MXPA06001762A - Piperazine derivatives for the treatment of hiv infections. - Google Patents

Piperazine derivatives for the treatment of hiv infections.

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Publication number
MXPA06001762A
MXPA06001762A MXPA06001762A MXPA06001762A MXPA06001762A MX PA06001762 A MXPA06001762 A MX PA06001762A MX PA06001762 A MXPA06001762 A MX PA06001762A MX PA06001762 A MXPA06001762 A MX PA06001762A MX PA06001762 A MXPA06001762 A MX PA06001762A
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Mexico
Prior art keywords
methyl
mmol
compound
preparation
piperazin
Prior art date
Application number
MXPA06001762A
Other languages
Spanish (es)
Inventor
David Howard Williams
Original Assignee
Pfizer
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Publication date
Priority claimed from GB0319149A external-priority patent/GB0319149D0/en
Priority claimed from GB0322153A external-priority patent/GB0322153D0/en
Priority claimed from GB0406656A external-priority patent/GB0406656D0/en
Application filed by Pfizer filed Critical Pfizer
Publication of MXPA06001762A publication Critical patent/MXPA06001762A/en

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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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 This invention relates to piperazine derivatives, to processes for their preparations, to compositions containing them and to their uses. More particularly, the present invention relates to | use of piperazine derivatives in the treatment of HIV, such as HIV-1, and genetically related retroviral infections (and the resulting acquired immunodeficiency syndrome, AIDS). The entry of HIV-1 into a target cell requires cell surface CD4 and additional host cell cofactors. It is recognized that for efficient entry into target cells, human immunodeficiency viruses require a chemokine receptor, such as CCR5 or CXCR-4, as well as the primary CD4 receptor. The main cofactor for entry mediated by the envelope glycoproteins of trophic strains for primary HIV-1 macrophages is CCR5, a receptor for the chemokines ß RANTES, MIP-1a and ß-1β (Deng et al., 1996, Nature, 38, 661-666). HIV binds to CD4 molecules in target cells through a region of its envelope protein, gp120. It is believed that the CD4 binding site on HIV gp120 interacts with the CD4 molecule on the surface of target cells and undergoes conformational changes, which allow it to bind to other cell surface receptors such as CCR5 or CXCR-4. This brings the viral envelope closer to the cell surface and allows the interaction between gp41 in the viral envelope and a fusion domain on the surface of host cells, the subsequent fusion with the cell membrane and, finally, the entry of the viral nucleus into the cell . Accordingly, compounds that inhibit the binding of gp120 with CD4, and thus prevent entry of HIV-1 into a target cell, should be useful in the treatment of HIV, such as HIV-1, and genetically retroviral infections. related (and the resulting acquired immunodeficiency syndrome, AIDS). According to a first aspect of the present invention, a compound of formula (I) is provided or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1 6 2 atoms or groups selected from halo, C 6 alkoxy, CF 3, OCF 3 or CN; R2 and R3 are independently H or C6 alkyl; R 4 is C 1 -C 6 alkyl; R5 is phenyl; naphthyl; or a C-, 6- to 10-membered, mono- or bicyclic, aromatic or partially saturated heterocycle, wherein said heterocycle contains from 1 to 4 nitrogen heteroatoms, 1 6 2 nitrogen heteroatoms and 1 oxygen heteroatom or 1 or 2 nitrogen heteroatoms and 1 sulfur heteroatom; wherein said phenyl, naphthyl or heterocycle are optionally substituted with 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 7 cycloaicyl, phenyl, OH, Ci-C 6 alkoxy, C 1 -C 6 alkoxy C- alkyl; -C6, O-fluoroalkyl Ci-C6, alkyiene C0-C2 NR6R7, halo, C0-C2 alkylene CN, C0-C2 alkylene C02R8, C0-C2 alkylene CONR6R7, C0-C2 alkylene SR9, C0-C2 alkylene SOR9, C0 alkylene -C2 S02R9, C0-C2 alkylene S02NR6R7, C0-C2 alkylene NR8COR9, C0-C2 alkylene NR8CONRBR7, C0-C2 alkylene NR8S02R9, or C0-C2 alkylene R0, or where R5 is a heterocycle, oxo; R6 and R7 are independently H, Ci-Ce alkyl, C3-C7 cycloaicil, phenyl or R; or when taken together with the nitrogen to which they are attached they form an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine ring; wherein said substituents are 1 or 2 groups selected from Ci-C6 alkyl or C0-C6 alkylene NH2; R8 is H, Ci-C6 alkyl or phenyl; R9 is d-C6 alkyl or phenyl; and R10 is imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl, each optionally substituted with 1 to 3 atoms or groups selected from Ci-C6 alkyl, Ci-C6 alkoxy, cyano or halo. The term "alkyl" as a group or as part of a group includes straight and branched chain groups. Examples of alkyl include methyl, ethyl, n-propyl, / -propyl, / 7-butyl, i-butyl, sec-butyl and butyl. The term "cycloalkyl 03.7" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "halo" means fluoro, chloro, bromo or iodo. In a further embodiment, R1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1 or 2 atoms or groups selected from halo. In another further embodiment, R1 is phenyl, fluorophenyl or pyridyl. In still another embodiment, R1 is phenyl. In still another embodiment, R2 is C1-C4 alkyl. In still another embodiment, R2 is methyl. In another further embodiment, R3 is H. In another further embodiment, R4 is C1-C4 alkyl. In still another embodiment, R 4 is methyl. In another further embodiment, R5 is a phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopiperidinyl or optionally substituted benzoxazolyl; wherein said substituents are from 1 to 3 atoms or groups selected from C6 alkyl, Ci-C6 alkoxy, halo, CN, C02R8, CONR6R7 or R10. In another further embodiment, R5 is phenyl or optionally substituted pyridyl, wherein said substituents are from 1 to 3 groups selected from C6 alkoxy, C02R8 or CONR6R7. In still another embodiment, R6 is H or C4 alkyl. In still another embodiment, R7 is H, C4 alkyl, or C3-C6 cycloalkyl. In still another embodiment, R8 is C4 alkyl. In another further embodiment, R 10 is imidazolium, pyrazolyl, triazolyl or oxadiazolyl, each optionally substituted with 1 to 3 atoms or groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano or halo. In still another embodiment, a compound of formula (la) is provided or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R1, R2, R3, R4 and R5 are as defined hereinabove with respect to the compound of formula (I), including all combinations of particular embodiments described in the same. In still another embodiment, a compound of formula (Ib) is provided or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R1, R2, R4 and R5 are as defined hereinabove for a compound of formula (I), including all combinations of particular embodiments described thereof. It will be understood that the invention includes all combinations of particular embodiments of the invention, as described above, consistent with the definition of compounds of formula (I). The compounds of the invention include compounds of formula (I) and salts, solvates or pharmaceutically acceptable derivatives thereof (wherein the derivatives include complexes, polymorphs, prodrugs and isotope-labeled compounds, as well as salts, solvates and solvates of salts of the same) and isomers thereof. In a further embodiment, the compounds of the invention are the compounds of formula (I) and the pharmaceutically acceptable salts and solvates thereof, in particular the compounds of formula (I). It will be understood that the compounds mentioned above in this document of the invention include polymorphs and isomers thereof. The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts and the base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts acetate, aspartate, benzoate, besylate, bicarbonate, bisulfate, borate, bromide, camsylate, carbonate, chloride, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, bromide, hydrochloride , hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / phosphate acid / diacid phosphate, saccharate, stearate, succinate , sulfate, tartrate, tosylate and trifluoroacetate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). The pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of three processes: (i) by reaction of the compound of formula (I) with the desired acid or base; (ii) by removal of an acid or base labile protecting group from a suitable precursor of the compound of formula (I) or by ring opening of a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by conversion of a salt of the compound of formula (I) into another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All these reactions are typically performed in solution. The salt can be precipitated from the solution and collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when said solvent is water. The complexes include clathrates, ie drug-host inclusion complexes in which, in contrast to the solvates mentioned above, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the pharmaceutical drug containing two or more organic and / or inorganic components may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For a review of such complexes, see J Pharm Sci, 64. (8), 1269-1288 of Haleblian (August 1975). The compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism, all of these polymorphic forms ("polymorphs") being included within the scope of the invention. Polymorphism in general may occur as a response to changes in temperature, pressure or both, and may also be the result of variations in the crystallization process. Polymorphs can be distinguished by various physical properties, and X-ray diffraction patterns, solubility behavior, and melting point of the compound are typically used to distinguish polymorphs. Certain derivatives of compounds of formula (I) which may have little or no pharmacological activity per se may, when administered in or on the body, be converted to compounds of formula (I) having the desired activity, for example, hydrolytic cleavage. Such derivatives are known as "prodrugs". Additional information about the use of prodrugs 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). The prodrugs according to the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain residues known to those skilled in the art as "pro-residues", as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985). Some examples of prodrugs according to the invention include: (i) when the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, substitution of hydrogen with alkyl (C- | -C6); (ii) when the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, substitution of hydrogen with alkanoyloxymethyl (C C6); and (ii) when the compound of formula (I) contains a primary or secondary amino functionality (-NH2 or -NHR, where R? H), an amide thereof, for example, substitution of one or both hydrogens with alkanoyl (C1-C10). Additional examples of substitution groups can be found in accordance with the above examples and examples of other types of prodrugs according to the invention in the references mentioned hereinabove. In addition, certain compounds of formula (I) can act by themselves as prodrugs of other compounds of formula (I). Also included within the scope of the invention are the metabolites of the compounds of formula (I), ie, compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include: (i) when the compound of formula (I) contains a methyl group, a hydroxymethyl derivative thereof (-CH3 -> -CH2OH); (ii) when the compound of formula (I) contains an alkoxy group, a hydroxy derivative thereof (-OR - > -OH); (iii) when the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -> -NHR1 or -NHR2); (iv) when the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2); (v) when the compound of formula (I) contains a phenyl residue, a phenol derivative thereof (-PH -> -PhOH); and (vi) when the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> -COOH). In view of the definition of R 4, the compounds of formula (I) contain one or more asymmetric carbon atoms and therefore exist as two or more optical isomers. When a compound of formula (I) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible, and when the compound contains, for example, a keto or oxime group or an aromatic moiety, it can be produced tautomérica isomería ("tautomería"). It is concluded that a single compound can show more than one type of isomerism. Within the scope of the present invention all optical isomers, geometric isomers and tautomeric forms of the compounds of formula (I) are included, including those compounds that display more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition salts or base salts in which the counterion is optically active, for example, D-lactate or L-lysine, or are rcemic, for example, DL-tartrate or DL-arginine. The cis trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, high pressure liquid chiral chromatography (HPLC) . Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or more diastereomers converted to the corresponding corresponding pure enantiomers by means well known to one skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20% and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate produces the enriched mixture. The stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).
The present invention also includes all the pharmaceutically acceptable isotope-labeled compounds of formula (I) in which one or more atoms are replaced with atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or number Mass found normally in nature.
Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen isotopes such as 2H and 3H, carbon, such as 11C, 3C and 14C, of chlorine, such as 36CI, of fluorine, such as 18F, of iodine, such as 123l and 125l, of nitrogen, such as 13N and 15N, of oxygen, such as 150, 1 0 and 180, of phosphorus, such as 32P and of sulfur, such as 35S. Certain compounds labeled with isotopes of formula (I), for example, those incorporating a radioactive isotope, are useful in studies of drug distribution and / or substrate in tissues. The radioactive isotopes tritium, that is, 3H, and carbon-14, that is, 1 C, are particularly useful for this purpose because of their ease of incorporation and easy detection. Substitution with heavier isotopes such as deuterium, ie, 2H, can produce certain therapeutic advantages produced by increased metabolic stability, for example, in vivo increase of half-life or reduction of dosage requirements and, thus, can Prefer in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Generally, compounds of formula (I) labeled with isotopes can be prepared by conventional techniques known to those skilled in the art or procedures analogous to those described in the Examples and Preparations attached using a suitable isotope-labeled reagent instead of the unlabeled reagent employed. previously. The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted isotopically, for example, D2O, d6-acetone, d6-DMSO. Preferred compounds of formula (I) include the compounds of Examples 1-94; and the pharmaceutically acceptable salts, solvates or derivatives thereof. Particularly preferred compounds of formula (I) include: (2S) -1 - [(2fi) -4-Benzoyl-2-methyl-piperazin-1-yl)] - 2- (3-methyl-1H-indazole-4) -iloxy) -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; Acid methylamide 5-. { (1S) -2 - [(2) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} Isoquinoline-1-carboxylic acid; (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-2-methylamino-quinolin-5-yloxy) -propan-1 -one; (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] "2- [1- (2H-pyrazol-3-ylamino) -soquinolin-5-yloxy] -propan -1-one; 4- { (1 S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-methyl-2-oxo-ethoxy.} - 3-methoxy-A / -methyl-benzamide; 5- ({(1S) -2 - [(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy acid methylamide} -4-methoxy-pyridine-2-carboxylic acid, 5- ({(1 S) -2 - [(2R) -4-benzoyl-2-methyl-piperazin-1-yl] - amide 1-Methyl-2-oxo-ethoxy, 4-methoxy-pyridine-2-carboxylic acid, 5- [{(1 S) -2 - [(2R) -4-benzoyl-2-methyl] -ethylamide -piperazin-1-yl] -1-methyl-2-oxo-ethoxy.} -4-methoxy-pyridine-2-carboxylic acid; cyclopropylamide of 5- { (1S) -2 - [(2f?) acid -4-benzoyl-2-methyl-p¡perazin-1-yl] -1-methyl-2-oxo-ethoxy.} -4-methoxy-pyridine-2-carboxylic acid; and pharmaceutically acceptable salts, solvates or derivatives thereof. In the general procedures and in the schemes shown below: R1 to R9 are as previously defined unless otherwise indicated; X is halo or hydroxy; And it is a leaving group, such as chlorine, bromine, tosylate, mesylate or hydroxy; DMF is N, N-dimethylformamide; DMSO is dimethylsulfoxide; THF is tetrahydrofuran, WSCDI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DCC is? /, '-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-azabenzotriazole; HOBt is 1-hydroxybenzotriazole hydrate; HBTU is O- (IH-benzotriazole-li - ^ / V.iV ^ / V'-tetramethyluronium hexafluorophosphate, PyBOP® is benzotriazole-1-xloxitris hexafluorophosphate (pyrrolidino) phosphonium, PyBrOP is bromo-tris hexafluorophosphate pyrrolidinophosphonium, Hunigs base is N-ethyldiisopropylamine, and ukaiyama reagent is 2-chloro-1-methylpyridinium iodide The compounds of formula (I) can be prepared by any known method for the preparation of compounds of analogous structure. of formula (I) and intermediates thereof can be prepared according to the schemes shown below.
Those skilled in the art will appreciate that certain methods described in the schemes for the preparation of compounds of formula (I) or intermediates thereof may not be applicable to some of the possible substituents. It will further be appreciated by those skilled in the art that it may be necessary or desirable to perform the transformations described in the schemes in an order different from that described, or to modify one or more of the transformations, to provide the desired compound of formula (I). In addition, those skilled in the art will appreciate that, as illustrated in the schemes shown below, it may be necessary or desirable at any stage in the synthesis of the compounds of formula (I) to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. In particular, it may be necessary or It is desirable to protect the amino groups. The protecting groups used in the preparation of compounds of formula (I) can be used in a conventional manner. See, for example, those described in "Protective Groups in Organic Synthesis" by Theodora W Green and Peter G M Wuts, third edition, (John Wiley and Sons, 1999), in particular in chapter 7, pages 10 494-653 ("Protection for the Amino Group"), incorporated herein by reference, which also describes procedures for the removal of such groups. The amino-boc, benzyloxycarbonyl, benzyl and acetyl protecting groups are of particular utility in the preparation of 15 formula (I) and intermediates thereof.
