WO2007064316A1 - Heterocycles bicycliques en tant qu'inhibiteurs de l'integrase du vih - Google Patents

Heterocycles bicycliques en tant qu'inhibiteurs de l'integrase du vih Download PDF

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WO2007064316A1
WO2007064316A1 PCT/US2005/043191 US2005043191W WO2007064316A1 WO 2007064316 A1 WO2007064316 A1 WO 2007064316A1 US 2005043191 W US2005043191 W US 2005043191W WO 2007064316 A1 WO2007064316 A1 WO 2007064316A1
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methyl
oxo
dimethyl
oxazine
fluoro
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PCT/US2005/043191
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English (en)
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B. Narasimhulu Naidu
Jacques Banville
Francis Beaulieu
Timothy P. Connolly
Mark R. Krystal
John D. Matiskella
Carl Ouellet
Serge Plamondon
Roger Remillard
Margaret E. Sorenson
Yasutsugu Ueda
Michael A. Walker
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Bristol-Myers Squibb Company
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Priority to PCT/US2005/043191 priority Critical patent/WO2007064316A1/fr
Publication of WO2007064316A1 publication Critical patent/WO2007064316A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • Recent statistics indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.
  • antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action, hi particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis.
  • non-nucleoside reverse transcriptase inhibitors nevaripine, delavirdine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients, hi the US, where combination therapy is widely available, the number of HlV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D.
  • HIV expresses three enzymes, reverse transcriptase, an aspartyl protease, and integrase.
  • AU three are targets for treating AIDS and HIV infection.
  • HIV integrase catalyzes insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle.
  • HIV integrase inhibitors belonging to a class of diketo acid compounds prevented viral integration and inhibited HIV-I replication in cells (Hazuda et al. Science 2000, 287, 646). And recently, HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Fut. 2002, 27, 1101).
  • the invention encompasses compounds of Formula I, including pharmaceutically acceptable salts and solvates, their pharmaceutical compositions, and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS.
  • One aspect of the invention are compounds of Formula I
  • R 1 is Ci ⁇ Ar ⁇ alkyl, C 1-6 (Ar 1 )(CON(R 8 )(R 9 ))alkyl, C 1-6 (Ar 1 )(CO 2 R 14 )alkyl, or C 1-6 (Ar 1 )oxyalkyl;
  • R 3 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 5-7 cycloalkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, Ci -6 alkylthio, C 1-6 haloalkoxy, N(R 8 )(R 9 ), NHAr 2 , N(R 6 )SO 2 R 7 , N(R 6 )COR 7 , N(R 6 )CO 2 R 7 , OCOR 7 , OCO 2 R 7 , OCON(R 8 )(R 9 ),
  • R 4 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or N(R 6 )(R 6 );
  • R 5 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, orN(R 6 )(R 6 );
  • R 6 is hydrogen, C 1-6 alkyl, or C 3-7 cycloalkyl
  • R 7 is C 1-6 alkyl or C 3-7 cycloalkyl
  • R is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1 . 6 (C 1-6 alkoxy)alkyl or Ci -6 (Ci -6 dialkylamino)alkyl;
  • R 9 is hydrogen, Ci -6 alkyl, Ci -6 hydroxyalkyl, C 1-6 (Ci -6 alkoxy)alkyl or C 1-6 (C 1-6 dialkylamino)alkyl; or
  • R 10 is hydrogen, C 1-6 alkyl, or C 1-6 hydroxyalkyl
  • R 11 is hydrogen, C 1-6 alkyl, C 3-7 cyclolkyl, COR 6 , or CO 2 R 6 ;
  • R 13 is azetidinonyl, pyrrolidinonyl, valerolactamyl, caprolactamyl, maleimido, oxazolidonyl, or dioxothiazinyl, and is substituted with 0-1 substituents selected from the group consisting of hydroxymethyl, acetoxymethyl, and aminomethyl;
  • R 14 is hydrogen or C 1-6 alkyl
  • Ar 2 is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is substituted with 0-2 substituents selected from the group consisting of halo, cyano, benzyl, Ci -6 alkyl 5 C 1-6 alkoxy, N(R 8 )(R 9 ), CON(R 8 )(R 9 ), CO 2 R 6 , CONHSO 2 N(R 6 )(R 6 ), CONHSO 2 N(R 6 )(phenyl), and CONHS O 2 N(R 6 )(halophen
  • Ar 3 is phenyl substituted with 0-2 substituents selected from the group consisting of halo, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, (C 1-6 alkoxy)methyl, C 1-6 haloalkyl,
  • X-Y-Z is C(R 14 ) 2 OC(R 14 ) 2; C(R 14 ) 2 OC(R 14 ) 2 C(R 14 ) 2 , or C(R 14 ) 2 OC(R 14 ) 2 C(R 14 ) 2 C(R 14 ) 2 ;
  • Another aspect of the invention is a compound of Formula I where R 1 is C w (Ar 1 )alkyL -
  • Another aspect of the invention is a compound of Formula I where R 1 is
  • Another aspect of the invention is a compound of Formula I where R 1 is
  • Another aspect of the invention is a compound of Formula I where R 2 is hydrogen.
  • Another aspect of the invention is a compound of Formula I where R 3 is hydrogen, halo, N(R 8 )(R 9 ), N(R 6 )COR 7 , OCON(R 8 )(R 9 ), CON(R 8 )(R 9 ), SOR 7 , SO 2 R 7 , SO 2 N(R 6 )(R 6 ), PO(OR 6 ) 2 , R 13 , or Ar 2 .
  • R 3 is hydrogen, halo, N(R 8 )(R 9 ), N(R 6 )COR 7 , OCON(R 8 )(R 9 ), CON(R 8 )(R 9 ), SOR 7 , SO 2 R 7 , SO 2 N(R 6 )(R 6 ), PO(OR 6 ) 2 , R 13 , or Ar 2 .
