KR20060037442A - Piperazine derivatives for the treatment of hiv infections - Google Patents

Abstract

This invention relates to a compound of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof, wherein R1 to R5 are defined in the description, and to processes for the preparation thereof, intermediates used in their preparation, compositions containing them and the uses of such derivatives. The compounds of the present invention inhibit the interaction of gp 120 with CD4 and are therefore of use in the treatment of HIV, a retroviral infection genetically related to HIV, or AIDS.

Description

PIPERAZINE DERIVATIVES FOR THE TREATMENT OF HIV INFECTIONS}

The present invention relates to piperazine derivatives, methods for their preparation, compositions containing them and their use.

More particularly, the present invention relates to the use of piperazine derivatives in the treatment of HIV, such as HIV-1 and genetically related retroviral infections (and hence AIDS).

Introduction of HIV-1 into target cells requires cell-surface CD4 and additional host cell cofactors. It has been recognized that human immunodeficiency virus requires chemokine receptors such as CCR5 or CXCR-4 as well as primary receptor CD4 for efficient introduction into target cells. The main cofactor for the introduction mediated by the envelope glycoprotein of the primary macrophage-uremic strain of HIV-1 is CCR5, a receptor for the β-chemokine RANTES, MIP-1α and MIP-1β (Deng et al. al., 1996, Nature, 38, 661-666]. HIV is attached via a region of its envelope protein gp120 to a CD4 molecule on a target cell. It is believed that the CD4 binding site on gp120 of HIV interacts with the CD4 molecule on the target cell surface, resulting in structural modifications that allow binding to additional cell-surface receptors such as CCR5 or CXCR-4. This brings the viral envelope close to the cell surface, enabling interaction between gp41 on the viral envelope and the fusion domain on the host cell surface, and subsequently fusion with the cell surface, ultimately introducing the viral core into the cell. Let's do it. Thus, compounds that inhibit the binding of gp120 to CD4 and thereby prevent the introduction of HIV-1 into target cells are infected with HIV, such as HIV-1, and genetically related retroviruses (and consequent AIDS syndrome). , AIDS).

According to a first aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof.

In the above formula,

R ¹ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with one or two atoms or groups selected from halo, C ₁ -C ₆ alkoxy, CF ₃ , OCF ₃ or CN;

R ² and R ³ are independently H or C ₁ -C ₆ alkyl;

R ⁴ is C ₁ -C ₆ alkyl;

R ⁵ is phenyl; Naphthyl; Or a C-bonded 6 to 10 membered mono- or bicyclic, aromatic or partially saturated heterocycle, wherein the heterocycle is 1 to 4 nitrogen heteroatom (s), 1 or 2 nitrogens and 1 oxygen Heteroatoms, or containing one or two nitrogens and one sulfur heteroatom; Wherein said phenyl, naphthyl or heterocycle is C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₃ -C ₇ cycloalkyl, phenyl, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ Alkoxy C ₁ -C ₆ alkyl, OC ₁ -C ₆ fluoroalkyl, C ₀ -C ₂ alkylene NR ⁶ R ⁷ , halo, C ₀ -C ₂ alkylene CN, C ₀ -C ₂ alkylene CO ₂ R ⁸ , C ₀ -C ₂ alkylene CONR ⁶ R ⁷ , C ₀ -C ₂ alkylene SR ⁹ , C ₀ -C ₂ alkylene SOR ⁹ , C ₀ -C ₂ alkylene S0 ₂ R ⁹ , C ₀ -C ₂ alkylene SO ₂ NR ⁶ R ⁷ , C ₀ -C ₂ alkylene NR ⁸ COR ⁹ , C ₀ -C ₂ alkylene NR ⁸ CONR ⁶ R ⁷ , C ₀ -C ₂ alkylene NR ⁸ SO ₂ R ⁹ or Optionally substituted with 1 to 3 atoms or groups selected from oxo when C ₀ -C ₂ alkylene R ¹⁰ , or R ⁵ is heterocycle;

R ⁶ and R ⁷ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl or R ¹⁰ ; Or together with the nitrogen to which they are attached form an azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine ring; Wherein the substituent is 1 or 2 groups selected from C ₁ -C ₆ alkyl or C ₀ -C ₆ alkylene NH ₂ ;

R ⁸ is H, C ₁ -C ₆ alkyl or phenyl;

R ⁹ is C ₁ -C ₆ alkyl or phenyl;

R ¹⁰ is imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, Isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyano or halo Optionally substituted with one to three atoms or groups selected from:

The term "alkyl" as a group or part of a group includes straight and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. The term "C _{3 -7-cycloalkyl"} refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "halo" means fluoro, chloro, bromo or iodo.

In a further embodiment, R ¹ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1 or 2 atoms or groups selected from halo.

In still further embodiments, R ¹ is phenyl, fluorophenyl or pyridyl.

In still further embodiments, R ¹ is phenyl.

In still further embodiments, R ² is C ₁ -C ₄ alkyl.

In still further embodiments, R ² is methyl.

In still further embodiments, R ³ is H.

In still further embodiments, R ⁴ is C ₁ -C ₄ alkyl.

In still further embodiments, R ⁴ is methyl.

In still further embodiments, R ⁵ is optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopiperidinyl or benzoxazolyl ; Wherein said substituent is 1 to 3 atoms or groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, CO ₂ R ⁸ , CONR ⁶ R ⁷ or R ¹⁰ .

In still further embodiments, R ⁵ is optionally substituted phenyl or pyridyl, wherein said substituent is 1 to 3 groups selected from C ₁ -C ₆ alkoxy, CO ₂ R ⁸ or CONR ⁶ R ⁷ .

In still further embodiments, R ⁶ is H or C ₁ -C ₄ alkyl.

In still further embodiments, R ⁷ is H, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl.

In still further embodiments, R ⁸ is C ₁ -C ₄ alkyl.

In still further embodiments, R ¹⁰ is imidazolyl, pyrazolyl, triazolyl or oxdiazolyl, each of 1 to 3 selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, cyano or halo Is optionally substituted with 2 atoms or groups.

In a further embodiment, there is also provided a compound of formula la, or a pharmaceutically acceptable salt, solvate or derivative thereof.

In the above formula,

R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above with respect to compounds of formula (I), including all combinations of these specifically described embodiments.

In a further embodiment, there is also provided a compound of formula (Ib) or a pharmaceutically acceptable salt, solvate or derivative thereof.

In the above formula,

R ¹ , R ² , R ⁴ and R ⁵ are as defined above with respect to compounds of formula (I), including all combinations of these specifically described embodiments.

It is to be understood that the present invention encompasses all combinations of particular embodiments of the invention as described above consistent with the definition of compounds of formula (I).

The compounds of the present invention are compounds of formula I and their pharmaceutically acceptable salts, solvates or derivatives wherein the derivatives are complexes, polymorphs, prodrugs and isotopically-labeled compounds as well as salts, solvates and salts thereof Solvates) and isomers thereof. In a further embodiment, the compounds of the invention are compounds of formula (I) and their pharmaceutically acceptable salts and solvates, in particular compounds of formula (I). It is to be understood that the abovementioned compounds of the present invention include their polymorphs and isomers.

Pharmaceutically acceptable salts of compounds of formula (I) include their acid addition salts and base salts.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetates, aspartates, benzoates, besylates, bicarbonates, bisulfates, borates, bromide, chamlates, carbonates, chlorides, citrates, edisylates, ecylates, formates, Fumarate, Gluceptate, Gluconate, Glucuronate, Hexafluorophosphate, Hibenzate, Hydrobromide, Hydrochloride, Hydroiodide, Iodide, Isetionate, Lactate, Maleate, Male Eate, malonate, mesylate, methyl sulphate, naphthylate, 2-lead silicate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate , Saccharides, stearates, succinates, sulfates, tartrates, tosylates and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula I may be prepared by one or more of the following three methods:

(i) reacting a compound of formula (I) with a preferred acid or base;

(ii) removing the acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or ring-opening a suitable cyclic precursor, such as lactone or lactam, using a preferred acid or base; or

(iii) a method of reacting one salt of a compound of formula (I) with a suitable acid or base or converting it to another using a suitable ion exchange column.

All three reactions are typically carried out in solution. Salts can be precipitated out of solution, collected by filtration, or recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to non-ionized.

The compounds of the present invention may exist in both unsolvated and solvated forms. The term “solvate” is used herein to describe molecular complexes comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

Complexes include clathrates, ie drug-host containing complexes in which the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the solvates mentioned above. Also included are complexes of pharmaceutical drugs containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complex can be ionized, partially ionized, or non-ionized. For a review of these complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

Compounds of the present invention may have the ability to crystallize into one or more unique forms known as polymorphisms, and all such polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism can generally occur as a reaction to change in temperature or pressure, or both, and can also result from deformation during the crystallization reaction. Polymorphs can be classified by a variety of physical properties, and typically the x-ray diffraction pattern, dissolution behavior and melting point of the compound are used to fractionate the polymorph.

When a specific derivative of a compound of formula (I) with little or no pharmaceutical activity per se is administered into or on the body, it may be converted into a compound of formula (I) with the desired activity, for example by hydrolytic cleavage. have. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs can be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and' Bioreversible Carriers in Drug Design ', Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

Prodrugs according to the present invention are known to those skilled in the art as, for example, suitable precursors present in compounds of formula (I) as "progen-residues" as described in, for example, "Design of Prodrug" by H Bundgaard (Elsevier, 1985). It can be prepared by replacing with a specific residue known to the.

Specific examples of prodrugs according to the present invention

(i) when the compound of formula (I) contains a carboxylic acid functional group (—COOH), its ester, eg, the substitution of hydrogen with (C ₁ -C ₆ ) alkyl;

(ii) when the compound of formula (I) contains an alcohol functional group (—OH), its ether, eg, the substitution of hydrogen with (C ₁ -C ₆ ) alkanoyloxymethyl;

(iii) when the compound of formula (I) contains a primary or secondary amino functional group (-NH ₂ or -NHR, where R ≠ H), an amide thereof, for example one or two hydrogens of (C ₁ -C ₁₀ ) includes substitution with alkanoyl.

Further examples of substituents according to the above examples and examples of other prodrug types according to the invention can be found in the abovementioned references.

In addition, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

Also included within the scope of the present invention include metabolites of the compounds of formula (I), ie compounds formed in vivo upon administration of the drug. Specific examples of metabolites according to the present invention

(i) where the compounds of formula (I) contain methyl groups, their hydroxymethyl derivatives (-CH _3-- CH ₂ 0H);

(ii) where the compounds of formula (I) contain alkoxy groups, their hydroxy derivatives (-OR->-OH);

(iii) where the compounds of formula (I) contain tertiary amino groups, their secondary amino derivatives (-NR ¹ R ^2- > -NHR ¹ or -NHR ² );

(iv) where the compounds of formula I contain secondary amino groups, primary amino derivatives thereof (-NHR ¹ -NH ₂ );

(v) where the compounds of formula (I) contain phenyl moieties, their phenol derivatives (-Ph -PhOH); And

(vi) When the compounds of formula (I) contain amide groups, their carboxylic acid derivatives (-CONH _2- > COOH) are included.

In view of the definition of R ⁴ , the compounds of formula I contain one or more asymmetric carbon atoms and exist as two or more optical isomers. If the compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible, and if the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomers Phenomenon ('Totomer phenomenon') may occur. This may result in one or more isomers of a single compound.

All optical isomers, geometric isomers and tautomers of the compounds of formula (I), including compounds exhibiting one or more isomers, and one or more mixtures thereof, are included within the scope of the present invention. Acid addition salts or base salts in which counter ions are optically active, such as D-lactate or L-lysine or racemates such as DL-tartrate or DL-arginine.

Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers are known in the art for chiral synthesis from suitable optically pure precursors or for the resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high pressure liquid chromatography (HPLC). It includes.

Alternatively, the racemate (or racemic precursor) may be a suitable optically active compound, such as an alcohol, or an acid or base, such as tartaric acid or 1-phenylethylamine, if the compound of formula I contains an acidic or basic moiety. Can be reacted with. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization to convert one or two diastereomers to the corresponding pure enantiomer (s) in a manner well known to those skilled in the art.

The chiral compounds (and their chiral precursors) of the invention are subjected to chromatography, typically carbohydrates, typically 0 to 50% isopropanol, typically 2 to 20%, and 0 to 5% alkylamine, typically 0.1 It can be obtained in enantiomeric-enhanced form using HPLC on an asymmetric resin using a mobile phase consisting of heptane or hexane containing% diethylamine. The eluate is concentrated to give a strengthened mixture.

Stereoisomeric aggregates can be separated by conventional methods known to those of skill in the art-see, eg, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).

The present invention also encompasses pharmaceutically acceptable isotopically-labeled compounds of formula (I) in which one or more atoms have the same atomic number but whose atomic weight or mass number is substituted with an atom different from the atomic weight or mass number generally found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, Iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and sulfur such as ³⁵ S.

Certain isotopically-labelled compounds of formula (I), for example compounds into which radioactive isotopes have been introduced, are useful for drug and / or substrate tissue distribution studies. Radioactive isotopes tritium, i.e. ³ H and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in that they are easy to incorporate and rapid means of detection.

Substitution with heavier isotopes such as deuterium, ie ² H, may be desirable in certain circumstances by providing certain therapeutic advantages due to greater metabolic stability, such as increased half-life or reduced dose required in vivo.

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful for Positron Emission Topography (PET) studies to study substrate receptor occupancy.

Isotope-labeled compounds of formula (I) are generally prepared by conventional techniques known to those skilled in the art, or by using the appropriate isotopically-labeled reagents in place of previously used non-labeled reagents and It can manufacture by the method similar to the method described in a manufacture example.

A pharmaceutically acceptable solvate thereof according to the invention the solvent of crystallization, for example, the isotope-substituted D ² O, d ₆ - include those which may be acetone, d ₆ -DMSO.

Preferred compounds of formula (I) include the compounds of Examples 1 to 94 below; And pharmaceutically acceptable salts, solvates or derivatives thereof. Particularly preferred compounds of formula I are

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (3-methyl-1H-indazol-4-yloxy) -propan-1-one ;

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [2- (2H-pyrazol-3-ylamino) -quinolin-5-yloxy ] -Propan-1-one;

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -isoquinoline-1-carboxylic acid Methylamide;

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-2-methylamino-quinolin-5-yloxy) -propane-1 -On;

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) -isoquinoline-5-yljade C] -propan-1-one;

4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -3-methoxy-N-methyl Benzamide;

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 Carboxylic acid methylamides;

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 Carboxylic acid amides;

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid ethylamide;

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid cyclopropylamide; And pharmaceutically acceptable salts, solvates or derivatives thereof.

