RS20050974A - Heterocyclically substituted pentanol derivatives,method for the production thereof,and use thereof as anti- inflammatory agents - Google Patents

Abstract

The invention relates to pentanol derivatives substituted by quinazoline, quinoxaline, quinoline, indazole, phthalazine, naphthyridine, benzothiazole, dihydroindolone, dihydroisoindolone, benzimidazole, or indole of general formula I, a process for their preparation and their use.

Description

Heterocyclic substituted pentanol-derivatives, the process for their preparation and their application as inflammation suppressors

The invention relates to heterocyclic substituted pentanol derivatives, especially pentanol derivatives substituted with quinazoline, quinoxaline, indazole, phthalazine, naphthyridine, benzothiazole, dihydroindolone, dihydroisoindolone, benzimidazole or indole, the process for their preparation and their use as inflammation suppressors.

From the state of the art WO 00/32584, DE 100 38 639 Al and WO 02/10143 inflammation suppressors of the general formula I are known

wherein the aryl moiety includes phthalides, thiophthalides, benzoxazinones or phthalazinones. These compounds have shown in an experiment the dissociation of action between anti-inflammatory and unwanted metabolic effects and are better than the non-steroidal glucocorticoids described so far or have at least as good an effect.

Further compounds are known from WO 03/059899, in which Q represents an aromatic carbocyclic residue.

However, the selectivity of the state of the art compounds towards other steroid receptors still needs improvement.

Therefore, the task of the proposed invention is to make available compounds whose selectivity with respect to other steroid receptors is improved.

This task is solved by compounds according to patent claims. The proposed invention therefore relates to compounds of the general formula I

in which

A stands for one aryl-, one benzyl- or phenethyl group, whereby the aryl-, benzyl- or phenethyl group in a given case can be substituted by one or more residues from the group Ci-C5-alkyl, Ci-C5- alkoxy, Ci-C5-alkylthio, Ci-C5-perfluoroalkyl,

halogen, hydroxy, cyano, nitro, -0-(CH 2VO-, -0-(CH2n).

-0-CH2-,-0-CH=CH-,-(CH2)n+2-,compressed= 1 or 2 and the last standing oxygen atoms and/or carbon atoms are connected to directly adjacent carbon atoms from the ring, or NR<4>R<5>

wherein R<4> and R<5> can independently be hydrogen, C1-C5-alkyl, or (CO)-C1-C5-alkyl

R 1 and R 2 independently of each other are hydrogen, one methyl or ethyl group or together with the carbon atom of the chain one C3-C6-Cycloal

clip ring,

R one in a given case independently of each other, once more groups, selected from halogen, hydroxy or Ci-C3-alk si, substituted CrC8-alkyl group, or some in a given case partially or fully fluorinated Ci-C3-alkyl group, one in a given case a substituted group selected from C2-C6-alkenyl, C2-C6-alkynyl, C3-C8-cycloalkyl, C3-C7-heterocyclyl, aryl, heteroaryl, (CrC8-alkyl)C3-C8-cycloalkyl, (CrC8-alk

yl)aryl, or (C1-C8-alkyl)heteroaryl,

B for one substituted in a given case by a methyl or ethyl group

methylene group or one carbonyl group and

Q means a quinazolinyl-, attached through an arbitrary position,

quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, benzothiazolyl-, dihydroindolonyl-, dihydropoisoindolonyl-, benzimidazole- or indolyl group, which may in a given case be substituted with one or more residues from the group CrC5-alkyl, d-Cs- alkoxy, CrC5-alkylthio, CrC5-periluoro-alkyl, halogen, hydroxy, cyano, nitro or NR<4>R<5>, wherein R<4> and R<5> can independently be hydrogen, Cp C5-alkyl, or (CO)-CrC5-alkyl,

with the exception of phthalazinones,

as well as their racemates or separately existing stereoisomers, and in a given case their physiologically tolerable salts.

Phthalazinones are exempted from prior art WO 98/54159 and WO 00/32584. They follow from the definition in claim 1 for Q = phthalazine in combination with a possible hydroxy substituent, since hydroxy phthalazines are in tautomeric equilibrium with phthalazinones.

One aspect of the invention are compounds of the general formula I in which

A stands for one aryl, one benzyl or one phenethyl group

wherein the aryl, benzyl or phenethyl groups can in a given case be substituted by one or more residues from the group C-Cs-alkyl, Ci-C5-alkoxy, CrC5-alkylthio, Ci-C5-perfluoroalkyl, halogen, hydroxy, cyano, nitro,

-0-(CH2)n-0-, -0-(CH2)„-0-CH2-,

-O-CHNCH-, -(CH2)n+2-, where n = 1 or 2 and the last standing oxygen atoms and/or carbon atoms are connected to directly adjacent carbon atoms from the ring,

or NR4R5

wherein R<4> and R<5> can be mutually independent

hydrogen, CrC5-alkyl, or (CO)-CrC5-alkyl,

R and R are mutually independently hydrogen, one methyl- or ethyl-group or together with the carbon atom of the chain one C3-C6-cycloal

clip ring,

R 3 is a Ci-C3-alkyl group and is in a given case partially

or a fully fluorinated Ci-C3-alkyl group,

B for one substituted in a given case by a methyl or ethyl group

methylene group or one carbonyl group and

Q means a quinazolinyl-, attached through an arbitrary position,

quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, or benzothiazolyl- group, which may in a given case be substituted with one or more residues from the group CrC5-alkyl, Ci-C5- alkoxy, CrC5-alkylthio, CrC5-perfluoro-alkyl, halogen, hydroxy, cyano, nitro or NR<4>R<5>, whereby

R<4> and R<5> can independently be hydrogen, CrC5-alkyl, or (CO)-CrC5-alkyl,

with the exception of phthalazinones,

as well as their racemates or separately existing stereoisomers, and in a given case their physiologically tolerable salts.

The subject of the invention are compounds of the general formula I

in which

A stands for one aryl-, one benzyl- or one phenethyl group

wherein the aryl-, benzyl- or phenethyl-group can in a given case be substituted by one or more residues from the group CrC5-alkyl, Ci-C5-alkoxy, Ci-C5-alkylthio, CrC5-perfluoroalkyl, halogen, hydroxy, cyano, nitro,

-0-(CH2)n-0-, -0-(CH2)„-0-CH2-,

-0-CH=CH-, -(CH2)n+2-, where n = 1 or 2 and the last standing oxygen atoms and/or carbon atoms are connected to directly adjacent carbon atoms from the ring,

or NR<4>R<5>

wherein R<4> and R<5> can independently be hydrogen, C1-C5-alkyl, or (CO)-C1-C5-alkyl,

R<1> and R<2> are mutually independently hydrogen, one methyl- or ethyl-group or together with the carbon atom of the chain one C3-C6-cycloal

clip ring,

R is a C1-C3-alkyl group or one in a given case partially

or a fully fluorinated Ci-C3-alkyl group,

B for one substituted in a given case with a methyl- or ethyl-hole

A methylene group or one carbonyl group i

Q means a quinazolinyl-, quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, benzothiazolyl- group, which can in a given case be substituted by one or more residues from the group CrC5-alkyl, Ci-C5- alkoxy, CrC5-alkylthio, CrC5-perfluoro-alkyl, halogen, hydroxy, cyano, nitro or NR<4>R<5>, where R<4> and R<5> can independently be hydrogen, Q-C5-alkyl, or (CO)-C,-C5-alkyl,

with the exception of phthalazinones,

as well as their racemates or separately existing stereoisomers, and in a given case their physiologically tolerable salts.

The subject of the invention are compounds of the general formula I, in which R<3> represents one in a given case independently of one another, one or more groups, selected from halogen, hydroxy or Ci-C3-alkoxy, a substituted Ci-C8-alkyl group, or some in a given case a partially or fully fluorinated Cp C3-alkyl group.

A particular subject of the invention are compounds of the general formula I in which R<3> is a C1-C3-alkyl group or, in a given case, a partially or fully fluorinated C1-C3-alkyl group. CF3-groups and C2F5-groups are favored.

C1-C5- or C1-C8-alkyl groups can be straight-chain or branched and stand for one methyl-, ethyl-, n-propyl-, iso-propyl-, n-butyl-, iso-butyl-, tert,-butyl- or n-pentyl-, 2,2-dimethylpropyl-, 2-methylbutyl- or 3-methylbutyl group. methyl or ethyl groups are preferred.

For partially or fully fluorinated Ci-C3-alkyl groups, for example, partially or fully fluorinated straight-chain or branched following groups come into consideration: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl. Of these, trifluoromethyl- or tetrafluoroethyl groups are preferred.

By a Ci-C5-perfluoroalkyl group is meant a fully fluorinated straight-chain or branched alkyl group, such as CF3, C2F5, C3F7, C4<F>9, C5<F>11.

The alkyl groups R<1> and R<2> can together with the carbon atom from the chain form a 3- to 6-membered ring. R and R are preferably methyl or ethyl groups.

As alkyl radicals R<4> and R<5> preference is given to Ci-C3-alkyls, whereby C1-C3-alkyl groups can be straight-chain or branched.

C1-C5-Alkoxy groups in A and Q can be straight chain or branched and stand for methoxy-, ethoxy-, n-propoxy-, iso-propoxy-, n-butoxy, iso-butoxy-, tert-butoxy- or n-pentoxy-, 2,2-dimethylpropoxy-, 2-methylbutoxy- or 3-methylbutoxy- groups. Methoxy- or ethoxy-groups are predominant.

The C 1 -C 5 -alkylthio groups in A and Q can be straight or branched and stand for methylthio-, ethylthio-, n-propylthio-, iso-propylthio-, n-butylthio-, iso-butylthio-, tert-butylthio- or n-pentylthio-, 2,2-dimethylpropylthio-, 2-methylbutylthio- or 3-methylbutylthio. Methylthio or ethylthio groups are preferred.

The designation halogenate or halogen means fluorine-, chlorine-, bromine- or iodate. Fluorine, chlorine or bromate are preferred.

The NR4R<5> group can for example mean NH2, N(H)CH3, N(CH3)2, N(H)(CO)CH3, N(CH3)(CO)CH3, N[(CO)CH3]2, N(H)CO2CH3, N(CH3)CO2CH3, N(CO2CH3)2.

As acyl residues R<4> and R<5> preference is given to (CO)-Ci-C3-alkyls, whereby the Cr C3-alkyl residue can be straight-chain or branched.

The C2-C6- or C2-C5-alkenyl group is straight-chain or branched, for example vinyl, propenyl, isopropenyl, butenyl, isobutenyl.

The C2-C6- or C2-C5-alkynyl group is straight-chain or branched, for example C=C, propynyl, isopropynyl, butynyl, isobutynyl.

Cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The C 1 -C 8 -alkyl(C 3 -C 8 )cycloalkyl group can be, for example, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl. The bond with the sequence follows through the alkyl group.

The heterocyclyl group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, piperidine.

For the aryl group, phenyl and naphthyl come into consideration, and for (CrC8)-alkylaryl, benzyl and homobenzyl. When A is an aryl group, the phenyl group is preferred.

Heteroaryl includes, for example, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, triazolyl, pyridyl and pyrimidinyl.

(C 1 -C 8 -alkyl)heteroaryl includes all combinations of the above definitions of alkyl with a monocyclic aromatic heterocycle, particularly by name of said heterocycle. The connection to the chain follows via the alkyl group, which is in turn connected to any chemically possible position of the heterocycle.

Substituents of the group R<3> can be CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-C6-alkoxy, halogen, hydroxy, NR<4>R<5.>

Substituted aryl, benzyl or phenethyl groups bear 1-4 or 1-3 substituents on the ring, preferably 2 substituents.

Substituents for A can be independently selected from the group consisting of CpCs-alkyl, CpCs-alkoxy, C1-C5-alkylthio, C1-C5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -(0)-(CH2)-0-, -0-(CH2)-CH2-, -0-CH=CH-, -(CH2)n+2- (where n = 1 or 2 and the last standing oxygen atoms and/or carbon atoms are bonded to directly adjacent carbon atoms of the ring), or NR<4>R<5> (wherein R<4> and R<5> are independently hydrogen, CpCs-alkyl, or

(CO)-C1-C8-alkyl)

C1-C5-alkyl, C1-C5-alkoxy, C1-C5-alkylthio, C1-C5-perfluoroalkyl, halogen, hydroxy, -(0)-(CH2)n-0-, -0-(CH2)n-CH2-, -O-CH=CH-, -(CH2)n+2- are preferred.

Particularly favorable are C1-C5-alkyl, C1-C5-alkoxy, C1-C5-alkylthio, C1-C5-perfluoroalkyl, halogen, hydroxy, -(0)-(CH2)n-0- and -0-(CH2)n-CH2-. A special subject of the invention are compounds whose substituents of A are selected from the group of C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkylthio, C1-C5-perfluoroalkyl, halogen and hydroxy.

A further object of the invention are compounds whose substituents of A are selected from the group -(0)-(CH2)n-0-, -0-(CH2)n-CH2-, -0-CH=CH- and -(CH2)n+2-primarily -(0)-(CH2)n-0- and -0-(CH2)n-CH2-.

A further object of the invention are the compounds of formula 1, in which A is a phenyl radical, the substituents of which are selected from the group of hydroxy, C1C5-alkoxy and halogen.

The following definition and form of substitution on ring A are a particular subject of the invention: 2,5-disubstituted phenyl derivatives and 2,4-disubstituted phenyl derivatives.

For residue B, unsubstituted methylene groups and carbonyl groups are preferred.

A special subject of the invention are the compounds of formula 1, according to claim 1, in which B stands for a methylene group substituted in a given case by a methyl or ethyl group.

The subject of the invention are the compounds according to claim 1, in which Q means a benzothiazole-, quinazolinyl-, quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl- or a 1,7- or 1,8-naphthyridyl group connected via an arbitrary position.

Preferred residues Q are quinazoline, benzothiazole, naphthydrine, indazole, indolone, benzimidazole and isoindolone. Quinazoline, indazole and benzimidazole are particularly suitable.

The residue Q may be linked through any arbitrary ring carbon atom to the (NH)-group of the chain. Suitable positions for the quinazoline ring, quinoxaline ring, quinoline and phthalazine ring are the 5- and 8-positions, for the naphthyridine ring positions 3 and 5, and for the dihydroisoidolone, benzimidazole, indazole, indole, and benzothiazole rings, positions 7 and 4.

The expression that Q "may be connected via any ring carbon atom or any arbitrary position" means in the sense of the invention any chemically possible connection between a carbon atom of the heterocycle Q and the NH-group of the compound of formula I.

Q may be substituted by one or more residues from the group Ci-C5-alkyl, CpCs- alkoxy, CpCs-alkylthio, Ci-Cs-perfluoroalkyl, halogen, hydroxy, cyano, nitro, NR<4>R<5>wherein R<4> and R<5> are independently hydrogen, CrC5-alkyl, or (CO)-CrC5-alkyl.

Ci-C3-alkyl groups, Ci-C5-alkoxy-groups, hydroxyl group, Cr-C5-perfluoroalkyl group and halogen atoms are preferred. C 3 -alkyl groups, hydroxyl groups and halogen atoms are particularly advantageous.

A further object of the proposed invention arises from the meanings of A, R<1>, R2, R3, R<4>, R<5>, B and Q and all possible combinations thereof in the examples published.

Compounds according to the invention of general formula I can exist as different stereoisomers due to the presence of asymmetric centers. Both racemates and separately existing stereoisomers belong to the subject of the proposed invention.

A particular subject of the proposed invention in terms of their potency are separately existing stereoisomers, which means (+)-enantiomers and (-)-enantiomers.

In the event that the compounds of general formula I exist as salts, this can be for example in the form of hydrochlorides, sulfates, nitrates, phosphates, pivalates, maleates, tartrates, bezoates, mesylates, citrates or succinates, which can be obtained in a manner known to a person skilled in the art.

The methods for obtaining compounds from WO 98/54159, WO 00/32584 and WO 02/10143 can also be applied to obtain compounds according to the invention. The following process steps can be carried out for the attachment of the characteristic benzothiazole-, quinazoline-, quinoxaline-, quinoline-, indazole-, phthalazine-, 1,7- and 1,8-naphthyridine-, dihydroindolone-, dihydroisoindolone-, bezimidazole- or idol groups for the compounds according to the invention:

Al)

for B = CO

A1)

fur B = CO

Some oketo-acid of the general formula (II), in which A, R 1 and R 0 have the meanings given for formula (I), is translated into n-ketoamide (III) with some derivatives of aminobenzotriazole, aminoquinazoline, aminoquinoxaline, amioquinoline or aminophthalazine (Q-NH2) in a manner known to the expert. For example, with the use of dehydrating reagents for coupling, as is known from peptide herniation, for example dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or by previous conversion of the acid to acid chloride, for example thionyl chloride or POCI3 and then by reaction with Q-NH2, o-ketoamide (III) is obtained. Compound (III) is translated either with an alkyl-methyl compound R<3->M, where R has the above meaning and M stands for an alkali metal (lithium, atrium or potassium) or MgX or ZnX with X = halogen (chlorine, bromine, iodine), or by reaction with compound (IV)

wherein R<3> has the above meaning and R<6> denotes some CrC5-alkyl group and the three R<6-> groupings do not have to be the same, in the presence of some catalyst, for example fluoride salts or bases, such as alkali carbonates, (J. Am. Chem. Soc. 1989, 111, 393) the compound of title (I).

A2)

FOR B = CO

□-Keto-acids (II) can alternatively esterify the compound (V) in which A, R 1 and R * y are defined as above and R 7 is Ci-C7-alkyl, according to the usual methods, for example with thionyl chloride in methanol or ethanol or with methyl iodide and alkali carbonates and in analogy with the reaction course Al) of (III) in (I) with alkylmethyl compounds of the formula R -M, in where R has the above meaning and M stands for an alkali metal (lithium, sodium or potassium) or MgX or ZnX with X = halogen (chlorine, bromine iodine), or with (R )Si-R translates the union (VI)

Ester (IV) is saponified in acid, under standard conditions, as an aqueous solution of alkali hydroxide (Via; R = H).

The acid (Via) is converted into the title compound (I) by coupling with an aminoquinazoline, aminoquinoxaline, aminoquinoline, aminoindazole, aminophthalazine, aminonaphthyridine, aminobenzothiazole, aminodihydroindolone, aminodihydroisoindolone, aminobenzimidazole or aminoindole using a common activating reagent, for example thionyl chloride, in this case in the presence of a catalyst, such as dimethylaminopyridine.

B)

For B = some methyl or ethyl substituted methylene in the given case

group

a)

A compound of general formula (VII) or (VIII),

in which A, B and R, R and R have the above meaning, and LG means an arbitrary leaving group such as halide or sulfonate, reacts with some compound of the general formula (IX) or (X)

in which R<9> represents hydrogen, a C1-C5-acyl group or an alkoxy or alkoxy-carbonyl group and Q has the above meaning, wherein the residue R<9> is cleaved off or some intermediately obtained oxazolidinone (compare for example S. J. Brickner, D. K. Hutchinson, M. R. Barbachvn, P. R. Manninen, D. A. Ulanowicz, S. A. Garmon, K.C. Grega, S. K. Hendges,

D, S. Toops, C.W. Ford, G. E. zurenkoJ. Med. Chem.1996,39,673) is cleaved with aqueous alkali hydroxides, in order to reach the compound from the title (I).

b)

Another way consists in that compounds of the general formula (VII) or

(VIII) react with nitrogen nucleophiles, for example azide or ammonia salts, whereby in the first case reduction is connected in a manner known to the expert, for example with complex hydride reagents, such as lithium aluminum hydride, or via some hydrogenolysis catalyzed by transition metals, in order to arrive at the compound of formula (XI).

the residues R 1 -R 3 , A and B have the same meanings as stated above,

c)

The compound (XI) can be translated into the compound from title (I) sub

by base catalysis, for example in the presence of tertiary amino bases or alkali carbonates or hydroxides, or with transition metal catalysis, for example palladium catalysis (J.P Wolfe, S. Wagw, J.F. Marcouks, S.L. Buchwald,Acc. Chem. Res.1998,31.805; J.F. HartwigAcc. Chem.Res.1998,31.852), with some halogenated quinazoline, quinoxaline, quinoline, idazole, phthalazine, naphthydrine, benzothiazole, dihydroindolone, dihydroisoidolone, benzimidazole or indole.

d)

Finally, the title compound (I) can also be synthesized reductively

amination of a compound of formula (XII), which can be obtained by methods known to the expert from compound (VI) by reduction or alkylation, with Q-NH2, whereby sodium cyanoborohydride, sodium triacetoxyborohydride or hydrogen with palladium catalysis as a reducing agent come into consideration.

R 8 means hydrogen, methyl and ethyl according to, for the methyl group in B defined substituents.

In case the compounds of general formula I exist as salts, this can then be in the form of hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, tartrate, benzoate, mesylate, citrate or succinate.

When the compounds of the invention exist as racemic mixtures, they can be separated into pure, optically active forms, according to methods common to those skilled in the art. For example, racemic mixtures can be separated into pure isomers by chromatography on a support material (CHIRALPAK AD<®>) that is itself optically active. It is also possible to esterify the free hydroxyl group in a racemic compound of general formula I with an optically active acid. The thus obtained diastereomeric esters can be separated by fractional crystallization or chromatography. The separated esters are then each saponified into optically pure isomers. For example, mandelic acid, camphoric acid or tartaric acid can be used as optical actinic acids.

The binding of substances to the glucocorticoid receptor (GR) and further steroid hormone receptors (mineralocorticoid receptor (MR), progesterone receptor (PR) and androgen receptor (AR)) is tested with the help of recombinantly obtained receptors. Cytosolic preparations from Sf9 cells, which are infected with recombinant baculoviruses encoding Gr, are used for binding tests. In comparison with the reference substance [H]-dexamethasone, the substances show high to very high affinity for GR.

In addition, the quinazoline, quinoxaline, quinoline, indazole, phthalazine, naphthydrine, bezothiazole, dihydroindolone, dihydroisoidolone, benzimidazole and indole substituted compounds of formula (I) described herein have a high selectivity for the glucocorticoid receptor. Thus, for example, Example 2 shows the following profile: IC 50 (GR) = 1.8 nM; IC50(MR),

IC50(PR), IC50(AR) > ln M and compounds from example 2 IC50(GR) = 10 nM; IC50(MR), IC50(PR), IC50(AR) > ln M.

Gr-mediated suppression of the transcription of cytokines, adhesion molecules, enzymes and other proinflammatory factors is considered to be an important molecular mechanism for the anti-inflammatory action of glucocorticoids. This suppression is caused by the interaction of GR with other transcription factors, for example AP-1 and NF-kappa-B. (for review see Cato, ACB ad Wade E, BioEssavs 18, 371 -378 1996)

Compounds of the invention of general formula I inhibit lipopolysaccharide-induced secretion of the cytokine IL-8 in the human monocyte cell line THP-1. Cytokine concentration is determined in the layer above with the help of commercially available ELISA kits.

The anti-inflammatory action of compounds of general formula I was tested in an animal experiment of croton-oil induced inflammation in rats and mice (J. Exp. Med. (1995), 182,99-108). For this, croton oil in an ethanolic solution was topically applied to the ears of the animals. Test substances were simultaneously or two hours before croton oil also applied topically or systemically. After 16-24 hours, ear weight was measured as a measure of inflammatory edema, peroxidase activity as a measure of granulocyte penetration, and elastase activity as a measure of neutrophil granulocyte penetration. The compounds of the general formula I suppress in this test both after topical and after systemic application the above mentioned three parameters of inflammation.

