WO2009062308A1 - Inhibitors of human immunodeficiency virus replication - Google Patents

Inhibitors of human immunodeficiency virus replication Download PDF

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Publication number
WO2009062308A1
WO2009062308A1 PCT/CA2008/002011 CA2008002011W WO2009062308A1 WO 2009062308 A1 WO2009062308 A1 WO 2009062308A1 CA 2008002011 W CA2008002011 W CA 2008002011W WO 2009062308 A1 WO2009062308 A1 WO 2009062308A1
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WIPO (PCT)
Prior art keywords
alkyl
alkylene
het
aryl
mmol
Prior art date
Application number
PCT/CA2008/002011
Other languages
French (fr)
Inventor
Youla S. Tsantrizos
Murray D. Bailey
Punit K. Bhardwaj
Christian Brochu
Paul J. Edwards
Lee Fader
Araz Jakalian
Stephen Kawai
Mathieu Parisien
Marc-André Poupart
Bruno Simoneau
Original Assignee
Boehringer Ingelheim International Gmbh
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Application filed by Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim International Gmbh
Priority to CA2705338A priority Critical patent/CA2705338A1/en
Priority to US12/743,146 priority patent/US8461180B2/en
Priority to EP08850525.0A priority patent/EP2220084B1/en
Priority to JP2010533401A priority patent/JP5269087B2/en
Priority to ES08850525.0T priority patent/ES2463720T3/en
Publication of WO2009062308A1 publication Critical patent/WO2009062308A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compounds, compositions and methods for the treatment of human immunodeficiency virus (HIV) infection.
  • HIV human immunodeficiency virus
  • the present invention provides novel inhibitors of HIV replication, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HIV infection.
  • the present invention provides novel inhibitors of the HIV integrase enzyme, pharmaceutical compositions containing such compounds and methods for using these compounds to reduce HIV replication and in the treatment of HIV infection.
  • HIV human immunodeficiency virus
  • Most currently approved therapies for HIV infection target the viral reverse transcriptase and protease enzymes.
  • resistance of HIV to existing drugs is a problem. Therefore, it is important to discover and develop new antiretroviral compounds.
  • WO 2007/000043 describes pyrazolo[3,4-B]pyridine-2-yl benzoic acid derivatives as HIV integrase inhibitors.
  • the present invention provides a novel series of compounds having inhibitory activity against HIV replication. Furthermore, representative compounds of the invention have activity as inhibitors in a cell-based HIV replication assay.
  • the compounds of the present invention have an affinity for the HIV integrase enzyme. Therefore, the compounds of the invention may be used to inhibit the activity of HIV integrase and may be used to reduce HIV replication. Further objects of this invention arise for the one skilled in the art from the following description and the examples.
  • One aspect of the invention provides an isomer, racemate, enantiomer or diastereomer of a compound of formula (I):
  • X is N when Y is N-R 7 ;
  • X is N-R 6 when Y is N;
  • R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3- 7 )cycloalkyl;
  • R 10 is in each instance independently selected from R 8 , -(C 1-6 )alkylene-R 8 ,
  • R 8 and R 9 are as defined above;
  • R 9 is in each instance independently selected from H, (C ⁇ alkyl and (C 3-7 )cycloalkyl;
  • R 3 is (Ci. 6 )alkylidene and bond c is a double bond; wherein W is O or S and R 31 is (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 2 . 6 )alkenyl, (C 2 - 6 )alkynyl, (C 3-7 )cycloalkyl, aryl, (C 3 .
  • (C ⁇ cycloalkyKC ⁇ alkyl-, aryl-(C 1-6 )alkyl-, Het-(C 1-6 )alkyl- and -W-R 31 is optionally substituted with 1 to 3 substituents each independently selected from (C 1-6 )alkyl, halo, cyano, oxo and -O(C 1-6 )alkyl;
  • R 4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1 . 6 )haloalkyl, (C 3-7 )cycloalkyl, (C 3 . 7 )cycloalkyl-(Ci.
  • Another aspect of this invention provides a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, as a medicament.
  • Still another aspect of this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition according to this invention additionally comprises at least one other antiviral agent.
  • the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of an HIV infection in a mammal having or at risk of having the infection.
  • a further aspect of the invention involves a method of treating an HIV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof, or a composition thereof as described hereinabove.
  • Another aspect of the invention involves a method of treating an HIV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent; or a composition thereof.
  • a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof for the treatment of an HIV infection in a mammal having or at risk of having the infection.
  • Another aspect of this invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of an HIV infection in a mammal having or at risk of having the infection.
  • An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat an HIV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by HIV; wherein the composition comprises a compound of formula (I) according to this invention or a pharmaceutically acceptable salt or ester thereof.
  • Still another aspect of this invention relates to a method of inhibiting the replication of HIV comprising exposing the virus to an effective amount of the compound of formula (I), or a salt or ester thereof, under conditions where replication of HIV is inhibited. 13-152
  • substituted as used herein and unless specified otherwise, is intended to mean an atom, radical or group which may be bonded to a carbon atom, a heteroatom or any other atom which may form part of a molecule or fragment thereof, which would otherwise be bonded to at least one hydrogen atom.
  • substituted in the context of a specific molecule or fragment thereof are those which give rise to chemically stable compounds, such as are recognized by those skilled in the art.
  • “(C 1-6 )alkyl” includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (/so-propyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1 ,1-dimethylethyl (te/?-butyl), pentyl and hexyl.
  • Me denotes a methyl group
  • Et denotes an ethyl group
  • Pr denotes a propyl group
  • iPr denotes a 1-methylethyl group
  • Bu denotes a butyl group
  • tBu denotes a 1 ,1-dimethylethyl group.
  • (C 1-n )alkylene as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean acyclic, straight or branched chain divalent alkyl radicals containing from 1 to n carbon atoms.
  • (C 1-6 )alkylene includes, but
  • (C 1-6 )alkylidene includes,
  • (C 2-n )alkylidene is understood to encompass individual stereoisomers where possible, including but not limited to (E) and (Z) isomers, and mixtures thereof.
  • a (C 2-n )alkylidene group is substituted, it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
  • (C 2-n )alkenyl as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight or branched chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a double bond.
  • examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl.
  • (C 2-n )alkenyl is understood to encompass individual stereoisomers where possible, including but not limited to (E) and (Z) isomers, and mixtures thereof.
  • (C 2-n )alkynyl as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight or branched chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a triple bond.
  • examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.
  • (C 3 . m )cycloalkyl as used herein, wherein m is an integer, either alone or in combination with another radical, is intended to mean a cycloalkyl substituent containing from 3 to m carbon atoms and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • (C 3 . m )cycloalkyl-(Ci -n )alkyl- as used herein, wherein n and m are both integers, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above which is itself substituted with a cycloalkyl radical containing from 3 to m carbon atoms as defined above.
  • alkyl- include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2- cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl and 2-cyclohexylethyl.
  • n )alkyl- group is substituted, it is understood that substituents may be attached to either the cycloalkyl or the alkyl portion thereof or both, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
  • aryl as used herein, either alone or in combination with another radical, is intended to mean a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • Aryl includes, but is not limited to, phenyl, indanyl, indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl and dihydronaphthyl.
  • aryl-(C 1- ⁇ )alkyl- as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above which is itself substituted with an aryl radical as defined above.
  • aryl-(Ci -n )alkyl- include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl.
  • substituents may be attached to either the aryl or the 13-152
  • carbocycle as used herein, either alone or in combination with another radical, is intended to mean a cyclic compound, either aromatic or non-aromatic, saturated or unsaturated, in which all of the ring members are carbon atoms.
  • the carbocycle group may containing 5 or 6 carbon atom and may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated.
  • the carbocycle may be substituted. When the carbocycle is substituted, it is understood that substituents may be attached to any carbon atom which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
  • Het as used herein, either alone or in combination with another radical, is intended to mean a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 , unless specified otherwise.
  • Het-(C 1- ⁇ )alkyl- as used herein and unless specified otherwise, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above which is itself substituted with a Het substituent as defined above.
  • Examples of Het-(C 1 _ n )alkyl- include, but are not 13-152
  • heteroatom as used herein is intended to mean O, S or N.
  • heterocycle as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a 3- to 7-membered saturated, unsaturated or aromatic heterocycle containing from 1 to 4 heteroatoms each independently selected from O, N and S; or a monovalent radical derived by removal of a hydrogen atom therefrom.
  • heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, tetrazole, piperidine, piperazine, azepine, diazepine, pyran, 1 ,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide, pyridazine, pyrazine and pyrimidine, and saturated, unsaturated and aromatic derivatives thereof.
  • heteropolycycle as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a heterocycle as defined above fused to one or more other cycle, including a carbocycle, a heterocycle or any other cycle; or a monovalent radical derived by removal of a hydrogen atom therefrom.
  • heteropolycycles include, but are not limited to, indole, isoindole, benzimidazole, benzothiophene, benzofuran, benzopyran, benzodioxole, benzodioxane, benzothiazole, quinoline, isoquinoline, and naphthyridine, and saturated, unsaturated and aromatic derivatives thereof.
  • halo as used herein is intended to mean a halogen substituent selected from fluoro, chloro, bromo or iodo.
  • (C 1-n )haloalkyl as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n 13-152
  • (C 1-n )haloalkyl examples include but are not limited to chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
  • n is an integer, either alone or in combination with another radical, is intended to mean an oxygen atom further bonded to an alkyl radical having 1 to n carbon atoms as defined above.
  • Examples of -O-(C 1-n )alkyl include but are not limited to methoxy (CH 3 O-), ethoxy (CH 3 CH 2 O-), propoxy (CH 3 CH 2 CH 2 O-), 1-methylethoxy (/so-propoxy; (CH 3 ) 2 CH-O-) and 1 ,1-dimethylethoxy (terf-butoxy; (CH 3 ) 3 C-O-).
  • -O-(Ci. n )haloalkyl wherein n is an integer, either alone or in combination with another radical, is intended to mean an oxygen atom further bonded to a haloalkyl radical having 1 to n carbon atoms as defined above.
  • a haloalkyl radical having 1 to n carbon atoms as defined above.
  • n is an integer, either alone or in combination with another radical, is intended to mean an sulfur atom further bonded to an alkyl radical having 1 to n carbon atoms as defined above.
  • Examples of -S-(C 1-n )alkyl include but are not limited to methylthio (CH 3 S-), ethylthio (CH 3 CH 2 S-), propylthio (CH 3 CH 2 CH 2 S-), 1-methylethylthio (/sopropylthio; (CHs) 2 CH-S-) and 1 ,1-dimethylethylthio (tert-butylthio; (CH 3 ) 3 C-S-).
  • cyano as used herein is intended to mean a carbon atom attached to a nitrogen atom as a substituent by a triple bond.
  • protecting group as used herein is intended to mean protecting groups that can be used during synthetic transformation, including but not limited to examples which are listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981), and more recent editions thereof.
  • salt thereof is intended to mean any acid and/or base addition salt of a compound according to the invention, including but not limited to a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt as used herein is intended to mean a salt of a compound according to the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a 13-152
  • pharmaceutically-acceptable acid addition salt as used herein is intended to mean those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, and organic acids including but not limited to acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2- hydroxyethanesulfonic acid (isethionic acid), lactic acid,
  • pharmaceutically-acceptable base addition salt as used herein is intended to mean those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases including but not limited to ammonia or the hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceutically-acceptable organic nontoxic bases include but are not limited to salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, 13-152
  • ethanolamine diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N 1 N'- dibenzylethylenediamine, polyamine resins and the like.
  • Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl
  • esters thereof as used herein is intended to mean any ester of a compound according to the invention in which any of the -COOH substituents of the molecule is replaced by a -COOR substituent, in which the R moiety of the ester is any carbon- containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, each of which being optionally further substituted.
  • esteer thereof includes but is not limited to pharmaceutically acceptable esters thereof.
  • esters of the compound according to the invention in which any of the COOH substituents of the molecule are replaced by a -COOR substituent, in which the R moiety of the ester is selected from alkyl (including, but not limited to, methyl, ethyl, propyl, 1-methylethyl, 1 ,1- dimethylethyl, butyl); alkoxyalkyl (including, but not limited to methoxymethyl); acyloxyalkyl (including, but not limited to acetoxymethyl); arylalkyl (including, but not limited to, benzyl); aryloxyalkyl (including, but not limited to, phenoxymethyl); and aryl (including, but not limited to phenyl) optionally substituted with halogen, (C 1-4 )alkyl or (C 1- 4 )alkoxy.
  • alkyl including, but not limited to, methyl, ethyl, propyl, 1-methylethyl, 1 ,1-
  • esters can be found in Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985), herein incorporated by reference. Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when injected into a mammal and transformed into the acid form of the compound according to the invention.
  • any alkyl moiety present preferably contains 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms. Any aryl moiety present in such esters preferably comprises a phenyl group.
  • the esters may be a (C 1-16 )alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at 13-152
  • mammal as used herein is intended to encompass humans, as well as non- human mammals which are susceptible to infection by HIV.
  • Non-human mammals include but are not limited to domestic animals, such as cows, pigs, horses, dogs, cats, rabbits, rats and mice, and non-domestic animals.
  • treatment is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient.
  • treatment also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
  • antiviral agent as used herein is intended to mean an agent that is effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • inhibitor of HIV replication is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.
  • HIV integrase or "integrase”, used herein interchangeably, means the integrase enzyme encoded by the human immunodeficiency virus type 1.
  • terapéuticaally effective amount means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds 13-152
  • a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • Core-A In one embodiment, the compounds of the invention are represented by formula (Ia):
  • R 2 , R 3 , R 4 , R 5 and R 7 are as defined herein.
  • R 2 , R 3 , R 4 , R 5 and R 7 are as defined herein.
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein.
  • R , R , R , R and R are as defined herein.
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein.
  • Core-G In another embodiment, the compounds of the present invention are 13-152
  • R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein.
  • R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3-7 )cycloalkyl;
  • R 2 -B In an alternative embodiment, R 2 is H, halo, (C 1-6 )alkylene-O-(C 1-6 )alkyl, (C 1- 6 )alkylene- O-aryl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkylene-(C 3 . 7 )cycloalkyl , -OH or -0(C ⁇ )alkyl.
  • R 2 -C In another embodiment, R 2 is Het, aryl, (C 1-6 )alkylene-Het and (Ci -6 )alkylene-aryl; wherein said aryl and Het are optionally substituted 1 to 2 times with (C 1-6 )alkyl, -O(C 1-6 )alkyl, or -O(C 1-6 )haloalkyl.
  • R 2 is halo, (C 1-6 )alkylene-O-(C 1-6 )alkyl, (C ⁇ alkylene- O- aryl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkylene-(C 3-7 )cycloalkyl , -OH Or -O(Ci- 6 )alkyl, Het, aryl, (Ci -6 )alkylene-Het and (C 1-6 )alkylene-aryl wherein said aryl and Het are optionally substituted with (C 1-6 )alkyl, -O(Ci -6 )alkyl, or -O(C 1-6 )haloalkyl.
  • R 2 -E In another embodiment, R 2 is (C ⁇ alkyl or (C 1-4 )haloalkyl.
  • R 2 -F In another embodiment, R 2 is -CH 3 or -CH 2 CH 3 .
  • R 2 -G In another embodiment, R 2 is -CH 3 .
  • R 2 any and each individual definition of R 2 as set out herein may be combined with any and each individual definition of the Core, c, R 3 , R 4 , R 5 , R 6 and R 7 as set out herein.
  • R 3 -A is (C 1 . 6 )alkyl, (C 1-6 )haloalkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, aryl-(C 1-6 )alkyl-, Het-(C 1-6 )alkyl- or -W-R 31 , and bond c is a single bond; or
  • R 3 is (C ⁇ alkylidene and bond c is a double bond; wherein W is O or S and R 31 is (C 1-6 )alkyl, (d ⁇ haloalkyl, (C 2 . 6 )alkenyl,
  • R 3 -B In one embodiment, R 3 is (C 1-6 )alkyl, (Ci -e )haloalkyl, (C 2 - 6 )alkenyl, (C 2 . 6 )alkynyl, (C 3 .
  • R 3 -C In another embodiment, R 3 is (C 1-6 )alkyl or (C 2 _ 6 )alkenyl; and bond c is a single bond.
  • R 3 -D is -W-(C 1-6 )haloalkyl, -W-(C 2-6 )alkenyl, -W-(C 2 . 6 )alkynyl, -W-(C 3 - 7 )cycloalkyl, -W-aryl, (C 3 -7)cycloalkyl-(C 1 .
  • R 3 is -O-(Ci -6 )alkyl, -O-(C-
  • R 3 -F is -O(C 1-6 )alkyl, -O-(C 1-6 )haloalkyl, -O-(C 2-6 )alkenyl, -O(C 2-6 )alkynyl, -O-(C 3-7 )cycloalkyl, -O-aryl, (C 3 .
  • R 3 is -O(C 1-6 )alkyl, -O-(C-
  • R 3 -H In another embodiment, R 3 is -O(C 1-4 )alkyl; and bond c is a single bond.
  • R 3 -l In another embodiment, R 3 is -OC(CH 3 ) 3 ; and bond c is a single bond.
  • R 3 -J In another embodiment, R 3 is selected from:
  • R 4 -A In one embodiment, R 4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, 13-152
  • R 4 is phenyl optionally substituted with 1 or 3 substituents each independently selected from halo, (Ci -4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, -OH, -O(C 1-4 )alkyl, -SH, -Std ⁇ alkyl, -NH 2 , -NH(C 1-4 )alkyl and -N ⁇ C ⁇ alkyl),.
  • substituents each independently selected from halo, (Ci -4 )alkyl, (C 2-4 )alkenyl, (C 1-4 )haloalkyl, (C 3-7 )cycloalkyl, -OH, -O(C 1-4 )alkyl, -SH, -Std ⁇ alkyl, -NH 2 , -NH(C 1-4 )alkyl and -N ⁇ C ⁇ alkyl),.
  • R 4 -C is phenyl optionally substituted with 1 or 2 substituents each independently selected from F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OH, -OCH 3 , -OCH 2 CH 3 , -SCH 3 , and N(CH 3 ) 2 .
  • R 4 -D In another embodiment, In another alternative embodiment, R 4 is phenyl or Het optionally substituted with 1 or 2 substituents each independently selected from halo, (C 1-6 )alkyl and -O(C 1-6 )alkyl; wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N, O and S.
  • R 4 is Het optionally substituted with 1 to 3 substituents each independently selected from halo, (C 1-6 )alkyl, (C 2 . 6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, -OH, -O(C 14 )alkyl, -SH, -S(C ⁇ )alkyl, -NH 2 , -NH(C 1 . 6 )alkyl and -N((C 1-6 )alkyl) 2 ; wherein the (C 1-6 )alkyl is optionally substituted with hydroxyl or -O(C 1-6 )alkyl.
  • R 4 is Het optionally substituted with 1 or 2 substituents each independently selected from halo, (C 1-6 )alkyl and -O(Ci -6 )alkyl; wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N,
  • R 4 -G In another alternative embodiment, R 4 is phenyl or Het optionally substituted with
  • R 4 -H In another alternative embodiment, R 4 is selected from: R 4 -l: In another alternative embodiment, R 4 is selected from: r 13-152
  • R 4 is selected from:
  • R 4 any and each individual definition of R 4 as set out herein may be combined with any and each individual definition of the Core, R 2 , c, R 3 , R 5 , R 6 and R 7 as set out herein.
  • R 8 is in each instance independently selected from H, (C 1-6 )alkyl,
  • R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3- 7 )cycloalkyl;
  • R 5 -B In an alternative embodiment, R 5 is H, halo, (C 1 . 6 )alkylene-O(C 1-6 )alkyl, (C 1- 6 )alkylene-O-aryl, (C 1 .
  • R 5 -C In another embodiment, R 5 is Het, aryl, (C 1-6 )alkylene-Het or (C 1-6 )alkylene-aryl; wherein said aryl and Het are optionally substituted 1 to 2 times with (C 1-6 )alkyl, -O(C 1-6 )alkyl, or -O(C 1-6 )haloalkyl.
  • R 5 is halo, (C 1-6 )alkylene-O(C 1 . 6 )alkyl, (C 1-6 )alkylene -O- aryl, (C 1-6 )haloalkyl, (C 3 . 7 )cycloalkyl, , -OH Or -O(C 1- 6 )alkyl, Het, aryl, (C 1-6 )alkylene-Het or (Ci -6 )alkylene-aryl wherein said aryl and Het are optionally substituted with (C 1-6 )alkyl, -O(C 1-6 )alkyl, or -O(C 1-6 )haloalkyl.
  • R 5 -E In another embodiment, R 5 is H or (C 1-4 )alkyl.
  • R 5 -F In another embodiment, R 5 is H 1 CH 2 CH 3 or CH 3 .
  • R 5 -G In another embodiment, R 5 is H or CH 3 .
  • R 5 any and each individual definition of R 5 as set out herein may be combined with any and each individual definition of the Core, c, R 2 , R 3 , R 4 , R 6 and R 7 as set out herein.
  • R 8 is in each instance independently selected from H, (C 1-6 )alkyl,
  • R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3 .
  • R 10 is in each instance independently selected from R 8 , -(C 1-6 )alkylene-R 8 ,
  • R 6 is Het, aryl, (C ⁇ alkylene-Het or (C 1-6 )alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (Ci- 6 )alkyl, -O(C 1-6 )alkyl, or -O(C 1-6 )haloalkyl.
  • R 6 -D In another embodiment, R 6 is (C 1-6 )alkylene-Het or (C 1-6 )alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (C 1-6 )alkyl,
  • R 6 is (C 1-6 )alkylene-Het or (C 1-6 )alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (d -6 )alkyl,
  • R 6 any and each individual definition of R 6 as set out herein may be combined with any and each individual definition of the Core, c, R 2 , R 3 , R 4 and R 5 as set out herein.
  • R 8 is in each instance independently selected from H, (d. 6 )alkyl
  • each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C 2 - 6 )alkenyl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl,
  • R 9 is in each instance independently selected from H, (C 1-6 )alkyl and (C 3- 7 )cycloalkyl;
  • R 10 is in each instance independently selected from R 8 , -(C-
  • R 7 is H, (Ci. 6 )alkylene-O(Ci. 6 )alkyl, (C 1-6 )alkylene- O-aryl, (C 1-6 )haloalkyl, (C 3 _ 7 )cycloalkyl, (C 1-6 )alkylene-(C 3-7 )cycloalkyl , -OH or -O(C 1-6 )alkyl.
  • R 7 is Het, aryl, (C 1-6 )alkylene-Het or (C ⁇ alkylene-aryl; wherein said aryl, Het, (C 1-6 )alkylene-Het and (Ci -6 )alkylene-aryl are all optionally substituted 1 to 2 times with (C 1-6 )alkyl, -O(C 1-6 )alkyl, or -O(Ci -6 )haloalkyl.
  • R 7 is H, (Ci -6 )alkylene-O(C 1-6 )alkyl, (C ⁇ alkylene-O-aryl, (C 1-6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkylene-(C 3-7 )cycloalkyl, Het, aryl, (C 1-6 )alkylene-Het or (C 1-6 )alkylene-aryl wherein said aryl, Het, (C 1-6 )alkylene-Het and (C 1-6 )alkylene-aryl are optionally substituted with (C 1 . 6 )alkyl, -O(C 1-6 )alkyl, or -O(C 1-6 )haloalkyl.
  • R 7 -E is (C 1-6 )alkylene-O(C 1-6 )alkyl, (C 1-6 )alkylene-O-aryl, (Ci -6 )haloalkyl, (C 3-7 )cycloalkyl, (C 1-6 )alkylene-(C 3-7 )cycloalkyl , -OH Or -O(C 1- 6 )alkyl, Het, aryl, (d.
  • Het is defined as:
  • R 7 -F In another embodiment, R 7 is H, CH 3 , CH 2 CH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 F,
  • R 7 -G In another embodiment, R 7 is selected from H, (C 1-6 )alkyl, (C 1-6 )haloalkyl, (C 3 .
  • R 21 is H, (C ⁇ alkyl, (C ⁇ haloalkyl, Het optionally substituted with (C 1-6 )alkyl, aryl optionally substituted with (C 1-6 )alkyl, (C 1-6 )alkyl-Het, (C 1-6 )alkyl- 13-152
  • R 7 any and each individual definition of R 7 as set out herein may be combined with any and each individual definition of the Core, c, R 2 , R 3 , R 4 and R 5 as set out herein.
  • enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like.
  • one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer.
  • one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the present invention from this disclosure and the knowledge in the art.
  • Compounds of the present invention may be administered to a mammal in need of treatment for HIV infection as a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt or ester thereof; and one or more conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the specific formulation of the composition is determined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice.
  • the pharmaceutical composition according to the present invention may be administered orally or systemically.
  • the pharmaceutical composition according to the invention may comprise a racemic mixture of the active ingredient, a mixture enriched in one enantiomer of the active ingredient or a pure enantiomer of the active ingredient.
  • the mixture enriched in one enantiomer of the active ingredient is contemplated to contain from more than 50% to about 100% of one enantiomer of the active ingredient and from about 0% to less than 50% of the other enantiomer of the active ingredient.
  • the composition comprises a mixture enriched in one enantiomer of the 13-152
  • the composition comprises from more than 50% to about 100% of, or only, the more physiologically active enantiomer and/or the less toxic enantiomer. It is well known that one enantiomer of an active ingredient may be the more physiologically active for one therapeutic indication while the other enantiomer of the active ingredient may be the more physiologically active for a different therapeutic indication; therefore the preferred enantiomeric makeup of the pharmaceutical composition may differ for use of the composition in treating different therapeutic indications.
  • the compound, or a pharmaceutically acceptable salt or ester thereof can be formulated in any orally acceptable dosage form including but not limited to aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets.
  • any orally acceptable dosage form including but not limited to aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets.
  • systemic administration including but not limited to administration by subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, and intralesional injection or infusion techniques, it is preferred to use a solution of the compound, or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable sterile aqueous vehicle.
  • compositions for various modes of administration are well-known to those of skill in the art and are described in pharmaceutical texts such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2005; and L.V. Allen, N. G. Popovish and H. C. Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th ed., Lippincott Williams & Wilkins, 2004, herein incorporated by reference.
  • the dosage administered will vary depending upon known factors, including but not limited to the activity and pharmacodynamic characteristics of the specific compound employed and its mode, time and route of administration; the age, diet, gender, body weight and general health status of the recipient; the nature and extent of the symptoms; the severity and course of the infection; the kind of concurrent treatment; the frequency of treatment; the effect desired; and the judgment of the treating physician.
  • the compound is most desirably administered at a dosage level that will generally afford antivirally effective results without causing any harmful or deleterious side effects. 13-152
  • a daily dosage of active ingredient can be expected to be about 0.001 to about 100 milligrams per kilogram of body weight, with the preferred dose being about 0.01 to about 50 mg/kg.
  • the pharmaceutical composition of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound ⁇ w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
  • the pharmaceutical composition according to the invention comprises a racemic mixture of the compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
  • An alternative embodiment provides a pharmaceutical composition comprising a mixture enriched in one enantiomer of the compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
  • a further embodiment provides a pharmaceutical composition comprising a pure enantiomer of the compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
  • Combination therapy is contemplated wherein a compound according to the invention, or a pharmaceutically acceptable salt or ester thereof, is co-administered with at least one additional antiviral agent.
  • the additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered, concurrently or sequentially, as part of a multiple dosage form.
  • composition of this invention comprises a combination of a compound according to the invention, or a pharmaceutically acceptable salt or ester 13-152
  • both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
  • the dosage of any or all of the active agents in the combination may be reduced compared to the dosage normally administered in a monotherapy regimen.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from:
  • NRTIs nucleoside or nucleotide reverse transcriptase inhibitors
  • ZT zidovudine
  • ddl didanosine
  • ddC zalcitabine
  • stavudine d4T
  • lamivudine 3TC
  • emtricitabine abacavir succinate, elvucitabine, adefovir dipivoxil, lobucavir (BMS-180194) lodenosine (FddA) and tenofovir including tenofovir disoproxil and tenofovir disoproxil fumarate salt
  • COMBIVIRTM contains 3TC and AZT
  • TRIZIVIRTM contains abacavir, 3TC and AZT
  • TRUVADATM contains tenofovir and emtricitabine
  • EPZICOM TM contains abacavir and 3TC
  • NRTIs nucleoside or nu
  • NNRTIs non-nucleoside reverse transcriptase inhibitors
  • nevirapine delaviradine
  • efavirenz efavirenz
  • etravirine etravirine
  • rilpivirine rilpivirine
  • protease inhibitors including but not limited to ritonavir, tipranavir, saquinavir, nelfinavir, indinavir, amprenavir, fosamprenavir, atazanavir, lopinavir, darunavir, lasinavir, brecanavir, VX-385 and TMC-114;
  • entry inhibitors including but not limited to
  • CCR5 antagonists including but not limited to maraviroc, vicriviroc, INCB9471 and TAK-652
  • CXCR4 antagonists including but not limited to AMD-11070
  • fusion inhibitors including but not limited to enfuvirtide (T-20), TR1-1144 and TR1-999) and
  • integrase inhibitors including but not limited to raltegravir (MK-0518), BMS-707035 and elvitegravir (GS 9137)); 13-152
  • immunomodulating agents including but not limited to levamisole
  • a compound according to the invention can be used with at least one other compound according to the invention or with one or more antifungal or antibacterial agents (including but not limited to fluconazole).
  • the pharmaceutical composition of this invention additionally comprises one or more antiviral agents.
  • a further embodiment provides the pharmaceutical composition of this invention wherein the one or more antiviral agent comprises at least one NNRTI.
  • the one or more antiviral agent comprises at least one NRTI.