In the general method and scheme,

R ¹ to R ⁹ are as defined above unless otherwise stated; X is halo or hydroxy; Y is a leaving group such as chloro, bromo, tosylate, mesylate or hydroxy; DMF is N, N-dimethylformamide; DMSO is dimethyl sulfoxide; THF is tetrahydrofuran; WSCDI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DCC is N, N'-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole; HOBt is 1-hydroxybenzotriazole hydrate; HBTU is O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; PyBOP® is benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate; PyBrOP is bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; Hunig's base is N-ethyldiisopropylamine; Mukaiyama reagent is 2-chloro-1-methylpyridinium iodide.

Compounds of formula (I) may be prepared by any method known for the preparation of compounds of similar structure.

Compounds of formula (I) and intermediates thereof can be prepared according to the following schemes.

It will be appreciated by those skilled in the art that the specific procedures described in the schemes for the preparation of compounds of formula (I), or intermediates thereof, may not be applicable to some possible substituents.

In addition, it will be appreciated by those skilled in the art that it may be necessary or desirable to perform the conversions described in the schemes in a different order than described, or to modify one or more conversions to provide the desired compounds of Formula (I).

In addition, it will be appreciated by those skilled in the art that it may be necessary or desirable to protect one or more sensitive groups in the molecule at any stage of the synthesis of the compound of formula (I) as shown in the following scheme to prevent undesired side reactions. . In particular, it may be necessary or desirable to protect the amino groups. The protecting groups used in the preparation of the compounds of formula (I) can be used in conventional manner. See, for example, 'Protective Groups in Organic Synthesis' by Theodora W Green and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), especially chapter 7, pages 494-653 (" Protection for the amino Group ")] (also described for the removal of these groups).

The amino protecting groups boc, benzyloxycarbonyl, benzyl and acetyl are particularly useful for the preparation of compounds of formula (I) and their intermediates.

With particular reference to Scheme 1, the conversions described herein can be carried out as follows:

(a)-(e) Acid-Amine Coupling Reactions

Typically acid chlorides or acid bromide of Formula (V), (VI) or (VIII) and appropriate piperazine of Formula (IV), (VII) or (IX) may optionally contain excess acid acceptors such as triethylamine or N-ethyl-N, N-diisopropylamine. With solvents such as haloalkanes (eg dichloromethane) or ethers (eg THF) for 1 to 24 hours at room temperature. The reaction can be conveniently carried out by reacting the relevant piperazine with 1.1 equivalents of the relevant acid chloride in dichloromethane for 1 hour at room temperature.

In further embodiments, an acid of Formula V, VI or VIII, suitable piperazine of Formula IV, VII or IX activated with a suitable reagent such as WSCDI / DCC and HOBt / HOAt, and excess acid acceptor such as triethylamine or N-ethyl-N, N-diisopropylamine is reacted in a solvent such as haloalkane (eg dichloromethane), ether (eg THF) or DMF for 4 to 48 hours at room temperature. The reaction can be conveniently carried out by reacting the relevant piperazine, 1.4 equivalents of WSCDI, 1.4 equivalents of HOBt, 2.2 equivalents of triethylamine and 1.1 equivalents of the relevant carboxylic acid in dichloromethane at room temperature for 18 hours.

Also in further embodiments, an acid of Formula V, VI or VIII, one of the appropriate piperazine of Formula IV, VII or IX, HBTU, PyBOP, PyBrOP or Mukaiyama reagent, and excess acid acceptor such as triethylamine or N -Ethyl-N, N-diisopropylamine can be reacted in a solvent such as haloalkane (eg dichloromethane) or ether (eg THF) at room temperature for 4 to 24 hours. The reaction can be conveniently carried out by reacting the relevant piperazine, 1.0 equivalent of carboxylic acid and 1.5 equivalent of HBTU in dichloromethane or DMF for 14 hours at room temperature.

(f) nucleophilic substitution

i) when Y = Cl, Br, mesylate, tosylate:

Typically compounds of formula II and III and acid acceptors such as triethylamine, N-ethyl-N, N-diisopropylamine or alkali metal carbonates are solvents such as haloalkanes (eg dichloromethane) In an ether (e.g. THF) or acetone at room temperature to reflux for 1 to 24 hours. The reaction can be conveniently carried out by reacting the compounds of formulas II and III with 1.0 equivalent of cesium carbonate in acetone at reflux for 14 hours.

ii) when Y = OH:

Typically, compounds of formulas II and III, triphenylphosphine or tri-o-tolylphosphine, and one of diethyl azodicarboxylate or di-isopropyl azodicarboxylate are solvents such as haloalkanes (eg For example, it is reacted in dichloromethane) or ether (eg THF) at a temperature from room temperature to reflux for 1 to 24 hours. The reaction can be conveniently carried out by reacting the compounds of the formulas II and III with 1.2 equivalents of triphenylphosphine and 1.1 equivalents of di-isopropyl azodicarboxylate in THF for 14 hours at room temperature.

Compounds of formula VI in reaction steps (a) and (d) can be prepared according to Scheme 1a below.

Wherein R is lower alkyl such as C ₁ -C ₆ alkyl.

(g) nucleophilic substitution

Nucleophilic substitution can be carried out according to the conditions described for step (f) above.

(h) ester hydrolysis

Typically, the compound of formula (XI), aqueous alkali metal hydroxide solution or aqueous hydrochloric acid solution, and any co-solvent such as ethanol or dioxane are heated at a temperature of 60-100 ° C. for 1-18 hours. The reaction can be conveniently carried out by heating the compound of formula XI in 1N aqueous sodium hydroxide solution and dioxane at 60 ° C. for 2 hours.

Certain intermediates described above are novel compounds, and all novel intermediates herein should be understood to form an additional aspect of the present invention. Compounds of formulas (II), (IV) and (VII) are major intermediates and represent a particular aspect of the invention.

Compounds of formula III, V, VIII, IX and X are known compounds or may be prepared by conventional chemistry.

According to another aspect, the present invention provides the following process for the preparation of the compound of formula (I).

According to the first method (A), compounds of formula (I) can be prepared by coupling an acid of formula (V) to piperazine of formula (IV) under conventional acid-amine coupling conditions.

Conveniently, the acid-amine coupling is carried out under the conditions described above in connection with steps (a)-(e) of Scheme 1.

According to a second method (B), compounds of formula (I) can be prepared by coupling an acid of formula (VI) with piperazine of formula (VII) under conventional acid-amine coupling conditions.

Conveniently, acid amine coupling is carried out under the conditions described above in connection with steps (a)-(e) of Scheme 1.

According to a third method (C), compounds of formula (I) can be prepared by nucleophilic substitution of compounds of formula (II) under the usual conditions with alcohol R ⁵ OH of formula (III).

Conveniently, the nucleophilic substitution is carried out under the conditions described above in connection with step (f) of Scheme 1.

According to the fourth method (D), compounds of formula (I) can be prepared by functional group interconversion of other compounds of formula (I) under conventional conditions. For example, compounds of formula (I) containing ester groups can be converted to the corresponding compounds of formula (I) containing primary or secondary amide groups by reaction with ammonia or primary amines, respectively.

The compounds of the present invention inhibit the interaction of gp120 with CD4 and are used for the treatment of HIV, retroviral infections genetically associated with HIV, and AIDS.

Thus, in another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use as a medicament.

In another aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of HIV, a retroviral infection genetically associated with HIV, or AIDS.

In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for the manufacture of a medicament for the treatment of HIV, a retroviral infection genetically associated with HIV, or AIDS. .

In another aspect, the invention includes treating a mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS with an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or derivative thereof To provide a method of treating the mammal.

The compounds of the present invention can be administered as crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Low frequency or high frequency drying may be used for this purpose.

They may be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or in any combination thereof). In general, they will be administered in a formulation combined with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipients will be broadly extended depending on such factors as the particular mode of administration, the effect of such excipients on solubility and stability and the nature of the dosage form.

Pharmaceutical compositions suitable for the delivery of the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutiacal Sciences', 19th Edition (Mack Publishing Company, 1995).

The compounds of the present invention can be administered orally. Oral administration may involve introducing the compound into the gastrointestinal tract by swallowing, and buccal or sublingual administration may be used to introduce the compound into the blood stream directly from the oral cavity.

Formulations suitable for oral administration include, but are not limited to, solid dosage forms such as tablets, capsules, liquids or powders containing particulates, lozenges (including liquid filled lozenges), chewing agents, multi- and nano-particulates, gels, solid solutions, Liposomes, films (including muco-adhesives), antiseptics, sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and are typically carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents. It includes. Liquid formulations can also be prepared by the reconstitution of a solid, for example from Shasei.

The compounds of the present invention can be used in fast-dissolving, fast-disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001).

For tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to drugs, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose Starch, pregelatinized starch and sodium alginate. In general, the disintegrant will comprise 1% to 25% by weight, preferably 5% to 20% by weight of the dosage form.

Generally binders are used to impart tack characteristics to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. In addition, the tablets will contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Can be.

In addition, tablets may optionally include surface active agents such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. If present, the surface active agent may comprise 0.2% to 5% by weight of the tablet, and the lubricant may comprise 0.2% to 1% by weight of the tablet.

In addition, tablets generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants generally comprise from 0.25% to 10% by weight, preferably from 0.5% to 3% by weight of the tablet.

Other possible ingredients include antioxidants, colorants, flavors, preservatives and taste-blockers.

Exemplary tablets contain up to about 80% drug, about 10% to about 90% by weight binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight disintegrant and about 0.25 It contains from about 10% by weight of lubricant.

Tablet blends may be compressed directly or by roller to form tablets. Alternatively, the tablet blend or a portion of the blend may be wet-, dry- or melt-granulated, melt solidified or extruded prior to tableting. The final formulation may comprise one or more layers and may or may not be coated; It can also be encapsulated.

Formulations of tablets are discussed in "Pharmaceutical Dosage Forms: Tablets Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid dosage forms for oral administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

Suitable modified release formulations for the purposes of the present invention are described in US Pat. No. 6,106,864. Other suitable release techniques such as high energy distribution and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Compounds of the invention can also be administered directly into the bloodstream, muscle, internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intradural, intraventricular, intraurethral, intraoral, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needles (including microneedle) syringes, needleless syringes and infusion techniques.

Parenteral formulations are typically aqueous solutions containing excipients such as salts, carbohydrates and buffers (preferably pH 3-9), but for some applications they are sterile, non-aqueous solutions or suitable vehicles such as sterile, pyrogen-free. It may be more suitably formulated as a dry form for use in combination with water.

Preparation of parenteral formulations under sterile conditions, such as lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the invention used in the preparation of parenteral solutions can be increased using suitable formulation techniques, such as by introducing solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release. Compounds of the invention can be formulated as solid, semi-solid or thixotropic liquid for administration as an implanted reservoir to provide modified release of the compounds. Examples of such formulations include drug-coated stents and PGLA microspheres.

In addition, the compounds of the invention may be administered topically to the skin or mucosa, ie dermis or transdermal. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting agents, dressings, foaming agents, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Representative carriers include alcohols, water, inorganic oils, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated—see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other methods of topical administration include electroporation, iontophoresis, sonication, sonophoresis, and micro or needleless delivery (eg, Powderject ™, Bioject ™, etc.) injections. Include.

Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

In addition, the compounds of the invention may be administered intranasally or inhaled, for example in dry powder form (alone, in a dry blend with a mixture, for example lactose, or as mixed component particles, for example phospholipids such as phosphatidylcholine Suitable propellants such as 1,1 from dry powder inhalers or from pressurized vessels, pumps, sprays, nebulizers (preferably nebulizers using electrohydrodynamics to generate fine mist) or nebulizers It can be administered with or without 1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise bioadhesives such as chitosan or cyclodextrins.

Pressurized vessels, pumps, sprays, nebulizers or nebulizers are, for example, ethanol (optionally aqueous ethanol) or other suitable dispersants, solubilizers or release extenders of compounds, solvents and optional surfactants such as sorbitan trioleate, oleic acid Or a solution or suspension of a compound comprising a propellant as oligolactic acid.

Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding method, such as spiral jet milling, fluid bed jet milling, supercritical fluid-processing to form nanoparticles, high pressure homogenization or spray drying.

Capsules (for example made from gelatin or HPMC), blisters and cartridges for use in an inhaler or blower are compounds of the invention, suitable powder substrates such as lactose or starch and performance modifiers such as l-leucine, mannitol Or by containing a powder mixture of magnesium stearate. Lactose may be in the form of anhydrides or monohydrates, preferably in the form of monohydrates. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers using an electrohydraulic motor that generate fine mist may contain between 1 μg and 20 mg of the compound of the present invention per operation, and the working volume may vary from 1 μl to 100 μl. Typical formulations may include the compounds of the present invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents such as menthol and levomenthol, or sweetening agents such as saccharin or saccharin sodium can be added to these formulations of the invention intended for inhalation / intranasal administration.

Formulations for inhalation / intranasal administration can be formulated to be immediate and / or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA). Pulsed, controlled, targeted, and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is determined using a valve that delivers a metered amount. Units according to the invention are typically adjusted to administer a metered dose or “puff” containing between 1 μg and 10 mg of a compound of the invention. The total daily dose will typically range from 1 μg to 200 mg, which may be administered in a single dose, more generally in divided doses throughout the day.

The compounds of the present invention can be administered rectally or vaginally, for example in the form of suppositories, suppositories, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

In addition, the compounds of the present invention may be administered directly to the eye or ear, typically in the form of mucus in undifferentiated suspensions or solutions in isotonic pH-controlled sterile saline. Other formulations suitable for ocular and ear administration include ointments, biodegradable (eg, absorbent gelatin sponges, collagen) and non-biodegradable (eg, silicone) implants, wafers, lenses, and particulate or vesicle systems such as niosomes. Or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methyl cellulose, heteropolysaccharide polymers such as gellan gum as preservatives such as benz It can be incorporated with alkonium chloride. Such formulations may also be delivered by iontophoresis.

Formulations for eye / ear administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted- and programmed release.

The compounds of the present invention are soluble macromolecular bodies such as cyclodextrins and their suitable derivatives or polyethylene glycol-containing polymers for use in any of the dosage forms mentioned above for their solubility, dissolution rate, taste-blocking, bioavailability and (Or) stability can be improved.

For example, drug-cyclodextrin complexes have generally been found useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to intimate complexation with the drug, cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent or solubilizer. Most commonly for this purpose alpha-, beta- and gamma-cyclodextrins are used, examples of which are found in WO 91/11172, WO 94/02518 and WO 98/55148. Can be.

