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US20090312325A1 - Quinoline Derivatives As Phosphodiesterase Inhibitors - Google Patents

Quinoline Derivatives As Phosphodiesterase Inhibitors Download PDF

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US20090312325A1
US20090312325A1 US12/474,324 US47432409A US2009312325A1 US 20090312325 A1 US20090312325 A1 US 20090312325A1 US 47432409 A US47432409 A US 47432409A US 2009312325 A1 US2009312325 A1 US 2009312325A1
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alkyl
methyl
optionally substituted
formula
compounds
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Ian Robert Baldwin
Michael David Barker
Anthony William Dean
Colin David Eldred
Brian Evans
Sharon Lisa Gough
Stephen Barry Guntrip
Julie Nicole Hamblin
Stuart Holman
Paul Jones
Mika Kristian Lindvall
Christopher James Lunniss
Tracy Jane Redfern
Alison Judith Redgrave
John Edward Robinson
Michael Woodrow
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Priority claimed from GB0311688A external-priority patent/GB0311688D0/en
Priority claimed from GB0326187A external-priority patent/GB0326187D0/en
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Priority to US12/474,324 priority Critical patent/US20090312325A1/en
Publication of US20090312325A1 publication Critical patent/US20090312325A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/12—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 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
    • C07D405/14—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the present invention relates to quinoline compounds, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds.
  • the invention also relates to the use of the quinoline compounds in therapy, for example as inhibitors of phosphodiesterases and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
  • COPD chronic obstructive pulmonary disease
  • asthma chronic obstructive pulmonary disease
  • rheumatoid arthritis allergic rhinitis
  • WO 02/20489 A2 (Bristol-Myers-Squibb Company) discloses 4-aminoquinoline derivatives wherein the 4-amino group NR 4 R 5 may represent an acyclic amino group wherein R 4 and R 5 may each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl etc.; NR 4 R 5 may alternatively represent an aliphatic heterocyclic group.
  • the compounds are disclosed as inhibitors of cGMP phosphodiesterase, especially type 5 (PDE5).
  • EP 0 480 052 discloses 4-aminoquinoline-3-carboxamides wherein the 4-amino group NHR 4 may represent an amino group wherein R 4 represents phenyl, tetrahydronaphthyl or naphthyl, optionally substituted with alkyl, halogen, alkoxy etc.; and the 3-carboxamide group CONR 2 R 3 represents a primary, secondary or tertiary carboxamide group.
  • the compounds are disclosed as inhibitors of gastric acid secretion, and as cytoprotective agents; inhibition of the ATPase activated by H + and K + at the gastric wall cells is also disclosed.
  • PDE4 phosphodiesterase type IV
  • R 3 is C 1-6 alkyl optionally substituted by one or more substituents selected from —OH, —NR 16 COR 15 , —NR 17 R 18 , —CO 2 R 24 , C 1-6 alkoxyCONR 25 —, —CONR 2 , R 27 , C 1-6 alkoxy-, C 1-6 alkylSO 2 NR 33 —, or a group having one of the following formulae;
  • C 3-7 cycloalkyl Aryl or aryl(C 1-6 alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C 1-6 alkyl-, halogen-, C 1-6 alkoxy-, —CO 2 R 28 , —CH 2 CO 2 H, —OH, aryl(optionally substituted by a C 1-6 alkoxy group), heteroaryl, —CONR 29 R 30 C 3-7 cycloalkoxy, C 3-7 cycloalkyl(C 1-6 alkoxy)-, —CF 3 ; Heteroaryl or heteroaryl(C 1-6 alkyl)- wherein the heteroaryl is optionally substituted by one or more C 1-6 alkyl or —CONR 29 R 30 groups; or Heterocyclyl which is optionally substituted by one of more substituents selected from C 1-6 alkyl-, C 1-6 alkylCO—, C 3-7 cycloalkylCO—, heteroarylCO
  • R 20 is hydrogen, C 1-6 alkyl, halogen or C 1-6 alkoxy;
  • R 7 and R 8 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
  • R 9 and R 10 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
  • R 17 and R 18 together with the nitrogen atom to which they are attached may form a heterocyclyl ring such as morpholine;
  • R 21 and R 22 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
  • R 26 and R 27 together with the nitrogen atom to which they are attached may form a hetero
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-6 alkyl means a straight or branched alkyl chain containing at least 1, and at most 6, carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl.
  • a C 1-4 alkyl group is preferred, for example methyl, ethyl or isopropyl.
  • the said alkyl groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethyl.
  • alkoxy refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.
  • a C 1-4 alkoxy group is preferred, for example methoxy or ethoxy.
  • the said alkoxy groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethoxy.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms.
  • C 3-7 cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms.
  • Examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a C 3-6 cycloalkyl group is preferred, for example cyclopentyl or cyclohexyl.
  • aryl refers to, unless otherwise defined, a mono- or bicyclic carbocyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl, optionally fused to a C 4-7 cycloalkyl or heterocyclyl ring.
  • heteroaryl ring and “heteroaryl” refer to, unless otherwise defined, a monocyclic five- to seven-membered heterocyclic aromatic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur. In a particular aspect such a ring contains 1-3 heteroatoms. Preferably, the heteroaryl ring has five or six ring atoms.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • heteroaryl ring and “heteroaryl” also refer to fused bicyclic heterocyclic aromatic ring systems containing at least one heteroatom selected from oxygen, nitrogen and sulfur, preferably from 1-4 heteroatoms, more preferably from 1 to 3 heteroatoms.
  • the fused rings each independently have five or six ring atoms.
  • fused aromatic rings include, but are not limited to, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl and benzothiadiazolyl.
  • the heteroaryl may attach to the rest of the molecule through any atom with a free valence.
  • heterocyclyl refers to a monocyclic three- to seven-membered saturated or non-aromatic, unsaturated ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur. In a particular aspect such a ring contains 1 or 2 heteroatoms. Preferably, the heterocyclyl ring has five or six ring atoms.
  • heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, and 1,4-dioxanyl.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • Preferred halogens are fluorine, chlorine and bromine.
  • Particularly preferred halogens are fluorine and chlorine.
  • the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. Where one or more substituents are referred to, this will refer for instance to 1 to 4 substituents, and preferably to 1 or 2 substituents.
  • R 1 is selected from:
  • Aryl optionally substituted by one or more substituents selected from: C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 alkoxy(C 1-4 alkyl)-, —CN, —(CH 2 ) m OH, —CF 3 , C 1-6 alkoxyC 2-6 alkoxy-, R 4 R 5 NCO, C 1-6 alkylCONR 6 —, R 7 R 8 N—, C 1-6 alkoxycarbonyl, HO(CH 2 ) 2-6 O—, C 1-6 alkylCO—, heteroaryl (optionally substituted by C 1-6 alkyl) particularly oxazolyl, pyrazolyl or 1,2,4-oxadiazolyl; Aryl(C 1-2 alkyl) wherein the aryl is optionally substituted by —OH; Aryl fused to a C 5-6 cycloalkyl ring wherein the cycl
  • Suitable aryl fused to a C 5-6 cycloalkyl ring include:
  • Suitable aryl fused to heterocyclyl rings include:
  • R 1 is selected from:
  • Aryl optionally substituted by one or more substituents selected from: methyl, ethyl, fluorine, chlorine, —CN, —CH 2 OH, —OMe, —OH, —NMe 2 , —O(CH 2 ) 2 OH, —CF 3 , —COMe, 1,2,4-oxadiazolyl substituted by methyl; particular substituted aryl groups include; 3-(methyloxy)phenyl, 3-methylphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluoro-3-(methyloxy)phenyl, 3-acetylphenyl, 4-hydroxy-3-(methyloxy)phenyl, 2-fluoro-3-chlorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl; Aryl fused to a cyclohexane or cyclopentane ring, wherein the cyclopentane ring is optionally substitute
  • Heteroaryl optionally substituted by one or more methyl, ethyl, flourine, chlorine or methoxy groups; in particular a pyridyl, benzimidazolyl, pyrazolyl or indazolyl group optionally substituted by one or more methyl, ethyl, flourine, chlorine, or methoxy groups; preferably 1-methyl-1H-benzimidazolyl-6-yl, 1-methyl-1H-indazol-6-yl, 5-(methyloxy)-3-pyridinyl, 3-pyridinyl, 1-ethyl-1H-pyrazol-5-yl, 5-methyl-3-pyridinyl, 1,3-benzothiazol-6-yl, 5-fluoro-3-pyridinyl, or 5-chloro-3-pyridinyl.
  • R 2 is hydrogen
  • R 3 is selected from:
  • C 1-6 alkyl which is optionally substituted by one or more substituents selected from —NR 16 COR 15 ; OH—, C 1-6 alkoxyCONR 25 —, —CONR 2 , R 27 , —NH 2 , —NR 17 R 11 , —CO 2 R 24 , C 1-6 alkoxy-; or a group having one of the following formulae:
  • C 3-7 cycloalkyl Aryl optionally substituted by one or more substituents selected from C 1-6 alkyl-, halogen-, C 1-6 alkoxy-, —CO 2 R 2 , —OH, —CONR 29 R 30 , C 3-7 cycloalkoxy, C 3-7 cycloalkyl(C 1-6 alkoxy); Aryl(C 1 alkyl) wherein the aryl is optionally substituted by one or more C 1-6 alkoxy groups; Heteroaryl or heteroaryl(C 1-6 alkyl) which is optionally substituted by one or more C 1-6 alkyl or —CONR 29 R 30 groups; or Heterocyclyl which is optionally substituted by one or more substituents selected from C 1-6 alkyl-, C 1-6 alkylCO—, C 3-7 cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C 1-4 alkyl-groups), C 1-6 alkoxyCO—, ary
  • R 3 is selected from:
  • R 9 and R 10 together with the nitrogen to which they are attached represent 4-morpholinyl.
  • R 4 , R 5 , R 6 , R 7 , R 8 , R 11-16 and R 21-25 and R 23-33 are independently selected from hydrogen and methyl.
  • R 26 and R 27 are independently selected from hydrogen, methyl, cyclopropyl, or 4-tetrahydropyranyl; or R 26 and R 27 together with the nitrogen to which they are attached form a heterocyclyl ring, in particular pyrrolidinyl or morpholinyl.
  • R 19 is hydrogen, C 1-6 alkyl or MeSO 2 —. In a further embodiment R 19 is hydrogen or methyl, especially hydrogen.
  • R 20 is hydrogen, halogen or C 1-6 alkyl.
  • R 20 is hydrogen, chlorine, fluorine, methyl or ethyl.
  • R 20 is methyl, ethyl or chlorine.
  • m is 0 or 1.
  • n 1 or 2, especially 2.
  • R 34 represents a group of formula:
  • Preferred compounds include:
  • Salts of the compounds of the present invention are also encompassed within the scope of the invention. Because of their potential use in medicine, the salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • a suitable inorganic or organic acid such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid
  • a pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt.
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • suitable solvent such as an organic solvent
  • oxalates or trifluoroacetates may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism).
  • the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.
  • the present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.
  • compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
  • R 34 , R 19 , and R 20 are as defined above, and X represents a halogen atom, by treatment with an amine of formula R 1 R 2 NH, wherein R 1 and R 2 are as defined above.
  • Suitable conditions for process a) include stirring in a suitable solvent such as acetonitrile, N,N-dimethylformamide or ethanol, at a suitable temperature, such as between room temperature and the reflux temperature of the solvent, for example at 80° C., optionally in the presence of a suitable base such as N,N-diisopropylethylamine, or in the presence of an acid catalyst such as the salt of an amine base, such as pyridine hydrochloride.
  • a suitable solvent such as acetonitrile, N,N-dimethylformamide or ethanol
  • process a) may be carried out under microwave irradiation, at a suitable power such as 100-300 W, for example at 150 W, in a suitable solvent such as N-methyl-2-pyrrolidinone or N,N-dimethylformamide, at a suitable temperature such as 60-200° C., for example at 150° C.
  • a suitable power such as 100-300 W, for example at 150 W
  • a suitable solvent such as N-methyl-2-pyrrolidinone or N,N-dimethylformamide
  • R 34 , R 19 , and R 20 are as defined above, by treatment with a suitable chlorinating agent, such as thionyl chloride, in the presence of a suitable catalyst such as N,N-dimethylformamide, followed by treatment with ammonia under suitable conditions, such as 880 ammonia at room temperature.
  • a suitable chlorinating agent such as thionyl chloride
  • a suitable catalyst such as N,N-dimethylformamide
  • R 34 , R 19 , and R 20 are as defined above, by hydrolysis with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as room temperature.
  • a suitable base such as aqueous sodium hydroxide
  • a suitable solvent such as ethanol
  • R 34 , R 19 , and R 20 are as defined above, by heating in a suitable solvent, such as diphenyl ether, at a suitable temperature such as 200-300° C., for example at 250° C.
  • a suitable solvent such as diphenyl ether
  • Suitable conditions include heating together compounds of formulae (VII) and (VIII) in a suitable solvent such as ethanol or in the absence of solvent, at a suitable temperature, such as 60-100° C., for example at 80° C.
  • compounds of formula (XIV) where n represents 2 may be prepared from compounds of formula (XIV) where n represents 0 by oxidation with a suitable oxidising agent, such as oxone, in a suitable solvent such as a mixture of methanol and water, at a suitable temperature such as room temperature.
  • a suitable oxidising agent such as oxone
  • Compounds of formula (XIV) where n represents 1 may be prepared from compounds of formula (XIV) where n represents 0 by oxidation with a suitable oxidising agent, such as ceric ammonium nitrate, in the presence of a suitable solid support such as hydrated silica gel, in a suitable solvent such as methylene chloride, at a suitable temperature such as 20-40° C., for example at room temperature.
  • Compounds of formula R 1 R 2 NH may contain amine or acid groups which are suitably protected.
  • suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3 ⁇ Ed., J. Wiley and Sons, 1999). Addition or removal of such protecting groups may be accomplished at any suitable stage in the synthesis of compounds of formula (I).
  • Suitable conditions include heating in the presence of a suitable catalyst, such as a palladium catalyst, for example tetrakistriphenylphosphine palladium (0), in a suitable solvent such as toluene, at a suitable temperature such as between 80° C. and 150° C., for example at 110° C.
  • a suitable catalyst such as a palladium catalyst, for example tetrakistriphenylphosphine palladium (0)
  • a suitable solvent such as toluene
  • R 1 , R 2 and R 20 are as defined above, and Z represents hydrogen, C 1-6 alkyl or halogen for example chlorine and Y represents hydrogen, chlorine, bromine or iodine, by treatment with a thiol of formula R 3 SH, or the sodium salt thereof, R 3 SNa, wherein R 3 is as defined above, with the proviso that at least one of Y and Z represent halogen.
  • Suitable conditions for process b) include heating in a suitable solvent such as toluene or N,N-dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • a suitable solvent such as toluene or N,N-dimethylformamide
  • a suitable temperature such as 60-150° C., for example at 110° C.
  • a suitable catalyst such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II)
  • a suitable ligand such as
  • conditions for process b) include heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or dimethoxyethane, at a suitable temperature such as 60-150° C., for example at 85° C., optionally in the presence of a suitable catalyst, such as a copper catalyst, for example copper (I) iodide, and in the presence of a suitable base such as potassium phosphate or potassium carbonate and optionally in the presence of a suitable ligand for example N,N-diethylsalicylamide.
  • a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or dimethoxyethane
  • a suitable temperature such as 60-150° C., for example at 85° C.
  • a suitable catalyst such as a copper catalyst, for example copper (I) iodide
  • a suitable base such as potassium phosphate or potassium
  • suitable conditions include stirring in a suitable solvent such as acetonitrile, at a suitable temperature, such as between room temperature and the reflux temperature of the solvent, for example at 80° C., optionally in the presence of a base such a N,N-diisopropylethylamine, or in the presence of an acid catalyst such as pyridine hydrochloride.
  • a suitable solvent such as acetonitrile
  • a suitable temperature such as between room temperature and the reflux temperature of the solvent, for example at 80° C.
  • a suitable temperature such as between room temperature and the reflux temperature of the solvent, for example at 80° C.
  • a suitable temperature such as between room temperature and the reflux temperature of the solvent, for example at 80° C.
  • a suitable temperature such as between room temperature and the reflux temperature of the solvent, for example at 80° C.
  • a suitable temperature such as between room temperature and the reflux temperature of the solvent, for example at 80° C.
  • an acid catalyst such as pyridine hydrochloride.
  • Suitable conditions for the reactions of Scheme 1 are: (A) heating together compounds of formulae (X) and (VIII) in the absence of solvent, at a suitable temperature, such as 60-100° C., for example at 80° C.; (B) heating compounds of formula (XI) in a suitable solvent, such as diphenyl ether, at a suitable temperature such as 200-300° C., for example at 250° C.; (C) hydrolysis of compounds of formula (XII) with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as room temperature; (D) treatment of compounds of formula (XIII) with a suitable halogenating agent, such as a chlorinating agent, for example thionyl chloride, in the presence of a suitable catalyst such as N,N-dimethylformamide, followed by treatment with ammonia under suitable conditions, such as 880 ammonia at room temperature.
  • a suitable halogenating agent such as a
  • Compounds of formula (X) are either known compounds (for example available from commercial suppliers such as Aldrich) or may be prepared by conventional means.
  • Suitable conditions for preparation of compounds of formula (V) from compounds of formula (XII) and a thiol of formula R 3 SH include heating in a suitable solvent such as toluene, at a suitable temperature such as 60-120° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • a suitable solvent such as toluene
  • a suitable temperature such as 60-120° C., for example at 110° C.
  • a suitable catalyst such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II)
  • R 1 R 2 NH and R 3 SH are either known compounds (for example available from commercial suppliers such as Aldrich) or may be prepared by conventional means.
  • Certain compounds of formula R 3 SH may be prepared from compounds of formula R 3 SSR 3 .
  • Suitable conditions include treatment with a suitable reducing agent such as a phosphine, for example triphenylphosphine, in the presence of an acid such as concentrated hydrochloric acid, in a suitable solvent such as a mixture of water and 1,4-dioxane, at a suitable temperature such as between 20° C. and 100° C., for example at 40° C.
  • a suitable reducing agent such as a phosphine, for example triphenylphosphine
  • an acid such as concentrated hydrochloric acid
  • a suitable solvent such as a mixture of water and 1,4-dioxane
  • Suitable conditions include treatment with a suitable reducing agent such as a phosphine, for example triphenylphosphine, in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as between 0° C. and 50° C., for example at 20° C.
  • a suitable reducing agent such as a phosphine, for example triphenylphosphine
  • a suitable solvent such as 1,4-dioxane
  • Compounds of formula R 1 R 2 NH may be used in the free base form, or in the form of a suitable salt, such as a hydrochloride salt. Where the free base form is commercially available, suitable salt forms may be prepared by conventional means. Similarly, where a salt form is commercially available, the free base form may be prepared by conventional means.
  • Compounds of formula R 3 SH may contain amine or acid groups which are suitably protected.
  • suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3 rd Ed., J. Wiley and Sons, 1999). Addition or removal of such protecting groups may be accomplished at any suitable stage in the synthesis of compounds of formula (I).
  • Compounds of formula (I) may also be prepared by a process of interconversion between compounds of formula (I).
  • a suitable oxidising agent such as oxone or ceric ammonium nitrate
  • a suitable solid support such as hydrated silica gel
  • a suitable solvent such as methylene chloride
  • R 34 represents R 3 S( ⁇ O) n —
  • R 3 represents an aryl group substituted by —CONR 29 R 30
  • R 19 represents hydrogen or C 1-6 alkyl
  • R 1 , R 2 , R 20 , R 29 , R 30 and n are as defined above, may alternatively be prepared from corresponding compounds of formula (I) in which R 3 represents an aryl group substituted by —COOH, namely compounds of formula (XVII);
  • R 19 represents hydrogen or C 1-6 alkyl
  • R 1 , R 2 , R 20 and n are as defined above
  • a primary or secondary amine in a suitable solvent, such as N,N-dimethylformamide
  • a suitable amide coupling reagent such as O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate
  • a suitable base such as N,N-diisopropylethylamine
  • R 19 represents hydrogen or C 1-6 alkyl, and R 1 , R 2 , R 20 and n are as defined above, by hydrolysis with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as 75° C.
  • a suitable base such as aqueous sodium hydroxide
  • a suitable solvent such as ethanol
  • a suitable thiol such as methyl 3-mercaptobenzoate or methyl 4-mercaptobenzoate (both commercially available from Toronto).
  • Suitable conditions for this include heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at a suitable temperature such as 60-150° C., for example at 85° C., in the presence of a suitable catalyst, such as a copper catalyst, for example copper (I) iodide, and in the presence of a suitable base such as potassium phosphate or potassium carbonate, optionally in the presence of a suitable ligand for example N,N-diethylsalicylamide.
  • a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
  • a suitable temperature such as 60-150° C., for example at 85° C.
  • a suitable catalyst such as a copper catalyst, for example copper (I) iodide
  • a suitable base such as potassium phosphate or potassium carbonate
  • steps (II) and (III) may be reversed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (III) followed by step (I).
  • compounds of formula (I), wherein R 34 represents R 3 S( ⁇ O) n — and R 3 represents a C 1-6 alkyl group substituted by —CONR 26 R 27 and wherein R 19 represents hydrogen or C 1-6 alkyl, and R 1 , R 2 , R 20 , R 26 , R 27 and n are as defined above, may alternatively be prepared from compounds of formula (III) where Z represents hydrogen or C 1-6 alkyl and a suitable thiol such as ethyl 3-mercaptopropionate (commercially available from Aldrich) as shown in the scheme below:
  • Steps (I) to (IV) of Scheme 2 use conditions as described in process d above.
  • step (I) may be prepared from compounds of formula (III) by step (IV) followed by step (II) followed by step (III) followed by step (I).
  • step (IV) followed by step (II) followed by step (I) followed by step (III).
  • R 3 is R 26 R 27 NCO(CH 2 ) 2 —.
  • R 1 , R 2 , R 20 and n are as defined above and R 19 represents hydrogen or C 1-6 alkyl, by treatment with an electrophile, such as an acylating agent, such as an acid chloride, in a suitable solvent, such as 1,4-dioxane, in the presence of a suitable base, such as an amine base, for example triethylamine, at a suitable temperature, such as room temperature.
  • an electrophile such as an acylating agent, such as an acid chloride
  • a suitable solvent such as 1,4-dioxane
  • a suitable base such as an amine base, for example triethylamine
  • Alternative electrophiles that may be used for this process include sulphonyl chlorides, alkyl chloroformates, alkyl halides and acid anhydrides.
  • R 1 , R 2 , R 20 and n are as defined above and R 19 represents hydrogen or C 1-6 alkyl, by treatment with a suitable reagent, such as a strong acid, for example trifluoroacetic acid, at a suitable temperature, such as room temperature (Step (II)).
  • a suitable reagent such as a strong acid, for example trifluoroacetic acid
  • a suitable oxidising agent such as oxone
  • a suitable solvent such as N,N-dimethylformamide
  • Suitable conditions for this process include heating in a suitable solvent such as dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • a suitable solvent such as dimethylformamide
  • a suitable temperature such as 60-150° C., for example at 110° C.
  • a suitable catalyst such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II)
  • a suitable ligand such as a phosphine ligand, for example (oxydi-2,1-phenylene)
  • step (IV) followed by step (II) followed by step (I) followed by step (111).
  • R 34 represents R 3 S( ⁇ O) n — and R 3 represents a C 1-6 alkyl which is substituted by —NR 17 R 18 , —NR 1 COR 15 , C 1-6 alkoxyCONR 25 — or C 1-6 alkylSO 2 NR 33 — and wherein R 1 , R 2 , R 20 , R 15 , R 17 , R 1 and n are as defined above, R 19 represents hydrogen or C 1-6 alkyl, and R 16 , R 25 and R 33 represent hydrogen may alternatively be prepared from compounds of formula (III), wherein R 1 , R 2 , Y and R 20 are as defined above and Z represents hydrogen or C 1-6 alkyl, and a thiol such as tert-butyl-N-(2-mercaptoethyl)carbamate (Aldrich), as is illustrated in the following Scheme (Scheme 3):
  • Steps (I) to (IV) of Scheme 3 use conditions as described in process e above.
  • R 34 represents C 1-6 alkylSO2-, wherein the C 1-6 alkyl group is substituted by R 15 CONR 16 —, C 1-6 alkoxyCONR 25 —, C 1-6 alkylSO 2 NR 33 — or R 17 R 11 N—.
  • R 34 represents R 3 S( ⁇ O) n — and R 3 represents an aryl group substituted by a C 1-6 alkoxy-, C 3-7 cycloalkoxy- or C 3-7 cycloalkyl(C 1-6 alkoxy)-group, R 1 , R 2 , R 20 and n are as defined above, and R 19 represents hydrogen or C 1-6 alkyl, may alternatively be prepared from compounds of formula (XXI);
  • R 1 , R 2 , R 20 and n are as defined above and R 19 represents hydrogen or C 1-6 alkyl, by coupling with a suitable alkylating agent, in a suitable solvent, such as acetonitrile, in the presence of a suitable base, such as potassium carbonate, at a suitable temperature, such as 0 to 100° C., for example the reflux temperature of the solvent.
  • a suitable solvent such as acetonitrile
  • a suitable base such as potassium carbonate
  • a suitable oxidising agent such as oxone
  • a suitable solvent such as N,N-dimethylformamide
  • Suitable conditions for this process include heating in a suitable solvent such as dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide, followed by deprotection with a suitable fluoride source such as tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran at a suitable temperature such as room temperature.
  • a suitable catalyst such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II)
  • a suitable ligand such as a phos
  • Compounds of formula (I) may also be prepared by a process of deprotection of protected derivatives of compounds of formula (I).
  • suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3 rd Ed., J. Wiley and Sons, 1999).
  • compounds of formula (I) containing a primary or secondary amine group may be prepared from compounds of formula (I) where that amine group is protected, such as a carbamate group, for example as a tert-butyl carbamate, by deprotecting under appropriate conditions, such as treating with a strong acid, for example trifluoroacetic acid.
  • a strong acid for example trifluoroacetic acid.
  • R 34 represents R 3 S( ⁇ O) n — and R 3 represents C 1-6 alkoxyethyl-, R 1 , R 2 , R 20 and n are as defined above, and R 19 represents hydrogen or C 1-6 alkyl may be prepared from compounds of formula (XXVIII);
  • R 1 , R 2 , R 20 and n are as defined above and R 19 represents hydrogen or C 1-6 alkyl, by alkylation with a suitable alkylating agent, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable base, such as sodium hydride, at a suitable temperature, such as 0 to 30° C., for example at room temperature.
  • a suitable solvent such as N,N-dimethylformamide
  • a suitable base such as sodium hydride
  • R 34 represents R 3 S( ⁇ O) n — and R 3 represents C 1-6 alkoxyethyl-, R 1 , R 2 , R 20 and n are as defined above, and R 19 represents hydrogen or C 1-6 alkyl
  • R 19 represents hydrogen or C 1-6 alkyl
  • Suitable conditions for this process include heating in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • a suitable solvent such as N,N-dimethylformamide
  • a suitable temperature such as 60-150° C., for example at 110° C.
  • a suitable catalyst such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II)
  • a suitable ligand such as a phosphine ligand, for example (oxy
  • a suitable oxidising agent such as oxone
  • a suitable solvent such as N,N-dimethylformamide of a mixture of N,N-dimethylformamide and anisole
  • R 1 , R 2 , R 20 , and n are as defined above, and R 19 represents hydrogen or C 1-6 alkyl
  • R 19 represents hydrogen or C 1-6 alkyl
  • a suitable alkylating agent such as ethyl 4-bromobutyrate in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 120° C.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human.
  • the compound or salt can be for use in the treatment and/or prophylaxis of any of the conditions described herein and/or for use as a phosphodiesterase inhibitor, for example for use as a phosphodiesterase 4 (PDE4) inhibitor.
  • “Therapy” may include treatment and/or prophylaxis.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
  • Phosphodiesterase 4 inhibitors are believed to be useful in the treatment and/or prophylaxis of a variety of diseases, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria, allergic rhinitis (seasonal or perennial), vasomotor rhinitis, nasal polyps, allergic conjunctivitis, vernal conjunctivitis, occupational conjunctivitis, infective conjunctivitis, eosinophilic syndromes, eosinophilic granuloma, psoriasis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis
  • the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, asthma, rheumatoid arthritis, psoriasis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD including chronic bronchitis and emphysema or asthma in a mammal (e.g. human). PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M. A. Giembycz, Drugs , February 2000, 59(2), 193-212; Z.
  • COPD chronic obstructive pulmonary disease
  • COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
  • the compounds of the present invention are usually administered as a pharmaceutical composition.
  • the present invention therefore provides in a further aspect a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.
  • the compounds of formula (I) and/or the pharmaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled, nasal, transdermal or rectal administration, or as topical treatments (e.g. ointments or gels).
  • the pharmaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous or intramuscular), inhaled or nasal administration. More preferably, the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human. Inhaled administration involves topical administration to the lung, e.g. by aerosol or dry powder composition.
  • a pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a solution, a syrup, a suspension or emulsion, a tablet, a capsule or a lozenge.
  • a liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or an oil, or a non-aqueous solvent, such as a surfactant, such as polyethylene glycol.
  • a suitable pharmaceutically acceptable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or an oil, or a non-aqueous solvent, such as a surfactant, such as polyethylene glycol.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations.
  • examples of such carriers include lactose and cellulose.
  • the tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example binding agents, lubricants such as magnesium stearate, and/or tablet disintegrants.
  • a pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures.
  • pellets containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule.
  • a dispersion, suspension or solution can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous solution, aqueous gum or an oil and the dispersion, suspension or solution then filled into a hard or soft gelatin capsule.
  • the compounds of formula (I) and/or the pharmaceutical composition may be administered by a controlled or sustained release formulation as described in WO 00/50011.
  • a parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil.
  • the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders.
  • the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation.
  • the preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • Aerosol formulations can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • a metering valve metered dose inhaler
  • the dosage form comprises an aerosol dispenser
  • it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC).
  • CFC chlorofluorocarbon
  • HFC hydrofluorocarbon
  • Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane.
  • Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device.
  • the container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUSTM device, marketed by GlaxoSmithKline.
  • the DISKUSTM inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
  • each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • Each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the pharmaceutically acceptable compounds or salts of the invention can be administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day, or a nasal or inhaled dose of 0.001 to 50 mg per day or 0.01 to 5 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with one or more other therapeutically active agents, for example, a ⁇ 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
  • a ⁇ 2 adrenoreceptor agonist for example, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more other therapeutically active agents, for example, a ⁇ 2 -adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
  • a ⁇ 2 -adrenoreceptor agonist for example, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
  • ⁇ 2 -adrenoreceptor agonists examples include salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol.
  • Long-acting ⁇ 2 -adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period, such as salmeterol or formoterol.
  • anti-histamines examples include methapyrilene or loratadine.
  • anti-inflammatory steroids examples include fluticasone propionate and budesonide.
  • anticholinergic compounds which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof are described in WO 03/011274 A2 and WO 02/069945 A2/US 2002/0193393 A1 and US 2002/052312 A1.
  • anticholinergic agents include muscarinic M3 antagonists, such as ipratropium bromide, oxitropium bromide or tiotropium bromide.
  • Suitable combinations include, for example, combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with other anti-inflammatory agents such as an anti-inflammatory corticosteroid; or a non-steroidal anti-inflammatory drug (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, an elastase inhibitor, a beta-2 integrin antagonist, an adenosine a2a agonist, a chemokine antagonist such as a CCR3 antagonist, or a 5-lipoxygenase inhibitor; or an antiinfective agent (e.g. an antibiotic or an antiviral).
  • NSAID non-steroidal anti-inflammatory drug
  • An iNOS inhibitor is preferably for oral administration.
  • Suitable iNOS inhibitors inducible nitric oxide synthase inhibitors
  • WO 93/13055 WO 98/30537
  • WO 02/50021 WO 95/34534
  • WO 99/62875 WO 99/62875
  • Suitable CCR3 inhibitors include those disclosed in WO 02/26722.
  • compositions comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.
  • the individual compounds of such combinations may be administered either sequentially or simultaneously in separate or in combined pharmaceutical compositions.
  • Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D) more strongly than they inhibit other PDE's such as PDE3 and/or PDE5.
  • Human recombinant PDE4B in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also in M. M. McLaughlin et al., “A low Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA”, J. Biol. Chem., 1993, 268, 6470-6476.
  • human recombinant PDE4B is described as being expressed in the PDE-deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 ⁇ M CuSO 4 , and 100,000 ⁇ g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.
  • HSPDE4D3A Human recombinant PDE4D is disclosed in P. A. Baecker et al., “Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE IV D )”, Gene, 1994, 138, 253-256.
  • Human recombinant PDE5 is disclosed in K. Loughney et al., “Isolation and characterisation of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase”, Gene, 1998, 216, 139-147.
  • PDE3 was purified from bovine aorta. Its presence in the tissue was reported by H. Coste and P. Grondin in “Characterisation of a novel potent and specific inhibitor of type V phosphodiesterase”, Biochem. Pharmacol., 1995, 50, 1577-1585.
  • PDE6 was purified from bovine retina. Its presence in this tissue was reported by: P. Catty and P. Deterre in “Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis”, Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. in “Purification of bovine retinal cGMP phosphodiesterase”, Methods in Enzymology, 1994, 238, 3-12; and/or D. Srivastava et al. in “Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase”, Biochem. J., 1995, 308, 653-658.
  • the activity of the compounds can be measured in the following Fluorescence Polarisation (FP) assay:
  • test compounds small volume, e.g. 0.5 ⁇ l, of solution in DMSO
  • PDE enzyme in 10 mM Tris-HCl buffer pH 7.2, 10 mM MgCl 2 , 0.1% (w/v) bovine serum albumin. 0.05% NaN 3 for 10-30 minutes. The enzyme level was set so that reaction was linear throughout the incubation.
  • Fluorescein adenosine 3′,5′-cyclic phosphate (Molecular Devices code: R7091) was added to give ⁇ 40 nM final concentration. Plates were mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding reagent (Molecular Devices code: R7207) was added (60 ⁇ l of a 1 in 400 dilution in binding buffer of the kit stock suspension) to terminate the assay. Plates were allowed to stand at ambient temperature for 1 hour. The FP ratio of parallel to perpendicular light was measured using an AnalystTM plate reader (from Molecular Devices Ltd).
  • the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly.
  • the pIC 50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R. Mobbs et al, “Comparison of the IMAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity”, poster presented at 2003 Molecular Devices UK & Europe User Meeting, 2 Oct. 2003, Down Hall, Harlow, Essex, United Kingdom).
  • Examples of compounds of the invention described above inhibit the catalytic activity at the PDE4B (human recombinant) enzyme with pIC 50 values in the range 6.0-11.7.
  • Biological Data obtained for some of the Examples is as follows:
  • Example No. PDE4B mean pIC 50 PDE5 mean pIC 50 27 8.4 4.8 70 7.3 5.0 92 7.7 ⁇ 4.5 125 6.6 5.5 265 11.3 5.2 307 10.5 ⁇ 4.6 309 10.1 ⁇ 4.9 312 9.4 ⁇ 4.5 369 9.5 5.1 380 11.4 ⁇ 7.0 399 >11.6 5.6 400 11.0 ⁇ 5.0 408 11.4 4.9 446 11.3 ⁇ 4.5 457 11.0 ⁇ 5.5 502 8.9 ⁇ 5 546 10.7 4.7
  • PDE4 inhibitors cause emesis and/or nausea to greater or lesser extents (e.g. see Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438, see especially pages 433-434 and references cited therein). Therefore, it would be preferable but not essential that a PDE4 inhibitory compound of the invention causes only limited or manageable emetic side-effects.
  • Emetic side-effects can for example be measured by the emetogenic potential of the compound when administered to ferrets; for example one can measure the time to onset, extent, frequency and/or duration of vomiting and/or writhing in ferrets after oral or parenteral administration of the compound. See for example A. Robichaud et al., “Emesis induced by inhibitors of PDE IV in the ferret” Neuropharmacology, 1999, 38, 289-297, erratum Neuropharmacology, 2001, 40, 465-465.
  • Solvent A 95% acetonitrile+0.05% formic acid
  • Solvent B 0.1% formic acid+10 mM ammonium acetate
  • Gradient Mixtures of Solvent A and Solvent B are used according to the following gradient profiles (expressed as % Solvent A in the mixture): 0% A/0.7 min, 0-100% A/3.5 min, 100% A/1.1 min, 100-0% A/0.2 min
  • the preparative column used was a Supelcosil ABZplus (10 cm ⁇ 2.12 cm internal diameter; particle size 5 ⁇ m)
  • UV detection wavelength 200-320 nm
  • Flow rate 20 ml/min
  • Solvent A 0.1% formic acid
  • Solvent B 95% acetonitrile+0.05% formic acid
  • Gradient systems mixtures of Solvent A and Solvent B are used according to a choice of 5 generic gradient profiles (expressed as % Solvent B in the mixture), ranging from a start of 0 to 50% Solvent B, with all finishing at 100% Solvent B to ensure total elution.
  • the preparative column used was a Supelcosil ABZplus (10 cm ⁇ 2.12 cm internal diameter; particle size 5 ⁇ m)
  • UV detection wavelength 200-320 nm
  • Flow rate 20 ml/min
  • Solvent A water+0.1% trifluoroacetic acid
  • Solvent B acetonitrile+0.1% trifluoroacetic acid
  • Gradient systems mixtures of Solvent A and Solvent B are used according to a choice of 5 generic gradient profiles (expressed as % Solvent B in the mixture), ranging from a start of 0 to 50% Solvent B, with all finishing at 100% Solvent B to ensure total elution.
  • Reference to column chromatography, SPE and preparative HPLC purification includes evaporation of the product containing fractions to dryness by an appropriate method.
  • ‘880 Ammonia’ or ‘0.880 ammonia’ refers to concentrated aqueous ammonia (specific gravity 0.880).
  • the aqueous phase was separated and washed with ethyl acetate (2 ⁇ 300 ml).
  • the aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate (3 ⁇ 400 ml).
  • the organic extracts of the acidic aqueous phase were combined, dried over sodium sulphate, and the solvent evaporated to leave a solid.
  • the solid was dissolved in hot ethyl acetate (100 ml) and 40-60 petrol (160 ml) was added to the hot solution. The solution was left to cool and the resulting solid filtered off, washed and dried to give the title compound (28.4 g)
  • 1,1-Dimethylethyl 4-nitro-1H-indazole-1-carboxylate (1.2 g) was dissolved in ethanol (150 ml) and stirred with 10% palladium on carbon (0.24 g) under an atmosphere of hydrogen (1 atmosphere pressure) for 18 h. The solution was filtered through a pad of celite and the filtrate concentrated in vacuo to give the title compound as a yellow-orange solid (1.03 g).
  • Example 377 To a mixture containing Example 377 (0.64 g) in anisole (9 ml) was added a solution of 95% trifluoroacetic acid in water (16 ml). The mixture was stirred for 1.5 h at room temperature and was then concentrated in vacuo. The residue was co-evaporated with toluene (2 ⁇ 20 ml), triturated with ethyl acetate and filtered to give a yellow solid. This residue was again triturated with ethyl acetate and filtered to give the title compound as a yellow solid (0.570 g).
  • Oxone (0.5 g) was added portionwise to a stirred solution of Intermediate 64 (0.12 g) in N,N-dimethylformamide (5 ml). The solution was stirred at room temperature under nitrogen for 21 h. More oxone (0.5 g) was added and the mixture was stirred for a further 3 h, quenched with a solution of sodium sulphite (1.5 g) in water (15 ml), diluted with water (50 ml) and extracted with ethyl acetate (3 ⁇ 50 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a yellow solid (0.15 g).
  • the aqueous layer was acidified with 2M hydrochloric acid to pH 4 and extracted with chloroform (5 ⁇ 80 ml), and the combined organic layers were washed with brine (20 ml), dried over magnesium sulphate and concentrated in vacuo to give the title compound as an orange oil (1.8 g).
  • Example 133 (0.010 g) was dissolved in N,N-dimethylformamide (2 ml) and anisole (0.013 ml) was added. Oxone (0.075 g) was added and the mixture stirred for 16 h at room temperature. After quenching with 1M aqueous sodium sulphite, the mixture was extracted with dichloromethane; the organic layer was dried over magnesium sulphate and evaporated in vacuo to give a yellow solid. Purification by mass directed HPLC (Method A) gave the title compound (0.005 g).
  • Example 187 0.130 g
  • dichloromethane 5 ml
  • trifluoroacetic acid 1 ml
  • the mixture was stirred at 20° C. for 1 h and then the solvent was removed in vacuo to give the title compound as a yellow gum (0.100 g).
  • Oxone (1.6 g) was added to a solution of the sulphide (0.370 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature for 1 h and was quenched with a solution of sodium sulphite (4 g) in water (150 ml). The mixture was extracted with ethyl acetate (2 ⁇ 100 ml) and the combined organic suspension washed with water (2 ⁇ 100 ml) and extracted in vacuo to a pale yellow solid. This was purified by recrystallisation from boiling methanol to give the title compound as a pale yellow powder (0.265 g).
  • Example 379 The following were synthesised in the same manner as Example 379, however potassium carbonate was used as a base instead of potassium phosphate and no N′N-diethylsalicylamide was added.
  • Example 379 (0.1 g) was dissolved in methanol (5 ml) and 2M aqueous sodium hydroxide (1 ml). The mixture was heated to 75° C. for 4 h before cooling and standing at ambient temperature for 18 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the aqueous layer was washed with diethyl ether (50 ml), acidifed to pH4 (2M hydrochloric acid) and extracted with ethyl acetate (2 ⁇ 150 ml). The combined ethyl acetate layers were washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a beige solid (0.082 g).
  • Example 393 was prepared, via Example 379, from Intermediate 45.
  • Example 393 To a solution of Example 393 (0.082 g) in N,N-dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.12 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.071 g). The mixture was stirred for 20 min before adding a solution of dimethylamine in tetrahydrofuran (2M, 0.8 ml, Aldrich). After a further 1 h more dimethylamine in tetrahydrofuran (2M, 0.8 ml) was added.
  • 2M tetrahydrofuran
  • Example Amine LCMS Number Starting Reagent/ LCMS R t (a) R 1 NH— R 20 — R 29 R 30 N— material Source MH + (min) 400 HCl H— Me 2 N— Example 395 dimethylamine 2 M solution in tetrahydrofuran/ Aldrich 505 2.52 401 HCl H— H 2 N— Example 395 Ammonia solution 880/Merck 477 2.42 402 HCl H— MeNH— Example 395 methylamine 2 M solution in tetrahydrofuran/ Aldrich 491 2.47 403 HCl H— Example 395 Pyrrolidine/ Lancaster 531 2.64 404 HCl H— Example 395 propylamine/ Aldrich 519 2.74 405 (b) H— Example 395 Isobutylamine/ Aldrich 533 2.76 406 HCl H— Example 395 Morpholine/ Lancaster 547 2.51 407 HCl H— Example 395 Ethanolamine/ Aldrich 521 2.38 408
  • Example 472 To a mixture containing Example 472 (1.3 g) in anisole (9 ml) was added a solution of 95% trifluoroacetic acid in water (45 ml). The mixture was stirred for 2 h at room temperature and was then concentrated in vacuo. The residue was co-evaporated with toluene (2 ⁇ 20 ml) and triturated with diethyl ether to give a yellow solid. The solid was partitioned between aqueous potassium carbonate (300 ml) and chloroform (300 ml) and the aqueous phase extracted with chloroform (3 ⁇ 200 ml). The combined organic extracts were washed with water (100 ml), dried and concentrated in vacuo to give the title compound as a yellow solid (1.1 g).
  • Example 421 (0.050 g) and triethylamine (0.025 ml) in dioxane (2 ml) was added benzoyl chloride (0.020 ml). The mixture was stirred under nitrogen for 18 h at room temperature and was then diluted with methanol (5 ml). The solution was applied to an aminopropyl cartridge and eluted with methanol. The eluent was evaporated and the residual gum purified by chromatography on SPE eluting with a gradient of methanol in chloroform (0% to 10%) to give the title compound as a yellow solid (0.043 g).
  • Example 423 To a mixture containing Example 423 (0.050 g) and triethylamine (0.025 ml) in N,N-dimethylformamide (2 ml) was added methyl iodide (0.0075 ml). The mixture was stirred under nitrogen for 18 h at room temperature and was concentrated by blowing down under nitrogen. Purification by chromatography on silica gel, eluting with dichloromethane/methanol (95:5), gave a white solid which was dissolved in dioxane (10 ml) and treated with 4M hydrogen chloride in 1,4 dioxane (0.100 ml). After evaporation by blowing down under nitrogen the title compound was obtained as a yellow solid (0.028 g).
