Classifications

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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
• • A—HUMAN NECESSITIES
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  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/55—Acids; Esters
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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  • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
  • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D411/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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  • C07D498/06—Peri-condensed systems

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 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 a nti retroviral compounds.
• the present invention provides a novel series of compounds having inhibitory activity against HIV replication. Therefore, the compounds of the invention may be used to inhibit the activity of HIV integrase and may be used to reduce HIV replication.
• One aspect of the invention provides a compound of Formula I and a racemate, enantiomer or diastereomer of a compound of formula (I):
• R 1 is (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 3-6 )cycloalkyl, wherein the (C 1-6 )alkyl is optionally substituted with -O(C 1-6 )alkyl or -S(C 1-6 )alkyl;
• R 2 is (C 1-8 )alkyl or (C 3-8 )cycloalkyl, wherein the (C 3-8 )cycloalkyl is optionally substituted with (C 1-6 )alkyl;
• R 3 is aryl, wherein the aryl is optionally fused to one or more cycles, at least one of which is a heterocycle, to form a heteropolycycle, and wherein the aryl or heteropolycycle is optionally substituted with 1 to 4 substituents each independently selected from (C 1-6 )alkyl, halo and -O(C 1-6 )alkyl;
• Another aspect of Formula (I) provides a compound of Formula Il and a racemate, enantiomer or diastereomer of a compound of formula (II):
• R 1 is (C 1-6 )alkyl, (C 2-6 )alkenyl or (C 3-6 )cycloalkyl, wherein the (C 1-6 )alkyl is optionally substituted with -O(C 1-6 )alkyl or -S(C 1-6 )alkyl;
• R 2 is (C 1-8 )alkyl or (C 3-8 )cycloalkyl, wherein the (C 3-8 )cycloalkyl is optionally substituted with (C 1-6 )alkyl;
• R 3 is aryl, wherein the aryl is optionally fused to one or more cycles, at least one of which is a heterocycle, to form a heteropolycycle, and wherein the aryl or heteropolycycle is optionally substituted with 1 to 4 substituents each independently selected from (C 1-6 )alkyl, halo and -O(C 1-6 )alkyl;
• R 54 is in each case independently selected from H and (C 1-3 )alkyl; wherein each of R 52 and R 53 is optionally substituted with 1 to 3 substituents each independently selected from R 55 , halo, -CN, -OR 56 , -SR 56 ,
• R 55 is in each case independently selected from R 56 , (C 2-8 )alkenyl and (C 2-8 )alkynyl, and
• Another aspect of this invention provides a compound of formula (I) or a pharmaceutically acceptable salt 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 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 human being having or at risk of having the infection.
• a further aspect of the invention involves a method of treating an HIV infection in a human being having or at risk of having the infection, the method comprising administering to the human being a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a composition thereof as described hereinabove.
• Another aspect of the invention involves a method of treating an HIV infection in a human being having or at risk of having the infection, the method comprising administering to the human being a therapeutically effective amount of a combination of a compound of formula (I) or a pharmaceutically acceptable salt 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 thereof for the treatment of an HIV infection in a human being 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 thereof, for the manufacture of a medicament for the treatment of an HIV infection in a human being 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 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 thereof, under conditions where replication of HIV is inhibited.
• 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.
• a given chemical formula or name shall encompass salts, including pharmaceutically acceptable salts thereof and solvates thereof, such as for instance hydrates, including solvates of the free compounds or solvates of a salt of the compound.
• the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purpose of the present invention.
• the present invention also provides all pharmaceutically-acceptable isotopically labeled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
• isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, for example 2H or 3H.
• isotopically labeled compounds of the present invention for example deuterated versions of the compounds, can be prepared by conventional techniques known to those skilled in the art or by synthetic processes analogous to those described in the present application using appropriate isotopically labeled reagents in place of the non- labeled reagent mentioned therein.
• (C 1-n )alkyl 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.
• “(C 1-6 )alkyl” includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (iso-propyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1 ,1-dimethylethyl (tert-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 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 (C 2-6 )alkenyl 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 )alkenyl group When a (C 2-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 "(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 (C 2-6 )alkynyl radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.
• a (C 2-n )alkynyl 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 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.
• Examples of (C 3-7 )cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• (C 5-n spirocycloalkyl) wherein n is an integer, either alone or in combination with another radical, denotes a cycloalkyl multi-ring system having two rings linked by one common atom.
• (C 5-14 )spirocycloalkyl radicals
• (C 3-m )cycloalkyl-(C 1-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 (C 3-7 )cycloalkyl-(C 1-6 )alkyl- include, but are not limited to, cyclopropylmethyl, cyclobutyl methyl, cyclopentylmethyl, cyclohexylmethyl, 1- cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2- cyclobutyl ethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl and 2-cyclohexylethyl.
• Aryl includes, but is not limited to, phenyl, indanyl, indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl and dihydronaphthyl.
• aryl-(C 1-n )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-(C 1-6 )alkyl- include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl.
• 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, unless specified otherwise.
• 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.
• Het-(C 1-n )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 1-6 )alkyl- include, but are not limited to, thienylmethyl, furylmethyl, piperidinylethyl, 2- pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, quinolinylpropyl, and the like.
• heteroatom as used herein is intended to mean O, S or N.
• carbocycle as used herein, either alone or in combination with another radical, is intended to mean a 3- to 8-membered saturated, unsaturated or aromatic cyclic radical in which all of the ring members are carbon atoms, and which may be fused to one or more 3- to 8-membered saturated, unsaturated or aromatic carbocyclic groups.
• 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.
• 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 carbon atoms as defined above wherein one or more hydrogen atoms are each replaced by a halo substituent. When two or more hydrogen atoms are replaced by halo substituents, the halo substituents may be the same or different.
• Examples of (C 1-6 )haloalkyl include but are not limited to chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, chlorobromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.
• -O-(C 1 _ n )alkyl 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-(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 (tert-butoxy; (CH 3 ) 3 C-O-).
• 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-).
• 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, herein incorporated by reference.