  • Another aspect of the invention is a compound of Formula I where X-Y-Z is C(R 14 ) 2 OCH 2, C(R 14 ) 2 OCH 2 CH 2, or C(
  • Another aspect of the invention is a compound of Formula I where X-Y-Z is CH 2 OCH 2, C(CH 3 )HOCH 2, C(CH 3 ) 2 OCH 2 , CH 2 OCH 2 CH 2 , C(CH 3 )HOCH 2 CH 2 , C(CH 3 ) 2 OCH 2 CH 2 , CH 2 OCH 2 CH 2 CH 2 , C(CH 3 )HOCH 2 CH 2 CH 2, or C(CH 3 ) 2 OCH 2 CH 2 CH 2 .
  • Another aspect of the invention is a compound of Formula I selected from the group of structures consisting of
  • Another aspect of the invention is a method for making a compound of formula II
  • R is hydrogen
  • R 4 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C ⁇ haloalkyl, C 1-6 haloalkoxy, orN(R 6 )(R 6 );
  • R 5 is hydrogen, halo, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, d-ehaloalkoxy, or N(R 6 )(R 6 );
  • R 6 is hydrogen, C 1-6 alkyl, or C 3-7 cycloalkyl
  • R 7 is C 1-6 alkyl or C 3-7 cycloalkyl
  • R 8 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 (C 1-6 alkoxy)alkyl or C 1-6 (C] . _6dialkylamino)alkyl;
  • R 9 is hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 (Ci -6 alkoxy)alkyl or C 1-6 (C 1-6 dialkylamino)alkyl; or
  • N(R 8 )(R 9 ) taken together is azetidinyl, pyrrolidinyl, (R 10 )-piperidinyl, N-(R ⁇ )-piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiazinyl;
  • R 10 is hydrogen, C 1-6 alkyl, or C 1-6 hydroxyalkyl
  • R 11 is hydrogen, Ci -6 alkyl, C 3-7 cyclolkyl, COR 6 , or CO 2 R 6 ;
  • R 12 is hydrogen, hydroxy, N(R 6 )(R 6 ), SO 2 R 7 , OSO 2 R 7 , or dioxothiazinyl;
  • R 13 is azetidinonyl, pyrrolidinonyl, valerolactamyl, caprolactamyl, maleimido, oxazolidonyl, or dioxothiazinyl, and is substituted with 0-1 substituents selected from the group consisting of hydroxymethyl, acetoxymethyl, and aminomethyl;
  • R 14 is hydrogen or C 1-6 alkyl
  • Ar 2 is tetrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridinyl, hydroxypyridinyl, quinolinyl, isoquinolinyl, or indolyl, and is substituted with 0-2 substituents selected from the group consisting of halo, cyano, benzyl, C 1-6 alkyl, C 1-6 alkoxy, N(R 8 )(R 9 ), CON(R 8 )(R 9 ), CO 2 R 6 , CONHSO 2 N(R 6 )(R 6 ), CONHSO 2 N(R 6 )(phenyl), and CONHSO 2 N(R 6 )(halophen
  • Ar 3 is phenyl substituted with 0-2 substituents selected from the group consisting of halo, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, (C 1-6 alkoxy)methyl, C 1-6 haloalkyl, Ci -6 haloalkoxy, N(R 8 )(R 9 ), CON(R 6 )(R 6 ), and CH 2 N(R 8 )(R 9 ), or is dioxolanylphenyl;
  • R 15 is C 1-6 alkyl with a compound of the formula C 1-6 (Ar 1 )alkylamine under basic conditions.
  • Another aspect of the invention is the method for making a compound of Formula II where the base is a C 1-4 trialkylamine, C 1-4 dialkylarnine, C 1-4 alkylamine, or ammonia.
  • Another aspect of the invention is the method for making a compound of
  • Another aspect of the invention is the method for making a compound of Formula II where the base is a C 1-4 trialkylamine.
  • Another aspect of the invention the method for making a compound of Formula II where the base is triethylamine or diisopropylethylamine.
  • Another aspect of the invention is the method for making a compound of Formula II where the conditions include a solvent selected from the group consisting of a C 1-4 alcohol, a (C 1-4 )dialkyl ether, tetrahydrofuran, dioxane, a (C 1-4 )-((C 1-4 )dialkoxy)alkane, DMF, DMSO, or methylene chloride.
  • a solvent selected from the group consisting of a C 1-4 alcohol, a (C 1-4 )dialkyl ether, tetrahydrofuran, dioxane, a (C 1-4 )-((C 1-4 )dialkoxy)alkane, DMF, DMSO, or methylene chloride.
  • Another aspect of the invention is the method for making a compound of Formula II further comprising heating a compound of the structure
  • Another aspect of the invention is a method for making a compound of Formula II comprising reacting a compound of the structure
  • R 15 is hydrogen with a compound of the formula C I-6 (Ar ⁇ alkylamine under peptide coupling conditions.
  • Another aspect of the invention is a method for making a compound of Formula II comprising transforming a compound of the structure
  • R 15 is hydrogen into the corresponding acyl chloride and reacting the acyl chloride with a compound of the formula C 1 . 6 (Ar I )alkylamine under basic conditions.
  • Another aspect of the invention is a compound of the structure
  • R 14 is hydrogen or C 1-6 alkyl and R 15 is C 1-6 alkyl.
  • Another aspect of the invention is a compound of the structure
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , Ar 1 , Ar 2 , Ar 3 , and X-Y-Z can be used independently with any scope of any other substituent.
  • Alkyl alkoxy
  • hydroxyalkyl and related terms with an alkyl moiety include straight and branched configurations.
  • a term such as “C 1-6 (R)alkyl” means a straight or branched alkyl group of one to six carbons substituted with the substituent R.
  • Haloalkyl and “halophenyl” include all permutations of halogenated alkyl or phenyl groups, from monohalo to perhalo.
  • Aryl means an aromatic ring system and includes carbocyclic and heterocyclic systems. Some substituents are divalent, such as X-Y-Z. Asymmetric divalent substituents may be attached in either of the two configurations.
  • C 1-6 (Ar 1 )oxyalkyl means Ar 1 is attached at the oxygen.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, rumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention also includes all solvated forms of the compounds, particularly hydrates.
