NL1026827C2 - Derivatives of piperazine. - Google Patents

Description

% »

Derivatives of piperazine This invention relates to derivatives of piperazine, to processes for the preparation of these derivatives, to preparations containing these derivatives and to applications of these derivatives.

More specifically, the present invention relates to the use of piperazine derivatives in the treatment of HIV, such as HIV-1, and genetically related retroviral infections (and the resulting acquired immunity deficiency syndrome, AIDS).

To enter HIV-1 into a target cell, cell surface CD4 and additional host cell co-factors are required. It is recognized that human immunodeficient viruses need a chemokine receptor such as CCR5 or CXCR-4, as well as the primary receptor CD4 to efficiently enter the target cells. The main cofactor for entering the envelope glycoproteins of primary macrophage-trophic strains of HIV-1 is CCR5, a receptor for the β-chemokines RANTES, ΜΙΡ-Ια and MIP-Ιβ (Deng et al., 1996, Nature , 38, 661-666). HIV attaches to the CD4 molecules of target cells via a portion of its envelope protein, gp120. It is believed that the CD4 binding site on the gpl20 of HIV interacts with the CD4 molecule on the surface of the target cell and undergoes changes in configuration, thereby allowing it to pass to further cell surface receptors such as CCR5 or CXCR-4 tie. This brings the viral envelope closer to the surface of the cell and allows interaction between gp41 on the viral envelope! and a fusion domain on the surface of the host cell, the! subsequent fusion with the cell merabrane and ultimately the entry of the viral core into the cell. As a result, compounds that inhibit the binding of gp120 to CD4, and thereby prevent the entry of HIV-1 109 * 827 (.2 into a target cell, would be useful in the treatment of HIV, such as HIV-1, and genetically related regimens. troviral infections (and the resulting acquired immunity deficiency syndrome, AIDS).

According to a first aspect of the present invention, there is provided a compound of formula (I) RV. R * o (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: R 1 is phenyl or pyridyl, said phenyl or pyridyl being optionally substituted with 1 or 2 atoms or groups selected from halogen, C 1 -C 6 alkoxy, CF 3, OCF 3 or CN; R 2 and R 3 are independently H or C 1 -C 6 alkyl; R 4 is C 1 -C 6 alkyl; R 5 phenyl; naphthyl; or a C-linked, 6- to 10-membered, mono- or bicyclic, aromatic or partially saturated, heterocyclic group, wherein said heterocyclic group is 1 to 4 nitrogen heteroatoms, 1 or 2 nitrogen heteroatoms and 1 oxygen heteroatom, or 1 or contains 2 nitrogen heteroatoms and 1 sulfur heteroatom; wherein said phenyl or naphthyl or heterocyclic group is optionally substituted with 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, phenyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6-35 fluoroalkyl, C 0 -C 2 alkylene-NR 6 R 7, halogen, C 0 -C 2 alkylene-CN, C 0 -C 2 alkylene-CO 2 R 8, C 0 -C 2 alkylene -CONR6R7, Co-C2 alkylene-SR9, Co-C2 alkylene-SÖR9, Co-C2-alkylene-SO2R9, Co-1026827 <2> 3 C2-alkylene-SO2NR6R7, Co-C2-alkylene-NRBCOR9, Co- C 2 -C 2 alkylene-NR 8 CONR 6 R 7, C 0 -C 2 alkylene-NR 8 SO 2 R 9, or C 0 -C 2 alkylene-R 10, or, when R 5 is a heterocyclic group, oxo; i "r"

. 1 I ί I

R 6 and R 7 independently represent H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, F 4; 1 are nyl or R10; or when taken together with the nitrogen to which they are attached form an optionally substituted azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine ring; wherein said substituents 1 are 10 or 2 groups selected from C 1 -C 6 alkyl or C 6 -C 6 alkylene NH 2; R8 is H, C1 -C6 alkyl or phenyl; R 9 is C 1 -C 6 alkyl or phenyl; and R10 imidazolyl, pyrazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinol-20-nyl, benzimidazolyl, indazoloxalazolazalazolazazalazinyl, vinylazolazalazyl-vinyl is each optionally substituted with 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano or halogen.

The term "alkyl" as a group or part of a group includes straight and branched groups. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. The term "C 3-7 cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "halogen" means fluorine, chlorine, bromine or iodine.

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

In a still further embodiment, R 1 is phenyl, fluoro-phenyl or pyridyl.

1026827 (»4

In a still further embodiment, R 1 is phenyl.

In yet a further embodiment, R 2 is C 1 -C 4 alkyl.

In yet a further embodiment, R2 is methyl.

In yet a further embodiment, R3 is H.

In yet a further embodiment, R 4 is C 1 -C 4 alkyl.

In a still further embodiment, R 4 is methyl.

In yet a further embodiment, R 5 is an optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzo piperidinyl or benzoxazolyl; wherein said substituents are 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, CN, CO 2 R 8, CONRe R 7 or R 10.

In yet a further embodiment, R 5 is an optionally substituted phenyl or pyridyl, wherein said substituents are 1 to 3 groups selected from C 1 -C 6 alkoxy, CO 2 R 8 or CONR 6 R 7.

In yet a further embodiment, R 6 is H or C 1 -C 4 alkyl.

In yet a further embodiment, R 7 is H, C 1 -C 4-20 alkyl or C 3 -C 6 cycloalkyl.

In a still further embodiment, R8 is C1 -C4 alkyl.

In yet a further embodiment, 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 halogen.

In yet a further embodiment, there is provided a compound of formula (Ia) R4 WR10 (la) 35 or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R1, R2, R3, R4 and R5 are such as 1026827 5 defined above with respect to a compound of formula (I), including all combinations or particularly defined embodiments thereof.

In yet a further embodiment, a compound of formula (Ib) is provided

O

R 4 is N (R 1) R (Ib) or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R 1, R 2, R 4 and R 5 are as defined above with respect to a compound of formula (I), including of all combinations or specifically described embodiments thereof.

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

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

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

1026827 t> 6

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate, bisulfate, borate, bromide, camsylate, carbonate, chloride, citrate, edisylate, esylate - formate, fumarate, glucate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrobromide, hydrochloride, hydroiodide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, sulfate, tartrate, tosylate and trifluoroacetate salts.

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

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

Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of three methods: (i) reacting the compound of formula (I) with the desired acid or base; (Ii) by removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I) or by opening the ring of a suitable cyclic precursor, for example a lactone or lactam, with using the desired acid or base; or 1026827 <1 7 (iii) by converting one salt of the compound of formula (I) to another by reaction with a suitable acid or base or by 1; (a suitable ion exchange column.

. ; All three reactions are typically carried out in solution; "argued. The salt can precipitate out of the solution and be collected by filtration or can be recovered by evaporating the solvent. The degree of ionization in the salt can vary from fully ionized to almost non-ionized.

The compounds of the invention can exist in both non-dissolved and dissolved 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.

Complexes include clathrates, i.e., drug-host inclusion complexes in which, unlike the aforementioned solvates, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Complexes also include complexes of the pharmaceutical drug containing two or more organic and / or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For an overview of such complexes, see J Pharra Sci, 64 (8), 1269 - 1288 by Haleblian (August 1975).

The compounds of the present invention may have the ability to crystallize in more than one form, a characteristic property known as polymorphism, and all such polymorphic forms ("polymorphs") fall within the scope of the invention. Poly-morphism can generally occur as a response to changes in temperature or pressure or both, and may also be due to variations in the crystallization process.

102ί> 82 7 * f 8

Polymorphs can be distinguished by various physical characteristic properties, and typically X-ray diffraction patterns, solubility behavior and melting point of the compound are used to distinguish polymorphs.

Certain derivatives of compounds of formula (I) which themselves have little or no pharmacological activity can, when administered in or on the body, be converted into compounds of formula (I) with the desired activity, e.g. 10 hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug 15 Design," Pergamon Press, 1987 (Ed. B. Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can be prepared, for example, by replacing suitable 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 or Prodrugs "by H. Bundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include: (i) where the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example replacement of the hydrogen with (C 1 -C 6) alkyl ; (ii) where the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example replacement of the hydrogen with (C 1 -C 6) alkanoyloxymethyl; and

(iii) where the compound of formula (I) has a primary or secondary amino functionality (-NH2 or -NHR where R

35 Φ H), an amide thereof, for example replacement of one or more hydrogens with (C1 -C10) alkanoyl.

1 0 26 82 7

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types in accordance with the invention can be found in the aforementioned references. ; 5 found.

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

The invention also encompasses metabolites of compounds of formula (I), i.e. compounds that are formed in vivo after drug administration. Some examples of metabolites in accordance with the invention include: (i) where the compound of formula (I) contains a methyl group, a hydroxymethyl derivative thereof (-CH 3 - -CH 2 OH); (ii) where the compound of formula (I) contains an alkoxy group, a hydroxy derivative thereof (-OR -> -OH); (iii) where the compound of formula (I) contains a tertiary amino group, a secondary amino derivative thereof (-NR1 * 2 -► -NHR1 or -NHR2); (iv) where the compound of formula (I) contains a secondary amino group, a primary derivative thereof (-NHR1 -► -NH2); (v) where the compound of formula (I) contains a phenyl moiety, a phenol derivative thereof (-Ph -PhOH); and (vi) where the compound of formula (I) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 - »COOH).

In view of the definition of R 4, compounds of formula (I) contain one or more asymmetric carbon atoms, and therefore they exist as two or more optical isomers. When a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible, and when the compound comprises, for example, a keto or oxime group or an aromatic radical. tautomeric isomeria (1tautomeria ') may occur. It follows that a single compound can exhibit more than one type of isomerism.

1026827 h 10 «»

All optical isomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomer, and mixtures of one or more thereof are included within the scope of the present invention. The invention also encompasses acid addition or base salts in which the counter ion is optically active, for example D-lactate or L-lysine, or racemically, for example DL-tartrate or DL-arginine.

Cis / trans isomers can be separated by conventional methods well known to those skilled in the art, for example, chromatography and fractional distillation.

Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or separation of the racemate (or the racemate of a salt or derivative) by using, for example, chiral high pressure liquid 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 acid or basic residue, 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 both of the diastereoisomers can be converted to the corresponding pure enantiomer (s) by methods well known to those skilled in the art.

Chiral compounds of the invention (and chiral precursors thereof) can be obtained in enatiomer-enriched form by using chromatography, typically HPLC, on an asymmetric mobile phase resin 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. Concentration of the eluate yields the enriched mixture.

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. Biel (Wiley, New York, 1994).

The present invention also encompasses all pharmaceutically acceptable isotope-labeled compounds of formula (I) wherein one or more atoms have been replaced with 10 atoms having the same atomic number, but with an atomic mass or mass number different from the atomic mass that or the mass number that is usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2 H and 3 H, carbon such as UC, 13 C and 14 C, chlorine such as 36 Cl, fluorine such as 18 F, iodine such as 123 I and 125 I, nitrogen such as 13 N and 15 N, oxygen such as 150, 170 and 180, phosphorus such as 32 P, and sulfur such as 35 S.

Certain isotope-labeled compounds of formula (I), for example those compounds in which a radioactive isotope is incorporated, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e.

14C are particularly useful for this purpose in view of the ease with which they are built in and the rapid method of detection.

Replacement with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic benefits that result from better metabolic stability, e.g., increased in vivo half-life or reduced dosing requirements, and may therefore be preferred in some circumstances.

Replacement with positron-emitting isotopes such as UC, 18F, 150 and 13N may be useful in positron emission topography (PET) examinations to investigate the utilization rate of substrate receptors.

1026827 * t 12

Isotope-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to the methods described in the attached Examples and Preparations using; made from a suitable isotope-labeled reagent instead of the unlabelled reagent used in previously.

Pharmaceutically acceptable solvates in accordance with the invention include solvates in which the crystallization solvent may be isotope substituted, e.g., D 2 O, d 6 acetone, d 6 DMSO.

Preferred compounds of formula (I) include the compounds of Examples 1-94; and pharmaceutically acceptable salts, solvates or derivatives thereof. Particularly preferred compounds of formula (I) include; (2S) -1-t (2R) -4-benzoyl-2-methylpiperazin-1-yl)] 2- (3-methyl-1H-indazol-4-yloxy) propane-1-one; 20 (2S) -1 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -2- [2- (2H-pyrazol-3-ylamino) quinoline-5-yloxy] propan-1-one ; 5 - {(IS) -2 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} isoquinoline-1-carboxylic acid methylamide; (2S) -1 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -2- (8-25 chloro-2-methylaminoquinoline-5-yloxy) propane-1-one; (2S) -1 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) isoquinoline-5-yloxy] propan-1-one; 4- {<IS) -2 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -3-methoxy-N-methylbenzamide; 5 - {(IS) -2 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -4-methoxypyridine-2-carboxylic acid methylamide; 5- {(IS) -2 - [(2R) -4-benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxoethoxy} -4-methoxy-pyridine-2-carboxylic acid amide; 5 - {(1 S) -2 - [(2 R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy] -4-methoxypyridine-2-carboxylic acid ethylamide; 1026827

0 I

13 5 - {(IS) -2 - [(2R) -4-benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy] -4-methoxypyridine-2-carboxylic acid (cyclopropylamide; and pharmaceutically acceptable salts, solvates, or derivatives thereof.

"i»

In the general methods and schemes that follow: R1 to R9 are as defined above unless otherwise specified; X is halogen or hydroxy; Y is a leaving group, such as chlorine, bromine, tosylate, mesylate or hydroxy; DMF is Ν, Ν-dimethylformamide; DMSO is dimethyl sulfoxide; THF is tetrahydrofuran; WSCDI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DCC is N, N'-dicyclohexylcarbodiimide; HOAT is 1-hydroxy-7-15 azabenzotriazole; HOBt is 1-hydroxybenzotriazole hydrate; HBTU is O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium hexafluorophosphate; PyBOP® is benzotriazole-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate; PyBrOP is bromo-tris-pyrrolidino-phosphonium hexafluorophosphate; Hu-20igs base is N-ethyl diisopropylamine; and Mukaiyama's reagent is 2-chloro-1-methylpyridinium iodide.

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

Compounds of formula (I) and intermediates therefor can be prepared according to the schemes that follow.

The skilled person will understand that certain methods described in the schemes for the preparation of compounds of formula (I) or intermediates therefor may not be applicable to some of the possible substituents.

The person skilled in the art will further understand that it may be possible or desirable to carry out the conversions described in the schemes in an order other than that described, or to modify one or more of the conversions to produce the desired compound of formula (I) to deliver.

1026827 4 to 14

The skilled person will further understand that, as shown in the schemes that follow, it may be possible or desirable at each step of the synthesis of compounds of formula (I) to protect one or more sensitive groups in the molecule to prevent undesirable prevent side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of compounds of formula (I) can be used in a conventional manner. See, for example, the protecting groups described in "Protective Groups in Organic Synthesis" by Theodora W. Green and Peter GM Wuts, third edition, (John Wiley and Sons, 1999), in particular Chapter 7, pages 494-653 (" Protection for the Amino Group ", which is incorporated by reference in this patent specification, which also describes methods for the removal of such groups.

The amino protecting groups boe, benzyloxycarbonyl, benzyl and acetyl are particularly useful in the preparation of compounds of formula (I) and intermediates therefor.

