in10 ml toluene was added 0.5ml 11.25N sodium hydroxide solution. After addition of 21mg (0.06mmol) of tetra-n-butylammonium hydrogen sulfate and 240mg (1.23mmol) of tert-butyl 2-bromoacetate, the reaction mixture is stirred at 70 ℃ for 16 h. After cooling to room temperature, it was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 170mg (51% of theory) of the desired product (racemate) are obtained.

LC-MS (method 9): r_t＝5.34min；m/z＝545(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.60(s，1H)，7.53-7.51(m，2H)，7.39-7.36(m，5H)，7.31-7.29(m，2H)，4.54-4.45(m，2H)，3.83(dd，2H)，3.30(s，2H)，2.69(q，2H)，1.55-1.49(m，1H)，1.39(s，9H)，1.24(t，3H)，0.73(s，9H).

Example 106

3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 2-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionic acid tert-butyl ester

To a mixture of 900mg (2.31mmol) of 3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } butan-2-ol, 1477mg (11.53mmol) of tert-butyl acrylate and 157mg (0.46mmol) of tetra-n-butylammonium hydrogen sulfate in10 ml of dichloromethane are added 2.2ml of 45% sodium hydroxide solution at 0 ℃ and stirred at this temperature for 1 hour. After a further 16 hours at room temperature, the reaction mixture was filtered and the filtrate was concentrated by evaporation in vacuo. The crude product was purified by preparative RP-HPLC (gradient: water/acetonitrile). 690mg (57% of theory) of the desired product are obtained as (R, S/S, R) racemate.

LC-MS (method 7): r_t＝4.82min；m/z＝519(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.53-7.50(m，2H)，7.42-7.36(m，5H)，7.03-6.99(m，2H)，5.43-5.37(m，1H)，3.81(s，3H)，3.49-3.45(m，1H)，3.41(t，2H)，2.24(t，2H)，1.31(s，9H)，1.19(d，3H)，0.88(d，3H).

Example 107

6- ({5- (4-methoxyphenyl) -6- [2- (trifluoromethyl) phenyl ] furan [2, 3-d ] pyrimidin-4-yl } amino) hexanoic acid methyl ester

To a mixture of 224mg (0.50mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 29mg (0.03mmol) tetrakis (triphenylphosphine) palladium (O) in 2.5ml 1, 2-dimethoxyethane was added 0.5ml of a 2M aqueous potassium carbonate solution. Next, 119mg (0.63mmol) of (2-trifluoromethyl) phenylboronic acid were added and the mixture was stirred at reflux for 15 h. The reaction mixture is filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 118mg (46% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.74min；m/z＝514(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.36(s，1H)，7.89(dd，1H)，7.69-7.63(m，2H)，7.44(dd，1H)，7.23(d，2H)，6.98(d，2H)，5.50(t，NH)，3.76(s，3H)，3.57(s，3H)，3.41(q，2H)，2.29(t，2H)，1.55-1.44(m，4H)，1.28-1.19(m，2H).

Example 108

6- { [6- (2-chlorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To a mixture of 220mg (0.49mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 17mg (0.03mmol) bis (triphenylphosphine) palladium (II) chloride in 2.2ml toluene, 229mg (1.08mmol) potassium phosphate was added. Next, 176mg (0.74mmol) of tetramethylethylene glycol (2-chlorophenyl) borate were added and the mixture was stirred at 80 ℃ for 15 h. The reaction mixture was purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 101mg (42% of theory) of the desired product are obtained.

LC-MS (method 10): r_t＝2.81min；m/z＝481(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.36(s，1H)，7.58(dd，1H)，7.50-7.44(m，2H)，7.36(dd，1H)，7.24(d，2H)，6.98(d，2H)，5.54(t，NH)，3.77(s，3H)，3.58(s，3H)，3.42(q，2H)，2.29(t，2H)，1.55-1.45(m，4H)，1.27-1.19(m，2H).

Example 109

6- { [6- (2, 6-difluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

150mg (0.34mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 106mg (0.70mmol) of (2, 6-difluorophenyl) boronic acid were dissolved in 3.5ml of toluene and 1.0ml of ethanol, and 0.34ml of 2M aqueous sodium carbonate and 25mg (0.03mmol) of 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride were added. Next, the mixture was stirred at 70 ℃ for 15 hours. The reaction mixture was purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 13mg (8% of theory) of the desired product are obtained.

LC-MS (method 10): r_t＝2.72min；m/z＝482(M+H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.37(s，1H)，7.63-7.57(m，1H)，7.26-7.10(m，4H)，6.98(d，2H)，5.65(t，NH)，3.78(s，3H)，3.57(s，3H)，3.42(q，2H)，2.29(t，2H)，1.55-1.47(m，4H)，1.28-1.24(m，2H).

Example 110

6- { [6- (2-methoxyphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To a mixture of 200mg (0.45mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 16mg (0.02mmol) bis (triphenylphosphine) palladium (II) chloride in10 ml dimethyl sulfoxide was added 0.45ml of a 2M aqueous sodium carbonate solution. Next, 85mg (0.56mmol) of (2-methoxyphenyl) boronic acid are added and the mixture is stirred at 80 ℃ for 15 h. The reaction mixture is filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 63mg (42% of theory) of the desired product are obtained.

LC-MS (method 10): r_t＝2.72min；m/z＝476(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.42(dd，1H)，7.30(dd，1H)，7.23(d，2H)，7.05(d，1H)，7.00-6.94(m，3H)，5.37(t，NH)，3.78(s，3H)，3.58(s，3H)，3.54(s，3H)，3.41(q，2H)，2.28(t，2H)，1.54-1.43(m，4H)，1.26-1.18(m，2H).

Example 111

6- { [5- (4-methoxyphenyl) -6- (2-vinylphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To a mixture of 224mg (0.50mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 29mg (0.03mmol) tetrakis (triphenylphosphine) palladium (0) in 2.5ml 1, 2-dimethoxyethane was added 0.5ml of a 2M aqueous potassium carbonate solution. Next, 92mg (0.63mmol) of (2-vinylphenyl) boronic acid were added and the mixture was stirred at reflux for 15 h. The reaction mixture is filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 82mg (35% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.77min；m/z＝472(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.35(s，1H)，7.70(d，1H)，7.46-7.42(m，1H)，7.30(d，2H)，7.23(d，2H)，6.97(d，2H)，6.61(dd，1H)，5.72(d，1H)，5.48(t，NH)，5.17(d，1H)，3.76(s，3H)，3.58(s，3H)，3.42(q，2H)，2.29(t，2H)，1.55-1.46(m，4H)，1.27-1.22(m，2H).

Example 112

6- { [6- (2-ethylphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To a mixture of 224mg (0.50mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 18mg (0.03mmol) bis (triphenylphosphine) palladium (II) chloride in 11.2ml DMSO, 0.50ml of a 2M aqueous sodium carbonate solution was added. Next, 187mg (1.25mmol) of (2-ethylphenyl) boronic acid was added and the mixture was stirred at 80 ℃ for 15 h. The reaction mixture is filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 69mg (29% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.83min；m/z＝474(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.33(s，1H)，7.39-7.31(m，2H)，7.26-7.17(m，4H)，6.98(d，2H)，5.42(t，NH)，3.76(s，3H)，3.58(s，3H)，3.41(q，2H)，2.49(q，2H)，2.29(t，2H)，1.55-1.44(m，4H)，1.27-1.19(m，2H)，1.00(t，3H).

Example 113

6- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To a mixture of 100mg (0.22mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 8mg (0.01mmol) bis (triphenylphosphine) palladium (II) chloride in 5.0ml DMSO, 0.22ml of a 2M aqueous sodium carbonate solution was added. Next, 39mg (0.28mmol) of (2-fluorophenyl) boronic acid are added and the mixture is stirred at 80 ℃ for 15 h. The reaction mixture is filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 69mg (29% of theory) of the desired product are obtained.

LC-MS (method 5): r_t＝2.82min；m/z＝464(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.35(s，1H)，7.48-7.41(m，2H)，7.31(d，2H)，7.26-7.21(m，2H)，7.03(d，2H)，5.43(t，NH)，3.80(s，3H)，3.58(s，3H)，3.41(q，2H)，2.29(t，2H)，1.54-1.42(m，4H)，1.22-1.18(m，2H).