• 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.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
• examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• such salts include acetates, ascorbates, aspartates, benzenesulfonates, benzoates, besylates, bicarbonates, bitartrates, bromides/hydrobromides, Ca- edetates/edetates, camsylates, carbonates, chlorides/hydrochlorides, citrates, cyclamates, edisylates, ethane disulfonates, estolates, esylates, fumarates, gentisates (salt of 2, 5-di hydroxy benzoic acid), gluceptates, gluconates, glutamates, glycinates, glycolates, glycollylarsnilates, hexylresorcinates, hydrabamines, hydroxymaleates, hydroxynaphthoates, iodides, isethionates, lactates, lactobionates, malates, maleates, malonates, mandelatelate
• salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like, (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. ScL, (1977), 66, 1-19 and Handbook of Pharmaceutical Salts, P.Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley- VCH, 2002, both of which are herein incorporated by reference).
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
• Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
• 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 (compound or biological) that is effective to inhibit the formation and/or replication of a virus in a human being, 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 human being.
• 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.
• the polypeptide sequence of the integrase enzyme of NL4.3 strain of HIV-1 is provided as SEQ ID NO: 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 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
• 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
• R 1 -A In at least one embodiment, R 1 is (C 1- 4 )alkyl, (C 2-4 )alkenyl or (C 3-5 )cycloalkyl, wherein the (C 1- 4 )alkyl is optionally substituted with -O(C 1 -3 )alkyl or -S(C 1- 3 )alkyl
• R 1 is selected from ⁇
• R 1 is (C 1- 4 )alkyl
• R 1 is -CH 3 R 2 :
• R 2 is (C 3-8 )alkyl or (C 3-8 )cycloalkyl wherein the (C 3-8 )cycloalkyl is optionally substituted with (C 1-6 )alkyl.
• R 2 is selected from:
• R 2 is (C 3-8 )alkyl.
• R 2 -D is (C 3-8 )alkyl.
• R 3 is phenyl or R 3 is phenyl fused to one or more cycles, at least one of which is a heterocycle, to form a 9- to 13-membered heteropolycycle having 1 or 2 heteroatoms, each independently selected from N, O and S; wherein the phenyl or heteropolycycle is optionally substituted with 1 to 4 substituents each independently selected from (C 1-6 )alkyl, halo and -O(C 1-6 )alkyl.
• R 3 is phenyl or a heteropolycycle selected from:
• R 3 is selected from:
• R 3 is selected from:
• the compounds of the invention will have a rotational axis of asymmetry and thus rotational isomers are possible.
• the rotational isomers When the energy barrier to rotation is relatively low, the rotational isomers rapidly interconvert at room temperature and are considered to be conformers. In contrast, when the energy barrier to rotation is relatively high, the rotational isomers interconvert so slowly at room temperature that they may be isolated and are considered to be atropisomers.
• the rotational isomers will exist as diastereomers.
• R 3 substituent bears a substituent R 3a at a position ortho to the bond attaching R 3 to Core, wherein R 3a is any atom or group other than hydrogen which is a substituent of R 3 by any definition of R 3 set forth herein, the following atropisomeric formulas A- 1 and A-2 are possible, where, in conformance with accepted stereochemical notation, the darkened and/or solid wedge bonds indicate the side or edge of the R 3 substituent that is projecting towards the viewer:
• R 3 is shown as phenyl un symmetrica I Iy substituted at the ortho position with a substituent R 3a in formulas A-1 and A-2, it will be clear to the person skilled in the art that analogous atropisomers exist for other unsymmetrically substituted R 3 substituents.
• the atropisomer with the formula similar to A-1 above, where the substituent on the R 3 group is on the opposite side of the plane of the pyridine ring from the -OR 2 group is in some cases more active against HIV, when measured, for example, by the procedure of Example 48 below, than the atropisomer with the formula similar to A-2 above, where the substituent on the R 3 group is on the same side of the plane of the pyridine ring as the -OR 2 group.
• R 4 R 4 -A: In at least one embodiment, R 4 is (C 1-6 )alkyl, -CN, halo or (C 1-6 )haloalkyl.
• R 4 is (C 1-6 )alkyl, -CN or halo.
• R 4 is selected from -CH 3 , -CN and -F.
• R 4 -D is selected from -CH 3 , -CN and -F.
• R 4 is (C 1-6 )alkyl.
• R 4 is -CH 3 .
• Core and R 5 /R 6 Core-A:
• a is a double bond and R 6 is absent such that the compound of the invention is a compound of formula (Ia):
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein.
• R 56 is in each case independently selected from H, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl-(C-
• (C 1-6 )alkyl, (C 1-6 )haloalkyl, halo, -O(C 1-6 )alkyl, -N((C 1-6 )alkyl) 2 and -NH(C O)(C 1 _ 6 )alkyl;
• 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.