  • Example 423 To a mixture containing Example 423 (0.050 g) in pyridine (2 ml) was added acetic anhydride (0.011 ml). The mixture was stirred under nitrogen for 18 h at room temperature, partitioned between chloroform (100 ml) and 10% sodium carbonate solution (100 ml), the layers separated by hydrophobic frit and the organic layer treated with 4M hydrogen chloride in 1,4-dioxane (0.100 ml). After evaporation by blowing down under nitrogen the title compound was obtained as a pale yellow solid (0.021 g).
  • Example 364 (0.052 g) in anisole (1 ml) was treated with a solution of 95% trifluoroacetic acid in water (5 ml). The mixture was stirred for 3 h at room temperature and was then concentrated in vacuo. The residue was trituated with ethyl acetate, and the resulting solid was collected by filtration, washed with ethyl acetate and ether and dried to give a yellow solid (0.031 g).
  • the solid was treated with dioxane (2 ml) and the suspension treated with N,N-diisopropylethylamine (0.04 ml) followed by isobutyryl chloride (0.015 ml, Aldrich) and the resulting solution stirred at room temperature under nitrogen for 2 h.
  • the solution was diluted with methanol (5 ml) and applied to an aminopropyl SPE cartridge. Elution with methanol gave a gum after evaporation of solvent.
  • the gum was purified by chromatography on silica gel eluting with a gradient of 0% to 6% methanol in chloroform to give the title compound as a yellow solid (0.017 g).
  • the residual gum was purified using an aminopropyl SPE cartridge eluting with methanol followed by chromatography on silica gel (SPE cartridge), eluting with a gradient of 0% to 8% methanol in chloroform, to give the title compound as a yellow solid (0.031 g).
  • Example 423 To a mixture containing Example 423 (0.050 g) in 1,4-dioxane (2 ml) was added methanesulphonyl chloride (0.009 ml). The mixture was stirred under nitrogen for 18 h at room temperature, partitioned between ethyl acetate (100 ml) and 10% sodium bicarbonate solution (100 ml), separated and dried. The solid obtained was dissolved in 1,4-dioxane and treated with 4M hydrogen chloride in 1,4-dioxane (0.100 ml). After evaporation the title compound was obtained as a pale yellow solid (0.021 g).
  • Tributyl phosphine (0.05 ml) was added to a stirred mixture of Example 360 (0.052 g), cyclopropylmethanol (0.028 g) and di-tert-butylazodicarboxylate (0.06 g) in tetrahydrofuran (1.5 ml) at 20° under nitrogen, and stirring was continued at 200 for 3 h.
  • the solvent was concentrated and the residue purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.09 g).
  • Example 360 A stirred mixture of Example 360 (0.05 g), iodoethane (0.35 ml) and potassium carbonate (0.02 g) in acetonitrile (1.5 ml) was heated under reflux temperature for 1 h. The solvent was evaporated to dryness. The resulting solid was partitioned between dichloromethane (2 ⁇ 15 ml) and water (30 ml). The extracts were dried (Na 2 SO 4 ) and concentrated. The residual solid was purified by mass directed HPLC (Method C) to give the title compound as a pale yellow solid (0.033 g).
  • Example Alkylating Number Starting Agent/ LCMS LCMS (a) R X O— Material Source MH + R t (min) 464 HCl
  • Example 360 Iodocyclopentane/ Aldrich 518 3.24 (a) Salt form: HCl hydrochloride.
  • Example 254 A stirred mixture of Example 254 (0.051 g), 3-furanboronic acid (0.017 g, Aldrich), tetrakis(triphenylphosphine) palladium(0) (0.05 g) and 2M sodium carbonate solution (1 ml) in dimethoxyethane (2 ml) was heated at 100° C. for 1 h. The mixture was cooled and poured into 2M sodium carbonate solution and extracted into dichloromethane (2 ⁇ 15 ml). The extracts were dried (Na 2 SO 4 ) and concentrated. The residue was purified by mass directed HPLC (Method C) to give the title compound as a yellow solid (0.026 g).

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Abstract

There are provided according to the invention novel compounds of formula (I)
Figure US20090312325A1-20091217-C00001
or pharmaceutically acceptable salts thereof, wherein R1, R2, R19, R20, and R34 are as described in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.

Description

  • The present invention relates to quinoline compounds, processes for their preparation, intermediates usable in these processes, and pharmaceutical compositions containing the compounds. The invention also relates to the use of the quinoline compounds in therapy, for example as inhibitors of phosphodiesterases and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis.
  • WO 02/20489 A2 (Bristol-Myers-Squibb Company) discloses 4-aminoquinoline derivatives wherein the 4-amino group NR4R5 may represent an acyclic amino group wherein R4 and R5 may each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl etc.; NR4R5 may alternatively represent an aliphatic heterocyclic group. The compounds are disclosed as inhibitors of cGMP phosphodiesterase, especially type 5 (PDE5).
  • EP 0 480 052 (Otsuka Pharmaceutical Co. Ltd.) discloses 4-aminoquinoline-3-carboxamides wherein the 4-amino group NHR4 may represent an amino group wherein R4 represents phenyl, tetrahydronaphthyl or naphthyl, optionally substituted with alkyl, halogen, alkoxy etc.; and the 3-carboxamide group CONR2R3 represents a primary, secondary or tertiary carboxamide group. The compounds are disclosed as inhibitors of gastric acid secretion, and as cytoprotective agents; inhibition of the ATPase activated by H+ and K+ at the gastric wall cells is also disclosed.
  • It is desirable to find new compounds which bind to, and preferably inhibit, phosphodiesterase type IV (PDE4).
  • According to the invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Figure US20090312325A1-20091217-C00002
  • wherein:
    • R1 is
  • C1-6 alkyl;
    C3-7cycloalkyl or C3-7cycloalkyl(C1-4alkyl)- wherein the C3-7cycloalkyl is optionally substituted by one or more substituents selected from ═O and OH;
    C4-7cycloalkyl fused to an aryl ring;
    Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl, C1-6alkylCONR6—, C1-6alkylCO—, halogen, —CF3, —(CH2)mOH, —OCF3, C1-6alkoxy-, C1-6alkoxy(C1-4alkyl)-, C1-6alkoxyC2-6alkoxy-, C1-6alkoxycarbonyl, —CN, R4R5NCO, R7R8N—, R9R10NCONR11—, HO(CH2)2-6O—, R12R13NSO2(CH2)m—, (4-morpholinyl)C2-6alkoxy, —NR14SO2C1-6alkyl, aryloxy, heteroaryl (optionally substituted by C1-6alkyl), CO2H, R21R22N(C1-4alkyl)-, C1-6alkoxyCONR23(CH2)m—, aryl(optionally substituted by C1-6alkyl);
    Aryl fused to a C4-7cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted by one or more ═O;
    Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, —COC1-4alkyl, C1-4alkyl;
    Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more substituents selected from: C1-6alkyl, aryl(C1-4alkyl), C1-6alkoxy, halogen, C1-6alkoxyCO; or
    Heterocyclyl optionally fused to an aryl or heteroaryl ring;
    R2 is hydrogen or C1-6alkyl;
    R34 is hydrogen or a group of formula:
  • Figure US20090312325A1-20091217-C00003
  • wherein R3 is
    C1-6alkyl optionally substituted by one or more substituents selected from —OH, —NR16COR15, —NR17R18, —CO2R24, C1-6alkoxyCONR25—, —CONR2, R27, C1-6alkoxy-, C1-6alkylSO2NR33—, or a group having one of the following formulae;
  • Figure US20090312325A1-20091217-C00004
  • C3-7cycloalkyl;
    Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl-, halogen-, C1-6alkoxy-, —CO2R28, —CH2CO2H, —OH, aryl(optionally substituted by a C1-6 alkoxy group), heteroaryl, —CONR29R30C3-7cycloalkoxy, C3-7cycloalkyl(C1-6alkoxy)-, —CF3;
    Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more C1-6alkyl or —CONR29R30 groups; or
    Heterocyclyl which is optionally substituted by one of more substituents selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl-groups), C1-6alkoxyCO—, arylCO—, R31R32NCO—, C1-6alkylSO2—, arylSO2, -heteroarylSO2 (optionally substituted by one or more C1-4alkyl or C1-4alkylCONH— groups) The heterocyclyl is linked to the S(═O)n moiety through a carbon atom.
    m is 0-6
    n is 0, 1 or 2;
    R19 is hydrogen, C1-6alkyl or a group of formula:
  • Figure US20090312325A1-20091217-C00005
  • R20 is hydrogen, C1-6alkyl, halogen or C1-6alkoxy;
    R4-18, R21-25, R28 and R31-33 all independently represent H, C1-6 alkyl;
    R26 and R27 independently represent H, C1-6 alkyl, C3-7cycloalkyl or heterocyclyl;
    R29 and R30 independently represent H, C1-6alkyl optionally substituted by OH;
    R7 and R8 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
    R9 and R10 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
    R17 and R18 together with the nitrogen atom to which they are attached may form a heterocyclyl ring such as morpholine;
    R21 and R22 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
    R26 and R27 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
    R29 and R30 together with the nitrogen atom to which they are attached may form a heterocyclyl ring such as morpholine;
    R31 and R32 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
    with the proviso that R34 and R19 cannot both represent R3S(═O)n—.
  • As used herein, the term “alkyl” refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-6alkyl means a straight or branched alkyl chain containing at least 1, and at most 6, carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, n-pentyl and n-hexyl. A C1-4alkyl group is preferred, for example methyl, ethyl or isopropyl. The said alkyl groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethyl.
  • As used herein, the term “alkoxy” refers to a straight or branched chain alkoxy group, for example, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy. A C1-4alkoxy group is preferred, for example methoxy or ethoxy. The said alkoxy groups may be optionally substituted with one or more fluorine atoms, for example, trifluoromethoxy.
  • As used herein, the term “cycloalkyl” refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C3-7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms. Examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C3-6cycloalkyl group is preferred, for example cyclopentyl or cyclohexyl.
  • When used herein, the term “aryl” refers to, unless otherwise defined, a mono- or bicyclic carbocyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl, optionally fused to a C4-7cycloalkyl or heterocyclyl ring.
  • As used herein, the terms “heteroaryl ring” and “heteroaryl” refer to, unless otherwise defined, a monocyclic five- to seven-membered heterocyclic aromatic ring containing one or more heteroatoms selected from oxygen, nitrogen and sulfur. In a particular aspect such a ring contains 1-3 heteroatoms. Preferably, the heteroaryl ring has five or six ring atoms. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl. The terms “heteroaryl ring” and “heteroaryl” also refer to fused bicyclic heterocyclic aromatic ring systems containing at least one heteroatom selected from oxygen, nitrogen and sulfur, preferably from 1-4 heteroatoms, more preferably from 1 to 3 heteroatoms. Preferably, the fused rings each independently have five or six ring atoms. Examples of fused aromatic rings include, but are not limited to, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl and benzothiadiazolyl. The heteroaryl may attach to the rest of the molecule through any atom with a free valence.
  • As used herein, the term “heterocyclyl” refers to a monocyclic three- to seven-membered saturated or non-aromatic, unsaturated ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur. In a particular aspect such a ring contains 1 or 2 heteroatoms. Preferably, the heterocyclyl ring has five or six ring atoms. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepinyl, azepinyl, tetrahydrofuranyl, tetrahydropyranyl, and 1,4-dioxanyl.
  • As used herein, the terms “halogen” or “halo” refer to fluorine, chlorine, bromine and iodine. Preferred halogens are fluorine, chlorine and bromine. Particularly preferred halogens are fluorine and chlorine.
  • As used herein, the term “optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • As used herein, the term “substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. Where one or more substituents are referred to, this will refer for instance to 1 to 4 substituents, and preferably to 1 or 2 substituents.
  • In one embodiment, R1 is selected from:
  • C3-7 cycloalkyl, in particular cyclohexyl; Aryl optionally substituted by one or more substituents selected from: C1-6alkyl, halogen, C1-6alkoxy, C1-6alkoxy(C1-4alkyl)-, —CN, —(CH2)mOH, —CF3, C1-6alkoxyC2-6alkoxy-, R4R5NCO, C1-6alkylCONR6—, R7R8N—, C1-6alkoxycarbonyl, HO(CH2)2-6O—, C1-6alkylCO—, heteroaryl (optionally substituted by C1-6alkyl) particularly oxazolyl, pyrazolyl or 1,2,4-oxadiazolyl;
    Aryl(C1-2alkyl) wherein the aryl is optionally substituted by —OH;
    Aryl fused to a C5-6 cycloalkyl ring wherein the cycloalkyl is optionally substituted by (═O);
    Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, C1-4alkyl;
    Heteroaryl optionally substituted by one or more C1-6alkyl, halogen (in particular chlorine or fluorine) or C1-6alkoxy groups in particular wherein heteroaryl represents benzothiazolyl, benzisoxazolyl, benzimidazolyl, indazolyl, pyridyl and pyrazolyl;
    Heteroaryl(C1-2alkyl) wherein the heteroaryl is optionally substituted by one or more C1-6alkyl groups, in particular wherein heteroaryl represents pyridyl, pyrazolyl; or
    Heterocyclyl, in particular tetrahydropyranyl.
  • Examples of suitable aryl fused to a C5-6 cycloalkyl ring include:
  • Figure US20090312325A1-20091217-C00006
  • Examples of suitable aryl fused to heterocyclyl rings include:
  • Figure US20090312325A1-20091217-C00007
  • The following aryl fused to heterocyclyl rings are further embodiments:
  • Figure US20090312325A1-20091217-C00008
  • In a further embodiment, R1 is selected from:
  • Aryl optionally substituted by one or more substituents selected from: methyl, ethyl, fluorine, chlorine, —CN, —CH2OH, —OMe, —OH, —NMe2, —O(CH2)2OH, —CF3, —COMe, 1,2,4-oxadiazolyl substituted by methyl; particular substituted aryl groups include; 3-(methyloxy)phenyl, 3-methylphenyl, 3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl, 4-fluoro-3-(methyloxy)phenyl, 3-acetylphenyl, 4-hydroxy-3-(methyloxy)phenyl, 2-fluoro-3-chlorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl;
    Aryl fused to a cyclohexane or cyclopentane ring, wherein the cyclopentane ring is optionally substituted by (═O); in particular the following fused systems:
  • Figure US20090312325A1-20091217-C00009
  • Aryl fused to a heterocyclyl ring, optionally substituted by methyl; in particular the following heterocyclyl ring fused aryl systems:
  • Figure US20090312325A1-20091217-C00010
  • or
  • Heteroaryl optionally substituted by one or more methyl, ethyl, flourine, chlorine or methoxy groups; in particular a pyridyl, benzimidazolyl, pyrazolyl or indazolyl group optionally substituted by one or more methyl, ethyl, flourine, chlorine, or methoxy groups; preferably 1-methyl-1H-benzimidazolyl-6-yl, 1-methyl-1H-indazol-6-yl, 5-(methyloxy)-3-pyridinyl, 3-pyridinyl, 1-ethyl-1H-pyrazol-5-yl, 5-methyl-3-pyridinyl, 1,3-benzothiazol-6-yl, 5-fluoro-3-pyridinyl, or 5-chloro-3-pyridinyl.
  • In one embodiment, R2 is hydrogen.
  • In one embodiment R3 is selected from:
  • C1-6 alkyl which is optionally substituted by one or more substituents selected from —NR16COR15; OH—, C1-6alkoxyCONR25—, —CONR2, R27, —NH2, —NR17R11, —CO2R24, C1-6alkoxy-; or a group having one of the following formulae:
  • Figure US20090312325A1-20091217-C00011
  • C3-7cycloalkyl;
    Aryl optionally substituted by one or more substituents selected from C1-6alkyl-, halogen-, C1-6alkoxy-, —CO2R2, —OH, —CONR29R30, C3-7cycloalkoxy, C3-7cycloalkyl(C1-6alkoxy);
    Aryl(C1alkyl) wherein the aryl is optionally substituted by one or more C1-6alkoxy groups;
    Heteroaryl or heteroaryl(C1-6alkyl) which is optionally substituted by one or more C1-6alkyl or —CONR29R30 groups; or
    Heterocyclyl which is optionally substituted by one or more substituents selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl-groups), C1-6alkoxyCO—, arylCO—, C1-6alkylSO2—.
  • In an alternative embodiment R3 is selected from:
  • methyl, ethyl, n-propyl, tert-butyl, isopropyl, MeCONH(CH2)2—, Me2NCO(CH2)2—;
    • Cyclopentyl;
  • Aryl optionally substituted by one or more methoxy, methyl, —CONH2 or —CONMe2 groups; in particular: 4-(methyloxy)phenyl, phenyl, 3-[(dimethylamino)carbonyl]phenyl, 4-methylphenyl, 3-[(methyloxy)carbonyl]phenyl, 3,4-bis(methyloxy)phenyl, 3,4,5-tris(methyloxy)phenyl, 3-(ethyloxy)phenyl;
    Heterocyclyl which is optionally substituted by one of more substituents selected from MeCO—, cyclopropylCO, 2-furylCO—, or MeSO2—; in particular wherein the heterocyclyl group is tetrahydropyran-4-yl; a tetrahydrofuran-3-yl; or piperidinyl substituted by one or more substituents selected from MeCO—, cyclopropylCO, 2-furylCO—, or MeSO2—, especially 1-acetyl-4-piperidinyl, 1-(2-furanylcarbonyl)-4-piperidinyl, 1-(cyclopropylcarbonyl)-4-piperidinyl;
    Heteroaryl wherein the heteroaryl represents 3-pyridyl which is optionally substituted by CONMe2, especially 5-[(dimethylamino)carbonyl]-3-pyridinyl.
  • In one embodiment R9 and R10 together with the nitrogen to which they are attached represent 4-morpholinyl.
  • In one embodiment R4, R5, R6, R7, R8, R11-16 and R21-25 and R23-33 are independently selected from hydrogen and methyl.
  • In one embodiment R26 and R27 are independently selected from hydrogen, methyl, cyclopropyl, or 4-tetrahydropyranyl; or R26 and R27 together with the nitrogen to which they are attached form a heterocyclyl ring, in particular pyrrolidinyl or morpholinyl.
  • In one embodiment R19 is hydrogen, C1-6alkyl or MeSO2—. In a further embodiment R19 is hydrogen or methyl, especially hydrogen.
  • In one embodiment R20 is hydrogen, halogen or C1-6alkyl. Alternatively R20 is hydrogen, chlorine, fluorine, methyl or ethyl. In a further embodiment R20 is methyl, ethyl or chlorine.
  • In one embodiment m is 0 or 1.
  • In one embodiment n is 1 or 2, especially 2.
  • In one embodiment R34 represents a group of formula:
  • Figure US20090312325A1-20091217-C00012
  • It is to be understood that the present invention covers all combinations of substituent groups referred to herein above.
  • It is to be understood that the present invention covers all combinations of particular and preferred groups described herein above.
  • Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable salts. Specific examples which may be mentioned include:
    • EXAMPLE 7
    • 4-[(3-methylphenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 8
    • 4-[(3-cyanophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 20
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 27
    • 4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 32
    • 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 35
    • 4-[(3-chlorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 43
    • 4-(1,3-benzothiazol-6-ylamino)-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 45
    • 4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 52
    • 4-[(3-cyanophenyl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 66
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 74
    • 4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 89
    • 6-(cyclopentylsulfonyl)-4-[(3-fluorophenyl)amino]-3-quinolinecarboxamide,
    EXAMPLE 128
    • 4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
    EXAMPLE 129
    • 6-[(1,1-dimethylethyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    EXAMPLE 130
    • 6-{[2-(acetylamino)ethyl]sulfonyl}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide.
    EXAMPLE 133
    • 6-[(1,1-dimethylethyl)thio]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    EXAMPLE 135
    • 6-{[2-(acetylamino)ethyl]thio}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    EXAMPLE 163
    • 4-[(1-methyl-1H-indazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 167
    • 4-{[4-hydroxy-3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 174
    • 4-[(3-acetylphenyl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 184
    • 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 185
    • 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(phenylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 186
    • 7-methyl-4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide,
    EXAMPLE 265
    • 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
    EXAMPLE 266
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
    EXAMPLE 267
    • 4-[(3-acetyl phenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 268
    • 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 269
    • 4-(2,3-dihydro-1,4-benzodioxin-5-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 270
    • 4-[(3-chlorophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 271
    • 4-[(3-cyanophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 272
    • 4-(1,3-benzothiazol-6-ylamino)-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 273
    • 4-[(3-fluorophenyl)amino]-8-methyl-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide
    EXAMPLE 285
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 287
    • 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 292
    • 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-[(4-methylphenyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 294
    • 4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 303
    • 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(phenylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 307
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 308
    • 8-methyl-6-(methylsulfonyl)-4-(3-pyridinylamino)-3-quinolinecarboxamide
    EXAMPLE 309
    • 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 311
    • 4-[(3-fluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 312
    • 4-[(3-cyanophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 315
    • 4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 316
    • 8-methyl-4-{[5-(methyloxy)-3-pyridinyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 317
    • 8-methyl-4-[(5-methyl-3-pyridinyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 369
    • 8-chloro-4-[(3-methylphenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 370
    • 8-chloro-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 371
    • 8-chloro-4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 372
    • 8-chloro-4-[(3-cyanophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 373
    • 8-chloro-4-[(3-fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 374
    • 8-chloro-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 379
    • methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoate
    EXAMPLE 380
    • 6-{[3,4-bis(methyloxy)phenyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
    EXAMPLE 381
    • 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[3,4,5-tris(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide hydrochloride
    EXAMPLE 382
    • 6-{[3,4-bis(methyloxy)phenyl]sulfonyl}-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
    EXAMPLE 383
    • 6-{[3-(ethyloxy)phenyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
    EXAMPLE 392
    • 6-{[2-(acetylamino)ethyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    EXAMPLE 399
    • 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    EXAMPLE 400
    • 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    EXAMPLE 408
    • 4-[(3-cyanophenyl)amino]-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
    EXAMPLE 409
    • 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-3-quinolinecarboxamide
    EXAMPLE 414
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide
    EXAMPLE 426
    • 6-[(1-acetyl-4-piperidinyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
    EXAMPLE 442
    • 6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
    EXAMPLE 443
    • 4-[(3-cyanophenyl)amino]-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide
    EXAMPLE 445
    • 6-{[1-(cyclopropylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
    EXAMPLE 446
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide
    EXAMPLE 447
    • 6-{[1-(cyclopropylcarbonyl)-4-piperidinyl]sulfonyl}-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide
    EXAMPLE 451
    • 6-[(1-acetyl-4-piperidinyl)sulfonyl]-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide
    EXAMPLE 457
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-({2-[(methylsulfonyl)amino]ethyl}sulfonyl)-3-quinolinecarboxamide
    EXAMPLE 459
    • 6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-3-quinolinecarboxamide
    EXAMPLE 475
    • 6-{[3-(dimethylamino)-3-oxopropyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide
    EXAMPLE 500
    • 4-[(2,3-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 501
    • 4-[(3-chloro-2-fluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 502
    • 4-[(3,5-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 539
    • 4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 540
    • 4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 546
    • 6-({5-[(dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
    EXAMPLE 579
    • 8-methyl-6-[(1-methylethyl)sulfonyl]-4-(3-pyridinylamino)-3-quinolinecarboxamide
    EXAMPLE 580
    • 6-[(1,1-dimethylethyl)sulfonyl]-8-methyl-4-(3-pyridinylamino)-3-quinolinecarboxamide
    EXAMPLE 584
    • 4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 585
    • 6-[(1,1-dimethylethyl)sulfonyl]-4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-3-quinolinecarboxamide
    EXAMPLE 588
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfinyl)-3-quinolinecarboxamide
    EXAMPLE 590
    • 4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 591
    • 8-ethyl-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 592
    • 8-ethyl-4-[(3-fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 593
    • 4-[(3-cyanophenyl)amino]-8-ethyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 598
    • 8-ethyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 599
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-ethyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 600
    • 8-ethyl-6-(methylsulfonyl)-4-(3-pyridinylamino)-3-quinolinecarboxamide
    EXAMPLE 624
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-fluoro-6-(methylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 666
    • 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-(ethylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 667
    • 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-(propylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 668
    • 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 669
    • 8-chloro-4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 670
    • 4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 671
    • 6-(ethylsulfonyl)-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide
    EXAMPLE 674
    • 6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide
    EXAMPLE 676
    • 8-chloro-4-[(5-fluoro-3-pyridinyl)amino]-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
    EXAMPLE 677
    • 8-chloro-6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-3-quinolinecarboxamide
    EXAMPLE 678 4-[(5-chloro-3-pyridinyl)amino]-6-(ethylsulfonyl)-8-methyl-3-quinolinecarboxamide EXAMPLE 679
    • 4-[(5-chloro-3-pyridinyl)amino]-8-methyl-6-(propylsulfonyl)-3-quinolinecarboxamide
    EXAMPLE 680
    • 4-[(5-chloro-3-pyridinyl)amino]-6-[(1,1-dimethylethyl)sulfonyl]-8-methyl-3-quinolinecarboxamide
      and pharmaceutically acceptable salts thereof.
  • Preferred compounds include:
    • 8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-{[4-(methyloxy)phenyl]sulfonyl}-3-quinolinecarboxamide,
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    • 8-methyl-4-[(1-methyl-1H-indazol-6-yl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide,
    • 4-[(3-cyanophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide,
    • 8-methyl-4-[(5-methyl-3-pyridinyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
    • 6-({3-[(dimethylamino)carbonyl]phenyl-sulfonyl)-8-methyl-4-[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide,
    • 4-[(3-cyanophenyl)amino]-6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-3-quinolinecarboxamide,
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-6-{[1-(2-furanylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-3-quinolinecarboxamide
    • 4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-({2-[(methylsulfonyl)amino]ethyl}sulfonyl)-3-quinolinecarboxamide
    • 4-[(3,5-difluorophenyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide
    • 6-({5-[(dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
    • 4-[(1-ethyl-1H-pyrazol-5-yl)amino]-8-methyl-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
    • 6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-8-methyl-3-quinolinecarboxamide
    • 8-chloro-6-[(1,1-dimethylethyl)sulfonyl]-4-[(5-fluoro-3-pyridinyl)amino]-3-quinolinecarboxamide
      and pharmaceutically acceptable salts thereof.
  • Salts of the compounds of the present invention are also encompassed within the scope of the invention. Because of their potential use in medicine, the salts of the compounds of formula (I) are preferably pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts can include acid or base addition salts. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, acetate, fumarate, citrate, tartrate, benzoate, p-toluenesulfonate, methanesulfonate or naphthalenesulfonate salt. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallisation and filtration. Other non-pharmaceutically acceptable salts, eg. oxalates or trifluoroacetates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • Also included within the scope of the invention are all solvates, hydrates and complexes of compounds and salts of the invention.
  • Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
  • The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working Examples.
    • Process a
  • Compounds of formula (I), wherein R34, R19, R20, R1 and R2 are as defined above, may be prepared from compounds of formula II;
  • Figure US20090312325A1-20091217-C00013
  • wherein R34, R19, and R20 are as defined above, and X represents a halogen atom, by treatment with an amine of formula R1R2NH, wherein R1 and R2 are as defined above.
  • Suitable conditions for process a) include stirring in a suitable solvent such as acetonitrile, N,N-dimethylformamide or ethanol, at a suitable temperature, such as between room temperature and the reflux temperature of the solvent, for example at 80° C., optionally in the presence of a suitable base such as N,N-diisopropylethylamine, or in the presence of an acid catalyst such as the salt of an amine base, such as pyridine hydrochloride. Alternatively, process a) may be carried out under microwave irradiation, at a suitable power such as 100-300 W, for example at 150 W, in a suitable solvent such as N-methyl-2-pyrrolidinone or N,N-dimethylformamide, at a suitable temperature such as 60-200° C., for example at 150° C.
  • Compounds of formula (II), wherein R34, R19, R20 and X are as defined above, may be prepared from compounds of formula (IV);
  • Figure US20090312325A1-20091217-C00014
  • wherein R34, R19, and R20 are as defined above, by treatment with a suitable chlorinating agent, such as thionyl chloride, in the presence of a suitable catalyst such as N,N-dimethylformamide, followed by treatment with ammonia under suitable conditions, such as 880 ammonia at room temperature.
  • Compounds of formula (IV), wherein R34, R19, and R20 are as defined above, may be prepared from compounds of formula (V);
  • Figure US20090312325A1-20091217-C00015
  • wherein R34, R19, and R20 are as defined above, by hydrolysis with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as room temperature.
  • Compounds of formula (V), wherein R34, R19, and R20 are as defined above, may be prepared from compounds of formula (VI);
  • Figure US20090312325A1-20091217-C00016
  • wherein R34, R19, and R20 are as defined above, by heating in a suitable solvent, such as diphenyl ether, at a suitable temperature such as 200-300° C., for example at 250° C. The preparation of compounds of formulae (IV), (V), and (VI) wherein R34 represents MeSO2—, R19 represents H and R20 represents H have been previously described in patent application WO 02/068394 A1 (Glaxo Group Limited).
  • Compounds of formula (VI), wherein R34, R19, and R20 are as defined above, may be prepared from compounds of formula (VII), wherein R34, R19, and R20 are as defined above, and the compound of formula (VIII);
  • Figure US20090312325A1-20091217-C00017
  • Suitable conditions include heating together compounds of formulae (VII) and (VIII) in a suitable solvent such as ethanol or in the absence of solvent, at a suitable temperature, such as 60-100° C., for example at 80° C.
  • Compounds of formula (VII) wherein R34, R19, and R20 are as defined above may be prepared by reduction of compounds of formula (XIV), wherein R34, R19, and R20 are as defined above;
  • Figure US20090312325A1-20091217-C00018
  • suitable conditions where n=1 or 2 include catalytic hydrogenation with hydrogen and a suitable catalyst, such as palladium on carbon, in a suitable solvent such as acetic acid. Suitable conditions where n=0 include reduction with a reducing agent such as iron in dilute acetic acid, at a suitable temperature such as 85-90° C.
  • Compounds of formula (XIV), wherein R34 represents R3S(═O)n—, R19 represents hydrogen or C1-6alkyl, n is 0 or 2, and R20 is as defined above, may be prepared from compounds of formula (XV), wherein R19 represents hydrogen or C1-6alkyl and R20 is as defined above and compounds of formula (XVI) wherein R3 is defined above and n=0 or 2;
  • Figure US20090312325A1-20091217-C00019
  • Suitable conditions where n=0 include treatment of the compound of formula (XV) with a thiol of formula (XVI) (n=0) in the presence of a suitable base such as potassium carbonate, in a suitable solvent such as acetonitrile, at a suitable temperature such as room temperature. Where n=2, suitable conditions include treatment of the compound of formula (XV) with the sodium salt of a sulphonic acid of formula (XVI) (n=2), in a suitable solvent such as dimethylacetamide, at a suitable temperature such as 30-100° C., for example at 50° C.
  • Alternatively, compounds of formula (XIV) where n represents 2 may be prepared from compounds of formula (XIV) where n represents 0 by oxidation with a suitable oxidising agent, such as oxone, in a suitable solvent such as a mixture of methanol and water, at a suitable temperature such as room temperature. Compounds of formula (XIV) where n represents 1 may be prepared from compounds of formula (XIV) where n represents 0 by oxidation with a suitable oxidising agent, such as ceric ammonium nitrate, in the presence of a suitable solid support such as hydrated silica gel, in a suitable solvent such as methylene chloride, at a suitable temperature such as 20-40° C., for example at room temperature.
  • Compounds of formula R1R2NH may contain amine or acid groups which are suitably protected. Examples of suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3<Ed., J. Wiley and Sons, 1999). Addition or removal of such protecting groups may be accomplished at any suitable stage in the synthesis of compounds of formula (I).
  • Compounds of formula (II) wherein R34 represents R3S(═O)n—, n represents O, R19 represents hydrogen or C1-6alkyl, X represents chlorine and R20 is as defined above may alternatively be prepared from compounds of formula (IX), wherein X represents chlorine, Y represents iodine, Z represents hydrogen or C1-6alkyl, and R20 is as defined above, by treatment with a trialkylstannane of formula R3SSnW3, wherein W represents a C1-6alkyl group such as an n-butyl group. Suitable conditions include heating in the presence of a suitable catalyst, such as a palladium catalyst, for example tetrakistriphenylphosphine palladium (0), in a suitable solvent such as toluene, at a suitable temperature such as between 80° C. and 150° C., for example at 110° C.
    • Process b
  • Compounds of formula (I), wherein R1, R2, R34, R19, and R20 are as defined above, and n=0, may alternatively be prepared from compounds of formula (III);
  • Figure US20090312325A1-20091217-C00020
  • wherein R1, R2 and R20 are as defined above, and Z represents hydrogen, C1-6alkyl or halogen for example chlorine and Y represents hydrogen, chlorine, bromine or iodine, by treatment with a thiol of formula R3SH, or the sodium salt thereof, R3SNa, wherein R3 is as defined above, with the proviso that at least one of Y and Z represent halogen.
  • Suitable conditions for process b) include heating in a suitable solvent such as toluene or N,N-dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • Alternatively, conditions for process b) include heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or dimethoxyethane, at a suitable temperature such as 60-150° C., for example at 85° C., optionally in the presence of a suitable catalyst, such as a copper catalyst, for example copper (I) iodide, and in the presence of a suitable base such as potassium phosphate or potassium carbonate and optionally in the presence of a suitable ligand for example N,N-diethylsalicylamide.
  • Compounds of formula (III), wherein R1, R2, R20, Y and Z are as defined above, may be prepared from compounds of formula (IX), wherein R20, X, Y and Z are as defined above, by treatment with an amine of formula R1R2NH, wherein R1 and R2 are as defined above;
  • Figure US20090312325A1-20091217-C00021
  • suitable conditions include stirring in a suitable solvent such as acetonitrile, at a suitable temperature, such as between room temperature and the reflux temperature of the solvent, for example at 80° C., optionally in the presence of a base such a N,N-diisopropylethylamine, or in the presence of an acid catalyst such as pyridine hydrochloride. Alternatively, preparation of compounds of formula (III) from compounds of formula (IX) may be carried out under microwave irradiation, at a suitable power such as 100-300 W, for example at 150 W, in a suitable solvent such as N-methyl-2-pyrrolidinone, at a suitable temperature such as 60-200° C. for example at 150° C.
  • The compounds of formula (IX) may be prepared according to the following synthetic scheme, Scheme 1, wherein R19, R20, Y and Z are as defined above:
  • Figure US20090312325A1-20091217-C00022
  • Suitable conditions for the reactions of Scheme 1 are: (A) heating together compounds of formulae (X) and (VIII) in the absence of solvent, at a suitable temperature, such as 60-100° C., for example at 80° C.; (B) heating compounds of formula (XI) in a suitable solvent, such as diphenyl ether, at a suitable temperature such as 200-300° C., for example at 250° C.; (C) hydrolysis of compounds of formula (XII) with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as room temperature; (D) treatment of compounds of formula (XIII) with a suitable halogenating agent, such as a chlorinating agent, for example thionyl chloride, in the presence of a suitable catalyst such as N,N-dimethylformamide, followed by treatment with ammonia under suitable conditions, such as 880 ammonia at room temperature.
  • Preparation of the compounds of formulae (XI) and (XII) wherein Y represents iodine and Z and R20 both represent hydrogen have been previously described in: Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 2002, 41B(3), 650-652. Preparation of the compound of formula (XIII) wherein Y represents iodine and Z and R20 both represent hydrogen has been previously described in: PCT Int. Appl. (1999), WO9932450 A1.
  • Compounds of formula (X) are either known compounds (for example available from commercial suppliers such as Aldrich) or may be prepared by conventional means.
  • Compounds of formula (V), wherein R34 represents R3S(═O)n—, R19 represents hydrogen or C1-6alkyl, R20 is as defined above and n=0, may be prepared by treatment of compounds of formula (XII), wherein Y and R20 are as defined above and Z represents hydrogen or C1-6alkyl with a thiol of formula R3SH, wherein R3 is as defined above, according to the following scheme:
  • Figure US20090312325A1-20091217-C00023
  • Suitable conditions for preparation of compounds of formula (V) from compounds of formula (XII) and a thiol of formula R3SH include heating in a suitable solvent such as toluene, at a suitable temperature such as 60-120° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • Compounds of formulae R1R2NH and R3SH are either known compounds (for example available from commercial suppliers such as Aldrich) or may be prepared by conventional means.
  • Certain compounds of formula R3SH may be prepared from compounds of formula R3SSR3. Suitable conditions include treatment with a suitable reducing agent such as a phosphine, for example triphenylphosphine, in the presence of an acid such as concentrated hydrochloric acid, in a suitable solvent such as a mixture of water and 1,4-dioxane, at a suitable temperature such as between 20° C. and 100° C., for example at 40° C. Alternatively certain compounds of formula R3SH may be prepared from compounds of formula R3SO2Cl. Suitable conditions include treatment with a suitable reducing agent such as a phosphine, for example triphenylphosphine, in a suitable solvent such as 1,4-dioxane, at a suitable temperature such as between 0° C. and 50° C., for example at 20° C.
  • Compounds of formula R1R2NH may be used in the free base form, or in the form of a suitable salt, such as a hydrochloride salt. Where the free base form is commercially available, suitable salt forms may be prepared by conventional means. Similarly, where a salt form is commercially available, the free base form may be prepared by conventional means.
  • Compounds of formula R3SH may contain amine or acid groups which are suitably protected. Examples of suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3rd Ed., J. Wiley and Sons, 1999). Addition or removal of such protecting groups may be accomplished at any suitable stage in the synthesis of compounds of formula (I).
    • Process c
  • Compounds of formula (I) may also be prepared by a process of interconversion between compounds of formula (I). For example, compounds of formula (I) where n=2 may be prepared from compounds of formula (I) wherein n=0 or 1, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such N,N-dimethylformamide or a mixture of N,N-dimethylformamide and anisole, at a suitable temperature such as room temperature. Compounds of formula (I) where n=1 may be prepared from compounds of formula (I) where n=0 by oxidation with a suitable oxidising agent, such as oxone or ceric ammonium nitrate, in the presence of a suitable solid support such as hydrated silica gel, in a suitable solvent such as methylene chloride, at a suitable temperature such as 20-40° C., for example at room temperature.
  • Alternative processes of interconversion between compounds of formula (I) may include, for example oxidation, reduction, hydrolysis, alkylation, dealkylation, amide bond formation, protection, deprotection, sulphonamide formation or substitution, using methods for functional group interconversion well known to those skilled in the art.
    • Process d
  • As a particular example of a process of interconversion, compounds of formula (I),
  • wherein R34 represents R3S(═O)n—, R3 represents an aryl group substituted by —CONR29R30, R19 represents hydrogen or C1-6alkyl, and wherein R1, R2, R20, R29, R30 and n are as defined above, may alternatively be prepared from corresponding compounds of formula (I) in which R3 represents an aryl group substituted by —COOH, namely compounds of formula (XVII);
  • Figure US20090312325A1-20091217-C00024
  • wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20 and n are as defined above, by coupling with a primary or secondary amine, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable amide coupling reagent, such as O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate, optionally in the presence of a suitable base, such as N,N-diisopropylethylamine, at a suitable temperature, such as room temperature. (Step (I))
  • Compounds of formula (XVII), wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20 and n are as defined above, may be prepared from compounds of formula XVIII;
  • Figure US20090312325A1-20091217-C00025
  • wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20 and n are as defined above, by hydrolysis with a suitable base, such as aqueous sodium hydroxide, in a suitable solvent, such as ethanol, at a suitable temperature such as 75° C. (Step (II))
  • Compounds of formula (XVIII) wherein n=2 may be prepared from compounds of formula (XVIII) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature. (Step (III))
  • Compounds of formula (XVIII), wherein R19 represents hydrogen or C1-6alkyl, R1, R2 and R20 are as defined above, and n=0, may be prepared from compounds of formula (III) wherein Z represents hydrogen or C1-6alkyl by treatment with a suitable thiol such as methyl 3-mercaptobenzoate or methyl 4-mercaptobenzoate (both commercially available from Toronto). Suitable conditions for this include heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at a suitable temperature such as 60-150° C., for example at 85° C., in the presence of a suitable catalyst, such as a copper catalyst, for example copper (I) iodide, and in the presence of a suitable base such as potassium phosphate or potassium carbonate, optionally in the presence of a suitable ligand for example N,N-diethylsalicylamide. (Step (IV))
  • The order of the steps comprising this process may be arranged in a number of different ways. For example the order of steps (II) and (III) may be reversed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (III) followed by step (I).
  • By a similar process, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents a C1-6 alkyl group substituted by —CONR26R27 and wherein R19 represents hydrogen or C1-6alkyl, and R1, R2, R20, R26, R27 and n are as defined above, may alternatively be prepared from compounds of formula (III) where Z represents hydrogen or C1-6alkyl and a suitable thiol such as ethyl 3-mercaptopropionate (commercially available from Aldrich) as shown in the scheme below:
  • Steps (I) to (IV) of Scheme 2 use conditions as described in process d above.
  • The order of the steps comprising this process may be arranged in a number of different ways. For example the order of steps may be changed so that compounds of formula (I) may be prepared from compounds of formula (III) by step (IV) followed by step (II) followed by step (III) followed by step (I).
  • Alternatively the order of steps may be changed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (I) followed by step (III).
  • Figure US20090312325A1-20091217-C00026
  • wherein R3 is R26R27NCO(CH2)2—.
    • Process e
  • As a particular example of a process of interconversion, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents a piperidinyl group which is substituted by a substituent selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl-groups), C1-6alkoxyCO—, arylCO—, R31R32NCO—, C1-6alkylSO2—, arylSO2— or heteroarylSO2— (optionally substituted by one or more C1-4alkyl or C1-4alkylCONH— groups) and wherein R1, R2, R20, R31, R32 and n are as defined above and R19 represents hydrogen or C1-6alkyl, may alternatively be prepared from compounds of formula (XIX);
  • Figure US20090312325A1-20091217-C00027
  • wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by treatment with an electrophile, such as an acylating agent, such as an acid chloride, in a suitable solvent, such as 1,4-dioxane, in the presence of a suitable base, such as an amine base, for example triethylamine, at a suitable temperature, such as room temperature. Alternative electrophiles that may be used for this process include sulphonyl chlorides, alkyl chloroformates, alkyl halides and acid anhydrides.
  • Alternatively, compounds of formula (I), wherein R34 represents R3S(═O)n— and R3 represents a piperidinyl which is substituted by a substituent selected from C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— (optionally substituted by one or more C1-4alkyl-groups), or arylCO—, and wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, may alternatively be prepared from compounds of formula (XIX), by coupling with a carboxylic acid, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable amide coupling reagent, such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, optionally in the presence of a suitable base, such as N,N-diisopropylethylamine, at a suitable temperature, such as room temperature. (Step (I))
  • Compounds of formula (XIX), wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, may be prepared from compounds of formula (XX);
  • Figure US20090312325A1-20091217-C00028
  • wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by treatment with a suitable reagent, such as a strong acid, for example trifluoroacetic acid, at a suitable temperature, such as room temperature (Step (II)).
  • Compounds of formula (XX) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=2, may be prepared from compounds of formula (XX) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature (Step (III)).
  • Compounds of formula (XX) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=0, may be prepared from compounds of formula (III) wherein R1, R2, Y and R20 are as defined above and Z represents hydrogen or C1-6alkyl, by treatment with 1,1-dimethylethyl 4-mercapto-1-piperidinecarboxylate (prepared as described in U.S. Pat. No. 5,317,025A) (Step (IV)).
  • Suitable conditions for this process include heating in a suitable solvent such as dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • The order of the steps comprising this process may be arranged in a number of different ways. For example the order of steps may be changed so that compounds of formula (I) may be prepared by step (IV) followed by step (II) followed by step (I) followed by step (111).
  • Similarly, compounds of formula (I) wherein R34 represents R3S(═O)n— and R3 represents a C1-6alkyl which is substituted by —NR17R18, —NR1COR15, C1-6alkoxyCONR25— or C1-6alkylSO2NR33— and wherein R1, R2, R20, R15, R17, R1 and n are as defined above, R19 represents hydrogen or C1-6alkyl, and R16, R25 and R33 represent hydrogen may alternatively be prepared from compounds of formula (III), wherein R1, R2, Y and R20 are as defined above and Z represents hydrogen or C1-6alkyl, and a thiol such as tert-butyl-N-(2-mercaptoethyl)carbamate (Aldrich), as is illustrated in the following Scheme (Scheme 3):
  • Steps (I) to (IV) of Scheme 3 use conditions as described in process e above.