One of the most common side effects of glucocorticoid therapy is the so-called steroid diabetes [cf. Hatz, HJ, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbh, Stuttgart, 1998]. The reason for this is the stimulation of gluconeogenesis in the liver by the induction of enzymes responsible for this and due to free amino acids, which are produced by the breakdown of proteins (catabolic effect of glucocorticoids). The key enzyme of catabolic metabolism in the liver is tyrosine aminotransferase (TAT). The activity of this enzyme can be determined photometrically from the liver homogenate and is a good measure for the unwanted metabolic action of glucocorticoids. In order to measure TAT induction, the animals are killed 8 hours after administration of the test substance, the liver is removed and TAT activity is measured in the liver homogenate. The compounds of general formula I do not induce tyrosine aminotransferase, or only to a small extent in this test, at doses in which they are anti-inflammatory effective.

On the basis of their anti-inflammatory and additionally anti-allergic, immuno-suppressive and antiproliferative effects, the compounds according to the invention of the general formula I can be used for the treatment or prophylaxis of the following disease states in mammals and humans: the term "DISEASE" stands for the following indications: (i) Lung diseases, which go together with inflammatory, allergic and/or proliferative processes: - chronic obstructive lung diseases of any genesis, primarily asthma bronchiale - all forms restrictive lung diseases, primarily allergic alveolitis, - all forms of pulmonary edema, primarily toxic pulmonary edema,

sarcoidosis and granulomatosis, especially Morbus Boeck,

(ii) rheumatic diseases / autoimmune diseases / joint diseases, which go together with inflammatory, allergic and/or proliferative processes: - all forms of rheumatic diseases, especially rheumatic arthritis, acute rheumatic fever, Polymyalgia rheumatica,

-reactive arthritis

- inflammatory soft tissue diseases of other genesis - arthritic symptoms in degenerative joint diseases (arthrosis)

-traumatic arthritis

-collagenoses of all kinds, for example, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis-Sjogren's syndrome

rom, Still syndrome, Felty syndrome

(iii) Allergies that go together with inflammatory, allergic and/or proliferative processes: - All forms of allergic reactions, for example Quinicke edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock, urticaria, contact

dermatitis

(iv) Inflammation of vessels (vasculitis)

-Panarteritis nodosa, arteritis temporaliserthema odosum

(v) Dermatological diseases that go together with inflammatory,

allergic and/or proliferative processes:

- atopic dermatitis (primarily in children)

-psoriasis

-Pitvriasis rubra pilaris

- Erythematous diseases, caused by different noxes, for example radiation, chemicals, burns, etc.

-bullous dermatoses

-diseases of lichenoid circular form

-pruritis (e.g. allergic genesis)

-seborrheic eczema

-Rosacea

-Pemphigus vulgaris

-Ervthema exsudativum multi forma

-balanitis

-vulvitis

-hair loss such as Alopecia areata

-cutaneous T-cell lymphomas

(vi) Renal diseases accompanied by inflammatory, allergic and/or proliferative processes:

-nephrotic syndrome

-all nephritis

(vii) Renal diseases that go together with inflammatory, allergic and/or proliferative processes:

-acute liver breakdown

-acute hepatitis of various genesis, for example induced virally, toxically, by drugs

- chronic aggressive and/or chronic intermittent hepatitis

(viii) Gastrointestinal diseases that go along with inflammatory, allergic and/or proliferative processes:

- regional enteritis (Crohn's disease)

-Ulcerative Colitis

-gastritis

-reflux esophagitis

-gastroenteritis of other genesis, for example domestic sprue

(ix) Proctological diseases that go together with inflammatory,

allergic and/or proliferative processes:

-anal eczema

-fissures

-hemorrhoids

-idiopathic proctitis

(x) eye diseases that go together with inflammatory, allergic and/or proliferative processes:

- allergic keratitis, uveitis, iritis

-conjunctivitis

-blepharitis

-Neuritis optica

-chorioditis

-ophthalmia svmpathica

(xi) Diseases of the ear-nose-throat area that go along with inflammatory,

allergic and/or proliferative processes:

-allergic rhinitis, hay fever

- otitis externa, for example caused by contact eczema, infection, etc.

-Otitis media

(xii) Neurological diseases that go along with inflammatory,

allergic and/or proliferative processes:

-Cerebral edema, primarily tumor-induced brain edema

-multiple sclerosis

-acute encephalomyelitis

-meningitis

-various forms of spasm attacks, for example BNS spasms

(xiii) Blood diseases accompanied by inflammatory, allergic and/or proliferative processes:

-acquired hemolytic anemia

- idiopathic thrombocytopenia

(xiv) Tumor diseases that go together with inflammatory, allergic and/or proliferative processes:

-acute lymphatic leukemia

-malignant lymphomas

-lymphogranulomatosis

-lymphosarcomas

-widespread metastases, primarily in mothers-, bronchial

prostate cancer

(xv) Endocrine diseases that go along with inflammatory, allergic and/or proliferative processes:

-endocrine orbitopathy

-thyrotoxic crisis

-De Quervain's thyroiditis

-Hashimoto's Thyroiditis

-Germoiditis

(xvi) Organ and tissue transplants, Graft-versus-host-disease (xvii) Severe shock conditions, for example anaphylactic shock, systemic

inflammatory response syndrome (SIRS)

(xviii) Substitution therapies in:

-congenital primary adrenal insufficiency, for example

post-infectious, tumors etc.

(xix) Emesis, which goes along with inflammatory, allergic and/or proliferative processes: for example in combination with some 5-HT3-antagonist in

vomiting caused by cytostatics.

(xx) Pains of inflammatory origin, for example lumbago.

In addition, the compounds according to the invention of the general formula I can be used in the treatment and prophylaxis of further disease states not listed above, for which synthetic glucocorticoids are currently used (Hatz, HJ, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbh, Stuttgart, 1998)

All of the above indications (i) and (xx) are described in detail in Hatz, HJ, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbh, Stuttgart, 1998.

For the therapeutic effect in the above-mentioned disease states, the appropriate dose is different and depends on, for example, the strength of the compound of general formula I, the host, the type of administration and the type and severity of the condition being treated, as well as the application as prophylactic or therapeutic.

The invention further provides

(i) using one of the compounds according to the invention according to formula I or a mixture thereof to obtain a medicament for the treatment of one of

DISEASES;

(ii) a method for treating any of the DISEASES, which method comprises administering a compound according to the invention, wherein the amount suppresses the disease, and wherein the amount of the compound is administered

the patient, who needs such medicine; (iii) some pharmaceutical composition for the treatment of one of the DISEASES whose treatment includes one of the compounds according to the invention or its mixture and at least one pharmaceutical auxiliary and/or carrier material.

In general, satisfactory results should be expected in animals, if the daily dose covers the range from 10 to 100,000 ug of the compound according to the invention per kg of body weight. In larger mammals, for example in humans, the recommended daily dose lies in the area of 100,000 µg of body weight. A dose of 10 ug to 30,000 ug of body weight is suitable, and a dose of 10 ug to 10,000 ug of body weight is even more favorable. For example, this dose is given several times a day for expediency. For the treatment of acute shock (for example, anaphylactic shock), individual doses may be given that lie significantly above those listed above.

The formulation of pharmaceutical preparations based on new compounds is followed in a manner known per se, by processing the active substance with usual carrier substances, fillers, substances that affect decomposition, binding agents, agents that retain moisture, sliding agents, absorption agents, dilution agents, taste correctors, coloring agents and so on and translate it into the desired form for application. Reference is made to Remigton's Pharmaceutical Science, 15th ed. MackPublishing Company, East Pennsylvania 1980.

For oral application, tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions are particularly suitable.

For parenteral application, injection and infusion preparations are possible

Appropriately prepared crystal suspensions can be used for intra-articular injections.

For intramuscular injections, aqueous and oily injection solutions or suspensions and appropriate depot preparations can be used.

For rectal application, the new compounds can be used in the form of suppositories, capsules, solutions, (for example in the form of enemas) and salves for both systemic and local therapy.

For pulmonary application of these compounds, they can be used in the form of aerosols and inhalations.

for local application on the eyes, external oral passage, middle ear, nasal cavity and sinus cavities, the new compounds can be used as drops, salves and tinctures in appropriate pharmaceutical preparations.

For topical application, there are formulations in gels, salves, fatty salves, creams, pastes, powders, milk and tinctures. The dosage of compounds of the general formula I in these preparations should be 0.01% - 20%, in order to achieve a satisfactory pharmacological effect.

The invention also includes compounds according to the invention of general formula I as a therapeutically active substance.

Furthermore, the invention also includes compounds of the general formula I as therapeutically active substances together with pharmaceutically acceptable and acceptable auxiliary active substances and carrier substances. The invention also includes a pharmaceutical composition containing one or more pharmaceutically active compounds according to the invention or their mixtures or their pharmaceutically acceptable salts or pharmaceutically acceptable excipients or carriers.

The following examples serve to further explain the invention without pretensions to limit it to them. Syntheses of important previous steps, which are not published within the experimental part, but are state of the art, and can be taken for example from WO 98/54159, (WO 00/32584) or WO 02/10143.

Experimental part

Example 1

4 - (5-Fluoro-2-methoxyphenyl)-4-methyl-1-(phthalazine-5-ylamino)-2-

(trifluoromethyl)-pentan-2-ol

4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal 0.81 ml (8.67 mmol) of oxalyl chloride was cooled in 15 ml of dichloromethane to -60°C and mixed with 1.6 ml (22.6 mmol) of dimethylsulfoxide in 10 ml of dichloromethane. After 15 minutes, 1.0 g (3.22 mmol) of 4-(5-Fluoro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentane-2-diol (WO 00/32548) in 10 ml of dichloromethane was added and the mixture was stirred for one hour at -60°C. Then 4.1 ml (29 mmol) of triethylamine was added and the mixture was allowed to warm to room temperature over 30 minutes. It is poured into 50 ml of water and extracted with CH2CI2. The combined organic extracts are washed with saturated NaCl solution, dried (Na2SO4) and evaporated in vacuo. After chromatography on silica gel with hexane-ethyl acetate (0-30%), 600 mg of the product is obtained.

1H-NMR (CDCl 3 ); δ = 1.38 (s, 3H), 1.47 (s, 3H), 2.23 (d, 1H), 3.36 (d, 1H), 3.86 (s, 3H), 6.77 (dd, 1H), 6.91 (ddd, 1H). 9.05 (s, IH).

200 mg (0.65 mmol) is added to 70 mg (0.48 mmol) of 5-Aminophthalazine (I.A. Shaikh, F. Johnson, A. P. Grollman J. Med. Chem. 1986, 26, 1329 - 1340) in 2 ml of acetic acid. 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal in 5 ml of toluene. The reaction solution is heated for 6 hours on a return cooler with the extraction of water, and for a further 4 hours it is refluxed over a molecular sieve (4A). The solvent is removed in vacuo and the acetic acid residues are removed by co-distillation with toluene. After chromatography on silica gel with hexane-ethyl acetate (0 - 70 %), 40 mg of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(phthalazin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol is obtained. 20 mg of palladium on charcoal is added to 10 mg of imine in 10 ml of ethyl acetate and 1 ml of triethylamine, and it is stirred for 2 hours in a nitrogen atmosphere at normal pressure. The solution is freed from the catalyst by filtration and evaporated. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 4 mg of the desired product is obtained.

1 H-NMR (CDCl 3 ); δ = 1.44 (s, 3H), 1.66 (s, 3H), 2.07 (d, 1H), 3.07 (d, 1H), 3.16 (d, 3H), 3.24 (d, 1H), 3.85 (s, 3H). 6.42 (d, IH), 6.76 (m, 2H), 7.11 (dd, IH), 7.30 (d, IH), 7.66 (dd, IH), 9.38 (s, IH), 9.48 (s, 1H).s

Example 2

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol

5-Amino-2-methylquinazoline

12.7 g (mmol) of 2-Methyl-5-nitro-3H-quinazolin-4-one (M. T. Bogert, V. J. ChambersJ. Org Chem. 1905, 649 - 658) and 37.5 g of phosphorus pentachloride are heated for 20 hours under reflux. After cooling, it is poured into a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated. 14 g of 4-chloro-2-methyl-5-nitroquinazoline are obtained, of which 4.5 g (20.2 mmol) are dissolved in 225 ml of ethyl acetate and 22.5 ml of triethylamine. 2 g of palladium on charcoal is added to it and stirred under ice cooling for 4 hours under a hydrogen atmosphere at normal pressure. The solution is filtered

it is freed from the catalyst through celite, washed with 200 ml of ethanol, and evaporated. After chromatography on silica gel with hexane-ethanol (0

- 10 %) yields 530 mg of product.

1 H-NMR (CDCl 3 ); 5 = 2.87 (s, 3H), 4.52 (n, 2H), 6.77 (d, IH), 7.33 (d, IH), 7.65 (t, IH), 9.40 (s, IH)

180 mg of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 50 mg of 5-Amino-2-methylquinazoline in 20 ml of dichloroethane and 2 ml of acetic acid are concentrated during 5 hours to 5 ml with continuous gentle removal of the solvent. The remaining solvent is removed in vacuo and the remaining acetic acid is removed by azeotropic co-distillation with toluene. After chromatography on silica gel with hexane-ethyl acetate (0 - 70 %), 58 mg of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol is obtained. Add 20 mg of palladium on charcoal to the imine in 10 ml of ethyl acetate and 1 ml of triethylamine and stir for 2 h under a hydrogen atmosphere at normal pressure. The solution is freed from the catalyst by filtration and evaporated. It is raised in 5 ml of chloroform and 200 mg of activated manganese dioxide is added and the meat is left for 30 min. It is filtered through celite and evaporated under vacuum. After chromatography on silica gel with hexane-ethyl acetate (0 - 70 %), 22 mg of the product is obtained.

1H-NMR (CDCl 3 ); δ = 1.47 (s, 3H), 1.56 (s, 3H), 2.38 (d, 1H), 2.77 (d, 1H), 2.83 (s, 3H), 3.16 (dd, 1H), 3.33 (dd, 1H). 3.85 (s, 3H), 4.70 (br, IH), 6.05 (d, IH), 6.77 (dd, IH), 6.88 (ddd, IH), 7.09 (dd, IH), 7.24 (d, IH), 7.56 (t, IH), 9.16 (s, IH).

Example 3

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-m

(trifluoromethyl)-pentan-2-ol

103 g (0.23 mmol) of 4<5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol in 10 ml of CH2Cl2 were mixed at 0°C with 5 ml of 1M boron tribromide-CH2Cl2 solution. After 10 hours, a further 5 ml of boron tribromide-CH2Cl2 solution was added, and after 72 hours at room temperature, the contents were poured into a saturated NaHCO3 solution for 20 minutes and extracted with CH2Cl2. The combined organic extracts are washed with water, dried (Na2SO4) and evaporated in vacuo. Chromatography with hexane-2-propanol 0

- 20 %) gives 80 mg of product.

1H-NMR (CDCl 3 ); δ = 1.51 (s, 3H), 1.58 (s, 3H), 2.37 (d, 1H), 2.81 (s, 3H), 2.91 (d, 1H), 3.25 (dd, 1H), 3.43 (dd, 1H). 5.05 (br, IH), 6.20 (d, IH), 6.54 (dd, IH), 6.69 (m, IH), 7.05 (dd, IH), 7.23 (d, IH), 7.59 (d, IH), 7.58 (d, IH), 8.32 (d, IH), 8.68 (d, IH).

Example 4

4-(2,5-Difluorophenyl)-4-methyl-1-(2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol

4-( 2, 5- Difluorophenyl)- 2- hydroxy- 4methyl- 2- trifluoromethyl- pentanal

5.4 g (15.5 mmol) of 4-(2,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl valeric acid ethyl ester (WO 02/1043) was dissolved in diethyl ether at 0°C and mixed with 1.76 g (46.5 mmol) of lithium aluminum hydride for 20 min. Allow to stir for 4 hours at room temperature, cautiously adding as much saturated NaHCO3 solution as possible, until gas evolution ceases to be observed. The mixture is diluted with ethyl acetate, mixed for another 15 minutes

minutes, and then the formed precipitate is filtered off. Evaporate and chromatograph on silica gel with hexane/ethyl acetate (50%). 2.45 g of 4-(2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol are obtained as a slightly yellowish crystalline oil. 800 mg (2.8 mmol) of 4-(2,5-Difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is placed in 20 ml of dichloromethane and 9.5 ml of DMSO and 1.95 ml of triethylamine are added to it at 0°C. The solution was gently mixed with 1.34 g (8.4 mmol) of SO 3 -pyridine complex and stirred for 2 h at 0°C. The mixture is partitioned between a saturated solution of ammonium chloride and MTBE, the phases are separated and the aqueous phase is extracted with MBTE. The combined organic phases are washed with water and saturated sodium hydrogencarbonate solution and dried with sodium sulfate. Evaporate and chromatograph on silica gel with hexane/ethyl acetate (30%). 710 mg of the desired product is obtained.

1 H-NMR (CDCl 3 ); δ = 1.41 (s, 3H), 1.48 (s, 3H), 2.39 (d, 2H), 3.02 (d, 1H), 3.61 (s, 1H), 6.84-7.18 (m, 3H), 9.23 (s, 1H).

(0.84 mmol) 4-(2,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 200 mg (1.26 mmol) of 5-Amino-2-methyl-quinazoline are first reacted analogously to example 2. After chromatography on silica gel with hexane/ethyl acetate (0 - 70%) 80 mg of 4-(2,5-Difluorophenyl)-4-methyl-1-pentanal is obtained. -(2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol which is taken up again in ethyl acetate/ethanol 1:1 and hydrogenated with 10 mg of palladium catalyst (10% on activated carbon) under a hydrogen atmosphere (latm). After 5 hours at room temperature, the catalyst is filtered off, and the filtrate is evaporated. The residue is taken up again in chloroform and reacted analogously to example 2 with manganese dioxide. After chromatographic purification, it is obtained

15 mg of the desired product as a red-brown film.

MS (ESI): 440 (M + H); 1 H-NMR (CDCl 3 ); δ = 1.48 (s, 3H), 1.62 (s, 3H), 2.29 (d, 1H), 2.61 (d, 1H), 2.79 (s, 3H), 3.19-3.35 (m, 2H), 3.61 (s, 1H).

4.69-4.73 (m, IH), 6.00 (d, IH), 6.83-691 (m, 2H), 7.08-7.14 (m, IH), 7.23 (d, IH), 7.52 (dd, IH), 9.14 (d, IH).

Example 5

4-(5-Fluoro-2-methoxyphenyl V4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-

trifluoromethylpentan-2-ol

200 mg (0.65 mmol) of 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 126 mg (0.77 mmol) of 7-Amino-2-methylbenzo-thiazole (Libeer et al. Buli. Soc. Chim. Belg.; 1971; 80; 43 - 47) are heated for 5 hours in 8 ml of acetic acid at 125 °C. After cooling to room temperature, it is mixed with 214 mg (1.01 mmol) of sodium triacetoxyborohydride and left to stir for 16 hours. After the addition of a further 100 mg (0.47 mmol) of sodium triacetoxyborohydride and stirring for two hours, toluene was added and evaporated in vacuo. The residue is taken up in ethyl acetate, the organic phase is washed with a saturated solution of sodium hydrogencarbonate and a saturated solution of sodium chloride and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-50%), 221 mg of the product is obtained.

1H-NMPv (CDCl 3 ); 5-1.45 (s, 3H), 1.58 (s, 3H), 2.25 (d, 1H), 2.78 (d, 1H), 2.82 (s, 3H), 3.14 (s, 1H), 3.16 (dd, 1H). 3.28 (dd, IH), 3.48 (dd, IH), 3.84 (s, 3H), 4.23 (d, IH), 5.97 (d, IH), 6.82 (dd, IH), 6.96 (ddd, 1H), 7.15 (dd, IH), 7.21 (t, IH), 7.42 (d, IH).

Example 6

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to example 3, 150 mg (0.13 mmol) of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylbenzothiazol-7-ylamino)-2-(trifluoromethyl)-pentan-2-ol in 15 ml of CH2CH2 are reacted with 6.18 ml of IM boron tribromide-CH2CH2 solution. After chromatography on silica gel with hexane/ethyl acetate (0 - 70%), 102 mg of product is obtained.

<!>H-NMR (CDCl3); δ = 1.50 (s, 3H), 1.59 (s, 3H), 2.31 (d, 1H), 2.78 (d, 1H), 2.79 (d, 1H), 2.80 (s, 3H), 3.27 (m, 2H). 3.40 (dd, IH), 3.54 (dd, IH), 6.02 (d, IH), 6.11 (br, IH), 6.65 (dd, IH), 6.82 (ddd, IH), 7.12 (dd, IH), 7.18 (t, IH), 7.40 (d, IH).

Example7

1-(Quinoxalin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentan-2-ol

In 80 ml (0.55 mmol) of 5-Aminoquinoxaline (J. Salon, V. Mlata, N. Pronavova, J. laskoMonatch. Chem.2000,131, 293-299) in 2 ml of acetic acid, add 140 mg (0.46 mmol) 4-(5-Fluoro-2-metolsphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, dissolved in 5 ml of dichloroethane. The reaction solution is refluxed for 5 hours over a molecular sieve (4A). The mixture is partitioned between water and dichloromethane and extracted (CH2C12). The combined organic phases are washed (saturated sodium chloride solution), dried (Na2SO4) and evaporated. After chromatographic purification on silica gel with hexane - ethyl acetate (0 - 50%), 82 mg of 1 -(Hinoclsalin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentan-2-ol are obtained, which are taken up in 3 ml of methanol and mixed with 100 ul of acetic acid and 10 mg (0.26 mmol) NaBLL,. The mixture is stirred for two days at room temperature, during which 10 mg of NaBFJ are added twice.4. The mixture is partitioned between water and dichloromethane and extracted (CH2C12). The combined organic phases are washed (saturated sodium chloride solution), dried (Na 2 SO 4 ) and evaporated.

The crude product is purified by chromatography on silica gel with hexane/ethyl acetate (10 - 50%). 40 mg of the desired product is obtained, which can be recrystallized from hexane/diethyl ether.

MS (ESI): 438 (M+H): 1H-NMR (CDCl 3 ): δ = 1.46 (s, 3H), 1.61 (s, 3H), 2.26 (d, 1H), 2.80 (d, 1H), 2.99 (s, 1H), 3.22-3.49 (m, 3H), 3.85 (s, 3H), 6.07 (d, IH), 6.81 (dd, IH), 6.91-6.99 (m, IH), 7.19 (dd, IH), 7.36 (dd, IH), 7.46 (d, IH), 8.61 (d, IH), 8.80 (d,lH).

Example 8

l-(Hinoclosalin-5-ylamino)-4-(5-fluoro-2-hydroxyphenin-4-methyl-2-(trifluoromethyl)-pentan-2-ol

Analogously to example 3, react 30 mg (68 mmol) of 1-(Hinoclosalin-5-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentan-2-ol dissolved in 3 ml of dichloromethane with 3 ml of boron tribromide solution (IM in CH2CI2) and stir for 24 hours at room temperature. The mixture is distributed between ethyl acetate and saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel with hexane/ethyl acetate (20%). 15 mg of the desired product is obtained.

MS (ESI): 424 (M+H): 1H-NMR (CDCl 3 ): δ = 1.46 (s, 3H), 1.53 (s, 3H), 2.28 (d, 1H), 2.58 (d, 1H), 2.97 (br, 1H), 3.30-3.56 (m, 4H), 6.18 (d, 3H), 6.56 (dd, IH), 6.76-6.83 (m, IH), 7.15 (dd, IH), 7.36 (d, IH), 7.46 (d, IH), 8.65 (d, IH), 8.83 (d, IH).

Example 9

l-(2-Chloro-5-fluorophenyl)-D-hydroxyl-U-(trifluoromethyl)cyclobutanepropanal

3.01 g (8.7 mmol) of 1-(2-Chloro-5-fluorophenyl)-D-hydroxy-D-(trifluoromethyl)cyclobutanepropionic acid ethyl ester (WO 02/10143) is reacted analogously to example 4 with 990 mg (26.1 mmol) of lithium aluminum hydride. 1.80 g of 1-(2-Chloro-5-fluorophenyl)-D-hydroxy-n-(trifluoromethyl)cyclobutane-propanol are obtained as a pale yellowish oil.

