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WO2012164085A1 - Glycine b antagonists - Google Patents

Glycine b antagonists Download PDF

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Publication number
WO2012164085A1
WO2012164085A1 PCT/EP2012/060433 EP2012060433W WO2012164085A1 WO 2012164085 A1 WO2012164085 A1 WO 2012164085A1 EP 2012060433 W EP2012060433 W EP 2012060433W WO 2012164085 A1 WO2012164085 A1 WO 2012164085A1
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Prior art keywords
methyl
chloro
carboxylic acid
oxo
quinoline
Prior art date
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Ceased
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PCT/EP2012/060433
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French (fr)
Inventor
Ulrich Abel
Angela Hansen
Falko Ernst Wolter
Bjoern Krueger
Valerjans Kauss
Jevgenijs Rozhkovs
Valentina SEMENIHINA
Irena Piskunova
Juris PELSS
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Merz Pharma GmbH and Co KGaA
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Merz Pharma GmbH and Co KGaA
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Publication of WO2012164085A1 publication Critical patent/WO2012164085A1/en
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to novel 2(1 H)-quinolinone derivatives which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.
  • Glutamate is a major excitatory transmitter in the central nervous system and it has become clear in recent years that it is also very important in the peripheral nervous system (PNS). Glutamate is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.
  • glycine B strychnine insensitive gly
  • Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation.
  • the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time.
  • glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
  • glycine B antagonists may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example neuropathy induced by nociception, inflammation, ischemia, viral infection (herpes zoster virus, HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), complex regional pain syndrome, carpal tunnel syndrome, arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • pain including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including,
  • Blood-brain barrier impermeable glycine B antagonists which are restricted to action in the PNS, may be particularly useful since such antagonists do not exhibit CNS side effects.
  • Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal
  • R 1 is e. g., hydrogen, alkyl, allyl or propargyl
  • R 2 is e.g, hydroxy, alkoxy, alkylamino, dialylamino etc.
  • R 3 and R 4 are, independently, hydrogen or alkyl
  • R 5 is hydrogen, chlorine or bromine
  • R represents e.g., hydrogen atom, an amino group, a carboxy or C 2- 6 alkoxycarbonyl group
  • R 1 is a group of part formula (i) wherein n is zero or 1 , preferably zero
  • T represents e.g, cyano, carboxy or five- or six-membered heteroaromatic ring
  • R 2 , R 3 , R 4 and R 5 represent e.g, hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, nitro, as selective non-competitive antagonists on NMDA receptors and/or antagonists of AMPA receptors.
  • R 1 , R 2 and R 3 areindependently, hydrogen, halogen, alkyl, nitro, cyano or aminosulfonyl, is disclosed in US Patent No. 5,536,709.
  • R 1 , R 2 and R 3 are as described above, which are useful (by blocking AMPA/kainate receptor) as inhibitors of the pathological phenomena associated with hyperactivation of the excitating amino acid dependant pathways of neurotransmission, from compounds of formula (3) is also disclosed.
  • W represents e.g, -O-, -S(O) r , -CR 3 R 4 -, -NR 5 -, (where R 3 , R 4 and R 5 represent hydrogen or alkyi);
  • R 1 represents e.g, hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;
  • R 2 represents e.g, hydrogen, alkyi, -OR 6 (where R 6 represents hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), -NR 7 R 8 (where R 7 and R 8 independently represent hydrogen, alkyi, alkenyl, alkynyl, acyl, aryl, etc.); R a represents hydrogen or alkyi;
  • X represents e.g, -
  • A denotes a single bond or methylene
  • V denotes a single bond or methylene
  • T denotes a hydroxyl group, amino group, alkoxycarbonyl, carboxyl
  • R denotes a nitro group or halogen atom
  • R 1 denotes a hydroxyl group or lower alkoxy group
  • n 0, 1 or 2;
  • X 1 represents halogen, nitro, or C-i -6 alkyl
  • X 2 represents hydrogen, halogen, nitro, trifluoromethyl, C h alky! or C-i-6alkoxy;
  • R represents hydrogen or Ci -6 alkyl;
  • R 3 represents hydrogen, C-i -6 alkyl, C 3-6 alkenyl, Ci -6 alkylsulfonyl, aryl, heteroaryl, cyclo- C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl -Chalky! or heteroaryl-C-i-6alkyl;
  • R 4 represents hydrogen, C-i -6 alkyl, C 3-6 alkenyl, Ci -6 alkylsulfonyl, aryl, heteroaryl, cyclo- C 3- i 2 alkyl, cyclo-C 3- i2alkyl-Ci -6 alkyl, aryl-Ci -6 alkyl, heteroaryl-Ci -6 alkyl, hydroxy-C-i -6 alkyl, carbamoyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl or C(O)-R 5 ; wherein R 5 represents COOH, Ci -6 alkyl, cyclo-C 3- i 2 alkyl optionally condensed to a benzene ring, cyclo-C 3- i 2 alkyl-Ci -6 alkyl, hydroxy-Ci -6 alkyl, carboxy-Ci -6 alkyl, amino- Ci-6alkyl, aryl, heteroaryl, heteroaryl-he
  • Such a compound of Formula I, wherein n is 1 and R 1 and R 2 together with the carbon atom to which they are attached represent a carbonyl group (C O).
  • R 5 represents aryl, heteroaryl, aryl- C-i-6alkyl, heteroaryl-C-i-6alkyl, arylcarbonyl, arylamino, heteroarylamino, or aryl- Ci-6alkylamino.
  • Such a compound of Formula I wherein the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, Ci_6alkoxy, nitro, C-
  • substituents selected from halogen, Ci_6alkoxy, nitro, C-
  • Such a compound of Formula I, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and imidazopyridazinyl.
  • the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyr
  • Such a compound of Formula I wherein R 5 represents adamantyl, adamantyl- methyl, cyclohexyl substituted by aryl, cyclopentyl subsituted by aryl, cyclobutyl optionally substituted by aryl, cyclopropyl optionally substituted by aryl or heteroaryl, piperidinyl substituted by aryl, isochromanyl, or tetrahydroisoquinolinyl.
  • Such a compound of Formula I, wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, C h alky!, cyclo- C 3- i 2 alkyl, C-i -6 alkoxy, hydroxy-C-i -6 alkyl, C-i ⁇ alkoxy-
  • Such a compound of Formula I wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent triazolyl optionally substituted by C h alky!, aryl, heteroaryl, cyclo-C 3- i 2 alkyl, aryl-Ci -6 alkyl, or heteroaryl-Ci -6 alkyl, pyrrolyl optionally substituted by C-i-6alkylcarbonyl, aryl -C h alky!, or heteroaryl-C-i-6alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
  • Such a compound of Formula I, wherein R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring selected from oxazole, thiazole, imidazole, pyrazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and benzothizaolyl, which may be optionally subsituted by aryl-C-i-6alkyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA:
  • Such a compound of Formula IA wherein R 5 represents COOH, Chalky!, hydroxy-C-i-6alkyl, carboxy-C-i-6alkyl, amino-Ci-6alkyl, aryl, heteroaryl, aryl-C-i-6alkyl, heteroaryl-C-i-6alkyl, arylcarbonyl, cyclo-Cs- ⁇ alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, or heterocyclyl.
  • Such a compound of Formula IA wherein R 5 represents aryl, heteroaryl, aryl- C-
  • Such a compound of Formula IA, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and imidazopyridazinyl.
  • the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl,
  • Such a compound of Formula IA wherein R 5 represents cyclo-Cs- ⁇ alkyl optionally substituted by aryl or heteroaryl, cyclo-C3-i2alkyl-Ci- 6 alkyl, or heterocyclyl optionally substituted by aryl.
  • Such a compound of Formula IA wherein R 5 represents adamantyl, adamantyl- methyl, cyclohexyl substitued by aryl, cyclopentyl subsituted by aryl, cyclobutyl optionally substituted by aryl, cyclopropyl optionally substituted by aryl or heteroaryl, piperidinyl substituted by aryl, isochromanyl, or tetrahydroisoquinolinyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IB:
  • Such a compound of Formula IB wherein R 4 represents Ci -6 alkyl, C 3-6 alkenyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci- 6 alkyl, aryl -C h alky!, heteroaryl- C-i- 6 alkyl, hydroxy-Ci ⁇ alkyl, carbamoyl-Ci- 6 alkyl or Ci- 6 alkoxy-Ci- 6 alkyl.
  • R 4 represents benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, or pyridinyl- methyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
  • Such a compound of Formula IC wherein X 1 represents halogen and X 2 represents hydrogen or halogen.
  • Such a compound of Formula IC wherein R 1 represents hydrogen or C h alky! (e.g., methyl).
  • Such a compound of Formula IC wherein R 4 represents hydrogen, C h alky!, C 3-6 alkenyl, aryl, heteroaryl, cyclo-C 3- i 2 alkyl, cyclo-Cs- ⁇ alkyl-C-i ⁇ alkyl, aryl-Ci -6 alkyl, heteroaryl-Ci -6 alkyl, hydroxy-Ci -6 alkyl, carbamoyl-Ci -6 alkyl or C-i ⁇ alkoxy-C-i ⁇ alkyl.
  • Such a compound of Formula IC wherein R 4 represents methyl, benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, pyridinyl-methyl, pyridinyl optionally substituted by one or more substituents selected from nitro, Ci-6alkylcarbonylamino, and CONH 2 , benzoxazole, or benzothiazole.
  • Such a compound of Formula IC wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, C-i -6 alkyl, cyclo-C 3- i 2 alkyl, C-i -6 alkoxy, hydroxy-C-i -6 alkyl, Ci -6 alkoxy-C
  • Such a compound of Formula IC wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent triazolyl optionally substituted by C h alky!, aryl, heteroaryl, cyclo-C 3- i 2 alkyl, aryl-C-i -6 alkyl, or heteroaryl-Ci -6 alkyl, pyrrolyl optionally substituted by C-i- 6 alkylcarbonyl, aryl -C h alky!, or heteroaryl-C-i- 6 alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula I
  • R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring which may be optionally fused to a benzene ring, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen; wherein the heteroaromatic ring may be optionally substituted by aryl-C-i-6alkyl, and wherein X 1 and X 2 are as defined above for Formula I.
  • Such a compound of Formula ID wherein X 1 represents halogen and X 2 represents hydrogen or halogen.
  • heteroaromatic ring selected from oxazole, thiazole, imidazole, pyrazole, 1 ,2,4- oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and benzothizaolyl, which may be optionally subsituted by aryl-C-i-6alkyl.
  • heteroaromatic ring selected from 1 ,2,4-oxadiazole, which may be optionally substituted by subsituted by aryl-Ci -6 alkyl, 1 ,3,4-oxadiazole, which may be optionally substituted by subsituted by aryl-Ci_6alkyl, and benzothiazolyl.
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use in therapy.
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.
  • Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (
  • Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex,
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.
  • the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission.
  • a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.
  • the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.
  • a further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.
  • the compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds.
  • suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj_j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C h alky! refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
  • Ci-6alkyl represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms
  • examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, neopentyl, n- hexyl, 2-hexyl, 3-hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 2-e
  • C3-6alkenyl represents straight or branched chain alkenyl groups having 3, 4, 5 or 6 carbon atoms.
  • cycloCs- ⁇ alkyl represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, wherein the "cycloC3-i 2 alkyl"-ring is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents selected from halogen, hydroxy, oxo, aryl, and heteroaryl.
  • Ci- 6 alkoxy represents straight or branched chain -O-Ci_ 6 alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, terf-butoxy.
  • Ci- 6 alkylamino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with a C h alky! group as defined above.
  • alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, te/?-butylamino.
  • di-(Ci-6alkyl)amino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two C h alky! groups, which may be the same or different, as defined above.
  • di-Ci- 6 alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino.
  • aryl represents phenyl or naphthyl, or phenyl substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH 2 , trifluoromethyl, C h alky!, phenyl, heteroaryl, heterocyclyl, hydroxy-Ci -6 alkyl, carboxy-Ci -6 alkyl, carbamoyl-Ci -6 alkyl, heteroaryl-Ci -6 alkyl, amino- Ci -6 alkyl, Ci -6 alkylcarbonyl, Ci -6 alkylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci- 6 alkyl)aminocarbonyl, hydroxy-Ci- 6 alkylaminocarbonyl; C-i ⁇ alkoxy, hydroxy- C-i-6alkoxy, trifluoromethoxy, phenoxy
  • heteroaryl represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents (e.g., 1, 2, 3, 4, or 5) selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH 2 , trifluoromethyl, Ci -6 alkyl, phenyl, imidazolyl, pyrazolyl, hydroxy-Ci -6 alkyl, carboxy-Ci -6 alkyl, carbamoyl- C-i-6alkyl, heteroaryl-C-i-6alkyl, amino-Ci-6alkyl, hetero
  • acyl represents C-i-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, carboxy-Ci-6alkylcarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C 3- i 2 alkylcarbonyl, aryl-Ci -6 alkylcarbonyl, heteroaryl- Ci_6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
  • heterocyclyl represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1, 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Chalky!, C2-6alkenyl, C-i ⁇ alkoxy, amino, hydroxy, nitro, cyano, Ci -6 alkoxycarbonyl, Ci -6 alkylcarbonyl, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, Ci -6 alkyl-
  • halogen represents fluorine, chlorine, bromine and iodine.
  • analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • reference molecule such as 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
  • Synthesis and screening of analogs ⁇ e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
  • analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers ⁇ e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
  • prodrug is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I.
  • Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy and amino groups.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal ⁇ e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • compositions of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • a subset of the compounds of Formula I may be prepared by "click" reaction of azides 14 with an appropriate acetylene derivative 15 in the presence of catalytic amount of copper salt as shown in Scheme 2.
  • Azide 14 may be prepared from corresponding bromide 13 which, in turn, is obtained by hydrolysis of ester 8.
  • Another subset of the compounds of Formula I may be prepared by reaction of bromides 8 via an in-situ formation of azides and subsequent reaction of the intermediates formed with an appropriate acetylene derivative 15 in the presence of a ruthenium catalyst as shown in Scheme 2 to yield derivatives 31.
  • HCI in dioxane may be used as an appropriate medium for the hydroylsis of the ester and the methoxy group present in derivatives 31 to yield compounds of Formula I.
  • Another subset of the compounds of Formula I may be prepared by alkylation of amine 16 with bromide 8 and cleavage of intermediate ester 17 by such a common reagents as HBr in acetic acid or HCI in dioxane, as shown in Scheme 3.
  • compounds of Formula I may be prepared by direct alkylation of amine 16 with bromide 13.
  • Scheme 3 Synthesis of compounds of Formula I by alkylation of amines with bromides 8 and 13
  • Compounds of Formula I may be prepared by condensation of carboxylic acid 20 with amine 16 in the presence of condensing agents commonly used for amide bond formation, as shown in Scheme 4.
  • Carboxylic acid 20 may be synthesized by reaction of bromide 8 with di-tert-butyl malonate, providing triester 18 which is selectively cleaved by trifluoroacetic acid to give monoester 19 which, in turn, is thermally decarboxylated.
  • a subset of the compounds of Formula I may be prepared by carbamoylation of bromide 8 by molybdenum carbonyl amine complex in diglyme [Ren W., Yamane M. J. Org. Chem. 2010, 75, 3017-3020.], as shown in Scheme 5.
  • the procedure may be performed by stepwise preparation of molybdenum pentacarbonyl amine (22) complex or via generation of complex 22 in situ and bromide 8 and tributylamine may be added to the same bulb.
  • Scheme 5 Synthesis of compounds of Formula I by carbamoylation of bromide 8 by molybdenum carbonyl amine complex
  • Compounds of Formula I may be prepared via functionalization of the amino group of aminoethylquinoline 25 which may be condensed with appropriate carboxylic acid, or may be alkylated, arylated or acylated by haloderivative 26, as shown in Scheme 6.
  • Amine 25 may be prepared by cleavage of N-tert-butoxycarbonyl group of quinoline 24, which, in turn, is synthesized from carboxylic acid 20 under treatment with diphenyl phosphoranylazide.
  • Compounds of Formula I may be prepared by hydrolysis of the ester group and the methoxy group of quinoline-3-carboxylic acid derivatives 28 and 30, as shown in Scheme 7.
  • HBr in acetic acid or HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • the quinoline-3-carboxylic acid derivatives 30 may, in turn, be synthesized by reaction of ester 28 with derivative 29, wherein R 4 may be alkyl, heteroaryl or acyl and X represents a halogen atom, in the presence of an appropriate base.
  • Inorganic base e.g., potassium carbonate
  • organic base e.g., triethylamine
  • quinoline-3-carboxylic acid derivatives 30 is via an amide bond formation reaction which involves reaction of amino-derivative 28 with carboxylic acid 29 (Scheme 7) in the presence of a condensing agent (e.g., EDCI with or without HOBT) in an appropriate solvent (e.g., DCM).
  • a condensing agent e.g., EDCI with or without HOBT
  • an appropriate solvent e.g., DCM
  • Quinolines 30 may also be prepared by condensation of carbaldehydes 12 with amines 16 followed by reduction of intermediate imine bond with e. g., sodium borohydride.
  • Quinoline derivatives 28 may, in turn, be prepared from amine 10 by the procedures analogous to the synthesis of quinoline derivatives 30.
  • amine 10 may be alkylated, heteroarylated or acylated with corresponding halogenide 26 in the presence of an appropriate inorqanic base (e.g., potassium carbonate) or organic base (e.g., triethylamine).
  • an appropriate inorqanic base e.g., potassium carbonate
  • organic base e.g., triethylamine
  • quinoline-3-carboxylic acid derivatives 28 may be synthesized by an amide bond formation reaction which involves reaction of amine 10 with carboxylic acid 26 in the presence of condensing agent (e.g., EDCI with or without HOBT) and base (e.g., DMAP and Et.3N) in an appropriate solvent (e.g., DCM).
  • condensing agent e.g., EDCI with or without HOBT
  • base e.g., DMAP and Et.3N
  • an appropriate solvent e.g., DCM
  • Necessary amines 10 may be prepared by reduction of azides 9, for example, by triphenylphosphazene reaction with water (Scheme 1 ).
  • Azides 9 may, in turn, be prepared by reaction of bromides 8 with sodium azide in an appropriate solvent (e.g., DMF).
  • Bromides 8 are synthesized by bromination of 8-methyl-quinolines 7 with NBS in the presence of dibenzoyi peroxide or AIBN. Bromination of 8-methyl-quinolines 7 with an excess of NBS in the presence of dibenzoyi peroxide or AIBN may be used to obtain dibromides 11.
  • Dibromides 11 may, in turn, be transformed to carbaldehydes 12 in hydrolytic conditions (e.g., calcium carbonate in a mixture of water and dioxane).
  • Esters 7 may be prepared by esterification of carboxylic acids 6 (e.g., in a mixture of thionyl chloride and methanol), which, in turn, may be obtained by reaction of 2-chloroquinolines 5 with a sodium methoxide solution in methanol.
  • Sodium methoxide solution in methanol may be prepared e. g., by reaction of sodium metal or sodium hydride with methanol.
  • Necessary esters of 2-chloro-8-methyl-quinoline-3-carboxylic acids 5 are synthesized by well known procedures from the corresponding anthranilic acids 1 , aminophenylmethyl alcohols 2, and/or aminobenzaldehydes 3 (Scheme 1 ).
  • aminobenzaldehydes 3 may be condensed with dimethyl malonate in the presence of piperidine to give the methyl ester of 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid 4 which, in turn, may be transformed to 2-chloro-8-methyl-quinoline-3-carboxylic acid 5 by reaction with phosphorous oxychloride in DMF.
  • Ketone 38 may be synthesized by reaction of amino carboxylic acid 32 with an appropriate reduction agent providing alcohol 33 which is subsequently oxidized to aldehyde 34, which in turn is iodinated to yield intermediate 35.
  • Intermediate 35 may be reacted with dimethyl malonate and POCI3 to yield compound 36 which may be converted to 37 by reaction with sodium hydride and methanol and subsequent treatment with thionylchloride in the presence of methanol.
  • ketone 38 starting from iodide 37.
  • HCI in dioxane may be used as an appropriate medium for the hydroylsis of the ester and the methoxy group present in derivatives 39 to yield compounds of Formula I.
  • Another subset of compounds of Formula I may be prepared by hydrolysis of the ester group and the methoxy group of urea derivatives 40, as schown in scheme 9.
  • HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • Urea derivatives 40 may be prepared from amines 10 by reaction with an appropriate isocyanide, which could be prepared in-situ by reaction of a carboxylic acid with diphenyl phosphorazidate (DPPA), in the presence of a base.
  • An alternative synthesis of urea derivatives 40 may be a reaction of amines 10 with an appropriate amine either in the presence of p-nitrophenylchloroformate or in the presence of phosgene.
  • Scheme 9 Synthesis of compounds of Formula I
  • Compounds of Formula ID' and ID" may be prepared by hydrolysis of the ester group and the methoxy group of heterocyclic derivatives 44 and 45, as schown in scheme 10.
  • Either trimethylsilyl iodide which can be prepared in situ using sodium iodide and trimethylsilyl chloride or HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • the heterocyclic derivatives 44 and 45 respectively, may be prepared from the carboxylic acid 43 by reaction with an appropriate hydrazide or N- hydroxyimidamide in the presence of a condensing agent (e.g. TBTU, CDI) and subsequent treatment with a dehydrating agent (e.g. POCI3).
  • Carboxylic acid 43 may be prepared starting from bromide 41 which may be reacted with allyl tributyltin in presence of a palladium catalyst to yield intermediate 42 which in turn may be reacted with sodium periodate.
  • Another subset of compounds of Formula ID'" may be prepared by hydrolysis of the ester group and the methoxy group of heterocyclic derivatives 46, as shown in scheme 11.
  • HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • Heterocyclic intermediates 46 may be prepared via Stille coupling of an appropriate tributyl stannane with bromides 41 in presence of a palladium catalyst.
  • R 2 /R 3 combine to form 5-membered heteroaromatic ring [001 1 1 ] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.
  • the reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization. Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures. Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.
  • Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
  • hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and like acids.
  • the salt may be converted to the free base by treatment with alkali.
  • Compounds of Formula I can form pharmaceutically acceptable salts with various basic compounds. Suitable base salts include, but are not limited to, ammonium, potassium, sodium, and choline salts.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use.
  • parenteral including intravenous or subcutaneous
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed.
  • Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
  • excipient applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered.
  • Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions.
  • These excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • A.R. Gennaro, 20 th Edition describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".
  • the excipients may also be combinations of solids and liquids.
  • the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount.
  • Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
  • the compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g. , buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route.
  • the compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 th Edition).
  • the orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
  • the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g.
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate
  • lubricants e.g.
  • the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g. , potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.
  • the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g.
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
  • preservatives ⁇ e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • the tablets may be coated by methods well known in the art.
  • the compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • the compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the instant compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas ⁇ e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
  • a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
  • the appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
  • Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50.
  • Compositions that exhibit large therapeutic indices are preferred.
  • the method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
  • Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
  • compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
  • DMF is defined as ⁇ , ⁇ -dimethylformamide
  • HCI hydrochloric acid
  • DMSO dimethyl sulfoxide
  • NH OH ammonium hydroxide solution
  • TAI tetrabutylammonium iodide
  • TAA trifluoroacetic acid
  • TAA triethylamine
  • MeCN acetonitrile
  • AcOH as acetic acid
  • TLC thin layer chromatography
  • HBT as 1 -hydroxybenzotriazole
  • EDC as 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EtOH as ethanol and "MeOH” as ethanol
  • the title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-trifluoromethoxy- phenyl)-acetic acid gives 6-chloro-2-methoxy-8- ⁇ [2-(2-trifluoromethoxy-phenyl)- acetylamino]-methyl ⁇ -quinoline-3-carboxylic acid methyl ester in 45% yield.
  • the product consists of a mixture - 6-chloro-2-methoxy-8-(1 -oxo-1 ,3- dihydro-isoindol-2-ylmethyl)-quinoline-3-carboxylic acid and its methyl ester (10 :90). Solvent is removed under reduced pressure and the residue is used in the next step without additional purification.

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Abstract

The invention relates to 2(1H)-quinolinone derivatives of formula (I) as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are glycine B antagonists and are therefore useful for the control and prevention of various disorders, including neurological disorders.

Description

GLYCINE B ANTAGONISTS
FIELD OF THE INVENTION
[0001 ] The present invention relates to novel 2(1 H)-quinolinone derivatives which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.
BACKGROUND OF THE INVENTION
[0002] Glutamate is a major excitatory transmitter in the central nervous system and it has become clear in recent years that it is also very important in the peripheral nervous system (PNS). Glutamate is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.
[0003] Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation. In the case of the NMDA receptor, the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time. Thus, glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
[0004] Therefore, glycine B antagonists, may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example neuropathy induced by nociception, inflammation, ischemia, viral infection (herpes zoster virus, HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), complex regional pain syndrome, carpal tunnel syndrome, arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
[0005] Blood-brain barrier impermeable glycine B antagonists, which are restricted to action in the PNS, may be particularly useful since such antagonists do not exhibit CNS side effects.
[0006] Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, chronic low back pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
[0007] A number of 2-(1 H)-quinolinone compounds, including 2-oxoquinoline-3- carboxylic acid derivatives, have been previously described.
[0008] A class of 1 ,2-dihydro-4-(optionally substituted)-amino-2-oxoquinoline-3- carboxylic acids, esters and amide derivatives of formula (1 )
Figure imgf000007_0001
wherein R1 is e. g., hydrogen, alkyl, allyl or propargyl; R2 is e.g, hydroxy, alkoxy, alkylamino, dialylamino etc.; R3 and R4 are, independently, hydrogen or alkyl; and R5 is hydrogen, chlorine or bromine are disclosed in US Patent No. 4,284,768 as antisecretory agents useful in the treatment of peptic ulcer disease.
[0009] International publication No. WO 93/10783 discloses 2-oxoquinolines of general formula (2)
Figure imgf000007_0002
wherein R represents e.g., hydrogen atom, an amino group, a carboxy or C2-6 alkoxycarbonyl group, R1 is a group of part formula (i) wherein n is zero or 1 , preferably zero; T represents e.g, cyano, carboxy or five- or six-membered heteroaromatic ring; R2, R3, R4 and R5 represent e.g, hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, nitro, as selective non-competitive antagonists on NMDA receptors and/or antagonists of AMPA receptors.
[0010] A method for the synthesis of 1 ,2-dihydro-2-oxoquinoline-3-carboxylic acids of formula (3)
Figure imgf000007_0003
wherein R1, R2 and R3 areindependently, hydrogen, halogen, alkyl, nitro, cyano or aminosulfonyl, is disclosed in US Patent No. 5,536,709.
A process for preparing the compounds of formula (4)
Figure imgf000008_0001
wherein R1, R2 and R3 are as described above, which are useful (by blocking AMPA/kainate receptor) as inhibitors of the pathological phenomena associated with hyperactivation of the excitating amino acid dependant pathways of neurotransmission, from compounds of formula (3) is also disclosed.
[001 1 ] 6,7-Dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (5)
Figure imgf000008_0002
has been reported to display antagonist activity at NMDA (glycine B) receptor with IC50 0.81 μΜ however with low selectivity over the AMPA/kainate receptor (J. Med. Chem. 1996, 39, 197).
[0012] 2-Oxoquinoline compounds, including 2-oxoquinoline-3-carboxylic acid derivatives, of general formula (
Figure imgf000008_0003
wherein W represents e.g, -O-, -S(O)r, -CR3R4-, -NR5-, (where R3, R4 and R5 represent hydrogen or alkyi); R1 represents e.g, hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl; R2 represents e.g, hydrogen, alkyi, -OR6 (where R6 represents hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), -NR7R8 (where R7 and R8 independently represent hydrogen, alkyi, alkenyl, alkynyl, acyl, aryl, etc.); Ra represents hydrogen or alkyi; X represents e.g, -COORb, -CONH2, -CONRc-Alka (where Rb and Rc represent hydrogen or alkyi) and more complex groups; have been disclosed in US Patent No. 6,509,352 as acting on cannabinoid receptors, particularly on peripheral type cannabinoid receptors.
[0013] Compounds represented by formula (7)
Figure imgf000009_0001
wherein A denotes a single bond or methylene, Y denotes a nitrogen atom or =CH-, V denotes a single bond or methylene, T denotes a hydroxyl group, amino group, alkoxycarbonyl, carboxyl, R denotes a nitro group or halogen atom, and R1 denotes a hydroxyl group or lower alkoxy group; are disclosed in US patent publication US 6562839 (May. 13, 2003) as antagonists against excitatory amino acid receptors effective for the therapy of disorder of cerebral nerve cells, in particular, selective antagonists against AMPA receptors.
THE PRESENT INVENTION
[0014] We have determined that certain 2(1 H)-quinolinone derivatives are glycine B antagonists. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve excitotoxicity and malfunctioning of glutamatergic neurotransmission. These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
OBJECTS OF THE INVENTION
[0015] It is an object of the present invention to provide novel pharmaceutical compounds which are glycine B antagonists and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable conditions, associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission by employing a compound of the invention or a pharmaceutical composition containing the same. [0016] An additional object of the invention is the provision of processes for producing the 2(1 H)-quinolinone derivatives.
[0017] Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled in the art.
SUMMARY OF THE INVENTION
[0018] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words:
A compound selected from those of Formula I:
Figure imgf000010_0001
wherein n = 0, 1 or 2;
X1 represents halogen, nitro, or C-i-6alkyl;
X2 represents hydrogen, halogen, nitro, trifluoromethyl, Chalky! or C-i-6alkoxy; R represents hydrogen or Ci-6alkyl;
R1 and R2, which may be the same or different, each independently represent hydrogen, C-i-6alkyl, aryl, a ryl -Chalky!, or heteroaryl-C-i-6alkyl, or R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group (C=O);
R3 represents hydrogen, C-i-6alkyl, C3-6alkenyl, Ci-6alkylsulfonyl, aryl, heteroaryl, cyclo- C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl -Chalky! or heteroaryl-C-i-6alkyl;
R4 represents hydrogen, C-i-6alkyl, C3-6alkenyl, Ci-6alkylsulfonyl, aryl, heteroaryl, cyclo- C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, hydroxy-C-i-6alkyl, carbamoyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl or C(O)-R5; wherein R5 represents COOH, Ci-6alkyl, cyclo-C3-i2alkyl optionally condensed to a benzene ring, cyclo-C3-i2alkyl-Ci-6alkyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, amino- Ci-6alkyl, aryl, heteroaryl, heteroaryl-heteroaryl, heteroaryl-aryl, heterocyclyl, aryl- Ci-6alkyl, wherein the alkyl portion may be optionally substituted by trifluoromethyl, amino, hydroxy, C-i-6alkoxy, aryl-C-i-6alkoxy, phenyl, heteroaryl or heterocyclyl, heteroaryl-Ci-6alkyl, arylamino, heteroarylamino, arylCi-6alkylamino, arylcarbonyl, or aryl-Ci-6alkylaminocarbonylCi-6alkyl; or R3 and R4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, Chalky!, C-i^alkoxy, hydroxy-C-i-6alkyl, Ci-6alkoxy-Ci-6alkyl, COOH, CONH2, Ci-6alkylaminocarbonyl, aryl, heteroaryl, aryl -Chalky!, wherein the alkyl portion may be optionally substituted by hydroxy, heteroaryl-Ci_6alkyl, wherein the alkyl portion may be optionally substituted by hydroxy, heterocyclyl-C-i-6alkyl, C-i-6alkylcarbonyl, and cyclo-C3-i2alkyl; or R2 and R3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring, which may be optionally fused to a benzene ring, in which case R1 and R4 are not present, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen; wherein the heteroaromatic ring may be optionally substituted by aryl- C-i-6alkyl, and wherein representative examples of such rings include oxazole, thiazole, imidazole, pyrazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole and tetrazole; wherein the term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, trifluoromethyl, Chalky!, phenyl, heteroaryl, heterocyclyl, hydroxy-C-i-6alkyl, carboxy- Ci-6alkyl, carbamoyl-Ci-6alkyl, heteroaryl-Ci-6alkyl, amino-Ci-6alkyl, Ci-6alkylcarbonyl, Ci-6alkylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, hydroxy- Ci-6alkylaminocarbonyl; C-i^alkoxy, hydroxy-Ci^alkoxy, trifluoromethoxy, phenoxy, Ci-6alkylamino, cyclo-Cs-^alkylamino, heteroarylamino, hydroxy-Ci-6alkylamino, Ci-6alkoxyalkylamino, di-(Ci.6alkyl)amino, acylamino, Ci-6alkylsulfonylamino, C-i^alkylaminocarbonyl-C-i^alkyl, cyclo-Cs-^alkylaminocarbonyl-C-i^alkyl, di- (Ci-6alkyl)aminocarbonyl-Ci-6alkyl, and Ci^alkylenedioxy; and the term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, trifluoromethyl, Chalky!, phenyl, imidazolyl, pyrazolyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, heteroaryl-Ci-6alkyl, amino-Ci-6alkyl, heterocyclyl-Ci-6alkyl, Ci-6alkylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, hydroxy-Ci-6alkylaminocarbonyl; Ci-6alkoxy, hydroxy-Ci-6alkoxy, Ci-6alkylamino, cyclo-C3-i2alkylamino, heteroarylamino, hydroxy-Ci-6alkylamino, Ci-6alkoxyalkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylsulfonylamino, Ci-6alkylaminocarbonyl-Ci-6alkyl, cyclo-Cs-^alkylaminocarbonyl- Ci-6alkyl, di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl, and Ci^alkylenedioxy; optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts and hydrates and solvates thereof.
[0019] Such a compound of Formula I, wherein n is 0 and R1 and R2 each represent hydrogen.
[0020] Such a compound of Formula I, wherein n is 1 and R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group (C=O).
[0021 ] Such a compound of Formula I, wherein n is 0, R1 represents Chalky! (e.g., methyl), and R2 represents hydrogen.
[0022] Such a compound of Formula I, wherein R4 represents hydrogen, Chalky!, aryl- Ci-6alkyl, heteroaryl-Ci-6alkyl, or heteroaryl.
[0023] Such a compound of Formula I, wherein R4 represents methyl, benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, pyridinyl-methyl, pyridinyl optionally substituted by one or more substituents selected from nitro, Ci-6alkylcarbonylamino, and CONH2, benzoxazole, or benzothiazole.
[0024] Such a compound of Formula I, wherein R4 represents C(O)-R5.
[0025] Such a compound of Formula I, wherein R5 represents COOH, carboxymethyl or aminomethyl. [0026] Such a compound of Formula I, wherein R5 represents aryl, heteroaryl, aryl- C-i-6alkyl, heteroaryl-C-i-6alkyl, arylcarbonyl, arylamino, heteroarylamino, or aryl- Ci-6alkylamino.
[0027] Such a compound of Formula I, wherein the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, Ci_6alkoxy, nitro, C-|.6alkylenedioxy, hydroxyl, Chalky!, trifluoromethyl, trifluoromethoxy, phenyoxy, amino, di-Ci-6alkylamino, tetrazolyl, imidazolyl, and triazolyl.
[0028] Such a compound of Formula I, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and imidazopyridazinyl.
[0029] Such a compound of Formula I, wherein R5 represents cyclo-Cs-^alkyl optionally substituted by aryl or heteroaryl, cyclo-Cs-^alkyl-C-i^alkyl, or heterocyclyl optionally substituted by aryl.
[0030] Such a compound of Formula I, wherein R5 represents adamantyl, adamantyl- methyl, cyclohexyl substituted by aryl, cyclopentyl subsituted by aryl, cyclobutyl optionally substituted by aryl, cyclopropyl optionally substituted by aryl or heteroaryl, piperidinyl substituted by aryl, isochromanyl, or tetrahydroisoquinolinyl.
[0031 ] Such a compound of Formula I, wherein R3 represents hydrogen or Chalky!.
[0032] Such a compound of Formula I, wherein R3 and R4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, Chalky!, cyclo- C3-i2alkyl, C-i-6alkoxy, hydroxy-C-i-6alkyl, C-i^alkoxy-C-i^alkyl, C-i-6alkylcarbonyl, COOH, CONH2, Ci-6alkylaminocarbonyl, aryl, heteroaryl, aryl -Chalky!, wherein the alkyl portion may be optionally substituted by hydroxy, heteroaryl-C-i-6alkyl, wherein the alkyl portion may be optionally substituted by hydroxy, and heterocyclyl-Ci-6alkyl.
[0033] Such a compound of Formula I, wherein R3 and R4 together with the nitrogen atom to which they are attached represent triazolyl optionally substituted by Chalky!, aryl, heteroaryl, cyclo-C3-i2alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, pyrrolyl optionally substituted by C-i-6alkylcarbonyl, aryl -Chalky!, or heteroaryl-C-i-6alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
[0034] Such a compound of Formula I, wherein R2 and R3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring selected from oxazole, thiazole, imidazole, pyrazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and benzothizaolyl, which may be optionally subsituted by aryl-C-i-6alkyl.
[0035] Such a compound of Formula I, wherein X1 represents halogen and X2 represents hydrogen or halogen.
[0036] Such a compound of Formula I, wherein X1 represents chloro and X2 represents hydrogen, fluoro, chloro, or bromo.
[0037] Such a compound of Formula I, wherein X1 represents chloro or bromo and X2 represents hydrogen.
[0038] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA:
Figure imgf000015_0001
IA wherein X1, X2, R3, and R5 are as defined above for Formula I.
[0039] Such a compound of Formula IA, wherein X1 represents halogen X2 represents hydrogen or halogen.
[0040] Such a compound of Formula IA, wherein X1 represents chloro and X2
represents hydrogen, fluoro, chloro, or bromo.
[0041] Such a compound of Formula IA, wherein X1 represents chloro or bromo and X2 represents hydrogen.
[0042] Such a compound of Formula IA, wherein R3 represents hydrogen or methyl.
[0043] Such a compound of Formula IA, wherein R5 represents COOH, Chalky!, hydroxy-C-i-6alkyl, carboxy-C-i-6alkyl, amino-Ci-6alkyl, aryl, heteroaryl, aryl-C-i-6alkyl, heteroaryl-C-i-6alkyl, arylcarbonyl, cyclo-Cs-^alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, or heterocyclyl.
[0044] Such a compound of Formula IA, wherein R5 represents aryl, heteroaryl, aryl- C-|.6alkyl, heteroaryl-Ci_6alkyl, arylamino, heteroarylamino, or aryl-Ci-6alkylamino, wherein the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, C-i^alkoxy, nitro, Ci^alkylenedioxy, hydroxyl, C-i- 6alkyl, trifluoromethyl, trifluoromethoxy, phenyoxy, amino, di-Ci-6alkylamino, tetrazolyl, imidazolyl, and triazolyl.
[0045] Such a compound of Formula IA, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and imidazopyridazinyl. [0046] Such a compound of Formula IA, wherein R5 represents cyclo-Cs-^alkyl optionally substituted by aryl or heteroaryl, cyclo-C3-i2alkyl-Ci-6alkyl, or heterocyclyl optionally substituted by aryl.
[0047] Such a compound of Formula IA, wherein R5 represents adamantyl, adamantyl- methyl, cyclohexyl substitued by aryl, cyclopentyl subsituted by aryl, cyclobutyl optionally substituted by aryl, cyclopropyl optionally substituted by aryl or heteroaryl, piperidinyl substituted by aryl, isochromanyl, or tetrahydroisoquinolinyl.
[0048] A further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IB:
Figure imgf000017_0001
wherein X1, X2, R3, and R5 are as defined above for Formula I.
[0049] Such a compound of Formula IB, wherein X1 represents halogen and X2 represents hydrogen or halogen.
[0050] Such a compound of Formula IB, wherein X1 represents chloro and X2
represents hydrogen, fluoro, chloro, or bromo.
[0051 ] Such a compound of Formula IB, wherein R3 represents hydrogen or methyl.
[0052] Such a compound of Formula IB, wherein R4 represents Ci-6alkyl, C3-6alkenyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl -Chalky!, heteroaryl- C-i-6alkyl, hydroxy-Ci^alkyl, carbamoyl-Ci-6alkyl or Ci-6alkoxy-Ci-6alkyl. [0053] Such a compound of Formula IB, wherein R4 represents benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, or pyridinyl- methyl.
[0054] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
Figure imgf000018_0001
wherein X1, X2, R1, R3, and R4 are as defined above for Formula I.
[0055] Such a compound of Formula IC, wherein X1 represents halogen and X2 represents hydrogen or halogen.
[0056] Such a compound of Formula IC, wherein X1 represents chloro and X2
represents hydrogen, fluoro, chloro, or bromo.
[0057] Such a compound of Formula IC, wherein R1 represents hydrogen or Chalky! (e.g., methyl).
[0058] Such a compound of Formula IC, wherein R3 represents hydrogen.
[0059] Such a compound of Formula IC, wherein R4 represents hydrogen, Chalky!, C3-6alkenyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-Cs-^alkyl-C-i^alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, hydroxy-Ci-6alkyl, carbamoyl-Ci-6alkyl or C-i^alkoxy-C-i^alkyl.
[0060] Such a compound of Formula IC, wherein R4 represents methyl, benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, pyridinyl-methyl, pyridinyl optionally substituted by one or more substituents selected from nitro, Ci-6alkylcarbonylamino, and CONH2, benzoxazole, or benzothiazole.
[0061 ] Such a compound of Formula IC, wherein R3 and R4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, C-i-6alkyl, cyclo-C3-i2alkyl, C-i-6alkoxy, hydroxy-C-i-6alkyl, Ci-6alkoxy-Ci-6alkyl, C-i-6alkylcarbonyl, COOH, CONH2, Ci-6alkylaminocarbonyl, aryl, heteroaryl, aryl -Chalky!, wherein the alkyl portion may be optionally substituted by hydroxy, heteroaryl-C-i-6alkyl, wherein the alkyl portion may be optionally substituted by hydroxy, and heterocyclyl-Ci-6alkyl.
[0062] Such a compound of Formula IC, wherein R3 and R4 together with the nitrogen atom to which they are attached represent triazolyl optionally substituted by Chalky!, aryl, heteroaryl, cyclo-C3-i2alkyl, aryl-C-i-6alkyl, or heteroaryl-Ci-6alkyl, pyrrolyl optionally substituted by C-i-6alkylcarbonyl, aryl -Chalky!, or heteroaryl-C-i-6alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
[0063] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula I
Figure imgf000019_0001
ID wherein R2 and R3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring which may be optionally fused to a benzene ring, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen; wherein the heteroaromatic ring may be optionally substituted by aryl-C-i-6alkyl, and wherein X1 and X2 are as defined above for Formula I.
[0064] Such a compound of Formula ID, wherein X1 represents halogen and X2 represents hydrogen or halogen.
[0065] Such a compound of Formula ID, wherein X1 represents chloro and X2
represents hydrogen.
[0066] Such a compound of Formula ID, wherein R2 and R3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered
heteroaromatic ring selected from oxazole, thiazole, imidazole, pyrazole, 1 ,2,4- oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and benzothizaolyl, which may be optionally subsituted by aryl-C-i-6alkyl.
[0067] Such a compound of Formula ID, wherein R2 and R3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered
heteroaromatic ring selected from 1 ,2,4-oxadiazole, which may be optionally substituted by subsituted by aryl-Ci-6alkyl, 1 ,3,4-oxadiazole, which may be optionally substituted by subsituted by aryl-Ci_6alkyl, and benzothiazolyl.
[0068] Specific compounds of Formula I within the present invention include but are not limited to:
8-Aminomethyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
8-[(2-Carboxy-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-[(2-thiophen-3-yl-acetylamino)-methyl]-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(thiophene-2-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-{[2-(3-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(thiophene-3-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-nitrophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(3-phenyl-propionylamino)-methyl]-1 ,2-dihydroquinoline-3-carboxylic acid,
8-{[(Benzofuran-2-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-{[(Benzo[b]thiophene-2-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-[(oxalyl-amino)-methyl]-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 8-(Benzoylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-{[(pyridine-3-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridine-4-carbonyl)-amino]-methyl}-1 ,2 dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(pyridin-3-yl)-acetylamino]-methyl}-1 ,2 dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-acetylamino]-methyl}-1 ,2 dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridine-2-carbonyl)-amino]-methyl}-1 ,2 dihydroquinoline-3- carboxylic acid,
6-Chloro-8-[(2-chloro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid, 6-Chloro-8-[(2-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-[(3-chloro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[(2,3-dihydro-benzo[1 ,4]dioxine-6-carbonyl)-amino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
8-[(2-Bromo-benzoylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-[(3-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(quinoline-3-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-(diphenylacetylamino-methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-8-[(4-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-[(4-fluoro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-[(3-fluoro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-o-tolyl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-pyrazin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-trifluoromethoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-naphthalen-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-hydroxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid, 6-Chloro-2-oxo-8-[(4-phenyl-butyrylamino)-methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(4-chloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-{[2-(2-Bromo-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(quinoline-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(4-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(thiazole-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(thiazole-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(thiazole-5-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[(3,4-dihydro-2H-benzo[b][1 ,4]dioxepine-7-carbonyl)-amino]-methyl}-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid,
8-{[(Benzothiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[(Benzothiazole-6-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid, 6-Chloro-8-{[2-(2,3-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-trifluoromethyl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(5-nitro-pyridin-2-ylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxyl acid,
6-Chloro-2-oxo-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-(1 -oxo-1 ,3-dihydro-isoindol-2-ylmethyl)-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(4-fluoro-2-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[(2-methyl-thiazole-4-carbonyl)-amino]-methyl}-2-oxo-1 ,2-dihydro-quinolin 3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(3-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline- carboxylic acid,
6-Chloro-2-oxo-8-{[(oxazole-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[(2-Amino-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-[(2-Amino-3-phenyl-propionylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3 carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline- carboxylic acid,
6-Chloro-2-oxo-8-{[(quinoline-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[2-(4-tert-Butyl-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-pyrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoli 3-carboxylic acid, 6-Chloro-2-oxo-8-{[(pyridazine-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[(Benzo[1 ,2,5]oxadiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyrimidine-5-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[2-(3-Amino-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-methyl-thiazol-4-yl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
8-[(3-Acetylamino-pyridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(pyrazine-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-iodo-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-(piperidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(pyrrolidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-pyridin-4-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(2-thiazol-5-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic,
8-{[2-(4-Amino-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[(Adamantane-1 -carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[(2-Adamantan-1 -yl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid, 8-((1 H-1 ,2,4-Triazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 8-((Benzyl(methyl)amino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-8-{[2-(2-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
6-Chloro-8-{[(6-imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-[1 ,2,4]triazol-4-yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(3-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-((1 H-pyrazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-8-({[1 -(2-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[(5-Carbamoyl-pyridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-({[1 -(2-chloro-6-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-thiazol-4-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[((S)-2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[((R)-2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,4,6-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-(pyridin-2-ylaminomethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid, 6,7-Dichloro-8-{[2-(2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-oxo-2-phenyl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid, 6-Chloro-8-{[2-(2-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,3,6-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[2-(3-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6,7-Dichloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-{[(6-Bromo-pyridine-3-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[(2-imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-(2-Acetyl-pyrrol-1 -ylmethyl)-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid, 8-[(3-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(3-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-[((S)-2-Amino-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(2-chloro-benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-(Benzylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-methylaminomethyl-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-[(2,6-difluoro-benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid, 8-[(2-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(1 -phenyl-cyclopentanecarbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-({[1 -(2-fluoro-phenyl)-cyclopropanecarbonyl]-amino}-methyl)-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
8-[(4-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-[(2-methoxy-2-phenyl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-phenyl)-2-methyl-propionylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((4-(1 -hydroxycyclohexyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-[4-(4-fluoro-phenyl)-[1 ,2,3]triazol-1 -ylmethyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(1 -phenyl-cyclopropanecarbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-methyl-2-phenyl-propionylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(1 -phenyl-cyclobutanecarbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(4-phenyl-piperidine-4-carbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(2-pyrazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(4-pyrazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid, 6-Chloro-8-((4-(3-(3,3-dimethyl-2-oxoazetidin-1 -yl)phenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-
2- OXO-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-pyrazol-1 -ylmethyl-1 ,2-dihydro-quinoline-3-carboxylic acid, 6,7-Dichloro-2-oxo-8-[1 ,2,4]triazol-1 -ylmethyl-1 ,2-dihydro-quinoline-3-carboxylic acid, 8-[((R)-2-Amino-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(2-imidazol-1 -yl-2-phenyl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-
3- carboxylic acid,
6-Chloro-8-{[2-(2,5-dimethoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(3-phenyl-ureido)-methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid, 6,7-Dichloro-2-oxo-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-2-pyrazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6,7-Dichloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-[(2-pyridin-3-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-(3-phenyl-pyrazol-1 -ylmethyl)-1 ,2-dihydro-quinoline-3-carboxylic, 6,7-Dichloro-2-oxo-8-[(2-pyridin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[3-(4-Bromo-phenyl)-ureidomethyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-[(2-pyrimidin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid, 8-Aminomethyl-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Bromo-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Bromo-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3-carboxylic acid, 8-((1 H-1 ,2,3-triazol-1 -yl)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-((4-benzyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-(3-hydroxyphenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-phenyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
(R)-6-chloro-8-((4-(hydroxy(phenyl)methyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
(S)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
(6-chloro-2-oxo-8-((4-(pyridin-2-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-2-oxo-8-((4-(2-(piperazin-1 -yl)ethyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(4-methoxyphenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(m-tolyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-isobutyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-(1 -methyl-1 H-imidazol-5-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(pyridin-4-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-2-oxo-8-((4-(pyridin-3-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid, 6-chloro-8-((4-(2-methoxyphenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(p-tolyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((4-(tert-butyl)-1 H-1 ,2,3-triazoM -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-cyclopropyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-(3-fluorophenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((4-(3-methoxyphenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(2-fluorobenzyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((4-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2,6-difluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((1 -(pyridin-3-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((3-(pyridin-2-yl)ureido)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid, 6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, 6-chloro-2-oxo-8-((4-(pyridin-2-ylmethyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((3-(pyridin-3-yl)ureido)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid, 6-chloro-2-oxo-8-((1 -(pyridin-2-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-2-oxo-8-((4-(thiazol-2-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2,6-difluorobenzyl)ureido)methyl)-2 -oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-dichloro-8-((3-methyl-1 H-1 ,2,4-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-dichloro-8-(((2-chloro-6-fluorobenzyl)amino)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-2-oxo-8-((3-(pyridin-2-ylmethyl)-1 H-pyrazol-1 -yl)methyl)-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((5-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((3-(2,6-difluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(R)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxyl acid,
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxyl acid,
8-(2-aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
8-carbamoyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(R)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
(S)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((pyrazine-2-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-((thiazole-4-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(1 H-tetrazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(4-Acetylpiperazin-1 -yl)-2-(2-fluorophenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2 dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-methylthiazole-4-carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline- carboxylic acid,
6,7-Dichloro-2-oxo-8-((thiazole-2-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(3-(1 H-pyrazol-1 -yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-hydroxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((N-methyl-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-8-((2-(3-chloropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(4-(1 H-imidazol-1 -yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-ethoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-(cyclopropanecarboxamidomethyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((2-(thiazol-2-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
8-((2-(2H-tetrazol-2-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2-fluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Bromo-8-((2-(2,6-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Bromo-8-((2-(2-chloro-6-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(2,6-difluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((frans-2-phenylcyclopropanecarboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-((2-(pyrimidin-2-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-7-fluoro-8-((2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2,6-difluorophenyl)acetamido)methyl)-7-fluoro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6- Chloro-7-fluoro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
7- Bromo-6-chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2,4-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-((2-phenyl-2-propoxyacetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
(S)-6-Chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
(R)-6-Chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8- [(2-Benzyloxy-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-((2-Butoxy-2-phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(3-fluoropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((3-(Benzylamino)-3-oxopropanamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-((2-(2,3,5-trifluorophenyl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(naphthalen-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-(1 -(2-methoxy-2-phenylacetamido)ethyl)-2 -oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-(1 -(2-(2,6-difluorophenyl)acetamido)ethyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-8-(1 -(2-(2-fluorophenyl)-2-methoxyacetamido)ethyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-(1 -(2-ethoxy-2-phenylacetamido)ethyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(4-ethoxy-2,6-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-morpholino-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2-ethoxyphenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2,6-difluoro-3-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((isochroman-1 -carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(3-ethoxy-2,4-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-Dichloro-8-((2-ethoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2,3-difluoro-6-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-ethoxy-2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(4-methoxypiperidin-1 -yl)-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-fluoro-6-(trifluoromethyl)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(3-oxo-3-(phenylamino)propyl)-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-8-((1 -(3-chloropyridin-2-yl)-1 H-pyrrole-2-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, 6-Chloro-8-((6-chloroimidazo[1 ,2-b]pyridazine-2-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((5-(3-chlorophenyl)oxazole-4-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(4-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((imidazo[1 ,2-a]pyridine-3-carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(3-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2-fluoro-5-methylphenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
(R)-6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-3-carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((2-(piperazin-1 -yl)-2-(p-tolyl)acetamido)methyl)-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((3-(4-methylpiperazin-1 -yl)-2-phenylpropanamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((1 ,2,3,4-tetrahydronaphthalene-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(5-Bromopyridin-3-yl)acetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(2-fluoro-6-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(1 H-1 ,2,3-triazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
8-((2-(2H-1 ,2,3-triazol-2-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6,7-Dichloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, 8-((2-(2-(1 H-tetrazol-1 -yl)phenyl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(1 -methyl-1 H-imidazol-4-yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(4-Aminopiperidin-1 -yl)-2-phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(6-chloro-2-fluoro-3-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(3-chloro-2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
(R)-6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(S)-6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-fluoro-5-(trifluoromethyl)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((1 -(pyridin-3-yl)cyclopropanecarboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-Dichloro-8-((2-(3-chloropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-{[2-(5-Amino-2-fluoro-phenyl)-acetylamino]methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-(Acetamidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((3-methoxy-2-phenylpropanamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-((2-(thiazol-5-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-8-((2-(3-chlorophenyl)cyclopropanecarboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((4-oxo-1 ,2,3,4-tetrahydronaphthalene-2-carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2,6-difluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-ethoxy-2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(S)-6-Chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
(R)-6-chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2,5-dimethyl-1 -((1 -methylpyrrolidin-3-yl)methyl)-1 H-pyrrole-3- carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((5-ethyl-1 -phenyl-1 H-1 ,2,4-triazole-3-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((2-(thiazol-4-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-(cyclobutanecarboxamidomethyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-2-piperazin-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(4-phenyl-imidazol-1 -ylmethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,5-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,4,5-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid, 6-Chloro-8-{1 -[2-(2-fluoro-phenyl)-acetylamino]-ethyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-2-ethoxy-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{1 -[2-(2-chloro-phenyl)-2-methoxy-acetylamino]-ethyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-chloro-phenyl)-2-ethoxy-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-4-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,3,4-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[2-(3-ethoxy-2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,3-difluoro-4-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(4-ethoxy-2,3-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-3-trifluoromethyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-4-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-3-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(4-chloro-2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-chloro-6-fluoro-3-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(6-chloro-2-fluoro-3-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-4-trifluoromethyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid, and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts, hydrates, and solvates thereof.
[0069] In a further aspect, the invention relates to a compound of Formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use in therapy.
[0070] Moreover, the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.
[0071 ] Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
[0072] Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids. [0073] Further, the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.
[0074] Further, the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission. Such a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.
[0075] Moreover, the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.
[0076] A further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.
[0077] The compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds. Examples of suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.
[0078] Further, the invention relates to a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles.
DETAILED DESCRIPTION OF THE INVENTION
[0079] For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj_j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, Chalky! refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
[0080] As used herein and as far as it is not defined in a different manner elsewhere in this description or the accompanying claims, the term "Ci-6alkyl" represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms, examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, neopentyl, n- hexyl, 2-hexyl, 3-hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, and 3-methylpentyl.
[0081 ] The term "C3-6alkenyl" represents straight or branched chain alkenyl groups having 3, 4, 5 or 6 carbon atoms.
[0082] The term "cycloCs-^alkyl" represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, wherein the "cycloC3-i2alkyl"-ring is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents selected from halogen, hydroxy, oxo, aryl, and heteroaryl.
[0083] The term "Ci-6alkoxy" represents straight or branched chain -O-Ci_6alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, terf-butoxy.
[0084] The term "Ci-6alkylamino" refers to an amino moiety in which the nitrogen atom of the amino group is substituted with a Chalky! group as defined above. Examples of such alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, te/?-butylamino.
[0085] The term "di-(Ci-6alkyl)amino" refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two Chalky! groups, which may be the same or different, as defined above. Examples of di-Ci-6alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino.
[0086] The term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, trifluoromethyl, Chalky!, phenyl, heteroaryl, heterocyclyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, heteroaryl-Ci-6alkyl, amino- Ci-6alkyl, Ci-6alkylcarbonyl, Ci-6alkylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, hydroxy-Ci-6alkylaminocarbonyl; C-i^alkoxy, hydroxy- C-i-6alkoxy, trifluoromethoxy, phenoxy, Ci-6alkylamino, cyclo-Cs-^alkylamino, heteroarylamino, hydroxy-Ci-6alkylamino, Ci-6alkoxyalkylamino, di-(Ci-6alkyl)amino, acylamino, Ci-6alkylsulfonylamino, C-i-ealkylaminocarbonyl-C-i-ealkyl, cyclo- C3-i2alkylaminocarbonyl-Ci-6alkyl, di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl, and C-i-6alkylenedioxy;
[0087] The term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents (e.g., 1, 2, 3, 4, or 5) selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH2, trifluoromethyl, Ci-6alkyl, phenyl, imidazolyl, pyrazolyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, carbamoyl- C-i-6alkyl, heteroaryl-C-i-6alkyl, amino-Ci-6alkyl, heterocyclyl-Ci-6alkyl,
Ci-6alkylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci-6alkyl)aminocarbonyl, hydroxy- Ci-6alkylaminocarbonyl; Ci-6alkoxy, hydroxy-Ci-6alkoxy, Ci-6alkylamino, cyclo- C3-i2alkylamino, heteroarylamino, hydroxy-Ci-6alkylamino, Ci-6alkoxyalkylamino, di- (Ci-6alkyl)amino, acylamino, Ci-6alkylsulfonylamino, Ci-6alkylaminocarbonyl-Ci-6alkyl, cyclo-C3-i2alkylaminocarbonyl-Ci-6alkyl, di-(Ci-6alkyl)aminocarbonyl-Ci-6alkyl, and Ci-6alkylenedioxy;; examples of such heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl.
[0088] The term "acyl" represents C-i-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, carboxy-Ci-6alkylcarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C3-i2alkylcarbonyl, aryl-Ci-6alkylcarbonyl, heteroaryl- Ci_6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
[0089] The term "heterocyclyl" represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1, 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Chalky!, C2-6alkenyl, C-i^alkoxy, amino, hydroxy, nitro, cyano, Ci-6alkoxycarbonyl, Ci-6alkylcarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, Ci-6alkoxyimino, A/-Ci-6alkylaminocarbonyl, Λ/,/V-di- (Ci-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci^alkylenedioxy; examples of such heterocyclyl groups include piperidinyl, morpholinyl, thiomorpholinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, or piperazinyl, wherein the heterocyclic ring or ring system is linked to the group to which it is attached optionally via nitrogen or a carbon atom..
[0090] The term "halogen" represents fluorine, chlorine, bromine and iodine.
[0091 ] The compounds of the present invention are named according to the lUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours, and "rt" for room temperature).
[0092] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs {e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
[0093] In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers {e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
[0094] The term "prodrug" is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug. Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I. Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy and amino groups. Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
[0095] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal {e.g., human). The term "pharmaceutically acceptable" may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
[0096] Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
[0097] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention ecompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein. [0098] Schemes 2-11 describe the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared by procedures described in Scheme 1 or following schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which procedures would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes are as defined below or as in the claims.
Scheme 1 Synthesis of startin materials 8, 9, 10 and 12
Figure imgf000051_0001
[0099] A subset of the compounds of Formula I may be prepared by "click" reaction of azides 14 with an appropriate acetylene derivative 15 in the presence of catalytic amount of copper salt as shown in Scheme 2. Azide 14 may be prepared from corresponding bromide 13 which, in turn, is obtained by hydrolysis of ester 8. [00100] Another subset of the compounds of Formula I may be prepared by reaction of bromides 8 via an in-situ formation of azides and subsequent reaction of the intermediates formed with an appropriate acetylene derivative 15 in the presence of a ruthenium catalyst as shown in Scheme 2 to yield derivatives 31. HCI in dioxane may be used as an appropriate medium for the hydroylsis of the ester and the methoxy group present in derivatives 31 to yield compounds of Formula I.
Scheme 2 Synthesis of compounds of Formula I by "click reaction"
Figure imgf000052_0001
[00101 ] Another subset of the compounds of Formula I may be prepared by alkylation of amine 16 with bromide 8 and cleavage of intermediate ester 17 by such a common reagents as HBr in acetic acid or HCI in dioxane, as shown in Scheme 3. Alternatively, compounds of Formula I may be prepared by direct alkylation of amine 16 with bromide 13. Scheme 3 Synthesis of compounds of Formula I by alkylation of amines with bromides 8 and 13
Figure imgf000053_0001
[00102] Compounds of Formula I may be prepared by condensation of carboxylic acid 20 with amine 16 in the presence of condensing agents commonly used for amide bond formation, as shown in Scheme 4. Carboxylic acid 20 may be synthesized by reaction of bromide 8 with di-tert-butyl malonate, providing triester 18 which is selectively cleaved by trifluoroacetic acid to give monoester 19 which, in turn, is thermally decarboxylated.
Scheme 4 Synthesis of compounds of Formula I by amidation of carboxylic acid
Figure imgf000054_0001
[00103] A subset of the compounds of Formula I may be prepared by carbamoylation of bromide 8 by molybdenum carbonyl amine complex in diglyme [Ren W., Yamane M. J. Org. Chem. 2010, 75, 3017-3020.], as shown in Scheme 5. The procedure may be performed by stepwise preparation of molybdenum pentacarbonyl amine (22) complex or via generation of complex 22 in situ and bromide 8 and tributylamine may be added to the same bulb. Scheme 5 Synthesis of compounds of Formula I by carbamoylation of bromide 8 by molybdenum carbonyl amine complex
Figure imgf000055_0001
I
[00104] Compounds of Formula I may be prepared via functionalization of the amino group of aminoethylquinoline 25 which may be condensed with appropriate carboxylic acid, or may be alkylated, arylated or acylated by haloderivative 26, as shown in Scheme 6. Amine 25 may be prepared by cleavage of N-tert-butoxycarbonyl group of quinoline 24, which, in turn, is synthesized from carboxylic acid 20 under treatment with diphenyl phosphoranylazide.
Scheme 6 Synthesis of compounds of Formula I from carboxylic acid
Figure imgf000056_0001
(X=OH, when R4=Acyl) 27 I
[00105] Compounds of Formula I may be prepared by hydrolysis of the ester group and the methoxy group of quinoline-3-carboxylic acid derivatives 28 and 30, as shown in Scheme 7. HBr in acetic acid or HCI in dioxane may be used as an appropriate medium for such hydrolysis. The quinoline-3-carboxylic acid derivatives 30 may, in turn, be synthesized by reaction of ester 28 with derivative 29, wherein R4 may be alkyl, heteroaryl or acyl and X represents a halogen atom, in the presence of an appropriate base. Inorganic base (e.g., potassium carbonate) or organic base (e.g., triethylamine) may be used.
cheme 7 Synthesis of compounds of Formula I.
Figure imgf000057_0001
(X=OH, when R4=Acyl) (X=OH, when R4=Acyl)
HBr/AcOH
Figure imgf000057_0002
1. R3-NH-R4 (16)
2. Reduction
Figure imgf000057_0003
12
[00106] An alternative synthesis of quinoline-3-carboxylic acid derivatives 30 is via an amide bond formation reaction which involves reaction of amino-derivative 28 with carboxylic acid 29 (Scheme 7) in the presence of a condensing agent (e.g., EDCI with or without HOBT) in an appropriate solvent (e.g., DCM). Quinolines 30 may also be prepared by condensation of carbaldehydes 12 with amines 16 followed by reduction of intermediate imine bond with e. g., sodium borohydride. Quinoline derivatives 28 may, in turn, be prepared from amine 10 by the procedures analogous to the synthesis of quinoline derivatives 30. Thus, amine 10 may be alkylated, heteroarylated or acylated with corresponding halogenide 26 in the presence of an appropriate inorqanic base (e.g., potassium carbonate) or organic base (e.g., triethylamine). Alternatively, quinoline-3-carboxylic acid derivatives 28 may be synthesized by an amide bond formation reaction which involves reaction of amine 10 with carboxylic acid 26 in the presence of condensing agent (e.g., EDCI with or without HOBT) and base (e.g., DMAP and Et.3N) in an appropriate solvent (e.g., DCM). Necessary amines 10 may be prepared by reduction of azides 9, for example, by triphenylphosphazene reaction with water (Scheme 1 ). Azides 9 may, in turn, be prepared by reaction of bromides 8 with sodium azide in an appropriate solvent (e.g., DMF). Bromides 8 are synthesized by bromination of 8-methyl-quinolines 7 with NBS in the presence of dibenzoyi peroxide or AIBN. Bromination of 8-methyl-quinolines 7 with an excess of NBS in the presence of dibenzoyi peroxide or AIBN may be used to obtain dibromides 11. Dibromides 11 may, in turn, be transformed to carbaldehydes 12 in hydrolytic conditions (e.g., calcium carbonate in a mixture of water and dioxane). Esters 7 may be prepared by esterification of carboxylic acids 6 (e.g., in a mixture of thionyl chloride and methanol), which, in turn, may be obtained by reaction of 2-chloroquinolines 5 with a sodium methoxide solution in methanol. Sodium methoxide solution in methanol may be prepared e. g., by reaction of sodium metal or sodium hydride with methanol. Necessary esters of 2-chloro-8-methyl-quinoline-3-carboxylic acids 5 are synthesized by well known procedures from the corresponding anthranilic acids 1 , aminophenylmethyl alcohols 2, and/or aminobenzaldehydes 3 (Scheme 1 ). Thus, aminobenzaldehydes 3 may be condensed with dimethyl malonate in the presence of piperidine to give the methyl ester of 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid 4 which, in turn, may be transformed to 2-chloro-8-methyl-quinoline-3-carboxylic acid 5 by reaction with phosphorous oxychloride in DMF.