• R 54 is in each case independently selected from H and (C 1-3 )alkyl; wherein each of R 52 and R 53 is optionally substituted with 1 to 3 substituents each independently selected from R 56 , halo, -CN, -OR 56 , -SR 56 , -SO 2 R 56 , -N(R 54 )R 56 , and -CON(R 54 )R 56 , wherein R 56 is in each case independently selected from H, (C 1-8 )alkyl,
• R 53 is selected from (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C ⁇ cycloalkyKC- ⁇ alkyl-, aryl, aryl-(C 1 _ 6 )alkyl-, Het, and Het-(C 1-6 )alkyl-, wherein Het and the Het portion of Het-(C 1-6 )alkyl- are in each case independently selected from:
• R 54 is in each case independently selected from H and (C 1-3 )alkyl; wherein each of R 52 and R 53 is optionally substituted with 1 to 3 substituents each independently selected from R 56 , halo, -CN, -OR 56 , -SR 56 , -SO 2 R 56 , -N(R 54 )R 56 and -CON(R 54 )R 56 , wherein R 56 is in each case independently selected from H, (d- 8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl-(C 1-6 )alkyl-, aryl, aryl-(C 1-6 )alkyl-, Het, and Het-(C 1-6 )alkyl-, wherein Het and the Het portion of Het-(C 1-6 )alkyl- are in each case independently selected from: wherein R 56 is, where possible, in each case independently optionally substituted with 1 to 3 substituents each independently selected
• a is a double bond
• R 6 is absent
• R 5 is selected from
• R 53 is selected from (d- 8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl-(Ci. 6 )alkyl-, aryl, aryl-(C 1 _ 6 )alkyl-, Het, and Het-(C 1-6 )alkyl-, wherein Het and the Het portion of Het-(C 1-6 )alkyl- are in each case independently selected from:
• R is in each case independently selected from H and (C 1-3 )alkyl; wherein each of R 52 and R 53 is optionally substituted with 1 to 3 substituents each independently selected from R 56 , halo, -CN, -OR 56 , -SR 56 , -SO 2 R 56 , -N(R 54 )R 56 and -CON(R 54 )R 56 , wherein R 56 is in each case independently selected from H, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3- 8)cycloalkyl-(C 1-6 )alkyl-, aryl, aryl-(C 1-6 )alkyl-, Het, and Het-(C 1-6 )alkyl-, wherein Het and the Het portion of Het-(C 1-6 )alkyl- are in each case independently selected from:
• a is a double bond, R 6 is absent and R 5 is R 51 or
• R 52 is selected from R 53 and (C 2-8 )alkenyl
• R 53 is selected from (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 7 . 12 )spirocycloalkyl, (C 3 - 8 )cycloalkyl-(Ci. 6 )alkyl-, aryl, aryl-(C 1-6 )alkyl-, Het, and Het-(C 1 _ 6 )alkyl-, wherein Het and the Het portion of Het-(C 1-6 )alkyl- are in each case independently selected from:
• R 54 is in each case independently selected from H and (C 1-3 )alkyl; wherein each of R 52 and R 53 is optionally substituted with 1 to 3 substituents each independently selected from R 56 , halo, -CN, -OR 56 , -SR 56 , -SO 2 R 56 , -N(R 54 )R 56 and -CON(R 54 )R 56 , wherein R 56 is in each case independently selected from H, (C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3- 8)cycloalkyl-(C 1-6 )alkyl-, aryl, aryl-(C 1-6 )alkyl-, Het, and Het-(C 1-6 )alkyl-, wherein Het and the Het portion of Het-(C 1-6 )alkyl- are in each case independently selected from:
• a given chemical formula or name shall encompass tautomers, and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers, atropisomers) resulting from all possible steriochemistry at a chiral center for which specific steriochemistry is not otherwise decsribed, and racemates thereof, as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist.
• enantiomers often exhibit strikingly different biological activity including but not limited to differences in pharmacokinetic properties, including but not limited to metabolism, protein binding, and the like, and pharmacological properties, including but not limited to 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.
• Preparation of pure stereoisomers e.g. enantiomers and diastereomers, or mixtures of desired enantiomeric excess (ee) or enantiomeric purity, are accomplished by one or 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.
• resolution methods generally rely on chiral recognition and include but are not limited to 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. Soc, 2000.
• PHARMACEUTICAL COMPOSITION Suitable preparations for administering the compounds of the invention will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders.
• the content of the pharmaceutically active compound(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.- % of the composition as a whole.
• Suitable tablets may be obtained, for example, by mixing one or more compounds according to the invention with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
• excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
• the tablets may also consist of several layers.
• 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 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.
• 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 pharmaceutical composition according to the invention comprises a racemic mixture of the compound of formula (I), or a pharmaceutically acceptable salt 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 thereof.
• a further embodiment provides a pharmaceutical composition comprising a pure enantiomer of the compound of formula (I), or a pharmaceutically acceptable salt thereof.
• the dose range of the compounds of the invention applicable per day is usually from 0.001 to 100 mg/kg of body weight, preferably from 0.01 to 50 mg/kg of body weight.
• Each dosage unit may conveniently contain from 5% to 95% active compound (w/w).
• Preferably such preparations contain from 20% to 80% active compound.
• the actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient's unique condition.
• composition of this invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic 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.
• Combination therapy is contemplated wherein a compound according to the invention, or a pharmaceutically acceptable salt 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.
• 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 human being, 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 human being.
• Such agents can be selected from: • NRTIs (nucleoside or nucleotide reverse transcriptase inhibitors) including but not limited to zidovudine/RETROVIR® (GSK), didanosine/VIDEX® (BMS), stavudine/ZERIT® (BMS), lamivudine/EPIVIR® (GSK/Shire), emtricitabine/EMTRIVA® (Gilead Sciences), abacavir/ZIAGEN® (GSK), and tenofovir/VIREAD® (Gilead Sciences), apricitabine (Avexa), elvucitabine (Achillion) and OBP-601 (Oncolys), amdoxovir (RFS Pharma); • NNRTIs (non-nucleoside reverse transcriptase inhibitors) including but not limited to nevirapine/VIRAMUNE® (Boehringer Ingelheim), delavirdine/RESCRIPTOR® (Pfizer),
• entry inhibitors including but not limited to
• CCR5 antagonists including but not limited to maraviroc/SELZENTRY® (Pfizer), vicriviroc (Schering-Plough), INCB9471 (Incyte), PF-232798 (Pfizer), PRO-140 (Progenies Pharm), GSK706769 (GSK), PF-232798 (Pfizer), TBR- 220 and TBR-652 (Tovira Therapeutics);
• CXCR4 antagonists including but not limited to AMD-1 1070 (Genzyme),
• fusion inhibitors including but not limited to enfuvirtide/FUZEON® (Trimeris), sifuvirtide (Fasogen), albuvirtide (Frontier Bio), FRI-1 144 (Trimeris); and
• BMS-488043 BMS-488043
• integrase inhibitors including but not limited to raltegravir/ISENTRESS® (Merck), elvitegravir (Gilead Sciences), GSK1349572 and GSK1265744 (GSK), JTK-656 (Japan Tobacco);
• maturation inhibitors including but not limited to bevirimat (Myriad Genetics), becon (Myriad Genetics); and
• immunomodulating agents including but not limited to levamisole/ERGAMISOL® (Janssen-Ortho); and
• 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.