493 ul (2.56 mmol) of oxalyl chloride was added to 20 ml of dichloromethane. At - 75°C, 802 µl (11.3 mmol) of DMSO is added dropwise and after 15 min of stirring, a solution of 800 mg (2.56 mmol) of 1-[(Chloro-5-fluorophenyl)-D-(hydroxy)-D-(trifluoromethyl)cyclobutanepropanol in 10 ml of dichloromethane. After another 15 min. 2.20 ml (15.8 mmol) of triethylamine is added dropwise and stirred for a further 30 min at -60°C and 30 min. at 0°C. The reaction is stopped by adding water, the phases are separated and extracted with dichloromethane. The combined organic phases are washed with water and saturated sodium chloride solution and dried with sodium sulfate. Evaporate and chromatograph on silica gel with hexane/ethyl acetate (30%), to give 810 mg of the desired product.

MS (ESI): 342 (M+NH4):<!>H-NMR (CDCl3): δ = 1.74-192 (m, IH), 2.00-2.70 (m, 5H), 2.86 (d, IH), 3.19 (d, IH), 3.52 (s, IH), 6.79-6.93 (m, IH), 7.10-7.24 (m, IH). 2H), 8.94 (s, 1H).

To 325 mg (0.96 mmol) of 5-Aminoquinoxaline (J. Salon, V. Mlata, N. Pronavova, J. LaskoMonatsh. Chem.2000,131, 293-299) in 3 ml of acetic acid, add 200 mg (0.64 mmol) of l-(2-Chloro-5-fluorophenyl)-D-hydroxy-□-(trifluoromethyl)cyclobutanepropanal in 2 ml. toluene and stir for 24 h at room temperature. The solution is divided between water and toluene, the aqueous phase is extracted with toluene, the combined organic phases are washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent is evaporated. Crude □-[quinoxylin-5-ylamino)methyl]-1-(2-chloro-5-fluorophenyl)-D-(trifluoromethyl)-cyclobutaneethanol was taken up in methanol/ethyl acetate 1:1 and mixed with 100 mg (2.26 mmol) of NaBH 4 . After 6 hours of stirring at room temperature, the reaction is stopped by adding a saturated solution of ammonium chloride and the mixture is diluted with dichloromethane. After extraction with dichloromethane, the combined organic phases are washed with saturated sodium chloride solution, dried with sodium sulfate, and the solvent is removed. 280 mg of product is obtained as a dark red resin, which can be crystallized from hexane/diethyl ether.

MS (ESI): 454 (M+H).

Example 10

4-f5-Fluoro-2-methoxyphenyl)-4-methyl-12-(2-methyl-1,8-natphyridin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol

l- Amino- 4-( 5- fluoro- 2- methoxyphenyl)- 4- methyl- 2-( trifluoro

1.0 g (3.4 mmol) of 2-[2-(5-Fluoro-2-methoxyphenyl-2-methylpropyl]-2-trifluoromethyl)oxirane (WO 00/32584) in 68 ml of THF was heated under reflux for 6 h with 1.1 g of sodium azide and 180 mg of ammonium chloride in 14 ml of water and 26 ml of ethanol. The contents are evaporated, diluted with ether, washed with water, dried over sodium sulfate and evaporated. Chromatography on silica gel with hexane-ethyl acetate (0-15%) gives 950 mg of 1-Azido-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)propan-2-ol. This is dissolved in 29 ml of THF and mixed with 270 mg of lithium aluminum hydride in portions. After 1 hour, the contents are treated with ethyl acetate and water and filtered through celite. The ethyl acetate phase is dried (Na2SO4) and evaporated in vacuo. 920 mg of amine is obtained.

1H-NMR (CDCl 3 ): 5-1.4 (s, 3H), 1.5 (s, 3H), 2.15 (d, IH), 2.45 (d, IH), 2.55 (d, IH), 2.75 (d, IH), 2.80 (m), 3.8 (s, 3H), 6.8 (dd, IH), 6.9 (td, IH), 7.05 (dd, IH).

202 mg (1.13 mmol) of 5-Chloro-2-methyl-1,8-naphthyridine (E.V. Brown, J. Org Chem1965, 1607-1609) was placed in 350 g (1.13 mmol) of 1-Amino-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentan-2-ol and 128 mg (1.13 mmol) of DABCO. It is heated for 1.5 hours at 150°C. After chromatography of the cooled solution on silica gel with dichloromethane/methanol (0-10%), 385 mg of the desired product is obtained. 1 H-NMR (CDCl 3 ); 5 = 1.46 (s, 3H), 1.58 (s, 3H), 2.45 (d, IH), 2.68 (s, 3H), 2.72 (d, IH), 3.20 (d, IH), 3.38 (d, IH), 3.83 (s, 3H), 5.86 (d, IH), 6.77 (dd, IH), 6.92 (ddd, IH), 7.08 (dd, IH), 7.11 (d, IH), 7.71 (d, IH), 8.50 (d, IH).

Example 11

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methyl-1,8-natphyridin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogously to example 3, mg (0.13 mmol) of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol in 15 ml of CH2Cl2 is reacted with ml of 1M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane-ethyl acetate (0-70 %), 102 mg of product is obtained.<1>H-NMR (CDC13); 5 = 1.50 (s, 3H), 1.59 (s, 3H), 2.31 (dlH), 2.79 (d, IH), 2.80 (s, 3H), 3.27 (m, 2H), 3.40 (dd, IH), 3.54 (dd, IH), 6.02 (d, IH), 6.11 (br, IH), 6.65 (dd, IH), 6.82 (ddd, IH), 7.12 (dd, IH), 7.18 (t, 1H), 7. (d, 1H). Example 12

1-(Quinolin-5-ylamino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethylVpentan-2-ol)

240 mg (0.78 mmol) of 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 170 mg (1.17 mmol) of 5-Aminoquinoline (J.R. Elkins, E.V. BrownJ. Heterocycl. Chem. 1968, 639-646) were dissolved in 10 ml of dichloroethane. 1 ml of acetic acid and 30 mg of powdered molecular sieve (4 A) are added to it, and refluxed for 6 h over a molecular sieve (4 A). The reaction mixture is partitioned between dichloromethane and water, the phases are separated

and the aqueous phase is extracted with CH 2 Cl 2 , the combined organic extracts are washed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and dried over sodium sulfate. Evaporate and chromatograph on silica gel with hexane/ethyl acetate (20 to 50%). 70 mg of 1-(quinolin-5-ylimino)-4-(5-fluoro-2-hydroxyphenyl)-4-methyl-2-(trifluoromethyl)-pentan-2-ol are obtained, of which 30 mg is taken up in THF and mixed with 10 mg (0.16 mmol) of sodium cyanoborohydride and 100 ml of acetic acid. After 6 h of stirring at room temperature, it is divided between water and CH2C12, so the phases are separated. The aqueous phase is extracted with CH 2 Cl 2 , the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. It is evaporated, the residue is raised again in chloroform, activated manganese dioxide is added to it on the tip of the spatula and stirred at room temperature for 2 hours. Manganese dioxide is then filtered off and the filtrate is evaporated. The crude product is chromatographed

on silica gel with hexane/ethyl acetate (20 bis 50%). 3.3 mg of the desired product is obtained as a red film.

MS (ESI): 438 (M+H); 1H-NMR (CDCl3): δ = 1.48 (s, 3H), 1.53 (s, 3H), 2.59 (dd, 2H), 3.13 (s, IH), 3.24 (dd, IH), 3.37 (dd, IH), 3.89 (s, 3H), 4.80-4.84 (m, IH), 6.47 (d, IH), 6.83 (dd, IH), 6.91-6.99 (m, IH), 7.05 (dd, IH), 7.76-7.87 (m, 2H), 8.11 (d, IH), 9.08 (d, IH).

Example 13

4-(5-Fluoro-2-methoxyphenyl-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol

5- Amino- 8- fluoro- 2- methylquinazoline

To a solution of 3.35 g (20.25 mmol) of chloral hydrate and 21.27 g (149.7 mmol) of sodium sulfate in 72 ml of water, a 50 °C warm solution of 2.4 g (18.6 mmol) of 2,5-Difluoroaniline in 11 ml of water and 1.6 ml of conc. sone kiselie (37%) which was pre-mixed at this temperature. It is stirred for a further 30 min at room temperature and heated after the addition of 4.09 g (58.9 mmol) of hydroxylammonium chloride in 19 ml of water during 45 min at 125 °C and this temperature is maintained for 5 min. After cooling and after the next hour, the precipitated light brown precipitate is filtered off, washed with water and dried. t 3.0 g (15.0 mmol) of hydroxylimine is obtained as an intermediate product, which is dissolved in portions in 15 ml of conc. sulfuric acid at 60 °C. After complete addition, it is heated for 2 hours at 80 °C and 4 hours at 90 °C. Allow to cool, then pour the solution onto 100 g of ice. It is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and evaporated. After chromatography on silica gel with hexane-ethyl acetate (0-45 %), 1.2 g (7.1 mmol) of 4,7-difluorizatin is obtained. 1.8 ml of a 30% hydrogen peroxide solution was added to 30 ml of 1 molar sodium hydroxide over 10 minutes. After 2 hours of stirring at room temperature, cool to 0 °C and add 5 ml of a 4 molar sodium acid and dilute with 50 ml of water. It is extracted with ethyl acetate, dried over sodium sulfate, evaporated to obtain quantitatively 1.27 g of 3,6-difluoroanthranilic acid, which is used without further purification.

3,6-difluoroanthranilic acid is heated in 8 ml of acetic anhydride for 45 min at 100 °C. After cooling, the resulting acetic acid and acetic anhydride in excess are removed by azeotropic distillation with toluene in a vacuum. The residue is mixed with 40 ml of 25% ammonia solution while cooling with ice and stirred for 72 hours. Dilute with water acidified with acetic acid. It is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and evaporated. The thus obtained 1.03 g (5.25 mmol) of 5,8-difluoro-2-methyl-3H-quinazolin-4-one and 6 g of phosphorus pentachloride are heated in 20 ml of phosphoryl chloride for 12 h at 125°C. After cooling, it is poured into a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase is dried and the solvent is removed. 1.7 g of 4-chloro-5,8-difluoro-2-methylquinazoline is obtained quantitatively, which is dissolved in 60 ml of ethyl acetate and 5 ml of triethylamine. To this is added 600 mg of palladium on charcoal and stirred for 2 h (480 ml of hydrogen uptake) under a hydrogen atmosphere at normal pressure. The solution is freed from the catalyst by filtration through celite, washed with 100 ml of ethanol, and evaporated. After chromatography on silica gel with hexane-ethylacetate-ethanol (0-40%), 550 mg of 5,8-Difluoro-2-methylquinazoline was obtained. 890 mg (13.7 mmol) of sodium azide was added to 240 mg (1.3 mmol) of 5,8-Difluoro-2-methylquinazoline, 300 mg (1.13 mmol) of 18-Krone-6 in 10 ml of DMF, and the mixture was heated for 8 h at 125°C. The solvent was removed

in vacuum and then chromatographed on silica gel with ethyl acetate to obtain 52 mg of product. 1 H-NMR (CDCl3); δ = 2.92 (s, 3H), 4.31 (br, 2H), 6.67 (dd, IH), 7.38 (dd, IH), 9.37 (s, IH). 50 mg of sodium acetate, 0.05 ml of trifluoroacetic acid and 0.1 ml of acetic acid are added to 200 mg (0.48 mmol) of 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 40 mg (0.23 mmol) of 5-Amino-8-fluoro-2-methylquinazoline in dichloroethane. It is heated with a reflux condenser, and after 4 hours the solvent is removed under vacuum with the addition of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 58 mg of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol are obtained. 20 mg of palladium on charcoal is added to the imine in 10 ml of ethyl acetate and 1 ml of triethylamine and stirred for 1 h under a hydrogen atmosphere at normal pressure. The solution is freed from the catalyst by filtration and evaporated. It is raised in 5 ml of chloroform and 200 mg of activated manganese dioxide is added to it and stirred for 30 min. It is filtered through celite and evaporated under vacuum. After chromatography on silica gel with hexane-ethyl acetate (0-70 %), 12 mg of the product is obtained.

<1>H-NMR (CDCl3); 8 = 1.46 (s, 3H), 1.55 (s, 3H), 2.37 (d, IH), 2.76 (d, IH), 2.90 (s, 3H), 3.13 (dd, IH), 3.27 (dd, IH), 3.85 (s, 3H), 4.50 (br, IH), 5.94 (dd, IH), 6.77 (dd, IH), 6.91 (ddd, IH), 7.08 (dd, IH), 7.30 (dd, 1H), 9.16 (s, 1H).

Example 14

4- f5- Fluoro- 2- hydroxyoxyphenyl)- 4- methyl- 1-( 8- fluoro- 2- methylquinazolm- 5-

ylamino)-2-fluoromethyl)-pentan-2-ol

Analogous to example 3, 20 mg (43 umol) of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol in 4 ml of CH2Cl2 are reacted with 2 ml of 1M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane/2-propanol (10%), 17 mg of product is obtained.

1H-NMR (CDCl 3 ); 8 = 1.50 (s, 3H), 1.57 (s, 3H), 2.35 (d, IH), 2.86 (s, 3H), 2.90 (d, IH), 3.21 (dd, IH), 3.36 (dd, IH), 4.72 (br, IH), 6.08 (dd, IH), 6.54 (dd, IH), 6.68 (ddd, IH), 7.03 (dd, IH), 7.33 (dd, IH), 9.19 (s,

IH).

Example 15

N-(2-Methylquinazolin-5-yl)-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)amide pethane acid

104 mg (0.41 mmol) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid (WO 00/32584) and 100 mg (0.63 mmol) of 5-Amino-2-methylquinazoline in 2 ml of DMF were mixed at room temperature under argon with 102 mg (4.49 mmol) of dicyclohexylcarbodiimide. It is left to stir at room temperature for 3 hours, the reaction mixture is poured into water, extracted with ethyl acetate, the organic phase and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 64.9 mg of amide N-(2-Methylquinazolin-5-yl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentanoic acid is obtained, which is dissolved in 2.2 ml of DMF and cooled to 0°C. The solution was mixed with 0.18 ml of (trifluoromethyl)trimethylsilane and 243 mg of cesium carbonate and stirred for 6 hours at room temperature. Water is added to it,

extracted with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate. The evaporated intermediate product is taken up in 2 ml of THF and 100 ul of 1 M solution of tetrabutylammonium fluoride is added to it. It is mixed for 30 minutes, water is added to it, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-65%), 14.7 mg of product is obtained.

1H-NMR (CDCl 3 ); 5 = 1.44 (s, 3H), 1.46 (s, 3H), 2.85 (d, IH), 2.91 (s, IH), 3.04 (d, IH), 3.89 (s, 3H), 4.18 (s, IH), 6.77 (m, 2H), 6.94 (dd, IH), 7.79 (d, IH), 7.86 (t, IH), 8.05 (d, IH), 9.08 (s, IH), 9.12 (s, IH).

Example 16

4-(5-Fluoro-2-methoxyphenyl-1-f1H-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

154 mg of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 80 mg of 1H-indazol-4-ylamine (see AuwersChem. Ber.,

1920,53,1213) was dissolved in 10 ml of toluene and 1.5 ml of acetic acid and stirred for 16 hours at room temperature. It is mixed with ethyl acetate and sodium hydrogen carbonate solution, the ethyl acetate phase is washed twice with sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated. After chromatography on silica gel with hexane/ethyl acetate (1.5+1), 172 mg of 4-(5-fluoro-2-methoxyphenyl)-1-(1H-indazol-4-ylimino)-4-methyl-2-(trifluoromethyl)pentan-2-ol are obtained.

MS(EI<+>): 423/424.

148 mg of imine was dissolved in 5 ml of methanol and 0.5 ml of acetic acid, combined with 60 mg of sodium cyanoborohydride, and stirred for 2 hours at 0°C and 6 hours at

room temperature. It is mixed with ethyl acetate and sodium hydrogen carbonate solution, the ethyl acetate phase is washed twice with sodium hydrogen carbonate solution, dried and evaporated. After chromatography on silica gel with hexane/ethyl acetate (1.5+1), 130 mg of 4-(5-Fluoro-2-methoxyphenyl)-1-(1H-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)-pentan-2-ol are obtained.

MS(EI<+>): 425/426, 1H-NMR (CDCl 3 ); 5 = 1.45 (s, 3H), 1.58 (s, 3H), 2.27 (d, IH), 2.78 (d, IH), 3.18 (d, IH), 3.35 (d, IH),), 3.85 (s, 3H), 5.67 (d, IH), 6.83 (dd, IH), 6.85 (d, IH), 6.95 (ddd, IH), 7.12 (dd, IH), 7.15 (dd, IH), 7.86(br, IH).

Example 17

4-(5-Fluoro-2-hydroxyphenyl)-1-(li/-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogous to example 3, 127 mg of 4-(5-Fluoro-2-methoxyphenyl)-1-(1H-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol is reacted with 10 ml of 1M boron tribromide-CH2Cl2 solution. After chromatography on silica gel with hexane/ethyl acetate (40%), 60 mg of 4-(5-Fluoro-2-hydroxyphenyl)-1-(1H-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)<p>enthan-2-ol is obtained.

M.p.: 164-165°C,

MS(EI<+>): 411/412 1 H-NMR (D 6 -DMSO); 5 = 1.37 (s, 3H), 1.55 (s, 3H), 1.92 (d, IH), 2.92 (dd, IH), 3.03-3.18 (2H), 5.16 (t(br), IH), 5.58 (d, IH), 5.82 (s, IH), 6.65 (d, IH), 6.81 (dd, IH), 6.85 (ddd, IH), 6.95 (dd, IH), 7.00 (dd, IH), 7.97 (s, IH), 9.75 (s, IH), 12.7 (s, IH)

Example 18

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(1-methyl-1H-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol

154 mg of 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 91 mg of 1-methyl-1H-indazol-4-ylamine (SureauChimia, 1961, 15, 195) are reacted as described in Example 15 in 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(1-methyl-1H-indazol-4-ylimino)-2-(trifluoromethyl)pentan-2-ol. MS(EI<+>): 437/438 and further reduced with sodium cyanoborohydride to 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(1-methyll//-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol.

MS(EI<+>): 439/440, 1 H-NMR (CDCl 3 ); 6 = 1.46 (s, 3H), 1.59 (s, 3H), 2.27 (d, IH), 2.77 (d, IH), 3.05-3.20 (3H), 3.38 (d, IH), 3.82 (s, 3H), 4.00 (s, 3H), 5.60 (d, IH), 6.75 (d, IH), 6.84 (dd, IH), 6.95 (ddd, IH), 7.12 (dd, IH), 7.16 (dd, IH), 7.75 (s, IH).

Example 19

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(1-methyl-1//-indazol-4-ylamino)-2-(trifluoromethylopentan-2-ol)

Analogous to example 3, 22 mg of 4-(5-fluoro-2-hydroxyphenyl)-4-methyl-1-(1-methyl-1#-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol are obtained from 84 mg of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(1-methyl-1/-indazol-4-ylamino)-2-(trifluoromethyl)peritan-2-ol.

M.p.: 193-194°C.

MS(E1<+>): 425/426, 1H-NMR (D6-DMSO); 5= 1.40 (s, 3H), 1.53 (s, 3H), 1.91 (d, IH), 2.95 (dd, IH), 3.09-3.20 (2H), 3.90 (s, 3H), 5.26 (t(br), IH), 5.62 (d, IH), 5.83 (s, IH), 6.73 (d, IH), 6.80 (dd, IH), 6.85 (ddd, IH), 6.99-7.05 (2H), 7.93 (s, IH), 9.75 (s, IH)

Example 20

4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methyl-2/f-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol

154 mg of 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 91 mg of 2-Methyl-2/f-indazol-4-ylamine (SureauChimia, 1961, 75, 195) are reacted as described in Example 15 in 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methyl-2//-indazol-4-ylimino)-4-methyl-2-(trifluoromethyl)pentan-2-ol [ Fp.: 92-94°C, MS(EI<+>): 437/438] is further reduced with sodium cyanoborohydride to 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(trifluoromethyl)pentan-2-ol. -(2-methyl-2H-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol.

MS(EI<+>): 439/440, 1H-NMR (CDCl 3 ); 5 = 1.47 (s, 3H), 1.56 (s, 3H), 2.30 (d, IH), 2.75 (d, IH), 3.14 (d, IH), 3.29 (d(br), IH), 3.33 (s(br), IH), 3.75 (s(br), IH), 3.85 (s, 3H), 4.15 (s, 3H), 5.55 (d, IH), 6.86 (d, IH), 6.95-7.07 (2H), 7.10 (dd, IH), 7.15 (dd, IH), 7.66 (s, IH)

Example 21

4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methyl-27Y-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol

Analogous to example 3, 100 mg of 4-(5-Fluoro-2-hydroxyphenyl)-4-methyl-1-(2-methyl-2/f-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol is obtained from 132 mg of 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(2-methyl-2/-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol.

M.p.: 182°C.

MS(EI<+>): 425/426, <1>H-NMR (D6-DMSO); 5 = 1.40 (s, 3H), 1.55 (s, 3H), 1.93 (d, IH), 2.89 (dd, IH), 3.05-3.17 (2H), 4.07 (s, 3H), 5.00 (t(br), IH), 5.38 (d, IH), 5.85 (s, IH), 6.72-6.90 (4H), 6.99 (dd, IH), 8.16 (s, IH), 9.73 (s, IH)

Example 22

4-(2.5-DifluorophenylVl-(l/f-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogous to example 3, 207 mg (0.73 mmol) of 4-(2,5-Difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is reacted with 150 mg (1.10 mmol) of 1H-indazol-4-ylamine (cf. AuwersChem. Ber., 1920, 53, 1213). 110 mg of 4-(2,5-Difluorophenyl)-1-(1H-indazol-4-ylimino)-4-methyl-2-(trifluoromethyl)pentan-2-ol are obtained. 50 mg (0.12 mmol) of that is reduced. analogously to example 7 with 27 mg (0.72 mmol) NaBFL,. After chromatography on silica gel with hexane/ethyl acetate (20-30%), 18 mg of the desired product is obtained.

1H-NMR(300 MHz, CDCl 3 ): □ = 1.48 (s, 3H), 1.62 (s, 3H), 2.27 (d, IH), 2.52 (d, IH), 3.23-3.38 (m, 2H), 5.67 (d, IH), 6.83-7.01 (m, 3H), 7.08-7.18 (m, 2H), 7.89 (s, IH)

Example 23

4-('4-Bromo-2-methoxyphenyl)-2-hydroxy-N-(1//-indazol-4-yl)-4-methyl-2-(trifluoromethyl)pentanoic acid amide

122 mg of 4-dimethylaminopyridine was dissolved in 3 ml of Sulfolan® under heat, cooled to room temperature and combined with 0.0525 ml of thionyl chloride. After 45 minutes at room temperature, it is mixed with 192 mg of 4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid (WO 98/54159) and stirred again for 45 minutes at room temperature. It is mixed with 90 mg of l/f-indazol-4-ylamine (see AuwersChem. Ber., 1920, 53,1213), heated for 1 hour at 80°C and combined with a solution of sodium hydrogencarbonate and ethyl acetate. The ethyl acetate phase is washed four times with water, dried and evaporated. After chromatography on silica gel with hexane/ethyl acetate (50%), 150 mg of pentanoic acid 4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-N-(1/7-indazol-4-yl)-4-methyl-2-(trifluoromethyl)amide is obtained.