  • the one or more antiviral agent comprises at least one protease inhibitor.
  • the one or more antiviral agent comprises at least one entry inhibitor.
  • the one or more antiviral agent comprises at least one integrase inhibitor.
  • a compound according to the present invention may also be used as a laboratory reagent or a research reagent.
  • a compound of the present invention may be used as positive control to validate assays, including but not limited to surrogate cell- based assays and in vitro or in vivo viral replication assays.
  • a compound according to the present invention may be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of 13-152
  • Another aspect of the invention provides a derivative of a compound of formula (I), the derivative comprising a detectable label.
  • a detectable label allows recognition either directly or indirectly of the derivative such that it can be detected, measured or quantified.
  • the detectable label may itself be detectable, measurable or quantifiable, or it may interact with one or more other moities which themselves comprise one or more detectable labels, so that the interaction therebetween allows the derivative to be detected, measured or quantified.
  • Such derivatives may be used as probes to study HIV replication, including but not limited to study of the mechanism of action of viral and host proteins involved in HIV replication, study of conformational changes undergone by such viral and host proteins under various conditions and study of interactions with entities which bind to or otherwise interact with these viral and host proteins.
  • Derivatives according to this aspect of the invention may be used in assays to identify compounds which interact with viral and host proteins, the assays including but not limited to displacement assays which measure the extent to which the derivative is displaced from interacting with the viral and host proteins.
  • a preferred use of derivatives according to this aspect of the invention is in displacement assays to identify HIV integrase inhibitors.
  • Such derivatives may also be used to form covalent or non-covalent interactions with the viral and host proteins or to identify residues of the viral and host proteins which interact with the compounds of the invention.
  • Detectable labels contemplated for use with derivatives of the compounds of the invention include, but are not limited to, fluorescent labels, chemiluminescent labels, chromophores, antibodies, enzymatic markers, radioactive isotopes, affinity tags and photoreactive groups.
  • a fluorescent label is a label which fluoresces, emitting light of one wavelength upon absorption of light of a different wavelength. Fluorescent labels include but are not 13-152
  • rhodamine dyes including but not limited to tetramethylrhodamine (TAMRA); Alexa dyes including but not limited to Alexa Fluor® 555; cyanine dyes including but not limited to Cy3; europium or lanthanide series based fluorescent molecules; and the like.
  • a chemiluminescent label is a label which can undergo a chemical reaction which produces light.
  • Chemiluminescent labels include but are not limited to luminol, luciferin, lucigenin, and the like.
  • a chromophore is a label which selectively absorbs certain wavelengths of visible light while transmitting or reflecting others, thereby causing the compounds which contain the chromophore to appear colored.
  • Chromophores include but are not limited to natural and synthetic dyes.
  • An antibody is a protein produced by a mammalian immune system in response to a specific antigen, which binds specifically to that antigen.
  • Antibodies contemplated for use as detectable labels according to the invention include but are not limited to antibodies against the following: polyhistidine tags, glutathione-S-transferase (GST), hemagglutinin (HA), FLAG ® epitope tags, Myc tag, maltose binding protein (MBP), green fluorescent protein (GFP) and the like.
  • An enzymatic marker is an enzyme whose presence may be detected by means of an assay specific to the catalytic activity of the enzyme.
  • Enzymatic markers contemplated for use as detectable labels according to the invention include but are not limited to luciferase, horseradish peroxidase (HRP), ⁇ -galactosidase and the like.
  • a radioactive isotope is an isotope of an atom which produces radiation upon radioactive decay.
  • Radioactive isotopes include but are not limited to 14 C, 3 H, 31 P, 121 1, 125 I and the like.
  • An affinity tag is a label which has a strong affinity for another moiety, designated herein as a binding partner. Such an affinity tag can be used to form a complex with the binding partner so that the complex may be selectively detected or separated from a mixture.
  • Affinity tags include but are not limited to biotin or a derivative thereof, a histidine 13-152
  • polypeptide a polyarginine, an amylose sugar moiety or a defined epitope recognizable by a specific antibody
  • suitable epitopes include but are not limited to glutathione-S- transferase (GST), hemagglutinin (HA), FLAG ® epitope tags, Myc tag, maltose binding protein (MBP), green fluorescent protein (GFP) and the like.
  • compounds of the invention used as probes may be labelled with a photoreactive group which is transformed, upon activation by light, from an inert group to a reactive species, such as a free radical. Such a group may be used to activate the derivative so that it can form a covalent bond with one or more residues of a viral or host protein.
  • Photoreactive groups include but are not limited to photoaffinity labels such as benzophenone and azide groups.
  • R 42 , R 43 , R 44 , R 45 and R 46 may either be substituents on the phenyl moiety or (R 42 and R 43 ), (R 43 and R 44 ), (R 44 and R 45 ) or (R 45 and R 46 ) may be linked so to as to form a carbocycle or heterocycle
  • W is iodo, bromo, chloro or OTf
  • V is B(OH) 2 or boronate esters such as B(OCH 3 ) 2 and B(OC(CH 3 ) 2 C(CH 3 ) 2 ⁇ )
  • I 1 SnR 3 wherein R is (C 1-6 )alkyl, ZnX wherein X is halo
  • P is a protecting group, such as commonly used protecting groups for carboxylic acids, including, but not limited to a methyl or ethyl ester. 13-152
  • intermediate (I) i.e. pyrazolopyridine scaffold
  • intermediate Il i.e. R 4 substituent
  • Suzuki cross-coupling between the boronic acid or boronate ester derivative of intermediate Il and the halo or triflate derivative of intermediate I copper catalyzed Ullmann cross-coupling between the iodo derivatives of intermediates I and II
  • Stille coupling between the arylltin reagent of intermediate Il and the bromo or iodo derivative of intermediate I as shown above can lead, after saponification, to the compounds of the invention of formula (I).
  • cross-coupling methods can be used by interchanging the coupling partners as shown below.
  • Suzuki, Negishi, and Stille type cross- coupling between boronic acid or boronate ester derivative, the arylzinc reagent or the arylltin reagent of pyrazolopyridine intermediate III and the required iodo, bromo, chloro or triflate derivative of intermediate IV can also lead, after saponification, to the compounds of formula (I).
  • R 42 , R 43 , R 44 , R 45 and, R 46 and Pare as defined above and W is iodo, bromo, chloro or OTf
  • V is B(OH) 2 or boronate esters such as B(OCH 3 ) 2 and B(OC(CH 3 ) 2 C(CH 3 ) 2 O), SnR 3 wherein R is (C 1-6 )alkyl, and ZnX wherein X is halo.
  • intermediate I i.e. the pyrazolopyridine scaffold
  • intermediate Il i.e. the R 4 substituent
  • modification at R 7 can easily be incorporated into the synthetic scheme by simply protecting the N7 with a suitable protecting group (e.g. para- methoxybenzyl , etc) during synthesis of the scaffold I and subsequent removal of the 13-152
  • L leaving group, such as Br or I
  • downstream modifications to the product can be contemplated, such as conversion of an aniline-type amine to a chloro or bromo substituent via Sandmeyers reaction or alkylation, or dehalogenation via reduction.
  • Preparative HPLC is carried out under standard conditions using a SunFireTM Prep C18 OBD 5 ⁇ M reverse phase column, 19 x 50 mm and a linear gradient employing 0.1%TFA/acetonitrile and 0.1%TFA/water as solvents. Compounds are isolated as TFA salts when applicable.
  • DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • DIAD diisopropyl azodicarboxylate
  • DIBAL diisobutyl aluminum hydride
  • Dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
  • IC 50 50% inhibitory concentration
  • 'Pr or i-Pr 1 -methylethyl (/so-propyl);
  • LiHMDS lithium hexamethyldisilazide
  • MOI multiplicity of infection
  • n-BuONa sodium n-butoxide
  • n-BuOH n-butanol
  • n-BuLI n-butyllithium
  • Ph phenyl
  • RT room temperature (approximately 18°C to 25°C);
  • SM starting material
  • tert-butyl or t-butyl 1 ,1-dimethylethyl
  • Tf trifluoromethanesulfonyl
  • Tf 2 O trifluoromethanesulfonic anhydride
  • TFA trifluoroacetic acid
  • Step 1
  • hydrochloride salt of 1f To the stirred suspension of this intermediate in dry acetonitrile (350 mL) is added dry NaI (59.6 g, 0.40 mol, pre-dried under vacuum at 120 0 C for about 2 h) and heated under Ar to 65°C for about 16 h. The reaction mixture is evaporated to dryness and diluted with saturated aqueous NaHCO 3 and extracted with CH 2 CI 2 (3X100 mL). The combined organic layers are washed with saturated aqueous Na 2 S 2 O 3 , water, and brine, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to afford 1g (30.0 g, 93% yield) which is used in the next reaction without further purification.
  • Step 11
  • the reaction mixture is quenched by adding ice water and then extracted with EtOAc.
  • the combined organic layers are washed with water, brine, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure.
  • the crude was combined with the crude of another batch starting from 1k (6.2 g, 12.2 mmol) and purified together by flash column chromatography with Petroleum ether: EtOAc (85:15 v/v) to afford a mixture of two diastereomers (11.6 g, 64% yield) as a white solid.
  • the diastereomers are separated (1.5g scale) by chromatography on a CombiFlash® Companion instrument using a very slow gradient of THF:hexane on a normal phase column.
  • the products are eluted with THF:hexane (20:80 v/v). The less polar product is identified to be the desired diastereomer 11 (0.75 g, 50% yield).
  • the water layer is acidified with 10% HCI and extracted with EtOAc and dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude acid.
  • the acid is dissolved in MeOH/toluene (2 mL/16 mL) and (trimethylsilyl) diazomethane (2 M in hexane, 2.1 mL, 4.3 mmol) is added.
  • the reaction mixture is stirred for about 12 h and the reaction is quenched with AcOH, stirred for about 5 min and concentrated under reduced pressure.
  • the pure intermediate 1m is isolated as white solid (0.91 g, 81% yield) after flash column chromatography with Hexanes:EtOAc (65:35 v/v).
  • Step i
  • crotononitrile 50 g, 0.745 mol
  • dry THF 200 ml_
  • hydrazine hydrate 39.2 g, 0.782 mol
  • p-Anisaldehyde 106.5 g, 0.782 mol
  • Step 11
  • Isolation of the desired enantiomer 2m is achieved using the Evan's chiral auxiliary (i.e. conversion of 2k to intermediate 2I) as described in Example 1 for the isolation of 1m from the mixture of enatiomers 1k.
  • Step i
  • the ketone 4b (127 mg, 0.64 mmol) is dissolved in EtOH (2 ml.) and treated with hydrazine hydrate (500 ⁇ L, 16 mmol). The mixture is heated to reflux for about 45 min before allowing it to cool to RT. The solvent is removed by evaporation and the residue is dissolved in diethylene glycol (1 mL) before being treated with KOH (108 mg, 1.92 mmol, 3 eq) and then heated to 110-120 0 C for about 2.5 h. The reaction mixture is diluted with EtOAc and the pH is adjusted with 1 N HCI to pH ⁇ 4. The organic phase is separated, washed with saturated brine, dried over anhydrous MgSO 4 , filtered and concentrated. The crude material is purified by CombiFlash® Companion (eluent: 0- 50% EtOAc/hexanes) to give intermediate 4c as a yellow oil (62 mg).
  • the phenol 4d (40 mg, 0.23 mmol) is dissolved in DCM (2 mL), cooled to O 0 C and treated with pyridine (95 ⁇ L, 1.17 mmol, 5 eq), followed by Tf 2 O (44 ⁇ L, 0.26 mmol, 1.1 eq).
  • the reaction is allowed to stir at this temperature for about 10 min before warming to RT over a period of about 1 h.
  • the reaction mixture is diluted with DCM and the organic phase washed with 10% citric acid and then brine.
  • the organic phase is dried over anhydrous MgSO 4 , filtered, concentrated and purified by CombiFlash® Companion (0-50% EtOAc/ hexanes) to give 4e as a yellow oil (67 mg, 94% yield).
  • This solution is de-gassed (with bubbling Ar) for about 10 min before adding PdCI 2 (dppf)- CH 2 CI 2 , (27 mg, 0.03 mmol, 0.15 eq).
  • the mixture is de-gassed a further 5 min before being heated to 9O 0 C for about 16 h.
  • the mixture is cooled to RT and diluted with EtOAc/water.
  • the organic phase is washed with saturated brine (3x), dried over anhydrous MgSO 4 , filtered and concentrated.
  • the crude material is purified by CombiFlash® Companion (0-70% EtOAc in hexanes) to afford the boronate 4f as a white solid (41 mg, 67% yield).
  • Step i
  • reaction mixture is allowed to cool to RT, dilute with EtOAc (150 ml_), washed with brine (3 x 100 ml_) and water (2 x 100 ml_), dried over anhydrous MgSO 4 , filtered and concentrated to dryness.
  • the residue is purified by CombiFlash® Companion (EtOAc/hexanes) to give the desired boronate 5f (389 mg, 65% yield) as a yellowish waxy solid.
  • Step 1
  • Diisopropylamine (21.0 mL, 121 mmol) in THF (330 mL) is treated with a solution of n- BuLi (2.5 M in hexanes, 48.2 mL, 121 mmol) at O 0 C. After 30 min at this temperature, the solution is cooled to -78°C and carbamate 6b (33.29 g, 109.7 mmol, 75 % pure) is added. The reaction is stirred at this temperature for about 30 min and then iodine (33.4 g, 132 mmol) is added. The solution is stirred for about 30 min at O 0 C and is then warmed to RT.
  • reaction mixture is quenched with water (250 mL) and the volatile organic solvents are removed under reduced pressure.
  • the aqueous phase is then extracted with EtOAc (3 x 100 mL), washed with 1 N HCI (1 x 200 mL), dry MgSO 4 , filtered and evaporated under reduced pressure to obtain 6c (18.6 g, 39% yield).
  • the iodocarbamate 6c (10 g, 28 mmol), propargyl alcohol (3.3 mL, 56 mmol), Pd(PPh 3 ) 4 (3.27 g, 2.83 mmol) and copper iodide (1.08 g, 5.66 mmol) are combined in diisopropylamine (39 mL, 39 mmol) in a sealable tube under Ar and heated at 100 0 C. After about 1 h, the reaction is cooled to RT and poured into EtOAc (10OmL) and this mixture is extracted with 10% HCI (2 x 100 mL). The organic layer is dried over MgSO 4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain the alcohol 6d (3.65 g, 46% yield).
  • Step 1
  • a solution of phenol 7a (0.91 g, 5.74 mmol) in dry DMF (1 ml_) is added dropwise to a slurry of NaH (60% in oil, 0.60 g, 15 mmol) in dry DMF (1 ml.) cooled to 10-15 0 C (cold water bath) and the mixture is stirred for about 20 min. This results in a thick, frothy white mixture.
  • a solution of 3-bromopropionic acid (1.1 g, 6.9 mmol) in dry DMF (0.5 ml_) is then added dropwise and the reaction stirred at RT overnight.
  • Intermediate 7c is analogous to intermediate 4b in Example 4; those skilled in the art would recognize that the same synthetic methodologies used to convert 4b to the boronate 4f can be applied for the conversion of 7c to the corresponding boronate 7d.
  • 2-Amino-/77-cresol 8a (5.7 g, 46.3 mmol) is dissolved in H 2 O (30 mL) and 1 ,4-dioxane (15 mL). The mixture is heated to reflux and then HBr (48%, 17 mL, 0.31 mol) is added dropwise over a period of about 20 min. The reflux is maintained for about an additional 15 min after the addition is complete. The reaction is cooled to O 0 C, and NaNO 2 in H 2 O (20 mL) is added over a period of about 30 min.
  • the stirring is continued for about 15 min at O 0 C, the mixture is then transferred in one shot to a stirring mixture of Cu(I)Br (7.64 g, 53.2 mmol, 1.15 eq) in H 2 O (20 mL) and HBr (48%, 17 mL, 0.31 mol) at O 0 C (protected from light).
  • the reaction is stirred for about 15 min at O 0 C, is warmed to 6O 0 C, is stirred for an additional 15 min, is cooled to RT and is then stirred overnight.
  • the reaction mixture is then transferred to a separatory funnel and extracted with EtOAc (3x).
  • the methyl ketone 8c (1.02 g, 6.8 mmol) is dissolved in EtOAc (15 mL) and CHCI 3 (15 mL) before being treated with Cu(II)Br 2 (3.03 g, 13.6 mmol, 2 eq). The mixture is heated to reflux for about 16 h. The mixture is cooled to RT, the product filtered and washed with EtOAc (1x). The solution is concentrated over silica to afford the mixture that is purified using the CombiFlash® Companion (10% EtOAc/hexanes) to afford the ⁇ - bromoketone 8d (710 mg, 46% yield) as an orange oil. This crude material is used in the next step without purification.
  • Zn dust pre-activation procedure Zinc dust (20 g, 350 mesh) is placed in a round bottom flask and 1 N HCI (50 mL) is added. This suspension is sonicated for about 1 min before decanting off the liquid. This procedure is repeated for a second time after which the solid is washed with EtOH (2x), Et 2 O (2x) and dried under high vacuum. To a solution of the ketone 8e (280 mg, 1.89 mmol) in AcOH (10 mL) pre-activated Zn dust (1.24 g, 18.9 mmol, 10 eq) is added. The reaction mixture is then heated to 75 0 C for 13-152
  • Step 1
  • the crude aminophenol 10b (6.37 g. 36.7 mmol) is dissolved in THF (100 mL) and tin powder (17.4 g, 147 mmol) is added followed by 1 N HCI (220 mL, 220 mmol). The resulting mixture is stirred vigorously at RT. After 16 h, the reaction is cooled to O 0 C, the acid neutralized with 10 N NaOH (22 mL) and the resulting milky suspension stirred vigorously for about 15 min. The mixture is then filtered through a pad of Celite® and the solids washed thoroughly with EtOAc (4 x 200 mL).
  • a solution of borane in THF (1.0 M, 18.5 mL, 18.5 mmol) is added dropwise to an ice- cold solution of lactam 10e (4.00 g, 15.2 mmol) in anhydrous THF (75 mL), and the reaction is allowed to warm to RT. After about 30 min, the solution is heated to gentle reflux under a N 2 atmosphere. After about 2 h, the reaction is cooled to O 0 C and carefully quenched with 1 N NaOH (19 mL) and stirred for about 15 min. The mixture is then diluted with water (30 mL) and the THF is evaporated.
  • Step 1
  • chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 ml_) is added to a suspension of zinc dust (108 g, 1.65 mol) in AcOH (150 ml_). The mixture is heated to 100 0 C and is stirred mechanically overnight. The mixture is then filtered through Celite® (washed with EtOAc, 10OmL), diluted with PhMe (300 ml_) and the solution is evaporated to give chroman intermediate 11b (8.45 g, 95% yield).
  • Step i
  • the phenol 12a (6.75 g, 47.3 mmol) is dissolved in DMF (270 ml.) and is treated with ally] bromide (6.55 ml_, 75.7 mmol, 1.6 eq).
  • NaH (60%, 4 g, 99.4 mmol, 2.1 eq) is added portionwise and stirring is continued overnight.
  • the reaction mixture is diluted with EtOAc (500 mL) and washed with H 2 O (3 x 500 ml_).
  • the organic layer is dried over MgSO 4 , filtered and concentrated to dryness to obtain the desired product 12b, which is used as such in the next step.
  • the ether 12b (9.67 g) is placed in a microwave vial neat with a stir bar and is heated to 24O 0 C for about 20 min at which point the Claisen rearrangement reaction is complete.
  • the crude product 12c (9.3 g) is used in the following step without further purification.
  • the chroman derivative 12e (5.26 g, 28.8 mmol) is dissolved in AcOH (70 mL) and is then treated with Br 2 in AcOH (40 mL). The reaction is stirred at RT for about 15 min, then diluted with toluene and concentrated to dryness. The residue is taken up in EtOAc (25 mL) and washed with saturated Na 2 S 2 O 3 (25 mL) and saturated NaHCO 3 (25 mL). The organic layer is dried over MgSO 4 , concentrated and purified by CombiFlash® Companion to obtain the desired product 12f (2.7 g, 36% yield).
  • the bromide 12f (2.71 g, 10.4 mmol) is dissolved in DMF (120 mL) and treated with bis[pinocolato]diborane (4 g, 15.5 mmol, 1.5 eq) and potassium acetate (3.45 g, 36.3 mmol, 3.5 eq).
  • the mixture is degassed (using an Ar balloon) before the introduction of the catalyst (PdCI 2 dppf, 845 mg, 1.04 mmol, 0.1 eq).
  • the mixture is then degassed again (using an Ar balloon) and heated to 95 0 C for about 16 h.
  • the mixture is cooled to RT, diluted with H 2 O (300 mL) and extracted with EtOAc (2 x 300 mL).
  • Step 1
  • Step 1
  • AIIyI bromide (9.3 ml_, 110 mmol) followed by potassium carbonate (20 g, 150 mmol) are added to a solution of 14a (1O g, 73 mmol) dissolved in DMF 110 ml_). The reaction is allowed to stir under Ar at RT overnight. The reaction is diluted with water (400 ml_) and extracted with EtOAc (400 ml_). The organic layer is washed with water (2 x 400 ml_), dried over Na 2 SO 4 and concentrated. The product is then purified by CombiFlash® Companion in two batches (120 g column) to provide allyl ether 14b (12g, 92% yield). 13-152
  • Step i
  • a solution of DIBAL in DCM (1 M, 42 mL, 42 mmol) is added dropwise over a period of about 25 min to a precooled (-78 0 C) solution of ester 15c (3.8 g, 19 mmol) in dry CH 2 CI 2 (100 mL).
  • the reaction is allowed to stir for about 2 h at -78°C.
  • the reaction is quenched at -78°C by the dropwise addition of 1 N HCI (8 mL).
  • Triethylamine (0.56 mL, 4.0 mmol) and diphenylphosphoryl azide (0.75 mL, 3.5 mmol) are added successively to a solution of acid 15h (714 mg, 3.4 mmol) in dry toluene (40 mL).
  • This mixture is heated to 85°C for about 2 h and then cooled to RT and treated with 6 N HCI (6 mL). The mixture is brought to reflux and is stirred at this temperature for about 2 h.
  • the reaction is then cooled to RT, diluted with EtOAc (100 mL) and washed with saturated NaHCO 3 (2 x 100 mL), water (2 x 100 mL) and brine (100 mL).
  • the organic layer is dried over MgSO 4 , filtered and evaporated to dryness.
  • the product is then purified by CombiFlash® Companion to give ketone 15i (269 mg, 44% yield). 13-152
  • Deoxofluor® (0.54 ml_, 2.9 mmol) is added to a solution of ketone 15i (270 mg, 1.5 mmol) in CH 2 CI 2 (0.6 ml_) and EtOH (17 ⁇ l_) in a sealed tube.
  • the sealed tube is heated to 40 0 C for about 24 h.
  • the tube is then unsealed, cooled to 0 0 C and the reaction quenched by the slow (Caution! Exothermic!) addition of saturated NaHCO 3 (1 ml_).
  • the crude reaction mixture is diluted with water (20 ml_) and extracted with DCM (3 x 20 ml_).
  • Step 11
  • Step i
  • Step i
  • Step i
  • Neat Tf 2 O (0.83 ml_, 4.9 mmol) is added dropwise to a cooled (0 0 C) solution of phenol 18a (0.50 g, 3.1 mmol) and pyridine (1.3 ml_, 17 mmol) in DCM (15 ml_). The reaction is allowed to warm to RT and stir overnight. The reaction is quenched by the addition of a 10% citric acid solution (50 mL) and the mixture is extracted with DCM (3 x 50 ml_). The combined organics are washed with water (50 mL), dried over MgSO 4 , filtered and concentrated. The product is purified by CombiFlash® Companion to give triflate 18b (500 mg, 94% yield).
  • Step three is performed as described in step 6 of Example 17 to provide boronic ester
  • Step 1
  • a solution of NaNO 2 (1.2 g, 17 mmol) in water (5 ml_) is slowly added to a precooled (O 0 C) suspension of aniline 19b (2.8 g, 15 mmol) in 12 N HCI (7 ml.) and ice (9.7 g), so as to maintain the temperature below 5°C.
  • the mixture is stirred for about 15 min and then is transferred to a solution of Kl (8.7 g, 52 mmol) in water (30 ml_) and the resulting mixture is stirred for about 2 h.
  • Step three is carried out as described in step 11 of Example 15 to provide boronic ester
  • Step i
  • AIIyI bromide (2.1 ml_, 25 mmol) followed by potassium carbonate (7.2 g, 52 mmol) are added to a solution of 6-chlororesorcinol 20a (10 g, 69 mmol) dissolved in DMF (120 ml_). The reaction is stirred overnight, diluted with EtOAc (500 mL) and washed with water (3 x 500 mL). The organic layer is dried over MgSO 4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain allyl ether 20b (1.8 g, 40% yield).
  • Step 3 is comprised of a sequence of steps as described in steps 2 through 6 of
  • Example 12 followed by step 1 of Example 13 to provide boronic ester 2Od.
  • Step 1
  • Step 6 is carried out as described in step 11 of Example 15 to provide boronic ester 21g.
  • Step 1
  • Step 3 follows the synthetic steps outlined in steps 10 and 11 of Example 15 to provide boronic ester 22d.
  • Step i
  • Neat Tf 2 O (056 mL, 3.3 mmol) is added dropwise to a cooled (0 0 C) solution of phenol 23a (350 mg, 2.1 mmol; prepared according to Doi et al Bull. Chem. Soc. Jpn. 2004 77, 2257-2263) and pyridine (0.91 mL, 11 mmol) in DCM (10 mL) under an Ar atmosphere.
  • the reaction is allowed to warm to RT and then is stirred for about 2 h.
  • the reaction is quenched by the addition of a 10% citric acid solution (20 mL) and extracted with DCM (3 x 20 mL).
  • the combined organic layers are washed with water (20 mL), dried over MgSO 4 , filtered and concentrated to dryness.
  • the crude product is purified by CombiFlash® Companion to provide triflate 23b (512 mg, 82% yield).
  • Step 1
  • Compound 24b is prepared from 24a following a synthetic sequence as described in steps 1 to 6 of Example 12.
  • Step i
  • Step 1
  • Step i
  • Step i
  • Step 1
  • Step i
  • Compound 30b is prepared from 30a following a synthetic sequence described in steps
  • Step i
  • Compound 32b is prepared from 32a following a synthetic sequence described in steps
  • Step i
  • Step 1
  • AIIyI bromide (3.0 mL, 35 mmol) followed by potassium carbonate (6.5 g, 47 mmol) are added to a solution of phenol 34b (5 g, 23 mmol) dissolved in DMF (100 mL). The reaction is stirred overnight, diluted with EtOAc (500 mL) and washed with water (3 x 500 mL). The organic layer is dried over Na 2 SO 4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain benzyl ether 34c (4.4 g, 75% yield).
  • Benzyl ether 34d and Pd-C (10% w/w, 100 mg, 0.094 mmol) are combined in EtOAc (5 mL) and the flask is evacuated and backfilled with a H 2 atmosphere (balloon). After stirring for about 3 h, the reaction is filtered through Celite® (EtOAc washing) and the filtrated concentrated to give phenol 34e (145 mg, 95% yield).
  • Compound 34f is prepared from 34e following a synthetic sequence described in steps 5 to 6 of Example 17.
  • Steps 1 through 4 are done in analogy to steps 3 through 6 from Example 17.
  • 4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) is dissolved in 50 mL ethyl acetate and solid tin(ll) chloride dihydrate (20.0 g, 86.9 mmol) is added.
  • the mixture is heated under nitrogen atmosphere at 70 0 C for about 2 h (note: temporary overheating to 100 0 C is observed! Caution should be exercised!).
  • the mixture is cooled down and is poured into 200 mL of ice-water. 50 mL of 5% aqueous NaHCO 3 solution is added (rapid foaming!), followed by 10 N aqueous NaOH to bring the pH to about 7-8. Large volume of gelatinous yellowish precipitate is formed.
  • the mixture is transferred into a separatory funnel, the organic layer is separated and the aqueous layer is washed with Et 2 O.
  • the aqueous layer is then transferred into a 500 ml_ Erlenmeyer flask and the pH of the solution is adjusted to approximately 6.3 (measured with a pH meter) by slowly adding a saturated solution of NaHCO 3 in water ( ⁇ 25 ml_, careful: foaming!).
  • the suspension is filtered off and the separated light-beige solid is washed with water and dried under high vacuum.
  • This crude product (383 mg) is triturated with Et 2 O /hexanes to give a first crop of the desired compound 36d as a free base (120 mg, 28% yield).
  • the mother liquors are concentrated under vacuum and are purified by reversed-phase HPLC using a CH 3 CN/H 2 O gradient containing 0.06% TFA 13-152
  • 1-bromo-4-chloro-2-nitrobenzene 37a is transformed to compound 37b using the procedure of example 36b, except for the fact that Et 2 O is used for the extractions instead of EtOAc.
  • Compound 37b (4.2 g, 20.3 mmol) is melted at 50 0 C in a 100 mL round-bottomed flask containing a stirring bar and immersed in an oil bath. A solution of zinc chloride (700 mg, 5.03 mmol) and ferric chloride (540 mg, 3.25 mmol) in 3.3 mL of water is added in one portion followed by 20 m L of absolute EtOH. The flask is stoppered with a rubber septa and a needle is inserted to avoid any pressure build-up. The mixture is warmed to 80 0 C and acrolein (1.68 mL, 24.4 mmol) is added via a syringe pump over a 2 h period.
  • acrolein (1.68 mL, 24.4 mmol
  • the mixture is stirred at 80 0 C for 1 h and an additional amount of solid ferric chloride is added (4.1 g, 25.3 mmol).
