WO2007038571A2 - Prolyl hydroxylase antagonists - Google Patents

Prolyl hydroxylase antagonists Download PDF

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WO2007038571A2
WO2007038571A2 PCT/US2006/037611 US2006037611W WO2007038571A2 WO 2007038571 A2 WO2007038571 A2 WO 2007038571A2 US 2006037611 W US2006037611 W US 2006037611W WO 2007038571 A2 WO2007038571 A2 WO 2007038571A2
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Prior art keywords
alkyl
oxo
dihydro
hydroxy
glycine
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PCT/US2006/037611
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French (fr)
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WO2007038571A3 (en
Inventor
Deping Chai
Mariela COLÓN
Kevin J. Duffy
Duke M. Fitch
Rosanna Tedesco
Michael N. Zimmerman
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Smithkline Beecham Corporation
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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
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • 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
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

This invention relates to certain 2-[(quinolin-3-yl)carbonyl]aminoacetic acid derivatives of formula (I), where the various groups are defined herein, and which are useful in treating anemia.

Description

Prolyl Hydroxylase Antagonists
FIELD OF THE INVENTION
This invention relates to 2-[(quinolm-3-yl)carbonyl]aminoacetic acid derivatives that are inhibitors of prolyl hydroxylases, and thus have use in treating diseases benefiting from the inhibition of this enzyme, anemia being one example. BACKGROUND OF THE INVENTION
Anemia occurs when there is a decrease or abnormality in red blood cells, which leads to reduced oxygen levels in the blood. Anemia occurs often in cancer patients, particularly those receiving chemotherapy. Anemia is often seen in the elderly population, patients with renal disease, and in a wide variety of conditions associated with chronic disease.
Frequently, the cause of anemia is reduced erythropoietin (Epo) production resulting in prevention of erythropoiesis (maturation of red blood cells). Epo production can be increased by inhibition of prolyl hydroxylases that regulate hypoxia inducible factor (HIF).
One strategy to increase erythropoietin (Epo) production is to stabilize and thus increase the transcriptional activity of the BDDF. HIF-alpha subunits (HOF-lalpha, HIF-2alpha, and HIF-3alpha) are rapidly degraded by proteosome under normoxic conditions upon hydroxylation of proline residues by prolyl hydroxylases (EGLNl, 2, 3). Proline hydroxylation allows interaction with the von Hippel Lindau (VHL) protein, a component of an E3 ubiquitin ligase. This leads to ubiquitination of HIF- alpha and subsequent degradation. Under hypoxic conditions, the prolyl hydroxylases are inhibited, HIF-alpha subunits are stabilized, and HIF-responsive genes, including Epo, are transcribed. Thus, inhibition of prolyl hydroxylases results in increased levels of HIF-alpha and thus increased Epo production.
The compounds of this invention provide a means for inhibiting these hydroxylases, increasing Epo production, and thereby treating anemia. Ischemia, stroke, and cytoprotection may also benefit by administering these compounds. SUMMARY OF THE INVENTION
This invention is comprised of several aspects, including compounds of formula I
Figure imgf000002_0001
wherein: R1 is hydrogen, -NR6R7, -N=CR13R14, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 heterocycloalkyl, aryl, aryl Ci-C10 alkyl, heteroaryl or heteroaryl Q.Cioalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, C3-C6 cycloalkylaryl, aryl Ci-Ci0 alkyl, aryl, heteroaryl or heteroaryl Ci.CiOalkyl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, halo-substituted Ci-C6 alkyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, halo, cyano, nitro, -OR8, -C(O)R8, -C(O)OR8, -SR8, -S(O)R8, -S(O)2R8, -NR9R10, -CONR9R10, and -SO2NR9R10; wherein R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-C10 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl or heteroaryl group where the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, halo, cyano, nitro, -OR8, -C(O)R8, -C(O)OR8, -SR8, -S(O)R8, -S(O)2R8, -NR9R10, -CONR9R10, and -SO2NR9R10; or
R6 and R7 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