  • Figure US20090312325A1-20091217-C00029
  • wherein R34 represents C1-6alkylSO2-, wherein the C1-6alkyl group is substituted by R15CONR16—, C1-6alkoxyCONR25—, C1-6alkylSO2NR33— or R17R11N—.
    • Process f
  • As a particular example of a process of interconversion compounds of formula (I), wherein
  • R34 represents R3S(═O)n— and R3 represents an aryl group substituted by a C1-6alkoxy-, C3-7cycloalkoxy- or C3-7cycloalkyl(C1-6alkoxy)-group, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl, may alternatively be prepared from compounds of formula (XXI);
  • Figure US20090312325A1-20091217-C00030
  • wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by coupling with a suitable alkylating agent, in a suitable solvent, such as acetonitrile, in the presence of a suitable base, such as potassium carbonate, at a suitable temperature, such as 0 to 100° C., for example the reflux temperature of the solvent.
  • Alternatively compounds of formula (I) wherein R34 represents R3S(═O)n— and R3 represents an aryl group substituted by a C1-6alkoxy-, C3-7cycloalkoxy- or C3-7cycloalkyl(C1-6alkoxy)-group, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl, may be prepared from compounds of formula (XXI) by coupling with a suitable alcohol in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as room temperature in the presence of a suitable coupling agent such as di-tert butylazodicarboxylate.
  • Compounds of formula (XXI) wherein n=2 may be prepared from compounds of formula (XXI) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature.
  • Compounds of formula (XXI) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=0, may be prepared from compounds of formula (III) wherein R1, R2, R20 and Y are as defined above, and wherein Z represents hydrogen or C1-6alkyl, by treatment with 4-{[tert-butyl(dimethyl)silyl]oxy}benzenethiol (prepared according to EP 465802 A1). Suitable conditions for this process include heating in a suitable solvent such as dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide, followed by deprotection with a suitable fluoride source such as tetrabutylammonium fluoride in a suitable solvent such as tetrahydrofuran at a suitable temperature such as room temperature.
  • The order of the steps comprising this process may be arranged in a number of different ways.
    • Process g
  • Compounds of formula (I) may also be prepared by a process of deprotection of protected derivatives of compounds of formula (I). Examples of suitable protecting groups and the means for their removal are well known in the art, see for instance T. W. Greene and P. G. M. Wuts ‘Protective Groups in Organic Synthesis’ (3rd Ed., J. Wiley and Sons, 1999).
  • As an example of this, compounds of formula (I) containing a primary or secondary amine group may be prepared from compounds of formula (I) where that amine group is protected, such as a carbamate group, for example as a tert-butyl carbamate, by deprotecting under appropriate conditions, such as treating with a strong acid, for example trifluoroacetic acid.
    • Process h
  • As a particular example of a process of interconversion, compounds of formula (I),
  • wherein R34 represents R3S(═O)n— and R3 represents C1-6alkoxyethyl-, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl may be prepared from compounds of formula (XXVIII);
  • Figure US20090312325A1-20091217-C00031
  • wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by alkylation with a suitable alkylating agent, in a suitable solvent, such as N,N-dimethylformamide, in the presence of a suitable base, such as sodium hydride, at a suitable temperature, such as 0 to 30° C., for example at room temperature.
  • Alternatively compounds of formula (I) wherein R34 represents R3S(═O)n— and R3 represents C1-6alkoxyethyl-, R1, R2, R20 and n are as defined above, and R19 represents hydrogen or C1-6alkyl may be prepared from compounds of formula (XXVIII) wherein R1, R2, R20 and n are as defined above and R19 represents hydrogen or C1-6alkyl, by coupling with a suitable alcohol in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as room temperature in the presence of a suitable coupling agent such as di-tert butylazodicarboxylate.
  • Compounds of formula (XXVIII) wherein R1, R2, and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n=2 may be prepared from compounds of formula (XXVIII) wherein n=0, by treatment with a suitable oxidising agent, such as oxone, in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as room temperature.
  • Compounds of formula (XXVIII) wherein R1, R2 and R20 are as defined above, R19 represents hydrogen or C1-6alkyl, and n is 0, may be prepared from compounds of formula (III) wherein R1, R2, R20 and Y are as defined above and Z represents hydrogen or C1-6alkyl, by treatment with 2-mercaptoethanol (available from Aldrich). Suitable conditions for this process include heating in a suitable solvent such as N,N-dimethylformamide, at a suitable temperature such as 60-150° C., for example at 110° C., in the presence of a suitable catalyst, such as a palladium catalyst, for example tris(dibenzylideneacetone) palladium (II), and a suitable ligand, such as a phosphine ligand, for example (oxydi-2,1-phenylene)bis(diphenylphosphine), and in the presence of a suitable base such as potassium tert-butoxide.
  • The order of the steps comprising this process may be arranged in a number of different ways.
    • Process i
  • Compounds of formula (I) wherein R34 represents hydrogen, R19 represents R3S(═O)n—, and R1, R2, R20 and n are as defined above, may be prepared from compounds of formula (XXIX) wherein Y represents chlorine, bromine or iodine, in particular iodine, n=1 or 2, and R1, R2, R3 and R20 are as defined above, by hydrogenation using a suitable hydrogenation process such as palladium on carbon in a suitable solvent such as ethanol.
  • Figure US20090312325A1-20091217-C00032
  • Compounds of formula (XXIX) wherein Y represents chlorine, bromine or iodine, in particular iodine, n=1 or 2, and R1, R2, R3 and R20 are as defined above, may be prepared from compounds of formula (XXIX) wherein n=0 by treatment with a suitable oxidising agent such as oxone in a suitable solvent such as N,N-dimethylformamide of a mixture of N,N-dimethylformamide and anisole at a suitable temperature such as room temperature.
  • Compounds of formula (XXIX) wherein Y represents chlorine, bromine or iodine, in particular iodine, R1, R2, R3 and R20 are as defined above, and n=0 may be prepared from compounds of formula (III) wherein R1, R2 and R20 are as defined above, Y represents chlorine, bromine or iodine, especially iodine, and Z represents chlorine, bromine or iodine, especially chlorine, and a thiol of formula R3SH by heating in a suitable solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, at a suitable temperature such as 60-150° C. for example at 100° C. in the presence of a suitable base such as potassium carbonate.
    • Process j
  • As a particular example of a process of interconversion, compounds of formula (I), wherein R34 represents R3S(═O)n— and wherein R3 represents:
  • Figure US20090312325A1-20091217-C00033
  • and wherein R1, R2, R20, and n are as defined above, and R19 represents hydrogen or C1-6alkyl, may be prepared from compounds of formula (XXVII) in scheme 3, wherein R1, R2, and R20 are as defined above and Z represents hydrogen or C1-6alkyl, by treatment with a suitable alkylating agent such as ethyl 4-bromobutyrate in a suitable solvent such as 1,4-dioxane at a suitable temperature such as 120° C.
  • The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance in a mammal such as a human. The compound or salt can be for use in the treatment and/or prophylaxis of any of the conditions described herein and/or for use as a phosphodiesterase inhibitor, for example for use as a phosphodiesterase 4 (PDE4) inhibitor. “Therapy” may include treatment and/or prophylaxis.
  • Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g. pharmaceutical composition) for the treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal such as a human.
  • Also provided is a method of treatment and/or prophylaxis of an inflammatory and/or allergic disease in a mammal (e.g. human) in need thereof, which comprises administering to the mammal (e.g. human) a therapeutically effective amount of a compound of formula (I) as herein defined or a pharmaceutically acceptable salt thereof.
  • Phosphodiesterase 4 inhibitors are believed to be useful in the treatment and/or prophylaxis of a variety of diseases, especially inflammatory and/or allergic diseases, in mammals such as humans, for example: asthma, chronic bronchitis, emphysema, atopic dermatitis, urticaria, allergic rhinitis (seasonal or perennial), vasomotor rhinitis, nasal polyps, allergic conjunctivitis, vernal conjunctivitis, occupational conjunctivitis, infective conjunctivitis, eosinophilic syndromes, eosinophilic granuloma, psoriasis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock, adult respiratory distress syndrome, multiple sclerosis or memory impairment (including Alzheimer's disease).
  • In the treatment and/or prophylaxis, the inflammatory and/or allergic disease is preferably chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema, asthma, rheumatoid arthritis, psoriasis or allergic rhinitis in a mammal (e.g. human). More preferably, the treatment and/or prophylaxis is of COPD including chronic bronchitis and emphysema or asthma in a mammal (e.g. human). PDE4 inhibitors are thought to be effective in the treatment of asthma (e.g. see M. A. Giembycz, Drugs, February 2000, 59(2), 193-212; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438; and refs cited therein) and COPD (e.g. see S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319; Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438; and refs cited therein). COPD is often characterised by the presence of airflow obstruction due to chronic bronchitis and/or emphysema (S. L. Wolda, Emerging Drugs, 2000, 5(3), 309-319).
  • For use in medicine, the compounds of the present invention are usually administered as a pharmaceutical composition.
  • The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers and/or excipients.
  • The pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.
  • The compounds of formula (I) and/or the pharmaceutical composition may be administered, for example, by oral, parenteral (e.g. intravenous, subcutaneous, or intramuscular), inhaled, nasal, transdermal or rectal administration, or as topical treatments (e.g. ointments or gels). Accordingly, the pharmaceutical composition is preferably suitable for oral, parenteral (e.g. intravenous, subcutaneous or intramuscular), inhaled or nasal administration. More preferably, the pharmaceutical composition is suitable for inhaled or oral administration, e.g. to a mammal such as a human. Inhaled administration involves topical administration to the lung, e.g. by aerosol or dry powder composition.
  • A pharmaceutical composition suitable for oral administration can be liquid or solid; for example it can be a solution, a syrup, a suspension or emulsion, a tablet, a capsule or a lozenge.
  • A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable pharmaceutically acceptable liquid carrier(s), for example an aqueous solvent such as water, ethanol or glycerine, or an oil, or a non-aqueous solvent, such as a surfactant, such as polyethylene glycol. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • A pharmaceutical composition suitable for oral administration being a tablet can comprise one or more pharmaceutically acceptable carriers and/or excipients suitable for preparing tablet formulations. Examples of such carriers include lactose and cellulose. The tablet can also or instead contain one or more pharmaceutically acceptable excipients, for example binding agents, lubricants such as magnesium stearate, and/or tablet disintegrants.
  • A pharmaceutical composition suitable for oral administration being a capsule can be prepared using encapsulation procedures. For example, pellets containing the active ingredient can be prepared using a suitable pharmaceutically acceptable carrier and then filled into a hard gelatin capsule. Alternatively, a dispersion, suspension or solution can be prepared using any suitable pharmaceutically acceptable carrier, for example an aqueous solution, aqueous gum or an oil and the dispersion, suspension or solution then filled into a hard or soft gelatin capsule.
  • The compounds of formula (I) and/or the pharmaceutical composition may be administered by a controlled or sustained release formulation as described in WO 00/50011.
  • A parenteral composition can comprise a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil. Alternatively, the solution can be lyophilised; the lyophilised parenteral pharmaceutical composition can be reconstituted with a suitable solvent just prior to administration.
  • Compositions for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions, drops, gels or dry powders.
  • For compositions suitable and/or adapted for inhaled administration, it is preferred that the compound or salt of formula (I) is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronisation. The preferable particle size of the size-reduced (e.g. micronised) compound or salt is defined by a D50 value of about 0.5 to about 10 microns (for example as measured using laser diffraction).
  • Aerosol formulations, e.g. for inhaled administration, can comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent. Aerosol formulations can be presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device or inhaler. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve (metered dose inhaler) which is intended for disposal once the contents of the container have been exhausted.
  • Where the dosage form comprises an aerosol dispenser, it preferably contains a suitable propellant under pressure such as compressed air, carbon dioxide or an organic propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC). Suitable CFC propellants include dichlorodifluoromethane, trichlorofluoromethane and dichlorotetrafluoroethane. Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropane and 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also take the form of a pump-atomiser.
  • Optionally, in particular for dry powder inhalable compositions, a pharmaceutical composition for inhaled administration can be incorporated into a plurality of sealed dose containers (e.g. containing the dry powder composition) mounted longitudinally in a strip or ribbon inside a suitable inhalation device. The container is rupturable or peel-openable on demand and the dose of e.g. the dry powder composition can be administered by inhalation via the device such as the DISKUS™ device, marketed by GlaxoSmithKline. The DISKUS™ inhalation device is for example described in GB 2242134 A, and in such a device at least one container for the pharmaceutical composition in powder form (the container or containers preferably being a plurality of sealed dose containers mounted longitudinally in a strip or ribbon) is defined between two members peelably secured to one another; the device comprises: a means of defining an opening station for the said container or containers; a means for peeling the members apart at the opening station to open the container; and an outlet, communicating with the opened container, through which a user can inhale the pharmaceutical composition in powder form from the opened container.
  • In the pharmaceutical composition, each dosage unit for oral or parenteral administration preferably contains from 0.01 to 3000 mg, more preferably 0.5 to 1000 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. Each dosage unit for nasal or inhaled administration preferably contains from 0.001 to 50 mg, more preferably 0.01 to 5 mg, of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • The pharmaceutically acceptable compounds or salts of the invention can be administered in a daily dose (for an adult patient) of, for example, an oral or parenteral dose of 0.01 mg to 3000 mg per day or 0.5 to 1000 mg per day, or a nasal or inhaled dose of 0.001 to 50 mg per day or 0.01 to 5 mg per day, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • The compounds, salts and/or pharmaceutical compositions according to the invention may also be used in combination with one or more other therapeutically active agents, for example, a β2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
  • The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof with one or more other therapeutically active agents, for example, a β2-adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent (including a steroid), an anticholinergic agent or an antiinfective agent (e.g. antibiotics or antivirals).
  • Examples of β2-adrenoreceptor agonists include salmeterol (e.g. as racemate or a single enantiomer such as the R-enantiomer), salbutamol, formoterol, salmefamol, fenoterol or terbutaline and salts thereof, for example the xinafoate salt of salmeterol, the sulphate salt or free base of salbutamol or the fumarate salt of formoterol. Long-acting β2-adrenoreceptor agonists are preferred, especially those having a therapeutic effect over a 24 hour period, such as salmeterol or formoterol.
  • Examples of anti-histamines include methapyrilene or loratadine.
  • Examples of anti-inflammatory steroids include fluticasone propionate and budesonide.
  • Examples of anticholinergic compounds which may be used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof are described in WO 03/011274 A2 and WO 02/069945 A2/US 2002/0193393 A1 and US 2002/052312 A1. For example, anticholinergic agents include muscarinic M3 antagonists, such as ipratropium bromide, oxitropium bromide or tiotropium bromide.
  • Other suitable combinations include, for example, combinations comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with other anti-inflammatory agents such as an anti-inflammatory corticosteroid; or a non-steroidal anti-inflammatory drug (NSAID) such as a leukotriene antagonist (e.g. montelukast), an iNOS inhibitor, a tryptase inhibitor, an elastase inhibitor, a beta-2 integrin antagonist, an adenosine a2a agonist, a chemokine antagonist such as a CCR3 antagonist, or a 5-lipoxygenase inhibitor; or an antiinfective agent (e.g. an antibiotic or an antiviral). An iNOS inhibitor is preferably for oral administration. Suitable iNOS inhibitors (inducible nitric oxide synthase inhibitors) incluse those disclosed in WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875. Suitable CCR3 inhibitors include those disclosed in WO 02/26722.
  • The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.
  • The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or in combined pharmaceutical compositions.
  • All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
  • The various aspects of the invention will now be described by reference to the following Biological Test Methods and Examples. These Examples are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
    • Biological Test Methods PDE3, PDE4B, PDE4D, PDE5 and PDE6 Primary Assay Methods
  • The activity of the compounds can be measured as described below. Preferred compounds of the invention are selective PDE4 inhibitors, i.e. they inhibit PDE4 (e.g. PDE4B and/or PDE4D) more strongly than they inhibit other PDE's such as PDE3 and/or PDE5.
    • 1. PDE Enzyme Sources and Literature References.
  • Human recombinant PDE4B, in particular the 2B splice variant thereof (HSPDE4B2B), is disclosed in WO 94/20079 and also in M. M. McLaughlin et al., “A low Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain: cloning and expression of cDNA, biochemical characterisation of recombinant protein, and tissue distribution of mRNA”, J. Biol. Chem., 1993, 268, 6470-6476. For example, in Example 1 of WO 94/20079, human recombinant PDE4B is described as being expressed in the PDE-deficient yeast Saccharomyces cerevisiae strain GL62, e.g. after induction by addition of 150 μM CuSO4, and 100,000×g supernatant fractions of yeast cell lysates are described for use in the harvesting of PDE4B enzyme.
  • Human recombinant PDE4D (HSPDE4D3A) is disclosed in P. A. Baecker et al., “Isolation of a cDNA encoding a human rolipram-sensitive cyclic AMP phoshodiesterase (PDE IVD)”, Gene, 1994, 138, 253-256.
  • Human recombinant PDE5 is disclosed in K. Loughney et al., “Isolation and characterisation of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3′,5′-cyclic nucleotide phosphodiesterase”, Gene, 1998, 216, 139-147.
  • PDE3 was purified from bovine aorta. Its presence in the tissue was reported by H. Coste and P. Grondin in “Characterisation of a novel potent and specific inhibitor of type V phosphodiesterase”, Biochem. Pharmacol., 1995, 50, 1577-1585.
  • PDE6 was purified from bovine retina. Its presence in this tissue was reported by: P. Catty and P. Deterre in “Activation and solubilization of the retinal cGMP-specific phosphodiesterase by limited proteolysis”, Eur. J. Biochem., 1991, 199, 263-269; A. Tar et al. in “Purification of bovine retinal cGMP phosphodiesterase”, Methods in Enzymology, 1994, 238, 3-12; and/or D. Srivastava et al. in “Effects of magnesium on cyclic GMP hydrolysis by the bovine retinal rod cyclic GMP phosphodiesterase”, Biochem. J., 1995, 308, 653-658.
    • 2. Inhibition of PDE3, PDE4B, PDE4D, PDE5 or PDE6 Activity: Radioactive Scintillation Proximity Assay (SPA)
  • The ability of compounds to inhibit catalytic activity at PDE4B or 4D (human recombinant), PDE3 (from bovine aorta), PDE5 (human recombinant) or PDE 6 (from bovine retina) was determined by Scintillation Proximity Assay (SPA) in 96-well format. Test compounds (preferably as a solution in DMSO, e.g. 2 microlitre (μl) volume) were preincubated at ambient temperature in Wallac Isoplates (code 1450-514) with PDE enzyme in 50 mM Tris-HCl buffer pH 7.5, 8.3 mM MgCl2, 1.7 mM EGTA, 0.05% (w/v) bovine serum albumin for 10-30 minutes. The enzyme concentration was adjusted so that no more than 20% hydrolysis of the substrate occurred in control wells without compound, during the incubation. For the PDE3, PDE4B and PDE4D assays [5′,8-3H]adenosine 3′,5′-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.559 or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK) was added to give 0.05 μCi per well and ˜10 nM final concentration. For the PDE5 and PDE6 assays [8-3H]guanosine 3′,5′-cyclic phosphate (Amersham Pharmacia Biotech, code TRK.392) was added to give 0.05 μCi per well and ˜36 nM final concentration. Plates e.g. containing approx. 100 μl volume of assay mixture were mixed on an orbital shaker for 5 minutes and incubated at ambient temperature for 1 hour. Phosphodiesterase SPA beads (Amersham Pharmacia Biotech, code RPNQ 0150) suspended in buffer were added (˜1 mg per well) to terminate the assay. Plates were sealed and shaken and allowed to stand at ambient temperature for 35 minutes to 1 hour to allow the beads to settle. Bound radioactive product was measured using a WALLAC TRILUX 1450 Microbeta scintillation counter. For inhibition curves, 10 concentrations (e.g. 1.5 nM-30 μM) of each compound were assayed; more potent compounds were assayed over lower concentration ranges (assay concentrations were generally between 30 μM and 50 μM). Curves were analysed using ActivityBase and XLfit (ID Business Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kingdom). Results were expressed as pIC50 values.
  • Alternatively, the activity of the compounds can be measured in the following Fluorescence Polarisation (FP) assay:
    • 3. Inhibition of PDE4B or PDE4D Activity: Fluorescence Polarisation (FP) Assay
  • The ability of compounds to inhibit catalytic activity at PDE4B (human recombinant) and PDE4D (human recombinant) was determined by IMAP Fluorescence Polarisation (FP) assay (Molecular Devices code: R8062) in 384-well format. Test compounds (small volume, e.g. 0.5 μl, of solution in DMSO) were preincubated at ambient temperature in black 384-well microtitre plates (supplier: NUNC, code 262260) with PDE enzyme in 10 mM Tris-HCl buffer pH 7.2, 10 mM MgCl2, 0.1% (w/v) bovine serum albumin. 0.05% NaN3 for 10-30 minutes. The enzyme level was set so that reaction was linear throughout the incubation.
  • Fluorescein adenosine 3′,5′-cyclic phosphate (Molecular Devices code: R7091) was added to give ˜40 nM final concentration. Plates were mixed on an orbital shaker for 10 seconds and incubated at ambient temperature for 40 minutes. IMAP binding reagent (Molecular Devices code: R7207) was added (60 μl of a 1 in 400 dilution in binding buffer of the kit stock suspension) to terminate the assay. Plates were allowed to stand at ambient temperature for 1 hour. The FP ratio of parallel to perpendicular light was measured using an Analyst™ plate reader (from Molecular Devices Ltd). For inhibition curves, 11 concentrations (0.5 nM-30 μM) of each compound were assayed; more potent compounds were assayed over lower concentration ranges (assay concentrations were generally between 30 μM and 50 fM). Curves were analysed using Activity Base and XLfit (ID Business Solutions Limited). Results were expressed as pIC50 values.
  • For a given PDE4 inhibitor, the PDE4B (or PDE4D) inhibition values measured using the SPA and FP assays can differ slightly. However, in a regression analysis of 100 test compounds, the pIC50 inhibition values measured using SPA and FP assays have been found generally to agree within 0.5 log units for PDE4B and PDE4D (linear regression coefficient 0.966 for PDE4B and 0.971 for PDE4D; David R. Mobbs et al, “Comparison of the IMAP Fluorescence Polarisation Assay with the Scintillation Proximity Assay for Phosphodiesterase Activity”, poster presented at 2003 Molecular Devices UK & Europe User Meeting, 2 Oct. 2003, Down Hall, Harlow, Essex, United Kingdom).
  • Examples of compounds of the invention described above inhibit the catalytic activity at the PDE4B (human recombinant) enzyme with pIC50 values in the range 6.0-11.7. Biological Data obtained for some of the Examples (PDE4B and PDE5 inhibitory activity) is as follows:
  • Example No. PDE4B mean pIC50 PDE5 mean pIC50
    27 8.4 4.8
    70 7.3 5.0
    92 7.7 <4.5
    125 6.6 5.5
    265 11.3 5.2
    307 10.5 <4.6
    309 10.1 <4.9
    312 9.4 <4.5
    369 9.5 5.1
    380 11.4 <7.0
    399 >11.6 5.6
    400 11.0 <5.0
    408 11.4 4.9
    446 11.3 <4.5
    457 11.0 <5.5
    502 8.9 <5
    546 10.7 4.7
    • 4. Emesis:
  • Many known PDE4 inhibitors cause emesis and/or nausea to greater or lesser extents (e.g. see Z. Huang et al., Current Opinion in Chemical Biology, 2001, 5, 432-438, see especially pages 433-434 and references cited therein). Therefore, it would be preferable but not essential that a PDE4 inhibitory compound of the invention causes only limited or manageable emetic side-effects. Emetic side-effects can for example be measured by the emetogenic potential of the compound when administered to ferrets; for example one can measure the time to onset, extent, frequency and/or duration of vomiting and/or writhing in ferrets after oral or parenteral administration of the compound. See for example A. Robichaud et al., “Emesis induced by inhibitors of PDE IV in the ferret” Neuropharmacology, 1999, 38, 289-297, erratum Neuropharmacology, 2001, 40, 465-465.
    • EXAMPLES
  • In this section, “intermediates” represent syntheses of intermediate compounds intended for use in the synthesis of the “Examples”.
    • Abbreviations Used Herein:
    • HPLC high performance liquid chromatography
    • NMR nuclear magnetic resonance
    • LC/MS liquid chromatography/mass spectroscopy
    • TLC thin layer chromatography
    • SPE solid phase extraction column. Unless otherwise specified the solid phase will be silica gel. C18 SPE refers to reverse phase SPE columns (eg Varian Bond Elut C18 columns). Aminopropyl SPE refers to a silica SPE column with aminopropyl residues immobilised on the solid phase (eg. IST Isolute™ columns). It is thought that compounds isolated by SPE are free bases.
    • SCX solid phase extraction (SPE) column with benzene sulfonic acid residues immobilised on the solid phase (eg. IST Isolute™ columns). When eluting with ammonia/methanol, it is thought that compounds isolated by SCX are free bases.
    General Experimental Details LC/MS (Liquid Chromatography/Mass Spectroscopy)
  • Waters ZQ mass spectrometer operating in positive ion electrospray mode, mass range
    100-1000 amu.
    UV wavelength: 215-330 nm
    Column: 3.3 cm×4.6 mm ID, 3 μm ABZ+PLUS
    Flow Rate: 3 ml/min
  • Injection Volume: 5 μl
  • Solvent A: 95% acetonitrile+0.05% formic acid
    Solvent B: 0.1% formic acid+10 mM ammonium acetate
    Gradient: Mixtures of Solvent A and Solvent B are used according to the following gradient profiles (expressed as % Solvent A in the mixture): 0% A/0.7 min, 0-100% A/3.5 min, 100% A/1.1 min, 100-0% A/0.2 min
    • Mass Directed Automated Preparative HPLC Column, Conditions and Eluent Method A
  • The preparative column used was a Supelcosil ABZplus (10 cm×2.12 cm internal diameter; particle size 5 μm)
  • UV detection wavelength: 200-320 nm
    Flow rate: 20 ml/min
    • Injection Volume: 0.5 ml
  • Solvent A: 0.1% formic acid
    Solvent B: 95% acetonitrile+0.05% formic acid
    Gradient systems: mixtures of Solvent A and Solvent B are used according to a choice of 5 generic gradient profiles (expressed as % Solvent B in the mixture), ranging from a start of 0 to 50% Solvent B, with all finishing at 100% Solvent B to ensure total elution.
  • It is thought that compounds isolated by this method are free bases, unless the R1 or R3 groups contain basic moieties, in which case formate salts may be formed.
    • Mass Directed Automated Preparative HPLC Column, Conditions and Eluent Method B
  • The preparative column used was a Supelcosil ABZplus (10 cm×2.12 cm internal diameter; particle size 5 μm)
  • UV detection wavelength: 200-320 nm
    Flow rate: 20 ml/min
    • Injection Volume: 0.5 ml
  • Solvent A: water+0.1% trifluoroacetic acid
    Solvent B: acetonitrile+0.1% trifluoroacetic acid
    Gradient systems: mixtures of Solvent A and Solvent B are used according to a choice of 5 generic gradient profiles (expressed as % Solvent B in the mixture), ranging from a start of 0 to 50% Solvent B, with all finishing at 100% Solvent B to ensure total elution.
  • It is thought that compounds isolated by this method are trifluoroacetate salts.
    • Mass Directed Automated Preparative HPLC Column, Conditions and Eluent Method C
  • This is identical to method A. After purification but before solvent removal an excess (between a few drops and 0.5 ml) of dilute hydrochloric acid is added to the product containing fractions.
  • It is thought that compounds isolated by this method are hydrochloride salts.
  • Product Isolation by Filtration Directly from the Reaction Mixture
  • It is thought that compounds isolated by this method from reactions involving displacement of a 4-chloroquinoline intermediate with an amine of formula R1R2NH are hydrochloride salts.
    • ‘Hydrophobic Frit’
  • This refers to a Whatman PTFE filter medium (frit), pore size 5.0 μm, housed in a polypropylene tube.
    • Oasis Cartridge
  • This refers to a Waters Oasis™ HLB Liquid Phase Extraction Cartridge
  • Evaporation of Product Fractions after Purification
  • Reference to column chromatography, SPE and preparative HPLC purification includes evaporation of the product containing fractions to dryness by an appropriate method.
    • Aqueous Ammonia Solutions
  • ‘880 Ammonia’ or ‘0.880 ammonia’ refers to concentrated aqueous ammonia (specific gravity 0.880).
    • INTERMEDIATES AND EXAMPLES
  • All reagents not detailed in the text below are commercially available from established suppliers such as Sigma-Aldrich.
    • Intermediate 1 1-(Cyclopentylthio)-4-nitrobenzene
  • Figure US20090312325A1-20091217-C00034
  • Cyclopentanethiol (1.0 g) (available from Aldrich) was dissolved in acetonitrile (10 ml) and potassium carbonate (1.35 g) was added. After 5 min, 1-fluoro-4-nitrobenzene (1.38 g) (available from Aldrich) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with ether. The organic layer was washed with 1M aqueous sodium hydroxide (20 ml), water (20 ml), and 1M aqueous hydrochoric acid (20 ml). The organic layer was separated and the solvent evaporated in vacuo to give the title compound as a yellow liquid (0.7 g).
  • 1HNMR (CDCl3) δ 8.12 (2H, m), 7.33 (2H, m), 3.75 (1H, m), 2.19 (2H, m), 1.87-1.62 (6H, m).
    • Intermediate 2 1-(Cyclopentylsulfonyl)-4-nitrobenzene
  • Figure US20090312325A1-20091217-C00035
  • Intermediate 1 (0.7 g) was dissolved in methanol (20 ml) and the solution cooled to 0° C. A solution of oxone (1.93 g) in water (20 ml) was added and the mixture was stirred under nitrogen for 2 h at room temperature. The mixture was extracted with dichloromethane, the layers were separated (hydrophobic frit), and the organic layer evaporated to give the title compound as a yellow oil which crystallised on standing (0.79 g).
  • LC/MS Rt 3.05 min, m/z 273 [MNH4 +]
    • Intermediate 3 4-(Cyclopentylsulfonyl)aniline
  • Figure US20090312325A1-20091217-C00036
  • Intermediate 2 (13.1 g) was dissolved in acetic acid (150 ml) and hydrogenated over palladium on activated carbon (1.6 g) with stirring overnight. The mixture was filtered through Celite filter aid, and the filtrate was evaporated to give a yellow/green oil. The oil was taken up in methanol and an insoluble precipitate filtered off; the filtrate was evaporated in vacuo to give a yellow solid. Trituration with ether and filtration gave the title compound as a pale yellow solid (8.1 g).
  • LC/MS Rt 2.5 min, m/z 243 [MNH4 +]
    • Intermediate 4 Diethyl ({[4-cyclopentylsulfonyl)phenyl]amino}methylidene)propanedioate
  • Figure US20090312325A1-20091217-C00037
  • Intermediate 3 (10.8 g) (Helvetica Chimica Acta 1983, 66(4), 1046-52) and diethyl (ethoxymethylene)malonate (11.4 g) (available from Aldrich) were heated at 130° C. for 2 h. After cooling, the brown oil was scratched around the edge of the flask which caused the oil to solidify. Trituration with methanol gave a beige solid, which was filtered off to give the title compound (12.3 g). The filtrate was evaporated in vacuo to give a brown oil. Purification by chromatography on silica gel, eluting with 5% ethyl acetate/cyclohexane followed by 10% ethyl acetate/cyclohexane, gave an orange solid; trituration with methanol and filtration gave the title compound as a yellow solid (2.5 g; total yield 14.8 g).
  • LC/MS Rt 3.27 min m/z 396 [MH+]
    • Intermediate 5 Ethyl 6-(cyclopentylsulfonyl)-4-oxo-1,4-dihydro-3-guinolinecarboxylate
  • Figure US20090312325A1-20091217-C00038
  • Intermediate 4 (14.7 g) was dissolved in diphenyl ether (150 ml) and the solution heated at 250° C. for 30 min. After cooling, the mixture was diluted with cyclohexane and the resulting precipitate filtered off and washed with further cyclohexane to give the title compound as a beige solid (10.9 g).
  • LC/MS Rt 2.46 min m/z 350 [MH+]
    • Intermediate 6 6-(Cyclopentylsulfonyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
  • Figure US20090312325A1-20091217-C00039
  • Intermediate 5 (10.9 g) was dissolved in ethanol (100 ml) and 2M sodium hydroxide (100 ml), and the mixture was heated under reflux for 3 h. After cooling, the solvent was evaporated in vacuo and the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with 2M hydrochloric acid to between pH 5 and pH 6 which caused a precipitate to form. The precipitate was filtered off, washed with water, and dried in vacuo overnight to give the title compound as a beige solid (9.47 g).
  • LC/MS Rt 2.65 min m/z 322 [MH+]
    • Intermediate 7 4-Chloro-6-(cyclopentylsulfonyl)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00040
  • Intermediate 6 (1.43 g) was suspended in thionyl chloride (20 ml) and N,N-dimethylformamide (5 drops) was added. The mixture was heated under reflux for 2 h. After cooling, the thionyl chloride was evaporated in vacuo and the resulting residue was azeotroped with toluene. 0.880 Ammonia (25 ml) was added dropwise to the yellow solid (caution: exotherm), and the suspension was stirred at room temperature for 16 h. The resulting precipitate was filtered off, washed with water, and dried in vacuo to give the title compound (0.71 g).
  • LC/MS Rt 2.47 min m/z 339 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00041
    Intermediate Starting material/ LCMS LCMS
    No. R3— R19— R20— source MH+ Rt (min)
    Intermediate 8 Ph— H— H— 4-(phenylsulfonyl)aniline/ 347 2.58
    Maybridge
    Intermediate 9 Me— H— H— 4-(methylsulphonyl)aniline/ 285 2.00
    Salor
    Intermediate 16 Ph— H— Me— Intermediate 15 361 2.78
    Intermediate 17 Me— Me— H— 1-fluoro-2-methyl-4- 299 2.19
    nitrobenzene/
    Aldrich
    Intermediate 95 tBu— H— H— 4-[(1,1- 327 2.40
    dimethylethyl)sulphonyl]aniline/
    Helvetica Chimica Acta
    (1983), 66(4), 1046-52
    • Intermediate 30 4-Chloro-6-[(1-methylethyl)sulfonyl]-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00042
  • This was made in the same manner as Intermediate 7 starting from 4-[(1-methylethyl)sulfonyl]aniline (Helvetica Chimica Acta (1983), 66(4), 1046-52).
  • LCMS Rt 2.27 min m/z 313 [MH+]
  • The following were also made in the same manner as Intermediate 7, with the proviso that the intermediates of formula
  • Figure US20090312325A1-20091217-C00043
  • were prepared from the appropriate 4-fluoronitrobenzene in a similar manner to Intermediate 15:
  • Figure US20090312325A1-20091217-C00044
    Starting Starting
    Nitroaryl Sulfinic LCMS
    Intermediate Compound/ Acid/ LCMS Rt
    Number R3SO2— R20— Supplier Supplier MH+ (min)
    Intermediate 31
    Figure US20090312325A1-20091217-C00045
         		H— 4- fluoronitrobenzene/ Aldrich Sodium 4- (methyloxy) benzenesulfinate/ WO 9830566 A1 379 2.72
    Intemediate 32
    Figure US20090312325A1-20091217-C00046
         		Me— 5-fluoro-2- nitrotoluene/ Aldrich Sodium 4- (methyloxy) benzenesulfinate/ WO 9830566 A1 391 2.91
    Intermediate 34
    Figure US20090312325A1-20091217-C00047
         		Me— 5-fluoro-2- nitrotoluene/ Aldrich Sodium 4- methylbenzene sulfinate/ Aldrich 375 2.93
    Intermediate 33 MeSO2— Me— 5-fluoro-2- Methanesulfinic 299 2.12
    nitrotoluene/ acid sodium salt/
    Aldrich Lancaster
    Intermediate 50 MeSO2— MeO— 4-fluoro-2- Methanesulfinic 315 1.99
    (methyloxy)-1- acid sodium salt/
    nitrobenzene/ Lancaster
    Maybridge
    • Intermediate 10 Diethyl {[(4-iodophenyl)amino]methylidene}propanedioate
  • Figure US20090312325A1-20091217-C00048
  • A mixture of 4-indoaniline (208 g) (available from Aldrich) and diethyl (ethoxymethylene)malonate (210 ml) (available from Aldrich) was heated to ca. 60° C., whereupon the mixture set solid. Heating was continued to 100° C., and then the mixture was removed from heating and broken up. Heating was continued at 100° C. for 1 h, and the solid was collected, washed with cyclohexane (1 L) and ethanol (2×500 ml), and dried in vacuo at 40° C. overnight to give the title compound as a white solid (356 g).
  • LC/MS Rt 3.57 min m/z 390 [MH+]
    • Intermediate 11 Ethyl 6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate
  • Figure US20090312325A1-20091217-C00049
  • Diphenyl ether (175 ml) was heated to reflux temperature, and Intermediate 10 was gradually added down an air condenser. Once all the reagent had been added the mixture was heated under reflux for a further 30 min. The mixture was then cooled and 2-methylpentane (200 ml) was added. The solid formed was collected by filtration to give the title compound (24.6 g).
  • 1HNMR (DMSO) δ 8.58 (1H, s), 8.42 (1H, d), 7.99 (1H, dd), 7.44 (1H, d), 4.21 (2H, q), 1.28 (3H, t)
    • Intermediate 12 6-Iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
  • Figure US20090312325A1-20091217-C00050
  • Sodium hydroxide (9.8 g) was dissolved in water (61 ml) and ethanol (30 ml) was added. The resultant solution was added to Intermediate 11, and the mixture was heated under reflux for 60 min with stirring under nitrogen. Concentrated hydrochloric acid was added, giving a white precipitate. After stirring for 16 h, the precipitate was filtered off, washed with water and dried in vacuo to give the title compound as a white solid (8.15 g).
  • LC/MS Rt 3.01 min m/z 316 [MH+]
    • Intermediate 13 4-Chloro-6-iodo-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00051
  • Intermediate 12 (8.1 g) was added portionwise to stirred thionyl chloride (60 ml). N,N-dimethylformamide (3 drops) was added and the mixture was heated under reflux with stirring under nitrogen for 1.75 h. The excess thionyl chloride was evaporated in vacuo and the residue was azeotroped with toluene (2×50 ml). The resulting pale yellow solid was added portionwise to stirred 0.880 ammonia (250 ml), and the mixture stirred at room temperature for 1.5 h. The solid was filtered off, washed with water and dried in vacuo at 60° C. for 16 h to give the title compound as a white solid (7.94 g).
  • LC/MS Rt 2.72 min m/z 332 [MH+]
  • The following were made in the same manner as Intermediate 13:
  • Figure US20090312325A1-20091217-C00052
    LCMS
    Intermediate Starting LCMS Rt
    Number R19— R20— Material MH+ (min)
    Intermediate 48 H— Me— 4-iodo-2- 347 3.06
    methylaniline/
    Aldrich
    Intermediate 49 H— Cl— 2-chloro-4- 367 2.99
    iodoaniline/
    Avocado
    Intermediate 72 H— Et— Intermediate 73 361 3.22
    Intermediate 87 H— F— 2-Fluoro-4-iodo 352 2.65
    aniline/Aldrich
    Intermediate 67 Cl— H— from 3-chloro-4- 367 3.07
    iodoaniline/
    Aldrich
    • Intermediate 68 4,7-Dichloro-8-methyl-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00053
  • Intermediate 68 was prepared from 2-methyl-3-chloroaniline (Aldrich) in a similar manner to Intermediate 13.
  • LC/MS Rt 3.00 min m/z 255 [MH+]
    • Intermediate 14 6-Iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00054
  • Intermediate 13 (5.0 g) was dissolved in ethanol (60 ml), 3-methoxyaniline (3.37 ml) (available from Aldrich) was added, and the mixture was heated under reflux for 2.5 h. The resulting precipitate was filtered off and washed with ether to give the title compound.
  • LC/MS Rt 2.59 min m/z 420 [MH+]
  • The following were made in the same manner as Intermediate 14, using acetonitrile as solvent:
  • Figure US20090312325A1-20091217-C00055
    LCMS
    Intermediate Starting Amine/ LCMS Rt
    Number (a) R1NH— R20— Material Source MH+ (min)
    Intermediate 38 HCl
    Figure US20090312325A1-20091217-C00056
         		Cl— Intermediate 49 3-methylaniline/ Aldrich 438 3.56
    Intermediate 35 HCl
    Figure US20090312325A1-20091217-C00057
         		Me— Intermediate 48 4-fluoro-3- methoxyaniline/ Apollo-Chem 452 2.78
    Intermediate 36 HCl
    Figure US20090312325A1-20091217-C00058
         		Me— Intermediate 48 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry (1980), 17(6), 1333-5. 446 2.81
    Intermediate 39 HCl
    Figure US20090312325A1-20091217-C00059
         		Cl— Intermediate 49 4-fluoro-3- methoxyaniline/ Apollo-Chem 472 3.29
    Intermediate 40 HCl
    Figure US20090312325A1-20091217-C00060
         		Cl— Intermediate 49 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry (1980), 17(6), 1333-5. 466 3.35
    Intermediate 41 HCl
    Figure US20090312325A1-20091217-C00061
         		Cl— Intermediate 49 3- aminobenzonitrile/ Aldrich 449 3.19
    Intermediate 42 HCl
    Figure US20090312325A1-20091217-C00062
         		Cl— Intermediate 49 3-fluoroaniline/ Aldrich 442 3.40
    Intermediate 43 HCl
    Figure US20090312325A1-20091217-C00063
         		Cl— Intermediate 49 1-methyl-1H- indazol-6-amine hydrochloride/ Synthetic Communications (1996), 26(13), 2443-2447. 477 3.05
    Intermediate 44 HCl
    Figure US20090312325A1-20091217-C00064
         		Me— Intermediate 48 1-methyl-1H- benzimidazol-6- amine/ Heterocycles (1991), 32(5), 1003-12. 458 2.03
    Intermediate 45 HCl
    Figure US20090312325A1-20091217-C00065
         		Me— Intermediate 48 3-methoxyaniline/ Aldrich 434 2.75
    Intermediate 46 HCl
    Figure US20090312325A1-20091217-C00066
         		Me— Intermediate 48 3- aminobenzonitrile/ Aldrich 429 2.93
    Intermediate 61 HCl
    Figure US20090312325A1-20091217-C00067
         		Me— Intermediate 48 3-fluoroaniline/ Aldrich 422 3.02
    Intermediate 74 HCl
    Figure US20090312325A1-20091217-C00068
         		Et— Intermediate 72 4-fluoro-3- methoxyaniline/ Apollo-Chem 466 2.92
    Intermediate 75 HCl
    Figure US20090312325A1-20091217-C00069
         		Et— Intermediate 72 3-fluoroaniline/ Aldrich 436 3.24
    Intermediate 76 HCl
    Figure US20090312325A1-20091217-C00070
         		Et— Intermediate 72 3-chloroaniline/ Aldrich 452 3.44
    Intermediate 77 HCl
    Figure US20090312325A1-20091217-C00071
         		Et— Intermediate 72 3-aminobenzonitrile/ Aldrich 443 3.12
    Intermediate 78 HCl
    Figure US20090312325A1-20091217-C00072
         		Et— Intermediate 72 3-methylaniline/ Aldrich 432 3.15
    Intermediate 79 HCl
    Figure US20090312325A1-20091217-C00073
         		Et— Intermediate 72 1-methyl-1H- indazol-6-amine hydrochloride/ Synthetic Communications (1996), 26(13), 2443-2447 472 2.8
    Intermediate 80 HCl
    Figure US20090312325A1-20091217-C00074
         		Et— Intermediate 72 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry (1980), 17(6), 1333-5. 460 2.97
    Intermediate 88 HCl
    Figure US20090312325A1-20091217-C00075
         		F— Intermediate 87 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry (1980), 17(6), 1333-5. 450 3.06
    Intermediate 89 HCl
    Figure US20090312325A1-20091217-C00076
         		F— Intermediate 87 3-fluoroaniline/ Aldrich 426 3.11
    Intermediate 90 HCl
    Figure US20090312325A1-20091217-C00077
         		F— Intermediate 87 3-chloroaniline/ Aldrich 442 3.19
    Intermediate 91 HCl
    Figure US20090312325A1-20091217-C00078
         		F— Intermediate 87 3-methylaniline/ Aldrich 422 3.15
    Intermediate 92 HCl
    Figure US20090312325A1-20091217-C00079
         		F— Intermediate 87 3- aminobenzonitrile/ Aldrich 433 2.88
    Intermediate 93 HCl
    Figure US20090312325A1-20091217-C00080
         		F— Intermediate 87 1-methyl-1H- indazol-6-amine hydrochloride/ Synthetic Communications (1996), 26(13), 2443-2447 462 2.87
    Intermediate 94 HCl
    Figure US20090312325A1-20091217-C00081
         		F— Intermediate 87 4-fluoro-3- methoxyaniline/ Apollo-Chem 456 3.11
    (a) Salt form: HCl = hydrochloride
    • Intermediate 63 7-Chloro-6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00082
  • Intermediate 63 was prepared from Intermediate 67 in a similar manner to Intermediate 14, using acetonitrile as solvent.