Scheme 1 With specific reference to scheme 1, the transformations represented in this scheme can be carried out as indicated below: (a) - (e) acid-amine coupling reactions. Typically, the acid chloride or the acid bromide of the formulas (V), (VI) or (VIII), and the appropriate piperazine of the formulas (IV), (VII) or (IX), optionally with an excess of Accepting of acid such as triethylamine or N-ethyl- / V, A / -diisopropylamine, is reacted in a solvent, such as a haioalkane (for example, dichloromethane) or an ether (for example, THF) at room temperature for 1 hour. -24 hours. The reactions can be conveniently carried out by reaction of the relevant piperazine with 1.1 equivalents of the relevant acid chloride in dichloromethane at room temperature for 1 hour. In a further embodiment, the acid of formulas (V), (VI) or (Vlil), activated with suitable reagents such as WSCDI / DCC and.HOBt / HOAt, the appropriate piperazine of formulas (IV), (VII) or ( IX), and an excess of an acid acceptor such as triethylamine or A / -i / V, / V-diisopropylamine, are reacted in a solvent such as a haioalkane (for example, dichloromethane), an ether ( for example, THF), or DMF at room temperature for 4 to 48 hours. The reactions can be conveniently carried out by reaction of the relevant piperazine, 1.4 equivalents of WSCDl, 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. In still another embodiment, the acid of formulas (V), (VI) or (VIII), the appropriate piperazine of formulas (IV), (VII) or (IX) and HBTU, PyBOP, PyBrOP or Mukaiyama reagent, and a excess of an acceptor of acids such as triethylamine or A / -ethyl-A /, A / -diisopropylamine, can be reacted in a solvent such as a haioalkane (for example, dichloromethane) or an ether (for example, THF) at room temperature environment for 4 to 24 hours. The reactions can be conveniently carried out by reaction of the relevant piperazine, 1.0 equivalents of the relevant carboxylic acid and 1.5 equivalents of HBTU in dichloromethane or DMF at room temperature for 14 hours. (f) Nucleophilic Substitution i) When Y = Cl, Br, mesylate or tosylate: Typically, the compounds of formulas (II) and (III), with an acid acceptor such as triethylamine, W-ethyl- / V, / δ-d-sopropylamine or an alkali metal carbonate, are reacted in a solvent such as a haloalkane (e.g., dichloromethane), an ether (e.g., THF) or acetone , at a temperature between the ambient temperature and the reflux temperature for 1 to 24 hours. The reactions can be conveniently carried out by reacting compounds of formulas (II) and (III) with 1.0 equivalents of cesium carbonate in acetone at the reflux temperature for 14 hours. ii) When Y = OH: Typically, the compounds of formulas (II) and (III), triphenylphosphine or tri-o-tolylphosphine, and diethyl azodicarboxylate or di-isopropyl azodicarboxylate, are reacted in a solvent such as a haloalkane (e.g., dichloromethane) or an ether (e.g., THF) at a temperature between room temperature and reflux temperature for 1 to 24 hours. Conveniently, the reactions can be carried out by reacting compounds of formulas (II) and (III) with 1.2 equivalents of triphenylphosphine and 1.1 equivalents of diisopropyl azodicarboxylate in THF at room temperature for 14 hours. The compounds of formula (VI) in reaction stages (a) and (d) can be prepared according to scheme 1a shown below.
Scheme 1a (X) (XI) W wherein R is a lower alkyl such as Ci-C6 alkyl. (g) Nucleophilic Substitution The nucleophilic substitution can be carried out according to the conditions described hereinabove for step (f). (h) Ester hydrolysis Typically, the compounds of formula (XI), an aqueous solution of an alkali metal hydroxide or an aqueous solution of hydrochloric acid, and an optional co-solvent such as ethanol or dioxane, are heated to a temperature between 60 and 100 ° C for 1 to 18 hours. The reactions can be conveniently carried out by heating compounds of formula (XI) in a 1 N aqueous solution of sodium hydroxide and dioxane heated at 60 ° C for 2 hours. Certain intermediates described above are new compounds and it should be understood that all of the novel intermediates in this document form additional aspects of the present invention. The compounds of formulas (II), (IV) and (VII) are key intermediates and represent a particular aspect of the present invention. The compounds of formulas (III), (V), (VIII), (IX) and (X) are known compounds or can be prepared by conventional chemistry. According to another aspect, the invention provides the following methods for preparing compounds of formula (I). According to a first process (A), the compounds of formula (1) can be prepared by coupling an acid of formula (V) with a piperazine of formula (IV), under standard conditions of acid-amine coupling.
Conveniently, the acid-amine coupling is carried out under the conditions described above with respect to scheme 1, steps (a) - (e). According to a second process (B), the compounds of formula (I) can be prepared by coupling an acid of formula (VI) with a piperazine of formula (VII), under conventional conditions of acid-amine coupling.
Conveniently, the acid-amine coupling is carried out under the conditions described above with respect to scheme 1, steps (a) - (e). According to a third method (C), the compounds of formula (I) can be prepared by nucleophilic substitution of a compound of formula (II) with an alcohol R5OH of formula (III) under standard conditions. Suitably, the nucleophilic substitution is carried out under the conditions described above with respect to scheme 1, step (f). According to a fourth process (D), the compounds of formula (I) can be prepared from other compounds of formula (I) by interconversion of a functional group under conventional conditions. For example, compounds of formula (I) containing an ester group can be converted to the corresponding compounds of formula (I) containing a primary or secondary amide group, by reaction of the former with ammonia or a primary amine, respectively. The compounds of the invention inhibit the interaction of gp120 with CD4 and, therefore, are useful in the treatment of HIV, a retroviral infection genetically related to HIV and AIDS. Accordingly, in another aspect, the 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 invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof for use in the treatment of HIV, of a retroviral infection genetically related to HIV or AIDS. In another aspect, the 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, of a retroviral infection genetically related to HIV or AIDS. In another aspect, the invention provides a method for the treatment of a mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof. The compounds of the invention can be administered in the form of crystalline or amorphous products. They can be obtd, for example, in the form of short solid beds, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose. They can 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). Generally, they will be administered in formulation form in conjunction with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound or compounds of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability and the nature of the dosage form. Pharmaceutical compositions suitable for the delivery of compounds of the 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 Pharmaceutical Sciences", 19th Edition (ack Publishing Company, 1995). The compounds of the invention can be administered orally.
Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids or powders, lozenges (including liquid-filled), chewing gums, multi and nano-particulates, gels, solid solution, liposomes, films (including muco-adhesives), ovules, sprayers and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in hard or soft capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example a seal. The compounds of the invention can also be used in rapidly dissolving and disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V (6), 981-986 of Liang and Chen (2001). For dosage forms in tablets, depending on the dose, the drug can be prepared from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the form of dosage. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinyl pyrrolidone, methyl cellulose, cellulose microcrystalline, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form. Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include cellulose microcrystalline, gelatin, sugars, polyethylene glycol, synthetic and natural gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sugar, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally comprise surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactants may comprise from 0.2 wt% to 5 wt% of the tablet and the glidants may comprise from 0.2 wt% to 1 wt% of the tablet. The tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate. The lubricants generally comprise from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include anti-oxidants, dyes, flavors, preservatives and flavor masking agents. Illustrative tablets contain up to about 80% of the drug, from about 10% by weight to about 90% by weight of binder, from about 0% by weight to about 85% by weight of diluent, about 2% by weight to about 10% by weight of disintegrant and about 0.25% by weight to about 10% by weight of lubricant. Tablet blends can be compressed directly or by rollers to form tablets. Blends of tablets or portions of the blends may, alternatively, be wet, dry or melt granulated, freeze by melting or extruded prior to compression. The final formulation may comprise one or more layers and may or may not be coated; it can even be encapsulated. The formulation of tablets is analyzed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1"by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-69 8-X). Solid formulations for oral administration can be formulated to be released immediately and / or modified. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Modified release formulations suitable for the purposes of the invention are described in the U.S. Pat.
No. 6,106,864. In Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) are details of other suitable release technologies such as high energy dispersions and osmotic and coated particles. The use of chewing gums to achieve a controlled release is described in WO 00/35298. The compounds of the invention can also be administered directly into the blood stream, into the muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needle injectors (including microneedle), waterless injectors, and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9), but, for some applications, may be more adequately formulated as a sterile non-aqueous solution or in a form dry to use together with a suitable vehicle such as sterile pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily performed using conventional 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 by the use of appropriate formulation techniques, such as the incorporation of agents that improve solubility. Formulations can be formulated for parenteral administration to be released immediately and / or modified. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In this way, the compounds of the invention can be formulated in the form of a solid, semi-solid or thixotropic liquid for administration in the form of an implanted reservoir that provides for the modified release of the compound. Examples of such formulations include drug-coated stents and PGLA microspheres. The compounds of the invention can also be administered topically to the skin or mucosa, i.e., dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include release by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be released immediately and / or modified. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, in the form of a mixture, for example, in a dry mixture with lactose, or in the form of a particle of mixed component, for example mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or in the form of an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a propellant suitable, such as 1,1,1,2-tetrafluoroethane or 1,1,1,3,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compound comprising, for example, ethanol (optionally, aqueous ethanol) or an alternative agent suitable for dispersing, solubilizing or expanding the release of the compound, the propellant or propellants in solvent form and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Before use in a suspension or dry powder formulation, 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 process, such as spiral jet grinding, fluid bed jet grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules (made of, for example, gelatin or HPMC), ampoules and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a modifier. of performance such as / -leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or it may be in the monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μ? at 100 μ ?. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, can be added to these formulations of the invention intended for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated for immediate and / or modified release using, for example, poly (DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that supplies a measured quantity. The units according to the invention are typically established to administer a metered dose or "puff containing from 1 g to 10 mg of the compound of the invention.The total daily dose will typically vary from 1 μg to 200 mg which can be administered in a single dose , or more usually, in divided doses throughout the day The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema.Cocoa butter is a traditional suppository base although various alternatives may be used as necessary Formulations for rectal / vaginal administration may be formulated to be released immediately and / or modified Modified release formulations include delayed release, sustained, pulsed, controlled, directed and programmed. The compounds of the invention can also be administered directly to the eye or ear, typically in the form of droplets of a suspension or micronized solution, in isotonic sterile pH adjusted saline. Other formulations suitable for ocular or aural administration include ointments, biodegradable implants (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methyl cellulose, or a heteropolysaccharide polymer, for example, gellan gum, together with a preservative, such as chloride may be incorporated. of benzalkonium. Such formulations can also be delivered by iontophoresis. Formulations for ocular / aural administration can be formulated to be released immediately and / or modified. Modified release formulations include delayed, sustained, pulsed, controlled, directed or programmed release. The compounds of the invention can also be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the modes of administration mentioned above. Drug-cyclodextrin complexes, for example, are considered to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, ie as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148. Since it may be desirable to administer a compound of the invention in combination with another therapeutic agent, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, containing at least one of which a compound of the invention, can be conveniently combined in the form of a kit suitable for the co-administration of the compositions. In this way, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, and means for separately retaining said compositions, such as a container, divided jar or divided laminated container. An example of such a kit is the family pack in ampoules used for packaging tablets, capsules and the like. AND! The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the compositions separated in different dosage ranges, or for titrating the compositions separated against each other. For compliance, the kit typically comprises instructions for administration and may be provided with the so-called reminder. For administration to human patients, weighing approximately 65 to 70 kg, the total daily dose of a compound of the invention is usually in the range of 1 to 10,000 mg, such as 10 to 1000 mg, for example 25 to 500 mg. mg, depending, of course, on the mode of administration, the age, condition and weight of the patient, and in any case ultimately depend on the judgment of the doctor. The total daily dose can be administered in a single dose or in divided doses. Therefore, in another aspect, the invention provides a pharmaceutical composition that includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diligenae or vehicles. The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives have the advantage that they are more selective, have a faster onset of action, are more potent, are better absorbed, are more stable, are more resistant to metabolism , have a reduced "food effect", have a better safety profile or have other more desirable properties (eg, with respect to solubility or hygroscopicity) than prior art compounds. The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives can be administered alone or as part of a combination therapy. Thus, embodiments encompassing the co-administration of, and compositions containing, in addition to a compound of the invention, one or more additional therapeutic agents are included within the scope of the present invention. Such multiple drug regimens, often referred to as combination therapy, can be used in the treatment and prevention of infections by the human immunodeficiency virus, HIV. The use of such a combination therapy is essentially relevant with respect to the treatment and prevention of infections and multiplication of the human immunodeficiency virus, HIV; and related pathogenic retroviruses in a patient in need of treatment or at risk of becoming a patient of this type. The ability of such retroviral pathogens to appear in a relatively short period of time in strains resistant to any monotherapy that has been administered to said patient is well known in the literature. A recommended treatment for HIV is a combination drug treatment called Highly Active Anti-Retroviral Therapy (HAART). TARAA combines three or more drugs for HIV. Thus, the methods of treatment and pharmaceutical compositions of the present invention may employ a compound of the invention in the form of monotherapy, although said methods and compositions may also be used in the form of combination therapy where one or more compounds of the invention are they co-administer in combination with one or more additional therapeutic agents such as those described in detail later in this document. In a further embodiment of the invention, combinations of the present invention include 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 the following: HIV protease, including but not limited to indinavir, ritonavir, saquinavir, nelflnavir, lopinavir, amprenavir, atazanavir, tipranavir, AG1859 and TC 114; non-nucleoside reverse transcriptase inhibitors (NN TI), including but not limited to nevirapine, delavirdine, capravirin, efavirenz, GW-8248, GW-5634 and TMC 125; inhibitors of nucleoside / nucleotide reverse transcriptase, including but not limited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir dipivoxil, fenofovir, emtricitabine and alovudine; CCR5 antagonists, including but not limited to: 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, 1-endo-. { 8 - [(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyI] -8-azabicyclo [3.2.1] oct-3-yl} Methyl-methyl-4,5,6,7-tetrahydro-1W-imidazo [4,5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, 3-endo-. { 8 - [(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} Methyl 2-methyl-4,5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, 1-e / 7-pho-. { 8 - [(3S) -3- (acetylamino) -3- (3-fluorophenyl) propyl] -8-azabicyclo [3.2.1] oct-3-yl} Ethyl 2-methyl-4,5,6,7-tetrahydro-1H-imidazo [4,5-c] pyridin-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, Sch- D, ONO-4128, GW-873140, AMD-887 and CMPD-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 entry of HIV into a target cell, including but not limited to enfuviritide, T1249, PRO 542 and PRO 140; integrase inhibitors, including but not limited to L-870.8 0; and RNaseH inhibitors. Also included within the scope of the present invention are combinations of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative, together with one or more additional therapeutic agents independently selected from the group consisting of proliferation inhibitors, by hydroxyurea example; immunomodulators, such as growth factors that stimulate granulocyte-macrophage colonies (eg, sargramostim), and various forms of interferon or interferon derivatives; other chemokine receptor agonists / antagonists, such as CXCR4 antagonists (eg, A D-070); tachykin receptor modulators (eg, NK1 antagonists) and various forms of interferon or interferon derivatives; agents that substantially inhibit, interrupt or diminish viral transcription or RNA replication such as inhibitors of att (trans transcriptional activator) or frn (negative regulatory factor); agents that substantially inhibit, interrupt or diminish the translation of one or more proteins expressed by the virus (including, but not limited to, negative regulation of protein expression or antagonism of one or more proteins) other than reverse transcriptase, such as Att or Fm; agents that influence, in particular, negatively regulate the expression of the CCR5 receptor; chemokines that induce the internalization of the CCR5 receptor such as ??? - 1, ??? - 1β, RANTES and derivatives thereof; and other agents that inhibit viral infection or improve the condition or consequences of individuals infected with HIV through different mechanisms. Agents that influence (in particular, negatively regulate) the expression of the CCR5 receptor include immunosuppressants, such as calcineurin inhibitors (eg, tacrolimus and cyclosporin A); steroids; agents that interfere with cytokine production or signaling, such as Janus kinase inhibitors (JAK) (eg, JAK-3 inhibitors, including 3- ({3 (3f?, 4R) -4-methyl-3- [met L- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -piperidin-1-yl.} - 3-oxo-propionitrile) and pharmaceutically acceptable salts, solvates or derivatives thereof; cytokine antibodies (e.g., antibodies that inhibit the etherleukin-2 receptor (IL-2), including basiliximab and daclizumab); and agents that interfere with cell activation or cell cycle, such as rapamycin. Also included within the scope of the present invention are combinations of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof, together with one or more additional therapeutic agents that slowly slow down the metabolism rate of the drug. compound of the invention, thus giving rise to an increase in exposure in patients. The increase in exposure performed in such a way is known as reinforcement. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as a non-reinforced dose. The metabolism of the compounds of the invention includes oxidative procedures performed by enzymes P450 (CYP450), particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulfation enzymes. Thus, among the agents that can be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes. CYP450 isoforms that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. Suitable agents that can be used to inhibit CYP 3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole. One skilled in the art will appreciate that a combination drug treatment, as described hereinabove, may comprise two or more compounds having the same or different mechanism of action. Thus, by way of illustration only, a combination may comprise a compound of the invention and: one or more NNRTI; one or more NRTI and a Pl; one or more NRTI and a CCR5 antagonist; a Pl; a Pl and an NNRTI; etc. In addition to the requirement of therapeutic efficacy, which may necessitate the use of therapeutic agents in addition to the compounds of the invention, there may be additional reasonable elements that highly compel or recommend the use of a combination of a compound of the invention and another therapeutic agent, such as in the treatment of diseases or conditions that directly result from or indirectly accompany the underlying or basic disease or condition. For example, it may be necessary or at least desirable to treat hepatitis C virus (HCV), hepatitis B virus (HBV), human papillomavirus (HPV), opportunistic infections (including bacterial and fungal infections), neoplasms and other conditions that occur as a result of the immunocompromised state of the patient to be treated. Other therapeutic agents can be used with the compounds of the invention, for example, to provide immuno-stimulation or to treat the pain and inflammation that accompany the initial and fundamental HIV infection. Accordingly, therapeutic agents for use in combination with the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives also include: interferons, pegylated interferons (e.g., peginterferon alfa-2a and peginterferon alfa-2b), lamivudine , ribavirin and emtricitabine for the treatment of hepatitis; antifungal agents such as fluconazole, itraconazo! and voriconazole; antibacterial agents such as azithromycin and clarithromycin; interferons, daunorubicin, doxorubicin and paclitaxel for the treatment of Kaposi's sarcoma related to AIDS; and cidofovir, fomivirsen, foscarnet, ganciclovir and valcite for the treatment of cytomegalovirus retinitis (C V). Additional combinations for use according to the invention include a combination of a compound of formula (I), or a pharmaceutically acceptable salt, solvate or derivative thereof with a CCR1 antagonist, such as BX-471; a beta adrenoceptor agonist, such as sameterol; a corticosteroid agonist, such as fluticasone propionate; an LTD4 antagonist, such as montelukast; a muscarinic antagonist, such as tiotropium bromide; a PDE4 inhibitor, such as cilomilast or roflumilast; a COX-2 inhibitor, such as celecoxib, valdecoxib or rofecoxib; an alpha-2-delta ligand, such as gabapentin or pregabalin; a beta interferon, such as REBIF; a TNF receptor modulator, such as a TNF-alpha inhibitor (e.g., adalimumab), an HG CoA reductase inhibitor, such as a statin (e.g., atorvastatin; or an immunosuppressant, such as cyclosporin or a macrolide) such as tacrolimus.