• Protected derivatives of compounds of formula (I) can be prepared by well known coupling reactions of intermediates Il and III, including but not limited to Suzuki cross-coupling between a boronic acid or boronate ester derivative III and a halo or triflate derivative II; copper catalyzed Ullmann cross-coupling between iodo derivatives Il and III; Negishi cross-coupling between an arylzinc reagent III and an iodo or triflate derivative II; and StMIe coupling between an arylltin reagent III and a bromo or iodo derivative II.
• the protected products of the coupling reaction are then deprotected, for example by saponification, to provide compounds of formula (I).
• intermediates IV and V wherein a, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L, M and P are as defined herein, may be coupled using the cross-coupling methods described above, followed by deprotection, to provide compounds of formula (I).
• Intermediates Vl and VIII wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein and P is a suitable protecting group, well known in the art, are commercially available or are prepared by reactions well known in the art or as set forth in the examples below.
• Intermediates Vl are conveniently transformed to intermediates VII using conditions well-known to those skilled in the art, including but not limited to a Sonogashira coupling between intermediates Vl and R 3 -l.
• Intermediates VII and VIII undergo a cyclocondensation reaction under well known conditions, including but not limited to reaction with (CF 3 SO 2 ) 2 O (triflic anhydride) in the presence of 2- chloropyridine to give intermediates IX.
• Deprotection of intermediate IX followed by oxidation of the primary alcohol using conditions well known in the art, including but not limited to oxidation with Dess-Martin periodinane followed by sodium chlorite oxidation, provides compounds of formula (Ia).
• transformations include but are not limited to alkylation, conversion of an aromatic primary amino group to a chloro or bromo substituent using a Sandmeyer reaction, and reductive dehalogenation.
• substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be protected and/or deprotected at intermediate steps in the preparation of a compound of formula (I), as will be recognized by the skilled person.
• reaction 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 (°C). 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 analyses are recorded using electrospray mass spectrometry.
• a number of intermediate and final products are purified using CombiFlash® Companion or RF apparatus, purchased from Teledyne lsco Inc, employing prepacked silica gel cartridges and EtOAc and hexanes as solvents. These cartridges are available either from Silicycle Inc (SiliaFlash, 40-63 ⁇ m silica) or from Teledyne lsco (RediSep, 40-63 ⁇ m silica).
• 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.
• analytical HPLC is carried out under standard conditions using a SunFireTM C18 (3.5 ⁇ m, 4.6x30 mm) reverse phase column at 220 nm, elution with a linear gradient as described in the following table (Solvent A is 0.06% TFA in H 2 O; solvent B is 0.06% TFA in CH 3 CN):
• analytical HPLC is carried out under standard conditions using a SunFireTM C18 (3.5 ⁇ m, 4.6x30 mm) reverse phase column at 220 nm, elution with a linear gradient as described in the following table (Solvent A is 0.06% TFA in H 2 O; solvent B is 0.06% TFA in CH 3 CN):
• analytical UPLC is carried out using a shorter run time using an AquityTM HSST3 (1.8 ⁇ m, 2.1x50 mm) reverse phase column at 220 nm, elution with a linear gradient as described in the following table (Solvent A is 0.06% TFA in H 2 O; solvent B is 0.06% TFA in CH 3 CN):
• analytical UPLC is carried out using a shorter run time using an
• Step 1
• Step 4 In a sealable reaction flask, a solution of the propargylic alcohol 1e (375 mg, 2.20 mmol) and Amberlyst® H-15 resin (150 mg) in hexane (3 ml.) is cooled to -78°C. lsobutene is then bubbled through the solution until the volume approximately doubles. The tube is then sealed, brought to RT and is stirred overnight. The tube is then cooled to -78°C, is opened and brought back to RT. The mixture is then filtered through a plug of SiO 2 (EtOAc wash) and concentrated under reduced pressure to provide pure tert-butyl ether 1f. Step 5:
• Step 6 To a mixture of 3,4-dimethylbenzaldehyde (1 i; 500 mg, 3.73 mmol) and Et 2 O (12 mL) is added ethylmagnesium bromide (3M, 1.4 mL, 1.2 mmol) dropwise. After 15 min, the reaction is quenched with saturated aqueous NH 4 CI (50 mL) and the layers are separated. The organic layer is washed with saturated aqueous NH 4 CI (50 mL), dried over Na 2 SO 4 and concentrated to give the intermediate benzyl alcohol.
• ethylmagnesium bromide 3M, 1.4 mL, 1.2 mmol
• Dess-Martin periodinane (71 mg, 0.17 mmol) is added to a mixture of alcohol 1 m (43 mg, 0.094 mmol) and DCM (1.7 mL). After 2 h, the reaction mixture is concentrated, the residue is dissolved in 1 :1 THF/tBuOH (2 mL), and 2,3-dimethyl-2- butene (1 M in THF, 0.75 mL, 0.75 mmol) is added. A separate mixture Of NaClO 2 (71 mg, 0.79 mmol) and NaH 2 PO 4 (71 mg, 0.59 mmol) in water (1 mL) is added to the first mixture and the mixture is stirred at RT. After 30 min, the mixture is diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic layer is dried over Na 2 SO 4 and concentrated. The residue is purified by preparative HPLC to give compound 1029 (Table 1).
• Step 1
• the bromopyridine 2d (191 g, HBr salt) is heated at reflux in POCI 3 (850 ml.) for 18 h and cooled to RT.
• the excess POCI 3 is removed by evaporation and the residue is poured onto ice.
• the mixture is adjusted to basic pH using 10 N NaOH and solid NaHCO 3 .
• the mixture is filtered and the filtrate extracted with DCM (3 x 800 mL) and dried over Na 2 SO 4 .
• the solution is passed through a SiO 2 (600 g) column and concentrated to afford 2e.
• Alternative procedure for step 3 Bromopyridine 2d (370 g, HBr salt) is heated at reflux in POCI 3 (1.25 L) for 18 h.
• the mixture is cooled and excess POCI 3 is evaporated.
• To the residue is added
• PhPOCI 2 (1.2 L) and the mixture is heated at 150°C for 28 h. The mixture is allowed to cool to RT and poured onto ice, then adjusted to basic pH with solid Na 2 CO 3 . The mixture is filtered and the filtrate is extracted with EtOAc (3 x 1500 mL), dried over Na 2 SO 4 and filtered. The filtrate is passed through a SiO 2 (600 g) column and concentrated, and the residue is triturated with EtOAc to give 2e (196 g). The filtrate is concentrated and purified by CombiFlash® Companion to give a second crop of 2e.