1 026 82 7 I, 15

Schedule 1

R1

5 p ^ NH

HN ^ αχ »ff A \ X ^ R1 (V) (b) Nv

4 RW r4 rW X

ps 1 ^ R '15 η ^ ο-ΛγΝ ^ T hnO ^ (VII) 0 (IV) <VI> s / \ / r4 \ / /' v'K '* / (®) <I "" "20 O / 0 ^ 110 / '/ X ^ R1 "" X / (d) (v)' (c '/ »ff / f W ^ · 25 / / O (II) R-OH (1H) / (f)

R \ X

R4 p ^ N ^ R1 RS> V ° ^ 0 (I) 35 With specific reference to scheme 1, the converters depicted therein can be established as follows: 1026827 * # 16 (a) - (e) Acidic amine coupling reactions

Typically, the acid chloride or acid bromide of formulas (V), (VI) or (VIII), and the appropriate piperazine, of formulas (IV), (VII) or (IX), optionally with an excess (i); 5 measure to an acid acceptor such as triethylamine or N-ethyl-N, N-diisopropylamine, converted for 1-24 hours in a solvent such as a haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at room temperature. The reactions can suitably be carried out by reacting the relevant piperazine with 1.1 equivalent of the relevant acid chloride in dichloromethane at room temperature for 1 hour.

In a further embodiment, the acid of formulas (V), (VI) or (VIII), are activated by suitable reagents such as WSCDI / DCC and HOBt / HOAt, the suitable piperazine of formulas (IV), (VII) or (IX ), and an excess of an acid acceptor such as triethylamine or N-ethyl-N, N-diisopropylamine, converted for 4-48 hours in a solvent such as a haloalkane (e.g. dichloromethane), an ether (e.g. THF) or DMF at room temperature . The reactions can suitably be carried out by reacting the relevant piperazine, 1.4 equivalent WSC-DI, 1.4 equivalent HOBt, 2.2 equivalents triethylamine and 1.1 equivalent of the relevant carboxylic acid in dichloromethane at room temperature for 18 hours.

In yet a further embodiment, the acid of formulas (V), (VI) or (VIII), the appropriate piperazine of formulas (IV), (VII) or (IX), and HBTÜ, PyBOP, PyBrOP or Mukaiyama's reagent, and an excess of an acid acceptor such as triethylamine or N-ethyl-N, N-diisopropylamine, can be converted for 4-24 hours into a solvent such as a haloalkane (e.g. dichloromethane) or an ether (e.g. THF) at room temperature. The reactions can suitably be carried out by reacting the relevant piperazine, 1.0 equivalent of the relevant carboxylic acid and 1.5 equivalent of HBTU in dichloromethane or DMF at room temperature for 14 hours.

1 0 26 82 7 f (17 (f) Nucleophilic substitution i) When Y is Cl, Br, mesylate, tosylate:

Typically, compounds of formulas (II) and (III) with an acid acceptor such as triethylamine, N-ethyl-5 N, N-diisopropylamine or an alkali metal carbonate are reacted for 1-24 hours in a solvent such as a haloalkane (e.g. dichloromethane), a ether (e.g. THF) or acetone at a temperature between room temperature and reflux temperature. The reactions can suitably be carried out by reacting the compounds of formulas (II) and (III) with 1.0 equivalent of cesium carbonate in acetone under reflux for 14 hours.

ii) When Y is OH:

Typically, compounds of formulas (II) and (III), triphenylphosphine or tri-o-tolylphosphine, and diethyl azodicarboxylate or diisopropylazodicarboxylate are converted for 1-24 hours 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. The reactions can suitably be carried out by reacting the compounds of formulas (II) and (III) with 1.2 equivalent of triphenylphosphine and 1.1 equivalent of diisopropylazodicarboxylate in THF at room temperature for 14 hours.

Compounds of formula (VI) in reaction steps (a) and (d) can be prepared in accordance with the following scheme 1a.

Diagram la 30 R4 RS- ° H (III) „4 R *

γVR R5 "° VR ^ VH

o (o) 35 (XI) (VI) 1026827 I * 18 wherein R is a lower alkyl such as C 1 -C 6 alkyl.

(g) Nucleophilic Substitution Nucleophilic substitution can be accomplished in accordance with the conditions described above in the patent specification for step (f).

(h) Ester hydrolysis

Typically, compounds of formula (XI) / aqueous alkali metal hydroxide solution or aqueous salt solution and any additional solvent such as ethanol or dioxane, are heated for 1-18 hours at a temperature between 60 and 100 ° C. The reactions can suitably be carried out by heating compounds of formula (XI) in aqueous 1 N sodium hydroxide solution and dioxane which are heated at 60 ° C for 2 hours.

Certain intermediates described above are novel compounds and it is to be understood that all novel intermediates herein constitute further aspects of the present invention. Compounds of formulas (II) / (IV) and (VII) are important intermediates and represent a particular aspect of the present invention.

Compounds of formulas (III), (V), (VIII), (IX) and (X) are either known compounds or can be prepared by conventional chemistry.

In another aspect, the invention provides the following methods for preparing compounds of formula (I).

According to a first method (A), compounds of formula (I) can be prepared by coupling an acid of formula (V)

O

35 X

X R (V) 1026827 with a piperazine of formula (IV) under conventional acid-amine coupling conditions.

»" V "0 (IV) 10 Acid-amine coupling is suitably effected under the conditions described above in this patent specification in relation to scheme 1, steps (a) - (e).

According to a second method (B), compounds of formula (I) can be prepared by coupling an acid of formula (VI) R 4 to VI (VI) with a piperazine of formula (VII) under conventional acid amine coupling conditions.

Rw X

A ^ hr-R1 30 H10 <% R (VII)

Suitably acid-amine coupling is effected under the conditions described above in this patent specification in relation to scheme 1, steps (a) - (e).

1026827 • 20

According to a third method (C), compounds of formula (I) can be prepared by nucleophilic substitution of a compound of formula (II)

"· VA

ArA

° (II) with an alcohol R 50 H of formula (III) under conventional conditions. Suitably, nucleophilic substitution is accomplished under the conditions described above in this patent specification in relation to scheme 1, step (f).

According to a fourth method (D), compounds of formula (I) can be prepared from other compounds of formula (I) by mutually converting the functional group under conventional conditions. For example, compounds of formula (I) containing an ester group can be converted to corresponding compounds of formula (I) containing a primary or secondary amide group by reacting the former with ammonia or a primary amine, respectively.

The compounds of the invention inhibit the interaction of gp120 with CD4 and are therefore 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 an HIV, a retroviral infection genetically related to HIV, or AIDS.

1026827

* * I

21

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

In another aspect, the invention provides a method for treating a mammal suffering from HIV, a retroviral infection genetically related to HIV, or AIDS treating the mammal with an effective amount of a compound of formula ( I) or a pharmaceutically acceptable salt, solvate or derivative thereof. j

The compounds of the invention can be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying.

Microwave or radio frequency drying can be used for this purpose.

They can be administered individually or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in any combination thereof). In general, they will be administered as a preparation together with one or more pharmaceutically acceptable excipients. The term "excipients" is used herein to describe any component other than the compound (s) of the invention. The choice of excipients will to a large extent depend on factors such as the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for the release 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 1026827 * 22 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995).

The compounds of the invention can become oral! | f administered. Oral administration may include swallowing, so that '1! 5 the compound enters the gastrointestinal tract, or buccal, t, | administration or administration under the tongue may cause the compound to enter the bloodstream directly from the mouth.

Preparations suitable for oral administration include solid preparations such as tablets, capsules containing particles, liquids or powders, tablets (including liquid-filled), chewable preparations, multiple and nanoparticles, gels, solid solution, liposome, films (including muco adhesive), ovules, sprays and liquid preparations.

Liquid preparations include suspensions, solutions, syrups and elixirs. Such compositions can be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstituting a solid, for example from a sachet.

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

For tablet dosage forms, depending on the dose, the drug may comprise from 1 weight% to 80 weight% of the dosage form, more typically from 5 weight% to 60 weight% of the dosage form. In addition to the drug, 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, microcrystalline cellulose, lower-alkyl-substituted hydroxypropyl cellulose, starch, starch, starch. In general, the disintegrant will comprise 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the content. lubrication form.

Binders are generally used to impart cohesion enhancing qualities to a tablet preparation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silica and talc. If present, surfactants may comprise 0.2% to 5% by weight of the tablet, and lubricants may constitute 0.2% to 1% by weight of the tablet.

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

Other possible ingredients include antioxidants, colorants, flavors, preservatives, and taste masking agents.

Typical tablets contain up to about 80% drug, about 10% to about 90% binder, about 0% to about 85%, by weight, diluted 1026827

4 I

24 wetting agent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant.

Tablet mixtures can be pressed directly or with a roller to form tablets. Tablet blends or portions of blends may alternatively be wet, dry or melt-granulated, solidified from the melt, or extruded prior to tableting. The final preparation may comprise one or more layers and may or may not be coated; the preparation can even be encapsulated.

The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1" by H.

Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 15 (ISBN 0-8247-6918-X).

Solid compositions for oral administration can be formulated for immediate and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

Preparations with suitable modified release for the purposes of the invention are described in US Patent No. 6106864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention can also be administered directly into the bloodstream, into muscles or into an internal organ. Suitable means for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intra-urethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle injectors (including micro needle injectors), needle-free injectors and infusion techniques.

1026827 «> 25

Parenteral compositions are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffering agents (preferably up to a pH of 3 to 9), but for some applications, they may be obtained in a (more suitable) manner. formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable medium such as sterile, pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by freeze-drying, can be easily accomplished using standard pharmaceutical methods well known to those skilled in the art.

The solubility of compounds of the invention used in the preparation of parenteral solutions can be increased by using suitable formulation techniques such as incorporating solubilizing agents.

Preparations for parenteral administration can be formulated for immediate and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release. Compounds of the invention can thus be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted depot that provides for modified release of the compound. Examples of such compositions include drug-covered stents and PGLA microspheres.

The compounds of the invention can also be applied topically to the skin or mucosa, i.e., dermally or transdermally. Typical compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, ointment / powder dressing, foams, films, skin patches, slabs, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers 1026827

• I

26 contain alcohol, water, mineral oil, liquid paraffin oil, white paraffin oil, glycerin, polyethylene glycol and propylene glycol. Penetration enhancing agents may be included - see, for example, J Pharm Sci, 8j) 5 (10), 955-958 by Finnin and Morgan (October 1999).

Other modes of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle injection or needle-free (e.g. Powerdject ™, Bioject ™, etc.) injection.

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

The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either separately, as a mixture, for example in a dry mixture with lactose, or as a particle consisting of mixed components , For example mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, sprayer (preferably a sprayer that uses electrohydro-dynamics to produce a fine mist) ), Or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin.

The container under pressure, pump, spray, spray or spray contains a solution or suspension of the compound which, for example, ethanol (optionally aqueous ethanol) or a suitable alternative means for dispersing, solubilizing or extending the release of the compound. compound, the propellant gas (s) as a solvent and an optional surfactant such as sorbitan trioleate, oleic acid or an oligoleic acid.

1026827 4 «27

Prior to use in a dry powder or suspension preparation, the drug product is divided into small particles to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any method of pulverizing, such as spiral jet milling, jet milling by means of a fluidized bed or supercritical liquid processing to form nanoparticles, homogenization under high pressure or spray drying.

Capsules (made from, for example, gelatin or HPMC), blister packs and fillings for use in an inhaler or blower may be formulated around a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch, and a performance-altering substance such as Γ -leucine, mannitol or magnesium stearate. The lactose can be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextrot, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution preparation for use in an atomizer using electrohydrodynamics to form a fine mist may contain 1 pg to 20 mg of the compound of the invention per atomization, and the atomization volume may vary from 1 μΐ to 100 μΐ. A typical preparation may contain a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

Suitable flavors such as menthol and letenstenthol or sweeteners such as saccharin or saccharin sodium can be added to the compositions of the invention intended for inhaled / intranasal administration. Preparations for inhaled / intranasal administration can be formulated for immediate and / or modified release using, for example, poly (DL-lactic acid-co-glycolic acid) (PGLA). Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release; , too.

I i; In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. Units in accordance with the invention are typically determined to administer a metered dose or puff containing 1 µg to 10 mg of the compound of the invention. The total daily dose will typically be between 1 pg and 200 mg, which can be administered in a single dose or, more preferably, as shared doses during 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, but various alternatives can be used as desired.

Preparations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified-release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops of a small particle-suspended suspension or solution in isotonic, pH-adjusted sterile saline solution. Other compositions suitable for ocular administration and administration via the ear include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particle or vascular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, e.g. benzalkonium chloride. Such preparations can also be 1 * 1 by iontophoresis. 5 issued.

1 Preparations for ocular administration and administration via the ear can be formulated for immediate and / or modified delivery. Modified-release preparations include delayed, sustained, pulsed, controlled, intended, or programmed release.

The compounds of the invention can be combined with soluble macromolecular units such as cyclodextrin and, suitable derivatives thereof or polyethylene glycol-containing polymers, to improve their solubility, solubility rate, taste masking, bioavailability and / or stability for use in any of the aforementioned. methods of administration.

Drug / cyclodextrin complexes, for example, have been found to be generally useful for most dosage forms and modes 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 a supportive additive, i.e. as a carrier, diluent or agent to increase solubility. The most frequently used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in international applications Nos. WO 91/11172, WO 94/02518 30 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 treatment of a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical preparations, at least one of which contains a compound of the invention, are conveniently combined in the form of a set suitable for parallel administration of the compositions.

The set of the invention thus 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 containing these compositions such as a holder, bottle divided into parts or foil pack divided into parts. An example of such a set is the known blister pack that is used for packaging tablets, capsules and the like.

The set of the invention is particularly suitable for administering different dosage forms, for example orally and parenterally, for administering the individual preparations at different dosing intervals, or for titrating the individual preparations against each other. To support the thrapia compliance, the set typically includes instructions for administration and the set 20 can be equipped with a so-called memory aid.

For administration to human patients weighing about 65 to 75 kg, the total daily dose of a compound of the invention is typically in the range of 1 to 10000 mg, such as 10 to 1000 mg, e.g. 25 to 500 mg, of course depending on the method of administration, the age, the condition and the weight of the patient, and it will in any case be the final decision of the doctor. The total daily dose can be administered in single or separate doses. Accordingly, in another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable excipients, diluents or carriers.

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives have the advantage that they are more selective, begin to work faster, are more powerful, are better absorbed, are more stable, have better resistance to metabolism, have a reduced 'nutritional effect', have an improved safety profile or have other more desirable properties (eg with regard to solubility or degree of hygroscopic) than the compounds of the prior art.

The compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives can be administered individually or as part of a combination therapy. Thus, all embodiments comprising parallel administration of one or more additional therapeutic agents are included within the scope of the present invention, and compositions comprising, in addition to a compound of the invention, one or more additional medicinal agents. Such multiple drug therapies, 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 combination therapy is particularly relevant with regard to the treatment and prevention of infection with and propagation of the human immunodeficiency virus, HIV, and related pathogenic retroviruses within a patient in need of treatment or at risk. to become such a patient. The ability of such retroviral pathogens to develop within a relatively short period of time into strains resistant to any single therapy administered to the patient is well known in the literature. A recommended treatment for HIV is a combination treatment with drugs called Very Active Anti-Retroviral Therapy or HAART. HAART combines three or more HIV-35 drugs. The treatment methods and pharmaceutical compositions of the present invention can thus use a compound of the invention in the form of single therapy, but these methods and compositions can also be used in the form of combination therapy in which one or more compounds of the invention are administered in parallel in combination with one or more additional therapeutic agents such as those described in further detail in this patent specification.