Example 114

6- { [5- (4-methoxyphenyl) -6- (2-methylphenyl) furan [2, 3-d ] pyrimidin-2-yl ] amino } hexanoic acid methyl ester

To a mixture of 224mg (0.50mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 29mg (0.03mmol) tetrakis (triphenylphosphine) palladium (0) in 2.5ml 1, 2-dimethoxyethane was added 0.5ml of a 2M aqueous potassium carbonate solution. Next, 85mg (0.63mmol) of (2-methylphenyl) boronic acid are added and the mixture is stirred at reflux for 15 h. The reaction mixture is filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 68mg (30% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝2.97min；m/z＝460(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.34-7.14(m，6H)，6.98(d，2H)，5.44(t，NH)，3.77(s，3H)，3.57(s，3H)，3.42(q，2H)，2.29(t，2H)，2.10(s，3H)，1.55-1.44(m，4H)，1.27-1.19(m，2H).

Example 115

6- { [6- (2-fluoro-6-methoxyphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

150mg (0.34mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furo [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 142mg (0.84mmol) of (2-fluoro-6-methoxyphenyl) boronic acid were dissolved in 2.0ml of 1, 2-dimethoxyethane and 0.34ml of 2M aqueous sodium carbonate and 24mg (0.03mmol) of 1, 1' -bis (diphenylphosphino) ferrocene palladium (II) chloride were added. Next, the mixture was stirred at 80 ℃ for 15 hours. The reaction mixture was purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 56mg (34% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.57min；m/z＝494(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.33(s，1H)，7.48(dd，1H)，7.20(d，2H)，6.98-6.94(m，3H)，6.86(dd，1H)，5.55(t，NH)，3.76(s，3H)，3.67(s，3H)，3.57(s，3H)，3.42(q，2H)，2.29(t，2H)，1.55-1.45(m，4H)，1.28-1.21(m，2H).

Example 116

6- ({5- (4-methoxyphenyl) -6- [2- (trifluoromethyl) phenyl ] furan [2, 3-d ] pyrimidin-4-yl } aminocaproic acid

In 2.5ml dioxane 85mg (0.17mmol)6- ({5- (4-methoxyphenyl) -6- [2- (trifluoromethyl) phenyl ] furan [2, 3-d ] pyrimidin-4-yl } amino) hexanoic acid methyl ester was dissolved and 0.5ml1N sodium hydroxide solution was added. After stirring for 16h at RT, 0.5ml of 1N hydrochloric acid and 6ml of ethyl acetate are added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 68mg (82% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.38min；m/z＝514(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.98(s，1H)，8.35(s，1H)，7.89(dd，1H)，7.69-7.63(m，2H)，7.44(dd，1H)，7.23(d，2H)，6.98(d，2H)，5.50(t，NH)，3.76(s，3H)，3.42(q，2H)，2.19(t，2H)，1.52-1.44(m，4H)，1.27-1.20(m，2H).

Example 117

6- { [6- (2-chlorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

In 2.5ml dioxane 65mg (0.14mmol) methyl 6- { [6- (2-chlorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate were dissolved and 0.5ml1N sodium hydroxide solution was added. After stirring for 16h at RT, 0.5ml of 1N hydrochloric acid and 6ml of ethyl acetate are added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 44mg (70% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.34min；m/z＝467(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.00(s，1H)，8.36(s，1H)，7.56(d，1H)，7.49-7.44(m，2H)，7.39-7.35(m，1H)，7.24(d，2H)，6.99(d，2H)，5.55(t，NH)，3.77(s，3H)，3.42(q，2H)，2.20(t，2H)，1.53-1.45(m，4H)，1.27-1.20(m，2H).

Example 118

6- { [6- (2-methoxyphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

In 2.5ml dioxane was dissolved 55mg (0.12mmol) methyl 6- { [6- (2-methoxyphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 0.5ml1N sodium hydroxide solution was added. After stirring for 16h at RT, 0.5ml of 1N hydrochloric acid and 6ml of ethyl acetate are added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 42mg (77% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.25min；m/z＝462(M+H)⁺

¹H-NMR(300MHz，DMSO-d₆)：δ＝12.00(s，1H)，8.32(s，1H)，7.42-7.37(m，1H)，7.29(dd，1H)，7.23(d，2H)，7.05(d，1H)，6.99(d，2H)，6.97-6.93(m，1H)，5.37(t，NH)，3.77(s，3H)，3.41(q，2H)，2.20(t，2H)，1.53-1.43(m，4H)，1.27-1.20(m，2H).

Example 119

6- { [5- (4-methoxyphenyl) -6- (2-vinylphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

The title compound was formed as a by-product in the synthesis of methyl 6- { [5- (4-methoxyphenyl) -6- (2-vinylphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate (example 111) and isolated by preparative RP-HPLC (gradient: water/acetonitrile). 36mg (16% of theory) of the title compound are obtained.

LC-MS (method 10): r_t＝2.58min；m/z＝458(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.33(s，1H)，7.69(d，1H)，7.45-7.40(m，1H)，7.31-7.26(m，2H)，7.22(d，2H)，6.98(d，2H)，6.61(dd，1H)，5.70(d，1H)，5.41(t，NH)，5.15(d，1H)，3.76(s，3H)，3.41(q，2H)，1.90(t，2H)，1.48-1.36(m，4H)，1.22-1.15(m，2H).

Example 120

6- { [6- (2-ethylphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

In 2.0ml dioxane was dissolved 45mg (0.10mmol) methyl 6- { [6- (2-ethylphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 0.5ml1N sodium hydroxide solution was added. After stirring for 16h at RT, 0.5ml of 1N hydrochloric acid and 5ml of ethyl acetate are added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 38mg (87% of theory) of the title compound are obtained.

LC-MS (method 10): r_t＝2.58min；m/z＝460(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.00(br.s，1H)，8.33(s，1H)，7.39-7.31(m，2H)，7.26-7.16(m，4H)，6.98(d，2H)，5.43(t，NH)，3.76(s，3H)，3.41(q，2H)，2.49(q，2H)，2.19(t，2H)，1.52-1.45(m，4H)，1.28-1.16(m，2H)，1.00(t，3H).

Example 121

6- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

In1.0ml dioxane was dissolved 25mg (0.05mmol) methyl 6- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate and 0.16ml 1N sodium hydroxide solution was added. Stirring was carried out at RT for 16h, after which 0.17ml of 1N hydrochloric acid and then 2ml of water and 5ml of dichloromethane were added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 23mg (92% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.52min；m/z＝450(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.01(br.s，1H)，8.35(s，1H)，7.49-7.42(m，2H)，7.31(d，2H)，7.26-7.21(m，2H)，7.03(d，2H)，5.41(t，NH)，3.80(s，3H)，3.41(q，2H)，2.29(t，2H)，1.51-1.42(m，4H)，1.27-1.18(m，2H).

Example 122

6- { [5- (4-methoxyphenyl) -6- (2-methylphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

In 2.5ml dioxane 65mg (0.14mmol) methyl 6- { [5- (2-methoxyphenyl) -6- (2-methylphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate were dissolved and 0.50ml1N sodium hydroxide solution was added. After stirring for 16h at RT, 0.50ml of 1N hydrochloric acid and then 6ml of methyl acetate are added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 53mg (82% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.35min；m/z＝446(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.00(br.s，1H)，8.34(s，1H)，7.34-7.16(m，6H)，6.98(d，2H)，5.45(t，NH)，3.77(s，3H)，3.42(q，2H)，2.29(t，2H)，2.10(s，3H)，1.50-1.45(m，4H)，1.28-1.20(m，2H).

Example 123

6- { [6- (2-fluoro-6-methoxyphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

42mg (0.09mmol) of methyl 6- { [6- (2-fluoro-6-methoxyphenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate were dissolved in1.0ml of dioxane and 0.26ml of 1N sodium hydroxide solution was added. Stirring was carried out at RT for 16h, after which 0.26ml of 1N hydrochloric acid and then 2ml of water and 5ml of dichloromethane were added. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. 39mg (96% of theory) of the title compound are obtained.

LC-MS (method 2): r_t＝2.22min；m/z＝480(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.99(s，1H)，8.33(s，1H)，7.48(dd，1H)，7.20(d，2H)，6.98-6.94(m，3H)，6.85(dd，1H)，5.55(t，NH)，3.76(s，3H)，3.68(s，3H)，3.42(q，2H)，2.19(t，2H)，1.53-1.45(m，4H)，1.29-1.21(m，2H).