• Step 4 To a solution of bromide 2e (105 g, 0.41 1 mol) in anhydrous THF (1.14 L) is added Cu(I)Br (15 g, 0.1 mol). To the resulting mixture at RT is added iPrMgCI-LiCI (400 mL, 0.52 mol, 1.3 M in THF) over 30 min. The mixture is allowed to stir for 1 h, methyl chlorooxoacetate (80 mL, 0.87 mol) is added and stirring is continued for 1 h. The reaction is quenched with saturated NaHCO 3 and solid NaHCO 3 and the mixture extracted with EtOAc (3 x 1.2 L). The organic extract is dried over Na 2 SO 4 , and filtered. The extract is passed through a SiO 2 (300 g) column, concentrated and the residue is purified by CombiFlash® Companion (EtOAc/ hexanes) to afford 2f. Step 5:
• Step 1
• Step 2 To a mixture of phenol 3b (6.37 g, 36.7 mmol) and THF (100 mL) is added tin powder (17.4 g, 147 mmol) followed by 1 N HCl (220 mL, 220 mmol) and the mixture is stirred vigorously at RT for 16 h. The mixture is cooled to 0°C and neutralized with 10 N NaOH (22 mL), and stirred vigorously for about 15 min.
• a solution of borane in THF (1.0 M, 18.5 mL, 18.5 mmol) is added dropwise to an ice-cold mixture of lactam 3e (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 2 h, the mixture is cooled to 0°C, carefully quenched with 1 N NaOH (19 mL) and stirred for about 15 min. The mixture is diluted with water (30 mL) and the THF is evaporated.
• Step 7 Palladium on activated charcoal (10% Pd by weight, 1.08 g) is added to a mixture of aryl chloride 3g (3.0 g, 10 mmol) and ammonium formate (6.4 g, 0.10 mol) in MeOH (75 mL).
• Step 1 To a solution of the dichloropyridine 2h (Example 2) (2.0 g, 6.25 mmol) and 3,4- dimethylphenylboronic acid 4a (1.12 g, 7.5 mmol) in DMF (20 mL) is added 2M Na 2 CO 3 (7.8 mL, 16 mmol) followed by PdCI 2 (PPh 3 ) 2 (440 mg, 0.62 mmol).
• the reaction mixture is degassed by bubbling with argon (10 min), the reaction vessel is sealed and the mixture is heated at 1 10°C for 16 h.
• the cooled mixture is diluted with EtOAc, washed with water and brine, dried over MgSO 4 and filtered.
• the residue is purified by CombiFlash® Companion (Hexanes/EtOAc) to give 4b.
• Step 2 To a solution of the dichloropyridine 2h (Example 2) (2.0 g, 6.25 mmol) and 3,4- dimethylphenyl
• Step 1
• Step 1 to Step 4 Intermediate 4b (Example 4) is transformed to intermediate 7d using the procedures described in steps 3 to 6 of Example 5.
• Step 1
• Step 2 Trimethylsilylmethylmagnesium bromide (90%, 1 M solution in Et 2 O, 0.34 mL, 0.31 mmol) is added dropwise to a stirred solution of aldehyde 8a (125 mg, 0.26 mmol) in anhydrous THF (2.0 mL) cooled to -35°C under a nitrogen atmosphere. After 1 h, additional trimethylsilylmethyl magnesium bromide solution (0.26 mL; 0.23 mmol) is added. After a further 2 h, the reaction is quenched with saturated NH 4 CI (1 mL) and the mixture is extracted with EtOAc (20 mL), and washed with 5% NaHCO 3 and brine.
• Step 3 To a stirred mixture of lactone 8b (98 mg; 0.183 mmol) and anhydrous THF (3.0 mL) under a nitrogen atmosphere is added dropwise tetrabutylammonium fluoride solution (1 M solution in THF; 0.27 mL; 0.27 mmol). The mixture is allowed to stir at 0°C for 30 min, then is allowed to warm to ambient temperature. After 1 h, the reaction is concentrated to dryness and the residue is dissolved in MeCN (10 mL).
• Step 1
• Step 1
• nitrile 10a 1.0 g, 3.2 mmol
• aqueous NaOH 10 N, 3.4 mL, 32 mmol
• EtOH 3.2 mL
• the mixture is cooled to RT and diluted with concentrated aqueous HCl (12N, 4 mL, 48 mmol) and water (50 mL).
• the mixture is extracted with EtOAc (3 x 50 mL) and the combined organic layers are dried over Na 2 SO 4 and concentrated to dryness.
• the rubber septum is secured by wrapping with electrical tape and DMF (20 mL) and MeOH (2.5 mL, 62 mmol) are added via syringe.
• a balloon of CO is connected to the reaction vessel using a short length of rubber tubing ( ⁇ 1 in.), a needle adapter and a 20 G needle.
• the inert atmosphere is then exchanged for carbon monoxide by briefly exposing the reaction vessel to vacuum (1-2 sec) and backfilling with carbon monoxide (3 times).
• the reaction mixture is heated at 120°C and stirred vigorously for 16 h, then is allowed to cool to room temperature, and is diluted with EtOAc (20 mL), combined and filtered through a plug of Celite (eluting with EtOAc).
• the filtrate is washed with water and brine, dried over MgSO 4 , filtered and concentrated.
• the residue is purified by CombiFlash® Companion (EtOAc/he ⁇ anes) to give the diester 10b
• Step 1 A mixture of nitrile 10a (Example 10) (1.7 g, 5.4 mmol), 2-aminophenylboronic acid (1.0 g, 7.3 mmol), bis[tri-t-butylphosphine]palladium(0) (276 mg, 0.54 mmol), NaHCO 3 (2.25 g, 26.7 mmol), DMA (50 mL) and water (5 mL) is degassed by bubbling Ar(g) under sonication for 5 min. The mixture is heated to 130°C and stirred for 15 h, then cooled to RT and partitioned between EtOAc (225 mL) and water (200 mL).