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 list : HIV protease inhibitors, including but not limited to indinavir, ritonavir, saquinavir, nelfinavir, lopinavir, amprenavir, atazanavir, tipranavir, AG1859 and TMC 114; non-nucleoside reverse transcriptase inhibitors (NNRTIs), including but not limited to nevirapine, delavirdine, capravirine, efavirenz, GW-8248, GW-5634 and TMC125; nucleoside / nucleotide reverse transcriptase inhibitors including but not limited to zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir dipivoxil, tenofovir, emtricitabine and alovudine; CCR5 antagonists, including but not limited to: N - {(IS) -3- [3- (3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl) -exo-8 -azabicyclo [3.2.1] oct-8-yl] -1-phenylpropyl} -4,4-difluorocyclohexanecarboxamide or a pharmaceutically acceptable salt, solvate or derivative thereof, methyl 1-endo- {8 - [(3S) -3 - (acetylamino) -3- (3-fluorophenyl) -30-propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-1H-imidazo [ 4,5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof, methyl 3-endo {8 - [(3S) -3- (acetylamino) -3- (3-fluorophenyl) - Propyl] -8-azabicyclo [3.2.1] oct-3-yl} -2-methyl-4,5,6,7-tetrahydro-3 H -imidazo [4,5-c] pyridine-5-carboxylate or a 1026827 • 33 pharmaceutically acceptable salt, solvate or derivative thereof, ethyl 1-endo- {8 - [(3S) -3- (acetylamino) -3- (3-fluorophenyl) -propyl] -8-azabicyclo [3.2.1 ] oct-3-yl} -2-methyl-4,5,6,7-5 tetrahydro-1 H -imidazo [4,5-c] pyridine-5-carboxylate or a pharmaceutically acceptable salt, solvate or derivative thereof,

Sch-D, ONO-4128, GW-873140, AMD-887 and CMPD-167; other agents that inhibit the interaction of gpl20 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-870,810; and RNaseH inhibitors.

Also 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 independently selected from the group consisting of proliferation inhibitors, e.g. hydroxyurea; immunomodulators such as granulocyte macrophage colony-promoting growth factors (e.g., sargramostim), and various forms of interferon or interferon derivatives; other chemokine receptor agonists / antagonists such as CXCR4-25 antagonists (e.g., AMD-070); tachykinin receptor modulators (e.g., NK1 antagonists) and various forms of interferon or interferon derivatives; agents that significantly inhibit, disrupt or decrease viral transcription or RNA replication such as tat (transcriptional trans-activator) or nef (negative regulatory factor) inhibitors; agents that significantly inhibit, disrupt, or lower translation of one or more proteins expressed by the virus (including but not limited to down-regulation of protein expression or antagonism of one or more proteins) other than reverse transcriptase, such as Tat or Nef; agents that affect CCR5 receptor expression, in particular down-regulate; chemokines that induce CCR5 receptor internalization such as ΜΙΡ-1α, MIP-1β, RANTES and derivatives thereof; and other agents that inhibit viral infection or improve the condition or outcome of HIV-infected individuals through I | ; 5 different mechanisms.

; Agents that affect CCR5 receptor expression (in particular down-regulate) include immunosuppressants such as calcineurin inhibitors (e.g., tacrolimus and cyclosporin A); steroids; agents that interfere with cytokine production or signaling such as Janus Kinase (JAK) inhibitors (e.g., JAK-3 inhibitors, including 3 - {(3R, 4R) -4-methyl-3- [methyl- (7H-pyrrole [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 interleukin-2 (IL-2) receptor, including basiliximab and daclizu-mab); and agents that interfere with cell activation or cell recycling, such as rapamycin.

Also 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 slow the metabolism rate of the compound of the invention , which results in increased patient exposure. Increasing exposure in such a way is known as driving up. This has the advantage of increasing the effect of the compound of the invention or decreasing the dose needed to achieve the same effect as a non-inflated dose. The metabolism of the compounds of the invention includes oxidative processes performed by P450 (CYP450) enzymes, in particular CYP 3A4 and conjugation by UDP-glucuronosyltransferase and sulfating enzymes. Thus, among the agents that can be used to increase a patient's exposure to a compound of the present invention are agents that can serve as 1026827 t, 35 as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes. The isoforms of CYP450 that can be advantageously inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and:; 5 CYP3A4. Suitable agents that can be used to inhibit CYP 3A4 include, but are not limited to, ritonavir, saquinavir or ketoconazole.

The person skilled in the art will understand that a combination treatment with drugs as described above in this patent description may comprise two or more compounds with the same or different mechanisms of action. Only by way of explanation can a combination thus be a compound of the invention and: one or more NN-RTIs; one or more NRTIs and a PI; one or more NRTIs and a CCR5 antagonist; a PI; a PI and an NNRTI; and so on.

In addition to the requirement for therapeutic efficacy that may require the use of therapeutic agents in addition to the compounds of the invention, there may be additional grounds that necessitate or strongly necessitate the use of a combination of a compound of the invention and another therapeutic agent such as in the treatment of, or indirectly accompanying, illnesses or conditions directly resulting from the underlying 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 condition where the immunity of the patient being treated has been compromised. Other therapeutic agents can be used with the compounds of the invention, e.g. to provide immunity promotion or to treat pain and inflammation that accompany the initial and fundamental HIV infection.

r - 1026827 36 *,

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 al-fa-2b ), lamivudine, ribavirin and emtricitabine for the treatment of hepatitis; antifungal agents such as fluconazole, itraconazole and voriconazole; antibacterial agents such as azithromycin and clarithromycin; interferons, daunorubicin, doxorubicin and paclitaxel for the treatment of AIDS-related Kaposi's sarcoma; and cidofo-vir, fomivirsen, foscarnet, ganciclovir and valcyte for the treatment of cytora galovirus (CMV) retinitis.

Further 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 salmeterol; a corticosteroid agonist such as fluticasone propionate; a 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-25 receptor modulator such as a TNF-alpha inhibitor (e.g. ada-limumab), an HMG 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 other therapeutic agent (s) in terms of dosage forms can be individually or together with each other and in terms of their Thus, the administration of one component may be administered prior to, simultaneously with, or after administration. the other constituent substance (s) take place.

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

It is to be understood that all references to treatments in this patent specification include healing, pain relieving and preventive treatments.

The invention is illustrated by the following Examples and Preparations in which the following further abbreviations can be used: 0.88 ammonia = concentrated ammonium hydroxide solution, specific weight 0.88 h * hour min = minute LRMS = low-resolution mass spectrum APCI + = chemical ionization at atmospheric pressure ESI + = electrospray ionization NMR = magnetic nuclear magnetic resonance tic - thin layer chromatography Me = methyl Example 1 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazine-1-yl] -2- ( quinoline-5-yloxy) propan-1-one 30 Cl T On VvtV ^ O Me 1 0 26 82 7 35 A solution of (2S) -2- (quinoline-5-yloxy) propionic acid sodium salt (Preparation 2) (1 , 0 g, 4.6 mmol), (3R) - (3-methylpiperazin-1-yl) phenylmethanone (J. Med. Chem. (2000), I k 38 43 (23), 4499) (0.94 g, 4.6 mmol), O- (1 H -benzotriazol-1-yl) -N, N, N ', Ν'-tetramethyluronium hexafluorophosphate (2.62 g, 6.9 mmol) and triethylamine (1.93 ml, 13.8 mmol) in N, N - (.alpha.-dimethylformamide (30 ml) was washed under a nitrogen for 14 hours. "! Stirred at room temperature for 5 atmospheres. The reaction mixture was diluted with dichloromethane (100 ml), washed with water (3 x 50 ml), dried (MgSO 4) and the solvent was allowed to evaporate under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2) to give the title compound as a white solid (0.91 g).

X H NMR (400 MHz, CDCl 3): δ: 8.90 (1 H, m), 8.60 (1 H, m), 7.70 (1 H, m), 7.55 (1 H, m), 7.20 - 7.40 (6 H, m), 6.85 (1 H, 15 m), 5.15 (1 H, m), 4.80 - 2.80 (7 H, m), 1.70 (3 H, d) , 0.90 (3 H, br s) ppm.

LRMS (APCI +): m / z (M + H) + 404.

Example 2 3- [2- ((2R) -4-Benzoyl-2-methylpiperazin-1-yl) -1-methyl-2-oxoethoxy] -2-methylbenzoic acid methyl ester

25 A

Me

MeONAyAQA ^ NvJ

O Me O Me Cesium carbonate (0.39 g, 1.2 mmol) was added portionwise to a solution of 1 - [(2 R) -4-benzoyl-2-methyl-piperazin-1-yl) -2-bromopropane -1-one (Preparation 3) (0.41 g, 1.2 mmol) and 3-hydroxy-2-methylbenzoic acid methyl ester (Tet. Lett. (2000), 41 (11), 1741) (0.2 g 1.2 mmol) in acetone (10 ml) and the mixture was heated under 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 extracts (organic extracts were dried (MgSO4) and allowed to evaporate under reduced pressure to remove the solvent. to provide a binding from the title as a white solid (0.5 g).

* H NMR (400 MHz, CDCl 3): δ: 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, br) s) ppm.

LRMS (APCI +): m / z [M + H] + 425.

Examples 3-12 were prepared in the manner described above for Example 1 using the corresponding acid of formula (VI) and piperazine of formula (VII). LRMS was with APCI + and the data is for [M + H] +.

1026827 * »40 example oossa spec.

nunner structure data 3 386 __O Me___ 4 μθ ^ ΑοVV ^ 380 _Me_O Me__ 5 408 HN ^ O Me - -

Me r '^ N' ^ Sr '^ 6 AVyY U 422 O Me ’.Jv ^ o-VV * -? "* Uncle

Me r ^ N ^ Y ^, ’ïV '^' Vv“ O Me _

More r ^ N

9 νΑΛο ^ ΥΥ ^ 405 ktY O Me 1026827 41, mass example _ _. spec.

numEr. structure, data

5 T -T

AVVv ^ 405 11 440 OMe O Me 12 407 N == O Me __Me__ Examples 13-45 were prepared in the manner described above for Example 2 using the corresponding compound of formula (II) and R5OH . LRMS was with APCI + and the data is for [M + H] + unless otherwise stated.

25 example mass romer structure spec * data 30 - Ö ---: - 13 386 __O Me__ 1 0 26 82 7 example mass number structure spec.

information 42 5

Me 14 ii 1 J 11 J 380

Me γ Ό'γ 'γ _Me_O Me____ 15 Me ^ o ^ yGN \ ï) 366

Me o 16 391 __CN_O Me__ 17 383 OMe O Me - f ^ ll Me 18 JL JL I i J l [J 393 O / 0 T \ \ = N O Me

O

Me Γ ^ Ν'Ν'Λν ^ 1 19 Jk X J (IJ 419 <H 0 Jf Y ^ \ ^ N O Me

Me 20 S ^ r Y ^ 367 ____ Me_O Me__

O

Me ΥΛνΥΛ 21 YiJj KJ 368 ___Me_O Me__ 1026827 I, 43, u mass example "_" spec.

nunner structure data Ö

Me 403 22 fV'vv ^ t? R.

O Me 'V> l Γ ^ Ν "τί ^ ι 23 A ^ yV ^ 421 U ^ N O Me" "i

Me O Me

O

25 T \ J 393 0 Me

O

AAAA Me r ^ N ^ Sf ^ i 26 KJ 402 __O Me__ 6A] Me A ° \ y ^ 403 NO Me 28 M ° VV ^ 403 N ^ Yy O Me 1026827 44, u mass example minnar structure 29 Λρ ^ τ ^ 402 0 Me 30 424 _O Me__ 31 440 __OMe O Me__ 32 454 OMe O Me _ l ^ ïl Μθ f ^ N ^ Y ^ i 33 ΗΝ ^ ν ^ Ο-γ ^ 407 N®5 ^ O Me

Me

O

Me n ^ Me' 34 Me n ^ Me ^ 35 368 Me 0__ 1026827 Example mass nunner structure sspec.

data 45 f? ; ! | Λ <Υ0 Me r ^ 'N'JSr ^ l 36 KJ 434 __O Me__ 37' tXXA ^^ O 417 O Me

O

Me r / ^ N '^ No ^ 1 38 kAAoX ^ O U 403 ___O Me__ (^ YS Me 39 N * J1 ^ A0X ^ J 1IJ 403 __O Me__ 40 m ^ Mq ^ YY1 421 N = \ O Me .__ Me__

HsN ^ V ^ n Me 41 U 426 _ OMe O Me - 'doi ^ x / o «__O Me__ -' ÓOLJv / o - __O Me__ 1 0 26 82 7 example mass runraer structure spec.

data * 46 ΗΗ, Ν- ^ Ο ° M ° ___ 45 xcxj ^ / o 405 __ 0 Me__ 15 Example 46 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazine-1-yl] -2 - [2-methoxy-4- (2H- [1,2 / 4] triazol-3-yl) phenoxy] propane-1-one on O CH 3 ch 3

The compound of Preparation 10 (125 mg, 0.26 inmol) was added portionwise to a stirred solution of hydrazine monohydrate (25 μΐ, 0.52 mmol) in glacial acetic acid (4 ml). The resulting solution was heated at 90 ° C for 3 hours. The reaction mixture was then evaporated under reduced pressure and the remaining colorless oil was partitioned between dichloromethane (50 ml) and saturated sodium hydrogen carbonate solution (8 ml). The organic phase was separated and the aqueous phase was extracted again with dichloromethane (30 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo to give a colorless foam. The foam 1026827 •, 47 was dried under reduced pressure to give the title compound in 94% yield, 110 mg.

LRMS (ES4): m / z [M + H] 4,450 Example 47 1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- [2-methyl-3- (1-) methyl-1H-pyrazol-3-yl) phenoxy] propan-1-one H 3 Cl -N Au 1 -S = J CH 3 O CH 3 The compounds of Preparations 17 (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 under reflux for 3.5 hours. The reaction mixture was then 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 re-extracted 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 an Isolute® flash silica column eluting with dichloromethane: methanol, 99: 1 to 97: 3, to give a colorless oil. This oil was azotroped with dichloromethane to give the title compound as a colorless foam with 89% yield, 210 mg.

LRMS (ES4): m / z [M + H] 4,447 y - 1 0 2 6 8 2 7

t I

Example 48 1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl-2- (2-methyl-3- [1,2,4] oxadiazol-5-yl-phenoxy) propane-1-one 48 ≤ y 9 L ° V x 1 -1 ^ 10 VN CH 3 O CH 3

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

LRMS (ES '): m / z [M-H]' 433! 1026827

Example 49 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- [3- (2H-pyrazol-3-yl) phenoxy] propane-1-one 49 10 0 CH 3 N = / 15 (3R) - (3-methylpiperazin-1-yl) phenylmethanone [(114 mg, 0.56 mmol), J. Med. Chem. 43 (23), 4499; 2000], 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-4 (3H) -one (167.5 mg, 0.56 mmol) and triethylamine (78 μΐ, 0.56 mmol) were added to a solution of the compound of Preparation 20 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® flash silica column eluting with dichloromethane: methanol, 98: 2 to 96: 4 to give a colorless foam. The foam was subjected to azeotropic distillation with dichloromethane and dried under reduced pressure to give the title compound in 85% yield, 198 mg.

LRMS (ES '): m / z [M-H] "417 1026827 • 1

Example 50 (2S) -1- [(2R) -4-.Benzoyl-2-methylpiperazin-1-yl] -2- [2-methyl-3- (2H-pyrazol-3-yl) phenoxy] propane-1 -on 50

S

'1; 5 O

IP O iP), γΥr u 10 II ° ch 3 N == 15 The title compound was prepared according to the method described above for Example 49 using the compound of Preparation 24 and <3R) - (3-methylpiperazine) -1-yl) phenylmethanone (J. Med. Chem. 43 (23), 4499; 2000).