  • LC/MS Rt 3.15 min m/z 452 [MH+]
    • Intermediate 66 7-Chloro-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00083
  • Intermediate 66 was prepared from Intermediate 68 using 3-methoxyaniline in a similar manner to Intermediate 14.
  • LC/MS Rt 2.80 min m/z 342 [MH+]
    • Intermediate 104 7-Chloro-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00084
  • Intermediate 104 was prepared from Intermediate 68 using 2,3-dihydro-1-benzofuran-4-amine in a similar manner to Intermediate 14, using acetonitrile as solvent.
  • LC/MS Rt 2.80 min m/z 354 [MH+]
    • Intermediate 15 3-Methyl-4-nitrophenyl phenyl sulphone
  • Figure US20090312325A1-20091217-C00085
  • 4-Fluoro-2-methyl-1-nitrobenzene (2.6 g) (available from Aldrich) and sodium benzenesulfinate (3.0 g) (available from Aldrich) were heated in N,N-dimethylacetamide (40 ml) at 50° C. for 16 h. After cooling the mixture was filtered, the filtrate collected and the solvent removed in vacuo. The residue was triturated with cyclohexane and the resultant precipitate collected by filtration to give the title compound as a white solid (3.5 g).
  • LC/MS Rt 3.22 min m/z 295 [MNH4 +]
    • Intermediate 18 3-Amino-N-hydroxybenzenecarboximidamide
  • Figure US20090312325A1-20091217-C00086
  • To a stirred solution of 3-aminobenzonitrile (4.0 g) (available from Aldrich) in ethanol (100 ml) was added hydroxylamine hydrochloride (4.7 g) and potassium carbonate (14.0 g) and the mixture heated under reflux for 22 h. After cooling to room temperature the mixture was filtered through ‘hyflo’ filter aid, the residue washed with ethanol, and the filtrates concentrated in vacuo to give the title compound as a viscous oil (5.3 g).
  • TLC SiO2 (ethyl acetate) Rf=0.34
    • Intermediate 19 3-(5-Methyl-1,2,4-oxadiazol-3-yl)aniline
  • Figure US20090312325A1-20091217-C00087
  • To a stirred solution of Intermediate 18 (5.3 g) in dry tetrahydrofuran (50 ml) was added 4 Å molecular sieves, followed by sodium hydride (60% dispersion in mineral oil; 1.5 g) and the mixture heated at 65° C. for 30 min. After cooling to room temperature methyl acetate (2.8 ml) was added and the mixture heated under reflux for 16 h. After cooling to 20° C. the mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound as a white solid (4.0 g).
  • TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.22
    • Intermediate 20 1-[2-Amino-3-chloro-6-(methyloxy)phenyl]-2-chloroethanone
  • Figure US20090312325A1-20091217-C00088
  • Boron trichloride (25 g) was added to dry dichloromethane (250 ml) at 0° C. and the resulting solution stirred for 10 min. A solution of 2-chloro-5-(methyloxy)aniline (30.6 g) (available from Pfaltz Bauer) in dichloromethane (100 ml) was added dropwise over 15 min to give a dark red/black mixture which was stirred for 20 min at 0° C. Chloroacetonitrile (29.5 ml) was added, followed by the portionwise addition of aluminum chloride (28.4 g). The mixture was stirred at room temperature for 1 h and then heated under reflux for 3 h. The mixture was cooled in an ice/water bath and 2M hydrochloric acid added, followed by 5M hydrochloric acid (200 ml). The resulting biphasic mixture was stirred at room temperature for 15 h and then heated at 80° C. for 30 min. After cooling to room temperature the organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulphate and concentrated in vacuo to give the title compound as a dark khaki solid (57.8 g).
  • TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.52
    • Intermediate 21 4-Amino-5-chloro-1-benzofuran-3(2H)-one
  • Figure US20090312325A1-20091217-C00089
  • To a stirred suspension of aluminum chloride (77.6 g) in dry dichloromethane (300 ml) was added dropwise a solution of Intermediate 20 (45 g) in dichloromethane (250 ml). The mixture was heated under reflux for 6 h and then cooled to room temperature. The mixture was decomposed by the dropwise addition of 2M hydrochloric acid, then methanol and dichloromethane were added and the organic layer collected. The aqueous layer was extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in boiling methanol and an excess of triethylamine added. The solvent was removed in vacuo and the residue absorbed onto silica gel. Purification by chromatography on silica gel eluting with a gradient of 20% to 50% ethyl acetate in cyclohexane gave the title compound as an orange/brown solid (46.9 g).
  • TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.66
    • Intermediate 22 N-(5-Chloro-3-oxo-2,3-dihydro-1-benzofuran-4-yl)-2,2,2-trifluoroacetamide
  • Figure US20090312325A1-20091217-C00090
  • To a stirred solution of Intermediate 21 (2 g) in dichloromethane (35 ml) at 0° C. was added triethylamine (2.1 ml) and trifluoroacetic anhydride (2.1 ml) and the mixture stirred at 0° C. for 30 min, then at room temperature for 30 min. The mixture was quenched by the dropwise addition of water, the organic layer washed with water and the combined aqueous layers re-extracted with dichloromethane. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Purification by chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane, gave the title compound as a bright yellow/orange solid (1.0 g).
  • TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.69
    • Intermediate 23 N-(5-Chloro-3-methylidene-2,3-dihydro-1-benzofuran-4-yl)-2,212-trifluoroacetamide
  • Figure US20090312325A1-20091217-C00091
  • To a mixture of potassium tert-butoxide (2.0) and methyltriphenylphosphonium iodide (7.1 g) was added dry toluene (70 ml) and the mixture stirred at room temperature for 30 min, then heated under reflux for 30 min. The mixture was cooled to room temperature, a solution of Intermediate 22 (1.0 g) in toluene (30 ml) added dropwise and the mixture heated under reflux for 30 min. The mixture was cooled and quenched by the dropwise addition of saturated ammonium chloride solution. The mixture was partitioned between ethyl acetate and water and the organic phase washed with water. The combined aqueous layers were re-extracted with ethyl acetate and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give a dark brown oil. Purification by column chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane, gave the title compound as a rose coloured solid (0.5 g).
  • TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.50
    • Intermediate 24 2,2,2-Trifluoro-N-(3-methyl-2,3-dihydro-1-benzofuran-4-yl)acetamide
  • Figure US20090312325A1-20091217-C00092
  • A solution of Intermediate 23 (0.10 g) in ethanol (20 ml) was added to 10% palladium on carbon (0.20 g) and the mixture stirred under an atmosphere of hydrogen for 20 h. The mixture was filtered through ‘hyflo’ filter aid, washed with ethanol and the solvent removed in vacuo to give the title compound as a white solid (0.092 g).
  • TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.53
    • Intermediate 25 3-Methyl-2,3-dihydro-1-benzofuran-4-amine
  • Figure US20090312325A1-20091217-C00093
  • To a stirred solution of Intermediate 24 (0.087 g) in 2:2:1 tetrahydrofuran:methanol:water (5 ml) was added lithium hyroxide (0.149 g) and the mixture stirred at room temperature for 47 h, then at 60° C. for 2.5 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The aqueous layer was re-extracted with dichloromethane and the combined organic layers dried over sodium sulphate and concentrated in vacuo to give the title compound as a colourless oil (0.049 g). TLC SiO2 (30% ethyl acetate in cyclohexane) Rf=0.69
    • Intermediate 26 3-(1-Methyl-1H-pyrazol-3-yl)aniline
  • Figure US20090312325A1-20091217-C00094
  • A solution of 3-(4-bromo-1-methyl-1H-pyrazol-3-yl)aniline (1.0 g) (available from Maybridge) in ethanol (20 ml) was added to a pre-hydrogenated suspension of 5% palladium on charcoal (0.5 g) in ethanol (40 ml). The resulting suspension was stirred under an atmosphere of hydrogen for 3 h. The mixture was filtered through ‘hyflo’ filter aid and the filter pad washed with ethanol (50 ml). The combined filtrate was evaporated in vacuo to give a brown gum. This gum was treated with 2M sodium carbonate solution (100 ml) and extracted with ethyl acetate (2×100 ml); the organic layer was dried over magnesium sulphate and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with diethyl ether, gave the title compound as a white crystalline solid (0.5 g).
  • TLC SiO2 (diethyl ether) Rf=0.28
    • Intermediate 27 1,2-Dimethyl-1H-benzimidazol-6-amine
  • Figure US20090312325A1-20091217-C00095
  • To a stirred solution of tin (II) chloride dihydrate (4.7 g) in concentrated hydrochloric acid (15 ml) was added 1,2-dimethyl-6-nitro-1H-benzimidazole (1 g) (J. Chem. Soc., 1931, 1143-1153), and the mixture was stirred at room temperature for 6 h. The mixture was poured onto ice and chloroform, and basified to pH 10 by the addition of 10M sodium hydroxide solution. The mixture was extracted several times with chloroform and the combined organic extracts dried and concentrated in vacuo to give a brown solid. This was crystallised from ethanol to give the title compound. TLC SiO2 (dichloromethane:methanol:880 ammonia 90:10:1) Rf 0.75.
    • Intermediate 28 3-Mercapto-N,N-dimethylbenzamide
  • Figure US20090312325A1-20091217-C00096
  • Iodine (1 g) was added to a stirred solution of 3-[(dimethylamino)carbonylbenzenesulfonyl chloride (2 g) (Borthwick et al, J. Med. Chem. 2002, 45(1), 1-18) and triphenylphosphine (8.4 g) in 1,4-dioxane at 0° C. The mixture was stirred for 0.5 h at ambient temperature. The mixture was poured into a sodium sulphite solution (50 ml), extracted into ethyl acetate (2×30 ml) and washed with 2N sodium hydroxide solution (2×40 ml). The alkaline extracts were acidified and re-extracted into dichloromethane (3×50 ml). The extracts were washed with water (100 ml), dried (Na2SO4) and evaporated to give the title compound as a colourless solid (1.1 g).
  • LC/MS Rt 2.32 min, m/z 182 [MH+]
    • Intermediate 28 3-Mercapto-N,N-dimethylbenzamide (alternative synthesis)
  • Figure US20090312325A1-20091217-C00097
  • A solution of 3,3′-dithiobis(N,N-dimethylbenzamide) (Ger. Offen. (1978), DE 2821410) (54.2 g) in 1,4-dioxane (400 ml) and water (100 ml) was warmed to 35° C. and concentrated hydrochloric acid (3 ml) was added. Triphenylphosphine (55 g) was added portionwise over 25 min maintaining the temperature below 42° C., then the mixture was stirred at 40° C. for 2.5 h. After cooling to ambient temperature the mixture was concentrated to ca. 200 ml, and partitioned between 2N aqueous sodium hydroxide solution (250 ml) and ethyl acetate (500 ml). The aqueous phase was separated and washed with ethyl acetate (2×300 ml). The aqueous phase was acidified with 5N hydrochloric acid and extracted with ethyl acetate (3×400 ml). The organic extracts of the acidic aqueous phase were combined, dried over sodium sulphate, and the solvent evaporated to leave a solid. The solid was dissolved in hot ethyl acetate (100 ml) and 40-60 petrol (160 ml) was added to the hot solution. The solution was left to cool and the resulting solid filtered off, washed and dried to give the title compound (28.4 g)
  • LC/MS Rt 2.24 min m/z 182 [MH+].
    • Intermediate 29 6-({3-[(Dimethylamino)carbonyl]phenyl}thio)-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide
  • Figure US20090312325A1-20091217-C00098
  • A stirred mixture of Intermediate 45 (0.5 g), Intermediate 28 (0.392 g), cuprous iodide (0.03 g) and potassium carbonate (0.38 g) in 1,3-dimethyltetrahydropyrimidin-2(1H)-one (7 ml) was heated at 100° C. for 16 h. The mixture was cooled, poured into water (100 ml) and extracted into ethyl acetate (3×40 ml). The extracts were washed with water (100 ml), dried (Na2SO4) and evaporated. The residual oil was triturated with ethyl acetate (10 ml) to give the title compound as a fawn coloured solid (0.263 g).
  • LC/MS Rt 2.67 min, m/z 487 [MH+]
    • Intermediate 37 1,1-Dimethylethyl [(6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinyl)carbonyl]carbamate
  • Figure US20090312325A1-20091217-C00099
  • To a stirred suspension of Intermediate 14 (6.93 g) in dichloromethane (170 ml) was added N,N-dimethyl-4-aminopyridine (2.42 g) followed by di-tert-butyldicarbonate (18 g) (Aldrich). The solution was stirred at room temperature for 25 min, then quenched by addition of aqueous citric acid (200 ml) and stirred vigorously for 30 min. The organic layer was separated and the aqueous layer washed with dichloromethane (50 ml). The combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was trituated in diethyl ether to give a yellow solid which was collected by filtration, washed with diethyl ether (3×15 ml) and dried in vacuo to give the title compound as a yellow solid (6.6 g).
  • LC/MS Rt 3.59 min m/z 520 [MH+]
    • Intermediate 47 6-[(4-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)thio]-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide
  • Figure US20090312325A1-20091217-C00100
  • A stirred mixture of Intermediate 37 (0.8 g) and 4-{[tert-butyl(dimethyl)silyl]oxy}benzenethiol (0.74 g, EP465802A1), with (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.05 g), potassium tert-butoxide (0.26 g) and tris(dibenzylideneacetone) dipalladium(0) (0.08 g) in toluene (30 ml) was heated at 106° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (25 ml) and washed with a sodium carbonate solution (30 ml). The organic extracts were washed with water (30 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate/diethyl ether (7:3) as the eluent. The appropriate fractions were concentrated in vacuo to give the title compound as a yellow foam (0.38 g).
  • LC/MS Rt 3.9 min, m/z 532 [MH+]
    • Intermediate 51 1,1-Dimethylethyl 4-amino-1H-indazole-1-carboxylate
  • Figure US20090312325A1-20091217-C00101
  • To a solution of 4-nitro-1H-indazole (1.57 g, Journal of Heterocyclic Chemistry 1979, 16(8), 1599-603) and di-tert-butyldicarbonate (2.33 g) in acetonitrile (30 ml) was added N,N-dimethyl-4-aminopyridine (0.059 g). The reaction mixture was stirred at room temperature for 30 min, then concentrated in vacuo to leave a brown solid which was purified by silica SPE, eluting sequentially with dichloromethane and diethyl ether to give 1,1-dimethylethyl 4-nitro-1H-indazole-1-carboxylate as a yellow solid (1.9 g).
  • LC/MS Rt 3.26 min, m/z 263 [MH+]
  • 1,1-Dimethylethyl 4-nitro-1H-indazole-1-carboxylate (1.2 g) was dissolved in ethanol (150 ml) and stirred with 10% palladium on carbon (0.24 g) under an atmosphere of hydrogen (1 atmosphere pressure) for 18 h. The solution was filtered through a pad of celite and the filtrate concentrated in vacuo to give the title compound as a yellow-orange solid (1.03 g).
  • LC/MS Rt 2.36 min, m/z 234 [MH+]
    • Intermediate 52 Ethyl 3-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)thio]propanoate
  • Figure US20090312325A1-20091217-C00102
  • A mixture containing Intermediate 35 (1.4 g), ethyl 3-mercaptopropionate (0.74 g, available from Aldrich), potassium tert-butoxide (0.64 g), tris(dibenzylideneacetone) dipalladium(0) (0.26 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.15 g) was dissolved in N,N-dimethylformamide (20 ml) and stirred under an atmosphere of nitrogen at 100° C. for 18 h. The solvents were concentrated in vacuo and the residue dissolved in methanol. This was purified by chromatography on an SPE column eluting with methanol and a solution of ammonia in methanol, to give the title compound as a brown foam (1.06 g).
  • LC/MS Rt 2.69 min, m/z 458 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00103
    LCMS
    Intermediate Starting LCMS Rt
    Number R1NH— Material MH+ (min)
    Intermediate 57
    Figure US20090312325A1-20091217-C00104
         		Intermediate 36 452 2.67
    Intermediate 58
    Figure US20090312325A1-20091217-C00105
         		Intermediate 62 411 2.36
    Intermediate 103
    Figure US20090312325A1-20091217-C00106
         		Intermediate 61 428 2.86
    • Intermediate 53 3-[(3-(Aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)thio]propanoic acid
  • Figure US20090312325A1-20091217-C00107
  • A solution of Intermediate 52 (0.95 g) in ethanol (10 ml) was treated with 2M sodium hydroxide (10 ml) and the resulting solution was left standing at room temperature overnight. The solvent was evaporated in vacuo. The residue was dissolved in water and acidified with 2M hydrochloric acid to pH 4. The resulting precipitate was filtered off, washed with water and dried in vacuo to give the title compound as an orange solid (0.8 g).
  • LC/MS Rt 2.3 min, m/z 430 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00108
    LCMS
    Intermediate Starting LCMS Rt
    Number R1NH— Material MH+ (min)
    Intermediate 59
    Figure US20090312325A1-20091217-C00109
         		Intermediate 103 400 2.39
    Intermediate 60
    Figure US20090312325A1-20091217-C00110
         		Intermediate 58 383 2.10
    • Intermediate 54 4-{[3-(Methyloxy)phenyl]amino}-6-(4-piperidinylsulfonyl)-3-quinolinecarboxamide trifluoroacetate
  • Figure US20090312325A1-20091217-C00111
  • To a mixture containing Example 377 (0.64 g) in anisole (9 ml) was added a solution of 95% trifluoroacetic acid in water (16 ml). The mixture was stirred for 1.5 h at room temperature and was then concentrated in vacuo. The residue was co-evaporated with toluene (2×20 ml), triturated with ethyl acetate and filtered to give a yellow solid. This residue was again triturated with ethyl acetate and filtered to give the title compound as a yellow solid (0.570 g).
  • LC/MS Rt 1.94 min, m/z 455 [MH+]
    • Intermediate 55 1,1-Dimethylethyl 4-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)sulfonyl]-1-piperidinecarboxylate
  • Figure US20090312325A1-20091217-C00112
  • To a solution of Intermediate 35 (1.0 g) in N,N-dimethylformamide (30 ml) under an atmosphere of nitrogen was added 1,1-dimethylethyl 4-mercapto-1-piperidinecarboxylate (0.89 g, U.S. Pat. No. 5,317,025A), potassium tert-butoxide (0.46 g), tris(dibenzylideneacetone) dipalladium(0) (0.19 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.11 g). The mixture was heated to 100° C. for 3 h, cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) then dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by SPE (eluting with a gradient of 0 to 5% methanol in chloroform) to give intermediate 1,1-dimethylethyl 4-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)thio]-1-piperidinecarboxylate as a yellow solid (1.1 g). This sulphide was dissolved in N,N-dimethylformamide (50 ml) and oxone (5.15 g) was added portionwise. The mixture was stirred at room temperature for 3 h, then quenched by addition of 1M sodium sulphite solution (500 ml). The mixture was extracted with chloroform (2×200 ml), and the organic layers were washed with 10% lithium chloride solution, dried over magnesium sulphate, filtered and concentrated to give the title compound as a pale yellow solid (0.71 g) after trituration with ether.
  • LC/MS Rt 3.04 min, m/z 573 [MH+]
  • Similarly prepared from Intermediate 35 and 1,1-dimethylethyl (2-mercaptoethyl) carbamate (available from Aldrich) was:
    • Intermediate 56 1,1-Dimethylethyl {2-[(3-(aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)sulfonyl]ethyl}carbamate
  • Figure US20090312325A1-20091217-C00113
  • LC/MS Rt 2.79 min, m/z 533 [MH+]
    • Intermediate 62 6-Iodo-8-methyl-4-(3-pyridinylamino)-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00114
  • To a solution of Intermediate 48 (1.1 g) in N,N-dimethylformamide (20 ml) was added 3-aminopyridine (0.8 g, available from Aldrich) and pyridine hydrochloride (0.7 g, available from Aldrich). The mixture was heated at 80° C. under nitrogen for 2 days. The solvent was evaporated in vacuo. The residue was triturated with methanol and the precipitate filtered off to give the title compound as a brown solid (0.9 g).
  • LC/MS Rt 2.32 min m/z 405 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00115
    Intermediate LCMS
    Number Starting Amine/ LCMS Rt
    (a) (b) R1NH— R20— Material Supplier MH+ (min)
    Intermediate 81 HCl
    Figure US20090312325A1-20091217-C00116
         		Et— Intermediate 72 3-pyridinamine/ Aldrich 419 2.52
    Intermediate 82 HCl
    Figure US20090312325A1-20091217-C00117
         		Et— Intermediate 72 5-chloro-3- pyridinamine/ Synchem OHG 453 3.19
    Intermediate 83 HCl
    Figure US20090312325A1-20091217-C00118
         		Et— Intermediate 72 5-fluoro-3- pyridinamine/ Synchem OHG 437 2.93
    Intermediate 84 HCl
    Figure US20090312325A1-20091217-C00119
         		F— Intermediate 87 5-fluoro-3- pyridinamine/ Synchem OHG 427 2.6
    Intermediate 85 HCl
    Figure US20090312325A1-20091217-C00120
         		F— Intermediate 87 5-chloro-3- pyridinamine/ Synchem OHG 443 2.88
    Intermediate 86 HCl
    Figure US20090312325A1-20091217-C00121
         		F— Intermediate 87 3-pyridinamine/ Aldrich 409 2.27
    96 HCl
    Figure US20090312325A1-20091217-C00122
         		Cl— Intermediate 49 3-pyridinamine/ Aldrich 425 2.52
    97 HCl
    Figure US20090312325A1-20091217-C00123
         		Me— Intermediate 48 5-chloro-3- pyridinamine/ Synchem OHG 439 2.95
    98 HCl
    Figure US20090312325A1-20091217-C00124
         		Me— Intermediate 48 5-fluoro-3- pyridinamine/ Synchem OHG 423 2.65
    99 HCl
    Figure US20090312325A1-20091217-C00125
         		Cl— Intermediate 49 5-fluoro-3- pyridinamine/ Synchem OHG 443 2.91
    100 HCl
    Figure US20090312325A1-20091217-C00126
         		Cl— Intermediate 49 5-chloro-3- pyridinamine/ Synchem OHG 459 2.94
    101 HCl
    Figure US20090312325A1-20091217-C00127
         		Me— Intermediate 48 1-ethyl-1H- pyrazol-5-amine/ Aldrich 422 2.58
    102 HCl
    Figure US20090312325A1-20091217-C00128
         		Cl— Intermediate 49 1-ethyl-1H- pyrazol-5-amine/ Aldrich 442 2.86
    (a) Salt form HCl = hydrochloride
    (b) All products isolated by trituration with acetonitrile and filtration.
    • Intermediate 73 2-Ethyl-4-iodoaniline
  • Figure US20090312325A1-20091217-C00129
  • To a stirred solution of 2-ethylaniline (1.88 g, available from Aldrich) and sodium acetate (1.27 g) in acetic acid (20 ml) was added iodine monochloride (1 ml, available from Aldrich). The mixture was stirred at 20° C. for 90 min and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The organic layer was dried using a hydrophobic frit and the solvent was removed in vacuo. Purification by C18 SPE eluting with 20% acetonitrile in water gave the title compound as a purple solid (0.402 g).
  • LC/MS Rt 3.23 min, m/z 248 [MH+]
    • Intermediate 64 7-({3-[(Dimethylamino)carbonyl]phenyl}thio)-6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00130
  • A stirred mixture of Intermediate 63 (0.4 g), Intermediate 28 (0.16 g) and potassium carbonate (0.38 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was heated at 100° C. under nitrogen for 3 h. A further portion of Intermediate 28 (0.07 g) was added and the mixture stirred at 60° C. for 23 h. The cooled mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×70 ml) and brine (70 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with methanol followed by mass directed preparative HPLC (Method A) to give the title compound as a yellow foam (0.12 g).
  • LC/MS Rt 2.94 min, m/z 599 [MH+]
    • Intermediate 65 7-({3-[(Dimethylamino)carbonyl]phenyl}sulfinyl)-6-iodo-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00131
  • Oxone (0.5 g) was added portionwise to a stirred solution of Intermediate 64 (0.12 g) in N,N-dimethylformamide (5 ml). The solution was stirred at room temperature under nitrogen for 21 h. More oxone (0.5 g) was added and the mixture was stirred for a further 3 h, quenched with a solution of sodium sulphite (1.5 g) in water (15 ml), diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a yellow solid (0.15 g).
  • LC/MS Rt 2.70 min, m/z 615 [MH+]
    • Intermediate 69 5-Mercapto-N,N-dimethyl-3-pyridinecarboxamide
  • Figure US20090312325A1-20091217-C00132
  • Sodium thiomethoxide (3 g) was added to a stirred solution of 5-bromo-N,N-dimethyl-3-pyridinecarboxamide (2.5 g, WO2000055168) in N,N-dimethylformamide (40 ml) and the suspension stirred at 100° C. for 4 h. The solvent was concentrated in vacuo, the residue dissolved in 2M sodium hydroxide (35 ml) and water (50 ml), and the solution washed with chloroform (4×75 ml). The aqueous layer was acidified with 2M hydrochloric acid to pH 4 and extracted with chloroform (5×80 ml), and the combined organic layers were washed with brine (20 ml), dried over magnesium sulphate and concentrated in vacuo to give the title compound as an orange oil (1.8 g).
  • LC/MS Rt 0.96 min, m/z 183 [MH+]
    • Intermediate 70 1-Methyl-4-nitro-2,3-dihydro-1H-indole
  • Figure US20090312325A1-20091217-C00133
  • To a stirred solution of 1-methyl-4-nitro-1H-indole (3.8 g, Organic Process Research and Development 2001 5 (6) 604) and borane-tetrahydrofuran complex (1M in tetrahydrofuran, 86.3 ml) at 0° C. under an atmosphere of nitrogen was added, dropwise, trifluoroacetic acid (88 ml). The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 90 min. The mixture was cautiously added to 2M sodium carbonate solution (750 ml) over 20 min and then stirred for 30 min. The mixture was extracted with ethyl acetate (2×300 ml), the combined organic extracts were dried over sodium sulphate and the solvent was removed in vacuo. Purification by column chromatography on silica gel, eluting with hexane:ethyl acetate (9:1) gave the title compound as a red solid (1.97 g).
  • TLC SiO2 (hexane:ethyl acetate (4:1)) Rf=0.61
    • Intermediate 71 1-Methyl-2,3-dihydro-1H-indol-4-amine
  • Figure US20090312325A1-20091217-C00134
  • A solution of Intermediate 70 (0.50 g) in ethanol (30 ml) was added to 10% palladium on carbon (0.050 g) and the mixture was stirred under an atmosphere of hydrogen for 20 min. The mixture was filtered through ‘hyflo’ filter aid and the solvent removed in vacuo to give the title compound as a brown oil (0.405 g).
  • TLC SiO2 (hexane:ethyl acetate (4:1)) Rf=0.25
    • EXAMPLES
  • Experimental details for the preparation of representative Examples are given in full below. Summary details for further Examples prepared by analagous methods are give in the accompanying tables.
    • Example 10 4-[(3-Fluorophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00135
  • Intermediate 9 (0.014 g) was suspended in acetonitrile (3 ml), 3-fluoroaniline (0.0056 g, available from Aldrich) was added, and the mixture was heated under reflux for 16 h. After cooling to room temperature, the mixture was cooled in a refrigerator for 2 h, filtered, and the residue purified by mass directed preparative HPLC (Method A) to give the title compound (0.011 g).
  • LC/MS Rt 1.95 min m/z 359 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00136
    Ex. Amine Isolation LCMS
    No. Starting Reagent/ Method LCMS Rt
    (a) R1NH— R3SO2— Material Source (b) MH+ (min)
    1 HCl
    Figure US20090312325A1-20091217-C00137
         		MeSO2— Intermediate 9 6-aminobenzo thiazole/ Lancaster (I) 399 1.9
    2 HCl
    Figure US20090312325A1-20091217-C00138
         		MeSO2— Intermediate 9 3-amino-N- methyl acetanilide/ Merlin synthesis (I) 413 1.89
    3 HCl
    Figure US20090312325A1-20091217-C00139
         		MeSO2— Intermediate 9 N,N-dimethyl benzene-1,3- diamine hydrochloride/ Aldrich (I) 385 1.83
    4 HCl
    Figure US20090312325A1-20091217-C00140
         		MeSO2— Intermediate 9 3,5- dimethoxyaniline/ Aldrich (I) 402 2.05
    5 HCl
    Figure US20090312325A1-20091217-C00141
         		MeSO2— Intermediate 9 1,2- benzoisoxazol- 5-amine/ Key organics Ltd (8W-0024) (I) 383 1.84
    6 HCl
    Figure US20090312325A1-20091217-C00142
         		MeSO2— Intermediate 9 methyl 3- amino benzoate hydrochloride/ Fluka (I) 400 1.99
    7 HCl
    Figure US20090312325A1-20091217-C00143
         		MeSO2— Intermediate 9 3-methylaniline hydrochloride/ TCI-JP (I) 356 2
    8 HCl
    Figure US20090312325A1-20091217-C00144
         		MeSO2— Intermediate 9 3-aminobenzo nitrile/ Aldrich (I) 367 2.26
    9
    Figure US20090312325A1-20091217-C00145
         		MeSO2— Intermediate 9 3-aminobenzyl alcohol/ Aldrich (II) 372 1.82
    11
    Figure US20090312325A1-20091217-C00146
         		MeSO2— Intermediate 9 1-methyl-1H- benzimidazol 6-amine/ Heterocycles, 1991, 32(5), 1003-12. (II) 396 1.65
    12
    Figure US20090312325A1-20091217-C00147
         		MeSO2— Intermediate 9 3-chloro-4- fluoroaniline/ ABCR (II) 394 2.37
    13 HCl
    Figure US20090312325A1-20091217-C00148
         		MeSO2— Intermediate 9 aniline/ Aldrich (I) 342 2.07
    15 HCl
    Figure US20090312325A1-20091217-C00149
         		MeSO2— Intermediate 9 6- aminobenzoxa zolinone/ WO 9845268 A1 (I) 399 1.99
    16 HCl
    Figure US20090312325A1-20091217-C00150
         		MeSO2— Intermediate 9 2,3-dihydro- 1H-inden-5- ylamine hydrochloride/ Aldrich (I) 382 2.48
    17 HCl
    Figure US20090312325A1-20091217-C00151
         		MeSO2— Intermediate 9 2,3-dihydro- 1,4- benzodioxin-6- amine hydrochloride/ Aldrich (I) 400 2.18
    18 HCl
    Figure US20090312325A1-20091217-C00152
         		MeSO2— Intermediate 9 2,3-dihydro- 1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1 (I) 400 2.2
    19 HCl
    Figure US20090312325A1-20091217-C00153
         		MeSO2— Intermediate 9 1-amino- 5,6,7,8- tetrahydro napthalene/ Aldrich (I) 396 2.57
    20 HCl
    Figure US20090312325A1-20091217-C00154
         		MeSO2— Intermediate 9 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry, 1980, 17(6), 1333-5. (I) 384 2.23
    21
    Figure US20090312325A1-20091217-C00155
         		MeSO2— Intermediate 9 7-amino-1,3- benzoxazol- 2(3H)-one/ Annales Universitatis Mariae Curie- Sklodowska, Sectio D: Medicina, 1980, Volume Date 1979, 35 121-8. (II) 399 1.93
    22 HCl
    Figure US20090312325A1-20091217-C00156
         		MeSO2— Intermediate 9 3-ethylaniline/ Aldrich (I) 370 2.33
    23 HCl
    Figure US20090312325A1-20091217-C00157
         		MeSO2— Intermediate 9 3- isopropylaniline/ APIN (I) 384 2.5
    24 HCl
    Figure US20090312325A1-20091217-C00158
         		MeSO2— Intermediate 9 3-chloro-4- methoxyaniline/ Aldrich (I) 406/408 2.2
    25
    Figure US20090312325A1-20091217-C00159
         		MeSO2— Intermediate 9 3- (methoxymethyl) aniline/ WO 0018721 A1 (II) 386 2.01
    26 HCl
    Figure US20090312325A1-20091217-C00160
         		MeSO2— Intermediate 9 2,5-dimethoxy aniline/ Aldrich (I) 402 2.37
    27 HCl
    Figure US20090312325A1-20091217-C00161
         		MeSO2— Intermediate 9 3- methoxyaniline/ Aldrich (I) 372 2.33
    28 HCl
    Figure US20090312325A1-20091217-C00162
         		MeSO2— Intermediate 9 3-hydroxy-4- methoxyaniline/ Aldrich (I) 388 2.0
    29 HCl
    Figure US20090312325A1-20091217-C00163
         		MeSO2— Intermediate 9 3- phenoxyaniline/ Aldrich (I) 434 2.97
    30 HCl
    Figure US20090312325A1-20091217-C00164
         		MeSO2— Intermediate 9 3-amino-2- methylphenol/ Aldrich (I) 372 2.2
    31 HCl
    Figure US20090312325A1-20091217-C00165
         		MeSO2— Intermediate 9 3-aminophenol hydrochloride/ TCI-US (I) 358 2.04
    32 HCl
    Figure US20090312325A1-20091217-C00166
         		MeSO2— Intermediate 9 4-fluoro-3- methoxyaniline/ Apollo-Chem (I) 390 1.92
    33 HCl
    Figure US20090312325A1-20091217-C00167
         		MeSO2— Intermediate 9 2-(3-amino phenoxy) ethanol hydrochloride/ J. Amer. Chem. Soc.; 1937, 59; 1716 (I) 402 1.8
    34 HCl
    Figure US20090312325A1-20091217-C00168
         		MeSO2— Intermediate 9 3- ethoxyaniline/ Aldrich (I) 386 2.04
    35 HCl
    Figure US20090312325A1-20091217-C00169
         		MeSO2— Intermediate 9 3-chloroaniline/ Aldrich (I) 376 2.09
    36 HCl
    Figure US20090312325A1-20091217-C00170
         		MeSO2— Intermediate 9 [3-(2-methoxy ethoxy)phenyl] amine hydrochloride/ EP 388165 A2 (I) 416 1.94
    37 HCl
    Figure US20090312325A1-20091217-C00171
         		MeSO2— Intermediate 9 4- methoxyaniline/ Aldrich (I) 372 1.88
    38 HCl
    Figure US20090312325A1-20091217-C00172
         		MeSO2— Intermediate 9 3,4-dimethoxy aniline/ Aldrich (I) 402 1.84
    39
    Figure US20090312325A1-20091217-C00173
         		PhSO2— Intermediate 8 3- ethoxyaniline/ Aldrich (II) 448 2.55
    40
    Figure US20090312325A1-20091217-C00174
         		PhSO2— Intermediate 8 [3-(2-methoxy ethoxy)phenyl] amine hydrochloride/ EP 388165 A2 (II) 478 1.42
    41
    Figure US20090312325A1-20091217-C00175
         		PhSO2— Intermediate 8 3-amino-N- methyl benzamide/ TCI-US (II) 461 2.37
    42
    Figure US20090312325A1-20091217-C00176
         		PhSO2— Intermediate 8 4-aminophenol hydrochloride/ Aldrich (II) 420 2.46
    43 HCl
    Figure US20090312325A1-20091217-C00177
         		PhSO2— Intermediate 8 6- aminobenzothi azole/ Lancaster (I) 461 2.67
    44 HCl
    Figure US20090312325A1-20091217-C00178
         		PhSO2— Intermediate 8 N-(3- aminophenyl) N-methyl acetamide/ Merlin Synthesis (I) 475 2.58
    45 HCl
    Figure US20090312325A1-20091217-C00179
         		PhSO2— Intermediate 8 1-methyl-1H- benzimidazol- 6-amine/ Gwyn Ellis Heterocycles, 1991, 32(5), 1003- 12. (I) 458 2.24
    46 HCl
    Figure US20090312325A1-20091217-C00180
         		PhSO2— Intermediate 8 3,5-dimethoxy aniline/ Aldrich (I) 464 2.89
    47 HCl
    Figure US20090312325A1-20091217-C00181
         		PhSO2— Intermediate 8 methyl 3- amino benzoate hydrochloride/ Fluka (I) 462 2.86
    48 HCl
    Figure US20090312325A1-20091217-C00182
         		PhSO2— Intermediate 8 4-(2- morpholin-4- ylethoxy) aniline EP 410358 A1 (I) 533 2.1
    49 HCl
    Figure US20090312325A1-20091217-C00183
         		PhSO2— Intermediate 8 3-fluoroaniline/ Aldrich (I) 422 2.96
    50 HCl
    Figure US20090312325A1-20091217-C00184
         		PhSO2— Intermediate 8 3-chloro-4- fluoroaniline/ Aldrich (I) 456 3.12
    51 HCl
    Figure US20090312325A1-20091217-C00185
         		PhSO2— Intermediate 8 3-methylaniline hydrochloride/ TCI-US (I) 418 2.87
    52 HCl
    Figure US20090312325A1-20091217-C00186
         		PhSO2— Intermediate 8 3-amino benzonitrile/ Aldrich (I) 429 2.91
    53
    Figure US20090312325A1-20091217-C00187
         		PhSO2— Intermediate 8 N-(4- aminophenyl) morpholine-4- carboxamide/ Peakdale Molecular Ltd (II) 532 2.34
    54
    Figure US20090312325A1-20091217-C00188
         		PhSO2— Intermediate 8 N,N-dimethyl benzene-1,3- diamine hydrochloride/ Aldrich (II) 447 2.75
    55
    Figure US20090312325A1-20091217-C00189
         		PhSO2— Intermediate 8 N-(3- aminophenyl) acetamide hydrochloride/ Acros Chimica (II) 461 2.4
    56
    Figure US20090312325A1-20091217-C00190
         		PhSO2— Intermediate 8 3-aminobenzyl alcohol/ Aldrich (II) 434 2.34
    57 HCl
    Figure US20090312325A1-20091217-C00191
         		PhSO2— Intermediate 8 aniline/ Aldrich (I) 404 2.73
    58 HCl
    Figure US20090312325A1-20091217-C00192
         		PhSO2— Intermediate 8 1-acetylindolin- 5-amine/ Maybridge (I) 487 2.52
    59 HCl
    Figure US20090312325A1-20091217-C00193
         		PhSO2— Intermediate 8 6-amino-1,3- benzoxazol 2(3H)-one/ WO 9845268 A1 (I) 461 2.48
    60 HCl
    Figure US20090312325A1-20091217-C00194
         		PhSO2— Intermediate 8 1-acetyl-6- aminoindoline/ SIGMA (I) 487 2.55
    61 HCl
    Figure US20090312325A1-20091217-C00195
         		PhSO2— Intermediate 8 6-amino-2,3- dihydro-1H- inden-1-one/ J. Med. Chem. 2003, 46(3), 399-408. (I) 458 2.67
    62 HCl
    Figure US20090312325A1-20091217-C00196
         		PhSO2— Intermediate 8 6-amino- 1,2,3,4- tetrahydro naphthalen-1- one/ Maybridge (I) 472 2.93
    63 HCl
    Figure US20090312325A1-20091217-C00197
         		PhSO2— Intermediate 8 2,3-dihydro- 1,4- benzodioxin-6- amine hydrochloride/ Aldrich (I) 462 2.69
    64 HCl
    Figure US20090312325A1-20091217-C00198
         		PhSO2— Intermediate 8 1-amino- 5,6,7,8- tetrahydro napthalene/ Aldrich (I) 458 3.07
    65 HCl
    Figure US20090312325A1-20091217-C00199
         		PhSO2— Intermediate 8 7-amino-1,3- benzoxazol 2(3H)-one/ Medicina 1980, Volume Date 1979, 35, 121-8. (I) 461 2.64
    66 HCl
    Figure US20090312325A1-20091217-C00200
         		PhSO2— Intermediate 8 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ Journal of Heterocyclic Chemistry 1980, 17(6), 1333-5. (I) 446 2.84
    67
    Figure US20090312325A1-20091217-C00201
         		PhSO2— Intermediate 8 2,3-dihydro- 1H-inden-5- amine hydrochloride/ Aldrich (II) 444 2.95
    68
    Figure US20090312325A1-20091217-C00202
         		PhSO2— Intermediate 8 2,3-dihydro- 1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1 (II) 462 2.69
    69 HCl
    Figure US20090312325A1-20091217-C00203
         		PhSO2— Intermediate 8 3-ethylaniline/ Aldrich (I) 432 2.92
    70 HCl
    Figure US20090312325A1-20091217-C00204
         		PhSO2— Intermediate 8 3-isopropyl aniline/ APIN (I) 446 3.04
    71 HCl
    Figure US20090312325A1-20091217-C00205
         		PhSO2— Intermediate 8 3-chloro-4- methoxyaniline/ Aldrich (I) 468 2.76
    72 HCl
    Figure US20090312325A1-20091217-C00206
         		PhSO2— Intermediate 8 8-amino-3,4- dihydro-1(2H)- naphthalenone/ WO 0160826 A2 (I) 472 2.86
    73
    Figure US20090312325A1-20091217-C00207
         		PhSO2— Intermediate 8 3- [(methyloxy) methyl]aniline/ WO 0018721 A1 (II) 448 2.60
    74 HCl
    Figure US20090312325A1-20091217-C00208
         		PhSO2— Intermediate 8 3-(methyloxy) aniline/ Aldrich (I) 434 2.77
    75 HCl
    Figure US20090312325A1-20091217-C00209
         		PhSO2— Intermediate 8 2-[(3- aminophenyl) oxy]ethanol hydrochloride/ J. Amer. Chem. Soc.; 1937, 59, 1716 (I) 464 2.21
    76 HCl
    Figure US20090312325A1-20091217-C00210
         		PhSO2— Intermediate 8 4-amino-N- methyl benzamide/ Buttpark (I) 461 2.2
    77
    Figure US20090312325A1-20091217-C00211
         		PhSO2— Intermediate 8 3-amino-2- methylphenol/ Aldrich (II) 434 2.57
    78 HCl
    Figure US20090312325A1-20091217-C00212
         		PhSO2— Intermediate 8 4- methoxyaniline hydrochloride/ Acros (I) 434 2.32
    79 HCl
    Figure US20090312325A1-20091217-C00213
         		PhSO2— Intermediate 8 3-[(trifluoro methyl)oxy] aniline/ Aldrich (I) 487 2.8
    80
    Figure US20090312325A1-20091217-C00214
         		PhSO2— Intermediate 8 3-(4- morpholinyl) aniline/ Journal of Organic Chemistry 2002, 67(9), 3029-3036. (II) 489 2.72
    81
    Figure US20090312325A1-20091217-C00215
         		PhSO2— Intermediate 8 3-aminophenol hydrochloride/ TCI-US (II) 420 2.6
    82
    Figure US20090312325A1-20091217-C00216
         		PhSO2— Intermediate 8 [3,4- bis(methyloxy) phenyl]amine hydrochloride/ Aldrich (II) 463 2.58
    83 HCl
    Figure US20090312325A1-20091217-C00217
    Figure US20090312325A1-20091217-C00218
         		Intermediate 7 6-aminobenzo thiazole/ Lancaster (I) 453 2.3
    84 HCl
    Figure US20090312325A1-20091217-C00219
    Figure US20090312325A1-20091217-C00220
         		Intermediate 7 N-(3- aminophenyl) N-methyl acetamide/ Merlin synthesis (I) 467 2.29
    85 HCl
    Figure US20090312325A1-20091217-C00221
    Figure US20090312325A1-20091217-C00222
         		Intermediate 7 N-(4- aminophenyl) 4-morpholine carboxamide/ Peakdale molecular Ltd (I) 524 2.21
    86 HCl
    Figure US20090312325A1-20091217-C00223
    Figure US20090312325A1-20091217-C00224
         		Intermediate 7 3,5-dimethoxy aniline/ Aldrich (I) 456 2.51
    87 HCl
    Figure US20090312325A1-20091217-C00225
    Figure US20090312325A1-20091217-C00226
         		Intermediate 7 methyl 3- amino benzoate hydrochloride/ Fluka (I) 454 2.48
    88 HCl
    Figure US20090312325A1-20091217-C00227
    Figure US20090312325A1-20091217-C00228
         		Intermediate 7 3-amino-N- methyl benzamide/ TCI-US (I) 453 2.17
    89 HCl
    Figure US20090312325A1-20091217-C00229
    Figure US20090312325A1-20091217-C00230
         		Intermediate 7 3-fluoroaniline/ Aldrich (I) 414 2.53
    90 HCl
    Figure US20090312325A1-20091217-C00231
    Figure US20090312325A1-20091217-C00232
         		Intermediate 7 3-chloro-4- fluoroaniline/ Aldrich (I) 448 2.72
    91 HCl
    Figure US20090312325A1-20091217-C00233
    Figure US20090312325A1-20091217-C00234
         		Intermediate 7 (3- methylphenyl) amine hydrochloride/ TCI-US (I) 410 2.49
    92
    Figure US20090312325A1-20091217-C00235
    Figure US20090312325A1-20091217-C00236
         		Intermediate 7 N,N-dimethyl- 1,3-benzene diamine hydrochloride/ Aldrich (II) 439 2.62
    93
    Figure US20090312325A1-20091217-C00237
    Figure US20090312325A1-20091217-C00238
         		Intermediate 7 N-(3- aminophenyl) acetamide hydrochloride/ Acros (II) 453 2.25
    94
    Figure US20090312325A1-20091217-C00239
    Figure US20090312325A1-20091217-C00240
         		Intermediate 7 2-chloroaniline/ Aldrich (II) 430 2.69
    95 HCl
    Figure US20090312325A1-20091217-C00241
    Figure US20090312325A1-20091217-C00242
         		Intermediate 7 aniline/ Aldrich (I) 396 2.58
    96 HCl
    Figure US20090312325A1-20091217-C00243
    Figure US20090312325A1-20091217-C00244
         		Intermediate 7 1-methyl-1H- benzimidazol 6-amine/ Heterocycles 1991, 32(5), 1003- 12. (I) 450 2.04
    97 HCl
    Figure US20090312325A1-20091217-C00245
    Figure US20090312325A1-20091217-C00246
         		Intermediate 7 3-ethylaniline/ Aldrich (I) 424 2.81
    98 HCl
    Figure US20090312325A1-20091217-C00247
    Figure US20090312325A1-20091217-C00248
         		Intermediate 7 3-isopropyl aniline/ TCI-US (I) 438 3.0
    99 HCl
    Figure US20090312325A1-20091217-C00249
    Figure US20090312325A1-20091217-C00250
         		Intermediate 7 3-methoxy aniline/ Aldrich (I) 426 2.58
    100
    Figure US20090312325A1-20091217-C00251
         		PhSO2— Intermediate 8 3- aminopyridine/ Aldrich (II) 405 2.41
    145 HCl
    Figure US20090312325A1-20091217-C00252
         		MeSO2— Intermediate 9 4-fluoro-3- methylaniline/ Aldrich (I) 396 1.77
    146 TFA
    Figure US20090312325A1-20091217-C00253
         		MeSO2— Intermediate 9 5-amino-2- methyl benzofuran hydrochloride/ Aldrich (III) 396 2.43
    147 TFA
    Figure US20090312325A1-20091217-C00254
         		MeSO2— Intermediate 9 1-methyl-1H- indazol-6- amine hydrochloride/ Synthetic Communications, 1996, 26(13), 2443- 2447. (III) 396 2.15
    148 TFA
    Figure US20090312325A1-20091217-C00255
         		MeSO2— Intermediate 9 1-methyl-1H- indazole-5- amine/ Bionet Research Ltd (III) 396 2.06
    149 TFA
    Figure US20090312325A1-20091217-C00256
         		MeSO2— Intermediate 9 1- (phenylmethyl)- 1H-indazol-5- amine/ WO 0283654 A1 (III) 472 2.56
    150 HCl
    Figure US20090312325A1-20091217-C00257
         		MeSO2— Intermediate 9 3-(trifluoro methyl)aniline/ Aldrich (I) 410 2.05
    151 HCl
    Figure US20090312325A1-20091217-C00258
         		MeSO2— Intermediate 9 1-(3- aminophenyl) ethanone/ Aldrich (I) 384 1.71
    152 HCl
    Figure US20090312325A1-20091217-C00259
         		MeSO2— Intermediate 9 3-(5-methyl- 1,2,4- oxadiazol-3- yl)aniline/ Intermediate 19 (I) 424 1.88
    153 HCl
    Figure US20090312325A1-20091217-C00260
         		MeSO2— Intermediate 9 1-(3- aminophenyl)- N,N-dimethyl methane sulfonamide/ Peakdale molecular Ltd (I) 463 1.78
    154 HCl
    Figure US20090312325A1-20091217-C00261
         		MeSO2— Intermediate 9 3-(3- thienyl)aniline/ US 6211220 B1 (I) 424 2.15
    155 HCl
    Figure US20090312325A1-20091217-C00262
         		MeSO2— Intermediate 9 3-methyl-2,3- dihydro-1- benzofuran-4- amine/ Intermediate 25 (I) 398 1.91
    156
    Figure US20090312325A1-20091217-C00263
         		MeSO2— Intermediate 9 4-amino-2- methyl-1H- isoindole- 1,3(2H)-dione/ Archiv der Pharmazie (Weinheim, Germany) 1989, 322(7), 419-26. (II) 425 2.35
    157 TFA
    Figure US20090312325A1-20091217-C00264
         		PhSO2— Intermediate 8 1,2- benzisoxazol 5-amine/ Key organics Ltd (III) 445 2.61
    158 TFA
    Figure US20090312325A1-20091217-C00265
         		PhSO2— Intermediate 8 1,2-dimethyl- 1H- benzimidazol- 6-amine/ Intermediate 27 (III) 472 2.15
    159 TFA
    Figure US20090312325A1-20091217-C00266
         		PhSO2— Intermediate 8 3,5- dichloroaniline/ Aldrich (III) 472 3.35
    160 TFA
    Figure US20090312325A1-20091217-C00267
         		PhSO2— Intermediate 8 2-methyl-1,3- benzoxazol-5- amine/ Collection of Czechoslovak Chemical Communications 1996, 61(3), 371- 380. (III) 459 2.33
    161 TFA
    Figure US20090312325A1-20091217-C00268
         		PhSO2— Intermediate 8 4-chloro-3- methoxyaniline/ Wychem (III) 468 3.08
    162 TFA
    Figure US20090312325A1-20091217-C00269
         		PhSO2— Intermediate 8 5-amino-2- methyl benzofuran hydrochloride/ Sigma Aldrich (III) 458 2.92
    163 TFA
    Figure US20090312325A1-20091217-C00270
         		PhSO2— Intermediate 8 1-methyl-1H- indazol-6- amine hydrochloride/ Heterocycles, 1995, 41(3), 487-96. (III) 458 2.67
    164 TFA
    Figure US20090312325A1-20091217-C00271
         		PhSO2— Intermediate 8 5-fluoro-2- methoxyaniline/ Wychem (III) 452 2.92
    165 TFA
    Figure US20090312325A1-20091217-C00272
         		PhSO2— Intermediate 8 1-methyl-1H- indazol-5- amine/ Bionet Research Ltd (III) 458 2.51
    166 TFA
    Figure US20090312325A1-20091217-C00273
         		PhSO2— Intermediate 8 1- (phenylmethyl)- 1H-indazol-5- amine/ WO 0283654 A1 (III) 534 2.97
    167 TFA
    Figure US20090312325A1-20091217-C00274
         		PhSO2— Intermediate 8 4-amino-2- (methyloxy) phenol hydrochloride/ Journal of Chemical Research, Synopses 1988, (9), 284-5. (III) 450 2.42
    168 TFA
    Figure US20090312325A1-20091217-C00275
         		PhSO2— Intermediate 8 3-fluoro-4- methylaniline/ Aldrich (III) 436 3.04
    169 TFA
    Figure US20090312325A1-20091217-C00276
         		PhSO2— Intermediate 8 2-methyl-1,3- benzothiazol 6-amine/ AslnEx Compound Collection (III) 475 2.73
    170 TFA
    Figure US20090312325A1-20091217-C00277
         		PhSO2— Intermediate 8 1H-indol-6- amine/ Lancaster Synthesis (III) 443 2.7
    171 TFA
    Figure US20090312325A1-20091217-C00278
         		PhSO2— Intermediate 8 3-chloro-5- (methyloxy) aniline/ J. Chem. Soc. Perkin 2, 1977, 14. (III) 468 3.17
    172 HCl
    Figure US20090312325A1-20091217-C00279
         		PhSO2— Intermediate 8 3-(2-methyl-4- pyrimidinyl) aniline/ Fluorochem (I) 496 2.23
    173 HCl
    Figure US20090312325A1-20091217-C00280
         		PhSO2— Intermediate 8 3-(trifluoro methyl)aniline/ Aldrich (I) 472 2.62
    174 HCl
    Figure US20090312325A1-20091217-C00281
         		PhSO2— Intermediate 8 1-(3- aminophenyl) ethanone/ Aldrich (I) 446 2.2
    175 HCl
    Figure US20090312325A1-20091217-C00282
         		PhSO2— Intermediate 8 3-(1,3-oxazol- 5-yl)aniline/ Fluorochem (I) 471 2.24
    176 HCl
    Figure US20090312325A1-20091217-C00283
         		PhSO2— Intermediate 8 3-(1-methyl- 1H-pyrazol-3- yl)aniline/ Intermediate 26 (I) 484 2.27
    177 HCl
    Figure US20090312325A1-20091217-C00284
         		PhSO2— Intermediate 8 3-(5-methyl- 1,2,4- oxadiazol-3- yl)aniline/ Intermediate 19 (I) 486 2.34
    178 HCl
    Figure US20090312325A1-20091217-C00285
         		PhSO2— Intermediate 8 1-(3- aminophenyl)- N,N-dimethyl methane sulfonamide/ Peakdale molecular Ltd (I) 525 2.23
    179 HCl
    Figure US20090312325A1-20091217-C00286
         		PhSO2— Intermediate 8 3-(3- thienyl)aniline/ US 6211220 B1 (I) 486 2.55
    180 HCl
    Figure US20090312325A1-20091217-C00287
         		PhSO2— Intermediate 8 3-methyl-2,3- dihydro-1- benzofuran-4- amine/ Intermediate 25 (I) 460 2.36
    181 HCl
    Figure US20090312325A1-20091217-C00288
         		PhSO2— Intermediate 8 2,2-dimethyl- 2,3-dihydro-1- benzofuran-7- amine/ DE 3526510 A1 (I) 474 2.34
    182
    Figure US20090312325A1-20091217-C00289
         		PhSO2— Intermediate 8 4-amino-2- methyl-1H- isoindole 1,3(2H)-dione/ Archiv der Pharmazie (Weinheim, Germany) 1989, 322(7), 419-26. (II) 487 2.85
    183
    Figure US20090312325A1-20091217-C00290
         		PhSO2— Intermediate 8 [4-(methyloxy)- 2-naphthalenyl] amine 4- methyl benzene sulfonate/ Sigma (I) 484 3.19
    590 HCl
    Figure US20090312325A1-20091217-C00291
    Figure US20090312325A1-20091217-C00292
         		Intermediate 95 5-chloro-3- pyridinamine/ Synchem OHG (I) 419 2.44
    589 HCl
    Figure US20090312325A1-20091217-C00293
    Figure US20090312325A1-20091217-C00294
         		Intermediate 95 3-pyridinamine/ Aldrich (I) 385 1.96
    (a) Salt forms:
    HCl = hydrochloride
    TFA = trifluoroacetate
    (b) Isolation Method:
    (I) Filtered off directly from the reaction mixture.