  • the mixture is stirred at 8O 0 C for about an extra 24 h and then concentrated under vacuum to give a semi-solid residue.
  • 200 mL of water is added followed by a 10 N aqueous solution of NaOH (20 mL) and 200 mL of CH 2 CI 2 .
  • the solid is filtered over a pad of Celite® and the filtrate is transferred into a separatory funnel. The organic layer is separated and the aqueous layer is extracted with CH 2 CI 2 .
  • Compound 37c is transformed to compound 37d using the procedure of example 36d.
  • Step i
  • Compound 38b is transformed to compound 38c using the procedure of example 36d.
  • a mixture of diisopropylethyl amine (46.5 ml_, 267 mmol) in dry DMF (250 ml.) is degassed with argon for about 30 min and is added to a mixture of compound 39e (30.0 g, 88.5 mmol), triphenylphosphine (7.70 g, 29.4 mmol), tris(dibenzylideneacetone)di- palladium(0)-chloroform adduct (9.21 g, 8.9 mmol).
  • the resulting mixture is stirred for about 5 min at 0°C and TMS-acetylene (13.4 g, 136 mmol) is added dropwise.
  • Step i
  • the boronic ester 11d (14.5 mg, 0.06 mmol), intermediate 40b (30 mg, 0.06 mmol), K 2 CO 3 (25.3 mg, 0.18 mmol) and Pd(PPh 3 ) 4 (0) (7 mg, 0.006 mmol) are mixed and the vial is flushed with Ar.
  • water (1 ml_) and DMF (3 ml.) are added and then heated to 80 0 C for about 2 h.
  • the mixture is neutralized with 1 N HCI and concentrated under reduced pressure.
  • the residue is dissolved in the mixture of THF (1.5 ml.) and MeOH (0.5 ml) and then 1 N NaOH solution (0.9 ml_, 0.9 mmol) is added.
  • intermediate 40a can be coupled to a variety of other optionally substituted alkyl-aryl or alkyl-Het groups, such as, Aryl-CH 2 - or Het-CH 2 - moieties using commercially available Aryl-CH 2 OH or Het-CH 2 -OH building blocks via a Mitsunobu reaction as shown for Example 40, Step 2.
  • a variety of boronates can be couple at the C-4 carbon using Suzuki cross-coupling reactions as shown in Example 40, Step 3.
  • the synthesis of selected boronates that are not commercially available and have been used to prepare compounds of this invention are shown in Examples 4 to 39.
  • An additional example that describes the formation of two final products is shown in Example 41 ; it would be obvious to those skilled in the art that the same methodology can be applied for the synthesis of other examples shown in Tables 1 and 2.
  • Step i
  • Example 43 C8166 HIV-1 Luciferase Assay (EC 50 )
  • C8166 cells are derived from a human T-lymphotrophic virus type 1 immortalized but nonexpressing line of cord blood lymphocytes (NIH AIDS reagent 404) and are highly permissive to HIV-1 infection.
  • the pGL3 Basic LTR/TAR plasmid is made by introducing the HIV-1 HxB2 LTR sequence from nucleotide -138 to +80 (Sca1-Hindlll) upstream of the luciferase gene in the pGL3 Basic Vector (a promoterless luciferase expression vector from Promega catalogue #E1751) with the gene for blasticidine resistance cloned in.
  • the reporter cells are made by electroporating C8166 cells with pGL3 Basic LTR/TAR and selecting positive clones with blasticidine. Clone C8166-LTRIuc #A8-F5- G7 was selected by 3 consecutive rounds of limiting dilution under blasticidine selection. Cultures are maintained in complete media (consisting of: Roswell Park Memorial Institute medium (RPMI) 1640 + 10% FBS + 10 "5 M ⁇ -mercaptoethanol + 10 ⁇ g/ml 13-152
  • blasticidine selection is removed from the cells before performing the viral replication assay.
  • Serial dilutions of HIV-1 inhibitor compounds are prepared in complete media from 10 mM DMSO stock solutions. Eleven serial dilutions of 2.5X are made at 8X desired final concentration in a 1 ml deep well titer plate (96 wells). The 12 th well contains complete media with no inhibitor and serves as the positive control. All samples contain the same concentration of DMSO ( ⁇ 0.1 % DMSO). A 25 ⁇ l aliquot of inhibitor is added, to triplicate wells, of a 96 well tissue culture treated clear view black microtiter plate (Corning Costar catalogue # 3904). The total volume per well is 200 ⁇ l_ of media containing cells and inhibitor. The last row is reserved for uninfected C8166 LTRIuc cells to serve as the background blank control and the first row is media alone.
  • C8166 LTRIuc cells are counted and placed in a minimal volume of complete RPMI 1640 in a tissue culture flask (ex. 30 X 10 6 cells in 10 ml media/25 cm 2 flask). Cells are infected with HIV-1 or virus with variant integrase generated as described below at a molecules of infection (moi) of 0.005. Cells are incubated for 1.5 hours at 37 0 C on a rotating rack in a 5% CO 2 incubator and re-suspended in complete RPMI to give a final concentration of 25,000-cells/175 ⁇ l. 175 ⁇ l of cell mix is added to wells of a 96 well microtiter plate containing 25 ⁇ l 8X inhibitors. 25,000 uninfected C8166- LTRIuc cells/well in 200 ⁇ l complete RPMI are added to the last row for background control. Cells are incubated at 37 0 C in 5% CO 2 incubator for 3 days.
  • the calculated % inhibition values are used to determine EC 50 , slope factor (n) and maximum inhibition (l max ) by the non-linear regression routine NLIN procedure of SAS using the following equation: o / ⁇ 7 - L -.- I ma ⁇ x [inhibitor]"
  • Compounds of the invention shown in Tables 1 to 2 are integrase inhibitors. Representative compounds selected from Tables 1 to 2 below have EC 50 values of no more than 20 ⁇ M when tested in the HIV-1 luciferase assay of Example 43.
  • Retention times (t R ) for each compound are measured using the standard analytical HPLC conditions described in the Examples.
  • retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different HPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual measurements taken on different occasions. 13-152

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Abstract

Compounds of formula (I): wherein c, X, Y, R2, R4 and R5 are defined herein, are useful as inhibitors of HIV replication.

Description

Inhibitors of Human Immunodeficiency Virus Replication
Related Applications
This application claims benefit of U.S. Serial No. 60/988579, filed November 16, 2007, which is herein incorporated by reference.
Field of the invention
The present invention relates to compounds, compositions and methods for the treatment of human immunodeficiency virus (HIV) infection. In particular, the present invention provides novel inhibitors of HIV replication, pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HIV infection. More specifically, the present invention provides novel inhibitors of the HIV integrase enzyme, pharmaceutical compositions containing such compounds and methods for using these compounds to reduce HIV replication and in the treatment of HIV infection.
Background of the invention
Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), particularly the HIV-1 strain. Most currently approved therapies for HIV infection target the viral reverse transcriptase and protease enzymes. There is additionally one approved drug targeting gp41 to inhibit viral entry and one approved drug targeting the integrase enzyme. Within the reverse transcriptase inhibitor and protease inhibitor classes, resistance of HIV to existing drugs is a problem. Therefore, it is important to discover and develop new antiretroviral compounds.
WO 2007/000043 describes pyrazolo[3,4-B]pyridine-2-yl benzoic acid derivatives as HIV integrase inhibitors.
Summary of the invention
The present invention provides a novel series of compounds having inhibitory activity against HIV replication. Furthermore, representative compounds of the invention have activity as inhibitors in a cell-based HIV replication assay. The compounds of the present invention have an affinity for the HIV integrase enzyme. Therefore, the compounds of the invention may be used to inhibit the activity of HIV integrase and may be used to reduce HIV replication. Further objects of this invention arise for the one skilled in the art from the following description and the examples.
One aspect of the invention provides an isomer, racemate, enantiomer or diastereomer of a compound of formula (I):
Figure imgf000003_0001
wherein represents either a single or double bond;
X is N when Y is N-R7; or
X is N-R6 when Y is N;
R2 and R5 are each independently selected from a) halo; b) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(C1-6)alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1-6)alkylene-C(=O)-O-R8, -(Ci-6)alkylene-O-R8, -(d.6)alkylene-S-R8, -(C,.6)alkylene-SO-R8 or -(C1-6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (C1-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3.7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C-ι_6)haloalkyl, (C3-7)cycloalkyl,
(C3-7)cycloalkyl-(C1-6)alkyh -OH, -O(Ci-6)alkyl, O-(C1-6)haloalkyl, -SH,
-S(C1-6)alkyl, -SO(C1-6)alkyl, -SO2(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and -NC(C1.
6)alkyl)2; ii) (C1-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(C1-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and c) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, -(C1-6)alkylene-N(R9)R10, -(Ci-6)alkylene-C(=O)-N(R9)R10, -(C1-6)alkylene- O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3- 7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C1-6)alkylene-R8,
-SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above; R6 and R7 are each independently selected from a) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(C1-6)alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1-6)alkylene-C(=O)-O-R8, -(Ci-6)alkylene-O-R8, -(C1-6)alkylene-S-R8, -(C1-6)alkylene-SO-R8 or -(Ci_6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (C1-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2.6)alkenyl, (Ci.6)haloalkyl, (C3-7)cycloalkyl,
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, O-(Ci-6)haloalkyl, -SH,
-S(C1-6)alkyl, -SO(Ci_6)alkyl, -SO2(Ci-6)alkyl, -NH2, -NHCd^alkyl and
-N((C1-6)alkyl)2; ii) (C1-6)alkyl optionally substituted with -OH, -O-(C.,.6)haloalkyl, or
-O-(C1-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and b) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, -(C1-6)alkylene-N(R9)R10, -(C1-6)alkylene-C(=O)-N(R9)R10, -(C1-6)alkylene- O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein
R9 is in each instance independently selected from H, (C^alkyl and (C3-7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(d^alkylene-R8, -SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above; R3 is (C1-6)alkyl, (C1-6)haloalkyl, (C2.6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl-(C1-6)alkyl-, 13-152
aryl-(C1-6)alkyl-, Het-(C1-6)alkyl- or -W-R31, and bond c is a single bond; or R3 is (Ci.6)alkylidene and bond c is a double bond; wherein W is O or S and R31 is (C1-6)alkyl, (C1-6)haloalkyl, (C2.6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, (C3.7)cycloalkyl-(Ci-6)alkyl-, aryl-(C1-6)alkyl- or Het-Cd^alkyl-; wherein each of the (Ci-6)alkylidene, (C1-6)alkyl, (C1-6)haloalkyl, (C2-6)alkenyl, (C2. 6)alkynyl, (C^cycloalkyKC^alkyl-, aryl-(C1-6)alkyl-, Het-(C1-6)alkyl- and -W-R31 is optionally substituted with 1 to 3 substituents each independently selected from (C1-6)alkyl, halo, cyano, oxo and -O(C1-6)alkyl;
R4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C1-6)alkyl, (C2-6)alkenyl, (C1.6)haloalkyl, (C3-7)cycloalkyl, (C3.7)cycloalkyl-(Ci.6)alkyl-, -OH, -O(C1-6)alkyl, -SH, -S(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and -N((C1-6)alkyl)2; wherein the (C1-6)alkyl is optionally substituted with hydroxy, -O(C1-6)alkyl, cyano or oxo; and wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S; wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO2; or a salt or an ester thereof.
Another aspect of this invention provides a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, as a medicament.
Still another aspect of this invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable carriers.
According to an embodiment of this aspect, the pharmaceutical composition according to this invention additionally comprises at least one other antiviral agent. The invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of an HIV infection in a mammal having or at risk of having the infection.
A further aspect of the invention involves a method of treating an HIV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt or ester thereof, or a composition thereof as described hereinabove.
Another aspect of the invention involves a method of treating an HIV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent; or a composition thereof.
Also within the scope of this invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, for the treatment of an HIV infection in a mammal having or at risk of having the infection.
Another aspect of this invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of an HIV infection in a mammal having or at risk of having the infection.
An additional aspect of this invention refers to an article of manufacture comprising a composition effective to treat an HIV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by HIV; wherein the composition comprises a compound of formula (I) according to this invention or a pharmaceutically acceptable salt or ester thereof.
Still another aspect of this invention relates to a method of inhibiting the replication of HIV comprising exposing the virus to an effective amount of the compound of formula (I), or a salt or ester thereof, under conditions where replication of HIV is inhibited. 13-152
Further included in the scope of the invention is the use of a compound of formula (I) to inhibit the activity of the HIV integrase enzyme.
Further included in the scope of the invention is the use of a compound of formula (I), or a salt or ester thereof, to inhibit the replication of HIV.
Detailed Description of the Invention
Definitions:
As used herein, the following definitions apply unless otherwise noted:
The term "substituent", as used herein and unless specified otherwise, is intended to mean an atom, radical or group which may be bonded to a carbon atom, a heteroatom or any other atom which may form part of a molecule or fragment thereof, which would otherwise be bonded to at least one hydrogen atom. Substituents contemplated in the context of a specific molecule or fragment thereof are those which give rise to chemically stable compounds, such as are recognized by those skilled in the art.
The term "(Chalky!" as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean acyclic, straight or branched chain alkyl radicals containing from 1 to n carbon atoms. "(C1-6)alkyl" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (/so-propyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1 ,1-dimethylethyl (te/?-butyl), pentyl and hexyl. The abbreviation Me denotes a methyl group; Et denotes an ethyl group, Pr denotes a propyl group, iPr denotes a 1-methylethyl group, Bu denotes a butyl group and tBu denotes a 1 ,1-dimethylethyl group.
The term "(C1-n)alkylene" as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean acyclic, straight or branched chain divalent alkyl radicals containing from 1 to n carbon atoms. "(C1-6)alkylene" includes, but
is not limited to, -CH2-, -CH2CH2-,
Figure imgf000007_0001
.
The term "(C1-n)alkylidene" as used herein, wherein n is an integer, either alone or in 13-152
combination with another radical, is intended to mean acyclic, straight or branched chain alkyl radicals containing from 1 to n carbon atoms which are bonded to a molecule or fragment thereof, as a substituent thereof, by a double bond. "(C1-6)alkylidene" includes,
H,CV
but is not limited to, CH2=, CH3CH=, CH3CH2CH=, 3 and
H3Cx
.C=
3 groups. Unless specified otherwise, the term "(C2-n)alkylidene" is understood to encompass individual stereoisomers where possible, including but not limited to (E) and (Z) isomers, and mixtures thereof. When a (C2-n)alkylidene group is substituted, it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "(C2-n)alkenyl", as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight or branched chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a double bond. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. Unless specified otherwise, the term "(C2-n)alkenyl" is understood to encompass individual stereoisomers where possible, including but not limited to (E) and (Z) isomers, and mixtures thereof. When a (C2-n)alkenyl group is substituted, it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "(C2-n)alkynyl", as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an unsaturated, acyclic straight or branched chain radical containing two to n carbon atoms, at least two of which are bonded to each other by a triple bond. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. When a (C2.n)alkynyl group is substituted, it is understood to be substituted on any carbon atom thereof which would 13-152
otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "(C3.m)cycloalkyl" as used herein, wherein m is an integer, either alone or in combination with another radical, is intended to mean a cycloalkyl substituent containing from 3 to m carbon atoms and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "(C3.m)cycloalkyl-(Ci-n)alkyl-" as used herein, wherein n and m are both integers, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above which is itself substituted with a cycloalkyl radical containing from 3 to m carbon atoms as defined above. Examples of (C3-7)cycloalkyl-(Ci.6)alkyl- include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2- cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl and 2-cyclohexylethyl. When a (C3-m)cycloalkyl-(C1.n)alkyl- group is substituted, it is understood that substituents may be attached to either the cycloalkyl or the alkyl portion thereof or both, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "aryl" as used herein, either alone or in combination with another radical, is intended to mean a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl and dihydronaphthyl.
The term "aryl-(C1-π)alkyl-" as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above which is itself substituted with an aryl radical as defined above. Examples of aryl-(Ci-n)alkyl- include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl. When an aryl-(C1-n)alkyl- group is substituted, it is understood that substituents may be attached to either the aryl or the 13-152
alkyl portion thereof or both, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "carbocycle" as used herein, either alone or in combination with another radical, is intended to mean a cyclic compound, either aromatic or non-aromatic, saturated or unsaturated, in which all of the ring members are carbon atoms. The carbocycle group may containing 5 or 6 carbon atom and may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. The carbocycle may be substituted. When the carbocycle is substituted, it is understood that substituents may be attached to any carbon atom which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "Het" as used herein, either alone or in combination with another radical, is intended to mean a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO2, unless specified otherwise. When a Het group is substituted, it is understood that substituents may be attached to any carbon atom or heteroatom thereof which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "Het-(C1-π)alkyl-" as used herein and unless specified otherwise, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n carbon atoms as defined above which is itself substituted with a Het substituent as defined above. Examples of Het-(C1_n)alkyl- include, but are not 13-152
limited to, thieny I methyl, furylmethyl, piperidinylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, quinolinylpropyl, and the like. When an Het-(Ci-π)alkyl- group is substituted, it is understood that substituents may be attached to either the Het or the alkyl portion thereof or both, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "heteroatom" as used herein is intended to mean O, S or N.
The term "heterocycle" as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a 3- to 7-membered saturated, unsaturated or aromatic heterocycle containing from 1 to 4 heteroatoms each independently selected from O, N and S; or a monovalent radical derived by removal of a hydrogen atom therefrom. Examples of such heterocycles include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, tetrazole, piperidine, piperazine, azepine, diazepine, pyran, 1 ,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide, pyridazine, pyrazine and pyrimidine, and saturated, unsaturated and aromatic derivatives thereof.
The term "heteropolycycle" as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a heterocycle as defined above fused to one or more other cycle, including a carbocycle, a heterocycle or any other cycle; or a monovalent radical derived by removal of a hydrogen atom therefrom. Examples of such heteropolycycles include, but are not limited to, indole, isoindole, benzimidazole, benzothiophene, benzofuran, benzopyran, benzodioxole, benzodioxane, benzothiazole, quinoline, isoquinoline, and naphthyridine, and saturated, unsaturated and aromatic derivatives thereof.
The term "halo" as used herein is intended to mean a halogen substituent selected from fluoro, chloro, bromo or iodo.
The term "(C1-n)haloalkyl" as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alkyl radical having 1 to n 13-152
carbon atoms as defined above wherein one or more hydrogen atoms are each replaced by a halo substituent. Examples of (C1-n)haloalkyl include but are not limited to chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
The terms "-O-(C1-n)alkyl" or "(Ci-n)alkoxy" as used herein interchangeably, wherein n is an integer, either alone or in combination with another radical, is intended to mean an oxygen atom further bonded to an alkyl radical having 1 to n carbon atoms as defined above. Examples of -O-(C1-n)alkyl include but are not limited to methoxy (CH3O-), ethoxy (CH3CH2O-), propoxy (CH3CH2CH2O-), 1-methylethoxy (/so-propoxy; (CH3)2CH-O-) and 1 ,1-dimethylethoxy (terf-butoxy; (CH3)3C-O-). When an -O-(C1-n)alkyl radical is substituted, it is understood to be substituted on the (C1-n)alkyl portion thereof, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "-O-(Ci.n)haloalkyl", wherein n is an integer, either alone or in combination with another radical, is intended to mean an oxygen atom further bonded to a haloalkyl radical having 1 to n carbon atoms as defined above. When an -O-(C1-n)haloalkyl radical is substituted, it is understood to be substituted on the (C1-n)alkyl portion thereof.
The terms "-S-(C1-n)alkyl" or "(C1.n)alkylthio" as used herein interchangeably, wherein n is an integer, either alone or in combination with another radical, is intended to mean an sulfur atom further bonded to an alkyl radical having 1 to n carbon atoms as defined above. Examples of -S-(C1-n)alkyl include but are not limited to methylthio (CH3S-), ethylthio (CH3CH2S-), propylthio (CH3CH2CH2S-), 1-methylethylthio (/sopropylthio; (CHs)2CH-S-) and 1 ,1-dimethylethylthio (tert-butylthio; (CH3)3C-S-). When -S-(C1-n)alkyl radical, or an oxidized derivative thereof, such as an -SO-(C1-n)alkyl radical or an -SO2-(C1-n)alkyl radical, is substituted, each is understood to be substituted on the (C1- n)alkyl portion thereof, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art.
The term "oxo" as used herein is intended to mean an oxygen atom attached to a carbon atom as a substituent by a double bond (=0). 13-152
The term "thioxo" as used herein is intended to mean a sulfur atom attached to a carbon atom as a substituent by a double bond (=S).
The term "cyano" as used herein is intended to mean a carbon atom attached to a nitrogen atom as a substituent by a triple bond.
The term "COOH" as used herein is intended to mean a carboxyl group (-C(=O)-OH). It is well known to one skilled in the art that carboxyl groups may be substituted by functional group equivalents. Examples of such functional group equivalents contemplated in this invention include, but are not limited to, esters, amides, imides, boronic acids, phosphonic acids, phosphoric acids, tetrazoles, triazoles, N-acylsulfamides (RCONHSO2NR2), and N-acylsulfonamides (RCONHSO2R).
The term "functional group equivalent" as used herein is intended to mean an atom or group that may replace another atom or group which has similar electronic, hybridization or bonding properties.
The term "protecting group" as used herein is intended to mean protecting groups that can be used during synthetic transformation, including but not limited to examples which are listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981), and more recent editions thereof.
The following designation is used in sub-formulas to indicate the bond which is connected to the rest of the molecule as defined.
The term "salt thereof as used herein is intended to mean any acid and/or base addition salt of a compound according to the invention, including but not limited to a pharmaceutically acceptable salt thereof.
The term "pharmaceutically acceptable salt" as used herein is intended to mean a salt of a compound according to the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a 13-152
reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically-acceptable acid addition salts and pharmaceutically-acceptable base addition salts. Lists of suitable salts are found in, for example, S. M. Berge et al., J. Pharm. ScL, 1977, 66, pp. 1-19, herein incorporated by reference.
The term "pharmaceutically-acceptable acid addition salt" as used herein is intended to mean those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid and the like, and organic acids including but not limited to acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2- hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p- toluenesulfonic acid, undecanoic acid and the like.
The term "pharmaceutically-acceptable base addition salt" as used herein is intended to mean those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases including but not limited to ammonia or the hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically-acceptable organic nontoxic bases include but are not limited to salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, 13-152
ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N1N'- dibenzylethylenediamine, polyamine resins and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
The term "ester thereof as used herein is intended to mean any ester of a compound according to the invention in which any of the -COOH substituents of the molecule is replaced by a -COOR substituent, in which the R moiety of the ester is any carbon- containing group which forms a stable ester moiety, including but not limited to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, each of which being optionally further substituted. The term "ester thereof includes but is not limited to pharmaceutically acceptable esters thereof.
The term "pharmaceutically acceptable ester" as used herein is intended to mean esters of the compound according to the invention in which any of the COOH substituents of the molecule are replaced by a -COOR substituent, in which the R moiety of the ester is selected from alkyl (including, but not limited to, methyl, ethyl, propyl, 1-methylethyl, 1 ,1- dimethylethyl, butyl); alkoxyalkyl (including, but not limited to methoxymethyl); acyloxyalkyl (including, but not limited to acetoxymethyl); arylalkyl (including, but not limited to, benzyl); aryloxyalkyl (including, but not limited to, phenoxymethyl); and aryl (including, but not limited to phenyl) optionally substituted with halogen, (C1-4)alkyl or (C1- 4)alkoxy. Other suitable esters can be found in Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985), herein incorporated by reference. Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when injected into a mammal and transformed into the acid form of the compound according to the invention. With regard to the esters described above, unless otherwise specified, any alkyl moiety present preferably contains 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms. Any aryl moiety present in such esters preferably comprises a phenyl group. In particular the esters may be a (C1-16)alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at 13-152
least one halogen, (C1-6)alkyl, (Ci-6)alkoxy, nitro or trifluoromethyl.
The term "mammal" as used herein is intended to encompass humans, as well as non- human mammals which are susceptible to infection by HIV. Non-human mammals include but are not limited to domestic animals, such as cows, pigs, horses, dogs, cats, rabbits, rats and mice, and non-domestic animals.
The term "treatment" as used herein is intended to mean the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and/or to reduce viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood, and the administration of a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life.
The term "antiviral agent" as used herein is intended to mean an agent that is effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
The term "inhibitor of HIV replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.
The term "HIV integrase" or "integrase", used herein interchangeably, means the integrase enzyme encoded by the human immunodeficiency virus type 1.
The term "therapeutically effective amount" means an amount of a compound according to the invention, which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds 13-152
have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
Preferred embodiments
In the following preferred embodiments, groups and substituents of the compounds of formula (I):
Figure imgf000017_0001
according to this invention are described in detail.
Core: Core-A: In one embodiment, the compounds of the invention are represented by formula (Ia):
Figure imgf000017_0002
wherein c, R2, R3, R4, R5 and R7 are as defined herein.
It will be apparent to a person skilled in the art that, when bond c is a single bond, the carbon atom bonded to the -COOH and R3 substituents can exist in two possible 13-152
stereochemical configurations, as shown in formulas (Ib) and (Ic) below:
Figure imgf000018_0001
(Ib) (Ic) wherein R2, R3, R4, R5 and R7 are as defined herein.
It has been found that compounds of formula (Ib) have improved activity over compounds of formula (Ic).
Core-B: Therefore, in one embodiment, the compounds of the present invention are represented by formula (Ib):
Figure imgf000018_0002
wherein R2, R3, R4, R5 and R7 are as defined herein.
Core-C: In another embodiment, the compounds of the present invention are represented by formula (Ic):
Figure imgf000018_0003
wherein R2, R3, R4, R5 and R7 are as defined herein.
Core-D: In another embodiment, the compounds of the present invention are represented by formula (Id): 13-152
Figure imgf000019_0001
wherein X, Y, R2, R3, R4 and R5 are as defined herein.
Core-E: In another embodiment, the compounds of the present invention are represented by formula (Ie):
Figure imgf000019_0002
wherein R2, R3, R4, R5 and R6 are as defined herein.
It will be apparent to a person skilled in the art that, when bond c is a single bond, the carbon atom bonded to the -COOH and R3 substituents can exist in two possible stereochemical configurations, as shown in formulas (If) and (Ig) below:
Figure imgf000019_0003
wherein R , R , R , R and R are as defined herein.
Core-F: In another embodiment, the compounds of the present invention are represented by formula (If):
Figure imgf000019_0004
wherein R2, R3, R4, R5 and R6 are as defined herein.
Core-G: In another embodiment, the compounds of the present invention are 13-152
represented by formula (ig):
Figure imgf000020_0001
wherein R2, R3, R4, R5 and R6 are as defined herein.
Any and each individual definition of the Core as set out herein may be combined with any and each individual definition of c, R2, R3, R4, R5, R6 and R7 as set out herein.
E!i
R2 -A: In one embodiment, R2 is selected from: a) halo; b) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(d^alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1-6)alkylene-C(=O)-O-R8, -(C^alkylene-O-R8, -(C1-6)alkylene-S-R8, -(C1-6)alkylene-SO-R8 or -(C1-6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (C1-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3.7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl,
Figure imgf000020_0002
-SH,
-S(C1-6)alkyl, -SO(C1-6)alkyl,
Figure imgf000020_0003
and
-NtfC^alkyl),; ii) (C1-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(C1-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and c) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, -(C1-6)alkylene-N(R9)R10, -(C1-6)alkylene-C(=O)-N(R9)R10, -(C^alkylene- O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein 13-152
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3-7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C1-6)alkylene-R8, -SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above. R2-B: In an alternative embodiment, R2 is H, halo, (C1-6)alkylene-O-(C1-6)alkyl, (C1- 6)alkylene- O-aryl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)alkylene-(C3.7)cycloalkyl , -OH or -0(C^)alkyl.
R2 -C: In another embodiment, R2 is Het, aryl, (C1-6)alkylene-Het and (Ci-6)alkylene-aryl; wherein said aryl and Het are optionally substituted 1 to 2 times with (C1-6)alkyl, -O(C1-6)alkyl, or -O(C1-6)haloalkyl.
R2-D: In another embodiment, R2 is halo, (C1-6)alkylene-O-(C1-6)alkyl, (C^alkylene- O- aryl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)alkylene-(C3-7)cycloalkyl , -OH Or -O(Ci- 6)alkyl, Het, aryl, (Ci-6)alkylene-Het and (C1-6)alkylene-aryl wherein said aryl and Het are optionally substituted with (C1-6)alkyl, -O(Ci-6)alkyl, or -O(C1-6)haloalkyl. R2-E: In another embodiment, R2 is (C^alkyl or (C1-4)haloalkyl. R2-F: In another embodiment, R2 is -CH3 or -CH2CH3. R2-G: In another embodiment, R2 is -CH3.
Any and each individual definition of R2 as set out herein may be combined with any and each individual definition of the Core, c, R3, R4, R5, R6 and R7 as set out herein.