Provided that it is desirable to administer a compound of the invention, for example in combination with another therapeutic agent for the purpose of treating a particular disease or condition, at least one of the compositions comprises two or more pharmaceutical compositions containing a compound of the invention, It is within the scope of the present invention that it can conveniently be combined in the form of a kit suitable for coadministration of this composition.

Thus, the kits of the present invention comprise at least two separate pharmaceutical compositions, wherein at least one of the compositions contains a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and a means for retaining said compositions individually, such as Container, divided bottle, or divided foil pockets. Examples of such kits are conventional blister packs used to package tablets, capsules and the like.

The kits of the invention are particularly suitable for the administration of individual compositions at different dosage intervals, or for administration in several dosage forms, for example oral and parenteral, to titrate separate compositions for the other. To aid in compliance, kits typically include instructions for administration that can provide a so-called memory helper.

For administration to a human patient having a body weight of about 65 to 70 kg, the total daily dose of a compound of the invention typically ranges from 1 to 10000 mg, such as from 10 to 10, depending of course on the dosage form, the age, symptoms and weight of the patient. 1000 mg, for example 25 to 500 mg, in any case will be the ultimate judgment of the physician. The total daily dose may be administered in single or divided doses.

Thus, in another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof in combination with one or more pharmaceutically acceptable excipients, diluents or carriers.

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives are those that are more selective, initiate faster action, more potent, better absorbed or more stable than prior art compounds. Or more resistant to metabolism, reduced "food effect", increased safety profile, or other more desired properties (eg, properties related to solubility and absorbency).

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives may be administered alone or as part of a combination therapy. Thus, embodiments comprising co-administration with one or more additional therapeutic agents in addition to the compounds of the present invention, and compositions containing them are included within the scope of the present invention. The multi-drug regimen, often referred to as combination therapy, can be used for the treatment and prevention of infections caused by human immunodeficiency virus, HIV. The use of such combination therapies is particularly suitable in view of the treatment and prevention of infection and proliferation of human immunodeficiency virus, HIV, and related pathogenic retroviruses in patients in need of treatment or at risk of becoming such patients. The ability of the retroviral pathogen to evolve into a strain that is resistant to any monotherapy administered to the patient within a relatively short period of time is well known in the literature. A recommended treatment for HIV is a so-called highly active anti-is a combination drug treatment called retroviral therapy (H ighly A ctive A nti- R etroviral herapy T), or HAART. HAART combines three or more HIV drugs. Thus, the therapeutic methods and pharmaceutical compositions of the present invention may use the compounds of the invention in the form of monotherapy, but the methods and compositions may further comprise one or more compounds of the invention, such as one or more additional therapeutic agents, such as herein. It may be used in the form of a combination therapy co-administered in combination with a therapeutic agent to be described in detail.

In a further embodiment of the invention, the combination of the invention comprises treatment with a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, and one or more additional therapeutic agents selected from: indinaby HIV protease inhibitors, including but not limited to le, ritonavir, saquinavir, nelpinavir, lopinavir, amprenavir, atazanavir, tipranavir, AG1859 and TMC 114; Non-nucleoside reverse transcription inhibitors (NNRTI), including but not limited to nevirapine, delavirdine, capravirin, epavirens, GW-8248, GW-5634 and TMC125; Nucleoside / nucleotide reverse transcriptase inhibitors including but not limited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abakavir, adefovir, dipoxyl, tenofovir, emtricitabine, and allodine; N-{(1S) -3- [3- (3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl) -exo-8-azabicyclo [3.2.1] oct -8-yl] -1-phenylpropyl} -4,4-difluorocyclohexanecarboxamide or a pharmaceutically acceptable salt, solvate or derivative thereof, methyl 1-endo- {8-[(3S)- 3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro- 1H-imidazo [4,5-c] pyridine-5-carboxylate or pharmaceutically acceptable salts, solvates or derivatives thereof, methyl 3-endo- {8-[(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-3H-imidazo [4 , 5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, ethyl 1-endo- {8-[(3S) -3- (acetylamino) -3- (3- Fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydrate Rho-1H-imidazo [4,5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, Sch-D, ONO-4128, GW-873140, AMD-887 and CMPD CCR5 antagonists, including but not limited to -167; Other agents that inhibit the interaction of gp120 with CD4, including but not limited to BMS806 and BMS-488043; Other agents that inhibit the introduction of HIV into target cells, including but not limited to, enfuvirides, T1249, PRO 542 and PRO 140; Integrase inhibitors including but not limited to L-870,810; And RNaseH inhibitors.

In addition, the compounds of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof may be added to proliferation inhibitors such as hydroxyureas, immunomodulators such as granulocyte macrophage colony stimulating growth factors (eg, Sarg Ramostim), and various forms of interferon or interferon analogs; Other chemokine receptor agonists / antagonists such as CXCR4 antagonists (eg AMD-070); Takinin receptor receptor gelling agents (eg, NK1 antagonists) and various forms of interferon or interferon derivatives; Agents that substantially inhibit, stop or reduce viral transcription or RNA replication, such as inhibitors of tat (transcriptional trans activator) or nef (negative regulator); Agents that substantially inhibit, disrupt or reduce transcription of one or more proteins expressed by a virus other than reverse transcriptase, including but not limited to downregulation of protein expression or antagonism of one or more proteins, For example Tat or Nef; In particular agents that influence downregulation of CCR5 receptor expression; Chemokines that induce CCR5 receptor internalization such as MIP-1α, MIP-1β, RANTES and derivatives thereof; And combinations with one or more additional therapeutic agents independently selected from the group consisting of other agents that inhibit viral infections or enhance the symptoms or outcome of HIV-infected individuals through various mechanisms.

Agents affecting (in particular downregulating) CCR5 receptor-expression include immunosuppressive agents such as calcineurin inhibitors (eg tacrolimus and cyclosporin A); Steroids; Agents that interfere with cytokine production or signaling, such as Janus Kinase (JAK) inhibitors (eg, JAK-3 inhibitors, such as 3-{(3R, 4R) -4-methyl-3- [methyl -(7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl} -3-oxo-propionitryl) and pharmaceutically acceptable salts thereof, Solvates or derivatives; Cytokine antibodies (eg, antibodies that inhibit interleukin-2 (IL-2) receptors, such as basiliximab and daclizumab); And agents that interfere with cell activation or cell cycle, such as rapamycin.

In addition, the combination of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, with one or more additional therapeutic agents that lower the metabolic rate of the compounds of the invention to increase exposure to the patient is within the scope of the invention. Included. Increased exposure in this manner is known as boosting. This has the advantage of increasing the efficacy of the compounds of the invention or reducing the dosage to achieve the same efficacy as compared to unboosted administration. Metabolism of the compounds of the present invention involves the oxidation process performed by P450 (CYP450) enzymes, in particular CYP3A4, conjugation by UDP glucuronosylated transferases and sulphating enzymes. Thus, among the agents that can be used to increase exposure of a compound of the invention to a patient, there are agents that can act as inhibitors of one or more isoforms of cytochrome P450 (CYP450) enzymes. Advantageously inhibited isoforms of CYP450 include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that can be used to inhibit CYP3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole.

It will be appreciated by those skilled in the art that the combination drug treatment as described herein above may comprise two or more compounds having the same or different mechanism of action. Thus, by way of example only, the combination may comprise a compound of the invention; And one or more NNRTIs; At least one NRTI and PI; One or more NRTI and CCR5 antagonists; PI; PI and NNRTI; And the like.

In addition to the essential requirements of therapeutic efficacy which may require the use of therapeutic agents in addition to the compounds of the present invention, for example in the treatment of diseases or conditions directly or indirectly accompanied by, or indirectly associated with, the primary or primary disease or condition, the compounds and There may be additional theories that force or strongly recommend the use of other therapeutic combinations. For example, it can reduce the immune-resistance of hepatitis C virus (HCV), hepatitis B virus (HBV), human papilloma virus (HPV), opportunistic infections (including bacterial and fungal infections), neoplasms and treated patients. It may be necessary or at least desirable to treat other symptoms resulting from the condition. Other therapeutic agents can be used with the compounds of the invention, for example, to provide immune stimulation or to treat pain and inflammation associated with early and basal HIV infection.

Thus, therapeutic agents for use in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives include interferons for the treatment of hepatitis, pegylated interferons (eg, peginterferon alpha-2a and Peginterferon alfa-2b), lamivudine, ribavidin and emtricitabine; Antifungal agents such as fluconazole, itraconazole and boleyconazole; Antibacterial agents such as azithromycin and clarithromycin; Interferon, daunorubicin, doxorubicin and paclitaxel for the treatment of AIDS related Kaposi's sarcoma; And sipofovir, pomivirsen, foscarnet, gancyclovir and valsite for the treatment of cytomegalovirus (CMV) retinitis.

Further combinations for use according to the invention include compounds of formula (I), or pharmaceutically acceptable salts, solvates or derivatives thereof, and CCR1 antagonists such as BX-471; Beta adrenergic receptor agonists such as salmeterol; Corticosteroid agonists such as fluticasone propionate; LTD4 antagonists such as montelukast; Muscarinic antagonists such as tiotropium bromide; PDE4 inhibitors such as silomylast or roflumilast; COX-2 inhibitors such as celecoxib, valdecoxib or rofocoxib; Alpha-2-delta ligands such as gabapentin or progabalin; Beta-interferons such as REBIF; TNF receptor modulators such as TNF-alpha inhibitors (eg adalimumab), HMG CoA reductase inhibitors such as statins (eg atorvastatin); Or immunosuppressive agents such as cyclosporin or macrolides such as tacrolimus.

In the combinations described above, the compounds of formula (I) or pharmaceutically acceptable salts, solvates or derivatives thereof and other therapeutic agents may be administered separately in connection with the dosage form or in combination with each other; In view of the time of administration, it may be administered simultaneously or sequentially. Thus, administration of one component formulation may be prior to, concurrent with or after administration of the other component formulation (s).

Accordingly, in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more additional therapeutic agents.

All references herein to treatment should be recognized to include healing, alleviation and prophylactic treatment.

The invention is illustrated by the following examples and preparations which may use the following additional abbreviations:

0.88 ammonia = concentrated ammonium hydroxide solution, 0.88 SG

h = hours

min = minutes

LRMS = low resolution mass spectrum

APCI ⁺ = Atmospheric Pressure Chemical Ionization

ESI ⁺ = Electrospray Ionization

NMR = nuclear magnetic resonance

tlc-thin layer chromatography

Me = methyl

Example 1

(2S)-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl) -2- (quinolin-5-yloxy) -propan-1-one

(2S) -2- (quinolin-5-yloxy) -sodium propionate salt in N, N-dimethylformamide (30 ml) (Preparation Example 2) (1.0 g, 4.6 mmol), (3R)-(3- Methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem. (2000), 43 (23), 4499) (0.94 g, 4.6 mmol), O- (1H-benzotriazole-1 A solution of -yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (2.62 g, 6.9 mmol) and triethylamine (1.93 ml, 13.8 mmol) at room temperature under nitrogen atmosphere for 14 hours. Was stirred. The reaction mixture was diluted with dichloromethane (100 ml), washed with water (3 × 50 ml), dried (MgSO ₄ ) and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2) to afford the title compound as a white solid (0.91 g).

Example 2

3- [2-((2R) -4-benzoyl-2-methyl-piperazin-1-yl) -1-methyl-2-oxo-ethoxy] -2-methyl-benzoic acid methyl ester

Cesium carbonate (0.39 g, 1.2 mmol) was dissolved in 1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2-bromo-propan-1-one in acetone (10 ml). Preparation Example 3) To a solution of (0.41 g, 1.2 mmol) and 3-hydroxy-2-methyl-benzoic acid methyl ester (Tet. Lett. (2000), 41 (11), 1741) (0.2 g, 1.2 mmol) The addition was added in portions and the mixture was heated to reflux for 14 hours. The cooled reaction mixture was evaporated to dryness under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (10 ml). The organic phase was separated, the aqueous phase extracted with dichloromethane (3 × 30 ml), the combined organic extracts were dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure to afford the title compound as a white solid (0.5 g).

Examples 3 to 12 were prepared by the method described above for Example 1 using the corresponding acid of Formula VI and piperazine of Formula VII. LRMS is by APCI ⁺ and the cited data is for [M + H] ⁺ .

Examples 13-45 were prepared by the method described above for Example 2 using the corresponding compound of Formula II and R ⁵ OH. Unless stated otherwise, LRMS is by APCI ⁺ and the cited data is for [M + H] ⁺ .

Example 46

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [2-methoxy-4- (2H- [1,2,4] triazole- 3-yl) -phenoxy] -propan-1-one

Compound of Preparation 10 (125 mg, 0.26 mmol) was added in portions to a stirred solution of hydrazine monohydrate (25 μl, 0.52 mmol) in glacial acetic acid (4 ml). The resulting solution was heated at 90 ° C. for 3 hours. The reaction mixture was then evaporated under reduced pressure and the remaining colorless oil was partitioned between dichloromethane (50 ml) and saturated sodium hydrogen carbonate solution (8 ml). The organic phase was separated and the aqueous phase was reextracted with dichloromethane (30 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give a colorless foam. The foam was dried under reduced pressure to give 110 mg of the title compound in 94% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 450

Example 47

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [2-methyl-3- (1-methyl-1H-pyrazol-3-yl) -phenoxy] Propane-1-one

The compound of Preparation 17 (100 mg, 0.53 mmol) and Compound 25 (180 mg, 0.53 mmol) and Cesium carbonate (172.7 mg, 0.53 mmol) in acetone (8 ml) were heated at reflux for 3.5 hours. Then, the reaction mixture was cooled down and evaporated under reduced pressure. The residue was partitioned between dichloromethane (30 ml) and water (8 ml). The organic phase was separated and the aqueous phase was reextracted with additional dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield a light brown oil. The oil was purified by chromatography using an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to 97: 3 to give a colorless oil. This oil was azeotropic with dichloromethane to afford 210 mg of the title compound in 89% yield as a colorless foam.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 447

Example 48

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl-2- (2-methyl-3- [1,2,4] oxadiazol-5-yl-phenoxy)- Propane-1-one

The compound of Preparation 29 (280 mg, 0.62 mmol) was heated in a mixture of glacial acetic acid (3 ml) and dioxane (3 ml) at 90 ° C. for 3.5 hours. The mixture was then cooled and evaporated under reduced pressure to yield a yellow oil. The oil was dissolved in ethyl acetate (50 ml) and washed with 10% sodium carbonate solution (10 ml) and water (10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a colorless foam. The foam was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to 97: 3 to give a colorless oil. This oil was azeotropic with dichloromethane to give 118 mg of the title compound in 44% yield as a colorless foam.