• Step 2 Aniline 12a is converted to intermediate 12b using the procedure described in step 2 of Example 5. Step 3:
• Step 1 A mixture of nitrile 12b (Example 12) (6 g, 15.4 mmol) and AcOH (100 mL) is treated with 10% Pd/C (1.64 g, 1.54 mmol). The mixture is purged with hydrogen gas and stirred at RT for 1.5 h. The flask is evacuated several times and the catalyst is removed by filtration through Celite® with EtOAc washes. The mixture is concentrated in vacuo and the residue is taken up in EtOAc, washed with saturated NaHCO 3 and saturated brine, dried over MgSO 4 , and concentrated. The residue is purified by CombiFlash® Companion (1-10% MeOH/DCM gradient with 1 % Et 3 N) to afford after concentration, amine 13a.
• CombiFlash® Companion (1-10% MeOH/DCM gradient with 1 % Et 3 N
• Step 1
• reaction mixture is treated with 10 N NaOH (1 12 ⁇ L, 1.12 mmol) for 4 h and concentrated to dryness, purified by preparative HPLC and lyophilized to give compound 3010 (Table 3).
• Step 1
• Step 3 To a stirred, ice cold, mixture of K 2 CO 3 (2.05 g, 14.8 mmol), aniline 15c (750 mg, 3.71 mmol) and DMF (5 mL) under nitrogen, is added chloroacetyl chloride (355 ⁇ L, 4.45 mmol) dropwise. The mixture is allowed to warm to RT over a period of about 15 min and is then heated to 60°C for 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 15d.
• Step 4 To a stirred, ice cold, mixture of K 2 CO 3 (2.05 g, 14.8 mmol), aniline 15c (750 mg, 3.71 mmol) and DMF (5 mL) under nitrogen, is added chloroacetyl chloride (355 ⁇ L,
• Step 1
• Neat Tf 2 O (0.56 mL, 3.3 mmol) is added dropwise to a cooled (0°C) mixture of phenol 16a (350 mg, 2.1 mmol; prepared according to Doi et al Bull. Chem. Soc. Jpn. 2004 77, 2257-2263) and pyridine (0.91 mL, 1 1 mmol) in DCM (10 mL) under an Ar atmosphere.
• the mixture is allowed to warm to RT and is stirred for 2 h.
• the reaction is quenched by the addition of a 10% citric acid solution (20 mL) and the mixture is extracted with DCM (3 x 20 mL).
• the combined organic layers are washed with water, dried over MgSO 4 , filtered and concentrated to dryness.
• Step 2 A mixture of the triflate 16b (510 mg, 1.7 mmol), bis[pinacolato]diborane (560 mg, 2.2 mmol) and potassium acetate (500 mg, 5.1 mmol) in DMF (18 mL) is degassed with Ar for 5 min, and PdCI 2 dppf-DCM complex (140 mg, 0.17 mmol) is added. The reaction mixture is degassed for an additional 5 min and heated to 100°C by microwave irradiation for 10 min, then cooled to RT.
• Step 1 A solution of phenol 17a (0.91 g, 5.74 mmol) in dry DMF (1 mL) is added dropwise to a mixture of NaH (60% in oil, 0.60 g, 15 mmol) in dry DMF (1 mL) cooled to 15°C and the mixture is stirred for 20 min. A solution of 3-bromopropionic acid (1.1 g, 6.9 mmol) in dry DMF (0.5 mL) is added dropwise and the mixture is stirred at RT overnight.
• Step 2 A mixture of 17b (1.53 g, 6.63 mmol) and polyphosphoric acid (7 g) is heated to
• Step 4 A mixture of anisole 17d (4.0 g, 20 mmol) and dry dichloromethane (40 ml.) is cooled to -78°C. A BBr 3 solution (1 M in DCM, 44 mL, 44 mmol) is added dropwise and then the reaction mixture is removed from the dry ice bath. After 45 min, the mixture is cooled (ca. 0°C) and the reaction is quenched with water (25 ml.) added dropwise. The mixture is diluted with water (400 ml.) and is carefully neutralized with saturated aqueous NaHCO 3 (final pH ca 8). This mixture is then extracted with DCM (300 ml.
• Step 5 Compound 17e is transformed to compound 17f using the procedure described in steps 1 and 2 of Example 16.
• Step 1
• Step 1
• Step 3 A mixture of the 6-iodochroman 19c (1.0 g, 3.85 mmol), bis[pinacolato]diborane (1.22 g, 4.81 mmol) and potassium acetate (1.10 g, 1 1.5 mmol) in DMF (36 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI 2 dppf-DCM complex (314 mg, 0.38 mmol). The reaction mixture is then degassed for about an additional 5 min and heated to 95°C for 5 h. The mixture is then cooled to RT, diluted with water and extracted with EtOAc (3 x 100 mL).
• Step 1 A mixture of phenol 20a (6.75 g, 47.3 mmol) and DMF (270 ml.) is treated with allyl bromide (6.55 mL, 75.7 mmol). To this mixture, NaH (60%, 4 g, 99.4 mmol) is added portionwise and stirring is continued overnight. The reaction mixture is diluted with EtOAc (500 ml.) and washed with H 2 O. The organic layer is dried over MgSO 4 , filtered and concentrated to dryness to obtain the desired product 20b.
• Step 2 A mixture of phenol 20a (6.75 g, 47.3 mmol) and DMF (270 ml.) is treated with allyl bromide (6.55 mL, 75.7 mmol). To this mixture, NaH (60%, 4 g, 99.4 mmol) is added portionwise and stirring is continued overnight. The reaction mixture is diluted with EtOAc (500 ml.) and washed with H 2 O. The organic layer is dried over M
• the ether 20b (8.6 g) is stirred and heated at 240°C for 20 min in a microwave vial to provide 20c.
• Step 7 Palladium on activated charcoal (10% Pd by weight, 0.63 mg, 0.59 mmol) is added to a solution of aryl chloride20 g (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 15 min, the reaction is cooled to RT and filtered through Celite®, and the Celite® pad is rinsed with MeOH. The filtrate is concentrated to dryness and the residue partitioned between water and EtOAc (10 mL each). The organic layer is dried over anhydrous MgSO 4 and concentrated to obtain boronic ester20 h.