R3-A: In one embodiment, R3 is (C1.6)alkyl, (C1-6)haloalkyl, (C2-6)alkenyl, (C2-6)alkynyl,
Figure imgf000021_0001
aryl-(C1-6)alkyl-, Het-(C1-6)alkyl- or -W-R31, and bond c is a single bond; or
R3 is (C^alkylidene and bond c is a double bond; wherein W is O or S and R31 is (C1-6)alkyl, (d^haloalkyl, (C2.6)alkenyl,
(C2-6)alkynyl, (C3-7)cycloalkyl, aryl, (C3.7)cycloalkyl-(C1_6)alkyl-, aryl-(C1-6)alkyl- or
Het-(C1-6)alkyl-; wherein each of the (C1-6)alkylidene, (C1-6)alkyl, (Ci_6)haloalkyl, (C2-6)alkenyl, (C2- 6)alkynyl, (C3-7)cycloalkyl-(C1-6)alkyl-, aryl-(C1-6)alkyl-, Het-(C1_6)alkyl- and -W-R31 is optionally substituted with 1 to 3 substituents each independently selected from (C1-6)alkyl, halo, cyano, oxo and -O(C1-6)alkyl; 13-152
R3-B: In one embodiment, R3 is (C1-6)alkyl, (Ci-e)haloalkyl, (C2-6)alkenyl, (C2.6)alkynyl, (C3.7)cycloalkyl-(C1-6)alkyl-, aryl-(C1-6)alkyl- or Het-(C1-6)alkyl-; wherein each of the (C1-6)alkyl, (C^haloalkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl-(C1-6)alkyl-, aryl-(C1-6)alkyl- and Het-(Ci.6)alkyl- is optionally substituted with 1 to 3 substituents each independently selected from (d-6)alkyl, halo, cyano, oxo and -O(C1-6)alkyl; and bond c is a single bond.
R3-C: In another embodiment, R3 is (C1-6)alkyl or (C2_6)alkenyl; and bond c is a single bond.
R3-D: In an alternative embodiment, R3 is
Figure imgf000022_0001
-W-(C1-6)haloalkyl, -W-(C2-6)alkenyl, -W-(C2.6)alkynyl, -W-(C3-7)cycloalkyl, -W-aryl, (C3-7)cycloalkyl-(C1.β)alkyl-W-, aryl-(C^)alkyl-W- or Het-(C1_6)alkyl-W-; wherein W is O or S; and wherein each of the -W-(C1-6)alkyl, -W-(C2-6)alkenyl, -W-(C2-6)alkynyl, -W-(C3-7)cycloalkyl, -W-aryl, (C3-7)cycloalkyl-(C1-6)alkyl-W-, aryl-(C1-6)alkyl-W- and Het-(C1-6)alkyl-W- is optionally substituted with 1 to 3 substituents each independently selected from (C1-6)alkyl, halo, cyano, oxo and -O(C1-6)alkyl; and bond c is a single bond.
R3-E: In another embodiment, R3 is -O-(Ci-6)alkyl, -O-(C-|.6)haloalkyl, -O-(C2-6)alkenyl, -O-(C2-6)alkynyl, -O-(C3-7)cycloalkyl, -O-aryl, (C3-7)cycloalkyl-(C1-6)alkyl-O-, aryl-(C1-6)alkyl-O- or Het-Cd^alkyl-O-; wherein each of the -O-(C1-6)alkyl, -O-(C2.6)alkenyl, -O-(C2.6)alkynyl, -O-(C3-7)cycloalkyl, -O-aryl, (C3_7)cycloalkyl-(C1-6)alkyl-O-, aryl-(C1-6)alkyl-O- and Het-(Ci-6)alkyl-O- is optionally substituted with 1 to 3 substituents each independently selected from (C1-6)alkyl, halo, cyano, oxo and -O(C1-6)alkyl; and bond c is a single bond.
R3-F: In another embodiment, R3 is -O(C1-6)alkyl, -O-(C1-6)haloalkyl, -O-(C2-6)alkenyl, -O(C2-6)alkynyl, -O-(C3-7)cycloalkyl, -O-aryl, (C3.7)cycloalkyl-(C1-3)alkyl-O- or Het-(C1-3)alkyl-O-; wherein Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; and wherein each of the -OO-^alkyl, -O-(C3-7)cycloalkyl and Het-(C1-3)alkyl-O- is optionally substituted with 1 to 3 substituents each independently selected from (Ci-3)alkyl, cyano, oxo and -O(d.6)alkyl; and 13-152
bond c is a single bond. R3-G: In another embodiment, R3 is -O(C1-6)alkyl, -O-(C-|.6)haloalkyl, -O(C2.6)alkenyl,
-O(C2.6)alkynyl or -O-(C3_7)cycloalkyl; wherein each of the -O(Ci-6)alkyl and -O-(C3-7)cycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from (C1-3)alkyl, cyano, oxo and -O(C1-6)alkyl; and bond c is a single bond. R3-H: In another embodiment, R3 is -O(C1-4)alkyl; and bond c is a single bond.
R3-l: In another embodiment, R3 is -OC(CH3)3; and bond c is a single bond. R3-J: In another embodiment, R3 is selected from:
-OCH3, -OCH2CH3,
Figure imgf000023_0001
-OCH2CH2CH2CH3, -OCH(CH3)CH2CH3,
Figure imgf000023_0002
Figure imgf000023_0003
Any and each individual definition of c and R3 as set out herein may be combined with any and each individual definition of the Core, R2, R4, R5, R6 and R7 as set out herein.
R4-A: In one embodiment, R4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, 13-152
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, -SH, -S(Ci-6)alkyl, -NH2, -NH(Ci- 6)alkyl and -N((C1-6)alkyl)2; wherein the (C1-6)alkyl is optionally substituted with hydroxy, -O(C1-6)alkyl, cyano or oxo.
R4-B: In another embodiment, R4 is phenyl optionally substituted with 1 or 3 substituents each independently selected from halo, (Ci-4)alkyl, (C2-4)alkenyl, (C1-4)haloalkyl, (C3-7)cycloalkyl, -OH, -O(C1-4)alkyl, -SH, -Std^alkyl, -NH2, -NH(C1-4)alkyl and -N^C^alkyl),.
R4-C: In another embodiment, R4 is phenyl optionally substituted with 1 or 2 substituents each independently selected from F, Cl, Br, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -SCH3, and N(CH3)2.
R4-D: In another embodiment, In another alternative embodiment, R4 is phenyl or Het optionally substituted with 1 or 2 substituents each independently selected from halo, (C1-6)alkyl and -O(C1-6)alkyl; wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N, O and S.
R4-E: In an alternative embodiment, R4 is Het optionally substituted with 1 to 3 substituents each independently selected from halo, (C1-6)alkyl, (C2.6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, -OH, -O(C14)alkyl, -SH, -S(C^)alkyl, -NH2, -NH(C1.6)alkyl and -N((C1-6)alkyl)2; wherein the (C1-6)alkyl is optionally substituted with hydroxyl or -O(C1-6)alkyl.
R4-F: In another alternative embodiment, R4 is Het optionally substituted with 1 or 2 substituents each independently selected from halo, (C1-6)alkyl and -O(Ci-6)alkyl; wherein the Het is a 5- or 6-membered heterocycle having 1 to 3 heteroatoms each independently selected from N, O and S; or the Het is a 9- or 10-membered heteropolycycle having 1 to 3 heteroatoms each independently selected from N,
0 and S.
R4-G: In another alternative embodiment, R4 is phenyl or Het optionally substituted with
1 to 3 substituents each independently selected from halo, (C1.6)alkyl and -O(Ci_β)alkyl; wherein the Het is selected from: 13-152
Figure imgf000025_0001
R4-H: In another alternative embodiment, R4 is selected from:
Figure imgf000025_0002
R4-l: In another alternative embodiment, R4 is selected from: r
Figure imgf000025_0003
13-152
Figure imgf000026_0001
13-152
Figure imgf000027_0001
One skilled in the art will recognize that when the R4 substituent is not symmetrically substituted about the axis of rotation of the bond attaching R4 to Core, rotational isomers or atropisomers are possible. Compounds of the invention in which the R4 substituent is not symmetrically substituted about the axis of rotation of the bond attaching R4 to Core and in which the carbon atom bonded to the -COOH and R3 substituents is chiral, as described above, will have two chiral centers, a chiral carbon atom and a rotational axis of asymmetry, and thus the atropisomers will exist as diastereomers. However, individual diastereomeric atropisomers may or may not be detectable and/or separable, depending upon the relative amounts of each atropisomer formed during synthesis, present at equilibrium, and the degree of steric hindrance to 13-152
rotation about the C-4 chiral axis, and therefore, the rate at which interconversion between these atropisomers occurs. Once separated, individual atropisomers may be very stable or interconvert, rapidly or slowly, with each other to form an equilibrium mixture of atropisomers.
R4-J: In another alternative embodiment, R4 is selected from:
Figure imgf000028_0001
13-152
Any and each individual definition of R4 as set out herein may be combined with any and each individual definition of the Core, R2, c, R3, R5, R6 and R7 as set out herein.
Bi;
R5-A: In one embodiment, R5 is selected from: a) halo; b) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(d^alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1.6)alkylene-C(=O)-O-R8, -(C^alkylene-O-R8, -(C1-6)alkylene-S-R8, -(C1-6)alkylene-SO-R8 or -(C1-6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (C1-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C^haloalkyl, (C3_7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl,
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, O-td^haloalkyl, -SH,
-S(C1-6)alkyl, -SO(C1-6)alkyl, -SO2(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and -NK(C1- β)alkyl)2; ii) (Ci-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(Ci-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and c) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, -(C1-6)alkylene-N(R9)R10, -(C1.6)alkylene-C(=O)-N(R9)R10, -(d.6)alkylene- O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3- 7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C1-6)alkylene-R8, -SO2-R8, -C(=0)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above. R5-B: In an alternative embodiment, R5 is H, halo, (C1.6)alkylene-O(C1-6)alkyl, (C1- 6)alkylene-O-aryl, (C1.6)haloalkyl, (C3-7)cycloalkyl, (C1-6)alkylene-(C3-7)cycloalkyl , -OH or -O(d.6)alkyl. 13-152
R5-C: In another embodiment, R5 is Het, aryl, (C1-6)alkylene-Het or (C1-6)alkylene-aryl; wherein said aryl and Het are optionally substituted 1 to 2 times with (C1-6)alkyl, -O(C1-6)alkyl, or -O(C1-6)haloalkyl.
R5-D: In another embodiment, R5 is halo, (C1-6)alkylene-O(C1.6)alkyl, (C1-6)alkylene -O- aryl, (C1-6)haloalkyl, (C3.7)cycloalkyl,
Figure imgf000030_0001
, -OH Or -O(C1- 6)alkyl, Het, aryl, (C1-6)alkylene-Het or (Ci-6)alkylene-aryl wherein said aryl and Het are optionally substituted with (C1-6)alkyl, -O(C1-6)alkyl, or -O(C1-6)haloalkyl.
R5-E: In another embodiment, R5 is H or (C1-4)alkyl.
R5-F: In another embodiment, R5 is H1CH2CH3 or CH3.
R5-G: In another embodiment, R5 is H or CH3.
Any and each individual definition of R5 as set out herein may be combined with any and each individual definition of the Core, c, R2, R3, R4, R6 and R7 as set out herein.
R6-A: In one embodiment, R6 is selected from: a) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(d^alkylene-R8, -(C1.6)alkylene-C(=O)-R8, -(C1-6)alkylene-C(=O)-O-R8, -(C1-6)alkylene-O-R8, -(C-|.6)alkylene-S-R8, -(Ci-6)alkylene-SO-R8 or -(C1-6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (C1-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C^haloalkyl, (C3-7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl,
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, O-(C1-6)haloalkyl, -SH,
-SCd^alkyl, -SO(C1-6)alkyl, -SO2(C1_6)alkyl, -NH2, -NH(C1-6)alkyl and -NK(C1.
6)alkyl)2; ii) (C1-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(C1-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and b) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, 13-152
-(d^alkylene-NCR^R10, -(C1-6)alkylene-C(=O)-N(R9)R10, -(C1-6)alkylene-
O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3.
7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C1-6)alkylene-R8,
-SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above. R6-B: In another embodiment, R6 is Het, aryl, (C^alkylene-Het or (C1-6)alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (Ci- 6)alkyl, -O(C1-6)alkyl, or -O(C1-6)haloalkyl. R6-D: In another embodiment, R6 is (C1-6)alkylene-Het or (C1-6)alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (C1-6)alkyl,
-O(Ci-6)alkyl, or -O(Ci-6)haloalkyl. R6-E: In another embodiment, R6 is (C1-6)alkylene-Het or (C1-6)alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (d-6)alkyl,
-O(C1-6)alkyl, or -O(C1-6)haloalkyl; wherein Het is defined as:
Figure imgf000031_0001
Any and each individual definition of R6 as set out herein may be combined with any and each individual definition of the Core, c, R2, R3, R4 and R5 as set out herein.
Ell
R7-A: In one embodiment, R7 is selected from: a) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8,
-(C1-6)alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1_6)alkylene-C(=O)-O-R8,
-(C^alkylene-O-R8, -(C1-6)alkylene-S-R8, -(C^alkylene-SO-R8 or
-(Ci-6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (d.6)alkyl,
(C2-6)alkenyl, (C2.6)alkynyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, aryl and Het; and 13-152
wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl,
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, O-(C1-6)haloalkyl, -SH,
-S(C1-6)alkyl, -SO(C1-6)alkyl, -SO2(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and -Nt(C1- 6)alkyl)2; ii) (C1-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(Ci-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and b) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10,
-(C1-6)alkylene-N(R9)R10, -(C1-6)alkylene-C(=O)-N(R9)R10, -(C1-6)alkylene-
O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3- 7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C-|.6)alkylene-R8,
-SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above.
R7-B: In an alternative embodiment, R7 is H, (Ci.6)alkylene-O(Ci.6)alkyl, (C1-6)alkylene- O-aryl, (C1-6)haloalkyl, (C3_7)cycloalkyl, (C1-6)alkylene-(C3-7)cycloalkyl , -OH or -O(C1-6)alkyl.
R7-C: In another embodiment, R7 is Het, aryl, (C1-6)alkylene-Het or (C^alkylene-aryl; wherein said aryl, Het, (C1-6)alkylene-Het and (Ci-6)alkylene-aryl are all optionally substituted 1 to 2 times with (C1-6)alkyl, -O(C1-6)alkyl, or -O(Ci-6)haloalkyl. R7-D: In another embodiment, R7 is H, (Ci-6)alkylene-O(C1-6)alkyl, (C^alkylene-O-aryl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)alkylene-(C3-7)cycloalkyl, Het, aryl, (C1-6)alkylene-Het or (C1-6)alkylene-aryl wherein said aryl, Het, (C1-6)alkylene-Het and (C1-6)alkylene-aryl are optionally substituted with (C1.6)alkyl, -O(C1-6)alkyl, or -O(C1-6)haloalkyl.
R7-E: In another embodiment, R7 is (C1-6)alkylene-O(C1-6)alkyl, (C1-6)alkylene-O-aryl, (Ci-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)alkylene-(C3-7)cycloalkyl , -OH Or -O(C1- 6)alkyl, Het, aryl, (d.6)alkylene-Het or (C^alkylene-aryl wherein said aryl, Het, (C1-6)alkylene-Het and (C1-6)alkylene-aryl are optionally substituted with (C1- 6)alkyl, -OtC^alkyl, or -O(C1-6)haloalkyl; 13-152
wherein Het is defined as:
Figure imgf000033_0001
R7-F: In another embodiment, R7 is H, CH3, CH2CH3, CH2CH2OCH3, CH2CH2F,
Figure imgf000033_0002
Figure imgf000033_0004
Figure imgf000033_0005
Figure imgf000033_0003
R7 -G: In another embodiment, R7 is selected from H, (C1-6)alkyl, (C1-6)haloalkyl, (C3.
7)cycloalkyl, (C1-6)alkyl-(C3-7)cycloalkyl ,-OH, -O(C1-6)alkyl, -SH, -S(C1-6)alkyl, -S- aryl, S-Het -SO2-aryl, SO2-Het , -NH2, -NH(C1-6)alkyl, -N((C1-6)alkyl)2, Het, aryl, (Ci-6)alkyl-Het and (C1-6)alkyl-aryl; wherein said alkyl, aryl, Het, cycloalkyl are optionally substituted 1 to 3 times with (C1-6)alkyl, halo, -0-R21, Het, oxo, -S(C1-6)alkyl, -SO(C1.6)alkyl, SO2(C1-6)alkyl; wherein R21 is H, (C^alkyl, (C^haloalkyl, Het optionally substituted with (C1-6)alkyl, aryl optionally substituted with (C1-6)alkyl, (C1-6)alkyl-Het, (C1-6)alkyl- 13-152
aryl.
Any and each individual definition of R7 as set out herein may be combined with any and each individual definition of the Core, c, R2, R3, R4 and R5 as set out herein.
Examples of preferred subgeneric embodiments of the present invention are set forth in the following tables, wherein each substituent group of each embodiment is defined according to the definitions set forth above: Table A:
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
13-152
Table B:
Figure imgf000037_0001
13-152
Figure imgf000038_0001
Examples of most preferred compounds according to this invention are each single compound listed in the following Tables 1 and 2.
In general, all tautomeric and isomeric forms and mixtures thereof, for example, individual tautomers, geometric isomers, stereoisomers, atropoisomers, enantiomers, diastereomers, racemates, racemic or non-racemic mixtures of stereoisomers, mixtures of diastereomers, or mixtures of any of the foregoing forms of a chemical structure or compound is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the compound name or structure.
It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of the present invention from this disclosure and the knowledge in the art.
Preparation of pure stereoisomers, e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or enantiomeric purity, are accomplished by one or 13-152
more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R.P.W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soα, 2000, herein incorporated by reference. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD, ORD, X-ray crystallography, or NMR.
Pharmaceutical composition
Compounds of the present invention may be administered to a mammal in need of treatment for HIV infection as a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt or ester thereof; and one or more conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The specific formulation of the composition is determined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice. The pharmaceutical composition according to the present invention may be administered orally or systemically.
When one enantiomer of a chiral active ingredient has a different biological activity than the other, it is contemplated that the pharmaceutical composition according to the invention may comprise a racemic mixture of the active ingredient, a mixture enriched in one enantiomer of the active ingredient or a pure enantiomer of the active ingredient. The mixture enriched in one enantiomer of the active ingredient is contemplated to contain from more than 50% to about 100% of one enantiomer of the active ingredient and from about 0% to less than 50% of the other enantiomer of the active ingredient. Preferably, when the composition comprises a mixture enriched in one enantiomer of the 13-152
active ingredient or a pure enantiomer of the active ingredient, the composition comprises from more than 50% to about 100% of, or only, the more physiologically active enantiomer and/or the less toxic enantiomer. It is well known that one enantiomer of an active ingredient may be the more physiologically active for one therapeutic indication while the other enantiomer of the active ingredient may be the more physiologically active for a different therapeutic indication; therefore the preferred enantiomeric makeup of the pharmaceutical composition may differ for use of the composition in treating different therapeutic indications.
For oral administration, the compound, or a pharmaceutically acceptable salt or ester thereof, can be formulated in any orally acceptable dosage form including but not limited to aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets. For systemic administration, including but not limited to administration by subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, and intralesional injection or infusion techniques, it is preferred to use a solution of the compound, or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable sterile aqueous vehicle.
Pharmaceutically acceptable carriers, adjuvants, vehicles, excipients and additives as well as methods of formulating pharmaceutical compositions for various modes of administration are well-known to those of skill in the art and are described in pharmaceutical texts such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2005; and L.V. Allen, N. G. Popovish and H. C. Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th ed., Lippincott Williams & Wilkins, 2004, herein incorporated by reference.
The dosage administered will vary depending upon known factors, including but not limited to the activity and pharmacodynamic characteristics of the specific compound employed and its mode, time and route of administration; the age, diet, gender, body weight and general health status of the recipient; the nature and extent of the symptoms; the severity and course of the infection; the kind of concurrent treatment; the frequency of treatment; the effect desired; and the judgment of the treating physician. In general, the compound is most desirably administered at a dosage level that will generally afford antivirally effective results without causing any harmful or deleterious side effects. 13-152
A daily dosage of active ingredient can be expected to be about 0.001 to about 100 milligrams per kilogram of body weight, with the preferred dose being about 0.01 to about 50 mg/kg. Typically, the pharmaceutical composition of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound {w/w). Preferably, such preparations contain from about 20% to about 80% active compound.
Therefore, according to one embodiment, the pharmaceutical composition according to the invention comprises a racemic mixture of the compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
An alternative embodiment provides a pharmaceutical composition comprising a mixture enriched in one enantiomer of the compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
A further embodiment provides a pharmaceutical composition comprising a pure enantiomer of the compound of formula (I), or a pharmaceutically acceptable salt or ester thereof.
Combination therapy
Combination therapy is contemplated wherein a compound according to the invention, or a pharmaceutically acceptable salt or ester thereof, is co-administered with at least one additional antiviral agent. The additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered, concurrently or sequentially, as part of a multiple dosage form.
When the pharmaceutical composition of this invention comprises a combination of a compound according to the invention, or a pharmaceutically acceptable salt or ester 13-152
thereof, and one or more additional antiviral agent, both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. In the case of a synergistic interaction between the compound of the invention and the additional antiviral agent or agents, the dosage of any or all of the active agents in the combination may be reduced compared to the dosage normally administered in a monotherapy regimen.
Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from:
• NRTIs (nucleoside or nucleotide reverse transcriptase inhibitors) including but not limited to zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), emtricitabine, abacavir succinate, elvucitabine, adefovir dipivoxil, lobucavir (BMS-180194) lodenosine (FddA) and tenofovir including tenofovir disoproxil and tenofovir disoproxil fumarate salt, COMBIVIR™ (contains 3TC and AZT), TRIZIVIR™ (contains abacavir, 3TC and AZT), TRUVADA™ (contains tenofovir and emtricitabine), EPZICOM ™ (contains abacavir and 3TC);
• NNRTIs (non-nucleoside reverse transcriptase inhibitors) including but not limited to nevirapine, delaviradine, efavirenz, etravirine and rilpivirine;
• protease inhibitors including but not limited to ritonavir, tipranavir, saquinavir, nelfinavir, indinavir, amprenavir, fosamprenavir, atazanavir, lopinavir, darunavir, lasinavir, brecanavir, VX-385 and TMC-114;
• entry inhibitors including but not limited to
• CCR5 antagonists (including but not limited to maraviroc, vicriviroc, INCB9471 and TAK-652),
• CXCR4 antagonists (including but not limited to AMD-11070),
• fusion inhibitors (including but not limited to enfuvirtide (T-20), TR1-1144 and TR1-999) and
• others (including but not limited to BMS-488043);
• integrase inhibitors (including but not limited to raltegravir (MK-0518), BMS-707035 and elvitegravir (GS 9137)); 13-152
• TAT inhibitors;
• maturation inhibitors (including but not limited to berivimat (PA-457));
• immunomodulating agents (including but not limited to levamisole); and
• other antiviral agents including hydroxyurea, ribavirin, IL-2, IL-12 and pensafuside.
Furthermore, a compound according to the invention can be used with at least one other compound according to the invention or with one or more antifungal or antibacterial agents (including but not limited to fluconazole).
Therefore, according to one embodiment, the pharmaceutical composition of this invention additionally comprises one or more antiviral agents.
A further embodiment provides the pharmaceutical composition of this invention wherein the one or more antiviral agent comprises at least one NNRTI.
According to another embodiment of the pharmaceutical composition of this invention, the one or more antiviral agent comprises at least one NRTI.
According to yet another embodiment of the pharmaceutical composition of this invention, the one or more antiviral agent comprises at least one protease inhibitor.
According to still another embodiment of the pharmaceutical composition of this invention, the one or more antiviral agent comprises at least one entry inhibitor.
According to a further embodiment of the pharmaceutical composition of this invention, the one or more antiviral agent comprises at least one integrase inhibitor.
A compound according to the present invention may also be used as a laboratory reagent or a research reagent. For example, a compound of the present invention may be used as positive control to validate assays, including but not limited to surrogate cell- based assays and in vitro or in vivo viral replication assays.
Furthermore, a compound according to the present invention may be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of 13-152
laboratory or medical personnel or patients who come in contact with such materials (e.g. blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection apparatuses and materials).
Derivatives comprising a detectable label
Another aspect of the invention provides a derivative of a compound of formula (I), the derivative comprising a detectable label. Such a label allows recognition either directly or indirectly of the derivative such that it can be detected, measured or quantified. The detectable label may itself be detectable, measurable or quantifiable, or it may interact with one or more other moities which themselves comprise one or more detectable labels, so that the interaction therebetween allows the derivative to be detected, measured or quantified.
Such derivatives may be used as probes to study HIV replication, including but not limited to study of the mechanism of action of viral and host proteins involved in HIV replication, study of conformational changes undergone by such viral and host proteins under various conditions and study of interactions with entities which bind to or otherwise interact with these viral and host proteins. Derivatives according to this aspect of the invention may be used in assays to identify compounds which interact with viral and host proteins, the assays including but not limited to displacement assays which measure the extent to which the derivative is displaced from interacting with the viral and host proteins. A preferred use of derivatives according to this aspect of the invention is in displacement assays to identify HIV integrase inhibitors. Such derivatives may also be used to form covalent or non-covalent interactions with the viral and host proteins or to identify residues of the viral and host proteins which interact with the compounds of the invention.
Detectable labels contemplated for use with derivatives of the compounds of the invention include, but are not limited to, fluorescent labels, chemiluminescent labels, chromophores, antibodies, enzymatic markers, radioactive isotopes, affinity tags and photoreactive groups.
A fluorescent label is a label which fluoresces, emitting light of one wavelength upon absorption of light of a different wavelength. Fluorescent labels include but are not 13-152
limited to fluorescein; Texas Red; aminomethylcoumarin; rhodamine dyes, including but not limited to tetramethylrhodamine (TAMRA); Alexa dyes including but not limited to Alexa Fluor® 555; cyanine dyes including but not limited to Cy3; europium or lanthanide series based fluorescent molecules; and the like.
A chemiluminescent label is a label which can undergo a chemical reaction which produces light. Chemiluminescent labels include but are not limited to luminol, luciferin, lucigenin, and the like.
A chromophore is a label which selectively absorbs certain wavelengths of visible light while transmitting or reflecting others, thereby causing the compounds which contain the chromophore to appear colored. Chromophores include but are not limited to natural and synthetic dyes.
An antibody is a protein produced by a mammalian immune system in response to a specific antigen, which binds specifically to that antigen. Antibodies contemplated for use as detectable labels according to the invention include but are not limited to antibodies against the following: polyhistidine tags, glutathione-S-transferase (GST), hemagglutinin (HA), FLAG® epitope tags, Myc tag, maltose binding protein (MBP), green fluorescent protein (GFP) and the like.
An enzymatic marker is an enzyme whose presence may be detected by means of an assay specific to the catalytic activity of the enzyme. Enzymatic markers contemplated for use as detectable labels according to the invention include but are not limited to luciferase, horseradish peroxidase (HRP), β-galactosidase and the like.
A radioactive isotope is an isotope of an atom which produces radiation upon radioactive decay. Radioactive isotopes include but are not limited to 14C, 3H, 31P, 1211, 125I and the like.
An affinity tag is a label which has a strong affinity for another moiety, designated herein as a binding partner. Such an affinity tag can be used to form a complex with the binding partner so that the complex may be selectively detected or separated from a mixture. Affinity tags include but are not limited to biotin or a derivative thereof, a histidine 13-152
polypeptide, a polyarginine, an amylose sugar moiety or a defined epitope recognizable by a specific antibody; suitable epitopes include but are not limited to glutathione-S- transferase (GST), hemagglutinin (HA), FLAG® epitope tags, Myc tag, maltose binding protein (MBP), green fluorescent protein (GFP) and the like.
Furthermore, compounds of the invention used as probes may be labelled with a photoreactive group which is transformed, upon activation by light, from an inert group to a reactive species, such as a free radical. Such a group may be used to activate the derivative so that it can form a covalent bond with one or more residues of a viral or host protein. Photoreactive groups include but are not limited to photoaffinity labels such as benzophenone and azide groups.
Methodology and Synthesis
The synthesis of compounds of formula (I) according to this invention is conveniently accomplished following the general procedure outlined in the schemes below wherein X, Y, c, R2, R3, R4, R5, R6 and R7 are as defined herein. Further instruction is provided to one skilled in the art by the specific examples set out herein below.
Scheme 1 : Assembly of inhibitors
1) Suzuki cross-coupling
Figure imgf000046_0002
2) Saponification
Figure imgf000046_0001
Intermediate I
Intermediate Il
wherein R42, R43, R44, R45 and R46 may either be substituents on the phenyl moiety or (R42 and R43), (R43 and R44), (R44 and R45) or (R45 and R46) may be linked so to as to form a carbocycle or heterocycle, W is iodo, bromo, chloro or OTf, V is B(OH)2 or boronate esters such as B(OCH3)2 and B(OC(CH3)2C(CH3)2θ), I1 SnR3 wherein R is (C1-6)alkyl, ZnX wherein X is halo, and P is a protecting group, such as commonly used protecting groups for carboxylic acids, including, but not limited to a methyl or ethyl ester. 13-152
Several coupling methods between the intermediate (I) (i.e. pyrazolopyridine scaffold) and the intermediate Il (i.e. R4 substituent) can be contemplated by those skilled in the art. For examples, but not limited to, Suzuki cross-coupling between the boronic acid or boronate ester derivative of intermediate Il and the halo or triflate derivative of intermediate I, copper catalyzed Ullmann cross-coupling between the iodo derivatives of intermediates I and II, Negishi cross-coupling between the arylzinc reagent of the intermediate Il and the iodo or triflate derivative of intermediate I, and Stille coupling between the arylltin reagent of intermediate Il and the bromo or iodo derivative of intermediate I as shown above can lead, after saponification, to the compounds of the invention of formula (I).
Alternatively, the same cross-coupling methods can be used by interchanging the coupling partners as shown below. For examples, Suzuki, Negishi, and Stille type cross- coupling between boronic acid or boronate ester derivative, the arylzinc reagent or the arylltin reagent of pyrazolopyridine intermediate III and the required iodo, bromo, chloro or triflate derivative of intermediate IV can also lead, after saponification, to the compounds of formula (I).