    (II) Mass Directed preparative HPLC Method A.
    (III) Mass Directed preparative HPLC Method B.
  • The following compounds were prepared by a similar method to Example 10:
  • Figure US20090312325A1-20091217-C00295
    Ex. Amine Isolation LCMS
    No. Starting Reagent/ Method LCMS Rt
    (a) R1NH— R3SO2— R20— Material Source (b) MH+ (min)
    187 HCl
    Figure US20090312325A1-20091217-C00296
         		MeSO2— H— Intermediate 9 1,1-dimethylethyl (3-aminophenyl) carbamate/ J. Med. Chem. 2003, 46(9) 1661- 1669 (I) 457 2.47
    188 HCl
    Figure US20090312325A1-20091217-C00297
         		MeSO2— H— Intermediate 9 1,1-dimethylethyl [(3-aminophenyl) methyl]carbamate/ J. Med. Chem. 2003, 46(9) 1661- 1669 (I) 471 2.39
    189
    Figure US20090312325A1-20091217-C00298
         		MeSO2— H— Intermediate 9 1,3-benzodioxol- 5-amine/ Aldrich (II) 386 1.98
    190 HCl
    Figure US20090312325A1-20091217-C00299
         		MeSO2— H— Intermediate 9 3-(1,3-oxazol-5- yl)aniline/ Maybridge (I) 409 1.82
    191 HCl
    Figure US20090312325A1-20091217-C00300
         		MeSO2— H— Intermediate 9 3-(3- aminophenyl)-1- methyl-1H- pyrazole/ Buttpark (I) 422 1.88
    192 HCl
    Figure US20090312325A1-20091217-C00301
         		MeSO2— H— Intermediate 9 3-chloro-2- fluoroaniline/ Aldrich (I) 394 2.46
    193 HCl
    Figure US20090312325A1-20091217-C00302
         		MeSO2— H— Intermediate 9 2,3-difluoroaniline/ Aldrich (I) 378 2.3
    194 HCl
    Figure US20090312325A1-20091217-C00303
         		MeSO2— H— Intermediate 9 3- aminobenzonitrile/ Aldrich (I) 367 2.07
    195 HCl
    Figure US20090312325A1-20091217-C00304
         		MeSO2— H— Intermediate 9 5-amino-2- fluorobenzonitrile/ Maybridge (I) 385 2.15
    196 HCl
    Figure US20090312325A1-20091217-C00305
         		MeSO2— H— Intermediate 9 3- isopropoxyaniline/ Maybridge (I) 400 2.35
    197 HCl
    Figure US20090312325A1-20091217-C00306
         		MeSO2— H— Intermediate 9 2-amino-5- fluorotoluene/ Aldrich (I) 374 2.2
    198 HCl
    Figure US20090312325A1-20091217-C00307
         		MeSO2— H— Intermediate 9 3,4-difluoroaniline/ Aldrich (I) 378 2.26
    199 HCl
    Figure US20090312325A1-20091217-C00308
         		MeSO2— H— Intermediate 9 4-fluoro-3- (trifluoromethyl) aniline/Avocado (I) 428 2.61
    200 HCl
    Figure US20090312325A1-20091217-C00309
         		MeSO2— H— Intermediate 9 2-fluoroaniline/ Aldrich (I) 360 2.04
    201 HCl
    Figure US20090312325A1-20091217-C00310
         		MeSO2— H— Intermediate 9 2,4-difluoroaniline/ Aldrich (I) 378 2.22
    202 HCl
    Figure US20090312325A1-20091217-C00311
         		MeSO2— H— Intermediate 9 2-chloro-4- fluoroaniline/ Aldrich (I) 394 2.43
    203 HCl
    Figure US20090312325A1-20091217-C00312
         		MeSO2— H— Intermediate 9 3-aminopyridine/ Aldrich (IV) 343 1.69
    204 HCl
    Figure US20090312325A1-20091217-C00313
         		MeSO2— H— Intermediate 9 4-aminobenzoic acid/Aldrich (I) 386 2
    205 TFA
    Figure US20090312325A1-20091217-C00314
         		MeSO2— H— Intermediate 9 4-chloro-3- methoxyaniline/ Wychem (III) 406 2.49
    206 TFA
    Figure US20090312325A1-20091217-C00315
         		MeSO2— H— Intermediate 9 1-methyl-1H- benzimidazol-6- amine/ Heterocycles. 1991, 32(5), 1003-12. (III) 396 1.77
    207 TFA
    Figure US20090312325A1-20091217-C00316
         		MeSO2— H— Intermediate 9 6-(methyloxy)-1,3- benzothiazol-4- amine J. Am. Chem. Soc, 1939, 61(8), 2013-2017. (III) 429 2.35
    208 TFA
    Figure US20090312325A1-20091217-C00317
         		MeSO2— H— Intermediate 9 3-fluoro-5-(3- pyridinyl)aniline J. Med. Chem. 2000, 43(6), 1123-1134. (III) 437 2.34
    209 TFA
    Figure US20090312325A1-20091217-C00318
         		MeSO2— H— Intermediate 9 5-fluoro-2- methoxyaniline/ Wychem (III) 390 2.3
    210 TFA
    Figure US20090312325A1-20091217-C00319
         		MeSO2— H— Intermediate 9 1-methyl-1H- 1,2,3- benzotriazol-5- amine/US 2003060453 A1 (III) 397 1.98
    211 TFA
    Figure US20090312325A1-20091217-C00320
         		MeSO2— H— Intermediate 9 3,5-difluoroaniline/ Aldrich (III) 378 2.51
    212 TFA
    Figure US20090312325A1-20091217-C00321
         		MeSO2— H— Intermediate 9 3-fluoro-4- methylaniline/ Aldrich (III) 374 2.43
    213 TFA
    Figure US20090312325A1-20091217-C00322
         		MeSO2— H— Intermediate 9 4-amino-2- fluorophenol/ Apollo (III) 376 2.01
    214 TFA
    Figure US20090312325A1-20091217-C00323
         		MeSO2— H— Intermediate 9 4-(methyloxy)-2- naphthalenamine/ Sigma (III) 422 2.73
    215 TFA
    Figure US20090312325A1-20091217-C00324
         		MeSO2— H— Intermediate 9 6-aminoindole/ Lancaster (III) 381 2.25
    216 TFA
    Figure US20090312325A1-20091217-C00325
         		MeSO2— H— Intermediate 9 methyl 4-amino-2- methoxy benzoate/ Avocado (III) 430 2.36
    217 HCl
    Figure US20090312325A1-20091217-C00326
         		MeSO2— H— Intermediate 9 1,3-benzodioxol- 4-amine J. Med. Chem. 1979, 22(11), 1354-7. (I) 386 2.06
    218 HCl
    Figure US20090312325A1-20091217-C00327
         		PhSO2— H— Intermediate 8 3- aminobenzonitrile/ Aldrich (I) 429 2.80
    219
    Figure US20090312325A1-20091217-C00328
         		PhSO2— H— Intermediate 8 1,3-benzodioxol- 5-amine/Aldrich (II) 448 2.63
    220
    Figure US20090312325A1-20091217-C00329
         		PhSO2— H— Intermediate 8 3-amino-N,N- dimethylbenzenes ulfonamide/WO 9737646 A1 (II) 511 2.94
    221
    Figure US20090312325A1-20091217-C00330
         		PhSO2— H— Intermediate 8 3-aminobenzene sulfonamide/ Fluka (II) 483 2.6
    222
    Figure US20090312325A1-20091217-C00331
         		PhSO2— H— Intermediate 8 4-amino-N- methylbenzene sulfonamide/ Zelinsky BB (II) 497 2.51
    223 TFA
    Figure US20090312325A1-20091217-C00332
         		PhSO2— H— Intermediate 8 6-(methyloxy)-1,3- benzothiazol-4- amine J. Am. Chem. Soc., 1939, 61(8), 2013- 2017. (III) 491 2.92
    224 TFA
    Figure US20090312325A1-20091217-C00333
         		PhSO2— H— Intermediate 8 3-fluoro-5-(3- pyridinyl)aniline/ J. Med. Chem., 2000, 43(6), 1123-1134. (III) 499 2.89
    225 TFA
    Figure US20090312325A1-20091217-C00334
         		PhSO2— H— Intermediate 8 Intermediate 51 (III) 444 3.21
    226 TFA
    Figure US20090312325A1-20091217-C00335
         		PhSO2— H— Intermediate 8 3,5-difluoroaniline/ Aldrich (III) 440 3.12
    227 TFA
    Figure US20090312325A1-20091217-C00336
         		PhSO2— H— Intermediate 8 4-amino-2- fluorophenol/ Apollo (III) 438 2.56
    228 TFA
    Figure US20090312325A1-20091217-C00337
         		PhSO2— H— Intermediate 8 3,4-difluoroaniline/ Aldrich (III) 440 3.03
    229 TFA
    Figure US20090312325A1-20091217-C00338
         		PhSO2— H— Intermediate 8 methyl 4-amino-2- methoxy benzoate/ Avocado (III) 492 2.89
    230 HCl
    Figure US20090312325A1-20091217-C00339
         		PhSO2— Me— Intermediate 16 2-(3- aminophenoxy) ethanol/Key Organics Ltd. (I) 478 2.22
    231 HCl
    Figure US20090312325A1-20091217-C00340
         		PhSO2— Me— Intermediate 16 3- aminothiophene- 2-carboxylic acid methyl ester/ Avocado (I) 482 2.79
    232 HCl
    Figure US20090312325A1-20091217-C00341
         		PhSO2— Me— Intermediate 16 5-amino-2- methoxyphenol/ Aldrich (I) 464 2.1
    233 HCl
    Figure US20090312325A1-20091217-C00342
         		PhSO2— Me— Intermediate 16 5-aminotetralin/ Aldrich (I) 472 2.64
    234 HCl
    Figure US20090312325A1-20091217-C00343
         		PhSO2— Me— Intermediate 16 ethyl 3- aminobenzoate/ Aldrich (I) 490 2.66
    235 HCl
    Figure US20090312325A1-20091217-C00344
         		PhSO2— Me— Intermediate 16 5-amino-2- methylphenol/TCI America (I) 448 2.31
    236 HCl
    Figure US20090312325A1-20091217-C00345
         		PhSO2— Me— Intermediate 16 1,1-dimethylethyl [(3-aminophenyl) methyl]carbamate/ J. Med. Chem. 2003, 46(9), 1661-1669. (I) 547 2.64
    237 HCl
    Figure US20090312325A1-20091217-C00346
         		PhSO2— Me— Intermediate 16 4-amino-N- methylbenzamide/ Buttpark (I) 475 2.27
    238 HCl
    Figure US20090312325A1-20091217-C00347
         		PhSO2— Me— Intermediate 16 3-aminobenzyl alcohol/Aldrich (I) 448 2.13
    239 TFA
    Figure US20090312325A1-20091217-C00348
         		PhSO2— Me— Intermediate 16 3-aminobenzoyl methylamide/ Buttpark (III) 475 2.55
    240 TFA
    Figure US20090312325A1-20091217-C00349
         		PhSO2— Me— Intermediate 16 3-aminophenol/ Aldrich (III) 434 2.64
    241 TFA
    Figure US20090312325A1-20091217-C00350
         		PhSO2— Me— Intermediate 16 5-amino-1- ethylpyrazole/ Aldrich (III) 436 2.75
    242 TFA
    Figure US20090312325A1-20091217-C00351
         		PhSO2— Me— Intermediate 16 3-cyano-4- fluoroaniline hydrochloride/ Combiblocks (III) 461 3.04
    243 TFA
    Figure US20090312325A1-20091217-C00352
         		PhSO2— Me— Intermediate 16 1-acetyl-6- aminoindoline/ Sigma (III) 501 2.59
    244 HCl
    Figure US20090312325A1-20091217-C00353
         		iPrSO2— H— Intermediate 30 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5. (I) 412 2.36
    245 HCl
    Figure US20090312325A1-20091217-C00354
         		iPrSO2— H— Intermediate 30 3-amino- acetophenone/ Aldrich (I) 412 2.33
    246 HCl
    Figure US20090312325A1-20091217-C00355
         		iPrSO2— H— Intermediate 30 1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447. (I) 424 2.22
    247 HCl
    Figure US20090312325A1-20091217-C00356
         		iPrSO2— H— Intermediate 30 4-fluoro-3- methoxyaniline/ Apollo-Chem (I) 418 2.38
    248 HCl
    Figure US20090312325A1-20091217-C00357
         		iPrSO2— H— Intermediate 30 2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1 (I) 428 2.30
    249 HCl
    Figure US20090312325A1-20091217-C00358
         		iPrSO2— H— Intermediate 30 3-chloroaniline/ Aldrich (I) 404 2.64
    250 HCl
    Figure US20090312325A1-20091217-C00359
         		iPrSO2— H— Intermediate 30 3- aminobenzonitrile/ Aldrich (I) 395 2.40
    251 HCl
    Figure US20090312325A1-20091217-C00360
         		iPrSO2— H— Intermediate 30 3-methylaniline hydrochloride/ TCI-US (I) 384 2.41
    252 HCl
    Figure US20090312325A1-20091217-C00361
         		iPrSO2— H— Intermediate 30 3-aminopyridine/ Aldrich (I) 371 1.92
    253 HCl
    Figure US20090312325A1-20091217-C00362
         		iPrSO2— H— Intermediate 30 6-aminobenzo thiazole/ Lancaster (I) 427 2.20
    254 HCl
    Figure US20090312325A1-20091217-C00363
    Figure US20090312325A1-20091217-C00364
         		H— Intermediate 31 3-iodoaniline/ Aldrich (I) 560 3.06
    255 HCl
    Figure US20090312325A1-20091217-C00365
    Figure US20090312325A1-20091217-C00366
         		H— Intermediate 31 3-amino- acetophenone/ Aldrich (I) 476 2.68
    256 HCl
    Figure US20090312325A1-20091217-C00367
    Figure US20090312325A1-20091217-C00368
         		H— Intermediate 31 1-methyl-1H- benzimidazol-6- amine/ Heterocycles, 1991, 32(5), 1003-12. (I) 488 2.17
    257 HCl
    Figure US20090312325A1-20091217-C00369
    Figure US20090312325A1-20091217-C00370
         		H— Intermediate 31 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5. (I) 476 2.76
    258 HCl
    Figure US20090312325A1-20091217-C00371
    Figure US20090312325A1-20091217-C00372
         		H— Intermediate 31 3-fluoroaniline/ Aldrich (I) 452 2.89
    259 HCl
    Figure US20090312325A1-20091217-C00373
    Figure US20090312325A1-20091217-C00374
         		H— Intermediate 31 4-fluoro-3- methoxyaniline/ Apollo-Chem (I) 482 2.78
    260 HCl
    Figure US20090312325A1-20091217-C00375
    Figure US20090312325A1-20091217-C00376
         		H— Intermediate 31 6-aminobenzo thiazole/ Lancaster (I) 491 2.61
    261 HCl
    Figure US20090312325A1-20091217-C00377
    Figure US20090312325A1-20091217-C00378
         		H— Intermediate 31 1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447. (I) 488 2.62
    262 HCl
    Figure US20090312325A1-20091217-C00379
    Figure US20090312325A1-20091217-C00380
         		H— Intermediate 31 3- aminobenzonitrile/ Aldrich (I) 459 2.86
    263 HCl
    Figure US20090312325A1-20091217-C00381
    Figure US20090312325A1-20091217-C00382
         		H— Intermediate 31 3-chloroaniline/ Aldrich (I) 468 3.02
    264 HCl
    Figure US20090312325A1-20091217-C00383
    Figure US20090312325A1-20091217-C00384
         		H— Intermediate 31 3-methylaniline hydrochloride/ TCI-US (I) 448 2.78
    265
    Figure US20090312325A1-20091217-C00385
    Figure US20090312325A1-20091217-C00386
         		Me— Intermediate 32 3-methoxyaniline/ Aldrich (II) 478 3.04
    266 TFA
    Figure US20090312325A1-20091217-C00387
    Figure US20090312325A1-20091217-C00388
         		Me— Intermediate 32 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6). 1333-5. (III) 490 2.45
    267 TFA
    Figure US20090312325A1-20091217-C00389
    Figure US20090312325A1-20091217-C00390
         		Me— Intermediate 32 3-amino- acetophenone/ Aldrich (III) 490 2.41
    268 TFA
    Figure US20090312325A1-20091217-C00391
    Figure US20090312325A1-20091217-C00392
         		Me— Intermediate 32 1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447. (III) 502 2.36
    269 TFA
    Figure US20090312325A1-20091217-C00393
    Figure US20090312325A1-20091217-C00394
         		Me— Intermediate 32 2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1 (III) 506 2.36
    270 TFA
    Figure US20090312325A1-20091217-C00395
    Figure US20090312325A1-20091217-C00396
         		Me— Intermediate 32 3-chloroaniline/ Aldrich (III) 482 2.72
    271 TFA
    Figure US20090312325A1-20091217-C00397
    Figure US20090312325A1-20091217-C00398
         		Me— Intermediate 32 3- aminobenzonitrile/ Aldrich (III) 473 2.62
    272 TFA
    Figure US20090312325A1-20091217-C00399
    Figure US20090312325A1-20091217-C00400
         		Me— Intermediate 32 6-aminobenzo thiazole/ Lancaster (III) 505 2.36
    273 TFA
    Figure US20090312325A1-20091217-C00401
    Figure US20090312325A1-20091217-C00402
         		Me— Intermediate 32 3-fluoroaniline/ Aldrich (III) 466 2.6
    274 HCl
    Figure US20090312325A1-20091217-C00403
    Figure US20090312325A1-20091217-C00404
         		H— Intermediate 31 2-(3- aminophenoxy) ethanol hydrochloride/ J. Am. Chem. Soc., 1937, 59; 1716 (I) 494 2.15
    275 HCl
    Figure US20090312325A1-20091217-C00405
    Figure US20090312325A1-20091217-C00406
         		H— Intermediate 31 3-aminophenol/ Aldrich (I) 450 2.15
    276 HCl
    Figure US20090312325A1-20091217-C00407
    Figure US20090312325A1-20091217-C00408
         		H— Intermediate 31 ethyl 3- aminobenzoate/ Aldrich (I) 506 2.51
    277 HCl
    Figure US20090312325A1-20091217-C00409
    Figure US20090312325A1-20091217-C00410
         		H— Intermediate 31 5-amino-2- methylphenol/TCI America (I) 464 2.27
    278 HCl
    Figure US20090312325A1-20091217-C00411
    Figure US20090312325A1-20091217-C00412
         		H— Intermediate 31 4-amino-N- methylbenzamide/ Buttpark (I) 491 2.16
    279 HCl
    Figure US20090312325A1-20091217-C00413
    Figure US20090312325A1-20091217-C00414
         		H— Intermediate 31 3-aminobenzyl- alcohol/Aldrich (I) 464 2.07
    280 TFA
    Figure US20090312325A1-20091217-C00415
    Figure US20090312325A1-20091217-C00416
         		H— Intermediate 31 methyl 3- aminothiophene- 2-carboxylate/ Avocado (III) 498 2.95
    281 TFA
    Figure US20090312325A1-20091217-C00417
    Figure US20090312325A1-20091217-C00418
         		H— Intermediate 31 5-amino-2- methoxyphenol/ Aldrich (III) 480 2.37
    282 TFA
    Figure US20090312325A1-20091217-C00419
    Figure US20090312325A1-20091217-C00420
         		H— Intermediate 31 3-amino-N- methylbenzamide/ Buttpark (III) 491 2.43
    283 TFA
    Figure US20090312325A1-20091217-C00421
    Figure US20090312325A1-20091217-C00422
         		H— Intermediate 31 1-amino-5,6,7,8- tetrahydro napthalene/ Aldrich (III) 488 2.96
    284 TFA
    Figure US20090312325A1-20091217-C00423
    Figure US20090312325A1-20091217-C00424
         		H— Intermediate 31 4-amino-2- methoxyphenol/ WO 2003049702 A2 (III) 480 2.34
    285 TFA
    Figure US20090312325A1-20091217-C00425
    Figure US20090312325A1-20091217-C00426
         		Me— Intermediate 34 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5. (III) 474 2.53
    286 TFA
    Figure US20090312325A1-20091217-C00427
    Figure US20090312325A1-20091217-C00428
         		Me— Intermediate 34 3-amino- acetophenone/ Aldrich (III) 474 2.49
    287 TFA
    Figure US20090312325A1-20091217-C00429
    Figure US20090312325A1-20091217-C00430
         		Me— Intermediate 34 1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447. (III) 486 2.41
    288 TFA
    Figure US20090312325A1-20091217-C00431
    Figure US20090312325A1-20091217-C00432
         		Me— Intermediate 34 2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1 (III) 490 2.43
    289 TFA
    Figure US20090312325A1-20091217-C00433
    Figure US20090312325A1-20091217-C00434
         		Me— Intermediate 34 3-chloroaniline/ Aldrich (III) 466 2.82
    290 TFA
    Figure US20090312325A1-20091217-C00435
    Figure US20090312325A1-20091217-C00436
         		Me— Intermediate 34 3-fluoroaniline/ Aldrich (III) 450 2.70
    291 TFA
    Figure US20090312325A1-20091217-C00437
    Figure US20090312325A1-20091217-C00438
         		Me— Intermediate 34 3- aminobenzonitrile/ Aldrich (III) 457 2.71
    292 TFA
    Figure US20090312325A1-20091217-C00439
    Figure US20090312325A1-20091217-C00440
         		Me— Intermediate 34 3-methoxyaniline/ Aldrich (III) 462 2.51
    293 HCl
    Figure US20090312325A1-20091217-C00441
         		MeSO2— Me— Intermediate 33 3-methoxyaniline/ Aldrich (I) 386 2.20
    294 HCl
    Figure US20090312325A1-20091217-C00442
         		MeSO2— Me— Intermediate 33 4-fluoro-3- methoxyaniline/ Apollo-Chem (I) 404 2.23
    295 HCl
    Figure US20090312325A1-20091217-C00443
         		MeSO2— MeO— Intermediate 50 3-methoxyaniline/ Aldrich (I) 402 2.09
    296 HCl
    Figure US20090312325A1-20091217-C00444
         		MeSO2— MeO— Intermediate 50 4-fluoro-3- methoxyaniline/ Apollo-Chem (I) 420 2.12
    297 HCl
    Figure US20090312325A1-20091217-C00445
         		PhSO2— Me— Intermediate 16 3-amino- acetophenone/ Aldrich (I) 460 2.82
    298 HCl
    Figure US20090312325A1-20091217-C00446
         		PhSO2— Me— Intermediate 16 1-methyl-1H- benzimidazol-6- amine/ Heterocycles, 1991, 32(5), 1003-12. (I) 472 2.24
    299 HCl
    Figure US20090312325A1-20091217-C00447
         		PhSO2— Me— Intermediate 16 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5 (I) 460 2.90
    300 HCl
    Figure US20090312325A1-20091217-C00448
         		PhSO2— Me— Intermediate 16 3-fluoroaniline/ Aldrich (I) 436 3.07
    301 TFA
    Figure US20090312325A1-20091217-C00449
         		PhSO2— Me— Intermediate 16 2,3-dihydro-1,4- benzodioxin-5- amine hydrochloride/ WO 9703067 A1 (III) 476 2.77
    302 HCl
    Figure US20090312325A1-20091217-C00450
         		PhSO2— Me— Intermediate 16 6-aminobenzo thiazole/ Lancaster (I) 475 2.75
    303 HCl
    Figure US20090312325A1-20091217-C00451
         		PhSO2— Me— Intermediate 16 1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447. (I) 472 2.74
    304 HCl
    Figure US20090312325A1-20091217-C00452
         		PhSO2— Me— Intermediate 16 3- aminobenzonitrile/ Aldrich (I) 443 3.01
    305 HCl
    Figure US20090312325A1-20091217-C00453
         		PhSO2— Me— Intermediate 16 3-chloroaniline/ Aldrich (I) 452 3.21
    306 HCl
    Figure US20090312325A1-20091217-C00454
         		PhSO2— Me— Intermediate 16 3-methylaniline/ Aldrich (I) 432 2.93
    307 HCl
    Figure US20090312325A1-20091217-C00455
         		MeSO2— Me— Intermediate 33 2,3-dihydro-1- benzofuran-4- amine hydrobromide/ J. Heterocyclic Chem., 1980, 17(6), 1333-5. (I) 398 2.38
    308 TFA
    Figure US20090312325A1-20091217-C00456
         		MeSO2— Me— Intermediate 33 3-aminopyridine/ Adlrich (III) 357 1.95
    309 HCl
    Figure US20090312325A1-20091217-C00457
         		MeSO2— Me— Intermediate 33 1-methyl-1H- indazol-6-amine hydrochloride/ Synth. Comm., 1996, 26(13), 2443-2447. (I) 410 2.28
    310 HCl
    Figure US20090312325A1-20091217-C00458
         		MeSO2— Me— Intermediate 33 3-chloroaniline/ Aldrich (I) 390 2.68
    311 HCl
    Figure US20090312325A1-20091217-C00459
         		MeSO2— Me— Intermediate 33 3-fluoroaniline/ Aldrich (I) 374 2.49
    312 HCl
    Figure US20090312325A1-20091217-C00460
         		MeSO2— Me— Intermediate 33 3- aminobenzonitrile/ Aldrich (I) 381 2.44
    313 HCl
    Figure US20090312325A1-20091217-C00461
         		MeSO2— Me— Intermediate 33 1-methyl-1H- benzimidazol-6- amine/ Heterocycles, 1991, 32(5), 1003-12. (I) 410 1.87
    314 HCl
    Figure US20090312325A1-20091217-C00462
         		MeSO2— Me— Intermediate 33 3-methylaniline/ Aldrich (I) 370 2.40
    315 HCl
    Figure US20090312325A1-20091217-C00463
         		MeSO2— Me— Intermediate 33 1-ethyl-1H- pyrazol-5-amine/ Aldrich (I) 374 2.22
    316 HCl
    Figure US20090312325A1-20091217-C00464
         		MeSO2— Me— Intermediate 33 5-(methyloxy)-3- pyridinamine/ Australian J. Chem., 1981, 34(4). 927-32 (I) 387 2.08
    317 HCl
    Figure US20090312325A1-20091217-C00465
         		MeSO2— Me— Intermediate 33 5-methyl-3- pyridinamine/ Synchem (I) 371 1.90
    318 HCl
    Figure US20090312325A1-20091217-C00466
         		MeSO2— Me— Intermediate 33 5-amino-2- fluorobenzonitrile/ Matrix Scientific (I) 399 2.38
    329 HCl
    Figure US20090312325A1-20091217-C00467
         		PhSO2— Me— Intermediate 16 2-methoxybenzyl amine/Aldrich (I) 462 2.26
    479 HCl
    Figure US20090312325A1-20091217-C00468
         		MeSO2— Me— Intermediate 33 1-methyl-1H- pyrazol-5-amine/ Apollo Chem (IV) 360 2.09
    496 HCl
    Figure US20090312325A1-20091217-C00469
         		MeSO2— Me— Intermediate 33 1,3-benzodioxol- 4-amine/J. Med. Chem., 2002, 45(19), 4128- 4139 (I) 400 2.22
    497 HCl
    Figure US20090312325A1-20091217-C00470
         		MeSO2— Me— Intermediate 33 4-fluoro-3- methylaniline/ Fluoro Chem (I) 388 2.35
    498 HCl
    Figure US20090312325A1-20091217-C00471
         		MeSO2— Me— Intermediate 33 3-chloro-4- fluoroaniline/ Aldrich (IV) 408 2.59
    499 HCl
    Figure US20090312325A1-20091217-C00472
         		MeSO2— Me— Intermediate 33 5,6,7,8- tetrahydro-1- naphthalenamine/ Fluka (I) 410 2.57
    500 HCl
    Figure US20090312325A1-20091217-C00473
         		MeSO2— Me— Intermediate 33 2,3-difluoroaniline/ Aldrich (IV) 392 2.52
    501 HCl
    Figure US20090312325A1-20091217-C00474
         		MeSO2— Me— Intermediate 33 3-chloro-2- fluoroaniline/ Aldrich (I) 408 2.67
    502 HCl
    Figure US20090312325A1-20091217-C00475
         		MeSO2— Me— Intermediate 33 3,5-difluoroaniline/ Aldrich (I) 392 2.60
    503 HCl
    Figure US20090312325A1-20091217-C00476
         		MeSO2— Me— Intermediate 33 1,3-benzothiazol- 6-amine/ Maybridge (I) 413 2.13
    504 HCl
    Figure US20090312325A1-20091217-C00477
         		MeSO2— Me— Intermediate 33 3,4-difluoroaniline/ Aldrich (I) 392 2.43
    505 HCl
    Figure US20090312325A1-20091217-C00478
         		MeSO2— Me— Intermediate 33 2,4-difluoroaniline/ Aldrich (I) 392 2.33
    508 HCl
    Figure US20090312325A1-20091217-C00479
         		MeSO2— Me— Intermediate 33 1-methyl-2,3- dihydro-1H-indol- 4-amine/ Intermediate 71 (IV) 411 2.2
    509 HCl
    Figure US20090312325A1-20091217-C00480
         		MeSO2— Me— Intermediate 33 1-methyl-1H- indazol-4-amine/ J. Med. Chem., 2002, 45(3), 740-743 (I) 410 2.21
    510 HCl
    Figure US20090312325A1-20091217-C00481
         		MeSO2— Me— Intermediate 33 2,3-dihydro-1- benzofuran-7- amine/ WO9517401 A1 (I) 398 2.15
    511 HCl
    Figure US20090312325A1-20091217-C00482
         		MeSO2— Me— Intermediate 33 2,3-dihydro-1H- inden-4-amine/ Aldrich (I) 396 2.46
    512 HCl
    Figure US20090312325A1-20091217-C00483
         		MeSO2— Me— Intermediate 33 4-amino-2,3- dihydro-1H-inden- 1-one/Davos (IV) 410 2.13
    520 HCl
    Figure US20090312325A1-20091217-C00484
         		MeSO2— Me— Intermediate 33 2-methyl-4- pyridinamine/ Asym Chem (I) 371 1.7
    542 HCl
    Figure US20090312325A1-20091217-C00485
         		MeSO2— Me— Intermediate 33 1,3-dihydro-2- benzofuran-4- amine/US 4521241 (I) 398 2.16
    587 HCl
    Figure US20090312325A1-20091217-C00486
         		MeSO2— Me— Intermediate 33 3,4-dihydro-2H- chromen-5- ylamine/J. Heterocyclic Chem., 1973, 10(4), 623-9 (I) 412 2.26
    (a) Salt forms:
    HCI = hydrochloride
    TFA = trifluoroacetate
    (b) Isolation Method:
    (I) Filtered off directly from the reaction mixture.
    (II) Mass Directed preparative HPLC Method A.
    (III) Mass Directed preparative HPLC Method B.
    (IV) Mass Directed preparative HPLC Method C.
    • Example 14 4-[(3-Chlorophenyl)(methyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00487
  • Intermediate 9 (0.023 g) was dissolved in 1-methyl-2-pyrrolidinone (1 ml), and 3-chloro-N-methylaniline (available from Avocado) (0.012 ml) was added. The mixture was stirred under microwave irradiation (power 150 W) for 10 min at 180° C. and for a further 10 min (power 150 W) at 150° C. Purification by mass directed HPLC (Method A) gave the title compound (0.015 g).
  • LC/MS Rt 2.58 min m/z 390 [MH+]
    • Example 112 4-({[2-(Methyloxy)phenyl]methyl}amino)-6-(phenylsulfonyl)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00488
  • Intermediate 8 (0.017 g) was taken up in acetonitrile (1.5 ml) to give a slurry. 2-Methoxy benzylamine (available from Aldrich) (0.021 g) and N,N-diisopropylethylamine (0.050 ml) were added and the resultant mixture was heated under reflux for 16 h. The mixture was cooled, the solvent evaporated in vacuo and the residue purified by mass directed HPLC (Method A) to give the title compound (0.014 g).