In the combinations described above, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof and one or more other therapeutic agents can be administered, as to dosage forms, separately or in conjunction with each other; and regarding its administration time, simultaneously or sequentially. In this way, the administration of a component agent can be before, concurrent with, or subsequent to the administration of the other or other component agents. 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 therapeutically additional agents. It will be appreciated that all references in this document to treatment include curative, palliative and prophylactic treatment. The invention is illustrated by the following Examples and Preparations in which the following abbreviations can be used: 0.88 ammonia = concentrated ammonium hydroxide solution, 0.88 GE h = hour min = minute EMBR = low resolution mass spectrum IQPA + = chemical ionization at atmospheric pressure IEN + = ionization by electrospray RN = nuclear magnetic resonance ccf = thin layer chromatography Me = Methyl Example 1 (2Sj-1-r (2R) -4-benzoyl-2-methyl-piperazin-1-ill-2- (quinolin-5-yloxy) -propan-1-one A solution of sodium salt of (2SJ-2- (quinolin-5-yloxy) -propionic acid (Preparation 2) (1.0 g, 4.6 mmol), (3f? - (3-methyl-piperazin-yl) -phenyl-methanone) (J. Med. Chem. (2000), 43 (23), 4499) (0.94 g, 4.6 mmol), hexafluorophosphate 0- (1 H -benzotriazol-1-yl) - / V, / V, / Tetramethyluronium (2.62 g, 6.9 mmol) and triethylamine (1.93 mL, 13.8 mmol) in A /, A / -dimethylformamide (30 mL) was stirred under an atmosphere of nitrogen at room temperature for 14 hours The reaction mixture was diluted in dichloromethane (100 ml), washed with water (3 x 50 ml), dried (MgSO 4) and the solvent It was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2), yielding the title compound as a white solid (0.91 g). 1 H NMR (400 MHz, CDCl 3): d: 8.90 (1H, m), 8.60 (H, m), 7.70 (1H, m), 7.55 (1H, m), 7.20 -7.40 (6H, m), 6.85 (1H, m), 5.15 (1H, m), 4.80-2.80 (7H, m), 1.70 (3H, d), 0.90 (3H, br) ppm. E BR (APCI +): m / z [M + H +] 404. EXAMPLE 2 3- [2 - ((2f?) - 4-Benzoyl-2-methyl-piperazin-1-yl) -1- methyl ester. Methyl-2-oxo-ethoxy-2-methyl-benzoic acid Cesium carbonate (0.39 g, 1.2 mmol) was added portionwise to a solution of 1 - [(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -2-bromo-propan- 1-one (Preparation 3) (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) in acetone (10 ml) 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 and the aqueous phase was extracted with dichloromethane (3 X 30 mL), the combined organic extracts were dried (MgSO.sub.4) and the solvent was evaporated under reduced pressure yielding the title compound as a white solid. , 5 g). 1H RN (400 MHz, CDCl 3): 5: 7.50-7.30 (6H, m), 7.15 (1H, m), 6.95 (1H, m), 4.95 (1H, m) , 4.80-2.80 (7H, m), 3.90 (3H, s), 2.40 (3H, s), 1.65 (3H, d), 1, 20 (3H, sa) ppm . LRMS (APCI +): m / z [M + H +] 425. Examples 3-12 were prepared by the procedure described above for Example 1, using the corresponding acid of formula (VI) and the piperazine of formula (VII). The LRMS was performed by IQPA + and the data recorded are for [M + H] +.
Examples 13-45 were prepared by the procedure described above for Example 2 using the corresponding compound of formula (II) and R5OH. The LRMS was performed by IQPA + and the data noted is for [M + H] +, unless otherwise indicated.
Example 46 (2Sl-1-f (2f?) - 4-benzoyl-2-methyl-piperazin-1-ill-2-f2-methoxy-4- ^ 2H-f 1, 2,41-triazole-3-in phenoxyl-propan-1 -one The compound of Preparation 10 (125 mg, 0.26 mmol) was added in portions to a stirred solution of hydrazine monohydrate (25 μ ?, 0.52 mmol) in glacial acetic acid (4 mL). The resulting solution was heated at 90 ° C for 3 hours. Then, the reaction mixture was evaporated under reduced pressure and the residual colorless oil was partitioned between dichloromethane (50 ml) and a saturated solution of sodium hydrogencarbonate (8 ml). The organic phase was separated and the aqueous phase was extracted again with dichloromethane (30 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to yield a colorless foam. The foam was dried under reduced pressure, yielding the title compound in 94% yield, 110 mg '. LRMS (ES1-): m / z [M + H +] 450 Example 47 1 -r (2f?) -4-benzoyl-2-methyl-piperazin-1 -ill-2- [2-methyl-3- (1 -methyl-1 H-pyrazol-3-yl) -phenoxyl-propan-1-one The compounds of preparations 7 (100 mg, 0.53 mmol) and 25 (180 mg, 0.53 mmol) and cesium carbonate (172.7 mg, 0.53 mmol) in acetone (8 mL) were heated to reflux for 3.5 hours. Then, the reaction mixture was cooled 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 extracted again with more dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give a light brown oil. The oil was chromatographed using a flash column of Isolute® silica, eluting with dichloromethane: methanol 99: 1 to 97: 3, to give a colorless oil. This oil was azeotropically distilled with dichloromethane, yielding the title compound as a colorless foam with a yield of 89%, 210 mg. LRMS (ES +): m / z [M + H +] 447 Example 48 1 -r (2R) -4-benzoyl-2-methyl-piperazin-1-yl-2- (2-methyl-3-H .2.41-oxadiazole -5-yl-phenoxp-propan-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. Then, the mixture was cooled and evaporated under reduced pressure to give a yellow oil. The oil was dissolved in ethyl acetate (50 ml) and washed with a 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 a flash column of Isolute® silica, eluting with dichloromethane: methanol 99: 1 to 97: 3, to give a colorless oil. The oil was azeotropically distilled with dichloromethane affording the title compound as a colorless foam, yield 44%, 118 mg. LRMS (ES "): m / z [MH]" 433 Example 49 (2S) -1-r (2R) -4-benzoyl-2-methyl-piperazin-1-ill-2-r3- (2H-pyrazole- 3-in-phenoxy-propan-1-one (3R) - (3-methyl-piperazin-1-yl) -phenyl-methanone [(114 mg, 0.56 mmol), J. Med. Chem. 43 (23), 4499; 2000], 3- (diethoxyphosphosiloxy) -1, 2,3-benzotriazin-4 (3H) -one (167.5 mg 0.57 mmol) and triethylamine (78 μ ?, 0.56 mmol) were added to a solution of the compound of Preparation 23 (130 mg, 0.56 mmol) in tetrahydrofuran (8 mL) and the resulting solution was stirred at room temperature for 48 hours. 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 hydrogen carbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column eluting with dichloromethane: methanol 98: 2 to 96: 4, to give a colorless foam. The foam was azeotropically distilled with dichloromethane and dried under reduced pressure, yielding the title compound in 85% yield, 198 mg. LRMS (ES "): m / z [-H] -417 Example 50 (2S) -1-rf2R) -4-benzoyl-2-methyl-DÍperazin-1-in-2-r2-methyl-3- (2H -pyrazol-3-ylV phenoxyl-propan-1 -one The title compound was prepared by the procedure described above for Example 49, using the compound of Preparation 24 and (3R) - (3-methyl-piperazin-1-) il) -phenyl-methanone (J. Med. Chem. 43 (23), 4499; 2000). LRMS (ES): m / z [-H] ~ 431 Example 51 1-yY 2f?) -4-benzoyl-2 -methyl-piperazin-1 - ?? 1-2-G4- (1 H-imidazol-2-n-2-methoxy-phenoxy-propan-1 -one) The compounds of Preparation 33 (30 mg, 0.16 mmol) and of Preparation 25 (53.5 mg, 0.6 mmol) and cesium carbonate (51.3 mg, 0.16 mmol) in N, / V-dimethylformamide (4 mL) was heated at 80 ° C for 18 hours. The reaction mixture was allowed to cool 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 extracted again with dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column, eluting with 99: 1 to 95: 5 dichloromethane: methanol yielding the title compound in the form of a beige foam in 74% yield, 52 mg. LRMS (ES +): m / z [M + H] + 449 Examples 52 to 53 The following compounds, of the general formula shown below, were prepared by the procedure described above for Example 51, using the compound of Preparation 25 and the appropriate phenol.
Examples 54 to 57 The following compounds, of the general formula shown below, were prepared by the procedure described above for Example 51, using the compound of Preparation 25 and the appropriate phenol.