  • Solvates do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. Solvates may form in stoichiometric amounts or may form from adventitious solvent or a combination of both.
  • One type of solvate is hydrate, and some hydrated forms include monohydrate, hemihydrate, and dihydrate.
  • the invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. An example of enantiomers is shown below. Methods of making and separating stereoisomers are known in the art.
  • the invention includes all tautomeric forms of the compounds.
  • An example of a tautomeric pair is shown below.
  • the compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section.
  • the variables shown in the synthetic schemes are distinct from and should not be confused with the variables in the claims or the rest of the specification.
  • the variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.
  • Some compounds can be synthesized from an appropriately substituted heterocycle 1-1 according to Scheme I, where R a and P can serve as protecting groups (see Greene, T. W. and Wutz, P. G. M. Protective Groups in Organic Synthesis, Second Edition, 1991, John Wiley and Sons, New York).
  • P When P is benzyl or substituted benzyl it can be removed by hydrogenolysis (H 2 -PdZC) or acid hydrolysis (trifluoroacetic acid) to yield intermediate 1-2.
  • 1-2 can be transaminated to 1-4 by reaction with amine 1-3. In a number of cases this reaction can be carried out by heating 1-3 and 1-2 together in the presence of base.
  • R a is a lower alkyl group
  • R a can be removed under ester hydrolysis conditions, such as treatment with NaOH, LiOH, or KOH to deliver the corresponding carboxylic acid I- 5.
  • R a can be removed by nucleophilic displacement using NaI.
  • R a is benzyl and substituted benzyl
  • R a can be removed by hydrogenolysis.
  • Intermediate 1-5 can be coupled using amide bond forming reagents such as BOP, DCC, EDCI, PyBrop, PyBop or other reagents (see March, J. Advanced Organic Chemistry, Fourth Edition 1992 John Wiley & Sons, New York).
  • the resulting intermediate 1-6 can be deprotected as described for intermediate 1-1.
  • intermediate II-3 can be prepared using methods similar to those described in Sunderland, J. S.; Botta, M.; Aime, S.; Raymond, K. N. Inorg. Chem. (2001), 40, 6756-6756, where II-l and II-2 are condensed, to provide intermediate II-3.
  • This reaction is usually conducted in the presence of a base such as sodium hydride (NaH), sodium ethoxide (EtONa) or lithium hexamethyldisilazide (LiHMDS).
  • II-3 can be condensed with an appropriately substituted amidine II-4 to form II-5.
  • Substituent B can be a leaving group, such as —halo (Cl, Br or I) or can be converted to a leaving group under appropriate conditions such as by forming the corresponding methylsulfonate ester.
  • substituent B is a methyl sulphide group it can be treated with iodomethane to form a dimethylsulfonium intermediate which is activated towards nucleophilic attack to effect ring closure.
  • intermediate II-3 can be condensed with a cyclic-amidine to yield intermediate 1-1.
  • Intermediate III-l can be prepared using known methods (see Patai, S. and Rappoport, Z. The Chemistry of Amidines and Imidates, Volume 2, 1991, John Wiley & Sons, New York).
  • nitrile IV-I possessing a potential leaving group B, can be reacted with hydroxylamine to form intermediate IV-2.
  • This intermediate can be reacted with a suitably protected alkyne to form IV-3 which can rearrange to from intermediate PV-4 according to literature methods (Culbertson, T. P. Journal of Heterocyclic Chemistry, 1979, 16, 1423-1424).
  • 2-(methylthio)ethanol can be alkylated with an appropriate ⁇ -haloacetic acid (V-I) wherein X is a leaving group such as Cl, Br, OTs, OMs or OTf, to deliver intermediate V-2.
  • V-I ⁇ -haloacetic acid
  • X is a leaving group such as Cl, Br, OTs, OMs or OTf
  • the carboxylic acid can be transformed to the corresponding amidine derivative using known synthetic methods (Geilen et al. Tetrahedron Letters 2002, 43, 419-421).
  • the amidine can further be reacted with intermediate V-5, in the presence of a base (for example, sodium ethoxide) affording intermediate V-6.
  • a base for example, sodium ethoxide
  • Methylation of the sulphide ether can be accomplished by treating V-6 with iodomethane and the resulting sulfonium derivative (V- 7) treated with base to form the bicyclic template V-8.
  • This intermediate can be used in the synthesis of final compounds using methods described in Scheme I.
  • R a -H, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 3 (CH 3 ) 3 A1, NH 4 Cl
  • Scheme VII Another method is illustrated in Scheme VII.
  • This synthetic path begins with an appropriately substituted ketone which can be transformed to the corresponding nitrile intermediate VII-I .
  • This in turn can be reacted with 2-chloroethanol to produce compound VII-2, which can be reacted with hydroxylamine and an acetylene dicarboxylate ester to yield intermediate VII-4. Heating of the intermediate can yield intermediate VII-5.
  • Synthesis of the corresponding amide derivatives can be accomplished according to Scheme I.
  • benzylation of the hydroxyl group of VII-5 can be achieved using benzyl bromide under basic conditions (for example, K 2 CO 3 or NaH).
  • Saponification of the ester group of VIII-I can provide VIII-2 which can be coupled with appropriately substituted amines (R 1 R 2 NH) using well known amide bond forming reagents, such as benzotriazole-1- yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) or 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).
  • PyBOP benzotriazole-1- yloxy-tris-pyrrolidino-phosphonium hexafluorophosphate
  • HATU 0-(7- azabenzotriazol-l-yl)-N,N,N',N'-t
  • the corresponding acid chloride can be formed, by treatment with oxalyl chloride, and reacted with an appropriate amine to form the amide bond. Removal of the benzyl group can be accomplished under a variety of conditions including treatment with CF 3 CO 2 H or H 2 (Pd-C).
  • some compounds of this invention can be synthesized according to Scheme IX.
  • Scheme IX pyrimidinone IX-3, can be produced using methods similar to those described in the previous schemes. This intermediate can be carried on to the final product according to a variety of paths.