[00107] Compounds of Formula I may be prepared by reductive amination of ketone 38 in the presence of 2-Methyl-2-propanesulfinamide, NaBH , and a suitable lewis acid, as shown in scheme 8. Ketone 38 may be synthesized by reaction of amino carboxylic acid 32 with an appropriate reduction agent providing alcohol 33 which is subsequently oxidized to aldehyde 34, which in turn is iodinated to yield intermediate 35. Intermediate 35 may be reacted with dimethyl malonate and POCI3 to yield compound 36 which may be converted to 37 by reaction with sodium hydride and methanol and subsequent treatment with thionylchloride in the presence of methanol. An acetylation in the presence of palladium may be used to prepare ketone 38 starting from iodide 37. HCI in dioxane may be used as an appropriate medium for the hydroylsis of the ester and the methoxy group present in derivatives 39 to yield compounds of Formula I.
Scheme 8 Synthesis of compounds of Formula I by reductive amination
Figure imgf000059_0001
[00108] Another subset of compounds of Formula I may be prepared by hydrolysis of the ester group and the methoxy group of urea derivatives 40, as schown in scheme 9. HCI in dioxane may be used as an appropriate medium for such hydrolysis. Urea derivatives 40 may be prepared from amines 10 by reaction with an appropriate isocyanide, which could be prepared in-situ by reaction of a carboxylic acid with diphenyl phosphorazidate (DPPA), in the presence of a base. An alternative synthesis of urea derivatives 40 may be a reaction of amines 10 with an appropriate amine either in the presence of p-nitrophenylchloroformate or in the presence of phosgene. Scheme 9 Synthesis of compounds of Formula I
1. RCOOH, DPPA, TEA.THF
°C
Figure imgf000060_0001
[00109] Compounds of Formula ID' and ID" may be prepared by hydrolysis of the ester group and the methoxy group of heterocyclic derivatives 44 and 45, as schown in scheme 10. Either trimethylsilyl iodide which can be prepared in situ using sodium iodide and trimethylsilyl chloride or HCI in dioxane may be used as an appropriate medium for such hydrolysis. The heterocyclic derivatives 44 and 45, respectively, may be prepared from the carboxylic acid 43 by reaction with an appropriate hydrazide or N- hydroxyimidamide in the presence of a condensing agent (e.g. TBTU, CDI) and subsequent treatment with a dehydrating agent (e.g. POCI3). Carboxylic acid 43 may be prepared starting from bromide 41 which may be reacted with allyl tributyltin in presence of a palladium catalyst to yield intermediate 42 which in turn may be reacted with sodium periodate.
cheme 10 Synthesis of compounds of Formula ID
Figure imgf000061_0001
[001 10] Another subset of compounds of Formula ID'" may be prepared by hydrolysis of the ester group and the methoxy group of heterocyclic derivatives 46, as shown in scheme 11. HCI in dioxane may be used as an appropriate medium for such hydrolysis. Heterocyclic intermediates 46 may be prepared via Stille coupling of an appropriate tributyl stannane with bromides 41 in presence of a palladium catalyst.
Scheme 11 S nthesis of compounds of Formula ID by Stille cou
Figure imgf000061_0002
R2/R3 combine to form 5-membered heteroaromatic ring [001 1 1 ] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions. The reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization. Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures. Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.
[001 12] It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.
[001 13] Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
[001 14] Pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselective^. Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention.
ADDITION SALTS
[001 15] For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3- propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4- methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2- hydroxybenzoic and like acids. Conversely, the salt may be converted to the free base by treatment with alkali. Compounds of Formula I can form pharmaceutically acceptable salts with various basic compounds. Suitable base salts include, but are not limited to, ammonium, potassium, sodium, and choline salts.
PHARMACEUTICAL COMPOSITIONS
[001 16] The active ingredients of the compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed. Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms. [001 17] The term "excipient" applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered. Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions. These excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A.R. Gennaro, 20th Edition, describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy". The excipients may also be combinations of solids and liquids.
METHOD OF TREATING
[001 18] Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
[001 19] The term "treat" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, the term "treat" also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
[00120] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
[00121 ] The compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g. , buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20th Edition). The orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
[00122] For oral administration in the form of a tablet or capsule, the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g. , magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g. , potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g. , ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives {e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
[00123] The tablets may be coated by methods well known in the art. The compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
[00124] The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
[00125] The compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The instant compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
[00126] For administration by inhalation, the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[00127] The formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[00128] The compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas {e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
[00129] The compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [00130] As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
[00131 ] Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50. Compositions that exhibit large therapeutic indices are preferred.
[00132] From the Examples described herein below, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
[00133] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions. [00134] The instant compounds of Formula I represent a novel class of glycine B antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS disorders, which involve excessive glutamate induced excitation.
[00135] These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
[00136] The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
[00137] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
EXPERIMENTAL PART
[00138] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. [00139] Hereinafter, "DMF" is defined as Ν,Ν-dimethylformamide, "HCI" as hydrochloric acid, "DMSO" as dimethyl sulfoxide, "NH OH" as ammonium hydroxide solution, "TBAI" as tetrabutylammonium iodide, "TFA" as trifluoroacetic acid, "TEA" as triethylamine, "MeCN" as acetonitrile, "AcOH" as acetic acid, "TLC" as thin layer chromatography, "HOBT" as 1 -hydroxybenzotriazole, "EDC" as 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, "EtOH" as ethanol and "MeOH" as methanol.
Preparation 1
(2-Amino-5-chloro-3-methyl-phenyl)-methanol (2a)
[00140] To an ice cooled suspension of LiAIH4 (2.60 g, 70.0 mmol) in dry THF (100 mL) a solution of 2-amino-5-chloro-3-methyl-benzoic acid (1a) (6.40 g, 35.0 mmol) in THF (100 mL) is added dropwise over one hour. Reaction mixture is stirred at rt overnight. Water (20 mL) and 1 N NaOH (20 mL) is added, the organic layer is separated and precipitates are washed with ethyl acetate (2x100 mL). The organic layers combined are washed with brine, water and dried over Na2SO4. After solvent evaporation the title compound 2a (5.30 g, 90%) is obtained as a solid. 1H NMR (400 MHz, CDCIs), δ (ppm): 2.15 (s, 3H); 4.14 (br s, 1 H); 4.62 (s, 2H); 6.92 (m, 1 H) and 7.01 (m, 1 H).
Preparation 2
2-Amino-5-chloro-3-methyl-benzaldehyde (3a)
[00141 ] To a suspension of MnO2 (10.15 g, 1 16.0 mmol) in dry diethyl ether (100 mL) is added dropwise a solution of (2-amino-5-chloro-3-methyl-phenyl)-methanol (2a) (5.0 g, 29.0 mmol) in diethyl ether (150 mL). The mixture is stirred at rt overnight. Precipitates are filtered off, solvent evaporated and crude product is purified by flash chromatography on silica gel (petroleum ether - DCM, 2: 1 ). The title compound 3a is obtained as a yellow solid (4.60 g, 92%). 1H NMR (400 MHz, CDCI3), δ (ppm): 2.16 (s, 3H); 6.20 (br s, 2H); 7.20 (m, 1 H); 7.35-7.33 (m, 1 H) and 9.80 (s, 1 H). Preparation 3
6-Chloro-8-methyl-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid methyl ester (4a)
[00142] A vial charged with 2-amino-5-chloro-3-methyl-benzaldehyde (3a) (4.50 g, 26.0 mmol), dimethyl malonate (8 mL), methanol (10 mL) and piperidine (0.5 mL) is heated for 2 days. To the reaction mixture methanol (30 mL) is added and precipitates are filtered off, washed with cold methanol and dried to give the title compound 4a which is used in the next step without additional purificartion.
Preparation 4
2,6-Dichloro-8-methyl-quinoline-3-carboxylic acid methyl ester (5a)
[00143] 6-Chloro-8-methyl-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid methyl ester (4a) is dissolved in dry POCI3 (30 mL) and DMF (1 mL). Resulting mixture is refluxed for 12 h. After evaporation of excess POCI3 the crude product is poured into ice and extracted with DCM (3x100 mL). The organic layers combined are washed with brine and dried over Na2SO4. After solvent evaporation the crude product is purified by flash chromatography (petroleum ether - ethyl acetate, 5:1 ). The title compound 5a is obtained as white solid (4.90 g, 69%). Mp: 160-162 °C. 1H NMR (400 MHz, CDCI3), δ (ppm): 2.75 (s, 3H); 4.09 (s, 3H); 7.62 (m, 1 H); 7.69-7.68 (m, 1 H) and 8.53 (s, 1 H).
Preparation 5
6-Chloro-2-methoxy-8-methyl-quinoline-3-carboxylic acid (6a)
[00144] To an ice cooled suspension of 2,6-dichloro-8-methyl-quinoline-3- carboxylic acid methyl ester (5a) (2.800 g, 10.36 mmol) in abs. methanol (120 mL) under an argon atmosphere is added NaH (2.49 g, 62.19 mmol) portionwise. Ice bath is removed and the mixture is stirred at rt for 1 h, and then at 70 °C for 43 h. The reaction mixture is cooled and concentrated under reduced pressure. The residue obtained is diluted with water (150 mL) and acidified by addition of 3N aqueous HCI solution. After 1 h of stirring the resulting solid is collected by filtration, washed with water and dried to give the title compound 6a (2.71 g, 99%). The crude product is used in the next step without additional purification. 1H NMR (200 MHz, DMSO-d6), δ (ppm): 2.63 (s, 3H); 4.04 (s, 3H); 7.68 (s, 1 H); 7.97 (d, 2 Hz, 1 H) and 8.66 (s, 1 H). LC-MS: 253.1 [M+H].
Preparation 6
6-Chloro-2-methoxy-8-methyl-quinoline-3-carboxylic acid methyl ester (7a)
[00145] Thionyl chloride (1 .17 ml_ 16.09 mmol) is added dropwise to an ice cooled suspension of 6-chloro-2-methoxy-8-methyl-quinoline-3-carboxylic acid (6a) (2.700 g, 10.73 mmol) in abs. methanol (60 ml_) and the mixture isstirred at 0-5 °C temperature for 1 h and at rt for 24 h. Solvent is evaporated, MeOH is added and the solid formed is filtered off, washed with diethyl ether and dried to give the title compound 7a. The crude product is used in the next step without further purification. . 1H NMR (200 MHz, DMSO- d6), δ (ppm): 2.63 (s, 3H); 3.87 (s, 3H); 4.05 (s, 3H); 7.70 (s, 1 H); 7.99 (s, 1 H); 8.72 (s, 1 H). LC-MS: 266.2 [M+H].
Preparation 7
8-Bromomethyl-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester (8a)
[00146] A mixture of 6-chloro-2-methoxy-8-methyl-quinoline-3-carboxylic acid methyl ester (7a) (2.10 g, 7.904 mmol), /V-bromosuccinimide (1 .407 g, 7.904 mmol), and benzoyl peroxide (0.191 g, 0.790 mmol) in CCI4 (200 ml_) is stirred at reflux for 1 1 h (LC-MS control). The reaction mixture is cooled and filtered. The filtrate is evaporated to dryness, the residue is heated in a mixture of hexane-EtOAc (7:1 ) and quickly filtered. Solid is washed twice with the same hot solvent mixture and dried in vacuo to give the title compound 8a (1.924 g, 70.6%). 1H NMR (400 MHz, CDCI3), δ (ppm): 3.96 (s, 3H); 4.19 (s, 3H); 5.02 (s, 2H); 7.73 (d, 2 Hz, 1 H); 7.76 (d, 2 Hz, 1 H) and 8.52 (s, 1 H). LC- MS: 346.2 [M+H].
Preparation 8
8-Azidomethyl-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester (9a) [00147] To a solution of 8-bromomethyl-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester (8a) (1.323 g, 3.84 mmol) in dry DMF (39 mL) is added NaN3 (0.374 g, 5.76 mmol) and the mixture is stirred at 50-55 °C for 7 h. The mixture is poured into 120 mL of ice-water and stirred for 40 min. White precipitate is collected by filtration, washed with cold water and dried to give the title compound 9a (1.100 g, 93%). 1H NMR (400 MHz, CDCIs), δ (ppm): 3.97 (s, 3H); 4.17 (s, 3H); 4.92 (s, 2H); 7.69 (d, 2 Hz, 1 H); 7.75 (d, 2 Hz, 1 H) and 8.53 (s, 1 H). LC-MS: 307.1 [M+H].
Preparation 9
Methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate hydrochloride (10a)
[00148] A mixture of 8-azidomethyl-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester (9a) (1642 mg, 5.354 mmol), PPh3 (1544.6 mg, 5.889 mmol) and H2O (0.96 mL, 53.536 mmol) in THF (1 10 mL) is stirred at rt for 2.5 days (LC-MS and TLC (CH2CI2/ MeOH, 6/1 ) control). The reaction mixture is cooled to 5 °C, 1 M HCI (24.6 mL) is slowly added dropwise, then the mixture is stirred at rt for 1 h. The resulting precipitate is collected by filtration, washed with EtOAc, abs. diethyl ether and dried over P2O5 in vacuo to give title compound as a white solid (1 .238 g, 72.9%), 1H NMR (400 MHz, DMSO-de), δ (ppm): 3.89 (s, 3H); 4.12 (s, 3H); 4.52 (s, 2H); 8.01 (d, 2 Hz, 1 H); 8.24 (d, 2 Hz, 1 H); 8.40 (br s, 3H) and 8.81 (s, 1 H). LC-MS: 281 .0 [M+H].
Example 1
8-Aminomethyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid hydrochloride
[00149] Methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate hydrochloride (10a) (93 mg, 0,2932 mmol) in 6N aqueous HCI/dioxane (1 .0/1 .0 mL) is stirred under reflux for 2 h (LC-MS control). After cooling to rt, the mixture is filtered and the precipitate is washed with EtOAc and dry Et.20 and dried over P2O5 under reduced pressure. The title compound is obtained as a white solid (54 mg, 64%). 1H-NMR (200 MHz, DMSO-d6), δ (ppm) 4.43 (br s, 2H); 7.96 (d, 2 Hz, 1 H); 8.25 (d, 2 Hz, 1 H); 8.34 (br s, 3H) and 8.95 (s, 1 H).
Example 2
8-[(2-Carboxy-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) 6-Chloro-8-[(2-ethoxycarbonyl-acetylamino)-methyl]-2-methoxy-quinoline-3- carboxylic acid methyl ester
[00150] To a suspension of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline- 3-carboxylate hydrochloride (10a) (300 mg, 0.946 mmol) in abs. CH2CI2 (100 mL) is added NEt3 (0.29 mL) and ethyl malonyl chloride (174 mg, 1 ,04 mmol) in abs. CH2CI2 (2.0 mL) at 0-5 °C. The mixture is stirred for 4 h at rt, then it is washed with water and dried over Na2SO4. Solvent is evaporated under reduced pressure to give the title compound (191 mg, 51 .1 %)
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .20 (t, 7 Hz, 3H); 3.37 (s, 2H); 3.88 (s, 3H); 4.06 (s, 3H); 4.1 1 (q, 7 Hz, 2H); 4.80 (d, 6 Hz, 2H); 7.67 (d, 2 Hz, 1 H); 8.08 (d, 2 Hz, 1 H); 8.64 (t, 6 Hz, 1 H); 8.76 (s, 1 H). b) 8-[(2-Carboxy-acetylamino)-methyl]-6-chloro-2-methoxy-quinoline-3-carboxylic acid
[00151 ] To a solution of 6-chloro-8-[(2-ethoxycarbonyl-acetylamino)-methyl]-2- methoxy-quinoline-3-carboxylic acid methyl ester (84 mg, 0.2128 mmol) in THF (3.0 mL) is added a solution of LiOH*H2O (35,7 mg, 0,8510 mmol) in water (1 .5 mL) and the mixture is stirred 1 .5 h at rt (LC-MS control). Solvent is evaporated at reduced pressure, the residue is dissolved in water (1 .5 ml) and acidified to pH 2-3 with 3N HCI. The product is filtered, washed with water and dried over P2Os in vacuo to give the title compound as a white solid (56 mg, 74.6%).
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.28 (s, 2H); 4.06 (s, 3H); 4.80 (d, 7 Hz, 2H); 7.71 (d, 2 Hz, 1 H); 8.06 (d, 2 Hz, 1 H); 8.60 (t, 7 Hz, 1 H); 8.70 (s, 1 H). c) 8-[(2-Carboxy-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00152] 8-[(2-Carboxy-acetylamino)-methyl]-6-chloro-2-methoxy-quinoline-3- carboxylic acid (17 mg, 0.0482 mmol) is stirred in 33%HBr in CH3COOH (0.5 mL) at 50 °C for 6 h. The solid is filtered and washed with ethyl acetate and hexane, and dried over P2O5 in vacuo to give the title compound as a pale powder (8.0 mg, 49%).
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.27 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.78 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.84 (t, 6 Hz, 1 H); 8.94 (s, 1 H) and 12.47 (br s, 1 H).
LC-MS: 337.0 [M-H] [35CI].
Example 3
6-Chloro-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3-carboxylic acid a) 6-Chloro-2-methoxy-8-(phenylacetylamino-methyl)-quinoline-3-carboxylic acid methyl ester
[00153] To a suspension of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline- 3-carboxylate hydrochloride (10a) (0.085 g, 0.268 mmol) in dry methylene chloride (33 mL) is added triethylamine (0.082 mL, 0.59 mmol). The mixture is cooled in an ice bath then a solution of phenylacetyl chloride (0.039 mL, 0.30 mmol) in dry methylene chloride (0.5 mL) is added dropwise and stirred for 30 min. Ice bath is removed and the mixture is stirred at rt for 24 h. Water is added, the organic layer is washed with saturated NaHCOs solution, dried over Na2SO4 and evaporated. The obtained solid is triturated with diethyl ether, filtered and dried to give the title compound (0.080 g, 75%) as a white solid.
1H NMR (400 MHz, CDCI3), δ (ppm): 3.60 (s, 2H); 3.76 (s, 3H); 3.96 (s, 3H); 4.82 (d, 6 Hz, 2H); 6.37 (t, 6 Hz, 1 H); 7.16-7.18 (m, 2H); 7.25-7.30 (m, 3H); 7.60 (d, 2 Hz, 1 H); 7.68 (d, 2 Hz, 1 H) and 8.50 (s, 1 H). LC-MS: 399.0 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3- carboxylic acid [00154] A mixture of 6-chloro-2-methoxy-8-(phenylacetylamino-methyl)-quinoline- 3-carboxylic acid methyl ester (0.033 g, 0.83 mmol) in 33% HBr/AcOH (0.9 ml_) is stirred at 50 °C for 14 h (LC-MS control). The reaction mixture is evaporated with heptane, water is added and the mixture is stirred for 4 h. The precipitated solid is collected on filter, washed with water and diethyl ether, and dried to give the title compound (0.019 g, 62%).
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 4.54 (d, 6 Hz, 2H); 7.20-7.31 (m, 5H); 7.61 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.81 (t, 6 Hz, 1 H) and 8.92 (s, 1 H). LC-MS: 369.3 [M-H].
Example 4
6-Chloro-2-oxo-8-[(2 hiophen-3-yl-acetylamino)-methyl]-1 ,2-dihydroquinoline-3- carboxylic acid a) 6-Chloro-8-{[2 hiophen-3-yl)-acetylamino]-methyl}-2-methoxy-quinoline-3- carboxylic acid methyl ester
[00155] To a mixture of thiophen-3-yl-acetic acid (0.0399 g, 0.28 mmol) in abs. CH2CI2 (5 ml_) is added EDC (54 mg, 0.281 mmol), DMAP (3 mg, 0.026 mmol) and Et3N (62 mg, 0.613 mmol). After 5 min methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline- 3-carboxylate hydrochloride (10a) is added. The reaction mixture is stirred at rt for 27 h (LC/MS control), then it is washed with NaHCO3, and water. The organic phase is separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (EtOAc:Hexane, 2:1 ) to give the title compound (49 mg, 47.5%) as white solid after drying over P2O5 in vacuo. 1H-NMR (400 MHz, CDCI3), δ (ppm): 3.63 (s, 2H); 3.87 (s, 3H); 3.97 (s, 3H); 4.84 (d, 6.4 Hz, 2H); 6.47 (t, 6.4 Hz, 1 H) 6.89 (d, 4 Hz, 1 H); 7.09 (s, 1 H); 7.29 (dd, 4 and 2 Hz, 1 H); 7.61 (d, 2 Hz, 1 H); 7.69 (d, 2 Hz, 1 H); and 8.51 (s, 1 H). b) 6-Chloro-2-oxo-8-[(2 hiophen-3-yl-acetylamino)-methyl]-1 ,2-dihydroquinoline- 3-carboxylic acid [00156] In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- thiophen-3-yl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 52% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.56 (s, 2H); 4.55 (d, 6 Hz, 2H); 7.03 (d, 4 Hz,
1 H); 7.29 (br s, 1 H); 7.48 (dd, 4 and 2 Hz, 1 H); 7.63 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H);
8.76 (t, 6 Hz, 1 H) and 8.92 (s, 1 H).
LC-MS: 375.0 [M-H] [35CI].
Example 5
6-Chloro-8-{[2-(2-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid a) 6-Chloro-8-{[2-(2-chloro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3- carboxylic acid methyl ester
[00157] A mixture of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3- carboxylate hydrochloride (10a) (0.090 g, 0.28 mmol), (2-chloro-phenyl)-acetic acid (0.053 g, 0.31 mmol), EDC (0.060 g, 0.31 mmol), HOBt (0.042 g, 0.31 mmol) and triethylamine (0.1 18 mL, 0.85 mmol) in dry methylene chloride (5.0 mL) is stirred at rt for 22 h. Then mixture is concentrated and the residue is dissolved in methylene chloride, washed with saturated aqueous NaHCO3 solution, water and dried over Na2SO4, and evaporated. The residue is purified by flash chromatography (CH2Cl2:MeOH, 6:1 ) to give the title compound (0.065 g, 52%).
1H NMR (400 MHz, CDCI3), δ (ppm): 3.71 (s, 2H); 3.85 (s, 3H); 3.97 (s, 3H); 4.85 (d, 6 Hz, 2H); 6.39 (t, 6 Hz, 1 H); 7.22-7.33 (m, 4H); 7.62 (d, 2 Hz, 1 H); 7.68 (d, 2 Hz, 1 H) and 8.51 (s, 1 H).
LC-MS: 435.1 [M+H]. b) 6-Chloro-8-{[2-(2-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (I-5)
[00158] In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2-(2- chloro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 55% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.71 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.28-7.32 (m, 2H); 7.38-7.44 (m, 2H); 7.68 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.74 (t, 6 Hz, 1 H) and 8.93 (s, 1 H).
LC-MS: 403.1 [M-H] [35CI]. Example 6
6-Chloro-2-oxo-8-{[(thiophene-2-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid a) 6-Chloro-2-methoxy-8-{[(thiophene-2-carbonyl)-amino]-methyl}-quinoline-3- carboxylic acid methyl ester
[00159] Prepared 0.084 g (80%) from methyl 8-aminomethyl-6-chloro-2-methoxy- quinoline-3-carboxylate hydrochloride (10a) (0.085 g, 0.27 mmol) and thiophene-2- carboxylic acid (0.038 g, 0.29 mmol) according to the procedure for described in Example 5a. Purified by flash chromatography (hexane:EtOAc, 1 :2).
1H NMR (400 MHz, CDCI3), δ (ppm): 3.88 (s, 3H); 4.07 (s, 3H); 4.99 (d, 6 Hz, 2H); 7.18 and 7.19 (both d, 5 and 4 Hz, 1 H); 7.60 (d, 2 Hz, 1 H); 7.79 (dd, 5 and 1 Hz, 1 H); 7.86 (dd, 4 and 1 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.78 (s, 1 H) and 9.03 (t, 6 Hz, 1 H).
LC-MS: 391 .1 [M+H]. b) 6-Chloro-2-oxo-8-{[(thiophene-2-carbonyl)-amino]-methyl}-1 ,2- dihydroquinoline-3-carboxylic acid
[00160] In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(thiophene-2-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 68% yield.
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.73 (d, 6 Hz, 2H); 7.18 and 7.19 (both d, both
5 Hz, 1 H); 7.71 (d, 2 Hz, 1 H); 7.79 (dd, 4 and 1 Hz, 1 H); 7.83 (dd, 5 and 1 Hz, 1 H); 8.15
(d, 2 Hz, 1 H); 8.94 (s, 1 H); 9.28 (t, 6 Hz, 1 H) and 12.47 (s, 1 H).
LC-MS: 363.0 [M-H].
Example 7 6-Chloro-8-{[2-(3-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
[00161 ] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (3-chlorophenyl)- acetic acid gives 6-chloro-2-methoxy-8-[2-(3-chlorophenyl)-acetylamino]-methyl}- quinoline-3-carboxylic acid methyl ester in 77% yield;
b) in analogy to the procedure described in Example 3(b), 6-chloro-2-methoxy-8-[2-(3- chlorophenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 52% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.56 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.23-7.36 (m, 4H); 7.60 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.83 (t, 6 Hz, 1 H); 8.93 (s, 1 H) and 12.41 (br s, 1 H).
LC-MS: 403.3 [M-H]. Example 8
6-Chloro-2-oxo-8-{[(thiophene-3-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid
[00162] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with thiophene-3- carboxylic acid gives 6-chloro-2-methoxy-8-{[(thiophene-3-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in good yield;
b) in analogy to the procedure described in Example 3(b), 6-chloro-2-methoxy-8- {[(thiophene-3-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 37.4% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.72 (d, 6 Hz, 2H); 7.53 (dd, 5 and 1 Hz, 1 H); 7.63 (dd, 5 and 2 Hz, 1 H); 7.72 (d, 2 Hz, 1 H); 8.15 (d, 2 Hz, 1 H); 8.22 (dd, 3 and 1 Hz, 1 H); 8.93 (s, 1 H) and 9.16 (t, 6 Hz, 1 H).
LC-MS: 361 .5 [M-H] [35CI]. Example 9
6-Chloro-8-{[2-(2-nitrophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00163] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-nitrophenyl)- acetic acid gives 6-chloro-2-methoxy-8-[2-(2-nitrophenyl)-acetylamino]-methyl}- quinoline-3-carboxylic acid methyl ester in good yield;
b) in analogy to the procedure described in Example 3(b), 6-chloro-2-methoxy-8-[2-(2- nitrophenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 58% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.00 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.53-7.58 (m, 2H); 7.68-7.72 (m, 2H); 8.04 (d, 8 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.81 (t, 6 Hz, 1 H); 8.94 (s, 1 H) and 12.36 (br s, 1 H).
LC-MS: 414.3 [M-H] [35CI].
Example 10
6-Chloro-2-oxo-8-[(3-phenyl-propionylamino)-methyl]-1 ,2-dihydroquinoline-3- carboxylic acid
[00164] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 3-phenylpropionic acid gives 6-chloro-2-methoxy-8-[(3-phenyl-propionylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 65% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.54 (t, 7.6 Hz, 2H); 2.88 (t, 7.6, 2H); 3.88 (s, 3H); 4.05 (s, 3H); 4.78 (d, 6 Hz, 2H); 7.15-7.28 (m, 5H); 7.48 (d, 2 Hz, 1 H); 8.07 (d, 2 Hz, 1 H); 8.34 (t, 6 Hz, 1 H); 8.76 (s, 1 H). [00165] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(3-phenyl-propionylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 62% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.51 (t, 8 Hz, 2H); 2.85 (t, 8 Hz, 2H); 4.52 (d, 6 Hz, 2H); 7.06-7.16 (m, 5H); 7.63 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.71 (t, 6 Hz, 1 H); 8.92 (s, 1 H) and 12.45 (br s, 1 H). LC-MS: 383.3 [M-H].
Example 11
8-{[(Benzofuran-2-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
[00166] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with benzofuran-2- carboxylic acid gives 8-{[(benzofuran-2-carbonyl)-amino]-methyl}-6-chloro-2-methoxy- quinoline-3-carboxylic acid methyl ester in 75% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.09 (s, 3H); 5.03 (d, 6 Hz, 2H); 7.35 (t, 8 Hz, 1 H); 7.47 (dd, 7.8 and 1 .2 Hz, 1 H); 7.50 (d, 1.2 Hz, 1 H); 7.67 (d, 8 Hz, 1 H); 7.76 (d, 2 Hz, 1 H); 7.79 (d, 8 Hz, 1 H); 8.1 1 (d, 2 Hz, 1 H); 8.79 (s, 1 H) and 9.28 (t, 6 Hz, 1 H).
[00167] b) in analogy to the procedure described in Example 3(b), 8- {[(benzofuran-2-carbonyl)-amino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 41 % yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.76 (d, 6 Hz, 2H); 7.35 (t, 8 Hz, 1 H); 7.49 (t, 8 Hz, 1 H); 7.62 (s, 1 H); 7.67 (d, 8 Hz, 1 H); 7.76 (d, 2 Hz, 1 H); 7.79 (d, 8 Hz, 1 H); 8.16 (d, 2 Hz, 1 H); 8.94 (s, 1 H) and 9.50 (t, 6 Hz, 1 H). LC-MS: 395.0 [M-H].
Example 12
8-{[(Benzo[b]thiophene-2-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00168] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with benzo[b]thiophene- 2-carboxylic acid gives 8-{[(benzo[b]thiophene-2-carbonyl)-amino]-methyl}-6-chloro-2- methoxy-quinoline-3-carboxylic acid methyl ester in 75% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.08 (s, 3H); 5.04 (d, 5.5 Hz, 2H); 7.43-7.50 (m, 2H); 7.68 (d, 2 Hz, 1 H); 7.96 (dd, 8 and 2 Hz, 1 H); 8.04 (dd, 8 and 1 .6 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.19 (s, 1 H); 8.79 (s, 1 H) and 9.29 (t, 5.5 Hz, 1 H).
[00169] b) in analogy to the procedure described in Example 3(b) 8- {[(benzo[b]thiophene-2-carbonyl)-amino]-methyl}-6-chloro-2-methoxy-quinoline-3- carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 41 % yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.79 (d, 6 Hz, 2H); 7.43-7.50 (m, 2H); 7.75 (d, 2 Hz, 1 H); 7.97 (d, 8 Hz, 1 H); 8.04 (d, 8 Hz, 1 H); 8.14 (s, 1 H); 8.17 (d, 2 Hz, 1 H); 8.95 (s, 1 H) and 9.50 (t, 6 Hz, 1 H).
LC-MS: 41 1 .0 [M-H].
Example 13
6-Chloro-8-[(oxalyl-amino)-methyl]-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00170] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 2(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with ethyl oxalyl chloride gives 6-chloro-8-[(ethoxyoxalyl-amino)-methyl]-2-methoxy-quinoline-3-carboxylic acid methyl ester in 93% yield; 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.28 (t, 6 Hz, 3H); 3.88 (s, 3H); 4.07 (s, 3H); 4.26 (q, 6 Hz, 2H); 4.87 (d, 6 Hz, 2H); 4.58 (d, 6 Hz, 2H); 7.63 (d, 2 Hz,1 H); 8.1 1 (d, 2 Hz, 1 H); 8.77 (s, 1 H) and 9.39 (t, 6 Hz, 1 H).
[00171 ] b) in analogy to the procedure described in Example 3(b) 6-chloro-8- [(ethoxyoxalyl-amino)-methyl]-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 75% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.58 (d, 6 Hz, 2H); 7.69 (d, 2 Hz,1 H); 8.14 (d, 2 Hz, 1 H); 8.92 (s, 1 H) and 9.51 (t, 6 Hz, 1 H).
LC-MS: 323.0 [M-H].
Example 14
8-(Benzoylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00172] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with benzoyl chloride gives 8-(benzoylamino-methyl)-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester in 84% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.08 (s, 3H); 5.02 (d, 6 Hz, 2H); 7.48-7.57 (m, 3H); 7.59 (d, 2 Hz, 1 H); 7.94 (dd, 8 and 1 .2 Hz, 2H); 8.09 (d, 2 Hz, 1 H); 8.78 (s, 1 H) and 9.05 (t, 6 Hz, 1 H).
[00173] b) in analogy to the procedure described in Example 3(b) 8-
(benzoylamino-methyl)-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 66% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.76 (d, 6 Hz, 2H); 7.48-7.59 (m, 3H); 7.73 (d,
2 Hz, 1 H); 7.89 (d, 8 Hz, 2H); 8.15 (d, 2 Hz, 1 H); 8.94 (s, 1 H); 9.33 (t, 6 Hz, 1 H) and
12.55 (br s, 1 H).
LC-MS: 355.5 [M-H].
Example 15
6-Chloro-2-oxo-8-{[(pyridine-3-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid (1-15)
[00174] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with nicotinoyi chloride gives 6-chloro-2-methoxy-8-{[(pyridine-3-carbonyl)-amino]-methyl}quinoline-3-carboxylic acid methyl ester in 80% yield; 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.07 (s, 3H); 5.04 (d, 6 Hz, 2H); 7.54 (dd, 8 and 5 Hz, 1 H); 7.66 (d, 2 Hz, 1 H); 8.1 1 (d, 2 Hz, 1 H); 8.24-8.28 (dt, 8 and 2 Hz, 1 H); 8.74 (br s, 1 H); 8.78 (s, 1 H); 9.09 (s, 1 H) and 9.21 (t, 6 Hz, 1 H).
[00175] b) in analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-{[(pyridine-3-carbonyl)-amino]-methyl}quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59.3% yield as hydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.79 (d, 6 Hz, 2H); 7.55 (dd, 8 and 5 Hz, 1 H); 7.75 (d, 2 Hz, 1 H); 8.16 (d, 2 Hz, 1 H); 8.24 (d, 8 Hz, 1 H); 8.74 (d, 4 Hz, 1 H); 8.94 (s, 1 H); 9.05 (s, 1 H); 9.45 (t, 6 Hz, 1 H) and 12.48 (br s, 1 H). LC-MS: 356.2 [M-H].
Example 16
6-Chloro-2-oxo-8-{[(pyridine-4-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid
[00176] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with isonicotinoyl chloride gives 6-chloro-2-methoxy-8-{[(pyridine-4-carbonyl)-amino]-methyl}-quinoline-3- carboxylic acid methyl ester in 77% yield; 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.07 (s, 3H); 5.03 (d, 5.5 Hz, 2H); 7.65 (d, 2 Hz, 1 H); 7.83 (d, 6 Hz, 2H); 8.1 1 (d, 2 Hz, 1 H); 8.75 (d, 6 Hz, 2H); 8.78 (s, 1 H); 9.29 (t, 5.5 Hz, 1 H).
[00177] b) in analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-{[(pyridine-4-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 63.3% yield as hydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.89 (d, 6 Hz, 2H); 7.74 (d, 2 Hz, 1 H); 7.92 (d, 5 Hz, 2H); 8.15 (d, 2 Hz, 1 H); 8.83 (d, 5 Hz, 2H); 8.94 (s, 1 H); 9.60 (t, 6 Hz, 1 H). LC- MS: 356.1 [M-H]. Example 17
6-Chloro-2-oxo-8-{[2-(pyridin-3-yl)-acetylami
carboxylic acid
[00178] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyridin-3-yl-acetic acid gives 6-chloro-2-methoxy-8-{[2-(pyridin-3-yl)-acetyl)-amino]-methyl}-quinoline-3- carboxylic acid methyl ester in 80.3% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.60 (s, 2H); 3.88 (s, 3H); 4.02 (s, 3H); 4.79 (d, 6 Hz, 2H); 7.34 (dd, 7.8 and 4.6 Hz, 1 H); 7.53 (d, 2 Hz, 1 H); 7.69-7.72 (m, 1 H); 8.08 (d, 2 Hz, 1 H); 8.45 (dd, 5.2 and 1 .6 Hz, 1 H); 8.50 (d, 1 .2 Hz, 1 H); 8.63 (t, 6 Hz, 1 H); 8.76 (s, 1 H).
[00179] b) in analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-{[2-(pyridin-3-yl)-acetyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 67.5% yield as hydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.49 (s, 2H); 4.59 (d, 5.6 Hz, 2H); 7.68 (d, 2 Hz, 1 H); 7.92 (dd, 7.8 and 5.6 Hz, 1 H); 8.14 (d, 2 Hz, 1 H); 8.35 (d, 8 Hz, 1 H); 8.77-8.79 (m, 2H); 8.93 (s, 1 H); 8.96 (t, 5.6 Hz, 1 H).
LC-MS: 370.2 [M-H].
Example 18
6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-acetylamino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid
[00180] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyridin-2-yl-acetic acid gives 6-chloro-2-methoxy-8-{[2-(pyridin-2-yl)-acetyl)-amino]-methyl}-quinoline-3- carboxylic acid methyl ester in 70% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.75 (s, 2H); 3.88 (s, 3H); 4.05 (s, 3H); 4.81 (d, 6 Hz, 2H); 7.28 (dd, 7.8 and 6 Hz, 1 H); 7.37 (d, 7.8 Hz, 1 H); 7.72-7.77 (m, 2H); 8.07 (d, 2 Hz, 1 H); 8.54 (d, 4 Hz, 1 H); 8.67 (t, 6 Hz, 1 H); 8.76 (s, 1 H).
[00181 ] b) in analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-{[2-(pyridin-2-yl)-acetyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 57% yield as hydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.74 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.28 (dd, 7.2 and 4.8 Hz, 1 H); 7.36 (d, 7.6 Hz, 1 H); 7.75 (td, 8 and 2 Hz, 1 H); 7.78 (d, 2H, 1 H); 8.1 1 (d, 2 Hz, 1 H); 8.51 (d, 4 Hz, 1 H); 8.87 (t, 6 Hz, 1 H); 8.92 (s, 1 H).
LC-MS: 370.2 [M-H].
Example 19
6-Chloro-2-oxo-8-{[(pyridine-2-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid
[00182] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyridine-2- carboxylic acid gives 6-chloro-2-methoxy-8-{[(pyridine-2-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 77% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.13 (s, 3H); 5.03 (d, 6 Hz, 2H); 7.62-7.65 (m, 2H); 8.00-8.1 1 (m, 3H); 8.68 (d, 2 Hz, 1 H); 8.79 (s, 1 H): 9.47 (t, 6 Hz, 1 H).
[00183] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(pyridine-2-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 34% yield as hydrobromide. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.73 (d, 6.4 Hz, 2H); 7.61 -7.65 (m, 1 H); 7.79 (d, 2 Hz, 2H); 7.99-8.03 (m, 2H); 8.14 (d, 2 Hz, 1 H); 8.68 (d, 4 Hz, 1 H); 8.92 (s, 1 H): 9.77 (t, 6.4 Hz, 1 H); 12.64 (br s, 1 H).
LC-MS: 356.1 [M-H] [35CI].
Example 20
6-Chloro-8-[(2-chloro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00184] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2-chlorobenzoyl chloride gives 6-chloro-8-[(2-chloro-benzoylamino)-methyl]-2-methoxy-quinoline-3- carboxylic acid methyl ester in 78% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.09 (s, 3H); 4.98 (d, 6 Hz, 2H); 7.41 -7.56 (m, 4H); 7.55 (d, 2 Hz, 1 H); 7.78 (d, 2 Hz, 1 H); 8.79 (s, 1 H): 9.04 (t, 6 Hz, 1 H).
[00185] b) in analogy to the procedure described in Example 3(b), 6-chloro-8-[(2- chloro-benzoylamino)-methyl]-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 47% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.75 (d, 6 Hz, 2H); 7.40-7.55 (m, 4H); 7.79 (d,
8 Hz, 1 H); 8.16 (d, 2 Hz, 1 H); 8.95 (s, 1 H); 9.23 (t, 6 Hz, 1 H).
LC-MS: 389.2 [M-H] [35CI].
Example 21
6-Chloro-8-[(2-hydroxybenzoylamino)-methyl]-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00186] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2-methoxybenzoyl chloride gives 6-chloro-2-methoxy-8-[(2-methoxy-benzoylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 62% yield;
b) in analogy to the procedure described in Example 3(b), 6-chloro-2-methoxy-8-[(2- methoxy-benzoylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 36% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.79 (d, 6 Hz, 2H); 6.90-6.96 (m, 2H); 7.41 (td, 6.4 and 1 .6 Hz, 1 H); 7.79 (s, 1 H); 7.84 (dd, 6 and 1 .6 Hz, 1 H); 8.15 (d, 2 Hz, 1 H); 8.94 (s, 1 H); 9.37 (t, 6 Hz, 1 H); 1 1 .79 (s, 1 H) and 12.60 (br s, 1 H).
LC-MS: 371 .4 [M-H].
Example 22
6-Chloro-8-[(3-chloro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00187] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 3-chlorobenzoic acid gives 6-chloro-8-[(3-chloro-benzoylamino)-methyl]-2-methoxy-quinoline-3- carboxylic acid methyl ester in 35% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.07 (s, 3H); 5.02 (d, 6 Hz, 2H); 7.54 (t, 8 Hz, 1 H); 7.63 (d, 2 Hz, 1 H); 7.63-7.65 (m, 1 H); 7.89 (dt, 8 and 1.3 Hz, 1 H); 7.97 (d, 2 Hz, 1 H); 8.1 1 (d, 2 Hz, 1 H); 8.78 (s, 1 H): 9.14 (t, 6 Hz, 1 H).
[00188] b) in analogy to the procedure described in Example 3(b), 6-chloro-8-[(3- chloro-benzoylamino)-methyl]-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 40% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.75 (d, 6 Hz, 2H); 7.55 (t, 8 Hz, 1 H); 7.65 (dd,
8 and 1 .2 Hz, 1 H); 7.73 (d, 2.4 Hz, 1 H); 7.86 (d, 8 Hz, 1 H); 7.93 (d, 1 .2 Hz, 1 H); 8.15 (d,
2.4 Hz, 1 H); 8.94 (s, 1 H); 9.40 (t, 6 Hz, 1 H).
LC-MS: 389.1 [M-H] [35CI].
Example 23 6-Chloro-8-{[(2,3-dihydro-benzo[1 ,4]dioxine-6-carbonyl)-amino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid
[00189] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2,3-dihydro- benzo[1 ,4]dioxine-6-carboxylic acid gives 6-chloro-8-{[(2,3-dihydro-benzo[1 ,4]dioxine-6- carbonyl)-amino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 73% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.07 (s, 3H); 4.27-4.32 (m, 4H); 4.97 (d, 6 Hz, 2H); 6.95 (d, 8 Hz, 1 H); 7.44-7.48 (m, 2H); 7.69 (dd, 8 and 1 Hz, 1 H); 7.54 (d, 2.4 Hz, 1 H); 8.10 (d, 2.4 Hz, 1 H); 8.78 (s, 1 H): 8.87 (t, 6 Hz, 1 H).
[00190] b) in analogy to the procedure described in Example 3(b), 6-chloro-8- {[(2,3-dihydro-benzo[1 ,4]dioxine-6-carbonyl)-amino]-methyl}-2-methoxy-quinoline-3- carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 56.3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.27 (d, 5.2 Hz, 2H); 4.29 (d, 5.2 Hz, 2H); 4.71 (d, 6 Hz, 2H); 6.95 (d, 8 Hz, 1 H); 7.40-7.43 (m, 2H); 7.70 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.93 (s, 1 H); 9.17 (t, 6 Hz, 1 H).
Example 24
8-[(2-Bromo-benzoylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00191 ] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2- bromobenzenecarboxylic acid gives 8-[(2-bromo-benzoylamino)-methyl]-6-chloro-2- methoxy-quinoline-3-carboxylic acid methyl ester in 76% yield; 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.09 (s, 3H); 4.97 (d, 6 Hz, 2H); 7.37-7.41 (m, 1 H); 7.46-7.49 (m, 2H); 7.69 (dd, 8 and 1 Hz, 1 H); 7.81 (d, 2.4 Hz, 1 H); 8.1 1 (d, 2.4 Hz, 1 H); 8.79 (s, 1 H): 9.03 (t, 6 Hz, 1 H);
[00192] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(pyridine-2-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 38% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.75 (d, 6 Hz, 2H); 7.37-7.43 (m, 1 H); 7.46- 7.48 (m, 1 H); 7.68 (d, 8 Hz, 1 H); 7.82 (d, 2.4 Hz, 1 H); 8.16 (d, 2.4 Hz, 1 H); 8.96 (s, 1 H); 9.23 (t, 6 Hz, 1 H).
Example 25
6-Chloro-8-[(3-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00193] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 3-methoxybenzoyl chloride gives 6-chloro-2-methoxy-8-[(3-methoxy-benzoylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 84.4% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.81 (s, 3H); 3.88 (s, 3H); 4.08 (s, 3H); 5.01 (d, 6 Hz, 2H); 7.13 (dd, 8 and 2 Hz, 1 H); 7.42 (t, 8 Hz, 1 H); 7.48 (t, 2 Hz, 1 H); 7.52 (d, 8 Hz, 1 H); 7.58 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.78 (s, 1 H): 9.03 (t, 6 Hz, 1 H).
[00194] b) in analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-[(3-methoxy-benzoylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 45% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.72 (d, 5.4 Hz, 2H); 6.93-6.96 (m, 1 H); 7.25- 7.30 (m, 3H); 7.71 (s, 1 H); 8.15 (s, 1 H); 8.94 (s, 1 H); 9.23 (t, 5.4 Hz, 1 H); 9.73 (s, 1 H).
Example 26 6-Chloro-2-oxo-8-{[(quinoline-3-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00195] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with quinoline-3- carboxylic acid gives 6-chloro-2-methoxy-8-[(quinoline-3-carbonylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 78.2% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.09 (s, 3H); 5.10 (d, 6 Hz, 2H); 7.68-7.74 (m, 2H); 7.88 (t, 8 Hz, 1 H); 8.09-8.13 (m, 3H); 8.79 (s, 1 H): 8.92 (d, 2 Hz, 1 H); 9.33-9.37 (m, 2H).
[00196] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(quinoline-3-carbonylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 46% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.85 (d, 5.5 Hz, 2H); 7.71 (t, 7.4 Hz, 1 H); 7.81 (s, 1 H); 7.89 (t, 7.4 Hz, 1 H); 8.08 - 8.17 (m, 3H); 8.90 (s, 1 H); 8.95 (s, 1 H); 9.32 (s, 1 H); 9.63 (t, 5.5 Hz, 1 H) and 12.53 (br s, 1 H).
Example 27
6-Chloro-8-(diphenylacetylamino-methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00197] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with diphenylacetic acid gives 6-chloro-8-(diphenylacetylamino-methyl)-2-methoxy-quinoline-3-carboxylic acid methyl ester in 78% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.87 (s, 3H); 3.98 (s, 3H); 4.82 (d, 5.6 Hz, 2H); 5.1 1 (s, 1 H); 7.22-7.26 (m, 2H); 7.27-7.37 (m, 8H); 7.43 (d, 2.4 Hz, 1 H); 8.06 (d, 2.4 Hz, 1 H); 8.75 (s, 1 H): 8.79 (t, 6 Hz, 1 H). [00198] b) in analogy to the procedure described in Example 3(b) 6-chloro-8- (diphenylacetylamino-methyl)-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 46% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.59 (d, 6 Hz, 2H); 5.05 (s, 1 H); 7.20 - 7.35 (m, 10H); 7.53 (d, 2.4 Hz, 1 H); 8.10 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 8.99 (t, 6 Hz, 1 H) and 12.39 (br s, 1 H).
Example 28
6-Chloro-8-[(4-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00199] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 4-methoxybenzoyl chloride gives 6-chloro-2-methoxy-8-[(4-methoxy-benzoylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 80% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.82 (s, 3H); 3.89 (s, 3H); 4.08 (s, 3H); 5.00 (d, 6 Hz, 2H); 7.03 (d, 8.8 Hz, 2H); 7.56 (t, 2.4 Hz, 1 H); 7.92 (d, 8.8 Hz, 2H); 8.09 (d, 2.4 Hz, 1 H); 8.78 (s, 1 H): 8.89 (t, 6 Hz, 1 H).
[00200] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(4-methoxy-benzoylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 61 % yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.71 (d, 6 Hz, 2H); 6.82 (d, 8 Hz, 2H); 7.72 (d, 2 Hz, 1 H); 7.77 (d, 8 Hz, 2H); 8.14 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 9.12 (t, 6 Hz, 1 H); 10.1 1 (s, 1 H).
Example 29
6-Chloro-8-[(4-fluoro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00201 ] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 3(a), acylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 4-fluorobenzoyl chloride gives 6-chloro-8-[(4-fluoro-benzoylamino)-methyl]-2-methoxy-quinoline-3- carboxylic acid methyl ester in 69.5% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.07 (s, 3H); 5.01 (d, 5.6 Hz, 2H); 7.31 -7.36 (m, 2H); 7.60 (d, 2.4 Hz, 1 H); 7.98-8.02 (m, 2H); 8.1 1 (d, 2.4 Hz, 1 H); 8.78 (s, 1 H): 9.05 (t, 5.6 Hz, 1 H).
[00202] b) in analogy to the procedure described in Example 3(b), 6-chloro-8-[(4- fluoro-benzoylamino)-methyl]- 2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59.3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.75 (d, 6 Hz, 2H); 7.31 -7.37 (m, 2H); 7.72 (d, 2 Hz, 1 H); 7.94-7.99 (m, 2H); 8.14 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 9.33 (t, 6 Hz, 1 H).
Example 30
6-Chloro-8-[(3-fluoro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00203] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 3- fluorobenzenecarboxylic acid gives 6-chloro-8-[(3-fluoro-benzoylamino)-methyl]-2- methoxy-quinoline-3-carboxylic acid methyl ester in good yield;
b) in analogy to the procedure described in Example 3(b), 6-chloro-8-[(3-fluoro- benzoylamino)-methyl]-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 55.5% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.76 (d, 5.4 Hz, 2H); 7.43 (dt, 8 and 2.4 Hz, 1 H); 7.53 - 7.60 (m. 1 H); 7.68 (d, 9 Hz, 1 H); 7.72 (d, 2.4 Hz, 1 H); 7.74 (d, 8 Hz, 1 H); 8.15 (d, 2.4 Hz, 1 H); 8.93 (s, 1 H); 9,37 (t, 5.4 Hz, 1 H) and 12.45 (br s, 1 H).
Example 31 6-Chloro-2-oxo-8-[(2-o^olyl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00204] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with o-tolylacetic acid gives 6-chloro-2-methoxy-8-[(2-o-tolyl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester in 75.6% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.26 (s, 3H); 3.58 (s, 2H); 3.88 (s, 3H); 4.01 (s, 3H); 4.79 (d, 6 Hz, 2H); 7.10-7.16 (m, 3H); 7.22-7.27 (m, 1 H); 7.55 (d, 2.4 Hz, 1 H); 8.07 (d, 2.4 Hz, 1 H); 8.44 (t, 6 Hz, 1 H); 8.76 (s, 1 H);
[00205] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-o-tolyl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 60% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.22 (s, 3H); 3.56 (s, 2H); 4.54 (d, 6 Hz, 2H); 7.10-7.17 (m 3H); 7.20 (dd, 8 and 2 Hz, 1 H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.68 (t, 6 Hz, 1 H); 8.93 (s, 1 H).
Example 32
6-Chloro-2-oxo-8-[(2-pyrazin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00206] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyrazin-2-ylacetic acid gives 6-chloro-2-methoxy-8-[(2-pyrazin-2-yl-acetylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 54.3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.84 (s, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 4.81 (d, 6 Hz, 2H); 7.70 (d, 2.4 Hz, 1 H); 8.08 (d, 2.4 Hz, 1 H); 8.54 (d, 2.8 Hz, 1 H); 8.60 (dd, 2.8 and 1 .2 Hz, 1 H); 8.64 (d, 1 .2 Hz, 1 H); 8.73 (t, 6 Hz, 1 H) 8.76 (s, 1 H); [00207] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-pyrazin-2-yl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as hydrobromide. 1H-NMR (400 MHz, DMSO-de), δ (ppm): 3.83 (s, 2H); 4.58 (d, 5.6 Hz, 2H); 7.74 (s, 1 H); 8.13 (s, 1 H); 8.54 (s, 1 H); 8.58 (s, 1 H); 8.63 (s, 1 H); 8.93 (br s, 2H).
Example 33
6-Chloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00208] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2,6- dichlorophenyl)-acetic acid gives 6-chloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]- methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 80% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 2H); 3.96 (s, 2H); 4.05 (s, 3H); 4.81 (d,
6 Hz, 2H); 7.32 (t, 8 Hz, 2H); 7.47 (d, 8 Hz, 2H); 7.65 (d, 2.4 Hz, 1 H); 8.08 (d, 2.4 Hz,
1 H); 8.63 (t, 6 Hz, 1 H) 8.76 (s, 1 H);
[00209] b) in analogy to the procedure described in Example 3(b) 6-chloro-8-{[2- (2,6-dichloro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as a light yellow solid in 67% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.93 (s, 2H); 4.57 (d, 5.5 Hz, 2H); 7.33 (t, 8 Hz, 1 H); 7.47 (d, 8 Hz, 2H); 7.68 (d, 1 .2 Hz, 1 H); 8.12 (d, 1.2 Hz, 1 H); 8.79 (t, 5.5 Hz, 1 H); 8.93 (s, 1 H).
Example 34
6-Chloro-2-oxo-8-{[2-(2-trifluoromethoxy-phenyl)-acetylamino]-methyl}-1 ,2- dihydro-quinoline-3-carboxylic acid
[00210] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-trifluoromethoxy- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(2-trifluoromethoxy-phenyl)- acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester in 45% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.68 (s, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 4.81 (d, 5.6 Hz, 2H); 7.30-7.40 (m, 3H); 7.46 (d, 6.8 Hz, 1 H); 7.60 (d, 2Hz, 1 H); 8.08 (d, 2 Hz, 1 H); 8.60 (t, 5.6 Hz, 1 H); 8.76 (s, 1 H).
[0021 1 ] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(2-trifluoromethoxy-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 71 % yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.66 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.28-7.46 (m 4H); 7.67 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.83 (t, 6 Hz, 1 H); 8.94 (s, 1 H).
Example 35
6-Chloro-8-[(2-naphthalen-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid
[00212] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with naphthalen-1 -yl- acetic acid gives 6-chloro-2-methoxy-8-[(2-naphthalen-1 -yl-acetylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 67.7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 3.97 (s, 3H); 4.05 (s, 3H); 4.80 (d, 6 Hz, 2H); 7.44-7.54 (m, 5H); 7.83 (dd, 7.2 and 1 .6 Hz, 1 H); 7.91 -7.94 (m, 1 H); 8.05 (d, 2.4 Hz, 1 H); 8.08-8.12 (m, 1 H); 8.58 (t, 5.6 Hz, 1 H); 8.74 (s, 1 H).
[00213] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-naphthalen-1 -yl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 67.5% yield. 1H-NMR (400 MHz, DMSO-de), δ (ppm): 4.02 (s, 2H); 4.54 (d, 6 Hz, 2H); 7.40-7.50 (m 4H); 7.61 (d, 2.4 Hz, 1 H); 7.84 (t, 5.2 Hz, 1 H); 7.92 (d, 8 Hz, 1 H); 7.98 (d, 8 Hz, 1 H); 8.10 (d, 2.4 Hz, 1 H); 8.74 (t, 6 Hz, 1 H); 8.91 (s, 1 H).
Example 36
6-Chloro-8-{[2-(2-hydroxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00214] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-hydroxyphenyl)- acetic acid gives 6-chloro-8-{[(2-hydroxyphenyl)-acetylamino]-methyl}-2-methoxy- quinoline-3-carboxylic acid methyl ester in 41 .6% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.52 (s, 2H); 3.88 (s, 3H); 4.02 (s, 3H); 4.79 (d, 6 Hz, 2H); 6.74 (td, 7.6 and 1 .2 Hz, 1 H); 6.81 (dd, 8 and 1 .2 Hz, 1 H); 7.06 (td, 7.6 and 1 .6 Hz, 1 H); 7.1 1 (dd, 7.2 and 1 .6 Hz, 1 H); 7.60 (d, 2.4 Hz, 1 H); 8.07 (d, 2.4 Hz, 1 H); 8.37 (t, 5.6 Hz, 1 H); 8.76 (s, 1 H); 9.61 (s, 1 H).
[00215] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[(2- hydroxyphenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 22% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.47 (s, 2H); 4.53 (d, 6 Hz, 2H); 6.73 (t, 7.6 Hz, 1 H); 6.79 (d, 7.6 Hz, 1 H); 7.05 (dd, 7.6 and 1 .6 Hz, 1 H); 7.09 (d, 7.6 Hz, 1 H); 7.68 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.55 (t, 5.6 Hz, 1 H); 8.93 (s, 1 H); 9.49 (s, 1 H)..
Example 37
6-Chloro-2-oxo-8-[(4-phenyl-butyrylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00216] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 4-phenylbutyric acid gives 6-chloro-2-methoxy-8-[(4-phenyl-butyrylamino)-methyl]-quinoline-3-carboxylic acid methyl ester in 75% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .86 (m, 2H); 2.24 (t, 7.2 Hz, 2H); 2.59 (t, 7.2 Hz, 2H); 3.88 (s, 3H); 4.06 (s, 3H); 4.79 (d, 6 Hz, 2H); 7.18 (d, 7.6 Hz, 2H; overlapping m, 1 H); 7.28 (t, 7.6 Hz, 2H); 7.57 (d, 2.4 Hz, 1 H); 8.07 (d, 2.4 Hz, 1 H); 8.35 (t, 6 Hz, 1 H); 8.76 (s, 1 H).
[00217] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(4-phenyl-butyrylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 67.5% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .82 (m, 2H); 2.21 (t, 7.2 Hz, 2H); 2.52 (t, 7.2 Hz, 2H); 4.54 (d, 6 Hz, 2H); 7.15 (d, 7.6 Hz, 2H; overlapping m, 1 H); 7.25 (t, 7.6 Hz, 2H); 7.69 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.73 (t, 6 Hz, 1 H); 8.93 (s, 1 H).
Example 38
6-Chloro-8-{[2-(4-chloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00218] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-chlorophenyl)- acetic acid gives 6-chloro-8-{[(4-chlorophenyl)-acetylamino]-methyl}-2-methoxy- quinoline-3-carboxylic acid methyl ester in 77.7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.56 (s, 2H); 3.88 (s, 3H); 4.02 (s, 3H); 4.77 (d, 5.6 Hz, 2H); 7.33 (d, 8.8 Hz, 2H); 7.37 (d, 8.8 Hz, 2H); 7.46 (d, 2.4 Hz, 1 H); 8.06 (d, 2.4 Hz, 1 H); 8.57 (t, 5.6 Hz, 1 H); 8.75 (s, 1 H).
[00219] b) in analogy to the procedure described in Example 3(b), 6-chloro-8-{[(4- chlorophenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59.7% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.54 (s, 2H); 4.54 (d, 6 Hz, 2H); 7.30 (d, 8 Hz, 2H); 7.36 (d, 8 Hz, 2H); 7.58 (d, 2.4 Hz, 1 H); 8.1 1 (d, 2.4 Hz, 1 H); 8.80 (t, 6 Hz, 1 H); 8.92 (s, 1 H).
Example 39
6-Chloro-2-oxo-8-[(2^henyl^ropionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid (I-39)
[00220] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2-phenyl-propionic acid gives 6-chloro-2-methoxy-8-[(2-phenyl-propionylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 57.7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .38 (d, 7 Hz, 3H); 3.76 (q, 7 Hz, 1 H); 3.87 (s, 3H); 4.00 (s, 3H); 4.70 (dd, 16.6 and 6 Hz, 1 H); 4.80 (dd, 16.6 and 6 Hz, 1 H); 7.24 (t, 7.2 Hz, 1 H); 7.30-7.38 (m, 5H); 7.30-7.38 (m, 5H); 8.03 (d, 2 Hz, 1 H); 8.47 (t, 6 Hz, 1 H); 8.74 (s, 1 H).
[00221 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-phenyl-propionylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 50.2% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .36 (d, 7 Hz, 3H); 3.70 (q, 7 Hz, 1 H); 4.48 (dd, 16 and 6 Hz, 1 H); 4.55 (dd, 16 and 6 Hz, 1 H); 7.20-7.24 (m 1 H); 7.26-7.33 (m 4H); 7.46 (d, 2 Hz, 1 H); 8.08 (d, 2 Hz, 1 H); 8.72 (t, 6 Hz, 1 H); 8.91 (s, 1 H).
Example 40
8-{[2-(2-Bromo-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00222] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-bromophenyl)- acetic acid gives 8-{[2-(2-bromo-phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy- quinoline-3-carboxylic acid methyl ester in 64% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.75 (s, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 4.81 (d, 5.8 Hz, 2H); 7.20 (td, 7.6 and 1 .6 Hz, 1 H); 7.34 (td, 7.6 and 1 .2 Hz, 1 H); 7.41 (dd, 8 and 2 Hz, 1 H); 7.60 (dd, 7.6 and 1 .6 Hz, 1 H); 7.66 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.55 (t, 5.8 Hz, 1 H); 8.76 (s, 1 H).
[00223] b) in analogy to the procedure described in Example 3(b), 8-{[2-(2-bromo- phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 53% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 3.72 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.21 (td, 7.6 and 1 .6 Hz, 1 H); 7.32-7.40 (m, 2H); 7.59 (d, 7.6 Hz, 1 H); 7.71 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.73 (t, 6 Hz, 1 H); 8.93 (s, 1 H).
Example 41
6-Chloro-2-oxo-8-{[(quinoline-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00224] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with quinoline-2- carboxylic acid gives 6-chloro-2-methoxy-8-[(quinoline-2-carbonylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 77% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.20 (s, 3H); 5.09 (d, 6 Hz, 2H); 7.70-7.76 (m, 2H); 7.87-7.91 (m, 1 H); 8.08-8.14 (m, 3H); 8.19 (d, 8 Hz, 1 H); 8.59 (d, 8 Hz, 1 H); 8.80 (s, 1 H); 9.61 (t, 6 Hz, 1 H).
[00225] b) in analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(quinoline-2-carbonylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 45.4% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.81 (d, 6.4 Hz, 2H); 7.74 (td, 7.4 and 1.2 Hz, 1 H); 7.85 (d, 2.4 Hz, 1 H); 7.89 (td, 7.4 and 1.2 Hz, 1 H); 8.08 - 8.16 (m, 3H); 8.17 (d, 8 Hz, 1 H); 8.59 (d, 8 Hz, 1 H); 8.93 (s, 1 H); 9.86 (t, 6.4 Hz, 1 H) and 12.64 (br s, 1 H).
Example 42
6-Chloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00226] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-fluorophenyl)- acetic acid gives 6-chloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-methoxy- quinoline-3-carboxylic acid methyl ester in 77.3% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm): 3.63 (s, 2H); 3.87 (s, 3H); 4.03 (s, 3H); 4.80 (d, 5.5 Hz, 2H); 7.10-7.40 (m, 4H); 7.58 (s, 1 H); 8.08 (s, 1 H); 8.62 (t, 5.5 Hz, 1 H); 8.76 (s, 1 H).
[00227] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (2-fluoro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 81 .4% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm: 3.61 (s, 2H); 4.57 (d, 2H); 7.10-7.40 (m, 4H); 7.65 (s, 1 H); 8.12 (s, 1 H); 8.81 (t, 1 H); 8.93 (s, 1 H).
Example 43
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00228] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2,6- difluorophenyl)-acetic acid gives 6-chloro-8-{[2-(2,6-difluoro-phenyl)-acetylamino]- methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 83% yield. 1H-NMR (200 MHz, DMSO-d6), δ (ppm): 3.67 (s, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 4.80 (d, 6 Hz, 2H); 7.09 (t, 8 Hz, 1 H); 7.37 (m, 1 H); 7.61 (s, 1 H); 8.09 (s, 1 H); 8.71 (t, 6 Hz, 1 H); 8.77 (s, 1 H).
[00229] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (2,6-difluoro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 82.8% yield. 1H-NMR (200 MHz, DMSO-de), δ (ppm: 3.65 (s, 2H); 4.56 (d, 5.6 Hz, 2H); 7.09 (t, 8 Hz, 1 H); 7.37 (m, 1 H); 7.64 (s, 1 H); 8.13 (s, 1 H); 8.88 (t, 5.6 Hz, 1 H); 8.93 (s, 1 H).