LRMS (ES ⁻ ): m / z [M ⁻ H] ⁻ 433

Example 49

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [3- (2H-pyrazol-3-yl) -phenoxy] -propane-1 -On

(3R)-(3-Methyl-piperazin-1-yl) -phenyl-methanone [(114 mg, 0.56 mmol), J. Med. Chem. 43 (23), 4499; 2000], 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) -one (167.5 mg, 0.56 mmol) and triethylamine (78 μl, 0.56 mmol) To a solution of compound of Preparation 23 (130 mg, 0.56 mmol) in furan (8 ml) was added and the resulting solution was stirred for 48 hours at room temperature. The mixture was then diluted with ethyl acetate (30 ml) and washed with water (10 ml), 10% citric acid (10 ml), water (10 ml) and sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting from 98: 2 to 96: 4 to give a colorless foam. This foam was azeotropic with dichloromethane and dried under reduced pressure to give 198 mg of the title compound in 85% yield.

^{LRMS (ES -): m /} z [MH] - 417

Example 50

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [2-methyl-3- (2H-pyrazol-3-yl) -phenoxy] Propane-1-one

The title compound was carried out using the compound of Preparation Example 24 and (3R)-(3-methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem. 43 (23), 4499; 2000) Prepared by the method described above for Example 49.

^{LRMS (ES -): m /} z [MH] - 431

Example 51

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [4- (1H-imidazol-2-yl) -2-methoxy-phenoxy] -propane- 1-on

The compound of Preparation 33 (30 mg, 0.16 mmol) and the compound of Preparation 25 (53.5 mg, 0.16 mmol) and cesium carbonate (51.3 mg, 0.16 mmol) in N, N-dimethylformamide (4 ml) were prepared at 80 ° C. Heated at for 18 h. The reaction mixture was cooled down and then evaporated under reduced pressure and the residue was partitioned between dichloromethane (30 ml) and water (8 ml). The aqueous phase was separated and reextracted with dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to 95: 5 to give 52 mg of the title compound as a beige foam in 74% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 449

Examples 52-53

The following compounds of formula shown below were prepared in the manner described above for Example 51 using the compound of Preparation 25 and the appropriate phenol.

Examples 54-57

The following compounds of formula shown below were prepared in the manner described above for Example 51 using the compound of Preparation 25 and the appropriate phenol.

Example 54: Phenol Prepared as Described in Preparation Example 67

Example 55 Phenol Prepared as Described in Preparation Example 68

Example 56 6-methoxy-2-naphthol is commercially available

Example 57 5-hydroxy-1-naphthalene sulfonamide is commercially available

Example 58

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (4-methanesulfonyl-2-methoxy-phenoxy) -propan-1-one

A solution of oxone (215 mg, 0.35 mmol) in water (2 ml) was added to a solution of the compound of Example 54 (100 mg, 0.23 mmol) in methanol (4 ml) and the mixture was stirred at rt for 18 h. . The solvent is then evaporated under reduced pressure and the residue is partitioned between water (20 ml) and dichloromethane (20 ml). The aqueous phase was separated and reextracted with dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 95: 5 to give 80 mg of the title compound as a white solid in 76% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 461

Example 59

N- {4- [2- (2R)-(4-benzoyl-2-methyl-piperazin-1-yl) -1-methyl-2-oxo-ethoxy] -3-methoxy-phenyl} -methane Sulfonamide

Triethylamine (0.08 ml, 0.57 mmol) was added to a solution of compound of Preparation 30 (150 mg, 0.38 mmol) in dichloromethane (3 ml) and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.03 ml, 0.42 mmol) was added dropwise and the reaction mixture was stirred for 18 hours at room temperature. The mixture was then diluted with additional dichloromethane (20 ml) and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was then purified by column chromatography on silica gel eluting with ethyl acetate: methanol, 98: 2 to give 88 mg of the title compound as a white solid in 49% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 476

Example 60

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (2-chloro-quinolin-5-yloxy) -propan-1-one

A solution of compound of Preparation 46 (1.8 g, 4.3 mmol) in phosphoric acid chloride (5 ml) was heated at 100 ° C. for 2 hours. The reaction mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (10 ml) and water (2 × 10 ml). The aqueous phase was basified with 1M sodium hydroxide solution and reextracted with ethyl acetate. The combined organic extracts were then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 20:80, 0: 100 to give 580 mg of the title compound as a light yellow solid in 31% yield.

Examples 61-62

Example 60 compound (30 mg, 0.069 mmol), tetrabutyl ammonium fluoride (18 mg, 0.14 mmol), triethylamine (96 μl, 0.69 mmol) and the appropriate amine (0.69 mmol) in dimethylsulfoxide (1 ml) ) Was heated at 100 ° C for 24 h. Then HPLC using a Phenomenex Luna C18 system eluting the reaction mixture with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 Purification directly to afford the desired compound of formula

Example 63

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (1-chloro-isoquinolin-5-yloxy) -propan-1-one

The title compound was prepared by the method described above for Example 60 using the compound of Preparation Example 63 and phosphorus acid chloride.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 438

Examples 64-65

Example 63 compound (45 mg, 0.1 mmol), tetrabutyl ammonium fluoride (27 mg, 0.2 mmol), triethylamine (140 μl, 1 mmol) and the appropriate amine (1 mmol) in dimethylsulfoxide (1 ml) ) Was heated at 130 ° C for 24 h. The reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95. The desired compound of formula is given below:

Example 66

(2S) -2- (2-Amino-quinolin-5-yloxy) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -propan-1-one

10% Pd / C (catalyst amount) and ammonium formate (10 mg, 0.15 mmol) are added to a solution of compound of Preparation 49 (15 mg, 0.03 mmol) in ethanol (1 ml) and the mixture is 70 for 2 hours. Heated at ° C. Additional ammonium formate (10 mg, 0.15 mmol) and Pd (OH) ₂ (catalyst amount) were added and the reaction mixture was heated at reflux for an additional 18 hours. The mixture was then cooled and filtered through Arbocel® and washed through ethanol (10 ml). Concentrate the filtrate under vacuum and HPLC using Phenomenex Luna C18 system, eluting the residue with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 Purification with 9.7 gave 9.7 mg of the title compound in 77% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 419

Example 67

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-quinolin-5-yloxy) -propan-1-one

A mixture of compound of Preparation 42 (30 mg, 0.07 mmol) and N-chlorosuccinimide (11 mg, 0.08 mmol) in acetonitrile (3 ml) was heated at 40 ° C. for 48 hours. Then the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (5 ml) and washed with water (2 × 5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by HPLC using Phenomenex Luna C18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 to give the title compound as a solid. 9.7 mg were obtained in 32% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 438

Examples 68-69

The following compounds of formula shown below were prepared by the method described above for Example 67 using the appropriate starting materials and N-chlorosuccinimide.

Examples 68 and 69 were purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to 96: 4.

Examples 70 and 71

A compound was prepared from the compound of Preparation Example 60 and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate) using a preparation analogous to Example 67 It was. The compound was converted into acetonitrile: water: trifluoroacetic acid (5: 95: 0.1) [solvent A] and acetonitrile- [solvent B] using two solvent eluents, Phenomenex Luna C18 (2) column 150 × 15 Purification was by HPLC using mm (10 micron particle size, 100 μs porosity). Solvent gradient was performed at a flow rate of 20 ml / min as shown in the table below.

Example 72

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-methyl-quinolin-5-yloxy) -propan-1-one

Compound of Preparation 44 (200 mg, 0.4 mmol), methyl boronic acid (74 mg, 1.2 mmol), bis (triphenylphosphine) palladium (II) chloride (29 in N, N-dimethylformamide (4 ml) (29) mg, 0.04 mmol) and potassium carbonate (229 mg, 1.6 mmol) were heated at 100 ° C. for 18 hours. tlc analysis showed that the reaction was not complete, so additional amounts of methyl boronic acid (74 mg) and bis (triphenylphosphine) palladium (II) chloride (29 mg) were added and the mixture was added for 24 hours Stirred at 100 ° C. The reaction mixture was then filtered through Arbocel® and washed through ethyl acetate (25 ml) and water (3 x 20 ml). The layers were separated and the aqueous phase was reextracted with ethyl acetate. The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by HPLC using Phenomenex Luna C18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95. The appropriate fraction was then azeotropic with diethyl ether to give 33 mg of the title compound in 19% yield as a yellow solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 418

Example 73

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [8- (2H-pyrazol-3-yl) -quinolin-5-yloxy] Propane-1-one

4M hydrochloric acid (2 ml) was added to a suspension of the compound of Preparation 45 (43 mg, 0.07 mmol) in methanol (2 ml) and the resulting solution was stirred at rt for 18 h. The reaction mixture was then evaporated under reduced pressure, the residue dissolved in water and washed twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 98: 2 to give 23 mg of the title compound as a yellow solid in 68% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 470

Example 74

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [2- (2H-pyrazol-3-ylamino) -quinolin-5-yloxy ] -Propane-1-one

A mixture of the compound of Example 60 (50 mg, 0.11 mmol), 3-aminopyrazole (29 mg, 0.33 mmol) and triethylamine (48 μl, 0.33 mmol) in 2-propanol (0.5 ml) at 90 ° C. Heat in Reactivial ™. After 18 hours cesium fluoride (33 mg, 0.22 mmol) was added and the mixture was heated at 100 ° C. for an additional 48 hours. The reaction mixture was then filtered and concentrated in vacuo to give an oily residue. The residue was purified by HPLC using Phenomenex Luna C18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 to give the title as a yellow solid. 3 mg of compound were obtained.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 485

Example 75

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -1 H-quinolin-2-one

The compound of Example 60 (200 mg, 0.46 mmol) and acetic acid (3 ml) were dissolved in water and the solution was heated at reflux for 24 hours. The reaction mixture was then diluted with water and washed with dichloromethane (3 x 10 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield a yellow oil. The oil was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 95: 5 to give 76 mg of the title compound as a pale yellow solid in 40% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 418

Example 76

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -8-chloro-1H-quinoline- 2-on

The title compound was prepared by the method described above for Example 67 using the compound of Example 75 and N-chlorosuccinimide.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 454

Example 77

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (2-methoxy-quinolin-5-yloxy) -propan-1-one

A mixture of the compound of Example 60 (20 mg, 0.04 mmol) and sodium methoxide (0.5 M in methanol, 0.7 ml) in N, N-dimethylformamide (0.5 ml) at 6O < 0 > C in Reactivial ™ for 6 hours Heated. The reaction mixture was cooled down and evaporated under reduced pressure. The residue was dissolved in dichloromethane (5 ml) and washed with brine (5 ml) and water (2 × 5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Phenomenex Luna C18 system dissolved in dimethylsulfoxide (0.5 ml) and eluted with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 Purified by HPLC using. The appropriate fraction was then azeotropic with ethyl ether to afford 7 mg of the title compound as a yellow solid in 40% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 434

Example 78

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -isoquinoline-1-carboxylic acid Methyl ester

Compound of Preparation Example 65 (80 mg, 0.18 mmol), dichloro-bis (triphenylphosphine) palladium (15 mg, 0.018 mmol) and triethylamine (51 μl, 0.37 mmol) were dissolved in methanol (5 ml) and And transferred to a sealed bottle. The bottle was heated to 100 ° C. and then the mixture was stirred for 42 hours under 100 psi of carbon monoxide gas. The reaction mixture was then filtered through Arbocel®, washed through methanol and the filtrate was concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to give 36 mg of the title compound as a white foam in 43% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 462

Example 79

5- {2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -quinoline-2-carboxylic acid methylamide

Compound of Preparation 48 (20 mg, 0.05 mmol), methylamine (33%, 30 mg, 0.5 mmol) in dichloromethane (1 ml), O- (1H-benzotriazol-1-yl) -N A mixture of, N, N ', N'-tetramethyluronium hexafluorophosphate (2 mg, 0.08 mmol) and triethylamine (62 μL, 0.5 mmol) was stirred at rt for 18 h. Additional methylamine (30 mg, 0.5 mmol) and triethylamine (62 μl, 0.5 mmol) were added to the reaction mixture and stirring continued for an additional 18 hours. The reaction mixture was then diluted with dichloromethane and washed with water (2 x 5 ml) and brine (5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 96: 4 to give 3 mg of the title compound as a white solid in 13% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 461

Example 80

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -isoquinoline-1-carboxylic acid Methylamide

The title compound was prepared by the method described above for Example 79 using the compound of Preparation Example 78 and methylamine.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 461

Example 81

4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -N-methyl-3-trifluoro Lomethoxy-Benzamide

The compound of Preparation 59 (100 mg, 0.2 mmol) and methylamine (33% in ethanol, 4 ml) were heated at 90 ° C. in Reactivial ™ for 18 hours. The solvent is then evaporated under reduced pressure and the residue is purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to 97: 3 to give 100 mg of the title compound as a pale orange foam in quantitative yield. Obtained.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ + 494

Example 82

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-2-methylamino-quinolin-5-yloxy) -propane-1 -On

Compound of Preparation 52 (60 mg, 0.12 mmol), methylamine hydrochloride (86 mg, 1.2 mmol), cesium fluoride (39 mg, 0.24 mmol) and triethylamine (0.18 ml in dimethylsulfoxide (1 ml) , 1.2 mmol) was heated with microwave at 170 ° C. for 8 minutes. The reaction mixture was then filtered and the filtrate was eluted with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 using a Phenomenex Luna C18 system. Purification by HPLC. The appropriate fraction was then azeotropic with diethyl ether to give 10.8 mg of the title compound in 19% yield as a brown solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 467

Example 83

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (1-methylamino-isoquinolin-5-yloxy) -propan-1-one

The title compound was prepared by the method described above for Example 82 using the compound of Preparation Example 63 and methylamine.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 433

Example 84

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-2-dimethylamino-quinolin-5-yloxy) -propane-1 -On

Compound of Preparation 52 (50 mg, 0.1 mmol), dimethylamine (86 mg, 1 mmol), cesium fluoride (32 mg, 0.2 mmol) and triethylamine (0.15 ml, 1 in dimethylsulfoxide (4 ml) mmol) was heated in Reactivial ™ at 170 ° C. for 18 hours. The reaction mixture was then filtered and the filtrate was eluted with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 using a Phenomenex Luna C18 system. Purification by HPLC gave 5 mg of the title compound as a white solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 481