Example 124

(3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetic acid tert-butyl ester

To a solution of 500mg (1.28mmol) of 3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } methyl) oxy } -2-methylpropan-1-ol in10 ml of toluene at 70 ℃ are added 1.14ml of a 12.5N sodium hydroxide solution. After addition of 44mg (0.13mmol) of tetra-n-butylammonium hydrogen sulfate and 500mg (2.56mmol) of tert-butyl bromoacetate, the reaction mixture is stirred at 70 ℃ for 20 h. After cooling to room temperature, the pH is adjusted to 7 with concentrated hydrochloric acid and extracted three times with 50ml of dichloromethane each time. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by evaporation in vacuo. The crude product was purified by preparative RP-HPLC (gradient: water/acetonitrile). 298mg (46% of theory) of the desired product are obtained as racemate.

LC-MS (method 8): r_t＝3.41min；m/z＝505(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.58(s，1H)，7.54(dd，2H)，7.51-7.37(m，5H)，7.03(d，2H)，4.35-4.26(m，2H)，3.85(s，2H)，3.82(s，3H)，3.19(d，2H)，2.02-1.97(m，1H)，1.39(s，9H)，0.76(d，3H).

Example 125

(3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetic acid tert-butyl ester (enantiomer 1)

298mg (0.59mmol) of rac- (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetic acid tert-butyl ester enantiomer were isolated by chiral-phase chromatography [ column: daicel Chiralpak IA, 250mm × 20 mm; flow rate: 15 ml/min; and (3) detection: 220 nm; temperature: 30 ℃; eluent: 50% iso-hexane/50% tert-butyl methyl ether ]. In this way 51mg (17% of theory) of enantiomer 1 are obtained.

HPLC：R_t7.46min [ column packing material as above, 250mm × 4.6 mm; flow rate: 1 ml/min; eluent: 50% iso-hexane/50% tert-butyl methyl ether; temperature: 25 deg.C]

LC-MS (method 2): r_t＝3.14min；m/z＝505(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.58(s，1H)，7.55-7.54(m，2H)，7.42-7.38(m，5H)，7.04-7.03(m，2H)，4.35-4.27(m，2H)，3.83(s，3H)，1.39(s，9H)，0.77(d，3H).

Example 126

(3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetic acid tert-butyl ester (enantiomer 2)

298mg (0.59mmol) of rac- (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetic acid tert-butyl ester enantiomer were isolated by chiral-phase chromatography [ column: daicel Chiralpak IA, 250mm × 20 mm; flow rate: 15 ml/min; and (3) detection: 220 nm; temperature: 30 ℃; eluent: 50% iso-hexane/50% tert-butyl methyl ether ]. In this way, 56mg (19% of theory) of enantiomer 2 are obtained.

HPLC：R_t7.94min [ column packing material, 250mm × 4.6 mm; flow rate: 1 ml/min; eluent: 50% iso-hexane/50% tert-butyl methyl ether; temperature: 25 deg.C]

LC-MS (method 8): r_t＝3.36min；m/z＝505(M+H)⁺

Example 127

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

70mg (0.14mmol) of tert-butyl rac- (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetate were dissolved in 2.0ml of 4N hydrogen chloride in dioxane and stirred at RT for 16 h. Purification was carried out directly by preparative RP-HPLC (gradient: water/acetonitrile). 48mg (76% of theory) of the desired product are obtained as racemate.

LC-MS (method 7): r_t＝3.86min；m/z＝449(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.64(br.s，1H)，8.58(s，1H)，7.55(d，2H)，7.41-7.36(m，5H)，7.03(d，2H)，4.35-4.27(m，2H)，3.88(s，2H)，3.81(s，3H)，3.19(d，2H)，2.01-1.97(m，1H)，0.76(d，3H).

Example 128

(+) - (3- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetic acid (enantiomer 1)

41mg (0.08mmol) of tert-butyl (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetate (enantiomer 1) were dissolved in 0.5ml of dioxane, 0.2ml of 4N hydrogen chloride in dioxane was added and stirred at RT for 48 h. Thereafter, 0.4ml of 4N hydrogen chloride in dioxane was added to the reaction mixture and stirred at RT for a further 16 h. The reaction solution was concentrated by evaporation under vacuum and the residue was then purified by preparative RP-HPLC (gradient: water/acetonitrile). 27mg (74% of theory) of the desired product are obtained as enantiomer.

LC-MS (method 8): r_t＝2.67min；m/z＝449(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.56-7.53(m，2H)，7.42-7.37(m，5H)，7.05-7.01(m，2H)，4.41-4.37(m，1H)，4.24-4.20(m，1H)，3.82(s，3H)，3.42(s，2H)，3.21-3.14(m，2H)，2.00-1.93(m，1H)，0.71(d，3H).

[α]_D ²⁰+21 °, c-0.400, chloroform.

Example 129

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

45mg (0.09mmol) of tert-butyl (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropoxy) acetate (enantiomer 2) were dissolved in 0.5ml of dioxane, 0.2ml of 4N hydrogen chloride in dioxane was added and stirred at RT for 48 h. Thereafter, 0.4ml of 4N hydrogen chloride in dioxane was added to the reaction mixture and stirred at RT for a further 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 21mg (53% of theory) of the desired product are obtained as enantiomer 2.

LC-MS (method 2): r_t＝2.45min；m/z＝449(M+H)⁺

Example 130

3- { [ (1R, 2R) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } propanoic acid

To 60mg (0.12mmol) tert-butyl 3- { [ (1R, 2R) -2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropyl ] oxy } propionate was added 1.2ml 4N hydrogen chloride in dioxane and stirred at RT for 16 h. The pH was then adjusted to 7 with 1N sodium hydroxide solution, the aqueous phase was extracted three times with 10ml each time of dichloromethane, and the combined organic extracts were dried over sodium sulfate and concentrated by evaporation in vacuo. 52mg (93% of theory) of the desired product are obtained.

LC-MS (method 7): r_t＝4.83min；m/z＝519(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.57(s，1H)，7.55(d，2H)，7.40-7.35(m，5H)，7.01(d，2H)，5.35(dt，1H)，3.81(s，3H)，3.52-3.40(m，3H)，2.26(t，2H)，1.16(d，3H)，0.88(d，3H).

Example 131

6- { [6- (3-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To a mixture of 100mg (0.22mmol) methyl 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate, 47mg (0.34mmol) 3-fluorophenylboronic acid and 145mg (0.45mmol) cesium carbonate in 5ml dioxane was added 3mg (0.01mmol) palladium trans-bis (dicyclohexylamine) acetate [ T.Bin, J.Org.Chem.2004, 69, 4330-. After addition of 95mg (0.45mmol) of potassium phosphate, 47mg (0.34mmol) of 3-fluorophenylboronic acid and a spatula tip of trans-bis (dicyclohexylamine) palladium (II) acetate are added and the reaction mixture is stirred for a further 4h at 80 ℃. The reaction mixture is then filtered and purified directly by preparative RP-HPLC (gradient: water/acetonitrile). 57mg (53% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.81min；m/z＝464(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.34(s，1H)，7.47-7.45(m，2H)，7.42-7.39(m，1H)，7.28-7.26(m，1H)，7.19-7.15(m，4H)，5.14(t，NH)，3.86(s，3H)，3.58(s，3H)，3.38-3.30(m，2H)，2.26(t，2H)，1.51-1.37(m，4H)，1.18-1.11(m，2H).

Example 132

6- { [6- (3-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

To a solution of 45mg (0.01mmol) methyl 6- { [6- (3-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate in 2.5ml dioxane was added 0.5ml1N sodium hydroxide solution and stirred at RT for 16 h. After addition of 0.75ml of 1N hydrochloric acid, the reaction solution was concentrated by vacuum evaporation. The residue was mixed with ether, filtered and dried under vacuum. 42mg (93% of theory) of the desired product are obtained.

LC-MS (method 5): r_t＝2.59min；m/z＝450(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.00(br.s，1H)，8.35(s，1H)，7.47-7.45(m，2H)，7.42-7.39(m，1H)，7.28-7.26(m，1H)，7.19-7.15(m，4H)，5.15(t，NH)，3.86(s，3H)，3.39-3.34(m，2H)，2.17(t，2H)，1.48-1.37(m，4H)，1.19-1.11(m，2H).