Example 44
6-Chloro-8-{[2-(4-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00230] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-dimethylamino- phenyl)-acetic acid gives 6-chloro-8-{[2-(4-dimethylamino-phenyl)-acetylamino]-methyl}-
2-methoxy-quinoline-3-carboxylic acid methyl ester in 69.7% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.86 (s, 6H); 3.40 (s, 2H); 3.88 (s, 3H); 4.01 (s,
3H); 4.75 (d, 6 Hz, 2H); 6.67 (d, 8.8 Hz, 2H); 7.12 (d, 8.8 Hz, 2H); 7.45 (d, 2.4 Hz, 1 H);
8.05 (d, 2.4 Hz, 1 H); 8.37 (t, 6 Hz, 1 H); 8.75 (s, 1 H).
[00231 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (4-dimethylamino-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as hydrobromide dihydrate in 75.8% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.03 (s, 6H); 3.51 (s, 2H); 4.53 (d, 6 Hz, 2H); 7.20 (unresolved m, 2H); 7.30 (d, 8 Hz, 2H); 7.61 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.81 (t, 1 H); 8.92 (s, 1 H).
Example 45 6-Chloro-2-oxo-8-{[(thiazole-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00232] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with thiazole-2- carboxylic acid gives 6-chloro-2-methoxy-8-{[(thiazole-2-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 79% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.10 (s, 3H); 5.01 (d, 5.6 Hz, 2H); 7.63 (d, 2.4 Hz, 1 H); 8.05-8.10 (m, 2H); 8.1 1 (d, 2.4 Hz, 1 H); 8.79 (s, 1 H); 9.44 (t, 6 Hz, 1 H).
[00233] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(thiazole-2-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 72.8% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.72 (d, 6 Hz, 2H); 7.76 (d, 2.4 Hz, 1 H); 8.06 (d, 2.8 Hz, 1 H); 8.08 (d, 2.8 Hz, 1 H); 8.15 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 9.65 (t, 6 Hz, 1 H).
Example 46
6-Chloro-2-oxo-8-{[(thiazole-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00234] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with thiazole-4- carboxylic acid gives 6-chloro-2-methoxy-8-{[(thiazole-4-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 94% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.12 (s, 3H); 5.00 (d, 6 Hz, 2H); 7.60 (d, 2.4 Hz, 1 H); 8.10 (d, 2.4 Hz, 1 H); 8.38 (d, 2 Hz, 1 H); 8.79 (s, 1 H); 9.12 (t, 6 Hz, 1 H); 9.22 (d, 2 Hz, 1 H). [00235] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(thiazole-4-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 50.3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.69 (d, 6.4 Hz, 2H); 7.76 (d, 2 Hz, 1 H); 8.14 (d, 2 Hz, 1 H); 8.40 (d, 2 Hz, 1 H); 8.92 (s, 1 H); 9.22 (d, 2 Hz, 1 H); 9.44 (t, 6.4 Hz, 1 H).
Example 47
6-Chloro-2-oxo-8-{[(thiazole-5-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00236] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with thiazole-5- carboxylic acid gives 6-chloro-2-methoxy-8-{[(thiazole-5-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 90% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.06 (s, 3H); 5.00 (d, 5.6 Hz, 2H); 7.66 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.56 (s, 1 H); 8.78 (s, 1 H); 9.22 (t, 5.6 Hz, 1 H); 9.26 (s, 1 H).
[00237] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(thiazole-5-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 63.9% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.76 (d, 6 Hz, 2H); 7.72 (d, 2.4 Hz, 1 H); 8.16 (d, 2 Hz, 1 H); 8.51 (s, 1 H); 8.94 (s, 1 H); 9.27 (s, 1 H); 9.43 (t, 6 Hz, 1 H).
Example 48
6-Chloro-8-{[(3,4-dihydro-2H-benzo[b][1 ,4]dioxepine-7-carbonyl)-amino]-methyl}- 2-OXO-1 ,2-dihydro-quinoline-3-carboxylic acid
[00238] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 3,4-dihydro-2H-1 ,5- benzodioxepine-7-carboxylic acid gives 6-chloro-8-{[(3,4-dihydro-2H-1 ,5- benzodioxepine-7-carbonyl)-amino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 71 % yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.14 (m, 2H); 3.88 (s, 3H); 4.07 (s, 3H); 4.16- 4.22 (m, 4H); 4.98 (d, 6 Hz, 2H); 7.04 (d, 8 Hz, 1 H); 7.52-7.58 (m, 3H); 8.09 (d, 2 Hz, 1 H); 8.78 (s, 1 H): 8.92 (t, 6 Hz, 1 H).
[00239] b) in analogy to the procedure described in Example 3(b), 6-chloro-8- {[(3,4-dihydro-2H-1 ,5-benzodioxepine-7-carbonyl)-amino]-methyl}-2-methoxy-quinoline- 3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 22.3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.14 (m, 2H); 4.15-4.22 (m, 4H); 4.72 (d, 6 Hz, 2H); 7.04 (d, 8 Hz, 1 H); 7.48-7.53 (m, 2H); 7.69 (d, 2 Hz, 1 H); 8.14 (d, 2 Hz, 1 H); 8.92 (s, 1 H); 9.20 (t, 6 Hz, 1 H).
Example 49
8-{[(Benzothiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00240] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with benzothiazole-5- carboxylic acid gives 8-{[(benzothiazole-5-carbonyl)-amino]-methyl}-6-chloro-2- methoxy-quinoline-3-carboxylic acid methyl ester in 81 % yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.09 (s, 3H); 5.08 (d, 6 Hz, 2H); 7.66 (d, 2 Hz, 1 H); 8.05 (dd, 8 and 1 .6 Hz, 1 H); 8.1 1 (d, 2 Hz, 1 H); 8.30 (d, 8 Hz, 1 H); 8.68 (s, 1 H); 8.79 (s, 1 H); 9.24 (t, 6 Hz, 1 H); 9.50 (s, 1 H).
[00241 ] b) In analogy to the procedure described in Example 3(b), 8- {[(benzothiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.81 (d, 5.6 Hz, 2H); 7.77 (d, 2.4 Hz, 1 H); 8.00 (dd, 8 and 1 .6 Hz, 1 H); 8.30 (d, 8 Hz, 1 H); 8.63 (s, 1 H); 8.94 (s, 1 H); 9.50 (s, 1 H overlaped by t, 5.6 Hz, 1 H).
Example 50
6-Chloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00242] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with imidazol-1 -yl-acetic acid gives 6-chloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-methoxy-quinoline-3- carboxylic acid methyl ester in 66.2% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.04 (s, 3H); 4.80 (s, 2H) 4.82 (d, 2H); 5.04 (s, 2H); 6.88 (s, 1 H); 7.13 (s, 1 H); 7.60 (s, 1 H); 7.65 (s, 1 H); 8.10 (s, 1 H); 8.64 (t, 1 H); 8.77 (s, 1 H).
[00243] b) in analogy to the procedure described in Example 3(b), 6-chloro-8-[(2- imidazol-1 -yl-acetylamino)-methyl]-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 61 .5% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm: 4.65 (s, 2H); 5.15 (s, 2H); 7.09 (t, 8 Hz, 1 H); 7.68-7.73 (m, 3H); 8.14 (s, 1 H); 8.94 (s, 1 H); 9.07 (br s, 2H.
Example 51
8-{[(Benzothiazole-6-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00244] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with benzothiazole-6- carboxylic acid gives 8-{[(benzothiazole-6-carbonyl)-amino]-methyl}-6-chloro-2- methoxy-quinoline-3-carboxylic acid methyl ester in 87% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.09 (s, 3H); 5.05 (d, 5.6 Hz, 2H);
7.66 (d, 2 Hz, 1 H); 8.08-8.12 (m, 2H); 8.19 (d, 8 Hz, 1 H); 8.75 (d, 1 .6 Hz, 1 H); 8.79 (s, 1 H); 9.18 (t, 5.6 Hz, 1 H); 9.55 (s, 1 H).
[00245] b) In analogy to the procedure described in Example 3(b), 8- {[(benzothiazole-6-carbonyl)-amino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 78% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.81 (d, 6 Hz, 2H); 7.76 (d, 2.4 Hz, 1 H); 8.04 (dd, 8.8 and 1 .6 Hz, 1 H); 8.16 (d, 2.4 Hz, 1 H); 8.19 (d, 8.8 Hz, 1 H); 8.73 (s, 1 H); 8.94 (s, 1 H); 9.47 (t, 6 Hz, 1 H); 9.55 (s, 1 H).
Example 52
6-Chloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00246] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-chloro-6- fluorophenyl)-acetic acid gives 6-chloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]- methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 81 % yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.79 (s, 2H); 3.88 (s, 3H); 4.05 (s, 3H); 4.81 (d,
6 Hz, 2H); 7.20-7.25 (m, 1 H); 7.32-7.37 (m, 2H); 7.73 (d, 2 Hz, 1 H); 8.08 (d, 2 Hz, 1 H);
8.67 (t, 6 Hz, 1 H); 8.76 (s, 1 H).
[00247] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound 66.7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 3.76 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.20-7.25 (m 1 H); 7.31 -7.40 (m, 2H); 7.67 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.84 (t, 6 Hz, 1 H); 8.94 (s, 1 H).
Example 53 6-Chloro-8-{[2-(2,3-difluoro^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00248] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2,3- difluorophenyl)-acetic acid gives 6-chloro-8-{[2-(2,3-difluoro-phenyl)-acetylamino]- methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 73% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.70 (s, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 4.81 (d,
6 Hz, 2H); 7.12-7.21 (m, 2H); 7.26-7.35 (m, 1 H); 7.58 (d, 2.4 Hz, 1 H); 8.08 (d, 2.4 Hz,
1 H); 8.63 (t, 6 Hz, 1 H); 8.76 (s, 1 H).
[00249] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (2,3-difluoro-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 51 .4% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 3.68 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.12-7.19 (m, 2H); 7.28-7.37 (m, 2H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.84 (t, 6 Hz, 1 H); 8.93 (s, 1 H).
Example 54
6-Chloro-2-oxo-8-{[2-(2-trifluoromethyl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
[00250] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-trifluoromethyl- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(2-trifluoromethyl-phenyl)- acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester in 73% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.82 (s, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 4.81 (d, 6 Hz, 2H); 7.47 (t, 7.6 Hz, 1 H); 7.50 (d, 7.6 Hz, 1 H); 7.59 (d, 2.4 Hz, 1 H); 7.62 (t, 7.6 Hz, 1 H); 7.69 (d, 7.6 Hz, 1 H); 8.08 (d, 2.4 Hz, 1 H); 8.56 (t, 6 Hz, 1 H); 8.76 (s, 1 H). [00251 ] b) n analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(2-trifluoromethyl-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 63.8% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm: 3.80 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.45-7.52 (m, 2H); 7.61 -7.66 (m, 2H); 7.69 (d, 8 Hz, 1 H); 8.1 1 (d, 2.4 Hz, 1 H); 8.73 (t, 6 Hz, 1 H); 8.91 (s, 1 H).
Example 55
6-Chloro-8-[(5-nitro^yridin-2-ylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00252] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 44(a), arylation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2-chloro-5- nitropyridine gives 6-chloro-2-methoxy-8-[(5-nitro-pyridin-2-ylamino)-methyl]-quinoline- 3-carboxylic acid methyl ester as a yellow solid in 79% yield.
[00253] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(5-nitro-pyridin-2-ylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 69% yield as a light grey solid. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.90 (d, 6 Hz, 2H); 6.72 (d, 8.8 Hz, 1 H); 7.71 (d, 2 HZ, 2H); 8.14 (d, 2 Hz, 1 H); 8.20 (dd, 8.8 and 2.4 Hz, 1 H); 8.63 (br s, 1 H); 8.93- 8.97 (m, 2H).
Example 56
6-Chloro-2-oxo-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline- 3-carboxylic acid
[00254] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with [1 ,2,4]triazol-1 -yl- acetic acid gives 6-chloro-2-methoxy-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 73.7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.05 (s, 3H); 4.83 (d, 5.5 Hz, 2H); 5.04 (s, 2H); 7.69 (s, 1 H); 7.99 (s, 1 H); 8.1 1 (d, 1 .6 Hz, 1 H); 8.74 (t, 5.5 Hz, 1 H); 8.77 (s, 1 H).
[00255] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 31 .7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.60 (d, 6 Hz, 2H); 5.04 (s, 2H); 7.69 (d, 2 Hz, 1 H); 8.00 (s, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.52 (s, 1 H); 8.82 (t, 6 Hz, 1 H); 8.93 (s, 1 H).
Example 57
6-Chloro-2-oxo-8-(1 -oxo-1 ,3-dihydro-isoindol-2-ylmethyl)-1 ,2-dihydro-quinoline-3- carboxylic acid
[00256] The title compound is prepared by the following reaction sequence:
a) A mixture of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate hydrochloride (10a) (87 mg, 0.27 mmol) and benzene-1 ,2-dicarbaldehyde (37 mg, 0.28 mmol) in acetonitrile (10 ml_) is stirred under reflux for 30 h (LC-MS control; product - 55%). Then acetonitrile (10 ml_) is added and the mixture is stirred under reflux for 65 h (LC-MS; product - 78.3%). Benzene-1 ,2-dicarbaldehyde (8 mg, 0.06 mmol) is added and the mixture is stirred under reflux for additional 45 h. According to LC-MS (conversion 95.5%) the product consists of a mixture - 6-chloro-2-methoxy-8-(1 -oxo-1 ,3- dihydro-isoindol-2-ylmethyl)-quinoline-3-carboxylic acid and its methyl ester (10 :90). Solvent is removed under reduced pressure and the residue is used in the next step without additional purification.
[00257] b) In analogy to the procedure described in Example 3(b), a mixture of 6- chloro-2-methoxy-8-(1 -oxo-1 ,3-dihydro-isoindol-2-ylmethyl)-quinoline-3-carboxylic acid and its methyl ester (10 :90) is treated with HBr in AcOH to give the title compound in 75% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm: 4.54 (s, 2H); 5.05 (s, 2H); 7.52 (t, 7.6 Hz, 1 H); 7.57-7.65 (m, 2H); 7.79 (d, 7.6 Hz, 1 H); 7.86 (d, 2.4 Hz, 1 H); 8.18 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H).
Example 58
6-Chloro-8-{[2-(4-fluoro-2-methyl^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00258] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-fluoro-2- methylphenyl)-acetic acid gives 6-chloro-8-{[2-(4-fluoro-2-methylphenyl)-acetylamino]- methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester in 76.2% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.26 (s, 3H); 3.57 (s, 2H); 3.88 (s, 3H); 4.02 (s,
3H); 4.79 (d, 6 Hz, 2H); 6.95 (td, 8.8 and 2.8 Hz, 1 H); 7.01 (dd, 9.2 and 2.8 Hz, 1 H);
7.26 (dd, 8 and 6 Hz, 1 H); 7.53 (d, 2.4 Hz, 1 H); 8.07 (d, 2.4 Hz, 1 H); 8.46 (t, 6 Hz, 1 H);
8.76 (s, 1 H).
[00259] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (4-fluoro-2-methylphenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 48% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 2.22 (s, 3H); 3.55 (s, 2H); 4.54 (d, 6 Hz, 2H); 6.95 (td, 8.4 and 2.4 Hz, 1 H); 7.00-7.04 (m, 1 H); 7.23 (t, 7.6 Hz, 1 H); 7.63 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.66 (t, 6 Hz, 1 H); 8.92 (s, 1 H).
Example 59
6-Chloro-8-{[(2-methyl-thiazole-4-carbonyl)-amino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00260] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2-methyl-thiazole- 4-carboxylic acid gives 6-chloro-2-methoxy-8-{[(2-methyl-thiazole-4-carbonyl)-amino]- methyl}-quinoline-3-carboxylic acid methyl ester in 63.4% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.72 (s, 3H); 3.89 (s, 3H); 4.12 (s, 3H); 4.96 (d, 6 Hz, 2H); 7.59 (d, 2 Hz, 1 H); 8.09 (d, 2 Hz, 1 H); 8.14 (s, 1 H); 8.78 (s, 1 H); 9.00 (t, 6 Hz, 1 H).
[00261 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(2-methyl-thiazole-4-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 71.2% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm: 2.71 (s, 3H); 4.66 (d, 6.4 Hz, 2H); 7.77 (d, 2.4 Hz, 1 H); 8.14 (d, 2 Hz, 1 H); 8.17 (s, 1 H); 8.92 (s, 1 H); 9.30 (s, 1 H).
Example 60
6-Chloro-2-oxo-8-{[2-(3-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid (I-62)
[00262] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (3-phenoxy- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(3-phenoxy-phenyl)-acetylamino]- methyl}-quinoline-3-carboxylic acid methyl ester.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 3.88 (s, 3H); 4.01 (s, 3H); 4.77 (d, 6 Hz, 2H); 6.87 (d, 7.2 Hz, 1 H); 6.97-7.02 (m, 3H); 7.07-7.15 (m, 2H); 7.36-7.39 (m, 3H); 7.48 (s, 1 H); 8.07 (s, 1 H); 8.54 (t, 6 Hz, 1 H); 8.75 (s, 1 H).
[00263] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(3-phenoxy-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound.
1H-NMR (200 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 4.54 (d, 5.6 Hz, 2H); 6.85-7.16 (m, 6H); 7.27-7.41 (m, 3H); 7.58 (s, 1 H); 8.1 1 (s, 1 H); 8.81 (t, 5.6 Hz, 1 H); 8.91 (s, 1 H).
Example 61 6-Chloro-2-oxo-8-{[(oxazole-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00264] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with oxazole-4- carboxylic acid gives 6-chloro-2-methoxy-8-{[(oxazole-4-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 3H); 4.10 (s, 3H); 4.96 (d, 6 Hz, 2H); 7.57 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.55 (s, 1 H); 8.69 (s, 1 H); 8.78 (s, 1 H); 8.91 (t, 6 Hz, 1 H).
[00265] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(oxazole-4-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.56 (d, 6 Hz, 2H); 7.73 (s, 1 H); 8.14 (s, 1 H); 8.56 (s, 1 H); 8.71 (s, 1 H); 8.92 (s, 1 H); 9.21 (t, 6 Hz, 1 H).
Example 62
8-[(2-Amino-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00266] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with tert- butoxycarbonylamino-acetic acid acid gives 8-[(2-tert-butoxycarbonylamino- acetylamino)-methyl]-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester as light yellow solid in 64.8% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm): 1 .39 (s, 9H); 3.61 (d, 6 Hz, 2H); 3.88 (s, 3H); 4.07 (s, 3H); 4.79 (d, 6 Hz, 2H); 7.18 (t, 7.2 Hz, 1 H); 7.64 (s, 1 H); 8.07 (s, 1 H); 8.33 (t, 6 Hz, 1 H); 8.77 (s, 1 H). [00267] b) In analogy to the procedure described in Example 3(b), 8-[(2-tert- butoxycarbonylamino-acetylamino)-methyl]-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as hydrobromide in 70.7% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm: 3.71 (s, 2H); 4.66 (d, 2H); 7.70 (s, 1 H); 8.00 (br s, 3H); 8.14 (s, 1 H); 8.94 (br, 2H).
Example 63
8-[(2-Amino-3-phenyl-propionylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00268] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 2-tert- butoxycarbonylamino-3-phenyl-propionic acid gives 8-[(2-tert-butoxycarbonylamino-3- phenyl-propionylamino)-methyl]-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester in 77% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm): 1 .31 (s, 9H); 2.73-3.03 (m, 2H); 3.88 (s, 3H); 4.06 (s, 3H); 4.21 (m, 1 H); 4.80 (d, 6 Hz, 2H); 7.10-7.27 (m, 6H); 7.61 (s, 1 H); 8.07 (s, 1 H); 8.47 (t, 6 Hz, 1 H); 8.76 (s, 1 H).
[00269] b) In analogy to the procedure described in Example 3(b), 8-[(2-tert- butoxycarbonylamino-3-phenyl-propionylamino)-methyl]-6-chloro-2-methoxy-quinoline- 3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as hydrobromide in 70% yield.
1H-NMR (200 MHz, DMSO-d6), δ (ppm: 3.02 (m, 2H); 4.08 (t, 2H); 4.57 (br s, 2H); 7.10- 7.17 (m, 5H); 7.58 (s, 1 H); 8.12 (s, 1 H); 8.26 (br s, 3H); 8.91 and 8.95 (s, 1 H overlaped by t, 1 H).
Example 64
6-Chloro-2-oxo-8-{[2-(2-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid [00270] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-phenoxy- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(2-phenoxy-phenyl)-acetylamino]- methyl}-quinoline-3-carboxylic acid methyl ester in 70% yield.
[00271 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(2-phenoxy-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.60 (s, 2H); 4.49 (d, 5 Hz, 2H); 6.74-6.80 (m, 3H); 7.01 (t, 7.6 Hz, 1 H); 7.1 1 (t, 7.6 Hz, 1 H); 7.18-7.24 (m, 3H); 7.37 (d, 7.2 Hz, 1 H);7.65 (s, 1 H); 8.09 (s, 1 H); 8.65 (t, 5 Hz, 1 H); 8.88 (s, 1 H).
Example 65
6-Chloro-2-oxo-8-{[(quinoline-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00272] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with quinoline-6- carboxylic acid gives 6-chloro-2-methoxy-8-[(quinoline-6-carbonylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 75% yield;
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.09 (s, 3H); 5.09 (d, 5.6 Hz, 2H); 7.62 (dd, 8 and 4 Hz, 1 H); 7.68 (d, 2 Hz, 1 H); 8.10-8.13 (m, 2H); 8.26 (dd, 8.8 and 1 .6 Hz, 1 H); 8.50 (d, 7.2 Hz, 1 H); 8.60 (s, 1 H); 8.79 (s, 1 H); 9.00 (m, 1 H); 9.28 (t, 5.6 Hz, 1 H).
[00273] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(quinoline-6-carbonylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 51 % yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.84 (d, 5.2 Hz, 2H); 7.68 (dd, 8 and 4 Hz, 1 H); 7.79 (d, 2 Hz, 1 H); 8.12-8.19 (m, 2H); 8.24 (d, 2 Hz, 1 H); 8.59 (d, 8 Hz, 1 H); 8.61 (s, 1 H); 8.95 (s, 1 H); 9.04 (d, 2 Hz,1 H); 9.59 (t, 5.2 Hz, 1 H).
Example 66
8-{[2-(4-tert-Butyl-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00274] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-tert-butyl- phenyl)-acetic acid gives 8-{[2-(4-tert-butyl-phenyl)-acetylamino]-methyl}-6-chloro-2- methoxy-quinoline-3-carboxylic acid methyl ester in 56.6% yield.
[00275] b) In analogy to the procedure described in Example 3(b), 8-{[2-(4-tert- butyl-phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 49% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .25 (s, 9H); 3.48 (s, 2H); 4.53 (br s, 2H); 7.19 (d, 8 Hz, 2H); 7.31 (d, 8 Hz, 2H); 7.58 (s, 1 H); 8.1 1 (s, 1 H); 8.78 (br s, 1 H); 8.91 (s, 1 H) and 12.47 (br s, 1 H).
LC-MS: 427.6 [M+H].
Example 67
6-Chloro-2-oxo-8-{[2-(4-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
[00276] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-tetrazol-1 -yl- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[(2-(4-tetrazol-1 -yl-phenyl)- acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester in 90.2% yield. [00277] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(4-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 57.6% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.67 (s, 2H); 4.56 (d, 6.4 Hz, 2H); 7.54 (d, 8 Hz, 2H); 7.61 (d, 2 Hz, 1 H); 7.85 (d, 8 Hz, 2H); 8.1 1 (d, 2 Hz, 1 H); 8.87 (t, 6 Hz,1 H); 8.91 (s, 1 H); 10.06 (s, 1 H) and 12.44 (br s, 1 H).
LC-MS: 437.3 [M-H] [35CI].
Example 68
6-Chloro-2-oxo-8-{[2-(4-pyrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
[00278] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-pyrazol-1 -yl- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[(2-(4-pyrazol-1 -yl-phenyl)- acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester in 86.7% yield.
[00279] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(2-(4-pyrazol-1 -yl-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 75.3% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.58 (s, 2H); 4.55 (d, 6.4 Hz, 2H); 6.53 (d, 2.2 Hz, 1 H); 7.39 (d, 8.4 Hz, 2H); 7.61 (d, 2 Hz, 1 H); 7.72 (d, 2 Hz, 1 H); 7.78 (d, 8.8 Hz, 2H); 8.12 (d, 2.4 Hz, 1 H); 8.46 (d, 2.4 Hz, 1 H); 8.82 (t, 6 Hz, 1 H); 8.92 (s, 1 H) and 12.48 (br s, 1 H).
LC-MS: 435.5 [M-H]. Example 69
6-Chloro-2-oxo-8-{[(pyridazine-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid
[00280] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyridazine-4- carboxylic acid gives 6-chloro-2-methoxy-8-{[(pyridazine-4-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 66.4% yield.
[00281 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(pyridazine-4-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 66.4% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.82 (d, 5.6 Hz, 2H); 7.78 (d, 2 Hz, 1 H); 8.04
(dd, 5.4 and 2.2 Hz, 1 H); 8.16 (d, 2 Hz, 1 H); 8.95 (s, 1 H); 9.46 (d, 4.8 Hz, 1 H); 9.58 (s,
1 H); 9.66 (t, 5.6 Hz, 1 H) and 12.42 (br s, 1 H).
LC-MS: 357.4 [M-H].
Example 70
8-{[(Benzo[1 ,2,5]oxadiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid
[00282] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with benzo[1 ,2,5]oxadiazole-5-carboxylic acid gives 8-{[(benzo[1 ,2,5]oxadiazole-5-carbonyl)- amino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester in 83% yield.
[00283] b) In analogy to the procedure described in Example 3(b), 8- {[(benzo[1 ,2,5]oxadiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-methoxy-quinoline-3- carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 69% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.82 (d, 5.6 Hz, 2H); 7.78 (s, 1 H); 7.97 (d, 9.6 Hz, 1 H); 8.10-8.20 (m, 2H); 8,60 (s, 1 H); 8.94 (s, 1 H); 9.59 (s, 1 H) and 12.44 (br s, 1 H). LC-MS: 397.2 [M-H] [35CI]. Example 71
6-Chloro-2-oxo-8-{[(pyrimidine-5-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid
[00284] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyrimidine-5- carboxylic acid gives 6-chloro-2-methoxy-8-{[(pyrimidine-5-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 61 .3% yield.
[00285] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(pyrimidine-5-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 93% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.81 (d, 6 Hz, 2H); 7.78 (d, 2 Hz, 1 H); 8.16 (d,
2.4 Hz, 1 H); 8.95 (s, 1 H); 9.21 (s, 2H); 9.34 (s, 1 H); 9.54 (t, 5.6 Hz, 1 H) and 12.46 (br s,
1 H).
LC-MS: 359.2 [M+H]. Example 72
8-{[2-(3-Amino-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00286] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (3-tert- butoxycarbonylamino-phenyl)-acetic acid gives 8-{[2-(3-tert-butoxycarbonylamino- phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester in 47.7% yield.
[00287] b) In analogy to the procedure described in Example 3(b), 8-{[2-(3-tert- butoxycarbonylamino-phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy-quinoline-3- carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as hydrobromide hydrate in 79.8% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.58 (s, 2H); 4.55 (d, 6 Hz, 2H); 7.08-7.18 (m, 3H); 7.36 (t, 8 Hz, 1 H); 7.63 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.85-8.95 (m, 2H) and 12.42 (br s, 1 H).
LC-MS: 386.4 [M+H].
Example 73
6-Chloro-8-{[2-(2-methyl^hiazol-4-yl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00288] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-methyl-thiazol-4- yl)-acetic acid gives 6-chloro-2-methoxy-8-{[(2-methyl-thiazol-4-yl)-acetylamino]- methyl}-quinoline-3-carboxylic acid methyl ester in 71 % yield.
[00289] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(2-methyl-thiazol-4-yl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 45.3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.62 (s, 3H); 3.63 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.25 (s, 1 H); 7.69 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.76 (t, 6 Hz, 1 H); 8.93 (s, 1 H) and12.46 (br s, 1 H).
LC-MS: 390.1 [M-H] [35CI].
Example 74
8-[(3-Acetylamino-pyridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-[(3-nitro-pyridin-2-ylamino)-methyl]-quinoline-3- carboxylate [00290] A mixture of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3- carboxylate hydrochloride (100 mg, 0.3 mmol), 2-chloro-3-nitropyridine (60 mg, 0.4 mmol) and potassium carbonate (108 mg, 0.8 mmol) in acetonitrile (3 mL) is stirred and heated at 1 10 °C for 5 h in closed reaction vial. After cooling, precipitates are filtered off, washed with cold acetonitrile, 20% aqueous acetic acid, water, and dried to give the title compound (1 15 mg, 90%) as a yellow solid.
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.10 (s, 3H); 5.29 (d ,5 Hz, 2H); 6.79 (m, 1 H); 7.64 (s, 1 H); 8.07 (s, 1 H); 8.43 (s, 1 H); 8.47 (s, 1 H); 8.78 (s, 1 H) and 9.09 (s, 1 H).
LC-MS: 403.3 [M+H]. b) 8-[(3-Acetylamino^yridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00291 ] To a suspension of methyl 6-chloro-2-methoxy-8-[(3-nitro-pyrdin-2- ylamino)-methyl]-quinoline-3-carboxylate (1 13 mg, 0.3 mmol) and zink dust (128 mg, 2.0 mmol) in DMF (25 mL) is added acetic acid (15 drops). The mixture is stirred at rt overnight. Precipitates are filtered off, solvent evaporated and the residue is washed with ether (5 mL) to give 1 .7 g of oily product. LC-MS: 373.4 [M+H]. The oily product is heated in HBr (33 wt% in AcOH, 3 mL) at 85 °C for 20 h. Solvents are evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel (MeOH/DCM/AcOH, 20 :1 : 0.3) to give the title compound as a yellow solid (13 mg, 1 1 %).
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.06 (s, 3H); 4.77 (d, 6.4 Hz, 2H); 6.67 (dd, 7.2 and 5.2 Hz, 1 H); 6.93 (t, 6.4 Hz, 1 H); 7.47 (d, 7.2 Hz, 1 H); 7.80 (d, 1 .6 Hz, 1 H); 8.00 (d, 5.2 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H) and 9.28 (s, 1 H).
LC-MS:387.5 [M+H].
Example 75
6-Chloro-2-oxo-8-{[(pyrazine-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid
[00292] The title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyrazine-2- carboxylic acid gives 6-chloro-2-methoxy-8-{[(pyrazine-2-carbonyl)-amino]-methyl}- quinoline-3-carboxylic acid methyl ester in 81 % yield.
[00293] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[(pyrazine-2-carbonyl)-amino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 77% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.74 (d, 6.4 Hz, 2H); 7.80 (d, 2 Hz, 1 H); 8.14
(d, 2 Hz, 1 H); 8.76 (s, 1 H); 8.90 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 9.19 (s, 1 H); 9.80 (t, 6.2
Hz, 1 H) and 12.53 (br s, 1 H).
LC-MS: 357.5 [M-H] [35CI].
Example 76
6-Chloro-2-oxo-8-{[2-(2-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
[00294] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-tetrazol-1 -yl- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(2-tetrazol-1 -yl-phenyl)-acetylamino]- methyl}-quinoline-3-carboxylic acid methyl ester in 80.7% yield.
[00295] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(2-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 56.8% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.60 (s, 2H); 4.44 (d, 6 Hz, 2H); 7.53-7.57 (m, 2H); 7.58-7.61 (m, 2H); 7.63 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.70 (t, 6 Hz, 1 H); 8.94 (s, 1 H); 9.68 (s, 1 H) and 12.27 (br s, 1 H).
LC-MS: 437.4 [M-H].
Example 77 6-Chloro-8-{[2-(2-iodo^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid
[00296] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-iodo-phenyl)- acetic acid gives 6-chloro-8-{[(2-iodo-phenyl)-acetylamino]-methyl}-2-methoxy- quinoline-3-carboxylic acid methyl ester in 66.2% yield.
[00297] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[(2- iodo-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 68.7% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.71 (s, 2H); 4.57 (d, 6.4 Hz, 2H); 6.99-7.05
(m, 1 H); 7.32-7.36 (m, 2H); 7.73 (s, 1 H); 7.84 (d, 8 Hz, 1 H); 8.1 1 (d, 8.4 Hz, 1 H); 8.67
(br s, 1 H); 8.93 (s, 1 H) and 12.44 ppm (br s, 1 H).
LC-MS: 497.1 [M+H] [35CI].
Example 78
6-Chloro-2-oxo-8-(piperidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-(piperidin-1 -ylmethyl)quinoline-3-carboxylate.
[00298] Piperidine (69.0 μΙ, 0.70 mmol, 1 .2 equiv.) and triethylamine (105 μΙ, 0.75 mmol, 1 .3 equiv.) are added to a suspension of methyl 8-(bromomethyl)-6-chloro-2- methoxyquinoline-3-carboxylate (200 mg, 0.58 mmol) in anhydrous THF (2 ml_). The mixture is stirred at rt for 16 h in a closed vessel. (TLC analysis (Hept/EtOAc; 4:1 ) indicates an incomplete conversion.) KOtBu (85 mg, 0.75 mmol, 1 .3 equiv.) is added and the stirring is continued for another 24 h. The reaction mixture is concentrated in vacuo and the residue is partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer is washed with saturated aqueous NaHCO3 solution, brine, dried over Na2SO4 and concentration to dryness to afford 1 16 mg (57%) of the title compound as a yellow solid. The product is used without further purification.
LC-MS: 349 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-(piperidin-1-ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid.
[00299] A mixture of methyl 6-chloro-2-methoxy-8-(piperidin-1 -ylmethyl)quinoline- 3-carboxylate (1 16 mg, 0.33 mmol) and HBr (33 wt% in AcOH, 4 mL) is heated at 50°C in a closed vessel for 16 h. The reaction mixture is concentrated under reduced pressure and the residue is treated with saturated aqueous NaHCO3 solution. The resulting suspension is filtered off to afford a yellow solid. The residue is triturated with methanol, filtered off and air dried to give 42 mg (39%) of the title compound as an off- white solid.
Mp: 208 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 1 .46-1.55 (m, 2H), 1 .60-1 .69 (m, 4H), 2.78-2.88 (m, 4H), 4.28 (s, 2H), 7.76 (d, 1 H), 8.1 1 (d, 1 H), 8.79 (s, 1 H).
LC-MS: 319 [M-H] [35CI].
Example 79
6-Chloro-2-oxo-8-(pyrrolidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-(pyrrolidin-1 -ylmethyl)quinoline-3-carboxylate.
[00300] Methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (200 mg, 0.58 mmol) is dispersed in anhydrous THF and pyrrolidine (52.4 μΙ, 0.64 mmol, 1 .1 equiv.) and triethylamine (97 μΙ, 0.70 mmol, 1 .2 equiv.) are added. The mixture is stirred at rt for 16 h. The reaction mixture is partitioned between saturated aqueous NaHCO3 solution and EtOAc. The organic layer is washed with brine, dried over Na2SO4 and concentration to dryness. The yellow residue is purified by flash column chromatography (silica, 2.5-5% MeOH in DCM) to give 1 16 mg (59%) of the title compound as a white solid.
LC-MS: 335 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-(pyrrolidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid.
[00301 ] Methyl 6-chloro-2-methoxy-8-(pyrrolidin-1 -ylmethyl)quinoline-3- carboxylate (1 16 mg, 0.346 mmol) is added to HBr (33 wt% in AcOH, 4.5 mL) and the mixture is heated at 50 °C in a closed vessel for 16 h. The reaction mixture is concentrated in vacuo and the residue is treated with saturated aqueous NaHCO3 solution. The resulting suspension is filtered off and air dried to give 82 mg (77%) of the title compound as a white solid. Mp: 274 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 1 .89-1 .98 (m, 4H), 3.14-3.22 (m, 4H), 4.56 (s, 2H), 7.81 (d, 1 H), 8.10 (d, 1 H), 8.69 (s, 1 H).
LC-MS: 307 [M+H] [35CI]. Example 80
6-Chloro-2-oxo-8-[(2^yridin-4-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00302] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with pyridin-4-yl-acetic acid hydrochloride gives 6-chloro-2-methoxy-8-[(2-pyridin-4-yl-acetylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 58.8% yield.
[00303] b) In analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-[(2-pyridin-4-yl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound as hydrobromide hydrate in 41 .6% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.90 (s, 2H); 4.59 (br s, 2H); 7.66 (s, 1 H); 7.83 (s, 2H); 8.14 (s,1 H); 8.78 (s, 2H); 8.93-8.98 (m, 2H) and 12.40 (br s, 1 H).
LC-MS: 372.6 [M+H].
Example 81
6-Chloro-2-oxo-8-[(2-thiazol-5-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00304] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with thiazol-5-yl-acetic acid gives 6-chloro-2-methoxy-8-[(2-thiazol-5-yl-acetylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 56.3% yield.
[00305] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-thiazol-5-yl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 54.5% yield as hydrobromide. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.88 (s, 2H); 4.58 (br s, 2H); 7.65 (s, 1 H); 7.74 (s, 1 H); 8.13 (s, 1 H); 8.88-9.00 (m, 3H) and 12.42 (br s, 1 H).
LC-MS: 378.4 [M+H] [35CI].
Example 82
8-{[2-(4-Amino-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid hydrate hydrobromide
[00306] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-tert- butoxycarbonylamino-phenyl)-acetic acid gives 8-{[2-(4-tert-butoxycarbonylamino- phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester in 65.3% yield.
[00307] b) In analogy to the procedure described in Example 3(b), 8-{[2-(4-tert- butoxycarbonylamino-phenyl)-acetylamino]-methyl}-6-chloro-2-methoxy-quinoline-3- carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 86.6% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 4.54 (d, 5.6 Hz, 2H); 7.12 (d, 7.2 Hz, 2H); 7.29 (d, 7.6 Hz, 2H); 7.62 (d, 2 Hz, 1 H); 8.12 (s, 1 H); 8.84 (t, 5.6 Hz, 1 H); 8.93 (s, 1 H) and 12.45 (br s, 1 H).
LC-MS: 386.4 [M+H].
Example 83 8-{[(Adamantane-1 -carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00308] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with adamantane-1 - carboxylic acid gives 8-{[(adamantane-1 -carbonyl)-amino]-methyl}-6-chloro-2-methoxy- quinoline-3-carboxylic acid methyl ester in 75% yield.
[00309] b) In analogy to the procedure described in Example 3(b), 8- {[(adamantane-1 -carbonyl)-amino]-methyl}-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 55% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .65-1 .66 (m, 6H); 1.79 (s, 6H); 1 .97 (s, 3H); 4.49 (d, 6 Hz, 2H); 7.62 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.36 (t, 6 Hz,1 H); 8.92 (s, 1 H) and 12.53 (br s, 1 H).
LC-MS: 413.2 [M-H].
Example 84
8-[(2-Adamantan-1 -yl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid
[00310] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with adamantan-1 -yl- acetic acid gives 8-[(2-adamantan-1 -yl-acetylamino)-methyl]-6-chloro-2-methoxy- quinoline-3-carboxylic acid methyl ester in 73.5% yield.
[0031 1 ] b) In analogy to the procedure described in Example 3(b), 8-[(2- adamantan-1 -yl-acetylamino)-methyl]-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 67.3% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .50-1 .64 (m, 12H); 1.86 (br s, 3H); 1 .94 (s, 2H); 4.55 (d, 5.6 Hz, 2H); 7.74 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.69 (t, 6.2 Hz, 1 H); 8.94 (s, 1 H) and 12.52 (br s, 1 H).
LC-MS: 427.3 [M-H] [35CI].
Example 85
6-Chloro-8-[(benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid a) Pentacarbonyl molybdene tetraethylammonium chloride complex
[00312] A mixture of hexacarbonyl molybdene (6.60 g, 25 mmol) and tetraethylammonium chloride (5.3 g, 32 mmol, 1 .28 equiv.) in THF (75 mL) is heated at reflux temperature for 2 h. The hot mixture is immediately filtered and the filtrate is concentrated to half the volume, heptane (60 mL) is added to the residue. The suspension is filtered off and air dried to afford 3.72 g (37%) of a brown/yellow powder. b) Benzylaminepentacarbonylmolybdenum
[00313] Benzyl amine (544 μΙ, 4.98 mmol, 2.0 equiv.) is added to a suspension of (CO)5MoCINEt (1 g, 2.48 mmol) in ethanol. The resulting mixture is stirred under an nitrogen atmosphere for 16 h. The reaction mixture is concentrated in vacuo and the residue taken on EtOAc and filtered over a plug of silica to afford 414 mg (48%) of the title compound as a brown/yellow semisolid.
1H NMR (400 MHz, CDCI3), δ (ppm) 2.43-2.53 (m, 2H), 3.79-3.90 (m, 2H), 7.21 -7.46 (m, 5H). c) Methyl 8-(2-(benzylamino)-2-oxoethyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00314] To a suspension of benzylaminepentacarbonylmolybdenum (314 mg, 0.91 mmol, 1 .26 equiv.) in diglyme (9 mL) under N2 atmosphere is added methyl 8- (bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (250 mg, 0.73 mmol) and tributylamine (190 μΙ, 0.80 mmol, 1 .10 equiv.). The resulting mixture is heated at 145 °C for 1 .5 h, filtered over kieselguhr and the filtrate is concentrated to dryness. The residue is purified by flash column chromatography (silica, 25-100% EtOAc in heptane) to afford 159 mg (55%) of the title compound as an off-white solid.
1H NMR (400 MHz, CDCI3), δ (ppm) 3.90 (s, 3H), 3.96 (s, 3H), 4.08 (s, 2H), 4.36 (d, 2H), 6.56 (br s, 1 H), 7.07-7.13 (m, 2H), 7.22-7.29 (m, 3H), 7.72 (s, 2H), 8.54 (s, 1 H). LC-MS: 399 [M+H] [35CI]. d) 6-Chloro-8-[(benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00315] A suspension of methyl 8-(2-(benzylamino)-2-oxoethyl)-6-chloro-2- methoxyquinoline-3-carboxylate (155 mg, 0.39 mmol) in HBr (33 wt% in AcOH, 4 ml_) is heated at 50 °C for 48 h. The mixture is poured into water and the resulting suspension is filtered off. The white residue is triturated with MeOH, washed with ether and air dried to leave 26 mg (18%) of the title compound.
Mp: 291 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.99 (s, 2H), 4.30 (d, 2H), 7.21 - 7.36 (m, 5H), 7.68 (d, 1 H), 8.12 (d, 1 H), 8.71 (t, 1 H), 8.94 (s, 1 H), 12.52 (br s, 1 H), 14.53 (br s, 1 H).
LC-MS: 369 [M-H] [35CI].
Example 86
8-((1 H-1 ,2,4-TriazoM -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 8-((1 H-1 ,2,4-triazoM -yl)methyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00316] Potassium carbonate (120 mg, 0.87 mmol, 1 .5 equiv.) is added to a solution of methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (200 mg, 0.58 mmol), and 1 H-1 ,2,4-triazole (48.1 mg, 0.70 mmol, 1 .2 equiv.) in anhydrous DMF (2 ml) and heated to 50 °C for 4 h. The reaction mixture is partitioned between water and EtOAc and the layers are separated. The organic layer is washed with brine, dried over Na2SO4 and concentrated to dryness. The residue is purified by flash column chromatography (silica, 15-100% EtOAc in heptane/DCM 3:4) to give 92 mg (47%) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3), δ (ppm) 3.97 (s, 3H), 4.14 (s, 3H), 5.87 (s, 2H), 7.54 (d, 1 H), 7.79 (d, 1 H), 7.98 (s, 1 H), 8.25 (s, 1 H), 8.55 (s, 1 H).
LC-MS: 333 [M+H] [35CI]. b) 8-((1 H-1 ,2,4-TriazoM -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00317] A mixture of methyl 8-((1 H-1 ,2,4-triazol-1 -yl)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate (92 mg, 0.27 mmol) and HBr (33 wt% in AcOH, 4 ml) is heated at 80 °C for 20 h. The reaction mixture is concentrated in vacuo and the residue is treated with saturated aqueous NaHCO3 solution. The suspension is filtered off and washed with water. The residue is dissolved with DCM/MeOH and the filtrate is concentrated in vacuo to yield a yellow solid. The product is triturated with water, filtered off and air dried to give 32 mg (38%) of the title compound as a white solid.
Mp: 288 °C; 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 5.80 (s, 2H); 7.15 (s, 1 H); 7.96 (s, 1 H); 8.00 (s, 1 H); 8.57 (s, 1 H) and 8.67 (s, 1 H).
LC-MS: 305 [M+H] [35CI].
Example 87
8-{[Benzyl(methyl)amino]methyl}-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 8-((benzyl(methyl)amino)methyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00318] Potassium carbonate (96 mg, 0.70 mmol, 1 .2 equiv.) is added to a mixture of methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (200 mg, 0.58 mmol) and N-methyl-1 -phenylmethanamine (77 mg, 0.64 mmol, 1 .1 equiv.) in anhydrous DMF (5 mL) and the mixture is stirred at 40 °C for 16 h. The reaction mixture is partitioned between EtOAc and water and the organic layer is washed with saturated aqueous NaHCOs solution, brine, dried over Na2SO4 and concentrated in vacuo to give a yellow solid. The residue is triturated with methanol, filtered off and air dried to give 133 mg (59%) of the title compound as a yellow solid.
LC-MS: 385 [M+H] [35CI]. b) 8-{[Benzyl(methyl)amino]methyl}-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid.
[00319] A mixture of methyl 8-((benzyl(methyl)amino)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate (133 mg, 0.34 mmol) and HBr (33 wt% in AcOH, 4 ml_) is heated at 50 °C in a closed vessel for 16 h. The reaction mixture is concentrated in vacuo and the residue is basified with saturated aqueous NaHCO3 solution. The resulting suspension is filtered off, washed with water and air dried to give 99 mg (88%) of the title compound as an off-white solid.
Mp: 245 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 2.16 s, 3H), 3.74 (s, 2H), 4.07 (s, 2H), 7.26-7.45 (m, 5H), 7.77 (s, 1 H), 8.12 (d, 1 H), 8.92 (s, 1 H).
LC-MS: 357 [M+H] [35CI].
Example 88
6-Chloro-8-{[2-(2-dimethylamino^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00320] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-dimethylamino- phenyl)-acetic acid gives 6-chloro-8-{[2-(2-dimethylamino-phenyl)-acetylamino]-methyl}- 2-methoxy-quinoline-3-carboxylic acid methyl ester in 62.4% yield.
[00321 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (2-dimethylamino-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 80.6% yield as dihydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.21 (s, 6H); 3.94 (s, 2H); 4.61 (d, 5.6 Hz, 2H); 7.38-7.45 (m, 2H); 7.53 (t, 7.6 Hz, 1 H); 7.70 (d, 2 Hz, 1 H); 7.90 (br s, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.93 (s, 1 H); 9.21 (br s, 1 H) and 12.40 (br s, 1 H).
LC-MS: 412.2 [M-H] [35CI]. Example 89
6-Chloro-8-{[(6-imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid
[00322] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with -6-imidazol-1 -yl- nicotinic acid gives 6-chloro-8-{[(6-imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2- methoxy-quinoline-3-carboxylic acid methyl ester in 86.7% yield.
[00323] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[(6- imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 53.8% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.83 (d, 6 Hz, 2H); 7.78 (d, 2.4 Hz, 1 H); 7.87 (s, 1 H); 8.16-8.20 (m, 2H); 8.50 (s, 1 H); 8.59-8.62 (m, 1 H); 8.95 (s, 1 H); 9.08 (d, 2 Hz, 1 H); 9.61 (t, 5.8 Hz, 1 H); 9.89 (s, 1 H) and 12.46 (br s, 1 H).
LC-MS: 424.3 [M+H] [35CI].
Example 90
6-Chloro-2-oxo-8-{[2-(4-[1 ,2,4]triazol-4-yl-phenyl)-acetylamino]-methyl}-1 ,2- dihydro-quinoline-3-carboxylic acid
[00324] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (4-[1 ,2,4]triazol-4- yl-phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(4-[1 ,2,4]triazol-4-yl-phenyl)- acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester in 48.5% yield.
[00325] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-{[2-(4-[1 ,2,4]triazol-4-yl-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 69.5% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.62 (s, 2H); 4.55 (d, 6.4 Hz, 2H); 7.46 (d, 8.8 Hz, 2H); 7.61 -7.66 (m, 3H); 8.12 (d, 2.4 Hz, 1 H); 8.85 (t, 6 Hz, 1 H); 8.92 (s, 1 H); 9.09 (s, 2H) and 12.45 (br s, 1 H).
LC-MS: 436.2 [M-H] [35CI].
Example 91
6-Chloro-8-{[2-(3-imidazol-1 -yl^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00326] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (3-imidazol-1 -yl- phenyl)-acetic acid gives 6-chloro-8-{[2-(3-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2- methoxy-quinoline-3-carboxylic acid methyl ester in 56.2% yield.
[00327] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-{[2- (3-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59.2% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.67 (s, 2H); 4.57 (d, 6.4 Hz, 2H); 7.41 (d, 7.6 Hz, 1 H); 7.54 (t, 8 Hz, 1 H); 7.62-7.67 (m, 4H); 8.05 (s, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.88- 8.92 (m, 2H) and 9.15 (s, 1 H).
LC-MS: 437.4 [M+H] [35CI].
Example 92
6-Chloro-2-oxo-8-[(1 H-pyrazol-1 -yl)methyl]-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 8-((1 H-pyrazol-1 -yl)methyl)-6-chloro-2-methoxyquinoline-3-carboxylate
[00328] Potassium carbonate (120 mg, 0.87 mmol, 2.0 equiv.) is added to a mixture of 1 H-pyrazole (47.4 mg, 0.696 mmol), methyl 8-(bromomethyl)-6-chloro-2- methoxyquinoline-3-carboxylate (200 mg, 0.580 mmol) in anhydrous DMF (2 ml) and heated at 50 °C for two days. Another 20 mg of pyrazole and 40 mg of K2CO3 is added and the heating is continued for 24 h. The reaction mixture is poured in water and extracted with EtOAc. The organic layer is washed with water and brine, dried over Na2SO4 and concentration in vacuo. The product is purified by flash column chromatography (silica, 15-100% EtOAc in heptane/DCM 3:4) to give 67 mg (34%) of the title compound as a light-yellow solid.
LC-MS: 332 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-[(1 H-pyrazol-1 -yl)methyl]-1 ,2-dihydroquinoline-3-carboxylic acid
[00329] A mixture of methyl 8-((1 H-pyrazol-1 -yl)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate (67 mg, 0.20 mmol) and HBr (33 wt% in AcOH, 2 ml) is heated at 80 °C for 48 h. The reaction mixture is concentrated in vacuo and the residue is treated with saturated aqueous NaHCO3 solution. The resulting suspension is filtered off and air dried to afford 50 mg (82%) of the title compound as a white solid.
Mp: >239 °C (decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 5.75 (s, 2H), 6.31 (s, 1 H), 6.79 (s, 1 H), 7.52 (s, 1 H), 7.91 (s, 2H), 8.56 (s, 1 H).
LC-MS: 304 [M+H] [35CI].
Example 93
6-Chloro-8-({[1 -(2-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid
[00330] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 1 -(2-fluoro-phenyl)- cyclohexanecarboxylic acid gives 6-chloro-8-({[1 -(2-fluoro-phenyl)- cyclohexanecarbonyl]-amino}-methyl)-2-methoxy-quinoline-3-carboxylic acid methyl ester in 83% yield.
[00331 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-8-({[1 - (2-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2-methoxy-quinoline-3- carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 69% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .28-1 .33 (m, 1 H); 1 .40-1 .60 (m, 5H); 1 .79- 1 .85 (m, 2H); 2.20-2.24 (m, 2H); 4.47 (d, 5.6 Hz, 2H); 7.02-7.07 (m, 1 H); 7.18-7.21 (m, 1 H); 7.27-7.32 (m, 1 H); 7.43-7.47 (m, 1 H); 7.51 (d, 2.4 Hz, 1 H); 8.09-8.12 (m, 2H); 8.93 (s, 1 H) and 12.40 (br s, 1 H).
LC-MS: 455.5 [M-H] [35CI].
Example 94
6-Chloro-8-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid a) Methyl 6-chloro-8-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-methoxy- quinoline-3-carboxylate
[00332] A mixture of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3- carboxylate hydrochloride (100 mg, 0.3 mmol), phthalic anhydride (53 mg, 0.3 mmol) and potassium carbonate (35 mg, 0.3 mmol) in acetonitrile (1 ml_) is stirred and heated at 155 °C for 24 h in closed reaction vial. After cooling the mixture is diluted with water (2 ml_) and precipitates are filtered off, washed with water and dried to give the title compound (77 mg, 52%) as a yellow solid.
LC-MS: 383.3 [M+H]. b) 6-Chloro-8-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00333] Methyl 6-chloro-8-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-methoxy- quinoline-3-carboxylate (77 mg, 0.2 mmol) is heated in HBr (33 wt% in AcOH, 2 ml_) at 65 °C for 23 h. The mixture is concentrated under reduced pressure and the residue is washed with hot hexane and dried to give the title compound (51 mg, 66%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 5.12 (s, 2H); 7.67 (d, 2.4 Hz, 1 H); 7.85- 7.92 (m, 4H); 8.14 (d, 2.4 Hz, 1 H); 8.93 (s, 1 H) and 12.27 (br s, 1 H).
LC-MS: 383.1 [M+H].
Example 95 8-[(5-Carbamoyl^yridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinolin 3-carboxylic acid a) Methyl 6-chloro-8-[(5-cyano^yridin-2-ylamino)-methyl]-2-methoxy-quinoline-3- carboxylate
[00334] A mixture of methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3- carboxylate hydrochloride (100 mg, 0.3 mmol), 6-chloronicotinonitrile (52 mg, 0.4 mmol) and potassium carbonate (108 mg, 0.8 mmol) in acetonitrile (3 mL) is stirred and heated at 130 °C for 24 h in closed reaction vial. After cooling precipitates are filtered off, washed with cold acetonitrile, water and dried to give the title compound (80 mg, 58%) as a yellow solid.
LC-MS: 383.3 [M+H]. b) 8-[(5-Carbamoyl-pyridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00335] Methyl 6-chloro-8-[(5-cyano-pyridin-2-ylamino)-methyl]-2-methoxy- quinoline-3-carboxylate (80 mg, 0.2 mmol) is heated in HBr (33 wt% in AcOH, 3 mL) at 60 °C for 20 h. After cooling, precipitates are filtered off, washed with water and dried to give the title compound (44 mg, 52%) as a yellow solid.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.78 (d, 6 Hz, 2H); 6.64 (d, 9.2 Hz, 1 H); 7.19 (br s, 1 H); 7.76-7.81 (m, 2H); 7.92-8.00 (m, 2H); 8.14 (d, 2.4 Hz, 1 H); 8.63 (s, 1 H); 8.93 (s, 1 H) and 13.70 (br s, 1 H).
LC-MS: 373.3 [M+H].
Example 96
6-Chloro-8-({[1 -(2-chloro-6-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)- 2-OXO-1 ,2-dihydro-quinoline-3-carboxylic acid
[00336] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with 1 -(2-chloro-6- fluoro-phenyl)-cyclohexanecarboxylic acid gives methyl 6-chloro-8-({[1 -(2-chloro-6- fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2-methoxy-quinoline-3-carboxylate in 40% yield.
[00337] b) In analogy to the procedure described in Example 3(b), methyl 6- chloro-8-({[1 -(2-chloro-6-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2- methoxy-quinoline-3-carboxylate is treated with HBr in AcOH to give the title compound in 73% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .30-1 .50 (m, 4H); 1 .65-1 .75 (m, 2H); 2.10- 2.30 (m, 4H); 4.45 (d, 6 Hz, 2H); 7.18-7.23 (m, 2H); 7.28-7.34 (m, 1 H); 7.61 (d, 2.4 Hz, 1 H); 8.1 1 (d, 2.4 Hz, 1 H); 8.16 (t, 6 Hz, 1 H); 8.93 (s, 1 H) and 12.36 (br s, 1 H). LC- MS:489.6 [M-H].
Example 97
6-Chloro-2-oxo-8-[(2-thiazol-4-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00338] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with -thiazol-4-yl-acetic acid gives 6-chloro-2-methoxy-8-[(2-thiazol-4-yl-acetylamino)-methyl]-quinoline-3- carboxylic acid methyl ester in 83.5% yield.
[00339] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[(2-thiazol-4-yl-acetylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 68% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.75 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.51 (s, 1 H);
7.73 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.79 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 9.06 (d, 2 Hz, 1 H) and 12.49 (br s, 1 H).
LC-MS: 378.4 [M+H].
Example 98 6-Chloro-2-oxo-8-[((S)-2^henyl^ropionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00340] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (S)-2-phenyl- propionic acid gives 6-chloro-2-methoxy-8-[((S)-2-phenyl-propionylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 82.2% yield.
[00341 ] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[((S)-2-phenyl-propionylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 81 .3% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .36 (d, 7.2 Hz, 3H); 3.70 (q, 7.2 Hz, 1 H); 4.45-
4.58 (m, 2H); 7.20-7.23 (m, 1 H); 7.27-7.32 (m, 4H); 7.46 (d, 2.4 Hz, 1 H); 8.09 (d, 2.4
Hz, 1 H); 8.72 (t, 6 Hz, 1 H); 8.91 (s, 1 H) and 12.40 (br s, 1 H).
LC-MS: 383.4 [M-H] [35CI].
Example 99
6-Chloro-2-oxo-8-[((R)-2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
[00342] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (R)-2-phenyl- propionic acid gives 6-chloro-2-methoxy-8-[((R)-2-phenyl-propionylamino)-methyl]- quinoline-3-carboxylic acid methyl ester in 79.5% yield.
[00343] b) In analogy to the procedure described in Example 3(b), 6-chloro-2- methoxy-8-[((R)-2-phenyl-propionylamino)-methyl]-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 78% yield. 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .36 (d, 7.2 Hz, 3H); 3.70 (q, 7.2 Hz, 1 H); 4.45- 4.58 (m, 2H); 7.20-7.23 (m, 1 H); 7.27-7.32 (m, 4H); 7.46 (d, 2.4 Hz, 1 H); 8.09 (d, 2.4 Hz, 1 H); 8.72 (t, 6 Hz, 1 H); 8.91 (s, 1 H) and 12.40 (br s, 1 H).
LC-MS: 383.4 [M-H] [35CI].
Example 100
6-Chloro-2-oxo-8-{[2-(2,4,6 rifluoro^henyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
[00344] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2,4,6-trifluoro- phenyl)-acetic acid gives 6-chloro-2-methoxy-8-{[2-(2,4,6-trifluoro-phenyl)-acetylamino]- methyl}-quinoline-3-carboxylic acid methyl ester in 79% yield.
[00345] b) In analogy to the procedure described in Example 3(b) 6-chloro-2- methoxy-8-{[2-(2,4,6-trifluoro-phenyl)-acetylamino]-methyl}-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59.6% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.62 (s, 2H); 4.57 (d, 6 Hz, 2H); 7.18 (t, 8.2 Hz, 2H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.85 (t, 6 Hz, 1 H); 8.93 (s, 1 H) and12.39 (br s, 1 H).
LC-MS:423.2 [M-H] [35CI]. Example 101
6-Chloro-2-oxo-8-(pyridin-2-ylaminomethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid a) 8-[(tert-Butoxycarbonyl-pyridin-2-yl-amino)-methyl]-6-chloro-2-methoxy- quinoline-3-carboxylic acid methyl ester.
[00346] To an ice cooled solution of pyridin-2-yl-carbamic acid tert-butyl ester (178 mg, 0.9 mmol) in abs. DMF (1 .5 ml_) under an argon atmosphere is added NaH (45 mg, 60% oil dispersion; 1 .1 mmol). The suspension is stirred vigorously for 20 min, then methyl 8-bromomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (300 mg, 0.9 mmol) is added. Ice bath is removed and the mixture is stirred at rt for 18 h, then suspension is diluted with water (10 ml_) and ethyl acetate (20 ml_).The organic layer is washed with water, 3% aqueous citric acid and concentrated in vacuo. The residue is purified by column chromatography (petroleum ether : ethyl acetate, 4 :1 ) to give the title compound as a white solid (370 mg, 93%).
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .29 (s, 9H); 3.87 (s, 3H); 3.95 (s, 3H); 5.57 (s, 2H), 7.14- 7.17 (m, 1 H), 7.46 (s, 1 H), 7.70- 7.82 (m, 2H), 8.07 (s, 1 H), 8.33 (d, 2 Hz, 1 H) and 8.76 (s, 1 H).
LC-MS: 458.6 [M+1 ]. b) 6-Chloro-2-oxo-8-(pyridin-2-ylaminomethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid
[00347] In analogy to the procedure described in Example 3(b), 8-[(tert- butoxycarbonyl-pyridin-2-yl-amino)-methyl]-6-chloro-2-methoxy-quinoline-3-carboxylic acid methyl ester is treated with HBr in AcOH to give the title compound in 59% yield as hydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.77 (br s, 2H); 6.91 -7.04 (m, 2H); 7.88-7.95 (m, 2H); 8.04 (d, 6.4 Hz, 1 H); 8.22 (d, 2,4 Hz, 1 H); 8.80 (br s, 1 H); 8.96 (s, 1 H) and 13.00 (br s, 1 H).
LC-MS: 330.4 [M+H] [35CI].
Example 102
6-Chloro-8-((dimethylamino)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00348] Dimethylamine; 2M in THF (1 .97 ml_, 3.95 mmol, 25 equiv.) is diluted with anhydrous THF (2 ml_) and a solution of 8-(bromomethyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (50 mg, 0.16 mmol) in anhydrous DMF (2 ml_) is added dropwise over 5 min. The mixture is stirred at rt for 1 h then concentrated in vacuo. The residue is treated with saturated aqueous NaHCO3 solution, the resulting suspension is filtered off and purified by reverse phase chromatography to give 22.5 mg (25%) of the title compound as a white solid. Mp: 279 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.62 (s, 6H), 4.37 (s, 2H), 7.74 (d, 1 H), 8.1 1 (d, 1 H), 8.73 (s, 1 H).
LC-MS: 281 [M+H] [35CI].
Example 103
6 -Dichloro-8-{[2-(2,6-difluoro^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00349] The title compound is prepared by the following reaction sequence:
a) 2-amino-4-chloro-3-methylbenzoic acid [WO 2007/43677 A1 , 2007.] (10.78 g, 0.0582 mol) in dry THF (120 mL) is added dropwise to an ice cooled solution of LiAIH (4.42 g, 0.1 16 mol) in dry THF (100 mL) and stirred overnight at room temperature. Water (10 mL) is added dropwise, followed by 2M aq. NaOH (50 mL). Product is extracted with ethyl acetate (2x70 mL). The organic layer is collected, dried over sodium sulphate, concentrated under reduced pressure and recrystallized from EtOAc/hexane to yield 7.15 g (72%) of (2-amino-4-chloro-3-methylphenyl)-methanol. 1H NMR (200 MHz, CDCIs), δ (ppm): 2.33 (s, 3H), 4.33 (bs, 2H), 4.63 (s, 2H), 6.74 and 6.85 (both d, 8 Hz, 2H).
[00350] b) (2-amino-4-chloro-3-methylphenyl)-methanol (6.15 g, 0.0357 mol) in dry Et.20 (270 mL) is added dropwise to a mixture of manganese dioxide (15.5g, 0.1787 mol) in dry Et^O (100 mL) and the mixture is stirred at rt for 24 h. The mixture is filtered through a celite and the solvent is removed at reduced pressure to give 2-amino-4- chloro-3-methyl-benzaldehyde as yellow solid (6.0 g, 99%) which is used in the next step without additional purification.
[00351 ] c) to an ice cooled solution of 2-amino-4-chloro-3-methylbenzaldehyde (6.0 g, 0.0354 mol) in dry DMF (75 mL) is added NCS (6.4 g, 0.0477 mol), then the mixture is stirred at rt overnight. EtOAc (100 mL) is added and the mixture is washed four times with brine and water (70 mL). The organic layer is collected, dried over Na2SO4, concentrated under reduced pressure and recrystallized from EtOAc/hexane to give 2-amino-4,5-dichloro-3-methylbenzaldehyde (4.41 g, 62%). 1H NMR (200 MHz, CDCIs), δ (ppm): 2.28 (s, 3H); 6.33 (br s, 2H); 7.46 (s,1 H) and 9.77 (s, 1 H).
[00352] d) to 2-amino-4,5-dichloro-3-methylbenzaldehyde (2.76 g, 0.0135 mol) in dry MeOH (20 mL) is added dimethyl malonate (4.3 mL ) and piperidine (0.4 mL), and the mixture is stirred under reflux for 48 h. After cooling to rt, the solid is filtered, washed with cold methanol and dried to give 3.4 g (88%) of methyl 6,7-dichloro-8-methyl-2-oxo- 1 ,2-dihydroquinoline-3-carboxylate. 1H NMR (200 MHz, CDCI3), δ (ppm): 2.84 (s, 3H); 3.82 (s, 3H), 8.09 (s, 1 H), 8.52 (s, 1 H).