Example 85

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) -isoquinoline-5-yljade -Propane-1-one

Example 63 compound (45 mg, 0.1 mmol), tetrabutyl ammonium fluoride (27 mg, 0.2 mmol), triethylamine (0.14 ml, 1 mmol) and 3-aminopyrazole in dimethylsulfoxide (1 ml) (83 mg, 1 mmol) was heated at 100 ° C for 24 h. The reaction mixture was then purified directly by HPLC using Phenomenex Luna C18 system eluting with water / acetonitrile / formic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 to give the title compound 19 mg was obtained in 39% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 485

Example 86

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl)]-2- (3,6-dimethyl-1H-indazol-4-yloxy) -propane- 1-on

4M hydrochloric acid in dioxane (1 ml) was added to the compound of Preparation 77 (45 mg, 86 μmol) in methanol, and the solution was stirred for 2 hours. The reaction mixture was evaporated under reduced pressure, the residue dissolved in dichloromethane and basified to pH 12 with 1M sodium hydroxide solution. The mixture was then passed through a phase separation column and the filtrate was concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 96: 4: 1 gave 20 mg of the title compound as a pale pink foam in 59% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 421

Example 87

(2S) -1-[(2R) -2-methyl-4- (pyridin-2-carbonyl) -piperazin-1-yl] -2- (quinolin-5-yloxy) -propan-1-one

Compound of Preparation 51 (150 mg, 0.5 mmol), picolinic acid (49 mg, 0.6 mmol) O- (1H-benzotriazol-1-yl) -N, N, N 'in dichloromethane (3 ml) A mixture of, N'-tetramethyluronium hexa fluorophosphate (190 mg, 0.75 mmol) and triethylamine (0.93 ml, 10 mmol) was stirred at rt for 18 h. The reaction mixture was then diluted with additional dichloromethane and washed with sodium hydroxide (10 ml) and water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to 95: 5 to give 99 mg of the title compound as a white solid in 49% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 405

Example 88

(2S) -1- [4- (2-Fluoro-benzoyl)-(2R) -2-methyl-piperazin-1-yl] -2- (quinolin-5-yloxy) -propan-1-one

A mixture of compound of Preparation 51 (150 mg, 0.5 mmol), 2-fluorobenzoyl chloride and triethylamine in dichloromethane (3 ml) was stirred at room temperature for 18 hours. Then the reaction mixture was diluted with dichloromethane and washed with water (2 × 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol, 98: 2 gave 153 mg of the title compound as a white solid in 73% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 422

Example 89

4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -3-methoxy-N-methyl -Benzamide

(3R)-(3-Methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem. (2000), 43 (23), 4499) in dry THF (250 ml) (22 g, 0.11 mol) and 1-N-hydroxybenza in a solution of (2S) -2- (2-methoxy-4-methylcarbamoyl-phenoxy) -propionic acid (25 g, 0.1 mol) (Preparation 5) Triazole monohydrate (20 g, 0.13 mol), 1-ethyl-3- (3'dimethylaminopropyl) carbodiimide. HCl (17 g, 0.09 mol) and diisopropylethylamine (17 ml, 0.1 mol) Was added. After stirring for 1 h, 1-ethyl-3- (3'dimethylaminopropyl) carbodiimide. After addition of an additional portion of HCl (17 g, 0.09 mol), additional diisopropylethylamine (17 ml, 0.1 mol) was added. After 1 hour, 1-ethyl-3- (3'dimethylaminopropyl) carbodiimide. After addition of an additional portion of HCl (17 g, 0.09 mol) was added to diisopropylethylamine (17 ml, 0.1 mol) Another part was added. The mixture was then stirred for an additional 16 hours. After this point, LCMS analysis showed that all propionic acid was consumed. The reaction mixture was evaporated to give a viscous oil which was treated with water (200 ml) and then concentrated aqueous hydrochloric acid was added slowly until the mixture reached pH 3. The resulting off-white precipitate was filtered off and washed with water (3 × 100 ml). The solid was recrystallized twice from ethanol: water (1: 1 by volume, 120 ml) to afford the title compound as a white solid (32 g).

Example 90

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid methyl ester

Di-tert-butyl azodicarboxylate (0.14 g, 0.6 mmol) and polymer supported triphenylphosphine (0.25 g, 0.75 mmol) were added to (2R) -1-[(2R) in dichloromethane (3 ml). -4-benzoyl-2-methyl-piperazin-1-yl) -2-hydroxy-propan-1-one (Preparation 76) (0.083 g, 0.3 mmol) and 5-hydroxy-4-methoxy- To a stirred solution of pyridine-2-carboxylic acid methyl ester (0.083 g, 0.45 mmol) (Tetrahedron Letters, 38, 1297 (1997)) was added at 0 ° C. After 1 hour, the reaction mixture was allowed to warm to room temperature and additional di-tert-butyl azodicarboxylate (0.14 g, 0.6 mmol) and polymer supported triphenylphosphine (0.25 g, 0.75 mmol) were added. After 18 hours, the reaction mixture was filtered through Arbocel® at room temperature and washed by passing through dichloromethane (10 ml). The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), then the organic phase was separated, dried (MgSO ₄ ) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane, 80:20, then ethyl acetate and finally ethyl acetate: methanol, 95: 5 to give 0.1 g of the title compound as a white solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 442

Example 91

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic Acid Methylamide

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2 in 33% w / w methylamine solution in ethanol (3 ml) A solution of -oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid methyl ester (Example 90) (0.2 g, 0.45 mmol) was heated in Reactivial ™ at 50 ° C. for 18 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: NH ₃ , 98: 2: 0.5 to 95: 5: 0.5 to give 0.18 g of the title compound as a white solid.

Example 92

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid amide

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2- in concentrated aqueous ammonia solution (2 ml) and methanol (1 ml) A solution of oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid methyl ester (Example 90) (0.2 g, 0.45 mmol) was heated in Reactivial ™ at 50 ° C. for 18 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: NH ₃ , 98: 2: 0.5 to 95: 5: 0.5 to give 0.16 g of the title compound as a white solid.

Example 93

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic Acid Ethylamide

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4 in ethylamine (1 ml) A solution of -methoxy-pyridine-2-carboxylic acid methyl ester (Example 90) (0.15 g, 0.34 mmol) was heated in Reactivial ™ at 50 ° C. for 18 hours. After cooling to room temperature the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 96: 4 to give 0.14 g of the title compound as a white solid.

Example 94

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid cyclopropylamide

5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy}-in cyclopropylamine (1 ml) A solution of 4-methoxy-pyridine-2-carboxylic acid methyl ester (Example 90) (0.12 g, 0.27 mmol) was heated in Reactivial ™ at 50 ° C. for 18 hours. After cooling to room temperature the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 95: 5 to afford 0.09 g of the title compound as a white solid.

Preparation Example 1

(2S) -2- (quinolin-5-yloxy) -propionic acid methyl ester

Triphenylphosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of di-isopropyl azodicarboxylate (1.47 ml, 7.56 mmol) in THF (25 ml) at -5 ° C. 5-hydroxyquinoline (1.0 g, 6.90 mmol) and methyl (R) -lactate (0.66 ml, 6.90 mmol) were then added and the solution was stirred for 14 hours at room temperature. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 ml). The solution was dried (MgSO ₄ ) and the solvent evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a gradient system changed from pentane: ethyl acetate (4: 1) to pentane: ethyl acetate (3: 2). The title compound was obtained as a white solid (1.30 g).

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 232.

Preparation Example 2

(2S) -2- (quinolin-5-yloxy) -sodium propionate salt

A solution of (S) -2- (quinolin-5-yloxy) -propionic acid methyl ester (Preparation Example 1) (1.30 g, 5.60 mmol) and 1N sodium hydroxide solution (5.62 ml) in dioxane (40 ml) was added 60 Heat at C for 2 h. After this point, tlc analysis showed that the starting material remained, so additional 1N sodium hydroxide solution (1.4 ml) was added and heating continued at 60 ° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure to afford the title compound as a yellow solid, which was used without further purification.

LRMS (ESI ⁺ ): m / z [M + H] ⁺ 218.

Preparation Example 3

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl) -2-bromo-propan-1-one

(3R)-(3-Methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem. (2000) in dichloromethane (60 ml) and N, N-dimethylformamide (2 ml) , 43 (23), 4499) (4.06 g, 19.6 mmol) in a solution of 2-bromopropionic acid (3.0 g, 19.6 mmol), O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (8.18 g, 21.6 mmol) and triethylamine (2.74 ml, 19.6 mmol) were added. The reaction mixture was stirred at rt for 48 h and then washed with water (50 ml), 10% w / v aqueous citric acid solution (50 ml) and saturated aqueous sodium hydrogen carbonate solution (50 ml). The solution was dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a gradient system changed from dichloromethane: methanol (99: 1) to dichloromethane: methanol (95: 5). The product was then further purified by column chromatography on silica gel eluting with a gradient system changed from ethyl acetate: dichloromethane (30:70) to ethyl acetate: dichloromethane (45:55) to give the title as a white solid (3.80 g). The compound was obtained.

LRMS (ESI ⁺ ): m / z [M + H] ⁺ 340.

Preparation Example 4

4-hydroxy-3-methoxy-N-methyl-benzamide

Carbonyldiimidazole (97 g, 0.6 mol) was added in portions to a mechanically stirred suspension of vanillic acid (84 g, 0.5 mol) in anhydrous THF (300 ml). Gas evaporation was observed and the mixture was homogenized after approximately 5 minutes. After stirring for an additional 30 minutes, an off-white precipitate formed, and the stirring was maintained for an additional 3 hours under nitrogen. After this point, LCMS analysis showed vanillic acid was consumed and a solution of 2M methylamine in THF (1000 ml, 2 mol) was added in one portion and the mixture was stirred for a further 16 hours to produce a tan precipitate. The precipitate was filtered off, washed with THF (2 × 250 ml), then with ether (300 ml) and dried under vacuum to afford the N-methylammonium salt (87 g, 82%) of the title compound.

LRMS (ESI ⁺ ): m / z [M + H] ⁺ 182.

A portion of ammonium salt (1.06 g, 5 mmol) was refluxed for 2 h under a stream of nitrogen in ethyl acetate. The reaction was evaporated to give an oily solid which was triturated with ethyl acetate to give the title compound as a tan solid (750 mg).

LRMS (ESI ⁺ ): m / z [M + H] ⁺ 182.

Preparation Example 5

(2S) -2- (2-methoxy-4-methylcarbamoyl-phenoxy) -propionic acid

Triphenylphosphine (42 g, 0.16 mol), 4-hydroxy-3-methoxy-N-methyl-benzamide (Preparation 4) (20 g, 0.11 mol) and methyl (in anhydrous THF (300 ml) To a stirred mixture of R) -lactate (12 g, 0.12 mol) was added a solution of di-isopropyl azodicarboxylate (32 ml, 0.16 mmol) in dry THF (100 ml) at -5 ° C for 30 minutes. Dropwise over. The solution was allowed to warm to room temperature and stirred for 2 hours. After this point, tlc analysis showed that the starting phenol was consumed. The crude reaction mixture was evaporated under reduced pressure to give a viscous oil. To a stirred solution of this oil in methanol (150 ml) was added lithium hydroxide monohydrate (5.4 g, 0.13 mol) and the mixture was stirred for 48 hours. After this point, LCMS analysis showed that the intermediate methyl ester was consumed. The crude reaction mixture was evaporated and partitioned between ether (500 ml) and water (150 ml). The aqueous phase was separated and washed with ether (2 x 300 ml) and ethyl acetate (2 x 300 ml). The aqueous phase was then acidified to pH 2 with concentrated aqueous hydrochloric acid to form a white precipitate. This precipitate was filtered off, washed with water (2 × 100 ml) and recrystallized from ethanol: water (1: 1 by volume, 80 ml per 20 g) to give the title compound as a white solid (21 g, 75%). Obtained.

LRMS (ESI ⁺ ): m / z [M + H] ⁺ 254.

Preparation Example 6

3-methoxy-4-[(1S) -1-methoxycarbonyl-ethoxy] -benzoic acid methyl ester

Diisopropyl azodicarboxylate (4 ml, 20 mmol) in tetrahydrofuran (15 ml) to methyl vanillate (3.64 g, 20 mol) in tetrahydrofuran (30 ml), methyl (R) -lactate (2.08 g, 20 mmol) and an ice-cold solution of triphenyl phosphine (5.24 g, 20 mmol) were added dropwise and the reaction mixture was stirred at rt for 18 h. The solvent is then evaporated under reduced pressure and the residue is stirred in a mixture of diethyl ether (50 ml) and hexane (50 ml). The resulting precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexanes: ethyl acetate, 85:15 to 75:25 to give 3.8 g of the title compound in 71% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 269

Preparation Example 7

4-[(1S) -1-carboxy-ethoxy] -3-methoxy-benzoic acid methyl ester

Lithium hydroxide monohydrate (4.2 g, 100 mmol) was added in portions to a solution of the compound of Preparation 6 (32 g, 120 mmol) in methanol (150 ml) and the mixture was stirred at rt for 18 h. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified to pH 4 with 2M hydrochloric acid and then extracted with ethyl acetate (3 × 150 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure to give 23 g of the title compound in 91% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 255

Preparation Example 8

4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -3-methoxy-benzoic acid methyl ester

Hunig's base (1.8 ml, 10.5 mmol) was added to the compound of Preparation 7 (1.8 g, 7 mmol), (3R)-(3-methyl-piperazin-1-yl) -phenyl- in dichloromethane (16 ml). Methanone [(1.6 g, 7.7 mmol), J. Med. Chem. 43 (23), 4499; 2000], and a solution of 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) -one (2.75 g, 9.1 mmol). The mixture was stirred for 4 hours and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200 ml) and washed with 10% sodium carbonate solution (2 × 50 ml) and brine (2 × 50 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexanes: ethyl acetate, 25:75 to 5:95 to give 2.95 g of the title compound in 95% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 441

Preparation Example 9

4-{(1S) -2-[(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxo-ethoxy} -3-methoxy-benzamide

The compound of Preparation 8 (0.46 g, 1.04 mmol) and 2M ammonia in methanol (10 ml) were heated to 120 ° C. for 18 hours in a sealed bottle. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 98: 2 to 92: 8 to give 243 mg of the title compound as a colorless foam in 55% yield. Obtained.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 426

Preparation Example 10

4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -N-dimethylaminomethylene-3- Methoxy-benzamide

The compound of Preparation 9 (240 mg, 0.56 mmol) and N, N-dimethylformamide dimethylacetal (10 ml) were heated at reflux for 7 hours. The reaction mixture was then evaporated under reduced pressure to yield a pale orange solid. The solid was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to 97: 3 to give a colorless oil. This oil was then azeotropic with dichloromethane and the resulting foam was dried at 40 ° C. for 3 hours to give 255 mg of the title compound in 94% yield.