Example 133

4- { [ (2R) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butanoic acid

To a solution of 100mg (purity 73%, 0.15mmol) methyl 4- { [ (2R) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butanoate in 3ml dioxane was added 0.6ml of 1N sodium hydroxide solution and stirred at RT for 16 h. 0.7ml of 1N hydrochloric acid was added thereto, followed by extraction with ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, dried over sodium sulfate and filtered. The filtrate was concentrated by evaporation in vacuo. The oily residue was taken up in acetonitrile and purified by preparative RP-HPLC (gradient: water/acetonitrile). 57mg (80% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝1.88min；m/z＝474(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.17(br.s，1H)，8.57(s，1H)，7.55-7.53(m，2H)，7.42-7.37(m，5H)，7.30-7.28(m，2H)，5.50-5.42(m，1H)，2.69(q，2H)，2.44-2.30(m，2H)，2.20(t，2H)，2.06(t，2H)，2.01(s，3H)，1.52-1.41(m，2H)，1.26-1.19(m，6H).

Example 134

6- { [6- (4-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid methyl ester

To 100mg (0.22mmol) of 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d]Pyrimidin-4-yl]Methyl amino } hexanoate, a mixture of 47mg (0.34mmol) 4-fluorophenylboronic acid and 95mg (0.45mmol) potassium phosphate in 5ml dioxane was added 3mg (0.01mmol) trans-bis (dicyclohexylamine) palladium (II) acetate [ t.bin, j.org.chem.2004,69，4330-4335]and stirred at 80 ℃ for 21 h. After filtering off the solids, the filtrate was concentrated by evaporation in vacuo. The residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 59mg (57% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝3.06min；m/z＝464(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.50-7.42(m，4H)，7.26-7.20(m，2H)，7.16-7.12(m，2H)，5.09(t，NH)，3.85(s，3H)，3.58(s，3H)，3.38-3.30(m，2H)，2.26(t，2H)，1.51-1.37(m，4H)，1.18-1.11(m，2H).

Example 135

6- { [6- (4-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid ethyl ester

To 100mg (0.22mmol) of 6- { [ 6-bromo-5- (4-methoxyphenyl) furan [2, 3-d]Pyrimidin-4-yl]Methyl amino } hexanoate, a mixture of 37mg (0.27mmol) of 4-fluorophenylboronic acid and 95mg (0.45mmol) of potassium phosphate in 5ml of ethanol was added 3mg (0.01mmol) of palladium (II) trans-bis (dicyclohexylamine) acetate [ T.bin, J.Org.chem.2004,69，4330-4335]and first stirred at RT for 16h and then at 80 ℃ for 3 h. After filtering off the solids, the filtrate was concentrated by evaporation in vacuo. The residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 28mg (26% of theory) of the desired product are obtained.

LC-MS (method 5): r_t＝3.07min；m/z＝478(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(s，1H)，7.49-7.43(m，4H)，7.25-7.20(m，2H)，7.15-7.13(m，2H)，5.09(t，NH)，4.04(q，2H)，3.85(s，3H)，3.38-3.30(m，2H)，2.24(t，2H)，1.51-1.37(m，4H)，1.18-1.11(m，5H).

Example 136

6- { [6- (4-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoic acid

To a solution of 169mg (0.37mmol) methyl 6- { [6- (4-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] amino } hexanoate in 5ml dioxane was added 1ml of 1N sodium hydroxide solution and stirred at RT for 16 h. After addition of 3ml of 1N hydrochloric acid, the reaction solution was concentrated by evaporation in vacuo. The residue was mixed with ether, filtered and dried under vacuum. 165mg (99% of theory) of the desired product are obtained.

LC-MS (method 2): r_t＝2.39min；m/z＝450(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝14.25-10.15(br.s，CO₂H)，8.33(s，1H)，7.49-7.43(m，4H)，7.25-7.21(m，2H)，7.15-7.13(m，2H)，5.13(br.t，NH)，3.85(s，3H)，3.39-3.34(m，2H)，2.17(t，2H)，1.48-1.37(m，4H)，1.19-1.11(m，2H).

Example 137

(6R) -6- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid

373mg (0.72mmol) tert-butyl (6R) -6- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate was dissolved in 4ml 4N hydrogen chloride in dioxane and stirred at RT for 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 171mg (51% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝2.78min；m/z＝465(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.98(br.s，1H)，8.60(s，1H)，7.55-7.50(m，2H)，7.33-7.28(m，4H)，6.94-6.91(m，2H)，5.40-5.33(m，1H)，3.77(s，3H)，2.14(t，2H)，1.60-1.55(m，2H)，1.48-1.40(m，2H)，1.31-1.17(m，3H)，1.28(d，3H).

Example 138

(+) -4- { [ (2S) -2- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butanoic acid

102mg (93% pure, 0.19mmol) tert-butyl 4- { [ (2S) -2- { [6- (2-fluorophenyl) -5- (4-methoxyphenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butyrate were dissolved in 1ml 4N hydrogen chloride in dioxane and stirred at RT for 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 48mg (52% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝1.68min；m/z＝494(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.11(br.s，1H)，8.60(s，1H)，7.55-7.50(m，2H)，7.33-7.28(m，4H)，6.93-6.91(m，2H)，5.60-5.53(m，1H)，3.77(s，3H)，2.47-2.37(m，2H)，2.31-2.33(m，2H)，2.13-2.05(m，5H)，1.54-1.46(m，2H)，1.28(d，3H).

[α]_D ²⁰+123 °, c-0.260, chloroform.

Example 139

4-tert-butoxy-N- [ (2S) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] -N-methyl-4-oxobutane-1-ammonium chloride

To a solution of 200mg (0.87mmol) tert-butyl 4- { [ (2S) -2-hydroxypropyl ] (methyl) amino } butyrate in2ml THF were added 43mg (1.08mmol) of sodium hydride (60% dispersion in mineral oil) with ice cooling. After stirring for ten minutes with ice-cooling, 338mg (0.91mmol) of 4-chloro-5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in 3ml of THF and 16mg (0.04mmol) of tetra-n-butylammonium iodide were added. The reaction mixture was stirred at RT for 16 h. After addition of water and ethyl acetate, the separated organic phase is washed with 1N hydrochloric acid and concentrated by evaporation in vacuo. The residue is taken up in acetonitrile/DMSO and purified by preparative RP-HPLC (gradient: water/acetonitrile). 94mg (19% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝2.06min；m/z＝530(M-HCl+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.77-9.55(m，NH)，8.65(s，1H)，7.56-7.51(m，2H)，7.44-7.40(m，4H)，7.35-7.32(m，2H)，5.80-5.64(m，1H)，3.16-2.76(m，4H)，2.71(q，2H)，2.66-2.59(m，2H)，2.33-2.29(m，2H)，2.24-2.16(m，2H)，1.77-1.53(m，2H)，1.38-1.33(m，12H)，1.09(t，3H).

Example 140

(+) -4- { [ (2S) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] (methyl) amino } butanoic acid

93mg (0.16mmol) of 4-tert-butoxy-N- [ (2S) -2- { [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propyl ] -N-methyl-4-oxobutane-1-ammonium chloride were dissolved in 3ml of 4N hydrogen chloride in dioxane and stirred at RT for 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 50mg (64% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝1.87min；m/z＝474(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.13(br.s，1H)，8.57(s，1H)，7.55-7.52(m，2H)，7.42-7.37(m，5H)，7.31-7.29(m，2H)，5.53-5.46(m，1H)，2.68(q，2H)，2.50-2.42(m，2H)，2.32-2.21(m，2H)，2.10-2.02(m，5H)，1.51-1.42(m，2H)，1.26-1.21(m，6H).

[α]_D ²⁰+171 °, c-0.200, chloroform.

Example 141

6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid

80mg (0.15mmol) tert-butyl 6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate were dissolved in2ml 4N hydrogen chloride in dioxane and stirred at RT for 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 12mg (16% of theory) of the desired product are obtained as racemate.

LC-MS (method 8): r_t＝3.06min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.98(br.s，1H)，8.61(s，1H)，7.55-7.51(m，2H)，7.33-7.28(m，4H)，7.21-7.19(m，2H)，5.38-5.32(m，1H)，2.63(q，2H)，2.02(t，2H)，1.57-1.52(m，2H)，1.43-1.37(m，2H)，1.27-1.18(m，8H).

Example 142

(-) - (6R) -6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid

420mg (0.81mmol) tert-butyl (6R) -6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoate were dissolved in 5.3ml 4N hydrogen chloride in dioxane and stirred at RT for 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 200mg (53% of theory) of the desired product are obtained.