MS(EI<+>): 499/501 1H-NMR (D 6 -DMSO); 5 = 1.38 (s, 3H), 1.50 (s, 3H), 2.17 (d, IH), 3.10 (d, IH), 3.83 (s, 3H), 6.65 (dd, IH), 6.97 (d, IH), 7.03 (d, IH), 7.08 (s, IH), 7.10 (d, IH), 7.27 (dd, IH), 7.31 (d, IH), 7.92 (s, IH), 9.45 (s, IH), 13.1 (s, IH)

Example 24

4-( 4- Bromo- 2- hydroxyphenin- 2- hydroxy- N-(' li/- indazol- 4- yn- 4- methyl- 2-( trifluoro- methyl) amide of pentanoic acid)

Analogously to example 3, 55 mg of pentanoic acid 4-(4-bromo-2-hydroxyphenyl)-2-hydroxy-N-(1/-indazol-4-yl)-4-methyl-2-(trifluoromethyl)amide is obtained from 100 mg of 4-(4-bromo-2-methoxyphenyl)-2-hydroxy-N-(1/-indazol-4-yl)-4-methyl-2-(trifluoromethyl)pentanoic acid.

MS(EI<+>): 485/487,<1>H-NMR(D6-DMSO); 5 = 1.42 (s, 3H), 1.48 (s, 3H), 2.23 (d, IH), 3.15 (d, IH), 6.54 (dd, IH), 6.83 (d, IH), 6.95 (d, IH), 7.00 (s, IH), 7.10 (d, IH), 7.25 (dd, IH), 7.30 (d, IH), 7.95 (s, IH), 9.61 (s, IH), 9.95 (s, IH), 13.12 (s, IH).

Example 25

4- ( 5- Fluoro- 2- methoxyoxyphenyl)- 4- methyl- 1-( 7- fluoro- 2- methylquinazoline- 5-

ylamino)-2-(trifluoromethyl)-pentan-2-ol

5- Amino- 7- fluoro- 2- methylquinazoline

17 g (70.5 mmol) of 3,6-Difluoro-2-N-pivaloylaminobenzaldehyde (L. Florvall, I Fagervall, L.-G- Larsson, S.B. Ross, Eur. J. Med. Chem. 34

(1999)137-151),9, 2 g of Acetamidine hydrochloride, 13.4 g of potassium carbonate and 10.4 g of molecular sieve (4A) were placed together in 70 ml of butyronitrile. It is heated with intense stirring for 17 hours at 145°C and the solvent is removed in a vacuum. After chromatography of the residue on silica gel with hexane/ethyl acetate (0-70%), 4.5 g of 7-Fluoro-5-N-pivaloylamino-2-methylquinazoline is obtained. lg (3.82 mmol) of 7-Fluoro-5-N-pivaloylamino-2-methylquinazoline was dissolved in 74 ml of toluene and cooled to -70 °C. During 30 min, 9.5 ml (11.4 mmol) of a 1.2 M diisobutylaluminum hydride solution in toluene was added dropwise. The reaction mixture was allowed to warm to -40°C and stirred for 4 hours at -40°C. Water is slowly added and stirred for 30 minutes at room temperature until a precipitate forms, which is removed by filtration through celite. The phases are separated, washed with saturated sodium chloride solution and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 64 mg of product is obtained. 1H-NMR (CDCl 3 ); δ = 2.83 (s, 3H), 4.67 (br, 2H), 6.50 (dd, IH), 6.93 (dd, IH), 9.23 (s, IH). To 22 mg (0.07 mmol) of 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 11 mg (0.06 mmol) of 5-Amino-7-fluoro-2-methylquinazoline in 4 ml of toluene is added 0.1 ml of titanium tetraethylate and the mixture is heated for 2.5 hours at 100 °C. After cooling, it is poured into water and stirred vigorously. The suspension is filtered through celite, washing thoroughly with ethyl acetate. The filtrate phases are separated and extracted once more with ethyl acetate. It is dried over sodium sulfate and the solvent is evaporated in a vacuum. The thus obtained crude 4-(5-fluoro-2-methoxyphenyl)-1-(7-fluoro-2-methylquinazolin-5-ylimino)-4-methyl-2-(trifluoromethyl)-pentan-2-ol in 8 ml of ethyl acetate, is placed in 5 ml of ethyl acetate and 0.5 ml of triethylamine with 20 mg of palladium on charcoal and shaken for 1 h under a hydrogen atmosphere at normal pressure. The solution is freed from the catalyst by filtration and evaporated. It is raised in 5 ml of chloroform, 50 mg of activated magnesium dioxide is added and stirred for 20 min. It is filtered through celite and evaporated under vacuum. After chromatography on silica gel with hexane-ethyl acetate (0-70 %), 18 mg of product is obtained. 1 H-NMR (CDCl3); 8 = 1.47 (s, 3H), 1.54 (s, 3H), 2.44 (d, IH), 2.70 (d, IH), 2.81 (s, 3H), 3.15 (dd, IH), 3.30 (dd, IH), 3.86 (s, 3H), 4.97 (br, IH), 5.83 (dd, IH), 6.79 (dd, IH), 6.85 (dd, IH), 6.92 (ddd, IH), 7.06 (dd, IH), 8.98 (s,lH).

Example 26

4-(5-Fluoro-2-methoxyphenyl)-1-(6-methyl-1//-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

Analogously to example 16, the desired product is obtained from 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 6-Methyl-1//-indazol-4-ylamine (cf. AuwersChem. Ber., 1920, 53,1213).<J>H-NMR (CD3OD); 5 = 1.45 (s, 3H), 1.64 (s, 3H), 2.01 (d, IH), 2.23 (s, 3H), 2.78 (d, IH), 3.01 (d, IH), 3.21 (d, IH), 3.86 (s, 3H), 5.96 (s, IH), 6.93 (m, 2H), 7.14 (dd, IH), 7.21 (s, IH), 7.73 (s, IH).

Example 27

4-(3-Fluoro-2-methoxyphenyl)-1-(2-methylquinazolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol

2, 6- Difluoroanisole

20 g (153.74 mmol) of 2,6-difluorophenol were dissolved in 200 ml of acetone and mixed with 42.5 g (307.48 mmol) of potassium carbonate under nitrogen. After the addition of 19.1 ml of methyl iodide (2 equivalents), it is boiled for three and a half hours in a reflux condenser. After cooling, the reaction mixture is filtered, the residue after filtration is washed with acetone and the filtrate is evaporated to dryness on a rotary evaporator.

The residue is chromatographed on silica gel (eluent ethyl acetate/hexane). 17.27 g (77.9 %) of the desired product is obtained

that the product is easily volatile. The temperature of the bath should not exceed 30°C and the vacuum of the rotary evaporator should be adjusted.

2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanenitrile\ Q

g (69.39 mol) of 2,6-Difluoroanisole was dissolved in 200 ml of toluene and mixed with 5.75 g (83.27 mmol) of isobutyric acid nitrile at room temperature. In the course of 35 minutes, 166.5 ml of a 0.5 molar solution of potassium umhexamethyldisilazide in toluene is added dropwise. This is followed by a slight rise in temperature to 27.5 °C. After stirring for 16 hours at room temperature, the reaction mixture is mixed with 200 ml of water and 400 ml of ethyl acetate and acidified with 10% sulfuric acid to pH 4. The organic phase is separated and the aqueous phase is diluted once with ethyl acetate (200 ml). The combined organic extracts are mixed once with water and salt. After drying, filtering and evaporation of the solvent on a rotary evaporator, the residue is chromatographed on silica gel (eluent ethyl acetate/hexane). 7.66 g (57.1%) of the desired product is isolated.

2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanal

7.66 g (39.64 mmol) of the above-mentioned nitrile are dissolved in 158 ml of toluene. At -65 to -60°C, 49.5 ml of a 1.2 molar solution of DIB AH in toluene are added dropwise over the course of 40 minutes. After stirring for one hour at this temperature, 493 ml of a 10% solution of L-(+)-tartaric acid are added dropwise. After 100 milliliters, the temperature rose to -10°C. The rest of the tartaric acid is quickly added and the contents are stirred vigorously at room temperature. The reaction mixture is stirred twice with 400 ml of diethyl ether each. The combined organic extracts are mixed with water and salt,

dry and the solvent is evaporated on a rotary evaporator. The resulting residue (7.8 g = 102 %) is used raw in the next step.

Ethylstar- ( E/ Z)- 4-( 3- Fluoro- 2- methoxy iphenyl)- 4- methylpent- 2- enic acids

21.3 ml of a 2 molar LDA solution in THF was added dropwise to a solution of 9.87 g (39.75 mmol) of 2-Ethoxy-phosphonoacetic acid triethyl ester in 40 ml of absolute THF at 0 °C. After stirring for 30 minutes at 0°C, 7.8 g (39.75 mmol) of 2-(3-Fluoro-2-methoxyphenyl)-2-methylpropanal, dissolved in 26 ml of THF, were continuously added dropwise. The cold bath is removed and the contents are stirred for 16 hours at room temperature. The reaction mixture was poured onto water and extracted twice with ethyl acetate. The combined organic extracts are washed with water and salt, dried, and after filtering the drying agent, the solvent is removed on a rotary evaporator. The residue is chromatographed on silica gel (eluent ethyl acetate/hexane). 8.39 g (68.2%) of the desired product is isolated.

(E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enic acid

8.39 g (27.03 mmol) of (E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enoic acid ethyl ester was mixed with 270 ml of one 1 N NaOH in ethanol/water (2:1) and stirred at room temperature for two days. Ethanol is removed on a rotary evaporator and the residue is extracted twice with 150 ml of diethyl ether. The combined organic extracts are washed with water and discarded after TH-control. The aqueous phases were acidified with conc. sodium acid to pH 3 and extracted twice with 300 ml of diethyl ether. Ether extracts are washed with water and salt, dried, the solvent is removed on a rotary evaporator and the rest (5.89 g = 77.2%) is used crudely in the next step.

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid

5.89 g (20.86 mmol) of (E/Z)-4-(3-Fluoro-2-methoxyphenyl)-4-methylpent-2-enic acid is mixed at room temperature with 126 ml of 1 molar sulfuric acid and after the addition of 21 ml of glacial acetic acid, it is stirred for 15 hours at 90°C bath temperature. The reaction mixture was carefully mixed (strong foaming) with solid potassium carbonate to pH 9. Extracted twice with diethyl ether. The combined organic extracts are washed with water and discarded after TH. The combined aqueous phases are with conc. acidified with sodium acid to pH 4 and extracted twice with diethyl ether. Ether extracts are washed with water and salt, dried and the solvent is removed on a rotary evaporator. Since the residue still contains acetic acid, it is evaporated twice with 100 ml of toluene on a rotary evaporator. The rest (4.14 g = 78.1%) is used raw in the next step.

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester

4.14 g (16.28 mmol) of 4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentane of this acid was dissolved in 97 ml of ethanol, mixed with 1.79 ml of sulfuric acid and refluxed for four hours. Ethanol is removed on a rotary evaporator and the residue is carefully mixed with a saturated solution of sodium hydrogencarbonate to pH 9. It is extracted twice with 100 ml of ethyl acetate and the combined organic extracts are washed with water and then with salt. After drying, separating the drying material by filtration and removing the solvent on a rotary evaporator, the residue is chromatographed on silica gel (eluent ethyl acetate/hexane). 4.16 g (90.6%) of the desired product is isolated.

Ethyl ester 4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethyl-

tillsilyloxypentanoic acid

4.16 g (14.74 mmol) of 4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester was dissolved in 24 ml of THF and mixed with 2.51 g of

(17.68 mmol) (trifluoromethyl)-trimethylsilane and 36.1 mg of tetrabutylammonium fluoride. After two and a half hours of mixing between 0 and 5° C, the contents are poured into 50 ml of ice water. It is extracted twice with 150 ml of diethyl ether each, and the combined organic extracts are processed as usual. After chromatography on silica gel (eluent ethyl acetate/hexane), 24 g (83.8%) of the desired product is obtained.

4-( 3- Fluoro- 2- methoxyphenyl)- 4- methyl- 2- trifluoromethyl- 2- trim

pentan-l-ol

5.24 g (12.34 mmol) of 4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentanoic acid ethyl ester was dissolved in 45 ml of diethyl ether and mixed with 936.9 mg (24.69 mmol) of LiAlFL in portions at 0 to 5 °C; . After stirring for four and a half hours at room temperature, the reaction mixture is carefully mixed with saturated sodium hydrogencarbonate solution while cooling with an ice bath and stirred for one hour in the cold and overnight at room temperature. After the usual work-up, 4.11 g (87.1%) of a mixture of the desired compound and the silylether-displaced compound is obtained. The mixture is used raw in the next step.

4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-<pe>nt^^

4.11 g (10.75 mmol) of 4-(3-Fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-2-trimethylsilyloxy-pentan-1-ol was dissolved in 61 ml of THF, mixed with 3.39 g (10.746 mmol) of Bu4NF trihydrate and stirred for one hour at room temperature. The reaction mixture was poured into water and extracted twice with diethyl ether. The organic phases are washed with water and salt as usual. After drying, separation of the drying agent by filtration and evaporation of the solvent on a rotary evaporator, the remaining part is chromatographed on

silica gel (eluent ethylacetate/hexane). 2.71 g (81.4%) of the desired product was isolated.

4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoro

765 mg (6.03 mmol) of oxalyl chloride in 13 ml of dichloromethane was placed in one heated flask. At -78 °C, 0.855 ml of DMSO, dissolved in n 2.5 ml of dichloromethane, was added, and the contents were stirred for another five minutes, after which 1.7 g (5.48 mmol) of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol, dissolved in 5 ml of dichloromethane, were added. After stirring for fifteen minutes, the contents are carefully mixed with 3.79 ml (27.40 mmol) of triethylamine, stirred for five minutes at -78 °C and then allowed to slowly reach room temperature. 20 ml of water is added, and the contents are stirred for another hour at room temperature. After phase separation, the aqueous phase is triturated once with dichloromethane. The combined organic extracts are washed with 1% sulfuric acid, 5% sodium bicarbonate solution and salt. According to the usual procedure, 1.617 g (96.2%) of aldehyde was obtained, which was used crudely in the next step. Analogous to example 25, the desired product is obtained from 4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 5-Amino-2-methylquinazoline.

1H-NMR (300 MHz, CDCl3): □ = 1.45 (3H), 1.57 (3H), 2.35 (IH), 2.75 (IH), 2.82 ( 3H), 3.00-3.40 (3H), 4.00 (3H), 4.75 (IH), 6.10 (IH), 6.90-7.02 (2H), 7.05-7.18 (IH), 7.25 (IH), 7.55 (IH), 9.10 (IH).

Example 28

4-(3-Fluoro-2-methoxyphenylH-U

methyl)pentan-2-ol

Analogous to example 16, the desired product is obtained from 4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1H-indazol-4-ylamine. 1 H-NMR (300 MHz, CDCl3): □ =1.49 (3H), 1.60 (3H), 2.30 (IH), 2.71 (IH), 3.18 (IH), 3.30 (IH), 4.05 (3H), 5.75 (IH), 6.85 (IH), 6.90-7.20 (4H), 7.80 (IH).

Example 29

4-(3-Fluoro-2-hydroxyphyll)-1-n//-indazol-4-ylamino)-4-methyl-2-(trifluoromethylopentan-2-ol)

Analogous to example 3, the desired product is obtained from 4-(3-Fluoro-2-methoxyphenyl)-1-(1/- indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol. <!>H-NMR (300 MHz, DMSO-d6): □ =1.42 (3H), 1.59 (3H), 1.95 (IH), 2.85-2.95 (IH), 3.03-3.18 (2H), 5.15 (IH), 5.55 (IH), 5.80 (IH), 6.65 (IH), 6.70-6.80 (IH), 6.90 (IH), 6.90-7.13 (2H), 7.95 (IH), 9.80 (IH), 12.70 (IH).

Example 30

2- IY5- Chloro- 1 H- indazol- 4- ylamino)- methyl- 1. 1, 1 - trifluoro- 4-( 3- fluoro- 2-

methoxyphenyl)-4-methylpentan-2-ol

5-Chloro-4-nitro-1H-indazole

In 100 ml of acetic acid, dissolve 2.24 g (12 mmol) of 4-Chloro-2-methyl-3-nitrophenylamine, obtained according to the literature (Mori et al, Chem. Pharm. Buli. 1986, 34, 4859ff. sowie Brand und Zoller, Chem. Ber. 1907, 3324ff.). At 10 °C, 6.0 ml of a 2 molar aqueous solution of sodium nitrite is dropped. The suspension is then added over 15 minutes to a boiling solution of acetic kidseline (150 ml) and the reaction mixture is left to reflux for 4 hours. After removing the acetic acid in a vacuum, the residue is taken up in ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is washed with saturated sodium hydrogencarbonate solution and dried over sodium sulfate. After removal of the solvent in vacuo, the crude product (1.81 g, 76%) was used further.

<1>H-NMR(300 MHz, DMSO-d6): δ = 7.65 (d, 1H), 7.97 (d, 1H), 8.32 (s, 1H), 13.97(s, 1H).

5-Chlor-1H-indazol-4-ylamine

A solution of 5-Chloro-4-nitro-1H-indazole (872 mg, 4.41 mmol) was mixed with 150 mg of palladium on charcoal (10% Tn) and stirred under a hydrogen atmosphere at room temperature. After 45 minutes, the catalyst is filtered through a frit and washed with methanol. The filtrate is evaporated and the residue is taken up in 200 ml of ethyl acetate and heated. After re-filtration and evaporation of the filtrate, purification on silica gel with hexane/ethyl acetate (100-33% hexane) follows. 296 mg (40% of theory) of product is obtained.

<1>H-NMR (300 MHz, DMSO-d6): δ = 5.97 (s, 2H), 6.66 (d, 1H), 7.05 (d, 1H), 8.19 (s, 1H), 12.83 (s, 1H).

2-[(5-Chloro-1H-indazol-4-ylamino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-

methoxyphenyl)-4-methyl-pentan-2-ol

A solution of 4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal (278 mg, 0.9 mmol) and 5-Chloro-1H-indazol-4-ylamine (121 mg, 0.72 mmol) in 20 ml of xylene was mixed with titanium(IV) ethylate (0.42 ml, 2.0 mmol) and refluxed for 10 hours. After cooling to room temperature, the xylene is distilled off and the residue is purified on silica gel with hexane/ethyl acetate (30-100% ethyl acetate). 123 mg (37% of theory) of product is obtained.

<1>H-NMR(400 MHz, CDCl 3 ): δ = 1.43 (s, 3H), 1.57 (s, 3H), 2.38 (d, IH), 3.22 (d, IH), 3.94 (d, 3H), 4.91 (s, IH), 6.41-6.52 (m, 2H), 6.90 (d, IH), 7.28 (d, IH), 7.38 (d, IH), 7.56 (s, IH), 7.72 (s, IH), 10.26 (br, IH).

2-[(5-Chloro-1H-indazol-4-ylamino)-methyl]-1,1,1-thfluoro-4-(3-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol

A solution of 2-[(5-Chloro-1H-indazol-4-ylimino)-methyl]-1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (49 mg, 0.11 mmol) in 5.0 ml of methanol was mixed with 15 mg of sodium borohydride and stirred at room temperature. Then, a total of 300 mg of sodium borohydride is added in portions over the course of four days. The reaction mixture is neutralized with 10% acetic acid. After removing the solvent, the residue is taken up in a saturated solution of sodium hydrogencarbonate and ethyl acetate. It is extracted with ethyl acetate, the organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After removal of the solvent in vacuo and purification of the residue by preparative thin-layer chromatography on silica gel with hexane/ethyl acetate (50% ethyl acetate), 24 mg (47%) of the product is obtained.

1H-NMR (300 MHz, CDCl 3 ): 5-1.48 (s, 3H), 1.59 (s, 3H), 2.39 (d, IH), 2.72 (d, IH), 3.55-3.59 (m, 2H), 4.01 (d, 3H), 4.80-4.84 (m, IH), 6.80 (d, IH), 6.86-6.98 (m, 2H), 7.11 (d, 1H), 7.22 (d, 1H), 7.70 (s, 1H).

Example 31

1. 1, 1 - Trilfluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-L¥-indazol-4-ylamino)-methyl1-pentan-2-ol

5- Methyl-1H-indazol-4-ylamine

A solution of 2,4-dimethylaniline (12.4 mL, 100 mmol) in 80 mL of concentrated sulfuric acid at 0 °C was mixed with 5.0 mL of fuming nitric acid and stirred for 20 min at 4 °C, then at room temperature for 30 min. The reaction mixture was poured into 600 ml of ice water, adjusted to pH 10 with 5N sodium hydroxide. The precipitate was removed by filtration, washed with water and dried. 15.72 g (95% of theory) of 2,4-dimethylnitrophenylamine are obtained as a mixture of regioisomers. In analogy with the preparation of 5-chloro-4-nitro-1//-indazole, 1.14 g (57% of theory) of the product was obtained as a mixture of both regioisomers by reacting 2,4-dimethylnitrophenylamine (2.0 g, 12 mmol) with 6.0 ml of a 2 molar aqueous solution of sodium nitrite in acetic acid (250 ml).

MS (ES+, acetonitrile/water 1:1 + 0.01% formic acid): m/z(%) 178 (M+1, 100).

In analogy to the preparation of 5-chloro-1H-indazol-4-ylamine, the mixture of regioisomers of the previous reaction (1.0 g, 5.64 mmol) is reacted with 100 mg of palladium on charcoal in methanol under a hydrogen atmosphere for 16 hours at room temperature. After purification on silica gel with hexane/ethyl acetate (33% hexane, then 100% ethyl acetate) 53 mg (6% of theory) of 5-Methyl-1H-indazol-4-ylamine was obtained.

<1>H-NMR (300 MHz, DMSO-d6): δ = 2.12 (s, 3H), 5.41 (s, 2H), 6.57 (d, 1H), 6.90 (d, 1H), 8.10 (s, 1H), 12.5 (s, 1H).

4-(3-Fluoro-2-methoxynyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal (308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol) were placed in 15.0 mL of xylene and mixed with titanium(IV) ethylate (0.42 mL, 2.0 mmol). After 3 hours at reflux, the reaction mixture is allowed to cool to room temperature. After the addition of ethyl acetate and saturated sodium chloride solution, it is stirred intensively for 30 minutes at room temperature. The precipitate is filtered off, the aqueous phase is separated and the organic phase is dried over sodium sulfate. Purification follows by chromatography on silica gel with hexane/ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)methyl]-pentan-2-ol are obtained. A solution of 1,1,1-Trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1/-indazol-4-ylimino)-methyl]-pentan-2-ol (151 mg, 0.34 mmol) dissolved in 20 ml of methanol was mixed with 30 mg of palladium on charcoal (10% Tn) and stirred at room temperature under a hydrogen atmosphere. After 20 hours, 30 mg of palladium on charcoal was added and the reaction mixture was left to stir for a further 28 hours at room temperature. The catalyst is filtered through celite and washed with methanol. After evaporation of the filtrate and purification of the residue by preparative thin-layer chromatography on silica gel with hexane/ethyl acetate (50% ethyl acetate), 28 mg of product is obtained (19% of theory).

'H-NMRC400 MHz, CDCl3): δ = 1.47 (s, 3H), 1.60 (s, 3H), 2.18 (s, 3H), 2.37 (d, IH), 2.70 (d, IH), 3.48 (s, 2H), 4.00 (d, 3H), 6.88-6.97 (m, 3H), 7.07 (d, IH), 7.11 (d, IH), 7.67 (s, IH).

Example 32

4-(Benzen[1.31dioxol-4-yl)-4-methyl-1-(2-methylquinazolin-5-ylamino)-2-(trifluoromethyl-pentan-2-ol)

l-(Benz[1,3]dioscol-4-yl)-l-methylethanol

25.5 g of 4-acetylbenzo[1,3]dioxole was mixed with 57.2 ml of methylmagnesium chloride, (3M solution in THF) in 375 ml of THF at room temperature under argon. It is stirred for 16 h at room temperature and placed on ice/2N acid solution. It is extracted with ethyl acetate and the organic phases are washed with water and salt and then dried with sodium sulfate. 27.89 g of 1-[benz(1,3)dioxol-4-yl]-1-methylethanol was obtained as a brown oil.