LRMS (ES ⁺ ): m / z [M + Na] ⁺ 503

Preparation Examples 11 to 13

The following compounds of formula shown below were prepared by the method described above for Preparation 10 using the appropriate ketone and dimethylformamide dimethylacetal.

Preparation Example 11 is described in Tetrahedron 25 (18), 4249; 1969) was used as 1- (3-methoxy-2-methyl-phenyl) -ethanone.

Preparation Example 14

3- (3-methoxy-2-methyl-phenyl) -1-methyl-1H-pyrazole

Compound of Preparation 11 (2.05 g, 9.35 mmol) was added in portions to a solution of methylhydrazine (547 μl, 10.28 mmol) in acetic acid (15 ml) and the mixture was heated at 90 ° C. for 2.5 h. The solvent was then evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with 10% sodium carbonate solution and saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give an orange oil. This oil was first purified by column chromatography on silica gel eluting with dichloromethane: ethyl acetate, 99: 1 to 97: 3. Then further purification using an Isolute® flash silica column eluting with dichloromethane: ethyl acetate, 99: 1 to 97: 3 gave 568 mg of the title compound as a yellow oil in 31% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 203

Preparation Examples 15 to 16

The following compounds of formula shown below were prepared by the method described above for Preparation 14 using the appropriate enamines and hydrazine monohydrate.

Preparation Example 17

2-methyl-3- (1-methyl-1H-pyrazol-3-yl) -phenol

Boron tribromide (1M in dichloromethane, 8.16 ml, 8.16 mmol) was added dropwise to an ice-cooled solution of compound of Preparation 14 (550 mg, 2.72 mmol) in dichloromethane (6 ml). The resulting solution was allowed to warm to rt and stirred for 2 h. The reaction mixture was then carefully poured onto ice and neutralized with 10% sodium carbonate solution. The mixture was extracted with dichloromethane (2 x 50 ml) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography using Isolut® flash silica column eluting with dichloromethane: methanol, 98: 2 to 97: 3 to give a brown oil. The oil was azeotropic with dichloromethane to afford 31O mg of the title compound as a brown foam in 61% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 189

Preparation Examples 18 to 20

The following compounds of formula shown below were prepared by the method described above for Preparation 17 using the appropriate methoxybenzene derivative and boron tribromide.

Preparation 18: The title compound was prepared by dealkylation of 3-methoxy-2-methylbenzamide (J. Chem. Soc. Perkin Trans. 1, 2389-2396; 1984).

Preparation Example 21

(2S) -2- [3- (2H-pyrazol-3-yl) -phenoxy] -propionic acid methyl ester

Diisopropyl azodicarboxylate (295 μl, 1.50 mmol) was added to the compound of Preparation 20 (240 mg, 1.5 mmol), methyl (R) -lactate (156 mg, 1.50 mmol) in tetrahydrofuran (5 ml). ) And triphenyl phosphine (393 mg, 1.5 mmol) were added drop wise. The reaction mixture was stirred at rt for 18 h, then diluted with diethyl ether (50 ml) and washed with water (2 × 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on an Isolute® flash silica column eluting with diethyl ether: dichloromethane, 80:20 to 95: 5 to give 200 mg of the title compound as a viscous yellow oil in 54% yield.

LRMS (ES ⁻ ): m / z [M ⁻ H] ⁻ 245

Preparation Example 22

(2S) -2- [2-Methyl-3- (2H-pyrazol-3-yl) -phenoxy] -propionic acid methyl ester

The title compound was prepared by the method described above for Preparation 21 using the compound of Preparation Example 19 and methyl (R) -lactate.

^{LRMS (ES -): m /} z [MH] - 259

Preparation Example 23

(2S) -2- [3- (2H-pyrazol-3-yl) -phenoxy] -propionic acid

Lithium hydroxide monohydrate (80.9 mg, 1.93 mmol) was added in portions to a solution of the compound of Preparation 21 (190 mg, 0.77 mmol) in methanol (6 ml) and the mixture was stirred at 60 ° C. for 8 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified to pH 4 with 2M hydrochloric acid and then extracted with ethyl acetate (3 × 30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure to give 135 mg of the title compound in 75% yield.

LRMS (ES ⁻ ): m / z [M ⁻ H] ⁻ 231

Preparation Example 24

(2S) -2- [2-Methyl-3- (2H-pyrazol-3-yl) -phenoxy] -propionic acid

The title compound was prepared by the method described above for Preparation 22 using the compound of Preparation 22 and lithium hydroxide.

LRMS (ES ⁻ ): m / z [M ⁻ H] ⁻ 245

Preparation Example 25

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2-bromo-propan-1-one

2-Bromopropionic acid (1.53 g, 10 mmol) was added to a solution of N, N'-dicyclohexylcarbodiimide (2.06 g, 10 mmol) in dichloromethane (40 ml) and cooled to -15 ° C. . The reaction mixture was stirred for 20 minutes, then (2R)-(3-methyl-piperazin-1-yl) -phenyl-methanone [(2.04 g, 10 mmol), J. Med in dichloromethane (16 ml) . Chem. 43 (23), 4499; 2000] in portions. The reaction mixture was stirred at −15 ° C. for 90 minutes, then diluted with diethyl ether (100 ml) and stirred for an additional 10 minutes. The mixture was then filtered through Celite, washed through diethyl ether and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexanes: ethyl acetate, 40:60 to 20:80 to give 2.5 g of the title compound in 76% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 340

Preparation Example 26

3- {2-[(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxo-ethoxy} -2-methyl-benzamide

The compound of Preparation 18 (180 mg, 1.19 mmol) and the compound of Preparation 25 (403.9 mg, 1.19 mmol) and cesium carbonate (387 mg, 1.19 mmol) in N, N-dimethylformamide (10 ml) were dried at 80 ° C. Heated at for 18 h. The cooled reaction mixture was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (10 ml). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with chloromethane: methanol, 99: 1 to 96: 4 to give a colorless foam. The foam was azeotropic with dichloromethane and dried under reduced pressure to give 475 mg of the title compound in 98% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 410

Preparation Example 27

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (3-methoxy-5-nitro-phenoxy) -propan-1-one

The title compound was prepared by the method described above for Preparation 26 using the compound of Preparation 25 and 2-methoxy-5-nitrophenol.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 428

Preparation Example 28

3- {2-[(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -N- (dimethylamino) methylene] -2-methylbenzamide

The title compound was prepared by the method described above for Preparation Example 10 using the compound of Preparation Example 26 and N, N-dimethylformamide dimethylacetal.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 465

Preparation Example 29

3- {2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -N-hydroxyaminomethylene-2-methyl-benz amides

Sodium hydroxide solution (1M, 1.06 ml, 1.06 mmol) was added dropwise to a suspension of hydroxylamine hydrochloride (73.6 mg, 1.06 mmol) in acetic acid (6 ml). Then, the compound of Preparation Example 28 (410 mg, 0.88 mmol) was added in portions and the resulting solution was stirred at room temperature for 30 minutes. The solvent is evaporated under reduced pressure and the oily residue is partitioned between dichloromethane (30 ml) and water (6 ml) and neutralized with 10% sodium carbonate solution. The organic phase was separated and the aqueous phase was reextracted with dichloromethane (30 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to 96: 4 to give 310 mg of the title compound as a colorless foam in 78% yield.

LRMS (ES ⁻ ): m / z [M ⁻ H] ⁻ 451

Preparation Example 30

2- (4-Amino-2-methoxy-phenoxy) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -propan-1-one

25% Pd / C (150 mg) and ammonium formate (443 mg, 7 mmol) are added to a solution of compound of Preparation 27 (600 mg, 1.4 mmol) in ethanol (30 ml) and the mixture is added at 70 ° C. Heated for 2 hours. The reaction mixture was then cooled, filtered through Arbocel® and washed through ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 95: 5 to give 443 mg of the title compound as a pale pink solid in 80% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 398

Preparation Example 31

4-benzyloxy-3-methoxy-benzamidine

ⁿ Butyl lithium (1.6M in hexanes, 35.9 ml, 57.47 mmol) was added dropwise to a solution of hexamethyldisilazane (11.64 ml, 55.17 mmol) in diethyl ether (60 ml), cooled to -5 ° C and reaction The mixture was stirred for 30 min at a constant temperature of 0 ° C. 3-methoxy-4- (phenylmethoxy) -benzonitrile (5.5 g, 22.99 mmol) was added in portions and the mixture was stirred at rt for 4 h. The reaction mixture was then poured into ice cold 2M hydrochloric acid (100 ml) and washed with diethyl ether (2 × 100 ml). The aqueous phase was basified to pH 10 using 6M sodium hydroxide solution and extracted with dichloromethane (3 × 100 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield 3.99 g of the title compound as a white solid in 68% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 257

Preparation Example 32

2- (4-benzyloxy-3-methoxy-phenyl) -1 H-imidazole

Compound of Preparation 31 (1 g, 3.90 mmol) in chloroform (40 ml) was added to a solution of chloroacetaldehyde (336 mg, 3.90 mmol) in chloroform (10 ml), and the mixture was stirred at room temperature for 18 hours. . The resulting white precipitate was filtered off and the filtrate was washed with saturated sodium bicarbonate solution (30 ml). The aqueous phase was reextracted with 10% methanol in dichloromethane (2 x 50 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 98: 2 to 96: 4 to give a brown foam. The foam was further purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99.5: 0.5 to 98: 2 to give a beige foam. The foam was then azeotropic with dichloromethane and dried at 40 ° C. to yield 180 mg of the title compound in 16% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 281

Preparation Example 33

4- (1H-imidazol-2-yl) -2-methoxy-phenol

To a solution of compound of Preparation 32 (170 mg, 0.61 mmol) in methanol (10 ml) was added 10% Pd / C (85 mg) and ammonium formate (191 mg, 3.03 mol) in portions. The mixture was heated at reflux for 2 hours. The reaction mixture was then cooled, filtered through Arbocell® and washed through a mixture of dichloromethane and methanol (50:50, 250 ml). The filtrate was concentrated in vacuo and the residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to 96: 4 to give 105 mg of the title compound as a white solid in 91% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 191

Preparation Example 34

2-methoxy-4- (2H-pyrazol-3-yl) -phenol

The title compound was prepared by the method described above for Preparation Example 33 using the compound of Preparation Example 16.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 191

Preparation 35

1-benzyloxy-4-bromo-2-methoxy-benzene

A mixture of 4-bromo-2-methoxyphenol (5 g, 24.63 mmol), benzyl bromide (4.21 g, 24.63 mmol) and cesium carbonate (8 g, 24.63 mmol) in acetone (60 ml) was refluxed for 4 hours. Under heating. The cooled reaction mixture was then evaporated under reduced pressure and the residue was partitioned between diethyl ether (200 ml) and water (80 ml). The aqueous phase was separated and reextracted with diethyl ether (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was azeotropic with dichloromethane to afford 7.19 g of the title compound as a white solid in 100% yield.

LRMS (ES ⁺ ): m / z [M + Na] ⁺ 317

Preparation Example 36

1- (4-benzyloxy-3-methoxy-phenyl) -1H-pyrazole

Compound of Preparation 35 (1.5 g, 5.12 mol), pyrazole (697 mg, 10.23 mmol), copper (I) iodide (195 mg, 1.02 mmol) in N, N-dimethylformamide (10 ml) and The mixture of calcium carbonate was heated at 140 ° C. for 18 hours. The cooled reaction mixture was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (50 ml) and water (30 ml). The aqueous phase was separated and reextracted with diethyl ether (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 100: 0 to 96: 4 to give 1.18 g of the title compound as a white solid in 82% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 281

Preparation Example 37

2-methoxy-4-pyrazol-1-yl-phenol

The title compound was prepared by the method described above for Preparation 33 using the compound of Preparation 36.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 191

Preparation Example 38

(2S) -2- (quinolin-5-yloxy) -propionic acid methyl ester

Triphenylphosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of diisopropyl azodicarboxylate (1.47 ml, 7.56 mmol) in tetrahydrofuran (25 ml) at -5 ° C. 5-hydroxyquinoline (1.0 g, 6.90 mmol) and methyl- (R) -lactate (0.66 ml, 6.90 mmol) were added and the solution was stirred at rt for 14 h. The reaction mixture was then diluted with ethyl acetate (50 ml) and washed with water (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 ml). The solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 80:20 to 60:40 to give 1.30 g of the title compound as a white solid in 81% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 232

Preparation Example 39

(2S) -2- (isoquinolin-5-yloxy) -propionic acid methyl ester

The title compound was prepared by the method described above for Preparation 38 using 5-hydroxyisoquinoline and methyl- (R) -lactate.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 232

Preparation Example 40

(2S) -2- (quinolin-5-yloxy) -sodium propionate salt

A solution of compound of Preparation 38 (1.30 g, 5.60 mmol) and 1M sodium hydroxide solution (5.62 ml) in 1,4-dioxane (40 ml) was heated at 60 ° C. for 2 hours. After this point, tlc analysis showed that the starting material remained, so additional 1N sodium hydroxide solution (1.4 ml) was added and heating continued at 60 ° C. for 1 hour. The reaction mixture was then concentrated in vacuo to afford the title compound in quantitative yield as a yellow solid.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 218

Preparation Example 41

(2S) -2- (isoquinolin-5-yloxy) -sodium propionate salt

The title compound was prepared by the method described above for Preparation Example 40 using the compound of Preparation Example 39.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 218

Preparation Example 42

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (quinolin-5-yloxy) -propan-1-one

Compound of Preparation 40 (1.0 g, 4.6 mmol), (3R)-(3-methyl-piperazin-1-yl) -phenyl-methanone [(0.94 g] in N, N-dimethylformamide (30 ml) 4.6 mmol), J. Med. Chem., 43 (23), 4499; 2000], O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (2.62 g, 6.9 mmol) and triethylamine (1.93 ml, 13.8 mmol) was stirred at rt for 14 h. The reaction mixture was then diluted with dichloromethane (100 ml), washed with water (3 x 50 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 98: 2 to give 0.91 g of the title compound as a white solid in 49% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 404

Preparation Example 43

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl) -2- (isoquinolin-5-yloxy) -propan-1-one

The title compound was prepared using the compound of Preparation Example 41 and (3R)-(3-methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem., 43 (23), 4499; 2000) Prepared by the method described above for Preparation 42.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 404

Preparation Example 44

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-bromo-quinolin-5-yloxy) -propan-1-one

A mixture of compound of Preparation 42 (450 mg, 1.1 mmol) and N-bromosuccinimide (795 mg, 4.4 mmol) in acetonitrile (90 ml) was stirred at room temperature for 2 hours. Then the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (50 ml) and washed with water (2 × 20 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane, 33:67 to 100: 0 to give 526 mg of the title compound as a white solid in 98% yield.