LC-MS (method 8): r_t＝3.03min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.97(br.s，1H)，8.61(s，1H)，7.56-7.50(m，2H)，7.33-7.27(m，4H)，7.21-7.19(m，2H)，5.39-5.31(m，1H)，2.63(q，2H)，2.12(t，2H)，1.58-1.53(m，2H)，1.47-1.38(m，2H)，1.28-1.18(m，8H).

[α]_D ²⁰-62 °, c-0.390, chloroform.

Example 143

(+) - (6S) -6- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid

50mg (0.11mmol) of rac-6- { [5- (4-methoxyphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } heptanoic acid were chromatographically separated into the enantiomers [ column: DaicelChiralpak AD-H, 5 μm, 250 mm. times.20 mm; flow rate: 20 ml/min; and (3) detection: 245 nm; temperature: 25 ℃; eluent: 93% iso-hexane/7% ethanol ]. 8mg (16% of theory) of the desired enantiomerically pure desired product are obtained.

HPLC: rt ═ 5.65min [ column: daicel Chiralpak AD-H, 5 μm, 250 mm. times.4 mm; flow rate: 1 ml/min; and (3) detection: 245 nm; temperature: 25 ℃; eluent: 85% iso-hexane/15% ethanol ]

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.97(br.s，1H)，8.61(s，1H)，7.56-7.50(m，2H)，7.33-7.28(m，4H)，7.21-7.19(m，2H)，5.39-5.31(m，1H)，2.63(q，2H)，2.12(t，2H)，1.58-1.53(m，2H)，1.47-1.39(m，2H)，1.28-1.18(m，8H).

[α]_D ²⁰+50 °, c-0.235, chloroform.

Example 144

(3- { [5- (4-methoxyphenyl) -6-phenylfuro [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylbutoxy) acetic acid

To a solution of 2.19g (5.41mmol) of 4- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } pentan-2-ol in 20ml of toluene was added 4.8ml of 11.25N sodium hydroxide solution. After addition of 184mg (0.54mmol) of tetra-n-butylammonium hydrogen sulfate and 2.11g (10.83mmol) of tert-butyl bromoacetate, the reaction mixture is stirred at 70 ℃ for 15 h. After cooling to room temperature, the pH is adjusted to 7 with concentrated hydrochloric acid and extracted three times with 50ml of dichloromethane each time. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and filtered. The filtrate was concentrated by evaporation in vacuo. The residue is taken up in ethyl acetate and purified by flash chromatography on silica gel (flow agent: first ethyl acetate and then ethyl acetate/methanol 5: 1). The product obtained is purified again by preparative RP-HPLC (gradient: water/acetonitrile). 0.29g (11% of theory) of the desired product is obtained as a racemic mixture of non-corresponding isomers.

LC-MS (method 8): r_t＝2.76min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆): [ minor stereoisomers in brackets ]]δ＝12.49(br.s，1H)，8.57(s，1H)，[8.55，s，1H]，7.55-7.52(m，2H)，7.42-7.37(m，5H)，7.04-6.99(m，2H)，5.53-5.46(m，1H)，[5.41-5.34，m，1H]，3.88(d，2H)，3.82(s，3H)，3.47-3.39(m，1H)，1.89-1.82(m，1H)，1.55-1.48(m，1H)，1.28(d，3H)，1.00(d，3H).

Example 145

(3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylbutoxy) acetic acid (enantiomer 1)

280mg (0.61mmol) of (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylbutoxy) acetic acid were chromatographed as the stereoisomer [ column: 670mm x 40mm based on the chiral silica phase of the selector poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide); flow rate: 80 ml/min; and (3) detection: 260 nm; temperature: 24 ℃; eluent: 60% iso-hexane/40% ethyl acetate ]. 108mg (39% of theory) of the diastereomerically pure desired enantiomer 1 are obtained.

HPLC：R_t3.40min [ as column packing material, 250mm × 4.6 mm; flow rate: 2 ml/min; eluent: 50% iso-hexane/50% ethyl acetate; temperature: 25 deg.C]

LC-MS (method 9): r_t＝3.79min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.50(br.s，1H)，8.57(s，1H)，7.55-7.52(m，2H)，7.42-7.37(m，5H)，7.03-7.00(m，2H)，5.53-5.45(m，1H)，3.88(d，2H)，3.81(s，3H)，3.47-3.39(m，1H)，1.88-1.81(m，1H)，1.55-1.48(m，1H)，1.28(d，3H)，1.00(d，3H).

Example 146

(3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylbutoxy) acetic acid (enantiomer 2)

280mg (0.61mmol) of (3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylbutoxy) acetic acid were chromatographed as the stereoisomer [ column: based on the selection agent poly (N-methacryloyl-L-leucine-dicyclopropylmethylamide chiral silica phase 670 mm. times.40 mm; flow rate: 80 ml/min; detection: 260 nm; temperature: 24 ℃ C.; eluent: 60% iso-hexane/40% ethyl acetate.) 116 (41% of theory) diastereoisomerically pure enantiomer 2 was obtained.

HPLC: rt ═ 3.80min [ as above column packing material, 250mm × 4.6 mm; flow rate: 2 ml/min; eluent: 50% iso-hexane/50% ethyl acetate; temperature: 25 deg.C)

LC-MS (method 9): r_t＝3.78min；m/z＝463(M+H)⁺

Example 147

[2- ({ [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } methyl) -3, 3-dimethylbutoxy ] acetic acid

To 155mg (0.29mmol) tert-butyl [2- ({ [5- (4-ethylphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } methyl) -3, 3-dimethylbutoxy ] acetate was added 1.0ml4N hydrogen chloride in dioxane and stirred at RT for 48 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 122g (88% of theory) of the desired product (racemate) are obtained.

LC-MS (method 9): r_t＝4.47min；m/z＝489(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.57(br.s，1H)，8.59(s，1H)，7.53-7.51(m，2H)，7.39-7.36(m，5H)，7.31-7.29(m，2H)，4.53(dd，1H)，4.47(dd，1H)，3.88(dd，2H)，3.38-3.29(m，2H)，2.68(q，2H)，1.54-1.49(m，1H)，1.24(t，3H)，0.71(s，9H).

Example 148

3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionic acid

To 500mg (0.96mmol) of tert-butyl 3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionate was added 4.0ml of 4N hydrogen chloride in dioxane and stirred at RT for 16 h. After concentration of the reaction solution by evaporation under vacuum, the residue was purified by preparative RP-HPLC (gradient: water/acetonitrile). 249mg (56% of theory) of the desired product are obtained as (R, S/S, R) racemate.

LC-MS (method 8): r_t＝2.72min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.09(br.s，1H)，8.57(s，1H)，7.54-7.51(m，2H)，7.42-7.36(m，5H)，7.03-6.99(m，2H)，5.41-5.34(m，1H)，3.81(s，3H)，3.50-3.41(m，3H)，2.27(t，2H)，1.18(d，3H)，0.88(d，3H).

Example 149

3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionic acid (enantiomer 1)

240mg (0.46mmol) of 3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionic acid ((R, S/S, R) -racemate) were separated by chiral phase chromatography [ column: the stereoisomer was separated based on the selector poly (chiral silica phase of N-methacryloyl-L-leucine-dicyclopropylmethylamide, 670 mm. times.40 mm; flow rate: 80 ml/min; detection: 260 nm; temperature: 24 ℃ C.; eluent: 60% iso-hexane/40% ethyl acetate.) the 119 (50% of theory) enantiomer 1 was obtained.

HPLC: rt ═ 3.60min [ as above column packing material, 250mm × 4.6 mm; flow rate: 2 ml/min; eluent: 50% iso-hexane/50% ethyl acetate; temperature: 25 deg.C)

LC-MS (method 8): r_t＝2.81min；m/z＝463(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.06(br.s，1H)，8.57(s，1H)，7.54-7.51(m，2H)，7.41-7.36(m，5H)，7.03-6.99(m，2H)，5.41-5.36(m，1H)，3.81(s，3H)，3.50-3.41(m，3H)，2.27(t，2H)，1.18(d，3H)，0.88(d，3H).

Example 150

3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionic acid (enantiomer 2)

240mg (0.46mmol) of 3- (2- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylpropoxy) propionic acid ((R, S/S, R) -racemate) were separated by chiral phase chromatography [ column: the enantiomer was separated based on the selection agent poly (chiral silica gel phase of N-methacryloyl-L-leucine-dicyclopropylmethylamide, 670 mm. times.40 mm; flow rate: 80 ml/min; detection: 260 nm; temperature: 24 ℃ C.; eluent: 60% iso-hexane/40% ethyl acetate.) enantiomer 110 (46% of theory) enantiomer 2 was obtained.