1H-NMR (CDCl 3 ), D (ppm) = 1.6 (s, 6H), 5.95 (s, 2H), 6.76 (dd, 1H), 6.82 (t, 1H), 6.91 (dd, 1H).

Ethyl ester of 4-(Benz[1,3]dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid

5.0 g of 1-(Benz[1,3]dioxol-4-yl)-1-methylethanol and 7.8 g of 2-trimethylsilyloxy-acrylic acid ethyl ester were mixed in 100 ml of dichloromethane at -70 °C with 2.4 ml of stannous chloride. After 5 minutes, the solution is placed on the potassium carbonate solution and mixed thoroughly. It is filtered through infusoryl earth, the phases are separated, and the aqueous phase is extracted with dichloromethane. The organic phase is washed with water and salt, dried over sodium sulfate and evaporated. After

chromatography on silica gel (hexane/ethyl acetate 0 -> 10%) gave 3.4 g of the title compound as a colorless oil.

1H-NMR (CDCl 3 ), □ (ppm) = 1.25 (t, 3H), 1.44 (s, 6H), 3.31 (s, 2H), 4.12 (q, 2H), 5.92 (s, 2H), 6.7 - 6.82 (m, 3H)

Ethyl ester 4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-

pentanoic acid

4.42 g of 4-(benz[1,3]dioxol-4-yl)-4-methyl-2-oxo-pentanoic acid ethyl ester and 6.9 ml of trifluoromethyl-trimethylsilane in 95 ml of THF were mixed gently at -70 °C with 3.2 ml of a solution of TBAF (IH in THF). It is mixed for 1 h at - 70 °C and 2 h at room temperature, then solid tetrabutylammonium fluoride (TBAF) is added to the top of the spatula. After stirring for 1 hour, it is poured into 0.1 N sodium acid and extracted with ethyl acetate. The organic phases are washed with water and salt, dried over sodium sulfate and evaporated. After chromatography on silica gel (hexane / ethyl acetate 0 -> 10%), 4.55 g of the title compound is obtained as a yellow oil. 1 H-NMR (CDCl3), □ (ppm) = 1.19 (t, 3H), 1.39 (s, 3H), 1.46 (s, 3H), 2.29 (d, IH), 2.74 (d, IH), 3.59 (dq, IH), 4.05 (dq, IH), 5.92 (s, IH), 5.98 (s, IH), 6.68 - 6.85 (m, 3H).

4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanol 2.92

g of 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanoic acid ethyl ester in 100 ml of diethyl ether was mixed in portions at 0 °C with 478 mg of lithium aluminum hydride. After mixing for 10 hours, it is placed on a saturated bicarbonate solution and filtered through an infusoria sieve. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and salt, dried with sodium sulfate and evaporated. After chromatography on silica gel (hexane / ethyl acetate 0 -> 10%), 2.44 g of the title compound is obtained as a yellow oil.

1H-NMR (CDCl3), □ (ppm) = 1.42 (s, 3H), 1.51 (s, 3H), 2.22 (d, IH), 2.36 (d, IH), 2.9 (bs, IH), 3.41 (d, IH), 3.51 (d, IH), 5.92 (s, IH), 5.95 (s, IH), 6.69 -6.85 (m, 3H)

4-(Benz[1,3]dioxol-4-yl)-2-hydrochyl-4-methyl-2-trifluoromethyl-pentanal

0.650 ml of oxalyl chloride in 16.0 ml of dichloromethane was mixed at -78 °C with 1.2 ml of DMSO in 3.0 ml of dichloromethane. After 5 min. 2 g of 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanol is added dropwise in 7.0 ml of dichloromethane at -78 °C. After 15 min. it is mixed with 4.6 ml of triethylamine and gently warmed to room temperature. It is washed with water and salt, dried with sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane / ethyl acetate 0 -> 5%), 1.64 g of the title compound is obtained as a yellow oil.

1H-NMR (CDCl3), □ (ppm) = 1.40 (s, 3H), 1.44 (s, 3H), 2.24 (d, IH), 3.1 (d, IH), 3.64 (bs, IH), 5.94 (s, IH), 5.99 (s, IH), 6.67 - 6.9 (m, 3H), 9.05

(with, IH)

Analogous to the preparation from example 2, the corresponding imine is obtained from 125 mg of 5-amino-2-methylquinazoline and 237 mg of 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and is reduced with palladium on activated carbon. Reoxidation is achieved by heating the product in xylene in the presence of palladium on activated carbon in air. 61 mg of the title compound is obtained.

<1>H-NMR (CDCl3), □ (ppm) = 1.48 (s, 3H), 1.56 (s, 3H), 2.35 (d, IH), 2.53 (d, IH), 2.85 (s, 3H), 3.23 (dd, IH), 3.41 (dd, IH), 4.74 (bt, IH), 5.90 (s, IH), 5.93 (s, IH), 6.17 (d, IH), 6.78 (dd, IH), 6.84-6.93 (m, 2H), 7.28 (d, IH), 7.58 (t, IH), 9.21 (s, IH)

Example 33

4-(Benz[31]dioxol-4-yl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol

90 mg of 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 50 mg of 5-amino-8-fluoro-2-methylquinazoline in 10 ml of toluene are reacted analogously to example 25. After chromatography on silica gel with hexane-ethyl acetate (0-70%), 58 mg of 4-(benz[1,3]dioxol-4-yl)-4-methyl-1-(2-methylquinazolin-5-ylimino)-2-(trifluoromethyl)-pentan-2-ol are obtained. 20 mg of palladium on charcoal is added to the imine in 10 ml of ethyl acetate and 1 ml of triethylamine, and it is stirred for 2 h under a hydrogen atmosphere at normal pressure. The solution is freed from the catalyst by filtration and evaporated. It is raised in 5 ml of chloroform and 200 mg of activated manganese dioxide is added to it, and it is mixed for 10 minutes. It is filtered through celite and evaporated under vacuum. After chromatography on silica gel (hexane / ethyl acetate 0 - 70%), 15 mg of the product is obtained.

1 H-NMR (CDCl 3 ); 6 = 1.26 (s, 3H), 1.48 (s, 3H), 2.34 (d, IH), 2.54 (d, IH), 2.91 (s, 3H), 3.19 (dd, IH), 3.34 (dd, IH), 4.58 (br, IH), 5.89 (d, IH), 5.94 (d, IH), 6.05 (dd, IH), 6.71-6.85 (m, 3H), 7.32 (dd, IH), 9.27 (s, IH).

Example 34

4- rBenznitrioldioxol-4-yl)-4-methyl-1-n//-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to the preparation of example 30, the corresponding imine is obtained from 168 mg of 4-amino-177-indazole and 383 mg of 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and is further reduced with 488 mg of sodium cyanoborohydride to give 240 mg of the title compound.

<!>H-NMR (CDCl3), □ (ppm) = 1.44 (s, 3H), 1.58 (s, 3H), 2.27 (d, IH), 2.54 (d, IH), 3.22 (dd, IH), 3.41 (dd, IH), 4.01-4.17 (m, IH), 5.81 (d, IH), 5.92 (s, 2H), 6.73-6.99 (m, 4H), 7.12 (t, IH), 7.88 (s, IH)

Example 35 and 36

(- V4-( Benzn, 31dioxol-4-yn-4-methyl-1-('1/- indazol-4-ylamino)-2-( trifluoromethyl)-pentan-2-ol and

(+)- 4-(Benz[1,31dioxol-4-yl)-4-methyl-1-('1/-indazol-4-ylamino)-2-(trifluoromethylD-pentan-2-ol

Separation of (+/-)-4-(benz[ 1,3]dioxol-4-yl)-4-methyl-1 -(l//-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol: The mixture of enantiomers is separated by chromatography on a chiral support material (CHIRALPAK AD<®>, Fa DAICEL) with hexane/ethanol (90 : 10, vw). That's how you get it

(-)-Enantiomer: MS (esi): M<+>+j= 422, [n]p -50.9° °(c = 1.0, CHC13) and (+)-Enantiomer: MS (esi): M<+>+l = 422, [rj]D +54.3° °(c = 1.0, CHC13)

Example37

4-( Benzf 1. 31dioxol- 4- iP- 1 -( 6- methyl- 1//- indazol- 4- ylaminoN4- methyl- 2-( trifluoromethyl) pentan- 2-ol

Analogous to example 16, it is obtained from 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 6-butyl-1H-indazol-4-ylamine (cf.

Auvers Chem. Ber., 1920, 53,1213) the desired product.

1 H-NMR (CD 3 OD); 5 = 1.44 (s, 3H), 1.65 (s, 3H), 2.06 (d, IH), 2.23 (s,

3H), 2.8 (d, 2H), 3.09 (d, IH), 5.89 (s, IH), 5.91 (s, IH), 6.05 (s, IH), 6.75 (dd, IH), 6.86 (t, IH), 6.94 (dd, IH), 7.22 (s, IH), 7.73 (s, lH).

Example 38

4- fBenzr 1, 31dioxol- 4- iD- 4- methyl- 1 - ( 2- methyl- benzothiazol-7- ylamino)- 2-( trifluoromethyl)- pentan- 2-ol

By analogy to the preparation from example 30, the corresponding imine is obtained from 100 mg of 7-Amino-2-methylbenzothiazole (Libeer et al. Bull. Soc. Chim. Belg. ;

1971;80;43-47) and 154 mg of 4-(benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-

of trifluoromethyl-pentanal and further reduced with 63 mg of sodium cyanoborohydride to give 8 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) = 1.42 (s, 3H), 1.53 (s, 3H), 2.01 (d, IH), 2.10 (d, IH), 2.78 (s, 3H), 5.29 (d, IH), 5.67 (d, IH), 6.00 (s, 2H), 6.13 (s, IH), 6.63-6.82 (m, 3H), 7.18-7.30 (m, 2H)

Example 39

4-fBenz[1,31dioxol-4-yl)-4-methyl-1-(2-methyl-1,8-na.ftyridin-5-ylamino)-2-(trifluoromethylVpentan-2-ol

Analogous to the example, 1-Amino-4-(benz[1,3]dioxol-4-yl)-4-methyl-2-(trifluoromethyl)propan-2-ol reacts with 5-Chloro-2-methyl-1,8-naphthyridine to give the desired product.

NMR (CDCl 3 ) □ (ppm) = 1.49 (s, 3H), 1.57 (s, 3H), 2.41 (d, IH), 2.49 (d, IH), 2.74 (s, 3H), 3.32 (d, IH), 3.50 (d, IH), 5.89 (s, IH), 5.93 (s, IH), 6.06 (d, IH), 6.76-6.92 (m, 3H), 7.23 (d, IH), 8.05 (d, IH), 8.61 (d,

IH).

Example 40

4-( 2, 3 - DihydrobenzofuranylV 4- methyl- 1 -( 1 //- indazol-4- ylamino)- 2-( trifluoromethyl)- pentan- 2-ol

4-( 2, S- Dihydrobenzofuranyl)- 2- hydroxy- 4- m

By analogy with the described synthesis method for 4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanol (Example 32), starting from 513 mg of 4-(2,3-dihydrobenzofuranyl)-4-methyl-2-oxo-pentanoic acid (WO 00/32584) 142 mg is obtained 4-(2,3-dihydrobenzofuranyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol as fraction 2 and 84 mg of the title compound as fraction 1, as a colorless oil.

Fraction 1: 1H-NMR (CDCl 3 ), □ (ppm) = 1.39 (s, 3H), 1.45 (s, 3H), 2.18 (d, 1H), 3.19 (t, 2H), 3.34 (d, IH), 3.62 (bs, IH), 4.51 -4.63 (m, 2H), 6.8 (t, IH), 6.91 (d ,1H), 7.11 (d, IH), 8.96 (s, IH)

Fraction 2: 1H-NMR (CDCl 3 ), □ (ppm) = 1.41 (s, 3H), 1.48 (s, 3H), 2.25 (d, IH), 2.48 (d, IH), 3.2 (t, 2H), 3.42 (bs, IH), 4.56 (t, 2H), 6.85 (t, IH), 7.06-7.15 (m, 2H).

Analogous to the preparation of Example 30, the corresponding imine is obtained from 32 mg of 4-Amino-1/-indazole and 75 mg of 4-(2,3-Dihydrobenzofuranyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further reduced with 134 mg of sodium cyanoborohydride to give 64 mg of the title compound.

1H-NMR (CDCl 3 ), □ (ppm) = 1.45 (s, 3H), 1.57 (s, 3H), 2.31 (d, IH), 2.64 (d, IH), 3.05-3.19 (m, 2H), 3.21 (d, IH), 3.39 (d, IH), 4.48-4.63 (m, 2H), 5.76 (d, IH), 6.85 (d, IH), 6.92 (t, IH), 7.05-7.23 (m, 3H), 7.85 (s,

IH)

Example 41

4-(3-Chloro-2-methoxyphenin-1-n//-indazol-4-ylamino)-4-methyl-2-(trifl

methyl)pentan-2-ol

3- Chloro-2- methoxybenzylcyanide

39.4 g (221.3 mmol) of NBS and 100 mg of benzoyl peroxide were added to 31.6 g (201.7 mmol) of 3-chloro-2-methoxytoluene in 500 ml of CCl4. It is heated for 16 hours under reflux, allowed to cool and filtered. The filtrate is freed from the solvent and dissolved in 214 ml of dimethylformamide and 142 ml of water. 20.9 g (322.1 mmol) of potassium cyanide were added to it at 0 °C and stirred for 16 hours. The reaction mixture was diluted with water and extracted several times with tert-butyl methyl ether. The organic phase is washed several times with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed in vacuo and after chromatographic purification on silica gel (hexane / ethyl acetate 20%) 29.7 g of product is obtained.

1H-NMR (CDCl 3 ): δ = 3.76 (s, 2H), 3.95 (s, 3H), 7.08 (t, 1H), 7.31 (d, 1H), 7.37 (d, 1H)

4- ( 3- Chloro- 2- methoxy- phenyl)- 4- methyl- 2- trifluoromethyl- pentane- 1, 2- diol

29.7 g (163.7 mmol) of 4-chloro-2-methoxybenzylcyanide and 46.5 g (327.4 mmol) of methyl iodide in 260 ml of DMF were mixed portionwise at 0 °C with 13.2 g (327.4 mmol) of sodium hydride (60% mg in oil). It is stirred overnight and then mixed with water and ethyl acetate. The phases are separated and the aqueous phase is extracted several times with ethyl acetate. It is washed several times with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 2.4 g of 2-(chloro-2-methoxy-phenyl)-2-methylpropionitrile is obtained as a colorless oil. 7 g (33.4 mmol) of nitrile was mixed slowly in toluene at -78 °C with 41.6 ml (50.1 mmol) of diisobutylaluminum hydride solution (20% in toluene) and after 3 h at -78 °C 5.55 ml of isopropanol was added dropwise. Allow it to warm to -5<C>C and add 380 ml of 10% tartaric acid solution. After dilution

with ether is mixed vigorously, the organic phase is separated, and the aqueous phase is extracted several times with ether. It is washed with salt, dried with sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 7.1 g of 2-(4-chloro-methoxy-phenyl)-2-methylpropanal is obtained as a colorless oil. A solution of 8.95 g (33.4 mmol) of 2-diethylphosphono-2-ethoxyacetic acid ethyl ester in 30 ml of tetrahydrofuran was mixed under ice-cooling for 20 minutes with 19 ml (38 mmol) of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-hptane-toluene and stirred at 0 °C. During 30 minutes, a solution of 7.1 g (33.4 mmol) of 2-(chloro-2-methoxyphenyl)-2-methylpropanal in 27 ml of tetrahydrofuran is added dropwise at 0°C. After 20 hours at room temperature, water is added and extracted several times with ether and ethyl acetate. It is washed with saturated ammonium chloride solution, dried over sodium sulfate and evaporated. The crude product is purified by column chromatography on silica gel (hexane / ethyl acetate 10%) and 8.5 g of ethyl ester of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-3-ethoxy-2-ene-valeric acid is obtained. The intermediate product is saponified with 80 ml of 3 M sodium hydroxide / 160 ml of ethanol. 5.3 g of acid is obtained, which is mixed with 80 ml of 2 N sulfuric acid at 90°C for 16 hours. After cooling, the medium is made basic with potassium carbonate, washed with ether and acidified with hydrochloric acid. After extraction with ethyl acetate, washing with saturated sodium chloride solution and removing the solvent, 4.0 g of 4-(3-chloro-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained. 6.6 g (24.3 mmol) of 4-(3-chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid and 2.74 ml (51.4 mmol) of sulfuric acid (96% alcohol) are heated in 150 ml of ethanol for 5 hours with reflux. The contents are evaporated in vacuo, and the residue is taken up in a saturated solution of sodium hydrogencarbonate. It is extracted several times with ethyl acetate, washed with a saturated solution of sodium hydrogencarbonate, dried (sodium sulfate) and evaporated in a vacuum. After chromatographic purification on silica gel (hexane / ethyl acetate 10%), 5.9 g of ethyl ester of 4-(chloro-2-methoxy-phenyl)-4-methyl-2-oxo-valeric acid is obtained. This ester and 3.4 g (23.8 mmol) of (trifluoromethyl)-trimethylsilane in 34 ml of THF were mixed with 49 mg of tetrabutylammonium fluoride at 0°C. It is stirred for 16 h at room temperature and then the reaction mixture is poured onto water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a vacuum. 2.96 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester are obtained as a yellow oil. This oil in 24 ml of diethyl ether was mixed with 510 mg of lithium aluminum hydride at 0°C and stirred for a further 4 hours at room temperature. At 0°C, 20 ml of a saturated solution of sodium hydrogencarbonate is cautiously added to the contents and stirred vigorously for another hour. It is extracted several times with tert.-butyl methyl ether, washed with water and saturated sodium chloride solution, dried with sodium sulfate and evaporated in a vacuum. The crude product was mixed with 1.8 g (5.79 mmol) of tetrabutylammonium fluoride trihydrate in 33 ml of THF and stirred for 16 hours. It is poured onto ice water, extracted several times with tert.-butyl methyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. After purification by chromatography on silica gel (hexane / ethyl acetate 25%), 1.8 lg of 4-(3-Chloro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is obtained.

1H-NMR (CDCl 3 ), □ (ppm) = 1.47 (s, 3H), 1.56 (s, 3H), 2.21 (d, IH), 2.54 (d, IH), 2.91 (s, IH), 3.31 (dd, IH), 3.42 (d, IH), 4.01 (s, 3H), 7.00 (t, IH), 7.20-7.35 (m, 2H)

4-(3-Chloro-2-methoxyphenyl)-2-hydroethyl-4-methyl-2-trifluoro

In 1.2 g (3.7 mmol) of diol in 24 ml of dichloromethane and 6.4 ml of DMSO, 1.87 g (18.5 mmol) of triethylamine and 1.17 g (7.4 mmol) of 6.92 pyridine-SO3 complex were added in portions over 10 min. It is stirred for 5 hours and 30 ml of saturated ammonium chloride solution is added to it. The mixture is stirred for another 15 min, the phases are separated and extracted with tert-butylethyl ether. It is washed with water and dried over sodium sulfate. The solvent is removed in vacuo and after chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%) 0.98 g of product is obtained. 1 H-NMR (CDCl 3 ): δ =1.44 (s, 3H), 1.50 (s, 3H), 2.29 (d, 2H), 3.28 (d, IH), 3.55 (s, IH), 4.01 (s, 3H) 6.95 (t, IH), 7.07 (dd, IH), 7.30 (dd, IH), 8.90 (s, IH).

Analogous to example 16, the desired product is obtained from 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1H-indazol-4-ylamine. 1 H-NMR (300 MHz, CD3OD): □ = 1.49 (3H), 1.68 (3H), 2.03 (IH), 3.00 (IH), 3.25 (IH), 3.35 (IH), 3.95 (3H), 5.60 (IH), 6.73-6.83 (2H), 7.03 (IH), 7.18 (IH), 7.30 (IH), 7.95 (IH). Example 42

4-(3-Chloro-2-hydroxyphenyl)-1-('1//-indazol-4-ylamino")-4-methyl-2-('trifluoro-

methylpentan-2-ol

Analogous to example 3, the desired product is obtained from 4-(3-chloro-2-methoxyphenyl)-1-(1/-indazol-4-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol. <!>H-NMR (300 MHz, CD3OD): □ = 1.50 (3H), 1.70 (3H), 2.03 (IH), 3.00 (IH), 3.25(1H), 3.35 (1H), 5.60 (1H), 6.73-6.83 (2H), 7.03 (1H), 7.18 (1H), 7.30 (1H), 7.95 (1H).

Example 43

4-(4-Fluoro-2-methoxyphenyl)-4-methyl-1-(1//-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-( 4- Fluoro- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoro

4-( 2- Fluoro- 4- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoromethyl) pe

Both products are obtained analogously according to the method of synthesis for 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol and 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol (Example 45) from 3-fluoroanisole and ethyl ester of 2-hydroxy-4-methylene-2-(trifluoromethyl)-valeric acid and then by reaction with lithium aluminum hydride. Separation is followed by chromatography on silica gel. 1. Fraction: 1H-NMR (CDCl 3 ), □ (ppm) = 1.40 (s, 3H), 1.52 (s, 3H), 2.25 (d, IH), 2.50 (d, IH), 2.83 (bs, IH), 3.36 (d, IH), 3.46 (d, IH), 3.85 (s, 3H), 6.54-6.69 (m, 2H), 7.19-7.30 (m, IH) 2. Fraction: 1H-NMR (CDCl3), □ (ppm) = 1.41 (s, 3H), 1.53 (s, 3H), 2.17 (d, IH), 2.3 (d, IH), 2.89 (bs, IH), 3.34 (bd, IH), 3.53 (d, IH), 3.78 (s, 3H), 6.58 (dd, IH), 6.63 (dd, 1H), 7.22 (t, IH)

4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

Analogously to the synthesis of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, starting from 3 g of 4-(4-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol, 1.81 g of the title compound was obtained as a cloudy oil.

1H-NMR (CDCl3), □ (ppm) = 1.38 (s, 3H), 1.46 (s, 3H), 2.19 (d, IH), 3.37 (d, IH), 3.58 (s, IH), 3.87 (s, 3H), 6.55-6.64 (m, 2H), 7.06 (dd, IH), 8.97 (s, IH).

In analogy to the preparation of example 30, the corresponding imine is obtained from 64 mg of 4-amino-1H-indazole and 150 mg of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, which is further reduced with 141 mg of sodium cyanoborohydride to give 53 mg of the title compound.

1H-NMR (CDCl 3 ), □ (ppm) = 1.44 (s, 3H), 1.59 (s, 3H), 2.29 (d, IH), 2.70 (d, IH), 3.18 (d, IH), 3.33 (d, IH), 3.84 (s, 3H), 5.64 (d, IH), 6.65 (dd, IH), 6.71 (dt, IH), 6.88 (d, IH), 7.12 (t, IH), 7.37 (dd, IH), 7.90 (s,

IH)

Example 44

4-(4-Fluoro-2-hydroxyphenyl)-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)pentan-2-ol

Analogous to the preparation of example 3, 4 mg of the title compound was obtained from the reaction of 45 mg of 4-(4-fluoro-2-methoxyphenyl)-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 1.65 ml of boron tribromide (IM in dichloromethane).