  • the hydroxyl group can be benzoylated to provide intermediate IX-4 which can be further treated with K 2 CO 3 to effect ring closure to form the bicyclic template IX-5.
  • direct treatment of IX-3 with K 2 CO 3 can provide intermediate IX-6.
  • Intermediates IX-5, an IX-6 can be used in the synthesis the final products using the methods described in Scheme I.
  • bicyclic intermediate XII-I prepared according to the methods described above, can be saponified using well known methods.
  • the resulting carboxylic acid, XII-3 can then be coupled to amine XII-2 using standard amide bond forming reagents and methods. Removal of the benzyl group, by hydrogenolysis or acid mediated hydrolysis provides the final products.
  • Scheme XII
  • Scheme XIV illustrates the synthesis of sulfonamide containing examples, starting from 5-fluoro-2-methylbenzen-l-sulfonlyl chloride.
  • Schemes XXIV and XXV further illustrate methods useful for the synthesis of some compounds of the invention.
  • Scheme XXIV
  • inte ⁇ nediate XXVI-I can be used to synthesize intermediates XXVI-2 via palladium catalyzed coupling. These intermediates can be further modified to provide some of the compounds of this invention.
  • a recombinant NL-Rluc vims was constructed in which a section of the nef gene from NL4-3 was replaced with the Renilla Luciferase gene.
  • the NL-RLuc virus was prepared by co-transfection of two plasmids, pNLRLuc and pVSVenv.
  • the pNLRLuc contains the NL-Rluc DNA cloned into pUC18 at the Pvull site, while the pVSVenv contains the gene for VSV G protein linked to an LTR promoter.
  • Transfecti ⁇ ns were performed at a 1 :3 ratio of pNLRLuc to pVSVenv on 293T cells using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, CA) according to manufactures instruction, and the pseudotype virus generated was titered in MT-2 cells.
  • Example 19 demonstrated synergistic or additive-synergistic HIV antiviral activity when used in conjunction with a variety of other antiviral agents, as described below.
  • the T-cell line, MT-2 was obtained through the AIDS Research and Reference Reagent Program.
  • MT-2 cells were sub-cultured twice a week in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2 mM L- glutamine, and 10 mM HEPES buffer pH 7.5.
  • the HIV-I 303B virus is a molecular clone derived from the NL4-3 strain of HIV-I that was obtained from the NIH AIDS Research and Reference Reagent Program. For combinations with enfuvirtide, the NL36G virus was used.
  • This NL4-3 derivative has the naturally occurring enfuvirtide resistance mutation in gp41 (36D) changed to a sensitive phenotype (D36G).
  • Virus stocks were made by transfecting 293T cells with a proviral DNA clone using LipofectAMINE PLUS (Invitrogen), according to the manufacturer's instructions. Three days post-transfection, virus was harvested and passaged once in MT-2 cells before titration in MT-2 cells.
  • Example 19 atazanavir, didanosine, stavudine, efavirenz, and enfuvirtide (T-20) were synthesized by Bristol-Myers Squibb using published or known reactions. Amprenavir, indinavir, nelfinavir, nevirapine, lopinavir, lamivudine, ritonavir, tenofovir, saquinavir, delavirdine and abacavir were extracted from commercial formulations of the prescribed drugs and purified using published or common techniques. Tenofovir was tested as tenofovir disopoxil fumerate. Zidovudine and zalcitabine were purchased from Sigma, and emtricitabine from Moravek Biochemicals.
  • MT-2 cells were infected with HIV- 1 303B (or NL36G), at an MOI of 0.001 , and seeded into 96-well microtiter plates (2.5 x 10 5 cells/ml) containing serial dilutions of test compounds.
  • the drug combinations were set up using ratios of the two drugs of 1:1, 1:2.5 and 2.5:1 times the EC 50 value determined for each drug in prior experiments.
  • Each drug ratio consisted of an array of 3-fold serial dilutions, and was performed with eight or more replicas on separate multi-well plates.
  • HIV infected cells were incubated at 37°C in 5% CO 2 , and on day five post-infection, the extent of virus replication was measured by determining cell viability using the CellTiter 96 Aqueous Non-Radioactive Cell Proliferation Assay (Promega). Maximal cell protection was typically seen in samples treated with the highest drug concentration.
  • the tetrazolium compound MTS (3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxyphenyl)-2-4-sulphophenyl-2H-tetrazolium) is added to cells, whereby enzymes in metabolically active cells convert it into a colored formazan product, which is quantitated by reading absorbance at 490nm.
  • Cytotoxicity assays were performed in parallel with the combination experiments. Here, uninfected cells were exposed to the same drug combinations, and assayed after five days for cell viability using the MTS assay. Analysis of Drug Combination Effects. For determination of combination index (CI) values, drugs were diluted in a fixed ratio and multiple ratios were analyzed. The drug serial dilutions spanned a range of concentrations near the EC 50 value of each compound, so that equivalent antiviral activities could be compared. The normalized responses from each therapy are fit to the four-parameter logistic model with a common minimum and maximum across all therapies. Conceptually, this equation can be written as D - A
  • Fa stands for "fraction affected,” and represents the fraction of the viral load that has been inactivated. For example, Fa of 0.75 indicates that viral replication had been inhibited by 75%, relative to the no-drug controls.
  • the EC 5 o represented by the Cj in the above equation, is the drug concentration that is expected to reduce the amount of virus by 50%, and the Bi are the parameters that reflects the slope of the concentration-response curve. For this assay, A is the bottom plateau common to all curves, D is the common top plateau, B j is the "slope" parameter for the jth therapy, and C j is the concentration that produces an effect equal to the average of A and D for the jth therapy.
  • Therapies 1 and 2 correspond to mono therapies 1 and 2, respectively.
  • Therapies 3, 4, and 5 correspond to the three combination therapies.
  • EC 50 values for each drug were determined from the single drug experiments, using the above equation. The equation was fit using a nonlinear regression routine (Proc Nlin) in PC SAS version 8.2 (SAS Institute Inc.).