[00353] e) a suspension of methyl 6,7-dichloro-8-methyl-2-oxo-1 ,2- dihydroquinoline-3-carboxylate (3.4 g, 0.01 18 mol) in POCI3 (20 mL) is refuxed overnight. The reaction mixture is cooled and concentrated under reduced pressure. The residue is slowly poured into ice water (80 mL), neutralized with NaHCO3 till pH 7 and the product is extracted with CH2CI2. Crude product is purified by flash chromatography on silica gel (hexane: EtOAc, 9:1 ) to give methyl 2,6,7-trichloro-8- methylquinoline-3-carboxylate as white solid (2.1 g, 58%). 1H NMR (200 MHz, CDCI3), δ (ppm): 2.88 (s, 3H); 4.00 (s, 3H); 7.86 (s, 1 H) and 8.54 (s, 1 H). LC-MS: 303 [M+].
[00354] f) suspension of methyl 2,6,7-trichloro-8-methylquinoline-3-carboxylate (5.15 g, 15.56 mmol) in dry methanol (215 mL) is cooled to 0 °C and sodium hydride (60% in mineral oil, 3.73 g, 93 mmol) is added portionwise. The mixture ias stirred at rt for 30 min and then heated at reflux for 2.5 h. The mixture is allowed to cool to rt, stirred overnigh, then it is concentrated under reduced pressure. The residue is diluted with water (150 mL) and acidified with 5N aq. HCI. The mixture is stirred for 1 h, precipitate is filtered off, washed with water (50 mL) and taken into ethanol (100 mL). The ethanol is evaporated and the process is repeated (2*) to remove residual water. Final co- evaporation with DCM and diethyl ether yields a pale yellow solid. The solid is suspended in dry methanol (1 10 mL) and thionyl chloride (3.02 g, 1 .84 mL, 25.4 mmol,) is carefully added, and the mixture is heated at reflux for 2 h. The reaction mixture is concentrated under reduced pressure and co-evaporated with MeOH to obtain a cream colored solid, which is triturated with 30 mL of MeOH. The suspension is diluted with diethyl ether (50 mL) and the precipitate is filtered off and air dried to give 4.14 g (84%) of methyl 6,7-dichloro-2-methoxy-8-methylquinoline-3-carboxylate as a cream colored solid.
[00355] g) a mixture of methyl 6,7-dichloro-2-methoxy-8-methylquinoline-3- carboxylate 1 .78 g, 0.01 mol) in abs. CCI4 with NBS (1 .06 g, 0.01 mol) and Bz2O2 (0.14 g) is heated at reflux for 4 h (by HPLC/MS mixture of the monobromide and dibromide (87.5% and 1 1 .5%, resp.)). After cooling, the reaction mixture is filtered, the filtrate is evaporated to dryness, the residue is heated in hexane/EtOAc (7:1 ) and quickly filtered. The solid is washed twice with the same hot mixture to give methyl 8-(bromomethyl)- 6,7-dichloro-2-methoxyquinoline-3-carboxylate (2.22 g, 70%). 1H NMR (400 MHz, DMSO-de), δ (ppm): 3.89 (s, 3H); 4.1 1 (s, 3H); 5.28 (s, 2H); 8.45 (d, 8.2 Hz, 1 H); 8.81 (s, 1 H).
[00356] h) to a solution of methyl 8-(bromomethyl)-6,7-dichloro-2- methoxyquinoline-3-carboxylate (2.19 g, 5.78 mmol) in abs. DMF (75 ml_) is added NaN3 0.45 g, 6.93 mmol) and the reaction mixture is stirred at rt overnight. The mixture is poured into ice-water (120 ml_) and stirred at rt for 1 h. Precipitate is filtered, washed with water and dried over P2O5. to give 0.99 g (96%) methyl 8-(azidomethyl)-6,7- dichloro-2-methoxyquinoline-3-carboxylate 7 as a white solid.
[00357] i) methyl 8-(azidomethyl)-6,7-dichloro-2-methoxyquinoline-3-carboxylate (1 .91 g, 5.6 mmol), PPh3 (2.20 g, 8.4 mmol) and water (1 ml_) are added to THF (125 ml_) and the mixture is stirred at rt for 22 h. The reaction mixture is cooled with ice and 1 M aq. HCI (15 ml_) is slowly added. The mixture is stirred at rt for 1 .5 h. The resulting precipitate is collected by filtration, washed with cold EtOAc and twice with absolute diethyl ether to give, methyl 8-(aminomethyl)-6,7-dichloro-2-methoxyquinoline-3- carboxylate hydrochloride (830 mg, 80%) as a white solid. 1H NMR (400 MHz, DMSO- de), δ (ppm): 3.90 (s, 3H); 4.16 (s, 3H); 4.69 (s, 2H); 8.31 (br s, 3H); 8.53 (d, 8.2 Hz, 1 H); 8.85 (s, 1 H).
[00358] j) in analogy to the procedure described in Example 5(a), condensation of methyl 8-(aminomethyl)-6,7-dichloro-2-methoxyquinoline-3-carboxylate with 2-(2,6- difluorophenyl)acetic acid gives methyl 6,7-dichloro-8-((2-(2,6- difluorophenyl)acetamido)methyl)-2-methoxyquinoline-3-carboxylate in 76% yield, k) in analogy to the procedure described in Example 3(b) methyl 6,7-dichloro-8-((2-(2,6- difluorophenyl)acetamido)methyl)-2-methoxyquinoline-3-carboxylate is treated with HBr in AcOH to give the title compound in 63% yield.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.59 (s, 2H); 4.75 (d, 5.6 Hz, 2H); 7.03-7.10 (m, 2H); 7.32-7.40 (m, 1 H); 8.39 (s, 1 H); 8.89 (s, 1 H); 9.1 1 (t, 5.6 Hz, 1 H) and 12.46 (br s, 1 H). LC-MS: 439.3 [M-H] [35CI].
Example 104
6-Chloro-2-oxo-8-[(2-oxo-2-phenyl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.76 (d, 6 Hz, 2H); 7.56-7.60 (m, 2H); 7.72- 7.76 (m, 2H); 8.03 (d, 2.4 Hz, 1 H); 8.05 (s, 1 H); 8.17 (d, 2.4 Hz, 1 H); 8.95 (s, 1 H); 9.57 (t, 6 Hz, 1 H) and 12.42 (br s, 1 H). LC-MS: 383.4 [M-H] [35CI].
Example 105
6-Chloro-8-{[2-(2-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.59 (s, 2H); 4.50 (d, 5.2 Hz, 2H); 7.54-7.59 (m, 5H); 7.75 (s, 1 H); 7.92 (s, 1 H); 8.13 (d, 1 .2 Hz, 1 H); 8.88-8.93 (m, 2H); 9.28 (s, 1 H) and 12.00-12.80 (br s, 1 H). LC-MS: 435.5 [M-H] [35CI].
Example 106
6-Chloro-2-oxo-8-{[2-(2,3,6-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.71 (s, 2H); 4.58 (d, 6 Hz, 2H); 7.1 1 -7.25 (m, 1 H); 7.40-7.48 (m, 1 H); 7.65 (d, 2.4 Hz, 1 H); 8.14 (d, 2 Hz, 1 H); 8.89-8.94 (m, 2H) and 12.38 (br s, 1 H). LC-MS: 423.2 [M-H] [35CI]. Example 107
6-Chloro-8-{[2-(3-dimethylamino^henyl)-acetylamino]-methyl}-2-oxo-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.97 (s, 6H); 3.53 (s, 2H); 4.55 (s, 2H); 6.85- 7.05 (m, 3H); 7.26 (brs, 1H); 7.63 (s, 1H); 8.12 (s, 1H); 8.83 (s, 1H); 8.92 (s, 1H)and 12.44 (brs, 1H). LC-MS: 414.3 [M+H] [35CI].
Example 108
6,7-Dichloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.57 (s, 2H); 4.75 (d, 6 Hz, 2H); 7.11-7.16 (m, 2H); 7.26-7.34 (m, 2H); 8.39 (s, 1H); 8.88 (s, 1H); 9.10 (t, 5.6 Hz, 1H)and 12.55 (brs, 1H). LC-MS: 421.2 [M-H] [35CI].
Example 109
6,7-Dichloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]-methyl}-2-oxo-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.86 (s, 2H); 4.76 (d, 5.6 Hz, 2H); 7.31 (t, 8.4 Hz, 1 H); 7.44 (d, 8.4 Hz, 2H); 8.39 (s, 1 H); 8.90 (s, 1 H); 9.06 (t, 5.6 Hz, 1 H) and 12.39 (brs, 1H). LC-MS: 471.0, 473.1 [M-H] [35CI].
Example 110
8-{[(6-Bromo-pyridine-3-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.78 (d, 5 Hz, 2H); 7.74 (s, 1H); 7.82 (d, 8 Hz, 1H); 8.10-8.20 (m, 2H); 8.85 (s, 1H); 8.93 (s, 1H); 9.46 (s, 1H)and12.45 (brs, 1H). LC- MS: 434.1, 436.1 [M-H] [35CI]. Example 111
6-Chloro-8-{[(2-imidazol-1-yl^yridine-3-carbonyl)-amino]-methyl}-2-oxo-1,2- dihydro-quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.72 (d, 6 Hz, 2H); 7.20 (s, 1H); 7.57 (s, 1H); 7.65-7.70 (m, 2H); 8.17 (d, 7.2 Hz, 2H); 8.52 (s, 1H); 8.69 (d, 4.4 Hz, 1H); 8.96 (s, 1H); 9.37 (d, 6 Hz, 1H)and 11.80-12.70 (brs, 1H). LC-MS: 422.1 [M-H] [35CI].
Example 112
8-(2-Acetyl-pyrrol-1-ylmethyl)-6-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.35 (s, 3H); 5.81 (s, 2H); 6.32 (s, 1H); 6.49 (s, 1H); 7.27 (s, 1H); 7.36 (s, 1H); 8.09 (s, 1H); 8.94 (s,1H)and 12.72 (brs, 1H). LC- MS:345.3 [M+H] [35CI].
Example 113
8-[(3-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1,2-dihydro-quinoline-3- carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.64 (s, 2H); 6.89 (d, 6.4 Hz, 1H); 7.20-7.25 (m, 3H); 7.74 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H) and 8.96 (s, 1 H). LC-MS: 371.3 [M+H] [35CI].
Example 114
6-Chloro-2-oxo-8-{[2-(3-tetrazol-1-yl-phenyl)-acetylamino]-methyl}-1,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.70 (s, 2H); 4.60 (s, 2H); 7.48 (d, 6.8 Hz, 1H); 7.58-7.61 (m, 2H); 7.79-7.85 (m, 2H); 8.11 (s, 1H); 8.91 (s, 2H); 10.08 (s, 1H)and 12.40 (brs, 1H). LC-MS: 439.4 [M+H] [35CI]. Example 115
8-[((S)-2-Amino-2^henyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
Isolated as hydrobromide.
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.60 (d, 5.2 Hz, 2H); 5.09 (s, 1 H); 7.36 (d, 2.4 Hz, 1 H); 7.46-7.52 (m, 5H); 8.09 (d, 2.4 Hz, 1 H); 8.65 (s, 2H); 8.91 (s, 1 H); 8.98 (t, 5.8 Hz, 1 H) and 12.27 (br s, 1 H). LC-MS: 386.1 [M+H] [35CI].
Example 116
6-Chloro-2-oxo-8-{[2-(4-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.52 (s, 2H); 4.56 (d, 6.4 Hz, 2H); 6.94-6.99 (m, 4H); 7.1 1 -7.15 (m, 1 H); 7.30 (d, 8 Hz, 2H); 7.38 (t, 8 Hz, 2H); 7.57 (s, 1 H); 8.10 (s, 1 H); 8.78 (t, 5.4 Hz, 1 H); 8.90 (s, 1 H) and 12.46 (br s, 1 H). LC-MS: 461 .4 [M-H] [35CI].
Example 117
6-Chloro-8-[(2-chloro-benzylcarbamoyl)-methyl]-2-oxo-1,2-dihydro-quinoline-3- carboxylic acid
[00359] 2-Chlorobenzylamine (133 μΙ, 1 .10 mmol, 2.0 equiv.) is added to a suspension of (CO)sMoCINEt (220 mg, 0.55 mmol) in diglyme (5 ml_). The resulting mixture is stirred at rt for 16 h. Methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate (170 mg, 0.49 mmol, 0.9 equiv.) and BU3N (144 μΙ, 0.60 mmol, 1 .1 equiv.) are added and the resulting mixture is stirred at 120 °C under a nitrogen atmosphere for 2 h. The reaction mixture is concentrated in vacuo and the residue is treated with HBr (33 wt% in AcOH, 2 ml_) and the mixture is stirred at 50 °C for 48 h. The mixture is allowed to cool to rt and water is added to the mixture. The resulting suspension is filtered off and the residue is washed with water, MeOH and ether. The residue (153 mg) is purified by reverse phase chromatography to afford 34 mg (17%) of the title compound as a white solid.
Mp: 293 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 4.02 (s, 2H), 4.36 (d, 2H), 7.26- 7.36 (m, 2H), 7.37-7.49 (m, 2H), 7.69 (s, 1 H), 8.1 1 (s, 1 H), 8.64-8.74 (m, 1 H), 8.93 (s, 1 H), 12.48 (br s, 1 H), 14.57 (br s, 1 H).
LC-MS: 403/405/407 [M-H] [double CI isotope pattern].
Example 118
8-(Benzylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid a) N-Benzyl-8-((benzylamino)methyl)-6-chloro-2-methoxyquinoline-3-carboxamide
[00360] A solution of methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate (200 mg, 0.58 mmol) in DCM (2 mL) is added dropwise to a solution of benzylamine (317 μΙ, 2.90 mmol, 5.0 equiv.) in DCM (3 mL). The mixture is stirred at rt for 16 h. The reaction mixture is diluted with saturated aqueous NaHCOs solution and DCM (5 mL each) and the layers are separated. The organic layer is washed with saturated aqueous NaHCOs solution, dried over Na2SO4 and concentrated to dryness. The residue is triturated with EtOAc and filtered to give 125 mg (48%) of the title compound as a white solid.
LC-MS: 446 [M+H] [35CI]. b) N-Benzyl-8-((benzylamino)methyl)-6-chloro-2-oxo-1,2-dihydroquinoline-3- carboxamide
[00361 ] N-Benzyl-8-((benzylamino)methyl)-6-chloro-2-methoxyquinoline-3- carboxamide (125 mg, 0.28 mmol) and HBr (33 wt% in AcOH, 4 mL) are combined and stirred at 50 °C for 2 days. The reaction mixture is concentrated in vacuo and the residue is treated with saturated aqueous NaHCOs solution. The resulting suspension is filtered off to give 103 mg (85%) of the title compound as a white solid.
1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.98 (br s, 2H), 4.31 (br s, 2H), 4.59 (d, 2H), 7.22-7.48 (m, 10H), 7.73 (br s, 1 H), 8.13 (br s, 1 H), 8.90 (s, 1 H), 10.08 (t, 1 H).
LC-MS: 432 [M+H] [35CI]. c) 8-(Benzylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid
[00362] N-Benzyl-8-((benzylamino)methyl)-6-chloro-2 -oxo-1 ,2-dihydroquinoline-3- carboxamide (80 mg, 0.185 mmol) is dispersed in aqueous 6N hydrochloric acid (3.09 mL, 18.52 mmol, 100 equiv.) and the mixture is heated to 130 °C in a closed vessel for 16 h. LC-MS analysis indicates incomplete conversion. Another 2 mL of cone. HCI solution is added and the heating is continued for 48 h. The reaction mixture is concentrated in vacuo and the residue is treated with saturated aqueous NaHCO3 solution. The resulting suspension is filtered off to give a dark yellow solid. The residue is triturated with water (50 °C), filtered off and air dried to give 25 mg (39%) of the title compound as a white solid.
Mp: >240 °C (gradual decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 4.12 (br s, 2H), 4.38 (br s, 2H), 7.33-7.55 (m, 5H), 7.68 (br s, 1 H), 8.02 (s, 1 H), 8.64 (s, 1 H).
LC-MS: 343 [M+H] [35CI].
Example 119
6-Chloro-8-methylaminomethyl-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid
[00363] In analogy to the procedure described in Example 102, methylamine reacts with 8-(bromomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid to give the title compound as a white solid in 44% yield.
Mp: 317 °C (decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 2.61 (s, 3H), 4,46 (s, 2H), 7.72 (d, 1 H), 8.07 (d, 2 Hz, 1 H), 8.63 (s, 1 H), 8.73 (br s, 2H).
LC-MS: 267 [M+H] [35CI].
Example 120
6-Chloro-8-[(2, 6-difluoro-benzylcarbamoyl)-methyl]-2 -oxo-1 ,2-dihydro-quinoline-3- carboxylic acid a) Methyl 6-chloro-8-(2-(2,6-difluorobenzylamino)-2-oxoethyl)-2-methoxyquinoline- 3-carboxylate.
[00364] A suspension of Mo(CO)6 (200 mg, 0.74 mmol) and Et4NCI (123 mg, 0.74 mmol) in diglyme (5 mL) is stirred at 80 °C for 30 min under Ar atmosphere, then 2,6- difluorobenzylamine (89 μΙ, 0.74 mmol) is added and stirring continued for 1 h. Tributylamine (194 μΙ, 0.81 mmol, 1 .10 equiv.) is added and after 15 min of stirring methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (242 mg, 0.70 mmol, 0.95 equiv.) is added. The mixture is stirred at 80 °C for 1 h. The mixture is allowed to cool to rt and concentrated in vacuo. The residue is taken in DCM and filtered over kieselguhr. The filtrate is washed with aqueous 1 N HCI solution, the organic layer is washed with brine, dried over Na2SO4 and concentrated to dryness. The residue is purified by flash column chromatography (silica, 10-100% EtOAc in heptane) to afford 88.7 mg (29%) of the title compound as a white solid.
LC-MS: 435 [M+H] [35CI]. b) 6-Chloro-8-[(2,6-difluoro-benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid.
[00365] Methyl 6-chloro-8-(2-(2,6-difluorobenzylamino)-2-oxoethyl)-2- methoxyquinoline-3-carboxylate (100 mg, 0.23 mmol) is dissolved in HBr (33 wt% in AcOH, 2 ml_) and stirred at 50 °C for 48 h. The reaction mixture is concentrated in vacuo and water is added to the residue. The resulting suspension is filtered off, washed with water. The residue is stirred with MeOH, filtered, washed with ether and air dried to afford 61 mg (65%) of the title compound as a solid.
Mp: 271 °C; 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.90 (s, 2H); 4.34 (d, 5 Hz, 2H); 7.09-7.13 (m, 2H); 7.38-7.45 (m, 1 H); 7.61 (d, 2 Hz, 1 H); 8.1 1 (d, 2 Hz, 1 H); 8.69 (t, 5 Hz, 1 H); 8.94 (s, 1 H); 12.45 (br s, 1 H) and 14.50 (br s, 1 H).
LC-MS: 405 [M-H] [35CI].
Example 121
6,7-Dichloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.70 (s, 2H); 4.75 (d, 5.6 Hz, 2H); 7.18-7.23 (m, 1 H); 7.29-7.38 (m, 2H); 8.39 (s, 1 H); 8.89 (s, 1 H); 9.1 1 (t, 5.6 Hz, 1 H); 12.42 (br s, 1 H). LC-MS: 455.4 [M-H] [35CI]. Example 122
8-[(2-Acetyl^henylamino)-methyl]-6-chloro-2-oxo-1,2-dihydro-quinoline-3- carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.56 (s, 3H); 4.78 (d, 5.2 Hz, 2H); 6.64 (t, 8 Hz, 1H); 6.73 (d, 8.4 Hz, 1H); 7.34 (t, 8.4 Hz, 1H); 7.67 (d, 2.4 Hz, 1H); 7.86 (d, 9.6 Hz, 1H); 8.10 (d, 2.4 Hz, 1H); 8.93 (s, 1H); 9.23 (d, 5.2 Hz, 1H); 12.73 (br s, 1H). LC-MS: 371.3 [M+H] [35CI].
Example 123
6-Chloro-2-oxo-8-{[(1^henyl-cyclopentanecarbonyl)-amino]-methyl}-1,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (200 MHz, DMSO-d6), δ (ppm): 1.40-1.70 (m, 4H); 1.70-1.90 (m, 2H); 4.44 (d, 6 Hz, 2H); 7.10-7.40 (m, 6H); 8.06 (s, 1H); 8.32 (t, 6 Hz, 1H); 8.90 (s, 1H); 12.25 (brs, 1H). LC-MS: 423.3 [M-H] [35CI].
Example 124
6-Chloro-8-({[1-(2-fluoro-phenyl)-cyclopropanecarbonyl]-amino}-methyl)-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.00-1.03 (m, 2H); 1.45 (m, 2H); 4.42 (d, 7 Hz, 2H); 7.19 (m, 2H); 7.41 (s, 1H); 7.61 (s, 1H); 7.75 (t, 7 Hz, 1H); 8.01 (s, 1H); 8.99 (s, 1H); 12.30 (brs, 1H).
Example 125
8-[(4-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1,2-dihydro-quinoline-3- carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.40 (s, 3H); 4.67 (s, 2H); 6.65 (d, 8.8 Hz, 2H); 7.65 (s, 1H); 7.73 (d, 8.8 Hz, 2H); 8.12 (s, 1H);8.96 (s, 1H); 12.55 (brs, 1H). LC-MS: 371.3 [M+H] [35CI]. Example 126
6-Chloro-8-[(2-methoxy-2^henyl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.28 (s, 3H); 4.53 (d, 6 Hz, 2H); 4.74 (s, 1 H); 7.31 -7.36 (m, 5H); 7.54 (d, 2.4 Hz, 1 H); 8.10 (d, 2.4 Hz, 1 H); 8.91 (s, 1 H); 8.96 (t, 6 Hz, 1 H), 12.41 (br s, 1 H). LC-MS: 399.4 [M-H] [35CI].
Example 127
6-Chloro-8-{[2-(2-fluoro-phenyl)-2-methyl-propionylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1 .41 (s, 6H); 4.51 (s, 2H); 7.21 (m, 1 H); 7.31 (m, 1 H); 7.45 (m, 1 H); 7.61 (s, 1 H); 8.15 (m, 2H); 8.91 (s, 1 H); 12.30 (br s, 1 H).
Example 128
6-Chloro-2-oxo-8-(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1 ,2-dihydroquinoline- 3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-(2-oxo-2-(thiazol-2-ylmethylamino)ethyl)- quinoline-3-carboxylate
[00366] Thiazol-2-yl-methylamine (104 μΙ, 1 .10 mmol, 2.0 equiv.) is added to a suspension of (CO)sMoCINEt (220 mg, 0.55 mmol) in ethanol (5 mL). The resulting mixture is stirred under a nitrogen atmosphere for 2 h. Diglyme (5 mL) is added to the mixture and heated to 120 °C with evaporation of ethanol. Tributylamine (144 μΙ, 0.60 mmol, 1 .10 equiv.) and methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate (170 mg, 0.49 mmol, 0.9 equiv.) are added and the mixture is heated at 130 °C for 2 h. The reaction mixture is filtered over kieselguhr and the filtrate is concentrated in vacuo. The residue is taken on hydromatrix and purified by flash column chromatography (silica, 1 -10% MeOH in DCM) to afford 89 mg (44%) of the title compound as a solid. 1H NMR (400 MHz, CDCI3), δ (ppm) 3.90 (s, 3H), 3.96 (s, 3H), 4.08 (s, 2H), 4.36 (d, 2H), 6.56 (br s, 1 H), 7.07-7.13 (m, 2H), 7.22-7.29 (m, 3H), 7.72 (s, 2H), 8.54 (s, 1 H). LC-MS: 399 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00367] Methyl 6-chloro-2-methoxy-8-(2-oxo-2-(thiazol-2- ylmethylamino)ethyl)quinoline-3-carboxylate (149 mg, 0.37 mmol) is dissolved in HBr (33 wt% in AcOH, 4 ml_) and stirred at 50 °C for 48 h. The reaction mixture is concentrated in vacuo and water is added to the residue. The resulting suspension is filtered off, washed with water. The residue is purified by reverse phase chromatography to afford 34 mg (24%) of the title compound as an off-white solid.
Mp: 234 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 4.01 (s, 2H), 4.60 (d, 2H), 7.64 (d, 1 H), 7.69-7.74 (m, 2H), 8.12 (d, 1 H), 8.94 (s, 1 H), 9.05 (t, 1 H), 12.46 (br s, 1 H), 14.50 (br s, 1 H).
LC-MS: 376 [M-H] [35CI]. Example 129
6-Chloro-8-((4-(1 -hydroxycyclohexyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid.
[00368] Sodium azide (128 mg, 1 .98 mmol, 1 .5 equiv.) is added to a solution of 8- (bromomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (417 mg, 1 .32 mmol) in anhydrous DMF (12.5 ml_) and the mixture is stirred at 50-55°C for 3 h. The mixture is allowed to cool to rt, then poured into 35 ml_ of ice-water and stirred for 10 min. The resulting suspension is filtered off, the residue is washed with water and dried to afford 263 mg (71 %) of the title compound as a solid. The product is used in the next step without further purification. LC-MS: 277 [M+H] [35CI]. b) General procedure for 'click reaction' of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid with acetylene of choice. [00369] L-Ascorbic acid sodium salt (4.98 mg, 0.025 mmol, 0.1 equiv.) and copper(ll) sulfate pentahydrate (3.14 mg, 0.013 mmol) are added to a mixture of 8- (azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (70 mg, 0.25 mmol) and acetylene of choice (0.25 mmol, 1 .0 equiv.) in a mixture of water (1 .5 mL) and DMF (1 .5 mL). The reaction mixture is heated at 100 °C for 30 min and then cooled to rt. The resulting suspension is diluted with EtOAc, the suspension is filtered off. The residue is washed with water, EtOAc, diethyl ether and air dried to afford the product in suitable purity. When the obtained material proved not to be of sufficient purity, the compound is either triturated with solvent of choice (i.e. MeOH or DCM) or purified by reverse phase chromatography. c) 6-Chloro-8-((4-(1 -hydroxycyclohexyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00370] Prepared according to the general procedure by reaction with 1 -ethynyl- cyclohexanol. Purified by reverse phase chromatography. Yield: 19%.
Mp: 299 °C (decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 1 .20-1 .33 (m, 1 H), 1 .35-
1 .46 (m, 2H), 1 .46-1 .56 (m, 1 H), 1 .58-1 .73 (m, 4H), 1 .77-1 .90 (m, 2H), 4.92 (br s, 1 H),
5.97 (s, 2H), 7.58 (d, 1 H), 8.01 (s, 1 H), 8.22 (d, 1 H), 8.94 (s, 1 H), 12.76 (br s, 1 H),
14.34 (br s, 1 H).
LC-MS: 401 [M-H] [35CI].
Example 130
6-Chloro-8-[4-(4-fluoro-phenyl)-[1 ,2,3]triazol-1 -ylmethyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00371 ] Prepared according to the general procedure (Example 129b) by reaction with 1 -ethynyl-4-fluorobenzene. Yield: 53%.
Mp: 290 °C (decomp.), LC-MS: 397 [M+H] [35CI]. 1H NMR (400 MHz, DMSO-d6), δ (ppm) 6.06 (s, 2H), 7.28 (t, 2H), 7.70 (s, 1 H), 7.88 (t, 2H), 8.24 (s, 1 H), 8.59 (s, 1 H), 8.94 (s, 1 H), 12.82 (br s, 1 H), 14.59 (br s, 1 H).
Example 131 6-Chloro-2-oxo-8-{[(1^henyl-cyclopropanecarbonyl)-amino]-methyl}-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.00-1.03 (m, 2H); 1.37-1.40 (m, 2H); 4.42 (d, 6 Hz, 2H); 7.32-7.40 (m, 5H); 7.60 (d, 2 Hz, 1H); 7.65 (t, 6 Hz, 1H); 8.11 (d, 2.4 Hz, 1H); 8.91 (s, 1H); 12.52 (brs, 1H). LC-MS: 395.1 [M-H] [35CI].
Example 132
6-Chloro-8-[(2-methyl-2-phenyl-propionylamino)-methyl]-2-oxo-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 1.48 (s, 6H); 4.47 (d, 6 Hz, 2H); 7.20-7.23 (m, 1H); 7.23-7.28 (m, 4H); 7.45 (d, 2 Hz, 1H); 8.09 (d, 2 Hz, 1H); 8.18 (t, 6 Hz, 1H); 8.92 (s, 1H); 12.34 (brs, 1H). LC-MS: 397.4 [M-H] [35CI].
Example 133
6-Chloro-2-oxo-8-{[(1-phenyl-cyclobutanecarbonyl)-amino]-methyl}-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (200 MHz, DMSO-d6), δ (ppm): 1.65-1.90 (m, 2H); 2.30-2.50 (m, 2H); 2.60- 2.80 (m, 2H); 4.46 (d, 5.8 Hz, 2H); 7.15-7.40 (m, 6H); 8.05 (s, 1H); 8.41 (t, 5.8 Hz, 1H); 8.89 (s, 1H); 12.32 (brs, 1H). LC-MS: 409.2 [M-H] [35CI].
Example 134
6-Chloro-2-oxo-8-{[(4-phenyl-piperidine-4-carbonyl)-amino]-methyl}-1,2-dihydro- quinoline-3-carboxylic acid
1H-NMR (400 MHz, DMSO-d6), δ (ppm): 2.06-2.12 (m, 2H); 2.50-2.60 (m, 2H); 2.85- 2.95 (m, 2H); 3.20-3.30 (m, 2H); 4.52 (d, 6 Hz, 2H); 7.28-7.36 (m, 6H); 8.08 (d, 2.4 Hz, 1H); 8.40 (brs, 2H); 8.56 (t, 6 Hz, 1H); 8.91 (s, 1H); 12.10 (brs, 1H). LC-MS: 440.5
[M+H] [35CI]. Example 135
6-Chloro-2-oxo-8-{[(2-pyrazol-1-yl-pyridine-3-carbonyl)-amino]-methyl}-1,2- dihydro-quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.72 (d, 6 Hz, 2H); 6.45 (s, 1H); 7.23 (s, 1H); 7.46-7.49 (m, 1H); 7.96-8.01 (m, 2H); 8.18 (d, 2 Hz, 1H); 8.47 (d, 2 Hz, 1H); 8.56 (d, 3.2 Hz, 1H); 8.99 (s, 1H); 9.18 (t, 6 Hz, 1H); 12.46 (br s, 1H). LC-MS: 422.1 [M-H] [35CI].
Example 136
6-Chloro-2-oxo-8-[(2-phenyl-2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.56-4.68 (m, 2H); 6.45 (s, 1H); 7.41-7.47 (m, 5H); 7.54 (d, 2 Hz, 1H); 8.03 (s, 1H); 8.11 (d, 2.4 Hz, 1H); 8.49 (s, 1H); 8.92-8.97 (m, 2H); 12.37 (br s, 1H). LC-MS: 436.1 [M-H] [35CI].
Example 137
6-Chloro-2-oxo-8-{[(4-pyrazol-1-yl-pyridine-3-carbonyl)-amino]-methyl}-1,2- dihydro-quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.81 (d, 5.6 Hz, 2H); 6.63 (s, 1H); 7.76 (d, 1.6 Hz, 1H); 7.89 (s, 1H); 8.03 (d, 8.8 Hz, 1H); 8.16 (s, 1H); 8.42-8.45 (m, 1H); 8.69 (d, 2 Hz, 1H); 8.94 (s, 2H); 9.46 (t, 5.6 Hz, 1H); 12.50 (brs, 1H). LC-MS: 422.1 [M-H] [35CI].
Example 138
6-Chloro-8-((4-(3-(3,3-dimethyl-2-oxoazetidin-1 -yl)phenyl)-1 H-1 ,2,3-triazoM - yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00372] Prepared according to the general procedure (Example 129b) by reaction with 1-(3-ethynyl-phenyl)-3,3-dimethyl-azetidin-2-one. Purified by reverse phase chromatography. Yield: 51%. Mp: >289 °C (decomp.), LC-MS: 476 [M-H] [35CI]. 1H NMR (400 MHz, DMSO-d6), δ (ppm) [broad signals] 1 .32 (s, 6H), 3.55 (s, 2H), 6.07 (br s, 2H), 7.22-7.92 (m, 5H), 8.22 (br s, 1 H), 8.65 (br s, 1 H), 8.93 (br s, 1 H), 12.80 (br s, 1 H), 14.75 (br s, 1 H).
Example 139
6-Chloro-2-oxo-8-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-(2-oxo-2-(pyridin-4-ylmethylamino)ethyl)- quinoline-3-carboxylate
[00373] A suspension of Mo(CO)6 (200 mg, 0.74 mmol) and Et4NCI (123 mg, 0.74 mmol) in diglyme (5 ml_) is stirred at 80 °C for 30 min under Ar atmosphere, then 4- (aminomethyl)pyridine (75 μΙ, 0.74 mmol) is added and stirring continued for 1 h. Tributylamine (194 μΙ, 0.81 mmol, 1 .10 equiv.) is added and after 15 min of stirring methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (242 mg, 0.70 mmol, 0.95 equiv.) is added. The mixture is stirred at 80 °C for 16 h. The mixture is allowed to cool to rt and concentrated in vacuo. The residue is taken in DCM, coated on hydromatrix and purified by flash column chromatography (silica, 0-5% MeOH in DCM) to afford 151 mg (51 %) of the title compound as a solid.
1H NMR (400 MHz, CDCI3), δ (ppm) 3.97 (s, 3H), 4.01 (s, 3H), 4.13 (s, 2H), 4.37 (d, 2H), 6.67 (br s, 1 H), 7.00 (d, 2H), 7.71 -7.77 (m, 2H), 8.46 (d, 2H), 8.56 (s, 1 H).
LC-MS: 400 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid.
[00374] Methyl 6-chloro-2-methoxy-8-(2-oxo-2-(pyridin-4- ylmethylamino)ethyl)quinoline-3-carboxylate (151 mg, 0.38 mmol) is dissolved in HBr (33 wt% in AcOH, 3 ml_) and stirred at 60°C for 16 h. The reaction mixture is concentrated in vacuo and water is added to the residue. The resulting suspension is filtered off, washed with water. The residue is purified by reverse phase chromatography to afford 16 mg (1 1 %) of the title compound after lyophilization. Mp: 285 °C; 1H NMR (400 MHz, DMSO-d6), δ (ppm) 4.04 (s, 2H), 4.33 (d, 2H), 7.29 (d, 2H), 7.70 (d, 1 H), 8.12 (d, 1 H), 8.50 (br s, 2H), 8.76 (t, 1 H), 8.93 (s, 1 H), 12.51 (br s, 1 H), 14.61 (br s, 1 H).
LC-MS: 370 [M-H] 370 [35CI].
Example 140
6-Chloro-2-oxo-8-{[(pyridin -ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-(2-oxo-2-(pyridin-3- ylmethylamino)ethyl)quinoline-3-carboxylate.
[00375] A suspension of Mo(CO)6 (200 mg, 0.74 mmol) and Et4NCI (123 mg, 0.74 mmol) in diglyme (5 ml_) is stirred at 80 °C for 30 min under Ar atmosphere, then 3- (aminomethyl)pyridine (76 μΙ, 0.74 mmol) is added and stirring continued for 1 hour. Tributylamine (194 μΙ, 0.81 mmol, 1 .10 equiv.) is added and after 15 min of stirring methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (242 mg, 0.70 mmol, 0.95 equiv.) is added. The mixture is stirred at 80 °C for 16 h. The mixture is allowed to cool to rt and concentrated in vacuo. The residue is taken in DCM, coated on hydromatrix and purified by flash column chromatography (silica, 0-5% MeOH in DCM) to afford 148 mg (50%) of the title compound as a solid.
1H NMR (400 MHz, CDCI3), δ (ppm) 3.97 (s, 6H), 4.09 (s, 2H), 4.37 (d, 2H), 6.62 (br s, 1 H), 7.19 (q, 1 H), 7.46 (d, 1 H), 7.70-7.75 (m, 2H), 8.39 (s, 1 H), 8.48 (d, 1 H), 8.55 (s, 1 H).
LC-MS: 400 [M+H] [35CI]. b) 6-Chloro-2-oxo-8-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid.
[00376] Methyl 6-chloro-2-methoxy-8-(2-oxo-2-(pyridin-3- ylmethylamino)ethyl)quinoline-3-carboxylate (148 mg, 0.37 mmol) is dissolved in HBr (33 wt% in AcOH, 3 ml_) and stirred at 60 °C for 16 h. The reaction mixture is concentrated in vacuo and water is added to the residue followed by the addition of saturated aqueous NaHCO3 solution. The resulting suspension is filtered off, washed with water. The residue is triturated with MeOH, filtered, washed with ether and air dried to afford 1 17 mg (86%) of the title compound as a solid.
Mp: >226 °C (decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 4.01 (s, 2H), 4.37 (d, 2H), 7.54 (q, 1 H), 7.69 (d, 1 H), 7.89 (d, 1 H), 8.13 (d, 1 H), 8.54-8.63 (m, 2H), 8.94 (s, 1 H), 12.49 (br s, 1 H).
LC-MS: 370 [M-H] [35CI].
Example 141
6,7-Dichloro-2-oxo-8-pyrazol-1 -ylmethyl-1 ,2-dihydro-quinoline-3-carboxylic acid
[00377] A mixture of 8-(bromomethyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (100 mg, 0.28 mmol) and pyrazole (58 mg, 0.85 mmol, 3.0 equiv.) in anhydrous DMF (1 mL) is heated at 80 °C for 16 h. The mixture is allowed to cool to rt and the solvent is removed under reduced pressure. The residue is triturated with DCM, filtered off and the residue is washed with DCM, ether and air dried to afford 65 mg (67%) of the title compound as a white solid.
Mp: >280 °C (decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 5.92 (s, 2H), 6.26 (t, 1 H), 7.43 (d, 1 H), 7.90 (d, 1 H), 8.44 (s, 1 H), 8.90 (s, 1 H), 12.67 (br s, 1 H), 14.19 (br s, 1 H).
LCMS: 336/338/340 [M-H] [double CI isotope pattern]. Example 142
6,7-Dichloro-2-oxo-8-[1 ,2,4]triazol-1 -ylmethyl-1 ,2-dihydro-quinoline-3-carboxylic acid
[00378] A mixture of 8-(bromomethyl)-6,7-dichloro-2-oxo-1 ,2dihydroquinoline-3- carboxylic acid (100 mg, 0.28 mmol) and 1 ,2,4-1 H-triazole (59 mg, 0.85 mmol, 3.0 equiv.) in anhydrous DMF (1 mL) is heated at 80 °C for 16 h. The mixture is allowed to cool to rt and the solvent is removed under reduced pressure. The residue is purified by reverse phase chromatography to afford 24 mg (25%) of the title compound as a white solid. Mp: >280 °C (gradual decomp.); 1H NMR (400 MHz, DMSO-d6), δ (ppm) 5.98 (s, 2H), 7.94 (s, 1 H), 8.46 (s, 1 H), 8.71 (s, 1 H), 8.91 (s, 1 H), 12.77 (br s, 1 H), 14.14 (br s, 1 H). LCMS: 339/341/343 [M+H] [double CI isotope pattern].
Example 143
8-[((R)-2-Amino-2^henyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
Isolated as ammonium salt.
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.64-4.67 (m, 2H); 4.90-5.10 (br s, 1 H); 7.09 (s, 1 H); 7.35-7.50 (m, 3H); 7.50-7.60 (m, 2H); 7.84 (s, 1 H); 8.53 (s, 1 H); 8.90 (br s, 1 H). LC-MS: 386.3 [M+H] [35CI].
Example 144
6-Chloro-8-[(2-imidazol-1 -yl-2-phenyl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.55-4.75 (m, 2H); 6.56 (s, 1 H); 7.40-7.55 (m, 6H); 7.67 (s, 1 H); 7.78 (s, 1 H); 8.13 (s, 1 H); 8.93 (s, 1 H); 9.21 (br s, 2H). LC-MS: 435.2 [M-H] [35CI].
Example 145
6-Chloro-8-{[2-(2,5-dimethoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.47 (s, 2H); 3.59 (s, 3H); 3.66 (s, 3H); 4.52 (d, 6 Hz, 2H); 6.77-6.80 (m, 2H); 6.86 (d, 8.4 Hz, 1 H); 7.65 (d, 2.4 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.53 (t, 6 Hz, 1 H); 8.94 (s, 1 H); 12.48 (br s, 1 H). LC-MS: 429.1 [M-H] [35CI].
Example 146
6-Chloro-2-oxo-8-[(3-phenyl-ureido)-methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid 1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.88 (d, 6.4 Hz, 2H); 6.92-7.00 (m, 2H); 7.24 (t, 8 Hz, 2H); 7.40 (d, 8 Hz, 2H); 7.78 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.94 (s, 1 H); 9.01 (s, 1 H); 12.82 (br s, 1 H). LC-MS: 370.1 [M-H] [35CI].
Example 147
6,7-Dichloro-2-oxo-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.78 (d, 5.2 Hz, 2H); 4.98 (s, 2H); 8.05 (s, 1 H); 8.40 (s, 1 H); 8.60 (s, 1 H); 8.89 (s, 1 H); 9.10 (br s, 1 H). LC-MS: 394.1 [M-H] [35CI].
Example 148
6-Chloro-2-oxo-8-[(2-phenyl-2-pyrazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.57-4.68 (m, 2H); 6.29 (s, 1 H); 6.33 (s, 1 H); 7.38 (s, 5H); 7.53 (s, 1 H); 7.58 (s, 1 H); 7.68 (s, 1 H); 8.1 1 (s, 1 H); 8.92 (s, 1 H); 8.97 (br s, 1 H); 12.40 (br s, 1 H). LC-MS: 437.3 [M+H] [35CI].
Example 149
6,7-Dichloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.82 (d, 6 Hz, 2H); 5.04 (s, 2H); 7.66 (s, 2H); 8.40 (s, 1 H); 8.89 (s, 1 H); 9.02 (s, 1 H); 9.22 (t, 6 Hz, 1 H). LC-MS: 395 [M+H] [35CI].
Example 150
6,7-Dichloro-2-oxo-8-[(2-pyridin-3-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline- 3-carboxylic acid
Isolated as hydrobromide hydrate. 1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.78 (s, 2H); 4.76 (d, 6 Hz, 2H); 7.87-7.91 (m, 1 H); 8.30 (d, 8 Hz, 1 H); 8.40 (s, 1 H); 8.75 (d, 5.2 Hz, 2H); 8.89 (s, 1 H); 9.19 (t, 6 Hz, 1 H). LC-MS: 404.0 [M-H].
Example 151
6-Chloro-8-{[2-(2-methoxy^henyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.50 (s, 2H); 3.65 (s, 3H); 4.53 (d, 6 Hz, 2H); 6.87-6.96 (m, 2H); 7.17-7.26 (m, 2H); 7.66 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.55 (t, 6 Hz, 1 H); 8.94 (s, 1 H); 12.49 (br s, 1 H). LC-MS: 399.3 [M-H].
Example 152
6,7-DiChloro-2-oxo-8-(3-phenyl-pyrazol-1 -ylmethyl)-1,2-dihydro-quinoline-3- carboxylic acid
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 5.79 (s, 2H); 6.81 (d, 2 Hz, 1 H); 7.30 (d, 7.2 Hz, 1 H); 7.38-7.42 (m, 2H); 7.52 (d, 2 Hz, 1 H); 7.82 (d, 7.2 Hz, 2H); 7.99 (d, 2.4 Hz, 1 H); 8.18 (d, 2.4 Hz, 1 H); 8.93 (s, 1 H); 12.77 (br s, 1 H). LC-MS: 380.2 [M+H].
Example 153
6,7-Dichloro-2-oxo-8-[(2-pyridin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline- 3-carboxylic acid
Isolated as hydrobromide.
1 H-NMR (400 MHz, DMSO-d6), δ (ppm): 3.92 (br s, 2H); 4.78 (d, 6 Hz, 2H); 7.60-7.75 (br s, 2H); 8.15-8.25 (br s, 1 H); 8.40 (s, 1 H); 8.65-8.75 (br s, 1 H); 8.89 (s, 1 H); 9.22 (t, 6 Hz, 1 H). LC-MS: 404.0 [M-H].
Example 154
8-[3-(4-Bromo-phenyl)-ureidomethyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid 1H-NMR (400 MHz, DMSO-d6), δ (ppm): 4.57 (d, 4.4 Hz, 2H); 6.95 (s, 1 H); 7.37-7.42 (m, 4H); 7.76 (s, 1 H); 8.13 (s, 1 H); 8.94 (s, 1 H); 9.06 (br s, 1 H); 12.72 (br s, 1 H). LC- MS: 448.4 [M-H].
Example 155
6 -Dichloro-2-oxo-8-[(2^yrimidin-2-yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid
Isolated as hydrobromide hydrate.
1H-NMR (400 MHz, DMSO-d6), δ (ppm):3.90 (s, 2H); 4.60 (d, 5.6 Hz, 2H); 7.42 (t, 4.8 Hz, 1 H); 7.90 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.77 (d, 4.4 Hz, 2H); 8.85-8.95 (br s, 2H). LC-MS:371.3 [M-H].
Example 156
8-Aminomethyl-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
Isolated as hydrochloride, crystallized with 0.25 molecules of dioxane.
1H-NMR (400 MHz, DMSO-d6), δ (ppm) 3.56 (s, 2H, dioxane); 4.59 (br s, 2H); 8.35 (br s, 3H); 8.48 (s, 1 H); 8.89 (s, 1 H).
Example 157
6-Bromo-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
[00379] The title compound is prepared by the following reaction sequence:
a) to a suspension of methyl 6-bromo-2-chloro-8-methylquinoline-3-carboxylate (1 .1 g, 3.5 mmol) in abs. MeOH (40 mL) at -4°C under argon is added 60% NaH in mineral oil (0.84 g, 21 .0 mmol) portionwise. The resulting mixture is stirred at rt for 1 h and at reflux for 72 h. (according to HPLC/MS, the mixture consisting of 6-bromo-2-methoxy-8- methylquinoline-3-carboxylic acid and its methyl ester in a ratio of 84:16). The reaction mixture is evaporated, cold water (80 mL) is added to the residue, and the resulting suspension is acidified with 3N aq. HCI (8 mL). Then mixture is stirred at rt for 2 h, filtered, solid is washed with water, and dried over P2O5. The obtained solid is suspended in abs. MeOH (30 mL), to this suspension 2N HCI solution in MeOH (3 mL) is added, and the resulting mixture is refluxed for 6 h. The solvent is evaporated, the residue is azeotropically dried with CH2CI2 (2 x 15 mL), triturated with petroleum ether (15 mL), filtered, and dried over P2O5 to give 0.95 g (95.4%) of methyl 6-bromo-2- methoxy-8-methylquinoline-3-carboxylate. LC-MS: 310 [M+H]+. 1 H NMR (400 MHz, CDCI3), δ (ppm): 2.66 (s, 3H); 3.95 (s, 3H); 4.14 (s, 3H); 7.64 (m, 1 H); 7.76 (d, 2.1 Hz, 1 H); 8.48 (s, 1 H).
[00380] b) a mixture of methyl 6-bromo-2-methoxy-8-methylquinoline-3- carboxylate (0.95 g, 3.06 mmol), NBS (0.55 g, 3.06 mmol), and Bz2O2 (0.075 g, 0.31 mmol) in abs. CCI4 (120 mL) is stirred at reflux for 6 h and at rt for 18 h at (HPLC/MS; complete conversion to a mixture of dibromide and tribromide (87.5% and -12%)). After cooling, the reaction mixture is filtered, the filtrate is evaporated to dryness, the residue (1.216 g) is stirred in a hot mixture of hexane/EtOAc (7:1 , 15 mL), filtered, and washed with hot hexane/EtOAc (7:1 , 10 mL). The obtained solid is dried to give a mixture (0.85 g, 94% purity). The solid is repeatedly chromatographed on silica gel (CH2CI2) to give 0.603 g (50.6%) of pure methyl 6-bromo-8-(bromomethyl)-2-methoxyquinoline-3- carboxylate. LC-MS: 389.9 [M+H]. 1 H NMR (400 MHz, CDCI3), δ (ppm): 3.96 (s, 3H); 4.19 (s, 3H); 5.01 (s, 2H); 7.89 (d, 2.2 Hz, 1 H); 7.90 (d, 2.2 Hz, 1 H); 8.51 (s, 1 H).
[00381 ] c) to a solution of methyl 6-bromo-8-(bromomethyl)-2-methoxyquinoline-3- carboxylate (0.57 g, 1 .47 mmol) in abs. DMF (25 mL) is added NaN3 (0.143 g, 2.20 mmol) and the reaction mixture is stirred at 50-55°C for 10 h and at rt overnight. The mixture is poured into ice-water (100 mL) and stirred at rt for 2 h. The precipitate is filtered, washed with water, and dried over P2O5 to give methyl 8-(azidomethyl)-6- bromo-2-methoxyquinoline-3-carboxylate (0.508 g, 98%). LC-MS: 351 [M+H]+. 1 H NMR (400 MHz, CDCI3), δ (ppm): 3.96 (s, 3H); 4.17 (s, 3H); 4.91 (s, 2H); 7.81 (m, 1 H); 7.91 (d, 2.1 Hz, 1 H); 8.52 (s, 1 H). [00382] d) to a solution of methyl 8-(azidomethyl)-6-bromo-2-methoxyquinoline-3- carboxylate (0.5 g, 1 .42 mmol) in THF (32 mL) is added PPh3 (0.56 g, 2.14 mmol) and water (0.26 mL, 14.2 mmol), and the resulting mixture is stirred at rt for 24 h. The reaction mixture is cooled to -3 °C, 1 M aq. HCI (6.5 mL) is slowly added at the same temperature, and the mixture is stirred at rt for 2 h. Then mixture is stored in a fridge overnight, the precipitate is filtered, washed with EtOAc (3x35 mL), diethyl ether (2x20 mL), and dried over P2O5 to give methyl 8-(aminomethyl)-6-bromo-2-methoxyquinoline- 3-carboxylate hydrochloride (0.407 g, 79%), m.p. 256-257°C. LC-MS: 325 [M+H]+. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.12 (s, 3H); 4.51 (s, 2H); 8.1 1 (d, 2.1 Hz, 1 H); 8.39 (d, 2.1 Hz, 1 H); 8.41 (b s, 3H); 8.81 (s, 1 H).
[00383] e) in analogy to the procedure described in Example 5(a), condensation methyl 8-(aminomethyl)-6-bromo-2-methoxyquinoline-3-carboxylate with 2-(2- fluorophenyl)acetic acid gives methyl 6-bromo-8-((2-(2-fluorophenyl)acetamido)methyl)-
2-methoxyquinoline-3-carboxylate as white solid in 73% yield.
f) in analogy to the procedure described in Example 3(b) methyl 6-bromo-8-((2-(2- fluorophenyl)acetamido)methyl)-2-methoxyquinoline-3-carboxylate is treated with HBr in
AcOH to give the title compound as light grey solid in 61 % yield.
1 H-NMR (400 MHz, DMSO-d6), δ (ppm: 3.61 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.12-7.20 (m,
2H); 7.28-7.38 (m, 2H); 7.76 (d, 2 Hz, 1 H); 8.26 (d, 2 Hz, 1 H); 8.79 (t, 6 Hz, 1 H); 8.92 (s,
1 H).
Example 158
6-Bromo-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3-carboxylic acid (1-158)
1 H NMR (400 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 4.54 (d, 6 Hz, 2H); 7.23-7.33 (m, 5H); 7.72 (d, 1 .6 Hz, 1 H); 8.25 (d, 1 .6 Hz, 1 H); 8.81 (t, 6 Hz, 1 H) and 8.91 (s, 1 H).
LC-MS: 413, 415 [M-H].
Example 159 8-((1 H-1 ,2,3-triazoM -yl)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
[00384] A mixture of 8-(bromomethyl)-6,7-dichloro-2-oxo-1 ,2dihydroquinoline-3- carboxylic acid (100 mg, 0.28 mmol) and 1 ,2,3-1 H-triazole (50 μΙ, 0.85 mmol, 3.0 equiv.) in anhydrous DMF (1 mL) was heated at 80°C for 16 hours. The mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was triturated with DCM, filtered off and the residue was washed with DCM, ether and air dried to afford a white solid. The residue was purified by preparative LCMS to afford 49 mg of a yellow solid. 1H-NMR analysis indicates presence of ammonium salts. The yellow solid was suspended in water and treated with aqueous 0.5 M KHSO4 solution. The resulting white suspension was filtered off, washed with water, MeOH and ether to affor 42 mg (43%) of the title compound as a white solid after air drying.
1H NMR δΗ (400 MHz; DMSO-d6): 6.14 (s, 2H), 7.45 (d, 1 H), 8.22 (s, 1 H), 8.48 (s, 1 H), 8.91 (s, 1 H), 12.88 (bs, 1 H).
ESI-MS: 337/339/341 ([M-H]", 100%, Cl2 isotope pattern). Example 160
8-((4-benzyl-1 H-1 ,2,3-triazoM -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00385] To a mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (120 mg, 0.43 mmol) and 3-phenyl-1 -propyne (50.0 mg, 0.43 mmol, 1.0 eq.) in DMF (1 .5 mL) and water (1 .5 mL) is added sodium L-ascorbate (8.53 mg, 10 mol%) and copper sulfate (5mg, 5 mol%). The mixture is heated to 100 °C for 45 minutes. Water is added to the mixture, and the yellow suspension is filtered off. The residue is washed with water, diethyl ether and air dried. The obtained material contains a product containing mass+14, indicating a methylated product. The residue is heated with HBr (33 wt% in AcOH, 3 mL) to 60°C for 1 hour and stirred overnight at room temperature. The mixture is diluted with heptane, and then concentrated in vacuo. Water is added to the residue, the mixture is stirred for 10 minutes, and the solids are filtered off. The solids are washed with water, MeCN, EtOAC and diethylether to obtain 134 mg of product. The material is further purified by preparative HPLC to afford 41 mg (24%) of the product as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 3.99 (s, 2H), 5.95 (s, 2H), 7.17-7.32 (m, 5H), 7.52 (s, 1 H), 7.97 (s, 1 H), 8.19 (d, 1 H), 8.90 (s, 1 H), 12.72 (bs, 1 H), 14.63 (bs, 1 H).
ESI-MS: 393/395 ([M+H]+, 100%, CI isotope pattern).
Example 161
6-chloro-8-((4-(3-hydroxyphenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00386] To a mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (78 mg, 0.28 mmol) and 3-hydroxyphenylacetylene (33.1 mg, 0.28 mmol, 1 .0 eq.) in DMF (1 .5 mL), Water (1 .5 mL) is added sodium L-ascorbate (5 mg, 10 mol%) and copper sulfate (3 mg, 5 mol%). The mixture is heated to 100 °C for 30 minutes and then allowed to cool to room temperature. Water is added to the mixture and the orange suspension is filtered off. The residue is washed with water, EtOAc, DCM and diethyl ether to afford 32 mg (28%) of the product as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 6.04 (s, 2H), 6.68-6.78 (m, 1 H), 7.18-7.29 (m, 3H), 7.96 (s, 1 H), 8.23 (s, 1 H), 8.54 (s, 1 H), 8.94 (s, 1 H), 9.52 (s, 1 H), 12.78 (bs, 1 H), 14.39 (bs, 1 H).
ESI-MS: 397/399 ([M+H]+, 100%, CI isotope pattern). Example 162
6-chloro-2-oxo-8-((4-phenyl-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid
[00387] To a mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (120 mg, 0.43 mmol) and ethynylbenzene (44.0 mg, 0.43 mmol, 1 .0 eq.) in DMF (1 .5 mL) and water (1 .5 mL) is added sodium L-ascorbate (8 mg, 10 mol%) and copper sulfate (5mg, 5 mol%). The mixture is stirred at 100 °C for one hour. The resulting suspension is filtered off, the residue washed with diethyl ether. The obtained material contains a product containing mass+14, indicating a methylated product. The residue is stirred in HBr (33 wt% in AcOH, 3 ml_, 0.43 mmol) for 30 minutes at 80 °C and at room temperature overnight. The mixture is concentrated in vacuo, and water is added to the residue. The solids are filtered off, washed with water and diethyl ether to obtain 1 12 mg of product. The material is submitted for purification by preparative LC, but the material failed to dissolve in DMSO. The suspension is filtered off, the residue washed with DCM and diethyl ether to afford 30 mg (18%) of the title compound as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 2.81 -3.29 (m, 8H), 4.01 (bs, 2H), 6.07 (s, 2H), 7.64 (s, 1 H), 8.23 (d, 1 H), 8.27 (s, 1 H), 8.85 (bs, 2H), 8.94 (s, 1 H), 12.77 (bs, 1 H), 14.29 (bs, 1 H).
ESI-MS: 403/405 ([M+H]+, 100%, CI isotope pattern). Example 163
(R)-6-chloro-8-((4-(hydroxy(phenyl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00388] To a mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (150 mg, 0.54 mmol) and (R)-1 -phenyl-2-propyn-1 -ol (670 μΙ, 0.54 mmol, 1.0 eq.) in DMF (1 .5 ml_) and water (1 .5 ml_) is added sodium L-ascorbate (10 mg, 10 mol%) and copper sulfate (7 mg, 5 mol%). The mixture is heated to 60 °C for 30 minutes and then allowed to cool to room temperature. Water is added to the mixture and the suspension is filtered off. The residue is washed with water, MeCN, DCM and diethyl ether to afford 174 mg (79%) of the product as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 5.81 (s, 1 H), 5.85-6.07 (m, 3H), 7.19-7.44 (m, 5H), 7.56 (s, 1 H), 8.02 (s, 1 H), 8.19 (s, 1 H), 8.90 (s, 1 H), 12.70 (bs, 1 H), 14.46 (bs, 1 H). ESI-MS: 41 1/413 ([M+H]+, 100%, CI isotope pattern).
Example 164
(8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 8-acetyl-6-chloro-2-methoxyquinoline-3-carboxylate [00389] A mixture of methyl 6-chloro-8-iodo-2-methoxyquinoline-3-carboxylate (500 mg, 1.32 mmol), lithium chloride (281 mg, 6.62 mmol, 5 eq.) and DIPEA (463 μΙ, 2.65 mmol, 2 eq.) in anhydrous DMF (13 mL) is degassed by evacuation of the vessel and refilling with argon three times. Acetic anhydride (622 μΙ, 6.62 mmol, 5 eq.) and Pd2(dba)3 (60.6 mg, 5 mol%) are added and the turbid mixture is degassed as described above. The mixture is heated to 80 °C for 16 hours. The reaction mixture is concentrated in vacuo, dissolved in EtOAc (50 mL), washed with saturated aqueous NaHCOs solution (3x20 mL), brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The product is purified using flash column chromatography (silica gel, 20-60% EtOAc in heptane) to give 230 mg (58%) of the product as a light yellow solid. b) Isopropyl 6-chloro-8-(1 -(1 ,1 -dimethylethylsulfinamido)ethyl)-2- methoxyquinoline-3-carboxylate
[00390] Methyl 8-acetyl-6-chloro-2-methoxyquinoline-3-carboxylate (100 mg, 0.34 mmol) and titanium(IV) isopropoxide (502 μΙ, 1 .70 mmol, 5 eq.) are combined in 1 ,4- dioxane (2 mL) and 2-methylpropane-2-sulfinamide (racemic) (41 .3 mg, 0.34 mmol, 1 eq.) are added. The mixture is heated to 90 °C for 16 hours. The reaction mixture is cooled to -10 °C and sodium borohydride (38.6 mg, 1 .02 mmol, 3 eq.) is added. The solid reaction mixture is slowly warmed to 5 °C to continue the reaction. The reaction mixture is quenched with methanol (5 mL) and water (5 mL). The suspension is filtered off, the residue is washed with dioxane and the filtrate is concentrated under reduced pressure. The product is purified using flash column chromatography (silica gel, 5-40% EtOAc in heptane with 1 % TEA) to give 36 mg (24%) of the product as a yellow oil/foam. c) 8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid hydrochloride
[00391 ] Isopropyl 6-chloro-8-(1 -(1 ,1 -dimethylethylsulfinamido)ethyl)-2- methoxyquinoline-3-carboxylate (36 mg, 0.084 mmol) is dissolved in 1 ,4-dioxane (2 mL) and hydrochloric acid; 37% (1 mL) is added. The mixture is heated at 100 °C for 16 hours. The reaction mixture is cooled to room temperature, diluted with water (4 mL) and the suspension is filtered off. The product is washed with cold water, acetonitrile and diethyl ether and dried on air to give 17 mg (66%) of the product as a white solid. 1H NMR δΗ (400 MHz; DMSO-d6): 1.56 (d, 3H), 5.23 (bs, 1 H), 8.04 (d, 1 H), 8.22 (d, 1 H), 8.59 (bs, 3H), 8.91 (s, 1 H), 12.69 (bs, 1 H).
ESI-MS: 265/267 ([M-H]", 100%, CI isotope pattern).
Example 165
(S)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) Isopropyl 6-chloro-8-((S)-1 -((R)-1 ,1 -dimethylethylsulfinamido)ethyl)-2- methoxyquinoline-3-carboxylate
[00392] Methyl 8-acetyl-6-chloro-2-methoxyquinoline-3-carboxylate (164a) (100 mg, 0.34 mmol) and titanium(IV) isopropoxide (301 μΙ, 1.02 mmol, 3 eq.) are combined in 1 ,4-dioxane (2 ml_) and (R)-2-methylpropane-2-sulfinamide (45 mg, 0.37 mmol, 1 .1 eq.) is added. The mixture is heated to 80 °C for 16 hours. The reaction mixture is cooled to 0 °C and sodium borohydride (13 mg, 0.34 mmol, 1 eq.) is added. The reaction mixture is slowly warmed to room temperature and stirred for 1 hour. The reaction mixture is quenched with methanol (5 ml_) and water (5 ml_). The suspension is filtered over kieselguhr, the residue is washed with EtOAc. The filtrate is concentrated under reduced pressure. The product is purified using flash column chromatography (silica gel, 5-40% EtOAc in heptane with 1 % TEA) to give 59 mg (40%) of the product as an off-white solid. b) (S)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00393] Isopropyl 6-chloro-8-(1 -(1 ,1 -dimethylethylsulfinamido)ethyl)-2- methoxyquinoline-3-carboxylate (55 mg, 0.13 mmol) is dissolved in 1 ,4-dioxane (1 ml_) and hydrochloric acid; 37% (1 ml_) is added. The mixture is heated at 90 °C for 16 hours. The reaction mixture is cooled to room temperature, diluted with water (4 ml_) and the suspension is filtered off. The product is washed with cold water, acetonitrile and diethyl ether and dried on air to give 15 mg (38%) of the product as a white solid. Isolated as hydrochloride salt. 1H NMR 5H (400 MHz; DMSO-d6): 1.56 (d, 3H), 5.24 (bs, 1 H), 8.06 (s, 1 H), 8.23 (s, 1 H), 8.60 (bs, 3H), 8.93 (s, 1 H), 12.72 (bs, 1 H), 14.32, (bs, 1 H).
ESI-MS: 267/269 ([M+H]+, 100%, CI isotope pattern).
Example 166
(6-chloro-2-oxo-8-((4-(pyridin-2-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00394] To a mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (120 mg, 0.43 mmol) and 2-ethynylpyridine (44.4 mg, 0.43 mmol, 1 .0 eq.) in DMF (1 .5 ml_) and water (1 .5 ml_) is added sodium L-ascorbate (8 mg, 10 mol%) and copper sulfate (5 mg, 5 mol%). The mixture is heated to 50 °C for 30 minutes, LCMS analysis indicates incomplete conversion, therefore the reaction mixture is heated to 60 °C for 30 minutes. Still incomplete conversion according to LCMS analysis. The mixture is subsequently heated at 100 °C for 30 minutes and cooled to room temperature. Another equivalent of 2-ethynylpyridine (44.4 mg, 0.43 mmol) is added as well as extra amounts of copper sulfate (5mg, 5 mol%) and sodium L- ascorbate (8 mg, 10 mol%), and the reaction mixture is heated to 100 °C for 16 hours. The mixture is allowed to cool to room temperature and water is added to the reaction mixture. The resulting suspension is filtered off. The residue is washed with water, DCM, MeCN and diethylether to obtain 169 mg of a purple solid. The residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % TFA in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to afford 18 mg (8%) of the compound as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 6.09 (s, 2H), 7.34 (t, 1 H), 7.69 (bs, 1 H), 7.89 (t, 1 H), 8.02 (d, 1 H), 8.20 (s, 1 H), 8.59 (d, 1 H), 8.71 (s, 1 H), 8.89 (s, 1 H).
ESI-MS: 382/384 ([M+H]+, 100%, CI isotope pattern).
Example 167
6-chloro-2-oxo-8-((4-(2-(piperazin-1 -yl)ethyl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid [00395] A reaction vial is charged with 8-(azidomethyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (129a) (120 mg, 0.43 mmol), sodium L-ascorbate (8.5 mg, 10 mol%), copper sulfate (5.4 mg, 5 mol%), 1 -(but-3-ynyl)piperazine dihydrochloride (91 mg, 0.43 mmol, 1 .0 eq.) and potassium carbonate (1 19 mg, 0.86 mmol, 2.0 eq.) in a mixture of DMF (1 .5 ml_) and water (1 .5 ml_). The reaction is stirred at 65 °C for 30 minutes. The mixture is cooled to room temperature and diluted with water. The resulting suspension is filtered off, washed with water, DCM, acetonitrile and diethyl ether to leave 52 mg (29%) of the title compound as a solid.
1H NMR δΗ (400 MHz; D2O): 3.29 (t, 2H), 3.61 -3.77 (m, 10H), 5.96 (s, 2H), 7.59-7.63 (m, 1 H), 7.86-7.90 (m, 1 H), 8.03 (s, 1 H), 8.70 (s, 1 H).