1H-NMR (CDCl3), □ (ppm) = 1.48 (s, 3H), 1.52 (s, 3H), 2.26 (d, IH), 2.84 (d, IH), 3.25 (d, IH), 3.41 (d, IH), 4.23 (bs, IH), 5.72 (d, IH), 6.44 (dd, IH), 6.64 (dt, IH), 6.83 (d, IH), 7.12 (t, IH), 7.33 (dd, IH), 7.96 (s,

IH)

Example 45

4-(4-Chloro-2-methoxyphenyl)-4-methyl-1-(17^-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-( 4- Chloro- 2- methoteiphenyl)- 2- hydrotei- 4- methyl- 2-( trifluoro

4-( 2- Chloro- 4- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( thfluoromethyl)^

A solution of 3 g of 2-hydroxy-4-methylene-2-(trifluoromethyl)-valeric acid ethyl ester in 22 ml of 3-chloroanisole was mixed portionwise at room temperature with aluminum trichloride. It is stirred for 48 h and then mixed with 2 N sodium acid and hexane and stirred for 1 hour. Then it is washed with 2 N sodium acid and water and the excess of 3-Chloranisole is distilled off in a vacuum. The residue is purified by chromatography on silica gel (hexane / ethyl acetate 0-10%). 2.85 g of a mixture of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeric acid ethyl ester and 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)valeric acid ethyl ester are obtained as a yellow oil. This mixture of substances in 90 ml of ether was mixed at 0°C with 445 mg of lithium aluminum hydride and stirred for 12 h. The contents are placed on a heated sodium hydrogencarbonate solution, filtered through infusoria, the phases are separated, and the aqueous phase is extracted with ethyl acetate. It is washed with water and salt, dried with sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane / ethyl acetate 95:5), 1.87 mg of 4-(4-chloro-2-methoxymyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol and 160 mg of 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol were obtained as the 1st fraction. colorless oils. 1. Fraction: 1 H-NMR (CDCl3), □ (ppm) = 1.41 (s, 3H), 1.51 (s, 3H), 2.24 (d, IH), 2.51 (d, IH), 2.84 (bs, IH), 3.36 (d, IH), 3.48 (d, IH), 3.85 (s, 3H), 6.88 (d, IH), 2. Fraction: 1 H-NMR (CDCl3), □ (ppm) = 1.52 (s, 3H), 1.62 (s, 3H), 2.18 (d, IH), 2.76 (d, IH), 2.93 (bs, IH), 3.33 (d, IH), 3.55 (d, IH), 3.80 (s, 3H), 6.78 (dd, IH), 6.90 (d, 1H), 7.38 (d, 1H)

4-( 4- Chloro- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( tri^

0.425 ml of oxalyl chloride in 10 ml of dichloromethane was mixed at -78°C with 0.77 ml of DMSO in 2.0 ml of dichloromethane. After 5 min. 1.38 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol are added dropwise in 6.0 ml of dichloromethane at -78 °C. After 15 min, it is mixed with 2.9 ml of triethylamine and gently warmed to room temperature. It is washed with salt and water, dried with sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 98:2), 1.16 g of 4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is obtained as a colorless oil.

1H-NMR (CDCl3), □ (ppm) =1.38 (s, 3H), 1.44 (s, 3H), 2.21 (d, IH), 3.34 (d, IH), 3.57 (bs, IH), 3.89 (s, 3H), 6.84 (d, IH), 6.87 (d, IH), 7.04 (d, IH), 9.02 (s, IH).

Analogously to the preparation of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-1-(2-methylphthalazin-1-on-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol (Example 27), the corresponding imine is obtained from 168 mg of 4-amino-1/-indazole and 410 mg 4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and further reduction with 580 mg of sodium cyanoborohydride to 303 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) = 1.44 (s, 3H), 1.59 (s, 3H), 2.26 (d, IH), 2.70 (d, IH), 3.17 (dd, IH), 3.31 (dd, IH), 3.85 (s, 3H), 4.08 (bs, IH), 5.53 (d, IH), 6.86 (d, IH), 6.89 (d, IH), 6.99 (dd, IH), 7.14 (t, IH), 7.34 (d, IH), 7.86 (s, IH)

Example 46 and 47

(-)-4-[4-Chloro-2-methoxyphenyl)-4-methyl-1-(1/7-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and

(+)- 4-(' 4- Chloro- 2- metolsiphenin- 4- methyl- 1- n/ 7- indazol- 4- ylaminoV2-( trifluoromethyl)- pentan- 2-ol

Separation of (+/-)-4-(4-Chloro-2-methoxyphenyl)-4-methyl-1-(17-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol: The enantiomeric mixture is separated by chromatography on a chiral carrier material (CHIRALPAK AD®, Fa DAICEL) with hexane/ethanol (80 : 20, vw). That's how you get it

(-)-Enantiomer: MS (esi): IVT+1 = 442/444, [D]D-60.8° °(c = 1.0, CHCl3) and

(+)-Enantiomer: MS (esi): M<+>+1 = 442/444, [D]D+43.0° °(c = 1.0, CHCl3).

Example 48 and 49

(-)- 4-( 4- Chloro-2- hydroxyphenyl- 4- methyl- 1-( 1/- indazol-4- ylamino)- 2-( trifluoromethine- pentan- 2-ol)

Analogous to the preparation of example 3, 11 mg of the title compound is obtained from the reaction of 100 mg (-)-4-(4-Chloro-2-methoxyphenyl)-4-methyl-1-(17<:>/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 3.6 ml of boron tribromide (IM in dichloromethane).

1H-NMR (CDCl 3 ), □ (ppm) - 1.49 (s, 3H), 1.62 (s, 3H), 2.25 (d, IH), 2.82 (d, IH), 3.25 (d, IH), 3.40 (d, IH), 5.63 (d, IH), 6.72 (d, IH), 6.84 (d, IH), 6.93 (d, IH), 7.14 (t, IH), 7.31 (d, IH), 7.95 (s, IH)

(+)- 4-( 4- Chloro-2- hydroxyphenyl)- 4- methyl- 1- n//- indazol- 4- ylamino)- 2-( trifluoromethylpentan- 2-ol

Analogous to the preparation of example 3, 2.17 g of the title compound is obtained from the reaction of 5.3 g of (+)-4-(4-chloro-2-methoxyphenyl)-4-methyl-1-(1 H -indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 190 ml of boron tribromide (1M in dichloromethane).

1H-NMR (CDCl3), □ (ppm) = 1.49 (s, 3H), 1.62 (s, 3H), 2.25 (d, IH), 2.82 (d, IH), 3.25 (d, IH), 3.40 (d, IH), 5.63 (d, IH), 6.72 (d, IH), 6.84 (d, IH), 6.93 (d, IH), 7.14 (t, IH), 7.31 (d, IH), 7.95 (s, IH)

Example 50

4-(4-Chloro-2-methoxyphyll)-4-methyl-1-f2-methyquinazolin-5-ylamino)-2-(trifluoromethylVpentan-2-ol)

Analogously to the preparation of example 2, it is obtained from 395 mg of 5-amino-2-methylquinazoline and 299 mg of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-

(trifluoromethyl)pentanal is reduced to the corresponding imine with palladium on activated carbon. Reoxidation is achieved by heating the product in xylene in the presence of palladium on activated carbon and in air. 11 mg of the title compound are obtained

1H-NMR (CDCl3), □ (ppm) = 1.50 (s, 3H), 1.59 (s, 3H), 2.45 (d, IH), 2.68 (d, IH), 2.86 (s, 3H), 3.18 (dd; IH), 3.36 (dd, IH), 3.89 (s, 3H), 6.08 (d, IH), 6.92 (d, IH), 6.98 (t, IH), 7.36 (d, IH), 7.54 (d, IH), 9.11 (s, IH)

Example 51

4-(4-Chloro-2-methoxyphenyl)-1-(8-fluoro-2-methylquinazolin-5-ylamino)-4-methyl-2-(trifluoromethyl)-pentan-2-ol

1.72 g (5.30 mmol) of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 0.85 g (4.80 mmol) of 5-amino-8-fluoro-2-methyl-quinazoline are first, analogously to example 2, reacted in 64 ml of dichloroethane and 13 ml of acetic acid. 600 mg of purified intermediate product is obtained. 200 mg (0.42 mmol) of this imine was dissolved in 7 ml of THF and 60 mg (0.84 mmol) of sodium cyanoborohydride was added at 0 °C. After 1 h, add a few drops of methanol/acetic acid (1:1) as well as another 15 mg (0.21 mmol) of sodium cyanoborohydride and stir for another 2 h. The reaction is stopped by the addition of concentrated ammonium chloride solution and processed analogously to example 26. The crude product is chromatographed on silica gel (eluent hexane/ethyl acetate 20%). This product is raised in a little chloroform, mixed with manganese dioxide from the tip of a spatula and stirred for 1 hour. Manganese dioxide

filtered off, the filtrate is evaporated and chromatographed over a little silica gel with hexane/ethyl acetate 20-50%. 5 mg of the desired product is obtained

1H-NMR (CDCl3), □ (ppm) = 1.49 (s, 3H), 1.56 (s, 3H), 2.45 (d, IH), 2.68 (d, IH), 2.88 (s, 3H), 3.16 (dd, IH), 3.30 (dd, IH), 3.89 (s, 3H), 5.92 (dd, IH), 6.85 (d, IH), 6.92 (dd, IH), 7.30 (dd, IH), 7.36 (d, IH), 9.19 (s, IH); MS (Cl): 486/488 (M+H).

Example 52

4- (4-Chloro-2-methoxyphenyl)-4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluoromethyl)pentan-2-ol

Analogous to example 10, 1-Amino-4-(4-chloro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)propan-2-ol reacts with 5-Chloro-2-methyl-1,8-naphthyridine to give the desired product.<1>H-NMR (CDCl3); 8 = 1.46 (s, 3H), 1.56 (s, 3H), 2.46 (d, IH), 2.62 (d, IH), 2.70 (s, 3H), 3.22 (d, IH), 3.38 (dd, IH), 3.84 (s, 3H), 5.89 (d, IH), 6.87 (d, IH), 6.94 (dd, IH), 7.14 (d, IH), 7.27 (d, IH), 7.82 (d, IH), 8.58 (s, IH).

Example 53

4-(4-Chloro-2-hydroxyphenyl)-4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to example 3, 4-(4-Chloro-2-methoxyphenyl)-4-methyl-1-(2-methyl-1,8-naphthyridin-5-ylamino)-2-(trifluoromethyl)pentan-2-ol is converted into the desired product

1H-NMR (CD 3 OD); 5 = 1.47 (s, 3H), 1.66 (s, 3H), 2.02 (d, IH), 2.18 (d, IH), 2.72 (s, 3H), 3.14 (d, IH), 3.24 (dd, IH), 5.94 (d, IH), 6.65 (d, IH), 6.76 (dd, IH), 7.31 (d, IH), 7.40 (d, IH), 8.26 (d, IH), 8.35 (s, IH).

Example 54

4-(2-Fluoro-4-methoxyphenyl)-4-methyl-1-(li/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-( 2- Fluoro- 4- methohyphenyl)- 2- hydrochi- 4- methyl- 2-( tri/ Iorme

Analogously to the synthesis of 4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (example 45), starting from 3 g of 4-(2-Fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol (example 47), 1.73 g of the title compound was obtained as a colorless oil.

1H-NMR (CDCl3), □ (ppm) = 1.39 (s, 3H), 1.46 (s, 3H), 2.26 (d, IH), 3.09 (d, IH), 3.63 (s, IH), 3.78 (s, 3H), 6.52-6.65 (m, 2H), 7.03 (t, IH), 9.04 (s, IH)

By analogy with the preparation of example 30, the corresponding imine is obtained from 82 mg of 4-amino-1H-indazole and 192 mg of 4-(2-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and it is further reduced with 281 mg of sodium cyanoborohydride to 152 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) = 1.47 (s, 3H), 1.61 (s, 3H), 2.23 (d, IH), 2.50 (d, IH), 3.24 (dd, IH), 3.37 (dd, IH), 3.78 (s, 3H), 4.00-4.11 (m, IH), 5.70 (d, IH), 6.61 (dd, IH), 6.72 (dd, IH), 6.87 (d, IH), 7.08 (t, lH), 7.33 (t, lH), 7.90 (s, lH)

Example 55

4-(2-Fluoro-4-hydroxyphenyl)-4-methyl-1-(1//-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

In analogy to the preparation of example 3, 76 mg of the title compound is obtained from the reaction of 80 mg of 4-(2-fluoro-4-methoxyphenyl)-4-methyl-1-(1/y-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 3 ml of boron tribromide (1M in dichloromethane).

1 H-NMR (CDCl3), □ (ppm) = 1.44 (s, 3H), 1.60 (s, 3H), 2.22 (d, IH), 2.49 (d, IH), 3.28 (d, IH), 3.37 (d, IH), 5.83 (d, IH), 6.58 (dd, IH), 6.66 (dd, IH), 6.85 (d, IH), 7.16 (t, IH), 7.27 (d, IH), 7.88 (s, IH)

Example 56

4-(2-Chloro-4-methoxyphenyl)-4-methyl-1-(1H-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-( 2- Chloro- 4- methophenyl)- 2- hydroxy- 4- methyl- 2-( trifluoro

Analogous to the synthesis of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (example 45), starting from 150 mg of 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol, 101 mg of the title compound is obtained as grain oil.

1H-NMR (CDCl 3 ), □ (ppm) = 1.52 (s, 3H), 1.54 (s, 3H), 2.24 (d, IH), 3.60 (d, IH), 3.65 (s, IH), 3.79 (s, 3H), 6.72 (dd, IH), 6.88 (d, lH), 7.19 (d, IH), 9.11 (s, IH)

In analogy to the preparation of example 30, the corresponding imine is obtained from 36 mg of 4-amino-1/-indazole and 90 mg of 4-(2-chloro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and it is further reduced with 114 mg of sodium cyanoborohydride to 54 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) - 1.56 (s, IH), 1.71 (s, 3H), 2.19 (d, IH), 3.01 (d, IH), 3.28 (d, IH), 3.37 (d, IH), 3.79 (s, 3H), 5.56 (d, IH), 6.83 (dd, IH), 6.86 (d, IH), 7.06 (t, lH), 7.49 (d, lH), 7.90 (s, IH)

Example 57

4-(2-Chloro-4-hydroxyphenyl)-4-methyl-1-(1/7-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to the preparation of example 3, 11 mg of the title compound was obtained from the reaction of 27 mg of 4-(2-chloro-4-methoxyphenyl)-4-methyl-1-(1H-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 0.93 ml of boron tribromide (IM in dichloromethane).

1 H-NMR (CDCl 3 ), □ (ppm) = 1.54 (s, 3H), 1.69 (s, 3H), 2.19 (d, IH), 3.00 (d, IH), 3.25-3.46 (m, 2H), 4.01 (bs, IH), 5.75 (d, IH), 6.77 (dd, IH), 6.82 (d, IH), 6.92 (d, IH), 7.11 (t, IH), 7.41 (d, IH), 7.86 (s, IH) Example 58

4-(4-Bromo-2-methoxyphenyl)-4-methyl-1-(l/f-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-(4-Bromo-2-methoxyphenyl)-4-methyl-2-(trifluoro

2.55 g (6.17 mmol) of 4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanoic acid ethyl ester (synthesized in two steps starting from 4-(4-Bromo-2-methoxyphenyl)-2-oxopentanoic acid (WO 98/54159) was dissolved in 102 ml of diethyl ether, stirred at 0 to -5°C in portions with 351.3 mg (9.256 mmol) of lithium aluminum hydride and stirred for three and a half hours at room temperature. The reaction mixture was mixed dropwise with saturated sodium hydrogencarbonate solution for 15 minutes at room temperature. The precipitate was filtered off and the filtrate was evaporated on a rotary evaporator chromatographed on silica gel (eluent ethyl acetate/hexane). In addition to 308 mg of aldehyde (see next step), 2.025 g (88.4%) of diol is obtained.

4-( 4- Bromo- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoro

2.03 g (5.442 mmol) of 4-(4-Bromo-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentane-1,2-diol is oxidized to the aldehyde according to Swem as described in Example 49. 1.839 g (91.4%) of the desired product was isolated.

1H-NMR (300 MHz, CDCl 3 ): □ = 1.39 (3H), 1.45 (3H), 2.23 (IH), 3.35 (IH), 3.58 (IH), 3.90 (3H), 6.93-7.09 (3H) 9.03 (IH).

Analogous to the preparation of example 30, the corresponding imine is obtained from 181 mg of 4-Amino-1/-indazole and 500 mg of 4-(4-Bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, then reduced with 334 mg of sodium cyanoborohydride to give 190 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) = 1.44 (s, 3H), 1.59 (s, 3H), 2.24 (d, IH), 2.71 (d, IH), 3.17 (dd, IH), 3.31 (dd, IH), 3.87 (s, 3H), 4.01-4.10 (m, IH), 5.52 (d, IH), 6.68 (d, IH), 7.05 (d, IH), 7.15 (dd, IH), 7.15 (t, IH), 7.27 (d, IH), 7.88 (s, IH)

Example 59

4-(4-Bromo-2-hydroxyphenyl)-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

In analogy to the preparation of example 3, 14 mg of the title compound is obtained from the reaction of 90 mg of 4-(4-Bromo-2-methoxyphenyl)-4-methyl-1-(1H-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 3.8 ml of boron tribromide (IM in dichloromethane).

1 H-NMR (CDCl3), □ (ppm) = 1.48 (s, 3H), 1.60 (s, 3H), 2.22 (d, IH), 2.86 (d, IH), 3.23 (d, IH), 3.39 (d, IH), 4.22 (bs, IH), 5.65 (d, IH), 6.83 (d, IH), 6.85 (d, IH), 7.04 (dd, IH), 7.15 (t, IH), 7.23 (d, IH), 7.95 (s,lH)

Example 60

4-(5-Chloro-2-methoxyphenyl)-1-(1^

methyl)pentan-2-ol

4-( 5- Chloro- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoro

2 g (6.12 mmol) of 4-(5-chloro-2-methoxyphenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is oxidized with 854.6 mg (6.733 mmol) of oxalylchloro-

and 1.05 ml (14.812 mmol) of DMSO as described by Swern in Example 49. After processing, 1.95 g (98.4%) of the desired aldehyde is obtained, which is used crudely in the next step.

1H-NMR (300 MHz, CDCl 3 ): □ = 1.39 (3H), 1.49 (3H), 2.27 (IH), 3.32 (IH), 3.59 (IH), 3.88 (3H), 6.78 (IH), 7.10 (IH), 7.20 (IH), 9.09 (IH).

Analogous to example 16, the desired product is obtained from 4-(5-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1H-indazol-4-ylamine.

1H-NMR (300 MHz, CDCl 3 ): □ = 1.45 (3H), 1.60 (3H), 2.25 (IH), 2.78 (IH), 3.13 (IH), 3.35 (IH), 3.83 (3H), 5.60 (IH), 6.82 (IH), 6.87 (2H), 7.15 (IH), 7.25 (IH), 7.40 (IH), 7.86 (1 H).

Example 61

4-( 6- Fluoro- 2- methoxyoxyphenine- 4- methyl- l-( 7- fluoro- 2- methylquinazoline- 5-

ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to example 25, 4-(6-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal with 5-Amino-7-fluoro-2-methylquinazoline is converted into the desired product.

1H-NMR (CDCl 3 ); 5 = 1.59 (d, 3H), 1.69 (d, 3H), 2.35 (d, IH), 2.65 (d, IH), 2.80 (s, 3H), 3.21 (dd, IH), 3.41 (dd, IH), 3.86 (s, 3H), 5.02 (br, IH), 5.89 (dd, IH), 6.62 (dd, IH), 6.67 (d, IH), 6.83 (dd, IH), 7.14 (ddd, IH), 8.98 (s, IH).

Example 62

4-(6-Fluoro-2-hydroxyoxyphenyl)-1-(7-fluoro-2-methylquinazolin-5-ylamino)-4

methyl-2-(trifluoromethyl)pentan-2-ol

Analogous to example 3, 4-(6-Fluoro-2-methoxyphenyl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol is converted into the desired product.

1 H-NMR (CDCl 3 ); 5 = 1.64 (d, 3H), 1.73 (d, 3H), 2.40 (d, IH), 2.73 (d, IH), 2.78 (s, 3H), 3.32 (dd, IH), 3.49 (dd, IH), 3.84 (s, IH), 5.13 (br, IH), 5.98 (dd, IH), 6.48 (d, IH), 6.54 (dd, IH), 6.80 (dd, IH), 6.93 (ddd, IH), 8.97 (s,lH).

Example 63

4-(6-Fluoro-2-methoxyphenyl)-4-methyl-1-(8-fluoro-2-methylquinazoline-5-

ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to example 25, 4-(6-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-Amino-8-fluoro-2-methylquinazoline into the desired product.

1H-NMR (CDCl 3 ); 5 = 1.58 (d, 3H), 1.68 (d, 3H), 2.35 (d, IH), 2.69 (d, IH), 2.90 (s, 3H), 3.04 (s, IH), 3.23 (dd, IH), 3.40 (dd, IH), 3.85 (s, 3H), 4.56 (br, IH), 6.05 (dd, IH), 6.58-6.68 (m, 2H), 7.14 (ddd, IH), 7.30 (dd, IH), 9.17 (s, IH).

Example 64

4-( 6- Fluoro- 2- hydroxyphenyl)- 4- methyl- l-( 8- fluoro- 2- methylquinazoline- 5-

ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to example 3, 4-(6-Fluoro-2-methoxyphenyl)-4-methyl-1-(8-fluoro-2-methylquinazolin-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol is converted into the desired product.

1H-NMR (CDCl 3 ); 5 = 1.62 (d, 3H), 1.74 (d, 3H), 2.26 (d, IH), 2.85 (d, IH), 2.63 (s, HH), 2.89 (s, 3H), 3.32 (dd, IH), 3.44 (dd, IH), 4.64 (br, IH), 6.10 (dd, IH), 6.46-6.58 (m, 2H), 6.93 (ddd, 1H), 7.31 (dd, 1H), 9.22 (s, 1H).

Example 65

4-( 3, 5- Difluoro- 2- methoxyphenin- 4- methyl- 1-( 1//- ndazol-4- iamino)- 2-( trifluoromethyl)- pentan- 2-ol

4-(3,5-Difluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-

pentanal

In analogy with the described method of synthesis of 4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, 90 mg of the title compound is obtained as a colorless oil.

<*>H-NMR (CDCl3), □ (ppm) = 1.39 (s, 3H), 1.45 (s, 3H), 2.33 (d, IH), 3.18 (d, IH), 3.59 (s, IH), 3.98 (d, 3H), 6.15 (dm, IH), 6.72 -6.82(m, IH), 9.24 (s, IH)

In analogy to the preparation of example 30, the corresponding imine is obtained from 35 mg of 4-Amino-1/-indazole and 85 mg of 4-(3,5-Difluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and is further reduced with 99 mg of sodium cyanoborohydride to give 43 mg of the title compound.

1H-NMR (CDCl3), D (ppm) = 1.45 (s, IH), 159 (s, 3H), 2.26 (d, IH), 2.71 (d, IH), 3.22 (d, IH), 3.34 (d, IH), 4.0<1>(d, 3H), 5.81 (d, IH), 6.78 (ddd, IH), 6.88 (d, IH), 6.93 (ddd, IH), 7.15 (t,lH), 7.90 (s, IH)

Example 66

4-(3,5-Difluoro-2-hydroxyphenin-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

In analogy to the preparation of example 3, 14 mg of the title compound was obtained from the reaction of 37 mg of 4-(3,5-Difluoro-2-methoxyphenyl)-4-methyl-1-(1H-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 1.3 ml of boron tribromide (IM in dichloromethane).

1H-NMR (CDCl3), □ (ppm) = 1.50 (s, 3H), 1.62 (s, 3H), 2.30 (d, IH), 2.81 (d, IH), 3.27 (d, IH), 3.39 (d, IH), 5.73 (d, IH), 6.78 (dt, IH), 6.87 (d, IH), 6.94 (dt, IH), 7.12 (t, IH), 7.89 (s, IH)

Example 67

4-(2,3-Dihydrobenzomranyl)-4-methyl-1-O/7-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

Analogous to the preparation of example 30, the corresponding imine is obtained from 32 mg of 4-Amino-1//-indazole and 75 mg of 4-(2,3-Dihydrobenzofuranyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and is further reduced with 134 mg of sodium cyanoborohydride to 64 mg of the title compound.