LRMS (ES "): m / z [MH]" 431 Example 51 1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- [4- (1H-imidazole-2) -yl) -2-methoxyphenoxy] propane-1-one

O

H ΟιΠ 30 H jTY O CH, CH,

The compounds of Preparation 33 (30 mg, 0.16 mmol) and Be-35 preparation (53.3 mg, 0.16 mmol) and cesium carbonate (51.3 mg, 0.16 mmol) in N, N-dimethylformamide (4 ml) were heated at 80 ° C for 18 hours. The reaction mixture was allowed to cool 1026827 51 and was then evaporated under reduced pressure and the residue was partitioned between dichloromethane (30 ml) and water (8 ml). The aqueous phase was separated and dissolved newly extracted with dichloromethane (30 ml). The combined 1 "; 5 combined organic extracts were dried over magnesium; sodium sulphate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column, eluting with dichloromethane: methanol, 99: 1 to 95: 5, to give the title compound as 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 in the manner described above for Example 51 using the compound of Preparation 25 and the appropriate phenol.

20, AX? 0 04 __CH3 _! F? wider data 30___ 52 LRMS (ES *): m / z [M-H] * 447 ___ 53, LRMS (ES): m / z [M + Na] * 471 1 0 26 82 7 52

Examples 54 to 57

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

1026827

1 I

53 - O CH 3 - R 5 LRMS (APCI +): m / z [M + H] + 10 54 f ”3 429

V

Example 55: Phenol prepared as described in Preparation 67 Example 55: phenol prepared as described in Preparation 67

Example 55: phenol prepared as described in Preparation 68

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

Example 57: 5-hydroxy-1-naphthalenesulfonamide is commercially available 1 0 26 82 7 54

Example 58> 1- [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (4-methane-sulfonyl-2-methoxyphenoxy) propane-1-one

:; | S

λ o ch3

H 3 C

A solution of oxone (215 mg, 0.35 inmol) in water (2 ml) was added to a solution of the compound of Example 54 (100 mg, 0.23 inmol) in methanol (4 ml) and the mixture was 18 stirred at room temperature for 1 hour. The solvent was then evaporated under reduced pressure and the residue was partitioned between water (20 ml) and dichloromethane (20 ml). The aqueous layer was separated and re-extracted with dichloromethane (30 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column, eluting with dichloromethane: methanol (95: 5) to give the title compound as a white solid in 76% yield, 80 mg.

LRMS (APCI +): m / z [M + H] + 461

Example 59 N- (4- [2- (2R) - (4-Benzoyl-2-methylpiperazin-1-yl) -1-methyl-2-oxoethoxy] -3-methoxyphenyl) methanesulfonamide 30 CHO 1026827 · 55

Triethylamine (0.08 ml, 0.57 mmol) was added to a solution of the compound of Preparation 30 (150 mg, 0.38 mmol) in dichloromethane (3 ml) and the mixture was cooled in an ice bath. Methane sulfonyl chloride (0.03 ml, 0.42 • 5 mmol) was added dropwise and allowed to react. Stir the mixture for 18 hours at room temperature. The mixture was then 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 then purified by column chromatography on silica gel, eluting with ethyl acetate: methanol (98: 2) to give the title compound as a white solid in 49% yield, 88 mg.

LRMS (APCI +): m / z [M + H] + 476 15

Example 60 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (2-chloroquinoline-5-yloxy) propan-1-one 0 ch 3

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. The reaction mixture was then cooled to room temperature and evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (10 ml) and water (2 x 10 ml). The aqueous phase was made basic with 1 M sodium hydroxide solution and was re-extracted 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 1 0 26 82 7 ________ 4 β 56 with pentane: ethyl acetate (20:80, 0: 100) to give the title compound as a pale yellow solid with 31% yield, 580 mg.

* Η NMR (400 MHz, CDCl 3) δ: 1.00 - 1.40 (m, 3H), 1.70 - 1.80 j 5 (m, 3H), 2.80 - 4.80 (m, 7H) ), 5.20 (m, 1H), 6.90 (m, 1H), j 7.20 - 7.45 (m, 6H), 7.55 - 7.70 (m, 2H), 8.55 (d, 1 H) j LRMS (APCl +): m / z [M + H] + 438

Examples 61 to 62 10

A mixture of the compound of Example 60 (30 mg, 0.069 mmol), tetrabutylammonium fluoride (18 mg, 0.14 mmol), triethylamine (96 μΐ, 0.69 mmol) and the appropriate amine (0.69 mmol) in dimethyl sulfoxide ( 1 ml) was heated at 100 ° C for 24 hours. The reaction mixtures were then immediately 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 to to yield the desired compounds of general formula which are shown below: 1026827 4.57

O

f O 15 -'v '- || 10 ch3

10 Re / NH

number R6 LRMS (APCI *): "1 / z [M-H] + 61 461 15 62? 463 461

HjCT ^ __ 20

Example 63 1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl) -2- (1-chloro-quinoline-5-yloxy) -propan-1-one 25% o ch3

30! T I

Cl

The title compound was prepared according to the method described above for Example 60 using the compound of Preparation 63 and phosphorus oxychloride.

1026827 * 58 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 inmol), triethylamine (140 μΐ, 1 mmol) and the appropriate amine (1 mmol) in dimethyl sulfoxide (1 mL) was heated at 130 ° C for 24 hours. The reaction mixtures were then immediately 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 , to provide the desired compounds of general formula shown below:

O

20 Ifï ^ ί T O CH,

N N

25 Rn Riner R6 R7 LRMS (APCI *): m / z [M-H] + 64 N - 5 H 485 65 CH3 CH3 447 t 0 2 R 8 2 7 59

Example 66 (2S) -2- (2-Aminoquinoline-5-yloxy) -1 - [(2R) -4-benzoyl-2-methylpiperazihe-1-yl] propane-1-one 5 8 # 6) CH 3 I NH 2 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 was heated at 70 ° C. Additional ammonium formate (10 mg, 0.15 mmol) and Pd (OH) 2 (cat) were added and the reaction mixture was again under 18 hours The mixture was then cooled and filtered through Arbocel®, washed with ethanol (10 ml), the filtrate was concentrated in vacuo, and the residue was purified by HPLC using a Phenomenex Luna Cl 8 system eluting with water ter / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, to give the title compound in 77% yield, 9.7 mg.

LRMS (ES +): m / z [M + H] + 419 30 1 0 26 82 7 60

Example 67 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (8-chloroquinoline-5-yloxy) propan-1-one " O ιΠ 10 'O * 0 CH »

A mixture of the compound of Preparation 42 (30 mg, 0.07 rranol) and N-chlorosuccinimide (11 mg, 0.08 mmol) in acetonitrile (3 ml) was heated at 40 ° C for 48 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in ethyl acetate (5 ml) and washed with water (2 x 5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by HPLC 20 using a Phenomenex Luna C18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, to remove the compound to give the title as a solid with 32% yield, 9.7 mg · 25 LRMS (APCI +): m / z [M + H] + 438

Examples 68 to 69

The following compounds, of the general formula shown below, were prepared in the manner described above for Example 67 using the appropriate starting material and N-chlorosuccinimide.

1026827 61; o ch3 ~~ X LRMS (APCI4): m / z [M-H] + runner '' * * * 10 68 N 439 69 C-F 456 15

Examples 68 and 69 were purified by column chromatography on silica gel, eluting with dichloromethane: methanol, 99: 1 to 96: 4 Examples 70 and 71

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 similar preparation to that of Example 67. The compounds were purified by HPLC using a Phenomenex Luna C18 (2) column 150 x 15 mm (particle size of 10 micrometers, 100 A porosity) using an eluent with two solvents of ace-30 tonitrile: water: trifluoroacetic acid (5: 95: 0.1) [solvent A] and acetonitil [solvent B]. A solvent gradient is performed at a flow rate of 20 ml / min as in the table below.

1026827 62

Time (min) __% B_ _0_5_ 0 / 6_5_ 9.5 __95_ 10.5 __95_ 10.6 __5_ 12 [5 Γ mc LRMS (APCI +): no structure ΓΠ / z [M + H] + 5 -, ------- - 70 4.99 422 O CH3 71 5.77 422

Jpcxc / o o ch3 20

Example 72 (2 S) -1 - [(2 R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (8-methylquinoline-5-yloxy) propane-1-one 30 1026827 63

A mixture of the compound of Preparation 44 (200 mg, 0.4 mmol), methyl boronic acid (74 mg, 1.2 itvmol), bis (triphenylphosphine) palladium (II) chloride (29 mg, 0.04 mmol) and potassium carbonate ( 229 mg, 1.6 mmol) in N, N-5 dimethylformamide (4 ml) was heated at 100 ° C for 18 hours. Tlc analysis indicated that the reaction was incomplete and thus additional amounts of methyl boronic acid (74 mg) and bis (triphenylphosphine) palladium (II) chloride (29 mg) were added, and the mixture was allowed to stir an additional 24 hours at 100 ° C . The reaction mixture was then filtered through Ar-bocel®, washed through with ethyl acetate (25 ml) and water (3 x 20 ml). The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to give 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) racetonitrile, 95: 5 to 5:95. The appropriate fraction was then subjected to azeotropic distillation with diethyl ether to give the title compound as a yellow solid with 19% yield, 33 mg.

LRMS (APCl +): m / z [M + H] + 418 Example 73 (2S) -1- [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- [8- (2H -pyrazol-3-yl) -quinoline-5-yloxy-3-propane-1-one

30 aN "N 0

^ "f \ r · f / τη nr ° tV u

35 ^ CHS

4 M Hydrochloric acid (2 ml) was added to a suspension of the compound of Preparation 45 (43 mg, 0.07 mmol) in methanol (2 ml), and the resulting solution was stirred at 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 layers were dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (98: 2) to give the title compound as a yellow solid with 68% yield, 23 mg.

LRMS (APCI +): m / z [M + H] + 470

Example 74 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl3-2- [2- (2H-pyrazol-3-ylamino) quinoline-5-yloxy] -propane-1 -on ”Cl

O CH 3 H

A mixture of the compound of Example 60 (50 mg, 0.01 mmol), 3-aminopyrazole (29 mg, 0.33 mmol) and triethylamine (48 μΐ, 0.33 mmol) in 2-propanol (0.5 ml) was heated in a Reactivial ™ at 90 ° C. After 18 hours, cesium fluoride (33 mg, 0.22 mmol) was added and the mixture was heated at 100 ° C for another 48 hours. The reaction mixture was then filtered and concentrated in vacuo to give an oily residue. The residue was purified by HPLC using a Phenomenex Luna G18 system eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95, to remove the compound deliver the title as a yellow solid, 3 mg.

LRMS (APCI +): m / z [M + H] + 485 - 1 0 2 fi P 2 7 65

Example 75 5 - {(1 S) -2 - [(2 R) -4-Benzoyl-2-methylpiperazine-1-yl] -1-methyl-2-oxoethoxy} -1H-quinoline-2-one

Xkj ^ o

10 O CHS

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

LRMS (APCI +): m / z [M + H] + 418 Example 76 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazine-1-yl] -1-methyl-2 -oxoethoxy) -8-chloro-1H-quinoline-2-one O ch3 35

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

LRMS (APCI +): m / z [M + H] + 454 · t '1 *. Example 77 ! (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl} -2- (2-methoxy-quinoline-5-yloxy) -propan-1-one ^ o ch3

A mixture of 1 the compound of Example 60 (20 mg, 0.04 mmol) and sodium methoxide (0.5 M in methanol, 0.7 ml) in N, N-dimethylformamide (0.5 ml) was added for 6 hours a Reac-tivial ™ heated at 70 ° C. 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 (2 x 5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (0.5 ml) and 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 then subjected to azeotropic distillation with diethyl ether to give the title compound as a yellow solid in 40% yield, 7 mg.

LRMS (APCI +): m / z [M + H] + 434 1 0 26 82 7 67

Example 78 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy) isoquinoline-1-carboxylic acid methyl ester I 10, CH 3, 10

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

LRM'S (APCI +): m / z [M + H] + 4 62 Example 79 5- {2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy) quinollne-2-carboxylic acid methylamide

O

30 fHa

O XOM'V U

o ch3

.NH

"C HgC ^ 35 3

A mixture of the compound of Preparation 48 (20 mg, 0.05 mmol), methylamine (33% in ethanol, 30 mg, 0.5 1026827

"I

68 mmol), 0- (ΙΗ-benzotriazol-1-yl) -Ν, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate (2 mg, 0.08 mmol) and triethylamine (62 μΐ, 0, 5 mmol) in dichloromethane (1 ml) was stirred at room temperature for 18 hours. Extra methylamine (30 mg, j

1, 0.5 mmol) and triethylamine (62 μΐ, 0.5 mmol) were added to I

The reaction mixture was added and the stirring was repeated Continued for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with water (2 x 5 ml) and brine (5 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow residue. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (96: 4) to give the title compound as a white solid in 13% yield, 3 mg.

LRMS (APCI +): m / z [M + H] + 4 61 Example 80 "| 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-20 methyl 2-oxoethoxy} isoquinoline-1-carboxylic acid methylamide

O

o ^ rrVi VYY ^ rV ^ O CHg

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

LRMS (APCI +): m / z [M + H) + 461 | 1 o 2fi 82 7

1 I

69

Example 81 4 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy) -N-methyl-3-trifluoromethoxy-benzamide t 1 1 ; 5 10 F 0.0 ch 3

F "V

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

LRMS (APCI +): m / z [M + H] + 4 94

Example 82 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl) -2- (8-25 chloro-2-methylaminoquinoline-5-yloxy) propane-1-one

O CH 3 H

A mixture of the compound of Preparation 52 (60 mg, 35.0, 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 dimethyl sulfoxide (1 ml) was heated in a microwave oven at 170 ° C for 8 minutes. The reaction mixture was then filtered and the filtrate was purified by HPLC using a Phenomenex Luna Cl8 system eluting with water / acetonitrile / trifluoro-5 acetic acid (5: 95: 0/1): acetonitrile, 95: 5 to 5 : 95. The appropriate fraction was then subjected to azeotropic distillation with diethyl ether to give the title compound as a brown solid with 19% yield, 10.8 mg.

10 LRMS (APCI +): m / z [M + H] + 467

Example 83 1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (1-methyl-aminoisoquinoline-5-yloxy) propan-1-one 15 20 H *

.NH

H3CΓ 25

The title compound was prepared according to the method described above for Example 82 using the compound of Example 63 and methyl amine.

LRMS (APCI +): m / z [M + H] + 433 1026827 * t 71

Example 84 (2S) -1- [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (8-chloro-2-dimethylaminoquinoline-5-yloxy) propan-1-one i. "; 5

•; ! O

aY \ f On 10 0 CH 3 N 3 ch 3

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) in dimethylsulfoxide (4 ml) was heated in a Reactivial ™ at 170 ° C for 18 hours. The reaction mixture was then 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, to give the title compound as a white solid, 5 mg.