1) cross-coupling
Figure imgf000047_0002
2) Saponification
Figure imgf000047_0001
Intermediate 111
Figure imgf000047_0003
wherein R42, R43, R44, R45 and, R46 and Pare as defined above and W is iodo, bromo, chloro or OTf, V is B(OH)2 or boronate esters such as B(OCH3)2 and B(OC(CH3)2C(CH3)2O), SnR3 wherein R is (C1-6)alkyl, and ZnX wherein X is halo.
Other coupling methods between intermediate I (i.e. the pyrazolopyridine scaffold) and intermediate Il (i.e. the R4 substituent) can also be contemplated by those skilled in the art. Furthermore, modification at R7 can easily be incorporated into the synthetic scheme by simply protecting the N7 with a suitable protecting group (e.g. para- methoxybenzyl , etc) during synthesis of the scaffold I and subsequent removal of the 13-152
protecting group to allow coupling of the N7 with an alkyl, aryl or heteroaryl group, all being optionally substituted; these can be achieved in numerous ways, including, but not limited to, alkylation using an alkyl halide under basic conditions, addition of an alkyl moiety or a benzylic-type moiety using the Mitsunobu reaction.
L= leaving group, such as Br or I
Figure imgf000048_0001
Furthermore, downstream modifications to the product can be contemplated, such as conversion of an aniline-type amine to a chloro or bromo substituent via Sandmeyers reaction or alkylation, or dehalogenation via reduction.
Examples
Other features of the present invention will become apparent from the following non- limiting examples which illustrate, by way of example, the principles of the invention. It will be apparent to a skilled person that the procedures exemplified below may be used, with appropriate modifications, to prepare other compounds of the invention as described herein.
As is well known to a person skilled in the art, reactions are performed in an inert atmosphere (including but not limited to nitrogen or argon) where necessary to protect reaction components from air or moisture. Temperatures are given in degrees Celsius (0C). Solution percentages and ratios express a volume to volume relationship, unless stated otherwise. Flash chromatography is carried out on silica gel (SiO2) according to the procedure of W.C. Still et al., J. Org. Chem., (1978), 43, 2923. Mass spectral 13-152
analyses are recorded using electrospray mass spectrometry. A number of intermediate and final products were are purified using CombiFlash® Companion apparatus, purchased from Teledyne lsco Inc, employing pre-packed silica gel cartridges and EtOAc and hexanes as solvents. These cartridges are available either from Silicycle Inc (SiliaFlash, 40-63 microns silica) or from Teledyne lsco (RediSep, 40-63 microns silica). Preparative HPLC is carried out under standard conditions using a SunFire™ Prep C18 OBD 5μM reverse phase column, 19 x 50 mm and a linear gradient employing 0.1%TFA/acetonitrile and 0.1%TFA/water as solvents. Compounds are isolated as TFA salts when applicable.
Analytical HPLC is carried out under standard conditions using a Combiscreen ODS-AQ C18 reverse phase column, YMC, 50 x 4.6 mm Ld., 5 μM, 120 A at 220 nM, elution with a linear gradient as described in the following table (Solvent A is 0.06% TFA in H2O; solvent B is 0.06% TFA in CH3CN):
Figure imgf000049_0001
13-152
Abbreviations or symbols used herein include:
Ac: acetyl;
AcOH: acetic acid;
Ac2O: acetic anhydride;
BOC or Boc: fert-butyloxycarbonyl;
Bu: butyl;
DABCO: 1 ,4-diazabicyclo[2.2.2]octane
DBU: 1 ,8-diazabicyclo[5.4.0]undec-7-ene;
DCE: dichloroethane;
DEAD: diethyl azodicarboxylate;
DCM: dichloromethane;
DIAD: diisopropyl azodicarboxylate;
DIBAL: diisobutyl aluminum hydride;
DME: 1 ,2-dimethoxyethane;
DMF: Λ/,Λ/-dimethylformamide;
DMSO: dimethylsulfoxide;
Dppf: 1 , 1 '-Bis(diphenylphosphino)ferrocene;
CD: circular dichroism
EC50: 50% effective concentration;
Eq: equivalence;
Et: ethyl;
Et3N : triethylamine;
Et2O: diethyl ether;
EtOAc: ethyl acetate;
EtOH: ethanol;
HPLC: high performance liquid chromatography;
IC50: 50% inhibitory concentration;
'Pr or i-Pr: 1 -methylethyl (/so-propyl);
LiHMDS: lithium hexamethyldisilazide;
Me: methyl;
MeCN: acetonitrile;
MeOH: methanol;
MOI: multiplicity of infection;
MS: mass spectrometry (ES: electrospray); 13-152
n-BuONa: sodium n-butoxide n-BuOH: n-butanol; n-BuLI: n-butyllithium;
NMR: nuclear magnetic resonance spectroscopy;
ORD: optimcal rotary dispersion;
Ph: phenyl;
PhMe: toluene;
PG: protecting group;
Pr: propyl;
RPMI: Roswell Park Memorial Institute (cell culture medium);
RT: room temperature (approximately 18°C to 25°C);
SM: starting material; tert-butyl or t-butyl: 1 ,1-dimethylethyl;
Tf: trifluoromethanesulfonyl;
Tf2O: trifluoromethanesulfonic anhydride;
TFA: trifluoroacetic acid;
THF: tetrahydrofuran;
TLC: thin layer chromatography; and
13-152
Example 1 : Synthesis of pyrazolopyridine scaffold 1m
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
13-152
Step 1 :
To a stirred solution of acrylonitrile (50.Og, 0.94 mol) in dry THF (200 ml_) cooled at O0C, hydrazine hydrate (49.5 g, 1.0 mol) is added over a period of about 20 min and the reaction mixture is stirred at RT for about 2 h. To the reaction mixture, p-anisaldehyde (134.7 g, 0.99 mol) is added over a period of about 15 min and stirred for about 3 h. The volatiles are evaporated under reduced pressure, then the reaction mixture is diluted with n-BuOH (200 mL). A solution of freshly prepared n-BuONa (90.1g, 0.94 mol) in n- BuOH (470 mL) is added dropwise at 250C for about 20 min and then the mixture is heated to 12O0C for about 3 h. The reaction mixture is cooled to RT and quenched by adding ice water (2 L). The crude product is extracted with Et2O (2 x 1 L). The combined organic layer is extracted with 1 N HCI (2 x 1 L). The pH of the aqueous layer is adjusted to approximately 14 with a 50% NaOH solution and extracted with CH2CI2 (2 x 1 L). The combined organic layer is washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product is triturated with petroleum ether and the suspension is filtered. The light yellowish solid obtained is dried under vacuum to afford intermediate 1a (115 g, 60% yield), which is used in the following step without purification.
Step 2:
In a stirred solution of 1a (15.0 g, 74 mmol) and diethyl acetylmalonate (15.0 g, 74 mmol), in POCI3 (110 mL) at O0C, a stream of dry HCI gas is passed over the solution for a period of about 15 min. The reaction mixture is gradually warmed to RT, stirred for about 2 h and then heated to 60 0C for about 4 h. POCI3 is distilled under reduced pressure. The reaction mixture is quenched with ice and extracted with EtOAc (3 x 75 mL). The combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure intermediate 1b (9.0 g, 31.5% yield) is isolated as a yellow oil by flash chromatography with Petroleum ethenEtOAc (85:15 v/v).
Step 3:
A solution of compound 1b (17.0 g, 44.10 mmol) in diphenyl ether (75 mL) is heated to 24O0C and stirred for about 3 h. The reaction mixture is cooled to RT and diluted with hexanes (400 mL). The solid which separates out is filtered, washed with hexanes and dried to afford 1c as a light brown solid (11.0 g, 70% yield). 13-152
Step 4:
A stirred solution of compound 1c (26.2 g, 77.0 mmol) in POCI3 (104 ml.) is heated to 80 0C for about 30 min. The POCI3 is distilled under reduced pressure and the residue is treated with ice cold water. The residue is then extracted with EtOAc (3 x 60 mL) and the combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The pure 1d is isolated as a yellow oil (24.3 g, 88% yield) by flash chromatography with Petroleum etherEtOAc (85:15 v/v).
Step 5:
To a stirred suspension of LiAIH4 (11.8 g, 0.32 mol) in THF (200 mL) at -78 0C under an Ar atmosphere, is added a solution of compound 1d (23.0 g, 64.10 mmol) in THF (50 mL) over a period of about 15 min. The mixture is then stirred for about 3 h. The reaction mixture is gradually warmed to -25 0C and stirred for about 2 h. The reaction is quenched by careful addition of saturated sodiumsulfate, 15% aqueous NaOH solution. The reaction is then diluted with EtOAc and filtered. The solid was washed 2 times with hot EtOAc. The combined organic layers are dried over anhydrous Na2SO4 and evaporated under reduced pressure. The product is purified by triturating with 2% EtOAc in hexanes to afford 1e (14.5 g, 71% yield) as a white solid.
Step 6:
To a stirred solution of compound 1e (14.5g, 45.6 mmol) in CH2CI2 (200 mL) cooled to 0 0C under an Ar atmosphere, is added, Dess-Martin Periodinane (29.0 g, 68.6 mmol). The reaction mixture is gradually warmed to RT and stirred for about 16 h. The reaction is quenched by adding saturated aqueous sodium thiosulphate solution and stirred for 30 min. The layers are separated and the organic layer is washed with saturated aqueous NaHCO3 solution, water, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The pure aldehyde 1f is isolated as an off white solid (12.0 g, 83% yield) by flash chromatography with DCMiMeOH (99:1 v/v).
Step 7:
A stirred solution of compound 1f (25.0 g, 79.0 mmol) in Et2O (200 mL), is cooled to 00C and is purged for about 30 min with dry HCI gas, then stirred at RT for about an additional 30 min. The solvent is evaporated and dried completely to afford the 13-152
hydrochloride salt of 1f. To the stirred suspension of this intermediate in dry acetonitrile (350 mL) is added dry NaI (59.6 g, 0.40 mol, pre-dried under vacuum at 120 0C for about 2 h) and heated under Ar to 65°C for about 16 h. The reaction mixture is evaporated to dryness and diluted with saturated aqueous NaHCO3 and extracted with CH2CI2 (3X100 mL). The combined organic layers are washed with saturated aqueous Na2S2O3, water, and brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 1g (30.0 g, 93% yield) which is used in the next reaction without further purification.
Step 8:
To a stirred and cooled solution (00C) of compound 1g (30.0 g, 73.7 mmol) in CH2CI2 (450 mL) is sequentially added solid ZnI2 (23.5 g, 73.7 mmol) and trimethylsilyl cyanide (29.5 mL, 0.22 mol) under Ar. The reaction mixture is gradually warmed to RT and stirred for about 1 h. The mixture is then diluted with ice water and extracted with CH2CI2 (3X100 mL). The combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1h (40 g, -100% yield) which is used as is in the next step without purification.
Step 9:
To a stirred and cooled (O0C) solution of compound 1h (40.0 g, 79.0 mmol) in MeOH (640 mL) is added concentrated H2SO4 (160 mL) dropwise over a period of about 30 min. The reaction mixture is gradually warmed to RT and then heated to 850C for about 5 h. The reaction mixture is poured into ice-water (3 times the reaction mixture volume) and the pH is adjusted to approximately 7 by careful addition of 50% aqueous NaOH. The mixture is extracted with EtOAc (3 x 60 mL) and the combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure intermediate 1i is isolated as a pale yellow semisolid (8.5 g, 23% yield) after flash chromatography with petroleum ether: EtOAc (70:30 v/v).
Step 10:
To a stirred solution of 1i (10.2 g, 22.0 mmol) in a mixture of tert-butyl acetate (280 mL, 2.08 mol) and CH2CI2 (560 mL) at RT, perchloric acid (4 mL, 66.1 mmol) is added and stirred for about 5 h. The pH of the reaction mixture is adjusted to approximately 8 by careful addition of aqueous saturated NaHCO3 solution. The organic layer is separated, 13-152
washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure intermediate 1j is isolated as a pale green semisolid (6.8g, 60% yield) after flash column chromatography with Petroleum etheπEtOAc (85:15 v/v).
Step 11 :
To a stirred solution of compound 1j (6.8 g, 13.0 mmol) in a mixture of THF (136 ml.) and MeOH (68 mL) at 0 0C is added, aqueous solution of NaOH (2.55 g, 63.7 mmol dissolved in 34 mL of H2O). The mixture is gradually warmed to RT and stirred for about 16 h. The reaction mixture is concentrated to 1/4th of its volume under reduced pressure, diluted with H2O and extracted with Et2O. The aqueous layer is cooled to O0C and acidified to about pH 3 with 1 N HCI solution and is then extracted with CH2CI2. The combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 1k (6.0 g, 91% yield) as a white solid, which is used in the following step without purification.
Step 12:
To a stirred solution of compound 1k (7.5 g, 14.7 mmol) and HBTU (14.5 g, 38.3 mmol) in dry THF ( 125 mL) at RT under an Ar atmosphere, diisopropylethylamine (15.8 mL, 88.70 mmol) is added and the reaction mixture is heated to ~35 0C for about 5 h. This reaction mixture is transferred via canula to a stirred mixture of NaH (60% dispersion in oil, 1.8 g, 44.1 mmol) and (R)-benzyloxazolidinone (7.8g, 44.1 mmol) in dry THF (100 mL) under an Ar atmosphere and stirred for about 30 min. The reaction mixture is quenched by adding ice water and then extracted with EtOAc. The combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude was combined with the crude of another batch starting from 1k (6.2 g, 12.2 mmol) and purified together by flash column chromatography with Petroleum ether: EtOAc (85:15 v/v) to afford a mixture of two diastereomers (11.6 g, 64% yield) as a white solid. The diastereomers are separated (1.5g scale) by chromatography on a CombiFlash® Companion instrument using a very slow gradient of THF:hexane on a normal phase column. The products are eluted with THF:hexane (20:80 v/v). The less polar product is identified to be the desired diastereomer 11 (0.75 g, 50% yield).
Step 13: 13-152
To a solution of 11 (1.4 g, 2.10 mmol) in THF/H2O (16 mL/8 mL) at O0C is added 30% H2O2 solution (660 μL, 6.5 mmol) followed by LiOH hydrate (90.4 mg, 2.10 mmol), stirred at O0C for about 2 h. The reaction is quenched at O0C with 10% Na2SO3 (2.5 mL) and allowed to stir for about 5 min. The pH is adjusted to ~4-5 with 1 N HCI and extracted with CH2CI2 (3x100 mL). The combined CH2CI2 layers are extracted with 0.5 N NaOH (3x50 mL). The water layer is acidified with 10% HCI and extracted with EtOAc and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude acid. The acid is dissolved in MeOH/toluene (2 mL/16 mL) and (trimethylsilyl) diazomethane (2 M in hexane, 2.1 mL, 4.3 mmol) is added. The reaction mixture is stirred for about 12 h and the reaction is quenched with AcOH, stirred for about 5 min and concentrated under reduced pressure. The pure intermediate 1m is isolated as white solid (0.91 g, 81% yield) after flash column chromatography with Hexanes:EtOAc (65:35 v/v).
Example 2: Synthesis of pyrazolopyridine scaffold 2m
13-152
Figure imgf000058_0001
Step i :
To a stirred solution of crotononitrile (50 g, 0.745 mol) in dry THF (200 ml_), hydrazine hydrate (39.2 g, 0.782 mol) is added slowly for about 20 min at 0 0C. Then the reaction is maintained at RT for about 2 h. p-Anisaldehyde (106.5 g, 0.782 mol) is added slowly for about 15 min to the reaction mixture and maintained for about 3 h at RT. The THF is evaporated, the crude is diluted with 200 mL of π-BuOH and freshly prepared /7-BuONa (71.5 g, 0.745 mol) in n-BuOH (470 mL) is added at 250C over a period of about 20 min 13-152
and this mixture is heated to 12O0C for about 3 h. The reaction mixture is diluted with water (2 L) and extracted with Et2O (2 x 1 L). The organic layer is separated and treated with 1 N HCI (2 x 1 L). The aqueous layer is separated and the pH is adjusted to about 14 with 50% NaOH solution. Product is extracted with CH2CI2 (2 x 1 L). The combined organic layers are washed with water, brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure. Crude is triturated with petroleum ether and the suspension is filtered to afford 2a (105.3 g, 65% yield) as a light yellow solid.
Step 2:
A stirred mixture of 2a (50.0 g, 0.23 mol) and diethyl acetylmalonate (46.5 g, 0.23 mol) in POCI3 (500 mL) is cooled to 00C. Then HCI gas is passed through the pre-cooled mixture until a clear solution is obtained. The reaction mixture is stirred at RT for about 2 h and heated to 55 0C for about 4 h. POCI3 is distilled completely, crude product is dissolved in EtOAc, quenched with ice carefully and extracted with EtOAc (2 x 150 mL). The combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure 2b (50.0 g, 54% yield) is isolated as a light yellow oil after flash chromatography with Petroleum etheπEtOAc (80:20).
Step: 3
A stirred solution of 2b (50.0 g, 0.124 mol) in diphenyl ether (200 mL) is heated to 220 0C for about 2 h. The diphenyl ether is removed and the compound is isolated by filtering through a silica gel column, eluting with hexanes, followed by EtOAc:hexanes mixture to afford 2c (37.6, 85% yield) as a white solid.
Step 4:
A stirred solution of compound 2c (38.0 g, 0.11 mol) in POCI3 (150 mL) is heated to 9O0C for about 2 h. The POCI3 is distilled under reduced pressure. The crude mass is quenched with ice and the product is extracted with EtOAc (3 x 60 mL). The combined organic layers are washed with water, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The pure 2d (38.0 g, 95% yield) is isolated as a greenish-yellow liquid after flash chromatography with Petroleum etheπEtOAc (85:15). 13-152
To a stirred suspension of lithium aluminium hydride (18.9 g, 0.51 mol) in THF (400 ml_) at -78°C is added slowly over about 15 min, a solution of 2d (38.0 g, 0.10 mol) in THF (100 ml.) and stirred for about 3 h. The reaction is allowed to warm to -20 0C and stirred for about 2 h. The reaction is carefully quenched with saturated solution of sodium sulfate (20 ml_), then a 15% NaOH solution is slowly added. The resulting mixture is diluted with EtOAc and filtered through Celite®. The residue is washed with EtOAc. The combined organic layers are dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue is triturated with hexanes to afford 2e (27 g, 80% yield) as a white solid
Step 6:
A stirred solution of compound 2e (27.5 g, 83.1 mmol) in CH2CI2 (300 ml_), is cooled and then Dess-Martin periodinane (52.8 g, 0.124 mol) is added. The solution is stirred at RT for about 3 h. The reaction mixture is quenched with saturated sodium thiosulphate solution and the organic layer was washed with saturated NaHCO3 solution (2 x 150 mL), water, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The pure 2f (21.8 g, 80% yield) is isolated as a white solid after flash column chromatography with Petroleum etheπEtOAc (85:15).
Step 7:
To a dried NaI (136.7 g, 0.91 mol), a solution of compound 2f (15 g, 45.6 mmol) in MeCN (300 mL) is added, cooled to O0C and acetyl chloride (9.7mL, 0.14 mol) is then added. The reaction is maintained at RT for about 1 h. The reaction mixture is quenched with water at O0C and neutralized with saturated NaHCO3. The crude product is extracted with CH2CI2. The combined organic layers are washed with saturated sodium thiosulphate solution, water, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 2g (18.2 g, 95% yield)
Step 8:
To a stirred solution of freshly distilled furan (1.03 mL, 14.2 mmol) in THF (50 mL), n- BuLi (1.2 M in hexane) (12 mL, 14.2 mmol) is added at -78 0C. The stirred mixture is allowed to warm to 0 0C and stirred for 1 h. The reaction mixture is again cooled to -78 0C, 2g ( 5.0 g, 11.9 mmol) in THF (25 mL) is added slowly. The reaction mixture is quenched with saturated NH4CI solution and extracted with EtOAc. The organic layer is 13-152
washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The pure 2h (2.9 g, 50% yield) is isolated as a white solid after flash column chromatograpy with Petroleum ether: EtOAc (80:20).
Step 9:
To a stirred suspension of 2h (2.5 g, 5.10 mmol) in CH2CI2 (30 ml_), dimethylaminopyridine (0.15 g, 1.3 mmol) and Et3N (0.85 ml_, 6.1 mmol) are added at O0C. This mixture is stirred for about 10 min. To this mixture, acetic anhydride (0.58ml_, 6.1 mmol) is added, then stirred at RT for about 1 h. The reaction mixture is quenched with water at 0 0C. The organic layer is separated and treated with HCI (1 N), washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2i (2.6 g, 95% yield) as an off-white solid. The product is used in the next reaction without purification.
Step 10:
To a stirred solution of NaIO4 (14.5 g, 68.0 mmol) in a mixture of MeCN, H2O, CCI4 (1.5:1 :1) (200 ml_), RuO2. H2O (0.06 g, 0.45 mmol) is added and stirred for about 30 min at RT. The reaction mixture is cooled to 20 0C, and to it is added slowly a solution of 2i (6 g, 11.3 mmol) in MeCN. The reaction mixture is quenched with water and then EtOAc is added. The organic layer is separated and concentrated under reduced pressure. The crude product is taken up in Et2O and treated with 1 N NaOH solution. The aqueous layer is separated and its pH is made acidic by using 1 N HCI. The product is extracted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the acid intermediate (3.9 g, 74% yield) as a crystalline solid. To a stirred solution of this acid intermediate (1O g, 21.4 mmol) in THF (100 ml_), excess diazomethane in Et2O is added at 00C. This solution is then stirred at 00C for about 1 h. The reaction mixture is quenched with AcOH and concentrated under reduced pressure. The residue is dissolved in CH2CI2 and washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure methyl ester intermediate 2j (4.9g, 48% yield) is isolated as a white solid after flash column chromatography with Petroleum ether: EtOAc (80:20).
Step 11 :
The conversion of the free alcohol 2j to its corresponding f-butyl ether 2k is achieved 13-152
following the same protocol as described for the conversion of intermediate 1 i to 1 j in Example 1.
Step 12:
Isolation of the desired enantiomer 2m is achieved using the Evan's chiral auxiliary (i.e. conversion of 2k to intermediate 2I) as described in Example 1 for the isolation of 1m from the mixture of enatiomers 1k.
Example 3: Synthesis of pyrazolopyridine scaffold 3i
Figure imgf000062_0001
The synthesis of intermediate 3a is achieved following the procedures described in the literature (Beyer, H. Zeitschrift fuer Chemie 1970, 10, 386). The conversion of 3a to 3i is achieved using the same experimental protocols as those described in Example 1 for the conversion of 1a to 1j. As it would be obvious to those skilled in the art, all intermediates in Example 3 are analogous to those described in Example 1 , steps 1-9.
Example 4: Synthesis of boronate fragment 4f 13-152
Figure imgf000063_0001
Step i :
To a solution of 4a (6 g, 37 mmol, 1 eq) in nitrobenzene (12 ml_), chloroacetyl chloride (4.6 ml_, 57.5 mmol, 1.5 eq) is added, followed by the addition Of AICI3 (20.4 g, 152 mmol, 4 eq). As the AICI3 is added, the mixture becomes viscous and gas evolution is observed. The resulting brown syrupy mixture is left to stir overnight at RT. (Reference: Y. Takeuchi et.al., Chem.Pharm.Bull. 1997, 45(12), 2011-2015.) The thick reaction mixture is cooled and ice water is added very carefully (exothermic) a few drops at a time. Once gas evolution and bubbling is subsided, cold water is further added followed by EtOAc. The mixture is stirred for about 5 min and the product extracted with EtOAc (3x). The combined organic layers are washed with brine (1x), dried over Na2SO4, filtered and concentrated to afford the uncyclized chloroketone (24 g of crude; contaminated with some nitrobenzene) as a pale yellow solid. This intermediate is then taken up in EtOH (100 ml_), NaOAc is added (20.4 g, 248 mmol, 6.5 eq) and the reaction is brought to reflux for about 40 min. The EtOH is evaporated, the residue is taken up in EtOAc (-300 mL) and washed with 5% K2CO3 (2 x 200 mL) and the aqueous layer then acidified with aqueous HCI (1 N; pH = ~5). This acidic layer is extracted with EtOAc (2 x 250 mL), washed with brine (1x), dried over Na2SO4, filtered and concentrated to afford the crude product. This material is purified by CombiFlash® Companion (120 g) to afford intermediate 4b as a yellow solid (4.7 g). 13-152
Step 2:
The ketone 4b (127 mg, 0.64 mmol) is dissolved in EtOH (2 ml.) and treated with hydrazine hydrate (500 μL, 16 mmol). The mixture is heated to reflux for about 45 min before allowing it to cool to RT. The solvent is removed by evaporation and the residue is dissolved in diethylene glycol (1 mL) before being treated with KOH (108 mg, 1.92 mmol, 3 eq) and then heated to 110-1200C for about 2.5 h. The reaction mixture is diluted with EtOAc and the pH is adjusted with 1 N HCI to pH <4. The organic phase is separated, washed with saturated brine, dried over anhydrous MgSO4, filtered and concentrated. The crude material is purified by CombiFlash® Companion (eluent: 0- 50% EtOAc/hexanes) to give intermediate 4c as a yellow oil (62 mg).
Step 3:
A solution of 4c (61 mg, 0.33 mmol) is cooled to -78 0C in DCM (2 mL) and then treated with BBr3 (1 M in DCM, 825 μL, 0.82 mmol, 2.5 eq). After ~15 min, the bath is removed and the reaction is allowed to reach RT. The reaction is then stirred for about 1.5 h. The reaction is cooled to O0C before quenching by the careful dropwise addition of water. The mixture is treated with saturated NaHCO3 (to about pH = 8) and the phases separated. The organic phase is washed with saturated brine, dried over MgSO4, filtered and concentrated to dryness. The product is purified by CombiFlash® Companion (0-50% EtOAc/hexanes) to give intermediate 4d as a colorless oil, which solidifies upon standing (40 mg, 71% yield).
Step 4:
The phenol 4d (40 mg, 0.23 mmol) is dissolved in DCM (2 mL), cooled to O0C and treated with pyridine (95 μL, 1.17 mmol, 5 eq), followed by Tf2O (44 μL, 0.26 mmol, 1.1 eq). The reaction is allowed to stir at this temperature for about 10 min before warming to RT over a period of about 1 h. The reaction mixture is diluted with DCM and the organic phase washed with 10% citric acid and then brine. The organic phase is dried over anhydrous MgSO4, filtered, concentrated and purified by CombiFlash® Companion (0-50% EtOAc/ hexanes) to give 4e as a yellow oil (67 mg, 94% yield).
Step 5:
To a solution of the triflate 4e (66 mg, 0.22 mmol) in DMF (2 mL), bispinacolatodiborane
(72 mg, 0.28 mmol, 1.3 eq) and potassium acetate (64 mg, 0.65 mmol, 3 eq) are added. 13-152
This solution is de-gassed (with bubbling Ar) for about 10 min before adding PdCI2(dppf)- CH2CI2, (27 mg, 0.03 mmol, 0.15 eq). The mixture is de-gassed a further 5 min before being heated to 9O0C for about 16 h. The mixture is cooled to RT and diluted with EtOAc/water. The organic phase is washed with saturated brine (3x), dried over anhydrous MgSO4, filtered and concentrated. The crude material is purified by CombiFlash® Companion (0-70% EtOAc in hexanes) to afford the boronate 4f as a white solid (41 mg, 67% yield).
Example 5: Synthesis of boronate fragment 5f
Figure imgf000065_0001
5f
Step i :
The nitrophenol 5a (5.23 g, 34.1 mmol) is dissolved in acetic acid (20 ml_) and the solution is cooled in an ice bath. Bromine (1.75 ml_, 34.15 mmol, dissolved in 5 ml_ acetic acid) is added dropwise with stirring. The mixture is stirred for about 1 h at 00C before being poured into ice water (250 ml_). The mixture is extracted with EtOAc (2 X 100 mL) and then washed with 5% NaHCO3 (2 X 50 ml.) before being dried over anhydrous MgSO4, filtered and concentrated to give the desired crude product 5b as an orange solid (8.2 g, 103% yield). This material is used in the next step without further purification. 13-152
Step 2:
To a well stirred ethanol solution (75 ml.) of 5b (8.1 g, 34.9 mmol), SnCI2 (20 g, 105 mmol, 3 eq) is added. The reaction mixture is stirred at reflux for about 2.5 h. After that period, the transformation is incomplete, therefore, more SnCI2 (2g, 10 mmol) is added. Reflux is continued for about 1 h before being cooled to RT. The mixture is poured onto 250 g of ice and the pH adjusted to approximately 7.5 with aqueous 5% NaHCO3. The product is extracted with EtOAc (3 X 100 mL) before being washed with saturated brine (2 X 100 mL). The organic phase is dried over anhydrous MgSO4, filtered and concentrated to dryness to give the aniline intermediate 5c as a gray solid (8.25 g, ~100% yield; this material contained some tin residues, nonetheless, it is used as such for the following step).
Step 3:
To a stirring, ice cold, DMF (5 mL) suspension of potassium carbonate (2.05 g, 14.8 mmol, 4 eq) and aniline 5c (750 mg, 3.71 mmol) under nitrogen, chloroacetyl chloride (355 μL, 4.45 mmol, 1.2 eq) is added dropwise. The mixture is allowed to warm to RT over a period of about 15 min and then heated to ~60°C for about 1 h. The mixture is allowed to cool to RT, is poured into a mixture of ice/water (250 mL) and is stirred for approximately 15 min. The suspension is centrifuged, and the supernatant is discarded. The solid material is left drying under suction overnight to give intermediate 5d (280 mg, 31% yield).