Example 54: Phenol was prepared as described in Preparation 67 Example 55: Phenol was prepared as described in Preparation 68 Example 56: 6-methoxy-2-naphthol is commercially available Example 57: 5-hydroxM- Naphthalene sulfonamide is available on the market Example 58 1-r (2R) -4-benzoyl-2-methyl-piperazin-1-yn-2- (4-methanesulfonyl-2-methoxy-phenoxD-propan-1-one) A solution of oxone (215 mg, 0.35 mmol) in water (20 mL) was added to a solution of the compound of Example 54 (100 mg, 0.23 mmol) in methanol (40 mL) and the mixture was stirred for 18 hours at room temperature. Then, the solvent was evaporated under reduced pressure and the residue was partitioned between water (20 ml) and dichloromethane (20 ml). The aqueous phase was separated and extracted again with dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column eluting with dichloromethane: methanol 95: 5, yielding the title compound as a white solid in 76% yield, 80 mg. E BR (APCI +): m / z [M + H] + 461 Example 59 N-. { 4-f2- (2?) - (4-benzoyl-2-methyl-piperazin-1-yl) -1-methyl-2-oxo-ethoxy-3-methoxy-phenyD-methanesulfonamide Triethylamine (0.08 ml, 0.57 mmol) was added to a solution of the compound of Preparation 30 (150 mg, 0.38 mmol) in dichioromethane (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 allowed to stir at room temperature for 18 hours. Then, the mixture was diluted with more dichloromethane (20 ml) and washed with water. 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: methanol, 98: 2, yielding the title compound as a white solid in 49% yield, 88 mg. LRMS (APCI +): m / z [M + Hf 476 Example 60 (2S) -1-r (2ra-4-benzoyl-2-methyl-piperazin-1-yn-2- (2-chloro-quinolin-5- Loxn-propan-1-one A solution of the compound of Preparation 46 (1.8 g, 4.3 mmol) in phosphorus oxychloride (5 mL) was heated at 100 ° C for 2 hours. Then, the reaction mixture was cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL) and water (2x10 mL). The aqueous phase was basified with a 1 M sodium hydroxide solution and extracted again 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 affording the title compound as a pale yellow solid in 31% yield, 580 mg. 1 H NMR (400 MHz, CDCl 3): d: 1.00-1, 40 (m, 3H), 1, 70, 1, 80 (m, 3H), 2.80-4.80 (m, 7H), 5.20 (m, 1H), 6.90 (m, 1H), 7.20-7.45 (m, 6H), 7.55-7.70 (m, 2H), 8.55 (d, 1H) E BR (APCI +): m / z [M + H +] 438 Examples 61 to 62 A mixture of the compound of Example 60 (30 mL, 0.069 mmol), tetrabutylammonium fluoride (18 mg, 0.14 mmol), triethylamine (96 μ ?, 0.69 mmol) and the appropriate amine (0.69 mmol) in dimethyl sulfoxide (1 mL) was heated at 100 ° C for 24 hours. Then, the reaction mixtures were purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifiuoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, yielding the desired compounds of the general formula shown below: Example 63 1-f (2R) -4-benzoyl-2-methyl-piperazin-1-ill-2-d-chloro-isoquinolin-5-yloxy) -propan-1-one The title compound was prepared by the procedure described above for Example 60, using the compound of Preparation 63 and phosphorus oxychloride. LRMS (APCI +): m / z [M + H] + 438 Examples 64 to 65 A mixture of the compound of Example 63 (45 mg, 0.1 mmol), tetrabutylammonium 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 hours. The reaction mixtures were 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, yielding the desired compounds of the general formula shown below: Examples 66 (2S) -2- (2-amino-quinolin-5-yloxyV1-f (2RM-benzoyl-2-methyl-piperazin-1-ill-propan-1-one) 10% Pd / C (cat) and ammonium formate (10 mg, 0.15 mmol) were added to a solution of the compound of Preparation 49 (15 mg, 0.03 mmol) in ethanol (1 mL) and the mixture it was heated at 70 ° C for 2 hours. Additional ammonium formate (10 mg, 0.15 mmol) and Pd (OH) 2 (cat) were added and the reaction mixture was heated to reflux for a further 18 hours. The mixture was then cooled and filtered through Arbocel®, washing thoroughly with ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, producing the compound of the title with a yield of 77%, 9.7 mg. LRMS (ES +): m / z [M + H] + 419 Example 67 (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-ill-2- (8-chloro-quinolin -5-yloxy) - propan-1-one A mixture of the 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 yield a yellow residue. The residue was purified by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, yielding the title compound as a solid with a yield of 32%, 9.7 mg. E BR (APCI +): m / z [M + Hf 438 Examples 68 to 69 The following compounds, of the general formula shown below, were prepared by the procedure described above for Example 67, using the appropriate starting material 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 to 71 The compounds were prepared from the compound of Preparation 60 and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate), using a Preparation similar to that of Example 67. The compounds were purified by HPLC using a Phenomenex column. Luna C18 (2) 150x15 mm (particle size 10 microns, porosity 100 Á), using an eluent of 2 acetonitrile solvents: water: trifluoroacetic acid (5: 95: 0.1) [solvent A] and acetonitrile [ solvent B]. A solvent gradient is developed at a flow rate of 20 ml / min as in the table shown below: Example 72 (2S; -1 - [(2ffl-4-benzoyl-2-methyl-piperazin-1-n-2- (8-methyl-quinolin-5-yloxy) -propan-1- ona A mixture of the compound of Preparation 44 (200 mg, 0.4 mmol), methylboronic acid (74 mg, 1.2 mmol), palladium (II) bis (triphenylphosphine) chloride (29 mg, 0.04 mmol) and potassium carbonate (229 mg, 1.6 mmol) in N, N-dimethylformamide (4 mL) was heated at 100 ° C for 18 hours. The Ccf analysis showed that the reaction was incomplete and additional amounts of methyl bromide (74 mg) and palladium (II) bis (triphenylphosphine) chloride (29 mg) were added, and the mixture was allowed to stir for a further 24 hours at 100 ° C. Then, the reaction mixture was filtered through Arbocel®, washing thoroughly with ethyl acetate (25 ml) and water (3x20 ml). The phases were separated and the aqueous phase was extracted again with ethyl acetate. The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to yield a yellow residue. The residue was purified by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95. Then, the appropriate fraction was azeotropically distilled with diethyl ether yielding the title compound as a yellow solid in a yield of 19%, 33 mg. HRMS (APCI +): m / z [M + H] + 418 Example 73 (2S) -1-r (2R) -4-benzoyl-2-methyl-p -perazin-1-in-2-r8- (2H -pyrazol-3-in-quinolin-5-yloxyl-propan-1-one Hydrochloric acid 4 (2 mL) was added to the suspension of the compound of Preparation 45 (43 mg, 0.07 mmol) in methanol (2 mL), and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed twice with dichloromethane. The combined organic phases 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, yielding the title compound as a yellow solid in 68% yield, 23 mg. LRMS (APCI +): m / z [M + H] + 470 Example 74 f2S) -1-r (2R) -4-benzoyl-2-methyl-piperazin-1-ill-2-r2- (2H-p) razol-3-ylaminoV quinolin-5-yloxy] -propan-1-one A mixture of the compound of Example 60 (50 mg, 0.11 mmol), 3-aminopyrazole (29 mg, 0.33 mmol) in triethylamine (48 μ ?, 0.33 mmol) in 2-propanol (0.5 ml) ) was heated to 90 ° C in a Reactivial ™. After 18 hours, cesium fluoride (33 mg, 0.22 mmol) was added and the mixture was heated at 100 ° C for a further 48 hours. Then, the reaction mixture was filtered and concentrated in vacuo to yield an oily residue. The residue was purified by HPLC using a Phenomenex Luna C 8 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, yielding the title compound in the form of a yellow solid, 3 mg. LRMS (APCI +): m / z [M + Hf 485 Example 75 5 - ((1 S) r 2 -r (2R) -4-benzoyl-2-methyl-piperazin-1-yn-1-methyl-2-oxo -ethoxy) -1H-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 to reflux for 24 hours. Then, the reaction mixture was diluted in water and washed with dichloromethane (3x10 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography on silica gel, eluting with 95: 5 dichloromethane: methanol yielding the title compound as a pale yellow solid in 40% yield, 76 mg. E B (APCI +): m / z [M + H] + 418 Example 76 5-. { (1 S) -2-r (2f?) -4-benzoyl-2-methyl-piperazin-1-yl-1-methyl-2-oxo-ethoxy-V-chloro-1 H-quinolin-2-one The title compound was prepared by the procedure described above for Example 67, using the compound of Example 75 and N-chlorosuccinimide. LRMS (APCI +): m / z [M + H] + 454 Example 77 (2S) -2-f (2ffl-4-benzoyl-2-methyl-piperazin-1-yl1-2- (2-methoxy-quinoline- 5-iloxQ-propan-1 -one A mixture of the compound of Example 60 (20 mg, 0.04 mmol) and sodium methoxide (0.5 in methanol, 0.7 ml) in A /, A / -dimethylformamide (0.5 ml) was heated in a Reactivial ™ at 70 ° C for 6 hours. The reaction mixture was cooled and evaporated under reduced pressure. The residue was dissolved in dichloromethane (5 ml) and washed with brine (5 ml) and water (2x5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (0.5 ml) and purified by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5: 95 Then, the appropriate fraction was azeotropically distilled with diethyl ether yielding the title compound as a yellow solid in a yield of 40%, 7 mg. LRMS (APCI +): m / z [M + H] + 434 Example 78 5 - ((1 S) -2 - [(2f?) - 4-benzoyl-2-methyl-piperazin-1 methyl ester -ill-1-methyl-2-oxo-ethoxy) -isoquinoline-1-carboxylic acid The compound of Preparation 65 (80 mg, 0.18 mmol), dichloro-bis (triphenylphosphine) palladium (15 mg, 0.08 mmol) and triethylamine (51 μ ?, 0.37 mmol) were dissolved in methanol ( 5 ml) and transferred to a sealed container. The vessel was heated to 100 ° C and the mixture was stirred at 100 psi (689.29 kPa) of carbon monoxide gas for 42 hours. Then, the reaction mixture was filtered through Arbocel®, washed meticulously with methanol and the filtrate was concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column, eluting with 99: 1 dichloromethane: methanol yielding the title compound as a white foam in 43% yield, 36 mg. LRMS (1 AP +): m / z [M + H] + 462 Example 79 Methylamide of 5- acid. { 2-r (2R) -4-Benzoyl-2-methyl-piperazin-1-n-1-methyl-2-oxo-ethoxy) -quinoline-2-carboxylic acid A mixture of the compound of Preparation 48 (20 mg, 0.05 mmol) methylamine (33% in ethanol, 30 mg, 0.5 mmol), 0- (1 H -benzotriazol-1-yl) -N hexafluorophosphate, / V, A / ', / V: etramethyluronium (2 mg, 0.08 mmol) and triethylamine (62 μ ?, 0.5 mmol) in dichloromethane (1 ml) was stirred at room temperature for 18 hours. Additional methylamine (30 mg, 0.5 mmol) and triethylamine (62 μ ?, 0.5 mmol) were added to the reaction mixture and stirring was continued for a further 8 hours. Then, the reaction mixture was diluted with dichloromethane and washed with water (2x5 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, yielding the title compound as a white solid in 13% yield, 3 mg. LRMS (APCI +): m / z [M + H] + 461 Example 80 Ethylamide of 5- (nS) -2-f (2f?) - 4-benzoyl-2-methyl-piperazin-1-in-1- acid methyl-2-oxo-ethoxy) -isoquinoline-1-carboxylic acid The title compound was prepared by the procedure described above for Example 79, using the compound of Example 78 and methylamine. LRMS (APCI +): m / z [M + Hf 461 Example 81 4 - ((1 SJ-2-r (2f?) -4-benzoyl-2-methyl-piperazin-1-yn-1-methyl -2-oxo-ethoxy) -N-methyl- The compound of Preparation 59 (100 mg, 0.2 mmol) and methylamine (33% in ethanol, 4 ml) were heated at 90 ° C in a Reactivial ™ for 18 hours. Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol 99: 1 to 97: 3, yielding the title compound as a pale orange foam with a quantitative yield, 100 mg. LRMS (APCI +): m / z [M + Hf 494 Example 82 (2SM-f (2ffl-4-benzoyl-2-methyl-piperazin-1-yn-2-f8-chloro-2-methylamino-quinolin-5- iloxy) -propan-1 -one A mixture of the 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) , 1.2 mmol) in dimethylsulfoxide (1 ml) was heated by microwave for 8 minutes at 170 ° C. After, the reaction mixture was filtered and the filtrate was purified 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 appropriate fraction was azeotropically distilled with diethyl ether yielding the title compound as a brown solid in a yield of 19%, 10.8 mg. LRMS (1 AP +): m / z [M + Hf 467 Example 83 1-f (2ffl-4-benzoyl-2-methyl-piperazin-1-yn-2- (1-methylamino-isoquinolin-5-yloxy) - propan-1-one The title compound was prepared by the procedure described above for Example 82, using the compound of Example 63 and methylamine. LRMS (APCI +): m / z [M + H] + 433 Example 84 (2SJ-1-f (2f?) -4-benzoyl-2-methyl-piperazin-1-yn-2- (8-chloro-2) -dimethylamino-quinolin-5-yloxy) -propan-1-one A mixture of the 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 mmol) was heated in dimethylsulfoxide (4 ml) at 170 ° C in a Reactivial ™ for 18 hours. Then, the reaction mixture was filtered and the filtrate was purified by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95 yielding the title compound as a white solid, 5 mg. LRMS (APCI +): m / z [M + H] + 481 Example 85 (2SJ-1-f (2RJ-4-benzoyl-2-methyl-piperazin-1-yl] -2-f1- (2H-pyrazole) 3-ylamino) -isoquinolin-5-yloxn-propan-1-one tetrabutylammonium fluoride (27 mg, 0.2 mmol), triethylamine (0.14 mL, 1 mmol) and 3-aminopyrazole (83 mg, 1 mmol) was heated in dimethylsulfoxide (1 mL) at 100 ° C for 24 hours. Then, the reaction mixture was purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / formic acid (5: 95: 0.1): acetonitrile, 95: 5 a 5:95 yielding the title compound in 39% yield, 19 mg. LRMS (APCI +): m / z [M + H] + 485 Example 86 (2SM -r (2R) -4-benzoyl-2-methyl-piperazin-1 -ill-2- (3,6-dimethyl-1 H -indazole-4-yloxy) -propan-1-one 4M Hydrochloric acid in dioxane (1 mL) was added to the compound of Preparation 77 (45 mg, 86 μp) in methanol and the solution was stirred for 2 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in dichloromethane and basified with a 1 M sodium hydroxide solution at pH 12. Then, it was passed to the mixture through a phase separation column and the The filtrate was concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, 96: 4: 1, afforded the title compound as a pale pink foam in 59% yield, 20 mg. E BR (APCI +): m / z [M + H] + 421 Example 87 (2S) -1-r (2R) -2-methyl-4- (pyridine-2-carbonin-p-Derazin-1-in- 2- (auinolin-5-iloxn-propan-1-one) A mixture of the compound of Preparation 51 (150 mg, 0.5 mmol), picolinic acid (49 mg, 0.6 mmol), 0- (1H-benzotriazole-1-α-1H / 4-hexafluorophosphate) tetramethyluronium (190 mg, 0.75 mmol) and triethylamine (0.93 mL, 10 mmol) in dichloromethane (3 mL) was stirred for 18 hours at room temperature, then the reaction mixture was diluted with more dichloromethane and washed with sodium hydroxide (10 ml) and water (2x10 ml) The organic phase was dried over magnesium sulfate and concentrated in vacuo, purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol, 99: 1 to 95: 5, gave the title compound as a white solid with a yield of 49%, 99 mg LRMS (APCI +): m / z [+ H 405 Example 88 (2S) -1-r4- ( 2-Fluoro-benzoylV (2f?) - 2-rnetyl-piperazin-1-ill-2- (quinolin-5-yloxy) - A mixture of the 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 (2x10 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, afforded the title compound as a white solid with a% yield, 153 mg. LRMS (APCI +): m / z [M + H] + 422 Example 89 4-α (1 S) -2-f (2R) -4-benzoyl-2-methyl-Pipezin-1 -ill-1 - methyl-2-oxo-ethoxy > -3- methoxy-N-methyl-benzamide To a solution of (3f?) - (3-methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem. (2000), 43 (23), 4499) (22 g, 0.11 mol) and (2S) -2- (2-methoxy-4-methylcarbamoyl-phenoxy) -propionic acid (25 g, 0.1 mol) (Preparation 5 ) in dry THF (250 ml) were added 1-N-hydroxybenzathiazole 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). After stirring for 1 hour an additional portion of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide.HCl (17 g, 0.09 mol) was added followed by additional diisopropylethylamine (17 ml, 0.1 mol). After another hour an additional portion of 1-ethyl-3- (3'-dimethylaminopropy!) Carbodiimide.HCl (17 g, 0.09 mol) followed by another portion of diisopropylethylamine (17 ml, 0.1 mol) was added. . Then, the mixture was stirred for a further 16 hours. After this, analysis by LCMS indicated that all the