R2, R3, R4, and R5, are each independently selected from the group consisting of hydrogen, nitro, cyano, halo, -C(O)R8, -C(O)OR8, -OR8, -SR8, -S(O)R8, -S(O)2R8, -NR9R10, -CONR9R10, -N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10, -P(O)(OR8)2, -SO2NR9R10, -N(R9)SO2R8, C1-Ci0 alkyl, C2-Ci0 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, aryl Ci-Ci0 alkyl, heteroaryl and heteroaryl Ci.C10alkyl group; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Q-C6 alkyl, Q-C6 haloalkyl, aryl, heteroaryl, halo, -OR8, -SR8, -NR9R10, cyano, nitro, -C(O)R8, -C(O)OR8, -S(O)R8, -S(O)2R8, protected -OH, -CONR9R10, -N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10, -P(O)(OR8)2, -SO2NR9R10, -N(R9)SO2R8, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C6 cycloalkyl, a 3-6-membered heterocycloalkyl ring, aryl or heteroaryl group; or R2 and R3 form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N;
R3 and R4 form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N; R4 and R5 form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N; eacή K" is independently selected from the group consisting of hydrogen, Ci-C10 alkyl, C2-C10 alkeαyl, C2.C,0 alkynyl, halo C1-C4 alkyl, -CO(CrC4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(C1-C4 alkyl), C3-Cg cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, aryl Ci.Cio alkyl, and heteroaryl Q.Qoalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting Of Ci-C4 alkyl, halo Ci-C4 alkyl, halo, hydroxyl, -0(Ci-C4 alkyl), cyano, nitro, -N(Ci-C4 alkyl)(CrC4 alkyl), -NH(Q-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(CrC4 alkyl), -CO2H, -C0N(CrC4 alkyl)(CrC4 alkyl), -CONH(Ci-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(Ci-C4 alkyl),-OCON(CrC4 alkyl)(CrC4 alkyl), -OCONH(CrC4 alkyl),-SO2N(Ci-C4 alkyl)(CrC4 alkyl), -SO2NH(Ci-C4 alkyl), -SO2(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO(aryl) and -CO(heteroaryl); R9 and R10 are each independently selected from the group consisting of hydrogen, Ci-Qo alkyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -C0(Q-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(Ci-C4 alkyl), C3-C8 cycloalkyl-Ci-C10 alkyl, a 3-8-membered heterocycloalkyl ring-Ci-C10 alkyl, aryl-Q-Cio alkyl or heteroaryl-Q-Qo alkyl group; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulfur, where the alkyl, cycloalkyl, heterocycloalkyl, aryl , heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl or heteroarylalkyl group or 5- or 6-membered ring is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Q-C4 alkyl, Ci-C4 haloalkyl, halo, hydroxyl, -0(Ci-C4 alkyl), cyano, nitro,
-N(Ci-C4 alkyl)(Ci-C4 alkyl), -NH(CrC4 alkyl), -NH2, aryl, heteroaryl, -CO2(Ci-C4 alkyl), -CO2H, -CON(Ci-C4 alkyl)(Ci-C4 alkyl), -CONH(Ci-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHC0N(CrC4 alkyl)(CrC4 alkyl), -NHCONH(CrC4 alkyl), -0C0N(CrC4 alkyl)(CrC4 alkyl), -OCONH(Ci-C4 alkyl),-SO2N(CrC4 alkyl)(CrC4 alkyl), -SO2NH(Ci-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl);
R11 is -OR12, or -NR9R10, where R12 is hydrogen, an alkali metal cation or other cationic salt- forming group, or an ester-forming group exemplified by C1-C10 alkyl wherein the C1-C10 alky group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl, wherein R9, and R10 are the same as defined above;
R13 and R14 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C2-Ci0 alkynyl, halo C1-C4 alkyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(Ci-C4 alkyl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-C14 aryl, heteroaryl, aryl C1-Ci0 alkyl, and heteroaryl Ci.C10alkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(C1-C4 alkyl)(d-C4 alkyl), -NH(C1- C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(d- C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(C1-C4 alkyl)(C1-C4 alkyl), -NHCON(C1-C4 alkyl)(d-C4 alkyl), -NHCONH(C1-C4 alkyl),-0C0N(d-C4 alkyl)(Ci-C4 alkyl), -OCONH(C1-C4 alkyl),-SO2N(d-C4 alkyl)(d-C4 alkyl), -SO2NH(C1-C4 alkyl), -SO2(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); or a pharmaceutically acceptable salt thereof. In a second aspect of the present invention, there is provided a compound of formula (I) or a salt or solvate thereof for use in mammalian therapy, e.g. treating amenia. An example of this therapeutic approach is that of a method for treating anemia by increasing the production of erythropoietin (Epo) by inhibiting prolyl hydroxylases, comprising administering a compound of formula (I) to a patient in need thereof, neat or admixed with a pharmaceutically acceptable excipient, in an amount sufficient to increase production of Epo.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a salt, solvate, or the like thereof, and one or more of pharmaceutically acceptable carriers, diluents and excipients.
In a fourth aspect, there is provided the use of a compound of formula (I) or a salt or solvate thereof in the preparation of a medicament for use in the treatment of a hematopoietic disorder, such as an anemia, that can be treated by inhibiting prolyl hydroxylases.