  • [Dm] ⁇ and [£>m] 2 are the concentrations of drugs that would individually produce a specific level of effect, while [D] 1 and [D] 2 are the concentrations of drugs in combination that would produce the same level of effect.
  • Example 19 Two-Drug Combinations of Example 19 with Nucleoside Reverse Transcriptase Inhibitors. Eight nucleoside RT inhibitors (didanosine, stavudine, zidovudine, lamivudine, abacavir, zalcitabine, emtricitibine and the nucleoside phosphonate, tenofovir) were combined with Example 19 at a range of concentrations near the EC 50 value of each compound, so that equivalent antiviral activities could be compared. All estimates were computed using SAS Proc NLIN, and a two-parameter logistic. Data is presented in Table 4 as the combination indices and the asymptotic confidence intervals for RT inhibitors at different molar ratios.
  • a lower bound of the asymptotic confidence interval greater than 1 indicates antagonisms, an upper bound of less than 1 indicates synergism and a value of 1 being contained in the interval indicates additivity.
  • the 95% confidence intervals are shown in parenthesis, and represent a measure of variability in the data.
  • a lower bound of the asymptotic confidence interval greater than 1 indicates antagonisms, an upper bound of less than 1 indicates synergism, and a value of 1 being contained in the interval indicates additivity.
  • the 95% confidence intervals are shown in parenthesis, and represent a measure of variability in the data.
  • Example 19 Two-Drug Combinations Involving Example 19 and HIV Protease Inhibitors. Evaluation of Example 19 for drug combination therapy with protease inhibitors was carried out using indinavir, amprenavir, nelfinavir, lopinavir, saquinavir, ritonavir and atazanavir. Results from this two-drug combination study are summarized in Table 6. Again, the combination indices observed with Example 19 and all protease inhibitors at almost all effective levels and molar ratios are suggestive of a synergistic relationship. This is especially true for saquinavir and atazanavir, where the confidence interval is below one at all concentrations and effective levels.
  • the upper range of the confidence interval is greater than one in only one condition for ritonavir, indinavir and lopinavir, so an additive relationship with Example 19 cannot be ruled out.
  • the upper range of the confidence interval for nelfinavir and amprenavir are slightly greater than 1 under a few conditions, suggestive of a synergistic-additive effect for these compounds with
  • Example 19 No cytotoxicity was observed at the highest concentrations used in any of these combination antiviral assays. Table 6. Two-Drag Combination using Example 19 and Protease Inhibitors.
  • a lower bound of the asymptotic confidence interval greater than 1 indicates antagonisms, an upper bound of less than 1 indicates synergism, and a value of 1 being contained in the interval indicates additivity.
  • the 95% confidence intervals are shown in parenthesis, and represent a measure of variability in the data.
  • a lower bound of the asymptotic confidence interval greater than 1 indicates antagonisms, an upper bound of less than 1 indicates synergism, and a value of 1 being contained in the interval indicates additivity.
  • the 95% confidence intervals are shown in parenthesis, and represent a measure of variability in the data.
  • HIV integrase inhibitors have been accepted into clinical trials for treating AIDS and HIV infection (Neamati Expert. Opin. Ther. Patents 2002, 12, 709, Pais and Burke Drugs Put 2002, 27, 1101).
  • another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with a pharmaceutically acceptable carrier.
  • nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is a non- nucleoside HJV reverse transcriptase inhibitor.
  • non-nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is an HIV protease inhibitor.
  • HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is an HIV fusion inhibitor.
  • Another aspect of the invention is a method wherein the HIV fusion inhibitor is enfuvirtide or T- 1249, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is an HIV attachment inhibitor.
  • Another aspect of the invention is a method wherein the agent is a CCR5 inhibitor.
  • Another aspect of the invention is a method wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140, and UK- 427,857, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor.
  • Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is an HIV budding or maturation inhibitor.
  • Another aspect of the invention is a method wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt, or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is an HIV integrase inhibitor.
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, with at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.
  • the agent is a nucleoside HIV reverse transcriptase inhibitor.
  • nucleoside HIV transcriptase inhibitor is selected from the group consisting of abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine, or a pharmaceutically acceptable salt or solvate thereof.
  • composition wherein the agent is a non- nucleoside HIV reverse transcriptase inhibitor.
  • composition wherein the non- nucleoside HIV reverse transcriptase inhibitor is selected from the group consisting of delavirdine, efavirenz, and nevirapine, or a pharmaceutically acceptable salt or solvate thereof.
  • composition wherein the agent is an HIV protease inhibitor.
  • composition wherein the HIV protease inhibitor is selected from the group consisting of amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and fosamprenavir, or a pharmaceutically acceptable salt or solvate thereof.
  • composition wherein the agent is an
  • HIV fusion inhibitor HIV fusion inhibitor
  • Another aspect of the invention is the composition method wherein the HIV fusion inhibitor is enfuvirtide or T- 1249, or a pharmaceutically acceptable salt or solvate thereof.
  • compositions wherein the agent are an HIV attachment inhibitor.
  • composition wherein the agent is a CCR5 inhibitor.
  • composition wherein the CCR5 inhibitor is selected from the group consisting of Sch-C, Sch-D, TAK-220, PRO-140, and UK-427,857, or a pharmaceutically acceptable salt or solvate thereof.
  • Another aspect of the invention is a method wherein the agent is a CXCR4 inhibitor.
  • Another aspect of the invention is a method wherein the CXCR4 inhibitor is AMD-3100 or a pharmaceutically acceptable salt or solvate thereof.
  • composition wherein the agent is an HIV budding or maturation inhibitor.
  • composition wherein the budding or maturation inhibitor is PA-457, or a pharmaceutically acceptable salt or solvate thereof.
  • composition wherein the agent is an HIV integrase inhibitor.
  • Combination means that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (HAART) as understood by practitioners in the field of AIDS and HIV infection.
  • HAART highly active antiretroviral therapy
  • “Therapeutically effective” means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
  • Patient means a person infected with the HIV virus and suitable for therapy as understood by practitioners in the field of AIDS and HIV infection.