HPLC: rt ═ 4.31min [ as above column packing material, 250mm × 4.6 mm; flow rate: 2 ml/min; eluent: 50% iso-hexane/50% ethyl acetate; temperature: 25 deg.C)

LC-MS (method 8): r_t＝2.80min；m/z＝463(M+H)⁺

Example 151

Ethyl (-) - { [ (2R) -3- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate

A solution of 397mg (90% purity, 1.01mmol) 4-chloro-5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidine and 250mg (2.5mmol) ethyl (-) - { [ (2S) -3-hydroxy-2-methylpropyl ] oxy } acetate in 2.8ml anhydrous THF was cooled to 0 ℃ and 1.27ml (1.27mmol) phosphazene base P4-t-Bu (1M solution in hexane) was added. After the addition was complete, heat to RT and stir at RT for 2.5h, after which water was added to the reaction mixture and neutralized with 1N hydrochloric acid. Extracted with dichloromethane, the organic phase dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (gradient: water/acetonitrile). The product fractions obtained are combined, concentrated by evaporation in vacuo and the residue is purified again by repeated chromatography on silica gel (gradient: cyclohexane/ethyl acetate 30: 1 → 5: 1). 121.1mg (24.3% of theory) of the title product are obtained.

LC-MS (method 8): r_t＝3.32min；m/z＝493(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.63(s，1H)，7.58-7.51(m，2H)，7.35-7.28(m，4H)，7.20(d，2H)，4.40(dd，1H)，4.35(dd，1H)，4.09(q，2H)，3.99(s，2H)，3.28(d，2H)，2.63(q，2H)，2.08(m，1H)，1.20-1.14(m，6H)，0.71(d，3H).

[α]_D ²⁰-9.1 °, c-0.455, chloroform.

Example 152

Ethyl (-) - { [ (2R) -3- { [5- (4-methoxyphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate

A solution of 359.5mg (1.01mmol) 4-chloro-5- (4-methoxyphenyl) -6- (2-fluorophenyl) furo [2, 3-d ] pyrimidine and 250mg (2.5mmol) ethyl (-) - { [ (2S) -3-hydroxy-2-methylpropyl ] oxy } acetate in 2.8ml dry THF was cooled to 0 ℃ and 1.27ml (1.27mmol) phosphazene base P4-t-Bu (1M solution in hexane) was added. After the addition was complete, heat to RT and stir at RT for 2.5h, after which water was added to the reaction mixture and neutralized with 1N hydrochloric acid. Extracted with dichloromethane, the organic phase dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (gradient: water/acetonitrile). 77.6mg (15.5% of theory) of the title product are obtained.

LC-MS (method 9): r_t＝4.11min；m/z＝495(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.62(s，1H)，7.55-7.50(m，2H)，7.34-7.28(m，4H)，6.94(d，2H)，4.44(dd，1H)，4.37(dd，1H)，4.06(q，2H)，4.02(s，2H)，3.78(s，3H)，3.32-3.28(m，2H)，2.09(m，1H)，1.18(t，3H)，0.85(d，3H).

[α]_D ²⁰-4.4 °, c-0.58, chloroform.

Example 153

(+) -3- { [ (1S) -2- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propionic acid tert-butyl ester

A solution of 487.1mg (90% purity, 1.24mmol) of 4-chloro-5- (4-ethylphenyl) -6- (2-fluorophenyl) furo [2, 3-d ] pyrimidine and 300mg (ca. 1.47mmol) of t-butyl (+) -3- [ (1S) -2-hydroxy-1-methylethoxy ] propionate in 3.5ml of anhydrous THF is cooled to 0 ℃ and 1.13ml (1.13mmol) of the phosphazene base P4-t-Bu (1M solution in hexane) is added. At the end of the addition, it was slowly heated to RT and stirred at RT for 2h, after which water was added to the reaction mixture and neutralized with 1N hydrochloric acid. Extracted with dichloromethane, the organic phase dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (gradient: water/acetonitrile). 101.2mg (15.6% of theory) of the title product are obtained.

LC-MS (method 9): r_t＝4.67min；m/z＝521(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.64(s，1H)，7.56-7.51(m，2H)，7.35-7.29(m，4H)，7.20(d，2H)，4.43(dd，1H)，4.38(dd，1H)，3.75-3.67(m，1H)，3.33-3.45(m，2H)，2.62(q，2H)，2.29(t，2H)，1.32(s，9H)，1.20(t，3H)，1.03(d，2H).

[α]_D ²⁰+19.5 °, c-0.47, chloroform.

Example 154

(-) - { [ (2R) -3- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetic acid

95.0mg (0.19mmol) of ethyl (-) - { [ (2R) -3- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate are dissolved in 1ml of THF and 0.3ml of methanol, and 0.96ml of 1N sodium hydroxide solution are added. The mixture was stirred at RT for 30min, then neutralized with 1N hydrochloric acid and extracted with dichloromethane. The organic phase was concentrated by vacuum evaporation. 57.1mg (63.7% of theory) of the title product are isolated from the residue after preparation of RP-HPLC (gradient: acetonitrile/water).

LC-MS (method 8): r_t＝2.98min；m/z＝465(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.62(s，1H)，7.58-7.51(m，2H)，7.35-7.28(m，4H)，7.21(d，2H)，4.45(dd，1H)，4.28(dd，1H)，3.45(s，2H)，3.23(d，2H)，2.63(q，2H)，2.04(m，1H)，1.20(t，3H)，0.78(d，3H).

[α]_D ²⁰-32.5 °, c-0.505, chloroform.

Example 155

(-) - { [ (2R) -3- { [5- (4-methoxyphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetic acid

80.5mg (0.16mmol) of ethyl (-) - { [ (2R) -3- { [5- (4-methoxyphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -2-methylpropyl ] oxy } acetate are dissolved in 0.9ml of THF and 0.25ml of methanol, and 0.81ml of 1N sodium hydroxide solution is added. The mixture was stirred at RT for 30min, then neutralized with 1N hydrochloric acid and extracted with dichloromethane. The organic phase was concentrated by vacuum evaporation. After preparation of RP-HPLC (gradient: acetonitrile/water), 17.2mg of the title product are isolated from the residue (22.7% of theory).

LC-MS (method 8): r_t＝2.73min；m/z＝467(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.62(s，1H)，7.57-7.50(m，2H)，7.35-7.28(m，4H)，6.95(d，2H)，4.47(dd，1H)，4.30(dd，1H)，3.79(s，3H)，3.47(s，2H)，3.28(d，2H)，2.05(m，1H)，0.79(d，3H).

[α]_D ²⁰-16.8 °, c-0.45, chloroform.

Example 156

3- [ (1S) -2- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propionic acid

78.5mg (0.151mmol) of tert-butyl (+) -3- [ (1S) -2- { [5- (4-ethylphenyl) -6- (2-fluorophenyl) furan [2, 3-d ] pyrimidin-4-yl ] oxy } -1-methylethoxy ] propionate were dissolved in 0.5ml of dichloromethane and 0.17ml of TFA were added at RT. After 1.5h at RT, a further 0.17ml of TFA was added and the reaction mixture was stirred for a further 30min at RT before concentration by evaporation in vacuo. The residue is taken up in dichloromethane, washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo. The crude product was purified by RP-HPLC (gradient: acetonitrile/water). 61.8mg (88.2% of theory) of the title product are obtained.

LC-MS (method 8): r_t＝2.87min；m/z＝465(M+H)⁺

¹H-NMR(400MHz，DMSO-d₆)：δ＝12.12(br.s，1H)，8.63(s，1H)，7.57-7.50(m，2H)，7.35-7.28(m，4H)，7.21(d，2H)，4.45-4.35(m，2H)，3.73-3.68(m，1H)，3.60-3.47(m，2H)，2.64(q，2H)，2.34(t，2H)，1.19(t，3H)，1.04(d，3H).

[α]_D ²⁰+30.5 °, c-0.48, chloroform.