DETAILED DESCRIPTION OF THE INVENTION
As noted above in the Background section, anemia occurs when there is a decrease or abnormality in red blood cells, which leads to reduced oxygen levels in the blood. Anemia occurs often in cancer patients, particularly those receiving chemotherapy. Anemia is often seen in the elderly population, patients with renal disease, and in a wide variety of conditions associated with chronic disease. Examples of diseases where anemia is involved, and where the instant compounds are expected to provide a therapeutic benefit are: anemia caused by impared kidney function, anemia caused by administration of a chemotherapeutic agent, treat anemia caused by a viral infection such as hepatitis, anemia caused by radiation therapy, anemia caused by iron deficiency, anemia caused by iii v, anemia causeα Dy cancer, anemia caused by chronic disease, anemia caused by inflammatory disease, and anemia caused by aplastic anemia or myelodysplastic syndrome.
Compounds of formula (I) and their derivatives may be combined with other therapeutic agents for increasing hematopoiesis. Without intending to limit combinations, some examples of types of therapeutic agents that might be combined (one or more) with the instant compounds are: DYRK/YAK inhibitors, specifically DYKR3/(YAK3) inhibitors; erythropoiesis-stimulating agent such as erythropoietin; an iron supplement; a vitamin B supplement; and/or a thrombopoietin agonist; and combined with granulocyte stimulating agents.
For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups the selected groups may be the same or different.
The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
An "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms, so for example, as used herein, the terms "Ci.C4-alkyl" and "C1-C10 alkyl" refers to an alkyl group having at least 1 and up to 4 or 10 carbon atoms respectively. Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl, and branched analogs of the latter 5 normal alkanes.
When the term "halo Ci-C4 alkyl" is used it refers to an alkyl group having at least 1 and up to 4 carbon atoms that is substituted with at least one halogen selected from F, Cl, Br, and I on any or all of the carbons. Examples include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-(trifluorornethyl)ethyl, and nonafluoro-tert-butyl.
When the term "alkenyl" (or "alkenylene") is used it refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propenylene). When the term "alkynyl" (or "alkynylene") is used it refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 5 carbon-carbon triple bonds. Examples include ethynyl (or ethynylene) and propynyl (or propynylene). When "cycloalkyl" is used it refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. So, for example, the term "C3-C8 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "C3- C8 cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term " C5-C8cycloalkenyl" refers to a non-aromatic monocyclic carboxycyclic ring having the specified number of carbon atoms and up to 3 carbon-carbon double bonds. "Cycloalkenyl" includes by way of example cyclopentenyl and cyclohexenyl.
Where the phrase "a 3-8-membered heterocycloalkyl" is used, it means a non-aromatic heterocyclic ring containing the specified number of ring atoms being, saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions selected from O, S and/or N. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane, tetrahydrofuran, dihydropyran, tetrahydropyran, 1,4- dioxane, 1,3-dioxane, piperidine, piperazine, 2,4-piperazinedione, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, morpholine, thiomorpholine, tetrahydrothiopyrane, tetrahydrothiophene, and the like.
"Aryl" refers to monocyclic and polycarbocyclic unfused or fused groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Hiickel's Rule. Such a ring may be optionally fused to one or more other "heterocyclic" ring(s) or cycloalkyl ring(s). Examples of aryl groups are phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, 5,6,7,8- tetrahydronaphthalenyl, indenyl, fluorenyl, 2,3-dihydro-l,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3- dihydro-1-benzofuranyl, 2,3-dihydro-l-benzothiophenyl, 2,3-dihydro-lH-indolyl, 2,3-dihydro-lH- benzimidazolyl, 2,3-dihydro-lH-benzoxazolyl, 2,3-dihydro-lH-benzothiazolyl, 3,4-dihydro-2H-l,4- benzoxazinyl, 3,4-dihydro-2H-l,4-benzothiazinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroquinoxalinyl, 3,4-dihydro-2H-l,4-chromenyl, 3,4-dihydro-2H-l,4-benzothiopyranyl and the like.
"Ηeteroaryl" means an aromatic monocyclic ring or polycarbocyclic fused ring system wherein at least one ring complies with Ηϋckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteratom selected from N, O, and/or S. Examples of "heteroaryl" groups include furanyls, thiophenyls, pyrrolyls, imidazolyls, pyrazolyls, triazolyls, tetrazolyls, oxazolyls, isoxazolyls, oxadiazolyls, oxo-pyridyls, thiadiazolyls, thiazolyls, isothiazolyls, pyridinyls, pyridazinyls, pyrazinyls, pyrimidinyls, triazinyls, quinolinyls, quinoxalinyls, quinazolinyls, isoquinolinyls, cinnolinyls, naphthyridinyls, benzofuranyls, benzothiophenyls, benzimidazolyls, benzoxazolyls, benzothiazolyls, isoindolyls, indolyls, purinyls, indazolyls, and carbazolyls; and derivatives thereof.
The term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s), which occur, and events that do not occur.