• Step 1 A mixture of 21a (1.0 g, 4.5 mmol), 21 b (0.72 g, 5.2 mmol), potassium carbonate (1.6 g, 12 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (0.36 g, 0.62 mmol) in DMF (8.3 mL) and water (0.88 mL) is heated under microwave for 15 min at 130°C. The mixture is partitioned between EtOAc (25 mL) and water (25 mL) and the organic layer is washed with water, dried over Na 2 SO 4 , filtered and concentrated. The residue is purified by CombiFlash® Companion using a gradient of EtOAc/hexanes to afford the desired alcohol 21c.
• Step 2 A mixture of 21a (1.0 g, 4.5 mmol), 21 b (0.72 g, 5.2 mmol), potassium carbonate (1.6 g, 12 mmol) and trans-dichlorobis(
• Step 3 A solution of the triflate 21d (1.2 g, 3.7 mmol), bis(pinacolato)diborane (1.4 g, 5.5 mmol) and potassium acetate (1.2 g, 13 mmol) in DMF (50 mL) is degassed with Ar for about 5 min followed by the addition of the PdCI 2 dppf-DCM complex (0.39 mg, 0.48 mmol). The reaction mixture is then degassed for about an additional 5 min before being heated to 95°C overnight. The reaction mixture is then cooled to RT, diluted with water (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts are washed with water, dried over Na 2 SO 4 , filtered and concentrated. The residue is purified by CombiFlash® Companion using a gradient of EtOAc/hexanes to give borane 21 e.
• EXAMPLE 22 A solution of the triflate 21d (1.2 g, 3.7 mmol),
• 4-Hydroxypyridone 22c is synthesized using the procedure described by T. Kato; Y.
• Step 2 Intermediate 22c is transformed to intermediate 22d using procedures described in step 2 of Example 2.
• Step 7 Intermediate 22h is transformed to intermediate 22i using procedures described in step 1 of Example 4.
• Step 1 1 ,3-acetonedicarboxylic acid 23a (30 g; 205.3 mmol) is added in portions to Ac 2 O (55 g; 587.7 mmol) and the mixture is stirred at 35°C for 23 h, then filtered. The filtrate is diluted with benzene (200 mL) and the solution stored at 5°C for 3 h. The precipitate is filtered and dried under vacuum to give intermediate 23b.
• Step 2 To a stirred solution of aniline 23c (7.5 g, 44 mmol) in AcOH (50 mL) is added 23b (8.0 g, 40 mmol) portionwise.
• aryl halide 23i (5 g, 20 mmol) Et 2 O (400 mL) under a nitrogen atmosphere is heated to 43°C then cooled to -75°C in a dry ice/acetone bath, n- Butyllithium solution (1.38 M in hexanes, 21.7 mL, 30 mmol) is added dropwise (4 min addition time, internal temp below 70°C). The mixture is stirred for an additional 5 min and n-butyllithium solution (880 ⁇ L, 1.2 mmol) is added. After 5 min, triisopropyl borate (16.9 mL, 72 mmoles) is added while the temperature is held at - 74°C.
• Step 1 To a cold (0°C) mixture of 25a (15.0 g, 1 18 mmol) and DMF (180 mL) is added K 2 CO 3 (48.9 g, 354 mmol) followed by dropwise addition of chloroacetyl chloride (9.40 mL, 1 18 mmol). The reaction mixture is allowed to warm to RT and then heated to 60°C for 2 h. The reaction mixture is cooled to RT, poured into ice-water (2.0 L) and stirred for 30 min. The mixture is filtered and the solid rinsed with water and dried under reduced pressure to provide 25b. Step 2:
• Step 1
• Step 1
• Step 1
• Step 1 Intermediates 10b (Example 10) and 3h (Example 3) are transformed to intermediate 30a using the procedure described in step 2 of Example 4.
• Step 2 :
• Step 1
• a mixture of DMA (15.8 mL) and distilled water (1.58 mL) is degassed for 10 min with nitrogen and added by syringe to a mixture of the intermediate 31a (1 g, 3.5 mmol), 6-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-chroman 19d (Example 19) (1 g, 3.85 mmol) and NaHCO 3 (1.47 gr, 17.5 mmol) under nitrogen atmosphere in a 48 imL resealeable vessel equipped with a magnetic stirring bar and fixed with a rubber septum.
• Step 5 A mixture of 31d (250 mg, 0.52 mmol), THF (2.5 mL) and MeOH (0.83 mL) is treated with a solution of 10 N NaOH (0.42 mL, 4.2 mmol) at 60°C for 18 h. The mixture is adjusted to pH 1 with 1 N HCl and extracted with DCM (3x). The combined organic layers are dried over MgSO 4 , filtered and concentrated in vacuo affording intermediate 31e.
• Step 6 A mixture of 31d (250 mg, 0.52 mmol), THF (2.5 mL) and MeOH (0.83 mL) is treated with a solution of 10 N NaOH (0.42 mL, 4.2 mmol) at 60°C for 18 h. The mixture is adjusted to pH 1 with 1 N HCl and extracted with DCM (3x). The combined organic layers are dried over MgSO 4 , filtered and concentrated in vacuo affording intermediate 31e.
• Step 6 A mixture of 31d (250 mg, 0.52 mmol), T
• Step 1
• Step 1
• Step 3 The mixture of alcohols 35b (362 mg, 0.90 mmol) in tert-butyl acetate (7.1 mL, 53 mmol) is cooled to 0°C in an ice bath and treated portionwise with perchloric acid (70% w/w in water, 1.2 mL, 13.4 mmol).
• Step 4 To a mixture of diester 35d (87 mg, 0.19 mmol), MeOH (0.4 mL) and THF (1.2 mL) is added 1 N LiOH (0.21 mL, 0.21 mmol).