ESI-MS: 417/419 ([M+H]+, 100%, CI isotope pattern).
Example 168
6-chloro-8-((4-(4-methoxyphenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00396] A mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (120 mg, 0.43 mmol), sodium L-ascorbate (8.5 mg, 10 mol%), copper sulfate (5.4 mg, 5 mol%) and 4-ethynylanisole (55.8 μΙ, 0.43 mmol, 1 .0 eq.) in a mixture of DMF (1 .5 mL) and water (1 .5 mL) is stirred at 65 °C for 45 minutes. The reaction mixture is cooled to room temperature and water (8 mL) was added. The resulting suspension is filtered. The resulting residue is sequentially washed with acetonitrile, EtOAc, DCM and diethyl ether to afford 10 mg (5%) of the title product (purity >85%).
1H NMR δΗ (400 MHz; DMSO-d6): 3.78 (s, 3H), 6.06 (s, 2H), 7.00 (d, 2H), 7.66 (s, 1 H), 7.76 (d, 2H), 8.22 (s, 1 H), 8.49 (s, 1 H), 8.92 (s, 1 H), 12.77 (bs, 1 H), 14.62 (bs, 1 H). ESI-MS: 41 1/413 ([M+H]+, 100%, CI isotope pattern).
Example 169
6-chloro-2-oxo-8-((4-(m-tolyl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid [00397] A mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (200 mg, 0.72 mmol), sodium L-ascorbate (14mg, 10 mol%), copper sulfate (9 mg, 5 mol%) and m-tolylacetylene (125 mg, 1 .08 mmol, 1 .5 eq.) in a mixture of DMF (2 ml_) and water (2 ml_) is stirred at 60 °C for 1 hour in a closed reaction vial. According to LCMS analysis the desired compound is formed. The mixture is diluted with water and the suspension is filtered off. The residue is washed sequentially with DCM, aqueous NH CI solution, water, acetonitrile and diethyl ether. The material is air dried to yield 166 mg (58%) of the title compound as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 2.35 (s, 3H), 6.06 (s, 2H), 7.15 (d, 1 H), 7.32 (t, 1 H), 7.58-7.72 (m, 3H), 8.23 (s, 1 H), 8.57 (s, 1 H), 8.93 (s, 1 H), 21 .80 (bs, 1 H), 14.67 (bs, 1 H).
ESI-MS: 395/397 ([M+H]+, 100%, CI isotope pattern). Example 170
6-chloro-8-((4-isobutyl-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00398] A reaction vial is charged with 8-(azidomethyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (129a) (200 mg, 0.72 mmol), sodium L-ascorbate (14 mg, 10 mol%), copper sulfate (9 mg, 5 mol%) and 4-methyl-1 -pentyne (88 mg, 1 .08 mmol, 1 .5 eq.) in a mixture of DMF (2 mL) and water (2 mL). The reaction mixture is stirred at 65 °C for 1 hour in a closed reaction vial. The mixture is diluted with water and the suspension is filtered off to afford 151 mg of crude product. The residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) to afford 62 mg (24%) of the title compound as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 0.87 (s, 3H), 0.89 (s, 3H), 1.81 -1 .93 (m, 1 H), 2.47- 2.53 (m, 2H, coincides with DMSO-peak), 5.96 (s, 2H), 7.45 (d, 1 H), 7.96 (s, 1 H), 8.21 (d, 1 H), 8.93 (s, 1 H), 12.70 (bs, 1 H), 14.31 (bs, 1 H).
ESI-MS: 361/363 ([M+H]+, 100%, CI isotope pattern).
Example 171 6-chloro-8-((4-(1 -methyl-1 H-imidazol-5-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00399] A mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (200 mg, 0.72 mmol), sodium L-ascorbate (14 mg, 10 mol%), copper sulfate (9 mg, 5 mol%) and 5-ethynyl-1 -methyl-1 H-imidazole (152 mg, 1 .43 mmol, 2.0 eq) in a mixture of DMF (2 mL) and water (2 mL) is stirred at 60 °C for one hour in a closed reaction vial. According to LCMS analysis the desired compound is formed. The mixture is diluted with water and the suspension is filtered off. The crude material (175 mg) is purified using reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % TFA in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to afford 66 mg (24%) of the product as a solid.
Product is isolated as trifluoro acetate salt.
1H NMR 5H (400 MHz; DMSO-d6): 3.90 (s, 3H), 7.46 (d, 1 H), 8.18 (d, 1 H), 9.94 (s, 1 H). ESI-MS: 385/387 ([M+H]+, 100%, CI isotope pattern).
Example 172
6-chloro-2-oxo-8-((4-(pyridin-4-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00400] A mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (200 mg, 0.72 mmol), 4-ethynylpyridine hydrochloride (100 mg, 0.72 mmol, 1 .0 eq.), sodium L-ascorbate (14mg, 10 mol%) and copper sulfate pentahydrate (9 mg, 5 mol%) in a mixture of water (2 mL) and DMF (2 mL) and heated to 65 °C in a sealed vessel for one hour. LCMS analysis indicates complete conversion. The reaction mixture is poured in water (10 mL) and the solid is filtered off to afford a blue solid. The product is purified using reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % TFA in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to give 34 mg (12%) of the title compound as a white solid.
Product is isolated as trifluoro acetate salt.
1H NMR δΗ (400 MHz; DMSO-d6): 6.09 (s, 2H), 7.74 (s, 1 H), 7.82 (d, 2H), 8.24 (s, 1 H), 8.63 (bs, 2H), 8.81 (s, 1 H), 8.93 (s, 1 H), 12.90 (bs, 1 H), 14.75 (bs, 1 H). ESI-MS: 382/384 ([M+H]+, 100%, CI isotope pattern). Example 173
6-chloro-2-oxo-8-((4-(pyridin-3-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00401 ] A mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (200 mg, 0.72 mmol), 3-ethynylpyridine (1 1 1 mg, 1 .08 mmol, 1 .5 eq.), sodium L-ascorbate (14 mg, 10 mol%) and copper sulfate pentahydrate (9 mg, 5 mol%) in a mixture of water (2 mL) and DMF (2 mL) and heated to 65 °C in a sealed vessel for one hour. LCMS analysis indicates complete conversion. The reaction mixture is poured in water (10 mL) and the solid is filtered off to afford an off-white solid. The product is purified using reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % TFA in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to give 60 mg (18%) of the title compound as an off-white solid.
Product is isolated as trifluoro acetate salt.
1H NMR δΗ (400 MHz; DMSO-d6): 6.1 1 (s, 2H), 7.62 (bs, 1 H), 7.77 (d, 1 H), 8.27 (d, 1 H), 8.32 (d, 1 H), 8.73 (s, 1 H), 8.97 (s, 1 H), 12.88 (bs, 1 H), 14.32 (bs, 1 H).
ESI-MS: 382/384 ([M+H]+, 100%, CI isotope pattern).
Example 174
6-chloro-8-((4-(2-methoxyphenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00402] 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (129a) (200 mg, 0.72 mmol), 2-ethynylanisole (139 μΙ, 1 .08 mmol, 1 .5 eq.), sodium L- ascorbate (14.2 mg, 10 mol%) and copper sulfate (8.9 mg, 5 mol%) are combined in a mixture of water (2 mL) and DMF (2 mL) and heated to 65 °C in a sealed vessel for 1 hour. LCMS analysis indicates complete conversion. The reaction mixture is concentrated in vacuo and the residue is triturated with aqueous saturated NH4CI solution (10 mL). The suspension is filtered off and the residue is washed with aqueous saturated NH CI solution, water, MeCN and diisopropylether to give a white solid. The product is triturated with water and filtered off to give 175 mg (59%) of the product as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 3.92 (s, 3H), 6.07 (s, 2H), 7.05 (t, 1 H), 7.14 (d, 1 H), 7.34 (t, 1 H), 7.61 (s, 1 H), 8.12 (d, 1 H), 8.21 (s, 1 H), 8.62 (s, 1 H), 8.92 (s, 1 H), 12.80 (bs, 1 H), 14.64 (bs, 1 H).
ESI-MS: 41 1/413 ([M+H]+, 100%, CI isotope pattern). Example 175
6-chloro-2-oxo-8-((4-(p-tolyl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid
[00403] A reaction vial is charged with 8-(azidomethyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (129a) (200 mg, 0.72 mmol), sodium L-ascorbate (14.2 mg, 10 mol%), copper sulfate (9 mg, 5 mol%) and p-tolylacetylene (125 mg, 1 .08 mmol, 1.5 eq.) in a mixture of DMF (2 mL) and water (2 mL). The mixture is stirred at 65 °C for 1 hour in a closed reaction vial. The mixture is diluted with water (8 mL), and the resulting suspension is filtered off. The crude material (200 mg) is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) to afford 49 mg (17%) of the title compound as a solid. 1H NMR δΗ (400 MHz; DMSO-d6): 2.32 (s, 3H), 6.05 (s, 2H), 7.24 (d, 2H), 7.68-7.75 (m, 3H), 8.24 (d, 1 H), 8.54 (s, 1 H), 8.95 (s, 1 H), 12.80 (bs, 1 H), 14.49 (bs, 1 H).
ESI-MS: 393/395 ([M-H]", 100%, CI isotope pattern).
Example 176
8-((4-(tert-butyl)-1 H-1 ,2,3-triazoM -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
[00404] A reaction vial is charged with 8-(azidomethyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (129a) (200 mg, 0.72 mmol), sodium L-ascorbate (14.2 mg, 10 mol%), copper sulfate (8.9 mg, 5 mol%) and tert-butylacetylene (179 μΙ, 1 .43 mmol, 2.0 eq.) in a mixture of DMF (2 mL) and water (2 mL). The mixture is stirred at 60 °C for 1 hour in a closed reaction vial. The mixture is diluted with water (8 mL), and the resulting suspension is filtered off. The crude material (191 mg) is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) to afford 77 mg (29%) of the title compound as a solid.
1H NMR δΗ (400 MHz; DMSO-d6): 1.26 (s, 9H), 5.94 (s, 2H), 7.56 (s, 1 H), 7.98 (s, 1 H), 8.21 (d, 1 H), 8.92 (s, 1 H), 12.72 (bs, 1 H), 14.54 (bs, 1 H).
ESI-MS: 359/361 ([M-H]", 100%, CI isotope pattern).
Example 177
6-chloro-8-((4-cyclopropyl-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00405] A mixture of 8-(azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (129a) (200 mg, 0.72 mmol), sodium L-ascorbate (14 mg, 10 mol%), copper sulfate (9 mg, 5 mol%) and cyclopropylacetylene (95 mg, 1 .43 mmol, 2.0 eq.) in a mixture of DMF (2 ml_) and water (2 ml_) is stirred at 60 °C for 1 hour in a closed reaction vial. According to LCMS analysis the desired compound is formed. The mixture is diluted with water and the suspension is filtered off. The crude material (196 mg) is purified using reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % TFA in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to afford 65 mg (26%) of the product as a solid. 1H NMR δΗ (400 MHz; DMSO-d6): 0.66-0.74 (m, 2H), 0.85-0.93 (m, 2H), 1 .90-1 .98 (m, 1 H), 5.93(s, 2H), 7.56 (s, 1 H), 7.92 (s, 1 H), 8.21 (s, 1 H), 8.93 (s, 1 H), 12.70 (bs, 1 H), 14.45 (bs, 1 H).
ESI-MS: 345/347 ([M+H]+, 100%, CI isotope pattern). Example 178
6-chloro-8-((4-(3-fluorophenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00406] 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (129a) (200 mg, 0.72 mmol) is combined with sodium L-ascorbate (14 mg, 10 mol%) and copper sulfate (8.9 mg, 5 mol%) in a mixture of DMF (2 mL) and water (2 mL) and 1 -ethynyl-3-fluorobenzene (124 μΙ, 1 .08 mmol, 1 .5 eq.) is added. The resulting suspension is heated to 65 °C in a sealed vessel for 1 hour. LCMS analysis (method C) indicates complete conversion. The reaction mixture is concentrated under reduced pressure and the residue is triturated with water and filtered off. The solid is washed with aqueous saturated NH4CI solution, water, MeCN and diisopropylether to give 270 mg of the product as an off-white solid. The product is purified using reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to give 89 mg (31 %) of the title compound as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 6.08 (s, 2H), 7.14-7.20 (m, 1 H), 7.46-7.52 (m, 1 H), 7.64-7.75 (m, 3H), 8.26 (d, 1 H), 8.64 (s, 1 H), 8.96 (s, 1 H), 12.82 (bs, 1 H), 14.44 (bs, 1 H).
ESI-MS: 413/415 ([M+H]+, 100%, CI isotope pattern). Example 179
6-chloro-8-((4-(3-methoxyphenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00407] 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (129a) (200 mg, 0.72 mmol) is combined with sodium L-ascorbate (14 mg, 10 mol%) and copper sulfate (8.9 mg, 5 mol%) in a mixture of DMF (2 ml_) and water (2 ml_) and 3-ethynylanisole (137 μΙ, 1 .08 mmol) is added. The resulting suspension is heated to 65 °C in a sealed vessel for 4 hours, then at room temperature for 16 hours. LCMS analysis indicates complete conversion to product and dimethylamide side product. The reaction mixture is concentrated under reduced pressure. The residue is stirred with 10 ml_ aqueous saturated NH4CI solution for 15 minutes and the solid is filtered off, washed with water, MeCN, methanol, EtOAc and diisopropylether. The solid is dried in vacuo to give 192 mg (65%) of the product as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 3.80 (s, 3H), 6.06 (s, 2H), 6.91 (d, 2H), 7.30-7.44 (m, 3H), 7.70 (s, 1 H), 8.26 (d, 1 H), 8.62 (s, 1 H), 8.95 (s, 1 H), 12.81 (bs, 1 H), 14.46 (bs, 1 H). ESI-MS: 41 1/413 ([M+H]+, 100%, CI isotope pattern).
Example 180 6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid a) 2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-1 -carboxylic acid
[00408] To a solution of 1 ,2,3, 4-tetrahydroisoquinoline-1 -carboxylic acid (0.5 g, 2.82 mmol) in 1 N NaOH (3 mL) and 10% NaHCO3 (3 mL) DCM (20mL) and BOC2O (0.677 g, 3.1 mmol) is added, the reaction mixture is stirred at room temperature for 4 h, left to stand at room temperature overnight and then diluted with water (20mL). The organic layer is separated, water layer is acidified with 1 N HCI to pH=4, extracted with EtOAc. Extract is dried over Na2SO4 and concentrated in vacuo to afford the title compound (0.504 g, 64.5%) as a colorless oil. b) Methyl 8-((2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-1 - carboxamido)methyl)-6-chloro-2-methoxyquinoline-3-carboxylate
[00409] A mixture of 2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-l - carboxylic acid (104 mg, 0.373 mmol), TBTU (150 mg, 0.466 mmol), NEt3 (65 μΙ_, 0.466 mmol) and anhydrous acetonitrile (5 mL) is stirred at room temperature for 1 h. Then NEt3 (65 L, 0.466 mmol) and methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate hydrochloride (88mg, 0.31 1 mmol) are added. The obtained mixture is stirred at room temperature for 8 hours, left to stand at room temperature overnight and diluted with water. The formed solid is collected by filtration, washed with 10% aqueous K2CO3 solution, water, MeOH and diethyl ether and dried giving the title compound (0.125 g, 62%) as a white powder. c) 6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00410] The compound methyl 8-((2-(tert-butoxycarbonyl)-1 ,2,3,4- tetrahydroisoquinoline-1 -carboxamido)methyl)-6-chloro-2-methoxyquinoline-3- carboxylate (1 19 mg, 0.220 mmol mmol) in 2 mL 33% HBr/AcOH is irradiated in microwave oven at 100 °C for 40 min. The reaction mixture is concentrated in vacuo, water/MeCN (4/1 , v/v) are added to the residue, stirred for 1 h. Formed precipitate is filtered, washed with water, MeOH, diethyl ether, crystallized from DMF/water, 4:1 . To give the title compound (74 mg, 82 %, as a pale yellow powder.
1H NMR (DMSO-de, 400 MHz) δ (ppm) 3.01 (m, 2H), 3.53 (m, 2H), 4.54 (d, 2H), 5.15 (m, 1 H), 7.20 (d, 2H), 7.25 (d, 1 H), 7.62 (s, 1 H), 8.1 1 (s, 1 H), 8.80 (s, 1 H), 9.33 (t, 1 H), 10.80 (br, 1 H).
APCI-MS: 412, 414 ([M+H]+, 100%). Example 181
6-chloro-8-((4-(2-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[0041 1 ] 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (129a) (150 mg, 0.54 mmol) is combined with sodium L-ascorbate (1 1 mg, 10 mol%)) and copper sulfate (6.7 mg, 5 mol%) in a mixture of DMF (2 ml_) and water (2 ml_) and 2-fluoro-2-(prop-2-ynyl)benzene (108 mg, 0.81 mmol) is added. The resulting suspension is heated to 65 °C in a sealed vessel for 2 hours. LCMS indicated full conversion. The mixture is concentrated under reduced pressure. The residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to afford 93.7 mg (42%) of the product as an off-white powder. The off-white powder is triturated with hot MeCN to afford 80.5 mg (36%) of the product as a white powder.
1H NMR δΗ (400 MHz; DMSO-d6): 4.02 (s, 2H), 5.95 (s, 2H), 7.1 1 -7.20 (m, 2H), 7.26- 7.33 (m, 2H), 7.54 (d, 1 H), 7.99 (s, 1 H), 8.21 (d, 1 H), 8.92 (s, 1 H), 12.72 (bs, 1 H), 14.39 (bs, 1 H).
ESI-MS: 413/415 ([M+H]+, 100%, CI isotope pattern). Example 182
6-chloro-8-((4-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00412] 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (129a) (150 mg, 0.54 mmol) is combined with sodium L-ascorbate (1 1 mg, 10 mol%) and copper sulfate (6.7 mg, 5 mol%) in a mixture of DMF (2 mL) and water (2 mL) and 1 ,3-difluoro-2-(prop-2-ynyl)benzene (50 wt%, 246 mg, 0.81 mmol) is added. The resulting suspension is heated to 65 °C in a sealed vessel for 2 hours. LCMS indicated full conversion.
[00413] The mixture is concentrated under reduced pressure. The residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to afford 61 .4 mg (26%) of the product as an off-white powder. The off-white powder is triturated (twice) with hot MeCN to afford 44.6 mg (19%) of the product as an off-white powder.
1H NMR δΗ (400 MHz; DMSO-d6): 4.02 (s, 2H), 5.93 (s, 2H), 7.08-7.14 (m, 2H), 7.32- 7.41 (m, 1 H), 7.53 (s, 1 H), 8.02 (s, 1 H), 8.20 (d, 1 H), 8.92 (s, 1 H), 12.72 (bs, 1 H), 14.41 (bs, 1 H).
ESI-MS: 431/433 ([M+H]+, 100%, CI isotope pattern). Example 183
6-chloro-8-((4-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00414] 8-(Azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (129a) (150 mg, 0.54 mmol) is combined with sodium L-ascorbate (1 1 mg, 10 mol%) and copper sulfate (6.7 mg, 5 mol%) in a mixture of DMF (2 mL) and water (2 mL) and 1 -chloro-3-fluoro-2-(prop-2-ynyl)benzene (205a) (47 wt%, 386 mg, 1 .08 mmol, 2.0 eq.) is added. The resulting suspension is heated to 65 °C in a sealed vessel for 2 hours. LCMS indicates full conversion.
[00415] The mixture is concentrated under reduced pressure. The residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) to afford 85 mg (35%) of the product as an off-white powder. [00416] The off-white powder is triturated with hot MeCN to afford 63.9 mg (26%) of the product as an off-white powder.
1H NMR δΗ (400 MHz; DMSO-d6): 4.13 (d, 2H), 5.93 (s, 2H), 7.22-7.30 (m, 1 H), 7.32- 7.40 (m, 2H), 7.49 (s, 1 H), 8.01 (s, 1 H), 8.20 (d, 1 H), 8.92 (s, 1 H), 12.71 (bs, 1 H), 14.42 (bs, 1 H).
ESI-MS: 447/449/451 ([M+H]+, 100%, C\2 isotope pattern). Example 184
6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-methoxyquinoline-3- carboxylate
[00417] 2-Fluorophenyl isocyanate (106 μΙ, 0.95 mmol, 1 .5 eq.) is added to a warm (70 °C) suspension of methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate hydrochloride (200 mg, 0.63 mmol) and TEA (175 μΙ, 1 .26 mmol, 2.0 eq.) in anhydrous DMF (4 ml_). The resulting solution is stirred at 70 °C for 2 hours. The mixture is concentrated under reduced pressure, the residue is triturated with EtOAc and filtered off. The white residue is washed with MeOH, Et2O and air dried to afford 171 mg (65%) of the product as a white solid. b) 6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00418] A mixture methyl 6-chloro-8-((3-(2-fluorobenzyl)ureido)methyl)-2- methoxyquinoline-3-carboxylate (220 mg, 0.49 mmol) and cone. HCI (1 .5 ml_) in dioxane (3 ml_) is heated at 80 °C for 3 hours. Within 30 minutes a solution is formed, after 1 hour a precipitate was formed. LCMS analysis indicates complete conversion to a product formation with desired target mass. The mixture is allowed to cool to room temperature and concentrated under reduced pressure. The residue is triturated from hot MeCN, filtered off, washed with diethyl ether and air dried to afford 104 mg (78%) of the product as a pale yellow solid. 1H NMR δΗ (300 MHz; DMSO-d6): 4.61 (d, 2H), 6.95-7.03 (m, 1 H), 7.09-7.15 (m, 1 H), 7.16-7.23 (m, 1 H), 7.25-7.30 (m, 1 H), 7.77 (d, 1 H), 8.00-8.07 (m, 1 H), 8.14 (d, 1 H), 8.70 (d, 1 H), 8.94 (s, 1 H), 12.72 (bs, 1 H).
ESI-MS: 390/392 ([M+H]+, 100%, CI isotope pattern).
Example 185
6-chloro-8-((3-(2,6-difluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 6-chloro-8-((3-(2,6-difluorophenyl)ureido)methyl)-2-methoxyquinoline-3- carboxylate
[00419] Methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (150 mg, 0.473 mmol) and triethylamine (132 μΙ, 0.95 mmol, 2.0 eq.) are added to a flask with DCM (10 ml_). A solution of 1 ,3-difluoro-2-isocyanatobenzene (1 10 mg, 0.71 mmol, 1 .5 eq.) in DCM (1 ml_) is added and the mixture is stirred at room temperature for 1 .5 hours. The reaction mixture is concentrated. The residue is dissolved in DCM and washed with saturated aqueous NaHCO3 solution, brine and water. The organic layer is concentrated under reduced pressure, and the residue is triturated with diethyl ether and filtered off to afford 163 mg (79%) of the title compound as an off-white powder. b) 6-chloro-8-((3-(2,6-difluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00420] A mixture of methyl 6-chloro-8-((3-(2,6-difluorophenyl)ureido)methyl)-2- methoxyquinoline-3-carboxylate (158mg, 0.36 mmol) and cone. HCI (1 ml_) in dioxane (2 ml_) is heated at 80 °C for 3 days. The mixture is concentrated under reduced pressure and the residue is diluted with water. The solids are filtered off and washed with diethyl ether affording 50 mg of a slightly yellow solid. The product is triturated with MeCN, filtered off and the residue washed with diethyl ether to afford 34 mg (23%) of the product as a pale yellow solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.54 (d, 2H), 7.05-7.22 (m, 3H), 7.23-7.35 (m, 1 H), 7.71 (s, 1 H), 8.14 (s, 1 H), 8.47 (s, 1 H), 8.94 (s, 1 H), 12.76 (bs, 1 H), 14.51 (bs, 1 H). ESI-MS: 408/410 ([M+H]+, 100%, CI isotope pattern). Example 186
8-((3-(4^romobenzyl)ureido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00421 ] A solution of (4-bromophenyl)methanamine (1 17 mg, 0.63 mmol, 1 .0 eq.) in toluene (10 ml_) is slowly added to a cooled (0 °C) solution of phosgene (20 wt% soln. in toluene, 0.332ml_, 0.63 mmol, 1 .0 eq.) in toluene (10 ml_) at 0 °C and stirred for 1 hour. Methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (200 mg, 0.63 mmol) and triethylamine (176 μΙ, 1 .26 mmol, 2.0 eq.) are added and the mixture is stirred at room temperature for 3 days. The mixture is concentrated under reduced pressure to afford a white powder. The residue is triturated with DMSO and filtered off. The residue is washed with water, MeCN, diethyl ether and air dried to afford 136 mg (44%) of the title compound as a white powder. b) 8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00422] A mixture of methyl 8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate (136 mg, 0.27 mmol) and cone. HCI (1 ml_) in dioxane (3 ml_) is heated at 80 °C for 16 hours. The mixture is concentrated under reduced pressure, the residue triturated with MeCN. The suspension is filtered off and the residue washed with MeCN and diethyl ether to afford 50 mg (39%) of the title compound as an off-white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.21 (d, 2H), 4.49 (d, 2H), 6.90 (bs, 1 H), 7.00 (bs, 1 H), 7.22 (d, 2H), 7.48 (d, 2H), 7.70 (s, 1 H), 8.13 (s, 1 H), 8.93 (s, 1 H), 13.07 (bs, 1 H), 14.59 (bs, 1 H).
ESI-MS: 464/466/468 ([M+H]+, 100%, Br/CI isotope pattern).
Example 187 6-chloro-2-oxo-8-((1 -(pyridin-3-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid a) 1 -(Pyridin-3-yl)cyclopropanecarboxylic acid
[00423] The title compound is prepared according to the procedure described for Example 192 (steps a and b) starting from ethyl 2-(pyridin-3-yl)acetate. Yield: 0.61 g (37% for two steps) as a white powder (purification by HPLC). b) 8-(Aminomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid hydrobromide
[00424] A mixture of methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate hydrochloride (1 .0 g, 3.15 mmol) and HBr solution in AcOH (33%, 20 mL) is subjected to microwave irradiation at 100 °C for 40 min. The reaction mixture is concentrated in vacuo, diluted with dry acetone and stirred for 30 min. The formed precipitate is collected by filtration, washed with acetone and diethyl ether and dried on air giving the titled compound (0.96 g, 91 %) as a white powder. c) 6-Chloro-2-oxo-8-((1 -(pyridin-3-yl)cyclopropanecarboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00425] A mixture of 1 -(pyridin-3-yl)cyclopropanecarboxylic acid (69mg, 0.420 mmol), TBTU (162mg, 0.504 mmol), Et3N (78pL, 0.563mmol) and anhydrous acetonitrile (3 mL) is stirred at room temperature for 1 h. Then EtsN (78 L, 0.563mmol) and 8-(aminomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid hydrobromide (134mg, 0.402mmol) are added. The obtained mixture is stirred at room temperature for 8 h, left to stand at room temperature overnight and diluted with water. The formed solid is collected by filtration, washed with water, MeOH, and diethyl ether, purified by prepHPLC (C18, acetonitrile/H2O) giving the titled compound (30 mg, 18%) as a white powder.
1H NMR (DMSO-de, 400 MHz) δΗ, 1 .15 (m, 2H), 1 .41 (m, 2H), 4.45 (d, 2H), 7.34 (m, 1 H), 7.55 (s, 1 H), 7.76 (m, 2H), 8.10 (s, 1 H), 8.57 (m, 2H), 8.87 (s, 1 H), 12.40 (br, 1 H). APCI-MS: 398, 400 ([M+H]+, 100%). Example 188
6-chloro-2-oxo-8-((3-(pyridin-2-yl)ureido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl)-2- methoxyquinoline-3-carboxylate
[00426] A solution of 2-aminopyridine (0.5 g, 5.31 mmol) in DCM (10 ml_) is slowly added to a solution of 4-nitrophenyl chloroformate (1 .07 g, 5.31 mmol, 1 .0 eq.) in DCM (10 ml_) at 0 °C under argon atmosphere. Pyridine (0.430 ml_, 5.31 mmol, 1 .0 eq.) is slowly added to the resulting suspension at 0 °C, a white precipitate formed upon addition. The solids are filtered and washed with DCM to afford 975 mg (70%) of 4- nitrophenyl pyridin-2-ylcarbamate as a white powder.
[00427] To a suspension of methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline- 3-carboxylate hydrochloride (225 mg, 0.71 mmol) and triethylamine (99 μΙ, 0.71 mmol, 1 .0 eq.) in MeCN (4 ml_) is added 4-nitrophenyl pyridin-2-ylcarbamate (220 mg, 0.85 mmol, 1 .2 eq.) are added and the mixture is heated to 80 °C for 3 days. The reaction mixture is concentrated under reduced pressure. The residue is triturated with DMSO filtered off and the residue washed with DCM to afford 203 mg (71 %) of the product as an off-white solid. b) 6-chloro-2-oxo-8-((3-pyridin-2-ylureido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid
[00428] A mixture of methyl 6-chloro-2-methoxy-8-((3-pyridin-2- ylureido)methyl)quinoline-3-carboxylate (203 mg, 0.51 mmol) and cone. HCI (1 ml_) in dioxane (2 ml_) is heated at 80 °C for 4 hours. The mixture is concentrated under reduced pressure. The residue is triturated with MeCN, filtered off, washed with diethyl ether and air dried to afford 125 mg (66%) of the product as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.70 (d, 2H), 7.16 (t, 1 H), 7.36 (d, 1 H), 7.36 (d, 1 H), 7.83 (d, 1 H), 7.99 (t, 1 H), 8.15 (d, 1 H), 8.24 (d, 1 H), 8.63 (bs, 1 H), 8.94 (s, 1 H), 1 1 .05 (bs, 1 H), 12.85 (bs, 1 H).
ESI-MS: 373/375 ([M+H]+, 100%, CI isotope pattern). Example 189
6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid a) 1 -(pyridin-2-yl)prop-2-yn-1 -ol
[00429] Ethynylmagnesium bromide (0.5M soln. in THF, 20.54 mL, 10.27 mmol, 1 .1 eq.) is placed under argon and cooled to -10 °C. A solution of picolinaldehyde (1 g, 9.34 mmol) in anhydrous THF (3 mL) is added dropwise. The mixture is stirred for 1 hour at -10 °C, then 1 hour at room temperature. The mixture is poured on saturated aqueous NH CI solution and extracted with EtOAc (3x 50 mL). The combined organic layers are washed with water (3x 50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to yield 960 mg (77%) of the product as a brown oil. b) Methyl 6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)- 2-methoxyquinoline-3-carboxylate
[00430] A suspension of sodium azide (75 mg, 1 .16 mmol) and methyl 8- (bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (400 mg, 1 .16 mmol) in anhydrous DMF (5 mL) is irradiated at 100 °C for 10 minutes. To the yellow solution is added copper(ll) sulfate pentahydrate (14 mg, 5 mol%) followed by sodium L-ascorbate (23 mg, 10 mol%) , 1 -(pyridin-2-yl)prop-2-yn-1 -ol (232 mg, 1 .74 mmol, 1 .5 eq.) and water (5 mL). The mixture is heated to 65 °C for 2 hours. The mixture is diluted with EtOAc and water and the layers were separated. The water layer is extracted with EtOAc (3x100 mL) and with DCM (3x100 mL). The organic layers are combined and washed with water (4x 100 mL) and brine (2x 100 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by flash chromatography (silica gel, 5% MeOH in DCM) to yield 280 mg (55%) of the product as a yellow solid. c) 6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid [00431 ] Methyl 6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazoM - yl)methyl)-2-methoxyquinoline-3-carboxylate (50 mg, 0.1 1 mmol) is dissolved in a mixture of acetic acid (3 ml_) and cone. HCI (0.5 ml_) (6:1 mixture). The mixture is heated to 50 °C for 40 hours. The mixture is then concentrated in vacuo and the residue is co-evaporated with MeCN. The residue is tritruated in MeCN and filtered off. The residue is rinsed with MeCN and /Pr2O and collected to yield 36 mg (77%) of the title compound as an off-white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 5.99 (s, 2H), 6.10 (s, 1 H), 7.62 (s, 1 H), 7.63 (m, 1 H), 7.84 (d, 1 H), 8.21 (d, 3H), 8.65 (d, 1 H), 8.94 (s, 1 H), 12.74 (bs, 1 H).
ESI-MS: 412/414 ([M+H]+, 100%, CI isotope pattern).
Example 190
6-chloro-2-oxo-8-((4-(pyridin-2-ylmethyl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid a) Methyl 6-chloro-2-methoxy-8-((4-(pyridin-2-ylmethyl)-1 H-1 ,2,3-triazoM - yl)methyl)quinoline-3-carboxylate
[00432] To methyl 6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazol-1 - yl)methyl)-2-methoxyquinoline-3-carboxylate (189b) (168 mg, 0.38 mmol) in anhydrous THF (3 ml_) is added sodium hydride (60 wt% disp. in mineral oil, 17 mg, 0.42 mmol, 1 .1 eq.) and the mixture is stirred for 30 minutes at room temperature. Carbon disulfide (35 μΙ, 0.57 mmol, 1 .5 eq.) is added and the mixture is stirred for another 10 minutes. Then iodomethane (36 μΙ, 0.57 mmol, 1.5 eq.) is added and the mixture is stirred for 1 hour. The mixture is quenched with water and diluted with EtOAc. The layers are separated and the aqueous layer is extracted with EtOAc (2x 50 ml_). The combined organic layers are washed with water (50 ml_) and brine (50 ml_), dried over Na2SO4 and concentrated in vacuo. The oily residue is dissolved in anhydrous toluene (4 ml_) under an argon atmosphere. AIBN (6 mg, 10 mol%) and tri-n-butyltin hydride (309 μΙ, 1 .15 mmol, 3 eq.) are added and the mixture is stirred at reflux temperature for 1 hour. The mixture is cooled to room temperature and concentrated in vacuo. The residue is diluted with water and DCM. The layers are separated and the aqueous layer is extracted with DCM (3x 20 ml_). The combined organic layers are washed with water (20 ml_) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, 0 - 5% MeOH in DCM) to yield 48 mg (30%) of the product as a white solid. b) 6-chloro-2-oxo-8-((4-(pyridin-2-ylmethyl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00433] Methyl 6-chloro-2-methoxy-8-((4-(pyridin-2-ylmethyl)-1 H-1 ,2,3-triazoM - yl)methyl)quinoline-3-carboxylate (48 mg, 0.1 1 mmol) is dissolved in a mixture of acetic acid (3 mL) and cone. HCI (0.5 mL) (6:1 mixture). The mixture is heated to 50 °C and stirred for 40 hours. The mixture is concentrated in vacuo and co-evaporated with MeCN. The residue is triturated with MeCN and /'Pr2O to yield 30 mg (67%) of the title compound as a white solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.41 (s, 2H), 5.99 (s, 2H), 7.59 (s, 1 H), 7.72 (d, 2H), 8.17 (d, 2H), 8.26 (m, 1 H), 8.71 (brs, 1 H), 8.90 (s, 1 H), 12.70 (bs, 1 H).
ESI-MS: 396/398 ([M+H]+, 100%, CI isotope pattern)
Example 191
6-chloro-2-oxo-8-((3-(pyridin-3-yl)ureido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 6-chloro-2-methoxy-8-((3-pyridin-3-ylureido)methyl)quinoline-3- carboxylate
[00434] A solution of pyridin-3-amine (250 mg, 2.66 mmol) in DCM (5 mL) is slowly added to a cooled (0 °C) solution of 4-nitrophenyl chloroformate (535 mg, 2.66 mmol) in DCM (5 mL) under argon atmosphere. Pyridine (0.215 mL, 2.66 mmol) is slowly added to the formed suspension, a yellow precipitate formed upon addition. The mixture is filtered off to afford 485 mg (70%) of the intermediate 4-nitrophenyl pyridin-3- ylcarbamate as a light yellow solid. Triethylamine (105 μΙ, 0.76 mmol, 1 .2 eq.) and 4- nitrophenyl pyridin-3-ylcarbamate (196 mg, 0.76 mmol, 1.2 eq.) are added to a suspension of methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (200 mg, 0.63 mmol) in MeCN (20 mL). The resulting mixture is heated at 70 °C for 6 hours. The mixture is concentrated under reduced pressure and the residue was triturated with DMSO. The solids are filtered off and washed with MeCN and diethyl ether to afford 60 mg (23%) of the product as a white solid. b) 6-chloro-2-oxo-8-((3^yridin-3-ylureido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid
[00435] A mixture of methyl 6-chloro-2-methoxy-8-((3-pyridin-3- ylureido)methyl)quinoline-3-carboxylate (60 mg, 0.15 mmol) and cone. HCI (1 ml_) in dioxane (2 ml_) is heated at 80 °C for 2 hours. The mixture is concentrated under reduced pressure and the residue is triturated with MeCN. The suspension is filtered off and the residue is washed with MeCN and diethyl ether to afford 40 mg (41 %) of the product as a pale yellow solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.64 (d, 2H), 7.56 (t, 1 H), 7.77 (d, 1 H), 7.89-7.96 (m, 1 H), 8.15 (d, 1 H), 8.37 (d, 1 H), 8.47 (d, 1 H), 8.95 (s, 1 H), 9.09 (s, 1 H), 10.64 (s, 1 H), 12.65 (bs, 1 H).
ESI-MS: 373/375 ([M+H]+, 100%, CI isotope pattern). Example 192
6-chloro-2-oxo-8-((1 -(pyridin-2-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid a) Ethyl 1 -(pyridin-2-yl)cyclopropanecarboxylate
[00436] To a solution of ethyl 2-(pyridin-2-yl)acetate (1 .65 g, 10 mmol) in anhydrous DMF (10 ml_) sodium hydride (1 .2 g, 30 mmol, 60% dispersion in mineral oil) is added and the reaction mixture is stirred for 10 min at RT. The solution is cooled to 0 °C and 1 ,2-dibromoethane (0.95 ml_, 1 1 mmol) is added. The resulting solution is allowed to stir at 0 oC for about 30 min. Then it is warmed to RT and stirred for 5 h. The reaction mixture is cooled to 0 °C, quenched with H2O and extracted 2 times with dichloromethane. The combined organic layers are washed with water and then concentrated under vacuum. The obtained material is purified by column chromatography (S1O2, 70:30 hexane: EtOAc) to give the title compound as a light yellow oil (0.61 g, 32%). b) 1 -(Pyridin-2-yl)cyclopropanecarboxylic acid
[00437] To a solution of ethyl 1 -(pyridin-2-yl)cyclopropanecarboxylate (2) (0.6 g, 3.1 mmol) in ethyl alcohol (5 mL) KOH (0.35 g, 6mmol) is added and the reaction mixture is stirred for 2 h at RT. The reaction mixture is acidified with 1 M HCI aqueous solution to reach pH ~ 2, concentrated and purified by prepHPLC to give the title compound as a white powder (0.42 g, 84%). c) 6-chloro-2-oxo-8-((1 -(pyridin-2-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00438] A mixture of 1 -(pyridin-2-yl)cyclopropanecarboxylic acid (0.250 g, 1 .531 mmol), TBTU (0.586 g, 1 .824 mmol), Et3N (0.285 mL, 2.052 mmol) and anhydrous acetonitrile (10 mL) is stirred at room temperature for 1 h. Then Et3N (0.285 mL, 2.052 mmol) and 8-(aminomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid hydrobromide (0.490g, 1 .466mmol) are added. The obtained mixture is stirred at room temperature for 8 h, left to stand at room temperature overnight and diluted with water. The formed solid is collected by filtration, washed with water, MeOH, and diethyl ether, purified by prepHPLC (C18, acetonitrile/H2O) giving the title compound (35 mg, 6%) as a white powder
1H NMR (DMSO-de, 400 MHz) δΗ, 1 .22 (m, 2H), 1 .37 (m, 2H), 4.53 (d, 2H), 7.25 (m, 2H), 7.73 (m, 2H), 8.13 (s, 1 H), 8.61 (m, 2H), 8.86 (s, 1 H), 12.30 (br, 1 H), 14.45 (br, 1 H).
APCI-MS: 398, 400 ([M+H]+, 100%). Example 193
6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a) Methyl 6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl)-2- methoxyquinoline-3-carboxylate
[00439] Diphenylphosphoryl azide (533 μΙ, 2.46 mmol, 3.9 eq.) is added to a mixture of 2-chloro-6-fluorobenzoic acid (330 mg, 1 .89 mmol, 3.0 eq.) and triethylamine (684 μΙ, 4.92 mmol, 7.8 eq.) in anhydrous THF (15 mL) under argon atmosphere. The mixture is stirred at room temperature for 1 hour, then added to a suspension of methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (200 mg, 0.63 mmol) and triethylamine (96 μΙ, 0.69 mmol, 1 .1 eq.) in anhydrous DMF (5 mL). The resulting mixture is heated at 70 °C for 3 hours in which time a solution is formed. The mixture is concentrated under reduced pressure, the solid residue diluted with EtOAc and the resulting suspension is filtered off to leave a white residue. The residue is washed with EtOAc and triturated with MeOH, filtered, washed with diethyl ether and air dried to leave 202 mg (71 %) of the product as a white solid. b) 6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00440] A mixture methyl 6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl-2- methoxyquinoline-3-carboxylate (187 mg, 0.41 mmol) and cone. HCI (1 mL) in dioxane (2 mL) is heated at 70 °C for 5 hours. LCMS analysis indicates complete conversion to the desired target mass. The mixture is allowed to cool to room temperature and concentrated under reduced pressure. The residue is triturated from hot MeCN, filtered off, washed with diethyl ether and air dried to afford 133 mg (76%) of the product as a pale yellow solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.54 (d, 2H), 7.16 (t, 1 H), 7.23-7.39 (m, 3H), 7.72 (d, 1 H), 8.14 (d, 1 H), 8.47 (s, 1 H), 8.94 (s, 1 H), 12.73 (bs, 1 H).
ESI-MS: 424/426/428 ([M+H]+, 100%, C\2 isotope pattern).
Example 194
6-chloro-2-oxo-8-((4-(thiazol-2-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid a) 2-((trimethylsilyl)ethynyl)thiazole
[00441 ] To a solution of 2-bromothiazole (550 μΙ, 6.1 mmol) in diisopropylamine (15 mL) is added PdCI2(MeCN)2 (79 mg, 5 mol%), Cu(OAc)2 (55 mg, 5 mol%) and triphenylphosphine (160 mg, 10 mol%). The mixture is thoroughly degassed with argon, then trimethylsilylacetylene (1 .04 mL, 7.32 mmol, 1 .2 eq.) is added and the mixture is heated at 45 °C for 5 hours. [00442] The mixture is concentrated under reduced pressure. The residue is diluted with diethylether and the solids are filtered off. The filtrate is concentrated under reduced pressure and purified by flash column chromatography (silica gel, DCM) to afford 480 mg (43%) of the product as a brown oil. The material is stored under argon in the refrigerator. b) 6-chloro-2-oxo-8-((4-(thiazol-2-yl)-1 H-1 ,2,3-triazol-1-yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00443] To a solution of 2-((trimethylsilyl)ethynyl)thiazole (195 mg, 1 .08 mmol, 1.5 eq.) in DMF (2 mL) is added potassium fluoride (125 mg, 2.15 mmol, 3.0 eq.). The resulting mixture is stirred at 50 °C for 2.5 hours. To the mixture is added 8- (azidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (200 mg, 0.72 mmol), sodium L-ascorbate (14 mg, 10 mol%), CuSO4 »5H2O (9 mg, 5 mol%) and water (2 mL). The mixture is heated at 65 °C for 1 hour. The mixture is concentrated under reduced pressure and the residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) twice to give poor result.
[00444] The fractions are collected and concentrated under reduced pressure. The liquid residue (most likely DMSO-solution of product) is added dropwise to water under vigorous stirring. The resulting suspension is filtered off, the residue is triturated with MeCN and filtered again. The residue is washed with MeCN, diethyl ether and air dried to afford 1 14 mg (41 %) of the product as an off-white solid.
1H NMR 5H (300 MHz; DMSO-d6): 6.10 (s, 2H), 7.76-7.80 (m, 2H), 7.92 (d, 1 H), 8.24 (d,
1 H), 8.79 (s, 1 H), 8.93 (s, 1 H).
ESI-MS: 388/390 ([M+H]+, 100%, CI isotope pattern).
Example 195
6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid a) 1 -(pyridin-3-yl)prop-2-yn-1 -ol
[00445] To a solution of nicotinaldehyde (1 .0 g, 9.34 mmol) in THF (5 mL) is added dropwise ethynylmagnesium bromide (0.5 M solution in THF, 20.54 mL, 10.27 mmol, 1 .1 eq.) at -10 °C. The resulting suspension is stirred at -10 °C for 1 hour and at room temperature for 1 hour. The reaction mixture is quenched with a saturated aqueous NH4CI solution (150 mL) and extracted three times with EtOAc. The combined organics are washed with brine, dried over Na2SO4 and evaporated in vacuo yielding 1 .14 grams (84%) of the title compound as a dark brown oil, which is used in the next step without further purification. b) Methyl 6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)- 2-methoxyquinoline-3-carboxylate
[00446] A suspension of methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3- carboxylate (400 mg, 1 .16 mmol) and sodium azide (75 mg, 1 .16 mmol, 1 .0 eq.) in anhydrous DMF (5 mL) is stirred at 100 °C for 10 minutes under microwave conditions. A yellow solution is formed. LCMS indicated full conversion into the azide. Then, copper(ll)sulfate pentahydrate (14.49 mg, 5 mol%) is added followed by sodium L- ascorbate (23.00 mg, 10 mol%), 1 -(pyridin-3-yl)prop-2-yn-1 -ol (252 mg, 1 .74 mmol, 1 .5 eq.) and water (5 mL) and the resulting mixture is stirred at 65 °C for 2 hours. Water (5 mL) is added and the solids are filtered off, washed with water twice, dried under vacuum and air current, yielding 464 mg (91 %) of the title compound as a greenish solid. c) 6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid
[00447] Methyl 6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-1 ,2,3-triazol-1 - yl)methyl)-2-methoxyquinoline-3-carboxylate (100 mg, 0.23 mmol) is dissolved in a mixture of concentrated HCI (2 mL) and dioxane (2 mL). The reaction mixture is stirred at 50 °C for 16 hours. An additional amount of concentrated HCI (1 mL) is added and the reaction mixture is stirred at 50 °C for 4 hours. Water (5 mL) is added and the solids are filtered off, washed with water twice, dried under vacuum and air current to yield 16.5 mg of the title compound as a white solid. The mother liquor is evaporated under vacuum. The remaining solids are triturated from MeCN and combined with the earlier obtained batch. This yielded 32 mg (34%) of the title compound as an off white solid. 1H NMR δΗ (300 MHz; DMSO-d6): 6.00 (s, 2H), 6.1 1 (s, 1 H), 7.64 (d, 1 H), 7.92 (m, 1 H), 8.22 (m, 2H), 8.43, (d, 1 H), 8.77 (d, 1 H), 8.88 (bs, 1 H), 8.93 (s, 1 H).
ESI-MS: 412/414 ([M+H]+, 100%, CI isotope pattern).
Example 196
6-chloro-8-((3-(2,6-difluorobenzyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 6-chloro-8-((3-(2,6-difluorobenzyl)ureido)methyl)-2-methoxyquinoline-3- carboxylate
[00448] Diphenylphosphoryl azide (533 μΙ, 2.46 mmol, 3.9 eq.) is added to a mixture of 2,6-difluorophenylacetic acid (326 mg, 1 .89 mmol, 3.0 eq.) and triethylamine (684 μΙ, 4.92 mmol, 7.8 eq.) in anhydrous toluene (10 ml_) under argon atmosphere. The mixture is stirred at 100 °C for 1 hour, then added to a suspension of methyl 8- (aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (200 mg, 0.63 mmol) and triethylamine (96 μΙ, 0.69 mmol, 1 .1 eq.) in anhydrous DMF (5 ml_). The resulting mixture is heated at 100 °C for 1 hour. The mixture is concentrated under reduced pressure, the solid residue diluted with EtOAc and the resulting suspension is filtered off to leave a white residue. The residue is washed with EtOAc and triturated with MeOH, filtered washed with diethyl ether and air dried to leave 233 mg (82%) of the product as a white solid. b) 6-chloro-8-((3-(2,6-difluorobenzyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00449] A mixture of methyl 6-chloro-8-((3-(2,6-difluorobenzyl)ureido)methyl)-2- methoxyquinoline-3-carboxylate (220 mg, 0.49 mmol) and cone. HCI (3 ml_) in dioxane (5 ml_) is heated at 80 °C for 3 hours. Within 30 minutes a solution is formed, after 1 hour a precipitate is formed. The mixture is allowed to cool to room temperature and concentrated under reduced pressure. The residue is triturated from hot MeCN, filtered off, washed with diethyl ether and air dried to afford 1 19 mg (58%) of the product as a pale yellow solid. Purification by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min) affords 68 mg (33%) of the title compound as a pale yellow solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.33 (d, 2H), 4.47 (d, 2H), 6.67 (t, 1 H), 6.85 (t, 1 H), 7.02-7.12 (m, 2H), 7.32-7.43 (m, 1 H), 7.69 (d, 1 H), 8.1 1 (d, 1 H), 8.92 (s, 1 H), 13.00 (bs, 1 H).
ESI-MS: 422/424 ([M+H]+, 100%, CI isotope pattern). Example 197
6,7-dichloro-8-((3-methyl-1 H-1 ,2,4-triazoM -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid a) Methyl 6,7-dichloro-2-methoxy-8-((3-methyl-1 H-1 ,2,4-triazoM - yl)methyl)quinoline-3-carboxylate
[00450] A mixture of methyl 8-(bromomethyl)-6,7-dichloro-2-methoxyquinoline-3- carboxylate (100 mg, 0.26 mmol) and 3-methyl-1 H-1 ,2,4-triazole (26 mg, 0.32 mmol, 1 .2 equiv.) in anhydrous DMF (1 mL) is heated at 80 °C for 16 hours. Analysis of the mixture shows the formation of two regio-isomers. The mixture is allowed to cool to room temperature and the solvent is removed under reduced pressure. The residue is purified by flash column chromatography (silica gel, 60-100% EtOAc in heptane) to afford 54 mg (27%) of the title compound. b) 6,7-dichloro-8-((3-methyl-1 H-1 ,2,4-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00451 ] A mixture of methyl 6,7-dichloro-2-methoxy-8-((3-methyl-1 H-1 ,2,4-triazol- 1 -yl)methyl)quinoline-3-carboxylic acid (104 mg, 0.27 mmol) in hydrobromic acid (33 wt% in AcOH, 2 mL) is heated at 80 °C for 2 hours. The mixture is allowed to cool to room temperature then concentrated under reduced pressure. The residue is triturated with DCM and filtered off to afford a white solid. The residue is purified by preparative LCMS afforded 62 mg (65 %) of the product as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 2.16 (s, 3H), 5.88 (s, 2H), 8.45 (s, 1 H), 8.53 (s, 1 H), 8.89 (s, 1 H), 12.76 (bs, 1 H), 14.21 (bs, 1 H). ESI-MS: 351/353/355 ([M+H]+, 100%, C\2 isotope pattern). Example 198
6,7-dichloro-8-(((2-chloro-6-fluorobenzyl)amino)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00452] A mixture of 8-(bromomethyl)-6,7-dichloro-2-oxo-1 ,2dihydroquinoline-3- carboxylic acid (100 mg, 0.28 mmol) and 2-chloro-6-fluorobenzylamine (1 10 μΙ, 0.85 mmol, 3.0 equiv.) in anhydrous DMF (1 ml_) is heated at 80°C for 16 hours. The mixture is allowed to cool to room temperature and the solvent is removed under reduced pressure. The residue is triturated with DCM, filtered off and the residue is washed with DCM, ether and air dried to afford a white solid. The product is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) to afford 37 mg (27%) of a white solid. Purification by preparative LCMS affords 15 mg (12.5 %) of the product as an off-white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.12 (s, 2H), 4.55 (s, 2H), 7.23 (t, 1 H), 7.30-7.35 (m, 1 H), 7.35-7.43 (m, 1 H), 8.30 (s, 1 H), 8.78 (s, 1 H), 8.98 (bs, 1 H).
ESI-MS: 427/429/431 ([M-H]", 100%, Cl3 isotope pattern).
Example 199
6-chloro-2-oxo-8-((3-(pyridin-2-ylmethyl)-1 H-pyrazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid a) 1 -(phenylsulfonyl)-l H-pyrazole
[00453] To a stirred mixture of 1 H-pyrazole (10 g, 147 mmol, 1 .1 eq.) and triethylamine (18.61 ml_, 134 mmol, 1 .0 eq.) in anhydrous MeCN (500 ml_) is added slowly benzenesulfonyl chloride (17.22 ml_, 134 mmol). The resulting colourless solution is stirred at room temperature for 16 hours. The resulting white suspension is filtered off and the filtrate is concentrated in vacuo to afford 35.2 g crude product as an off-white solid. The residue is dissolved in DCM and washed with aqueous 1 N HCI solution. The organic layer is dried over Na2SO4 and concentrated under reduced pressure to afford 20.4 g (73%) of the product as a white crystalline solid. b) 2-((1 -(phenylsulfonyl)-l H-pyrazol-5-yl)methyl)pyridine
[00454] To a stirred solution of 1 -(phenylsulfonyl)-1 H-pyrazole (1 .37 gr, 6.59 mmol) in anhydrous THF (15 mL) at -78 °C is drop-wise added n-butyllithium (2.5M in hexanes, 2.77 mL, 6.92 mmol, 1 .05 eq.) with a syringe in ~ 5 minutes. The resulting yellow suspension is stirred at -78 °C for 15 minutes. Thereupon a filtered solution of freshly liberated 2-(bromomethyl)pyridine (1.36 gr, 7.91 mmol, 1 .2 eq.) in anhydrous THF (10 mL) is added drop-wise. The resulting red suspension is stirred at -78 °C for 2 hours. The reaction mixture is quenched in saturated aqueous NH4CI solution and extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to yield 1 .84 g crude product as a yellow oil. The residue is purified by flash column chromatography (silica gel, 10 - 100% EtOAcin heptane) to afford 630 mg of the title product, which contains 45% dipyrido[1 ,2-a:1 ',2'-d]pyrazine as main impurity according to LCMS analysis. c) 2-((1 H-pyrazol-5-yl)methyl)pyridine
[00455] To a stirred solution of 2-((1 -(phenylsulfonyl)-1 H-pyrazol-5- yl)methyl)pyridine (630 mg, 2.10 mmol) in methanol (60 mL) is added aqueous K2CO3 solution (0.4 M, 21 .05 mL, 8.42 mmol, 4.0 eq.). The resulting mixture is stirred at room temperature for two hours. Water is added (100mL) and the volatile solvents are removed under reduced pressure. The resulting aqueous phase is extracted with DCM. The combined organic phases are dried over Na2SO4 and concentrated in vacuo to yield 265 mg (17% over two steps) of the title compound as a colourless oil d) Methyl 6-chloro-2-methoxy-8-((3-(pyridin-2-ylmethyl)-1 H-pyrazol-1 - yl)methyl)quinoline-3-carboxylate
[00456] To a stirred colourless clear solution of 2-((1 H-pyrazol-5-yl)methyl)pyridine (265 mg, 1 .16 mmol) in anhydrous DMF (5 mL) is added methyl 8-(bromomethyl)-6- chloro-2-methoxyquinoline-3-carboxylate (402 mg, 1 .16 mmol, 1 .0 eq.) and K2CO3 (483 mg, 3.50 mmol, 3.0 eq.). The resulting red suspension is stirred at 50 °C for 16 hours. The reaction mixture is quenched in saturated aqueous NH CI solution and extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to afford 581 mg crude product as a brown oil. The residue is purified by flash chromatography (silica gel, 20 - 100% EtOAc in heptane) to afford 107 mg (20%) of the title product. e) 6-chloro-2-oxo-8-((3-(pyridin-2-ylmethyl)-1 H-pyrazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00457] To 107 mg methyl 6-chloro-2-methoxy-8-((3-(pyridin-2-ylmethyl)-1 H- pyrazol-1 -yl)methyl)quinoline-3-carboxylate (107 mg, 0.25 mmol) in acetic acid (4 ml_) is added concentrated HCI (2 ml_). The resulting mixture is stirred at 50 °C for 48 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to afford 101 mg (92%) of the title compound as a white solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.40 (s, 2H), 5.67 (s, 2H), 6.32 (d, 1 H), 7.80-7-91 (m, 3H), 8.13 (d, 1 H), 8.40 (t, 1 H), 7.49 (s, 1 H), 8.77 (d, 1 H), 8.89 (s, 1 H), 12.4 (bs, 1 H). ESI-MS: 395/397 ([M+H]+, 100%, CI isotope pattern).
Example 200
6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a) (1 H-pyrazol-1 -yl)methanol
[00458] 1 H-Pyrazole (10 g, 147 mmol) is placed in the two-necked flask, anhydrous THF (400 ml_) is added at room temperature to give a clear solution. Formaldehyde (37% in water, 12.03 ml_, 162 mmol, 1 .1 eq.) is added and the resulting mixture is stirred at 20 °C overnight. Subsequently the solvent is removed under reduced pressure. The resulting crude product was dried to air affording 12.32 g (85%) of the product as a white solid. b) 5-(2-fluorobenzyl)-1 H-pyrazole
[00459] (1 H-pyrazol-1 -yl)methanol (2 g, 20.39 mmol) is dissolved in anhydrous THF (30 ml_). The resulting solution is subsequently cooled to -78 °C and n-butyllithium (1 .6M in hexanes, 28.0 ml_, 44.9 mmol) is added dropwise. The reaction is continued while warming up approximately -20 °C for 25 minutes. Thereupon the resulting heterogeneous solution is cooled to -78 °C and 1 -(bromomethyl)-2-fluorobenzene (3.85 g, 20.39 mmol) is added dropwise. The reaction is then continued overnight while warming up to room temperature. Subsequently the reaction mixture is quenched in saturated aqueous ammonium chloride solution at 0 °C. The resulting aqueous phase is extracted with diethyl ether. This is subsequently carefully extracted three times with aqueous HCI (2N). The aqueous extracts are combined and basified and the resulting aqueous layer is extracted with diethyl ether, dried over Na2SO4 and concentrated in vacuo. The resulting crude product is purified using column chromatography (silica gel, 0 - 30% EtOAc in heptane) affording 465 mg of the product as a colorless oil. c) Methyl 6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol-1-yl)methyl)-2- methoxyquinoline-3-carboxylate and methyl 6-chloro-8-((5-(2-fluorobenzyl)-1 H- pyrazol-1 -yl)methyl)-2-methoxyquinoline-3-carboxylate
[00460] The title compounds were prepared in close analogy to Example 199b, starting from methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (243 mg, 0.70 mmol), K2CO3 (195 mg, 1 .41 mmol, 2.0 eq.), and 5-(2-fluorobenzyl)-1 H- pyrazole (135 mg, 0.70 mmol, 1 .0 eq.) yielding 75 mg (89%) as a mixture of isomers. d) 6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00461 ] The isomeric mixture of methyl 6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol- 1 -yl)methyl)-2-methoxyquinoline-3-carboxylate and methyl 6-chloro-8-((5-(2- fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-methoxyquinoline-3-carboxylate (75 mg, 0.17 mmol) is dissolved in acetic acid (1 ml_). Concentrated HCI (0.5 ml_) is added and the resulting mixture is stirred at 50 °C for 16 hours. Subsequently the reaction mixture is diluted with water and the resulting precipitate is filtered off to afford 65 mg of crude product which is separated by preparative LCMS to afford 21 mg (28%) of the title compound as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 3.92 (s, 2H), 5.67 (s, 2H), 6.08 (s, 1 H), 7.06-7.29 (m, 5H), 7.81 (d, 1 H), 8.10 (d, 1 H), 8.60 (s, 1 H).
ESI-MS: 412/414 ([M+H]+, 100%, CI isotope pattern). Example 201
6-chloro-8-((5-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00462] The isomeric mixture (Example 200b) of methyl 6-chloro-8-((3-(2- fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-methoxyquinoline-3-carboxylate and methyl 6- chloro-8-((5-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-methoxyquinoline-3-carboxylate (75 mg, 0.17 mmol) is dissolved in acetic acid (1 ml_). Concentrated HCI (0.5 ml_) is added and the resulting mixture is stirred at 50 °C for 16 hours. Subsequently the reaction mixture is diluted with water and the resulting precipitate is filtered off to afford 65 mg of crude product which is separated by preparative LCMS to afford 12 mg (16%) of the title compound as a white solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.10 (s, 2H), 5.70 (s, 2H), 6.05 (s, 1 H), 6.74 (s, 1 H), 6.97-7.20 (m, 4H), 7.50 (s, 1 H), 7.99 (s, 1 H), 8.78 (s, 1 H), 12.6 (bs, 1 H).
ESI-MS: 412/414 ([M+H]+, 100%, CI isotope pattern).
Example 202
6-chloro-8-((3-(2,6-difluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a) 5-(2,6-difluorobenzyl)-1 H-pyrazole
[00463] The title compound is prepared in close analogy to Example 200a, starting from (1 H-pyrazol-1 -yl)methanol (2 g, 20.4 mmol) and 2,6-difluorobenzyl bromide (4.22 g, 20.4 mmol, 1 .0 eq.) yielding 73 mg (9%) of the product as a yellow oil. b) Methyl 6-chloro-8-((3-(2,6-difluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2- methoxyquinoline-3-carboxylate
[00464] The title compound is prepared in close analogy to Example 199b, starting from 5-(2,6-difluorobenzyl)-1 H-pyrazole (270 mg, 1 .39 mmol), methyl 8- (bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (479 mg, 1 .39 mmol), and K2CO3 (577 mg, 4.17 mmol) yielding 220 mg of the product as isomeric mixture together with methyl 6-chloro-8-((5-(2,6-difluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2- methoxyquinoline-3-carboxylate as a white solid. c) 6-chloro-8-((3-(2,6-difluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00465] The isomeric mixture of Example 202b (75 mg, 0.17 mmol) is dissolved in acetic acid (4 mL). Hereto is subsequently added concentrated HCI (2 mL). The resulting mixture is stirred at 50 °C overnight. Subsequently the reaction mixture is diluted with water and the resulting precipitate is filtered off. The precipitate is separated by preparative LCMS to afford 51 mg (24%) of of the titled compound as a white solid. 1H NMR δΗ (300 MHz; DMSO-d6): 3.93 (s, 2H), 5.65 (s, 2H), 6.05 (s, 1 H), 7.03-7.08 (t, 2H), 7.17 (s, 1 H), 7.27-7.37 (m, 1 H), 7.79 (d, 1 H), 8.12 (d, 1 H), 8.89 (s, 1 H), 12.65 (bs, 1 H).
ESI-MS: 430/432 ([M+H]+, 100%, CI isotope pattern). Example 203
6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a) 2-(2-fluorophenyl)-N'-hydroxyacetimidamide
[00466] Hydroxylamine (50 wt.% in water; 1 .81 mL, 29.6 mmol, 2 eq.) is added to a mixture of 2-(2-fluorophenyl)acetonitrile (2 g, 14.80 mmol) in absolute ethanol (10 mL). The reaction mixture is heated at reflux temperature for 3 hours. The mixture is concentrated under reduced pressure to obtain a yellowish solid. The residue is triturated with diethyl ether/heptane and filtered off to afford 2.25 g (90%) of the product as a white solid. b) Methyl 6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2- methoxyquinoline-3-carboxylate
[00467] 2-(6-Chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)acetic acid (200 mg, 0.64 mmol) is dispersed in dichloromethane (20 mL) and CDI (105 mg, 0.64 mmol, 1 eq.) was added. The mixture is stirred at room temperature, giving a clear orange solution after 5 minutes. 2-(2-Fluorophenyl)-N'-hydroxyacetimidamide (109 mg, 0.64 mmol, 1 eq.) is added and the mixture is stirred at room temperature for 1 hour. Phosphorus oxychloride (1 .8 mL, 19 mmol) and toluene (20 mL) are added and the mixture is heated 75 °C for 16 hours.
[00468] The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between aqueous saturated NaHCOs solution and EtOAc. The organic layer is washed with aqueous saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo to afford 140 mg of a brown oily solid. The residue is purified by flash column chromatography (silica gel, 10-50% EtOAc in heptane) to give 50 mg (17%) of the product as a yellow solid. c) 6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00469] Methyl 6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2- methoxyquinoline-3-carboxylate (40 mg, 0.091 mmol) is dissolved in 1 ,4-dioxane (3 mL) and cone. HCI (1 .7 mL) is added. The mixture is heated at 80 °C in a sealed vessel. The reaction mixture is concentrated in vacuo and the residue is triturated with water and filtered off. The product is washed with diethyl ether and air dried to give 18 mg (48%) of the product as a white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.05 (s, 2H), 4.72 (s, 2H), 7.09-7.21 (m, 2H), 7.28- 7.37 (m, 2H), 7.87 (d, 1 H), 8.19 (d, 1 H), 8.94 (s, 1 H), 12.73 (bs, 1 H), 14.46 (bs, 1 H) ESI-MS: 414/416 ([M+H]+, 100%, CI isotope pattern).