LRMS (ES ⁺ ): m / z [M + H] ⁺ 482/484

Preparation Example 45

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- {8- [2- (2-trimethylsilanylethoxymethyl) -2H-pyrazole -3-yl] -quinolin-5-yloxy} -propan-1-one

Tetrakis (triphenylphosphine) palladium (0) (6 mg, catalytic amount) in water (0.5 ml), 1-[[(2- (trimethylsilyl) ethoxy] methyl] pyrazolyl-5-boronic acid [( 50 mg, 0.1 mmol), J. Med. Chem. 41 2019-2028; 1998] and sodium carbonate (175 mg, 1.6 mmol) were prepared in Example 44 compound (50 mg, 0.1 mmol) in tetrahydrofuran (2 ml). And the mixture was heated at reflux for 18 h The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with water (5 ml) and brine (2 x 5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give an orange oil, which was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to 96: 4 to give the title compound as a yellow solid. Obtained.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 600

Preparation Example 46

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-oxy-quinolin-5-yloxy) -propan-1-one

Meta-chloroperbenzoic acid (1.54 g, 4.44 mmol) was added to an ice cooled solution of compound of Preparation 42 (1.5 g, 3.7 mmol) in dichloromethane (15 ml) and the mixture was stirred at rt for 3 h. The reaction mixture was then diluted with dichloromethane (10 ml) and washed with saturated aqueous potassium carbonate solution (10 ml) and water (2 × 10 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 1.8 g of the title compound as a white solid in quantitative yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 420

Preparation 47

5- {2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -quinoline-2-carboxylic acid methyl ester

The chloro compound of Preparation 66 (130 mg, 0.3 mmol), dichloro-bis (triphenylphosphine) palladium (24 mg, 0.03 mmol) and triethylamine (83 μl, 0.6 mmol) were added to methanol (3 ml) and N. Was dissolved in a mixture of, N-dimethylformamide (0.5 ml) and transferred to a sealed bottle. The bottle was heated to 100 ° C. and the mixture was stirred for 42 h under 100 psi of carbon monoxide gas. The reaction mixture was then filtered through Arbocel®, washed through methanol and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane, 75:25 to 100: 0 to give 50 mg of the title compound in 41% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 462

Preparation Example 48

5- {2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -quinoline-2-carboxylic acid

1 M sodium hydroxide solution (130 μl, 0.135 mmol) was added to a solution of compound of preparation 47 (40 mg, 0.09 mmol) in dioxane (3 ml) and the mixture was heated at 60 ° C. for 3 hours. Then the solvent was evaporated under reduced pressure and the residue was dissolved in water (20 ml) and washed with ethyl acetate. The phases were separated and the organic phase was decanted. The aqueous phase was acidified with glacial acetic acid and reextracted with ethyl acetate. The remaining organic phase (twice washed) was dried over magnesium sulfate and concentrated in vacuo to give 26 mg of the title compound as a pale yellow solid in 67% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 448

Preparation 49

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (2-benzylamino-quinolin-5-yloxy) -propan-1-one

Example 60 compound (50 mg, 0.11 mmol), tetrabutyl ammonium fluoride (30 mg, 0.22 mmol), triethylamine (0.16 ml, 1.1 mmol) and benzylamine (0.13 ml) in dimethylsulfoxide (1 ml) , 1.1 mmol) was heated at 120 ° C. for 72 hours. The reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95. The title compound was obtained in 34% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 509

Preparation 50

(3R) -3-methyl-4-[(2S) -2- (quinolin-5-yloxy) -propionyl] -piperazin-1-carboxylic acid tert-butyl ester

1-hydroxybenzotriazole hydrate (249 mg, 1.87 mmol) was added to a suspension of compound of Preparation 40 (400 mg, 1.7 mmol) in N, N-dimethylformamide to form a solution. 1-ethyl-3- (3-dimethyl amino propyl) carbodiimide (351 mg, 1.87 mmol) and triethylamine (0.7 ml, 5.1 mmol) were added and the solution was stirred for 5 minutes. (3S) -3-methyl-piperazine-1-carboxylic acid tert-butyl ester (335 mg, 1.7 mmol) was added and the mixture was stirred for 18 hours. Then the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 ml) and washed with water (20 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give 332 mg of the title compound in 48% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 400

Preparation Example 51

(2S) -1-[(2R) -2-methyl-piperazin-1-yl] -2- (quinolin-5-yloxy) -propan-1-one; Hydrochloride

The compound of Preparation 50 (300 mg, 0.75 mmol) was stirred in 4M hydrochloric acid in dioxane (3 ml) for 2 hours. The reaction mixture was concentrated in vacuo and 348 mg of the title compound was obtained in quantitative yield as a light yellow solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 300

Preparation Example 52

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (2,8-dichloro-quinolin-5-yloxy) -propan-1-one

A mixture of Example 60 compound (200 mg, 0.4 mmol) and N-chlorosuccinimide (61 mg, 0.4 mmol) in acetonitrile (10 ml) was heated at 40 ° C. for 48 hours. The solvent is then evaporated under reduced pressure and the residue is dissolved in dichloromethane (20 ml) and washed with water (2 × 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 98: 2 to give 169 mg of the title compound as a white solid in 78% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 472

Preparation Example 53

(2S) -1-[(2R) -2-Methyl-4- (pyridin-2-carbonyl) -piperazin-1-yl] -quinolin-5-yloxy) -propan-1-one

Compound of Preparation 51 (150 mg, 0.5 mmol), picolinic acid (49 mg, 0.6 mmol), O- (1H-benzotriazol-1-yl) -N, N, N in dichloromethane (3 ml) A mixture of ', N'-tetramethyluronium hexafluorophosphate (190 mg, 0.75 mmol) and triethylamine (0.93 ml, 10 mol) was stirred for 18 hours at room temperature. The reaction mixture was then diluted with additional dichloromethane and washed with sodium hydroxide (10 ml) and water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to 95: 5 to give 99 mg of the title compound as a white solid in 49% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 405

Preparation Example 54

(2S) -1- [4- (2-Fluoro-benzoyl)-(2R) -2-methyl-piperazin-1-yl] -2- (quinolin-5-yloxy) -propan-1-one

A mixture of compound of Preparation 51 (150 mg, 0.5 mmol), 2-fluorobenzoyl chloride and triethylamine in dichloromethane (3 ml) was stirred at room temperature for 18 hours. Then the reaction mixture was diluted with dichloromethane and washed with water (2 × 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol, 98: 2 gave 153 mg of the title compound as a white solid in 73% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 422

Preparation Example 55

4-Bromo-2-trifluoromethoxy-phenol

Bromine (449 mg, 2.81 mmol) is added to a solution of 2- (trifluoromethoxy) phenol (500 mg, 2.81 mmol) and sodium acetate (169 mg, 2.81 mmol) in acetic acid (5 ml), and the solution is 1 Stir for hours. Then the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2 x 50 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give a colorless oil. The oil was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 85:15 to give the title compound as a white solid in 23% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 255/257

Preparation Example 56

(2S) -2- (4-Bromo-2-trifluoromethoxy-phenoxy) -propionic acid methyl ester

Diisopropyl azodicarboxylate (414 μl, 2.14 mmol) was added to the compound of Preparation 55 (500 mg, 1.95 mmol), methyl (R) -lactate (202 mg, 1.95 mmol) in tetrahydrofuran (20 ml). ) And triphenyl phosphine (614 mg, 2.34 mmol) were added drop wise. The reaction mixture was stirred at rt for 18 h and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 10% potassium carbonate solution (2 × 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 95: 5 to give 638 mg of the title compound as a colorless oil in 76% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 305/307

Preparation Example 57

(2S) -2- (4-Bromo-2-trifluoromethoxy-phenoxy) -propionic acid

A mixture of compound of Preparation 56 (574 mg, 1.67 mmol) and 1M sodium hydroxide solution (4.2 ml, 4.2 mmol) in dioxane (10 ml) was stirred at 55 ° C. for 3 hours. Then the solvent is evaporated under reduced pressure and the residue is dissolved in water (30 ml). The aqueous solution was acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate (2 × 50 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a yellow solid in 80% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 327

Preparation 58

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (4-bromo-2-trifluoromethoxy-phenoxy) -propane-1- On

Compound of Preparation 57 (150 mg, 0.46 mmol), (3R)-(3-methyl-piperazin-1-yl) -phenyl-methanone [(93 mg, 0.46 mmol) J in dichloromethane (30 ml) J Med. Chem., 43 (23), 4499; 2000], O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (260 mg, 0.69 mmol) and triethylamine (0.13 mol, 0.92 mmol) was stirred at rt for 18 h. Then the reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The aqueous phase was reextracted with dichloromethane (50 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to give 213 mg of the title compound as a white foam in 90% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 537/539

Preparation Example 59

4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -3-trifluoromethoxy-benzoic acid Methyl ester

Compound of Preparation 58 (190 mg, 0.37 mmol), dichloro-bis (triphenylphosphine) palladium (30 mg, 0.04 mmol) and triethylamine (0.10 ml, 0.74 mmol) were dissolved in methanol (10 ml) and And transferred to a sealed bottle. The bottle was heated to 100 ° C. and the mixture was stirred for 42 h under 100 psi of carbon monoxide gas. The reaction mixture was filtered through Arbocel®, washed through methanol and the filtrate was concentrated in vacuo. The residue was purified on an Isolute® flash silica column eluting with dichloromethane: methanol, 97: 3 to give 155 mg of the title compound as an orange solid in 85% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 495

Preparation Examples 60-61

The following compounds of formula shown below were prepared by the method described above for Preparation 26 using the compound of Preparation 25 and the appropriate hydroxyquinoline or hydroxyisoquinoline.

The following compounds of formula shown below were prepared in the same manner as described above for Preparation 46 using the compounds of Preparation Examples 60 and 61 and meta-chloroperbenzoic acid.

Preparation Example 64

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (1-oxy-isoquinolin-5-yloxy) -propan-1-one

The title compound was prepared by the method described above for Example 46 using the compound of Preparation Example 43.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 420

Preparation 65

(2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (1-chloro-isoquinolin-5-yloxy) -propan-1-one

Phosphorous acid chloride (0.20 ml, 2.18 mmol) was added to a solution of the compound of Preparation 64 (305 mg, 0.73 mmol) in dichloromethane (15 ml) and the reaction mixture was heated at 100 ° C. for 2 hours. Then the mixture was cooled to room temperature and poured into water (75 ml). The resulting aqueous mixture was basified with concentrated ammonia solution and extracted with dichloromethane (2 × 75 ml). The combined organic extracts were then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to give 127 mg of the title compound as a white foam in 40% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 438

Preparation 66

1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (2-chloro-quinolin-5-yloxy) -propan-1-one

The title compound was prepared by the method described above for Example 65 using the compound of Preparation Example 62.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 438

Preparation Example 67

2-methoxy-4-methylsulfanyl-phenol

^t butyl lithium (1.7 M in pentane, 14.5 ml, 24.6 mmol) was added dropwise to a solution of 4-bromo-2-methoxyphenol (2.00 g, 9.85 mmol) in tetrahydrofuran (25 ml), -78 ° C. Cooled to. The mixture was stirred for 15 minutes, then warmed to -40 ° C and stirred for an additional 30 minutes. Dimethyl disulfide (1.06 ml, 11.8 mmol) was added and the mixture was stirred at rt for 18 h. Water was then added to the reaction and the resulting mixture was acidified to pH 1 with 2M hydrochloric acid. The aqueous phase was separated and reextracted with ethyl acetate. The combined organic fractions were then dried over magnesium sulfate and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel eluting with pentane: diethyl ether, 95: 5 to 80:20 to give 800 mg of the title compound as a white solid in 48% yield.

Preparation Example 68

6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one

Lithium iodide (0.32 g, 2.41 mmol) and 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one (0.5 g) in 2,4,6-collidine (10 ml) , 2. 41 mmol) was heated at 130 ° C. for 18 hours. The solvent was then evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 96: 4 to give 0.19 g of the title compound as a light yellow solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 194

Preparation Example 69

Acetic acid 3-acetoxy-5-methyl-phenyl ester

Acetic anhydride (22.6 ml, 0.24 mol) was added to an ice-cooled solution of 3,5-dihydroxytoluene (9.93 g, 0.08 mol) and triethylamine (56 ml, 0.40 mol) in dichloromethane (86 ml). . The reaction mixture was allowed to warm to rt and stirred for 60 h. Then water (100 ml) was added and the mixture was vigorously stirred for 3 hours. The organic layer was separated and the aqueous phase was reextracted with dichloromethane (3 x 80 ml). The combined organic extracts were washed with brine (80 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane, 66:33 to give 15.7 g of the title compound as a colorless oil in 94% yield.