propionic acid had been consumed. The reaction mixture was evaporated to give a viscous oil which was treated with water (200 ml) followed by slow addition of concentrated aqueous hydrochloric acid until the mixture had pH 3. The resulting off-white precipitate was filtered off and washed with water (3x100 mi). The solid was crystallized two more times in ethanohagua (1: 1 by volume, 120 ml) yielding the title compound as a white solid (32 g). TI ivi ^ 4uu Mi-iz, uuLri3: o: f, au - (, ou (ÜI-I, mj, (, ¿? ^?? - ?, rru, b, and Í / IH, m), 6, 08 (1 H, sa), 5.1 (11H, ma), 4.09-2.80 (7H, m), 3.90 (3H, sa), 3.00 (3H, sa), 2, 40 (3H, s), 1, 70 (3H, da), 1, 40-0.9 (3H, m) ppm LRMS (ESI +): m / z [+ Hf 440 [a] D-26.9 ° (1 mg / ml in MeOH, 25 ° C, wavelength 589 nm) Example 90 5- ({1S) -2-f (2R) -4-benzoyl-2-methyl-piperazin methyl ester -1-in-1-methyl-2-oxo-ethoxy >; -4-methoxy-pyridine-2-carboxylic acid Di-fer-butyl azodicarboxylate (0.14 g, 0.6 mmol) and triphenylphosphine with polymeric support (0.25 g, 0.75 mmol) were added to a stirred solution of (2R) -1 - [(2) ) -4-benzoyl-2-methyl-piperazin-1-yl) -2-hydroxy-propan-1 -one (Preparation 76) (0.083 g, 0.3 mmol) and 5-hydroxy-5-hydroxyethyl ester 4-methoxy-pyridine-2-carboxylic acid (0.083 g, 0.45 mmol) (Tetrahedron Letters, 38, 1297 (1997)) in dichloromethane (3 mL) at 0 ° C. After 1 hour, the reaction mixture was allowed to warm to room temperature and more azodicarboxylic acid di-t-butyl (0.14 g, 0.6 mmol) and triphenylphosphine were added with polymeric support (0.25 g, 0.75 g). mmol). After 18 hours at room temperature the reaction mixture was filtered through Arbocel®, washing thoroughly with dichloromethane (10 ml). The filtrate was washed with a saturated aqueous solution of sodium hydrogencarbonate (20 ml), then the separated organic phase was dried (MgSO 4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with ethyl acetate: pentane 80:20, then ethyl acetate and finally ethyl acetate: methanol, 95: 5, afforded the title compound in Torma of a soiiao I plan, ü, l g. LRMS (APCI +): m / z [M + H] + 442 Example 91 Ethylamide of 5- acid. { (1 S) -2-f (2?) -4-benzoyl-2-methyl-piperazin-1-ill-1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid A solution of 5- methyl acid ester. { (1 S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy-H-methoxy-pyridine-2-carboxylic acid (Example 90) (0) , 2 g, 0.45 mmol) in a 33% w / w solution of methylamine in ethanol (3 mL) was heated on a 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: NH3, 98: 2: 0.5 to 95: 5: 0.5, yielding the title compound as a white solid, , 18 g 1H RN (400 MHz, CD3OD): d: 8.05 (1H, s), 7.75 (1H, s), 7.50-7.40 (5H, m), 5.40 (1H , m), 4.60-3.00 (8H, m), 3.95 (3H, sa), 2.90 (3H, s), 1.60-1.00 (6H, m) ppm. Found C, 61.65; H, 6.47; N, 12.41. 0.1 mol CH2Cl2 requires C, 61.80; H, 6.33; N, 12.48% E BR (APCI +): miz [M + H] + 441 [a] D-15.5 ° (1 mg / ml in eOH, 25 ° C, wavelength 589 nm) Example 92 Amide of 5 - ((1 S) -2-r (2Rj-4-benzoyl-2-methyl-piperazin-1-yl-1-methyl-2-oxo-ethoxy-methoxy-pyridine-2-carboxylic acid A solution of 5- methyl acid ester. { (1 S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} 4-methoxy-pyridine-2-carboxylic acid (Example 90) (0.2 g, 0.45 mmol) in a concentrated aqueous solution of ammonia (2 mL) and methanol (1 mL) was heated in Reacti-vial ™ to 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: NH3, 98: 2: 0.5 to 95: 5: 0.5, yielding the title compound as a white solid, 16 g. 1 H NMR (400 MHz, CD 3 OD): d: 8.05 (1H, s), 7.75 (1H, s), 7.50-7.40 (5H, m), 5.40 (1H, m) , 4.60-3.00 (9H, m), 3.95 (3H, sa), 1.60-1.00 (6H, m) ppm. Found C, 59.67; H, 6.11; N, 12.49. C22H26 4O5. 0.25 mol CH2Cl2 requires C, 59.78; H, 5.97; N, 12.54% LRMS (APCI +): m / z [M + H] +427 Example 93: 5-f (1S) -2-r (2f? J-4-benzoyl-2-methyl-piperazine) ethylamide -1-il1-1-methyl-2-oxo-ethoxy) -4-methoxy-pyridine-2-carboxylic acid A solution of 5- methyl acid ester. { (1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1 -yl] -1-methyl-2-oxo-ethoxy} 4-methoxy-pyridine-2-carboxylic acid cjeti ij-wu a / a, 10 y, o, n iiiiuiy m tíindmind ^ 1 mi ae Caieüíü aít rteacíl-vial ™ 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, yielding the title compound as a white solid, 0.14 g 1H RN (400 MHz, CD3OD): d: 8 , 05 (1H, s), 7.80 (1H, s), 7.50-7.40 (5H, m), 5.40 (1H, m), 4.60-3.00 (8H, m ), 4.00 (3H, sa), 3.45 (2H, c), 1.60-1.00 (6H, m), 1.20 (3H, t) ppm. Found C, 60.89; H, 6.72; N, 11.93. C24H30 4O5. 0.25 mol CH2Cl2 requires C, 61.22; H, 6.46; N, 11.78% LRMS (APCI +): m / z [M + H] +455 Example 94 Cyclopropylamide of 5- acid. { (S) -2 - [(2) -4-Benzoyl-2-methyl-piperazin-1-in- 1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid A solution of 5- methyl acid ester. { (1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} 4-methoxy-pyridine-2-carboxylic acid (Example 90) (0.12 g, 0.27 mmol) in cyclopropylamine (1 mL) was heated in Reacti-vial ™ 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, yielding the title compound as a white solid, 0.09 g 1 H NMR (400 MHz, CD 3 OD): d: 8 , 05 (1H, s), 7.70 (1H, s), 7.50-7.40 (5H, (6H, m), 0.8 (2H, m), 0.6 (2H, m) ppm. Found C, 63.02; H, 6.63; N, 11.83. C25H3oN405. 0.13 mol CH2CIZ requires C, 63.20; H, 6.39; N, 11.73% LRMS (APCI +): m / z [+ H] +467 Preparation 1 (2S) -2- (quinolin-5-yloxy) -propionic acid methyl ester Triphenylphosphine (2.17 g, 8.27 mmol) was added to the stirred suspension of diisopropyl azodicarboxylate (1.47 mL, 7.56 mmol) in THF (25 mL) at -5 ° C. Then 5-hydroxyquinoline (1.0 g, 6.90 mmol) and (R) -methyl lactate (0.66 ml, 6.90 mmol) were added and the solution was allowed to stir at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (30 ml), saturated potassium carbonate solution (30 ml) and brine (30 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 of pentane: ethyl acetate (4: 1) changing to pentane: ethyl acetate (3: 2). The title compound was obtained as a white solid (1.30 g). E BR (APCI +): m / z [M + Hf 232 Preparation 2 Sodium salt of (2S) -2- (quinolin-5-yloxy) -propionic acid propionic (Preparation 1) (1.30 g, 5.60 mmol) and a solution of 1 N sodium hydroxide (5.62 ml) were heated in dioxane (40 ml) at 60 ° C for 2 hours. After this time, the ccf analysis indicated that there was still starting material so that an additional solution of 1 N sodium hydroxide (1.4 ml) was added and heating was continued at 60 ° C for 1 hour. Then, the reaction mixture was concentrated under reduced pressure yielding the title compound as a yellow solid which was used without further purification. LRMS (ESI +): m / z [M + Hf 218 Preparation 3 1-f (2f?) - 4-benzoyl-2-methyl-piperazin-1-n-2-bromo-propan-1-one To one solution of (3R) - (3-methyl-piperazin-1-yl) -phenyl-methanone (J. Med. Chem. (2000), 43 (23), 4499) (4.06 g, 19.6 mmol) in dichloromethane (60 ml) and / V, / v-dimethylformamide (2 ml) were added 2-bromopropionic acid (3.0 g, 19.6 mmol), 0- (1 H-benzotriazol-1-yl) hexafluorophosphate) -N, A /, NW-tetramethyluronium (8.18 g, 21.6 mmol) and triethylamine (2.74 ml, 19.6 mmol). The reaction mixture was stirred at room temperature for 48 hours and then washed with water (50 ml), a 10% w / v aqueous citric acid solution (50 ml) and a saturated aqueous sodium hydrogencarbonate solution (50 ml). ). The solution was dried (MgSO) and the solvent was evaporated under reduced pressure. The product was punched by column chromatography on silica gel, eluting with a gradient system of dichloromethane: methanol (99: 1) to dichloromethane: methanol (95: 5). Then, the product was further purified by column chromatography on silica gel eluting with a gradient system of ethyl acetate: dichloromethane (30:70) changing to ethyl acetate: dichloromethane (45:55) yielding the title compound in the form of a white solid (3.80 g). E BR (ESI +): m / z [M + Hf 340 Preparation 4 4-hydroxy-3-methoxy-N-methyl-benzamide To a mechanically stirred suspension of vanillic acid (84 g, 0.5 mol) in dry THF (300 ml) was added portionwise carbonyldiimidazole (97 g, 0.6 mol). Gaseous evolution was observed and the mixture became homogeneous after approximately 5 minutes. After further stirring for 30 minutes an off-white precipitate was formed and kept under stirring for an additional 3 hours under nitrogen. After this time, LC S analysis indicated that vanillic acid had been consumed and a solution of 2 M methylamine in THF (1000 ml, 2 mol) was added in one portion and the mixture was stirred for a further 16 hours generating a precipitate Brown. The precipitate was filtered, washed in THF (2x250 ml) followed by ether (300 ml) and dried in vacuo to give the N-methylammonium salt of the title compound (87 g, 82%) LRMS (ESI +): m / z [M + H] + 182 A portion of the ammonium salt (1.06 g, 5 mmol) was heated to reflux in acetone in the presence of a nitrogen stream for hours. 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 + Hf 182 Preparation 5 Acid (2S ) -2- (2-methoxy-4-methylcarbamoyl-phenoxy) -propionic To a stirred mixture of triphenylphosphine (42 g, 0.16 mol), 4-hydroxy-3-methoxy-N-methyl-benzamide (Preparation 4) (20 g, 0.11 mol) and (R) -methyl lactate (12 g, 0.12 mol) in dry THF (300 ml) at -5 ° C was added dropwise a solution of diisopropyl azodicarboxylate (32 ml, 0.16 mmol) in dry THF (100 ml) for 30 minutes. minutes The solution was allowed to warm to room temperature and was stirred for 2 hours. After this time, the ccf analysis indicated that the starting phenol had been 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 time, analysis by LC S indicated that the intermediate methyl ester had been 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 (2x300 mL) and ethyl acetate (2x300 mL). Then, the aqueous phase was acidified to pH 2 using concentrated aqueous hydrochloric acid resulting in the formation of a white precipitate. This precipitate was removed by filtration, washed with water (2x100 ml) and recrystallized from ethanol: water (1: 1 by volume, 80 ml per 20 g) producing the compound or the mixture in a Dianco solution. ig, 75%) E BR (1EN +): m / z [M + Hf 254 Preparation 6 3-Methoxy-4-f (1S) -1-methoxycarbonyl-ethoxyl-benzoic acid methyl ester Diisopropyl azodicarboxylate (4 mL, 20 mmol) in tetrahydrofuran (15 mL) was added dropwise to an ice-cold solution of methyl vanillyl (3.64 g, 20 mmol), (R) -methyl lactate ( 2.08 g, 20 mmol) and triphenylphosphine (5.24 g, 20 mmol) in tetrahydrofuran (30 ml) and the reaction mixture was stirred at room temperature for 18 hours.
Then, the solvent was evaporated under reduced pressure and the residue was stirred in a mixture of diethyl ether (50 ml) and hexane (50 ml). The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with ethyl hexanoacetate, 85:15 to 75:25 afforded the title compound in 71% yield, 3.8 g EMBR (EN +): m / z [M + H] + 269 Preparation 7 4-f (1 S) -1-carboxy-ethoxy] -3-methoxy-benzoic acid methyl ester mmol) was added to a solution of the compound of Preparation 6 (32 g, 120 mmol) in methanol (150 mL) and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified with 2M hydrochloric acid to pH 4 and then extracted with ethyl acetate (3x150 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure yielding the title compound in 91% yield, 23 g. LRMS (ES +): m / z [M + H] + 255 Preparation 8 Methyl ester of 4 - ((1 S) -2-((2R) -4-benzoyl-2-methyl-piperazin-1-ill- 1- methyl-2-oxo-ethoxy) -3-methoxy-benzoic acid Hüning's base (1.8 ml, 10.5 mmol) was added to a solution of the compound of Preparation 7 (1.8 g, 7 mmol) , (3R) - (3-methyI-piperazin-1-yl) -phenyl-methanone [(1.6 g, 7.7, mmol) J. Med. Chem. 43 (23), 4499; 2000], and 3- (diethoxyphosphoryloxy) -1, 2,3-benzotriazin-4- < 3 H) -one (2.75 g, 9.1 mmol) in dichloromethane (16 mL). The mixture was stirred for 4 hours and then evaporated under reduced pressure. The residue was taken up in ethyl acetate (200 ml) and washed with a 10% sodium carbonate solution (2x50 ml) and brine (2x50 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The purification of the residue by chromatography in 5:95 gave the title compound in 95% yield, 2.95 9-LRMS (ES +): m / z [M + H] + 441 Preparation 9 4 - ((1 S) -2-K2f?) -4-benzoyl-2-methylpiperazin-1 -11-1-methyl-2-oxo-ethoxy-3-methoxy-benzamide The compound of Preparation 8 (0.46 g, 1.04 mmol) and 2 M ammonia in methanol (10 mL) were heated in a sealed container at 120 ° C for 18 hours. Then, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol, 98: 2 to 92: 8, yielding the title compound as a colorless foam with a yield of 55%, 243 mg LRMS (ES +): m / z [M + H] + 426 Preparation 10 4 - ((1 S) -2-r (2f?) - 4-benzoyl-2-methyl-piperazin -1-ill-1-methyl-2-oxo-ethoxy-VN-dimethylaminomethylene-3-methoxy-benzamide dimethylformamide dimethylacetal (10 ml) were heated at reflux for 7 hours. Then, the reaction mixture was evaporated under reduced pressure to give a pale orange solid. The solid was purified by column chromatography on silica gel, eluting with dichloromethane: methanol, 99: 1 to 97: 3, to provide a colorless oil. Then, the oil was distilled azeotropically with dichloromethane and the resulting foam was dried at 40 ° C for 3 hours yielding the title compound in 94% yield, 255 mg. LRMS (ES +): m / z [M + Na] + 503 Preparations 11 to 13 The following compounds, of the general formula shown below, were prepared by the procedure described above for Preparation 10 using the appropriate ketone and dimethylformamide dimethylacetal.
Preparation 11 uses 1- (3-methoxy-2-methyl-phenyl) -ethanone, prepared as described in Tetrahedron 25 (8) 4249: 1969 Preparation 14 3- (3-methoxy-2-methyl-phenyl) -1 -methyl-1 H-pyrazole The 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 to 90 g. ° C for 2.5 hours. Then, the solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with a 10% sodium carbonate solution and a saturated sodium hydrogencarbonate solution. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give an orange oil. The oil was first purified by column chromatography on silica gel, eluting with dichloromethane: ethyl acetate 99: 1 to 97: 3. This was followed by further purification using an Isolute® ultrafast silica column, eluting with dicyoromethane: ethyl acetate, 99: 1 to 97: 3, yielding the title compound as a yellow oil in 31% yield, 568 mg . LRMS (ES +): m / z [+ H 203 Preparations 15 to 16 The following compounds, of the general formula shown below, were prepared by the procedure described above for Preparation 14 using the appropriate enamine and hydrazine monohydrate.
Preparation 17 2-methyl-3- (1-methyl-1rt-pyrazole-3-in-phenol Boron tribromide (in 1 M dichloromethane, 8.16 ml, 8.16 mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 14 (550 mg, 2.72 mmol) in "dichloromethane (6 mM). The resulting solution was allowed to warm to room temperature and stirred for 2 hours, then the reaction mixture was carefully poured into ice and neutralized with a 10% sodium carbonate solution, the mixture was extracted with dichloromethane ( 2x50 ml) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo, the residue eluting with dichloromethane: methane, 98: 2 to 97: 3 to give a brown oil.The oil was azeotropically distilled with dichloromethane producing the title compound in the form of a brown foam with a yield of 61%, 310 mg E BR (EN +): m / z [M + H] + 189 Preparations 18 to 20 The following compounds, of the general formula shown Then, they were prepared by the procedure described previously for Preparation 17 using the appropriate derivative of methoxybenzene and boron tribromide.
Methoxy-2-methylbenzamide (J. Chem.Soc.Perkin Trans. 1, 2389-2396; 1984) Preparation 21 (2S) -2- [3- (2H-pyrazol-3-yl) -phenoxyl) methyl ester propionic Diisopropyl azodicarboxylate (295 μl, 1.5 mmol) was added dropwise to an ice-cold solution of the compound of Preparation 20 (240 mg, 1.5 mmol) and (ft) -methyl lactate (156 mg , 1.50 mmol) and triphenylphosphine (393 mg, 1.5 mmol) in teirahydrofuran (5 mL). The reaction mixture was stirred at room temperature for 18 hours and then diluted with diethyl ether (50 ml) and washed with water (2x10 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® ultrafast silica column, eluting with diethyl ether: dichloromethane, 80:20 to 95: 5, yielding the title compound as a yellow viscous oil in 54% yield, 200 mg.