  • LC/MS Rt 2.73 min m/z 448 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00489
    Ex. Isolation LCMS
    No Starting Amine reagent/ Method LCMS Rt
    (a) R1NH R3SO2 Material Source (b) MH+ (min)
    101 (c) HCl
    Figure US20090312325A1-20091217-C00490
         		MeSO2— Intermediate 9 1-phenylmethanamine/ Aldrich (I) 356 2.07
    102
    Figure US20090312325A1-20091217-C00491
         		MeSO2— Intermediate 9 tetrahydro-2H-pyran- 3-amine hydrochloride/ Anales de Quimica, Serie C: Quimica Organica y Bioquimica, 1988, 84(2), 148-55. (II) 350 1.78
    103
    Figure US20090312325A1-20091217-C00492
         		PhSO2— Intermediate 8 2-(aminomethyl) phenol/Buttpark (I) 434 2.56
    104
    Figure US20090312325A1-20091217-C00493
         		PhSO2— Intermediate 8 2,3-dihydro-1H-inden- 2-amine hydrochloride/ Aldrich (I) 444 2.85
    105
    Figure US20090312325A1-20091217-C00494
         		PhSO2— Intermediate 8 cyclopropylamine/ Aldrich (I) 368 2.37
    106
    Figure US20090312325A1-20091217-C00495
         		PhSO2— Intermediate 8 [4-(aminomethyl) phenyl]dimethylamine hydrochloride/ Aldrich (I) 461 2.69
    107
    Figure US20090312325A1-20091217-C00496
         		PhSO2— Intermediate 8 N-[3-(aminomethyl)phenyl] methanesulfonamide trifluoroacetate/ J. Med. Chem., 1999, 42(14), 2504-2526. (I) 511 2.52
    108
    Figure US20090312325A1-20091217-C00497
         		PhSO2— Intermediate 8 2-aminocyclohexanol/ TCI-US (I) 426 2.49
    109
    Figure US20090312325A1-20091217-C00498
         		PhSO2— Intermediate 8 [(1-methyl-1H-pyrazol- 4-yl) methyl]amine/ Zelinsky-BB; CA 400877-05-6 (I) 422 2.28
    110
    Figure US20090312325A1-20091217-C00499
         		PhSO2— Intermediate 8 (2-pyridinylmethyl) amine hydrochloride/ Aldrich (I) 419 2.35
    111
    Figure US20090312325A1-20091217-C00500
         		PhSO2— Intermediate 8 1,2,3,4-tetrahydro-1- naphthalenamine hydrochloride/ Aldrich (I) 458 2.92
    113
    Figure US20090312325A1-20091217-C00501
         		PhSO2— Intermediate 8 (cyclohexylmethyl) amine/Aldrich (I) 424 2.87
    114
    Figure US20090312325A1-20091217-C00502
         		PhSO2— Intermediate 8 {[4-(methyloxy)phenyl] methyl}amine hydrochloride/ Aldrich (I) 448 2.69
    115
    Figure US20090312325A1-20091217-C00503
         		PhSO2— Intermediate 8 (phenylmethyl)amine hydrochloride/ Aldrich (I) 418 2.67
    116
    Figure US20090312325A1-20091217-C00504
         		PhSO2— Intermediate 8 cyclohexylamine hydrochloride/ Acros (II) 410 2.59
    117
    Figure US20090312325A1-20091217-C00505
         		PhSO2— Intermediate 8 2-methyl-1- propanamine trifluoroacetate/ Aldrich (II) 384 2.43
    118
    Figure US20090312325A1-20091217-C00506
         		PhSO2— Intermediate 8 [2-(3-pyridinyl)ethyl] amine/Lancaster (II) 433 2.08
    119
    Figure US20090312325A1-20091217-C00507
         		PhSO2— Intermediate 8 [2-(4-pyridinyl)ethyl] amine/Maybridge (II) 433 2.01
    120
    Figure US20090312325A1-20091217-C00508
         		PhSO2— Intermediate 8 2-phenylethanamine/ Aldrich (II) 432 2.68
    121
    Figure US20090312325A1-20091217-C00509
         		PhSO2— Intermediate 8 (3-pyridinylmethyl) amine/Aldrich (II) 419 2.12
    122
    Figure US20090312325A1-20091217-C00510
         		PhSO2— Intermediate 8 {[3,5- bis)methyloxy)phenyl] methyl}amine hydrochloride/ Aldrich (II) 478 2.68
    123
    Figure US20090312325A1-20091217-C00511
         		PhSO2— Intermediate 8 tetrahydro-2H-pyran- 3-amine hydrochloride/ Anales de Quimica, Serie C: Quimica Organica y Bioquimica, 1988, 84(2), 148-55. (II) 412 2.20
    124
    Figure US20090312325A1-20091217-C00512
         		PhSO2— Intermediate 8 4-amino cyclohexanone/ Nouveau Journal de Chimie, 1984, 8(7), 459-67. (II) 424 2.15
    125 (c) HCl
    Figure US20090312325A1-20091217-C00513
         		PhSO2— Intermediate 8 {[3-chloro-4- (methyloxy)phenyl] methyl}amine/ Apin Chemicals (I) 482 2.56
    126
    Figure US20090312325A1-20091217-C00514
    Figure US20090312325A1-20091217-C00515
         		Intermediate 7 cyclohexylamine/ Aldrich (II) 402 2.49
    127
    Figure US20090312325A1-20091217-C00516
    Figure US20090312325A1-20091217-C00517
         		Intermediate 7 2-methyl-1- propanamine/ Aldrich (II) 376 2.34
    (a) Salt forms: HCl = hydrochloride
    (b) Isolation Method:
    (I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are free bases, apart from Examples 101 and 125 which are thought to be hydrochloride salts.
    (II) Mass Directed preparative HPLC Method A.
    (c) No N,N-diisopropylethylamine was used in the preparation of Examples 101 and 125.
  • The following were made in a similar manner to Example 112:
  • Figure US20090312325A1-20091217-C00518
    Ex. Isolation LCMS
    No. Starting Amine Reagent/ Method LCMS Rt
    (a) R1R2N— R3SO2— R20— Material Source (b) MH+ (min)
    319
    Figure US20090312325A1-20091217-C00519
         		PhSO2— H— Intermediate 8 N,3-dimethylaniline/ Acros (II) 432 2.97
    320
    Figure US20090312325A1-20091217-C00520
         		PhSO2— H— Intermediate 8 3-chloro-N- methylaniline/ Maybridge (II) 452 3.00
    321 TFA
    Figure US20090312325A1-20091217-C00521
         		PhSO2— H— Intermediate 8 3-aminoquinuclidine dihydrochloride/ Aldrich (III) 437 1.98
    330 TFA
    Figure US20090312325A1-20091217-C00522
         		PhSO2— Me— Intermediate 16 (3-pyridinylmethyl) amine/Aldrich (III) 433 2.08
    331 HCl
    Figure US20090312325A1-20091217-C00523
    Figure US20090312325A1-20091217-C00524
         		H— Intermediate 31 2-(aminomethyl) phenol/Buttpark (I*) 464 2.14
    332 TFA
    Figure US20090312325A1-20091217-C00525
    Figure US20090312325A1-20091217-C00526
         		H— Intermediate 31 (3-pyridinylmethyl) amine/Aldrich (III) 449 2.06
    333 TFA
    Figure US20090312325A1-20091217-C00527
    Figure US20090312325A1-20091217-C00528
         		H— Intermediate 31 [2-(4-pyridinyl)ethyl] amine/Maybridge (III) 463 1.93
    334 HCl
    Figure US20090312325A1-20091217-C00529
         		MeSO2— Me— Intermediate 33 2-methyl-2- propanamine/Aldrich (IV) 336 2.04
    (a) Salt forms:
    HCl = hydrochloride
    TFA = trifluoroacetate
    (b) Isolation Method:
    (I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are free bases.
    (I*) No base is used in the reaction procedure. Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are hydrochloride salts.
    (II) Mass Directed HPLC Method A; it is thought that compounds isolated by this method are free bases unless the R1 or R3 groups contain basic moieties, in which case formate salts may be formed.
    (III) Mass Directed HPLC Method B; it is thought that compounds isolated by this method are trifluoroacetate salts.
    (IV) Mass Directed HPLC Method C; it is thought that compounds isolated by this method are hydrochloride salts.
    • Example 133 6-[(1,1-Dimethylethyl)thio]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00530
  • Intermediate 14 (0.050 g), potassium tert-butoxide (0.015 g) and tert-butylmercaptan (0.0135 ml) were added to a stirred solution of tris(dibenzylidineacetone)dipalladium (0) (0.007 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.005 g) in toluene (2 ml), and the mixture was heated at 100° C. for 3.5 h and left to cool. The solvent was evaporated in vacuo to leave a brown solid (0.072 g), which was purified by Mass Directed Preparative HPLC (Method A) to give the title compound (0.008 g).
  • LC/MS Rt 2.83 min m/z 382 [MH+].
  • Similarly prepared from Intermediate 14 were the following:
  • Figure US20090312325A1-20091217-C00531
    Isolation LCMS
    Ex. Thio reagent/ Method LCMS Rt
    No. R3S— Source (b) MH+ (min)
    132
    Figure US20090312325A1-20091217-C00532
         		cyclohexanethiol/ Aldrich (II) 4.08 2.99
    135
    Figure US20090312325A1-20091217-C00533
         		N-(2-mercaptoethyl) acetamide/Aldrich (II) 411 2.11
    136
    Figure US20090312325A1-20091217-C00534
         		2,6-dichlorobenzene thiol/Aldrich (II) 471 2.77
    137
    Figure US20090312325A1-20091217-C00535
         		2-methyl-1- propanethiol/ Aldrich (II) 382 2.66
    138
    Figure US20090312325A1-20091217-C00536
         		1,3-oxazole-2(3H)- thione/ Can. J. Chem., 1972, 50(18), 3082-3. (II) 393 2.29
    139
    Figure US20090312325A1-20091217-C00537
         		5-methyl-1,3,4- oxadiazole-2(3H)- thione/ U.S. Pat. No. 5670526 A (II) 408 2.22
    140
    Figure US20090312325A1-20091217-C00538
         		phenylmethane thiol/ Aldrich (II) 416 2.66
    141
    Figure US20090312325A1-20091217-C00539
         		4-fluorobenzene thiol/ Aldrich (IV) 420 2.87
    142
    Figure US20090312325A1-20091217-C00540
         		4-(methyloxy) benzenethiol/ Aldrich (II) 432 2.90
    143
    Figure US20090312325A1-20091217-C00541
         		cyclopentanethiol/ Aldrich (I) 394 2.98
    144
    Figure US20090312325A1-20091217-C00542
         		benzenethiol/ Aldrich (I) 402 2.96
    (b) Isolation Method:
    (I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are free bases.
    (II) Mass Directed preparative HPLC Method A.
    (IV) Purified by chromatography on silica gel, eluting with dichloromethane followed by ethyl acetate. It is thought that compounds isolated by this method are free bases.
  • The following were prepared in a similar manner to Example 133, using N,N-dimethylformamide as the reaction solvent:
  • Figure US20090312325A1-20091217-C00543
    Isolation LCMS
    Ex. Starting Thiol Reagent/ Method LCMS Rt
    No. R1NH— R3S— R20— Material Source (b) MH+ (min)
    337
    Figure US20090312325A1-20091217-C00544
    Figure US20090312325A1-20091217-C00545
         		Me- Inter- mediate 35 2-mercapto- ethanol/Sigma (I) 402 2.19
    338
    Figure US20090312325A1-20091217-C00546
    Figure US20090312325A1-20091217-C00547
         		Me- Inter- mediate 35 1,2,4-triazole-3- thiol/Aldrich (I) 425 2.12
    339
    Figure US20090312325A1-20091217-C00548
    Figure US20090312325A1-20091217-C00549
         		Me- Inter- mediate 35 1-methyl-2- mercapto- imidazole/ Aldrich (I) 438 2.15
    340
    Figure US20090312325A1-20091217-C00550
    Figure US20090312325A1-20091217-C00551
         		Me- Inter- mediate 35 2-mercapto- imidazole Aldrich (I) 424 1.96
    341
    Figure US20090312325A1-20091217-C00552
    Figure US20090312325A1-20091217-C00553
         		Me- Inter- mediate 35 2-benzimidazol- ethiol/Aldrich (I) 474 2.54
    342
    Figure US20090312325A1-20091217-C00554
    Figure US20090312325A1-20091217-C00555
         		Me- Inter- mediate 35 4-methyl-1,3- oxazole-2(3H)- thione J. Org. Chem., 1967, 32(7), 2079-81. (I) 439 2.67
    343
    Figure US20090312325A1-20091217-C00556
    Figure US20090312325A1-20091217-C00557
         		Me- Inter- mediate 35 2-furanyl methanethiol/ Aldrich (I) 438 2.79
    344
    Figure US20090312325A1-20091217-C00558
    Figure US20090312325A1-20091217-C00559
         		Me- Inter- mediate 36 1,1-dimethylethyl (2-mercaptoethyl) carbamate/ Aldrich (V) 495 2.73
    345
    Figure US20090312325A1-20091217-C00560
    Figure US20090312325A1-20091217-C00561
         		Me- Inter- mediate 36 1,1-dimethylethyl 4-mercapto-1- piperidine- carboxylate/ U.S. Pat. No. 5317025 A (V) 535 3.22
    563
    Figure US20090312325A1-20091217-C00562
    Figure US20090312325A1-20091217-C00563
         		Me- Inter- mediate 62 tetrahydro-3- furanthiol/Advan. Carbohydrate Chem. (1963), 18 123-99 (I) 381 2.17
    564
    Figure US20090312325A1-20091217-C00564
    Figure US20090312325A1-20091217-C00565
         		Me- Inter- mediate 61 tetrahydro-3- furanthiol/Advan. Carbohydrate Chem. (1963), 18 123-99 (I) 398 2.65
    565
    Figure US20090312325A1-20091217-C00566
    Figure US20090312325A1-20091217-C00567
         		Me- Inter- mediate 61 tetrahydro-2H- pyran-4-thiol/ WO98/05635 (I) 412 2.70
    566
    Figure US20090312325A1-20091217-C00568
    Figure US20090312325A1-20091217-C00569
         		Me- Inter- mediate 62 tetrahydro-2H- pyran-4-thiol/ WO98/05635 (I) 395 2.20
    569
    Figure US20090312325A1-20091217-C00570
    Figure US20090312325A1-20091217-C00571
         		Me- Inter- mediate 62 1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ U.S. Pat. No. 5317025 A (I) 494 2.80
    570
    Figure US20090312325A1-20091217-C00572
    Figure US20090312325A1-20091217-C00573
         		Me- Inter- mediate 61 N-(2- mercaptoethyl) acetamide/Aldrich (I) 413 2.20
    572
    Figure US20090312325A1-20091217-C00574
    Figure US20090312325A1-20091217-C00575
         		Me- Inter- mediate 62 N-(2- mercaptoethyl) acetamide/Aldrich (V) 396 1.90
    516
    Figure US20090312325A1-20091217-C00576
    Figure US20090312325A1-20091217-C00577
         		Me- Inter- mediate 35 1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ U.S. Pat. No. 5317025A (V) 541 3.10
    517
    Figure US20090312325A1-20091217-C00578
    Figure US20090312325A1-20091217-C00579
         		Me- Inter- mediate 35 1,1-dimethylethyl (2-mercaptoethyl) carbamate/ Aldrich (V) 501 3.68
    528
    Figure US20090312325A1-20091217-C00580
    Figure US20090312325A1-20091217-C00581
         		Me- Inter- mediate 36 2-mercapto- ethanol/Aldrich (I) 396 2.20
    603
    Figure US20090312325A1-20091217-C00582
    Figure US20090312325A1-20091217-C00583
         		Me- Inter- mediate 61 1,1-dimethylethyl (2-mercaptoethyl) carbamate (I) 471 2.80
    634
    Figure US20090312325A1-20091217-C00584
    Figure US20090312325A1-20091217-C00585
         		Me- Inter- mediate 62 ethanethiol/ Aldrich (I) 339 2.32
    635
    Figure US20090312325A1-20091217-C00586
    Figure US20090312325A1-20091217-C00587
         		Me- Inter- mediate 62 1-propanethiol/ Aldrich (I) 353 2.71
    636
    Figure US20090312325A1-20091217-C00588
    Figure US20090312325A1-20091217-C00589
         		Me- Inter- mediate 62 2-propanethiol/ Aldrich (I) 353 2.47
    637
    Figure US20090312325A1-20091217-C00590
    Figure US20090312325A1-20091217-C00591
         		Me- Inter- mediate 62 2-methyl-2- propanethiol/ Aldrich (I) 367 2.58
    638
    Figure US20090312325A1-20091217-C00592
    Figure US20090312325A1-20091217-C00593
         		Cl— Inter- mediate 96 ethanethiol/ Aldrich (I) 359 2.59
    639
    Figure US20090312325A1-20091217-C00594
    Figure US20090312325A1-20091217-C00595
         		Cl— Inter- mediate 96 1-propanethiol/ Aldrich (I) 373 2.76
    640
    Figure US20090312325A1-20091217-C00596
    Figure US20090312325A1-20091217-C00597
         		Cl— Inter- mediate 96 2-propanethiol/ Aldrich (I) 373 2.71
    641
    Figure US20090312325A1-20091217-C00598
    Figure US20090312325A1-20091217-C00599
         		Cl— Inter- mediate 96 2-methyl-2- propanethiol/ Aldrich (I) 387 2.93
    642
    Figure US20090312325A1-20091217-C00600
    Figure US20090312325A1-20091217-C00601
         		Me- Inter- mediate 62 ethanethiol/ Aldrich (I) 373 2.81
    643
    Figure US20090312325A1-20091217-C00602
    Figure US20090312325A1-20091217-C00603
         		Me- Inter- mediate 97 1-propanethiol/ Aldrich (I) 387 3.06
    644
    Figure US20090312325A1-20091217-C00604
    Figure US20090312325A1-20091217-C00605
         		Me- Inter- mediate 97 2-propanethiol/ Aldrich (I) 387 2.95
    645
    Figure US20090312325A1-20091217-C00606
    Figure US20090312325A1-20091217-C00607
         		Me- Inter- mediate 97 2-methyl-2- propanethiol/ Aldrich (I) 401 3.16
    646
    Figure US20090312325A1-20091217-C00608
    Figure US20090312325A1-20091217-C00609
         		Cl— Inter- mediate 100 ethanethiol/ Aldrich (I) 393 3.1 
    647
    Figure US20090312325A1-20091217-C00610
    Figure US20090312325A1-20091217-C00611
         		Cl— Inter- mediate 100 1-propanethiol/ Aldrich (I) 407 3.3 
    648
    Figure US20090312325A1-20091217-C00612
    Figure US20090312325A1-20091217-C00613
         		Cl— Inter- mediate 100 2-propanethiol/ Aldrich (I) 407 3.25
    649
    Figure US20090312325A1-20091217-C00614
    Figure US20090312325A1-20091217-C00615
         		Cl— Inter- mediate 100 2-methyl-2- propanethiol/ Aldrich (I) 421 3.33
    650
    Figure US20090312325A1-20091217-C00616
    Figure US20090312325A1-20091217-C00617
         		Me- Inter- mediate 98 ethanethiol/ Aldrich (I) 357 2.59
    651
    Figure US20090312325A1-20091217-C00618
    Figure US20090312325A1-20091217-C00619
         		Me- Inter- mediate 98 1-propanethiol/ Aldrich (I) 371 2.84
    652
    Figure US20090312325A1-20091217-C00620
    Figure US20090312325A1-20091217-C00621
         		Me- Inter- mediate 98 2-propanethiol/ Aldrich (I) 371 2.84
    653
    Figure US20090312325A1-20091217-C00622
    Figure US20090312325A1-20091217-C00623
         		Me- Inter- mediate 98 2-methyl-2- propanethiol/ Aldrich (I) 385 2.94
    654
    Figure US20090312325A1-20091217-C00624
    Figure US20090312325A1-20091217-C00625
         		Cl— Inter- mediate 99 ethanethiol/ Aldrich (I) 377 2.88
    655
    Figure US20090312325A1-20091217-C00626
    Figure US20090312325A1-20091217-C00627
         		Cl— Inter- mediate 99 1-propanethiol/ Aldrich (I) 391 3.07
    656
    Figure US20090312325A1-20091217-C00628
    Figure US20090312325A1-20091217-C00629
         		Cl— Inter- mediate 99 2-propanethiol/ Aldrich (I) 391 3.03
    657
    Figure US20090312325A1-20091217-C00630
    Figure US20090312325A1-20091217-C00631
         		Cl— Inter- mediate 99 2-methyl-2- propanethiol/ Aldrich (I) 405 3.14
    658
    Figure US20090312325A1-20091217-C00632
    Figure US20090312325A1-20091217-C00633
         		Cl— Inter- mediate 102 ethanethiol/ Aldrich (I) 376 2.94
    659
    Figure US20090312325A1-20091217-C00634
    Figure US20090312325A1-20091217-C00635
         		Cl— Inter- mediate 102 1-propanethiol/ Aldrich (I) 390 3.08
    660
    Figure US20090312325A1-20091217-C00636
    Figure US20090312325A1-20091217-C00637
         		Cl— Inter- mediate 102 2-propanethiol/ Aldrich (I) 390 3.02
    661
    Figure US20090312325A1-20091217-C00638
    Figure US20090312325A1-20091217-C00639
         		Cl— Inter- mediate 102 2-methyl-2- propanethiol/ Aldrich (I) 404 3.21
    662
    Figure US20090312325A1-20091217-C00640
    Figure US20090312325A1-20091217-C00641
         		Me- Inter- mediate 101 ethanethiol/ Aldrich (I) 356 2.5 
    663
    Figure US20090312325A1-20091217-C00642
    Figure US20090312325A1-20091217-C00643
         		Me- Inter- mediate 101 1-propanethiol/ Aldrich (I) 370 2.65
    664
    Figure US20090312325A1-20091217-C00644
    Figure US20090312325A1-20091217-C00645
         		Me- Inter- mediate 101 2-propanethiol/ Aldrich (I) 370 2.61
    665
    Figure US20090312325A1-20091217-C00646
    Figure US20090312325A1-20091217-C00647
         		Me- Inter- mediate 101 2-methyl-2- propanethiol/ Aldrich (I) 384 2.89
    681
    Figure US20090312325A1-20091217-C00648
    Figure US20090312325A1-20091217-C00649
         		Me- Inter- mediate 61 N-(2- mercaptoethyl)- N-methyl- acetamide/Tetra- hedron 1986, 42 (5), 1449 (I) 427 2.30
    (b) Isolation Method:
    (I) These were purified by SCX column, eluting with ammonia/methanol.
    (V) These were purified by chromatography on silica gel (eluting with ethyl acetate/cyclohexane) followed by trituration with cyclohexane to give the pure product; it is thought that compounds isolated by this method are free bases.
    • Example 577 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylthio)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00650
  • A stirred mixture of Intermediate 36 (0.2 g), sodium thiomethoxide (0.058 g), tris(dibenzylideneacetone)dipalladium(0) (0.076 g), (oxidi-2,1-phenylene)-bis(diphenylphosphine) (0.045 g), and potassium tert-butoxide (0.047 g) in N,N-dimethylformamide (10 ml) was heated at 100° C. under nitrogen for 18 h. The cooled reaction mixture was applied directly to an SCX cartridge (10 g) and eluted with methanol (150 ml) followed by 2M ammonia in methanol (100 ml). Evaporation of the methanol/ammonia fraction gave the title compound as a yellow solid (0.13 g).
  • LC/MS Rt 2.48 min, m/z 366 [MH+]
  • The following were prepared in a similar manner to Example 577, but without adding potassium tert-butoxide to the reaction mixture:
  • Figure US20090312325A1-20091217-C00651
    LCMS
    Ex. Starting LCMS Rt
    No. R1NH— R20— Material MH+ (min)
    577
    Figure US20090312325A1-20091217-C00652
         		Me- Intermediate 36 382 2.00
    604
    Figure US20090312325A1-20091217-C00653
         		Et- Intermediate 74 386 2.57
    605
    Figure US20090312325A1-20091217-C00654
         		Et- Intermediate 75 356 2.76
    606
    Figure US20090312325A1-20091217-C00655
         		Et- Intermediate 76 372 2.95
    607
    Figure US20090312325A1-20091217-C00656
         		Et- Intermediate 77 363 2.71
    608
    Figure US20090312325A1-20091217-C00657
         		Et- Intermediate 78 352 2.65
    609
    Figure US20090312325A1-20091217-C00658
         		Et- Intermediate 79 392 2.44
    610
    Figure US20090312325A1-20091217-C00659
         		Et- Intermediate 80 380 2.62
    611
    Figure US20090312325A1-20091217-C00660
         		Et- Intermediate 81 339 2.2 
    612
    Figure US20090312325A1-20091217-C00661
         		Et- Intermediate 82 357 2.55
    613
    Figure US20090312325A1-20091217-C00662
         		Et- Intermediate 83 373 2.73
    614
    Figure US20090312325A1-20091217-C00663
         		F— Intermediate 85 363 2.69
    615
    Figure US20090312325A1-20091217-C00664
         		F— Intermediate 86 329 2.16
    616
    Figure US20090312325A1-20091217-C00665
         		F— Intermediate 84 347 2.53
    617
    Figure US20090312325A1-20091217-C00666
         		F— Intermediate 89 346 2.87
    618
    Figure US20090312325A1-20091217-C00667
         		F— Intermediate 90 363 3.06
    619
    Figure US20090312325A1-20091217-C00668
         		F— Intermediate 91 342 2.91
    620
    Figure US20090312325A1-20091217-C00669
         		F— Intermediate 92 353 2.77
    621
    Figure US20090312325A1-20091217-C00670
         		F— Intermediate 93 382 2.56
    622
    Figure US20090312325A1-20091217-C00671
         		F— Intermediate 94 376 2.88
    623
    Figure US20090312325A1-20091217-C00672
         		F— Intermediate 88 370 2.81
    682
    Figure US20090312325A1-20091217-C00673
         		Cl— Intermediate 38 358 3.27
    683
    Figure US20090312325A1-20091217-C00674
         		Cl— Intermediate 39 392 3.06
    684
    Figure US20090312325A1-20091217-C00675
         		Cl— Intermediate 40 386 3.10
    685
    Figure US20090312325A1-20091217-C00676
         		Cl— Intermediate 41 369 3.01
    686
    Figure US20090312325A1-20091217-C00677
         		Cl— Intermediate 42 362 3.20
    687
    Figure US20090312325A1-20091217-C00678
         		Cl— Intermediate 43 398 2.82
    • Example 134 4-{[3-(Methyloxy)phenyl]amino}-6-({[4-(methyloxy)phenyl]methyl}thio)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00679
  • Intermediate 14 (0.020 g), potassium tert-butoxide (0.0061 g) and [4-(methyloxy)phenyl]methanethiol (available from Aldrich) (0.007 ml) were added to a stirred solution of tris(dibenzylidineacetone)dipalladium(0) (0.002 g) and (oxydi-2,1-phenylene)bis (diphenylphosphine) (0.002 g) in N,N-dimethylformamide (1.5 ml), and the mixture was heated under microwave irradiation at 60° C. for 8 min. The solvent was evaporated in vacuo, and the residue purified by Mass Directed Preparative HPLC (Method A) to give the title compound (0.0048 g).
  • LC/MS Rt 2.93 min m/z 446 [MH+]
    • Example 129 6-[(1,1-Dimethylethyl)sulfonyl]-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00680
  • Example 133 (0.010 g) was dissolved in N,N-dimethylformamide (2 ml) and anisole (0.013 ml) was added. Oxone (0.075 g) was added and the mixture stirred for 16 h at room temperature. After quenching with 1M aqueous sodium sulphite, the mixture was extracted with dichloromethane; the organic layer was dried over magnesium sulphate and evaporated in vacuo to give a yellow solid. Purification by mass directed HPLC (Method A) gave the title compound (0.005 g).
  • LC/MS Rt 2.48 min m/z 414 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00681
    Isolation LCMS
    Ex. Method LCMS Rt
    No. R3SO2— Starting Material (b) MH+ (min)
    128
    Figure US20090312325A1-20091217-C00682
         		Example 142 (II) 464.09 2.83
    130 (a)
    Figure US20090312325A1-20091217-C00683
         		Example 135 (II) 443.1 2.11
    (a) No anisole was used in the reaction mixture in this Example.
    (b) Isolation Method: (II) Mass Directed preparative HPLC (Method A).
  • The following were prepared in a similar manner to Example 129, but without the addition of anisole to the reaction mixture:
  • Figure US20090312325A1-20091217-C00684
    Ex. Isolation
    No. Starting method LCMS LCMS
    (a) R1NH— R3SO2— R20— Material (b) MH+ Rt (min)
    346 HCl
    Figure US20090312325A1-20091217-C00685
    Figure US20090312325A1-20091217-C00686
         		Me— Example 337 (IV) 434 2.10
    347 HCl
    Figure US20090312325A1-20091217-C00687
    Figure US20090312325A1-20091217-C00688
         		Me— Example 338 (IV) 457 2.30
    348 HCl
    Figure US20090312325A1-20091217-C00689
    Figure US20090312325A1-20091217-C00690
         		Me— Example 339 (IV) 470 2.46
    349 HCl
    Figure US20090312325A1-20091217-C00691
    Figure US20090312325A1-20091217-C00692
         		Me— Example 340 (IV) 456 2.27
    350 HCl
    Figure US20090312325A1-20091217-C00693
    Figure US20090312325A1-20091217-C00694
         		Me— Example 341 (IV) 506 2.79
    351 HCl
    Figure US20090312325A1-20091217-C00695
    Figure US20090312325A1-20091217-C00696
         		Me— Example 343 (IV) 470 2.66
    352 HCl
    Figure US20090312325A1-20091217-C00697
    Figure US20090312325A1-20091217-C00698
         		Me— Example 345 (V) 567 3.08
    353 HCl
    Figure US20090312325A1-20091217-C00699
    Figure US20090312325A1-20091217-C00700
         		Me— Example 344 (VI) 527.5 2.76
    369 HCl
    Figure US20090312325A1-20091217-C00701
         		MeSO2— Cl— Example 682 (IV) 390 2.77
    370 HCl
    Figure US20090312325A1-20091217-C00702
         		MeSO2— Cl— Example 683 (IV) 424 2.63
    371 HCl
    Figure US20090312325A1-20091217-C00703
         		MeSO2— Cl— Example 684 (IV) 418 2.77
    372 HCl
    Figure US20090312325A1-20091217-C00704
         		MeSO2— Cl— Example 685 (IV) 401 2.57
    373 HCl
    Figure US20090312325A1-20091217-C00705
         		MeSO2— Cl— Example 686 (IV) 394 2.70
    374 HCl
    Figure US20090312325A1-20091217-C00706
         		MeSO2— Cl— Example 687 (IV) 430 2.51
    478
    Figure US20090312325A1-20091217-C00707
    Figure US20090312325A1-20091217-C00708
         		Me— Intermediate 29 (VI) 519 2.55
    602
    Figure US20090312325A1-20091217-C00709
    Figure US20090312325A1-20091217-C00710
         		Me— Example 603 (VII) 503 2.90
    515
    Figure US20090312325A1-20091217-C00711
    Figure US20090312325A1-20091217-C00712
         		Me— Example 562 (VI) 449 2.60
    (a) Salt forms: HCl = hydrochloride.
    (b) Isolation Method:
    (IV) Mass Directed preparative HPLC (Method C).
    (V) Column chromatography on silica gel.
    (VI) Aqueous work-up.
    (VII) Trituration from acetonitrile.
  • The following were prepared in a similar manner to Example 129 without the addition of anisole to the reaction mixture:
  • Figure US20090312325A1-20091217-C00713
    Ex. Isolation
    No. Method LCMS LCMS
    (a) R1NH— R20— R3SO2— Starting Material (b) MH+ Rt (min)
    522
    Figure US20090312325A1-20091217-C00714
         		Me—
    Figure US20090312325A1-20091217-C00715
         		Example 521 (II) 448 2.33
    591 HCl
    Figure US20090312325A1-20091217-C00716
         		Et— MeSO2— Example 604 (IV) 418 2.39
    592 HCl
    Figure US20090312325A1-20091217-C00717
         		Et— MeSO2— Example 605 (IV) 388 2.51
    593 HCl
    Figure US20090312325A1-20091217-C00718
         		Et— MeSO2— Example 607 (IV) 395 2.46
    594 HCl
    Figure US20090312325A1-20091217-C00719
         		Et— MeSO2— Example 612 (IV) 389 2.32
    595 HCl
    Figure US20090312325A1-20091217-C00720
         		Et— MeSO2— Example 613 (IV) 405 2.47
    596 HCl
    Figure US20090312325A1-20091217-C00721
         		Et— MeSO2— Example 608 (IV) 384 2.41
    597 HCl
    Figure US20090312325A1-20091217-C00722
         		Et— MeSO2— Example 606 (IV) 404 2.70
    598 HCl
    Figure US20090312325A1-20091217-C00723
         		Et— MeSO2— Example 609 (IV) 424 2.34
    599 HCl
    Figure US20090312325A1-20091217-C00724
         		Et— MeSO2— Example 610 (IV) 412 2.44
    600 HCl
    Figure US20090312325A1-20091217-C00725
         		Et— MeSO2— Example 611 (IV) 370 1.99
    624
    Figure US20090312325A1-20091217-C00726
         		F— MeSO2— Example 623 (II) 402 2.52
    625
    Figure US20090312325A1-20091217-C00727
         		F— MeSO2— Example 617 (II) 378 2.54
    626
    Figure US20090312325A1-20091217-C00728
         		F— MeSO2— Example 618 (II) 395 2.70
    627
    Figure US20090312325A1-20091217-C00729
         		F— MeSO2— Example 619 (II) 374 2.61
    628
    Figure US20090312325A1-20091217-C00730
         		F— MeSO2— Example 620 (II) 385 2.42
    629
    Figure US20090312325A1-20091217-C00731
         		F— MeSO2— Example 621 (II) 414 2.27
    630
    Figure US20090312325A1-20091217-C00732
         		F— MeSO2— Example 622 (II) 408 2.45
    631
    Figure US20090312325A1-20091217-C00733
         		F— MeSO2— Example 615 (II) 361 1.91
    632
    Figure US20090312325A1-20091217-C00734
         		F— MeSO2— Example 614 (II) 395 2.32
    633
    Figure US20090312325A1-20091217-C00735
         		F— MeSO2— Example 616 (II) 379 2.09
    (a) Salt forms: HCl = hydrochoride.
    (b) Isolation method:
    (II) Mass Directed preparative HPLC (Method A).
    (IV) Mass Directed preparative HPLC (Method C).
    • Example 184 8-Methyl-4-{[3-(methyloxy)Phenyl]-amino}-6-(phenylsulfonyl)-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00736
  • Intermediate 16 (0.036 g) was suspended in acetonitrile (2 ml), 3-methoxyaniline (available from Aldrich) (0.012 g) was added, and the mixture was heated under reflux for 16 h. After cooling to room temperature the mixture was filtered and the residue dried to give the title compound as a beige solid (0.020 g).
  • LC/MS Rt 2.86 min m/z 448 [MH+]
  • Similarly prepared was:
  • Figure US20090312325A1-20091217-C00737
    Ex. Isolation
    No. Amine Reagent/ Method LCMS LCMS
    (a) R1NH— R3SO2— Starting Material Source (b) MH+ Rt (min)
    185 HCl
    Figure US20090312325A1-20091217-C00738
         		PhSO2— Intermediate 16 4-fluoro-3- methoxyaniline/ Apollo-Chem (I) 466 2.89
    (b) Isolation method:
    (I) Filtered off from the reaction mixture.
    • Example 186 7-Methyl-4-{[3-(methyloxy)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00739
  • Intermediate 17 (0.058 g) was suspended in acetonitrile (2 ml), 3-methoxyaniline (0.024 g) (available from Aldrich) was added, and the mixture was heated under reflux for 4 h. After cooling to room temperature the mixture was filtered and the residue dried to give the title compound as a beige solid (0.042 g).
  • LC/MS Rt 2.21 min m/z 386 [MH+]
    • Example 335 4-[(3-Aminophenyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide trifluoroacetate
  • Figure US20090312325A1-20091217-C00740
  • To a stirred mixture of Example 187 (0.130 g) in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml). The mixture was stirred at 20° C. for 1 h and then the solvent was removed in vacuo to give the title compound as a yellow gum (0.100 g).
  • LC/MS Rt 1.87 min m/z 357 [MH+]
  • Similarly prepared from example 188 was:
    • Example 336 4-{[3-(Aminomethyl)phenyl]amino}-6-(methylsulfonyl)-3-quinolinecarboxamide trifluoroacetate
  • Figure US20090312325A1-20091217-C00741
  • LC/MS Rt 1.65 min m/z 371 [MH+]
    • Example 376 1,1-Dimethylethyl 4-({3-(aminocarbonyl)-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-quinolinyl}sulfonyl)-1-piperidinecarboxylate
  • Figure US20090312325A1-20091217-C00742
  • A mixture containing Intermediate 44 (0.500 g), 1,1-dimethylethyl 4-mercapto-1-piperidinecarboxylate (0.442 g, synthesised according to U.S. Pat. No. 5,317,025A), potassium tert-butoxide (0.248 g), tris(dibenzylideneacetone) dipalladium (0.093 g) and (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.091 g) was dissolved in N,N-dimethylformamide (20 ml) and stirred under an atmosphere of nitrogen at 100° C. for 2 h. The solvents were concentrated in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic extract was washed with sodium bicarbonate solution followed by brine, dried over magnesium sulfate and concentrated in vacuo to an orange solid. This was purified by flash chromatography on silica gel eluting with a gradient of ethanol (0% to 10%) in ethyl acetate, to give the intermediate sulphide 1,1-dimethylethyl 4-({3-(aminocarbonyl)-8-methyl-4-[(1-methyl-1H-benzimidazol-6-yl)amino]-6-quinolinyl}thio)-1-piperidinecarboxylate as a yellow solid (0.375 g).
  • LC/MS Rt 2.63 min, m/z 547 [MH+]
  • Oxone (1.6 g) was added to a solution of the sulphide (0.370 g) in N,N-dimethylformamide (10 ml). The mixture was stirred at room temperature for 1 h and was quenched with a solution of sodium sulphite (4 g) in water (150 ml). The mixture was extracted with ethyl acetate (2×100 ml) and the combined organic suspension washed with water (2×100 ml) and extracted in vacuo to a pale yellow solid. This was purified by recrystallisation from boiling methanol to give the title compound as a pale yellow powder (0.265 g).
  • LC/MS Rt 2.47 min, m/z 579 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00743
    Ex. Isolation LCMS
    No. Starting Thiol Reagent/ Method LCMS Rt
    (a) R1NH— R1SO2— R20— Material Source (b) Solvent MH+ (min)
    354
    Figure US20090312325A1-20091217-C00744
    Figure US20090312325A1-20091217-C00745
         		H— Intermediate 37 Methyl 4- mercaptobenzoate/ Toronto Research Chemicals (II) Toluene 492 2.76
    355
    Figure US20090312325A1-20091217-C00746
    Figure US20090312325A1-20091217-C00747
         		H— Intermediate 37 Methyl 3- mercaptobenzoate/ Toronto Research Chemicals (II) Toluene 492 2.76
    356
    Figure US20090312325A1-20091217-C00748
    Figure US20090312325A1-20091217-C00749
         		H— Intermediate 37 3-methylbenzene thiol/Aldrich (VII) Toluene 448 2.90
    357 HCl
    Figure US20090312325A1-20091217-C00750
    Figure US20090312325A1-20091217-C00751
         		H— Intermediate 14 3,4-dimethylthio phenol/Aldrich (IV) Toluene 462 3.02
    358
    Figure US20090312325A1-20091217-C00752
    Figure US20090312325A1-20091217-C00753
         		H— Intermediate 14 3-fluorobenzene thiol/Avocado (V) Toluene 452 2.83
    359 HCl
    Figure US20090312325A1-20091217-C00754
    Figure US20090312325A1-20091217-C00755
         		H— Intermediate 14 4-(trifluoromethyl) thiophenol/ Fluorochem (IV) Toluene 502 3.16
    361
    Figure US20090312325A1-20091217-C00756
    Figure US20090312325A1-20091217-C00757
         		H— Intermediate 37 3-chlorothiophenol/ Adrich (II) Toluene 468 2.96
    362
    Figure US20090312325A1-20091217-C00758
    Figure US20090312325A1-20091217-C00759
         		H— Intermediate 37 4-tert-butylthio phenol/Lancaster (II) Toluene 490 3.26
    363
    Figure US20090312325A1-20091217-C00760
    Figure US20090312325A1-20091217-C00761
         		H— Intermediate 37 3,5-dimethyl benzenethiol/Aldrich (II) Toluene 462 3.05
    364
    Figure US20090312325A1-20091217-C00762
    Figure US20090312325A1-20091217-C00763
         		H— Intermediate 37 1,1-dimethylethyl (2-mercaptoethyl) carbamate/Aldrich (V) Toluene 469 2.59
    365 HCl
    Figure US20090312325A1-20091217-C00764
    Figure US20090312325A1-20091217-C00765
         		H— Intermediate 37 [4-(methyloxy) phenyl] methanethiol/ Aldrich (IV) Toluene 478 2.63
    366
    Figure US20090312325A1-20091217-C00766
    Figure US20090312325A1-20091217-C00767
         		H— Intermediate 37 4-bromothiophenol/ Aldrich (VI) Toluene 513 3.02
    367 HCl
    Figure US20090312325A1-20091217-C00768
    Figure US20090312325A1-20091217-C00769
         		H— Intermediate 37 2-mercaptoanisole/ Lancaster (IV) Toluene 464 2.52
    368 HCl
    Figure US20090312325A1-20091217-C00770
    Figure US20090312325A1-20091217-C00771
         		H— Intermediate 37 (4-chlorophenyl) methanediol/ Aldrich (IV) Toluene 482 2.91
    375 HCl
    Figure US20090312325A1-20091217-C00772
    Figure US20090312325A1-20091217-C00773
         		H— Intermediate 37 3-methoxybenzene thiol/Aldrich (VIII) N,N- dimethyl- formamide 464 2.76
    377
    Figure US20090312325A1-20091217-C00774
    Figure US20090312325A1-20091217-C00775
         		Me— Intermediate 45 1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ US 5317025 A (V) N,N- dimethyl- formamide 555 2.97
    378
    Figure US20090312325A1-20091217-C00776
    Figure US20090312325A1-20091217-C00777
         		Me— Intermediate 46 1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ US 5317025 A (V) N,N- dimethyl- formamide 550 3.01
    472
    Figure US20090312325A1-20091217-C00778
    Figure US20090312325A1-20091217-C00779
         		H— Intermediate 14 1,1-dimethylethyl 4-mercapto-1- piperidine carboxylate/ US 5317025 A (V) N,N- dimethyl- formamide 541 2.89
    (a) Salt forms: HCl = hydrochloride
    (b) Isolation Method:
    (II) Mass Directed preparative HPLC (Method A).
    (IV) Mass Directed preparative HPLC (Method C).
    (V) Column chromatography on silica gel. Compounds isolated by this method are free bases.
    (VI) Aqueous workup only with no further chromatography. Compounds isolated by this method are free bases.
    (VII) Recrystallised from methanol
    (VIII) Mass Directed preparative HPLC (Method A), followed by treatment with 2 M HCl in ethanol.
    • Example 360 6-[(4-Hydroxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide
  • Figure US20090312325A1-20091217-C00780
  • Oxone (3.9 g) was added to a stirred solution of Intermediate 47 (1.1 g) in dry N,N-dimethylformamide (30 ml) at room temperature for 18 h. The mixture was poured into aqueous sodium sulphite solution (200 ml) and extracted with ethyl acetate (3×100 ml). The organic extracts were washed with water (2×100 ml), dried (Na2SO4) and concentrated. A solution of the residual oil in tetrahydrofuran (20 ml) was stirred with a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (4 ml) for 1 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (2×25 ml) and water (2×50 ml). The organic extracts were dried (Na2SO4) and concentrated to give the title compound as a yellow solid (0.67 g).
  • LC/MS Rt 2.58 min, m/z 450 [MH+]
    • Example 379 Methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoate
  • Figure US20090312325A1-20091217-C00781
  • To Intermediate 45 (0.47 g) in dimethoxyethane (10 ml) was added methyl 3-mercaptobenzoate (0.34 ml), potassium phosphate (0.42 g), copper (I) iodide (0.028 g) and N,N-diethylsalicylamide (0.39 g). The mixture was heated at 85° C. for 4 h before adding further methyl 3-mercaptobenzoate (0.34 ml) and copper (I) iodide (0.028 g). After a further 16 h the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (150 ml) and water (150 ml). The organic layers were washed with brine (100 ml), dried over sodium sulfate and concentrated in vacuo to yield a crude product which was triturated with diethyl ether (20 ml). The solid obtained was collected by filtration, washed with diethyl ether (2×10 ml) to give methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)thio]benzoate as a beige solid (0.37 g).
  • LC/MS Rt 3.09 min m/z 474 [MH+]
  • To a solution of the methyl 3-[(3-(aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)thio]benzoate (0.367 g) in N,N-dimethylformamide (10 ml) was added oxone (1.91 g). The mixture was stirred at room temperature for 18 h before quenching with aqueous sodium sulphite solution and extracting with chloroform (3×200 ml). The organic layers were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo and purified by chromatography on silica gel, eluting with 2:1 ethyl acetate: cyclohexane, to give the title compound as a yellow solid (0.100 g).
  • LC/MS Rt 3.03 min m/z 506 [MH+]
  • The following were synthesised in the same manner as Example 379, however potassium carbonate was used as a base instead of potassium phosphate and no N′N-diethylsalicylamide was added.
  • Figure US20090312325A1-20091217-C00782
    Purifi-
    Ex. cation
    No. Starting Thiol Reagent/ Method LCMS LCMS
    (a) R3SO2— R20— Material Source (b) MH+ Rt (min)
    380
    Figure US20090312325A1-20091217-C00783
         		Me— Intermediate 45 3,4- dimethoxythiophenol Aldrich (V) 508 2.81
    381 HCl
    Figure US20090312325A1-20091217-C00784
         		Me— Intermediate 45 3,4,5-tris(methyloxy) benzenethiol J. Am. Chem. Soc., 2002, 124(17), 4642-4646 (IV) 538 2.92
    382 HCl
    Figure US20090312325A1-20091217-C00785
         		H— Intermediate 14 3,4- dimethoxythiophenol/ Avocado (IV) 494 2.59
    383 HCl
    Figure US20090312325A1-20091217-C00786
         		Me— Intermediate 45 3-ethoxythiophenol/ Aldrich (IV) 492 3.08
    (a) Salt forms: HCl = hydrochloride
    (b) Isolation Method:
    (IV) Mass Directed preparative HPLC (Method C).