LRMS (APCI ⁺ ): m / z [M + NH ₄ ] ⁺ 226

Preparation Example 70

1- (2,6-dihydroxy-4-methyl-phenyl) -ethanone

A solution of the compound of Preparation 69 (10.12 g, 48.6 mmol) in chlorobenzene (10 ml) was added dropwise to a suspension of aluminum chloride (19.44 g, 145.8 mmol) in chlorobenzene (50 ml), warmed to 90 ° C., The mixture was stirred for 1 hour. The reaction mixture was then cooled and carefully pipetted onto a mixture of ice and 2M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 × 200 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 84:16, 80:20, 75:25 to give 5.31 g of the title compound as a yellow solid in 66% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 167

Preparation Example 71

3,6-dimethyl-1H-indazol-4-ol

A solution of the compound of Preparation 70 (4.15 g, 25 mmol) in ethylene glycol (70 ml) was added dropwise to a solution of hydrazine monohydrate (2.4 ml, 50 mmol) in ethylene glycol (15 ml), and the mixture was stirred at 1 room temperature. For hour, stirred at 150 ° C. for 80 min. The cooled reaction mixture was then poured into water and acidified to pH 6 with acetic acid. The aqueous mixture was extracted with ethyl acetate (4 x 200 ml) and the combined extracts were washed with 5% sodium sulfite (200 ml) and brine (200 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane, 50:50 to give 3.84 g of the title compound in 95% yield as a yellow solid.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 163

Preparation Example 72

4- (tert-butyl-dimethyl-silanyloxy) -3,6-dimethyl-1H-indazole

tert-butyldimethylchlorosilane (511 mg, 3.39 mmol) and imidazole (1.05 g, 15.4 mmol) were added to a solution of compound of Preparation 71 (500 mg, 3.08 mmol) in N, N-dimethylformamide, The reaction mixture was stirred at 0 ° C. for 1 hour and at room temperature for 18 hours. Additional tert-butyldimethylchlorosilane (511 mg, 3.39 mmol) was added and the reaction mixture was heated at 80 ° C for 48 h. Then the solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated, washed with brine (2 x 10 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 15:85 to give the title compound in 23% yield as an orange oil.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 27

Preparation Example 73

4- (tert-Butyl-dimethyl-silanyloxy) -3,6-dimethyl-indazole-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (503 mg, 2.3 mmol) and 4-dimethylaminopyridine (51 mg, 0.4 mmol) were added to the compound of Preparation 72 (580 mg, 2 mmol) in dichloromethane (5 ml). And the reaction mixture was stirred for 18 hours. Then water was added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (3 × 10 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 95: 5 to give 527 mg of the title compound as a colorless oil in 66% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 377

Preparation Example 74

4-hydroxy-3,6-dimethyl-indazole-1-carboxylic acid tert-butyl ester

Tetrabutylammonium fluoride solution (1M in tetrahydrofuran, 21 ml, 2.1 mmol) was added dropwise to a solution of compound of Preparation 73 (527 mg, 1.4 mmol) in tetrahydrofuran (9 ml) and the solution was 0 ° C. Stirred for 30 minutes at room temperature and for 5 minutes at room temperature. Water was then added to the mixture, and the aqueous mixture was extracted with ethyl acetate (2 x 10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with pentane: ethyl acetate, 70:30 to 60:40 gave 280 mg of the title compound as a white solid in 76% yield.

^{LRMS (APCI -): m /} z [MH] - 261

Preparation 75

(2R) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2-benzyloxy-propan-1-one

1-hydroxybenzotriazole hydrate (825 mg, 5.3 mmol), N-methylmorpholine (808 μl, 7.3 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.13 g , 5.8 mmol) and (3R)-(3-methyl-piperazin-1-yl) -phenyl-methanone [(1.0 g, 4.9 mmol), J. Med. Chem. 43 (23), 4499; 2000] was added to a solution of (R)-(+)-2-benzyloxypropionic acid (972 mg, 5.3 mmol) in dichloromethane (10 ml) and the mixture was stirred for 18 hours. Additional (R)-(+)-2-benzyloxypropionic acid (486 mg, 2.65 mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.65 mg, 2.9 mmol), 1- Hydroxybenzotriazole hydrate (413 mg, 2.65 mmol) and N-methylmorpholine (808 μl, 7.3 mmol) were added and the mixture was heated at reflux for 3 hours. Water was then added to the reaction mixture and the aqueous solution was extracted with dichloromethane (2 x 10 ml). The combined organic extracts were washed with 2M hydrochloric acid, 1M sodium hydroxide solution and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with pentane: ethyl acetate, 50:50 followed by ethyl acetate: methanol, 90:10 gave 1.45 g of the title compound as a white foam in 81% yield.

^{LRMS (APCI -): m /} z [MH] - 367

Preparation Example 76

(2R) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2-hydroxy-propan-1-one

Pd (OH) ₂ (300 mg, 2.2 mmol) and ammonium formate (1.37 g, 22 mmol) were added to a solution of compound of Preparation 75 (1.45 g, 3.9 mmol) in ethanol (30 ml) and the mixture was Heat at 60 ° C. for 2 hours. The tlc analysis then showed that the reaction was not complete, therefore, after addition of additional Pd (OH) ₂ (300 mg, 2.2 mmol), ammonium formate (1.37 g, 22 mmol) was added to all starting materials. It was added at 45 minute intervals until it was consumed. The reaction mixture was then cooled and filtered through Arbocel® and washed through ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 95: 5 to give 1 g of the title compound as a white gum in 91% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 277

Preparation Example 77

4-[(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy] -3,6-dimethyl-indazole -1-carboxylic acid tert-butyl ester

The compound of Preparation 76 (70 mg, 0.25 mol), di-tert-butyl azodicarboxylate (233 mg, 1.01 mmol) and polymer-supported triphenyl phosphine (380 mg, 1.13 mmol) were diluted with dichloromethane (3 to a solution of compound of Preparation 74 (70 mg, 0.25 mmol) in ml) and the reaction mixture was stirred at 0 ° C. for 30 min and at rt for 18 h. The reaction mixture was then filtered through a filter tube and washed by passing through dichloromethane. The filtrate was washed with sodium hydroxide solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate, 40:60 to 20:80 to give 45 mg of the title compound as a white foam in 34% yield.

LRMS (APCI ⁺ ): m / z [M + H] ⁺ 521

Biological data

The ability to modulate gp120 activity, in particular the interaction of gp120 with CD4, to inhibit the compounds of Formula I and their pharmaceutically acceptable salts, solvates and derivatives, gp160 to determine the IC ₅₀ value of compounds for HIV-1 fusion Proven using induced cell-cell fusion assay. The gp160 induced cell-cell fusion assay used HeLa P4 cell line and CHO-Tat10 cell line.

HeLa P4 cell lines express CCR5 and CD4 and were transfected with HIV-1 LTR-β-galactosidase. Medium for this cell line contains 10% fetal bovine serum (FCS), 2 mM L-glutamine penicillin / streptomycin (Pen / Strep; 100U / ml penicillin + 10 mg / ml streptomycin) and 1 μg / ml puromycin Is Dulbecco modified eagle medium (D-MEM) (without L-glutamine).

The CHO cell line is a Tat (transcriptional trans activator) -expressing clone from the CHO JRR17.1 cell line transfected with pTat furo plasmid. The medium for this cell line was a mammal originally developed at the Roswell Park Memorial Institute containing 10% FCS, 2 mM L-glutamine, 5 mg / ml hygromycin B and 12 μg / ml furomycin. RPM1640 (without L-glutamine), a rich medium for cell culture. The CHO JRR17.1 strain is a clone that is selective for its ability to express gp160 (JRFL) and fuse with CCR5 / CD4 expressing cell lines.

Upon cell fusion, Tat present in CHO cells can transactivate HIV-1 long terminal repeats (LTR) present in HeLa cells resulting in expression of β-galactosidase enzyme. This expression is then measured using Fluor Ace ™ β-galactosidase reporter assay kit (Bio-Rad Cat. No. 170-3150). This kit is a quantitative fluorescence assay that measures the expression level of β-galactosidase using 4-methylumbeliferol-galactopyranoside (MUG) as a substrate. β-galactosidase hydrolyzes the fluorogenic substrate to allow the release of the fluorescent molecule 4-methylumbelliferone (4MU). The fluorescence of 4-methylumbelliferone is then measured on a fluorometer using an excitation wavelength of 360 nm and an emission wavelength of 4602 nm.

Compounds that inhibit fusion will reduce the signal and, after solubilization in the appropriate solvent and dilution in the culture medium, the dose-response curves for each compound can be used to calculate IC ₅₀ values.

All examples of the invention had an IC ₅₀ value of less than 1.5 μM according to the above method. IC ₅₀ values for the compounds of Examples 12, 29 and 44 were 15 nM, 134 nM and 825 nM.

The ability of compounds of formula (I) to inhibit the interaction of gp120 with CD4 was further demonstrated using enzyme linked immunosorbent assay (ELISA). Maxisorp plates (Nunc) were coated with 2 μg anti-gp120 antibody (D7324) per well. 100 μl of gp120 (diluted before measurement as appropriate) was added to each well and incubated for 90 minutes at room temperature. Samples were removed and wells washed with PBS (phosphate buffered saline) + 0.01% TWEEN® (polyethylene glycol sorbitan monolaurate). 50 μl of compound per well was added, followed by 50 μl (0.1 μg) of soluble CD4 conjugated to horseradish peroxidase (Autogen Bioclear). The plate was incubated for 90 minutes at room temperature and the wells washed again. Substrate OPD (o-phenylenediamine, Sigma) was added at a concentration of 0.5 mg / ml and the plate was incubated in the dark for 3 minutes at room temperature and 3M HCl was added to terminate the reaction. Compounds that inhibit the interaction of gp120 with soluble CD4 will result in reduced absorbance at 492 nm.

All examples of the invention had an IC ₅₀ value of less than 1.5 μM according to the above method. IC ₅₀ values for the compounds of Examples 1, 11 and 12 were 0.92 μM, 1.0 μM and 0.75 μM.

Claims (25)

A compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof. <Formula I>

In the above formula, R ¹ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with one or two atoms or groups selected from halo, C ₁ -C ₆ alkoxy, CF ₃ , OCF ₃ or CN; R ² and R ³ are independently H or C ₁ -C ₆ alkyl; R ⁴ is C ₁ -C ₆ alkyl; R ⁵ is phenyl; Naphthyl; Or a C-bonded 6 to 10 membered mono- or bicyclic, aromatic or partially saturated heterocycle, wherein the heterocycle is 1 to 4 nitrogen heteroatom (s), 1 or 2 nitrogens and 1 oxygen Heteroatoms, or containing one or two nitrogens and one sulfur heteroatom; Wherein said phenyl, naphthyl or heterocycle is C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, C ₃ -C ₇ cycloalkyl, phenyl, OH, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, OC ₁ -C ₆ fluoroalkyl, C ₀ -C ₂ alkylene NR ⁶ R ⁷ , halo, C ₀ -C ₂ alkylene CN, C ₀ -C ₂ alkylene CO ₂ R ⁸ , C ₀ -C ₂ alkylene CONR ⁶ R ⁷ , C ₀ -C ₂ alkylene SR ⁹ , C ₀ -C ₂ alkylene SOR ⁹ , C ₀ -C ₂ alkylene S0 ₂ R ⁹ , C _0- C ₂ alkylene SO ₂ NR ⁶ R ⁷ , C ₀ -C ₂ alkylene NR ⁸ COR ⁹ , C ₀ -C ₂ alkylene NR ⁸ CONR ⁶ R ⁷ , C ₀ -C ₂ alkylene NR ⁸ SO ₂ R ⁹ Or optionally substituted with 1 to 3 atoms or groups selected from oxo when C ₀ -C ₂ alkylene R ¹⁰ , or R ⁵ is heterocycle; R ⁶ and R ⁷ are independently H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl, phenyl or R ¹⁰ ; Or together with the nitrogen to which they are attached form an azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine ring; Wherein the substituent is 1 or 2 groups selected from C ₁ -C ₆ alkyl or C ₀ -C ₆ alkylene NH ₂ ; R ⁸ is H, C ₁ -C ₆ alkyl or phenyl; R ⁹ is C ₁ -C ₆ alkyl or phenyl; R ¹⁰ is imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxdiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl , Isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyano or halo Optionally substituted with one to three atoms or groups. The compound of claim 1, wherein R ¹ is phenyl or pyridyl, wherein phenyl or pyridyl is optionally substituted with one or two atoms or groups selected from halo. The compound of claim 1 or 2, wherein R ¹ is phenyl, fluorophenyl or pyridyl. The compound of any one of claims 1-3, wherein R ¹ is phenyl. The compound of any one of claims 1-4, wherein R ² is C ₁ -C ₄ alkyl. The compound of any one of claims 1-5, wherein R ² is methyl. The compound of any one of claims 1-6, wherein R ³ is H. 8. 8. The compound of claim 1, wherein R ⁴ is C ₁ -C ₄ alkyl. The compound of any one of claims 1-8, wherein R ⁴ is methyl. The compound according to any one of claims 1 to 9, wherein R ⁵ is optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzo Piperidinyl or benzoxazolyl; Wherein said substituent is 1 to 3 atoms or groups selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo, CN, CO ₂ R ⁸ , CONR ⁶ R ⁷ or R ¹⁰ . The compound of claim 1, wherein R ⁵ is optionally substituted phenyl or pyridyl, wherein the substituent is ₁ selected from C ₁ -C ₆ alkoxy, CO ₂ R ⁸ or CONR ⁶ R ⁷ To 3 groups of compounds. The compound of any one of claims 1-11, wherein R ⁶ is H or C ₁ -C ₄ alkyl. The compound of any one of claims 1-12, wherein R ⁷ is H, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl. The compound of any one of claims 1-13, wherein R ⁸ is C ₁ -C ₄ alkyl. 15. The compound of any one of claims 1-14, wherein R ¹⁰ is imidazolyl, pyrazolyl, triazolyl or oxadizolyl, each being C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, cyano Or optionally substituted with one to three atoms or groups selected from halo. The compound according to any one of claims 1 to 15, which is a compound of formula la or a pharmaceutically acceptable salt, solvate or derivative thereof. <Formula Ia>

In said formula, R <^1> , R <^2> , R <^3> , R <^4> and R <^5> are as defined in any one of Claims 1-15. The compound of claim 16, which is a compound of Formula Ib or a pharmaceutically acceptable salt, solvate or derivative thereof. <Formula Ib>

In said formula, R <^1> , R <^2> , R <^4> and R <^5> are as defined in any one of Claims 1-15. The method of claim 1, (2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (3-methyl-1H-indazol-4-yloxy) -propan-1-one ; (2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [2- (2H-pyrazol-3-ylamino) -quinolin-5-yloxy ] -Propan-1-one; 5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -isoquinoline-1-carboxylic acid Methylamide; (2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-2-methylamino-quinolin-5-yloxy) -propane-1 -On; (2S) -1-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) -isoquinoline-5-yljade C] -propan-1-one; 4-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -3-methoxy-N-methyl Benzamide; 5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 Carboxylic acid methylamides; 5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 Carboxylic acid amides; 5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid ethylamide; 5-{(1S) -2-[(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2 -Carboxylic acid cyclopropylamide; And pharmaceutically acceptable salts, solvates or derivatives thereof. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any one of claims 1 to 18 together with one or more pharmaceutically acceptable excipients, diluents or carriers. The pharmaceutical composition of claim 19 comprising at least one additional therapeutic agent. The compound according to any one of claims 1 to 18 for use as a medicament. The compound of any one of claims 1-18 for use in the treatment of HIV, retroviral infection genetically related to HIV, or AIDS. 19. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of HIV, HIV-associated retroviral infection, or AIDS. Use of A mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS with an effective amount of a compound of formula (I) according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate or derivative thereof Comprising treating the mammal. Compounds of Formula II, IV or VII.