LRMS (EN "): m / z [? -?] '245 Preparation 22 (2S) -2-r2-Methyl-3- (2H-pyrazol-3-yl) -phenoxy-propionic acid methyl ester The title compound was prepared by the procedure described above for Preparation 21 using the compound of Preparation 19 and (R) -methyl lactate. LRMS (ES "): m / z [M-H] ~ 259 Preparation 23 Acid (2Sj-2-f3- (2H-pyrazol-3-yl) -phenoxy-1-propionic acid Lithium hydroxide monohydrate (80.9 mg, 1.93 mmol) was added portionwise to a solution of the compound of Preparation 21 (90 mg, 0.77 mmol) in methanol (6 mL) and the mixture was stirred at 60 ° C. ° C for 8 hours. Then, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified with 2M hydrochloric acid to pH 4 and then extracted with ethyl acetate (3x30 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure yielding the title compound yield 75%, 135 mg. E BR (EN "): m / z [-H]" 231 Preparation 24 (2S) -2-r2-Methyl-3- (2H-pyrazol-3-yl) -phenoxy-1-propionic acid The title compound was prepared by the procedure described above for Preparation 22 using the compound of Preparation 22 and lithium hydroxide. U LRMS (hN): m / Z [-H] ~ 24¾ Preparation 25 1 -G (2R) -4-benzoyl-2-methyl-piperazin-1-in-2-bromo-propan-1 -one 2-Bromopropionic acid (1.53 g, 10 mmol) was added to a solution of? /,? / '-dicyclohexylcarbodiimide (2.06 g, 10 mmol) in dichloromethane (40 mL), cooled to -15 ° C. . The reaction mixture was stirred for 20 minutes before adding dropwise (2R) - (3-methyl-piperazin-1-yl) -phenyl-methanone (2.04 g, 10 mmol), J. Meo. Chem. 43 (23), 4499; 2000] in dichloromethane (16 ml). The reaction mixture was stirred at -15 ° C for 90 minutes and then diluted with diethyl ether (100 ml) and stirred for a further 10 minutes. Then, the mixture was filtered through Celite, washing thoroughly with diethyl ether and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with hexane: ethyl acetate 40:60 to 20:80 yielding the title compound in 76% yield, 2.5 g. E BR (EN +): m / z [M + Hf 340 Preparation 26 3-. { 2-r (2 J-4-benzoyl-2-methylpiperazin-1-n-1-methyl-2-oxo-ethoxy> 2-methyl-benzamide I ns as I ns I I »Pr nprarion 18 I1 R0 mci 1 19 mmnl \ v! = > Preparation 25 (403.9 mg, 1.19 mmol) and cesium carbonate (387 mg, 1.19 mmol) in? /, / V-dimethylformamide (10 mL) were heated at 80 ° C for 18 hours. Then, the cooled reaction mixture was 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® ultrafast silica column, eluting with dichloromethane: methanol 99: 1 to 96: 4, to give a colorless foam. The foam was azeotropically distilled with dichloromethane and dried under reduced pressure yielding the title compound in 98% yield, 475 mg. LRMS (ES +): m / z [M + H] + 410 Preparation 27 1-f (2) -4-benzoyl-2-methyl-piperazin-1-yn-2- (3-methoxy-5-nitro-phenoxy) ) -propan- 1 -one The title compound was prepared by the procedure described above for Preparation 26 using the compound of Preparation 25 and 2-methoxy-5-nitrophenol. LRMS (APCI +): miz [M + Hf 428 Preparation 28 3-. { 2-f (2R) -4-benzoyl-2-methylpiperazin-1-yn-1-methyl-2-oxoethoxy > - / \ / - (dimethylamino) methylene-2-methylbenzamide The title compound was prepared by the procedure described above for Preparation 10 using the compound of Preparation 26 and N, A / -dimethylformamide dimethylacetal. LRMS (APCI +): m / z [M + Hf 465 Preparation 29 3-f2-r (2ffl-4-benzoyl-2-methyl-piperazin-1-in-1-methyl-2-oxo-ethoxy) -N- hydroxyaminomethylene-2-methyl-benzamide A solution of sodium hydroxide (1 M, 0.06 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 28 (410 mg, 0.88 mmol) was added in portions and the resulting solution was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the oily residue was partitioned between dichloromethane (30 ml) and water (6 ml), and neutralized with a 10% sodium carbonate solution. The organic phase was separated and the aqueous phase was extracted again with dichloromethane (30 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a Isolute® ultrafast silica column, eluting with dichloromethane: methanol 99: 1 to 96: 4, yielding the title compound as a colorless foam, in 78% yield, 310 mg. E BR (EN "): m / z [M-Hf 451 ^ repair JU 2- (4-amino-2-methoxy-phenoxy) -1-f (2f?) - 4-benzoyl-2-methyl-Diperazin- 1-n-propan-1-one 25% Pd / C (150 mg) and ammonium formate (443 mg, 7 mmol) were added to a solution of the compound of Preparation 27 (600 mg, 1.4 mmol) in ethanol (30 mL) and the mixture was stirred. heated at 70 ° C for 2 hours. Then, the reaction mixture was cooled and filtered through Arbocel®, washing thoroughly with ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanoi 95: 5, yielding the title compound as a pale pink solid, with a yield of 80%, 443 mg. LRMS (APCI +): m / z [+ H] + 398 Preparation 31 4-benzyloxy-3-methoxy-benzamidine "Butyllithium (1.6 M in hexane, 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 room temperature. -5 ° C, and the reaction mixture was stirred for a few minutes at constant temperature to u "U. £ > and 3-methoxy-4- (phenylmethoxy) -benzonitrile (5.5 g, 22.99 mmol) was added portionwise and the mixture was stirred at room temperature for 4 hours. Then, the reaction mixture was poured into 2 M hydrochloric acid cooled with ice (100 ml) and washed with diethyl ether (2x00 ml). The aqueous phase was basified to pH 10 with a 6M sodium hydroxide solution and extracted with dichloromethane (3x100 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a white solid in 68% yield, 3.99 g. LRMS (ES +): m / z [M + H] + 257 Preparation 32 2- (4-benzyloxy-3-methoxy-phenyl) -1H-imidazole The compound of Preparation 31 was added (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 removed by filtration and the filtrate was washed with a saturated solution of sodium hydrogencarbonate (30 ml). The aqueous phase was extracted again with 10% methanol in dichloromethane (2x50 ml) and the combined organic extracts were dried-c.nncontrarnri > i xrar.in Fl ro < iHi m ¾P nurifiro in a column of ultrafluid silica Isolute®, eluting with dichloromethane: methanol, 98: 2 to 96: 4, to give a brown foam. The foam was further purified on a Isolute® ultrafast silica column, eluting with dichloromethane: methanol 99.5: 0.5 to 98: 2, to give a beige foam. The foam was then azeotropically distilled with dichloromethane and dried at 40 ° C, yielding the title compound in 16% yield, 180 mg. LRMS (ES +): m / z [M + Hf 281 Preparation 33 4- (1H-imidazol-2-yl) -2-methoxy-phenol To a solution of the compound of Preparation 32 (170 mg, 0.61 mmol) in methanol (10 mL) was added portionwise Pd / C (85 mg) and ammonium formate (191 mg, 3.03 mmol). ). The mixture was refluxed for 2 hours. Then, the reaction mixture was cooled and filtered through Arbocel®, washing thoroughly with 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 and yielding the title compound as a white solid in 91% yield 105 mg LRMS (ES +): m / z [M + H] + 191 Preparation 34 2-methoxy-4- (2H-pyrazol-3-yl) ~ phenol The title compound was prepared by the procedure described above for Preparation 33 using the compound of Preparation 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 heated to reflux for 4 hours. Then, the cooled reaction mixture was evaporated under reduced pressure and the residue was partitioned between diethyl ether (200 ml) and water (80 ml). The aqueous phase was separated and extracted again with diethyl ether (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was azeotropically distilled with dichloromethane, yielding the title compound as a white solid in 100% yield, 7.19 g. LRMS (ES +): m / z [M + Naf 317 Preparation 36 1 - (4-bertyloxy-3-methoxy-phenifl-1 H-pyrazole A mixture of the compound of Preparation 35 (1.5 g, 5.12 mmol), pyrazole (697 mg, 10.23 mmol), copper iodide (I) (195 mg, 1.02 mmol) and potassium carbonate in WW-dimethylformamide (10 ml) 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 extracted again 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, yielding the title compound as a white solid in 82% yield, 1.18 g. LRMS (ES +): m / z [M + Hf 281 Preparation 37 2-methoxy-4-pyrazol-1-yl-phenol The title compound was prepared by the procedure described above for Preparation 33 and using the compound of Preparation 36. LRMS (ES +): m / z [+ H] + 191 Preparation 38 (2S) -2- (quinolin-5-yloxfl-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) and tetrahydrofuran (25 mL) at -5 ° C. 5-Hydroxyquinoline (1.0 g, 6.90 mmol) and (R) -methyl lactate (0.66 ml, 6.90 mmol) were added and the solution was allowed to stir at room temperature for 14 hours. Then, the reaction mixture was diluted with ethyl acetate (50 ml), 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, affording the title compound as a white solid in 81% yield, 1.30. g. LRMS (ES +): m / z [M + H] + 232 Preparation 39 (2S) -2- (Isoquinolin-5-yloxy) -propyonic acid methyl ester The title compound was prepared by the procedure described above for Preparation 38 using 5-hydroxyisoquinoline and (R) -methyl lactate. LRMS (APCI +): miz [M + Hf 232 Preparation 40 Sodium salt of (2S) -2- (quinolin-5-yloxy-propionic acid) A solution of the compound of Preparation 38 (1, 30 g, 5.60 mmol) and a solution of sodium hydroxide 1 (5.62 ml) n, 4-dioxane (40 ml) was heated at 60 ° C for 2 hours. After this, the analysis by ccf indicated that there was still starting material, so more 1 M sodium hydroxide solution (1.4 ml) was added and heating was continued at 60 ° C for 1 hour. Then, the reaction mixture was concentrated in vacuo, yielding the title compound as a yellow solid in quantitative yield. LRMS (ES +): miz [M + H] + 218 »Preparation 41 Sodium salt of (25) -2- (isoquinolin-5-yloxy-propionic acid) The title compound was prepared by the procedure described above for Preparation 40 using the compound of Preparation 39. LRMS (APCI +): m / z [M + H] + 218 Preparation 42 (2S) -1-f (2R) -4-benzoii-2-methyl-piperazin-1-yl1-2- (quinolin-5-iioxn-propan-1-one) A solution of the compound of Preparation 40 (1.0 g, 4.6 mmol), 3RW3-methyl-nioerazin-1-i-fRnil-mf¾ † 3none IY0 94 p? 6 mmoH ./. Mprf Chem. 43 (23), 4499; 2000], hexafluorophosphate 0- (H-benzotriazol-1-yl) -? /,? /,? / '? '-tetramethyluronium (2.62 g, 6.9 mmol) and triethylamine (1.93 mL, 13.8 mmol) in V, / V-dimethylformamide (30 mL) was stirred at room temperature for 14 hours. Then, the reaction mixture was diluted with dichloromethane (100 ml), washed with water (3 × 50 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane.methanol 98: 2, yielding the title compound as a white solid in 49% yield, 0.91 g. LRMS (ES +): m / z [M + H] + 404 Preparation 43 (2S) -1-f (2R) -4-benzoyl-2-methyl-piperazin-1-yl) -2- (isoquinolyl) 5-yloxy) -propan -one The title compound was prepared by the procedure described above for Preparation 42 using the compound of Preparation 41 and (3R) - (3-methyl-piperazin-1-yl) -phenyl -metanone (J. Meo, Chem., 43 (23), 4499, 2000). E BR (APCI +): m / z [M + H] + 404 Preparation 44 (2S) -1-f (2 /?) -4-benzoyl-2-methyl-piperazin-1-in-2- (8- bromine-quinolin-5-yloxy) -propan-1-one A mixture of the 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, yielding the title compound as a white solid in 98% yield, 526 mg . LRMS (ES +): m / z [M + H] + 482/484 Preparation 45 (2SM-r (2f?) -4-benzoyl-2-methyl-piperazin-1-ill-2- (8-r2- ( 2- • trimethylsilanylethoxymethyl) -2H-pyrazol-3-yl-1-quinolin-5-yloxy> -propa Palladium tetrakis (triphenylphosphine) (Q) (6 mg, cat), 1 - [[2- (Trimethylsilyl) ethoxy] methyl] pyrazolyl-5-boric acid [(50 mg, 0.1 mmol) was added. , J. Med. Chem. 41 2019-2028; 1998] and sodium carbonate (175 mg, 1.6 mmol) in water (0.5 ml) to a compound of Preparation 44 (50 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and the mixture was heated to reflux for 18 hours. it was dissolved in dichloromethane and washed with water (5 ml) and brine (2x5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give an orange oil. The oil was purified by column chromatography on silica gel, eluting with dichloromethane: methanol. 99: 1 to 96: 4, yielding the title compound as a yellow solid EMBR (APCI +): m / z [M + H] + 600 Preparation 46 (2S) -1-f (2ffl-4-benzoyl- 2-methyl-piperazin-1-ill-2- (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 the compound of Preparation 42 (1.5 g, 3.7 mmol) in dichloromethane (15 mL) and the mixture it was stirred at room temperature for 3 hours. Then, the reaction mixture was diluted with dichloromethane (10 ml) and washed with a saturated aqueous solution of potassium carbonate (10 ml) and with water (2x10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid with a quantitative yield, 1.8 g. E BR (APCI +): m / z [M + H] + 420 Preparation 47 5- (2-f (2f?) - 4-benzoyl-2-methyl-piperazin-1-in-1-methyl acid methyl ester - 2-oxo-ethoxy.]. -quinoline-2-carboxylic acid or The chloro compound of Preparation 66 (130 mg, 0.3 mmol), dichloro bis (triphenylphosphine) palladium (24 mg, 0.03 mmol) and triethylamine (83 μ ?, 0.6 mmol) were dissolved in a mixture of methanol (3 ml) and N, N-dimethylformamide (0.5 ml) and transferred to a sealed container. The vessel was heated to 00 ° C and the mixture was stirred at 100 psi (689.29 kPa) of gaseous carbon monoxide for 42 hours. Then, the reaction mixture was filtered through Arbocel®, washed thoroughly with methanol and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with ethyl acetate.pentane, 75:25 to 100: 0, afforded the title compound in 41% yield, 50 mg. E BR (APCI +): miz [+ Hf 452 Preparation 48 Acid 5- (2-r (2R) -4-benzoyl-2-methyl-piperazin-1-in-1-methyl-2-oxo-ethoxy) -quinolin -2-carboxylic A solution of sodium hydroxide 1 (130 μl, 0.135 mmol) was added to a solution of the compound of Preparation 47 (40 mg, 0.09 mmol).