  • compositions comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients.
  • a therapeutically effective amount is that which is needed to provide a meaningful patient benefit.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions.
  • Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges.
  • the liquid composition will be in a unit dosage range of 1-100 mg/mL.
  • Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other antiretroviral agents used clinically.
  • the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.
  • the invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection. Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, immunomodulators, and anti- infectives.
  • the compound of Formula I will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement.
  • Table 8 lists some agents useful in treating AIDS and HIV infection which are suitable for this invention.
  • Ethyl 5-benzyloxy-2- ⁇ (2-(dimethylsulfonium)ethoxy)methyl ⁇ -6-oxo ⁇ l, 6- dihydropyrimidine-4-carboxylate iodide A solution of intermediate 4, ethyl 5- benzyloxy-2- ⁇ (2-(methylthio)ethoxy)methyl ⁇ -6-oxo-l,6-dihydropyrimidine-4- carboxylate, (0.555 g, 1.47 mmol) in dichloromethane (10 ml) was treated at 22 °C with iodomethane (2.0 ml, 21.5 mmol) for 10 days.
  • Ethyl 5-(benzyloxy)-2-(l-(2-hydroxyethoxy) ⁇ 3-(methylthio)propyl)-6-oxo-l,6- dihydropyrimidine-4-carboxylate Ethyl 2-(benzyloxy)acetate (7.76 g, 0.04 mole)and diethyloxalate (5.84 g, 0.04 mole) in 80 mL of tetrahydrofuran were treated with one equivalent of NaH and a few drops of ethanol. The resulting mixture was stirred for 1.5 hours after which the solvent was removed under vacuum and replaced with 30 mL of ethanol.
  • the crude intermediate above (43.9g) prepared from a similar experiment described above was dissolved in hot methanol (45 mL).
  • the resulting solution was diluted with ethyl acetate (400 mL) and water (11.5 mL).
  • the solution was heated at reflux to distill out the bulk of the methanol. Heating was stopped when the distillate reached 71.5 0 C.
  • the resulting solution was diluted with 100 mL of ethyl acetate and 1 mL of methanol (needed to prevent oiling), seeded with a sample of crystalline monohydrate and let slowly cool to room temperature over night.
  • Acetone (5.80g, 99.8 mmol) was added and the mixture was heated to 60 °C. After stirring for 4 h at 60 °C, the reaction mixture was cooled to 30-35 °C, diluted with water (1.70L) and extracted with CH 2 Cl 2 (1 X 680 mL and 1 X 340 mL). The combined CH 2 Cl 2 extracts were washed with 0.5M sodium bicarbonate (510 mL), followed by water (3 X 510 mL). The dichloromethane solution (1210 mL) contained 152 g of 2-(2- chloroethoxy)-2-methylpropanenitrile by GC quantification, GC purity: 94.7%.
  • the ethyl acetate solution contained ethyl 2-(2-ethoxy-2-oxoethyi)-8,8-dimethyl ⁇ 2,5,6,8-tetrahydro-[l,2,4]oxadiazolo[3,2-c][l,4]oxazine-2-carboxylate.
  • Estimated amount of the titled intermediate in the solution by HPLC was 130 g, HPLC AP 79.0.
  • a sample was purified by reverse-phase chromatography giving an oil of 99% purity by HPLC.
  • Portion A isolation without charcoal treatment The CH 2 Cl 2 solution (315 mL) was concentrated to 80 mL at atmospheric pressure. Isopropanol (160 mL) was added and the solution was concentrated to 140 mL at atmospheric pressure. The solution was cooled slowly with stirring to 20-25 °C. The resulting slurry was further cooled to 0-5 0 C and stirred for 2 h.
  • Portion B isolation with charcoal treatment The CH 2 Cl 2 solution (315 mL) was concentrated to 80 mL at atmospheric pressure. Isopropanol (160 mL) was added and the solution was concentrated to 160 mL at atmospheric pressure. Another portion of isopropanol ( 160 mL) was added followed by charcoal (10 g). The mixture was stirred at reflux temperature (about 82 °C) for 15 min. Charcoal was removed by filtration, the charcoal cake washed with hot (about 80 °C) isopropanol (120 mL) and combined with the filtrate. The combined isopropanol solution was concentrated to 140 mL at atmospheric pressure. The solution was cooled slowly with stirring to 20-25 °C.
  • reaction mixture was cooled to 0-5 °C and the pH (7.0) was adjusted to pH (8) with IM sodium carbonate( 3.0 mL). Diethyl acetylenedicarboxylate (2.92 g, 17.18 mmoles) was added over 25 min keeping the temperature below 10 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. Ethyl acetate (45 mL) and water (15 mL) were added.
  • the resulting dark mixture was cooled to 20-25 0 C and diluted with water (50 mL).
  • the product was extracted into 0.5M Na 2 CO 3 (2 x 50 mL).
  • the organic layer was discarded.
  • the aqueous phases were combined and washed with CH 2 Cl 2 (40 mL).
  • the organic wash was discarded.
  • the aqueous solution was acidified to pH 2.0 with 6M sulfuric acid (9.0 mL ) and the product extracted into CH 2 Cl 2 (2 x 20 mL).
  • the combined CH 2 Cl 2 layers were evaporated in vacuo.
  • the residue was redissolved in isopropanol (75 mL) at 75 0 C and the solution was treated with activated charcoal (0.85 g) at 75 -80°C for 20 min.
  • the reaction was then concentrated to a thick paste and azeotroped under vacuum with ethanol/water (1:1, 100 mL), water (100 mL) and finally ethanol (100 mL). The residue was taken up in ethanol/water (1:1, 160 mL), cooled (0 0 C), and treated with diethyl acetylenedicarboxylate (30.1 mL, 0.188 mol). The reaction was stirred at room temperature for 2 hours, then diluted with water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with water (200 mL) and brine (100 mL),then dried (sodium sulfate), filtered and concentrated in-vacuo. The crude product was purified by column chromatography over silica gel, eluting with 10% to 40% ethyl acetate in hexanes to afford the title compound (25.7 g) as a yellow oil.