Example 204
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a) 2-(2-chloro-6-fluorophenyl)acetohydrazide
[00470] Hydrazine hydrate (960 μΙ, 19.74 mmol, 2 eq.) is added to a mixture of methyl 2-(2-chloro-6-fluorophenyl)acetate (2 g, 9.87 mmol, 1 eq.) in absolute ethanol (8 mL). The reaction mixture is heated at 75 °C for 16 hours. The mixture is allowed to cool to room temperature and the resulting suspension is diluted with water, filtered and air dried to yield 1 .76 gr (88%) of the product as white needles. b) Methyl 6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- methoxyquinoline-3-carboxylate
[00471 ] 2-(6-Chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)acetic acid (200 mg, 0.65 mmol) and 2-(2-chloro-6-fluorophenyl)acetohydrazide (144 mg, 0.71 mmol, 1 .1 eq) are added to anhydrous MeCN (5 mL) and cooled to 0 °C. DIPEA (338 μΙ, 1 .94 mmol, 3.0 eq) is added followed by TBTU (228 mg, 0.71 mmol, 1 .1 eq.). The mixture is warmed up to room temperature and stirred for 1 hour. The mixture is filtered off and the residue is rinsed with MeCN and Et2O to afford a white solid. The residue is suspended in POCI3 (10 mL) and heated to 100 °C for 5 hours. The remaining solution is cooled to room temperature and concentrated in vacuo and co-evaporated with toluene. The residue is diluted with EtOAc and water and the layers are separated. The aqueous layer is extracted with EtOAc (3x 20 mL). The organic layers are combined and washed with water (3x 20 mL) and brine (20 mL), dried over Na2SO4 and concentrated in vacuo to give 182 mg (59%) of crude product as a yellow solid. c) 6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00472] Methyl 6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-methoxyquinoline-3-carboxylate (182 mg, 0.38 mmol) is suspended in anhydrous MeCN (5 mL) and sodium iodide (286 mg, 1 .91 mmol, 5 eq.) is added.
[00473] The mixture is irradiated at 40 °C for 5 minutes. TMS-CI (244 μΙ, 1 .91 mmol, 5 eq.) is added and the mixture irradiated at 100 °C for 15 minutes. The mixture is filtered off and the residue is rinsed with aqueous 1 N Na2S2O3 solution, water and MeOH. The residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min) to yield 19 mg (1 1 %) of the title compound as beige solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.36 (s, 2H), 4.61 (s, 2H), 7.26 (t, 1 H), 7.37 (m, 2H), 7.78 (s, 1 H), 8.15 (s, 1 H), 8.90 (s, 1 H), 12.63 (bs, 1 H). ESI-MS: 448/450/452 ([M+H]+, 100%, C\2 isotope pattern). Example 205
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid a) (3-(2-chloro-6-fluorophenyl)prop-1 -ynyl)trimethylsilane
[00474] To a cooled (0 °C) solution of trimethylsilylacetylene (2.85 mL, 20.0 mmol, 2.0 eq.) in anhydrous THF (15 mL) is added dropwise isopropyl magnesium chloride (2 M soln. in THF, 10.0 mL, 20.0 mmol, 2.0 eq.). After addition the mixture is allowed to stir for 30 minutes at the same temperature, then 10 minutes at room temperature. Copper(l) bromide (861 mg, 6.0 mmol, 0.6 eq.) is added and stirring continued for another 30 minutes. To the suspension, 2-chloro-6-fluorobenzylbromide (2.23 gr, 10.0 mmol) is added and the mixture is heated at reflux temperature for 16 hours. The mixture is quenched with saturated aqueous NH CI solution and extracted with diethyl ether (3x). The combined organic extracts are washed with saturated aqueous NH CI solution (2x), brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is filtered over a plug of silica (eluted with diethyl ether), the filtrate is concentrated to dryness to afford 2.45 gr ('102'%, 67 wt%) of a yellow oil. Product contains some starting bromide, product used without further purification. b) 1 -chloro-3-fluoro-2-(prop-2-ynyl)benzene
[00475] Potassium carbonate (1 .88 gr, 13.64 mmol, 2.0 eq.) is added to a solution of (3-(2-chloro-6-fluorophenyl)prop-1 -ynyl)trimethylsilane (2.45 gr, 67 wt%, 6.82 mmol) in methanol (30 mL). The mixture is stirred at room temperature for 2 hours. The mixture is poured in water and extracted with diethyl ether (3x). The combined organic layers are washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1 .84 gr (47 wt%, 75%) of a yellow oil. The product is used without further purification. c) Methyl 6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2- methoxyquinoline-3-carboxylate [00476] A suspension of sodium azide (37.7 mg, 0.58 mmol, 1 .0 eq.) and methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (200 mg, 0.58 mmol) in anhydrous DMF (4 mL) is irradiated in a microwave oven (intensity high) at 100 °C for 10 minutes. The light yellow solution is purged with argon for 5 minutes and 1 -chloro-3- fluoro-2-(prop-2-ynyl)benzene (47 wt%, 208 mg, 0.58 mmol, 1 .0 equiv.) is added followed by RuCICp*(PPh3)2 (28 mg, 6 mol%). The resulting orange suspension is irradiated in a microwave oven (intensity high) at 120 °C for 30 minutes. The mixture is concentrated under reduced pressure and the residue is purified by flash column chromatography (silica gel, 10-40% EtOAc in heptane) to afford 60.5 mg (21 %) of the product as a light brown powder. d) 6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00477] A solution of methyl 6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3- triazol-1 -yl)methyl)-2-methoxyquinoline-3-carboxylate (60.5 mg, 0.12 mmol) in a mixture of acetic acid and cone. HCI (3 mL, 5:1 ) is stirred at room temperature for 3 days. Some extra cone. HCI (-0.5 mL) is added and the mixture is heated at 50 °C for 20 hours. The mixture is concentrated under reduced pressure and the residue is triturated with MeCN. The solid is filtered, the residue washed with MeCN and Et2O and air dried to afford 44.9 mg (80%) of the product as an off-white solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.22 (d, 2H), 5.99 (s, 2H), 6.92 (d, 1 H), 7.16-7.23 (m, 1 H), 7.28-7.36 (m, 2H), 7.38 (s, 1 H), 8.17 (d, 1 H), 8.95 (s, 1 H), 12.75 (bs, 1 H).
ESI-MS: 447/449/451 ([M+H]+, 100%, C\2 isotope pattern).
Example 206
(R)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) Isopropyl 6-chloro-8-((R)-1 -((S)-1 ,1 -dimethylethylsulfinamido)ethyl)-2- methoxyquinoline-3-carboxylate
[00478] The title compound is prepared in close analogy to Example 165a, starting from methyl 8-acetyl-6-chloro-2-methoxyquinoline-3-carboxylate (200 mg, 0.68 mmol), titanium(IV) isopropoxide (599 μΙ, 2.04 mmol, 3 eq.), (S)-2-methylpropane-2- sulfinamide (91 mg, 0.75 mmol, 1 .1 eq.), and sodium borohydride (26 mg, 0.68 mmol, 1 eq.) yielding 9 mg (30%) of the product as a yellow oil. b) (R)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00479] The title compound is prepared in close analogy to Example 165b, starting from isopropyl 6-chloro-8-(1 -(1 ,1 -dimethylethylsulfinamido)ethyl)-2- methoxyquinoline-3-carboxylate (55 mg, 0.13 mmol) yielding 15 mg (38%) of the product as a white solid.
The product is isolated as hydrochloride salt.
1H NMR δΗ (400 MHz; DMSO-d6): 1.57 (d, 3H), 5.23 (d, 1 H), 8.02 (s, 1 H), 8.20 (s, 1 H), 8.58 (bs, 3H), 8.88 (s, 1 H), 12.69 (bs, 1 H), 14.50, (bs, 1 H).
ESI-MS: 267/269 ([M+H]+, 100%, CI isotope pattern).
Example 207
8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00480] A solution of 2-(tributylstannyl)benzo[d]thiazole (100 mg, 0.24 mmol, 1 .1 eq.), methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (74 mg, 0.22 mmol) and DIPEA (560 μΙ, 0.32 mmol, 1.5 eq.) in anhydrous DMF (5 mL) is degassed with nitrogen for 10 minutes. Then Pd(PPh3) (7 mg, 3 mol%) is added and the reaction mixture is irradiated at 100 °C in a microwave for 15 minutes (absorption level normal). The reaction mixture is diluted with EtOAc and washed sequentially with aqueous KF solution (1 .7 M, 3 x 10 mL), NaOH (3 x 10 mL) and brine (3 x 10 mL). The organic layer is dried over Na2SO and concentrated under reduced pressure. The crude product is purified by flash column chromatography (silica gel, 0 - 70% EtOAc in heptane in 30 min) to afford 34 mg (39%) of the product as a yellow solid. b) 8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid [00481 ] Methyl 8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-methoxyquinoline-3- carboxylate (38 mg, 0.095 mmol) is dissolved in dioxane (2 mL) and cone. HCI (2 mL) is added. The reaction mixture is heated to 90 °C for 16 hours. The reaction mixture is concentrated in vacuo and the residue is purified by reverse phase chromatography (Reveleris, 40 gr C18, 0.1 % formic acid in water/ 5 - 100% MeCN in 16 min., 40 mL/min.) to afford 6 mg (17%) of the product as a yellow solid.
1H NMR δΗ (400 MHz; DMSO-d6): 4.95 (s, 2H), 7.39 (t, 1 H), 7.46 (t, 1 H), 7.82-7.93 (m, 2H), 8.03 (d, 1 H), 8.15 (s, 1 H), 8.90 (s, 1 H), 12.71 (bs, 1 H), 14.58 (bs, 1 H).
ESI-MS: 371/373 ([M+H]+, 100%, CI isotope pattern).
Example 208
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl 8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00482] Methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (300 mg, 0.95 mmol), 2-chlorobenzo[d]oxazole (160 mg, 1 .04 mmol, 1 .1 eq.) and potassium carbonate (392 mg, 2.84 mmol, 3 eq.) are combined in anhydrous DMF (2 mL) and the mixture is stirred at 80 °C for 1 .5 hours and at room temperature for 16 hours. The reaction mixture is poured out onto water (5 mL) and the solids are filtered off, washed twice with water and dried in a vacuum oven at 40 °C for 2 hours. This yields 361 mg (90%) of the title compound as a yellow solid. b) 8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1,2-dihydroquinoline-3- carboxylic acid
[00483] Methyl 8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate (358 mg, 0.841 mmol) is dissolved in concentrated HCI (10 mL) and 1 ,4-dioxane (10 mL) and the reaction mixture is stirred at 50 °C for 16 hours. Water (10 mL) is added and the solids are filtered off, washed twice with water and once with 2-propanol, yielding 185 mg (60%) of the title compound as a yellow solid. 1H NMR δΗ (300 MHz; DMSO-d6): 4.84 (d, 2H), 7.03 (t, 1 H), 7.14 (t, 1 H), 7.31 (d, 1 H), 7.40 (d, 1 H), 7.79 (d, 1 H), 8.16 (d, 1 H), 8.62 (t, 1 H), 8.94 (s, 1 H).
ESI-MS: 370/372 ([M+H]+, 100%, CI isotope pattern).
Example 209
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid a) Methyl-8-((benzo[d]thiazol-2-ylamino)methyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00484] The title compound is prepared in close analogy to Example 209a, starting from methyl 8-(aminomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate hydrochloride (200 mg, 0.63 mmol), 2-chlorobenzo[d]thiazole (150 mg, 0.88 mmol, 1 .4 eq.), and potassium carbonate (261 mg, 1 .89 mmol, 3 eq.) yielding 121 .5 mg (40%) of the title compound as an off white solid. b) 8-((benzo[d]thiazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00485] The title compound is prepared in close analogy to Example 209b, starting from methyl 8-((benzo[d]thiazol-2-ylamino)methyl)-6-chloro-2-methoxyquinoline- 3-carboxylate (1 19 mg, 0.25 mmol) yielding 37 mg (39%) of the title compound as an off white solid.
1H NMR δΗ (300 MHz; DMSO-d6): 4.92 (d, 2H), 7.12 (t, 1 H), 7.33 (t, 1 H), 7.63 (d, 1 H), 7.75 (d, 1 H), 7.85 (s, 1 H), 8.18 (s, 1 H), 8.94 (s, 1 H), 9.10 (br s, 1 H).
ESI-MS: 386/388 ([M+H]+, 100%, CI isotope pattern).
Example 210
8-(2-aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) (E)-methyl 8-(3-(benzyloxy)-3-oxoprop-1 -enyl)-6-chloro-2-methoxyquinoline-3- carboxylate [00486] To a degassed (argon, balloon) solution of methyl-6-chloro-8-iodo-2- methoxyquinoline-3-carboxylate (500 mg, 1 .32 mmol) and benzyl acrylate (1 .07 gr, 6.62 mmol, 5 equiv.) in 1 ,2-dimethoxyethane (20 mL) is added CS2CO3 (1.29 gr, 3.97 mmol, 3 equiv.), Pd(OAc)2 (29.7 mg, 0.13 mmol, 10 mol%) and triphenylphosphine (72.9 mg, 0.28 mmol, 20 mol%). The yellow suspension is stirred at 90 °C for 18 hours. The green-black suspension is allowed to cool to room temperature and partitioned between EtOAc (100 mL) and water (50 mL). The layers are separated and the organic layer is washed with brine (100 mL) and dried over Na2SO4 and concentrated to dryness. The residue is purified by flash column chromatography (silica gel, 5 - 25% EtOAc in heptane) to give 374 mg (68%) of the title compound as a yellow solid. b) 3-(6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)propanoic acid
[00487] To a solution of (E)-methyl 8-(3-(benzyloxy)-3-oxoprop-1 -enyl)-6-chloro-2- methoxyquinoline-3-carboxylate (374 mg, 0.91 mmol) in a 2:1 mixture of absolute ethanol (10 mL) and ethyl acetate (20 mL) is added 10% (w/w) palladium on carbon (97 mg, 0.091 mmol, 0.1 eq.) and the black suspension is stirred under a hydrogen atmosphere at room temperature. After 2 hours, the reaction mixture is purged with N2 for a few minutes and filtered over kieselguhr. The residue is rinsed with 2x 5 mL of methanol and the filtrate is concentrated to give an off-white solid, which is triturated in heptane/DIPE (3:1 , ~8 mL). The solids are filtered off, washed with ~3 mL of heptane/DIPE (3:1 ) and air dried to afford 261 mg (79%) of the product as an off-white powder. c) Methyl 8-(2-(tert-butoxycarbonylamino)ethyl)-6-chloro-2-methoxyquinoline-3- carboxylate
[00488] A solution of 3-(6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8- yl)propanoic acid (261 mg, 0.81 mmol), triethylamine (157 μΙ, 1 .13 mmol, 1.4 equiv.) and diphenylphosphonic azide (191 μΙ, 0.89 mmol, 1 .1 equiv.) in tert-butanol (10 mL) is heated at 90 oC under a N2 atmosphere over night. The reaction mixture is allowed to cool to room temperature, concentrated and the crude product is purified by flash column chromatography (silica gel, 5 - 25% EtOAc in heptane) to give 176 mg (55%) of the product as an off white solid. d) 8-(2-Aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00489] A solution of methyl 8-(2-(tert-butoxycarbonylamino)ethyl)-6-chloro-2- methoxyquinoline-3-carboxylate (22) (176 mg, 0.44 mmol) in hydrobromic acid (33 wt% in AcOH, 5 mL) is stirred at 80 oC for 3 hours. After cooling to room temperature, the off-white solid is filtered off and washed with diisopropyl ether (3 x 1 mL) followed by diethyl ether (2 x 1 mL) and air dried to afford 131 mg (85%) of the title compound as an off-white fluffy solid.
The product is isolated as hydrobromide salt.
1H NMR δΗ (400 MHz; DMSO-d6): 3.07 (2H, bs), 3.21 (2H, t), 7.38 (3H, bs), 7.40 (1 H, s), 8.14 (1 H, s), 8.94 (1 H, s), 12.39 (1 H, bs), 14.43 (1 H, bs).
ESI-MS: 267/269 ([M+H]+, 100%, CI isotope pattern).
Example 211
8-carbamoyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid a) Methyl 6-chloro-8-cyano-2-methoxyquinoline-3-carboxylate
[00490] Methyl 8-bromo-6-chloro-2-methoxyquinoline-3-carboxylate (2 g, 6.05 mmol) and zinc cyanide (710 mg, 6.05 mmol, 1 eq.) are combined in anhydrous DMF (30 mL) and degassed by vacuum and argon three times. Then Pd(PPh3) (350 mg, 5 mol%) is added and the mixture is heated at 90 °C for 16 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in EtOAc and filtered over hyflo. The filtrate is absorbed on hydromatrix and purified using flash column chromatography (silica gel, 10-50% EtOAc in heptane) to give 1 .37 gr (78%) of the product as a light- yellow solid. b) 8-carbamoyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
[00491 ] Methyl 6-chloro-8-cyano-2-methoxyquinoline-3-carboxylate (50 mg, 0.18 mmol) is combined with hydrobromic acid (33 wt.% in HOAc, 2 mL) and heated to 100 °C in a sealed vessel. The reaction mixture is concentrated in vacuo and the residue is triturated with water and filtered off. The residue is washed with water, acetonitrile and diisopropyl ether to give 40 mg (83%) of the title compound as a white solid. 1H NMR δΗ (400 MHz; DMSO-d6): 8.27 (s, 1 H), 8.42 (d, 1 H), 8.73 (s, 1 H), 8.93 (s, 1 H), 13.47 (s, 1 H), 14.05 (bs, 1 H).
ESI-MS: 267/269 ([M+H]+, 100%, CI isotope pattern). Example 212
6-Chloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00492] The title compound is obtained by condensation of 2-(4-(tert- butoxycarbonyl)piperazin-1 -yl)-2-(2-fluorophenyl)acetic acid with methyl 8-aminomethyl- 6-chloro-2-methoxy-quinoline-3-carboxylate in DMF in analogy to the procedure described in Example 5a, followed by HCI aq./dioxane hydrolysis in analogy to the procedure described in Example 1. Isolated as hydrochloride. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.50-2.70 (m, 4H); 3.05-3.20 (m, 4H); 4.55-4.70 (m, 3H); 7.20-7.26 (m, 2H); 7.36-7.44 (m, 2H); 7.66 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.69 (br s, 2H); 8.93 (s, 1 H); 9.07 (t, 6 Hz, 1 H); 12.40 (br s, 1 H). LC-MS: 473, 475 [M+H].
Example 213
(R)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)methyl)- 1 ,2-dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.42 (s, 3H); 4.52-4.58 (m, 1 H); 4.65-4.70 (m, 1 H); 7.36-7.44 (m, 5H); 7.55 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 9.13 (t, 6 Hz, 1 H); 12.20 (br s, 1 H). LC-MS: 467, 469 [M-H].
Example 214
(S)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)methyl)- 1 ,2-dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.42 (s, 3H); 4.52-4.58 (m, 1 H); 4.65-4.70 (m, 1 H); 7.36-7.44 (m, 5H); 7.55 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 9.13 (t, 6 Hz, 1 H); 12.20 (br s, 1 H). LC-MS: 467, 469 [M-H]. Example 215
6,7-Dichloro-2-oxo-8-((pyrazine-2-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 5.01 (d, 5.2 Hz, 2H); 8.37 (s, 1 H); 8.73 (s, 1 H); 8.87 (s, 2H); 9.17 (s, 1 H); 9.59 (br s, 1 H); 12.48 (br s, 1 H). LC-MS: 391 , 393 [M-H].
Example 216
6,7-Dichloro-2-oxo-8-((thiazole-4-carboxamido)methyl)-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.95 (d, 5.6 Hz, 2H); 8.38-8.39 (m, 2H); 8.89 (s, 1 H); 9.19 (d, 2 Hz, 1 H); 9.29 (br s, 1 H); 12.56 (br s, 1 H). LC-MS: 396, 398 [M-H].
Example 217
8-((2-(1 H-tetrazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.81 (d, 5.2 Hz, 2H); 5.30 (s, 2H); 8.40 (s, 1 H); 8.89 (s, 1 H); 9.20 (t, 5.2 Hz, 1 H); 9.35 (s, 1 H); 12.31 (br s, 1 H). LC-MS: 395, 397 [M-H].
Example 218
8-((2-(4-Acetylpiperazin-1 -yl)-2-(2-fluorophenyl)acetamido)methyl)-6-chloro-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .96 (s, 3H); 2.80-3.80 (m, 8H); 4.55-4.65 (m, 2H); 7.20-7.40 (m, 2H); 7.40-7.60 (m, 3H); 8.12 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 9.19 (br s, 1 H); 12.30 (br s, 1 H). LC-MS: 515, 517 [M+H].
Example 219 6,7-Dichloro-8-((2-methylthiazole-4-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm) ): 2.69 (s, 3H); 4.92 (d, 5.2 Hz, 2H); 8.16 (s, 1 H); 8.37 (s, 1 H); 8.88 (s, 1 H); 9.15 (br s, 1 H); 12.55 (br s, 1 H). LC-MS: 410, 412 [M-H].
Example 220
6,7-Dichloro-2-oxo-8-((thiazole-2-carboxamido)methyl)-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.96 (d, 5.2 Hz, 2H); 8.02-8.06 (m, 2H); 8.39 (s, 1 H); 8.90 (s, 1 H); 9.51 (t, 5.2 Hz, 1 H); 12.44 (br s, 1 H). LC-MS: 396, 398 [M-H].
Example 221
8-((2-(3-(1 H-pyrazol-1 -yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.63 (s, 2H); 4.57 (d, 6 Hz, 2H); 6.53 (t, 1 .8 Hz, 1 H); 7.20-7.22 (m, 1 H); 7.40-7.44 (m, 1 H); 7.62 (d, 2.4 Hz, 1 H); 7.68-7.71 (m, 2H); 7.77 (s, 1 H); 8.1 1 (d, 2.4 Hz, 1 H); 8.42 (d, 2.4 Hz, 1 H); 8.87 (t, 6 Hz, 1 H); 8.92 (s, 1 H); 12.44 (br s, 1 H). LC-MS: 435, 437 [M-H].
Example 222
6-Chloro-8-((2-hydroxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00493] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate with 2-(methoxymethoxy)-2- phenylacetic acid [Chem. Commun. 201 1 , 47, 10608.] gives methyl 6-chloro-2-methoxy- 8-((2-(methoxymethoxy)-2-phenylacetamido)methyl)quinoline-3-carboxylate as light yellow solid in 89% yield. [00494] b) methyl 6-chloro-2-methoxy-8-((2-(methoxymethoxy)-2- phenylacetamido)-methyl)quinoline-3-carboxylate (100 mg, 0.22 mmol in 10N aq. HCI/dioxane (1 :2, 2.5 ml_) is stirred at 55-60 °C for 18 h, then concentrated under reduced pressure. Water is added to the crude residue and the mixture is stirred at rt for 1 h. The precipitate is filtered off, washed with water and diethyl ether, and dried at to give the title compound (49 mg, 58%) as grey solid. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.44-4.57 (m, 2H); 4.99 (d, 4 Hz, 1 H); 6.40 (d, 4 Hz, 1 H); 7.26-7.33 (m, 3H); 7.40 (d, 7.2 Hz, 2H); 7.59 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.91 (s, 1 H); 8.95 (t, 6 Hz, 1 H); 12.50 (br s, 1 H). LC-MS: 385, 387 [M-H].
Example 223
6-Chloro-8-((N-methyl-2^henylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
[00495] The title compound is prepared by the following reaction sequence:
a) to a solution of methyl 8-(bromomethyl)-6-chloro-2-methoxyquinoline-3-carboxylate (210 mg; 0.61 mmol) in abs. THF (10 ml_) is added 2M CH3NH2/THF (1 .22 ml_; 2.438 mmol) and the resulting mixture is stirred at rt for 24 h, then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (twice) (EtOAc/hexane, 2:1 and 1 :1 ) to give 70 mg of methyl 6-chloro-2-methoxy-8- ((methylamino)methyl)quinoline-3-carboxylate as a white solid.
1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.62 (s, 3H); 3.89 (s, 3H); 4.13 (s, 3H); 4.57 (s, 2H); 8.00 (d, 2.4 Hz, 1 H); 8.27 (d, 2.4 Hz, 1 H) and 8.82 (s, 1 H).
[00496] b) in analogy to the procedure described in Example 5(a), condensation of methyl 6-chloro-2-methoxy-8-((methylamino)methyl)quinoline-3-carboxylate with phenylacetic acid gives methyl 6-chloro-2-methoxy-8-((N-methyl-2- phenylacetamido)methyl)quinoline-3-carboxylate in 41.7% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.90 and 3.09 (both s, total 3H); 3.75 and 3.86 (both s, total 2H); 3.88 and 3.89 (both s, total 3H); 4.04 and 4. (both s, total 3H); 5.02 and 5.14 (both s, total 2H); 7.18-7.35 (m, 5H); 7.35 and 7.38 (both br s, total 1 H); 8.08 and 8.10 (both d, 2.4 Hz, total 1 H); 8.76 and 8.78 (both s, total 1 H).
[00497] c) methyl 6-chloro-2-methoxy-8-((N-methyl-2- phenylacetamido)methyl)quinoline-3-carboxylate (34 mg; 0.082 mmol) is stirred in 4N HCI/dioxane (1 .5 ml_) at 50-55 °C for 52 h. After cooling to rt, the dioxane is removed in vacuo. The crude residue is stirred for 1 h in abs. diethyl ether. The precipitate is filtered off, washed with abs. diethyl ether, and dried at 40°C over P2O5 under reduced pressure to give the title compound (17.04 mg, 53%) as a white solid. 1H NMR (400 MHz, DMSO- d6), δ (ppm): 3.03 (s, 3H); 3.84 (s, 2H); 4.76 (s, 2H); 7.21 -7.32 (m, 5H); 7.80 (d, 2 Hz, 1 H); 8.17 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 12.51 (br s, 1 H). LC-MS: 385, 387 [M+H].
Example 224
6-Chloro-8-((2-(3-chloropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.91 (s, 2H); 4.59 (d, 6 Hz, 2H); 7.35-7.38 (m, 1 H); 7.84 (d, 2 Hz, 1 H); 7.91 -7.93 (m, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.47-8.49 (m, 1 H); 8.85 (t, 6 HZ, 1 H); 8.94 (s, 1 H); 12.42 (br s, 1 H). LC-MS: 404, 406, 408 [M-H].
Example 225
8-((2-(4-(1 H-imidazol-1 -yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.67 (s, 2H); 4.60 (s, 2H); 7.52 (d, 7.6 Hz, 2H); 7.64 (s, 1 H); 7.73 (d, 7.6 Hz, 2H); 7.86 (s, 1 H); 8.13 (s, 1 H); 8.22 (s, 1 H); 8.92 (s, 2H); 9.53 (s, 1 H); 12.30-12.70 (br s, 1 H). LC-MS: 437, 439 [M+H].
Example 226
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): ): 4.57 (d, 5.6 Hz, 2H); 4.91 (s, 2H); 6.28 (s, 1H); 7.49 (s, 1H); 7.69 (s, 1H); 7.75 (s, 1H); 8.12 (s, 1H); 8.64 (br s, 1H); 8.93 (s, 1H); 12.42 (br s, 1 H). LC-MS: 361 , 363 [M+H].
Example 227
6-Chloro-8-((2-ethoxy-2^henylacetamido)methyl)-2-oxo-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): ): 1.18 (t, 7 Hz, 3H); 3.40-3.50 (m, 2H); 4.54 (d, 6 Hz, 2H); 4.82 (s, 1H); 7.30-7.38 (m, 5H); 7.54 (s, 1H); 8.10 (d, 2 Hz, 1H); 8.87 (t, 6 Hz, 1 H); 8.90 ( s, 1 H); 12.43 (br s, 1 H). LC-MS: 413, 415 [M-H].
Example 228
6-Chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.11 (d, 6 Hz, 3H); 1.15 (d, 6 Hz, 3H); 3.56- 3.62 (m, 1H); 4.53 (d, 6 Hz, 2H); 4.92 (s, 1H); 7.28-7.34 (m, 3H); 7.38 (d, 7 Hz, 2H); 7.55 (d, 2 Hz, 1H); 8.10 (d, 2 Hz, 1H); 8.78 (t, 6 Hz, 1H); 8.91 (s, 1H); 12.46 (br s, 1H). LC-MS: 427, 429 [M-H].
Example 229
6-Chloro-8-(cyclopropanecarboxamidomethyl)-2-oxo-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 0.71-0.79 (m, 4H); 1.60-1.66 (m, 1H); 4.57 (d, 6 Hz, 2H); 7.71 (d, 2 Hz, 1H); 8.15 (d, 2 Hz, 1H); 8.92 (s, 1H); 8.97 (t, 6 Hz, 1H); 12.53 (br s, 1H). LC-MS: 319, 321 [M-H].
Example 230
6-Chloro-2-oxo-8-((2-(thiazol-2-yl)acetamido)methyl)-1,2-dihydroquinoline-3- carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.04 (s, 2H); 4.60 (d, 5 Hz, 2H); 7.65 (s, 1H); 7.73 (s, 2H); 8.13 (s, 1H); 8.93 (s, 1H); 8.97 (brs, 1H); 12.44 (brs, 1H). LC-MS: 378, 380 [M+H].
Example 231
8-((2-(2H etrazol-2-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1,2-dihydroquinoline- 3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.82 (d, 5 Hz, 2H); 5.53 (s, 2H); 8.41 (s, 1H); 8.89 (s, 1H); 8.97 (s, 1H); 9.19 (brs, 1H); 12.32 (brs, 1H). LC-MS: 395, 397, 399 [M-H].
Example 232
6-Chloro-8-((2-(2-fluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.28 (s, 3H); 4.57 (d, 6.4 Hz, 2H); 4.99 (s, 1H); 7.18-7.22 (m, 2H); 7.37-7.42 (m, 2H); 7.63 (s, 1H); 8.12 (d, 2 Hz, 1H); 8.92 (s, 1H); 9.00 (brs, 1H); 12.43 (brs, 1H). LC-MS: 417, 419 [M-H].
Example 233
6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.29 (s, 3H); 4.57 (d, 6.4 Hz, 2H); 5.09 (s, 1H); 7.32-7.39 (m, 3H); 7.45-7.47 (m, 1H); 7.66 (d, 2 Hz, 1H); 8.12 (d, 2 Hz, 1H); 8.93 (s, 1H); 9.02 (t, 6.4 Hz, 1H); 12.13 (brs, 1H). LC-MS: 433, 435, 437 [M-H].
Example 234
6-Bromo-8-((2-(2,6-difluorophenyl)acetamido)methyl)-2-oxo-1,2-dihydroquinoline- 3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.65 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.07-7.1 1 (m, 2H); 7.35-7.39 (m, 1 H); 7.76 (d, 2 Hz, 1 H); 8.27 (d, 2 Hz, 1 H); 8.86 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.39 (br s, 1 H). LC-MS: 451 , 453 [M+H].
Example 235
6-Bromo-8-((2-(2-chloro-6-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.76 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.21 -7.25 (m, 1 H); 7.32-7.37 (m, 2H); 7.78 (d, 2 Hz, 1 H); 8.26 (d, 2 Hz, 1 H); 8.84 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.38 (br s, 1 H). LC-MS: 467, 469, 471 [M+H].
Example 236
6-Chloro-8-((2-(2,6-difluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.31 (s, 3H); 4.52-4.66 (m, 2H); 5.16 (s, 1 H); 7.09-7.13 (m, 2H); 7.44-7.51 (m, 1 H); 7.71 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.94 (s, 1 H); 9.01 (t, 6 Hz, 1 H); 12.44 (br s, 1 H). LC-MS: 435, 437 [M-H].
Example 237
6-Chloro-2-oxo-8-((irans-2-phenylcyclopropanecarboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .22-1 .26 (m, 1 H); 1 .42-1 .46 (m, 1 H); 1 .93-1 .98 (m, 1 H); 2.31 -2.36 (m, 1 H); 4.55-4.66 (m, 2H); 7.12-7.19 (m, 3H); 7.25-7.28 (m, 2H); 7.70 (d, 2 Hz, 1 H); 8.15 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 8.98 (t, 6 Hz, 1 H); 12.52 (br s, 1 H). LC-MS: 395, 397 [M-H].
Example 238
6-Chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid [00498] The title compound is prepared by the following reaction sequence:
a) ethyl 2-aminoacetate hydrochloride (128 mg, 0.91 mmol) is suspended in abs. CH2CI2 (15 mL) at 0 °C, then Et3N (0.2 mL) and a solution of 6-chloro-8-formyl-2- methoxy-quinoline-3-carboxylic acid methyl ester (200 mg, 0.72 mmol) in abs. MeOH (46 mL) is added and the mixture is stirred for 4 h. After the addition of NaBH3CN (99.3 mg, 1 .5 mmol) the mixture is stirred overnight. Then water is added and the mixture is extracted with CH2CI2. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by column chromatography (Et.2O/hexane, 3:1 ) to give methyl 6-chloro-8-(((2-ethoxy-2-oxoethyl)amino)methyl)-2- methoxyquinoline-3-carboxylate (158 mg, 60%) as white solid. 1H NMR (400 MHz, CDCI3), δ (ppm): 1 .24 (t, 7.2 Hz, 3H); 3.44 (s, 2H); 3.95 (s, 3H); 4.12-4.17 (m, 5H); 7.65 (d, 2 Hz, 1 H); 7.68 (d, 2Hz, 1 H); 8.52 (s, 1 H).
[00499] b) to a suspension of methyl 6-chloro-8-(((2-ethoxy-2- oxoethyl)amino)methyl)-2-methoxyquinoline-3-carboxylate (74.12 mg, 0.2 mmol) in abs. toluene (1 .5 mL) and EtsN (34.6 mg, 0.34 mmol) is added 1 -isocyanato-4- methylbenzene (50.6 mg, 0.38 mmol) and the mixture is stirred for 3,5 h at rt. Then a solution of Et3N (34.2 mg, 0.34 mmol) in toluene (0.5 mL) is added and stirring is continued for 19 h at rt, then for 8 h at 50-55 °C. The mixture is dissolved in EtOAc, washed with 5% aq. HCI, saturated aq. NaHCO3 and water, dried over Na2SO4. After evaporation of solvent the residue is purified by column chromatography (petrol ether/EtOAc, 1 .5:1 ) to give methyl 6-chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1 - yl)methyl)-2-methoxyquinoline-3-carboxylate (46 mg, 53%) as white solid. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.34 (s, 3H); 3.38 (s, 2H); 3.88 (s, 2H); 3.89 (s, 3H); 4.08 (s, 3H); 4.14 (s, 2H); 5.08 (s, 2H); 7.26 (d, 8.8 Hz, 2H); 7.28 (d, 8.8 Hz, 2H); 7.90 (d, 2 Hz, 1 H); 8.16 (d, 2Hz, 1 H); 8.79 (s, 1 H).
[00500] c) in analogy to the procedure described in Example 223(c), methyl 6- chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1 -yl)methyl)-2-methoxyquinoline-3- carboxylate is treated with in 4N HCI/dioxane to give the title compound as white solid. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.35 (s, 3H); 4.14 (s, 2H); 4.91 (s, 2H); 7.26- 7.31 (m, 4H); 7.89 (s, 1 H); 8.17 (s, 1 H); 8.93 (s, 1 H); 12.26 (br s, 1 H). LC-MS: 424, 426 [M-H].
Example 239
6,7-Dichloro-2-oxo-8-((2-(pyrimidin-2-yl)acetamido)methyl)-1 ,2-dihydroquinoli 3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.85 (s, 2H); 4.79 (d, 5.6 Hz, 2H); 7.38 (t, 5 Hz, 1 H); 8.40 (s, 1 H); 8.71 (d, 5 Hz, 2H); 8.89 (s, 1 H); 9.19 (br s, 1 H); 12.52 (br s, 1 H) LC- MS: 405, 407, 409 [M-H].
Example 240
6-Chloro-7-fluoro-8-((2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00501 ] The title compound is prepared by the following reaction sequence:
a) To a mixture of 6-fluoro-7-methylindoline-2,3-dione [Pat. US 4670462 A1 (1987) and J. Med. Chem. 1991 , 34 (1 ), 217-222.] (8.0 g, 0.045 mol) and TCCA (trichloroisocyanuric acid) (10.4 g, 0.045 mol) is added cone. H2SO4 (28 mL) at 0 °C. The reaction mixture is allowed to warm to rt, stirred for 30 min and then poured to ice water (300 mL). The formed precipitates are filtered off and washed with water to give 5-chloro-6-fluoro-7-methylindoline-2,3-dione. Additional amount of product is obtained by extraction of reaction mixture with CH2CI2. The product is used in the next step without further purification. Yield 3.04 g (32%).
[00502] b) to a solution of 5-chloro-6-fluoro-7-methylindoline-2,3-dione (3.04 g, 0.0143 mol) in 2N aq. NaOH (43 mL) is added dropwise 30% H2O2 (4 mL) at rt. The reaction mixture is stirred for 1 h, then acidified with 1 N HCI to pH 2-3 and filtered to give solid 2-amino-5-chloro-4-fluoro-3-methylbenzoic acid 1 .85 g (63%) which is used in the next step without further purification. [00503] c) 2-amino-5-chloro-4-fluoro-3-methylbenzoic acid (1 .85 g, 0.0091 mol) in dry THF (7 mL) is added dropwise to an ice cooled solution of LiAIH4 (0.69 g, 0.0181 mol) in dry THF (7 mL) and stirred overnight at rt. Water (1 mL) is added dropwise, followed by 1 M aqueous NaOH (1 mL). The mixture is extracted with EtOAc (2x70 mL). The organic extract is dried over Na2SO4, concentrated and purified by column chromatography to give (2-amino-5-chloro-4-fluoro-3-methylphenyl)methanol (0.34 g, 20%). 1H NMR (200 MHz, CDCI3), δ (ppm): 1 .64 (br s, 1 H); 2.09 (d, 4 Hz, 3H); 4.28 (br s, 2H); 4.59 (s, 2H); 6.94 (d, 8 Hz, 1 H).
[00504] d) a solution of (2-amino-5-chloro-4-fluoro-3-methylphenyl)methanol (0.34 g, 0.00178 mol) in dry Et2O (20 mL) is added drop-wise to a mixture of manganese dioxide (0.62 g, 0.00715 mol) in dry Et2O (15 mL) and the mixture is stirred at rt for 24 h. Then it is filtered through a celite and the solvent is removed at reduced pressure. The crude product is purified by flash chromatography on silica gel (hexane: EtOAc, 3:1 ) to give 2-amino-5-chloro-4-fluoro-3-methylbenzaldehyde as yellow solid (0.31 g, 94%). 1H NMR (200 MHz, CDCI3), δ (ppm): 2.08 (d, 2 Hz, 3H); 6.36 (br s, 2H); 7.39 (d, 8 Hz, 1 H), 9.73 (s, 1 H).
[00505] e) to a solution of 2-amino-5-chloro-4-fluoro-3-methylbenzaldehyde
(0.31 g, 0.00165 mol) in dry MeOH (2.5 mL) is added dimethyl malonate (0.49 mL) and piperidine (0.05 mL), and the mixture is stirred under reflux for 48 h. After cooling to rt, the solid is filtered, washed with cold methanol and dried to give 0.29 g (66%) of methyl 6-chloro-7-fluoro-8-methyl-2-oxo-1 ,2-dihydroquinoline-3-carboxylate. The product is used in the next step without further purification.
[00506] f) methyl 6-chloro-7-fluoro-8-methyl-2-oxo-1 ,2-dihydroquinoline-3- carboxylate (0.85 g, 0.0036 mol) in phosphorous oxychloride (4 mL) is refuxed overnight. The reaction mixture is cooled, and concentrated under reduced pressure. The residue is carefully poured into a mixture of ice and water (15 mL). After
neutralization with aq. NaHCO3, the mixture is extracted with CH2CI2. The crude product is purified by flash chromatography on silica gel (hexane: EtOAc, 3:1 ) to give methyl 2,6-dichloro-7-fluoro-8-methylquinoline-3-carboxylate as white solid (0.21 g, 27%). 1H NMR (200 MHz, CDCI3), δ (ppm): 2.69 (d, 2 Hz, 3H); 4.00 (s, 3H); 7.79 (d, 6 Hz, 1 H), 8.56 (s, 1 H). LC-MS: 288 [M+].
[00507] g) to a suspension of methyl 2,6-dichloro-7-fluoro-8-methylquinoline-3- carboxylate (0.380 g, 1.32 mmol) in anh. MeOH (30 mL) at 0-3 °C under Ar atmosphere a 60% suspension of NaH in mineral oil (0.630 g, 15.75 mmol) is added portionwise. The reaction mixture is stirred at rt for 1 h and at 60 °C for 24 h. The mixture is evaporated, the residue is mixed with ice water (50 mL), the obtained suspension is acidified with 3N HCI (6.5 mL), and stirred at rt for 2.5 h. The precipitate is filtered, washed with water, and dried in vacuo over P2O5 to give 6-chloro-7-fluoro-2-methoxy-8- methylquinoline-3-carboxylic acid (0.500 g) which is used in the next step without an additional purification. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.57 (d, 2.7 Hz, 3H); 4.05 (s, 3H); 8.17 (d, 8.3 Hz, 1 H); 8.65 (s, 1 H). LCMS ESI (m/z): 270 [M+H]+.
[00508] h) to a suspension of crude 6-chloro-7-fluoro-2-methoxy-8- methylquinoline-3-carboxylic acid (0.500 g) n anh. MeOH (25 mL) a 2N HCI solution in methanol (3.8 mL) is added and the reaction mixture is refluxed for 3 h. The solvent is evaporated and the residue (0.489 g) is purified by chromatography on silica gel (80 mL) with CHCI3 as eluent to give methyl 6-chloro-7-fluoro-2-methoxy-8-methylquinoline- 3-carboxylate (0.259 g). 1H NMR (400 MHz, CDCI3), δ (ppm): 2.62 (d, 2.7 Hz, 3H), 3.95 (s, 3H); 4.16 (s, 3H); 7.69 (d, 8.0 Hz, 1 H); 8.50 (s, 1 H). LCMS ESI (m/z): 284 [M+H]+.
[00509] i) a mixture of methyl 6-chloro-7-fluoro-2-methoxy-8-methylquinoline-3- carboxylate (0.259 g, 0.912 mmol), NBS (0.162 g, 0.912 mmol), and Bz2O2 (0.022 g, 0.09 mmol) in anh. CCI4 (37 mL) is refluxed for 2.5 h. After cooling to rt, the reaction mixture is filtered, the filtrate is evaporated to dryness and the obtained solid material is washed with DCM (3 x 3 mL) to give methyl 8-(bromomethyl)-6-chloro-7-fluoro-2- methoxyquinoline-3-carboxylate (0.316 g, 95.5%). 1H NMR (400 MHz, CDCI3), δ (ppm): 3.96 (s, 3H); 4.21 (s, 3H); 5.07 (d, 1.9 Hz, 2H); 7.83 (d, 7.9 Hz, 1 H); 8.53 (s, 1 H). 19F- NMR (CDCI3) δ: -109.0. LCMS ESI (m/z): 362 [M+H]+.
[00510] j) to a solution of methyl 8-(bromomethyl)-6-chloro-7-fluoro-2- methoxyquinoline-3-carboxylate (0.310 g, 0.85 mmol) in dry DMF (10 mL) under Ar atmosphere solid NaN3 (0.061 g, 0.94 mmol) is added and the reaction mixture is stirred at rt for 2 h. The mixture is poured into ice water (75 mL) and stirred for 2 h. The precipitate is filtered, washed with water, and dried in vacuo over P2O5 to give 8- (azidomethyl)-6-chloro-7-fluoro-2-methoxyquinoline-3-carboxylate (0.270 g, 97.2%). 1H NMR (400 MHz, CDCI3), δ (ppm): 3.96 (s, 3H); 4.19 (s, 3H); 4.93 (d, 2.0 Hz, 2H); 7.86 (d, 8.0 Hz, 1 H); 8.54 (s, 1 H). LCMS ESI (m/z): 325 [M+H]+.
[0051 1 ] k) a mixture of methyl 8-(azidomethyl)-6-chloro-7-fluoro-2- methoxyquinoline-3-carboxylate (0.270 g, 0.83 mmol), PPh3 (0.330 g, 1 .25 mmol), and water (0.150 g, 8.3 mmol) in THF (20 mL) is stirred at rt for 4 days. The reaction mixture is cooled to 5 °C in an ice bath and slowly 1 N HCI (4.5 mL) is added. The mixture is allowed to warm to rt and stirred for 1 h. The precipitate is filtered and washed successively with EtOAc (3 x 10 mL), Et2O (3 mL), and DCM (3 mL) to give 0.129 g of a white solid. The filtrate is evaporated, the residue is triturated with EtOAc (25 mL), filtered, and washed successively with EtOAc (3 x 3 mL), Et2O (2 mL), and DCM (2 mL) to give an additional amount (0.056 g) of the white solid. The both portions of the solid material were combined, washed successively with EtOAc (3 mL), Εί2Ο (5 mL), and DCM (5 mL), and dried in vacuo over P2O5 to give methyl 8-(aminomethyl)-6-chloro-7- fluoro-2-methoxyquinoline-3-carboxylate hydrochloride (0.176 g, 63.3%), M.p. 235-237 °C. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.89 (s, 3H); 4.16 (s, 3H); 4.52 (b s, 2H); 8.34 (b s, 3H); 8.52 (d, 8.2 Hz, 1 H); 8.85 (s, 1 H). LCMS ESI (m/z): 299 [M-CI"]+.
[00512] I) in analogy to the procedure described in Example 5a, condensation of methyl 8-(aminomethyl)-6-chloro-7-fluoro-2-methoxyquinoline-3-carboxylate with 2-(2- fluorophenyl)acetic acid gives methyl 6-chloro-7-fluoro-8-((2-(2- fluorophenyl)acetamido)methyl)-2-methoxyquinoline-3-carboxylate in 82% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.47 (s, 2H); 3.88 (s, 3H); 4.01 (s, 3H); 4.84 (d, 5 Hz, 2H); 7.05-7.13 (m, 2H); 7.22-7.29 (m, 2H); 8.25 (t, 5 Hz, 1 H); 8.80 (s, 1 H).
[00513] m) in analogy to the procedure described in Example 3(b) methyl 6- chloro-7-fluoro-8-((2-(2-fluorophenyl)acetamido)methyl)-2-methoxyquinoline-3- carboxylate is treated with HBr in AcOH to give the title compound in 84% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.54 (s, 2H); 4.61 (d, 5 Hz, 2H); 7.1 1 -7.16 (m, 2H); 7.29-7.32 (m, 2H); 8.36 (d, 8 Hz, 1 H); 8.90 (s, 1 H); 9.00 (t, 5 Hz, , 1 H); 12.52 (br s, 1 H) LC-MS: 407, 409 [M+H].
Example 241
6-Chloro-8-((2-(2,6-difluorophenyl)acetamido)methyl)-7-fluoro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.56 (s, 2H); 4.62 (d, 4.4 Hz, 2H); 7.04-7.08 (m, 2H); 7.32-7.40 (m, 1 H); 8.36 (d, 8 Hz, 1 H); 8.90 (s, 1 H); 9.00 (br s, 1 H); 12.46 (br s, 1 H) LC-MS: 425, 427 [M+H].
Example 242
6- Chloro-7-fluoro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.24 (s, 3H); 4.60 (d, 5.2 Hz, 2H); 4.66 (s, 1 H); 7.30 (s, 5H); 8.32 (d, 6.8 Hz, 1 H); 8.88 (s, 1 H); 8.99 (br s, 1 H); 12.44 (br s, 1 H). LC-MS: 417, 419 [M-H].
Example 243
7- Bromo-6-chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00514] The title compound is prepared by the following reaction sequence:
a) to a suspension of methyl 7-bromo-2,6-dichloro-8-methylquinoline-3-carboxylate (0.19 g, 0.54 mmol) in abs. MeOH (10 mL) at -3-0°C under argon is added 60% NaH in mineral oil (0.13 g, 3.27 mmol) portionwise. The resulting mixture is stirred at rt for 1 h and at reflux for 22 h. (HPLC/MS, 7-bromo-6-chloro-2-methoxy-8-methylquinoline-3- carboxylic acid and its methyl ester (75 and 21 %, accordingly). The reaction mixture is evaporated, cold water (15 mL) is added to the residue, and the resulting suspension is acidified with 3N HCI (1 .3 mL). The obtained mixture is stirred at rt for 2.5 h, filtered, washed with water, and dried over P2O5 to give solid material. The obtained solid is suspended in abs. MeOH (10 mL), to this suspension 2N HCI solution in MeOH (0.64 mL) is added, and the resulting mixture is refluxed for 4.5 h. The mixture is
supplemented with 2N HCI solution in MeOH (0.2 mL) and refluxing is continued for another 3 h. The solvent is evaporated, the residue is azeotropically dried with CH2CI2 (2 x 15 mL), triturated with petroleum ether, filtered, washed with petroleum ether, and dried over P2O5 to give 0.175 g (93.3%) of methyl 7-bromo-6-chloro-2-methoxy-8- methylquinoline-3-carboxylate. LC-MS: 346 [M+H]+. 1H NMR (400 MHz, CDCI3), δ (ppm): 2.89 (s, 3H); 3.96 (s, 3H); 4.16 (s, 3H); 7.78 (s, 1 H); 8.49 (s, 1 H).
[00515] b) a mixture of methyl 7-bromo-6-chloro-2-methoxy-8-methylquinoline-3- carboxylate (0.175 g, 0.51 mmol), NBS (0.091 g, 0.51 mmol), and Bz2O2 (0.012 g, 0.051 mmol) in abs. CCI4 (20 mL) is stirred at reflux temperature for 4 h (HPLC/MS, complete conversion) After cooling, the reaction mixture is filtered, the filtrate is evaporated to dryness, the residue is dissolved in CCI4 (30 mL), filtered, and again evaporated. The obtained solid is dried to give methyl 7-bromo-8-(bromomethyl)-6-chloro-2- methoxyquinoline-3-carboxylate (0.22 g, quant.). LC-MS: 423.9 [M+H]+. 1H NMR (400 MHz, CDCI3), δ (ppm): 3.96 (s, 3H); 4.21 (s, 3H); 5.31 (b s, 2H); 7.89 (s, 1 H); 8.51 (s, 1 H).
[00516] c) to a solution of methyl 7-bromo-8-(bromomethyl)-6-chloro-2- methoxyquinoline-3-carboxylate (0.216 g, 0.51 mmol) in abs. DMF (7 mL) is added NaN3 (0.036 g, 0.56 mmol) and the reaction mixture is stirred at rt for 1 h and at 50°C for 2 h. The mixture is poured into ice-water (35 mL) and stirred at rt for 24 h. The precipitate is filtered, washed with water, and dried over P2O5 to give methyl 8- (azidomethyl)-7-bromo-6-chloro-2-methoxyquinoline-3-carboxylate (0.134 g, 68%). LC- MS: 387 [M+H].
[00517] d) to a solution of methyl 8-(azidomethyl)-7-bromo-6-chloro-2- methoxyquinoline-3-carboxylate (0.134 g, 0.347 mmol) in THF (10 mL) is added PPh3 (0.136 g, 0.51 mmol) and water (0.063 mL, 3.5 mmol), and the resulting mixture is stirred at rt for 48 h. The reaction mixture is cooled to -1 °C, 1 M aq. HCI (1 .6 mL) is slowly added at the same temperature, and the resulting mixture is stirred at rt for 3 h. The mixture is evaporated to dryness, the obtained solid is triturated with EtOAc (20 ml_), filtered, washed with EtOAc (2x 1 0 ml_), diethyl ether (20 ml_), CH2CI2 (3x 1 0 ml_), and dried over P2O5 to give methyl 8-(aminomethyl)-7-bromo-6-chloro-2- methoxyquinoline-3-carboxylate hydrochloride (0.066 g, 48%), m.p. 235-237°C. LC-MS: 361 [M+H]. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.90 (s, 3H); 4.16 (s, 3H); 4.72 (b s, 2H); 8.36 (b s, 3H); 8.51 (s, 1 H); 8.84 (s, 1 H).
[00518] e) in analogy to the procedure described in Example 5(a), condensation of methyl 8-(aminomethyl)-7-bromo-6-chloro-2-methoxyquinoline-3-carboxylate with 2- methoxy-2-phenylacetic acid gives methyl 7-bromo-6-chloro-2-methoxy-8-((2-methoxy- 2-phenylacetamido)methyl)quinoline-3-carboxylate in 53% yield.
[00519] f) in analogy to the procedure described in Example 222(b), methyl 7- bromo-6-chloro-2-methoxy-8-((2-methoxy-2-phenylacetamido)methyl)quinoline-3- carboxylate is treated with 10N aq. HCI/dioxane (1 :4) to give the title compound as a white solid.
1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.24 (s, 3H); 4.69 (s, 1 H); 4.82 (d, 5.2 Hz, 2H); 7.28-7.36 (m, 5H); 8.33 (s, 1 H); 8.84 (s, 1 H); 8.86 (s, 1 H); 12.39 (br s, 1 H). LC-MS: 476, 478, 480 [M-H].
Example 244
6-Chloro-8-((2-(2,4-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.60 (s, 2H); 4.55 (d, 6.4 Hz, 2H); 7.02-7.07 (m, 1 H); 7.18-7.23 (m, 1 H); 7.37-7.43 (m, 1 H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.78 (br s, 1 H); 8.93 (s, 1 H); 12.42 (br s, 1 H). LC-MS: 407, 409 [M+H].
Example 245
6-Chloro-2-oxo-8-((2-phenyl-2-propoxyacetamido)methyl)-1 ,2-dihydroq
carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 0.86 (t, 7.4 Hz, 3H); 1 .55-1 .60 (m, 2H); 3.27- 3.40 (m, 2H); 4.54 (d, 6 Hz, 2H); 4.81 (s, 1 H); 7.28-7.38 (m, 5H); 7.55 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.83 (t, 6 Hz, 1 H); 8.91 (s, 1 H); 12.44 (br s, 1 H). LC-MS: 427, 429 [M-H].
Example 246
(S)-6-Chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.28 (s, 3H); 4.53 (d, 6.4 Hz, 2H); 4.74 (s, 1 H); 7.31 -7.37 (m, 5H); 7.54 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.91 (s, 1 H); 8.96 (t, 6.4 Hz, 1 H); 12.41 (br s, 1 H). LC-MS: 399, 401 [M-H].
Example 247
(R)-6-Chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.28 (s, 3H); 4.53 (d, 6.4 Hz, 2H); 4.74 (s, 1 H); 7.31 -7.37 (m, 5H); 7.54 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.91 (s, 1 H); 8.96 (t, 6.4 Hz, 1 H); 12.41 (br s, 1 H). LC-MS: 399, 401 [M-H].
Example 248
8-[(2-Benzyloxy-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.50 (d, 2.4 Hz, 2H); 4.55 (d, 6 Hz, 2H); 4.92 (s, 1 H); 7.28-7.42 (m, 10H); 7.54 (s, 1 H); 8.10 (s, 1 H); 8.90-8.92 (m, 2H); 12.43 (br s, 1 H). LC-MS: 475, 477 [M-H].
Example 249
8-((2-Butoxy-2-phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 0.80-0.85 (m, 3H); 1 .32-1 .36 (m, 2H); 1 .50-1 .58 (m, 2H); 3.34-3.43 (m, 2H); 4.54 (d, 6 Hz, 2H); 4.80 (s, 1 H); 7.30-7.38 (m, 5H); 7.56 (d, 2 Hz, 1 H); 8.10 (d, 2 Hz, 1 H); 8.82 (t, 6 Hz, 1 H); 8.91 (s, 1 H); 12.44 (br s, 1 H). LC-MS: 441 , 443 [M-H].
Example 250
6-Chloro-8-((2-(3-fluoropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.82 (d, 2 Hz, 2H); 4.58 (d, 6 Hz, 2H); 7.38- 7.43 (m, 1 H); 7.68-7.72 (m, 1 H); 7.79 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.37 (d, 4.4 Hz, 1 H); 8.90 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.43 (br s, 1 H). LC-MS: 388, 390 [M-H].
Example 251
8-((3-(Benzylamino)-3-oxopropanamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00520] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate with 3-(tert-butoxy)-3- oxopropanoic acid in DMF gives methyl 8-((3-(tert-butoxy)-3-oxopropanamido)methyl)- 6-chloro-2-methoxyquinoline-3-carboxylate as a light yellow solid in 84% yield. 1H NMR (200 MHz, DMSO-de), δ (ppm): 1 .40 (s, 9H); 3.25 (s, 2H); 3.88 (s, 3H); 4.06 (s, 3H); 4.80 (d, 6 Hz, 2H); 7.67 (s, 1 H); 8.10 (s, 1 H); 8.58 (t, 6 Hz, 1 H); 8.77 (s, 1 H).
[00521 ] b) methyl 8-((3-(tert-butoxy)-3-oxopropanamido)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate (230 mg, 0.54 mmol) is added to TFA (3 mL) and the mixture is stirred overnight. Then toluene is added and the mixture is concentrated under reduced pressure 3 times. Et.2O is added to the residue and the mixture is placed in ultasound bath for 10 min. The precipitate is filtred, washed with Et2O and dried to give 3-(((6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)methyl)amino)-3- oxopropanoic acid (190 mg, 82%). LC-MS: 367 [M+H].
[00522] c) in analogy to the procedure described in Example 5(a), condensation of 3-(((6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)methyl)amino)-3- oxopropanoic acid with benzylamine in DMF gives methyl 8-((3-(benzylamino)-3- oxopropanamido)methyl)-6-chloro-2-methoxyquinoline-3-carboxylate as a light yelow solid with 45% yield.
[00523] d) in analogy to the procedure described in Example 222(b), methyl 8-((3- (benzylamino)-3-oxopropanamido)methyl)-6-chloro-2-methoxyquinoline-3-carboxylate is treated with 10N aq. HCI/dioxane (1 :4) to give the title compound as a light yellow solid in 55% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.22 (s, 2H); 4.30 (d, 4.4 Hz, 2H); 4.57 (d, 4 Hz, 2H); 7.25-7.30 (m, 5H); 7.78 (s, 1 H); 8.13 (s, 1 H); 8.58 (br s, 1 H); 8.84 (br s, 1 H); 8.94 (s, 1 H); 12.54 (br s, 1 H). LC-MS: 428, 430 [M+H].
Example 252
6-Chloro-2-oxo-8-((2-(2,3,5-trifluorophenyl)acetamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.61 (s, 2H); 4.56 (d, 4 Hz, 2H); 7.49-7.53 (m, 2H); 7.63 (s, 1 H); 8.13 (s, 1 H); 8.78 (br s, 1 H); 8.93 (s, 1 H); 12.38 (br s, 1 H). LC-MS: 425, 427 [M+H].
Example 253
6-Chloro-8-((2-(naphthalen-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.72 (s, 2H); 4.67 (d, 4.4 Hz, 2H); 7.30-7.35 (m, 1 H); 7.45-7.55 (m, 3H); 7.80-7.90 (m, 5H); 8.57 (s, 1 H); 8.65 (br s, 1 H). LC-MS: 421 , 423 [M+H]. Example 254
6-Chloro-8-(1 -(2-methoxy-2^henylacetamido)ethyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
Mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.44 (d, 6.4 Hz, 3H); 3.27 (s, 3H); 4.69 and 4.70 (both s, total 1 H); 5.57-5.61 (m, 1 H); 7.27-7.39 (m, 5H); 7.64 and 7.74 (both d, 2.4 Hz, total 1 H); 8.04 and 8.06 (both d, 2.4 Hz, total 1 H); 8.88-8.93 (m, 2H); 12.43 (br s, 1 H). LC-MS: 413, 415 [M-H].
Example 255
6-chloro-8-(1 -(2-(2,6-difluorophenyl)acetamido)ethyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .40 (d, 6.4 Hz, 3H); 3.56-3.65 (m, 2H); 5.56- 5.60 (m, 1 H); 7.02-7.06 (m, 2H); 7.31 -7.34 (m, 1 H); 7.73 (d, 2 Hz, 1 H); 8.09 (d, 2 Hz, 1 H); 8.92 (s, 1 H); 8.95 (d, 6.8 Hz, 1 H); 12.51 (br s, 1 H). LC-MS: 421 , 423 [M+H].
Example 256
6-Chloro-8-(1 -(2-(2-fluorophenyl)-2-methoxyacetamido)ethyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
Mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.46 and 1 .48 (both d, 6.4 Hz, total 3H); 3.29 and 3.32 (both s, total 3H); 4.96 (s, 1 H); 5.60-5.66 (m, 1 H); 7.12-7.23 (m, 2H); 7.37-7.42 (m, 2H); 7.74 and 7.82 (both s, total 1 H); 8.06 and 8.09 (both s, total 1 H); 8.90-8.97 (m, 2H); 12.45 (br s, 1 H). LC-MS: 431 , 433 [M-H].
Example 257
6-Chloro-8-(1 -(2-ethoxy-2-phenylacetamido)ethyl)-2-oxo-1,2-dihydroquinoline-3- carboxylic acid
Mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.16-1 .22 (m, 3H); 1 .45 (d, 6.4 Hz, 3H); 3.34-3.51 (m, 2H); 4.79 and 4.80 (both s, total 1 H); 5.56-5.60 (m, 1 H); 7.26-7.40 (m, 5H); 7.63 and 7.74 (both d, 2.4 Hz, total 1 H); 8.03-8.06 (m, 1 H); 8.82-8.89 (m, 2H); 12.44 (br s, 1 H). LC-MS: 427, 429 [M-H].
Example 258
6-Chloro-8-((2-(4-ethoxy-2,6-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .31 (t, 6.8 Hz, 3H); 3.53 (s, 2H); 4.03 (q, 6.8 Hz, 2H); 4.55 (d, 6 Hz, 2H); 6.70 (d, 9.2 Hz, 2H); 7.64 (d, 2 Hz, 1 H); 8.13 (d, 2 Hz, 1 H); 8.77 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.41 (br s, 1 H). LC-MS: 449, 451 [M-H].
Example 259
6-Chloro-8-((2-morpholino-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
Isolated as hydrochloride. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.10-3.90 (m, 8H); 4.54-4.70 (m, 2H); 5.32 (br s, 1 H); 7.28 (s, 1 H); 7.46-7-48 (m, 3H); 7.57-7.59 (m, 2H); 8.08 (d, 2.4 Hz, 1 H); 8.89 (s, 1 H); 9.63 (br s, 1 H); 10.70-1 1.10 (br s, 1 H); 12.20 (br s, 1 H). LC-MS: 454, 456 [M-H].
Example 260
6-Chloro-8-((2-(2-ethoxyphenyl)acetamido)methyl)-2-oxo-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm) 1.10 (t, 7.2 Hz, 3H); 3.49 (s, 2H); 3.90-3.95 (m, 2H); 4.54 (d, 6 Hz, 2H); 6.87-6.94 (m, 2H); 7.18-7.22 (m, 2H); 7.67 (d, 2 Hz, 1 H); 8.12 (d, 2 Hz, 1 H); 8.51 (t, 6 Hz, 1 H); 8.92 (s, 1 H); 12.54 (br s, 1 H). LC-MS: 415, 417 [M+H].
Example 261
6-Chloro-8-((2-(2,6-difluoro-3-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.64 (s, 2H); 3.81 (s, 3H); 4.56 (d, 6 Hz, 2H); 6.99-7.04 (m, 1 H); 7.07-7.13 (m, 1 H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.36 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.40 (br s, 1 H). ). LC-MS: 435, 437 [M-H].
Example 262
6-Chloro-8-((isochroman-1 -carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.67-2.75 (m, 1 H); 2.91 -2.97 (m, 1 H); 3.82-3.84 (m, 1 H); 4.1 1 -4.14 (m, 1 H); 4.53 (d, 6 Hz, 2H); 5.22 (s, 1 H); 7.14-7.16 (m, 3H); 7.40 (d, 7.2 Hz, 1 H); 7.56 (s, 1 H); 8.10 (s, 1 H); 8.86 (br s, 1 H); 8.91 (s, 1 H); 12.40 (br s, 1 H). ). LC-MS: 413, 415 [M+H].
Example 263
6-Chloro-8-((2-(3-ethoxy-2,4-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .26 (br s, 3H); 3.59 (s, 2H); 4.10 (br s, 2H); 4.56 (br s, 2H); 7.07 (br s, 2H); 7.65 (s, 2H); 8.13 (s, 1 H); 8.78 (br s, 1 H); 8.93 (s, 1 H); 12.40 (br s, 1 H) ). LC-MS: 451 , 453 [M+H].
Example 264
6,7-Dichloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.24 (s, 3H); 4.68 (s, 1 H); 4.77 (d, 6 Hz, 2H); 7.28-7.36 (m, 5H); 8.36 (s, 1 H); 8.88-8.92 (m, 2H); 12.39 (br s, 1 H). LC-MS: 433, 435, 437 [M-H].
Example 265
6,7-Dichloro-8-((2-ethoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .13 (t, 6.8 Hz, 3H); 3.39-3.49 (m, 2H); 4.77 (s, 3H); 7.26-7.36 (m, 5H); 8.35 (s, 1 H); 8.82-8.87 (m, 2H); 12.40 (br s, 1 H). LC-MS: 447, 449, 451 [M-H].
Example 266
6-Chloro-8-((2-(2,3-difluoro-6-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.64 (s, 2H); 3.81 (s, 3H); 4.56 (d, 6 Hz, 2H); 6.99-7.04 (m, 1 H); 7.07-7.13 (m, 1 H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.83 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.40 (br s, 1 H). LC-MS: 435, 437 [M-H].