LRMS (APCI +): m / z [M + H) + 481 25

Example 85 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) isoquinoline-5-yioxypropane-1-one

Vnh ^ 0 CHs

35 N

A mixture of the compound of Example 63 (45 mg, 0.1 mmol), tetrabutylammonium fluoride (27 mg, 0.2 mmol), 1026827 I, 72 triethylamine (0.14 ml, 1 inmol) and 3-aminopyrazole (83 mg 1 mmol) in dimethyl sulfoxide (1 ml) was heated at 100 ° C for 24 hours. The reaction mixture was then immediately purified by HPLC using a Phenomenex Luna Cl8 system eluting with water / acetonitrile / formic acid (5: 95: 0.1) racetonitrile, 95: 5 to 5:95, to provide the compound from the title to be delivered with a 39% yield, 19 mg.

LRMS (APCI +): m / z [M + H] + 485 10

Example 86 (2S) -1 - ((2R) -4-Benzoyl-2-methylpiperazin-1-yl) 1-2- (3,6-dimethyl-1H-indazol-4-yloxy) propane-1-one 15 20 N \ O CH 3 CH 3 4 M Hydrochloride in dioxane (1 ml) was added to the compound of Preparation 77 (45 mg, 86 pmol) 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 1 M sodium hydroxide solution to pH 12. The mixture was then passed through a phase separation column and the filtrate was concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (96: 4: 1) gave the title compound as a pale pink foam with 59% yield, 20 mg.

LRMS (APCI +): m / z [M + H] + 421 35 0 0 7 7, 73

Example 87 (2S) -1 - [(2R) -2-Methyl-4- (pyridin-2-carbonyl) piperazin-1-yl] -2- (quinolin-5-yloxy) propane-1-one tio 'VV u O ch3 10

A mixture of the compound of Preparation 51 (150 mg, 0.5 mmol), picolinic acid (49 mg, 0.6 inmol), 0- (1H-benzotriazol-1-yl) -N, N, N1, N'- tetramethyluronium hexafluorophosphate (190 mg, 0.75 mmol) and triethylamine (0.93 mL, 10 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with more dichloromethane and washed with sodium hydroxide (10 ml) and water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. 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 in 49% yield, 99 mg.

LRMS (APCI +): m / z [M + H] + 405 25

Example 88 (2S) -1- [4- (2-Fluoro-benzoyl) - (2R) -2-methylpiperazin-1-yl] -2- (quinolin-5-yloxy) propane-1-one o ch 3 35

A mixture of the compound of Preparation 51 (150 mg, 0.5 mmol), 2-fluorobenzoyl chloride and triethylamine in 1 0 26 82 7 *, 74 dichloroethethane (3 ml) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on 1 silica gel, eluting with dichloromethane: methanol (98: 2), gave the title compound as a white solid in 73% yield, 153 mg.

LRMS (APCI +): m / z [M + H] + 422

Example 89 4 - {(IS) -2 ~ [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -3-methoxy-N-methylbenzamide 0 OMe O Me 20

To a solution of (3R) - (3-methyl-piperazin-1-yl) -phenylmethanone (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 25 (250 ml) 1-N-hydroxybenzatriazole monohydrate (20 g) , 0.13 mol), 1-ethyl-3- (31-dimethylaminopropyl) carbodiimide.HCl (17 g, 0.09 mol) and diisopropylethylamine (17 ml, 0.1 mol) added. After stirring for 1 hour, another portion of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide.HCl (17.5 g, 0.09 mol) was added, followed by additional diisopropylethylamine (17 ml, 0.1 mol). After another hour an additional 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide.HCl (17 g, 0.09 mol) was added, followed by a further portion of diisopropylethylamine (17 ml, 0.1 mol). The mixture was then stirred for another 16 hours. After this time, LCMS analysis indicated that all propionic acid had been used up. The reaction mixture was evaporated to give a viscous oil that was treated with water (200 ml) followed by the slow addition of concentrated hydrochloric acid until the pH of the mixture was 3. The result! The resulting off-white precipitate was filtered off and washed with water (3 x 100 ml). The solid became 1-1 twice; ; recrystallized from ethanol: water (1: 1 volume / volume, 120 ml) to give the title compound as a white solid (32 g).

* H NMR (400 MHz, CDCl3): δ: 7.50 - 7.30 (6H, m), 7.27 (1H, 10 m), 6.9 (1H, m) 6.08 (1H, br s), 5.1 (11 H, br s), 4.90 - 2.80 (7 H, m), 3.90 (3 H, br s), 3.00 (3 H, br s), 2.40 ( 3 H, s), 1.70 (3 H, br d), 1.40 - 0.9 (3 H, m) ppm.

LRMS (ESI +): m / z [M + H] + 440 [a] D -26.9 ° (1 mg / ml in MeOH, 25 ° C, wavelength 589 nm) 15

Example 90 5- {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -4-methoxypyridine-2-carboxylic acid methyl ester

VO

XOno OMe O Me

Di-tert-butyl azodicarboxylate (0.14 g, 0.6 mmol) and triphenylphosphine on a polymer support (0.25 g, 0.75 mmol) were added to a stirred solution of (2R) -1-30 [( 2 R) -4-Benzoyl-2-methyl-piperazin-1-yl] -2-hydroxy-propan-1-one (Preparation 76) (0.083 g, 0.3 mmol) and 5-hydroxy-4-methoxy -pyridine-2-carboxylic acid methyl ester (0.083 g, 0.45 mmol) (Tetrahedron Letters, 38, 1297 (1997)) in dichloromethane (3 ml) at 0 ° C. After one hour, the reaction was allowed to 35 warm the mixture to room temperature and additional di-tert-butyl azodicarboxylate (0.14 g, 0.6 mmol) and triphenylphosphine on a polymer support (0.25 g, 0.75 mmol) were added 1026827 β 76. After 18 hours at room temperature, the reaction mixture was filtered through Arbocel®, washed through with dichloromethane (10 ml). The filtrate was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), then the organic phase was separated, dried (MgSO 4) and evaporated under reduced pressure. 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) to give the title compound as a white solid, 0.1 g.

LRMS (APCI + j: m / z [M + H] + 442 Example 91 5 - {(IS) -2 - ((2R) -4-Benzoyl-2-methylpiperazin-1-yl3-1-methyl-2) -oxoethoxy} -4-methoxypyridine-2-carboxylic acid methylamide Mev JL / N. Jl OMe O Me 25 A solution of 5 - {(IS) -2 - [(2R) -4-benzoyl-2-methyl-piperazine -1-yl] -1-methyl-2-oxo-ethoxy} -4-methoxy-pyridine-2-carboxylic acid methyl ester (Example 90) (0.2 g, 0.45 mmol) in a 33% w / w solution of methylamine in ethanol (3 ml) was heated at 50 ° C for 18 hours in a Reactivial ™.

After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: NH 3, 98: 2: 0.5 to 95: 5: 0.5, to give the title compound as a white solid, 0.18 g.

1026827 4 77 * H NMR (400 MHz, CD3 OD): δ: 8.05 (1 H, s), 7.75 (1 H, s), 7.50 - 7.40 (5 H, m), 5.40 ( 1 H, m), 4.60 - 3.00 (8 H, m), 3.95 (3 H, br s), 2.90 (3 H, s), 1.60 - 1.00 (6 H, m) ppm.

Found C, 61.65; H, 6.47; N, 12.41. C23 H23 N4 O5. 0.1 mol of CH 2 Cl 2 requires C, 61.80; H, 6.33; N, 12.48% LRMS (APCI +): m / z [M + H] + 441 [a] D -15.5 ° (1 mg / ml in MeOH, 25 ° C, wavelength 589 nm) Example 92 10 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy) -4-methoxypyridine-2-carboxylic acid amide OMe O Me

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

X H NMR (400 MHz, CD3 OD):: 8.05 (1 H, s), 7.75 (1 H, s), 7.50 - 7.40 (5 H, m), 5.40 (1 H, m) ), 4.60-3.00 (9H, m), 3.95 (3H, br s), 1.60-1.00 (6H, m) ppm.

Found C, 59.67; H, 6.11; N, 12.49. C22 H26 N4 O5. 0.25 mol of CH 2 Cl 2 requires C, 59.78; H, 5.97; N, 12.54% LRMS (APCI +): m / z [M + H] + 427 35 1026 82 7 * *! 78 i

Example 93 5 - {(1 S) -2 - [(2 R) - 4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -4-ntethoxypyridine-2-carboxylic acid / ethylamide • 5 OMe O Me

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

X H NMR (400 MHz, CD3 OD): δ: 8.05 (1 H, s), 7.80 (1 H, s), 7.50 - 7.40 (5 H, m), 5.40 (1 H, m) , 4.60 - 3.00 (8 H, m), 4.00 (3 H, br s), 3.45 (2 H, q), 1.60 - 1.00 (6 H, m), 1.20 (3 H, t) ppm.

Found C, 60.89; H, 6.72; N, 11.93. C24 H30 N4 O5. 0.25 mol of CH 2 Cl 2 requires C, 61.22; H, 6.46; N, 11.78% LRMS (APCI +): m / z [M + H] + 455 30 1026827

* I

79

Example 94 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -4-methoxypyridine-2-carboxylic acid cyclopropylamide 5 Δ S ? ΎΤΧ τ O ίΓΊ VAV u 10 OMe O Me

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

X H NMR (400 MHz, CD 3 OD): δ: 8.05 (1 H, s), 7.70 (1 H, s), 7.50 - 7.40 (5 H, m), 5.40 (1 H, m) , 4.60 - 3.00 (8 H, m), 3.95 (3 H, br s), 2.85 (1 H, m), 1.60 - 1.00 (6 H, m), 0.8 25 (2H, m), 0.6 (2H, m) ppm.

Found C, 63.02; H, 6.63; N, 11.83. C25 H30 N4 O5. 0.13 mole CH 2 Cl 2 requires C, 63.20; H, 6.39; N, 11.73% LRMS (APCI +): m / z [M + H] + 4 67 30 Preparation 1 (2S) -2- (Chinolin-5-yloxy) -propionic acid methyl ester U 8 1026827 I (80

Triphenyl phosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of diisopropyl azodicarboxylate (1.47 ml, 7.56 mmol) in THF (25 ml) at -5 ° C. 5-

Hydroxyquinoline (1.0 g, 6.90 mmol) and methyl (R) lactate (0.66 mL, 6.90 mmol) were then added and allowed to dry; ! stir the solution for 14 hours at room temperature. The reac

I

The 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 silica gel column chromatography eluting with a pentane: ethyl acetate (4: 1) gradient system that changed to pentane: ethyl acetate (3: 2). The title compound was obtained as a white solid (1.30 g).

LRMS (APCI +): m / z [M + H] + 232.

Preparation 2 (2S) -2- (Chinolin-5-yloxy) -propionic acid sodium salt 20 (^ Ίΐ Μβ Μγ Na * o 25 A solution of (S) -2- (quinoline-5-yloxy) propionic acid methyl ester (Preparation 1 (1.30 g, 5.60 mmol) and 1 N sodium hydroxide solution (5.62 mL) in dioxane (40 mL) was heated at 60 ° C for two hours After this time, tlc analysis indicated that starting material remained thus, -x-30 tra 1 N sodium hydroxide solution (1.4 ml) was added and heating was continued for one hour at 60 ° C. The reaction mixture was then concentrated under reduced pressure to give the title compound as a yellow solid. to be used that was used without further purification.

LRMS (ESI +): m / z [M + H] + 218.

1026827 1 * 81

Preparation 3 1 - [(2 R) -4-Benzoyl-2-methylpiperazin-1-yl] -2-bromopropane-1-one; s O Me 10

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

LRMS (ESI +): m / z [M + H] + 340.

1 0 26 82 7

82 I

j

Preparation 4 4-Hydroxy-3-methoxy-N-methylbenzamide V,

With a mechanically stirred suspension of vanillic acid (84 g, 0.5 mol) in dry THF (300 ml) was added carbonyldiimidazole (97 g, 0.6 mol) in portions. Gas evolution was observed and the mixture became homogeneous after about 5 minutes. After further stirring for 30 minutes, an off-white precipitate formed and stirring was continued for another 3 hours under nitrogen. After this time, LCMS analysis indicated the vanillic acid had been used up, and a solution of 2 M methylamine in THF (1000 ml, 2 mol) was added in one portion, and the mixture was stirred for another 16 hours to give a yellow-brown precipitate to shape. The precipitate was filtered, washed with THF (2 x 250 ml) followed by ether (300 ml) and dried under vacuum 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 refluxed in ethyl acetate under a stream of nitrogen for 2 hours. The reaction was evaporated to yield an oily solid, which was crushed with ethyl acetate to give the title compound as a tan solid (750 mg).

LRMS (ESI +): m / z [M + H] + 182.

1026827 * 83

Preparation 5 (2S) -2- (2-Methoxy-4-methylcarbamoylphenoxy) propionic acid o Me 10 To a stirred mixture of triphenylphosphine (42 g, 0.16 mol), 4-hydroxy-3-methoxy-N-methylbenzamide (Preparation 4) (20 g, 0.11 mol) and methyl (R) lactate (12 g, 0.12 mol) in dry THF (300 ml) at -5 ° C became a solution of diisopropyl azodicarboxylate (32 minutes) ml, 0.16 (15 mmol) in dry THF (100 ml) added dropwise. The solution was allowed to warm to room temperature and the solution was stirred for 2 hours. After this time, tlc analysis indicated that the starting phenol had been used up. 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, LCMS analysis indicated that the methyl ester intermediate was used up. The crude reaction mixture was evaporated and partitioned between ether (500 ml) and water (150 ml). The aqueous phase was separated and washed with ether (2 x 300 ml) and ethyl acetate (2 x 300 ml). The aqueous phase was then acidified to pH 2 using concentrated hydrochloric acid, resulting in the formation of a white precipitate. This precipitate was filtered off, washed with water (2 x 100 ml) and recrystallized from ethanol: water (1: 1 by volume, 80 ml per 20 g) to give the title compound as a white solid (21 g, 75%).

35 LRMS (ESI +): m / z [M + H] + 254 1026827 I 0 84

Preparation 6 3- Methoxy-4 - [(IS) -1-methoxycarbonylethoxy] benzoic acid methyl ester ::? H ’hsc '° 10 3

Diisopropyl azodicarboxylate (4 ml, 20 mmol) in tetrahydrofuran (15 ml) was added dropwise to an ice-cooled solution of methyl vanillaate (3.64 g, 20 mmol), methyl (R) lactate (2.08 g, 20 mmol) and triphenyl phosphide (5/24 g, 20 mmol) in tetrahydrofuran (30 ml), and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then 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 filtered off and the filtrate was concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with hex on ethyl acetate, 85:15 to 75:25, gave the title compound in 71% yield, 3.8 g.

LRMS (ES +): m / z [M + H] + 269

Preparation 7 4- [(IS) -1-Carboxyethoxy] -3-methoxybenzoic acid methyl ester

30 O

JQ O

35 H 3 Cl 2 0 26 82 7 * t 85

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

LRMS (ES +): m / z [M + H] + 255 15

Preparation 8 4- {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -3-methoxybenzoic acid methyl ester 1 O ch3

25 HsC

Hunigs 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-methylpiperazin-1-yl) phenylmethanone [( 1.6 g, 7.7 mmol), J. Wed. Chem. 43 (23), 4499; 2000] and 3- (diethoxyphosphoryloxy) -1,2,3-benzotriazine-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 10% sodium carbonate solution (2 x 50 ml) and brine (2 x 50 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 hexane: ethyl acetate, 25:75 to 5:95, gave the title compound in 95% yield, 2.95 g.