• Step 5 A mixture of acid 35e (30 mg, 0.06 mmol) and NMP (1 mL) is treated with TBTU (40 mg, 0.12 mmol) and Et 3 N (35 ⁇ L, 0.25 mmol). The mixture is allowed to stir at RT for 5 min then trans-4-methylcyclohexyl amine (25 ⁇ L, 0.19 mmol) is added. The reaction is allowed to stir at RT (2 h) and is then diluted with EtOAc. The organic phase is washed with saturated NH 4 CI, H 2 O, and brine, dried over MgSO 4 , filtered and concentrated to dryness to afford the amide 35f. Step 6:
• Step 1
• Step 1
• Step 1 To 12d (1 g, 2.5 mmol) and Et 3 N (481 ⁇ L, 3.5 mmol) in THF (13 mL) at 0°C is added isobutyl chloroformate (448 ⁇ L, 3.5 mmol) dropwise. The mixture is stirred at 0°C for 1 h. A diazomethane solution (0.67 M in diethyl ether, 37 mL, 25 mmol) is added slowly and the mixture is allowed to reach 23°C. After 1 h, the mixture is concentrated in vacuo and then EtOAc and water are added.
• Step 2 To a solution of 38a (828 mg, 2.5 mmol) in THF (16 mL) at 0°C is added dropwise an HBr solution (48% aq, 1.09 mL, 9.6 mmol). The mixture is stirred for 1 h at 0°C. The solution is diluted with EtOAc, washed with NaHCO 3 (sat), water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuo to provide 38b.
• Step 3 To 38b (50 mg, 0.1 mmol) in a mixture of EtOH (750 ⁇ L) and acetone (150 ⁇ L) is added NaHCO 3 (8.1 mg, 0.1 1 mmol) and 2-amino-5-chloropyridine (14.7 mg, 0.1 1 mmol) in a sealed tube. The mixture is heated at 85°C for 30 min then concentrated in vacuo. The residue is diluted with THF (1 mL), MeOH (300 ⁇ L) and a NaOH solution (5 N, 103 ⁇ L, 0.52 mmol) and the resulting mixture is then stirred for 15 min at 60°C. The mixture is cooled to 23°C and the pH is adjusted to -5-6 with AcOH.
• Step 1
• Step 2 To 39b (1 1 g, 37.8 mmol) dissolved in dry 1 ,4-dioxane (120 mL) is added bis(pinacolato)diboron (13.7 g, 54 mmol) and potassium acetate (9.9 g, 101 mmol) before being deoxygenated by bubbling a stream of argon for 15 min. To this mixture is added 1 ,1 '-bis(diphenylphosphino)ferrocene (2.75 g, 3.4 mmol). This mixture is degassed a further 5 min before being refluxed at 100°C for 16 h. The cooled mixture is diluted with EtOAc and water and then filtered through Celite. The phases are separated and the organic layer is washed with water, brine, dried (MgSO 4 ), filtered and concentrated. The resulting residue is purified by CombiFlash® Companion to give intermediate 39c. EXAMPLE 40
• Step 1 Intermediate 10a (4.0 g, 12.9 mmol) is treated with boronate 39c (5.2 g, 15.5 mmol) using the procedure described in step 1 of Example 12 to afford 40a.
• Aniline 40b (2.86 g, 6.84 mmol) is converted to intermediate 40c using the procedure described in step 2 of Example 5.
• the atropisomers are separated at this stage by CombiFlash® Companion to give 40c.
• Step 4 Diester 40c is converted to mono-acid 4Od using the procedure described in step 4 of Example 12.
• Step 6 To a solution of 4-methoxy-2-quinoline carboxylic acid (302 mg, 1.5 mmol) and DMF (15 ⁇ L) in DCM (7 ml.) is added oxalyl chloride as a 2M solution in DCM (968 ⁇ L, 1.94 mmol) dropwise at RT (with evolution of gas). After 20 min, the solution is concentrated to dryness and then dissolved in THF (2 mL). To this solution is added intermediate 4Oe (294 mg, 0.74 mmol) and DIPEA (650 ⁇ L, 3.72 mmol) then heated at 50°C for 2h.
• the cooled reaction mixture is diluted with EtOAC and washed consecutively with a NH 4 CI solution (sat), a NaHCO 3 solution (sat) and brine.
• the organic phase is dried (MgSO 4 ), filtered and concentrated to dryness.
• the solution of the crude ester (431 mg, 0.74 mmol) in THF (4 mL) and MeOH (2 mL) is heated at 50°C before being treated with 5 N NaOH (743 ⁇ L, 3.72 mmol).
• the reaction is stopped after 1 h by quenching with AcOH (500 ⁇ L) and the mixture is concentrated to dryness.
• the residue is taken up into MeOH and purified by preparative HPLC to give, after lyophilization, compound 1453.
• Step 1
• Compound 41a is converted to 41 b using dimsyl sodium and methyl- triphenylphosphoium bromide as described in J. Am. Chem. Soc, 1980, 102, 1404- 1408.
• Step 1
• Step 1 To a solution of compound 43a (1.9 g, 10 mmol) in THF is added tin powder and 1 N HCl (50 mL, 50 mmol). After 1 h of vigorous stirring, 1 N NaOH (50 ml.) is added slowly to the reaction. The mixture is filtered on Celite and the filter cake is washed with EtOAc (200 mL). The filtrate is extracted with EtOAc and the combined organic layers are dried (Na 2 SO 4 ) and concentrated to dryness to give compound 43b.
• Step 1
• Step 1 Intermediate 10b is transformed to intermediate 36a using the procedure described in step 1 of Example 12
• Step 2 t-Butyl nitrite (90% w/w, 1.0 mL, 7.9 mmol) is added to a stirred suspension of CuBr 2
• Step 1
• Step 1
• C8166 cells are derived from a human T-lymphotrophic virus type 1 immortalized but nonexpressing line of cord blood lymphocytes (obtained from J. Sullivan and originally produced in the laboratory of R. GaIIo, Virology 1983; 129: 51-64) 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 is 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 gentamycin) with 5 ⁇ g/ml blasticidine, however, blasticidine selection is removed from the cells before performing the viral replication assay.
• RPMI Roswell Park Memorial Institute medium
• 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.
• 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 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°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.
• 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:
• Retention times (t R ) for each compound are measured using the standard analytical HPLC or, where indicated, UPLC 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 or UPLC instruments. Even when measured on the same instrument, the values may vary when measured, for example, using different individual HPLC or UPLC 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.

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