Step 4:
To an ice cold THF (6 mL) solution of the cyclic amide 5d (280 mg, 1.16 mmol) under nitrogen, a borane-THF solution (1M in THF, 1.74 mL, 1.74 mmol, 1 ,5 eq) is added slowly. The reaction mixture is slowly allowed to warm to RT, then is stirred at RT for approximately 1.5 h and then gently heated to reflux for about 1 h to complete the conversion. The mixture is cooled in an ice bath and is carefully quenched with aqueous 1 M NaOH (4 mL) over about 10 min. The reaction mixture is partitioned between EtOAc (150 mL) and water (25 mL). The organic layer is washed with aqueous 1 N NaOH (20 mL), saturated aqueous NaCI, and finally dried over anhydrous MgSO4, filtered and concentrated to give the crude 5e as an amber oil (212 mg, 81% yield). This product is used as such for next transformation. 13-152
Step 5:
A well stirred DMF (15 ml.) solution of the arylbromide 5e (0.50 g, 2.19 mmol, 1 eq), potassium acetate (0.728 g, 7.67 mmol, 3.5 eq) and bis(pinacolato)diborane (0.83 g, 3.3 mmol, 1.5 eq) is degassed by bubbling Ar through the solution for about 20 min. PdCI2(dppf)-DCM (320 mg, 0.44 mmol, 0.20 eq) is added and degassing is continued for about 15 min. The system is sealed (teflon screw cap vessel) under Ar and heated to ~90°C for about 5 h. The reaction mixture is allowed to cool to RT, dilute with EtOAc (150 ml_), washed with brine (3 x 100 ml_) and water (2 x 100 ml_), dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue is purified by CombiFlash® Companion (EtOAc/hexanes) to give the desired boronate 5f (389 mg, 65% yield) as a yellowish waxy solid.
Example 6: Synthesis of boronate fragment 6i
Figure imgf000067_0001
Step 8
Figure imgf000067_0002
13-152
Step 1 :
Sodium hydride (60%, 7.78 g, 194 mmol) is added to a well stirred suspension of 6a (12.5 g, 97.2 mmol) in THF (100 ml_). After stirring the reaction mixture for about 1 h, N,N-diethylcarbamoyl chloride (24.64 ml_, 194 mmol) is added at RT. After stirring the reaction overnight, the reaction mixture is quenched with water (100 ml_), extracted 3 X 50 mL with EtOAc , is dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to obtain 6b (33 g, 75% yield) in high purity.
Step 2:
Diisopropylamine (21.0 mL, 121 mmol) in THF (330 mL) is treated with a solution of n- BuLi (2.5 M in hexanes, 48.2 mL, 121 mmol) at O0C. After 30 min at this temperature, the solution is cooled to -78°C and carbamate 6b (33.29 g, 109.7 mmol, 75 % pure) is added. The reaction is stirred at this temperature for about 30 min and then iodine (33.4 g, 132 mmol) is added. The solution is stirred for about 30 min at O0C and is then warmed to RT. After approximately 2 h, the reaction mixture is quenched with water (250 mL) and the volatile organic solvents are removed under reduced pressure. The aqueous phase is then extracted with EtOAc (3 x 100 mL), washed with 1 N HCI (1 x 200 mL), dry MgSO4, filtered and evaporated under reduced pressure to obtain 6c (18.6 g, 39% yield).
Step 3:
The iodocarbamate 6c (10 g, 28 mmol), propargyl alcohol (3.3 mL, 56 mmol), Pd(PPh3)4 (3.27 g, 2.83 mmol) and copper iodide (1.08 g, 5.66 mmol) are combined in diisopropylamine (39 mL, 39 mmol) in a sealable tube under Ar and heated at 1000C. After about 1 h, the reaction is cooled to RT and poured into EtOAc (10OmL) and this mixture is extracted with 10% HCI (2 x 100 mL). The organic layer is dried over MgSO4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain the alcohol 6d (3.65 g, 46% yield).
Step 4:
Alkyne 6d (3.63 g, 12.9 mmol) is dissolved in EtOAc (81 mL) and treated with Rh-AI2O3 (5% w/w, 3.45 g, 1.68 mmol). The flask is evacuated and charged with 1 atmosphere of H2 (balloon) and the reaction is stirred overnight at RT. The reaction mixture is filtered through Celite® (EtOAc wash) and the filtrate is concentrated under reduced pressure. 13-152
The residue is then purified by CombiFlash® Companion to obtain alcohol 6e (3.7 g, 71% yield).
Step 5:
Solid NaOH (920 mg, 23 mmol) is added to a solution of the carbamate 6e (2.63 g, 9.20 mmoL) in EtOH (93 ml.) and the mixture is heated to reflux and is stirred overnight. The mixture is then cooled to RT and the organic solvent removed under reduced pressure. Water is added (100 ml_) and the mixture extracted with Et2O (3 x 100 ml_), dried over MgSO4, filtered and evaporated under reduced pressure to obtain phenol 6f (869 mg, 51 % yield).
Step 6:
Diethylazodicarboxylate (953 μl_, 6.05 mmol) is added dropwise to a solution of phenol 6f (869 g, 4.66 mmol) and PPh3 (1.59 g, 6.053 mmol) in THF (65 mL) and the reaction is stirred at RT. After about 4 h, the reaction mixture is evaporated under reduced pressure. The residue is then purified by CombiFlash® Companion to obtain the chroman intermediate 6g (387 mg, 49% yield).
Step 7:
Iodine (583 mg, 2.295 mmol) is added to a solution of chroman 6g (387 mg, 2.29 mmol) and AgNO3 (429 mg, 2.52 mmol) in MeOH (23 mL). After 20 min, a 0.5 M solution of sodium thiosulfate (10 mL) is added and the aqueous phase extracted with EtOAc (3 x 25 mL). The combined organic phases are washed with brine, then dried (MgSO4), filtered and evaporated to obtain aryl iodide 6h (647 mg, 96% yield).
Step 8:
A solution of iodo intermediate 6h (647 mg, 2.20 mmol), bis(pinocolato)diborane (0.725 g, 2.86 mmol) and potassium acetate (0.626 g, 6.59 mmol) in DMF (17 mL) is degassed with Ar for about 10 min. PdCI2(dppf)-DCM complex (179 mg, 0.22 mmol) is then added and the mixture is degassed with Ar for approximately another 5 min. The reaction is then heated to 950C in a sealable tube and is stirred overnight. The reaction is cooled to RT and EtOAc (100 mL) is added. The solution is washed with brine (3 x 150 mL), water (1 x 150 mL), dried over MgSO4, filtered and solvent removed under reduced pressure. The residue is purified by CombiFlash® Companion to afford boronate ester 6i (260 mg, 13-152
40% yield).
Example 7: Synthesis of boronate fragment 7d
Figure imgf000070_0001
Step 1 :
A solution of phenol 7a (0.91 g, 5.74 mmol) in dry DMF (1 ml_) is added dropwise to a slurry of NaH (60% in oil, 0.60 g, 15 mmol) in dry DMF (1 ml.) cooled to 10-150C (cold water bath) and the mixture is stirred for about 20 min. This results in a thick, frothy white mixture. A solution of 3-bromopropionic acid (1.1 g, 6.9 mmol) in dry DMF (0.5 ml_) is then added dropwise and the reaction stirred at RT overnight. After about 16 h, methanol (1.2 ml.) is added to help break up the thick, pasty reaction mixture which is then added to dilute HCI (-12 ml. 1 N HCI in 100 ml. water) and extracted with EtOAc (80 ml_; the pH of the aqueous phase is adjusted to pH <3). The organic layer is dried over anhydrous Na2SO4 and evaporated to give 7b as a white solid material, contaminated with some unreacted SM (1.29 g of crude material). This material is used in the next step without purification.
Step 2:
The crude compound 7b (1.53 g, 6.63 mmol) is combined with polyphosphoric acid (approximately 7 g) and heated to 750C to give a cherry red colored solution. During the reaction time, the reaction mixture becomes viscous and stirring becomes difficult. After about 4 h, ice and water are slowly added with rapid stirring to give a thick suspension. This mixture is transferred to a separatory funnel where the product is extracted with EtOAc (100 ml.) and washed with water (100 ml_), saturated NaHCO3 (2 x 100 ml.) and brine (75 ml_). The organic phase is dried over anhydrous MgSO4 and evaporated to give a sticky violet solid which is used as such (compound 7c, 1.29 g crude). 13-152
Intermediate 7c is analogous to intermediate 4b in Example 4; those skilled in the art would recognize that the same synthetic methodologies used to convert 4b to the boronate 4f can be applied for the conversion of 7c to the corresponding boronate 7d.
Example 8: Synthesis of boronate fragment 8h
Figure imgf000071_0001
8h
Step 1 (Sandmever reaction)
2-Amino-/77-cresol 8a (5.7 g, 46.3 mmol) is dissolved in H2O (30 mL) and 1 ,4-dioxane (15 mL). The mixture is heated to reflux and then HBr (48%, 17 mL, 0.31 mol) is added dropwise over a period of about 20 min. The reflux is maintained for about an additional 15 min after the addition is complete. The reaction is cooled to O0C, and NaNO2 in H2O (20 mL) is added over a period of about 30 min. The stirring is continued for about 15 min at O0C, the mixture is then transferred in one shot to a stirring mixture of Cu(I)Br (7.64 g, 53.2 mmol, 1.15 eq) in H2O (20 mL) and HBr (48%, 17 mL, 0.31 mol) at O0C (protected from light). The reaction is stirred for about 15 min at O0C, is warmed to 6O0C, is stirred for an additional 15 min, is cooled to RT and is then stirred overnight. The reaction mixture is then transferred to a separatory funnel and extracted with EtOAc (3x). The organic layers are combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated over silica to afford a mixture that is purified using the CombiFlash® Companion (20% EtOAc/hexanes) to afford the desired bromide 8b (1.46 g, 17% yield) as a red-brown oil.
Step 2:
To a solution of the bromide 8b (1.36 g; 7.27 mmol; 1.0 eq) and (PPh3)2PdCI2 (766 mg,
1.09 mmol, 15 mol%) in DMF (12 mL), 1-ethoxyvinyl-tri-n-butyltin (2.7 mL, 8.0 mmol, 1.1 13-152
eq) is added. The mixture is capped and heated in a microwave at 1600C for 15 min. HPLC and LC-MS analysis indicate approximately 70% conversion. More 1-ethoxyvinyl- tri-n-butyltin (2.7 mL; 8.0 mmol, 1.1 eq) and catalyst (PPh3)2PdCI2 (380 mg, 0.05 mol%) are added and the solution is again subjected to the same microwave conditions. The reaction is quenched with 6N HCI (1.5 mL) and stirred at RT for about 1 h to effect hydrolysis of the intermediate. The mixture is poured into EtOAc (150 mL), washed with brine (3x), dried over MgSO4, filtered and concentrated over silica to afford the mixture that is purified using the CombiFlash® Companion to afford the desired ketone 8c (947 mg, 87% yield) as an orange oil.
Step 3:
The methyl ketone 8c (1.02 g, 6.8 mmol) is dissolved in EtOAc (15 mL) and CHCI3 (15 mL) before being treated with Cu(II)Br2 (3.03 g, 13.6 mmol, 2 eq). The mixture is heated to reflux for about 16 h. The mixture is cooled to RT, the product filtered and washed with EtOAc (1x). The solution is concentrated over silica to afford the mixture that is purified using the CombiFlash® Companion (10% EtOAc/hexanes) to afford the α- bromoketone 8d (710 mg, 46% yield) as an orange oil. This crude material is used in the next step without purification.
Step 4:
To a solution of the bromoketone 8d (710 mg, 3.1 mmol) in anhydrous DMF (12 mL), KF (400 mg, 6.95 mmol, 2.2 eq) is added. The reaction is stirred at RT for about 16 h. The mixture is taken up in EtOAc (150 mL), washed with brine (3x), dried over anhydrous MgSO4, filtered and concentrated over silica to afford the mixture that is purified using the CombiFlash® Companion (20% EtOAc/hexanes) to afford the cyclic ketone 8e (280 mg, 61% yield) as a pale orange solid.
Step 5:
Zn dust pre-activation procedure: Zinc dust (20 g, 350 mesh) is placed in a round bottom flask and 1 N HCI (50 mL) is added. This suspension is sonicated for about 1 min before decanting off the liquid. This procedure is repeated for a second time after which the solid is washed with EtOH (2x), Et2O (2x) and dried under high vacuum. To a solution of the ketone 8e (280 mg, 1.89 mmol) in AcOH (10 mL) pre-activated Zn dust (1.24 g, 18.9 mmol, 10 eq) is added. The reaction mixture is then heated to 750C for 13-152
about 2 h. The reaction mixture is filtered (with EtOAc washing of the solids). The solvent is evaporated over silica and the mixture is directly purified using the CombiFlash® Companion (10% EtOAc/hexanes) to afford the desired dihyrobenzofuran 8f (174 mg, 69% yield) as a colorless oil.
Step 6:
To a solution of the dihydrobenzofuran 8f (240 mg, 1.8 mmol) in MeOH (5 ml_), AgNO3 (304 mg, 1.79 mmol) is added followed by iodine (453 mg, 1.79 mmol). The yellow mixture is stirred at RT for about 1 h. To the reaction mixture is added a solution of 10% Na2S2O3 and the mixture is stirred for about 15 min at RT. The mixture is diluted with EtOAc (100 ml_), and the organic layer is washed with brine (3x) and 10% Na2S2O3 (2x). The organic phase is dried over anhydrous MgSO4, filtered and concentrated over silica to give a mixture. This mixture is purified using the CombiFlash® Companion (10% EtOAc/hexanes) to afford the iodo derivative 8g (400 mg, 86% yield) as a white amorphous solid.
Step 7:
A mixture of the iodo derivative 8g (400 mg, 1.54 mmol), bis(pinocolato)diborane (585 mg, 2.31 mmol, 1.5 eq), potassium acetate (511 mg, 5.4 mmol, 3.5 eq) in DMF (20 mL) is deoxygenated (Ar balloon and sonication for about 5 min); then the catalyst (PdCI2dppf, 188 mg, 0.23 mmol, 0.15 eq) is added with additional degassing (Ar balloon and sonication for about 2 min). The mixture is then heated to approximately 950C for about 4 h. The mixture is cooled, EtOAc (200 mL) is added, washed with brine (3x), water (2x), dried over anhydrous MgSO4, filtered and solvent evaporation over silica affords the mixture that is purified using the CombiFlash® Companion (10 % EtOAc/hexanes) to afford the desired boronate 8h (315 mg, 79% yield) as a yellow oil.
Example 9: Synthesis of boronate fragment 9b
Figure imgf000073_0001
13-152
Anhydrous DMF (60 ml.) is added to a flask charged with bromide 9a (5.00 g, 22.2 mmol), jb/s-(pinacolato)diboron (8.48 g, 33.4 mmol) and potassium acetate (6.35 g, 66.8 mmol) and the resulting suspension is deoxygenated by bubbling a stream of N2 gas through the mixture for about 45 min. 1 , 1 '-bis(diphenylphosphino)ferrocene (2.73 g, 3.34 mmol) is then added and the mixture is deoxygenated for approximately a further 5 min and is then heated to 950C. After about 16 h, the dark reaction mixture is cooled, extracted with EtOAc (500 mL and 300 mL) and washed with 1 :1 water/brine (600 ml.) and brine (600 mL). The combined extracts are dried over anhydrous MgSO4, filtered and evaporated to a black syrup which is purified by flash column chromatography (EtOAc / hexanes) to afford the boronate 9b as white solid contaminated with <25 % of the diboron reagent (4.24 g, 62% yield).
Example 10: Synthesis of boronate fragment 1Og
Figure imgf000074_0001
Step 6
Figure imgf000074_0002
Step 1 :
2-Chloro-6-fluoronitrobenzene 10a (6.62 g, 37.7 mmol) and LiOH monohydrate (6.33 g, 13-152
151 mmol) are dissolved in THF (45 ml.) and water (65 mL) and an aqueous solution of H2O2 (30%, 8.60 mL, 80.0 mmol) added. The resulting turbid solution is sealed and is heated to 6O0C with rapid stirring. After about 3 days, the dark orange mixture is cooled and is added to half-saturated aqueous sodium thiosulfate (200 mL) and shaken vigorously in a separatory funnel. The mixture is then acidified to pH < 3 with 1 N HCI, extracted with EtOAc (400 mL + 100 mL) and washed with brine (400 mL). The combined extracts are dried over magnesium sulfate, filtered and evaporated to a deep yellow oil (aminophenol 10b) containing some solid particles (residual starting material) which is used as such (6.37 g, 97% yield).
Step 2:
The crude aminophenol 10b (6.37 g. 36.7 mmol) is dissolved in THF (100 mL) and tin powder (17.4 g, 147 mmol) is added followed by 1 N HCI (220 mL, 220 mmol). The resulting mixture is stirred vigorously at RT. After 16 h, the reaction is cooled to O0C, the acid neutralized with 10 N NaOH (22 mL) and the resulting milky suspension stirred vigorously for about 15 min. The mixture is then filtered through a pad of Celite® and the solids washed thoroughly with EtOAc (4 x 200 mL). The filtrate is transferred to a separatory funnel and the aqueous phase acidified with 1 N HCI (4 mL), diluted with brine (400 mL) and the organic phase washed with brine (400 mL). The extract is then dried over sodium sulfate, filtered and evaporated to afford aminophenol 10c as a waxy, pale brown solid (2.91 g, 55% yield).
Step 3:
Chloroacetyl chloride (1.94 mL, 24.3 mmol) is added to an ice-cold mixture of aminophenol 10c (2.91 g, 20.3 mmol) and potassium carbonate (8.40 g, 60.8 mmol) in anhydrous DMF (200 mL) under a N2 atmosphere. After 5 min, the reaction is allowed to warm to RT and, after a further 45 min, is heated to 5O0C. After about 15 h, the reaction is cooled and extracted with EtOAc (600 mL) and washed with water/brine (1 L), half- saturated sodium bicarbonate (1 L) and brine (600 mL). The organic phase is then dried over MgSO4, filtered and evaporated to afford lactam 10d as a fibrous, pale-olive solid (3.15 g, 85% yield).
Step 4:
Bromine (1.8 mL; 35 mmol) is slowly added dropwise to a stirred solution of lactam 10d 13-152
(3.15 g; 17.1 mmol) in anhydrous DCM (40 mL) at RT. After 3 h, the resulting suspension is slowly added to saturated aqueous sodium thiosulfate (200 mL) and extracted with DCM (4 x 100 m L). The combined extracts are then washed with brine (200 mL), dried over magnesium sulfate, filtered and evaporated to afford the bromide 10e as a pale beige powder (4.00 g, 89% yield).
Step 5:
A solution of borane in THF (1.0 M, 18.5 mL, 18.5 mmol) is added dropwise to an ice- cold solution of lactam 10e (4.00 g, 15.2 mmol) in anhydrous THF (75 mL), and the reaction is allowed to warm to RT. After about 30 min, the solution is heated to gentle reflux under a N2 atmosphere. After about 2 h, the reaction is cooled to O0C and carefully quenched with 1 N NaOH (19 mL) and stirred for about 15 min. The mixture is then diluted with water (30 mL) and the THF is evaporated. The aqueous residue is then extracted with EtOAc (400 mL + 50 mL) and washed with water/brine (200 mL), 0.5 N NaOH (200 mL) and brine (100 mL). The combined extracts are dried over magnesium sulfate, filtered and evaporated to afford the morpholine derivative 10f as a yellow syrup (3.90 g, quantitative, yield).
Step 6:
Anhydrous DMF (30 mL) is added to a flask charged with aryl bromide 10f (1.84 g, 7.42 mmol), ό/s(pinacolato)diborane (2.83 g, 11.1 mmol) and potassium acetate (2.47 g, 26.0 mmol) and the resulting suspension is then deoxygenated by bubbling a stream of N2 gas through the mixture for about 15 min. 1 ,1'-bis(diphenylphosphino)ferrocene (909 mg, 1.11 mmol) is then added and the mixture is deoxygenated for about a further 5 min and then heated to 950C. After about 16 h, the dark reaction mixture is cooled, extracted with EtOAc (300 mL) and washed with 1 :1 water/brine (500 mL) and brine (200 mL). The extract is then dried over MgSO4, filtered and evaporated to a brown syrup which is chromatographed over silica gel (EtOAc/hexanes) to afford the boronate 10g as a white solid contaminated with 0.8 eq of the diboron reagent (1.52 g, 69% yield).
Example 11 : Synthesis of boronate fragment 11d 13-152
Figure imgf000077_0001
11d
Step 1 :
Commercially available chromanone 11a (9.78 g, 66.0 mmol) dissolved in AcOH (20 ml_) is added to a suspension of zinc dust (108 g, 1.65 mol) in AcOH (150 ml_). The mixture is heated to 1000C and is stirred mechanically overnight. The mixture is then filtered through Celite® (washed with EtOAc, 10OmL), diluted with PhMe (300 ml_) and the solution is evaporated to give chroman intermediate 11b (8.45 g, 95% yield).
Step 2:
AgNO3 (12.0 g, 70.6 mmol) and I2.(15.8 g, 62.3 mmol) are added sequentially to a solution of 11b (8.45 g, 63.0 mmol) dissolved in MeOH (225 ml_). The reaction is allowed to stir for about 1 h, filtered on Celite® and the filtrate concentrated under reduced pressure. The crude mixture is diluted with EtOAc (250 mL) and washed with saturated sodium thiosulfate (250 mL). The organic layer is washed with water (200 mL) and then dried over Na2SO4, filtered and concentrated. The crude mixture is further purified by CombiFlash® Companion to give 6-iodochroman 11c (12.1 g, 74% yield).
Step 3:
A solution of the 6-iodochroman 11c (1.O g, 3.85 mmol), bis[pinocolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.1O g, 11.5 mmol) in DMF (36 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 950C for about 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash® Companion using a gradient of EtOAc/hexanes to afford the borane fragment 11d (840 mg, 84% yield). 13-152
Example 12: Synthesis of boronate fragment 12g
Figure imgf000078_0001
Step i :
The phenol 12a (6.75 g, 47.3 mmol) is dissolved in DMF (270 ml.) and is treated with ally] bromide (6.55 ml_, 75.7 mmol, 1.6 eq). To this solution, NaH (60%, 4 g, 99.4 mmol, 2.1 eq) is added portionwise and stirring is continued overnight. The reaction mixture is diluted with EtOAc (500 mL) and washed with H2O (3 x 500 ml_). The organic layer is dried over MgSO4, filtered and concentrated to dryness to obtain the desired product 12b, which is used as such in the next step.
Step 2:
The ether 12b (9.67 g) is placed in a microwave vial neat with a stir bar and is heated to 24O0C for about 20 min at which point the Claisen rearrangement reaction is complete. The crude product 12c (9.3 g) is used in the following step without further purification.
Step 3:
To a solution of the allyl intermediate 12c (9.3 g, 45.8 mmol) in anhydrous THF (300 mL) at O0C, borane (1 M in THF, 96 mL, 96 mmol, 2.1 eq) is added. The solution is allowed to warm to RT and then is stirred for about 2.5 h. The solution is then cooled to O0C and treated with 10 N NaOH dropwise, followed by slow addition of 30% H2O2 (104 ml, 916 mmol, 20 eq). The resulting mixture is allowed to warm to RT and then is stirred at RT for about 1 h. The reaction mixture is diluted with HCI (10%, 10OmL) and extracted with EtOAc (3 x 20OmL). The combined organic phases are dried over MgSO4 and 13-152
concentrated. The crude product 12d is purified by CombiFlash® Companion to give 7.1g (77% yield).
Step 4:
To a solution of the diol 12d (7.1 g, 35.3 mmol) in THF (500 ml_), PPh3 (12 g, 45.9 mmol,
1.3 eq), followed by DEAD (7.2 ml_, 45.9 mmol, 1.3 eq) are added. The solution is stirred at RT for about 4 h. The reaction mixture is evaporated under reduced pressure and purified by CombiFlash® Companion to obtain the desired product 12e (5.26 g, 82% yield).
Step 5:
The chroman derivative 12e (5.26 g, 28.8 mmol) is dissolved in AcOH (70 mL) and is then treated with Br2 in AcOH (40 mL). The reaction is stirred at RT for about 15 min, then diluted with toluene and concentrated to dryness. The residue is taken up in EtOAc (25 mL) and washed with saturated Na2S2O3 (25 mL) and saturated NaHCO3 (25 mL). The organic layer is dried over MgSO4, concentrated and purified by CombiFlash® Companion to obtain the desired product 12f (2.7 g, 36% yield).
Step 6:
The bromide 12f (2.71 g, 10.4 mmol) is dissolved in DMF (120 mL) and treated with bis[pinocolato]diborane (4 g, 15.5 mmol, 1.5 eq) and potassium acetate (3.45 g, 36.3 mmol, 3.5 eq). The mixture is degassed (using an Ar balloon) before the introduction of the catalyst (PdCI2dppf, 845 mg, 1.04 mmol, 0.1 eq). The mixture is then degassed again (using an Ar balloon) and heated to 950C for about 16 h. The mixture is cooled to RT, diluted with H2O (300 mL) and extracted with EtOAc (2 x 300 mL). The combined organic layers are washed with water (3 x 300 mL) dried over MgSO4, filtered and concentrated. The product is then purified by CombiFlash® Companion. The semi- purified product is then triturated with hexanes (3x 50 mL) in order to remove the excess disborane and obtain clean compound 12g (1.74 g, 54% yield).
Example 13: Synthesis of boronate fragment 13a 13-152
Figure imgf000080_0001
Step 1 :
Palladium on activated charcoal (10% Pd by weight, 0.63 mg, 0.59 mmol) is added to a solution of aryl chloride 12g (0.91 g, 2.95 mmol) and ammonium formate (1.92 g, 30.4 mmol) dissolved in MeOH and the mixture is heated to reflux. After about 15 min, the reaction is cooled to RT and filtered through Celite® (MeOH rinse). The filtrate is evaporated to dryness and the residue partitioned between water and EtOAc (10 ml_ each). The organic layer is dried over anhydrous MgSO4 and concentrated to obtain boronic ester 13a (0.78 g, 97% yield).
Example 14: Synthesis of boronate fragment 14g
Figure imgf000080_0002
Step 1 :
AIIyI bromide (9.3 ml_, 110 mmol) followed by potassium carbonate (20 g, 150 mmol) are added to a solution of 14a (1O g, 73 mmol) dissolved in DMF 110 ml_). The reaction is allowed to stir under Ar at RT overnight. The reaction is diluted with water (400 ml_) and extracted with EtOAc (400 ml_). The organic layer is washed with water (2 x 400 ml_), dried over Na2SO4 and concentrated. The product is then purified by CombiFlash® Companion in two batches (120 g column) to provide allyl ether 14b (12g, 92% yield). 13-152
A solution of n-BuLi in hexanes (2.5 M, 6.4 ml_, 16 mmol) is added dropwise to a precooled (-780C) suspension of methyltriphenylphosphonium bromide (6.6 g, 19 mmol) in THF (90 ml_). The resulting bright yellow mixture is stirred for about 5 min at -780C, warmed to RT over approximately 5 min and then recooled to -78°C. Aldehyde 14b (2.4 g, 14 mmol) dissolved in THF (10 mL) is added dropwise and the reaction is allowed to proceed for about 10 min at -78°C before being allowed to warm to RT and stir overnight. The reaction is quenched with brine (100 mL), diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer is then washed with water (2 x 100 mL), dried over Na2SO4 and concentrated. The crude yellow liquid is then taken up in about 1 mL of EtOAc and diluted with hexanes (about 20 mL), after which Ph3PO precipitates as a white solid. The solid is removed by filtration, washed with 1 :9 EtOAc: hexanes (about 50 mL) and the filtrates are evaporated to dryness. The product is purified by CombiFlash® Companion to give diene 14c (1.3 g, 54% yield).
Step 3:
Grubb's second generation catalyst (50 mg, 0.075 mmol) is added to a degassed solution of diene 14c (1.3 g, 7.5 mmol). After stirring under Ar for about 2.5 h, the reaction is concentrated onto SiO2 (about 2g) and the product purified by CombiFlash® Companion to give benzopyran 14d (940 mg, 86% yield) as a clear oil.
Step 4:
Solid Pd-C (10% w/w, 680 mg, 0.64 mmol) is added to a solution of benzopyran 14d
(940 mg, 6.4 mmol) in EtOH (8.5 mL) and the flask is evacuated and backfilled with H2 gas (balloon). After stirring the reaction at RT for about 2.5 h, the mixture is filtered through Celite® (EtOAc washing) and then the filtrate is concentrated to dryness. The product is purifed by CombiFlash® Companion to provide chroman 14e (800 mg, 84% yield).
Step 5:
Neat Br2 (275 μL, 5.4 mmol) is added dropwise to a solution of chroman 14e (800 mg, 5.4 mmol) dissolved in AcOH (25 mL). The reaction is then diluted with water (50 mL) and EtOAc (50 mL). The organic layer is washed with water (2 x 50 mL) and saturated NaHCO3 (2 x 50 mL). The organic layer is dried over Na2SO4 and concentrated to dryness. The product is purified by CombiFlash® Companion to give bromide 14f as a 13-152
mixture with the dibromide (1.3 g, 68% by mass 14f, 51% yield).
Step 6:
A solution of the bromide 14f (950 mg, 2.8 mmol), bis[pinocolato]diborane (840 mg, 3.3 mmol) and potassium acetate (920 g, 9.6 mmol) in DMF (30 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (290 mg, 0.36 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 950C for about 3 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 20 mL). The combined organics are washed with water (2 x 20 mL). The organic phase is then dried over Na2SO4, filtered and concentrated. The crude mixture is further purified by CombiFlash® Companion to afford boronic ester 14g (403 mg, 53% yield) as a pale yellow solid.