  • Solvent was removed by rotary evaporator and the residue, dissolved in water (50 mL), was brought to pH 1 using 6.0 N HCl. The solution was extracted with ethyl acetate (4 x 25 mL). The combined organic layers were dried (sodium sulfate) and filtered.
  • (2-(Aminomethyl)-5-fluorophenyl)(morpholino)methanone hydrochloride To a solution of intermediate 43, (2-(azidomethyl)-5- fluorophenyl)(morpholino)methanone, (770 mg, 2.92 mmol,) in ethanol (20 mL) was added 4N HCl (1 mL) and 10% Pd-C (100 mg), and the mixture hydrogenated at 1 atm ofH 2 for 3 hrs. The catalyst was removed by filtration and the filtrate concentrated.
  • 5-Fluoro-2,N,N-trimethyl ⁇ benzenesulfonamide To a solution of 5-fluoro-2- methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in tetrahydrofuran (25 mL) was added, dropwise, a solution of diniethylamine in tetrahydrofura ⁇ (2M, 25 mL, 50 mmol) over 15 min. and the mixture stirred for 5 min. The insoluble materials were filtered and the filtrate concentrated.
  • 5-Fluoro-2,N-dimethyl-benzenesulfonamide To a solution of 5-fluoro-2- methyl-benzenesulfonyl chloride (4.1S g, 20 mmol) in acetone (20 mL) was added a 40% aqueous solution of methylamine (4.5 mL, 60 mmol) under nitrogen and the mixture stirred for 5 min. Acetone was removed in vacuo and the aqueous residue extracted with CH 2 Cl 2 .
  • 3-m-Tolyl-3-trifluoromeihyl-3H-diazirine To a cold stirring solution of 3-m- tolyl-3-trifluoromethyl-diaziridine (2.0 g, 10 mtnol. prepared using the methods described in Doucet-Personeni C. et al, J Med. Chem., 2001, 44, 3203 and Nassal, M. Liebigs Ann. Chem. 1983, 1510-1523 or in Stromgaard, K et al., J. Med. Chem., 2002, 45, 4038-46) in ethanol (20 mL) was added triethylamine (1.5 g, 15 mmol).
  • 2-(Aminomethyl)-5-fluorohenzenamine hydrochloride 2-Amino-4- fluorobenzonitrile (Fritz Hunziker et al. Eur. J. Med. Chem. 1981, 16, 391) (0.300 g, 1.68 mmol), was dissolved in acetic anhydride (5 mL) and the solution was stirred at 23 0 C for 18 h. An additional portion of acetic anhydride (3 mL) was added to dissolve the JV-(2-cyano-5-fluorophenyl)acetamide. Then palladium (10% on charcoal) (25 mg) was added and the mixture was agitated under H 2 (34 psi) for 72 h.
  • 4-Fluoro-2-methoxybenzylamine hydrochloride To a mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (800 mg, 5.3 mmol) and conc.HCl (0.53 mL, 6.36 mmol, 1.2 eq.) in ethanol (20 mL) was added 10% Pd-C (100 mg; Aldrich), and the mixture hydrogenated at 1 atm hydrogen for 15 hrs at room temperature. To this mixture was added an additional amount of conc.HCl (1 mL) and 10% Pd-C (200 mg) and the reaction allowed to continue for another 40 hrs. The mixture was filtered through Celite and the filtrate concentrated in vacuo to dryness.
  • Dimethyl-carbamic acid 2-aminomethyl-5-fluoro-phenyl ester hydrochloride To a solution of intermediate 132, dimethyl-carbamic acid 2-cyano-5-fluoro-phenyl ester, (340 mg, 1.63 mmol) in ethyl acetate (20 mL) and ethanol (20 mL), was added conc.HCl (0.4 mL) and 10% Pd-C (100 mg) and the mixture hydrogenated in a Parr Shaker at 55psi of hydrogen for 20 hrs. The reaction mixture was filtered through Celite, and the filtrate concentrated in vacuo to give an oil which was partitioned between ethyl acetate (10 mL) and water (10 mL).
  • the title compound can be prepared from intermediate 16, 3-benzyloxy-9-methyl-4-oxo-4,6,7,9- tetrahydropyrimido[2,l-c][l,4]oxazine-2-carboxylic ack? and 4-fluorobenzylamine.
  • the title compound can be prepared from 3-(benzyloxy)-9-ethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,l- c][l,4]oxazine-2-carboxylic acid which was synthesized using the method described for the synthesis or intermediates 7 and 16, and intermediate 69, (4-fluoro-2-(lH- l,2,4-triazol-l-yl)phenyl)methanamine.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4- oxo-4,6,7,9-tetrahydropyrimido-[2, 1 -c][l ,4]oxazine-2-carboxylic acid and intermediate 85, (4-fluoro-2-(3-methyl-lH-l,2,4-triazol-l-yl)phenyl)methanamine.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4- oxo-4,6,7,9-tetrahydropyrimido-[2, 1 -c] [ 1 ,4] oxazine-2-carboxylic acid and intermediate 87, (2-fluoro-4-(3-methyl-lH-l,2,4-triazol-l-yl)prienyl)metrianamine.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo- 4,6,7,9-tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid and intermediate 44, (2-(aminomethyl)-5-fluorophenyl)(morpholino)methanone.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4- oxo ⁇ j ⁇ jP-tetrahydropyrimido-Pjl-cJfl ⁇ Joxazine ⁇ -carboxylic acid and intermediate 131, 2-(2-(aminomethyl)-5-fluorophenoxy)-l-morpholinoetlianone.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo- 4,6,7,9-tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid and l-(2- (aminometliyl)-5-fluoroplienyl) ⁇ yrrolidin-2-one, derived from reduction of intermediate 111, 4-fluoro-2-(2-oxopyrrolidin- 1 -yl)benzonitrile.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9- tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid and 3-(2- (aminomethyl)phenyl)oxazolidin-2-one, derived from reduction of intermediate 116, 2-(2-oxooxazolidin-3-yl)benzonitrile.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9- tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid and l-(2- (aminomethyl)phenyl)azetidin-2-one, derived from reduction of intermediate 115, 2- (2-oxoazetidin-l-yl)benzonitrile.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9- dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido- [2, 1 -c] [ 1 ,4] oxazine-2-carboxylic acid and N-(2-(aminomethyl)-5-fluoroplienyl)-5-methyl-l ,3,4-thiadiazol-2-amine, derived from reduction of intermediate 124, 4-fluoro-2-(5-methyl-l,3,4-thiadiazol-2- ylamino)benzonitrile.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo- 4,6,7,9-tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid and 3-(2- (aminomethyl)-5-fluorophenyl)oxazolidin-2-one, derived from reduction of intermediate 117, 4-fluoro-2-(2-oxooxazolidin-3-yl)benzonitrile.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4 5 6,7,9-tetrahydropyrimido-[2, 1 - c][l,4]oxazine-2-carboxylic acid and (S)-l-(2-(aminomethyl)-5-fluorophenyl)-5- ((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 122, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxo ⁇ yrrolidin-l- yl)-4-fluorobenzonitrile
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2, 1 - c][l,4]oxazine-2-carboxylic acid and (S)-l-(2-(aminomethyl)-5-fluorophenyl)-5- ((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 121, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-l- yl)-4-fluorobenzonitrile.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo- 4,6,7,9-tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid N-(2- (arninomethyl)-5-fluoroprienyl)-N-metliylacetamide, derived from reduction of intermediate 114, N-(2-cyano-5-fluorophenyl)-N-methylacetamide.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9- tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid 2-(aminomethyl)-5- fluorobenzenamine.