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 discarded. The aqueous phase was acidified with glacial acetic acid and extracted again with ethyl acetate. The retained organic phase (2nd wash) was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a pale yellow solid in 67% yield, 26 mg. LRMS (APCI *): m / z [M + H] + 448 Preparation 49 (2S) -1- 2ffl-4-benzoyl-2-methyl-piperazin-1-IV2- (2-benzylamino- quinolin-5-yloxy) -propan-1-one A mixture of the compound of Example 60 (50 mg, 0.11 mmol) and tetrabutylammonium fluoride (30 mg, 0.22 mmol), triethylamine (0.16 mL, 1.1 mmol) and benzylamine (0.13 mL, 1.1 mmol) in dimethylsulfoxide (1 ml) was r.¾¾¾p > n + (at 190 ° O Hurantp 79 hnras np¾r > i | p G ??? g, ??? purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0, 1): acetonitrile, 95: 5 at 5:95, giving the title compound in a yield of 34% E BR (APCI +): m / z [+ Hf 509 Preparation 50 Ferric-acid butyl ester (3ff) - 3-methyl-4-α (2S) -2- (auinolin-5-yloxy) -propionin-piperazine-1-carboxylic acid Hydroxybenzotriazole hydrate (249 mg, 1.87 mmol) was added to a suspension of the compound of Preparation 40 (400 mg, 1.7 mmol) in /, / V-dimethylformamide to form a solution. 1-Ethyl-3- (3-dimethylaminopropyl) 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 afford the title compound in 48% yield, 332 mg. LRMS (APCI +): m / z [M + Hf 400 Preparation 51] Hydrochloride of (2SJ-1 -r (2R) -2-methyl-piperazin-1 -ill-2- (quinolin-5-yloxy) -propan-1 -one The compound of Preparation 50 (300 mg, 0.75 mmol) was stirred in 4 M hydrochloric acid and dioxane (3 mL) for 2 hours. The reaction mixture was concentrated in vacuo yielding the title compound as a pale yellow solid in quantitative yield, 348 mg. LRMS (APCI +): m / z [M + Hf 300 Preparation 52 (2S) -1-r (2 /? M-benzoyl-2-methyl-piperazin-1-n-2- (2,8-dichloro-auinolin- 5-iloxn-propan-1-one A mixture of the compound of Example 60 (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. Then, the solvent was evaporated under reduced pressure and the residue was 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-dimethanol, 98: 2, yielding the title compound in the form SMI (APCI +): m / z [M + H] + 472 Preparation 53 (2S) -1 - [(2f?) - 2-methyl-4- (pyridine-2-carbonyl-piperazin-1-n-2) - (quinolin-5-yloxy) -propan-1-one A mixture of the compound of Preparation 51 (150 mg, 0.5 mmol), picolinic acid (49 mg, 0.6 mmol), 0- (1 H-benzotriazol-1-yl) - / V, A / hexafluorophosphate , V ', A / 4-tetramethururonium (190 mg, 0.75 mmol) and tritylamine (0.93 mL, 10 mmol) in dichloromethane (3 mL) was stirred for 18 hours at room temperature. Then, the reaction mixture was diluted with more dichloromethane and washed with sodium hydroxide (10 mL) and water (2x10 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol 99: 1 to 95: 5, afforded the title compound as a white solid in 49% yield, 99 mg. LRMS (APCI +): m / z [+ H] + 405 Preparation 54 f2S) -1-r4- (2-fluoro-benzoyl) -r2 /:?) -2-methyl-piperazin-1-in-2- ( quinolin-5-yloxy) -propan-1-one A mixture of the 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 in dichloromethane and washed with water (2x10 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, afforded the title compound as a white solid in 73% yield, 153 mg. LRMS (APCI +): m / z [+ Hf 422 Preparation 55 4-bromo-2-trifluoromethoxy-phenol Bromine (449 mg, 2.81 mmol) was added to a solution of 2- (trifluoromethoxy) pheno! (500 mg, 2.81 mmol) and sodium acetate (169 mg, 2.81 mmol) and acetic acid (5 mL) and the solution was stirred for 1 hour. Then, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2 × 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, yielding the title compound as a white solid with a yield of LRMS (APCI +): m / z [M + H] + 255/257 Preparation 56 (2Sj-2- (4-bromo-2-trifluoromethoxy-phenoxy) -propionic acid methyl ester Diisopropyl azodicarboxylate (414 μ ?, 2.14 mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 55 (500 mg, 1.95 mmol), (R) -methyl lactate (202 mg , 1.95 mmol) and triphenylphosphine (614 mg, 2.34 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a 10% potassium carbonate solution (2x10 ml). The organic phase was dried over magnesium sulfate and concentrated to! empty. The residue was purified by column chromatography on silica gel, eluting with dichloromethane.methanol, 95: 5, yielding the title compound as a colorless oil in 76% yield, 638 mg. LRMS (1 AP +): m / z [M + Hf 305/307 Preparation 57 Acid (2SJ-2- (4-bromo-2-trifluoromethoxy-phenoxy) Propionic A mixture of the compound of Preparation 56 (574 mg, 1.67 mmol) and a solution of 1M sodium hydroxide (4.2 mL, 4.2 mmol) in dioxane (10 mL) was stirred at 55 ° C for 3 hours. hours. Then, the solvent was evaporated under reduced pressure and the residue was dissolved in water (30 ml). The aqueous solution was acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate (2x50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow solid in 80% yield. LRMS (APCI +): m / z [M + H] + 327 Preparation 58 (2S) -1-f (2f?) -4-benzoyl-2-methyl-piperazin-1-yl1-2- (4-bromo- 2-trifluoromethoxy-phenoxy) -propan-1 -one A solution of the compound of Preparation 57 (150 mg, 0.46 mmol), (3R) - (3-methyl-piperazin-1-yl) -phenii-methanone [93 mg, 0.46 mmol) J. Med. Chem., 43 (23), 4499; 2000], 0- (1 H -benzotriazol-1-yl) - / V, / V, / V ', and V-tetramethyluronium hexafluorophosphate (260 mg, 0.69 mmol) and triethylamine (0.13 mL, 0, 92 mmol) in dichloromethane (30 ml) was stirred at room temperature for 18 hours. Then, the reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The aqueous phase became dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column, eluting with 99: 1 dichloromethane: methanol, yielding the title compound as a white foam in 90% yield, 213 mg. LRMS (APCI +): m / z [+ Hf 537/539 Preparation 59 4- (1 S) -2-f (2f?) - 4-benzoyl-2-methyl-piperazine-1-methyl ester n-1-methyl-2-oxo-ethoxy) -3-trifluoromethoxy-benzoic acid The compound of Preparation 58 (190 mg, 0.37 mmol), palladium dichloro bis (triphenylphosphine) (30 mg, 0.04 mmol) and triethylamine (0.10 mL, 0.74 mmol) were dissolved in methanol ( 10 ml) and they were transferred to a hermetically sealed container. The vessel was heated to 100 ° C and the mixture was 5 stirred at 100 psi (689.29 kPa) of gaseous carbon monoxide for 42 hours. Then, the reaction mixture was filtered through Arbocel®, washing meticulously with methanol and the filtrate was concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column, eluting with dichloromethane: methanol, 97: 3 yielding the title compound in 0 form of an orange solid, 85%, 55 mg. E B (APCI +): miz [M + H 495 Preparations 60 to 61 The following compounds, of the general formula shown below, were prepared by the procedure described above ID for the repair of the compounding of the Preparation and the > hydroxyquinoline or appropriate hydroxyisoquinoline.
The following compounds, of the general formula shown below, were prepared by the procedure described above for Preparation 46 using the compounds of preparations 60 and 61 and meia-chloroperbenzoic acid Preparation 64 (2S) -1-r (2R) -4-Benzoyl-2-methyl-piperazin-1-yl1-2- (1-oxy-isoquinol-n-5-yloxy) -propan-1-one The title compound was prepared by the procedure described above for Preparation 46 using the compound of Preparation 43. LRMS (APCI *): m / z [M + Hf 420 Preparation 65 (2S) -1-y (2f? J -4-Benzoyl-2-methyl-piperazin-1-ill-2- (1-chloro-isoquinolin-5-yloxyV-propan-1-one) Phosphorus oxychloride (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 to 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 a concentrated ammonia solution and extracted with dichloromethane (2x75 mL). Then, the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol, 99: 1, afforded the title compound as a white foam in 40% yield, 127 mg. LRMS (APCI +): m / z [M + H] + 438 Preparation 66 1 -f (2f? H -benzoyl-2-methyl-piperazin-1-in-2- (2-chloro-quinolin-5-yloxy) propan-1 -one above for Preparation 65 using the compound Preparation 62. LRMS (APCI +): m / z [M + H] + 438 Preparation 67 2-methoxy-4-methylsulfanyl-phenol Illithium (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) cooled to -78 ° C. The mixture was stirred for 15 minutes and then warmed to -40 ° C and stirred for a further 30 minutes. Dimethyl disulfide (1.06 ml, 11.8 mmol) was added and the mixture was stirred at room temperature for 18 hours. Water was then added to the reaction and the resulting mixture acidified to pH 1 and hydrochloric acid 2. The aqueous phase was separated and extracted again with ethyl acetate. Then, the combined organic fractions were 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, yielding the title compound as a white solid in 48% yield, 800 mg. 1 H NMR (400 MHz, CDCl 3): d: 2.40 (s, 3 H), 3.90 (s, 3 H), 5.50 (br s, 1 H), 6.80-6.90 (m, 3 H) ) Preparation 68 6-Hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one - ^, -OH A mixture of lithium iodide (0.32 g, 2.41 mmol) and 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one (0.5 g, 2.41 mmol) in 2 , 4,6-coidine (10 ml) was heated at 130 ° C for 18 hours. Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanoi, 96: 4, yielding the title compound as a pale yellow solid, 0.19 g . E BR (APCI +): m / z [M + Hf 194 Preparation 69 Acetic acid 3-acetoxy-5-methyphenyl 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 warmed to room temperature and stirred for 60 hours. Then water (100 ml) was added and the mixture was stirred vigorously for 3 hours. The organic phase was separated and the aqueous phase was extracted again with dichloromethane (3x80 ml). The combined organic extracts were washed non-brine (RO concentrated in vacuo) The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: pentane 66:33 yielding the title compound as a colorless oil with a yield of 94%, 15.7 g E BR (APCI +): m / z [M + NH4f 226 Preparation 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), was heated to 90 ° C and the mixture was stirred for one hour. Then, the reaction mixture was cooled and carefully pipetted onto a mixture of ice and 2M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3x200 ml) and the combined organic phases were washed with brine, dried over sulfate of magnesium 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 the title compound as a yellow solid in 66% yield 5.31 g. LRMS (APCI +): m / z [+ H] + 167 Preparation 71 3.6-dimethyl-1 H-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 room temperature for 1 hour and at 150 ° C for 80 minutes. Then, the cooled reaction mixture was poured into water and acidified to pH 6 with acetic acid. The aqueous mixture was extracted with ethyl acetate (4x200 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. Purification of the residue by column chromatography on silica gel, eluting with ethyl acetate: pentane, 50:50, gave the title compound as a yellow solid in 95% yield, 3.84 g. LRMS (1 AP +): m / z [+ H] + 163 Preparation 72 4- (tert-butyl-dimethyl-siianyloxn-3,6-dimethyl-1H-indazole Ferd -Butyldimethylchlorosilane (511 mg, 3.39 mmol) and imidazole (1.05 g, 15.4 mmol) were added to a solution of the compound of Preparation 71 (500 mg, 3.08 mmol) in fyW-dimethylformamide and the reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 18 hours. More urea-butyldimethylchlorosium (5 mg, 3.39 mmol) was added and the reaction mixture was heated at 80 ° C for 48 hours, 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 (2x10 ml), dried with magnesium sulfate and concentrated in vacuo.The residue was purified by column chromatography on silica gel, eluting with pentane: ethyl acetate, : 85, yielding the title compound as an orange oil with a yield of 23% LRMS (APCI +): m / z [M + Hf 27 Preparation 73 Ferric-butyl ester of 4- (fer-butyl-dimethyl- silanyloxy) -3,6-dimethyl-indazole-1-carboxylic acid 2-fluorobenzoyl chloride and triethylamine in dichloromethane (3 ml) was stirred at room temperature for 18 hours, then the reaction mixture was diluted in dichloromethane and washed with water (2x10 ml) The organic phase was dried over magnesium sulfate and The reaction was concentrated in vacuo, purification by column chromatography on silica gel, eluting with dichloromethane: methanol, 98: 2, afforded the title compound as a white solid in 73% yield, 153 mg. LRMS (APCI +): m / z [M + H] + 422 Preparation 55 4-bromo-2-trifluoromethoxy-phenol Bromine (449 mg, 2.81 mmol) was added to a solution of 2- (trifluoromethoxy) phenol (500 mg, 2.81 mmol) and sodium acetate (169 mg, 2.81 mmol) and acetic acid (5 mL). and the solution was stirred for 1 hour. Then, the reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (2 × 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, yielding the title compound as a white solid in 23% yield. LRMS (APCI +): m / z [M + H] + 255/257 Preparation 56 Methyl ester of 2S) -2-f4-bromo-2-trifluoromethoxy-phenoxy) -propionic acid Diisopropyl azodicarboxylate (414 μ ?, 2.14 mmol) was added dropwise to an ice-cold solution of the compound of Preparation 55 (500 mg, 1.95 mmol), (R) -methyl lactate (202 mg 1.95 mmol) and triphenylphosphine (614 mg, 2.34 mmol) in tetrahydrofuran (20 mL). The reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with a 10% potassium carbonate solution (2x10 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, yielding the title compound as a colorless oil in 76% yield, 638 mg. LRMS (APCI +): m / z [M + Hf 305/307 Preparation 57 Acid (2S) -2- (4-bromo-2-trifluoromethoxy-phenoxy) -propionic A mixture of the compound of Preparation 56 (574 mg, 1.67 mmol) and a solution of 1M sodium hydroxide (4.2 mL, 4.2 mmol) in dioxane (10 mL) was stirred at 55 ° C for 3 hours. hours. Then, the solvent was evaporated under reduced pressure and the residue was dissolved in water (30 ml). The aqueous solution was acidified to pH 2 with 2M hydrochloric acid and extracted with ethyl acetate (2x50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow solid in 80% yield. LRMS (APCI +): m / z [M + H] + 327 Preparation 58 (2S) -1-r (2R) -4-benzoyl-2-methyl-piperazin-1-yl1-2- (4-bromo-2 -trifluoromethoxy-phenoxy-propan-1-one A solution of the compound of Preparation 57 (150 mg, 0.46 mmol), (3R) - (3-methyl-piperazin-1-yl) -phenyl-methanone [93 mg, 0.46 mmol) J. Med. Chem., 43 (23), 4499; 2000], 0- (1 H -benzotriazol-1-yl) - / V, / V, / V ', / V-tetramethyluronium hexafluorophosphate (260 mg, 0.69 mmol) and triethylamine (0.13 mL, , 92 mmol) in dichloromethane (30 ml) was stirred at room temperature for 18 hours. Then, the reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The aqueous phase was back extracted 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® ultrafast silica column, eluting with 99: 1 dichloromethane: methanol, yielding the title compound as a white foam in 90% yield, 213 mg. LRMS (APCI +): m / z [M + H] + 537/539 Preparation 59 Methyl ester of 4- S) -2-f (2R) -4-benzoyl-2-methyl-piperazin-1-in-1 -methyl-2-oxo-ethoxy) -3-trifluoromethoxy-benzoic acid The compound of Preparation 58 (190 mg, 0.37 mmol), palladium dichloro bis (triphenylphosphine) (30 mg, 0.04 mmol) and triethylamine (0.10 mL, 0.74 mmol) were dissolved in methanol ( 10 ml) and they were transferred to a hermetically sealed container. The vessel was heated to 100 ° C and the mixture was stirred at 100 psi (689.29 kPa) of gaseous carbon monoxide for 42 hours. Then, the reaction mixture was filtered through Arbocel®, washing meticulously with methanol and the filtrate was concentrated in vacuo. The residue was purified on an Isolute® ultrafast silica column, eluting with dichloromethane: methanol, 97: 3 yielding the title compound as an orange solid, 85%, 155 mg. LRMS (APCI +): m / z [M + H] + 495 Preparations 60 to 61 The following compounds, of the general formula shown below, were prepared by the procedure described above for Preparation 26 using the compound of Preparation 25 and the appropriate hydroxyquinoline or hydroxyisoquinoline.
The following compounds, of the general formula shown below, were prepared by the procedure described above for Preparation 46 using the compounds of Preparations 60 and 61 and acid / nefa-chloroperbenzoic Preparation 64 (2S) -1-r (2RH-benzoyl-2-methyl-piperazin-1H1-2- (1-oxo-5-quinolin-5-yloxy) -propan-1-one The title compound was prepared by the procedure described above for Preparation 46 using the compound of Preparation 43. LRMS (APCI +): m / z [M + H] + 420 Preparation 65 (2SM - [(2f?) - 4 -benzoyl-2-methyl-piperazin-1 -i! 1-2- (1-chloro-isoquinolin-5-yloxO-propan-1-one) Phosphorus oxychloride (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 to 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 a concentrated ammonia solution and extracted with dichloromethane (2x75 mL). Then, the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol, 99: 1, afforded the title compound as a white foam in 40% yield, 127 mg. LRMS (APCI +): m / z [M + H] + 438 Preparation 66 1-r (2f?) -4-benzoyl-2-methyl-piperazin-1-ill-2- (2-chloro-quinolin-5-) iloxy) -propan-1-one The title compound was prepared by the procedure described above for Preparation 65 using the compound of Preparation 62. LRMS (APCI +): m / z [M + H] + 438 Preparation 67 2-methoxy-4-methylsulfanyl-phenol 'Butyllithium (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) cooled to -78 ° C. The mixture was stirred for 15 minutes and then warmed to -40 ° C and stirred for a further 30 minutes. Dimethyl disulfide (1.06 ml, 11.8 mmol) was added and the mixture was stirred at room temperature for 18 hours. Water was then added to the reaction and the resulting mixture was acidified to pH 1 and 2M hydrochloric acid. The aqueous phase was separated and extracted again with ethyl acetate. Then, the combined organic fractions were 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, yielding the title compound as a white solid in 48% yield, 800 mg. 1H RN (400 MHz, CDCl 3): d: 2.40 (s, 3H), 3.90 (s, 3H), 5.50 (sa, 1 H), 6.80-6.90 (m, 3H) ) Preparation 68 6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one A mixture of lithium iodide (0.32 g, 2.41 mmol) and 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one (0.5 g, 2.41 mmol) in 2,4,6-collidine (10 mL) was heated at 130 ° C for 18 hours. Then, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol, 96: 4, yielding the title compound as a pale yellow solid, 0.19 g .