Example 15: Synthesis of boronate fragment 151
Figure imgf000082_0001
15a 15b 15c 15d
Step 4
Figure imgf000082_0002
151
Step i :
An ethereal solution of diazomethane (0.7 M, 100 mL) is added to a solution of 15a (5.0 13-152
g, 30 mmol) in ether (20 ml_). After consumption of the SM (TLC monitoring), the reaction is concentrated onto SiO2 (about 10 g) and the product purified by CombiFlash® Companion to yield ester 15b (5.2 g, 95% yield).
Step 2:
A solution of NaNO2 (2.1 g, 30 mmol) in water (10 ml_) is slowly added to a solution of aniline 15b (5.0 g, 28 mmol) dissolved in AcOH (50 mL) and 2 M HCI (75 mL) at O0C. The resulting mixture is stirred at this temperature for about 1 h. Solid CuCI (8.4 g, 85 mmol) is added portionwise (over about 2 min). The reaction is allowed to come to RT, is stirred for about 30 min and then is warmed to 6O0C for about 40 min. The mixture is poured into water (200 mL) and extracted with EtOAc (2 x 200 mL). The organic layer is dried with MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash® Companion to afford aryl chloride 15c (3.8 g, 68% yield).
Step 3:
A solution of DIBAL in DCM (1 M, 42 mL, 42 mmol) is added dropwise over a period of about 25 min to a precooled (-780C) solution of ester 15c (3.8 g, 19 mmol) in dry CH2CI2 (100 mL). The reaction is allowed to stir for about 2 h at -78°C. The reaction is quenched at -78°C by the dropwise addition of 1 N HCI (8 mL). The reaction is allowed to warm to RT and the organic phase washed with a 5% solution of Rochelle's salt (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give crude benzyl alcohol 15d (3.2 g, 99% yield), which is used in the next step without any further purification.
Step 4:
Solid Dess Martin reagent (8.7 g, 20 mmol) is added to a precooled (00C) solution of alcohol 15d in dry CH2CI2 (100 mL). The reaction is allowed to stir for about 2 h while slowly warming to RT. At this time, another 0.5 g of Dess Martin Periodinane is added and the reaction continues for about another 1 h. A 1 :1 mixture of saturated NaHCO3 and 0.5 M Na2S2O3 (100 mL) is added and this mixture is stirred vigorously until the phases become clear (approximately 30 min). The organic phase is separated and the aqueous phase is extracted with DCM (100 mL) and washed with saturated NaHCO3 (10OmL). The combined organic phases are then dried over MgSO4 and evaporated. The product is purified by CombiFlash® Companion to give aldehyde 15e (2.9 g, 90% 13-152
yield).
Step 5:
A solution of methyl ether 15e (720 mg, 4.2 mmol) in anhydrous CH2CI2 (20 mL) is added slowly to a precooled (-300C) solution of BBr3 (1 M, 8.4 mL, 8.4 mmol). The solution is warmed to O0C and is stirred for about 3 h. The reaction is quenched carefully with methanol (1 mL) and washed with saturated NaHCO3 and then brine (25 mL each). The organic layer is dried over MgSO4, filtered and concentrated and the product is purified by CombiFlash® Companion to give phenol 15f (530 mg, 80% yield).
Step 6:
A mixture of the aldehyde 15f (1.1 g, 7.2 mmol), acrylonitrile (2.4 mL, 36 mmol) and
DABCO (190 mg, 1.7 mmol) are refluxed for about 5 h. The reaction mixture is cooled to
RT, diluted with EtOAc (50 mL) and washed with 1 N NaOH (20 mL) and then with 1 N
HCI (20 mL). The organic phase is dried over MgSO4 and concentrated to dryness. The product is purified by CombiFlash® Companion to afford the nitrile 15g 650 mg, 47% yield).
Step 7:
A mixture of nitrile 15g (650 mg, 3.4 mmol), 10% NaOH (10 mL, 25 mmol) and EtOH (95%, 0.5 mL) is heated to reflux for about 5 days. The reaction is then cooled to RT and 1 N HCI is then added until about pH = 4. The precipitate is then collected by filtration, washed with water and dried in vacuo to give acid 15h (740 mg, >99% yield).
Step 8:
Triethylamine (0.56 mL, 4.0 mmol) and diphenylphosphoryl azide (0.75 mL, 3.5 mmol) are added successively to a solution of acid 15h (714 mg, 3.4 mmol) in dry toluene (40 mL). This mixture is heated to 85°C for about 2 h and then cooled to RT and treated with 6 N HCI (6 mL). The mixture is brought to reflux and is stirred at this temperature for about 2 h. The reaction is then cooled to RT, diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (2 x 100 mL), water (2 x 100 mL) and brine (100 mL). The organic layer is dried over MgSO4, filtered and evaporated to dryness. The product is then purified by CombiFlash® Companion to give ketone 15i (269 mg, 44% yield). 13-152
Step 9:
Deoxofluor® (0.54 ml_, 2.9 mmol) is added to a solution of ketone 15i (270 mg, 1.5 mmol) in CH2CI2 (0.6 ml_) and EtOH (17 μl_) in a sealed tube. The sealed tube is heated to 400C for about 24 h. The tube is then unsealed, cooled to 00C and the reaction quenched by the slow (Caution! Exothermic!) addition of saturated NaHCO3 (1 ml_). The crude reaction mixture is diluted with water (20 ml_) and extracted with DCM (3 x 20 ml_). The combined organics are washed with water (20 ml.) and the organic phase is dried over MgSO4, filtered and concentrated. The product is purified by CombiFlash® Companion to provide difluorochroman 15j (225 mg, 71% yield).
Step 10:
Solid silver nitrate (187 mg, 1.1 mmol) and iodine (279 mg, 1.1 mmol) are added successively to a solution of difluorochroman 15j (225 mg, 1.1 mmol) dissolved in MeOH (7.8 ml_). The reaction is stirred at RT for about 90 min and then filtered through a pad of Celite®. The filtrate is treated with a drop of 0.5 N Na2S2O3 (orange color dissipated) then concentrated under reduced pressure. The residue is partitioned between H2O, 0.5N Na2S2O3 and EtOAc (20 ml. each). The water layer is extracted with EtOAc (3 x 20 mL) and the combined organics are washed with brine (20 ml_), dried over MgSO4, filtered and concentrated. The product is purified by CombiFlash® Companion to give aryl iodide 15k (158 mg, 44% yield).
Step 11 :
A solution of the aryl iodide 15k (150 mg, 0.45 mmol), bis[pinocolato]diborane (150 mg, 0.59 mmol) and potassium acetate (130 mg, 1.4 mmol) in DMF (5 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (44 mg, 0.054 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 850C for approximately 9 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted with EtOAc (3 x 10 mL). The combined organics are washed with water (10 mL) and brine (10 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash® Companion to afford boronic ester 151 (123 mg, 70% pure by NMR, 57% yield).
Example 16: Synthesis of boronate fragment 16c 13-152
Figure imgf000086_0001
Step i :
Solid NaBH4 (342 mg, 9.0 mmol) is added to a solution of ketone 4b (1.5 g, 7.5 mmol) dissolved in MeOH (10 ml.) and THF (25 ml.) at O0C is then added. The reaction is warmed to RT and is allowed to stir for about 1 h. The reaction is quenched with aqueous HCI (1 N, 5 ml_), the MeOH is removed by concentration and the product extracted with EtOAc (2 x 50 mL). The organic layer is washed with brine (50 ml_), dried over Na2SO4, filtered and concentrated to afford alcohol 16a (1.52 g >99% yield). This material is used as is in the next step.
Step 2:
TFA (2.9 mL) is added dropwise to a solution of crude alcohol 16a (1.5 g; 7.47 mmol) in CH2CI2(28 mL) at O0C. The solution is stirred for about 30 min, then concentrated to dryness. The residue is taken up in EtOAc, washed with NaHCO3 (saturated), brine, dried over Na2SO4, filtered and concentrated to a pale yellow gum. The product is purified by CombiFlash® Companion to afford benzofuran 16b (0.30 g, 22% yield) as a white solid.
Step 3:
Compound 16c is prepared from 16b following a synthetic sequence described in steps
3 to 5 of Example 4.
Example 17: Synthesis of boronate fragment 17g 13-152
Figure imgf000087_0001
Step i :
Zn dust (7.89 g, 121 mmol) is added to a solution of 17a (5.0 g, 24 mmol) in AcOH (100 ml_). The reaction mixture is then heated to 1000C and is stirred overnight. The reaction is cooled to RT and the mixture is filtered (EtOAc washing), the solvent is evaporated and the residue purified by CombiFlash® Companion to afford aniline 17b (3.06 g, 72% yield) as a yellow solid.
Step 2:
A solution of NaNO2 (640 mg, 9.3 mmol) in water (3 ml.) is slowly added to a solution of aniline 17b (1.5 g, 8.5 mmol) dissolved in AcOH (12 mL) and 2 M HCI (25 mL) at O0C. The resulting mixture is stirred at this temperature for about 1 h. Solid CuCI (2.6 g, 26 mmol) is added portionwise (over about 2 min) and the reaction is allowed to come to RT, is then stirred for about 30 min and then is warmed to 6O0C for about 40 min. The mixture is poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The organic layer is dried with MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash® Companion to afford aryl chloride 17c (1.11 g, 99% yield) as a pale yellow solid.
Step 3:
Solid pre-activated Zn dust is added to a solution of ketone 17c in AcOH. The reaction mixture is then heated to 1000C and stirred at that temperature for about 4 h. The reaction mixture is filtered (EtOAc washing), the filtrate is evaporated to dryness and the product purified by CombiFlash® Companion to afford indane 17d (902 mg, 88% yield) as a white crystalline solid. 13-152
Step 4:
A solution of BBr3 in DCM (1 M, 9.9 ml_, 9.9 mmol) is added dropwise to a precooled (- 780C) solution of methyl ether 17d (902 mg, 4.9 mmol) dissolved in DCM (20 ml_). The reaction solution is stirred at this temperature for about 10 min and allowed to warm to RT. After stirring for about 1.5 h, water (50 ml_) is added (caution! Exothermic!) and the mixture is extracted with DCM (3 x 50 ml_). The combined organic layers are dried over MgSO4, filtered and evaporated to dryness. The product is purified by CombiFlash® Companion to afford phenol 17e (700 mg, 84% yield) as an off-white solid.
Step 5:
Tf2O (1.05 ml_, 12 mmol) is added to a precooled (00C) solution of phenol 17e (700 mg, 4.1 mmol) and Et3N (1.7 mL, 12 mmol) in DCM (20 ml_). The resulting dark solution is allowed to warm to RT. After about 25 min, the reaction is quenched with saturated NaHCO3 (10 mL), diluted with DCM, and the organic layer washed with water, brine, dried over MgSO4 and evaporated to dryness. The product is purified by CombiFlash® Companion to afford triflate 17f (1.21 g, 97% yield) as a yellow oil.
Step 6:
A solution of triflate 17f (1.2 g, 4.0 mmol), bis[pinocolato]diborane (1.5 g, 6.0 mmol) and potassium acetate (1.3 g, 14 mmol) in DMF (20 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (490 mg, 0.60 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 950C for 5 h. The reaction is then cooled to RT. The crude reaction mixture is diluted with water and the product is extracted 3 times with EtOAc (3 x 100 mL). The combined organics are washed with water (100 mL) and brine (100 mL). The organic phase is then dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash® Companion to afford boronic ester 17g (593 mg, 53% yield) as a pale yellow solid.
Example 18: Synthesis of boronate fragment 18d 13-152
Figure imgf000089_0001
18d
Step i :
Neat Tf2O (0.83 ml_, 4.9 mmol) is added dropwise to a cooled (00C) solution of phenol 18a (0.50 g, 3.1 mmol) and pyridine (1.3 ml_, 17 mmol) in DCM (15 ml_). The reaction is allowed to warm to RT and stir overnight. The reaction is quenched by the addition of a 10% citric acid solution (50 mL) and the mixture is extracted with DCM (3 x 50 ml_). The combined organics are washed with water (50 mL), dried over MgSO4, filtered and concentrated. The product is purified by CombiFlash® Companion to give triflate 18b (500 mg, 94% yield).
Step 2:
Deoxyfluor® (0.83 mL, 4.2 mmol) followed by EtOH (10 uL, 0.2 mmol) are added to neat triflate 18b (500 mg, 1.7 mmol) in a sealable tube. The tube is sealed and the reaction is heated in an oil bath at 850C and is stirred overnight. The reaction is then cooled to 00C and quenched by the slow addition of NaHCO3 (100 μL, CAUTION! Exothermic!). The mixture is diluted with water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers are washed with water (50 mL) and brine (50 mL). The organic phase is then dried over MgSO4, filtered and concentrated. The crude product is purified by CombiFlash® Companion to provide the difluorotetrahydronaphtyl triflate 18c (175 mg, 33% yield).
Step 3:
Step three is performed as described in step 6 of Example 17 to provide boronic ester
18d
Example 19: Synthesis of boronate fragment 19d 13-152
Figure imgf000090_0001
19d
Step 1 :
Solid N-chlorosuccinimide (2.2 g, 16 mmol) is added in portions over about 5 min to a solution of naphthylamine 19a (2.3 g, 16 mmol) dissolved in CCI4 (150 ml_). The reaction is then heated to 500C and is stirred for about 40 min. The reaction is then cooled to RT, solids are removed by filtration and the filtrate is washed with water (100 ml_), dried over MgSO4 and evaporated to dryness to provide chloroaniline 19b (2.8 g, 96% yield).
Step 2:
A solution of NaNO2 (1.2 g, 17 mmol) in water (5 ml_) is slowly added to a precooled (O0C) suspension of aniline 19b (2.8 g, 15 mmol) in 12 N HCI (7 ml.) and ice (9.7 g), so as to maintain the temperature below 5°C. The mixture is stirred for about 15 min and then is transferred to a solution of Kl (8.7 g, 52 mmol) in water (30 ml_) and the resulting mixture is stirred for about 2 h. The mixture is extracted with Et2O (3 x 100 ml_) and the combined organic layers washed successively with 3 N NaOH (2 x 50 ml_), 5% NaHSO3 (50 mL) and brine (100 ml_). The organic phase is dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by flash chromatography (EtOAc/hexanes) to provide aryl iodide 19c (2.4 g, 54% yield).
Step 3:
Step three is carried out as described in step 11 of Example 15 to provide boronic ester
19d
Example 20: Synthesis of boronate fragment 2Od 13-152
Figure imgf000091_0001
Step i :
AIIyI bromide (2.1 ml_, 25 mmol) followed by potassium carbonate (7.2 g, 52 mmol) are added to a solution of 6-chlororesorcinol 20a (10 g, 69 mmol) dissolved in DMF (120 ml_). The reaction is stirred overnight, diluted with EtOAc (500 mL) and washed with water (3 x 500 mL). The organic layer is dried over MgSO4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain allyl ether 20b (1.8 g, 40% yield).
Step 2:
Methyl iodide (1.2 mL, 20 mmol) followed by potassium carbonate (3.8 g, 27 mmol) are added to a solution of phenol 20b (1.8 g, 9.8 mmol) dissolved in DMF (12 mL). The reaction is stirred for about 2 h, diluted with EtOAc (50 mL) and washed with water (3 x
50 mL). The organic layer is dried over MgSO4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain methyl ether 20c (1.8 g, 40% yield).
Step 3:
Step 3 is comprised of a sequence of steps as described in steps 2 through 6 of
Example 12, followed by step 1 of Example 13 to provide boronic ester 2Od.
Example 21: Synthesis of boronate fragment 21g 13-152
Figure imgf000092_0001
Step 1 :
Solid CuBr2 (7.9 g; 35 mmol) is added to a solution of 21a (4.0 g, 23 mmol) dissolved in EtOAc (32 ml.) and CHCI3 (32 ml_). The mixture is heated to reflux and is stirred for about 8 h. CuBr2 (3.9 g, mmol) is then added and the mixture continues to stir at reflux for about an additional 15 h. The mixture is cooled to RT, the solids removed by filtration (EtOAc washing). The filtrate is concentrated to afford the crude bromoketone 21b (6.3 g), which is used directly in the next step.
Step 2:
Solid KF (2.5 g, 43 mmol) is added to a solution of crude bromoketone 21b (6.3 g, ~23 mmol) dissolved in DMF (21 ml_). The reaction is stirred at RT for about 3 h and then taken up in ether (300 ml_), washed with brine (3 x 100 ml_), dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by CombiFlash® Companion to afford ether 21c (2.1 g, 49% yield over two steps).
Step 3:
Solid NaBH4 (270 mg, 7.1 mmol) is added to a precooled (O0C) solution of ketone 21c (1.0 g, 5.9 mmol) dissolved in MeOH (20 ml_). The reaction is allowed to stir for about 1 h and then quenched with aqueous HCI (1 N, 1 ml_). The volatiles are removed in vacuo and the product extracted with EtOAc (1 x 20 ml_). The organic layer is washed with brine (20 ml_), dried (Na2SO4), filtered and concentrated to afford the crude alcohol 21d (1.0 g), which is used directly in the next step.
Step 4:
Solid AgNO3 (LO g, 6.1 mmol) followed by I2 (1.6 g, 6.2 mmol) are added to a solution of 13-152
alcohol 21 d (1.0 g, 6.2 mmol) dissolved in MeOH (58 ml_). The mixture is stirred at RT for about 1 h and then a solution of Na2S2O4 (0.5 M, 10 ml_) is added and the mixture is stirred for about 30 min. The MeOH is removed in vacuo and the residue taken up in EtOAc (50 ml_), washed with water (1 x 50 ml_), brine (1 x 50 ml_), dried (Na2SO4), filtered and concentrated to afford aryl iodide 21 e (1.6 g), which is used directly in the next step.
Step 5:
Crude alcohol 21e (1.6 g; -5 mmol) is dissolved in a mixture of DCM (20 ml.) and TFA (2.2 ml_). The reaction is stirred for about 45 min and then concentrated to dryness. The residue is taken up in EtOAc (50 ml_), washed with saturated NaHCO3 (50 ml.) and brine (50 ml_). The organic layer is dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified by CombiFlash® Companion to provide benzofuran 21f (978 mg, 65% yield over 3 steps).
Step 6:
Step 6 is carried out as described in step 11 of Example 15 to provide boronic ester 21g.
Example 22: Synthesis of boronate fragment 22d
Figure imgf000093_0001
22d
Step 1 :
Neat 3-bromo-2-methylpropene (1.7 ml_, 16 mmol) is added to a suspension of phenol 22a (3.0 g, 14 mmol) and potassium carbonate (5.6 g, 41 mmol) in DMF (35 ml_). The reaction is stirred for about 2 h and then quenched with water (100 ml_) and extracted with hexanes (2 x 100 mL). The organic phase is washed with brine (2 x 100 ml_) and concentrated to give ether 22b (3.3 g, 87% yield).
Step 2:
Neat tributyltin hydride (2.3 mL, 8.8 mmol) is added to a solution of aryliodide 22b (2.0 g, 13-152
7.3 mmol) and AIBN (120 mg, 0.73 mmol) in PhMe (40 mL) and the reaction is then stirred at reflux under N2. After about 1 h, the reaction is concentrated to dryness and the crude product purified by CombiFlash® Companion to provide dihydrobenzofuran 22c (785 mg, 73% yield).
Step 3:
Step 3 follows the synthetic steps outlined in steps 10 and 11 of Example 15 to provide boronic ester 22d.
Example 23: Synthesis of boronate fragment 23c
Figure imgf000094_0001
23c
Step i :
Neat Tf2O (056 mL, 3.3 mmol) is added dropwise to a cooled (00C) solution of phenol 23a (350 mg, 2.1 mmol; prepared according to Doi et al Bull. Chem. Soc. Jpn. 2004 77, 2257-2263) and pyridine (0.91 mL, 11 mmol) in DCM (10 mL) under an Ar atmosphere. The reaction is allowed to warm to RT and then is stirred for about 2 h. The reaction is quenched by the addition of a 10% citric acid solution (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers are washed with water (20 mL), dried over MgSO4, filtered and concentrated to dryness. The crude product is purified by CombiFlash® Companion to provide triflate 23b (512 mg, 82% yield).
Step 2:
A solution of the triflate 23b (510mg, 1.7 mmol), bis[pinocolato]diborane (560 mg, 2.2 mmol) and potassium acetate (500 mg, 5.1 mmol) in DMF (18 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI2dppf-DCM complex (140 mg, 0.17 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 1000C by microwave irradiation for 10 min. The reaction is then cooled to RT. The crude reaction mixture is diluted with EtOAc (60 mL) and washed with brine 13-152
(3 x 60 ml_). The organic layer is dried over MgSO4 and filtered and concentrated. The crude mixture is further purified by CombiFlash® Companion to afford boronic ester 23c (200 mg, 42% yield).
Example 24: Synthesis of boronate fragment 24b
Figure imgf000095_0001
24b
Step 1 :
Compound 24b is prepared from 24a following a synthetic sequence as described in steps 1 to 6 of Example 12.
Example 25: Synthesis of boronate fragment 25b
Figure imgf000095_0002
25b
Step i :
Compound 25b is prepared from 25a following a synthetic sequence described in steps
1 to 6 of Example 12.
Example 26: Synthesis of boronate fragment 26b
Figure imgf000095_0003
26b 13-152
Step 1 :
Compound 26b is prepared from 26a following a synthetic sequence described in steps
1 to 6 of Example 12.
Example 27: Synthesis of boronate fragment 27b
Figure imgf000096_0001
27b
Step i :
Compound 27b is prepared from 27a following a synthetic sequence described in steps
1 to 6 of Example 14.
Example 28: Synthesis of boronate fragment 28b
Figure imgf000096_0002
28b
Step i :
Compound 28b is prepared from 28a following a synthetic sequence described in steps
1 to 8 of Example 6.
Example 29: Synthesis of boronate fragment 29b 13-152
Figure imgf000097_0001
29b
Step 1 :
Compound 29b is prepared from 29a following a synthetic sequence described in steps
1 to 6 of Example 14.
Example 30: Synthesis of boronate fragment 30b
Figure imgf000097_0002
30b
Step i :
Compound 30b is prepared from 30a following a synthetic sequence described in steps
2 and 3 of Example 18.
Example 31 : Synthesis of boronate fragment 31b
Figure imgf000097_0003
31b
Step i:
Compound 31b is prepared from 31a following a synthetic sequence described in steps
9 to 11 of Example 15. 13-152
Example 32: Synthesis of boronate fragment 32b
Figure imgf000098_0001
32b
Step i :
Compound 32b is prepared from 32a following a synthetic sequence described in steps
5 to 6 of Example 17.
Example 33: Synthesis of boronate fragment 33b
Figure imgf000098_0002
33b
Step i :
Compound 33b is prepared from 33a following a synthetic sequence described in steps
1 and 4 of Example 11.
Example 34: Synthesis of boronate fragment 34f
Figure imgf000098_0003
34a 34b 34c
Step 3 I
Figure imgf000098_0004
34f 13-152
Step 1 :
Benzyl bromide (25 ml_, 210 mmol) followed by potassium carbonate (44 g, 320 mmol) are added to a solution of 2-methylresorcinol 34a (38 g, 310 mmol) dissolved in DMF (1
L). The reaction is stirred overnight, diluted with EtOAc (2 L) and washed with water (3 x
2 L). The organic layer is dried over Na2SO4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain benzyl ether 34b (18.6 g, 39% yield).
Step 2:
AIIyI bromide (3.0 mL, 35 mmol) followed by potassium carbonate (6.5 g, 47 mmol) are added to a solution of phenol 34b (5 g, 23 mmol) dissolved in DMF (100 mL). The reaction is stirred overnight, diluted with EtOAc (500 mL) and washed with water (3 x 500 mL). The organic layer is dried over Na2SO4 and concentrated to dryness. The crude product is purified by CombiFlash® Companion to obtain benzyl ether 34c (4.4 g, 75% yield).
Step 3:
Compound 34d is prepared from 34c following a synthetic sequence described in steps
2 to 4 of Example 12.
Step 4:
Benzyl ether 34d and Pd-C (10% w/w, 100 mg, 0.094 mmol) are combined in EtOAc (5 mL) and the flask is evacuated and backfilled with a H2 atmosphere (balloon). After stirring for about 3 h, the reaction is filtered through Celite® (EtOAc washing) and the filtrated concentrated to give phenol 34e (145 mg, 95% yield).
Step 5:
Compound 34f is prepared from 34e following a synthetic sequence described in steps 5 to 6 of Example 17.
Example 35: Synthesis of boronate fragment 35e 13-152
Figure imgf000100_0001
35e 35d
Steps 1 through 4 are done in analogy to steps 3 through 6 from Example 17.
Example 36: Synthesis of boronate fragment 36d
Figure imgf000100_0002
Step i:
4-bromo-3-nitrotoluene 36a (5.0 g, 22.9 mmol) is dissolved in 50 mL ethyl acetate and solid tin(ll) chloride dihydrate (20.0 g, 86.9 mmol) is added. The mixture is heated under nitrogen atmosphere at 700C for about 2 h (note: temporary overheating to 1000C is observed! Caution should be exercised!). The mixture is cooled down and is poured into 200 mL of ice-water. 50 mL of 5% aqueous NaHCO3 solution is added (rapid foaming!), followed by 10 N aqueous NaOH to bring the pH to about 7-8. Large volume of gelatinous yellowish precipitate is formed. This heterogeneous mixture is shaken with 200 mL EtOAc and the mixture is centrifuged in 50 mL portions, resulting in good separation of a yellowish solid. The clear supernatant is decanted and is extracted with EtOAc. Combined organic phase is washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum to give an orange oily residue. This residue is re-dissolved in 100 mL of ether and the solution is washed with 10% Na2CO3 (20 mL) followed by 2.5 M aqueous NaOH (20 mL). The dark brown organic solution is then stirred with MgSO4 and active charcoal and filtered to give a light yellow solution, which 13-152
darkened rapidly on standing in open flask. The solvent is removed under vacuum to give the desired compound 36b as a brown-red oil which is used in the next step without further purification (3.31 g, 78% yield).
Step 2:
A mixture of compound 36b (3.3 g, 17.7 mmol), glycerin (3.3 g, 35.5 mmol), nitrobenzene (2.2 g, 17.7 mmol) and 75% aqueous sulfuric acid (10 ml_, 138 mmol) is stirred at 1500C for 3 h (mixture turns black and viscous). The reaction mixture is cooled down, poured into 200 ml. ice-water and 10 N aqueous NaOH is added (30 ml_, 300 mmol). The black mixture is then shaken with 100 ml. EtOAc and is centrifuged in 50 ml_ portions. The upper EtOAc layers are combined and the bottom aqueous layers containing the black tar are shaken with EtOAc and re-centrifuged. All EtOAc extracts are combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 4.8 g of a brown-red oil. This material is chromatographed on 80 g silica gel column (CombiFlash® Companion apparatus, hexanes-EtOAc gradient). The fractions containing the compound are concentrated under vacuum to afford compound 36c as a white solid (3.26 g, 83% yield).
Step 3:
To a cooled (-78 0C) solution of compound 36c (500 mg, 2.25 mmole) in 20 ml_ of anhydrous Et2O, is added over about 5 minutes under an Ar atmosphere a 1.6 M solution of A7-BuLi in hexane (3.5 ml_, 5.60 mmol). The mixture is stirred at - 78 °C for about 50 minutes, triisopropylborate (2.00 ml_, 8.55 mmol) is then added dropwise and the mixture is stirred for about 2 h at that temperature. The mixture is slowly allowed to reach RT over about a 2 h period and it is poured into 1 M aqueous HCI (30 ml_). The mixture is transferred into a separatory funnel, the organic layer is separated and the aqueous layer is washed with Et2O. The aqueous layer is then transferred into a 500 ml_ Erlenmeyer flask and the pH of the solution is adjusted to approximately 6.3 (measured with a pH meter) by slowly adding a saturated solution of NaHCO3 in water (~25 ml_, careful: foaming!). The suspension is filtered off and the separated light-beige solid is washed with water and dried under high vacuum. This crude product (383 mg) is triturated with Et2O /hexanes to give a first crop of the desired compound 36d as a free base (120 mg, 28% yield). The mother liquors are concentrated under vacuum and are purified by reversed-phase HPLC using a CH3CN/H2O gradient containing 0.06% TFA 13-152
(ODS-AQ, C-18 column, 75 x 30 mm, 5-μm particle size). After lyophilization, a second crop of compound 36d is obtained as a TFA salt (102 mg, 15% yield), (total yield: 43%).
Example 37: Synthesis of boronate fragment 37d
Figure imgf000102_0001
1-bromo-4-chloro-2-nitrobenzene 37a is transformed to compound 37b using the procedure of example 36b, except for the fact that Et2O is used for the extractions instead of EtOAc.