LRMS (ES +): m / z [M + H] + 441 5

Preparation 9 4 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl3-1-methyl-2-oxoethoxy} -3-methoxybenzamide JQOCH,

H3C

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

LRMS (ES +): m / z [M + H] + 426 25 1026827 87

Preparation 10 4 - {(IS) -2 - [(2 R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxoethoxy) -N-dimethylaminomethylene-3-yl; methoxybenzamide: "*! s

t, I

h3C ^ / CH3 ΐΛα ^ οχι λ o ch3

Hf '

The compound of Preparation 9 (240 mg, 0.56 mmol) and N, N-15 dimethylformamide dimethyl acetal (10 ml) were heated under reflux for 7 hours. The reaction mixture was then 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 give a colorless oil. The oil was then subjected to azeotropic distillation with dichloromethane and the resulting foam was dried at 40 ° C for 3 hours to give the title compound in 94% yield, 255 mg.

LRMS (ES +): m / z [M + Na] + 503 Preparations 11 to 13 The following compounds, having the general formula shown below, were prepared in the manner described above for Preparation 10 using the appropriate ketone and dimethylformamide dimethyl acetal.

1026827 88

Rb ifV0 ^ 0 y YCH ’10 ^ muma -, ______ LRMS (ES4 !: m / z [Μ + ΗΓ_ 11 CHa η 220 15 12 Η H 206 13 H OCH2-Ph 312 20 ----

In preparation 11, 1- (3-methoxy-2-methylphenyl) ethanone is prepared as described in Tetrahedron 25 (18), 4249; 1969 used.

Preparation 14 3- (3-Methoxy-2-methylphenyl) -1-methyl-1H-pyrazole 30 δ

/ N-J

H, C

35

The compound of Preparation 11 (2.05 g, 9.35 µrnol) was added portionwise to a solution of methyl hydrazine 1026827 89 (547 μΐ, 10.28 mmol) in acetic acid (15 ml) and the mixture was 2.5 hours heated at 90 ° C. The solvent was then evaporated under reduced pressure and the residue was dissolved in dichloromethane and washed with 10% sodium carbonate solution and saturated sodium hydrogen carbonate 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® flash silica column eluting with dichloromethane: ethyl acetate, 99: 1 to 97: 3, to yield the title compound as a yellow oil with 31% yield, 568 mg.

LRMS (ES +): m / z [M + H] + 203

Preparations 15 to 16 The following compounds, of the general formula shown below, were prepared in the manner described above for Preparation 14 using the appropriate enamine and hydrazine monohydrate.

1026827 90

Rb

; ; 5 VV

N = ^ 2 nmer Ra _R ^ __ LRMS (ES *): (Tl / z fM + H] * _ 15 Η H 175 ~ 16 H OCH2 Ph 281 15 ___L__

Preparation 17 2-Methyl-3- (1-methyl-1H-pyrazol-3-yl) phenol CC, 25 h3c

Boron tribromide {1 M in 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 ml). The resulting solution was allowed to warm to room temperature and the solution was stirred for 2 hours. The reaction mixture was then carefully poured onto ice and neutralized with 10% sodium carbonate solution. The mixture was extracted with dichloromethane (2 x 50 ml) and the combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed using an Isolute® flash silica column eluting with dichloromethane: methanol, 98: 2 to 97: 3, to yield a brown oil. The oil was subjected to azeotropic distillation with dichloromethane to give the title compound as a brown foam with a 61% yield, 310 mg.

LRMS (ES +): m / z [M + H] * 189 10

Preparations 18 to 20

The following compounds, with the general formula shown below, were prepared in the manner described above. Preparation 17 has been described using the appropriate methoxybenzene derivative and boron tribromide.

__ Rc __ nunner Ra I Rc I LRMS (ES *): m / z ΓΜ + ΗΓ 1 18 CH3 j? 152 25____ 19 CH3 J1 175 __ \ lz___ 20 H n 161

30 l \ j ~~ l_I

Preparation: 18: title compound is prepared by dealkylation of 3-methoxy-2-methylbenzaiiu.de (J. Chem. 35 Soc. Perkin Trans. 1, 2389-2396; 1984) 1 0 26 82 7 • * 92

Preparation 21 (2S) -2- [3- (2H-Pyrazol-3-yl) phenoxy] propionic acid methyl ester CH 3

[f ^ 0 10 CHS

O 0 10 Ht 7 N = /

Diisopropyl azodicarboxylate (295 μΐ, 1.50 iranol) was added dropwise to an ice-cooled solution of the compound of Preparation 20 (240 mg, 1.5 mmol), methyl (R) lactate (156 mg, 1.50 mmol) and triphenylphosphine (393 mg, 1.5 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature for 18 hours and was then diluted with diethyl ether (50 ml) and washed with water.

The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified on an Isolute® flash silica column eluting with diethyl ether: dichloromethane, 80:20 to 95: 5, to give the title compound as a viscous yellow oil in 54% yield, 200 mg.

LRMS (ES-): m / z [M-H] 245

Preparation 22 (2S) -2- [2-Methyl-3- (2H-pyrazol-3-yl) phenoxy] propionic acid methyl ester 30 CH 3 CL O CH 3

35 X

HN ^ N = / 1026827 *> 93

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

LRMS (ES '): m / z [M-H] 239

Preparation 23 (2 S) -2- [3- (2 H-Pyrazol-3-yl) phenoxy] propionic acid 10 ch3

irv ° V

u ° 15 Hfw N—— '

Lithium hydroxide monohydrate (80.9 mg, 1.93 mmol) was added in portions to a solution of the compound of Preparation 21 (19 mg, 0.77 mmol) in methanol (6 mL) and the mixture was kept for 8 hours stirred at 60 ° C. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was acidified with 2 M hydrochloric acid to pH 4 and then extracted with ethyl acetate (3 x 30 ml).

The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting foam was dried under reduced pressure to give the title compound in 75% yield, 135 mg.

LRMS (ES "): m / z [M-H] 231 1026827 • 94

Preparation 24 (2S) -2- [2-Methyl-3- (2 H -pyrazol-3-yl) phenoxy] propionic acid 9 H 3 ii) 5; ! (TV Π LX 0 J CH,

Hn '^) 10 \ / N == /

The title compound was prepared according to the method described above for Preparation 22 using the compound of Preparation 22 and lithium-15 hydroxide.

LRMS (ES-): m / z [M-H] 245

Preparation 25 1- [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2-bromopropane-20 1-one och9 2- Bromopropionic acid (1.53 g, 10 mmol) was added to a solution of Ν, Ν'-dicyclohexylcarbodiimide (2.06 g, 10 mmol) in dichloromethane (40 ml), cooled to -15 ° C.

The reaction mixture was stirred for 20 minutes before (2 R) - (3-methyl-piperazin-1-yl) phenylmethanone [(2.04 g, 10 mmol), J. Med. Chem. 43 (23), 4499; 2000] in dichloromethane (16 ml) was added dropwise. The reaction mixture was stirred for 90 minutes at -15 ° C and was then diluted with diethyl ether (100 ml) and stirred for another 10 minutes. The mixture was then filtered through Celite, washed through 1026827 * 95 with diethyl ether and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with hexane: ethyl acetate, 40:60 to 20:80, to give the title compound in 76% yield, 2.5 g.

LRMS (ES +): m / z [M + H] + 340

Preparation 26 3- {2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-10 oxoethoxy} -2-methylbenzamide O CHg O CHg

The compounds of Preparation 18 (180 mg, 1.19 mmol) and Preparation 25 (403.9 mg, 1.19 mmol) and cesium carbonate (387 mg, 1.19 mmol) in N, N-dimethylformamide (10 mL) were heated at 80 ° 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 (10 ml). The organic phase was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash silica column, eluting with dichloromethane: methanol, 99: 1 to 96: 4, to give a colorless foam. The foam was subjected to azeotropic distillation with dichloromethane and dried under reduced pressure to give the title compound in 98% yield, 475 mg.

LRMS (ES +): m / z [M + H] + 410 1 026 82 7 96

Preparation 27 1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (3-methoxy-5-nitrophenoxy) propane-1-one • H ° X ^ 10 o ch 3

The title compound was prepared according to the method described above for Preparation 26 using the compound of Preparation 25 and 2-15 methoxy-5-nitrophenol.

LRMS (APCI +): m / z [M + H] + 428

Preparation 28 3- {2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-20 oxoethoxy} -N- (dimethylamino) methylene} -2-methylbenzamide Λχνχ / ο ö CH 3 O CH 3

The title compound was prepared according to the method described above for Preparation 10 using the compound of Preparation 26 and N, N-dimethylformamide dimethyl acetal.

LRMS (APCI +): m / z [M + H] + 4 65 1026827 • # 97

Preparation 29 3- {2- [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -1-methyl-2-oxo-ethoxy} -N-hydroxyaminomethylene-2-methylbenzamide /:: O CH3 o CHg 10

Sodium hydroxide solution (1 M, 1.06 ml, 1.06 in mol) was added dropwise to a suspension of hydroxylamine hydrochloride (73.6 mg, 1.06 mmol) in acetic acid (6 ml). The compound of Preparation 28 (410 mg, 0.88 mmol) was then 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 10% sodium carbonate solution. The organic phase was separated and the aqueous phase was re-extracted with dichloromethane (30 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified on an Isolute® flash-silica column eluting with dichloromethane imethanol, 99: 1 to 96: 4, to give the title compound as a colorless foam in 78% yield, 310 mg.

LRMS (ES-): m / z [M-H] +451 30 1026827 98

Preparation 30 2- (4-Amino-2-methoxyphenoxy) -1 - [(2R) -4-benzoyl-2-methylpyperazin-1-yl] propan-1-one och 3 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 heated at 70 ° C for 2 hours. The mixture was then cooled and filtered through Arbocel®, washed through with ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane imethanol (95: 5) to give the title compound as a pale pink solid with 80% yield, 443 mg.

LRMS (APCI +): m / z (M + H] + 398 25

Preparation 31 4-Benzyloxy-3-methoxybenzamidine 30 Π

rY

35 1 I

NH 2 CHg 1026827 ≤ 99 "Butyllithium (1.6 M in hexane, 35.9 ml, 57.47 iranol) was added dropwise to a solution of hexamethyldisilazane (11.64 ml, 55.17 mmol) in diethyl ether ( 60 ml), cooled to -5 ° C, and the reaction mixture was stirred for 30 minutes at a constant temperature of 0 ° C. 3-Methoxy-4- (phenylmethoxy) benzonitrile (5.5 g, 22.99 mmol) ) was added in portions and the mixture was stirred at room temperature for 4 hours The reaction mixture was then poured onto ice-cold 2 M hydrochloric acid (100 ml) and washed with diethyl ether (2 x 100 ml) The aqueous phase was basified to pH 10 with 6 M sodium hydroxide solution and was extracted with dichloromethane (3 x 100 ml) The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid with 68% yield , 3.99 g.

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

Preparation 32 2- (4-Benzyloxy-3-methoxyphenyl) -1H-imidazole

P

The compound of Preparation 31 (1 g, 3.90 mmol) in chloroform (40 ml) was added to a solution of chloroacetaldehyde (336 mg, 3.90 mmol) in chloroform (10 ml) and the mixture was stirred at room temperature for 18 hours The resulting white precipitate was filtered off and the filtrate was washed with saturated sodium hydrogen carbonate solution (30 ml) The aqueous phase was re-extracted with 10% methanol in dichloromethane (2 1028827 *) > 100 x 50 ml) and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuo.

The residue was purified on an Isolute® flash. silica column eluting with dichloromethane 1 * 15 thane: methanol, 98: 2 to 96: 4, to give up a brown foam; ' to deliver. The foam was further purified on an Isolute® flash silica column, eluting with dichloromethane: methanol, 99.5: 0.5 to 98: 2, to yield a beige foam. The foam was subjected to azeotropic distillation with dichloromethane at 40 ° C to give the title compound in 16% yield, 180 mg.

LRMS (ES +): m / z [M + H] + 281

Preparation 33 4- (1H-Imidazol-2-yl) -2-methoxyphenol

To a solution of the compound of Preparation 32 (170 mg, 0.61 mmol) in methanol (10 mL) was added 10% Pd / C (85 mg) and ammonium formate (191 mg, 3.03 mmol) in portions. The mixture was heated under reflux for 2 hours. The reaction mixture was then cooled and filtered through Arbocel®, washed through 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, to give the title compound as a white solid with 91% yield, 105 mg. LRMS (ES +): m / z [M + H] + 191 35 102682 7 101

Preparation 34 2-Methoxy-4- (2 H -pyrazol-3-yl) phenol

. ", * H \\ T

: "\ ch3

The title compound was prepared according to the method 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-methoxybenzene 20 ^ h3c

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 for 4 hours under 25 refluxes. The cooled reaction mixture was then evaporated under reduced pressure and the residue was partitioned between diethyl ether (200 ml) and water (80 ml). The aqueous phase was separated and re-extracted with diethyl ether (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to azeotropic distillation with dichloromethane to give the title compound as a white solid in 100% yield, 7.19 9-35 LRMS (ES +): m / z [M + Na] + 317 L 0 26 82 7 • · 102

Preparation 36 1- (4-Benzyloxy-3-methoxyphenyl) -1H-pyrazole

H, C

A mixture of the compound of Preparation 35 (1.5 g, 5.12 inmol), pyrazole (697 mg, 10.23 mmol), copper (I) iodide (195 mg,: 1.02 mmol) and potassium carbonate in N, N-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 re-extracted with diethyl ether (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane / methanol 100: 0 to 96: 4 to give the title compound as a white solid with 82% yield, 1.18 g.

LRMS (ES +): m / z [M + H] + 281 25

Preparation 37 2- Methoxy-4-pyrazol-1-yl-phenol

30 ^ / N - ^ - ° H

O

/ h3c 35 The title compound was prepared according to the method described above for Preparation 33 using the compound of Preparation 36.

LRMS (ES +): m / z [M + H] + 191 Preparation 38 '(2S) -2- (Chinolin-5-yloxy) propionic acid methyl ester: CH 2 R 11 °

O

10

Triphenyl phosphine (2.17 g, 8.27 mmol) was added to a stirred suspension of diisopropylazodicarboxylate (1.47 ml, 7.56 mmol) in tetrahydrofuran (25 ml) at -5 ° C.

5-Hydroxyquinoline (1.0 g, 6.90 mmol) and methyl (R) -15 lactate (0.66 mL, 6.90 mmol) were added and the solution was allowed to stir for 14 hours at room temperature. The reaction mixture was then 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, to give the title compound as a white solid with 81% yield, 1.30 g.

LRMS (ES +): m / z [M + H] + 232

Preparation 39 (2S) -2- (Isoquinoline-5-yloxy) propionic acid methyl ester CH

O

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

LRMS (APCI +): m / z [M + H] + 232 Preparation 40 (2S) -2- (Chinolin-5-yloxy) propionic acid sodium salt 11 CHa 10 II n ° 'Na' o

A solution of the compound of Preparation 38 (1.30 g, 5.60 iranol) and 1 M sodium hydroxide solution (5.62 ml) in 1,4-dioxane (40 ml) was heated at 60 ° C for 2 hours. After this time, tlc analysis indicated that starting material remained, so additional 1 M sodium hydroxide solution (1.4 ml) was added and heating was continued at 60 ° C for one hour. The reaction mixture was then concentrated in a vacuum to give the title compound as a yellow solid in quantitative yield. LRMS (ES +): m / z [M + H] + 218 Preparation 41 (2S) -2- (Isoquinoline-5-yloxy) propionic acid sodium salt CH3

Na + 30 I II °

O

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

LRMS (APCI +): m / z [M + H] + 218 1026827 -.