1H-NMR (CDCl 3 ), □ (ppm) = 1.45 (s, 3H), 1.57 (s, 3H), 2.31 (d, IH), 2.64 (d, IH), 3.05-3.19 (m, 2H), 3.21 (d, IH), 3.39 (d, IH), 4.48-4.63 (m, 2H), 5.76 (d, IH), 6.85 (d, IH), 6.92 (t, IH), 7.05-7.23 (m, 3H), 7.85 (s,

IH)

Example 68

4-(4,5-Difluoro-2-methoxyphenyl-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-( 4, 5- Difluoro- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoromethyl) pentanal

In analogy with the described method of synthesis of 4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, 695 mg of the compound is obtained from a colorless oil.

1H-NMR (CDCl3), □ (ppm) = 1.38 (s, 3H), 1.44 (s, 3H), 2.23 (d, IH), 3.29 (d, IH), 3.56 (s, IH), 3.83 (s, 3H), 6.76 (dd, IH), 6.96 (dd, lH), 9.08 (s, IH)

In analogy to the preparation of example 30, the corresponding imine is obtained from 82 mg of 4-Amino-1/-indazole and 200 mg of 4-(4,5-Difluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and is further reduced with 319 mg of sodium cyanoborohydride to 155 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) = 1.44 (s, 3H), 1.58 (s, 3H), 2.24 (d, IH), 2.71 (d, IH), 3.19 (d, IH), 3.32 (bd, IH), 3.82 (s, 3H), 5.63 (d, IH), 6.70 (dd, IH), 6.87 (d, IH), 7.13 (t, IH), 7.24 (dd, IH), 7.87 (s, IH).

Example 69

4-('4-Chloro-5-fluoro-2-methoxyphenyl)-4-methyl-1-(1//-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

4-( 4- Chloro- 5- fluoro- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoromethyl) pentanal

In analogy with the described method of synthesis of 4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanol, 1.55 g of 4-(4-Chloro-5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal are obtained as fraction 1 and 1.32 g 4-(4-Chloro-5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanol as fraction 2.

Fraction 1:'H-NMR (CDCl 3 ), □ (ppm) = 1.36 (s, 3H), 1.43 (s, 3H), 2.28 (d, IH), 3.27 (d, IH), 3.57 (s, IH), 3.85 (s, 3H), 6.84 (d, IH), 6.93 (d, IH), 9.11 (s, IH).

Fraction 2:<!>H-NMR (CDCl3), D (ppm) - 1.4 (s, 3H), 1.48 (s, 3H), 2.23 (d, IH), 2.47 (d, IH), 2.91 (s, IH), 3.35 (dd, IH), 3.5 dd, IH), 3.83 (s, 3H), 6.87 (d, IH), 7.1 (d, IH)

In analogy to the preparation of example 30, the corresponding imine is obtained from 72 mg of 4-Amino-1/7-indazole and 200 mg of 4-(4,5-Difluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and is further reduced with 280 mg of sodium cyanoborohydride to 116 mg of the title compound. 1 H-NMR (CDCl 3 ), □ (ppm) = 1.43 (s, 3H), 1.58 (s, 3H), 2.23 (d, IH), 2.71 (d, IH), 3.19 (d, IH), 3.31 (bd, IH), 3.83 (s, 3H), 5.55 (d, IH), 6.85 (s, IH), 6.87 (d, IH), 7.14 (t, 1H), 7.21 (d, IH), 7.88 (s, IH). Example 70

4- (4-Chloro-5-fluoro-2-hydroxyphenyl)-4-methyl-1-(1//-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

By analogy with the preparation of example 3, 30 mg of the title compound is obtained from the reaction of 100 mg of 4-(4-Chloro-5-fluoro-2-methoxyphenyl)-4-methyl-1-(17;/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 3.3 ml of boron tribromide (IM in dichloromethane). T.Klj. = 171 - 173°C

Example 71

4-(4-Chloro-5-fluoro-2-methoxyoxyphenyl)-4-methyl-1-f8-fluoro-2-methylquinazolin-5-ylaminoV2-(trifluoromethyl)-pentan-2-ol

Analogous to example 25, 4-(4-chloro-5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-amino-8-fluoro-2-methylquinazoline into the desired product. 1 H-NMR (CDCl3); 5 = 1.45 (s, 3H), 1.56 (s, 3H), 2.30 (d, IH), 2.73 (d, IH), 2.90 (s, 3H), 2.99 (s, IH), 3.14 (dd, IH), 3.22 (dd, IH), 3.83 (s, 3H), 4.48 (br, IH), 5.88 (dd, 1H), 6.79 (d, 1H), 7.17 (d, 1H), 7.31 (dd, 1H), 9.20 (s, 1H).

Example 72

4- Methyl- 1 -( 2- methylquinazolin- 5- ylamino)- 4- phenyl- 2- rtrifluoromethyl)- pentan- 2-ol

2- Hydroxy- 4- methyl- 4- phenyl- 2- trifluoromethyl- pentanal

10.4 g of 4-Methyl-2-oxo-4-phenylpentanoic acid (W098/54159) in 250 ml of dimethylformamide was mixed at -5°C with 4.1 ml of thionyl chloride and after 15 min with 4 ml of methanol. After 15 h at room temperature, the contents are diluted with water and extracted with ethyl acetate. The organic extracts are washed with water, dried over sodium sulfate and evaporated, whereby 9.3 g of 4-Methyl-2-oxo-4-phenylpentanoic acid methyl ester is obtained. This was mixed in 558 ml of DMF at -5°C with 15.5 ml (104.63 mmol) of (trifluoromethyl)-trimethylsilane and 20.5 g (63.28 mmol) of cesium carbonate and stirred for 16 h at room temperature. Water is added to this, extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. The evaporated intermediate product is taken up in 200 ml of THF and then 50 ml of one 1 is added

M solution of tetrabutylammonium fluoride in THF. It is stirred for two hours, water is added to it, it is extracted with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. After chromatography on silica gel with hexane-ethyl acetate (0-30%), 8.35 g of 2-Hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanoic acid methyl ester were obtained. The ester (8.3 g, 28.59 mmol) was dissolved in 180 ml of THF, and 1.52 g (36.20 mmol) of lithium aluminum hydride was added in small portions over 2.5 hours. After the complete reaction, 5 ml of ethyl acetate is added dropwise, and after another 10 minutes, 10 ml of water is cautiously added. It is filtered from the formed precipitate and carefully washed with ethyl acetate. After chromatography on silica gel with hexane-ethyl acetate (0-35%), 5.40 g of 4-Methyl-4-phenyl-2-(trifluoromethyl)pentane-1,2-diol is obtained. 5.7 ml (40.3 mmol) of triethylamine was added to 2.5 g (9.53 mmol) of diol in 75 ml of dichloromethane and 28 ml of DMSO, and 5 g of the pyridine-SO3-complex was added in portions over 20 min. It is stirred for two hours and then 40 ml of saturated ammonium chloride solution is added. The mixture is stirred for another 15 min, the phases are separated and extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed in vacuo to give 3 g of product.

1H-NMR (CDCl 3 ): δ = 1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3.64 (s, 1H), 7.03-7.41 (m, 4H), 8.90 (s, 1H).

Analogous to example 25, 2-Hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-pentanal is converted with 5-Amino-2-methylquinazoline into the desired product.

1H-NMR (CDCl 3 ); 5 = 1.46 (s, 3H), 1.59 (s, 3H), 2.30 (d, IH), 2.37 (d, IH), 2.84 (s, 3H), 3.10 (dd, IH), 3.27 (dd, IH), 4.70 (br, IH), 6.12 (d, ? IH), 7.26 (d, IH), 7.28 (t, 1H), 7.39 (t, 2H), 7.48 (d, 2H), 7.58 (t, 1H), 9.22 (s, 1H).

Example 73

4-(2,5-Difluorophenyl)-4-methyl-1-(2-methyl-benzothiazol-7-ylamino)-2-(trifluoromethyl)-pentan-2-ol

110 mg (0.66 mmol) of 2-Methyl-benzothiazol-7-ylamine in 1 ml of acetic acid is mixed with 150 mg (0.53 mmol) of 4-(2,5-Difluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal, dissolved in 10 ml of dichloroethane, refluxed for 4 h over a molecular sieve (4 A) and stirred for another 16 h at room temperature. temperature. The mixture is divided between water and dichloromethane, extracted with dichloromethane, and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. After chromatography on silica gel with hexane/ethyl acetate (20%), the obtained intermediate product (97 mg) was taken up in acetic acid, mixed with 10 mg of NaBH4, and the mixture was stirred for 4 h at room temperature. It is divided between water and dichloromethane, extracted, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 90 mg of product is obtained, which can be crystallized from hexane/diethyl ether.

MS (Cl): 445 (M+H); <J>H-NMR (CDCl 3 ): δ = 1.61 (s, br, 6H), 2.26 (d, IH), 2.50 (d, IH), 2.83 (s, 3H), 3.15 (s, IH), 3.27 (d, br, 2H), 3.49 (m, IH), 6.02 (d, IH), 6.82-7.02 (m, 2H), 7.10-7.25 (m, 2H), 7.45 (dd, IH).

Example 74

4-(2-Chlorophenyl)-4-methyl-1-(2-methyl-benzothiazol-7-ylamino)-2-(trifluoromethine-pentan-2-ol)

In analogy with example 5, the desired product is obtained from 7-Amino-2-methylbenzothiazole (Libeer et al. BullSoc . Chim . BeI« . ; 1971; 80; 43-47) and 4-(2-Chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal.

1H-NMR (300 MHz, CDCl 3 ): □ = 1.60 (3H), 1.73 (3H), 2.20 (IH), 2.80 (3H), 3.09 (IH), 3.18 (IH), 3.23 (4H), 5.78 (IH), 7.13 (IH), 7.20-7.35 (2H), 7.37-7.45 (2H), 7.60 (1H).

Example 75

4-(2-Methoxyphenyl)-4-methyl-1-(1/-indazol-4-ylamino)-2-trifluoromethyl)-pentan-2-ol

4-(2-Methoxyphene)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

In analogy with the described method of synthesis of 4-(Benz[1,3]dioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (Example 32), starting from 28.6 g of 4-(2-Methoxyphenyl)-4-methyl-2-oxo-pentanoic acid ethyl ester (WO 98/54159), 7.9 mg of the title compound is obtained as a colorless oil.

1H-NMR (CDCl3), □ (ppm) = 1.40 (s, 3H), 1.47 (s, 3H), 2.2 (d, IH), 3.46 (d, IH), 3.60 (s, IH), 3.88 (s, 3H), 6.83 - 6.94 (m, 2H), 7.13 (dd, IH), 7.24 (dt, IH), 8.94 (s, IH).

By analogy with the preparation of example 30, the corresponding imine is obtained from 139 mg of 4-Amino-1/-indazole and 300 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and is further reduced with 627 mg of sodium cyanoborohydride to 310 mg of the title compound.

1H-NMR (CDCl 3 ), □ (ppm) = 1.48 (s, 3H), 1.60 (s, 3H), 2.33 (d, IH), 2.77 (d, IH), 3.17 (dd, IH), 3.36 (dd, IH), 3.88 (s, 3H), 3.98-4.08 (m, IH), 5.66 (d, IH), 6.83 (d, IH), 6.94 (dd, IH), 7.04 (dt, IH), 7.09 (t, IH), 7.32 (dt, IH), 7.43 (dd, IH), 7.86 (s, IH)

Example76

4-(2-Hydroxyphenyl)-4-methyl-1-(1//-indazol-4-ylamino)-2-(trifluoromethine-

pentan-2-ol

By analogy with the preparation of example 3, 15 mg of the title compound is obtained from the reaction of 20 mg of 4-(2-Methoxyphenyl)-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and 0.75 ml of boron tribromide (IM in dichloromethane).

1H-NMR (CDCl3), □ (ppm) = 1.52 (s, 3H), 1.62 (s, 3H), 2.32 (d, IH), 2.90 (d, IH), 3.23 (d, IH), 3.43 (dd, IH), 4.22 (bs, IH), 5.75 (d, IH), 6.72 (d, IH), 6.79 (d, IH), 6.97 (t, IH), 7.04-7.16 (m, 2H), 7.39 (d, IH), 7.93

(with, IH)

Example 77 and 78

(-)- 4-(2-Hydroxyphenyl)-4-methyl-1-(li/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol and

(+)-4-(2-Hydroxyphenyl)-4-methyl-1-(1/7-indazol-4-ylamino V2-(trifluoromethyl)-pentan-2-ol

Separation of (+/-)-4-(2-Hydroxyphenyl)-4-methyl-1-(1/-indazol-4-ylamino)-2-(trifluoromethyl)-pentan-2-ol

The mixture of enantiomers is separated by chromatography on a chiral carrier material (CHIRALPAK AD®, Fa DAICEL) with hexane/ethanol (70 : 30, vvv). Enantiomer A is thus obtained: MS (ei) M<+>= 392 i

enantiomer B: MS (ei) M<+>= 392

Example 79

4- (4-Chlorophenyl)-4-methyl-1-(1/7-indazol-4-ylamino)-2-('trifluoromethine-

pentan-2-ol

2-( 4- Chlorophenyl)- 2- methylpropanal

10 g of 4-Chlorobenzylcyanide and 14.3 ml of methyl iodide in 140 ml of DMF were mixed in portions at 0°C with sodium anhydride (60% in oil). It is stirred overnight and then mixed with water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. It is thoroughly extracted with water, washed with salt, dried over sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane/ethyl acetate 95:5), 73 g of 2-(4-Chlorophenyl)-2-methylpropionitrile is obtained as a colorless oil. This is gently mixed with 55.4 ml of diisobutylaluminum hydride solution (20% in toluene) in toluene at -78°C and after 4 h at -78°C 50 ml of ethyl acetate is added dropwise. It is mixed while heating to room temperature, then water is added. After filtering through diatomaceous earth, the phases are separated, and the aqueous phase is extracted with ethyl acetate. It is washed with water and salt, dried with sodium sulfate and evaporated in a vacuum. After chromatography on silica gel (hexane / ethyl acetate 95:5) 10.2 g of 2-(4-Chlorophenyl)-2-methylpropane as a colorless oil.

1H-NMR (CDCl3), □ (ppm) = 1.46 (s, 6H), 7.20 (d, 1H), 7.29-7.43 (m, 3H), 9.48 (s, 1H)

4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid

A solution of 15.04 g of 2-Diethylphosphono-2-ethoxyacetic acid ethyl ester in 50 ml of tetrahydrofuran was mixed with ice-cooling for 20 minutes with 30 ml of a 2 M solution of lithium diisopropylamide in tetrahydrofuran-heptane-toluene and stirred for 15 minutes at 0°C. During 30 minutes, a solution of 10.2 g of 2-(4-Chlorophenyl)-2-methylpropanal in 50 ml of tetrahydrofuran at 0°C is added dropwise. After 20 hours at room temperature, 2 N sulfuric acid is added, extracted with ethyl acetate, dried over sodium sulfate and evaporated. The crude product is saponified with 200 ml of 2 M sodium hydroxide / 400 ml of ethanol. 13.8 g of acid is obtained, which is heated for 3 hours with 300 ml of 2 N sulfuric acid and 100 ml of glacial acetic acid with vigorous stirring under reflux. After extraction with ethyl acetate and washing with water, 10.9 g of 4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid is obtained as a red oil.

1H-NMR (CDCl3), □ (ppm) = 1.47 (s, 6H), 3.28 (s, 2H), 7.28 (m, 4H), 7.73 (bs, 1H)

4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentan-1-al

By analogy with the synthesis of 4-(3-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal (Example 45), it is obtained by esterifying 10.9 g of 4-(4-Chlorophenyl)-4-methyl-2-oxo-valeric acid in ethanol/sulfuric acid, then by reacting the product with (Trifluoromethyl)trimethylsilane and tetrabutylammonium fluoride and reducing the product hydroxyester with lithium aluminum hydride, 4.22 g of 4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol as a colorless oil.

1H-NMR (CDCl3), □ (ppm) = 1.39 (s, 3H), 1.49 (s, 3H), 2.07 (d, IH), 2.19 (d, IH), 2.83 (bs, IH), 3.27 (d, IH), 3.41 (d, IH), 7.26-7.38 (m, 4H). To 2 g (6.7 mmol) of diol in 50 ml of dichloromethane and 22 ml of DMSO, add 6.8 ml (33.3 mmol) of triethylamine and 1.5 g of pyridine-SO3 complex in portions over 20 min. It is stirred for 5 hours, then 40 ml of saturated ammonium chloride solution is added to it. The mixture is stirred for another 15 min, the phases are separated, and then extracted with dichloromethane. It is washed with water and dried over sodium sulfate. The solvent is removed under vacuum, and after chromatography on silica gel (hexane / ethyl acetate 0-30%), 1.27 g of the product is obtained.

1H-NMR (CDCl 3 ): δ = 1.34 (s, 3H), 1.44 (s, 3H), 2.34 (d, 2H), 2.66 (d, 1H), 3.64 (s, 1H), 7.23-7.31 (m, 4H), 8.90 (s, 1H).

Analogous to Example 30, the corresponding imine is obtained from 158 mg of 4-Amino-1/-indazole and 350 mg of 4-(4-Chlorophenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal, and then 100 mg of the imine is further reduced with 216 mg of sodium cyanoborohydride to give 68 mg of the title compound.

1H-NMR (CDCl3), □ (ppm) = 1.42 (s, 3H), 1.59 (s, 3H), 2.19 (d, IH), 2.31 (d, IH), 3.11 (d, IH), 3.22 (d, IH), 5.67 (d, IH), 6.90 (d, IH), 7.18 (t, IH), 7.35 (d, 2H), 7.42 (d, 2H), 7.89 (s, 1H).

Example 80

4-(, 4- ChlorophenylV4- methyl- 1-( 8- fluoro- 2- methylquinazolin- 5- ylamino)- 2-

(trifluoromethylVpentan-2-ol

Analogous to example 25, 4-Chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-Amino-8-fluoro-2-methylquinazoline into the desired product. 1 H-NMR (CDCl3); 5 = 1.45 (s, 3H), 1.58 (s, 3H), 2.29 (d, IH), 2.36 (d, IH), 2.79 (br, IH), 2.90 (s, 3H), 3.05 (dd, IH), 3.20 (dd, IH), 4.37 (br, IH), 5.98 (dd, IH), 7.29 (dd, 1H), 7.38 (t, 2H), 7.49 (d, 2H), 9.21 (s, 1H).

Example 81

4- ([ 4-( 5- Fluoro- 2- methoxyphenin- 2- hydroxy- 4- methyl- 2-( trifluoromethyl) pentyllamino|- 1. 3- dihydroindol- 2- ori

Dimethyl-2-(2,6-dinitrophenyl)-malonate

42.95 g (311.03 mmol) of dimethylmalonate was dissolved in 300 ml of N,N-Dimethylformamide and mixed in portions with 35.15 g (296.22 mmol) of potassium tert.-butylate. After the resulting tert-butanol was distilled off, the reaction mixture was cooled to 20°C. 30 g (148.11 mmol) of 2,6-dichlorobenzene was added to the mixture in portions without interruption. After three hours of mixing at 90°C, it is mixed overnight at room temperature. The reaction mixture was poured into 800 ml of 1% NaOH solution (ice-cooled) and extracted three times with methyl tert-butyl ether. The combined ether phases are discarded after thin-layer control. The aqueous phase was carefully acidified with cooling in an ice bath with conc. nitric acid (w = 65 %). It is extracted six times with methyl-tert-butyl ether, the usual treatment of the combined organic extracts (water, salt, drying of the filtrations and evaporation of the solvent on a rotary evaporator) gives a residue, which is chromatographed on silica gel (eluent ethylacetate/hexane). 12.09 g (27.09 %) of the desired product is isolated.

Methyl- (2, 6-Din itrophen yl)-acetate

10.08 g (33.8 mmol) of Dimethyl-2-(2,6-dinitrophenyl)-malonate was mixed in 54 ml of glacial acetic acid with 2.7 ml of perchloric acid and heated to 125°C under reflux. The resulting ethyl acetate is distilled off. After 90 minutes, the reaction is stopped, since there is no more starting material according to the thin layer roll. The reaction mixture was poured onto ice water and extracted three times with ethyl acetate. The combined organic extracts are mixed with a 5% solution of sodium hydrogen carbonate, with water and salt. After drying the organic phase, separating the drying agent by filtering and evaporating the solvent on a rotary evaporator, a residue remains, which is chromatographed on silica gel (eluent ethyl acetate/hexane). 4.69 g of (2,6-Dinitrophenyl)-acetic acid was isolated, which was then esterified with methanol (16 ml) and concentrated sulfuric acid (0.4 ml). Therefore, the reagents and acid are boiled for seven hours with a reflux condenser. The methanol is removed on a rotary evaporator and the residue is worked up in the usual way. After chromatography on silica gel (eluent ethylacetate/hexane), 4.43 g (89%) of the desired ester is obtained.

4- Amino-1, 3- dihydroindol-2-one

4.43 g (18.45 mmol) of Methyl-(2,6-Dinitrophenyl)-acetate was added to 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for four hours. This results in heating to 40 to 60°C. The reaction mixture was poured onto ice water, mixed with ethyl acetate and stirred gently for ten minutes. The mixture is filtered through a glass fiber filter, the organic phase is separated and the aqueous phase is extracted two more times with ethyl acetate. The combined organic extracts are washed with salt, dried, and the solvent is evaporated on a rotary evaporator after filtration of the desiccant. The residue is chromatographed on silica gel (eluent methanol/dichloromethane). 2.38 g of 4-Nitro-indol-2-one was isolated. The nitro compound is mixed again with 2.7 g of powdered iron in ice-cold acetic acid/water, and the cycle described above is performed once more. 1.63 g of the desired amine is now isolated.

Analogous to example 27, 4-(5-Fluoro-2-methoxyphenyl)-2-hydroxy-2-trifluoromethyl-pentanal is converted with 4-Amino-1,3-dihydroindol-1-one into the desired product.

1 H-NMR (CDCl3): δ = 1.44 (s, 3H), 1.58 (s, 3H), 2.23 (d, IH), 2.70 (d, IH), 3.04 (s, IH), 3.09 (d, IH), 3.19 (s, 2H), 3.21 (d, IH), 3.85 (s, 3H), 5.71 (d, IH), 6.32 (d, IH), 6.84 (dd, IH), 6.92-7.01 (m, 2H), 7.14 (dd, IH), 7.78 (s, br, IH)

Example 82

4- (\ 4 -( 5- Chloro-2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2-( trifluoromethyl)pentynamino|- 1, 3- dihydro- 6- fluoroindol- 2-one

180 mg (0.60 mmol) of 4-(4-Chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 100 mg (0.60 mmol) of 4-Amino-6-fluorindol-2-one are placed in 15 ml of dichloroethane and 3 ml of acetic acid, add ca. 100 mg of powdered molecular sieve (4 A) and the mixture is heated for 6 h with reflux. After cooling, it is filtered, the filtrate is divided between dichloromethane and a saturated solution of sodium hydrogencarbonate, and the phases are separated. The aqueous phase is extracted several times with dichloromethane, the combined organic phases are washed with water and saturated sodium chloride solution and dried with sodium sulfate. The solvents are removed and the crude product is chromatographed on silica gel: (eluent hexane/ethyl acetate 20-100%). 40 mg of imine is obtained, which is dissolved in 5 ml of methanol, mixed with a few drops of acetic acid and ca. 20 mg of sodium cyanoboride and stir for 2 h at room temperature. The mixture is stopped by the addition of a saturated solution of sodium hydrogencarbonate. It is extracted

dichloromethane, washed with saturated sodium chloride solution and dried with sodium sulfate. Chromatographic purification of the crude product (silica gel, eluent hexane/ethyl acetate 20-100%) afforded 4 mg of the desired product. MS (ESI): 475/477 (M+H); 1H-NMR (CDCl 3 ): δ = 1.46 (s, 3H), 1.57 (s, 3H), 2.29 (d, IH), 2.60 (d, IH), 2.78 (s, IH), 2.99-3.21 (m, 4H), 3.47 (t, br, IH), 3.88 (s, 3H), 5.52 (dd, IH), 6.08 (dd, IH), 6.89 (d, IH), 7.00 (dd, IH), 7.32 (dd, IH), 7.68 (s, no, IH).