    (V) Column chromatography on silica gel; it is thought that compounds isolated by this method are free bases.
    • Example 386 6-(Ethylsulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00787
  • Intermediate 37 (0.100 g) was combined with (oxydi-2,1-phenylene)bis(diphenylphosphine) (0.011 g), potassium tert-butoxide (0.025 g) and tris(dibenzylideneacetone) dipalladium(o) (0.008 g) in 1,4-dioxane (1 ml). Ethanethiol (available from Aldrich, 0.023 ml) was added and the mixture was stirred under microwave irradiation (power 40 W) for 8 min at 90° C. The reaction was quenched by addition of 4M HCl in dioxane, then partitioned between ethyl acetate and sodium bicarbonate solution. The organic layer was concentrated in vacuo to give 0.090 g of crude 6-(ethylthio)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide.
  • The crude sulphide was dissolved in N,N-dimethylformamide (5 ml) and treated with an excess of oxone (0.375 g) and stirred at room temperature for 4 h. The reaction was quenched by the addition of 1M aqueous sodium sulphite solution, then partitioned between dichloromethane and sodium bicarbonate solution. The solvent was removed in vacuo and the residue was purified by mass directed preparative HPLC (Method C). After evaporation of solvent the title compound was obtained as a yellow solid.
  • LC/MS Rt 2.30 min, m/z 386 [MH+]
  • The following were prepared in the same manner as Example 386:
  • Figure US20090312325A1-20091217-C00788
    Ex. LCMS
    No. Starting Thiol Reagent/ LCMS Rt
    (a) R3SO2— R20— Material Source MH+ (min)
    384 (b)
    Figure US20090312325A1-20091217-C00789
         		H— Intermediate 14 Isobutyl mercaptan/ Aldrich 414 2.56
    387 HCl
    Figure US20090312325A1-20091217-C00790
         		H— Intermediate 37 1-butanethiol/ Aldrich 414 2.67
    388 HCl
    Figure US20090312325A1-20091217-C00791
         		H— Intermediate 37 Methyl-3- mercaptopropionate/ Fluka 444 2.39
    389 HCl
    Figure US20090312325A1-20091217-C00792
         		H— Intermediate 37 Phenethyl mercaptan/Aldrich 462 2.88
    390 HCl
    Figure US20090312325A1-20091217-C00793
         		H— Intermediate 37 2- furanylmethanethiol/ Aldrich 438 2.46
    391 HCl
    Figure US20090312325A1-20091217-C00794
         		H— Intermediate 37 2,2,2- trifluoroethanethiol/ Aldrich 440 2.6 
    392 HCl
    Figure US20090312325A1-20091217-C00795
         		Me— Intermediate 45 N-(2-mercaptoethyl) acetamide/Aldrich 457 2.25
    (a) Salt forms: HCl = hydrochloride
    (b) Isolation method: Mass Directed preparative HPLC (Method A).
    • Example 393 3-[(3-(Aminocarbonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-6-quinolinyl)sulfonyl]benzoic acid
  • Figure US20090312325A1-20091217-C00796
  • Example 379 (0.1 g) was dissolved in methanol (5 ml) and 2M aqueous sodium hydroxide (1 ml). The mixture was heated to 75° C. for 4 h before cooling and standing at ambient temperature for 18 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The layers were separated and the aqueous layer was washed with diethyl ether (50 ml), acidifed to pH4 (2M hydrochloric acid) and extracted with ethyl acetate (2×150 ml). The combined ethyl acetate layers were washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a beige solid (0.082 g).
  • LC/MS Rt 2.82 min m/z 492 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00797
    Isolation
    Example Starting Method LCMS LCMS
    Number R3SO2— Material (b) MH+ Rt (min)
    394
    Figure US20090312325A1-20091217-C00798
         		Example 354 (II) 478 2.67
    395
    Figure US20090312325A1-20091217-C00799
         		Example 355 (II) 478 2.65
    (b) Isolation Method:
    (II) Mass Directed HPLC Method A
  • The following were prepared from the intermediates shown in the table in a similar manner to the method by which Example 393 was prepared, via Example 379, from Intermediate 45.
  • Figure US20090312325A1-20091217-C00800
    Example Isolation
    Number Starting Method LCMS LCMS
    (a) R1NH— Material (b) MH+ Rt (min)
    396 HCl
    Figure US20090312325A1-20091217-C00801
         		Intermediate 44 (IV) 516 2.25
    397 HCl
    Figure US20090312325A1-20091217-C00802
         		Intermediate 46 (IV) 487 2.9 
    398
    Figure US20090312325A1-20091217-C00803
         		Intermediate 36 (I) 504 2.83
    (a) Salt forms: HCl = hydrochloride
    (b) Isolation Method:
    (I) filtered off and used crude.
    (IV) Mass Directed HPLC Method C; it is thought that compounds isolated by this method are hydrochloride salts.
    • Example 399 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00804
  • To a solution of Example 393 (0.082 g) in N,N-dimethylformamide (3 ml) was added N,N-diisopropylethylamine (0.12 ml) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.071 g). The mixture was stirred for 20 min before adding a solution of dimethylamine in tetrahydrofuran (2M, 0.8 ml, Aldrich). After a further 1 h more dimethylamine in tetrahydrofuran (2M, 0.8 ml) was added. After 1 h the reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (200 ml) and aqueous sodium bicarbonate (100 ml). The organic layers were washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. Purification by mass directed HPLC (Method C) gave the title compound as a yellow solid (0.022 g).
  • LC/MS Rt 2.61 min m/z 519 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00805
    Example Amine LCMS
    Number Starting Reagent/ LCMS Rt
    (a) R1NH— R20— R29R30N— material Source MH+ (min)
    400 HCl
    Figure US20090312325A1-20091217-C00806
         		H— Me2N— Example 395 dimethylamine 2 M solution in tetrahydrofuran/ Aldrich 505 2.52
    401 HCl
    Figure US20090312325A1-20091217-C00807
         		H— H2N— Example 395 Ammonia solution 880/Merck 477 2.42
    402 HCl
    Figure US20090312325A1-20091217-C00808
         		H— MeNH— Example 395 methylamine 2 M solution in tetrahydrofuran/ Aldrich 491 2.47
    403 HCl
    Figure US20090312325A1-20091217-C00809
         		H—
    Figure US20090312325A1-20091217-C00810
         		Example 395 Pyrrolidine/ Lancaster 531 2.64
    404 HCl
    Figure US20090312325A1-20091217-C00811
         		H—
    Figure US20090312325A1-20091217-C00812
         		Example 395 propylamine/ Aldrich 519 2.74
    405 (b)
    Figure US20090312325A1-20091217-C00813
         		H—
    Figure US20090312325A1-20091217-C00814
         		Example 395 Isobutylamine/ Aldrich 533 2.76
    406 HCl
    Figure US20090312325A1-20091217-C00815
         		H—
    Figure US20090312325A1-20091217-C00816
         		Example 395 Morpholine/ Lancaster 547 2.51
    407 HCl
    Figure US20090312325A1-20091217-C00817
         		H—
    Figure US20090312325A1-20091217-C00818
         		Example 395 Ethanolamine/ Aldrich 521 2.38
    408 HCl
    Figure US20090312325A1-20091217-C00819
         		Me— Me2N— Example 397 dimethylamine 2 M solution in tetrahydrofuran/ Aldrich 514 2.71
    409 HCl
    Figure US20090312325A1-20091217-C00820
         		Me— Me2N— Example 396 dimethylamine 2 M solution in tetrahydrofuran/ Aldrich 543 2.19
    410 HCl
    Figure US20090312325A1-20091217-C00821
         		Me— H2N— Example 396 Ammonia solution 880/Merck 515 2.13
    411 HCl
    Figure US20090312325A1-20091217-C00822
         		Me— MeNH— Example 396 methylamine 2 M solution in tetrahydrofuran/ Aldrich 529 2.17
    412 HCl
    Figure US20090312325A1-20091217-C00823
         		Me— H2N— Example 397 dimethylamine 2 M solution in tetrahydrofuran/ Aldrich 486 2.61
    413 HCl
    Figure US20090312325A1-20091217-C00824
         		Me— MeNH— Example 397 methylamine 2 M solution in tetrahydrofuran/ Aldrich 500 2.69
    414 (c)
    Figure US20090312325A1-20091217-C00825
         		Me— Me2N— Example 398 dimethylamine 2 M solution in tetrahydrofuran/ Aldrich 531 2.65
    (a) Salt form: HCl = hydrochloride
    (b) Example 405 was isolated by Mass Directed preparative HPLC (Method A).
    (c) Example 414 was isolated by aqueous work up.
  • Similarly prepared from Example 394 were the following:
  • Figure US20090312325A1-20091217-C00826
    Example Isolation
    Number Amine Reagent/ method LCMS LCMS
    (a) R29R30N— Source (b) MH+ Rt (min)
    415 HCl H2N— Ammonia solution 880/ Merck (I) 477 2.45
    416 HCl MeHN— methylamine 2 M solution in tetrahydrofuran/ Aldrich (I) 491 2.51
    417 HCl
    Figure US20090312325A1-20091217-C00827
         		Pyrrolidine/Lancaster (I) 531 2.66
    418 HCl
    Figure US20090312325A1-20091217-C00828
         		propylamine/Aldrich (I) 519 2.75
    419 HCl Me2N— dimethylamine 2 M solution in tetrahydrofuran/ Aldrich (I) 505 2.53
    420
    Figure US20090312325A1-20091217-C00829
         		Isobutylamine/Aldrich (II) 533 2.8 
    (a) Salt form: HCl = hydrochloride
    (b) Isolation Method:
    (I) Mass Directed preparative HPLC (Method C).
    (II) Mass Directed preparative HPLC (Method A).
    • Example 421 4-{[3-(Methyloxy)phenyl]amino}-6-(4-piperidinylsulfonyl)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00830
  • To a mixture containing Example 472 (1.3 g) in anisole (9 ml) was added a solution of 95% trifluoroacetic acid in water (45 ml). The mixture was stirred for 2 h at room temperature and was then concentrated in vacuo. The residue was co-evaporated with toluene (2×20 ml) and triturated with diethyl ether to give a yellow solid. The solid was partitioned between aqueous potassium carbonate (300 ml) and chloroform (300 ml) and the aqueous phase extracted with chloroform (3×200 ml). The combined organic extracts were washed with water (100 ml), dried and concentrated in vacuo to give the title compound as a yellow solid (1.1 g).
  • LC/MS Rt 1.94 min, m/z 441 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00831
    Ex. Isolation LCMS
    No. Starting Method LCMS Rt
    (a) R1NH— R20— R3SO2— Material (b) MH+ (min)
    422 TFA
    Figure US20090312325A1-20091217-C00832
         		Me—
    Figure US20090312325A1-20091217-C00833
         		Example 353 (I) 1.98 427
    423
    Figure US20090312325A1-20091217-C00834
         		Me—
    Figure US20090312325A1-20091217-C00835
         		Example 352 (II) 467 1.97
    470 TFA
    Figure US20090312325A1-20091217-C00836
         		Me—
    Figure US20090312325A1-20091217-C00837
         		Example 378 (III) 450 2.03
    474 TFA
    Figure US20090312325A1-20091217-C00838
         		Me—
    Figure US20090312325A1-20091217-C00839
         		Example 376 (I) 479 1.77
    476
    Figure US20090312325A1-20091217-C00840
         		Me—
    Figure US20090312325A1-20091217-C00841
         		Intermediate 55 (II) 473 2.10
    477
    Figure US20090312325A1-20091217-C00842
         		Me—
    Figure US20090312325A1-20091217-C00843
         		Intermediate 56 (II) 433 2.03
    561
    Figure US20090312325A1-20091217-C00844
         		Me—
    Figure US20090312325A1-20091217-C00845
         		Example 602 (IV) 403 1.93
    567 HCl
    Figure US20090312325A1-20091217-C00846
         		Me—
    Figure US20090312325A1-20091217-C00847
         		Example 568 (V) 426 1.80
    (a) Salt forms: TFA = trifluoroacetate
    (b) Isolation Method:
    (I) Filtered off directly from the reaction mixture; it is thought that compounds isolated by this method are trifluoroacetate salts.
    (II) Aqueous workup of the crude reaction mixture without further purification; it is thought that compounds isolated by this method are free bases.
    (III) Crude product was trituated to give the desired product and no further purification was carried out; it is thought that compounds isolated by this method are trifluoroacetate salts.
    (IV) Product isolated by SCX ion exchange to give the free base
    (V) Reaction mixture evaporated to dryness; it is assumed that this method gave the hydrochloride salt.
    • Example 424 4-{[3-(Methyloxy)phenyl]amino}-6-{[1-(phenylcarbonyl)-4-piperidinyl]sulfonyl}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00848
  • To a mixture containing Example 421 (0.050 g) and triethylamine (0.025 ml) in dioxane (2 ml) was added benzoyl chloride (0.020 ml). The mixture was stirred under nitrogen for 18 h at room temperature and was then diluted with methanol (5 ml). The solution was applied to an aminopropyl cartridge and eluted with methanol. The eluent was evaporated and the residual gum purified by chromatography on SPE eluting with a gradient of methanol in chloroform (0% to 10%) to give the title compound as a yellow solid (0.043 g).
  • LC/MS Rt 2.63 min, m/z 545 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00849
    Ex. Isolation LCMS
    No. Starting Electrophile/ Method LCMS Rt
    (a) R1NH— R20— RX— Material Source (b) MH+ (min)
    425
    Figure US20090312325A1-20091217-C00850
         		H—
    Figure US20090312325A1-20091217-C00851
         		Example 421 Methyl chloroformate/ Aldrich (II) 499 2.48
    426
    Figure US20090312325A1-20091217-C00852
         		H—
    Figure US20090312325A1-20091217-C00853
         		Example 421 Acetyl chloride/ Aldrich (II) 483 2.27
    427
    Figure US20090312325A1-20091217-C00854
         		H—
    Figure US20090312325A1-20091217-C00855
         		Example 421 Methane sulphonyl chloride/ Aldrich (V) 519 2.43
    428
    Figure US20090312325A1-20091217-C00856
         		H—
    Figure US20090312325A1-20091217-C00857
         		Example 421 3-methylbutanoyl chloride/Aldrich (III) 525 2.61
    429
    Figure US20090312325A1-20091217-C00858
         		H—
    Figure US20090312325A1-20091217-C00859
         		Example 421 Cyclopropane carbonyl chloride/ Aldrich (III) 509 2.42
    430
    Figure US20090312325A1-20091217-C00860
         		H—
    Figure US20090312325A1-20091217-C00861
         		Example 421 2-furancarbonyl chloride/Aldrich (III) 535 2.5
    431
    Figure US20090312325A1-20091217-C00862
         		H—
    Figure US20090312325A1-20091217-C00863
         		Example 421 5-methyl-3- isoxazolecarbonyl chloride/Maybridge (III) 550 2.55
    432
    Figure US20090312325A1-20091217-C00864
         		H—
    Figure US20090312325A1-20091217-C00865
         		Example 421 Benzene sulphonyl chloride/ Aldrich (IV) 581 2.9
    433
    Figure US20090312325A1-20091217-C00866
         		H—
    Figure US20090312325A1-20091217-C00867
         		Example 421 3,5-dimethyl-4- isoxazolesulfonyl chloride/Avocado (IV) 600 2.88
    434
    Figure US20090312325A1-20091217-C00868
         		H—
    Figure US20090312325A1-20091217-C00869
         		Example 421 2-(acetylamino)-4- methyl-1,3- thiazole-5-sulphonyl chloride/Aldrich (IV) 659 2.69
    435
    Figure US20090312325A1-20091217-C00870
         		H—
    Figure US20090312325A1-20091217-C00871
         		Example 421 1-butanesulphonyl chloride/Aldrich (IV) 561 2.75
    436
    Figure US20090312325A1-20091217-C00872
         		H—
    Figure US20090312325A1-20091217-C00873
         		Example 421 1-methylimidazole 4-sulphonyl chloride/Maybridge (IV) 585 2.35
    437
    Figure US20090312325A1-20091217-C00874
         		H—
    Figure US20090312325A1-20091217-C00875
         		Example 421 Isoxazole-5- carbonyl chloride/ Lancaster (III) 536 2.37
    438
    Figure US20090312325A1-20091217-C00876
         		H—
    Figure US20090312325A1-20091217-C00877
         		Example 421 2-furancarbonyl chloride/Maybridge (III) 535 2.42
    439
    Figure US20090312325A1-20091217-C00878
         		H—
    Figure US20090312325A1-20091217-C00879
         		Example 421 Isobutyryl chloride/ Aldrich (III) 511 2.42
    440
    Figure US20090312325A1-20091217-C00880
         		H—
    Figure US20090312325A1-20091217-C00881
         		Example 421 Propionyl chloride/ Aldrich (III) 597 2.31
    441
    Figure US20090312325A1-20091217-C00882
         		H—
    Figure US20090312325A1-20091217-C00883
         		Example 421 1- pyrrolidinecarbonyl chloride/Lancaster (III) 538 2.44
    442
    Figure US20090312325A1-20091217-C00884
         		Me—
    Figure US20090312325A1-20091217-C00885
         		Intermediate 54 2-furancarbonyl chloride/Aldrich (I) 549 2.65
    443
    Figure US20090312325A1-20091217-C00886
         		Me—
    Figure US20090312325A1-20091217-C00887
         		Example 470 2-furancarbonyl chloride/Aldrich (I) 544 2.69
    444
    Figure US20090312325A1-20091217-C00888
         		Me—
    Figure US20090312325A1-20091217-C00889
         		Example 470 Cyclopropane carbonyl chloride/ Aldrich (I) 518 2.63
    445
    Figure US20090312325A1-20091217-C00890
         		Me—
    Figure US20090312325A1-20091217-C00891
         		Intermediate 54 Cyclopropane carbonyl chloride/ Aldrich (I) 523 2.57
    446
    Figure US20090312325A1-20091217-C00892
         		Me—
    Figure US20090312325A1-20091217-C00893
         		Example 423 2-furancarbonyl chloride/Aldrich (I) 561 2.66
    447
    Figure US20090312325A1-20091217-C00894
         		Me—
    Figure US20090312325A1-20091217-C00895
         		Example 423 Cyclopropane carbonyl chloride/ Aldrich (I) 535 2.58
    448 HCl
    Figure US20090312325A1-20091217-C00896
         		Me—
    Figure US20090312325A1-20091217-C00897
         		Example 423 Methyl chloroformate/ Aldrich (VI) 525 2.57
    (a) Salt forms: HCl = hydrochloride
    (b) Isolation Method:
    (I) Purified by chromatography on an SPE column.
    (II) Aqueous workup of the crude reaction mixture without further purification.
    (III) Purified using an SPE cartridge (aminopropyl solid phase) followed by chromatography using a silica SPE column.
    (IV) Purified using an SPE cartridge (aminopropyl solid phase) followed by trituration.
    (V) Aqueous workup of the crude reaction followed by trituration of the crude product.
    (VI) Aqueous workup of the crude reaction followed by addition of dilute HCl in dioxane and evaporation; it is thought that compounds isolated by this method are hydrochloride salts.
    • Example 449 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-[(1-methyl-4-piperidinyl)sulfonyl]-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00898
  • To a mixture containing Example 423 (0.050 g) and triethylamine (0.025 ml) in N,N-dimethylformamide (2 ml) was added methyl iodide (0.0075 ml). The mixture was stirred under nitrogen for 18 h at room temperature and was concentrated by blowing down under nitrogen. Purification by chromatography on silica gel, eluting with dichloromethane/methanol (95:5), gave a white solid which was dissolved in dioxane (10 ml) and treated with 4M hydrogen chloride in 1,4 dioxane (0.100 ml). After evaporation by blowing down under nitrogen the title compound was obtained as a yellow solid (0.028 g).
  • LC/MS Rt 1.99 min, m/z 481 [MH+]
    • Example 450 6-[(1-Acetyl-4-piperidinyl)sulfonyl]-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00899
  • To a mixture containing Example 423 (0.050 g) in pyridine (2 ml) was added acetic anhydride (0.011 ml). The mixture was stirred under nitrogen for 18 h at room temperature, partitioned between chloroform (100 ml) and 10% sodium carbonate solution (100 ml), the layers separated by hydrophobic frit and the organic layer treated with 4M hydrogen chloride in 1,4-dioxane (0.100 ml). After evaporation by blowing down under nitrogen the title compound was obtained as a pale yellow solid (0.021 g).
  • LC/MS Rt 2.32 min, m/z 509 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00900
    Ex. Electro Isolation LCMS
    No Starting phile/ Method LCMS Rt
    (a) R1NH— R20— R3SO2— Material Source (b) MH+ (min)
    451
    Figure US20090312325A1-20091217-C00901
         		Me—
    Figure US20090312325A1-20091217-C00902
         		Example 476 Acetic anhydride/ Aldrich (II) 515 2.31
    452 HCl
    Figure US20090312325A1-20091217-C00903
         		Me—
    Figure US20090312325A1-20091217-C00904
         		Example 422 Acetyl chloride/ Aldrich (V) 469 2.14
    453 HCl
    Figure US20090312325A1-20091217-C00905
         		Me—
    Figure US20090312325A1-20091217-C00906
         		Example 477 Acetic anhydride/ Aldrich (I) 475 2.15
    454 HCl
    Figure US20090312325A1-20091217-C00907
         		Me—
    Figure US20090312325A1-20091217-C00908
         		Example 477 Methane- sulphonyl chloride/ Aldrich (IV) 511 2.23
    455 HCl
    Figure US20090312325A1-20091217-C00909
         		Me—
    Figure US20090312325A1-20091217-C00910
         		Example 477 Methyl chloroformate/ Aldrich (IV) 491 2.29
    456
    Figure US20090312325A1-20091217-C00911
         		Me—
    Figure US20090312325A1-20091217-C00912
         		Example 422 Methyl chloroformate/ Aldrich (VI) 485 2.36
    457
    Figure US20090312325A1-20091217-C00913
         		Me—
    Figure US20090312325A1-20091217-C00914
         		Example 422 Methane- sulphonyl chloride/ Aldrich (VI) 505 2.31
    531
    Figure US20090312325A1-20091217-C00915
         		Me—
    Figure US20090312325A1-20091217-C00916
         		Example 567 Acetic anhydride/ Aldrich (III) 468 2.00
    (a) Salt forms: HCl = hydrochloride.
    (c) Isolation Method:
    (I) As for Example 450
    (II) Mass Directed HPLC (Method A)
    (IlI) Purified by silica SPE eluting with ethyl acetate/methanol
    (IV) Mass Directed preparative HPLC (Method C).
    (V) Aqueous work-up followed by addition of 4 M HCl in 1,4-dioxane to a chloroform solution of the free base to give the hydrochloride salt.
    (VI) Aminopropyl SPE column.
    • Example 473 4-{[3-(Methyloxy)phenyl]amino}-6-({2-[(2-methylpropanoyl)amino]ethyl}sulfonyl)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00917
  • A solution of Example 364 (0.052 g) in anisole (1 ml) was treated with a solution of 95% trifluoroacetic acid in water (5 ml). The mixture was stirred for 3 h at room temperature and was then concentrated in vacuo. The residue was trituated with ethyl acetate, and the resulting solid was collected by filtration, washed with ethyl acetate and ether and dried to give a yellow solid (0.031 g). The solid was treated with dioxane (2 ml) and the suspension treated with N,N-diisopropylethylamine (0.04 ml) followed by isobutyryl chloride (0.015 ml, Aldrich) and the resulting solution stirred at room temperature under nitrogen for 2 h. The solution was diluted with methanol (5 ml) and applied to an aminopropyl SPE cartridge. Elution with methanol gave a gum after evaporation of solvent. The gum was purified by chromatography on silica gel eluting with a gradient of 0% to 6% methanol in chloroform to give the title compound as a yellow solid (0.017 g).
  • LC/MS Rt 2.22 min, m/z 471 [MH+]
    • Example 458 6-{[1-(1H-Imidazol-4-ylcarbonyl)-4-piperidinyl]sulfonyl}-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00918
  • To a solution containing Intermediate 54 (0.041 g) in N,N-dimethylformamide (3 ml) were added imidazole-4-carboxylic acid (0.012 g, Aldrich), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBop) (0.053 g) and N,N-diisopropylethylamine (0.03 ml). The solution was stirred under nitrogen at room temperature for 18 h and was then concentrated in vacuo. The residual gum was purified using an aminopropyl SPE cartridge eluting with methanol followed by chromatography on silica gel (SPE cartridge), eluting with a gradient of 0% to 8% methanol in chloroform, to give the title compound as a yellow solid (0.031 g).
  • LC/MS Rt 2.32 min, m/z 549 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00919
    Example
    Number Starting Amine Reagent/ LCMS LCMS
    (a) RX— Material Source MH+ Rt (min)
    459
    Figure US20090312325A1-20091217-C00920
         		Example 474 2-furoic acid/Aldrich 573 2.15
    460
    Figure US20090312325A1-20091217-C00921
         		Example 474 Cyclopropylmethanoic acid/Aldrich 547 2.12
    • Example 461 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[1-(methylsulfonyl)-4-piperidinyl]sulfonyl}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00922
  • To a mixture containing Example 423 (0.050 g) in 1,4-dioxane (2 ml) was added methanesulphonyl chloride (0.009 ml). The mixture was stirred under nitrogen for 18 h at room temperature, partitioned between ethyl acetate (100 ml) and 10% sodium bicarbonate solution (100 ml), separated and dried. The solid obtained was dissolved in 1,4-dioxane and treated with 4M hydrogen chloride in 1,4-dioxane (0.100 ml). After evaporation the title compound was obtained as a pale yellow solid (0.021 g).
  • LC/MS Rt 2.5 min, m/z 545 [MH+]
    • Example 462 6-{[4-(Cyclopropylmethoxy)phenyl]sulfonyl}-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00923
  • Tributyl phosphine (0.05 ml) was added to a stirred mixture of Example 360 (0.052 g), cyclopropylmethanol (0.028 g) and di-tert-butylazodicarboxylate (0.06 g) in tetrahydrofuran (1.5 ml) at 20° under nitrogen, and stirring was continued at 200 for 3 h. The solvent was concentrated and the residue purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.09 g).
  • LC/MS Rt 3.4 min, m/z 504 [MH+]
    • Example 463 6-[(4-Ethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]quinoline-3-carboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00924
  • A stirred mixture of Example 360 (0.05 g), iodoethane (0.35 ml) and potassium carbonate (0.02 g) in acetonitrile (1.5 ml) was heated under reflux temperature for 1 h. The solvent was evaporated to dryness. The resulting solid was partitioned between dichloromethane (2×15 ml) and water (30 ml). The extracts were dried (Na2SO4) and concentrated. The residual solid was purified by mass directed HPLC (Method C) to give the title compound as a pale yellow solid (0.033 g).
  • LC/MS Rt 2.87 min, m/z 478 [MH+]
  • The following examples were similarly prepared:
  • Figure US20090312325A1-20091217-C00925
    Example Alkylating
    Number Starting Agent/ LCMS LCMS
    (a) RXO— Material Source MH+ Rt (min)
    464 HCl
    Figure US20090312325A1-20091217-C00926
         		Example 360 1-iodopropane/ Aldrich 492 3.07
    465 HCl
    Figure US20090312325A1-20091217-C00927
         		Example 360 2-iodopropane/ Aldrich 492 3.00
    466 HCl
    Figure US20090312325A1-20091217-C00928
         		Example 360 Iodocyclopentane/ Aldrich 518 3.24
    (a) Salt form: HCl = hydrochloride.
    • Example 467
    • 4-{[3-(3-Furyl)phenyl]amino}-6-[(4-methoxyphenyl)sulfonyl]quinoline-3-carboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00929
  • A stirred mixture of Example 254 (0.051 g), 3-furanboronic acid (0.017 g, Aldrich), tetrakis(triphenylphosphine) palladium(0) (0.05 g) and 2M sodium carbonate solution (1 ml) in dimethoxyethane (2 ml) was heated at 100° C. for 1 h. The mixture was cooled and poured into 2M sodium carbonate solution and extracted into dichloromethane (2×15 ml). The extracts were dried (Na2SO4) and concentrated. The residue was purified by mass directed HPLC (Method C) to give the title compound as a yellow solid (0.026 g).
  • LC/MS Rt 2.93 min, m/z 500 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00930
    Ex. Starting Boronic Acid/ LCMS LCMS
    No. R1NH— R3SO2— Material Source MH+ Rt (min)
    468 (a)
    Figure US20090312325A1-20091217-C00931
    Figure US20090312325A1-20091217-C00932
         		Example 366 [4-(methyloxy)phenyl] boronic acid/Aldrich 540 3.18
    469 (b)
    Figure US20090312325A1-20091217-C00933
    Figure US20090312325A1-20091217-C00934
         		Example 366 3-furanboronic acid/ Aldrich 500 3.02
    (a) Example 468 was isolated as the free base by trituration with ether.
    (b) Example 469 was isolated as the free base by chromatography on silica gel, eluting with ethyl acetate.
    • Example 475 6-{[3-(Dimethylamino)-3-oxopropyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00935
  • A solution of Intermediate 53 (0.04 g) in N,N-dimethylformamide (3 ml) was treated with oxone (0.22 g) and the resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition on 1M sodium sulphite solution (1 ml) and extracted into dichloromethane. The combined organic layers were dried using a hydrophobic frit and evaporated in vacuo, and the product was dissolved in N,N-dimethylformamide (2 ml) and treated with O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.016 g). After 5 min, dimethylamine hydrochloride (0.065 g) and N,N-diisopropylethylamine (0.015 ml) in N,N-dimethylformamide (2 ml) were added. The resulting solution was left standing at room temperature overnight. Chromatographic purification by SCX (IST Isolute™, 10 g), eluting with methanol and 2M ammonia/methanol gave a yellow oil. Further purification by mass-directed HPLC (Method C) gave the title compound as a yellow solid (0.009 g).
  • LC/MS Rt 2.34 min, m/z 489 [MH+]
    • Example 540 4-[(5-Chloro-3-pyridinyl)amino]-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00936
  • To a solution of Intermediate 33 (0.050 g) in N,N-dimethylformamide was added 5-chloro-3-pyridineamine (0.032 g; Specs) and pyridine hydrochloride (0.029 g) and the mixture heated at 90° C. for 16 h. The solvent was blown off under a stream of nitrogen at 45° C. The residue was triturated with acetonitrile and the resultant precipitate collected by filtration to give the title compound as a brown solid.
  • LC/MS Rt 2.25 min m/z 391 [MH+]
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00937
    Ex. Amine Isolation LCMS
    No. Starting Reagent/ Method LCMS Rt
    (a) R1NH— R3SO2— Material Source (b) MH+ (min)
    539
    Figure US20090312325A1-20091217-C00938
         		MeSO2— Intermediate 33 5-Fluoro-3- pyridinamine/ Synchem OHG (I) 375 2.2 
    541 HCl
    Figure US20090312325A1-20091217-C00939
         		MeSO2— Intermediate 33 6-Methyl-3- pyridinamine/ AsymChem (IV) 371 1.79
    543 HCl
    Figure US20090312325A1-20091217-C00940
         		MeSO2— Intermediate 33 4-Amino-2- benzofuran- 1(3H)-one/ EP0529636A1 (II) 412 2.25
    601
    Figure US20090312325A1-20091217-C00941
         		MeSO2— Intermediate 33 2,6-dimethyl-3- pyridylamine/ Lancaster (III) 385 1.76
    (a) Salt form: HCl = hydrochoride
    (b) Isolation method:
    (I) Trituration with acetonitrile followed by elution through an aminopropyl SPE cartridge with methanol.
    (II) Reaction was performed at 80° C. in acetonitrile and the product isolated by filtration of the reaction mixture.
    (III) Mass Directed preparative HPLC (Method A) followed by chromatography on silica gel eluting with 3% methanol in dichloromethane.
    (IV) Trituration with acetonitrile followed by isolation of the product by filtration.
    • Example 480 Ethyl 3-{[3-(aminocarbonyl)-4-(2,3-dihydro-1-benzofuran-4-ylamino)-8-methyl-6-quinolinyl]sulfonyl}propanoate
  • Figure US20090312325A1-20091217-C00942
  • To a solution of Intermediate 57 (0.82 g) in N,N-dimethylformamide (25 ml) was added oxone (4.5 g). The mixture was stirred at room temperature for 2 h before quenching with aqueous sodium sulphite solution and extracting with dichloromethane (2×25 ml). The organic layers were combined, washed with water, dried using a hydrophobic frit, concentrated in vacuo and purified by chromatography on silica gel, eluting with an ethyl acetate: cyclohexane gradient, to give the title compound as a yellow solid (0.12 g).
  • LC/MS Rt 2.61 min m/z 484 [MH+].
    • Example 481 3-[(3-(Aminocarbonyl)-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-quinolinyl)sulfonyl]propanoic acid hydrochloride
  • Figure US20090312325A1-20091217-C00943
  • To a solution of Intermediate 53 (0.8 g) in N,N-dimethylformamide (10 ml) was added oxone (4.6 g). The mixture was stirred at room temperature for 48 h before quenching with aqueous sodium sulphite solution and extracting with dichloromethane (3×25 ml). The aqueous layers were combined and applied to an Oasis cartridge, eluting with water and methanol. The methanol fractions were combined and concentrated in vacuo. The residue was applied to an SPE cartridge (Isolute, aminopropyl solid phase), eluting with methanol and 2M ammonia/methanol; evaporation of the methanol/ammonia fraction gave an orange oil. Further purification by mass directed preparative HPLC (Method C) gave the title compound as a yellow oil (0.003 g).
  • LC/MS Rt 2.23 min m/z 462 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00944
    Example LCMS
    Number Starting LCMS Rt
    (a) R1NH— Material MH+ (min)
    549 HCl
    Figure US20090312325A1-20091217-C00945
         		Intermediate 59 432 2.38
    550 HCl
    Figure US20090312325A1-20091217-C00946
         		Intermediate 60 415 1.92
    (a) Salt forms: HCl = hydrochloride
    • Example 482 4-{[4-Fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-{[3-(4-morpholinyl)-3-oxopropyl]sulfonyl}-3-guinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00947
  • To a solution of Example 481 (0.035 g) in N,N-dimethylformamide (2 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.029 g). After 5 min, morpholine (0.007 ml, available from Aldrich) and N,N-diisopropylethylamine (0.026 ml) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST Isolute™, 5 g). Elution with methanol and 2M ammonia/methanol gave an orange residue, which was further purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.006 g).
  • LC/MS Rt 2.37 min m/z 531 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00948
    Example Amine Isolation
    Number Starting reagent/ Method LCMS LCMS
    (a) R3SO2— R1NH— Material Source (b) MH+ Rt (min)
    483 HCl
    Figure US20090312325A1-20091217-C00949
    Figure US20090312325A1-20091217-C00950
         		Example 481 tetrahydro-2H- pyran-4-amine/ Aldrich (II) 545 2.22
    484 HCl
    Figure US20090312325A1-20091217-C00951
    Figure US20090312325A1-20091217-C00952
         		Example 481 1-methyl piperazine/ Aldrich (II) 544 1.84
    506 HCl
    Figure US20090312325A1-20091217-C00953
    Figure US20090312325A1-20091217-C00954
         		Example 550 1-methyl piperazine/ Aldrich (II) 497 1.75
    507 HCl
    Figure US20090312325A1-20091217-C00955
    Figure US20090312325A1-20091217-C00956
         		Example 549 1-methyl piperazine/ Aldrich (II) 514 1.98
    (a) Salt form HCl = hydrochloride
    (b) Isolation Method:
    (II) Mass Directed preparative HPLC (Method C).
    • Example 551 6-{[3-(Dimethylamino)-3-oxopropyl]thio}-4-[(3-fluorophenyl)amino]-8-methyl-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C00957
  • To a solution of Intermediate 59 (0.04 g) in N,N-dimethylformamide (1 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.038 g). After 5 min, dimethylamine hydrochloride (0.026 g) and N,N-diisopropylethylamine (0.07 ml) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST Isolute™, 5 g), eluting with methanol followed by 2M ammonia in methanol to give the title compound as an orange oil (0.038 g).
  • LC/MS Rt 2.39 min m/z 427 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00958
    LCMS
    Example Starting Amine reagent/ LCMS Rt
    Number R26R27N— R1NH— Material Source MH+ (min)
    552
    Figure US20090312325A1-20091217-C00959
    Figure US20090312325A1-20091217-C00960
         		Intermediate 59 tetrahydro-2H- pyran-4-amine/ Aldrich 483 2.34
    553
    Figure US20090312325A1-20091217-C00961
    Figure US20090312325A1-20091217-C00962
         		Intermediate 59 cyclopropyl(methyl) amine/Karl Industries 453 2.56
    554
    Figure US20090312325A1-20091217-C00963
    Figure US20090312325A1-20091217-C00964
         		Intermediate 50 Morpholine/ Aldrich 469 2.36
    555
    Figure US20090312325A1-20091217-C00965
    Figure US20090312325A1-20091217-C00966
         		Intermediate 59 Pyrrolidine/Aldrich 453 2.49
    556
    Figure US20090312325A1-20091217-C00967
    Figure US20090312325A1-20091217-C00968
         		Intermediate 60 Dimethylamine/ Aldrich 410 2.03
    557
    Figure US20090312325A1-20091217-C00969
    Figure US20090312325A1-20091217-C00970
         		Intermediate 60 tetrahydro-2H- pyran-4-amine/ Aldrich 466 2.01
    558
    Figure US20090312325A1-20091217-C00971
    Figure US20090312325A1-20091217-C00972
         		Intermediate 60 cyclopropyl(methyl) amine/Karl Industries 436 2.20
    559
    Figure US20090312325A1-20091217-C00973
    Figure US20090312325A1-20091217-C00974
         		Intermediate 60 Morpholine/ Aldrich 452 2.03
    560
    Figure US20090312325A1-20091217-C00975
    Figure US20090312325A1-20091217-C00976
         		Intermediate 60 Pyrrolidine/Aldrich 436 2.13
    • Example 485 6-{[3-(Dimethylamino)-3-oxopropyl]sulfonyl}-4-[(3-fluorophenyl)amino]-8-methyl-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C00977
  • To a solution of the Example 551 (0.038 g) in N,N-dimethylformamide (2 ml) was added oxone (0.22 g). The mixture was stirred at room temperature for 2 h before quenching with aqueous sodium sulphite solution and extracting with dichloromethane. The organic layers were combined, dried by filtration through a hydrophobic frit and concentrated in vacuo. Purification by mass directed preparative HPLC (Method C) gave the title compound as a yellow solid (0.015 g).
  • LC/MS Rt 2.31 min m/z 459 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C00978
    Example Isolation
    Number Starting Method LCMS LCMS
    (a) R3SO2— material R20— R1NH— (b) MH+ Rt (min)
    486 HCl
    Figure US20090312325A1-20091217-C00979
         		Example 552 Me—
    Figure US20090312325A1-20091217-C00980
         		(II) 515 2.39
    487 HCl
    Figure US20090312325A1-20091217-C00981
         		Example 553 Me—
    Figure US20090312325A1-20091217-C00982
         		(II) 485 2.62
    488 HCl
    Figure US20090312325A1-20091217-C00983
         		Example 554 Me—
    Figure US20090312325A1-20091217-C00984
         		(II) 501 2.38
    489 HCl
    Figure US20090312325A1-20091217-C00985
         		Example 555 Me—
    Figure US20090312325A1-20091217-C00986
         		(II) 485 2.49
    490 HCl
    Figure US20090312325A1-20091217-C00987
         		Example 556 Me—
    Figure US20090312325A1-20091217-C00988
         		(II) 442 1.98
    491 HCl
    Figure US20090312325A1-20091217-C00989
         		Example 557 Me—
    Figure US20090312325A1-20091217-C00990
         		(II) 498 1.95
    492 HCl
    Figure US20090312325A1-20091217-C00991
         		Example 558 Me—
    Figure US20090312325A1-20091217-C00992
         		(II) 468 2.1
    493 HCl
    Figure US20090312325A1-20091217-C00993
         		Example 559 Me—
    Figure US20090312325A1-20091217-C00994
         		(II) 484 1.96
    494 HCl
    Figure US20090312325A1-20091217-C00995
         		Example 560 Me—
    Figure US20090312325A1-20091217-C00996
         		(II) 468 2.04
    525 HCOOH
    Figure US20090312325A1-20091217-C00997
         		Example 563 Me—
    Figure US20090312325A1-20091217-C00998
         		(I) 413 2.00
    526
    Figure US20090312325A1-20091217-C00999
         		Example 564 Me—
    Figure US20090312325A1-20091217-C01000
         		(I) 430 2.50
    527
    Figure US20090312325A1-20091217-C01001
         		Example 681 Me—
    Figure US20090312325A1-20091217-C01002
         		(III) 459 2.30
    529
    Figure US20090312325A1-20091217-C01003
         		Example 565 Me—
    Figure US20090312325A1-20091217-C01004
         		(IV) 444 2.5 
    530 HCl
    Figure US20090312325A1-20091217-C01005
         		Example 566 Me—
    Figure US20090312325A1-20091217-C01006
         		(II) 427 2.00
    532
    Figure US20090312325A1-20091217-C01007
         		Example 570 Me—
    Figure US20090312325A1-20091217-C01008
         		(V) 445 2.20
    533 HCl
    Figure US20090312325A1-20091217-C01009
         		Example 571 Me—
    Figure US20090312325A1-20091217-C01010
         		(II) 442 2.3 
    534 HCOOH
    Figure US20090312325A1-20091217-C01011
         		Example 572 Me—
    Figure US20090312325A1-20091217-C01012
         		(I) 428 1.8 
    535 HCOOH
    Figure US20090312325A1-20091217-C01013
         		Example 573 Me—
    Figure US20090312325A1-20091217-C01014
         		(I) 467 2.6 
    538 HCl
    Figure US20090312325A1-20091217-C01015
         		Example 574 Me—
    Figure US20090312325A1-20091217-C01016
         		(II) 520 2.83
    568
    Figure US20090312325A1-20091217-C01017
         		Example 569 Me—
    Figure US20090312325A1-20091217-C01018
         		(VI) 526 2.60
    578 HCl
    Figure US20090312325A1-20091217-C01019
         		Example 635 Me—
    Figure US20090312325A1-20091217-C01020
         		(II) 385 2.13
    579 HCl
    Figure US20090312325A1-20091217-C01021
         		Example 636 Me—
    Figure US20090312325A1-20091217-C01022
         		(II) 385 2.08
    580 HCl
    Figure US20090312325A1-20091217-C01023
         		Example 637 Me—
    Figure US20090312325A1-20091217-C01024
         		(II) 399 2.22
    581 HCl
    Figure US20090312325A1-20091217-C01025
         		Example 634 Me—
    Figure US20090312325A1-20091217-C01026
         		(II) 371 1.95
    582 HCl
    Figure US20090312325A1-20091217-C01027
         		Example 638 Cl—
    Figure US20090312325A1-20091217-C01028
         		(II) 391 2.07
    583 HCl
    Figure US20090312325A1-20091217-C01029
         		Example 662 Me—
    Figure US20090312325A1-20091217-C01030
         		(II) 388 2.33
    584 HCl
    Figure US20090312325A1-20091217-C01031
         		Example 664 Me—
    Figure US20090312325A1-20091217-C01032
         		(II) 402 2.4 
    585 HCl
    Figure US20090312325A1-20091217-C01033
         		Example 665 Me—
    Figure US20090312325A1-20091217-C01034
         		(II) 416 2.54
    666 HCl
    Figure US20090312325A1-20091217-C01035
         		Example 646 Cl—
    Figure US20090312325A1-20091217-C01036
         		(II) 425 2.52
    667 HCl
    Figure US20090312325A1-20091217-C01037
         		Example 647 Cl—
    Figure US20090312325A1-20091217-C01038
         		(II) 439 2.73
    668 HCl
    Figure US20090312325A1-20091217-C01039
         		Example 648 Cl—
    Figure US20090312325A1-20091217-C01040
         		(II) 439 2.56
    669 HCl
    Figure US20090312325A1-20091217-C01041
         		Example 649 Cl—
    Figure US20090312325A1-20091217-C01042
         		(II) 453 2.66
    670 HCl
    Figure US20090312325A1-20091217-C01043
         		Example 644 Me—
    Figure US20090312325A1-20091217-C01044
         		(II) 419 2.47
    671 HCl
    Figure US20090312325A1-20091217-C01045
         		Example 650 Me—
    Figure US20090312325A1-20091217-C01046
         		(II) 389 2.28
    672 HCl
    Figure US20090312325A1-20091217-C01047
         		Example 651 Me—
    Figure US20090312325A1-20091217-C01048
         		(II) 403 2.49
    673 HCl
    Figure US20090312325A1-20091217-C01049
         		Example 652 Me—
    Figure US20090312325A1-20091217-C01050
         		(II) 403 2.35
    674 HCl
    Figure US20090312325A1-20091217-C01051
         		Example 653 Me—
    Figure US20090312325A1-20091217-C01052
         		(II) 417 2.47
    675 HCl
    Figure US20090312325A1-20091217-C01053
         		Example 655 Cl—
    Figure US20090312325A1-20091217-C01054
         		(II) 423 2.49
    676 HCl
    Figure US20090312325A1-20091217-C01055
         		Example 656 Cl—
    Figure US20090312325A1-20091217-C01056
         		(II) 423 2.43
    677 HCl
    Figure US20090312325A1-20091217-C01057
         		Example 657 Cl—
    Figure US20090312325A1-20091217-C01058
         		(II) 437 2.54
    678 HCl
    Figure US20090312325A1-20091217-C01059
         		Example 642 Me—
    Figure US20090312325A1-20091217-C01060
         		(II) 405 2.38
    679 HCl
    Figure US20090312325A1-20091217-C01061
         		Example 643 Me—
    Figure US20090312325A1-20091217-C01062
         		(II) 419 2.53
    680 HCl
    Figure US20090312325A1-20091217-C01063
         		Example 645 Me—
    Figure US20090312325A1-20091217-C01064
         		(II) 433 2.67
    (a) Salt form HCl = hydrochloride HCOOH = formate
    (b) Isolation Method:
    (I) Mass Directed Preparative HPLC (Method A)
    (II) Mass Directed Preparative HPLC (Method C)
    (III) Aqueous work-up
    (IV) SCX ion exchange eluting with 2 M ammonia in methanol
    (V) Trituration with methanol and collection of the product by filtration
    (VI) Chromatography on silica gel eluting with methanol/ethyl acetate mixtures
    • Example 495 4-{[4-Fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-{[2-(2-oxo-1-pyrrolidinyl)ethyl]sulfonyl}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C01065
  • To a solution of Example 477 (0.03 g) in 1,4-dioxan (5 ml) was added ethyl 4-bromobutyrate (0.01 ml, available from Aldrich). The mixture was heated at 120° C. for 48 h. The solvent was evaporated in vacuo. Purification by mass directed preparative HPLC (Method C) gave the title compound as a yellow solid (0.007 g).