Example 267
6-Chloro-8-((2-ethoxy-2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .16 (t, 7 Hz, 3H); 3.39-3.56 (m, 2H); 4.59 (d, 6 Hz, 2H); 5.07 (s, 1 H); 7.16-7.21 (m, 2H); 7.36-7.40 (m, 2H); 7.62 (s, 1 H); 8.1 1 (d, 2.4 Hz, 1 H); 8.90-8.93 (m, 2H); 12.46 (br s, 1 H). LC-MS: 431 , 433 [M-H].
Example 268
6-Chloro-8-((2-(4-methoxypiperidin-1 -yl)-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
Isolated as hydrochloride. 1H NMR (200 MHz, DMSO-d6), δ (ppm): 1.30-2.20 (m, 4H); 3.16 (s, 3H); 3.00-4.30 (m, 5H); 4.55 (br s, 2H); 7.20-7.60 (m, 6H); 8.03 (br s, 1 H); 8.84 (s, 1 H); 8.90-9.20 (br s, 1 H). LC-MS: 483, 485 [M-H].
Example 269
6-Chloro-8-((2-(2-fluoro-6-(trifluoromethyl)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.81 (s, 2H); 4.57 (d, 5.2 Hz, 2H); 7.56-7.63 (m, 4H); 8.13 (s, 1 H); 8.82 (br s, 1 H); 8.93 (s, 1 H); 12.35 (br s, 1 H). LC-MS: 457, 459 [M+H].
Example 270
6-Chloro-2-oxo-8-(3-oxo-3-(phenylamino)propyl)-1 ,2-dihydroquinoline-3- carboxylic acid
[00524] The title compound is prepared by the following reaction sequence:
a) a solution of di-terf-butyl malonate (0.93 g, 4.3 mmol) in dry DMF (2 mL) is added dropwise to a chilled suspension of 60% NaH in oil (0.19 g, 4.7 mmol) in DMF (20 mL). The reaction mixture is stirred at 0°C for 0.5 h and a solution of methyl 8-(bromomethyl)- 6-chloro-2-methoxyquinoline-3-carboxylate (1 .49 g, 4.3 mmol) in DMF (5 mL) is added dropwise. The resulting mixture is stirred at rt for 3 h and then diluted with water. The product is filtered off and washed with water and petroleum ether to give di-tert-butyl 2- ((6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)methyl)malonate (1 .88 g, 91 %). 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .32 (s, 18H); 3.49 (d, 7.7 Hz, 2H); 3.85 (t, 7.7 Hz, 1 H); 3.88 (s, 3H); 4.04 (s, 3H); 7.67 (d, 2.4 Hz, 1 H); 8.07 (d, 2.4 Hz, 1 H); 8.75 (s, 1 H).
[00525] b) trifluoroacetic acid (10 mL) was added dropwise to a solution of di-tert- butyl 2-((6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)methyl)malonate (1 .88 g, 3.9 mmol) in CH2CI2 (10 mL). The reaction mixture is stirred at room temperature for 24 h and then evaporated to dryness. Water was added to the residue and the product is filtered off and washed with water to give 2-((6-chloro-2-methoxy-3- (methoxycarbonyl)quinolin-8-yl)methyl)malonic acid (1.31 g, 91 %). 1H NMR (400 MHz, DMSO-de), δ (ppm): 3.52 (d, 7.7 Hz, 2H); 3.88 (s, 3H); 3.91 (t, 7.7 Hz, 1 H); 4.04 (s, 3H); 7.64 (d, 2.4 Hz, 1 H); 8.06 (d, 2.4 Hz, 1 H); 8.74 (s, 1 H), 12.76 (br s, 2H).
[00526] c) 2-((6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8- yl)methyl)malonic acid (1 .31 g, 3.6 mmol) is heated at 190 °C until the gas evolution ended. After the cooling, water is added to the residue and the product is filtered off and washed with water to give 3-(6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8- yl)propanoic acid. (1 .09 g, 95%). M.p. 184-186 °C. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.71 (t, 7.6 Hz, 2H); 3.32 (t, 7.6 Hz, 2H); 3.88 (s, 3H); 4.04 (s, 3H); 7.68 (d, 2.4 Hz, 1 H); 8.03 (d, 2.4 Hz, 1 H); 8.73 (s, 1 H); 12.13 (s, 1 H). LC ESI-MS (m/z): 322 [M-H].
[00527] d) in analogy to the procedure described in Example 5(a), condensation of 3-(6-chloro-2-methoxy-3-(methoxycarbonyl)quinolin-8-yl)propanoic acid with aniline in DMF gives methyl 6-chloro-2-methoxy-8-(3-oxo-3-(phenylamino)propyl)quinoline-3- carboxylate as a white solid in 79% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.80 (t, 7.6 Hz, 2H), 3.41 (t, 7.6 Hz, 2H), 3.88 (s, 3H), 4.07 (s, 3H), 7.01 (t, 7.4 Hz, 1 H), 7.27 (t, 7.8 Hz, 1 H), 7.53 (d, 8.0 Hz, 2H), 7.70 (d, 2.4 Hz, 1 H), 8,03 (d, 2.4 Hz, 1 H), 8,74 (s, 1 H), 9.83 (br.s, 1 H).
[00528] e) a mixture of methyl 6-chloro-2-methoxy-8-(3-oxo-3- (phenylamino)propyl)quinoline-3-carboxylate (52 mg; 0.13 mmol) in 10N aq. HCI/AcOH (1 :5) (2.0 mL) is stirred at rt for 96 h. The mixture is filtered and the precipitate is washed with cold H2O and abs. diethyl ether to give the title compound as a white solid in 54% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.67 (t, 7 Hz, 2H); 3.27 (t, 7 Hz, 2H); 7.00-7.04 (m, 1 H); 7.26-7.30 (m, 2H); 7.53 (d, 8 Hz, 2H); 7.69 (d, 2 Hz, 1 H); 8.06 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 9.86 (s, 1 H); 12.61 (br s, 1 H). LC-MS: 369, 371 [M-H].
Example 271
6-Chloro-8-((1 -(3-chloropyridin-2-yl)-1 H-pyrrole-2-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.59 (d, 6 Hz, 2H); 6.33-6.35 (m, 1 H); 7.01 - 7.03 (m, 1 H); 7.17-7.18 (m, 1 H); 7.49-7.52 (m, 1 H); 7.66 (d, 2.4 Hz, 1 H); 8.01 -8.03 (m, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.41 -8.42 (m, 1 H); 8.93 (s, 1 H); 9.05 (t, 6 Hz, 1 H); 12.39 (br s, 1 H). LC-MS: 455, 457, 459 [M-H]. Example 272
6-Chloro-8-((6-chloroimidazo[1 ,2-b]pyridazine-2-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.71 (d, 6.4 Hz, 2H); 7.49 (d, 9.6 Hz, 1 H); 7.77 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.27 (d, 9.6 Hz, 1 H); 8.75 (s, 1 H); 8.92 (s, 1 H); 9.49 (t, 6.4 Hz, 1 H); 12.60 (br s, 1 H). LC-MS: 430, 432, 434 [M-H].
Example 273
6-Chloro-8-((5-(3-chlorophenyl)oxazole-4-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.71 (d, 6.4 Hz, 2H); 7.52-7.57 (m, 2H); 7.78 (d, 2.4 Hz, 1 H); 8.07-8.10 (m, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.39 (t, 1 .2 Hz, 1 H); 8.68 (s, 1 H); 8.92 (s, 1 H); 9.39 (t, 6.4 Hz, 1 H); 12.55 (br s, 1 H). LC-MS: 456, 458, 460 [M-H].
Example 274
6-Chloro-8-((2-(4-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 4.54 (d, 6.4 Hz, 2H); 7.1 1 -7.15 (m, 2H); 7.30-7.33 (m, 2H); 7.59 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.79 (t, 6.4 Hz, 1 H); 8.92 (s, 1 H); 12.45 (br s, 1 H). LC-MS: 387, 389 [M-H].
Example 275
6-Chloro-8-((imidazo[1 ,2-a]pyridine-3-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (200 MHz, DMSO-d6), δ (ppm): 4.83 (br s, 2H); 7.48-7.55 (m, 1 H); 7.78 (s, 1 H); 7.88-8.03 (m, 2H); 8.15 (s, 1 H); 8.86 (s, 1 H); 8.94 (s, 1 H); 9.60-9.63 (m, 1 H); 9.85 (br s, 1 H); 12.30-12.70 (br s, 1 H). LC-MS: 395, 397 [M-H]. Example 276
6-Chloro-8-((2-(3-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.57 (s, 2H); 4.55 (d, 6.4 Hz, 2H); 7.05-7.13 (m, 3H); 7.32-7.38 (m, 1 H); 7.60 (s, 1 H); 8.12 (s, 1 H); 8.82 (t, 6.4 Hz, 1 H); 8.92 (s, 1 H); 12.43 (br s, 1 H). LC-MS: 389, 391 [M+H].
Example 277
6-Chloro-8-((2-(2-fluoro-5-methylphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.24 (s, 3H); 3.55 (s, 2H); 4.56 (d, 6 Hz, 2H); 7.01 -7.12 (m, 3H); 7.65 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.79 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.43 (br s, 1 H). LC-MS: 403, 405 [M+H].
Example 278
(R)-6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-3-carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00529] a) to a suspension (R)-2-(tert-butoxycarbonyl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (390 mg, 1 .41 mmol) in dry CH2CI2 (5 mL) is added EDC (262 mg, 1 .69 mmol) and 1 -hydroxypyrrolidine-2,5-dione (194,2 mg, 1 .7 mmol). The mixture is stirred at rt for 20 h. Then water (15 mL) is added. The mixture is filtered and the solid is washed with water, 2% aqueous citric acid and water. The crude product is recrystallized from isopropyl alcohol to give (R)-2-tert-butyl 3-(2,5- dioxopyrrolidin-1 -yl) 3,4-dihydroisoquinoline-2,3(1 H)-dicarboxylate (172 mg) as colorless solid. LC-MS: 375 [M+H].
[00530] b) to a mixture of 8-(aminomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid hydrochloride (1 19.3 mg, 0.41 mmol) and NaHCO3 (173.4 mg, 2.06 mmol) in aqueous acetonitrile (1 :1 , 6 mL) is added (R)-2-tert-butyl 3-(2,5- dioxopyrrolidin-1 -yl) 3,4-dihydroisoquinoline-2,3(1 H)-dicarboxylate (170 mg, 0.45 mmol). The mixture is stirred at rt for 18 h, then it is filtered and washed with acetonitrile. Solid material is acidified with 20% aq. citric acid, filtered, and washed with water to give (R)- 8-((2-(tert-butoxycarbonyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamido)methyl)-6- chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (1 12 mg) as yellow solid. The filtrate is diluted with water to give additional amount (22 mg, 60% total) of the product. M.p. 156-164 °C. LC-MS: 512 [M+H].
[00531 ] c) a solution of (R)-8-((2-(tert-butoxycarbonyl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid (105 mg, 0.21 mmol) in TFA (2 mL) is stirred at rt for 2 days. Heptane is added and the mixture is evaporated under reduced pressure. The residue is treated with diethyl ether anf filtered to give the title compound trifluoroacetate (107 mg) as yellow solid. M.p. 172-179 °C. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.03-3.10 (m, 1 H); 4.30-4.40 (m, 3H); 4.66 (dd, 5.2 and 16 Hz, 1 H); 4.78 (dd, 6 and 16 Hz, 1 H); 7.20- 7.30 (m, 4H); 7.69 (s, 1 H); 8.16 (s, 1 H); 8.94 (s, 1 H); 9.26 (br s, 1 H); 9.54 (br s, 2H); 12.10-12.70 (br s, 1 H). LC-MS: 412, 414 [M+H].
Example 279
6-Chloro-2-oxo-8-((2-(piperazin-1 -yl)-2-(p-tolyl)acetamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
[00532] The title compound is prepared by the following reaction sequence:
a) to a suspension of 2-(4-(terf-butoxycarbonyl)piperazin-1 -yl)-2-(p-tolyl)acetic acid (59 mg, 0.18 mmol) in dry CH2CI2 (5 mL) is added EDC (32.9 mg, 0.21 mmol) and 1 - hydroxypyrrolidine-2,5-dione (24.4 mg, 0.2 mmol). The mixture is stirred at rt for 3 days. Then water (5 mL) is added, the organic phase is separated, dried with magnesium sulfate, filtered and evaporated under reduced pressure to give tert-butyl 4-(2-((2,5- dioxopyrrolidin-1 -yl)oxy)-2-oxo-1 -(p-tolyl)ethyl)piperazine-1 -carboxylate (75 mg) as colorless foam. LC-MS: 432 [M+H]. [00533] b) to a mixture of 8-(aminomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid hydrochloride (45.7 mg, 0.16 mmol) and NaHCO3 (66.4 mg, 0.79 mmol) in aqueous acetonitrile (1 :1 , 2 ml_) is added tert-butyl 4-(2-((2,5-dioxopyrrolidin-1 - yl)oxy)-2-oxo-1 -(p-tolyl)ethyl)piperazine-1 -carboxylate (75 mg, 0.17 mmol). The mixture is stirred at rt for 18 h, then it is filtered and washed with acetonitrile. Solid material is acidified with 20% aq. citric acid, filtered, and washed with water to give 8-((2-(4-(tert- butoxycarbonyl)piperazin-1 -yl)-2-(p-tolyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid (35 mg) as yellow solid. The filtrate is diluted with water to give additional amount (27 mg, 67% total) of the product.
[00534] c) a solution of 8-((2-(4-(tert-butoxycarbonyl)piperazin-1 -yl)-2-(p- tolyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid (35 mg, 0.06 mmol) in TFA (2 ml_) is stirred at rt for 24 h. Heptane is added and the mixture is evaporated under reduced pressure. The residue is treated with diethyl ether anf filtered to give the title compound trifluoroacetate (33 mg) as yellow solid. M.p. 245-250 °C. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.26 (s, 3H); 2.40-2.60 (m, 4H); 3.05-3.15 (m, 4H); 4.03 (s, 1 H); 4.55 (d, 5.6 Hz, 2H); 7.12 (d, 8 Hz, 2H); 7.22 (d, 8 Hz, 2H); 7.45 (s, 1 H); 8.05 (s, 1 H); 8.51 (br s, 2H); 8.85-8.94 (m, 2H); 12.00-12.40 (br s, 1 H). LC-MS: 469, 471 [M+H].
Example 280
6-Chloro-8-((3-(4-methylpiperazin-1 -yl)-2^henylpropanamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00535] The title compound is prepared by the following reaction sequence:
a) to a solution of methyl 3-bromo-2-phenylpropanoate [J. Heterocycl. Chem. 1972, 9, 21 .] (0.20 g, 0.82 mmol) in acetonitrile (2 ml_) are added DIPEA (0.1 1 g, 0.82 mmol) and /V-methylpiperazine (0.10 g, 0.99 mmol). The reaction mixture is stirred at rt for 19 h. The solvent is then removed under reduced pressure, and the residue is purified by silica gel column chromotography (C^C^/MeOH, 10:1 ) to give methyl 3-(4- methylpiperazin-1 -yl)-2-phenylpropanoate (0.120 g, 56%) as a colorless oil. 1H NMR (400 MHz, CDCIs), δ (ppm): 1 .97 (br s, 1 H); 2.27 (s, 3H); 2.40-2.65 (m, 3H); 2.56 (dd, 12.4 and 4.6 Hz, 1 H); 3.21 (dd, 12.4 and 1 1 Hz, 1 H); 3.84 (dd, 1 1 and 4.6 Hz, 1 H); (m, 10H); 3.67 (s, 3H); 7.23-7.33 (m, 5H).
[00536] b) to a solution of methyl 3-(4-methylpiperazin-1 -yl)-2-phenylpropanoate 0.1 1 g, 0.43 mmol) in 1 ,4-dioxane (4 mL) is added cone, hydrochloric acid (1 mL). The reaction mixture is stirred at 65 °C for 18 h. The mixture is then cooled and concentrated under reduced pressure. The residue is crystallized from MeOH l/EtOAc to give 3-(4-methylpiperazin-1 -yl)-2-phenylpropionic acid dihydrochloride (0.102 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.78 (s, 3H); 3.00-4.00 (m, 10H); 4.20 (br s, 1 H); 7.30-7.41 (m, 5H).
[00537] c) to a solution of 3-(4-methylpiperazin-1 -yl)-2-phenylpropionic acid dihydrochloride 0.08 g, 0.25 mmol) in DMF (1 mL) are added HOBt hydrate (0.04 g, 0.26 mmol), EDC (0.05 g, 0.26 mmol) and DIPEA (0.10 g, 0.79 mmol). The reaction mixture is stirred at rt for 5 min then methyl 8-aminomethyl-6-chloro-2-methoxy- quinoline-3-carboxylate hydrochloride (0.05 g, 0.16 mmol) is added, and stirring is continued for 20 h. Then water is added, and the precipitate is filtered off. Obtained solid is purified by silica gel column chromatography (C^C^ MeOH, 10:1 ) to give methyl 6-chloro-8-((3-(4-methylpiperazin-1 -yl)-2-phenylpropanamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylate (0.022 g, 27%) as a yellow oil. 1H NMR (400 MHz, CDCIs), δ (ppm): 1 .86 (br s, 2H); 2.17 (br s, 3H); 2.10-2.65 (m, 7H); 3.13-3.18 (m, 1 H); 3.65-3.69 (m, 1 H); 3.96 (s, 3H); 4.06 (s, 3H); 4.89-4.99 (m, 2H); 7.20-7.32 (m, 5H); 7.62 (d, 2.4 Hz, 1 H); 7.68 (d, 2.4 Hz, 1 H); 7.93 (t, 5.6 Hz, 1 H); 8.51 (s, 1 H).
[00538] d) to a solution of methyl 6-chloro-8-((3-(4-methylpiperazin-1 -yl)-2- phenylpropanamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylate (0.02 g, 0.04 mmol) in 4M HCI in 1 ,4-dioxane (2.5 mL) is added water (0.5 mL), and the mixture is heated at 55 °C for 19 h. After cooling to rt, the mixture is evaporated to dryness. The crude is then dissolved in CHsCN/MeOH (2:1 ) and evaporated again. Resulting solid is crystallized from MeOH to give the title compound dihydrochloride (0.015 g, 63%) as a yellow solid. 1H NMR (200 MHz, DMSO-d6), δ (ppm): 2.74 (br s, 3H); 2.80-4.00 (br s, 10H); 4.05-4.25 (br s, 1H); 4.54 (br s, 2H); 7.25-7.40 (br s, 5H); 7.46 (d, 2 Hz, 1H); 8.10 (d, 2 Hz,1H); 8.91 (s, 1H); 9.04 (s, 1H).). LC-MS: 481, 483 [M-H].
Example 281
6-Chloro-2-oxo-8-((1 ,2,3,4-tetrahydronaphthalene-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.61 (br s, 1 H); 1.90-1.95 (m, 3H); 2.66-2.77 (m, 2H); 3.71-3.74 (m, 1H); 4.59 (d, 5.6 Hz, 2H); 6.97-7.13 (m, 4H); 7.70 (d, 2 Hz, 1H); 8.14 (d, 2 Hz, 1H); 8.78 (t, 5.6 Hz, 1H); 8.93 (s, 1H); 12.45 (br s, 1H). LC-MS: 411, 413 [M+H].
Example 282
6-chloro-8-((2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.68 (s, 2H); 4.58 (d, 5.6 Hz, 2H); 7.32-7.33 (m, 2H); 7.39-7.40 (m, 1H); 7.65 (d, 2 Hz, 1H); 8.13 (d, 2 Hz, 1H); 8.86 (t, 5.6 Hz, 1H); 8.93 (s, 1H); 12.40 (brs, 1H). LC-MS: 473, 475 [M+H].
Example 283
8-((2-(5-Bromopyridin-3-yl)acetamido)methyl)-6-chloro-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (200 MHz, DMSO-d6), δ (ppm): 3.63 (s, 2H); 4.57 (d, 5 Hz, 2H); 7.64 (s, 1H); 7.96 (s, 1H); 8.14 (s, 1H); 8.46 (s, 1H); 8.59 (s, 1H); 8.80-9.00 (m, 2H); 12.37 (brs, 1H). LC-MS: 450, 452, 454 [M+H].
Example 284
6-Chloro-8-((2-(2-fluoro-6-methoxyphenyl)acetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.53 (s, 2H); 3.70 (s, 3H); 4.53 (d, 4.4 Hz, 2H); 6.78-6.85 (m, 2H); 7.25-7.31 (m, 1H); 7.64 (s, 1H); 8.13 (s, 1H); 8.65 (brs, 1H); 8.94 (s, 1 H); 12.43 (br s, 1 H). LC-MS: 419, 421 [M+H].
Example 285
8-((2-(1H-1,2,3 riazol-1-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (200 MHz, DMSO-d6), δ (ppm): 4.79 (d, 5.5 Hz, 2H); 5.18 (s, 2H); 7.74 (s, 1H); 8.08 (s, 1H); 8.41 (s, 1H); 8.90 (s, 1H); 9.16 (d, 5.5 Hz, 1H); 12.20-12.60 (brs, 1H). LC- MS: 396, 398, 400 [M+H].
Example 286
8-((2-(2H-1,2,3-triazol-2-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (200 MHz, DMSO-d6), δ (ppm): 4.79 (br s, 2H); 5.19 (s, 2H); 7.81 (d, 1.8 Hz, 2H); 8.41 (s, 1H); 8.90 (s, 1H); 9.12 (brs, 1H); 12.20-12.60 (brs, 1H). LC-MS: 396, 398, 400 [M+H].
Example 287
6,7-Dichloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.26 (s, 3H); 4.81 (d, 5.4 Hz, 2H); 5.03 (s, 1H); 7.29-7.44 (m, 4H); 8.37 (s, 1H); 8.89 (s, 1H); 8.96 (t, 5.4 Hz, 1H); 12.40 (brs, 1H). LC- MS: 467, 469, 471, 473 [M-H].
Example 288
8-((2-(2-(1 H-tetrazol-1 -yl)phenyl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.60 (s, 2H); 4.60 (d, 6 Hz, 2H); 7.52-7.61 (m, 4H); 8.41 (s, 1 H); 8.91 (s, 1 H); 8.98 (t, 6 Hz, 1 H); 9.62 (s, 1 H); 12.30 (br s, 1 H). LC-MS: 471 , 473, 475 [M-H].
Example 289
6-Chloro-8-((2-(1 -methyl-1 H-imidazol-4-yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
Isolated as hydrochloride. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.76 (s, 2H); 3.83 (s, 3H); 4.59 (d, 6 Hz, 2H); 7.51 (s, 1 H); 7.70 (d, 2.4 Hz, 1 H); 8.14 (d, 2.4 Hz, 1 H); 8.93- 8.99 (m, 3H). LC-MS: 373, 375 [M-H].
Example 290
8-((2-(4-Aminopiperidin-1 -yl)-2-phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00539] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxyquinoline-3-carboxylate with 2-(4-((tert- butoxycarbonyl)amino)piperidin-1 -yl)-2-phenylacetic acid gives methyl 8-((2-(4-((tert- butoxycarbonyl)amino)piperidin-1 -yl)-2-phenylacetamido)methyl)-6-chloro-2- methoxyquinoline-3-carboxylate as a white solid in 67% yield.
[00540] b) to a solution of 8-((2-(4-((tert-butoxycarbonyl)amino)piperidin-1 -yl)-2- phenylacetamido)methyl)-6-chloro-2-methoxyquinoline-3-carboxylate (0.08 g, 0.13 mmol) in 4N HCI/dioxane (4 ml_) is added 1 ml_ of distilled water, and the resulting mixture is heated at 65 °C for 4 h. Then the reaction mixture is evaporated to dryness, and the residue is suspended in acetonitrile and stirred for 30 min at rt. The precipitate is filtered off, washed with acetonitrile, and then dried over P2O5 at 45 °C to give the title compound dihydrochloride (0.065 g, 89%) as a light-yellow solid. 1H NMR (400 MHz, DMSO-de), δ (ppm): 1 .80-2.25 (m, 4H); 2.71 -3.09 (m, 1 H); 3.10-3.70 (m, 4H); 4.52-4.65 (m, 2H); 5.15 and 5.39 (both m, total 1 H); 7.27 (s, 1 H); 7.35-7.61 (m, 5H); 8.06 (d, 2.4 Hz, 1 H); 8.38 and 8.50 (both br s, total 3H); 8.86 (s, 1 H); 9.58 and 9.67 (both br s, total 1 H); 10.58 (br s, 1 H); 12.13 (br s, 1 H). LC-MS: 467, 469 [M-H].
Example 291
6-Chloro-8-((2-(6-chloro-2-fluoro -methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.73 (s, 2H); 3.84 (s, 3H); 4.56 (d, 5.5 Hz, 2H); 7.1 1 -7.15 (m, 1 H); 7.24-7.26 (m, 1 H); 7.66 (s, 1 H); 8.12 (s, 1 H); 8.80 (t, 5,5 Hz, 1 H); 8.93 (s, 1 H); 12.39 (br s, 1 H). LC-MS: 451 , 453, 455 [M-H].
Example 292
6-Chloro-8-((2-(3-chloro-2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.68 (s, 2H); 4.57 (d, 5.4 Hz, 2H); 7.16-7.20 (m, 1 H); 7.32-7.35 (m, 1 H); 7.47-7.50 (m, 1 H); 7.64 (d, 2.4 Hz, 1 H); 8.13 (d, 2.4 Hz, 1 H); 8.83 (t, 5.4 Hz, 1 H); 8.93 (s, 1 H); 12.39 (br s, 1 H). LC-MS: 421 , 423, 425 [M-H].
Example 293
(R)-6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.28 (s, 3H); 4.57 (d, 6 Hz, 2H); 5.09 (s, 1 H); 7.33-7.39 (m, 3H); 7.45-7.47 (m, 1 H); 7.66 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 9.02 (t, 6 Hz, 1 H); 12.42 (br s, 1 H). LC-MS: 433, 435, 437 [M-H].
Example 294
(S)-6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm) 3.28 (s, 3H); 4.57 (d, 6 Hz, 2H); 5.09 (s, 1 H); 7.33-7.39 (m, 3H); 7.45-7.47 (m, 1 H); 7.66 (d, 2.4 Hz, 1 H); 8.12 (d, 2.4 Hz, 1 H); 8.92 (s, 1 H); 9.02 (t, 6 Hz, 1 H); 12.42 (br s, 1 H). LC-MS: 433, 435, 437 [M-H].
Example 295
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00541 ] The title compound is prepared by the following reaction sequence:
a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- (aminomethyl)-6,7-dichloro-2-methoxyquinoline-3-carboxylate with 2-(4-(tert- butoxycarbonyl)piperazin-1 -yl)-2-(2-fluorophenyl)acetic acid gives methyl 8-((2-(4-(tert- butoxycarbonyl)piperazin-1 -yl)-2-(2-fluorophenyl)acetamido)methyl)-6,7-dichloro-2- methoxyquinoline-3-carboxylate in 38% yield. 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .34 (s, 9H); 2.24 (br s, 4H); 3.20 (br s, 4H); 3.88 (s, 3H); 4.02 (s, 3H); 4.30 (s, 1 H); 5.03 (d, 5 Hz, 2H); 7.10-7.16 (m, 2H); 7.30-7.35 (m, 1 H); 7.48 (t, 7.6 Hz, 1 H); 8.33 (t, 5 Hz, 1 H); 8.80 (s, 1 H)
[00542] b) methyl 8-((2-(4-(tert-butoxycarbonyl)piperazin-1 -yl)-2-(2- fluorophenyl)acetamido)methyl)-6,7-dichloro-2-methoxyquinoline-3-carboxylate (60 mg, 0.09 mmol) is dissolved in 4N HCI/dioxane (2 ml_) and heated for 40 h at 50 °C, then solvent is removed under reduced pressure, 10N aq. HCI/AcOH (1/5, 2 ml_) is added and the mixture is stirred at rt for 4 days. AcOH is removed under reduced pressure. Cold water (20 ml_) is added to the residue and the mixture is stirred for one day. The mixture is filtered and the solid is washed with water, Et.2O and dried to give the title compound hydrochloride (38 mg, 77%) as a light yellow solid. 1H NMR (400 MHz, DMSO-de), δ (ppm): 3.00-3.20 (br s, 4H); 3.20-3.60 (br s, 4H); 4.53 (s, 1 H); 4.79-4.83 (m, 2H); 7.16-7.21 (m, 2H); 7.36-7.43 (m, 2H); 8.38 (s, 1 H); 8.62-8.66 (br s, 2H); 8.90 (s, 1 H); 9.00 (br s, 1 H); 12.25-12.40 (br s, 1 H). 1 H); LC-MS: 507, 509, 51 1 [M+H].
Example 296 6-Chloro-8-((2-(2-fluoro-5-(trifluoromethyl)phenyl)acetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.74 (s, 2H); 4.59 (d, 4.4 Hz, 2H); 7.40-7.44 (m, 1H); 7.64-7.78 (m, 3H); 8.13 (s, 1H); 8.88 (brs, 1H); 8.93 (s, 1H); 12.40 (brs, 1H). LC- MS: 457, 459 [M+H].
Example 297
6,7-Dichloro-2-oxo-8-((1-(pyridin-3-yl)cyclopropanecarboxamido)methyl)-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.21-1.22 (m, 2H); 1.49-1.51 (m, 2H); 4.70 (d, 5.2 Hz, 2H); 7.82-7.85 (m, 1H); 8.00-8.02 (m, 1H); 8.28-8.30 (m, 1H); 8.36 (s, 1H); 8.75 (br s, 1 H); 8.81 (s, 1 H); 8.89 (s, 1 H); 12.20-12.40 (br s, 1 H). LC-MS: 432, 434, 436
[M+H].
Example 298
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 4.77 (d, 4.8 Hz, 2H); 4.85 (s, 2H); 6.25 (s, 1H); 7.43 (s, 1 H); 7.69 (s, 1 H); 8.39 (s, 1 H); 8.88 (s, 1 H); 8.99 (br s, 1 H); 12.00-12.60 (br s, 1H). LC-MS: 395, 397, 399 [M+H].
Example 299
6,7-Dichloro-8-((2-(3-chloropyridin-2-yl)acetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.86 (s, 2H); 4.78 (d, 5.2 Hz, 2H); 7.32-7.35 (m, 1H); 7.88-7.90 (m, 1H); 8.39-8.41 (m, 2H); 8.89 (s, 1H); 9.14 (brs, 1H); 12.42 (brs, 1H). LC-MS: 440, 442, 444, 446 [M+H]. Example 300
8-{[2-(5-Amino-2-fluoro^henyl)-acetylamino]methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.60 (s, 2H); 4.51 (d, 6 Hz, 2H); 7.15-7.22 (m, 3H); 7.61 (d, 2.4 Hz, 1 H); 8.08 (d, 2.4 Hz, 1 H); 8.85-8.95 (m, 2H); 12.20-12.60 (br s, 1 H). LC-MS: 404, 406 [M+H].
Example 301
8-(Acetamidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .93 (s, 3H); 4.53 (d, 6 Hz, 2H); 7.70 (d, 2 Hz, 1 H); 8.14 (d, 2 Hz, 1 H); 8.75 (t, 6 Hz, 1 H); 8.93 (s, 1 H); 12.58 (br s, 1 H). LC-MS: 295, 297 [M+H].
Example 302
6-Chloro-8-((3-methoxy-2-phenylpropanamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
[00543] The title compound is prepared by the following reaction sequence:
a) to a solution of acid 3-methoxy-2-phenylpropanoic acid [J. Am. Chem. Soc. 2010, 132 (33), 1 1629.] (70 mg, 0.38 mmol) in DMF (1 ml_) is added CDI (60 mg, 0.39 mmol). The mixture is heated for 30 min at 50 °C, then it is cooled to rt and DIPEA (60 mg, 0.47 mmol) and methyl 8-aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (100 mg, 0.32 mmol) are added. The mixture is stirred at rt for 19 h, then water (6 ml_) is added. Resulting suspension is filtered. Solid is washed with water, dried and purified by flash chromatography (petroleum ether/EtOAc, 2:1 ) to give methyl 6-chloro-2-methoxy-8-((3- methoxy-2-phenylpropanamido)methyl)quinoline-3-carboxylate (96 mg, 68%) as white solid. 1H NMR (400 MHz, CDCI3), δ (ppm): 3.35 (s, 3H); 3.65 - 3.75 (m, 2H); 3.94 (s, 3H); 3.96 (s, 3H); 3.95 - 4.05 (m, 1 H); 4.88 (d, 6 Hz, 2H); 6.62 (t, 6 Hz, 1 H); 7.20 - 7.30 (m, 5H); 7.59 (d, 2 Hz, 1 H); 7.66 (d, 2 Hz, 1 H) and 8.49 (s, 1 H). [00544] b) to a solution of methyl 6-chloro-2-methoxy-8-((3-methoxy-2- phenylpropanamido)-methyl)quinoline-3-carboxylate (90 mg, 0.2 mmol) in 4N
HCI/dioxane (5 ml_) is added water (1 ml_). The mixture is stirred at rt for 2 h, then heated at 55 °C for 2.5 h. After cooling to room temperature, the mixture is evaporated to dryness. The crude residue is redissolved in MeOH and evaporated again. The solid obtained is washed with small amount of acetonitrile, then dried in vacuo over P2O5 at 40 °C to give the title product (55 mg, 66%) as a light-yellow solid. 1H NMR (200 MHz, DMSO-de), δ (ppm): 3.62 (s, 3H); 3.34-3.55 (m, 1 H); 3.83-3.97 (m, 2H); 4.43-4.64 (m, 2H); 7.22-7.33 (m, 5H); 7.51 (d, 2.4 Hz, 1 H); 8.09 (d, 2.4 Hz, 1 H); 8.88-8.92 (m, 2H); 12.40 (br s, 1 H). LC-MS: 413, 415 [M-H].
Example 303
6,7-Dichloro-2-oxo-8-((2-(thiazol-5-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.85 (s, 2H); 4.80 (d, 5.6 Hz, 2H); 7.73 (s, 1 H); 8.43 (s, 1 H); 8.93 (s, 1 H); 8.99 (s, 1 H); 9.14 (br s, 1 H); 12.53 (br s, 1 H). LC-MS: 412, 414, 416 [M+H].
Example 304
6-Chloro-8-((2-(3-chlorophenyl)cyclopropanecarboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1 .31 -1 .37 (m, 1 H); 1 .42-1 .47 (m, 1 H); 1 .98-2.07 (m, 1 H); 2.34-2.39 (m, 1 H); 4.54-4.66 (m, 2H); 7.12 (d, 7.2 Hz, 1 H); 7.22-7.24 (m, 2H); 7.27-7.31 (m,1 H); 7.70 (d, 2 Hz,1 H); 8.14 (d, 2 Hz, 1 H); 8.93 (s, 1 H); 8.96 (t, 6 Hz, 1 H); 12.51 (br s, 1 H). LC-MS: 429, 431 , 433 [M-H].
Example 305
6-Chloro-2-oxo-8-((4-oxo-1 ,2,3,4-tetrahydronaphthalene-2-carboxamido)methyl)- 1 ,2-dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 2.74-2.85 (m, 2H); 3.14-3.21 (m, 3H); 4.50-4.61 (m, 2H); 7.31-7.34 (m, 2H); 7.50-7.53 (m, 1H); 7.61 (d, 2 Hz, 1H); 7.83 (d, 7.2 Hz, 1H); 8.12 (d, 2 Hz, 1H); 8.82 (t, 5.6 Hz, 1H); 8.92 (s, 1H); 12.34 (brs, 1H). LC-MS: 423, 425 [M-H].
Example 306
6,7-Dichloro-8-((2-(2,6-difluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.27 (s, 3H); 4.84 (s, 2H); 5.06 (s, 1H); 7.00- 7.20 (m, 2H); 7.40-7.60 (m, 1H); 8.37 (s, 1H); 8.90 (s, 2H); 12.38 (brs, 1H). LC-MS: 471, 473, 475 [M+H].
Example 307
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.25 (s, 3H); 4.81 (d, 6 Hz, 2H); 4.94 (s, 1H); 7.15-7.19 (m, 2H); 7.34-7.38 (m, 2H); 8.36 (s, 1H); 8.88-8.92 (m, 2H); 12.39 (brs, 1H). LC-MS: 453, 455, 457 [M+H].
Example 308
6,7-Dichloro-8-((2-ethoxy-2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.12 (t,7 Hz, 3H); 3.49 (q, 7 Hz, 2H); 4.75-4.85 (m, 2H); 5.02 (s, 1H); 7.14-7.18 (m, 2H); 7.33-7.39 (m, 2H); 8.36 (s, 1H); 8.86 (t, 5.6 Hz, 1H); 8.88 (s, 1H); 12.38 (brs, 1H). LC-MS: 467, 469, 471 [M+H].
Example 309
(S)-6-Chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.11 (d, 6 Hz, 3H); 1.15 (d, 6 Hz, 3H); 3.56- 3.62 (m, 1H); 4.53 (d, 6 Hz, 1H); 4.92 (s, 1H); 7.26-7.30 (m, 3H); 7.32-7.34 (m, 2H); 7.38 (d, 6.8 Hz, 1H); 7.55 (d, 1.2 Hz, 1H); 8.09 (d, 1.2 Hz, 1H); 8.78 (t, 6 Hz, 1H); 8.90 (s, 1H); 12.45 (brs, 1H). LC-MS: 427, 429 [M-H].
Example 310
(R)-6-chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm) 1.11 (d, 6 Hz, 3H); 1.15 (d, 6 Hz, 3H); 3.56-3.62 (m, 1H); 4.53 (d, 6 Hz, 1H); 4.92 (s, 1H); 7.26-7.30 (m, 3H); 7.32-7.34 (m, 2H); 7.38 (d, 6.8 Hz, 1 H); 7.55 (d, 1.2 Hz, 1 H); 8.09 (d, 1.2 Hz, 1 H); 8.78 (t, 6 Hz, 1 H); 8.90 (s, 1 H); 12.45 (brs, 1H). LC-MS: 427, 429 [M-H].
Example 311
6-Chloro-8-((2,5-dimethyl-1 -((1 -methylpyrrolidin-3-yl)methyl)-1 H-pyrrole-3- carboxamido)methyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, CD3OD), δ (ppm): 1.25-1.35 (br s, 1 H); 2.25 (br s, 2H); 2.60 (d, 5.2 Hz, 2H); 2.92 (s, 3H); 2.94 (s, 3H); 3.35 (s, 3H); 3.60-3.75 (m, 6H); 4.01 (brs, 1H); 4.70 (s, 1H); 7.76 (s, 1H); 7.94 (s, 1H); 8.93 (s, 1H). LC-MS: 469, 471 [M-H].
Example 312
6-Chloro-8-((5-ethyl-1 -phenyl-1 H-1 ,2,4-triazole-3-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.22 (t, 7.2 Hz, 3H); 2.80 (q, 7.2 Hz, 2H); 4.70 (d, 4.8 Hz, 2H); 7.60 (s, 5H); 7.77 (s, 1 H); 8.15 (s, 1 H); 8.93 (s, 1 H); 9.42 (br s, 1 H); 12.49 (brs, 1H). LC-MS: 452, 454 [M+H].
Example 313 6,7-Dichloro-2-oxo-8-((2-(thiazol-4-yl)acetamido)methyl)-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 3.73 (s, 2H); 4.76 (s, 2H); 7.46 (s, 1H); 8.39 (s, 1H); 8.88 (s, 1H); 9.00 (s, 1H); 9.13 (brs, 1H); 12.60 (brs, 1H). LC-MS: 412, 414, 416 [M+H].
Example 314
6-Chloro-8-(cyclobutanecarboxamidomethyl)-2-oxo-1,2-dihydroquinoline-3- carboxylic acid
1H NMR (400 MHz, DMSO-d6), δ (ppm): 1.93-1.98 (m, 2H); 2.02-2.19 (m, 4H); 3.06-3.14 (m,1H); 4.52 (d, 6 Hz, 2H); 7.65 (s, 1H); 8.13 (d, 2 Hz, 1H); 8.57 (t, 6 Hz, 1H); 8.92 (s, 1H); 12.60 (brs, 1H). LC-MS: 333, 335 [M-H].
Table 1
Figure imgf000252_0001
Example No. n X1 X2 R1 R2 R3 R4
1 0 CI H H H H H
2 0 CI H H H H C(O)CH2COOH
3 0 CI H H H H C(O)CH2Ph
4 0 CI H H H H ■XX>
Figure imgf000253_0001
Example No. n X1 X2 R1 R2 R3 R4
19 0 CI H H H H
0
20 0 CI H H H H
21 0 CI H H H H
22 0 CI H H H H
23 0 CI H H H H
0
24 0 CI H H H H
25 0 CI H H H H
0
26 0 CI H H H H
0
Ph
27 0 CI H H H H
0
28 0 CI H H H H
0
29 0 CI H H H H
0
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Example No. n X1 X2 R1 R2 R3 R4
OMe
246 0 CI H H H H
0
OMe
247 0 CI H H H H
0
OCH2Ph
248 0 CI H H H H <ΊΤ Ph
0
249 0 CI H H H H
F
250 0 CI H H H H
251 0 CI H H H H
O 0
F
252 0 CI H H H H
F
253 0 CI H H H H
OMe
254 0 CI H Me H H
0
F
255 0 CI H Me H H
OMe F
256 0 CI H Me H H
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Table 2
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Table 3
Figure imgf000280_0002
Figure imgf000280_0003
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS [00545] With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be
therapeutically applied by the oral, rectal, parenteral, and additional routes.
Representative pharmaceutical compositions follow.
(a) Tablets suitable for oral administration, which contain the active ingredient, may be prepared by conventional tabletting techniques.
(b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a
polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature.
(c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility.
[00546] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
FORMULATION EXAMPLES
[00547] The following examples are again given by way of illustration only and are not to be construed as limiting.
EXAMPLE 1
Tablet Formulation
A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows:
Mg
Active Ingredient 10
Lactose 61
Microcrystalline Cellulose 25 Talcum
Magnesium stearate
Colloidal silicon dioxide
EXAMPLE 2
Tablet Formulation
Another suitable formulation for a tablet containing 100 mg is as follows:
mg
Active Ingredient 100
Polyvinylpyrrolidone, crosslinked 10
Potato starch 20
Polyvinylpyrrolidone 19
Magnesium stearate 1
Microcrystalline Cellulose 50
Film coated and colored.
The film coating material consists of:
Hypromellose 10
Microcryst. Cellulose 5
Talcum 5
Polyethylene glycol 2
Color pigments 5
EXAMPLE 3
Capsule Formulation
A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
Mg
Active Ingredient 50
Corn starch 26
Dibasic calcium phosphate 50
Talcum 2 Colloidal silicon dioxide filled in a gelatin capsule.
EXAMPLE 4
Solution for injection
A suitable formulation for an injectable solution is as follows
Active Ingredient
Sodium chloride
Water for Injection
EXAMPLE 5
Liquid oral formulation
A suitable formulation for 1 liter of an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
Mg
Active Ingredient 2
Saccharose 250
Glucose 300
Sorbitol 150
Orange flavor 10
Colorant q.s.
Purified water Add 1000 mL
EXAMPLE 6
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
G Active Ingredient 20.00
Tragacanth 7.00
Glycerol 50.00
Saccharose 400.00
Methylparaben 0.50
Propylparaben 0.05
Black currant-flavor 10.00
Soluble Red color 0.02
Purified water Add 1000 ml_
EXAMPLE 7
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
G
Active Ingredient 2
Saccharose 400
Bitter orange peel tincture 20
Sweet orange peel tincture 15
Purified water Add 1000 mL
EXAMPLE 8
Aerosol formulation
180 g aerosol solution contain:
G
Active Ingredient 10
Oleic acid 5
Ethanol 81
Purified Water 9 Tetrafluoroethane
15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.
EXAMPLE 9
TDS formulation
100 g solution contain:
Active Ingredient 10.0
Ethanol 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0
Hydroxyethylcellulose 0.4
Purified water 19.6
1 .8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use.
EXAMPLE 10
Nanoparticle formulation
10 g of polybutylcyanoacrylate nanoparticles contain:
G
Active Ingredient 1 .00
Poloxamer 0.10
Butylcyanoacrylate 8.75
Mannitol 0.10
Sodium chloride 0.05 Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
PHARMACOLOGY
[00548] The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics:
METHODS
BINDING ASSAYS FOR THE CHARACTERIZATION OF GLYCINE B ANTAGONIST PROPERTIES
[3H]MDL-105,519 Displacement Studies
[00549] For the evaluation of the binding affinity of the test compounds on the glycine binding pocket of the NMDA receptor, [3H]-MDL-105,519 (Perkin Elmer ,
Rodgau, Germany) displacement studies are performed using a 384-well plate robotic platform (Tecan Deutschland GmbH, Crailsheim, Germany). MDL-105,519 (Baron et al., J Pharmacol Exp Ther 1996, 279(1 ), 62-68; Baron et al., European Journal of
Pharmacology, 1997, 323(2-3), 181 -192; Hoffner & Wanner, Neuroscience Letters, 1997, 226(2), 79-82) is a selective, high affinity antagonist at the NMDA receptor glycine site.
Preparation of cortical membranes:
[00550] Tissue preparation is performed according to Foster & Wong (Br J
Pharmacol, 1987, 91 , 403-409) with some modifications. Anaesthetised male Sprague- Dawley rats (200-250 g, Janvier, Le Genest-lsle, France) are decapitated and their brains removed rapidly. The cortex is dissected out and processed as described by Parsons, et al. (J Pharmacol Exp Ther, 1997, 283(3), 1264-1275). For isolation of the cell membranes, the cortices are homogenized in 20 volumes of ice-cold 0.32 M sucrose (Sigma-Aldrich, Taufkirchen, Germany) using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000 x g for 10 minutes, the pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes. The resulting pellet is re- suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000 x g. The supernatant and the buffy coat are then centrifuged six times (48,000 x g for 20 minutes) in the presence of 5 mM Tris-HCI, pH 7.5. All centrifugation steps are carried out at 4°C. After resuspension in 5 volumes of 5 mM Tris-HCI, pH 7.5, the membrane suspension is frozen rapidly at -80°C. On the day of assay, the membranes are thawed, centrifuged (48,000 x g for 20 minutes) and then resuspended in 50 mM Tris-HCI, pH 7.5 (assay buffer). The amount of protein in the final membrane preparation is
determined according to the method of Lowry, et al. (J. Biological Chemistry, 1951 , 193, 256-275) with some modifications (Hartree, Analytical Biochemistry, 1972, 48, 422-427). The final protein concentration used for our studies is 200 g / ml.
Displacement studies
[00551 ] A robotic system designed for 384-well format displacement studies (Tecan Deutschland GmbH) is loaded with the membrane solution, test compounds, bound control (DMSO 100 %), unlabeled glycine (1 mM, Sigma-Aldrich) for evaluation of non-specific binding and radioligand.
[00552] Before performing displacement studies, saturation experiments are performed to determine the equilibrium dissociation constant (Kd) of [3H]-MDL-105,519, which is a parameter for the affinity of the radioligand to the binding site. The
protein/receptor concentration is held constant whereas the amount of specific bound radioligand is determined using increasing concentrations of ligand.
[00553] On the basis of the saturation experiments, a final [3H]-MDL-105,519 concentration of 3 nM is selected. The Multiscreen HTS glass fibre (type B) filter 384- well assay plates (Millipore, Schwalbach, Germany) are loaded in the following order with 55 μΙ buffer (50 mM Tris-HCI, pH 7.5), 10 μΙ radioligand, 10 μΙ test compound, bound or non-specific and finally with 25 μΙ membrane solution. Compounds are tested as dose response curves (7 concentrations, n = 4, 9 compounds per plate). The final DMSO concentration is 1 %. After mixing, the reaction mix is shaken for 1 h at 4°C. The solution is then exhausted as rapidly as possible via a vacuum manifold under a constant vacuum of 450 mbar. The membranes are washed four times with cold assay buffer (100 μΙ_). 10 μί of Ultima Gold scintillation cocktail (PerkinElmer) is added to dried filter plates (1 h at 50 °C and at least 5 h at RT) and incubated at room
temperature for at least 2.5 h before counting the disintegration per minutes using a liquid scintillation counter (MicroBeta, PerkinElmer).
Analysis of data
[00554] For the evaluation of the binding affinity of the test compound to the glycine B binding site and its potency to displace [3H]-MDL-105,519, the measured radioactivity of the radioligand alone is set as 100 % bound control and the non-specific binding of the radioligand (which could not be displaced by glycine, 1 mM) represented the 0 % control. The residual radioactivity after displacement of the test compound is then corrected with respect to the set controls. Data processing and analysis is done with the help of Pipeline Pilot software (Accelrys, Cambridge, U.K.) for IC50 and Ki-value determination.
FUNCTIONAL SCREENING FOR THE CHARACTERIZATION OF GLYCINE B ANTAGONIST PROPERTIES
[00555] Antagonistic potencies of the test compounds in central and peripheral nerve cell preparations are functionally evaluated using electrophysiological whole cell patch-clamp recordings and/or fluorometric intracellular Ca2+-imaging by means of a Functional Drug Screening System (FDSS 7000, Hamamatsu, Herrsching, Germany).
Whole cell patch-clamp recordings
Preparation and cultivation of rat hippocampal neurons
[00556] Cell preparation is performed as described by Parsons, et al.
(Neuropharmacology, 1998, 37(6), 719-727). The anaesthetised female Sprague- Dawley rat (Charles River, Sulzfeld, Germany) is sacrificed by cervical dislocation. After opening the abdominal cavity, embryos (E20) are removed and stored in ice cold Ca2+- and Mg -free Hank's Buffered Salt Solution (pH 7.3), containing 4 g/l glucose (HBSS- CMF, Invitrogen, Darmstadt, Germany). Hippocampi are then isolated from the brains of at least 8 embryos after decapitation, transferred into ice cold HBSS-CMF and washed 3 to 4 times.
[00557] Hippocampi are pre-incubated for 8 min with a 0.66% trypsin (Sigma- Aldrich) and 0.1 % (20 U/ml) DNAase solution (Sigma-Aldrich) in Ca2+-free Phosphate Buffered Saline (PBS-CF, Biochrom, Berlin, Germany) and washed 3 times with HBSS- CMF. Cells are then mechanically dissociated by trituration in a PBS-CF solution containing 0.05% (10 U/ml) DNAase and 0.3% of the trypsin inhibitor ovomucoid (all from Sigma-Aldrich). The cells are then centrifuged at 180 x g for 10 minutes, and the cell pellet re-suspended in basal Minimum essential medium (MEM, Invitrogen), again carefully triturated to ensure maximal dissociation and finally plated in the flexiPERM inserts (Thermo Fisher Scientific, Langenselbold, Germany) at a density of 15 x 103 cells/cm2 (0.5 ml/insert) onto poly-DL-ornithine (Sigma) and mouse laminin (Invitrogen) pre-coated plastic petri dishes. After 1 hour the cells become attached to the bottom of the dish and the inserts may be removed. The cells are then nourished with 2 ml MEM supplemented with 5% foetal calf serum (FCS) and 5% horse serum (all from Biochrom) and incubated at 37°C with 95% air and 5% CO2 at 95% humidity. After 4 days in vitro (DIV) further glial mitosis is inhibited by adding 10 μΙ of AraC (5 μΜ endconcentration, Sigma-Aldrich). The medium is completely exchanged after an additional 2 DIV and again, but only partly (50 %), after 8 DIV. The cells are used for electrophysiological recordings after 1 1 -15 DIV.
Preparation and cultivation of rat dorsal root ganglia neurons
[00558] For the peripheral glycine B site antagonistic potency evaluation, compounds are functionally tested using dorsal root ganglia (DRG) neurons from 3 - 5 week old male rats, modified from Li et al. (Pain, 2004, 109, 443-452).
[00559] Sprague-Dawley rats (Janvier) are anaesthetised by placing in a CO2- euthanasia chamber and sacrificed by decapitation. The vertebral column is isolated and collected in ice cold Ca2+- and Mg2+-free Phosphate Buffered Saline. After opening the vertebral column, the spinal cord is removed and the dorsal root ganglia are harvested bilaterally from the thoracic to lumbosacral regions. They are collected in ice- cold HBSS-CMF in a 12-well plate, transferred to 35 mm dishes with fresh ice-cold HBSS-CMF and cleared from contaminating connective tissue and the dura mater spinalis. For further washing, purified ganglia are placed back in a 12 well plate containing fresh ice cold HBSS-CMF. After cutting the ganglia with small scissors, the ganglia digest is performed in 6-well plates by adding Liberase TM (Roche Diagnostics, Mannheim, Germany) dissolved in HBSS-CMF and incubating at RT and 37°C in an incubator for approximately 10 minutes, followed by a mechanical dissociation step performed with two canulaes. Enzymatic digestion is terminated by centrifugation at 180 g for 5 minutes and rinsing the cells with Neurobasal A medium (Invitrogen) without supplements but containing 10% FCS and 0.1 mg/ml DNase I (Sigma-Aldrich). After another centrifugation step at 180 g for 5 minutes, the cells are suspended in
Neurobasal A medium containing 2% B-27 supplement, GlutaMax (0.5 mM, both from Invitrogen), and D-AP5 (100 μΜ, Sigma-Aldrich), and then mechanically dissociated by trituration. The cell suspension is plated onto 35-mm culture dishes coated with poly- DL-ornithine (Sigma-Aldrich) and mouse laminin from Invitrogen containing flexiPERM inserts.
[00560] Two hours after seeding, when the cells had settled, the inserts are removed. After an overnight incubation a 75% medium exchange is performed. The cultures are maintained at 37°C in a humidified atmosphere of 95% air and 5% CO2.
[00561 ] DRG neurons are used for electrophysiological recordings 48 hours after cell preparation.
Whole cell patch-clamp recordings
[00562] Cells are visualised using an inverted microscope and selected for patching based upon their position and morphology. Voltage clamp recordings are made in the whole cell configuration of the patch clamp technique at a holding potential of -70 mV with the aid of an EPC-10 amplifier (Heka Elektronik, Lambrecht, Germany) in combination with pipette manipulator. Patch clamp pipettes are pulled from borosilicate glass using a horizontal puller (P-97 Puller, Sutter Instruments, USA) and, when filled with intracellular solution, have resistances of 1 - 4 ΜΩ.
[00563] Solutions are delivered via a home-made gravity driven very fast perfusion system (< 10 ms) including valves to switch flow on and off in combination with a stepper motor-driven double-barrelled theta glass application pipette in order to expose cells to either agonist-free or agonist-containing solutions in presence or absence of antagonist.
[00564] The intracellular solution used consists of: 120 mM CsCI, 10 mM EGTA, 1 mM MgC , 200 μΜ CaC^, 10 mM glucose and 22 mM tetraethyl ammonium chloride (TEA-CI). The corresponding extracellular bath solution contains: 140 mM NaCI, 3 mM KCI, 10 mM glucose, 10 mM HEPES, 1 .5 mM CaCI2 and 4.5 mM sucrose (all from Sigma-Aldrich) pH 7.3, and is supplemented with 0.3 μΜ tetrodotoxin (TTX, Tocris, Bristol, U.K.) to block voltage-activated sodium channels and 0.25 μΜ bicuculline (Sigma-Aldrich) to block GABAA receptors.
[00565] For the determination of concentration-dependency of blockade, 5 control traces are recorded with application of NMDA (200 μΜ) and D-Serine (1 μΜ) or Glycine (10 μΜ, all from Sigma-Aldrich) in case of DRG neurons for 5 seconds in order to reduce the effect of rundown, then the highest concentration of the test-substance is applied for 1 minute before applying the agonists for 5 seconds in the presence of antagonist. Three recordings are made in the presence of the antagonist and 3 recovery traces are recorded after it's removal. The procedure is repeated for three to four further concentrations of antagonist with declining concentrations e.g. 10, 3, 1 , 0.3, and 0.1 μΜ. For the final recovery, agonists are again applied five times after wash-out of the test substance.
[00566] Alternatively cumulative compound application protocols could be used, in which the agonists are applied, then 5 concentrations of antagonist are sequentially coapplied before the antagonist is removed and the current is allowed to recover. The cumulative protocol enables a fast determination of the concentration-dependency of blockade - i.e. cells do not have to remain stable for long recording durations.
Analysis of data
[00567] Data are analysed using TIDA 5.0 (Heka Elektronik). With the help of Microsoft Excel, data are pooled and finally GraFit software (Erithacus Software Ltd., Surrey, U.K.) is used to fit the data e.g. with the four parameter logistic equation for determining IC5o values. For normalization of the calculated IC5o values of the tested glycine B antagonists, depending on the agonist affinity (EC50) in the test system, the equilibrium dissociation constant (Kb) is determined according to the Cheng & Prusoff (Biochemical Pharmacology, 1973, 22, 3099-108) equation. Alternatively, Pipeline Pilot protocols are implemented for data processing and analysis. For all data points, the value given is the mean ± S.E.M. (standard error of the mean) of results from at least 4 individual cells per concentration.
Calcium FDSS 7000 studies
Preparation and cultivation of rat cortical neurons
[00568] Primary neurons are prepared from cortices of embryonal rats at day 17 of pregnancy as described by Dichter (Brain Res., 1987, 149, 279). Sprague-Dawley rat embryos (E 17, Charles River) are decapitated and neocortices are dissected, trypsinized and carefully triturated. The cell suspension is plated on poly-d-lysine pre- coated 384-well Plates (Aurora Biotechnologies, Carlsbad, USA) at a cell density of 15.000 cells /well. The neurons are cultivated in Neurobasal media containing B27- Supplement (Invitrogen) and 0.5 μΜ L-Glutamine (Biochrom) at 37°C in a humidified atmosphere of 5% CO2 / 95% air. Medium is exchanged completely at day 4 and to 50% on day 7. At the time of experiments neurons are 1 1 - 13 days in vitro.
Calcium FDSS 7000 studies
[00569] The increase of intracellular calcium after stimulation with 12 μΜ NMDA (EC80) is measured using the Functional Drug Screening System (FDSS 7000,
Hamamatsu) and the Calcium-4-Kit (Molecular Devices, Ismaning, Germany) in 384- well format. No D-Serine is added, since the endogenous co-agonist concentrations are sufficient. Test compound dilution series (6 different concentrations, n = 4, 9 compounds per plate) are performed on a Tecan pipette robot. Prior to addition of agonist or antagonist the medium is aspirated before loading with 45 μΙ_ of loading buffer (1 h at room temperature), consisting of Ca-4 sensitive dye reconstituted in extracellular patch-clamp bath solution, pH 7.3. Subsequently, 384-plates are transferred to FDSS 7000 to detect increases in intracellular calcium after the addition of agonist, measured as relative fluorescence units (RFU). Antagonists are pre- incubated with the cells for 10 min at room temperature before the addition of the agonist.
Data analysis
[00570] The fluorescence signal increase after addition of agonist reflects the increase of intracellular calcium. For the evaluation of the antagonistic potency, the calcium changes in response to different concentrations of antagonist are determined using an area under the curve (AUC) calculation. All responses (RFU-values) are determined as percentage of control at agonist EC80 (12 μΜ NMDA). For data processing and IC50 value calculations Pipeline Pilot is used. Due to high intrinisic glycine site co-agonist concentrations within the assay system, resulting in a full activation of the receptor, Kb calculations are not possible since EC5o's for D-serine could not be determined.
[00571 ] Results for respresentative compounds of the invention are shown in Tables 4-7.
Table 4 - [3H]-MDL-105,519 Displacement Studies
Compound Chemical Name Ki [μΜ]
6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-acetyl)-
Example 18 amino]-methyl}-1 ,2 dihydroquinoline-3-carboxylic 0.451 acid 6-Chloro-8-[(3-fluoro-benzoylamino)-methyl]-2-
Example 30 0.709 oxo-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-
Example 43 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.086 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[(thiazole-2-carbonyl)-amino]-
Example 45 0.299 methyl}-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-chloro-6-fluoro-phenyl)-
Example 52 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.134 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(2-trifluoromethyl-phenyl)-
Example 54 acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 0.315 carboxylic acid
6-Chloro-2-oxo-8-(1 -oxo-1 ,3-dihydro-isoindol-2-
Example 57 3.38 ylmethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[(2-methyl-thiazole-4-carbonyl)-
Example 59 amino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- 0.498 carboxylic acid
6-Chloro-2-oxo-8-{[(oxazole-4-carbonyl)-amino]-
Example 61 1 .019 methyl}-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-methyl-thiazol-4-yl)-
Example 73 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 1 .031 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-[(2-thiazol-5-yl-acetylamino)-
Example 81 0.693 methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid
8-{[2-(4-Amino-phenyl)-acetylamino]-methyl}-6-
Example 82 chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic 0.363 acid
8-{[(Adamantane-1 -carbonyl)-amino]-methyl}-6-
Example 83 chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic 0.986 acid 6-Chloro-8-{[2-(2-dimethylamino-phenyl)-
Example 88 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.856 quinoline-3-carboxylic acid
6-Chloro-8-{[2-(3-imidazol-1 -yl-phenyl)-
Example 91 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 1 .073 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-[(2-thiazol-4-yl-acetylamino)-
Example 97 0.436 methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chlorc-2-oxo-8-[((S)-2-phenyl-
Example 98 propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- 0.534 carboxylic acid
6-Chloro-2-oxo-8-{[2-(2,4,6-trifluoro-phenyl)-
Example 100 acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 0.221 carboxylic acid
6,7-Dichloro-8-{[2-(2,6-difluoro-phenyl)-
Example 103 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.017 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-[(2-oxo-2-phenyl-acetylamino)-
Example 104 0.768 methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(2,3,6-trifluoro-phenyl)-
Example 106 acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 0.146 carboxylic acid
6,7-Dichloro-8-{[2-(2-fluoro-phenyl)-
Example 108 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.009 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(3-tetrazol-1 -yl-phenyl)-
Example 1 14 acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 0.535 carboxylic acid
8-[((S)-2-Amino-2-phenyl-acetylamino)-methyl]-
Example 1 15 6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- 2.239 carboxylic acid 6,7-Dichloro-8-{[2-(2-chloro-6-fluoro-phenyl)-
Example 121 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.018 quinoline-3-carboxylic acid
6-Chloro-8-({[1 -(2-fluoro-phenyl)-
Example 124 cyclopropanecarbonyl]-amino}-methyl)-2-oxo- 0.236
1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-[(2-methoxy-2-phenyl-acetylamino)-
Example 126 methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic 0.207 acid
6-Chloro-8-((4-(1 -hydroxycyclohexyl)-1 H-1 ,2,3-
Example 129 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 1 .744 carboxylic acid
8-[((R)-2-Amino-2-phenyl-acetylamino)-methyl]-
Example 143 6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- 1 .529 carboxylic acid
6,7-Dichloro-2-oxo-8-[(2-pyridin-3-yl-
Example 150 acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- 0.039 carboxylic acid
8-[3-(4-Bromo-phenyl)-ureidomethyl]-6,7-
Example 154 dichloro-2-oxo-1 ,2-dihydro-quinoline-3- 0.327 carboxylic acid
8-Aminomethyl-6,7-dichloro-2-oxo-1 ,2-
Example 156 0.081 dihydroquinoline-3-carboxylic acid
6-Bromo-2-oxo-8-(phenylacetylamino-methyl)-
Example 158 0.249
1 ,2-dihydroquinoline-3-carboxylic acid
8-((1 H-1 ,2,3-triazol-1 -yl)methyl)-6,7-dichloro-2-
Example 159 0.391 oxo-1 ,2-dihydro-quinoline-3-carboxylic acid
8-((4-benzyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-
Example 160 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.421 acid 6-chloro-8-((4-(3-hydroxyphenyl)-1 H-1 ,2,3-
Example 161 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 1 .210 carboxylic acid
6-chloro-2-oxo-8-((4-phenyl-1 H-1 ,2,3-triazol-1 -
Example 162 1 .463 yl)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid
(R)-6-chloro-8-((4-(hydroxy(phenyl)methyl)-1 H-
Example 163 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 0.422 dihydroquinoline-3-carboxylic acid
(8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-
Example 164 0.396 dihydroquinoline-3-carboxylic acid
(S)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-
Example 165 0.382 dihydroquinoline-3-carboxylic acid
(6-chloro-2-oxo-8-((4-(pyridin-2-yl)-1 H-1 ,2,3-
Example 166 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 1 .660 carboxylic acid
6-chloro-2-oxo-8-((4-(2-(piperazin-1 -yl)ethyl)-1 H-
Example 167 1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 1 .437 carboxylic acid
6-chloro-8-((4-(4-methoxyphenyl)-1 H-1 ,2,3-
Example 168 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 0.909 carboxylic acid
6-chloro-2-oxo-8-((4-(m-tolyl)-1 H-1 ,2,3-triazol-1 -
Example 169 1 .533 yl)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((4-isobutyl-1 H-1 ,2,3-triazol-1 -
Example 170 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 0.924 carboxylic acid
6-chloro-8-((4-(1 -methyl-1 H-imidazol-5-yl)-1 H-
Example 171 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 1 .806 dihydroquinoline-3-carboxylic acid 6-chloro-2-oxo-8-((4-(pyridin-4-yl)-1 H-1 ,2,3-
Example 172 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 1 .079 carboxylic acid
6-chloro-2-oxo-8-((4-(pyridin-3-yl)-1 H-1 ,2,3-
Example 173 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 1 .275 carboxylic acid
6-chloro-8-((4-(2-methoxyphenyl)-1 H-1 ,2,3-
Example 174 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 0.484 carboxylic acid
6-chloro-2-oxo-8-((4-(p-tolyl)-1 H-1 ,2,3-triazol-1 -
Example 175 1 .465 yl)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid
8-((4-(tert-butyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-
Example 176 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.560 acid
6-chloro-8-((4-cyclopropyl-1 H-1 ,2,3-triazol-1 -
Example 177 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 0.854 carboxylic acid
6-chloro-8-((4-(3-fluorophenyl)-1 H-1 ,2,3-triazol-
Example 178 1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 1 .953 carboxylic acid
6-chloro-8-((4-(3-methoxyphenyl)-1 H-1 ,2,3-
Example 179 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 1 .666 carboxylic acid
6-chloro-2-oxo-8-((1 ,2,3,4-
Example 180 tetrahydroisoquinoline-1 -carboxamido)methyl)- 1 .777
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((4-(2-fluorobenzyl)-1 H-1 ,2,3-triazol-
Example 181 1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 0.334 carboxylic acid 6-chloro-8-((4-(2,6-difluorobenzyl)-1 H-1 ,2,3-
Example 182 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 0.199 carboxylic acid
6-chloro-8-((4-(2-chloro-6-fluorobenzyl)-1 H-
Example 183 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 0.104 dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-
Example 184 0.098 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2,6-
Example 185 difluorophenyl)ureido)methyl)-2-oxo-1 ,2- 0.025 dihydroquinoline-3-carboxylic acid
8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2-
Example 186 0.898 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((1 -(pyridin-3-
Example 187 yl)cyclopropanecarboxamido)-methyl)-1 ,2- 1 .030 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((3-(pyridin-2-yl)ureido)methyl)-
Example 188 0.595
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-
Example 189 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 0.636 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((4-(pyridin-2-ylmethyl)-1 H-
Example 190 1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 0.619 carboxylic acid
6-chloro-2-oxo-8-((3-(pyridin-3-yl)ureido)methyl)-
Example 191 0.606
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((1 -(pyridin-2-
Example 192 yl)cyclopropanecarboxamido)-methyl)-1 ,2- 1 .006 dihydroquinoline-3-carboxylic acid 6-chloro-8-((3-(2-chloro-6-
Example 193 fluorophenyl)ureido)methyl)-2-oxo-1 ,2- 0.050 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((4-(thiazol-2-yl)-1 H-1 ,2,3-
Example 194 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 1 .392 carboxylic acid
6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-
Example 195 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 0.657 dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2,6-
Example 196 difluorobenzyl)ureido)methyl)-2-oxo-1 ,2- 0.102 dihydroquinoline-3-carboxylic acid
6,7-dichloro-8-((3-methyl-1 H-1 ,2,4-triazol-1 -
Example 197 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 5.662 carboxylic acid
6,7-dichloro-8-(((2-chloro-6-
Example 198 fluorobenzyl)amino)methyl)-2-oxo-1 ,2- 3.600 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((3-(pyridin-2-ylmethyl)-1 H-
Example 199 pyrazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 6.923 carboxylic acid
6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol-1 -
Example 200 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 4.692 carboxylic acid
6-chloro-8-((5-(2-fluorobenzyl)-1 H-pyrazol-1 -
Example 201 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 7.476 carboxylic acid
6-chloro-8-((3-(2,6-difluorobenzyl)-1 H-pyrazol-1 -
Example 202 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 5.243 carboxylic acid 6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-
Example 203 5-yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 2.606 carboxylic acid
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-
Example 204 oxadiazol-2-yl)methyl)-2-oxo-1 ,2- 3.844 dihydroquinoline-3-carboxylic acid
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-
Example 205 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 7.477 dihydroquinoline-3-carboxylic acid
(R)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-
Example 206 3.629 dihydroquinoline-3-carboxylic acid
8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-oxo-
Example 207 9.217
1 ,2-dihydroquinoline-3-carboxylic acid
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-
Example 208 5.961
2-OXO-1 ,2-dihydroquinoline-3-carboxylic acid
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-
Example 209 2.520
2-OXO-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -
Example 212 yl)acetamido)methyl)-2-oxo-1 ,2- 0.074 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-
Example 213 2-phenylpropanamido)methyl)-1 ,2- 0.958 dihydroquinoline-3-carboxylic acid
(S)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-
Example 214 2-phenylpropanamido)methyl)-1 ,2- 1 .326 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((pyrazine-2-
Example 215 carboxamido)methyl)-1 ,2-dihydroquinoline-3- 0.654 carboxylic acid 6,7-Dichloro-2-oxo-8-((thiazole-4-
Example 216 carboxamido)methyl)-1 ,2-dihydroquinoline-3- 0.253 carboxylic acid
8-((2-(1 H-tetrazol-1 -yl)acetamido)methyl)-6,7-
Example 217 dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.870 acid.