LRMS (APCI +): m / z [M + H] + 194 Preparation 69 3-Acetoxy-5-methyl-phenyl acetic acid 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 warmed to room temperature and stirred for 60 hours. Then water (100 ml) was added and the mixture was stirred vigorously for 3 hours. The organic phase was separated and the aqueous phase was extracted again with dichloromethane (3x80 ml). The combined organic extracts were washed with brine (80 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: pentane 66:33 affording the title compound as a colorless oil in 94% yield, 15.7 g. LRMS (APCI +): m / z [M + NH4] + 226 Preparation 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), was heated to 90 ° C and the mixture was stirred for one hour. Then, the reaction mixture was cooled and carefully pipetted onto a mixture of ice and hydrochloric acid 2. The resulting mixture was extracted with ethyl acetate (3x200 mL) and the combined organic phases 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 the title compound as a yellow solid in 66% yield 5.31 g. LRMS (APCI +): m / z [M + H] + 167 Preparation 71 3,6-dimethyl-1 H-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 room temperature for 1 hour and at 150 ° C for 80 minutes. Then, the cooled reaction mixture was poured into water and acidified to pH 6 with acetic acid. The aqueous mixture was extracted with ethyl acetate (4x200 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. Purification of the residue by column chromatography on silica gel, eluting with ethyl acetate: pentane, 50:50, gave the title compound as a yellow solid in 95% yield, 3.84 g. LRMS (APCI +): m / z [M + H] + 163 Preparation 72 4- (tert-butyl-dimethyl-silanyloxy) -3,6-dimethyl-1 H-indazole Itert-butyldimethylchlorosilane (511 mg, 3.39 mmol) and imidazole (1.05 g, 15.4 mmol) were added to a solution of the compound of Preparation 71 (500 mg, 3.08 mmol) in / V, A / -dimethylformamide and the reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 18 hours. More urea-butyldimethylchlorosilane (511 mg, 3.39 mmol) was added and the reaction mixture was heated at 80 ° C for 48 hours. 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 (2x10 ml), dried with magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with pentane: ethyl acetate, 15:85, yielding the title compound as an orange oil in 23% yield. LRMS (APCI +): m / z [M + H] + 27 Preparation 73 (tert-Butyl-dimethyl-silanyloxy) -B-dimethyl-indazole-carboxylic acid ferric-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 8 hours. Then water was added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (3x10 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane: ethyl acetate; 95: 5, gave the title compound as a colorless oil, with a yield of 66%, 527 mg. LRMS (APCI +): m / z [M + Hf 377 Preparation 74-4-Idroxy-3,6-dimethyl-indazole-1-carboxylic acid ferric-butyl ester A solution of tetrabutylammonium fluoride (1 M in tetrahydrofuran, 21 mL, 2.1 mmol) was added dropwise to a solution of the compound of Preparation 73 (527 mg, 1.4 mmol) in tetrahydrofuran (9 mL) and the The solution was stirred at 0 ° C for 30 minutes and at room temperature for 5 minutes. Then, water was added to the mixture and the aqueous mixture was extracted with ethyl acetate (2x10 ml). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane: ethyl acetate, 70:30 to 60:40, gave the title compound as a white solid, with a yield of 76%, 280 mg . LRMS (APCI-): m / z [MH] "261 Preparation 75 (2f?) - 1-r (2? J-4-benzoyl-2-methyl-piperazin-1-n-2-benzyloxy-propan- 1-one 1-Hydroxybenzotriazole hydrate (825 mg, 5.3 mmol), N-methylmorpholine (808 μ ?, 7.3 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.13 g, 5 g) were added. , 8 mmol) and (3R) - (3-methyl-piperazin-1-yl) -phenyl-methanone [(1.0 g, 4.9 mmol), J. Meo. Chem. 43 (23), 4499, 2000] 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 . More (R) - (+) - 2-benzyloxypropionic acid (486 mg) was added2.65 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.65 mg, 2.9 mmol), 1-hydroxybenzotriazole hydrate (413 mg, 2.65 mmol) and N- methylmorpholine (808 [mu], 7.3 mmol) and the mixture was refluxed for 3 hours. Then, water was added to the reaction mixture and the aqueous solution was extracted with dichloromethane (2 × 0 ml). The combined organic extracts were washed with 2 M hydrochloric acid, 1 M sodium hydroxide solution and brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane: ethyl acetate, 50:50, followed by ethyl acetate: methanol, 90:10 afforded the title compound as a white foam, with a 81% yield, 1.45 g. E BR (IQPA-): m / z [-H] '367 Preparation 76 I2 /? J-1-r (2 /?) - 4-benzoyl-2-methyl-piperazin-1-in-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 the compound of Preparation 75 (1.45 g, 3.9 mmol) in Ethanol (30 mL) and the mixture was heated at 60 ° C for 2 hours. Analysis by ccf showed that the reaction had not yet finished, so additional Pd (OH) 2 (300 mg, 2.2 mmol) was added, followed by ammonium formate (1.37 g, 22 mmol) in intervals of 45 minutes until all the starting material was consumed. Then, the reaction mixture was cooled and flushed through Arbocel®, washing thoroughly with ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane-dimethane, 95: 5, yielding the title compound as a white gum in 91% yield, 1 g. E BR (APCI +): m / z [M + H] + 277 Preparation 77 Ferric-butyl ester of 4-α (1 S) -2-r (2R) -4-benzoyl-2-methyl-piperazin-1 acid -yl1-1-methyl-2-oxo-ethoxy1-3.6-dimethy1-indazole-1-carboxylic acid The compound of Preparation 76 (70 mg, 0.25 mmol), di-tert-butyl azodicarboxylate (233 mg, 1.01 mmol) and triphenylphosphine with polymeric support (380 mg, 1.13 mmol) were added to a Solution of the compound of Preparation 74 (70 mg, 0.25 mmol) in dichloromethane (3 mL) was added and the reaction mixture was stirred at 0 ° C for 30 minutes and at room temperature for 18 hours. Then, the reaction mixture was filtered through a filter tube, washing thoroughly with dichloromethane. The filtrate was washed with a sodium hydroxide solution, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with pentane: ethyl acetate 40:60 to 20:80 afforded the title compound as a white foam, in 34% yield, 45 mg E BR (APCI +): m / z [M + H] + 521 Biological Data The ability of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate the activity of gp120, in particular to inhibit the interaction of gp120 with CD4, is demonstrated using a cell-cell fusion assay induced by gp160 to determine the IC50 values of the compounds against the HIV-1 fusion. The cell-cell fusion assay induced by gp160 uses a HeLa P4 cell line and a CHO-Att10 cell line. The HeLa.P4 cell line expresses CCR5 and CD4 and has been transfected with HIV-1 LTR-galactosidase. The medium for this cell line is Dulbecco's modified eagle medium (D-MEM) (without L-glutamine) containing 10% fetal calf serum (FCS), 2 mM L-glutamine, penicillin / streptomycin (pen / strep). 100 U / ml penicillin + 10 mg / ml streptomycin) and 1 μg / ml puromycin. The CHO cell line is a clone expressing Att (trans transcriptional activator) of a CHO JRR17.1 cell line that has been transfected with pure pAtt plasmid. The medium for this cell line is a rich medium for mammalian cell culture that originally developed in Roswell Park Memorial Institute RPMI1640 (without L-glutamine) containing 10% FCS, 2 mM L-glutamine, 0.5 mg / ml of hygromycin B and 12 μg / ml of puromycin. The CHO JRR17.1 line expresses gp160 (JRFL) and is a clone that has been selected with respect to its ability to fuse with a cell line expressing CCR5-CD4. After cell fusion, Att present in the CHO cell can transactivate the long repeated terminal sequence (LTR) of HIV-1 present in the HeLa cell that leads to the expression of the enzyme β-galactosidase. Then, this expression is measured using a Fluor Ace ™ β-galactosidase indicator assay kit (Bio-Rad cat .. No. 170-3150). This kit is a quantitative fluorescent assay that determines the level of expression of β-galactosidase using 4-methylumbelliferyl-galactopyranoside (MUG) as a substrate. The β-galactosidase hydrolyzes the fluorogenic substrate that results in the release of the fluorescent molecule 4-methylumbelliferone (4MU). After, the fluorescence of 4-methylumbelliferone is measured in a fluorometer using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Compounds that inhibit fusion will cause a reduced signal and, after solubilization in an appropriate solvent and dilution in culture medium, a dose-response curve for each compound can be used to calculate Cl50 values. All the Examples of the invention have Cl 50 values, according to the above procedure, of less than 1.5 μ. The Cl 50 values for the compounds of Examples 12, 29 and 44 are, respectively, 15 nM, 134 n and 825 nM. The ability of the compounds of formula (I) to inhibit the interaction of gp120 with CD4 is further demonstrated using an enzyme-linked immunosorbent assay (ELISA). Maxisorp plates (Nunc) are coated with 2 g / well anti-gp 20 antibody (D7324). 100 μ? of gp120 (predetermined dilution by titration) to each well and incubated for 90 minutes at room temperature. The sample is removed and the wells are washed with PBS (phosphate buffered saline) + 0.01% TWEEN® (polyethylene glycol sorbitan monolaurate). 50 μ? / Well of compound followed by 50 μ? (0.1 g) of soluble CD4 conjugated with horseradish peroxidase (Autogen Bioclear). The plate is incubated for 90 minutes at room temperature before washing the wells again. The substrate OPD (o-phenylenediamine, Sigma) is added at a concentration of 0.5 mg / ml and the plate is incubated in the dark at room temperature for 3 minutes before 3 M HCl is added to stop the reaction. Compounds that inhibit the interaction of gp120 with soluble CD4 will provide a reduced absorbance at 492 nm. All the examples of the invention have Cl 50 values, according to the previous procedure, lower than 15 μ ?. The Cl 50 values for the compounds of Examples 1, 11 and 12 are, respectively, 0.92 μ, 1.0 μ? and 0.75 μ ?.

Claims (1)

  1. CLAIMS A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: R1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1 or 2 atoms or groups selected from halo, alkoxy CrC-6, CF3) OCF3 or CN; R2 and R3 are independently H or C6 alkyl; R4 is Ci-C6 alkyl; R5 is phenyl; naphthyl; or a C-, 6- to 10-membered, mono- or bicyclic, aromatic or partially saturated heterocycle, wherein said heterocycle contains from 1 to 4 nitrogen heteroatoms, 1 or 2 nitrogen heteroatoms and 1 oxygen heteroatom, or 1 or 2 nitrogen heteroatoms and 1 sulfur heteroatom; wherein said phenyl, naphthyl or heterocycle are optionally substituted with 1 to 3 atoms or groups selected from CrC6 alkyl, Ci-C6 fluoroalkyl, C3-C7 cycloalkyl, phenyl, OH, Ci-C6 alkoxy, CrC6 alkoxy Ci-C6 alkyl, O- Ci-C6 fluoroalkyl, C0-C2 alkylene NR6R7, halo, C0-C-2 CN alkylene, C0-C2 alkylene C02R8, C0-C2 alkylene CONR6R7, C0-C2 alkylene SR9, C0-C2 alkylene SOR9, C0-C2 alkylene S02R9 , C0-C2 alkylene S02NR6R7, C0-C2 alkylene NR8COR9, C0-C2 alkylene NR8C0NR6R7, C0-C2 alkylene NR8S02R9, or C0-C2 alkylene R10, or where R5 is a heterocycle, oxo; R6 and R7 are independently H, C6 alkyl, C3-C7 cycloalkyl, phenyl or R10; or when taken together with the nitrogen to which they are attached they form an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine ring; wherein said substituents are 1 or 2 groups selected from C 1 -C 6 alkyl or C 0 -C 6 alkylene NH 2; R8 is H, C-i-Ce alkyl or phenyl; R9 is C6 alkyl or phenyl; and R 0 is imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted with 1 to 3 atoms or groups selected from CrC6 alkyl, C6 alkoxy, cyano or halo. 2. A compound according to claim 1, wherein R1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1 or 2 atoms or groups selected from halo. 3. A compound according to claim 1 or 2, wherein R is phenyl, fluorophenyl or pyridyl. 4. A compound according to any of claims 1 to 3 wherein R 1 is phenyl. 5. A compound according to any one of the preceding claims, wherein R 2 is C 1 -C 4 alkyl. 6. A compound according to any of the preceding claims, wherein R 2 is methyl. 7. A compound according to any one of the preceding claims wherein R3 is H. 8. A compound according to any one of the preceding claims, wherein R 4 is C 1 -C 4 alkyl. 9. A compound according to any of the preceding claims wherein R 4 is methyl. 10. A compound according to any one of the preceding claims wherein R5 is phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzopiperidinyl or optionally substituted benzoxazolyl; wherein said substituents are from 1 to 3 atoms or groups selected from Ci-C6 alkyl, C1-C6 alkoxy, halo, CN, C02R8, CONR6R7 or R 0. 11. A compound according to any one of the preceding claims, wherein R5 is phenyl or optionally substituted pyridyl, wherein said substituents are from 1 to 3 groups selected from C ^ -C6 alkoxy, C02R8 or CONR6R7. 12. A compound according to any one of the preceding claims, wherein R6 is H or C1-C4 alkyl. 13. A compound according to any of the preceding claims, wherein R 7 is H, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl. 14. A compound according to any one of the preceding claims, wherein R8 is CfC4 alkyl. 15. A compound according to any of the preceding claims, wherein R 10 is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl, each optionally substituted with 1 to 3 atoms or groups selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyano or halo. 16. A compound according to any of the preceding claims of formula (la) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R1, R2, R3, R4 and R5 are as defined in any of claims 1 to 15. 17. A compound according to claim 16 of formula (Ib) Or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R1, R2, R4 and R5 are as defined in any of the claims 1 to 15. 18. A compound according to claim 1 which is selected from: (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl)] - 2- (3-methyl-1H-indazole -4-yloxy) -propan-1 -one; (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -2- [2- (2-yl-pyrazol-3-ylamino) -quinolin-5-yloxy] propan-1 -one; Acid methylamide 5-. { (S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} isoquinoline-1-carboxylic acid; (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -2- (8-chloro-2-methylamino-quinolin-5-yloxy) -propan-1-one; (2S) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) -isoquinolin-5-yloxy] -propan -1-one; 4-. { (1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1 -yl] -1-methyl-2-oxo-ethoxy} -3-methoxy- / v * -methyl-benzamide; Acid methylamide 5-. { (1S) -2 - [(2f?) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid; Amide of acid 5-. { (1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid; Acid ethylamide 5-. { (1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methy1-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid; 5- Cyclopropylamide. { (1S) -2 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid; and pharmaceutically acceptable salts, solvates or derivatives thereof. 19. A pharmaceutical composition which includes a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any of the preceding claims, together with one or more pharmaceutically acceptable excipients, diluents or vehicles. 20. A pharmaceutical composition according to claim 19 which includes one or more additional therapeutic agents. 21. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 18 for use as a medicament. compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 18 for use in the treatment of HIV, of a retroviral infection genetically related to HIV or AIDS. 23. The use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof as claimed in any one of claims 1 to 18 for the manufacture of a medicament for treating HIV, a retroviral infection genetically related to HIV or AIDS. 24. A method for treating a mammal suffering from HIV, a retroviral infection genetically related to HIV or AIDS comprising treating said mammal with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any of claims 1 to 18. 25. A compound of formula (II), (IV) or (VII).
MXPA06001762A 2003-08-14 2004-08-04 Piperazine derivatives for the treatment of hiv infections. MXPA06001762A (en)

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