Example 157

(+/-) -2-methoxy-3- { [5- (4-methoxyphenyl) -6-phenyl-furan [2, 3-d ] pyrimidin-4-yl ] oxy } propoxy) acetic acid tert-butyl ester

550mg (1.35mmol) (+/-) -2-methoxy-3- { [5- (4-methoxyphenyl) -6-phenyl-furo [2, 3-d ] pyrimidin-4-yl ] oxy } propan-1-ol together with 1.0ml (6.77mmol) tert-butyl bromoacetate and 92mg (0.27mmol) tetrabutylammonium hydrogen sulfate are placed in 15ml dichloromethane and cooled to 0 ℃. 2.75ml of 50% sodium hydroxide solution are added and stirred at 0 ℃ for a few minutes. After which it was allowed to return to RT and stirred at RT overnight. Next, it was diluted with dichloromethane and water, acidified with 10% citric acid solution and the phases separated. The aqueous phase was extracted once more with dichloromethane. The dichloromethane phases were combined and washed once with saturated sodium chloride solution. Drying over magnesium sulfate, concentration by evaporation and purification of the residue by chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 85: 15). 550mg (78.1% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝4.50min；m/z＝521(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.52(s，1H)，7.61(m，2H)，7.41(d，2H)，7.30(m，3H)，6.98(d，2H)，4.67-4.62(m，1H)，4.50-4.44(m，1H)，3.90(s，2H)，3.87(s，3H)，3.60(m，1H)，3.52-3.45(m，2H)，3.31(s，3H)，1.47(s，9H).

Example 158

(+/-) - (2-methoxy-3- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] oxy } propoxy) acetic acid

500mg (0.96mmol) (+/-) -2-methoxy-3- { [5- (4-methoxyphenyl) -6-phenyl-furan [2, 3-d ] pyrimidin-4-yl ] oxy } propoxy) acetic acid tert-butyl ester are dissolved in10 ml dichloromethane. 2.5ml (32.4mmol) of trifluoroacetic acid are added and stirring is carried out for a further 1h at RT. After which it is concentrated by evaporation and dried under high vacuum. 390mg (87.4% of theory) of the title compound are obtained.

LC-MS (method 9): r_t＝3.46min；m/z＝465(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.52(s，1H)，7.61(m，2H)，7.45(d，2H)，7.40(m，3H)，6.97(d，2H)，4.70-4.65(m，1H)，4.46-4.42(m，1H)，4.10-3.96(dd，2H)，3.88(s，3H)，3.64-3.53(m，2H)，3.36(s，3H)，3.36-3.30(m，1H).

Practice ofExample 159

6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } heptanoic acid methyl ester

1.00g (3.80mmol) methyl 6- { [ (1R) -1-phenylethyl ] amino } heptanoate were hydrogenated in10 ml methanol and 1ml acetic acid overnight under normal pressure in the presence of 100mg palladium on charcoal (10%). After this time, it is filtered off with suction over celite, washed with methanol and concentrated by evaporation. Since the conversion was still incomplete according to HPLC, it was again hydrogenated in the presence of 100mg of palladium on charcoal (10%) at 4bar in10 ml of methanol and 1ml of acetic acid for 6 h. It is filtered again with suction over kieselguhr, washed with methanol and concentrated by evaporation (HPLC: starting material is no longer present). The methyl 6-aminoheptanoate thus obtained is used directly as starting material in further reactions.

To 200mg (0.59mmol) of 4-chloro-5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidine in 1ml of DMSO were added 260mg (approx. 1.19mmol) of the methyl 6-aminoheptanoate obtained above and 307mg (2.38mmol) of N, N-diisopropylamine and stirred at 100 ℃ overnight. It is then allowed to cool and concentrated by evaporation. The residue was purified by preparative HPLC. 80mg (29.3% of theory) of the title compound are obtained.

LC-MS (method 7): r_t＝4.32min；m/z＝460(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.39(s，1H)，7.55(m，2H)，7.39(d，2H)，7.27(m，3H)，7.08(d，2H)，4.52(d，1H)，4.28-4.17(m，1H)，3.91(s，3H)，3.65(s，3H)，2.27(t，2H)，1.62-1.52(m，2H)，1.44-1.13(m，4H)，1.06(d，3H).

HPLC [ column: daicel Chiralpak AD 250mm × 2 mm; eluent: 99% n-heptane, 1% ethanol and 0.2% trifluoroacetic acid; flow rate: 0.2 ml/min; and (3) detection: 322 nm; temperature: 25 deg.C)

Enantiomer 1: r_t＝29.8min，18.6％

Enantiomer 2: r_t＝32.7min，81.4％

ee＝62.8％.

Example 160

6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } heptanoic acid

In 2.5ml of THF were placed 65mg (0.141mmol) of methyl 6- { [5- (4-methoxyphenyl) -6-phenylfuran [2, 3-d ] pyrimidin-4-yl ] amino } heptanoate. 1.42ml (1.42mmol) of 1N sodium hydroxide solution are added and stirred at RT overnight. Then diluted with t-butyl methyl ether and adjusted to about pH 5-6 with 10% citric acid solution. The aqueous phase is extracted once with tert-butyl methyl ether and the combined organic phases are dried over magnesium sulfate and concentrated by evaporation. 59.5mg (94.4% of theory) of the title compound are obtained.

LC-MS (method 8): r_t＝2.75min；m/z＝446(M+H)⁺

¹H-NMR(400MHz，CDCl₃)：δ＝8.39(s，1H)，7.53(m，2H)，7.39(d，2H)，7.26(m，3H)，7.05(d，2H)，4.51(d，1H)，4.26-4.17(m，1H)，3.91(s，3H)，2.30(t，2H)，1.64-1.54(m，2H)，1.40-1.15(m，4H)，1.06(d，3H).

B. Evaluation of pharmacological Effect

The pharmacological effects of the compounds according to the invention can be shown in the following tests:

B-1.study of binding to prostacyclin receptor (IP-receptor) of human blood coagulation cell membrane

The thrombocyte membranes were obtained by centrifugation of 50ml of human blood (buffy coat with CDP Stabilizer from Maco Pharma, Langen) at 160Xg for 20 min. The supernatant (platelet rich plasma, PRP) was removed and then centrifuged again at 2000xg for 10min at room temperature. The precipitate was resuspended in 50mM tris- (hydroxymethyl) -aminomethane, which had been adjusted to pH 7.4 with 1N hydrochloric acid, and stored at-20 ℃ overnight. On the following day, the suspension was centrifuged at 80000Xg and 4 ℃ for 30 min. Discarding the supernatant. The precipitate was resuspended in 50mM tris- (hydroxymethyl) -aminomethane/hydrochloric acid, 0.25mM ethylenediaminetetraacetic acid (EDTA), pH 7.4, and then centrifuged again at 80000Xg and 4 ℃ for 30 min. The membrane precipitate was absorbed in binding buffer (50mM tris- (hydroxymethyl) -aminomethane/hydrochloric acid, 5mM magnesium chloride, pH 7.4) and stored at 70 ℃ until binding assay.

For the binding assay, 3nM were incubated with 300-1000. mu.g/ml human coagulation cell membrane/charge (0.2 ml maximum) in the presence of the test substance at room temperature³H-Iloprost (592GBq/mmol, from Amersham bioscience)60 min. After stop, cold binding buffer was added to the membrane and washed with 0.1% bovine serum albumin. After addition of Ultima goldsignillator, radioactivity bound to the membrane was quantified using a scintillation counter. Nonspecific binding is defined as the radioactivity in the presence of 1 μ M Iloprost (from Cayman Chemical, Ann Arbor) and is typically < 25% of the total radioactivity bound. The bound data (IC) was determined using the program GraphPad Prism Version 3.02₅₀Value).

Representative results for the compounds according to the invention are shown in table 1:

TABLE 1

Example No. 2	IC₅₀[nM]
		1	206
4	34
		14	49
15	82
		33	64
36	217
		45	895
49	159
		63	37
69	9
		80	22
83	20
		85	470
92	219
		95	10
113	51
		117	84
122	48
		128	33
138	53
		140	52
142	2.5
		146	7
152	3.7
		154	3.8
156	13

B-2.IP-receptor stimulation on whole cells

The IP-agonism of the test substances was determined by the Human Erythroleukemia Line (HEL), which endogenously represents the IP-receptor [ Murray, r., FEBS Letters 1989, 1: 172-174]. For this purpose, cells were suspended (4X 10)⁷Cells/ml) in buffer [10mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid)/PBS (phosphate buffered saline from Oxoid, UK) at 30 ℃]1mM calcium chloride, 1mM magnesium chloride, 1mM IBMX (3-isobutyl-1-methylxanthine), pH 7.4]With the respective test substance for 5 minutes. Next, the reaction was stopped by adding cold ethanol at 4 ℃ and the mass was stored for another 30 minutes at 4 ℃. The sample was then centrifuged at 10000Xg and 4 ℃. The resulting supernatant was discarded and the pellet was used in a commercially available cAMP-radioimmunoassay (IBL, hamburger) to determine the concentration of adenosine monophosphate (cAMP). In this assay, IP agonists lead to an increase in cAMP concentration, but IP antagonists have no effect. Effective Concentration (EC) was determined using the program GraphPad Prism Version 3.02₅₀Value).