8-((2-(4-Acetylpiperazin-1 -yl)-2-(2-
Example 218 fluorophenyl)acetamido)methyl)-6-chloro-2-oxo- 0.822
1 ,2-dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-methylthiazole-4-
Example 219 carboxamido)methyl)-2 -oxo-1 ,2- 0.108 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((thiazole-2-
Example 220 carboxamido)methyl)-1 ,2-dihydroquinoline-3- 0.339 carboxylic acid
8-((2-(3-(1 H-pyrazol-1 -
Example 221 yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- 0.622 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-hydroxy-2-
Example 222 phenylacetamido)methyl)-2-oxo-1 ,2- 0.250 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((N-methyl-2-
Example 223 phenylacetamido)methyl)-2-oxo-1 ,2- 1 .271 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(3-chloropyridin-2-
Example 224 yl)acetamido)methyl)-2-oxo-1 ,2- 0.305 dihydroquinoline-3-carboxylic acid
8-((2-(4-(1 H-imidazol-1 -
Example 225 yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- 0.959 dihydroquinoline-3-carboxylic acid 8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6-
Example 226 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.884 acid
6-Chloro-8-((2-ethoxy-2-
Example 227 phenylacetamido)methyl)-2-oxo-1 ,2- 0.070 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-isopropoxy-2-
Example 228 phenylacetamido)methyl)-2-oxo-1 ,2- 0.067 dihydroquinoline-3-carboxylic acid
6-Chloro-8-(cyclopropanecarboxamidomethyl)-2-
Example 229 0.626 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-(thiazol-2-
Example 230 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 0.415 carboxylic acid
8-((2-(2H-tetrazol-2-yl)acetamido)methyl)-6,7-
Example 231 dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.140 acid
6-Chloro-8-((2-(2-fluorophenyl)-2-
Example 232 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.144 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 233 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.159 dihydroquinoline-3-carboxylic acid
6-Bromo-8-((2-(2,6-
Example 234 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.102 dihydroquinoline-3-carboxylic acid
6-Bromo-8-((2-(2-chloro-6-
Example 235 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.121 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-(2,6-difluorophenyl)-2-
Example 236 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.286 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((trans-2-
Example 237 phenylcyclopropanecarboxamido)methyl)-1 ,2- 0.639 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1 -
Example 238 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 1 .696 carboxylic acid
6,7-Dichloro-2-oxo-8-((2-(pyrimidin-2-
Example 239 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 0.094 carboxylic acid
6-Chloro-7-fluoro-8-((2-(2-
Example 240 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.044 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,6-
Example 241 difluorophenyl)acetamido)methyl)-7-fluoro-2- 0.035 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-7-fluoro-8-((2-methoxy-2-
Example 242 phenylacetamido)methyl)-2-oxo-1 ,2- 0.047 dihydroquinoline-3-carboxylic acid
7-Bromo-6-chloro-8-((2-methoxy-2-
Example 243 phenylacetamido)methyl)-2-oxo-1 ,2- 0.020 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,4-
Example 244 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.234 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-phenyl-2-
Example 245 propoxyacetamido)methyl)-1 ,2-dihydroquinoline- 0.104
3-carboxylic acid (S)-6-Chloro-8-((2-methoxy-2-
Example 246 phenylacetamido)methyl)-2-oxo-1 ,2- 0.570 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-8-((2-methoxy-2-
Example 247 phenylacetamido)methyl)-2-oxo-1 ,2- 0.122 dihydroquinoline-3-carboxylic acid
8-[(2-Benzyloxy-2-phenyl-acetylamino)-methyl]-
Example 248 6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- 1 .740 carboxylic acid
8-((2-Butoxy-2-phenylacetamido)methyl)-6-
Example 249 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.580 acid
6-Chloro-8-((2-(3-fluoropyridin-2-
Example 250 yl)acetamido)methyl)-2-oxo-1 ,2- 0.325 dihydroquinoline-3-carboxylic acid
8-((3-(Benzylamino)-3-oxopropanamido)methyl)-
Example 251 6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.291 acid
6-Chloro-2-oxo-8-((2-(2,3,5-
Example 252 trifluorophenyl)acetamido)methyl)-1 ,2- 0.229 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(naphthalen-2-
Example 253 yl)acetamido)methyl)-2-oxo-1 ,2- 0.436 dihydroquinoline-3-carboxylic acid
6-Chloro-8-(1 -(2-methoxy-2-
Example 254 phenylacetamido)ethyl)-2-oxo-1 ,2- 0.685 dihydroquinoline-3-carboxylic acid
6-chloro-8-(1 -(2-(2,6-
Example 255 difluorophenyl)acetamido)ethyl)-2-oxo-1 ,2- 0.536 dihydroquinoline-3-carboxylic acid 6-Chloro-8-(1 -(2-(2-fluorophenyl)-2-
Example 256 methoxyacetamido)ethyl)-2-oxo-1 ,2- 0.392 dihydroquinoline-3-carboxylic acid
6-Chloro-8-(1 -(2-ethoxy-2-
Example 257 phenylacetamido)ethyl)-2-oxo-1 ,2- 0.195 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(4-ethoxy-2,6-
Example 258 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.156 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-morpholino-2-
Example 259 phenylacetamido)methyl)-2-oxo-1 ,2- 3.579 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-
Example 260 ethoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 1 .472 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,6-difluoro-3-
Example 261 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 0.095 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((isochroman-1 -
Example 262 carboxamido)methyl)-2 -oxo-1 ,2- 0.528 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(3-ethoxy-2,4-
Example 263 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.524 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-methoxy-2-
Example 264 phenylacetamido)methyl)-2-oxo-1 ,2- 0.025 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-ethoxy-2-
Example 265 phenylacetamido)methyl)-2-oxo-1 ,2- 0.01 1 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-(2,3-difluoro-6-
Example 266 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 0.109 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-ethoxy-2-(2-
Example 267 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.054 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(4-methoxypiperidin-1 -yl)-2-
Example 268 phenylacetamido)methyl)-2-oxo-1 ,2- 5.679 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluoro-6-
Example 269 (trifluoromethyl)phenyl)acetamido)methyl)-2-oxo- 0.121
1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-(3-oxo-3-
Example 270 (phenylamino)propyl)-1 ,2-dihydroquinoline-3- 0.926 carboxylic acid
6-Chloro-8-((1 -(3-chloropyridin-2-yl)-1 H-pyrrole-
Example 271 2-carboxamido)methyl)-2-oxo-1 ,2- 0.154 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((6-chloroimidazo[1 ,2-b]pyridazine-2-
Example 272 carboxamido)methyl)-2 -oxo-1 ,2- 0.533 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((5-(3-chlorophenyl)oxazole-4-
Example 273 carboxamido)methyl)-2 -oxo-1 ,2- 0.923 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(4-
Example 274 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.357 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((imidazo[1 ,2-a]pyridine-3-
Example 275 carboxamido)methyl)-2 -oxo-1 ,2- 0.877 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-(3-
Example 276 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.295 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluoro-5-
Example 277 methylphenyl)acetamido)methyl)-2-oxo-1 ,2- 0.199 dihydroquinoline-3-carboxylic acid
(R)-6-chloro-2-oxo-8-((1 ,2,3,4-
Example 278 tetrahydroisoquinoline-3-carboxamido)methyl)- 1 .540
1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-(piperazin-1 -yl)-2-(p-
Example 279 tolyl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 0.688 carboxylic acid
6-Chloro-8-((3-(4-methylpiperazin-1 -yl)-2-
Example 280 phenylpropanamido)methyl)-2-oxo-1 ,2- 2.278 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((1 ,2,3,4-
Example 281 tetrahydronaphthalene-1 -carboxamido)methyl)- 0.272
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((2-(2-fluoro-5-
Example 282 (trifluoromethoxy)phenyl)acetamido)methyl)-2- 0.641 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
8-((2-(5-Bromopyridin-3-yl)acetamido)methyl)-6-
Example 283 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.330 acid
6-Chloro-8-((2-(2-fluoro-6-
Example 284 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 0.099 dihydroquinoline-3-carboxylic acid
8-((2-(1 H-1 ,2,3-triazol-1 -yl)acetamido)methyl)-
Example 285 6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- 0.763 carboxylic acid 8-((2-(2H-1 ,2,3-triazol-2-yl)acetamido)methyl)-
Example 286 6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- 0.094 carboxylic acid
6,7-Dichloro-8-((2-(2-chlorophenyl)-2-
Example 287 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.010 dihydroquinoline-3-carboxylic acid
8-((2-(2-(1 H-tetrazol-1 -
Example 288 yl)phenyl)acetamido)methyl)-6,7-dichloro-2-oxo- 0.1 14
1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(1 -methyl-1 H-imidazol-4-
Example 289 yl)acetamido)methyl)-2-oxo-1 ,2- 0.481 dihydroquinoline-3-carboxylic acid
8-((2-(4-Aminopiperidin-1 -yl)-2-
Example 290 phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2- 0.745 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(6-chloro-2-fluoro-3-
Example 291 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 0.140 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(3-chloro-2-
Example 292 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.196 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 293 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.165 dihydroquinoline-3-carboxylic acid
(S)-6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 294 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.193 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-(piperazin-
Example 295 1 -yl)acetamido)methyl)-2-oxo-1 ,2- 0.027 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-(2-fluoro-5-
Example 296 (trifluoromethyl)phenyl)acetamido)methyl)-2-oxo- 0.323
1 ,2-dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((1 -(pyridin-3-
Example 297 yl)cyclopropanecarboxamido)methyl)-1 ,2- 0.348 dihydroquinoline-3-carboxylic acid
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6,7-
Example 298 dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 0.056 acid
6,7-Dichloro-8-((2-(3-chloropyridin-2-
Example 299 yl)acetamido)methyl)-2-oxo-1 ,2- 0.018 dihydroquinoline-3-carboxylic acid
8-{[2-(5-Amino-2-fluoro-phenyl)-
Example 300 acetylamino]methyl}-6-chloro-2-oxo-1 ,2-dihydro- 0.224 quinoline-3-carboxylic acid
8-(Acetamidomethyl)-6-chloro-2-oxo-1 ,2-
Example 301 1 .826 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((3-methoxy-2-
Example 302 phenylpropanamido)methyl)-2-oxo-1 ,2- 0.741 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((2-(thiazol-5-
Example 303 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 0.102 carboxylic acid
6-Chloro-8-((trans-2-(3-
Example 304 chlorophenyl)cyclopropanecarboxamido)methyl)- 0.984
2-OXO-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((4-oxo-1 , 2,3,4-
Example 305 tetrahydronaphthalene-2-carboxamido)methyl)- 0.403
1 ,2-dihydroquinoline-3-carboxylic acid 6,7-Dichloro-8-((2-(2,6-difluorophenyl)-2-
Example 306 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.033 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-
Example 307 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.016 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-ethoxy-2-(2-
Example 308 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.009 dihydroquinoline-3-carboxylic acid
(S)-6-Chloro-8-((2-isopropoxy-2-
Example 309 phenylacetamido)methyl)-2-oxo-1 ,2- 0.164 dihydroquinoline-3-carboxylic acid
(R)-6-chloro-8-((2-isopropoxy-2-
Example 310 phenylacetamido)methyl)-2-oxo-1 ,2- 0.044 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2,5-dimethyl-1 -((1 -methylpyrrolidin-
Example 31 1 3-yl)methyl)-1 H-pyrrole-3-carboxamido)methyl)- 0.683
2-OXO-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-8-((5-ethyl-1 -phenyl-1 H-1 ,2,4-triazole-
Example 312 3-carboxamido)methyl)-2-oxo-1 ,2- 0.241 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((2-(thiazol-4-
Example 313 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 0.028 carboxylic acid
6-Chloro-8-(cyclobutanecarboxamidomethyl)-2-
Example 314 0.580 oxo-1 ,2-dihydroquinoline-3-carboxylic acid Table 5 - Functional Calcium FDSS 7000 studies in rat cortical neurons
Compound Chemical Name ICso [μΜ]
6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-acetylamino]-
Example 18 4.891 methyl}-1 ,2 dihydroquinoline-3-carboxylic acid
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-
Example 43 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.712 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[(thiazole-2-carbonyl)-amino]-
Example 45 2.329 methyl}-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-chloro-6-fluoro-phenyl)-
Example 52 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 1.26 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(2-trifluoromethyl-phenyl)-
Example 54 acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 2.65 carboxylic acid
6-Chloro-2-oxo-8-(1 -oxo-1 ,3-dihydro-isoindol-2-
Example 57 15.58 ylmethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[(2-methyl-thiazole-4-carbonyl)-
Example 59 amino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- 3.96 carboxylic acid
6-Chloro-2-oxo-8-{[(oxazole-4-carbonyl)-amino]-
Example 61 7.24 methyl}-1 ,2-dihydro-quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-methyl-thiazol-4-yl)-
Example 73 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 8.65 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-[(2-thiazol-5-yl-acetylamino)-
Example 81 3.89 methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid 8-{[2-(4-Amino-phenyl)-acetylamino]-methyl}-6-
Example 82 chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic 1.66 acid hydrate hydrobromide
8-{[(Adamantane-1 -carbonyl)-amino]-methyl}-6-
Example 83 chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic 6.60 acid
6-Chloro-8-{[2-(2-dimethylamino-phenyl)-
Example 88 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 3.72 quinoline-3-carboxylic acid
Example 97 6-Chloro-2-oxo-8-[(2-thiazol-4-yl-acetylamino)-
4.00 methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid
Example 98 6-Chloro-2-oxo-8-[((S)-2-phenyl- propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- 3.43 carboxylic acid
Example 100 6-Chloro-2-oxo-8-{[2-(2,4,6-trifluoro-phenyl)- acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 0.963 carboxylic acid
Example 103 6,7-Dichloro-8-{[2-(2,6-difluoro-phenyl)- acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.0992 quinoline-3-carboxylic acid
Example 106 6-Chloro-2-oxo-8-{[2-(2,3,6-trifluoro-phenyl)- acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 1 .28 carboxylic acid
Example 108 6,7-Dichloro-8-{[2-(2-fluoro-phenyl)- acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.0707 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(3-tetrazol-1 -yl-phenyl)-
Example 1 14 acetylamino]-methyl}-1 ,2-dihydro-quinoline-3- 2.85 carboxylic acid 6,7-Dichloro-8-{[2-(2-chloro-6-fluoro-phenyl)-
Example 121 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.104 quinoline-3-carboxylic acid
6-Chloro-8-[(2-methoxy-2-phenyl-acetylamino)-
Example 126 methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic 1.02 acid
Example 129 6-Chloro-8-((4-(1 -hydroxycyclohexyl)-1 H-1 ,2,3- triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 12.0 carboxylic acid
Example 150 6,7-Dichloro-2-oxo-8-[(2-pyridin-3-yl- acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- 0.713 carboxylic acid
Example 156 8-Aminomethyl-6,7-dichloro-2-oxo-1 ,2-
1.38 dihydroquinoline-3-carboxylic acid
6-Bromo-2-oxo-8-(phenylacetylamino-methyl)-
Example 158 3.25
1 ,2-dihydroquinoline-3-carboxylic acid
8-((1 H-1 ,2,3-triazoM -yl)methyl)-6,7-dichloro-2-
Example 159 4.688 oxo-1 ,2-dihydro-quinoline-3-carboxylic acid
8-((4-benzyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-
Example 160 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 4.430 acid
6-chloro-8-((4-(3-hydroxyphenyl)-1 H-1 ,2,3-
Example 161 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 6.888 carboxylic acid
(R)-6-chloro-8-((4-(hydroxy(phenyl)methyl)-1 H-
Example 163 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 4.310 dihydroquinoline-3-carboxylic acid
(8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-
Example 164 2.707 dihydroquinoline-3-carboxylic acid
(S)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-
Example 165 1 .706 dihydroquinoline-3-carboxylic acid (6-chloro-2-oxo-8-((4-(pyridin-2-yl)-1 H-1 ,2,3-
Example 166 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 10.850 carboxylic acid
6-chloro-2-oxo-8-((4-(2-(piperazin-1 -yl)ethyl)-1 H-
Example 167 1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 19.720 carboxylic acid
6-chloro-8-((4-(4-methoxyphenyl)-1 H-1 ,2,3-
Example 168 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 24.250 carboxylic acid
6-chloro-2-oxo-8-((4-(m-tolyl)-1 H-1 ,2,3-triazol-1 -
Example 169 26.570 yl)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((4-isobutyl-1 H-1 ,2,3-triazol-1 -
Example 170 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 9.862 carboxylic acid
6-chloro-8-((4-(1 -methyl-1 H-imidazol-5-yl)-1 H-
Example 171 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 26.360 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((4-(pyridin-4-yl)-1 H-1 ,2,3-
Example 172 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 1 1 .650 carboxylic acid
6-chloro-2-oxo-8-((4-(pyridin-3-yl)-1 H-1 ,2,3-
Example 173 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 16.240 carboxylic acid
6-chloro-8-((4-(2-methoxyphenyl)-1 H-1 ,2,3-
Example 174 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 5.428 carboxylic acid
8-((4-(tert-butyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-
Example 176 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 6.623 acid 6-chloro-8-((4-cyclopropyl-1 H-1 ,2,3-triazoM -
Example 177 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 12.700 carboxylic acid
6-chloro-2-oxo-8-((1 ,2,3,4-
Example 180 tetrahydroisoquinoline-1 -carboxamido)methyl)- 17.460
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((4-(2-fluorobenzyl)-1 H-1 ,2,3-triazol-
Example 181 1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 2.459 carboxylic acid
6-chloro-8-((4-(2,6-difluorobenzyl)-1 H-1 ,2,3-
Example 182 triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 2.603 carboxylic acid
6-chloro-8-((4-(2-chloro-6-fluorobenzyl)-1 H-
Example 183 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 1 .332 dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-
Example 184 1 .909 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2,6-
Example 185 difluorophenyl)ureido)methyl)-2-oxo-1 ,2- 0.286 dihydroquinoline-3-carboxylic acid
8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2-
Example 186 16.570 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((1 -(pyridin-3-
Example 187 yl)cyclopropanecarboxamido)-methyl)-1 ,2- 12.670 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((3-(pyridin-2-yl)ureido)methyl)-
Example 188 4.816
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-
Example 189 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 4.451 dihydroquinoline-3-carboxylic acid 6-chloro-2-oxo-8-((4-(pyridin-2-ylmethyl)-1 H-
Example 190 1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 6.536 carboxylic acid
6-chloro-2-oxo-8-((3-(pyridin-3-yl)ureido)methyl)-
Example 191 8.387
1 ,2-dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((1 -(pyridin-2-
Example 192 yl)cyclopropanecarboxamido)-methyl)-1 ,2- 9.162 dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2-chloro-6-
Example 193 fluorophenyl)ureido)methyl)-2-oxo-1 ,2- 0.839 dihydroquinoline-3-carboxylic acid
6-chloro-2-oxo-8-((4-(thiazol-2-yl)-1 H-1 ,2,3-
Example 194 triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- 12.180 carboxylic acid
6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-
Example 195 1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- 7.456 dihydroquinoline-3-carboxylic acid
6-chloro-8-((3-(2,6-
Example 196 difluorobenzyl)ureido)methyl)-2-oxo-1 ,2- 2.674 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -
Example 212 yl)acetamido)methyl)-2-oxo-1 ,2- 1 .053 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-
Example 213 2-phenylpropanamido)methyl)-1 ,2- 10.920 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((pyrazine-2-
Example 215 carboxamido)methyl)-1 ,2-dihydroquinoline-3- 7.402 carboxylic acid 6,7-Dichloro-2-oxo-8-((thiazole-4-
Example 216 carboxamido)methyl)-1 ,2-dihydroquinoline-3- 2.368 carboxylic acid
8-((2-(1 H-tetrazol-1 -yl)acetamido)methyl)-6,7-
Example 217 dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 10.090 acid.
8-((2-(4-Acetylpiperazin-1 -yl)-2-(2-
Example 218 fluorophenyl)acetamido)methyl)-6-chloro-2-oxo- 6.994
1 ,2-dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-methylthiazole-4-
Example 219 carboxamido)methyl)-2 -oxo-1 ,2- 1 .069 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((thiazole-2-
Example 220 carboxamido)methyl)-1 ,2-dihydroquinoline-3- 2.854 carboxylic acid
8-((2-(3-(1 H-pyrazol-1 -
Example 221 yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- 4.697 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-hydroxy-2-
Example 222 phenylacetamido)methyl)-2-oxo-1 ,2- 3.168 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((N-methyl-2-
Example 223 phenylacetamido)methyl)-2-oxo-1 ,2- 9.396 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(3-chloropyridin-2-
Example 224 yl)acetamido)methyl)-2-oxo-1 ,2- 2.865 dihydroquinoline-3-carboxylic acid
8-((2-(4-(1 H-imidazol-1 -
Example 225 yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- 7.447 dihydroquinoline-3-carboxylic acid 8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6-
Example 226 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 5.622 acid
6-Chloro-8-((2-ethoxy-2-
Example 227 phenylacetamido)methyl)-2-oxo-1 ,2- 0.612 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-isopropoxy-2-
Example 228 phenylacetamido)methyl)-2-oxo-1 ,2- 0.896 dihydroquinoline-3-carboxylic acid
6-Chloro-8-(cyclopropanecarboxamidomethyl)-2-
Example 229 5.61 1 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-(thiazol-2-
Example 230 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 5.506 carboxylic acid
8-((2-(2H-tetrazol-2-yl)acetamido)methyl)-6,7-
Example 231 dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 1 .939 acid
6-Chloro-8-((2-(2-fluorophenyl)-2-
Example 232 methoxyacetamido)methyl)-2-oxo-1 ,2- 1 .970 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 233 methoxyacetamido)methyl)-2-oxo-1 ,2- 2.195 dihydroquinoline-3-carboxylic acid
6-Bromo-8-((2-(2,6-
Example 234 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 1 .145 dihydroquinoline-3-carboxylic acid
6-Bromo-8-((2-(2-chloro-6-
Example 235 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 1 .326 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-(2,6-difluorophenyl)-2-
Example 236 methoxyacetamido)methyl)-2-oxo-1 ,2- 3.405 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((trans-2-
Example 237 phenylcyclopropanecarboxamido)methyl)-1 ,2- 5.531 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1 -
Example 238 yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- 9.635 carboxylic acid
6,7-Dichloro-2-oxo-8-((2-(pyrimidin-2-
Example 239 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 1 .320 carboxylic acid
6-Chloro-7-fluoro-8-((2-(2-
Example 240 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.801 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,6-
Example 241 difluorophenyl)acetamido)methyl)-7-fluoro-2- 0.492 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-7-fluoro-8-((2-methoxy-2-
Example 242 phenylacetamido)methyl)-2-oxo-1 ,2- 0.787 dihydroquinoline-3-carboxylic acid
7-Bromo-6-chloro-8-((2-methoxy-2-
Example 243 phenylacetamido)methyl)-2-oxo-1 ,2- 0.435 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,4-
Example 244 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 3.762 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-phenyl-2-
Example 245 propoxyacetamido)methyl)-1 ,2-dihydroquinoline- 2.084
3-carboxylic acid (S)-6-Chloro-8-((2-methoxy-2-
Example 246 phenylacetamido)methyl)-2-oxo-1 ,2- 7.595 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-8-((2-methoxy-2-
Example 247 phenylacetamido)methyl)-2-oxo-1 ,2- 1 .694 dihydroquinoline-3-carboxylic acid
8-[(2-Benzyloxy-2-phenyl-acetylamino)-methyl]-
Example 248 6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- 19.290 carboxylic acid
8-((2-Butoxy-2-phenylacetamido)methyl)-6-
Example 249 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 8.251 acid
6-Chloro-8-((2-(3-fluoropyridin-2-
Example 250 yl)acetamido)methyl)-2-oxo-1 ,2- 3.558 dihydroquinoline-3-carboxylic acid
8-((3-(Benzylamino)-3-oxopropanamido)methyl)-
Example 251 6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 4.341 acid
6-Chloro-2-oxo-8-((2-(2,3,5-
Example 252 trifluorophenyl)acetamido)methyl)-1 ,2- 3.572 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(naphthalen-2-
Example 253 yl)acetamido)methyl)-2-oxo-1 ,2- 7.895 dihydroquinoline-3-carboxylic acid
6-Chloro-8-(1 -(2-methoxy-2-
Example 254 phenylacetamido)ethyl)-2-oxo-1 ,2- 6.056 dihydroquinoline-3-carboxylic acid
6-chloro-8-(1 -(2-(2,6-
Example 255 difluorophenyl)acetamido)ethyl)-2-oxo-1 ,2- 5.661 dihydroquinoline-3-carboxylic acid 6-Chloro-8-(1 -(2-(2-fluorophenyl)-2-
Example 256 methoxyacetamido)ethyl)-2-oxo-1 ,2- 5.421 dihydroquinoline-3-carboxylic acid
6-Chloro-8-(1 -(2-ethoxy-2-
Example 257 phenylacetamido)ethyl)-2-oxo-1 ,2- 2.391 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(4-ethoxy-2,6-
Example 258 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 4.055 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-
Example 260 ethoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 12.220 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,6-difluoro-3-
Example 261 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 1 .512 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((isochroman-1 -
Example 262 carboxamido)methyl)-2 -oxo-1 ,2- 5.733 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(3-ethoxy-2,4-
Example 263 difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 7.455 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-methoxy-2-
Example 264 phenylacetamido)methyl)-2-oxo-1 ,2- 0.232 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-ethoxy-2-
Example 265 phenylacetamido)methyl)-2-oxo-1 ,2- 0.239 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2,3-difluoro-6-
Example 266 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 1 .677 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-ethoxy-2-(2-
Example 267 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.871 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluoro-6-
Example 269 (trifluoromethyl)phenyl)acetamido)methyl)-2-oxo- 2.142
1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-8-((1 -(3-chloropyridin-2-yl)-1 H-pyrrole-
Example 271 2-carboxamido)methyl)-2-oxo-1 ,2- 2.558 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((6-chloroimidazo[1 ,2-b]pyridazine-2-
Example 272 carboxamido)methyl)-2 -oxo-1 ,2- 6.937 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(4-
Example 274 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 4.187 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(3-
Example 276 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 3.154 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluoro-5-
Example 277 methylphenyl)acetamido)methyl)-2-oxo-1 ,2- 1 .874 dihydroquinoline-3-carboxylic acid
(R)-6-chloro-2-oxo-8-((1 ,2,3,4-
Example 278 tetrahydroisoquinoline-3-carboxamido)methyl)- 20.300
1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-(piperazin-1 -yl)-2-(p-
Example 279 tolyl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 3.369 carboxylic acid
6-Chloro-2-oxo-8-((1 ,2,3,4-
Example 281 tetrahydronaphthalene-1 -carboxamido)methyl)- 5.333
1 ,2-dihydroquinoline-3-carboxylic acid 6-chloro-8-((2-(2-fluoro-5-
Example 282 (trifluoromethoxy)phenyl)acetamido)methyl)-2- 1 1 .440 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
8-((2-(5-Bromopyridin-3-yl)acetamido)methyl)-6-
Example 283 chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 6.200 acid
6-Chloro-8-((2-(2-fluoro-6-
Example 284 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 2.210 dihydroquinoline-3-carboxylic acid
8-((2-(1 H-1 ,2,3-triazoM -yl)acetamido)methyl)-
Example 285 6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- 10.740 carboxylic acid
8-((2-(2H-1 ,2,3-triazol-2-yl)acetamido)methyl)-
Example 286 6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3- 1 .316 carboxylic acid
6,7-Dichloro-8-((2-(2-chlorophenyl)-2-
Example 287 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.282 dihydroquinoline-3-carboxylic acid
8-((2-(2-(1 H-tetrazol-1 -
Example 288 yl)phenyl)acetamido)methyl)-6,7-dichloro-2-oxo- 1 .691
1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(1 -methyl-1 H-imidazol-4-
Example 289 yl)acetamido)methyl)-2-oxo-1 ,2- 6.667 dihydroquinoline-3-carboxylic acid
8-((2-(4-Aminopiperidin-1 -yl)-2-
Example 290 phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2- 7.648 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(6-chloro-2-fluoro-3-
Example 291 methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- 2.751 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((2-(3-chloro-2-
Example 292 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 2.851 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 293 methoxyacetamido)methyl)-2-oxo-1 ,2- 2.844 dihydroquinoline-3-carboxylic acid
(S)-6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 294 methoxyacetamido)methyl)-2-oxo-1 ,2- 3.921 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-(piperazin-
Example 295 1 -yl)acetamido)methyl)-2-oxo-1 ,2- 0.774 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-(2-fluoro-5-
Example 296 (trifluoromethyl)phenyl)acetamido)methyl)-2-oxo- 7.670
1 ,2-dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((1 -(pyridin-3-
Example 297 yl)cyclopropanecarboxamido)methyl)-1 ,2- 5.322 dihydroquinoline-3-carboxylic acid
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6,7-
Example 298 dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic 1 .351 acid
6,7-Dichloro-8-((2-(3-chloropyridin-2-
Example 299 yl)acetamido)methyl)-2-oxo-1 ,2- 0.472 dihydroquinoline-3-carboxylic acid
8-{[2-(5-Amino-2-fluoro-phenyl)-
Example 300 acetylamino]methyl}-6-chloro-2-oxo-1 ,2-dihydro- 3.760 quinoline-3-carboxylic acid
8-(Acetamidomethyl)-6-chloro-2-oxo-1 ,2-
Example 301 16.490 dihydroquinoline-3-carboxylic acid 6-Chloro-8-((3-methoxy-2-
Example 302 phenylpropanamido)methyl)-2-oxo-1 ,2- 13.380 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((2-(thiazol-5-
Example 303 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 1 .585 carboxylic acid
6-Chloro-8-((trans-2-(3-
Example 304 chlorophenyl)cyclopropanecarboxamido)methyl)- 38.090
2-OXO-1 ,2-dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((4-oxo-1 , 2,3,4-
Example 305 tetrahydronaphthalene-2-carboxamido)methyl)- 1 1 .460
1 ,2-dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-(2,6-difluorophenyl)-2-
Example 306 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.601 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-
Example 307 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.496 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-8-((2-ethoxy-2-(2-
Example 308 fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- 0.392 dihydroquinoline-3-carboxylic acid
(S)-6-Chloro-8-((2-isopropoxy-2-
Example 309 phenylacetamido)methyl)-2-oxo-1 ,2- 5.261 dihydroquinoline-3-carboxylic acid
(R)-6-chloro-8-((2-isopropoxy-2-
Example 310 phenylacetamido)methyl)-2-oxo-1 ,2- 1 .217 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2,5-dimethyl-1 -((1 -methylpyrrolidin-
Example 31 1 3-yl)methyl)-1 H-pyrrole-3-carboxamido)methyl)- 15.740
2-OXO-1 ,2-dihydroquinoline-3-carboxylic acid 6-Chloro-8-((5-ethyl-1 -phenyl-1 H-1 ,2,4-triazole-
Example 312 3-carboxamido)methyl)-2-oxo-1 ,2- 6.046 dihydroquinoline-3-carboxylic acid
6,7-Dichloro-2-oxo-8-((2-(thiazol-4-
Example 313 yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- 0.772 carboxylic acid
6-Chloro-8-(cyclobutanecarboxamidomethyl)-2-
Example 314 15.520 oxo-1 ,2-dihydroquinoline-3-carboxylic acid
Table 6 - Functional Patch-clamp studies in rat hippocampal neurons
Compound Chemical Name Ki [μΜ]
6-Chloro-8-{[2-(2-chlorophenyl)-
Example 5 acetylamino]-methyl}-2-oxo-1 ,2- 0.0318 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[(thiophene-2-carbonyl)-
Example 6 amino]-methyl}-1 ,2-dihydroquinoline-3- 0.0376 carboxylic acid
6-Chloro-8-{[2-(3-chlorophenyl)-
Example 7 acetylamino]-methyl}-2-oxo-1 ,2- 0.0444 dihydroquinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-nitrophenyl)-acetylamino]-
Example 9 methyl}-2-oxo-1 ,2-dihydroquinoline-3- 0.0398 carboxylic acid
8-{[(Benzofuran-2-carbonyl)-amino]-
Example 1 1 methyl}-6-chloro-2-oxo-1 ,2- 0.169 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(pyridin-3-yl)-acetyl)-
Example 17 amino]-methyl}-1 ,2 dihydroquinoline-3- 0.0889 carboxylic acid 6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-
Example 18 acetylamino]-methyl}-1 ,2 dihydroquinoline- 0.077
3-carboxylic acid
6-Chloro-8-[(3-chloro-benzoylamino)-
Example 22 methyl]-2-oxo-1 ,2-dihydro-quinoline-3- 0.0258 carboxylic acid
6-Chloro-8-{[(2,3-dihydro- benzo[1 ,4]dioxine-6-carbonyl)-amino]-
Example 23 0.0462 methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid
6-Chloro-8-[(4-hydroxy-benzoylamino)-
Example 28 methyl]-2-oxo-1 ,2-dihydro-quinoline-3- 0.1 10 carboxylic acid
6-Chloro-2-oxo-8-[(2-pyrazin-2-yl-
Example 32 acetylamino)-methyl]-1 ,2-dihydro-quinoline- 0.148
3-carboxylic acid
6-Chloro-8-{[2-(2-fluoro-phenyl)-
Example 42 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.0267 quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-
Example 43 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.016 quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[(thiazole-4-carbonyl)-
Example 46 amino]-methyl}-1 ,2-dihydro-quinoline-3- 0.106 carboxylic acid
6-Chloro-8-{[2-(2-methyl-thiazol-4-yl)-
Example 73 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.0737 quinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-dimethylamino-phenyl)-
Example 88 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.0613 quinoline-3-carboxylic acid 6-Chloro-8-((2-(3-chloropyridin-2-
Example 224 yl)acetamido)methyl)-2-oxo-1 ,2- 0.058 dihydroquinoline-3-carboxylic acid
6-Chloro-8-((2-isopropoxy-2-
Example 228 phenylacetamido)methyl)-2-oxo-1 ,2- 0.023 dihydroquinoline-3-carboxylic acid
6-Chloro-2-oxo-8-((2-(thiazol-2-
Example 230 yl)acetamido)methyl)-1 ,2-dihydroquinoline- 0.168
3-carboxylic acid
6-Chloro-8-((2-(2-chlorophenyl)-2-
Example 233 methoxyacetamido)methyl)-2-oxo-1 ,2- 0.033 dihydroquinoline-3-carboxylic acid
(S)-6-Chloro-8-((2-methoxy-2-
Example 246 phenylacetamido)methyl)-2-oxo-1 ,2- 0.075 dihydroquinoline-3-carboxylic acid
(R)-6-Chloro-8-((2-methoxy-2-
Example 247 phenylacetamido)methyl)-2-oxo-1 ,2- 0.021 dihydroquinoline-3-carboxylic acid
Table 7 - Functional Patch-clamp studies in rat DRG neurons
Compound Chemical Name Ki [μΜ]
6-Chloro-8-{[2-(2-chlorophenyl)-
Example 5 acetylamino]-methyl}-2-oxo-1 ,2- 0.066 dihydroquinoline-3-carboxylic acid
6-Chloro-8-{[2-(2-nitrophenyl)-acetylamino]-
Example 9 methyl}-2-oxo-1 ,2-dihydroquinoline-3- 0.060 carboxylic acid 6-Chloro-2-oxo-8-{[2-(pyridin-3-yl)-
Example 17 acetylamino]-methyl}-1 ,2 dihydroquinoline- 0.1 17
3-carboxylic acid
6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-
Example 18 acetylamino]-methyl}-1 ,2 dihydroquinoline- 0.1 10
3-carboxylic acid
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-
Example 43 acetylamino]-methyl}-2-oxo-1 ,2-dihydro- 0.020
quinoline-3-carboxylic acid
6-Chloro-2-oxo-8-{[(thiazole-4-carbonyl)-
Example 46 amino]-methyl}-1 ,2-dihydro-quinoline-3- 0.082
carboxylic acid
6-Chloro-8-((2-isopropoxy-2-
Example 228 phenylacetamido)methyl)-2-oxo-1 ,2- 0.045
dihydroquinoline-3-carboxylic acid
CONCLUSIONS
[00572] In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages.
[00573] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are
responsible for and authorized to pass judgment on such questions. [00574] The instant quinoline derivatives represent a novel class of glycine B antagonists. In view of their potency, they will be useful therapeutics in a wide range of disorders, including CNS / PNS disorders, which involve excessive glutamate induced excitation.
[00575] These compounds accordingly find application in the treatment of the following disorders of a living animal body, especially a human: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
[00576] These compounds also find application in the treatment of the following disorders of a living animal body, especially a human: acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS- related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive
impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced
dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic
convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder,
schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
[00577] The method -of -treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. [00578] Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a
compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
[00579] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
* * * * *
[00580] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
[00581 ] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

CLAIMS compound selected from those of Formula I:
Figure imgf000335_0001
wherein n = 0, 1 or 2;
X1 represents halogen, nitro, or d-6alkyl;
X2 represents hydrogen, halogen, nitro or Ci-6alkyl;
R1 and R2, which may be the same or different, each independently represent hydrogen, Ci-6alkyl, aryl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, or R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group (C=O);
R3 represents hydrogen, Ci-6alkyl, C3-6alkenyl, Ci-6alkylsulfonyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl or heteroaryl-Ci-6alkyl;
R4 represents hydrogen, Ci-6alkyl, C3-6alkenyl, Ci-6alkylsulfonyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, hydroxy-Ci-6alkyl, carbamoyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl or C(O)-R5; wherein R5 represents COOH, Ci-6alkyl, cyclo-C3-i2alkyl optionally condensed to a benzene ring, cyclo-C3-i2alkyl-Ci-6alkyl, hydroxy-Ci-6alkyl, carboxy-Ci-6alkyl, amino-Ci-6alkyl, aryl, heteroaryl, heteroaryl-heteroaryl, heteroaryl-aryl,
heterocyclyl, aryl -Chalky!, wherein the alkyl portion may be optionally substituted by trifluoromethyl, amino, hydroxy, Ci-6alkoxy, aryl-Ci-6alkoxy, phenyl, heteroaryl or heterocyclyl, heteroaryl-Ci-6alkyl, arylamino, heteroarylamino, arylCi- 6alkylamino, arylcarbonyl, or aryl-Ci-ealkylaminocarbonylCi-ealkyl; or R3 and R4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to an aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, Ci-6alkyl, Ci-6alkoxy, hydroxy-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl, COOH, CONH2, Ci-6alkylaminocarbonyl, aryl, heteroaryl, aryl-Ci-6alkyl, wherein the alkyl portion may be optionally substituted by hydroxy, heteroaryl-Ci_6alkyl, wherein the alkyl portion may be optionally substituted by hydroxy, heterocyclyl-Ci-6alkyl,
Ci-6alkylcarbonyl, and cyclo-C3-i2alkyl; or R2 and R3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring, which may be optionally fused to a benzene ring, in which case R1 and R4 are not present, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen, wherein the heteroaromatic ring may be optionally substituted by aryl-Ci-6alkyl; and optical isomers, polymorphs, analogs, derivatives, prodrugs, and
pharmaceutically-acceptable acid and base addition salts and hydrates and solvates thereof.
2. The compound as claimed in Claim 1 , wherein n is 0 and R1 and R2 each represent hydrogen.
3. The compound as claimed in Claim 1 , wherein n is 1 and R1 and R2 together with the carbon atom to which they are attached represent a carbonyl group (C=O).
4. The compound as claimed in Claim 1 , wherein n is 0, R1 represents Chalky!, and R2 represents hydrogen.
5. The compound as claimed in any of Claims 1 to 4, wherein R4 represents
hydrogen, Ci-6alkyl, aryl-Ci-6alkyl, heteroaryl-Ci-6alkyl, or heteroaryl.
6. The compound as claimed in Claim 5, wherein R5 represents COOH,
carboxymethyl, or aminomethyl.
7. The compound as claimed in Claim 5, wherein R5 represents aryl, heteroaryl, aryl- Ci-6alkyl, heteroaryl-Ci-6alkyl, arylcarbonyl, arylamino, heteroarylamino, or aryl- Ci-6alkylamino.
8. The compound as claimed in Claim 7, wherein the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen,
Ci-6alkoxy, nitro, Ci-6alkylenedioxy, hydroxyl, Ci-6alkyl, trifluoromethyl,
trifluoromethoxy, phenyoxy, amino, di-Ci-6alkylamino, tetrazolyl, imidazolyl, and triazolyl.
9. The compound as claimed in Claim 8, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl,
benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and
imidazopyridazinyl.
10. The compound as claimed in Claim 5, wherein R4 represents methyl, benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, pyridinyl-methyl, pyridinyl optionally substituted by one or more
substituents selected from nitro and Ci-6alkylcarbonylamino, benzoxazolyl, or benzothiazolyl.
1 1 . The compound as claimed in any preceding claim, wherein R3 represents
hydrogen or d-6alkyl.
12. The compound as claimed in any of Claims 1 to 4, wherein R3 and R4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7- membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, Ci-6alkyl, cyclo-C3-i2alkyl, Ci-6alkoxy, hydroxy-Ci- 6alkyl, Ci-6alkoxy-Ci-6alkyl, Ci-6alkylcarbonyl, COOH, CONH2, Ci_
6alkylaminocarbonyl, aryl, heteroaryl, aryl-Ci^alkyl, wherein the alkyl portion may be optionally substituted by hydroxy, and heteroaryl -Chalky I, wherein the alkyl portion may be optionally substituted by hydroxy.
13. The compound as claimed in Claim 12, wherein R3 and R4 together with the
nitrogen atom to which they are attached represent triazolyl optionally substituted by Ci-6alkyl, aryl, heteroaryl, cyclo-C3-i2alkyl, aryl-Ci-6alkyl, or heteroaryl-Ci-6alkyl, pyrrolyl optionally substituted by Ci-6alkylcarbonyl, aryl-Ci-6alkyl, or heteroaryl- Ci-6alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
14. The compound as claimed in any preceding claim, wherein X1 represents halogen and X2 represents hydrogen or halogen.
15. The compound as claimed in Claim 14, wherein X1 represents chloro and X2 represents hydrogen or halogen.
16. The compound as claimed in Claim 1 , which is selected from:
8-Aminomethyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
8-[(2-Carboxy-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-thiophen-3-yl-acetylamino)-methyl]-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-{[(thiophene-2-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-{[2-(3-chlorophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-{[(thiophene-3-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-nitrophenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(3-phenyl-propionylamino)-methyl]-1 ,2-dihydroquinoline-3- carboxylic acid,
8-{[(Benzofuran-2-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-{[(Benzo[b]thiophene-2-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-[(oxalyl-amino)-methyl]-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 8-(Benzoylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-{[(pyridine-3-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-2-oxo-8-{[(pyridine-4-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(pyridin-3-yl)-acetylamino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(pyridin-2-yl)-acetylamino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridine-2-carbonyl)-amino]-methyl}-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-[(2-chloro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(2-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(3-chloro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[(2,3-dihydro-benzo[1 ,4]dioxine-6-carbonyl)-amino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
8-[(2-Bromo-benzoylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(3-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(quinoline-3-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-(diphenylacetylamino-methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-[(4-hydroxy-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(4-fluoro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(3-fluoro-benzoylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(2-o-tolyl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid, 6-Chloro-2-oxo-8-[(2-pyrazin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-trifluoromethoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-naphthalen-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[2-(2-hydroxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(4-phenyl-butyrylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(4-chloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[2-(2-Bromo-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-{[(quinoline-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(4-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(thiazole-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(thiazole-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(thiazole-5-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid, 6-Chloro-8-{[(3,4-dihydro-2H-benzo[b][1 ,4]dioxepine-7-carbonyl)-amino]-methyl}-2- oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-{[(Benzothiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[(Benzothiazole-6-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,3-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-trifluoromethyl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(5-nitro-pyridin-2-ylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-(1 -oxo-1 ,3-dihydro-isoindol-2-ylmethyl)-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(4-fluoro-2-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[(2-methyl-thiazole-4-carbonyl)-amino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(3-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(oxazole-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[(2-Amino-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[(2-Amino-3-phenyl-propionylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-{[2-(2-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(quinoline-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[2-(4-tert-Butyl-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-pyrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridazine-4-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[(Benzo[1 ,2,5]oxadiazole-5-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyrimidine-5-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-{[2-(3-Amino-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[2-(2-methyl-thiazol-4-yl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-[(3-Acetylamino-pyridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyrazine-2-carbonyl)-amino]-methyl}-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-iodo-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-(piperidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-(pyrrolidin-1 -ylmethyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-pyridin-4-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid, 6-Chloro-2-oxo-8-[(2-thiazol-5-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic,
8-{[2-(4-Amino-phenyl)-acetylamino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
8-{[(Adamantane-1 -carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
8-[(2-Adamantan-1 -yl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-[(benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-((1 H-1 ,2,4-Triazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
8-((Benzyl(methyl)amino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid
6-Chloro-8-{[(6-imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-[1 ,2,4]triazol-4-yl-phenyl)-acetylamino]-methyl}-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(3-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-((1 H-pyrazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-8-({[1 -(2-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-(1 ,3-dioxo-1 ,3-dihydro-isoindol-2-ylmethyl)-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-[(5-Carbamoyl-pyridin-2-ylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-({[1 -(2-chloro-6-fluoro-phenyl)-cyclohexanecarbonyl]-amino}-methyl)-2- oxo-1 ,2-dihydro-quinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-[(2-thiazol-4-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[((S)-2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[((R)-2-phenyl-propionylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,4,6-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(pyridin-2-ylaminomethyl)-1 ,2-dihydro-quinoline-3-carboxylic acid,
6,7-Dichloro-8-{[2-(2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-oxo-2-phenyl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-imidazol-1 -yl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,3,6-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(3-dimethylamino-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6,7-Dichloro-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6,7-Dichloro-8-{[2-(2,6-dichloro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-{[(6-Bromo-pyridine-3-carbonyl)-amino]-methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[(2-imidazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
8-(2-Acetyl-pyrrol-1 -ylmethyl)-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-[(3-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid, 6-Chloro-2-oxo-8-{[2-(3-tetrazol-1 -yl-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-[((S)-2-Amino-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(4-phenoxy-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-chloro-benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-(Benzylamino-methyl)-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid, 6-Chloro-8-methylaminomethyl-2-oxo-1 ,2-dihydro-quinoline-3-carboxylic acid, 6-Chloro-8-[(2,6-difluoro-benzylcarbamoyl)-methyl]-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-8-{[2-(2-chloro-6-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
8-[(2-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-{[(1 -phenyl-cyclopentanecarbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-({[1 -(2-fluoro-phenyl)-cyclopropanecarbonyl]-amino}-methyl)-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
8-[(4-Acetyl-phenylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-[(2-methoxy-2-phenyl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-phenyl)-2-methyl-propionylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(2-oxo-2-((thiazol-2-ylmethyl)amino)ethyl)-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((4-(1 -hydroxycyclohexyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-[4-(4-fluoro-phenyl)-[1 ,2,3]triazol-1 -ylmethyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-{[(1 -phenyl-cyclopropanecarbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-methyl-2-phenyl-propionylamino)-methyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(1 -phenyl-cyclobutanecarbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(4-phenyl-piperidine-4-carbonyl)-amino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(2-pyrazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(4-pyrazol-1 -yl-pyridine-3-carbonyl)-amino]-methyl}-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-((4-(3-(3,3-dimethyl-2-oxoazetidin-1 -yl)phenyl)-1 H-1 ,2,3-triazol-1 - yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridin-4-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-2-oxo-8-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6,7-Dichloro-2-oxo-8-pyrazol-1 -ylmethyl-1 ,2-dihydro-quinoline-3-carboxylic acid, 6,7-Dichloro-2-oxo-8-[1 ,2,4]triazol-1 -ylmethyl-1 ,2-dihydro-quinoline-3-carboxylic acid,
8-[((R)-2-Amino-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-[(2-imidazol-1 -yl-2-phenyl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,5-dimethoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(3-phenyl-ureido)-methyl]-1 ,2-dihydro-quinoline-3-carboxylic acid, 6,7-Dichloro-2-oxo-8-[(2-[1 ,2,4]triazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-2-pyrazol-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid,
6,7-Dichloro-8-[(2-imidazol-1 -yl-acetylamino)-methyl]-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6,7-Dichloro-2-oxo-8-[(2-pyridin-3-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-(3-phenyl-pyrazol-1 -ylmethyl)-1 ,2-dihydro-quinoline-3- carboxylic,
6,7-Dichloro-2-oxo-8-[(2-pyridin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-[3-(4-Bromo-phenyl)-ureidomethyl]-6,7-dichloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-[(2-pyrimidin-2-yl-acetylamino)-methyl]-1 ,2-dihydro-quinoline- 3-carboxylic acid,
8-Aminomethyl-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Bromo-8-{[2-(2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Bromo-2-oxo-8-(phenylacetylamino-methyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
8-((1 H-1 ,2,3-triazol-1 -yl)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydro-quinoline-3- carboxylic acid,
8-((4-benzyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-(3-hydroxyphenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-phenyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid, (R)-6-chloro-8-((4-(hydroxy(phenyl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
(S)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, (6-chloro-2-oxo-8-((4-(pyridin-2-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(2-(piperazin-1 -yl)ethyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(4-methoxyphenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(m-tolyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-isobutyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((4-(1 -methyl-1 H-imidazol-5-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(pyridin-4-yl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(pyridin-3-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(2-methoxyphenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(p-tolyl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((4-(tert-butyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((4-cyclopropyl-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(3-fluorophenyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(3-methoxyphenyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, 6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(2-fluorobenzyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(2,6-difluorobenzyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2-fluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-((3-(2,6-difluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((3-(4-bromobenzyl)ureido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-2-oxo-8-((1 -(pyridin-3-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((3-(pyridin-2-yl)ureido)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(hydroxy(pyridin-2-yl)methyl)-1 H-1 ,2,3-triazoM -yl)methyl)-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((4-(pyridin-2-ylmethyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((3-(pyridin-3-yl)ureido)methyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((1 -(pyridin-2-yl)cyclopropanecarboxamido)-methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2-chloro-6-fluorophenyl)ureido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-2-oxo-8-((4-(thiazol-2-yl)-1 H-1 ,2,3-triazoM -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((4-(hydroxy(pyridin-3-yl)methyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid, 6-chloro-8-((3-(2,6-difluorobenzyl)ureido)methyl)-2 -oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-dichloro-8-((3-methyl-1 H-1 ,2,4-triazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6,7-dichloro-8-(((2-chloro-6-fluorobenzyl)amino)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-2-oxo-8-((3-(pyridin-2-ylmethyl)-1 H-pyrazol-1 -yl)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((5-(2-fluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-chloro-8-((3-(2,6-difluorobenzyl)-1 H-pyrazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((3-(2-fluorobenzyl)-1 ,2,4-oxadiazol-5-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((5-(2-chloro-6-fluorobenzyl)-1 H-1 ,2,3-triazol-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(R)-8-(1 -aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 8-(benzo[d]thiazol-2-ylmethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((benzo[d]oxazol-2-ylamino)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
8-(2-aminoethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
8-carbamoyl-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, (R)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)methyl)- 1 ,2-dihydroquinoline-3-carboxylic acid,
(S)-6-Chloro-2-oxo-8-((3,3,3-trifluoro-2-methoxy-2-phenylpropanamido)methyl)- 1 ,2-dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((pyrazine-2-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6,7-Dichloro-2-oxo-8-((thiazole-4-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(1 H-tetrazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
8-((2-(4-Acetylpiperazin-1 -yl)-2-(2-fluorophenyl)acetamido)methyl)-6-chloro-2-oxo- 1 ,2-dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-methylthiazole-4-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((thiazole-2-carboxamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(3-(1 H-pyrazol-1 -yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-hydroxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((N-methyl-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(3-chloropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
8-((2-(4-(1 H-imidazol-1 -yl)phenyl)acetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-ethoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid, 6-Chloro-8-(cyclopropanecarboxamidomethyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-((2-(thiazol-2-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
8-((2-(2H-tetrazol-2-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(2-fluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Bromo-8-((2-(2,6-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Bromo-8-((2-(2-chloro-6-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2,6-difluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((frans-2-phenylcyclopropanecarboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2,4-dioxo-3-(p-tolyl)imidazolidin-1 -yl)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((2-(pyrimidin-2-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-7-fluoro-8-((2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2,6-difluorophenyl)acetamido)methyl)-7-fluoro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6- Chloro-7-fluoro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
7- Bromo-6-chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2,4-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid, 6-Chloro-2-oxo-8-((2-phenyl-2-propoxyacetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
(S)-6-Chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(R)-6-Chloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-[(2-Benzyloxy-2-phenyl-acetylamino)-methyl]-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-((2-Butoxy-2-phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(3-fluoropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
8-((3-(Benzylamino)-3-oxopropanamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((2-(2,3,5-trifluorophenyl)acetamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(naphthalen-2-yl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-(1 -(2-methoxy-2-phenylacetamido)ethyl)-2 -oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-chloro-8-(1 -(2-(2,6-difluorophenyl)acetamido)ethyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-(1 -(2-(2-fluorophenyl)-2-methoxyacetamido)ethyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-(1 -(2-ethoxy-2-phenylacetamido)ethyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(4-ethoxy-2,6-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-morpholino-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(2-ethoxyphenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-8-((2-(2,6-difluoro-3-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((isochroman-1 -carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(3-ethoxy-2,4-difluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-methoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-ethoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(2,3-difluoro-6-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-ethoxy-2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(4-methoxypiperidin-1 -yl)-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-fluoro-6-(trifluoromethyl)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(3-oxo-3-(phenylamino)propyl)-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((1 -(3-chloropyridin-2-yl)-1 H-pyrrole-2-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((6-chloroimidazo[1 ,2-b]pyridazine-2-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((5-(3-chlorophenyl)oxazole-4-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(4-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((imidazo[1 ,2-a]pyridine-3-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(3-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid, 6-Chloro-8-((2-(2-fluoro-5-methylphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(R)-6-chloro-2-oxo-8-((1 ,2,3,4-tetrahydroisoquinoline-3-carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((2-(piperazin-1 -yl)-2-(p-tolyl)acetamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((3-(4-methylpiperazin-1 -yl)-2-phenylpropanamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((1 ,2,3,4-tetrahydronaphthalene-1 -carboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
6-chloro-8-((2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(5-Bromopyridin-3-yl)acetamido)methyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6-Chloro-8-((2-(2-fluoro-6-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(1 H-1 ,2,3-triazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(2H-1 ,2,3-triazol-2-yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(2-(1 H-tetrazol-1 -yl)phenyl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(1 -methyl-1 H-imidazol-4-yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(4-Aminopiperidin-1 -yl)-2-phenylacetamido)methyl)-6-chloro-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(6-chloro-2-fluoro-3-methoxyphenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(3-chloro-2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, (R)-6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(S)-6-Chloro-8-((2-(2-chlorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-(piperazin-1 -yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2-(2-fluoro-5-(trifluoromethyl)phenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((1 -(pyridin-3-yl)cyclopropanecarboxamido)methyl)-1 ,2- dihydroquinoline-3-carboxylic acid,
8-((2-(1 H-pyrazol-1 -yl)acetamido)methyl)-6,7-dichloro-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6,7-Dichloro-8-((2-(3-chloropyridin-2-yl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
8-{[2-(5-Amino-2-fluoro-phenyl)-acetylamino]methyl}-6-chloro-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
8-(Acetamidomethyl)-6-chloro-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid, 6-Chloro-8-((3-methoxy-2-phenylpropanamido)methyl)-2-oxo-1 ,2-dihydroquinoline- 3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((2-(thiazol-5-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-((2-(3-chlorophenyl)cyclopropanecarboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-((4-oxo-1 ,2,3,4-tetrahydronaphthalene-2-carboxamido)methyl)- 1 ,2-dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2,6-difluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-(2-fluorophenyl)-2-methoxyacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-8-((2-ethoxy-2-(2-fluorophenyl)acetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid, (S)-6-Chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
(R)-6-chloro-8-((2-isopropoxy-2-phenylacetamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((2,5-dimethyl-1 -((1 -methylpyrrolidin-3-yl)methyl)-1 H-pyrrole-3- carboxamido)methyl)-2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid,
6-Chloro-8-((5-ethyl-1 -phenyl-1 H-1 ,2,4-triazole-3-carboxamido)methyl)-2-oxo-1 ,2- dihydroquinoline-3-carboxylic acid,
6,7-Dichloro-2-oxo-8-((2-(thiazol-4-yl)acetamido)methyl)-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-8-(cyclobutanecarboxamidomethyl)-2-oxo-1 ,2-dihydroquinoline-3- carboxylic acid,
6-Chloro-2-oxo-8-[(2-phenyl-2-piperazin-1 -yl-acetylamino)-methyl]-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-(4-phenyl-imidazol-1 -ylmethyl)-1 ,2-dihydro-quinoline-3- carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-4-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,5-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-2-oxo-8-{[2-(2,4,5-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{1 -[2-(2-fluoro-phenyl)-acetylamino]-ethyl}-2-oxo-1 ,2-dihydro-quinoline- 3-carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-phenyl)-2-ethoxy-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{1 -[2-(2-chloro-phenyl)-2-methoxy-acetylamino]-ethyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-chloro-phenyl)-2-ethoxy-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-4-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid, 6-Chloro-2-oxo-8-{[2-(2,3,4-trifluoro-phenyl)-acetylamino]-methyl}-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(3-ethoxy-2,6-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,3-difluoro-4-methoxy-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(4-ethoxy-2,3-difluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-3-trifluoromethyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-4-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2,6-difluoro-3-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(4-chloro-2-fluoro-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2-dihydro- quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-chloro-6-fluoro-3-methoxy-phenyl)-acetylamino]-methyl}-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(6-chloro-2-fluoro-3-methyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid,
6-Chloro-8-{[2-(2-fluoro-4-trifluoromethyl-phenyl)-acetylamino]-methyl}-2-oxo-1 ,2- dihydro-quinoline-3-carboxylic acid, and optical isomers, polymorphs, analogs, derivatives, prodrugs, and pharmaceutically- acceptable acid and base addition salts, hydrates, and solvates thereof.
17. A pharmaceutical composition comprising as active ingredient a compound as claimed in any preceding claim, optionally together with one or more
pharmaceutically acceptable excipients.
18. A compound as claimed in any of Claims 1 to 16 for use in the prevention and/or treatment of a condition selected from: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including
rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis); acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias,
neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity;
psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease
(GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
19. A compound as claimed in Claim 18, wherein the condition is selected from: pain, acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
20. Use of a compound as claimed in any of Claims 1 to 16 for the manufacture of a medicament for the treatment or prevention of a condition selected from: pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis); acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive
impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy,
dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease
(GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids.
21 . Use as claimed in Claim 20, wherein the medicament is manufactured for the
treatment or prevention of a condition selected from: pain, acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including
rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
22. A method of treating or preventing a condition selected from pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post- operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer,
chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis); acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex, AIDS-related dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, Korsakoff syndrome, vascular dementia, and corticobasal degeneration; neurological disorders, including tinnitus, hearing loss, sound- or drug-induced tinnitus, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, spasmodic torticollis, blepharospasm, focal and generalized dystonia, nystagmus, Parkinson's dementia, mild cognitive
impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy,
dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, neurodegenerative cerebellar ataxias, centrally induced neuropathic pain, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, tremor, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, dementia, hereditary cerebellar ataxias, sleep disorders, movement disorders, essential tremor, muscle spasms, and spasticity; psychological/psychiatric disorders, including generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, post-operative cognitive deficit (POCD), cognitive impairment, learning impairment, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), dementia, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, major depressive disorder, major depression, depression, bipolar manic-depressive disorder, sleep disorders, agoraphobia, bulimia nervosa, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, and hyperactivity in children; drug/alcohol abuse, including craving (e.g., for drugs of abuse), abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, and amphetamine abuse; skin diseases, including atopic dermatitis, itching, skin lesions induced by severe itching or atopic dermatitis, systemic sclerosis, pruritic conditions, and pruritis; diseases of the gastro-intestinal tract and metabolic diseases, including diarrhoea, hepatic encephalopathy, hypoglycaemia, gastroesophageal reflux disease
(GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, vomiting, urinary incontinence, and regurgitation; diseases of the immune system, including Sjogren's syndrome, systemic lupus erythematosus, and multiple sclerosis (MS); eye diseases, including eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, and macular degeneration; diseases of the respiratory tract, including respiratory tract infection, chronic laryngitis, asthma, reflux-related asthma, and lung disease; migraine; autism; restless leg syndrome (RLS); Tourette syndrome; micturition disorders; neuromuscular disorder in the lower urinary tract; and drug tolerance to opioids, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound of Claim 1 .
The method of Claim 22, wherein the condition is selected from pain, acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
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JP2025515374A (en) * 2022-04-29 2025-05-14 ノエティクス ファルマ エルエルシー Prevention and treatment of postoperative cognitive dysfunction (POCD)
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