  • LC/MS Rt 2.3 min m/z 501 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C01066
    Example
    Number Starting LCMS LCMS
    (a) R1NH— Material MH+ Rt (min)
    514 HCl
    Figure US20090312325A1-20091217-C01067
         		Example 561 471 2.29
    (a) Salt form HCl = hydrochloride
    • Example 518 6-{[2-(Dimethylamino)ethyl]sulfonyl}-4-{[4-fluoro-3-(methyloxy)phenyl]amino}-8-methyl-3-quinolinecarboxamide formate salt
  • Figure US20090312325A1-20091217-C01068
  • To a stirred mixture of Example 477 (0.05 g) in dry N,N-dimethylformamide (1 ml) was added methyl iodide (0.033 g) and triethylamine (0.032 ml), and the mixture was stirred under nitrogen for 18 h. The mixture was applied directly to an SPE cartridge (1 g) and eluted with 4% methanol in chloroform; the eluent was evaporated in vacuo and the residue purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.003 g).
  • LC/MS Rt 2.01 min, m/z 461 [MH+]
    • Example 519 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-6-{[2-(dimethylamino)ethyl]sulfonyl}-8-methyl-3-quinolinecarboxamide formate salt Example 519 was prepared by a similar method to Example 518 from Example 422 to give the title compound as a yellow solid (0.005 g)
  • Figure US20090312325A1-20091217-C01069
  • LC/MS Rt 1.94 min, m/z 455 [MH+]
    • Example 521 4-{[4-Fluoro-3-(methyloxy)phenyl]amino}-8-methyl-6-{[2-(methyloxy)ethyl]thio}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01070
  • To a solution of Example 337 (0.05 g) in dry N,N-dimethylformamide (2 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0.015 g). The mixture was stirred at room temperature for 10 min when methyl iodide (0.0078 ml) was added; the mixture was stirred at room temperature for 18 h and the solvent evaporated in vacuo. The residue was partitioned between chloroform and water, the layers separated by hydrophobic frit, and the organic layer evaporated. The crude product was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.025 g).
  • LC/MS Rt 2.46 min, m/z 416 [MH+]
  • Similarly prepared from Example 528 was the following:
    • Example 571 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[2-(methyloxy)ethyl]thio}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01071
  • LC/MS Rt 2.40 min, m/z 410 [MH+]
    • Example 523 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-6-[(2-hydroxyethyl)sulfonyl]-8-methyl-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01072
  • To a solution of Example 528 (0.05 g) in N,N-dimethylformamide (2 ml) was added oxone (0.311 g). The mixture was stirred at room temperature for 3 h before quenching with aqueous sodium sulphite solution and extracting with ethyl acetate (50 ml). The organic layer was dried (Na2SO4) and concentrated in vacuo, and the mixture purified by mass directed preparative HPLC (Method A) to give the title compound as a white solid (0.035 g).
  • LC/MS Rt 2.1 min m/z 428 [MH+].
    • Example 524 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-{[2-(methyloxy)ethyl]sulfonyl}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01073
  • To a solution of Example 523 (0.018 g) in dry N,N-dimethylformamide (1 ml) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 0.0017 g). The mixture was stirred at room temperature for 10 min when methyl iodide (0.0026 ml) was added, stirring was continued for 18 h at room temperature and the solvent evaporated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer dried (MgSO4) and evaporated. The crude product was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.0024 g).
  • LC/MS Rt 2.3 min, m/z 442 [MH+]
    • Example 536 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfinyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01074
  • To a mixture containing Example 544 (0.10 g) in N,N-dimethylformamide (10 ml) was added oxone (0.253 g). The mixture was stirred under nitrogen for 3 h at room temperature and was then quenched with a solution of sodium sulphite (0.25 g) in water (10 ml), diluted with water (30 ml) and extracted with ethyl acetate (2×30 ml). The combined organic extracts were evaporated to dryness and the residue purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.028 g).
  • LC/MS Rt 2.24 min, m/z 503 [MH+]
    • Example 537 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-4-[(3-hydroxyphenyl)amino]-8-methyl-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01075
  • A solution of borontribromide in dichloromethane (1.0M, 2.2 ml) was added dropwise to an ice-cooled mixture containing Example 478 (0.35 g) in dichloromethane (25 ml) under nitrogen. The mixture was stirred at room temperature for 20 h, and was then treated with a further portion of borontribromide in dichloromethane (1.0M, 2.2 ml) and stirred for a further 5 h. The mixture was quenched with methanol (10 ml) and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml), the organic extract evaporated to dryness in vacuo, and the residue purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.075 g).
  • LC/MS Rt 2.46 min, m/z 505 [MH+]
    • Example 575 7-({3-[(Dimethylamino)carbonyl]phenyl}sulfinyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01076
  • A mixture containing Intermediate 65 (0.15 g), 10% palladium on activated carbon (0.04 g) and triethylamine (5 ml) in ethanol (25 ml) and N,N-dimethylformamide (10 ml) was hydrogenated at room temperature for 4 h. The suspension was filtered through celite, the residue washed with ethanol/N,N-dimethylformamide (3:1, 50 ml), and the filtrate concentrated in vacuo. The residue was purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.035 g).
  • LC/MS Rt 2.32 min, m/z 489 [MH+]
    • Example 545 7-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01077
  • Oxone (0.22 g) was added portionwise to a stirred solution of Example 575 (0.035 g) in N,N-dimethylformamide (4 ml). The mixture was stirred at room temperature under nitrogen for 24 h, a further portion of oxone (0.17 g) was added, and the mixture stirred for a further 5 h. The reaction was quenched with a solution of sodium sulphite (1.2 g) in water (15 ml), diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a buff solid (0.035 g).
  • LC/MS Rt 2.66 min, m/z 505 [MH+]
    • Example 576 6-({5-[(Dimethylamino)carbonyl]-3-pyridinyl}thio)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide, formate salt
  • Figure US20090312325A1-20091217-C01078
  • A stirred mixture of Intermediate 45 (0.47 g), Intermediate 69 (0.37 g), copper iodide (0.06 g), and potassium carbonate (0.47 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 ml) was heated at 10° C. under nitrogen for 4 h. The mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with water (2×200 ml) and brine (200 ml), and the organic layers dried over magnesium sulphate and concentrated in vacuo. The residue was purified by mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.1 g).
  • LC/MS Rt 2.35 min, m/z 488 [MH+]
    • Example 547 6-({5-[(Dimethylamino)carbonyl]-3-pyridinyl}sulfinyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride and Example 546 6-({5-[(Dimethylamino)carbonyl]-3-pyridinyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C01079
  • Oxone (1.2 g) was added portionwise to a stirred solution of Example 576 (0.1 g) in N,N-dimethylformamide (6 ml). The solution was stirred at room temperature under nitrogen for 2 h and then quenched with a solution of sodium sulphite (3 g) in water (30 ml). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (4×50 ml) and the combined organic layers were washed with water (2×50 ml) and brine (50 ml), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using mass directed preparative HPLC (Method C) to give Example 546 as a yellow solid (0.010 g) and Example 547 as a yellow solid (0.041 g).
    • Example 546
  • LC/MS Rt 2.57 min, m/z 520 [MH+]
    • Example 547
  • LC/MS Rt 2.12 min, m/z 504 [MH+]
    • Example 586 8-Methyl-4-[(3-methyl-5-isoxazolyl)amino]-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C01080
  • To a stirred suspension of sodium hydride (0.008 g; 60% dispersion in mineral oil) in dry N,N-dimethylformamide (1 ml) was added [(3-methyl-5-isoxazolyl)methyl]amine (available from Aldrich) (0.020 g) and the mixture heated at 80° C. for 30 min. A suspension of Intermediate 33 (0.020 g) in dry N,N-dimethylformamide (0.5 ml) was added and the mixture heated at 80° C. for 3 h. The mixture was quenched by the dropwise addition of ethanol (0.1 ml). The mixture was loaded onto a 2 g SCX cartridge, washed with methanol, and the product eluted with 10% ‘880’ ammonia in methanol. The solvent was removed in vacuo and the residue purified by mass directed preparative HPLC (Method C) to give the title compound as a pale yellow solid (0.009 g)
  • LC/MS Rt 2.23 min, m/z 361 [MH+]
    • Example 544 6-({3-[(Dimethylamino)carbonyl]phenyl}thio)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01081
  • A stirred mixture of Intermediate 45 (50 g), Intermediate 28 (40 g), and potassium carbonate (40 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (500 ml) was purged of air (by evacuation of the vessel and refilling with nitrogen three times) and left under nitrogen. Copper (I) iodide (5 g) was added and the mixture was warmed at 90° C. for 23 h. The mixture was cooled to 20° C. and poured into water (2.5 L). The precipitated solid was filtered off, washed with water and sucked partially dry. The damp solid was dissolved in chloroform (4 L) and washed with 1N sodium hydroxide solution (1 L), followed by water (2×1 L) and brine (1 L). The organic phase was dried over sodium sulphate and the solvent evaporated to leave a sticky solid. The solid was crystallised from hot ethanol (650 ml) to give the title compound as a solid (45.1 g).
  • LC/MS Rt 2.60 min m/z 487 [MH+].
  • Similarly prepared were the following:
  • Figure US20090312325A1-20091217-C01082
    Example Isolation
    Number Starting method LCMS LCMS
    (a) R1NH— R3S— Material (b) MH+ Rt (min)
    562
    Figure US20090312325A1-20091217-C01083
    Figure US20090312325A1-20091217-C01084
         		Intermediate 45 (I) 417 2.27
    573 HCl
    Figure US20090312325A1-20091217-C01085
    Figure US20090312325A1-20091217-C01086
         		Intermediate 35 (II) 435 2.56
    574
    Figure US20090312325A1-20091217-C01087
    Figure US20090312325A1-20091217-C01088
         		Intermediate 36 (III) 487 2.86
    (a) Salt form: HCl = hydrochoride
    (b) Isolation method:
    (I) Aqueous work-up followed by trituration with ether and filtration.
    (II) Mass directed preparative HPLC (Method C).
    (III) Trituration with ether and filtration.
    • Example 544 6-({3-[(Dimethylamino)carbonyl]phenyl}thio)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (alternative synthesis)
  • Figure US20090312325A1-20091217-C01089
  • Intermediate 45 (5.0 g), Intermediate 28 (2.89 g), copper iodide (0.506 g) and potassium carbonate (2.94 g) were added to 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 25 ml) and the resulting stirred slurry was heated to 100° C. under nitrogen. The mixture was stirred at 100° C. for 7 h, allowed to cooled to room temperature and stirred overnight. DMPU (20 ml) and water (80 ml) containing pyridine (0.43 ml) were added and the slurry was heated to 100° C. The resulting solution was seeded with crystals of Example 544 and stirred for 1 h at 10° C. The suspension was cooled gradually over 6 h, allowing the product to crystallise. The product was isolated by filtration, washed with water (2×50 ml) and dried at 40° C. in vacuo to give the title compound as a pale yellow solid (3.9 g).
  • LC/MS Rt 2.58 min m/z 487 [MH+].
    • Example 478 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (alternative synthesis)
  • Figure US20090312325A1-20091217-C01090
  • To a solution of Example 544 (29 g) in N,N-dimethylformamide (290 ml) cooled in a water bath was added oxone (87 g) in portions over 10 min. The mixture was stirred for 2 h, then poured into a cold (5° C.) solution of sodium metabisulphite (45 g) in water (2 L). After stirring for 35 min the mixture was extracted with chloroform (2 L+3×800 ml). The combined chloroform extracts were washed with water (3×600 ml), and the aqueous washes were extracted with chloroform (600 ml). The combined organic phases were dried over sodium sulphate and the solvent evaporated to leave a solid which was dried in vacuo at 40° C. for 3 days providing the title compound (27.8 g).
  • LC/MS Rt 2.62 min m/z 519 [MH+].
  • The solid was crystallised from hot ethanol containing 20% water (5 L) to give the title compound (20.2 g).
  • LC/MS Rt 2.62 min m/z 519 [MH+].
    • Example 478 6-({3-[(Dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide (alternative procedure)
  • Figure US20090312325A1-20091217-C01091
  • To a solution of Example 544 (3.5 g) in glacial acetic acid (18 ml) and water (3.5 ml) was added oxone (5.76 g) portionwise over 15 min. The mixture was stirred for 1.5 h at 20° C. and excess oxone quenched with a solution of sodium sulphite (0.545 g) in water (3.5 ml). The mixture was diluted with glacial acetic acid (11 ml) and water (21 ml), heated to 90°, treated dropwise over 30 min with 2M aqueous sodium hydroxide (20 ml), and cooled to 25° C. over 30 min. The resulting precipitate was collected by filtration, washed with water (25 ml×3) and dried in vacuo to give the title compound as a pale yellow solid (3.0 g).
  • LC/MS Rt 2.54 min m/z 519 [MH+].
    • Example 588 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfinyl)-3-quinolinecarboxamide formate salt
  • Figure US20090312325A1-20091217-C01092
  • To a suspension of Example 577 (0.04 g) in methanol (10 ml) was added sodium periodate (0.023 g) in water (0.2 ml). The mixture was stirred at room temperature for 4 days and the solvents evaporated in vacuo. The residue was purified using mass directed preparative HPLC (Method A) to give the title compound as a yellow solid (0.017 g).
  • LC/MS Rt 2.0 min, m/z 382 [MH+]
    • Example 307 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-6-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride (alternative synthesis)
  • Figure US20090312325A1-20091217-C01093
  • To a solution of Example 577 (0.04 g) in N,N-dimethylformamide (1 ml) was added oxone (0.337 g). The mixture was stirred at room temperature for 18 h, and quenched by addition of 10% sodium sulphite solution (15 ml). The mixture was extracted with ethyl acetate (50 ml), and the organic layer dried (Na2SO4) and evaporated in vacuo. The residue was purified using mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.018 g).
  • LC/MS Rt 2.2 min, m/z 398 [MH+]
    • Example 688 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-7-(methylthio)-3-quinolinecarboxamide
  • Figure US20090312325A1-20091217-C01094
  • A stirred mixture of Intermediate 104 (0.50 g), sodium methanethiolate (0.35 g), potassium carbonate (0.43 g) and copper (I) iodide (0.025 g) in dry N,N-dimethylformamide (3 ml) was heated at 100° under nitrogen for 18 h. The mixture was cooled, poured into water (50 ml) and stirred for 15 min. The solid material was filtered off, dried in vacuo at 800 for 2 h, and boiled in ethanol:water 15:1 (50 ml) for 30 min. The insoluble material was filtered off, and the filtrate evaporated to dryness to give the title compound as a pale yellow solid (0.163 g).
  • LC/MS Rt 2.40 min m/z 366 [MH+]
    • Example 548 4-(2,3-Dihydro-1-benzofuran-4-ylamino)-8-methyl-7-(methylsulfonyl)-3-quinolinecarboxamide hydrochloride
  • Figure US20090312325A1-20091217-C01095
  • Example 548 was prepared from Example 688 by a similar method to Example 129, but without the addition of anisole to the reaction mixture, using 10:1 N,N-dimethylformamide: water as solvent, and purifying by mass directed preparative HPLC (method C).
  • LC/MS Rt 2.50 min m/z 398 [MH+]

Claims (16)

1.-24. (canceled)
25. A method for the treatment of COPD (chronic obstructive pulmonary disease) in a human in need thereof, which comprises administration of a therapeutically effective amount of a compound of formula (I)
Figure US20090312325A1-20091217-C01096
or a pharmaceutically acceptable salt thereof
wherein:
R1 is C1-6 alkyl; C3-7cycloalkyl or C3-7cycloalkyl(C1-4alkyl)- wherein the C3-7cycloalkyl is optionally substituted by one or more substituents selected from ═O and OH; C4-7cycloalkyl fused to an aryl ring; Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl, C1-6alkylCONR6—, C1-6alkylCO—, halogen, —CF3, —(CH2)mOH, —OCF3, C1-6alkoxy-, C1-6alkoxy(C1-4alkyl)-, C1-6alkoxyC2-6alkoxy-, C1-6alkoxycarbonyl, —CN, R4R5NCO, R7R3N—, R9R10NCONR11—, HO(CH2)2-6O—, R12R13NSO2(CH2)m—, (4-morpholinyl)C2-6alkoxy, —NR14SO2C1-6alkyl, aryloxy, heteroaryl (optionally substituted by C1-6alkyl), CO2H, R21R22N(C1-4alkyl)-, C1-6alkoxyCONR23(CH2)m—, aryl(optionally substituted by C1-6alkyl); Aryl fused to a C4-7cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted by one or more ═O; Aryl fused to a heterocyclyl ring, wherein the heterocyclyl ring is optionally substituted by one or more substituents selected from ═O, —COC1-4alkyl, C1-4alkyl; Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more substituents selected from: C1-6alkyl, aryl(C1-4alkyl), C1-6alkoxy, halogen, C1-6alkoxyCO; or Heterocyclyl optionally fused to an aryl or heteroaryl ring;
R2 is hydrogen or C1-6alkyl;
R34 is a group of formula:
Figure US20090312325A1-20091217-C01097
R3 is C1-6alkyl optionally substituted by one or more substituents selected from —OH, —NR16COR15, —NR17R18, —CO2R24, C1-6alkoxyCONR25—, —CONR26R27, C1-6alkoxy-, C1-6alkylSO2NR33—, or a group having one of the following formulae:
Figure US20090312325A1-20091217-C01098
C3-7cycloalkyl; Aryl or aryl(C1-6alkyl)- wherein the aryl is optionally substituted by one or more substituents selected from C1-6alkyl-, halogen-, C1-6alkoxy-, —CO2R28, —CH2CO2H, —OH, aryl(optionally substituted by a C1-6 alkoxy group), heteroaryl, —CONR29R30, C3-7cycloalkoxy, C3-7cycloalkyl(C1-6alkoxy)-, —CF3; Heteroaryl or heteroaryl(C1-6alkyl)- wherein the heteroaryl is optionally substituted by one or more C1-6alkyl or —CONR29R30 groups; or Heterocyclyl linked to the S(═O)n moiety through a carbon atom which is optionally substituted by one of more substituents selected from C1-6alkyl-, C1-6alkylCO—, C3-7cycloalkylCO—, heteroarylCO— optionally substituted by one or more C1-4alkyl-groups, C1-6alkoxyCO—, arylCO—, R31R32 NCO—, C1-6alkylSO2—, arylSO2, -heteroarylSO2 optionally substituted by one or more C1-4alkyl or C1-4alkylCONH— groups;
m is 0-6;
n is 0, 1 or 2;
R19 is hydrogen or C1-6alkyl;
R20 is hydrogen, C1-6alkyl, halogen or C1-6alkoxy;
R4-18, R21-25, R28 and R31-33 all independently represent H, C1-6 alkyl;
R26 and R27 independently represent H, C1-6 alkyl, C3-7cycloalkyl or heterocyclyl;
R29 and R30 independently represent H, C1-6alkyl optionally substituted by OH;
R7 and R8 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R9 and R10 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R17 and R18 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R21 and R22 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R26 and R27 together with the nitrogen atom to which they are attached may form a heterocyclyl ring;
R29 and R30 together with the nitrogen atom to which they are attached may form a heterocyclyl ring; and
R31 and R32 together with the nitrogen atom to which they are attached may form a heterocyclyl ring.
26. The method of claim 25 wherein the administration comprises inhaled administration.
27. The method of claim 25, further comprising the administration of a second therapeutic agent selected from a β2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent, an anticholinergic agent, and an antiinfective agent.
28. The method of claim 25, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
29. The method of claim 25, wherein the therapeutically effective amount of a compound is administered as a formulation comprising the compound and a pharmaceutically acceptable carrier or excipient.
30. A method for the treatment of COPD (chronic obstructive pulmonary disease) in a human in need thereof, which comprises administration of a therapeutically effective amount of a compound of formula
Figure US20090312325A1-20091217-C01099
or a pharmaceutically acceptable salt thereof.
31. The method of claim 30 wherein the administration comprises inhaled administration.
32. The method of claim 30, further comprising the administration of a second therapeutic agent selected from a 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent, an anticholinergic agent, and an antiinfective agent.
33. The method of claim 30, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
34. The method of claim 30, wherein the therapeutically effective amount of a compound is administered as a formulation comprising the compound and a pharmaceutically acceptable carrier or excipient.
35. A method for the treatment of COPD in a human in need thereof, which comprises administration of a therapeutically effective amount of 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-(methyloxy)phenyl]amino}-3-quinolinecarboxamide.
36. The method of claim 35 wherein the administration comprises inhaled administration.
37. The method of claim 35, further comprising the administration of a second therapeutic agent selected from a 2 adrenoreceptor agonist, an anti-histamine, an anti-allergic agent, an anti-inflammatory agent, an anticholinergic agent, and an antiinfective agent.
38. The method of claim 35, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
39. The method of claim 35, wherein the therapeutically effective amount of a compound is administered as a formulation comprising the compound and a pharmaceutically acceptable carrier or excipient.
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Cited By (2)

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US8367829B2 (en) 2010-05-10 2013-02-05 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US8394829B2 (en) 2010-05-10 2013-03-12 Gilead Sciences, Inc. Bi-functional quinoline analogs

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GB0316290D0 (en) 2003-07-11 2003-08-13 Glaxo Group Ltd Novel compounds
GB0411056D0 (en) 2004-05-18 2004-06-23 Novartis Ag Organic compounds
PE20060272A1 (en) 2004-05-24 2006-05-22 Glaxo Group Ltd (2R, 3R, 4S, 5R, 2'R, 3'R, 4'S, 5'S) -2.2 '- {TRANS-1,4-CYCLOHEXANODIYLBIS- [IMINO (2 - {[2- (1-METHYL- 1H-IMIDAZOL-4-IL) ETHYL] AMINO} -9H-PURIN-6,9-DIYL)]} BIS [5- (2-ETHYL-2H-TETRAZOLE-5-IL) TETRAHYDRO-3,4-FURANODIOL] AS AN A2A AGONIST
GB0425572D0 (en) * 2004-11-19 2004-12-22 Glaxo Group Ltd 1,7-Naphthyridines
EP1841780B1 (en) 2005-01-10 2011-07-27 Glaxo Group Limited Androstane 17-alpha-carbonate derivatives for use in the treatment of allergic and inflammatory conditions
GB0503955D0 (en) * 2005-02-25 2005-04-06 Glaxo Group Ltd Novel compounds
GB0505621D0 (en) * 2005-03-18 2005-04-27 Glaxo Group Ltd Novel compounds
GB0514809D0 (en) 2005-07-19 2005-08-24 Glaxo Group Ltd Compounds
WO2007030567A2 (en) * 2005-09-07 2007-03-15 Plexxikon, Inc. Pparactive compounds
GB0521563D0 (en) 2005-10-21 2005-11-30 Glaxo Group Ltd Novel compounds
PE20071068A1 (en) 2005-12-20 2007-12-13 Glaxo Group Ltd 3- (4 - {[4- (4 - {[3- (3,3-DIMETHYL-1-PIPERIDINYL) PROPYL] OXY} PHENYL) -1-PIPERIDINYL] CARBONYL} -1-NAPHTHALENYL) PROPANOIC OR PROPENOIC ACID, SALTS OF THE SAME, AS ANTAGONISTS OF THE H1 AND H3 RECEPTORS
GB0601951D0 (en) 2006-01-31 2006-03-15 Novartis Ag Organic compounds
ES2462240T3 (en) * 2006-02-28 2014-05-22 Dart Neuroscience (Cayman) Ltd Therapeutic piperazines as PDE4 inhibitors
US8927546B2 (en) 2006-02-28 2015-01-06 Dart Neuroscience (Cayman) Ltd. Therapeutic piperazines
EP1996574A1 (en) * 2006-03-08 2008-12-03 Amgen Inc. Quinoline and isoquinoline derivatives as phosphodiesterase 10 inhibitors
GB0605462D0 (en) * 2006-03-17 2006-04-26 Glaxo Group Ltd Novel compounds
EA200801997A1 (en) 2006-04-20 2009-04-28 Глаксо Груп Лимитед NEW CONNECTIONS
WO2007125952A1 (en) * 2006-04-28 2007-11-08 Shionogi & Co., Ltd. Amine derivative having npy y5 receptor antagonist activity
GB0611587D0 (en) 2006-06-12 2006-07-19 Glaxo Group Ltd Novel compounds
CL2007001829A1 (en) 2006-06-23 2008-01-25 Smithkline Beecham Corp N- [4-Chloro-2-hydroxy-3- (piperazine-1-sulfonyl) phenyl] -n- (2-chloro-3-fluorophenyl) urea P-toluenesulfonate; preparation process; pharmaceutical composition; pharmaceutical combination; and use in the treatment of a disease mediated by chemokine il-8, such as asthma and epoc.
MX2009004715A (en) 2006-10-30 2009-05-20 Novartis Ag Heterocyclic compounds as antiinflammatory agents.
TW200829555A (en) * 2006-11-10 2008-07-16 Astrazeneca Ab Chemical compounds
PE20081889A1 (en) 2007-03-23 2009-03-05 Smithkline Beecham Corp INDOL CARBOXAMIDES AS INHIBITORS OF IKK2
JP5584138B2 (en) 2008-01-11 2014-09-03 ノバルティス アーゲー Pyrimidines as kinase inhibitors
US20110160249A1 (en) 2008-05-23 2011-06-30 Schaab Kevin Murray 5-lipoxygenase-activating protein inhibitor
US8163743B2 (en) 2008-06-05 2012-04-24 GlaxoGroupLimited 4-carboxamide indazole derivatives useful as inhibitors of PI3-kinases
US8729097B2 (en) 2008-10-06 2014-05-20 The Johns Hopkins University Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and SIRT1, and methods of treating disorders
JP2012513464A (en) * 2008-12-23 2012-06-14 ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク Phosphodiesterase inhibitors and uses thereof
KR20110100679A (en) 2009-01-13 2011-09-14 글락소 그룹 리미티드 Pyrimidine Carboxamide Derivatives as Inhibitors of SW Kinase
WO2010094643A1 (en) 2009-02-17 2010-08-26 Glaxo Group Limited Quinoline derivatives and their uses for rhinitis and urticaria
US8524751B2 (en) 2009-03-09 2013-09-03 GlaxoSmithKline Intellecutual Property Development 4-oxadiazol-2-YL-indazoles as inhibitors of P13 kinases
EP2406249A1 (en) 2009-03-10 2012-01-18 Glaxo Group Limited Indole derivatives as ikk2 inhibitors
US20120058984A1 (en) 2009-03-17 2012-03-08 Catherine Mary Alder Pyrimidine derivatives used as itk inhibitors
EP2408915A2 (en) 2009-03-19 2012-01-25 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF GATA BINDING PROTEIN 3 (GATA3) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20120035247A1 (en) 2009-03-19 2012-02-09 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 6 (STAT6) Gene Expression Using Short Interfering Nucleic Acid (siNA)
US20120016011A1 (en) 2009-03-19 2012-01-19 Merck Sharp & Dohme Corp. RNA Interference Mediated Inhibition of Connective Tissue Growth Factor (CTGF) Gene Expression Using Short Interfering Nucleic Acid (siNA)
MX2011009724A (en) 2009-03-19 2011-10-14 Merck Sharp & Dohme RNA INTERFERENCE MEDIATED INHIBITION OF BTB AND CNC HOMOLOGY 1, BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR 1 (BACH 1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) SEQUENCE LISTING.
WO2010111490A2 (en) 2009-03-27 2010-09-30 Merck Sharp & Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE THYMIC STROMAL LYMPHOPOIETIN (TSLP) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
EP2411018A2 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF THE NERVE GROWTH FACTOR BETA CHAIN (NGFß) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (SINA)
JP2012521760A (en) 2009-03-27 2012-09-20 メルク・シャープ・エンド・ドーム・コーポレイション RNA interference-mediated inhibition of apoptosis signal-regulated kinase 1 (ASK1) gene expression using small interfering nucleic acids (siNA)
EP2411019A2 (en) 2009-03-27 2012-02-01 Merck Sharp&Dohme Corp. RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
MX2011010072A (en) 2009-03-27 2011-10-06 Merck Sharp & Dohme RNA INTERFERENCE MEDIATED INHIBITION OF THE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1)GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA).
WO2010122088A1 (en) 2009-04-24 2010-10-28 Glaxo Group Limited Pyrazole and triazole carboxamides as crac channel inhibitors
UY32571A (en) 2009-04-24 2010-11-30 Glaxo Group Ltd COMPOUNDS DERIVED FROM PIRAZOL AMIDA
WO2010125082A1 (en) 2009-04-30 2010-11-04 Glaxo Group Limited Oxazole substituted indazoles as pi3-kinase inhibitors
EP2507223A1 (en) 2009-12-03 2012-10-10 Glaxo Group Limited Benzpyrazole derivatives as inhibitors of p13 kinases
EP2507226A1 (en) 2009-12-03 2012-10-10 Glaxo Group Limited Novel compounds
JP2013512880A (en) 2009-12-03 2013-04-18 グラクソ グループ リミテッド Indazole derivatives as PI3-kinase inhibitors
WO2011110575A1 (en) 2010-03-11 2011-09-15 Glaxo Group Limited Derivatives of 2-[2-(benzo- or pyrido-) thiazolylamino]-6-aminopyridine, useful in the treatment of respiratoric, allergic or inflammatory diseases
GB201007203D0 (en) 2010-04-29 2010-06-16 Glaxo Group Ltd Novel compounds
WO2012032065A1 (en) 2010-09-08 2012-03-15 Glaxo Group Limited Indazole derivatives for use in the treatment of influenza virus infection
DK2614058T3 (en) 2010-09-08 2015-09-28 Glaxosmithkline Ip Dev Ltd Polymorphs, and the salts of N- [5- [4- (5 - {[(2R, 6S) -2,6-dimethyl-4-morpholinyl] methyl} -1,3-oxazol-2-yl) -1H-indazole -6-yl] -2- (methyloxy) -3-pyridinyl] methanesulfonamide.
WO2012034095A1 (en) 2010-09-09 2012-03-15 Irm Llc Compounds and compositions as trk inhibitors
UY33597A (en) 2010-09-09 2012-04-30 Irm Llc COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF THE TRK
WO2012035055A1 (en) 2010-09-17 2012-03-22 Glaxo Group Limited Novel compounds
EP2630127A1 (en) 2010-10-21 2013-08-28 Glaxo Group Limited Pyrazole compounds acting against allergic, inflammatory and immune disorders
WO2012052458A1 (en) 2010-10-21 2012-04-26 Glaxo Group Limited Pyrazole compounds acting against allergic, immune and inflammatory conditions
GB201018124D0 (en) 2010-10-27 2010-12-08 Glaxo Group Ltd Polymorphs and salts
WO2012061557A2 (en) * 2010-11-05 2012-05-10 Glaxosmithkline Llc Chemical compounds
AU2012220572A1 (en) 2011-02-25 2013-08-29 Irm Llc Compounds and compositions as trk inhibitors
SG192769A1 (en) * 2011-03-04 2013-09-30 Glaxosmithkline Ip No 2 Ltd Amino-quinolines as kinase inhibitors
EP2683716A1 (en) 2011-03-11 2014-01-15 Glaxo Group Limited Pyrido[3,4-b]pyrazine derivatives as syk inhibitors
GB201104153D0 (en) 2011-03-11 2011-04-27 Glaxo Group Ltd Novel compounds
TWI547494B (en) 2011-08-18 2016-09-01 葛蘭素史克智慧財產發展有限公司 Aminoquinazolines as kinase inhibitors
WO2013066736A1 (en) * 2011-11-03 2013-05-10 Merck Sharp & Dohme Corp. QUINOLINE CARBOXAMIDE AND QUINOLINE CARBONITRILE DERIVATIVES AS mGluR2-NEGATIVE ALLOSTERIC MODULATORS, COMPOSITIONS, AND THEIR USE
AR092529A1 (en) 2012-09-13 2015-04-22 Glaxosmithkline Llc AMINOQUINAZOLINE COMPOUND, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND USE OF THIS COMPOSITE FOR THE PREPARATION OF A MEDICINAL PRODUCT
AR092530A1 (en) 2012-09-13 2015-04-22 Glaxosmithkline Llc AMINO-QUINOLINE COMPOSITE, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND USE OF THIS COMPOUND FOR THE PREPARATION OF A MEDICINAL PRODUCT
CN104968200B (en) 2013-02-01 2018-03-06 维尔斯达医疗公司 Amine compounds having anti-inflammatory, antifungal, antiparasitic and anticancer activity
TWI630203B (en) 2013-02-21 2018-07-21 葛蘭素史克智慧財產發展有限公司 Quinazolines as kinase inhibitors
RU2016112266A (en) 2013-10-17 2017-11-20 Глаксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед PI3K inhibitor for the treatment of respiratory disease
AU2014336250A1 (en) 2013-10-17 2016-04-14 Glaxosmithkline Intellectual Property Development Limited PI3K inhibitor for treatment of respiratory disease
AU2015260841A1 (en) 2014-05-12 2016-12-01 Glaxosmithkline Intellectual Property (No. 2) Limited Pharmaceutical compositions comprising danirixin for treating infectious diseases
NZ735044A (en) * 2015-03-24 2018-10-26 Shanghai Yingli Pharm Co Ltd Condensed ring derivative, and preparation method, intermediate, pharmaceutical composition and use thereof
GB201602527D0 (en) 2016-02-12 2016-03-30 Glaxosmithkline Ip Dev Ltd Chemical compounds
US20190161480A1 (en) 2016-08-08 2019-05-30 Glaxosmithkline Intellectual Property Development Limited Chemical Compounds
US20200085782A1 (en) * 2016-12-22 2020-03-19 Mavupharma, Inc. Compositions and methods of enhancing or augmenting type i ifn production
GB201706102D0 (en) 2017-04-18 2017-05-31 Glaxosmithkline Ip Dev Ltd Chemical compounds
GB201712081D0 (en) 2017-07-27 2017-09-13 Glaxosmithkline Ip Dev Ltd Chemical compounds
CN111875594A (en) * 2020-07-21 2020-11-03 中国药科大学 Indazole heterocycles having phosphodiesterase 4B inhibitory activity
TW202430172A (en) * 2023-01-17 2024-08-01 大陸商瑞石生物醫藥有限公司 Pde4 inhibitors, preparation method and medical use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030096834A1 (en) * 2000-04-07 2003-05-22 Jenkins Richard John Pharmaceutical compositions

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2340735A1 (en) * 1976-02-11 1977-09-09 Roussel Uclaf NEW DERIVATIVES OF 3-QUINOLEINE CARBOXYLIC ACID, THEIR METHOD OF PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT
IE46886B1 (en) 1977-05-17 1983-10-19 Allen & Hanburys Ltd Aminoalkyl-benzene derivatives
EP0048005A3 (en) * 1980-09-17 1983-01-19 ALFA-Institut für hauswirtschaftliche Produkt- und Verfahrens-Entwicklung GmbH Device for storing crockery
GB9004781D0 (en) 1990-03-02 1990-04-25 Glaxo Group Ltd Device
KR920701162A (en) * 1990-03-28 1992-08-11 오츠카 아끼히코 Quinoline derivative, an anti-ulcer agent containing the derivative and a method for producing the derivative
US5214191A (en) 1990-05-22 1993-05-25 Cortech, Inc. Oxidant sensitive and insensitive aromatic esters as inhibitors of human neutrophil elastase
MX9200299A (en) 1991-02-07 1992-12-01 Roussel Uclaf NEW NITROGENATED BICYCLE DERIVATIVES, THEIR PROCEDURE FOR PREPARING THE NEW INTERMEDIATE COMPOUNDS OBTAINED THEIR APPLICATION AS MEDICINES AND THE PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.
GB9127376D0 (en) 1991-12-24 1992-02-19 Wellcome Found Amidino derivatives
EP1281770B1 (en) 1993-03-10 2010-03-03 GlaxoSmithKline LLC Human brain phosphodiesterase and screening method
FR2705346B1 (en) 1993-05-18 1995-08-11 Union Pharma Scient Appl New derivatives of piperidinyl thio indole, processes for their preparation, pharmaceutical compositions containing them, useful in particular as analgesics.
DK122693D0 (en) 1993-10-29 1993-10-29 Hempels Skibsfarve Fab J C MARIN STRUCTURE
ES2189322T3 (en) 1994-06-15 2003-07-01 Wellcome Found USEFUL INTERMEDIARIES IN THE PREPARATION OF INHIBITORS OF ENCIMAS.
WO1997044322A1 (en) * 1996-05-20 1997-11-27 Darwin Discovery Limited Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors
PT912559E (en) 1996-07-13 2003-03-31 Glaxo Group Ltd HETEROCYCLIC COMPOUNDS FUSED AS PROTEIN INHIBITORS TYROSINE KINASE
EP0929526B1 (en) 1996-09-25 2005-07-27 AstraZeneca AB Qinoline derivatives inhibiting the effect of growth factors such as vegf
GB9712761D0 (en) 1997-06-17 1997-08-20 Chiroscience Ltd Quinolines and their therapeutic use
MY117948A (en) 1997-01-13 2004-08-30 Glaxo Group Ltd Nitride oxide synthase inhibitors.
RU2220960C2 (en) 1997-12-22 2004-01-10 Фармация Энд Апджон Компани 4-hydroxy-3-quinolinecarboxamides and hydrazides, pharmaceutical composition and treatment method based on thereof
GB9811599D0 (en) 1998-05-30 1998-07-29 Glaxo Group Ltd Nitric oxide synthase inhibitors
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
KR100705142B1 (en) 1998-09-29 2007-04-06 와이어쓰 홀딩스 코포레이션 Substituted 3-cyanoquinolines as Protein Tyrosine Kinase Inhibitors
EP1950201A1 (en) 1998-09-29 2008-07-30 Wyeth Holdings Corporation Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors
MY121142A (en) 1999-02-23 2005-12-30 Smithkline Beecham Corp Controlled release formulation for treating copd
AU3517700A (en) 1999-03-15 2000-10-04 Abbott Laboratories 6-o-substituted macrolides having antibacterial activity
US20020052312A1 (en) 2000-05-30 2002-05-02 Reiss Theodore F. Combination therapy of chronic obstructive pulmonary disease using muscarinic receptor antagonists
NZ523749A (en) 2000-07-26 2005-03-24 Smithkline Beecham P Aminopiperidine quinolines and their azaisosteric analogues with antibacterial activity
US6576644B2 (en) * 2000-09-06 2003-06-10 Bristol-Myers Squibb Co. Quinoline inhibitors of cGMP phosphodiesterase
GB0023918D0 (en) 2000-09-29 2000-11-15 King S College London Antiparasitic compounds
ES2527688T3 (en) 2000-09-29 2015-01-28 Glaxo Group Limited Morpholin-acetamide derivatives for the treatment of inflammatory diseases
DE10110772A1 (en) 2001-03-07 2002-09-12 Boehringer Ingelheim Pharma New drug compositions based on anticholinergics and PDE-IV inhibitors
US20020193393A1 (en) 2001-03-07 2002-12-19 Michel Pairet Pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors
US7067532B2 (en) 2000-11-02 2006-06-27 Astrazeneca Substituted quinolines as antitumor agents
EP1337513A1 (en) 2000-11-02 2003-08-27 AstraZeneca AB 4-substituted quinolines as antitumor agents
GB0031179D0 (en) 2000-12-21 2001-01-31 Glaxo Group Ltd Nitric oxide synthase inhibitors
GB0104422D0 (en) 2001-02-22 2001-04-11 Glaxo Group Ltd Quinoline derivative
SE0101675D0 (en) * 2001-05-11 2001-05-11 Astrazeneca Ab Novel composition
UY27304A1 (en) 2001-05-24 2002-12-31 Avanir Pharmaceuticals INHIBITORS OF THE INHIBITOR FACTOR OF MIGRATION OF MACROPHAGES AND METHODS FOR IDENTIFICATION
PE20030008A1 (en) 2001-06-19 2003-01-22 Bristol Myers Squibb Co DUAL INHIBITORS OF PDE 7 AND PDE 4
JP2003005355A (en) 2001-06-20 2003-01-08 Fuji Photo Film Co Ltd Negative type resist composition for electron beam or x-ray
GB0118373D0 (en) 2001-07-27 2001-09-19 Glaxo Group Ltd Novel therapeutic method
JP4623962B2 (en) 2001-10-22 2011-02-02 ザ・リサーチ・ファウンデーション・オブ・ステイト・ユニバーシティ・オブ・ニューヨーク Protein kinases and phosphatase inhibitors, methods of designing them, and methods of using them
US20050009815A1 (en) 2001-11-27 2005-01-13 Devita Robert J. 4-Aminoquinoline compounds
AR037641A1 (en) 2001-12-05 2004-11-17 Tularik Inc INFLAMMATION MODULATORS
US7109213B2 (en) 2002-01-29 2006-09-19 Glaxo Group Limited Aminopiperidine compounds, process for their preparation, and pharmaceutical compositions containing them
DE10215316C1 (en) 2002-04-02 2003-12-18 Schering Ag Quinoline and isoquinoline derivatives, a pharmaceutical agent and their use as anti-inflammatory agents
AU2003243091A1 (en) 2002-06-20 2004-01-06 Biovitrum Ab (Publ) New compounds useful for the treatment of obesity, type ii diabetes and cns disorders
WO2004067513A1 (en) 2003-01-27 2004-08-12 Oy Juvantia Pharma Ltd Antagonists for alpha-2 adrenoceptors
MXPA05009722A (en) 2003-03-10 2006-03-09 Schering Corp Heterocyclic kinase inhibitors: methods of use and synthesis.
GB0322722D0 (en) * 2003-09-27 2003-10-29 Glaxo Group Ltd Compounds
GB0322726D0 (en) * 2003-09-27 2003-10-29 Glaxo Group Ltd Compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030096834A1 (en) * 2000-04-07 2003-05-22 Jenkins Richard John Pharmaceutical compositions

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8367829B2 (en) 2010-05-10 2013-02-05 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
US8394829B2 (en) 2010-05-10 2013-03-12 Gilead Sciences, Inc. Bi-functional quinoline analogs
US8450490B2 (en) 2010-05-10 2013-05-28 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds

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