  • the title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9- tetrahydropyrimido-[2,l-c][l,4]oxazine-2-carboxylic acid and 2-(aminomethyl)-N- ethyl-5-fluorobenzenamine.

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Abstract

L’invention concerne une série de composés cycliques de pyrimidinone bicyclique de formule I constituant des inhibiteurs de l'intégrase du VIH et permettant d'empêcher l’intégration virale dans l’ADN humain. Cette action rend ces composés utiles pour le traitement des infections VIH et du SIDA. L’invention concerne également des compositions pharmaceutiques et des procédés de traitement des patients infectés au VIH.
PCT/US2005/043191 2005-11-30 2005-11-30 Heterocycles bicycliques en tant qu'inhibiteurs de l'integrase du vih WO2007064316A1 (fr)

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US7981879B2 (en) 2005-03-31 2011-07-19 Instituto di Ricerchi di Biologia Molecolare P. Angeletti S.p.A. HIV integrase inhibitors
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US8513234B2 (en) 2008-10-06 2013-08-20 Merck Sharp & Dohme Corp. HIV integrase inhibitors
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WO2005061490A1 (fr) * 2003-12-22 2005-07-07 Shionogi & Co., Ltd. Derive d'hydroxypyrimidone presentant une activite d'inhibition de l'integrase du vih
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WO2004058757A1 (fr) * 2002-12-27 2004-07-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Tetrahydro-4h-pyrido[1,2-a]pyrimidines et composes associes utilises en tant qu'inhibiteurs de l'integrase du vih
WO2004058756A1 (fr) * 2002-12-27 2004-07-15 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Tetrahydro-4h-pyrido[1,2-a]pyrimidines et composes connexes convenant comme inhibiteurs de l'integrase du vih
WO2005061490A1 (fr) * 2003-12-22 2005-07-07 Shionogi & Co., Ltd. Derive d'hydroxypyrimidone presentant une activite d'inhibition de l'integrase du vih
WO2005118593A1 (fr) * 2004-05-28 2005-12-15 Bristol-Myers Squibb Company Heterocycles bicycliques servant d'inhibiteurs d'integrase du vih

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US7981879B2 (en) 2005-03-31 2011-07-19 Instituto di Ricerchi di Biologia Molecolare P. Angeletti S.p.A. HIV integrase inhibitors
EP2543368A1 (fr) 2007-12-11 2013-01-09 Viamet Pharmaceuticals, Inc. Inhibiteurs de métalloenzymes utilisant des fractions de liaison à un métal en combinaison avec des fractions de ciblage
WO2009120841A1 (fr) * 2008-03-27 2009-10-01 Bristol-Myers Squibb Company Forme cristalline de n-[[4-fluoro-2-(5-méthyl-1h-1,2,4-triazol-1-yl)phényl]méthyl]-4,6,7,9-tétrahydro-3-hydroxy-9,9-diméthyl-4-oxo-pyrimido[2,1-c][1,4]oxazine-2-carboxamide, sel de sodium monohydrate
CN102046637A (zh) * 2008-03-27 2011-05-04 百时美施贵宝公司 N-[[4-氟-2-(5-甲基-1H-1，2，4-三唑-1-基)苯基]甲基]-4，6，7，9-四氢-3-羟基-9，9-二甲基-4-氧代-嘧啶并[2，1-c][1，4]噁嗪-2-甲酰胺钠盐一水合物的晶体形式
CN102046637B (zh) * 2008-03-27 2013-10-02 百时美施贵宝公司 N-[[4-氟-2-(5-甲基-1H-1,2,4-三唑-1-基)苯基]甲基]-4,6,7,9-四氢-3-羟基-9,9-二甲基-4-氧代-嘧啶并[2,1-c][1,4]噁嗪-2-甲酰胺钠盐一水合物的晶体形式
US8513234B2 (en) 2008-10-06 2013-08-20 Merck Sharp & Dohme Corp. HIV integrase inhibitors
WO2013162716A2 (fr) 2012-04-27 2013-10-31 Dow Agrosciences Llc Compositions pesticides et procédés correspondants
CN112028816A (zh) * 2020-09-11 2020-12-04 江阴迈康升华医药科技有限公司 一种取代异吲哚啉的合成方法
CN112028816B (zh) * 2020-09-11 2022-10-14 江阴迈康升华医药科技有限公司 一种取代异吲哚啉的合成方法

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