Examples 83 - 92

General work regulation for obtaining N-Methylbenzimidazole-derivatives:

0.70 mmol of substituted pentanals and 1.05 mmol of the amine component (4-Methyl-l//-benzimidazol-4-ylamine, (compare for example V. Milata, D. Ilavsky, J. Saloo, Buli. Soc. Chim. Belg. 1997, 106, 731-732; 3-Methyl-3H-benzimidazol-4-ylamine, vgl. z.B. M. Kamel, M.L. Kamel, 22, 3354) is placed in 10 ml of acetic acid and after cooling, the mixture is mixed with phosphate buffer (1 M, pH 7). Aqueous phase is extracted several times with dichloromethane, the combined organic phases are washed with water saturated with sodium chloride solution and dried over sodium sulfate. The solvent is removed on a rotary evaporator and the intermediate product is purified by chromatography on silica gel (eluent hexane/ethyl acetate). The resulting imine was taken up again in a little methanol, and a few drops of acetic acid and NaCNBH3 (2-3 equivalents) were added to it. The solution was stirred for 3 h at room temperature, the reaction was terminated by adding phosphate buffer solution (1 M, pH 7) and extracted with dichloromethane. The combined organic phases are washed with water and saturated sodium chloride solution and dried over sodium sulfate. The crude product is chromatographed over silica gel with hexane/ethyl acetate.

General rule of thumb for methylether splitting with methylbenzimidazole derivatives: Ca. 0.1 mmol of methyl ether is placed in ca. 3 ml of dichloromethane, then add ca. 1 ml of BBr3 solution (1 M in dichloromethane). It is mixed for 2 h at room temperature, diluted with ethyl acetate, the solution is poured into a saturated sodium bicarbonate solution, the phases are separated and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution and dried over sodium sulfate. The crude product is crystallized from diethylether/hexane. Yields of approx. 50% Example 93

4- ([ 4-( 5- Fluoro- 2- methoxyfeiiy2- hydroxy- 4- methyl- 2^

(trifluoromethinepentyl]

2-Methyl-S-nitrobenzoic acid methyl ester

30 g (165.6 mmol) of 2-Methyl-3-nitrobenzoic acid is placed in 150 ml of methanol and, after the addition of 2.9 ml of concentrated sulfuric acid, it is boiled for two days on a reflux condenser. After cooling, the crystallizate is filtered (25.55 g = 79%) and used as such in the next step.

2-(Bromomethyl)-3-nitrobenzoic acid methyl ester

25.55 g (130.9 mmol) of 2-Methyl-3-nitrobenzoic acid methyl ester was placed in 300 ml of carbon tetrachloride and mixed with 25.6 grams (141.7 mmol) of N-Bromosuccinimide and 62.8 mg of benzoyl peroxide. After seven days of cooking in a return cooler, the succiimide is filtered after cooling, and the filtrate is then evaporated to dryness on a rotary evaporator. The desired compound remains, which is used crudely in the next step.

2-(Azidomethyl)-3-nitrobenzoic acid methyl ester

10 g (36.5 mmol) of 2-(Bromomethyl)-3-nitrobenzoic acid methyl ester were mixed with 36 ml of N,N-Dimethylformamide and 24 ml of water. After adding 3.54 g of sodium azide, the contents are stirred overnight. The reaction mixture was diluted with methyl tert-butyl ether, and washed twice with water and once with brine. After drying over sodium sulfate, it is filtered and the solvent is removed on a rotary evaporator. The desired azide is obtained in a yield of 89.6% (7.72

g) and uses it further raw.

4- Amino- 2, 3- dihydro iso indol- 1- one

1 g (4.2 mmol) of 2-(Azidomethyl)-3-nitrobenzoic acid methyl ester was placed in 10 ml of ethanol and 2 ml of glacial acetic acid and mixed with 148.5 mg of Pd/C. After stirring overnight at room temperature under a hydrogen atmosphere, the catalyst was filtered off through a glass fiber filter and evaporated to dryness. The residue is chromatographed on silica gel (ethyl acetate). 391.5 mg (62.4%) of the desired compound is isolated.

Analogous to example 30, 4-(5-Fluoro-2-methyloxyphenyl)-2-hydroxy-2-trifluoromethyl-pentanal is converted with 4-Amino-2,3-dihydroisoindol-1-one into the desired product.

1H-NMR (DMSOD6):5 = 1.37 (s, 3H), 1.54 (s, 3H), 2.03 (d, IH), 2.81 (d, IH), 2.81 (d, IH), 2.90 (dd, IH), 3.02 (dd, IH), 3.33 (s, IH), 3.81 (s, 3H), 4.01-4.14 (m, 2H), 4.77 (br, IH), 5.76 (s, IH), 6.17 (d, IH), 6.88 (d, IH), 7.01-7.16 (m, 4H), 8.35 (s, IH).

Example 94

4-(5-Fluoro-2-hydroxyoxyphenyl)-1-(1//-indol-4-ylamino)-4-methyl-2-(trifluoromethylopentan-2-ol)

Analogous to example 3, 4-(5-Fluoro-2-methoxyphenyl)-4-methyl-1-(1H-indol-5-ylamino)-2-(trifluoromethyl)-pentan-2-ol is converted into the desired product.

1H-NMR (CDCl 3 ); 5 = 1.49 (s, 3H), 1.61 (s, 3H), 2.31 (d, IH), 2.75 (d, IH), 3.26 (d, IH), 3.43 (d, IH), 3.60 (s, IH), 5.67 (d, IH), 6.33 (m, IH), 6.63 (dd, IH), 6.86-6.97 (m, 3H), 7.10 (dd, IH), 7.15 (dd, IH), 8.14 (br,

IH)

Example 95

1, 1, 1 - Tritluoro-2-[(8-fluoro-2-methyl-quinazolin-5-ylamino)-methyl-4-(3-methoxyphenyl)-4- methyl-pentan-2-ol

The compound was synthesized, starting from the appropriate precursor, analogously to that described in 13. 26.9 mg (17.8%) of the desired compound was isolated in the last step.

1H-NMR (300 MHz, CD3OD): □ = 1.49 (3H), 1.69 (3H), 2.19 (IH), 2.56 (IH), 2.85 (3H), 2.93 (IH), 3.12 (IH), 3.64 (3H), 5.90 (IH), 6.58 (IH), 7.00 (IH). 7.03-7.20 (2H), 7.38(1H), 9.38(1H).

Example 96

3-( 4, 4, 4- Trifluoro- 3- r( 8- fluoro- 2- methyl- quinazolim- 5- ylamino)- methyl- 3-

hydroxy-1, 1 - dimethyl-butyl) - phenol

The compound was obtained, starting from the ether described in Example 95, by ether cleavage with BBr 3 . 6 mg 29.5%) of the desired compound was isolated in the last step.

1H-NMR (300 MHz, CD3OD): □ = 1.49 (3H), 1.65 (3H), 2.15 (IH), 2.50 (IH), 2.82 (3H), 2.95 (IH), 3.17 (IH), 6.02 (IH), 6.53 (IH), 6.90-7.13 (3H), 7.39 (IH). 9.38 (IH).

Example 97

(+)- 1, 1, 1 - Trifluoro- 2-[( 8- lfluoro- 2- methyl- quinazolin- 5- ylaminoVmethyl- 4-( 3- methoxyphenyl)- 4- methyl- pentan- 2-ol

The compound obtained according to example 95 is separated into its enantiomers on a chiral column (Chiralpak AD 20D, eluent hexane/isopropanol).

(+)-Enantiomer: Example 97;

(-)-Enantiomer: Example 98.

Example 98

(-)- 1, 1, 1 - Trifluoro- 2- r(' 8- fluoro- 2- methyl- quinazolin- 5- ylamino)- methine- 4- r3-

methoxyphenolV4-methyl-pentan-2-ol

See Example 97 for conditions for separation of racemates.

Example 99

3- ri-(3- Chloro-2- methoxyphenylVc^

methyl-quinazolin-5-ylamino)-methyl-1-propan-2-ol

The compound was synthesized, starting from the appropriate precursors, analogously to that described in the above examples. 32 mg (31.9%) of the desired compound was isolated in the last step.

<!>H-NMR (CDCl3); 5 = 1.00-2.50 (12H), 2.60-3.30 (6H), 3.79 (3H), 4.15-4.55 (IH), 5.60-5.85 (IH), 6.82 (IH), 6.95 (IH), 7.10-7.50 (2H), 9.10

(IH).

Example 100

f-)- 4-[ 4-( 4- Chloro- 2- methoxyphenyl)- 2- hydroxy- 4- methyl- 2- trifluoromethyl-

pentylaminol-1,3-dihydro-indol-2-one

The compound was synthesized, starting from the appropriate precursors, analogously to that described in the above examples. 117.1 mg (97.7 %) of the desired compound as a racemate was isolated in the last step.

1H-NMR (300 MHz, CDCl 3 ): □ = 1.44 (3H), 1.58 (3H), 2.09 (IH), 2.20 (IH), 2.65 (IH), 2.95-3.27 (3H), 3.88 (3H), 5.99 (IH), 6.34 (IH), 6.85-7.08 (3H), 7.32 (1H), 7.99(1H).

The separation of the racemates was then carried out. After chromatography on a chiral column (Chiralpak AD 20 □, eluent hexane/ethanol) both enantiomers were obtained. (-)-Enantiomer: Beispiel 100;

(+)-Enantiomer: Beispiel 101.

Example 101

(+ V4- r4-( 4- Chloro- 2- methoxyphenylV2- hydroxy- 4- methyl- 2- trifluoromethyl-

pentylamino]-1,3-dihydro-indol-2-one

See Example 101 for conditions for separation of racemates.

Example 102

C- V4-(' 4-(' 4- Chloro- 2- hydroxyphenylV2- hydroxy- 4- methyl- 2- trifluoromethyl-

pentylaminol-1.3-dihydro-indol-2-one

The compound was synthesized by ether cleavage in Example 100 of the described compound.

1H-NMR (300 MHz, CD3OD): □ = 1.32 (3H), 1.49 (3H), 2.43 (IH), 2.59 (IH), 3.10 (IH), 3.21-3.40 (3H), 5.87 (IH), 6.24 (IH), 6.58 (IH), 6.69 (IH), 6.95 (IH). 7.18 (IH).

Example 103

(+)- 444-( 4- Chloro- 2- hydroxyphenine- 2- hydroxy- 4- methyl- 2- trifluoro^

pentylamino]-1, 3-dihydro-indol-2-one

The compound was synthesized by ether cleavage in Example 101 of the described compound. For<!>NMR data see Example 102.

Example 104

6- Fluoro- 4-|" 4-( 2- fluoro- 6- methoxyphenyl)- 2- hydroxy- 4- methyl- 2- trifluoromethyl-

pentylamino~ l- 2, 3- dihydro-isoindol-l- one

The compound was synthesized, starting from the appropriate precursors, analogously to that described in the above examples. In the last step, 62.5 mg (77.8%) of the desired compound was isolated.

1H-NMR (300 MHz, CD3OD): □ = 1.53 (3H), 1.79 (3H), 1.98 (IH), 2.95-3.12 (2H), 3.25 (IH), 3.90 (3H), 4.09-4.28 (2H), 6.00 (IH), 6.62 (IH), 6.71 (IH), 6.83 (1H), 7.19 (1H).

Example 105

6- Fluoro- 4-[ 4-( 2- fluoro- 6- hydroxyphenyl- 2- hydroxy^

pentylamino]- 2. 3- dihydro-isoindol-l-one

The compound was obtained by ether cleavage of the compound described in the previous example with BJ3r3. 37.5 mg (69.7%) of the desired compound was isolated.

1H-NMR (300 MHz, CD3OD): □ = 1.54 (3H), 1.82 (3H), 1.89 (IH), 3.05 (IH), 3.20-3.40 (2H), 4.10-4.28 (2H), 6.05 (IH), 6.47 (IH), 6.58 (IH), 6.70 (IH), 6.98 (IH).

Example 106

1,1,1-Trifluoro-4-(2-fluoro-6-methoxyphenyl)-2-[(1/Y-indazol-4-ylamino)-methyl]-4-methyl-pentan-2-ol

The compound was synthesized, starting from the appropriate precursors, analogously to that described in the above examples. In the last step, 51.2 mg (72.8%) of the desired compound was isolated.

1H-NMR (300 MHz, CD30D): □ = 1.54 (3H), 1.80 (3H), 2.03 (1H), 3.00-3.19

(2H), 3.35 (1H), 3.85 (3H), 5.65 (1H), 6.63 (1H), 6.70-6.84 (2H), 7.08 (1H), 7.18

(1H), 7.93(1H).

Example107

1, 1, 1 - Trifluoro-4-(2-fluoro-6-hydroxyphenyl)-2-r(1H-indazol-4-ylamino)-methyl-4-methyl-pentan-2-ol

The compound was obtained by ether cleavage of the compound described in Example 106 with BBr3. 20.8 mg (54.2%) of the desired compound was isolated.

1H-NMR (300 MHz, CD3OD): □ = 1.57 (3H), 1.80 (3H), 1.92 (1H), 3.15 (1H), 3.20-3.50 (2H), 5.70 (1H), 6.40-6.60 (2H), 6.75 (IH), 6.88-7.10 (2H), 7.90 (1H).

Claims (13)

1. Compounds of general formula I in which they mean A stands for one aryl-, one benzyl- or phenethyl group, whereby aryl-, benzyl- or phenethyl groups in a given case can be substituted by one or more residues from the group Ci-C5-alkyl, Ci-C5- alkoxy, Ci-C5-alkylthio, CrC5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -0-(CH2)n-0-, -0-(CH2n-O-CH2-,-0-CH=CH-,-(CH2)n+2-, wherein 1 or 2 and the last standing oxygen atoms and/or carbon atoms are connected to directly adjacent carbon atoms from the ring, or NR4R5 wherein R<4> and R<5> can independently be hydrogen, CrC5-Alkyl, or (CO)-CrC5-Alkyl 12 • R and R are mutual independently hydrogen, one methyl- or ethyl- group or together with the carbon atom of the chain one C3-C6-cycloalkyl ring, R one in a given case independently of each other, once or multiple groups selected from halogen, hydroxy or CrC3-alkyl, a substituted CpC8-alkyl group, or some optionally partially or fully fluorinated Ci-C3-alkyl group, one optionally substituted group selected from C2-C6-alkenyl, C2-C6-Alkynyl, C3-C8-cycloalkyl, C3-C7-heterocyclyl, aryl, heteroaryl, (C 1 -C 8 -alkyl)C 3 -C 8 -cycloalkyl, (C 1 -C 8 -alkyl)aryl, or (C 1 -C 8 -alkyl)heteroaryl, B for one in a given case by a methyl or ethyl group a substituted methylene group or one carbonyl group and Q means some, attached via an arbitrary position, quinazolinyl-, quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, benzothiazolyl-, dihydroindolonyl-, dihydropoisoindolonyl-, benzimidazole- or indolyl group, which may in a given case be substituted with one or more residues from the group Ci-C5-alkyl, Ci-C5- alkoxy, Ci-C5-alkylthio, CrC5-perfluoro-alkyl, halogen, hydroxy, cyano, nitro or NR<4>R<5>, wherein R<4> and R<5> can independently be hydrogen, Cr C5-alkyl, or (CO)-CrC5-alkyl, whereby phthalazinones are exempted, as well as their racemates or separately existing stereoisomers, and in a given case their physiologically tolerable salts. 2. Compounds of general formula I according to claim 1 in which A stands for one aryl-, one benzyl- or one phenethyl group where aryl-, benzyl- or benethyl-groups can in a given case be substituted by one or more residues from the group Ci-Cs-alkyl, CrC5-Alkoxy, CrC5-alkylthio, CrC5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -0-(CH2)n-0-, -0-(CH2)n-0-CH2-, -0-CH=CH-, -(CH2)n+2-, at where n = 1 or 2 and the last standing oxygen atoms and/or carbon atoms are connected to directly adjacent carbon atoms from the ring, or NR4R5 wherein R<4> and R<5> can independently be hydrogen, C1-C5-alkyl, or (CO)-C1-C5-alkyl, R<1>i R<2> are independently hydrogen, one methyl- or ethyl- group or together with the carbon atom of the chain one C3-C6-cycloalkyl-ring, R<3>one, in the given case mutually independent once or more groups selected from halogen, hydroxy or Cr C3-alkoxy substituted C1-C8-alkyl group or one in a given case partially or fully fluorinated C1-C3-alkyl group, B for one in a given case by a methyl or ethyl group a substituted methylene group or one carbonyl group and Q means a quinazolinyl-, attached via an arbitrary position quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, benzothiazolyl-, dihydroindolonyl-, dihydropoisoindolonyl-, benzimidazole- or indolyl-group, which may in a given case be substituted with one or more residues from the group Ci-C5-alkyl, C1-C5-Alkoxy, C1-C5-Alkylthio, C1-C5-perfluoro-alkyl, halogen, hydroxy, cyano, nitro or NR<4>R<5>, wherein R<4> and R<5> can independently be hydrogen, C1-C5-alkyl, or (CO)-C1-C5-alkyl, with the exception of phthalazinones, as well as their racemates or separately existing stereoisomers, and in a given case their physiologically tolerable salts. 3. Compounds of the general formula I according to claim 1, in which A stands for one aryl, one benzyl or one phenethyl group where aryl-, benzyl- or phenethyl-groups can in a given case be substituted by one or more residues from the group CrC5-alkyl, CrC5- alkoxy, CrC5-alkylthio, CrC5-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -0-(CH2)n-0-, -0-(CH2)n-0-CH2-, -0-CH=CH-, -(CH2)n+2-, at where n = 1 or 2 and the last standing oxygen atoms and/or carbon atoms are connected to directly adjacent carbon atoms from the ring, or NR<4>R<5> wherein R<4> and R<5> can independently be hydrogen, d-C5-alkyl, or (CO)-CrC5-alkyl, R and R are mutually independently hydrogen, one methyl- or ethyl- group or together with the carbon atom of the chain one C3-C6-cycloalkyl-ring, R<3>one C1-C3-alkyl group or one in a given case partially or a fully fluorinated Ci-C3-alkyl group, B for one in a given case by a methyl or ethyl group a substituted methylene group or one carbonyl group and Q means a quinazolinyl-, quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, or benzothiazolyl-, a group which may in a given case be substituted by one or more residues from the group CrC5-alkyl, CrC5- alkoxy, CrC5-Alkylthio, Ci-C5-perfluoro-alkyl, halogen, hydroxy, cyano, nitro or NR<4>R<5>, where R<4>i They can independently of each other to be hydrogen, CrC5-alkyl, or (CO)-CrC5-alkyl, with the exception of phthalazinones, as well as their racemates or separately existing stereoisomers, and in a given case their physiologically tolerable salts. 4. Compounds according to one of the previous requirements, characterized by the fact that A begins in the given listen to a substituted fail-group. 5. Compounds according to the preceding claims, characterized in that A is a phenyl radical substituted by one hydroxyl group or one methoxy group and one halogen atom. 6. Compounds according to one of the preceding claims, characterized in that Q means a benzothiazolyl-quinazolinyl-quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl- or 1,7- or 1,8-naphthyridinyl group attached via an arbitrary position. 7. Compounds according to one of the preceding claims, characterized in that Q means a benzothiazolyl-quinazolinyl-quinoxalinyl-, quinolinyl-, phthalazinyl-, 1,7- or 1,8-naphthyridinyl-, indazolyl-, dihydroindolonyl-, dihydroisoindolonyl-, benzimidazole- or indolyl group attached via an arbitrary position. 8. Compounds according to the preceding claims, characterized in that they are (+) enantiomers. 9. Compounds according to the preceding claims, characterized in that they are (-) enantiomers. 10. Process for obtaining compounds of the general formula I, indicated by the fact that B = CO A is an n-keto acid of the formula (II) 12 * in which A, R und R independently of each other mean hydrogen, one methyl- or ethyl group or together with a carbon atom from the chain one C3-C6-cycloalkyl ring, which with some amine of the formula Q<1->NH2 wherein Q is benzothiazole, quinazoline, quinoxaline, quinoline or phthalazine translates to n-ketoamide (III) in the given case in the presence of dehydrating coupling reagents or after activation of the acid function in a manner known to a person skilled in the art, then reacts either with an alkylmetal compound of the general formula (IVa) in which M stands for alkali metal MgX or ZnX, X for halogen and R 3 for one in a given case independently of one or more groups selected from halogen, hydroxy or C 1 -C 3 -Alkoxy substituted C 1 -C 8 -alkyl group, or a partially or fully fluorinated C 1 -C 3 -alkyl group, one optionally substituted group selected from C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -Cycloalkyl, C 3 -C 7 -heteroalkyl, aryl, heteroaryl, (C1-C8-alkyl), C3-C8-cycloalkyl, (C1-C8-alkyl)aryl, or (C1-C8-alkyl)heteroaryl, or with some silicon compound of formula (IV) in which R6 means one C1-C5-alkyl group and R has the above meaning, or B one n-keto acid (II) is esterified in a manner known to the expert method, the octeoester (V) is then reacted as described in A with an alkylmetal compound (IVa) or a silicon compound of the formula (IV), in the given ester, the ester is cleaved according to a method known to the expert, and the compound of formula (VI) is obtained in which R<7> means CpCs-alkyl or hydrogen, and this then reacts with an amine of the formula wherein Q is quinazolinyl, quinoxalinyl, quinolinyl, indazolyl, phthalazinyl, naphthyridinyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl, in a given case after the activation of the oxygen function and/or in a given case in the presence of a catalyst or in the event that B means a methylene group substituted by a methyl or ethyl group, or eco compound of formula (VII) or (VIII) 12 3 wherein A, B, R , R and R have the above meanings and LG means an arbitrary leaving group, reacts with some compound of formula (IX) or (X) in which R<9>contains a hydrogen atom, one a Ci-C5-acyl group or a Ci-C5-alkoxy group or an aryloxycarbonyl group and Q means a quinazolinyl-, quinoxalinyl-, quinolinyl-, indazolyl-, phthalazinyl-, naphthyridinyl-, benzothiazolyl-, dihydroindolonyl-, dihydroisoindolonyl-, benzimidazole- or indolyl-group and one of the intermediately obtained oxazolidinone is cleaved with aqueous alkali hydroxides, or compounds of formula (VII) or (VIII) react with azide or ammonia salts, and in this case it is reduced with reagents known to the expert or hydrogenation catalyzed by transition metals is carried out to obtain the compound of formula (XI) which then reacts in a given case with base catalysis or transition metal catalysis with some methods known to the expert halogenated derivatives of the heterocycle of quinazoline, quinoxaline, quinoline, indazole, Phthalazine, Naphthvridin, Benzothiazole, Dihydroindolone, Dihydroisoindolone, Benzimidazole or Indole or by means of methods known to the expert, from the compound (VI) by means of reduction or alkylation, the compound of the formula (XII) is obtained in which R o means hydrogen, methyl m l oder ethyl tl, under reductive amination conditions it reacts with compounds of the formula wherein Q has the above meaning. 11. Pharmaceutical preparations, which contain at least one compound according to one of the previous requirements, or their mixtures as well as pharmaceutically acceptable carriers. 12. Application of the compound according to claim 1 to obtain a drug. 13. Application of the compound according to claim 1, to obtain a drug for the treatment of inflammatory diseases.