B-3.Inhibition of coagulation in vitro

Inhibition of thrombocyte coagulation was measured using blood from healthy subjects. Part 9 of the blood was mixed with a part of 3.8% sodium citrate solution as coagulant. The blood was centrifuged at 900 rpm for 20 min. The pH of the platelet-rich plasma obtained was adjusted to pH 6.5 with ACD-solution (sodium citrate/citric acid/glucose). The thrombocytes were then removed by centrifugation, absorbed in buffer and centrifuged again. The thrombocyte pellet was taken up in buffer and resuspended in an additional 2mmol/l calcium chloride.

To determine coagulation, aliquots of the thrombocyte suspension were incubated with the test substance at 37 ℃ for 10 min. Next, coagulation was induced at 37 ℃ by the addition of ADP and was determined by turbidimetry in an Aggregometer according to Born [ Born G.V.R., J.Physiol. (London)168，178-179(1963)]。

B-4.Determination of blood pressure in anesthetized mice

Male Wistar rats weighing 300-. After tracheotomy, the femoral artery was catheterized to measure blood pressure. The test substance is administered orally as a solution in a suitable carrier, either through the esophagus or intravenously through the femoral vein.

C.Examples of the use of the pharmaceutical ingredients

The compounds according to the invention can be converted into the following pharmaceutical preparations:

sheet:

composition (A):

100mg of the compound according to the invention, 50mg of lactose (monohydrate), 50mg of corn starch (domestic), 10mg of polyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg. Diameter 8mm, radius of curvature: ()12mm。

Production:

the mixture of the compound according to the invention, lactose and starch, is granulated with a 5% solution (w/w) of PVP in water. After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture was compressed using a conventional tablet press (tablet size: see above). The pressing force guideline value for compression is 15 kN.

Suspension for oral administration:

composition (A):

1000mg of a compound according to the invention, 1000mg of ethanol (96%), 400mg(xanthan gum from the company FMC, Pa., USA) and 99g of water.

10ml of oral suspension corresponds to a single dose with 100mg of the compound according to the invention.

Generating:

rhodigel is suspended in ethanol and a compound according to the invention is added to the suspension. Water was added while stirring. Stir for about 6h until the Rhodigel swelling stops.

Solutions for oral administration:

composition (A):

500mg of a compound according to the invention, 2.5g of polysorbate and 97g of polyethylene glycol 400. 20g of oral solution corresponds to a single dose with 100mg of the compound according to the invention.

Production:

the compound according to the invention is suspended in a mixture of polyethylene glycol and polysorbate with stirring. Stirring is continued until the compound according to the invention is completely dissolved.

In vivo solution:

the compounds according to the invention are dissolved in physiologically acceptable solvents (e.g. isotonic sodium chloride solution, glucose solution 5% and/or PEG 400 solution 30%) at concentrations below the saturation solubility. The solution was sterile filtered and filled into sterile, pyrogen-free syringe containers.

Claims

1. A compound having the following formula (I)

Wherein

A represents O, and the compound A represents O,

Is represented by and CHR³The point of attachment of the group,

and

q represents O or N-R⁶Wherein

z represents a group of the formula

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

or

n and o, independently of one another, represent the numbers 0, 1, 2 or 3,

wherein for when R¹Or R²When present multiple times, their meaningEach of which may be the same or different,

and

R⁴represents hydrogen or (C)₁-C₃) An alkyl group, a carboxyl group,

and salts thereof.

2. A compound according to claim 1 having formula (I) wherein

A represents O, and the compound A represents O,

Is represented by and CHR³The point of attachment of the group,

and

z represents a group of the formula

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

or

Two radicals R bound to adjacent carbon atoms of the respective phenyl rings¹And/or R²Together form a compound having the formula-O-CH₂-O-, -O-CHF-O-or-O-CF₂-a group of-O-,

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

R³represents hydrogen, methyl or ethyl

And

R⁴represents hydrogen, and is selected from the group consisting of,

and salts thereof.

3. A compound according to claim 1 having formula (I) wherein

A represents O, and the compound A represents O,

Is represented by and CHR³The point of attachment of the group,

and

z represents a group of the formula

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

R¹and R²Independently of one another, represents a radical selected from fluorine, chlorine, cyano, (C)₁-C₅) Alkyl radical (C)₂-C₅) Alkenyl (C)₃-C₆) Cycloalkyl group, (C)₄-C₆) Cycloalkenyl radical, (C)₁-C₄) Alkoxy, trifluoromethylTrifluoromethoxy group, (C)₁-C₄) Alkylthio (C)₁-C₅) Acyl, amino, mono- (C)₁-C₄) Alkylamino, di- (C)₁-C₄) Alkylamino and (C)₁-C₄) A substituent of the acylamino group,

or

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

R³represents hydrogen, methyl or ethyl

And

R⁴represents hydrogen, and is selected from the group consisting of,

and salts thereof.

4. A compound according to one of claims 1, 2 or 3 of formula (I), wherein

A represents O, and the compound A represents O,

Is represented by and CHR³The point of attachment of the group,

and

q represents O or N (CH)₃) Wherein

Z represents a group of the formula

Wherein

# denotes the point of attachment to the group L

And

R⁷represents hydrogen, a methyl group or an ethyl group,

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

wherein for when R¹Or R²When present twice, each of their meanings may be

The same or different for each of the first and second,

R³represents hydrogen, methyl or ethyl

And

R⁴represents hydrogen, and is selected from the group consisting of,

and salts thereof.

5. A process for the production of compounds of formula (I) as defined in claims 1 to 4, characterized in that

[A] A compound having the following formula (II)

Wherein R is¹，R²，R⁴N and o have the respective meanings given in one of claims 1 to 4

And

X¹represents chlorine and is selected from the group consisting of,

Wherein A, L and R³Having the respective meanings given in one of claims 1 to 4

And

y represents the number 0

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

reacted to a compound having the following formula (IV)

Wherein A, L, R¹，R²，R⁴N and o have the respective meanings given in one of claims 1 to 4, and

y represents the number 0

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

or

[B] A compound having the following formula (V-1)

Wherein R is¹，R⁴，X¹And n has the respective meaning given in one of claims 1 to 4,

Wherein A, L, R¹，R³，R⁴And n has the respective meaning given in one of claims 1 to 4,

y represents the number 0

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

and then brominated in an inert solvent to a compound of the formula (VII-1)

Wherein A, L, R¹，R³，R⁴And n has the respective meaning given in one of claims 1 to 4, and

y represents the number 0

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

Wherein R is²And o has the meaning given in one of claims 1 to 4,

to a compound having formula (IV)

Or

[C] A compound having the following formula (V-2)

Wherein R is²，R⁴，X¹And o have the respective meanings given in one of claims 1 to 4,

Wherein A, L, R²，R³，R⁴And o have the respective meanings given in one of claims 1 to 4, and

y represents the number 0

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

followed by bromination in an inert solvent to give a compound of the following formula (VII-2)

y represents the number 0

And

R^7Ais represented by (C)₁-C₄) An alkyl group, a carboxyl group,

Wherein R is¹And n has the same meaning asThe meaning given in one of claims 1 to 4,

to a compound having formula (IV)

And the respective resulting compound of the formula (IV) is then reacted via the ester or cyano group Z¹Is converted to a carboxylic acid having the following formula (I-A)

Wherein A, L, R¹，R²，R³，R⁴N and o have the respective meanings given in one of claims 1 to 4, and

y represents the number 0

And if necessary these are converted into their salts with the corresponding bases or acids.

6. Use of a compound of formula (I) as defined in any one of claims 1 to 4 for the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases.

7. A pharmaceutical product comprising a compound of formula (I) as defined in any one of claims 1 to 4 together with inert, non-toxic, pharmacologically acceptable excipients.

8. A pharmaceutical product according to claim 7 for use in the treatment and/or prevention of cardiovascular diseases.