105

Preparation 42 (2S) -1- [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl] -2- (quinolin-5-yloxy) propan-1-one 5VoArV u O CH 3 10

A solution of the compound of Preparation 40 (1.0 g, 4.6 mmole), (3 R) - (3-methyl-piperazin-1-yl) -phenylmethanone [(0.94 g, 4.6 mmol) J Med Chem., 43 (23), 4499; 2000], O- (ΙΗ-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium-hexa-fluorophosphate (2.62 g, 6.9 mmol) and triethylamine (1.93 mL, 13.8 mmol) in N, N-dimethylformamide (30 ml) was stirred for 14 hours at room temperature. The reaction mixture was then diluted with dichloromethane (100 ml), washed with water (3 x 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) to give the title compound as a white solid with 49% yield, 0.91 g.

LRMS (ES +): m / z [M + H] + 404

Preparation 43 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl} -2- (isoquinoline-5-yloxy) propane-1-one 30 N-10 CH, 1026827 106

The title compound was prepared according to the method described above for Preparation 42 using the compound of Preparation 41 and {3R) - (3 -, methyl-piperazin-1-yl) phenylmethanone (J. Med. Chem. .

'', 5 43 (23), 4499; 2000).

,! LRMS (APCI +): m / z [M + H] + 404

Preparation 44 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (8-10 bromoquinoline-5-yloxy) propane-1-one

Xi ^ c / u 0 oh3

A mixture of the compound of Preparation 42 (450 mg, 1.1 mmol) and N-bromosuccinimide (795 mg, 4.4 mmol) in ace-20 tonitrile (90 ml) was stirred for 2 hours at room temperature. The solvent was then evaporated under reduced pressure and the residue was dissolved in ethyl acetate (50 ml) and washed with water (2 x 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 ipentane, 33:67 to 100: 0, to give the title compound as a white solid in 98% yield, 526 mg. LRMS (ES +): m / z [M + H] + 482/484 30 1026827 107

Preparation 45 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- {8- [2- (2-trimethylsilanylethoxymethyl) -2H-pyrazol-3-yl] quino- i-line-5-yloxy} propane-1-one: s i 1; 1 H3 ^ n ^ n ^ o II f rv in fSr-vv h O ch 3 Tetrakis (triphenylphosphine) palladium (O) (6 mg, cat), 1 - [[(2- (trimethylsilyl) ethoxy) methyl] pyrazolyl-5 -boronic acid [(50 mg, 0.1 mmol), J. Med. Chem. 41, 2019-2028; 1998] and sodium carbonate (175 mg, 1.6 mmol) in water (0.5 ml) were added to the compound of Preparation 44 (50 mg, 0.1 20 mmol) in tetrahydrofuran (2 ml), and the mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated under reduced pressure and the residue 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, to give the title compound as a yellow solid.

LRMS (APCI +): m / z [M + H] + 600 yy y! 1026827 5 108 * »

Preparation 46 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (1-oxy-quinolin-5-yloxy) -propan-1-one oo ch3 meta-chloroperbenzoic acid (1.54 g, 4.44 in mol) 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 was Stirred at room temperature for 3 hours. The reaction mixture was then diluted with dichloromethane (10 ml) and washed with saturated aqueous potassium carbonate solution (10 ml) and water (2 x 10 ml). The organic layer was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid in quantitative yield, 1.8 g.

LRMS (APCI +): m / z [M + H] + 420 Preparation 47 5- (2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxo-ethoxy } quinoline-2-carboxylic acid methyl ester

O

·· 3 / CH 0

Jo h3c 35 3

The chlorine compound of Preparation 66 (130 mg, 0.3 mmol), dichlorobis (triphenylphosphine) palladium (24 mg, 0.03 mmol) .1026827 •> 109 and triethylamine (83 μΐ, 0.6 παηοΐ) were dissolved in a mixture of methanol (3 ml) and N, N-dimethylformamide (0.5 ml) and transferred to a sealed vessel. The vessel was heated to 100 ° C and the mixture was stirred under 100 psi of carbon monoxide gas for 42 hours. The reaction mixture was then filtered through Arbocel®, washed with ethanol 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, gave the title compound in 41% yield, 50 mg.

LRMS (APCI +): m / z [M + H] + 4 62 Preparation 48 15 5 - {2 - (2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} quinoline-2-carboxylic acid r5W / ° CH3

OH

25 1 M Sodium hydroxide solution (130 μΐ, 0.135 mmol) was added to a solution of the compound of Preparation 47 (40 mg, 0.09 mmol) in dioxane (3 mL) and the mixture was heated at 60 ° C for 3 hours. The solvent was then 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 removed. The aqueous phase was acidified with glacial acetic acid and re-extracted with ethyl acetate. The retained organic phase (second wash) was dried over magnesium sulfate and concentrated in vacuo to give the title compound of 1026827 r.101 as a pale yellow solid with 67% yield, 26 mg.

LRMS (APCI +): m / z [M + H] + 448 / · "i" 1 "! Preparation 49 i; (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl) -2- (2-benzylaminoquinoline-5-yloxy) propane-1-one 10] ch3 15 l

20 cS

A mixture of the compound of Example 60 (50 mg, 0.11 in mol), tetrabutylammonium fluoride (30 mg, 0.22 mmol), triethylamine (0.16 ml, 1.1 mmol) and benzylamine (0.13 ml, 25 1.1 mmol) in dimethyl sulfoxide (1 mL) was heated at 120 ° C for 72 hours. The reaction mixture was then immediately 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 to title compound with 34% yield.

LRMS (APCI +): m / z [M + H] + 509 1026827 1 111

Preparation 50 (3R) -3-Methyl-4 - [(2S) -2- (quinolin-5-yloxy) propionyl] -piperazine-1-carboxylic acid tert-butyl ester ^ 1 Λ 10 O CH 3 1-Hydroxybenzotriazole hydrate (249 mg, 1.87 mmol) was added to a suspension of the compound of Preparation 40 (400 mg, 1.7 mmol) in Ν, Ν-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. The solvent was then evaporated under reduced pressure and the residue was dissolved in ethyl acetate (30 ml) and washed with water (20 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give the title compound in 48% yield, 332 mg.

LRMS (APCI +): m / z [M + H] + 400

Preparation 51 (2S) -1 - [(2R) -2-Methylpiperazin-1-yl] -2- (quinoline-5-30 yloxy) propane-1-one hydrochloride fr "

RVV

O CHa 1 h 6 82 7 112

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

1 ι! LRMS (APCI +): m / z [M + H] + 300

Preparation 52 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (2.8-10 dichloroquinoline-5-yloxy) propane-1-one o ch 3

A mixture of the compound of Example 60 (200 mg, 20.0, 4 mmol) and N-chlorosuccinimide (61 mg, 0.4 mmol) in acetonitrile (10 ml) was heated at 40 ° C for 48 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in dichloromethane (20 ml) and washed with water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (98: 2) to give the title compound as a white solid in 78 30% yield, 169 mg.

LRMS (APCI +): m / z [M + H] + 472 1026827 113 * »

Preparation 53 (2S) -1 - [(2R) -2-Methyl-4- (pyridin-2-carbonyl) piperazin-1-yl] -2- (quinolin-5-yloxy) propane-1-one 1 ' titi 5 o

: A r OrA

O CHa 10

A mixture of the compound of Preparation 51 (150 mg, 0.5 mmole), picolinic acid (49 mg, 0.6 mmol), 0- (1H-benzo-triazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (190 mg, 0.75 mmol) and triethylamine (0.93 mL, 10 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours. The reaction mixture was then diluted with more dichloromethane and washed with sodium hydroxide (10 ml) and water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. 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 in 49% yield, 99 mg.

LRMS (APCI +): m / z [M + H] + 405 25

Preparation 54 (2S) -1- [4- (2-Fluorobenzoyl) - (2R) -2-methylpiperazin-1-yl] -2- (quinolin-5-yloxy) propan-1-one

A £ o \ S

rVAV u o ch3 35

A mixture of the compound of Preparation 51 (150 mg, 0.5 mmol), 2-fluorobenzoyl chloride and triethylamine in dichloromethane (3 ml) in 1026827 114 was stirred for 18 hours at room temperature. The reaction mixture was then diluted with dichloromethane and washed with water (2 x 10 ml). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2) gave the title compound as a white solid in 73% yield, 153 mg.

LRMS (APCI +): m / z [M + H) + 422

Preparation 55 4-Bromo-2-trifluoromethoxyphenol A%

Br 20 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) in acetic acid (5 mL) and the solution was stirred for 1 hour. The reaction mixture was then diluted with water (30 ml) and extracted with ethyl acetate (2 x 50 ml). The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to give a colorless oil. The oil was purified by column chromatography on silica gel, eluting with pentane: ethyl acetate (85:15) to give the title compound as a white solid in 23% yield.

LRMS (APCI +): m / z [M + H] + 255/257 1026827 115

Preparation 56 (2S) -2- (4-Bromo-2-trifluoromethoxyphenoxy) propionic acid methyl ester

5 ΗΛ O CHS

O

Diisopropyl azodicarboxylate (414 μΐ, 2.14 mmol) was added dropwise to an ice-cooled solution of the compound of Preparation 55 (500 mg, 1.95 mmol), methyl (R) 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 10% potassium carbonate solution (2 x 10 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol (95: 5) to give the title compound as a colorless oil in 76% yield, 638 mg.

LRMS (APCI +): m / z [M + H] + 305/307 1026827 116 * »

Preparation 57

(2 S) -2- (4-Bromo-2-trifluoromethoxyphenoxy) propionic acid; Hsc OH

: 5 aK

Br - A j) - O O

10 F

A mixture of the compound of Preparation 56 (574 mg, 1.67 mmol) and 1 M sodium hydroxide solution (4.2 ml, 4.2 mmol) in dioxane (10 ml) was stirred at 55 ° C for 3 hours. The solvent was then evaporated under reduced pressure and the residue was dissolved in water (30 ml). The aqueous solution was acidified with 2 M hydrochloric acid to pH 2 and extracted with ethyl acetate (2 x 50 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 25 (2S) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (4-bromo-2) -trifluoromethoxyphenoxy) propan-1-one - TiwA5 VO O CH 3 A solution of the compound of Preparation 57 (150 mg, 0.46 mmol), (3R) - (3-methylpiperazin-1-yl) phenylmethanone ((93 mg, 0.46 mmol) J. Med Chem., 43 (23), 4499; 2000], O-10 6827 117 (benz-benzotriazol-1-yl) -Ν, Ν, Ν ', N' tetramethyluronium hexafluorophosphate (260 mg, 0.69 in mol) and triethylamine (0.13 ml, 0.92 mmol) in dichloromethane (30 ml) were stirred at room temperature for 18 hours. dichloromethane (50 ml) and washed with water (50 ml) The aqueous phase was re-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® 10 flash silica column, eluting with dichloromethane: methanol (99: 1) to remove the compound from t itel as a white foam with a 90% yield, 213 mg. LRMS (APCI +): m / z [M + H] + 537/539 Preparation 59 4 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl -2-oxoethoxy} -3-trifluoromethoxybenzoic acid methyl ester 20 fv ° ° * H *

The compound of Preparation 58 (190 mg, 0.37 mmol), dichlorobis (triphenylphosphine) palladium (30 mg, 0.04 mmol) and triethylamine (0.10 mL, 0.74 mmol) were dissolved in methanol (10 mL ) and transferred to a sealed container. The vessel was heated to 100 ° C and the mixture was stirred under 100 psi of carbon monoxide gas for 42 hours. The reaction mixture was then filtered through Arbocel®, washed with ethanol and the filtrate was concentrated in vacuo. The residue was purified on an Isolute® flash column 1026827 118 eluting with dichloromethane: methanol (97: 3) to give the title compound as an orange solid in 85% yield, 155 mg.

5 LRMS (APCI +): m / z [M + H] + 495 Preparations 60 to 61

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

O ch3 ram R5 LRMS (APC1 +): m / z fM + H? 60 t 404 25 OCj __N __ 61 t 404 nL Jn. Λ * 30 ___

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

1 0 26 82 7 • t 119

O

f 0V1; : O CH3 nunner IR5 LRMS (APCI +): m / z ΓΜ + ΗΓ 62 420

ίο T

___o___ 15 63 420 -O> also 20 --—--

Preparation 64 (2 S) -1 - [(2 R) -4-Benzoyl-2-methylpiperazin-1-yl] 2- (1-oxy-isoquinoline-5-yloxy) propan-1-one onςχ) / vX, 0 C »3 30 / τη

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

LRMS (APCI +): m / z [M + H] + 420 10 2 6 8 2 7 120

Preparation 65 (2S) -1 - [(2R-4-Benzoyl-2-methylpiperazin-1-yl] -2- (1-chloroisoquinolin-5-yloxy) propane-1-one A 0 ch3 10 11 Ί

Cl

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 stirred for 2 hours at 100 ° C heated. The mixture was then cooled to room temperature and poured into water (75 ml). The resulting aqueous mixture was made basic with concentrated ammonia solution and extracted with dichloromethane (2 x 75 ml). The combined organic extracts were then dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol (99: 1), gave the title compound as a white foam with a 40% yield, 127 mg.

LRMS (APCI +): m / z [M + H] + 438 102682 7 121

Preparation 66 1- ((2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (2-chloro-quinoline-5-yloxy) propan-1-one rVA3 O CHg 10 cm

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

LRMS (APCI +): m / z [M + H] + 438

Preparation 67 2- Methoxy-4-methylsulfanylphenol 20

25 HsC

4-methyl lithium (1.7 M in pentane, 14.5 ml, 24.6 mmol) was added dropwise to a solution of 4-bromo-2-methoxyphenol (2.00 g, 9.85 mmol) in tetrahydrofuran (25 ml ), cooled to -78 ° C. The mixture was stirred for 15 minutes and then heated to -40 ° C and stirred for another 30 minutes. Dimethyldisulfide (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 with 2 M hydrochloric acid to pH 1. The aqueous phase was separated and re-extracted with ethyl acetate. The combined organic fractions were then dried over magnesium sulfite

J

122 and concentrated in vacuo to give an orange oil. This oil was purified by column chromatography on silica gel, eluting with pentane diethyl ether, 95: 5 to 80:20, to remove the compound from the compound. 5 to provide a title as a white solid with 48% yield; yield, 800 mg.

1 HNMR (CDCl 3, 400 MHz) δ: 2.40 (s, 3H), 3.90 (s, 3H), 5.50 (brs, 1H), 6.80 - 6/90 (m, 3H) 10 Preparation 68 6-Hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one γύύοη ΗΝγϋ ^ ΑΟΜθ 15 q

A mixture of lithium iodide (0.32 g, 2.41 mmol) and 6,7-dimethoxy-3,4-dihydro-2H-isoquinoline-1-one (0.5 g, 2.41 mmol) in 2.4 6-collidine (10 ml) was heated at 130 ° C for 18 hours. The solvent was then evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (96: 4) to give the title compound as a pale yellow solid, 0.19 g .

LRMS (APCI +): m / z [M + H] + 194

Preparation 69

Acetic acid 3-acetoxy-5-methylphenyl ester

O

30 X

Q CHa

a

Hs <1026827 123

Acetic anhydride (22.6 ml, 0.24 mol) was added to an ice-cooled solution of 3,5-dihydroxy toluene (9.93 g, 0.08 mol) and triethylamine (56 ml, 0.40 mol) in <· ' dichloromethane (86 ml). The reaction mixture was

I i I

; It was heated at 5 m temperature and stirred for 60 hours. Water (100 ml) was then added and the mixture was stirred vigorously for 3 hours. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane (3 x 80 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) to give the title compound as a colorless oil with 94% yield, 15.7 g.