Step 2:
Compound 37b (4.2 g, 20.3 mmol) is melted at 500C in a 100 mL round-bottomed flask containing a stirring bar and immersed in an oil bath. A solution of zinc chloride (700 mg, 5.03 mmol) and ferric chloride (540 mg, 3.25 mmol) in 3.3 mL of water is added in one portion followed by 20 m L of absolute EtOH. The flask is stoppered with a rubber septa and a needle is inserted to avoid any pressure build-up. The mixture is warmed to 800C and acrolein (1.68 mL, 24.4 mmol) is added via a syringe pump over a 2 h period. After the addition, the mixture is stirred at 800C for 1 h and an additional amount of solid ferric chloride is added (4.1 g, 25.3 mmol). The mixture is stirred at 8O0C for about an extra 24 h and then concentrated under vacuum to give a semi-solid residue. 200 mL of water is added followed by a 10 N aqueous solution of NaOH (20 mL) and 200 mL of CH2CI2. After shaking the mixture for a few minutes, the solid is filtered over a pad of Celite® and the filtrate is transferred into a separatory funnel. The organic layer is separated and the aqueous layer is extracted with CH2CI2. The combined organic extracts are washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give 3.69 g of a brown solid. This solid is triturated in hot CH3CN and filtered. The solid is discarded and the filtrate is concentrated under vacuum to give 2.3 g of a brown semi-solid. This material is purified on a CombiFlash® Companion apparatus on 40 g silica gel column eluted with EtOAc/hexanes gradient. After evaporation of the solvent 13-152
under vacuum, the desired compound 37c is isolated as a yellow solid (390 mg, 8% yield).
Step 3:
Compound 37c is transformed to compound 37d using the procedure of example 36d.
Example 38: Synthesis of boronate fragment 38c
38a 38b 38c
Step i :
2-bromoaniline 38a is transformed to compound 38b using the procedure of example
37c except that methyl vinyl ketone is used instead of acrolein.
Step 2:
Compound 38b is transformed to compound 38c using the procedure of example 36d.
Example 39: Synthesis of boronate fragment 39k
13-152
Figure imgf000104_0001
Reference: FeNu, L.; Ajana, W.; Alvarez, M.; Joule, J.A. Tetrahedron 1997, 53, 4511.
Step i:
Meldrum's acid 39b (47.04 g, 326 mmol) is taken in trimethyl orthoformate (360 ml_) and refluxed for about 2 h. Then 2,5-dimethoxy aniline 39a (50 g, 326 mmol) is added and the mixture is refluxed for about an extra 5 h. The reaction mixture is cooled down to RT and the solid which forms upon cooling is collected by filtration. It is further crystallized from MeOH to afford compound 39c as a yellow solid (63 g, 63% yield).
Step 2:
Compound 39c (62.00 g, 202 mmol) is dissolved in diphenyl ether (310 ml_) and refluxed at 240 0C for about 30 min. The mixture is then cooled down to RT and n-hexane is added, which causes a brown precipitate to form. This solid is separated by filtration and is washed with n-pentane and n-hexane to remove non-polar impurities and the remaining dark brown solid (compound 39d) is used as is in the next step (27 g, 65% yield).
Step 3:
A mixture of compound 39d (30.0 g, 146 mmol), DMAP (3.75 g, 30.7 mmol) and 2,6- lutidine (24.4 mL; 208 mmol) in DCM (1.4 L) is cooled to 00C and trifluoromethanesulphonic anhydride (29.6 mL, 175 mmol) is added slowly at 00C. The 13-152
resulting mixture is stirred at 00C for about 2 h and at RT for about 1 h. It is then diluted with DCM, washed with H2O and brine and dried (Na2SO4). The solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (20% EtOAc / petroleum ether). The desired compound 39e is isolated as a yellow solid (35 g, 71% yield).
Step 4:
A mixture of diisopropylethyl amine (46.5 ml_, 267 mmol) in dry DMF (250 ml.) is degassed with argon for about 30 min and is added to a mixture of compound 39e (30.0 g, 88.5 mmol), triphenylphosphine (7.70 g, 29.4 mmol), tris(dibenzylideneacetone)di- palladium(0)-chloroform adduct (9.21 g, 8.9 mmol). The resulting mixture is stirred for about 5 min at 0°C and TMS-acetylene (13.4 g, 136 mmol) is added dropwise. The temperature is raised to RT and the mixture is stirred for about 4 h. Diethyl ether and water is added, the aqueous layer is separated and washed with diethyl ether. The combined organic layers are washed with H2O and brine. After drying on Na2SO4, the solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (30% EtOAc / petroleum ether). Compound 39f is isolated as a yellow solid (18 g, 70% yield).
Step 5:
A solution of eerie ammonium nitrate (42.3 g, 77.2 mmol) in H2O (47 mL) is added under argon atmosphere to a solution of compound 39f (11.0 g, 38.3 mmol) in acetonitrile (366 mL). The reaction mixture is degassed with argon for about 10 min and the mixture is stirred at RT for about 20 min. Water is then added and the solution is extracted with CH2CI2. The organic extracts are combined, washed with H2O, brine and dried (Na2SO4). The solvent is removed under reduced pressure and the residue is purified by flash chromatography on silica gel (40% EtOAc / petroleum ether). The desired compound 39g is isolated as a yellow solid (5.0 g, 52% yield).
Step 6:
Compound 39g (1.80 g, 7.1 mmol) is taken in distilled acetic acid (72 mL) under argon atmosphere. Ammonium chloride (7.55 g, 141 mmol) is added and the reaction is refluxed for about 45 min. The reaction mixture is cooled to RT, H2O is added and the solution is washed with EtOAc. The aqueous layer is neutralized with a saturated 13-152
aqueous solution of NaHCO3 and is extracted with EtOAc. The combined organic extracts are washed with H2O, brine and dried (Na2SO4). The solvent is removed under reduced pressure to afford compound 39h as a brown solid (250 mg, 19% yield).
Step 7:
Compound 39h (230 mg, 1.24 mmol) is dissolved in absolute EtOH (11 mL) and 10% palladium on carbon is added (10% w/w, 23 mg) under nitrogen atmosphere. The mixture is stirred for about 15 h under one atmosphere of hydrogen. The reaction is degassed with nitrogen, filtered through Celite®, and the Celite® bed is washed with an EtOH-CHCI3 mixture. The solvent is removed under reduced pressure to give compound 39i as a brown sticky solid (200 mg, 86% yield).
Step 8:
Compound 39i (600 mg, 3.21 mmol) is taken in dry CH2CI2 (30 mL) under nitrogen atmosphere. The solution is cooled to 00C and triethylamine (0.891 mL, 6.42 mmol) is added dropwise followed by trifluoromethanesulfonic anhydride (0.650 mL, 3.87 mmol). The temperature is raised to RT and the reaction mixture is stirred for about 2 h. The mixture is diluted with CH2CI2 and is washed with H2O, brine and dried (Na2SO4). The solvent is removed under reduced pressure to afford a residue which is purified by flash chromatography (10% EtOAc / hexanes). Compound 39j is isolated as a brown solid (630 mg, 61% yield).
Step 9:
In a dry (oven-dried for about 30 min.) 5-mL glass microwave vessel containing a magnetic stirring bar, are added compounds 39j (250 mg, 0.783 mmol), bis(pinacolato)diboron (250 mg, 0.984 mmol), anhydrous potassium acetate (150 mg, 1.51 mmol), Pd(PCy3J2 (62.0 mg, 0.0910 mmol) and anhydrous, deoxygenated (argon bubbling for about 30 min) 1 ,4-dioxane (4 mL). The vial is capped tightly with a septum- cap and the vessel is flushed with argon. The mixture is stirred at 95°C (oil bath temperature) under an atmosphere of argon for about 16 h. The reaction mixture is then concentrated under vacuum, the brown oily residue is dissolved in 7 mL of glacial AcOH and is filtered via 45 μm membrane filter. The dark brown solution is divided into 5x1.5 mL portions and is injected on an automatic preparative reversed-phase HPLC-MS apparatus (CH3CN/H2O gradient containing 0.06% TFA, ODS-AQ, C-18 column, 50 x 19 13-152
mm, 5-μm particle size). The collected fractions are lyophylized to give the desired compound 39k as a yellow amorphous solid (115 mg, 45% yield for the TFA salt).
Example 40: Synthesis of compound 1029
Figure imgf000107_0001
Step i :
To a stirred solution of 1m (1.9 g, 3.63 mmol) in a mixture of acetonitrile (52 ml.) and water (26 mL) is added eerie ammonium nitrate (5.97 g, 10.9 mmol) and stirred for 20 min. The reaction is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The pure intermediate 40a is isolated as a white solid (1.27 g, 87% yield) after flash chromatography with hexanes: EtOAc (60:40 v/v).
Step 2:
To a solution of triphenylphosphine (0.43g, 1.65 mmol) in DCM (5 mL) and THF (5 mL) at 00C is added diisopropylazodicarboxylate (0.33 ml, 1.65 mmol), stirred for about 1 h at 00C. In another flask, a solution of 40a (0.39 mg, 0.96 mmol) and 2-pyridinemethanol (0.16 ml, 1.65 mmol) is taken and cooled to 00C. To this cold solution is added slowly, 13-152
pre-formed solution of diisopropylazodicarboxylate and triphenylphosphine. This is allowed to come to RT and is then stirred for about 3 h. The reaction mixture is concentrated under reduced pressure. The pure 40b (0.24 mg, 50% yield) is isolated after flash chromatography with hexanes:EtOAc (55:45 v/v).
Step 3:
In the 8 ml vial, the boronic ester 11d (14.5 mg, 0.06 mmol), intermediate 40b (30 mg, 0.06 mmol), K2CO3 (25.3 mg, 0.18 mmol) and Pd(PPh3)4 (0) (7 mg, 0.006 mmol) are mixed and the vial is flushed with Ar. To the reaction mixture, water (1 ml_) and DMF (3 ml.) are added and then heated to 800C for about 2 h. The mixture is neutralized with 1 N HCI and concentrated under reduced pressure. The residue is dissolved in the mixture of THF (1.5 ml.) and MeOH (0.5 ml) and then 1 N NaOH solution (0.9 ml_, 0.9 mmol) is added. The reaction is stirred at 550C for about 12 h, then neutralized with 1 N HCI and concentrated under reduced pressure. The residue is dissolved in a mixture of 0.5 ml_ of AcOH and 1 ml. of DMSO and purified with preparative reversed phase LCMS (H2O/Acetonitrile + 0.06% TFA). The pure fractions are pooled, frozen and lyophilized to afford compound 1029 as a white solid (19.5 mg, 66% yield).
It would be obvious to those skilled in the art that intermediate 40a can be coupled to a variety of other optionally substituted alkyl-aryl or alkyl-Het groups, such as, Aryl-CH2- or Het-CH2- moieties using commercially available Aryl-CH2OH or Het-CH2-OH building blocks via a Mitsunobu reaction as shown for Example 40, Step 2. Furthermore, a variety of boronates can be couple at the C-4 carbon using Suzuki cross-coupling reactions as shown in Example 40, Step 3. The synthesis of selected boronates that are not commercially available and have been used to prepare compounds of this invention are shown in Examples 4 to 39. An additional example that describes the formation of two final products is shown in Example 41 ; it would be obvious to those skilled in the art that the same methodology can be applied for the synthesis of other examples shown in Tables 1 and 2.
Example 41: Synthesis of compounds 1043 and 2001 13-152
Figure imgf000109_0001
Step i :
To a solution of triphenylphosphine (48.7 mg, 0.186 mmol) in a mixture of CH2CI2 (0.4 ml.) and THF (0.4 mL) at 0°C is added diisopropylazodicarboxylate (36.8 μl_, 0.186mmol). The solution is stirred for about 1 h at 00C. In another flask, a solution of intermediate 40a (50 mg, 0.124 mmol) and 4-(difluoromethoxy)benzyl alcohol (32.4 mg, 0.186 mmol) in a mixture of THF (0.5 mL), CH2CI2 (0.5 mL) is cooled to 0°C. To this cold solution is added slowly, pre-formed solution of diisopropylazodicarboxylate and triphenylphosphine. This is allowed to warm to RT and is stirred for about 3 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in a mixture of AcOH (0.5 mL) and DMSO (1 mL) and purified with preparative reversed phase LCMS (H2O/MeCN + 0.06% trifluoroacetic acid). The pure fractions are pooled, frozen and lyophilized to afford 41a (45.7mg, 66% yield) and 41b (22.0 mg); the latter sample is contaminated with an impurity. These products are used in a Suzuki coupling reaction with boronate 11d, followed by saponification to afford compounds 1043 and 2001.
Example 42: Synthesis of racemic compound 1026 13-152
Figure imgf000110_0001
In an 8 ml vial, 3i (40.0 mg, 0.09 mmol), boronic acid (18.3mg, 0.12mmol), K2CO3 (37mg, 0.27mmol) and the Pd(PPh3)4 (0) (10.0 mg, 0.009 mmol) are mixed. The vial is flushed with Ar, then water (1 mL) and DMF (3 mL) are added. The reaction mixture is heated to 8O0C for about 12 h. Then the mixture is neutralized with 1 N HCI and concentrated under reduced pressure. The residue is dissolved in a mixture of THF (1.5 mL) and MeOH (0.5 mL) and to it is added a 1 N NaOH solution (0.9 mL, 0.9 mmol). The mixture is stirred at 55°C for about 12 h. The reaction is neutralized with 1 N HCI, concentrated under reduced pressure and the residue is dissolved in 1.5 mL of AcOH and purified with reversed phase preparative LCMS (H2O/MeCN + 0.06% trifluoroactic acid). The pure fractions are pooled, frozen and lyophilized to afford compound 1026 (23.0 mg, 60% yield) as a white solid.
Example 43: C8166 HIV-1 Luciferase Assay (EC50)
C8166 cells are derived from a human T-lymphotrophic virus type 1 immortalized but nonexpressing line of cord blood lymphocytes (NIH AIDS reagent 404) and are highly permissive to HIV-1 infection. The pGL3 Basic LTR/TAR plasmid is made by introducing the HIV-1 HxB2 LTR sequence from nucleotide -138 to +80 (Sca1-Hindlll) upstream of the luciferase gene in the pGL3 Basic Vector (a promoterless luciferase expression vector from Promega catalogue #E1751) with the gene for blasticidine resistance cloned in. The reporter cells are made by electroporating C8166 cells with pGL3 Basic LTR/TAR and selecting positive clones with blasticidine. Clone C8166-LTRIuc #A8-F5- G7 was selected by 3 consecutive rounds of limiting dilution under blasticidine selection. Cultures are maintained in complete media (consisting of: Roswell Park Memorial Institute medium (RPMI) 1640 + 10% FBS + 10"5 M β-mercaptoethanol + 10 μg/ml 13-152
gentamycin) with 5 μg/ml blasticidine, however, blasticidine selection is removed from the cells before performing the viral replication assay.
Luciferase Assay Protocol
Preparation of Compounds
Serial dilutions of HIV-1 inhibitor compounds are prepared in complete media from 10 mM DMSO stock solutions. Eleven serial dilutions of 2.5X are made at 8X desired final concentration in a 1 ml deep well titer plate (96 wells). The 12th well contains complete media with no inhibitor and serves as the positive control. All samples contain the same concentration of DMSO (< 0.1 % DMSO). A 25 μl aliquot of inhibitor is added, to triplicate wells, of a 96 well tissue culture treated clear view black microtiter plate (Corning Costar catalogue # 3904). The total volume per well is 200 μl_ of media containing cells and inhibitor. The last row is reserved for uninfected C8166 LTRIuc cells to serve as the background blank control and the first row is media alone.
Infection of Cells
C8166 LTRIuc cells are counted and placed in a minimal volume of complete RPMI 1640 in a tissue culture flask (ex. 30 X 106 cells in 10 ml media/25 cm2 flask). Cells are infected with HIV-1 or virus with variant integrase generated as described below at a molecules of infection (moi) of 0.005. Cells are incubated for 1.5 hours at 37 0C on a rotating rack in a 5% CO2 incubator and re-suspended in complete RPMI to give a final concentration of 25,000-cells/175 μl. 175 μl of cell mix is added to wells of a 96 well microtiter plate containing 25 μl 8X inhibitors. 25,000 uninfected C8166- LTRIuc cells/well in 200 μl complete RPMI are added to the last row for background control. Cells are incubated at 37 0C in 5% CO2 incubator for 3 days.
Luciferase Assay
50 μl Steady GIo (luciferase substrate
Figure imgf000111_0001
hours Promega catalogue # E2520) is added to each well of the 96 well plate. The relative light units (RLU) of luciferase is determined using the LUMIstar Galaxy luminometer (BMG LabTechnologies). Plates are read from the bottom for 2 seconds per well with a gain of 240. 13-152
The level of inhibition (% inhibition) of each well containing inhibitor is calculated as follows:
RLU - well- RLU -blank
% ■ inhibition= \ 1- *100
RLU -control- RLU -blank
The calculated % inhibition values are used to determine EC50, slope factor (n) and maximum inhibition (lmax) by the non-linear regression routine NLIN procedure of SAS using the following equation: o/ ■ 7 -L -.- I maχ x [inhibitor]"
% • inhibition = -2^ — —
[inhibitor]" + IC so"
TABLES OF COMPOUNDS
Compounds of the invention shown in Tables 1 to 2 are integrase inhibitors. Representative compounds selected from Tables 1 to 2 below have EC50 values of no more than 20 μM when tested in the HIV-1 luciferase assay of Example 43.
Retention times (tR) for each compound are measured using the standard analytical HPLC conditions described in the Examples. As is well known to one skilled in the art, retention time values are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient, and the like are used, the retention time values may vary when measured, for example, on different HPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC columns, or, when measured on the same instrument and the same individual column, the values may vary, for example, between individual measurements taken on different occasions. 13-152
TABLE 1
Figure imgf000113_0001
Figure imgf000113_0002
13-152
Figure imgf000114_0001
13-152
Figure imgf000115_0001
13-152
Figure imgf000116_0001
13-152
Figure imgf000117_0001
13-152
Figure imgf000118_0001
13-152
Figure imgf000119_0001
13-152
Figure imgf000120_0001
13-152
Figure imgf000121_0001
13-152
Figure imgf000122_0001
13-152
TABLE 2
Figure imgf000123_0001
Figure imgf000123_0002
Each of the references, including ail patents, patent applications and publications, listed in the present application is incorporated herein by reference in its entirety, as if each of them is individually incorporated. Further, it would be appreciated that, in the above teaching of invention, the skilled in the art could make certain changes or modifications to the invention, and these equivalents would still be within the scope of the invention defined by the appended claims of the application.

Claims

13-152CLAIMS
1. An isomer, racemate, enantiomer or diastereomer of a compound of formula (I):
Figure imgf000124_0001
wherein represents either a single or double bond;
X is N when Y is N-R7; or
X is N-R6 when Y is N;
R2 and R5 are each independently selected from a) halo; b) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(C1-6)alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1-6)alkylene-C(=O)-O-R8, -(Ci-6)alkylene-O-R8, -(Ci-6)alkylene-S-R8, -(C1-6)alkylene-SO-R8 or -(Ci.6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (C1-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl,
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, O-(C1-6)haloalkyl, -SH,
-S(C1-6)alkyl, -SO(C1-6)alkyl, -SO2(Ci-6)alkyl, -NH2, -NH(d.6)alkyl and -N((Ci_
6)alkyl)2; ii) (Ci-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(C1-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and c) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, -(C1-6)alkylene-N(R9)R10, -(C1-6)alkylene-C(=O)-N(R9)R10, -(C1-6)alkylene- O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein 13-152
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3- 7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C1-6)alkylene-R8,
-SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above; R6 and R7 are each independently selected from a) R8, -C(=O)-R8, -C(=O)-O-R8, -O-R8, -S-R8, -SO-R8, -SO2-R8, -(C1-6)alkylene-R8, -(C1-6)alkylene-C(=O)-R8, -(C1-6)alkylene-C(=O)-O-R8, -(Ci-6)alkylene-O-R8, -(Ci-6)alkylene-S-R8, -(C1-6)alkylene-SO-R8 or -(Ci-6)alkylene-SO2-R8; wherein R8 is in each instance independently selected from H, (Ci-6)alkyl,
(C2-6)alkenyl, (C2-6)alkynyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, aryl and Het; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents each independently selected from: i) halo, oxo, thioxo, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7) cycloa Iky I,
(C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, 0-(C1-6)haloalkyl, -SH1
-S(C1-6)alkyl, -SO(C1-6)alkyl, -SO2(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and
-N((C1-6)alkyl)2; ii) (C1-6)alkyl optionally substituted with -OH, -O-(C1-6)haloalkyl, or
-O-(C1-6)alkyl; and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or (C1-6)alkyl; and b) -N(R9)R10, -C(=O)-N(R9)R10, -O-C(=O)-N(R9)R10, -SO2-N(R9)R10, -(C1-6)alkylene-N(R9)R10, -(C1-6)alkylene-C(=O)-N(R9)R10, -(C1-6)alkylene- O-C(=O)-N(R9)R10, or -(C1-6)alkylene-SO2-N(R9)R10 wherein
R9 is in each instance independently selected from H, (C1-6)alkyl and (C3-7)cycloalkyl; and
R10 is in each instance independently selected from R8, -(C1-6)alkylene-R8, -SO2-R8, -C(=O)-R8, -C(=O)OR8 and -C(=O)N(R9)R8; wherein R8 and R9 are as defined above;
R3 is (C1-6)alkyl, (C1-6)haloalkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl-(C1-6)alkyl-, aryl-(C1-6)alkyl-, Het-(C1-6)alkyl- or -W-R31, and bond c is a single bond; or
R3 is (C1-6)alkylidene and bond c is a double bond; 13-152
wherein W is O or S and R31 is (C1-6)alkyl, (C1-6)haloalkyl, (C2-6)alkenyl, (C2-6)alkynyl, (C3-7)cycloalkyl, aryl, (C3-7)cycloalkyl-(C1-6)alkyl-, aryl-(C1-6)alkyl- or Het-(C1-6)alkyl-; wherein each of the (C1-6)alkylidene, (C1-6)alkyl, (C1-6)haloalkyl, (C2-6)alkenyl, (C2- β)alkynyl, (C3-7)cycloalkyl-(C1-6)alkyl-, aryl-(C1-6)alky!-, Het-(Ci-6)alkyl- and -W-R31 is optionally substituted with 1 to 3 substituents each independently selected from (Ci-6)alkyl, halo, cyano, oxo and -O(C1-6)alkyl;
R4 is aryl or Het, wherein each of the aryl and Het is optionally substituted with 1 to 5 substituents each independently selected from halo, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C3-7)cycloalkyl-(C1-6)alkyl-, -OH, -O(C1-6)alkyl, -SH, -S(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and -N((C1-6)alkyl)2; wherein the (C1-6)alkyl is optionally substituted with hydroxy, -O(C1-6)alkyl, cyano or oxo; and wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S; or a salt or an ester thereof.
2. A compound according to claim 1 having the formula (Ib):
Figure imgf000126_0001
wherein R2, R3, R4, R5 and R7 are as defined in claim 1.
3. A compound according to claim 1 having the formula (If):
Figure imgf000126_0002
wherein R , R , R , R and R are as defined in claim 1. 13-152
4. A compound according to any one of claims 1 to 3 wherein R2 is (C1-4)alkyl or (Ci-4)haloalkyl.
5. A compound according to claim 4 wherein R2 is -CH3 or -CH2CH3.
6. A compound according to any one of claims 1 to 5 wherein R3 is -O(C1-6)alkyl, -O-(C1-6)haloalkyl, -O(C2-6)alkenyl, -O(C2.6)alkynyl or -O-(C3-7)cycloalkyl; wherein each of the -O(Ci-6)alkyl and -O-(C3-7)cycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from (C1-3)alkyl, cyano, oxo and -O(Ci-6)alkyl; and bond c is a single bond.
7. The compound according to claim 6 wherein R3 is -O(C1-4)alkyl.
8. The compound according to any one of claims 1 to 7 wherein R4 is phenyl optionally substituted with 1 or 3 substituents each independently selected from halo, (Ci-4)alkyl, (C2-4)alkenyl, (C1-4)haloalkyl, (C3.7)cycloalkyl, -OH, -O(Ci.4)alkyl, -SH, -S(C1-4)alkyl, -NH2, -NH(C1-4)alkyl and -N((C1-4)alkyl)2.
9. The compound according to any one of claims 1 to 8 wherein R4 is Het optionally substituted with 1 to 3 substituents each independently selected from halo, (C1. 6)alkyl, (C2-6)alkenyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, -OH, -OCd^alkyl, -SH, -S(C1-6)alkyl, -NH2, -NH(C1-6)alkyl and -N((C1-6)alkyl)2; wherein the (C1-6)alkyl is optionally substituted with hydroxyl or -O(C1-6)alkyl.
10. The compound according to any one of claims 1 to 9 wherein R4 is phenyl or Het optionally substituted with 1 to 3 substituents each independently selected from halo, (C1-6)alkyl and -O(d.6)alkyl; and Het is selected from:
Figure imgf000127_0001
13-152
11. The compound according to any one of claims 1 to 10 wherein R5 is H, halo, (C1- 6)alkylene-O(C1-6)alkyl, (C1-6)alkylene-O-aryl, (Ci-6)haloalkyl, (C3-7)cycloalkyl, (C1- 6)alkylene-(C3-7)cycloalkyl , -OH, -O(Ci-6)alkyl or (C1-4)alkyl.
12. The compound according to claim 11 wherein R5 is H, CH2CH3 or CH3.
13. The compound according to any one of claims 1 to 12 wherein R6 is Het, aryl, (C1-6)alkylene-Het or (C1-6)alkylene-aryl; wherein said aryl and Het are all optionally substituted 1 to 2 times with (C1-6)alkyl, -O(Ci-6)alkyl, or -CKCi-fOhaloalkyl.
14. The compound according to any one of claims 1 to 13 wherein R7 is H, (C1- 6)alkylene-O(C1-6)alkyl, (C1-6)alkylene-O-aryl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1- 6)alkylene-(C3-7)cycloalkyl , -OH or -O(C1-6)alkyl.
15. The compound according to any one of claims 1 to 13 wherein R7 is H, (C1- 6)alkylene-O(C1-6)alkyl, (Ci-6)alkylene-O-aryl, (C1-6)haloalkyl, (C3-7) cycloa Iky I, (C1- 6)alkylene-(C3-7)cycloalkyl, Het, aryl, (C1-6)alkylene-Het or (C1-6)alkylene-aryl wherein said aryl, Het, (C1-6)alkylene-Het and (Ci-6)alkylene-aryl are optionally substituted with (C1-6)alkyl, -O(C1-6)alkyl, or -O(C1.6)haloalkyl.
16. The compound according to any one of claims 1 to 13 wherein R7 is (C1- 6)alkylene-O(C1-6)alkyl, (Ci-6)alkylene-O-aryl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1- 6)alkylene-(C3-7)cycloalkyl , -OH or -O(C1-6)alkyl, Het, aryl, (Ci-6)alkylene-Het or (C1-6)alkylene-aryl wherein said aryl, Het, (C1-6)alkylene-Het and (Ci-6)alkylene- aryl are optionally substituted with (Ci.6)alkyl, -O(C1-6)alkyl, or -O(C1-6)haloalkyl; and Het is:
Figure imgf000128_0001
17. The compound according to any one of claims 1 to 13 wherein R7 is seleted from the group consisting of H, CH3, CH2CH3, CH2CH2OCH3, CH2CH2F, CH(CH3)2, 13-152
CH2CHF2, CH(CH3)CH2OCH3,
Figure imgf000129_0001
Figure imgf000129_0002
18. The compound according to any one of claims 1 to 13 wherein R7 is selected from H, (Ci-6)alkyl, (C1-6)haloalkyl, (C3-7)cycloalkyl, (C1-6)alkyl-(C3-7)cycloalkyl ,-OH, -O(C1-6)alkyl, -SH, -S(C1-6)alkyl, -S-aryl, S-Het -SO2-aryl, SO2-Het , -NH2, -NH(C1-6)alkyl, -N((C1-6)alkyl)2, Het, aryl, (C1-6)alkyl-Het and (d.6)alkyl-aryl; wherein said alkyl, aryl, Het, cycloalkyl are optionally substituted 1 to 3 times with (C1-6)alkyl, halo, -O-R21, Het, oxo, -S(Ci_6)alkyl, -SO(C1-6)alkyl, SC^C^alkyl; wherein R21 is H, (C1-6)alkyl, (C1-6)haloalkyl, Het optionally substituted with (C1-6)alkyl, aryl optionally substituted with (C1-6)alkyl, (C1-6)alkyl-Het, (C1-6)alkyl- aryl.
19. The compound according to claim 1 having the following formula:
Figure imgf000130_0001
wherein R3, R4, R5 and R7 are defined as:
Figure imgf000130_0002
Figure imgf000131_0001
Figure imgf000132_0001
-152
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
13-152
Figure imgf000139_0002
or a salt thereof.
20. The compound according to claim 1 having the following formula:
Figure imgf000139_0001
wherein R , R , R and R are defined as:
Figure imgf000139_0003
or a salt thereof.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt or ester thereof; and one or more 13-152
pharmaceutically acceptable carriers.
22. The pharmaceutical composition according to claim 21 additionally comprising at least one other antiviral agent.
23. Use of a pharmaceutical composition according to claim 21 or 22 for the treatment of an HIV infection in a mammal having or at risk of having the infection.
24. A method of treating an HIV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 20, a pharmaceutically acceptable salt or ester thereof, or a composition according to claim 21 or 22.
25. A method of treating an HIV infection in a mammal having or at risk of having the infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent.
26. Use of a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or ester thereof, for the treatment of an HIV infection in a mammal having or at risk of having the infection.
27. Use of a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of an HIV infection in a mammal having or at risk of having the infection.
28. An article of manufacture comprising a composition effective to treat an HIV infection; and packaging material comprising a label which indicates that the composition can be used to treat infection by HIV; wherein the composition comprises a compound of formula (I) according to any one of claims 1 to 20 or a 13-152
pharmaceutically acceptable salt or ester thereof.
29. A method of inhibiting the replication of HIV comprising exposing the virus to an effective amount of the compound of formula (I) according to any one of claims 1 to 20, or a salt or ester thereof, under conditions where replication of HIV is inhibited.
30. Use of a compound of formula (I) according to any one of claims 1 to 20 to inhibit the activity of the HIV integrase enzyme.
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