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

Preparation 70 1- (2,6-Dihydroxy-4-methylphenyl) ethanone 25

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) , heated to 90 at 30 ° C, and the mixture was stirred for one hour. The reaction mixture was then cooled and carefully pipetted onto a mixture of ice and 2 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 200 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 1026827 t, 124 (84:16, 80:20, 75:25) to give the title compound as a yellow solid with 66% yield , 5.31 g · LRMS (APCI +): m / z [M + H] + 167 5

Preparation 71 3,6-Dimethyl-1H-indazole-4-ol-H CH,

10 RV

X I / N

A solution of the compound of Preparation 70 (4.15 g, 15 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. The cooled reaction mixture was then poured into water and acidified with acetic acid to pH 6. The aqueous mixture was extracted with ethyl acetate (4 x 200 ml) and the combined extracts were washed with 5% sodium sulfite (200 ml) and brine (200 ml) ). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with ethyl acetate: pentane (50:50), gave the title compound in 95% yield, 3.84 g.

LRMS (APCI +): m / z [M + H] + 163 30 1 0 2682 7 125 •.

Preparation 72 4- (tert-Butyldimethylsilanyloxy) -3,6-dimethyl-1H-indazole Λμ CHa

5 PV

5 H, c-Si - (- CH, Η> (γγ0 chs tVch · 10 ÏT "tert-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 N, N-dimethylformamide and the reaction mixture was stirred at 0 ° C for 1 hour and at room temperature for 18 hours Extra tert-butyldimethylchlorosilane (511 mg, 3, 39 mmol) was added and the reaction mixture was heated at 80 ° C for 48 hours The solvent was then evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water The organic phase was separated, washed with brine (2 x 10 ml) ), dried with magnesium sulfate and concentrated in vacuo The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (15:85) to give the title compound as an orange oil with 23% yield .

LRMS (APCI +): m / z [M + H] 4 27 7 102682? "> 126

Preparation 73 4- (tert-Butyldimethylsilanyloxy) -3,6-dimethyl-indazole-1-carboxylic acid tert-butyl ester. 5 fH3 CH3; : H3C - CH3

Vy ~

N-N

A 0 15 Di-tert-butyl dicarbonate (503 mg, 2.3 mmole) and 4-dimethylaminopyridine (51 mg, 0.4 mmol) were added to the compound of Preparation 72 (580 mg, 2 mmol) in dichloromethane (5 ml ), and the reaction mixture was stirred for 18 hours. Water was then added to the reaction mixture and the aqueous mixture was extracted with dichloromethane (3 x 10 ml). 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 pentane: ethyl acetate (95: 5) gave the title compound as a colorless oil in 66% yield, 527 mg. LRMS (APCI +): m / z [M + H] + 377 1026827 127

Preparation 74 4-Hydroxy-3,6-dimethylindazole-1-carboxylic acid tert-butyl ester

5 H 3 C ^ n ^^ / 0H

N-n HSC- / Ύ 10 β6Λ o H3 ° CH3

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

LRMS (APCI '): m / z [M-H] 261 1026827> 128

Preparation 75 (2R) -1 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2-benzyl-oxypropan-1-one; ·.

6-Hydroxybenzotriazole hydrate (825 mg, 5.3 mmol), N-methyl morpholine (808 μΐ, 7.3 mmol), 1- (3-dimethylamino-15-propyl) -3- ethylcarbodiimide hydrochloride (1.13 g, 5.8 mmol) and (3R) - (3-methyl-piperazin-1-yl) phenylmethanone [(1.0 g, 4.9 mmol), J. Med. Chem. 43 (23), 4499; 2000] were added to a solution of (R) - (+) -2-benzyloxypropionic acid (972 mg, 5.3 mmol) in dichloromethane (10 ml), and the mixture was stirred for 18 hours Extra (R) - (+) - 2-benzyloxypropionic acid (486 mg, 2.65 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.65 mg, 2.9 mmol), 1- hydroxybenzotriazole hydrate (413 mg, 2.65 mmol) and N-methyl morpholine (808 μΐ, 7.3 mmol) were added and the mixture was heated under reflux for 3 hours. Water was then added to the reaction mixture and the aqueous The solution was extracted with dichloromethane (2 x 10 ml.) The combined organic extracts were washed with 2 M hydrochloric acid, 1 M sodium hydroxide solution and br The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluting with pentane-ethyl acetate (50:50) followed by ethyl acetate: methanol (90:10) gave the title compound as a white foam with 81% yield, 1.45 g.

LRMS (APCI "): m / z [Μ-ΗΓ 367 1026827>.

129

Preparation 76 (2R) -1 - [(2R) -4-Benzoyl-2-methyl-piperazin-1-yl) -2-hydroxy-propan-1-one: s (.

Pd (OH) 2 (30 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. Tlc analysis then indicated that the reaction was not complete, so additional Pd (OH) 2 (300 mg, 2.2 mmol) was added, followed by ammonium formate (1.37 g, 22 mmol) that was added at intervals of 45 minutes until all starting material was used up. The reaction mixture was then cooled and filtered through Arbocel®, washed through with ethanol (10 ml). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane methanol (95: 5) to give the title compound as a white gum with 91% yield, 1 g .

LRMS (APCI +): m / z [M + H] + 277 1026827 * * 130

Preparation 77 4 - [(1 S) -2 - [(2 R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy] -3,6-dimethyl-indazole-1-carboxylic acid - tert-butyl ester 5 ^ n-VI H ^ y ^ YY ^ N - ^ O CH 3 ch 3

The compound of Preparation 76 (70 mg, 0.25 inmol), di-tert-butylazodicarboxylate (233 mg, 1.01 mmol) and triphenylphosphine on a polymer 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), and the reaction mixture was stirred at 0 ° C for 30 minutes and at room temperature for 18 hours. The reaction mixture was then filtered through a filter tube, washed through with dichloromethane. The filtrate was washed with 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, gave the title compound in 34% yield, 45 mg.

LRMS (APCI +): m / z [M + H] + 521

Biological Data 30

The ability of the compounds of formula (I) and their pharmaceutically acceptable salts, solvates and derivatives to modulate the action of gpl20, in particular to inhibit the interaction of gpl20 with CD4, is demonstrated using a gpl60-induced cell cell fusion assay to determine the IC 50 values of compounds against HIV-1 fusion. The gp160-induced cell cell fusion assay uses a HeLa P4 cell line and a CHO-Tat10 cell line.

The HeLa P4 cell line expresses CCR5 and CD4 and this cell line is transfected with HIV-1 LTR-β-5 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 puromy-10 cine.

The CHO cell line is a Tat (transcriptional trans-activator) -expressive clone of a CHO JRR17.1 cell line transfected with pTat puroplasmide. The medium for this cell line is rich medium for mammalian cell culture originally developed at Roswell Park Memorial Institute RPMI1640 (without L-glutamine) containing 10% FCS, 2 mM L-glutamine, 0.5 mg / ml Hygromycin B and 12 pg / ml of puromycin. THE CHO JRR17.1 cell line expresses gp160 (JRFL) and this cell line is a clone selected for the ability to fuse with a CCR5 / CD4 expressive cell line.

After cell fusion, Tat present in the CHO cell is able to transactivate the long terminal repeat (long terminal repeat, LTR) of HIV-1 present in the Hela cell leading to the expression of the β-galactosidase enzyme. This expression is then measured using a Fluor Ace ™ β-Galactosidase reporter assay kit (Bio-Rad cat no. 170-3150). This kit is a quantitative fluorescence assay that determines the degree of expression of β-galactosidase using 4-methylumbelliferulgalactopyranoside (MUG) as a substrate. β-Galactosidase hydrolyses the fluorogenic substrate resulting in the release of the fluorescent molecule 4-methylumbelliferone (4MU). Fluorescence of 4-methylumbliferiferone is then measured on a fluorometer using an excitation wavelength of 360 nm and emission wavelength of 460 nm.

1026827 132

Compounds that inhibit fusion will give rise to a reduced signal, and after dissolution in a suitable solvent and dilution in culture medium, a {dose / response curve can be used for each compound ""! 5 to calculate IC 50 values.

i; All Examples of the invention have an IC50 value, according to the above method, of less than 1.5 μΜ. IC 50 values for the compounds of Examples 12, 29 and 44 are 15 nM, 134 nM and 825 nM, respectively. The ability of compounds of formula (I) to inhibit the interaction of gp120 with CD4 is further demonstrated by using an enzyme-linked immunosorbent assay (ELISA). Maxisorp plates (Nunc) are coated with 2 µg / well anti-gp120 antibody (D7324). 15 100 μΐ gpl20 (predilution by titration) is added 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 μΐ / well compound is added followed by 50 μΐ (0.1 pg) soluble CD4 conjugated to horseradish peroxidase (Autogen Bio-clear). The plate is incubated for 90 minutes at room temperature before the wells are washed again. The substrate OPD (o-phenylenediamine, Sigma) is added at a concentration of 0.5 mg / ml and the plate is incubated for 3 minutes in the dark at room temperature before 3 M HCl is added to stop the reaction. Compounds that inhibit the interaction of gp120 with soluble CD4 will give rise to a reduced absorption at 492 nm.

All Examples of the invention have an IC50 value, according to the above method, of less than 15 μΜ. IC50 values for the compounds of Examples 1, 11, 35 and 12 are 0.92 μΜ, 1.0 μΜ, and 0.75 μΜ, respectively.

1026827

Claims (23)

1. Compound of formula (I) i · r "1"! 5, vA · 0 (0 10 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 or 2 atoms or groups selected from halogen, C1 -C6 alkoxy, CF3, OCF3 or CN; R2 and R3 are independently H or C1 -C6 alkyl; 2. A compound according to claim 1 wherein R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1 or 2 atoms or groups selected from halogen. A compound according to claim 1 or 2 wherein R 1 is phenyl, fluorophenyl or pyridyl. A compound according to any one of claims 1 to 3 wherein R 1 is phenyl. A compound according to any one of the preceding claims wherein R 2 is C 1 -C 4 alkyl. 35 A compound according to any one of the preceding claims wherein R 2 is methyl. 102682 7 • » A compound according to any one of the preceding claims wherein R 3 is H. S ’i * t * f; 8. A compound according to any one of the preceding claims wherein R 4 is C 1 -C 4 alkyl. S n or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R 1, R 2, R 4 and R 5 are as defined in any one of claims 1 to 15. A compound according to any one of the preceding claims wherein R 4 is methyl. 10 A compound according to any one of the preceding claims wherein R 5 is an optionally substituted phenyl, naphthyl, pyridyl, indazolyl, benzimidazolyl, quinolinyl, isoquinolyl, quinazolinyl, benzopiperidinyl or benzoxazolyl; Wherein said substituents are 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, CN, CO 2 R 8, CONR 6 R 7 or R 10. R® is H, C1 -C6 alkyl or phenyl; R9 is C1 -C4 alkyl or phenyl; and R10 imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolal, or any other, benzoxazolalxyl substituted with 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1-20 C 6 alkoxy, cyano or halogen. A compound according to any one of the preceding claims wherein R 5 is an optionally substituted phenyl or pyridyl, wherein said substituents are 1 to 3 groups selected from C 1 -C 6 alkoxy, CO 2 R 8 or CONR 6 R 7. A compound according to any one of the preceding claims wherein R 6 is H or C 1 -C 4 alkyl. A compound according to any one of the preceding claims wherein R 8 is H, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl. A compound according to any one of the preceding claims wherein R8 is C1 -C4 alkyl. A compound according to any one 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 halogen. 102682 7 • * A compound according to any one of the preceding claims of formula (Ia) R 'vA <10 ° <la> or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein R 1, R 2, R 3, R 4 and R 5 are as defined in one of claims 1 to 15. 15 A compound according to claim 16 of formula (Ib) O R 4 r 4 N 4 R 1 "% VV 18. A compound according to claim 1 selected from: (2S) -1 - ((2R) -4-Benzoyl-2-methylpiperazin-1-yl)] 2- (3- methyl-1H-indazole-4-) yloxy) propan-1-one; (2S) -Ir [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- [2- (2H-pyrazol-3-ylamino) quinolin-5-yloxy] propan-1-one; 5 - {(1S) -2 - ((2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy) isoquinoline-1-carboxylic acid methylamide; 35 (2 S) -1 - [(2 R) -4-Benzoyl-2-methylpiperazin-1-yl] -2- (8-chloro-2-methylaminoquinoline-5-yloxy) propane-1-one; 1026827 • ♦ (2S) -1- [(2R) -4-Benzc-yl-2-inethyl-piperazin-1-yl] -2- [1- (2H-pyrazol-3-ylamino) isoquinoline-5-yloxy] propane -l-one; 4- {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -3-methoxy-N-methylbenzamide; 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -4-methoxypyridine-2-carboxylic acid methylamide; 5- {(1S) -2 - [(2R) -4-Ben2oyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy} -4-raethoxypyridine-2-carboxylic acid amide; 5 - {(IS) -2 - [(2R) -4-Benzoyl-2-methylpiperazin-1-yl] -1-methyl-2-oxoethoxy] -4-methoxypyridine-2-carboxylic acid ethylamide; 5 - {(1 S) -2 - [(2 R) -4-benzoyl-2-methylpiperazine-1-yl] -1-methyl-2-oxoethoxy] -4-methoxypyridine-2-carboxylic acid cyclopropylamide; and pharmaceutically acceptable salts, solvates or derivatives thereof. A pharmaceutical composition containing 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 carriers. A pharmaceutical composition according to claim 19 which contains one or more additional therapeutic agents. R 4 is C 1 -C 6 alkyl; R 5 is phenyl; naphthyl; or a C bonded, 6 to 10 membered, mono- or bicyclic, aromatic or partially saturated, heterocyclic group, wherein said heterocyclic group is 1 to 4 nitrogen heteroatoms, 1 or 2 nitrogen heteroatoms and 1 oxygen heteroatom, or 1 or 2 contains nitrogen heteroatoms and 1 sulfur heteroatom; wherein said phenyl, naphthyl or heterocyclic group is optionally substituted with 1 to 3 atoms or groups selected from C 1 -C 6 alkyl, C 1 -C 4 fluoroalkyl, C 3 -C 7 cycloalkyl, phenyl, OH, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, OC 1 -C 1 fluoroalkyl, C 0 -C 2 alkylene-NR 8 R 7, halogen, C 1 -C 2 alkylene-CN, C 0 -C 2 alkylene-CO 2 R 8, Co -C 2 alkylene-CONR 6 R 7, C 0 -C 2 alkylene-SR 9, C 0 -C 2 alkylene-SOR9, C 0 -C 2 alkylene-SO 2 R 9, C 0 -C 2 alkylene-35 SO 2 NR 6 R 7, C 0 -C 2 alkylene-NR 8 COR 9, C 0- C 2 alkylene-NR 8 CONR 6 R 7, C 0 -C 2 alkylene-NR 6 SO 2 R 9, or C 1 -C 2 alkylene-R 10, or, when R 5 is a heterocyclic group, oxo; R 6 and R 7 are independently H, C 1 -C 6 alkyl, C 1-6 cycloalkyl, phenyl or R 10; or when taken together with the nitrogen to which they are attached, 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 1 - C 6 alkylene NH 2; 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. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof according to any one of claims 1 to 18 for use in the treatment of an HIV, a retroviral infection genetically related to HIV, or AIDS. 1026827 Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or derivative thereof, according to any one of claims 1 to 18 for the preparation. 5 of a drug for the treatment of an HIV, a retroviral infection genetically related to HIV, or AIDS. 1026827-