The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
Herein, the term "pharmaceutically-acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. These pharmaceutically-acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
In certain embodiments, compounds according to Formula I may contain an acidic functional group, one acidic enough to form salts. Representative salts include pharmaceutically-acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc salts; carbonates and bicarbonates of a pharmaceutically-acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and zinc; pharmaceutically-acceptable organic primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine. In certain embodiments, compounds according to Formula I may contain a basic functional group and are therefore capable of forming pharmaceutically-acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically-acceptable inorganic acids amd pharmaceutically-acceptable organic acids. Representative pharmaceutically-acceptable acid addition salts include hydrochloride, hydrobromide, nitrate, methylnitrate, sulfate, bisulfate, sulfamate, phosphatei acetate, hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, citrate, salicylate, p- aminosalicyclate, glycollate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o- acetoxybenzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate), p- aminobenzenesulfonate, p-toluenesulfonate (tosylate), and napthalene-2-sulfonate. The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, e.g. as the hydrate. This invention includes within its scope stoichiometric solvates (e.g. hydrates) as well as compounds containing variable amounts of solvent (e.g. water). Certain of the compounds described herein may contain one or more chiral atoms, or may otherwise be capable of existing as two enantiomers. The compounds claimed below include mixtures of enantiomers as well as purified enantiomers or enantiomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds represented by formula (I), or claimed below, as well as any wholly or partially equilibrated mixtures thereof. The present invention also covers the individual isomers of the claimed compounds as mixtures with isomers thereof in which one or more chiral centers are inverted. Also, it is understood that any tautomers and mixtures of tautomers of the claimed compounds are included within the scope of the compounds of formula (I). The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospeciiϊc or asymmetric syntheses.
While it is possible that, for use in therapy, a compound of formula (I), as well as salts, solvates and the like may be administered as a neat preparation, i.e. no additional carrier, the more usual practice is to present the active ingredient confected with a carrier or diluent. Accordingly, the invention further provides pharmaceutical compositions, which includes a compound of formula (I) and salts, solvates and the like, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I) and salts, solvates, etc, are as described above. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the formula (I), or salts, solvates etc, with one or more pharmaceutically acceptable carriers, diluents or excipients.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable prodrugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31, pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Preferred prodrugs for compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphatides, glycosides, ethers, acetals and ketals.
Where it is possible for compounds of formula (I) to exist in one or more tautomeric forms, all such tautomers and mixtures thereof are included in the scope of the invention.
Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the formula (I), depending on the condition being treated, the route of administration and the age, weight and condition of the patient, or pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage compositions are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association a compound of formal (I) with the carrier(s) or excipient(s).
Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound of formula (I). Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.
Where appropriate, dosage unit pharmaceutical compositions for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like. Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents. The pharmaceutical compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. A therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the intended recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant prescribing the medication. However, an effective amount of a compound of formula (I) for the treatment of anemia will generally be in the range of 0.1 to 100 mg/kg body weight of recipient per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same or intermittently, such as once every other day. An effective amount of a salt or solvate, etc., may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above. Exemplary Compounds
Compounds of formula (I) of particular interest are those where: R1 is hydrogen, -NR6R7, -N=CR6R7, Ci-Ci0 alkyl, C3-C8 cycloalkyl, aryl, aryl Ci-Ci0 alkyl,
C3-C6 cycloalkylaryl, heteroaryl or heteroaryl Q.Qoalkyl; where the alkyl, cycloalkyl, C3-C6 cycloalkylaryl, aryl, aryl Ci-Ci0 alkyl, heteroaryl or heteroaryl Q.Qoalky group is unsubstituted, or substituted on the alkyl group, or on the aromatic group, with one or more substituents independently selected from the group consisting of C1-C6 alkyl, halo, halo-substituted-Ci_C6 alkyl, C3-C6 cycloalkyl, a
C3-C8heterocyclic ring, aryl, heteroaryl, cyano, nitro, -C(O)R8, -C(O)OR8, -NR9R10, and -CONR9R10; wherein R6 and R7 are each independently hydrogen, Ci-Ci0 alkyl, or aryl C1-Ci0 alkyl; R2 is hydrogen, Ci-Ci0 alkyl, -OR8, or halo; R3 is hydrogen, halo, -OR8, Ci-Ci0 alkyl, halo Ci_C4-alkyl, nitro, or NR9R10;
R4 is hydrogen, -OR8, nitro, NR9R10, halo, Ci-C10 alkyl, halo Ci.C4-alkyl, -C(O)OR8; or R3 and R4 are combined to form a 3 or 4-membered heterocycloalkyl ring having 2 oxygens;
R5 is hydrogen or halo; where, for R2, R3, and R4, the C1-C10 alkyl group is unsubstituted or substituted or substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, halo, -OR8, -NR9R10, -C(O)R8, -C(O)OR8, protected -OH, -CONR9R10, -N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10; each R8 is independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, haloCi.C4-alkyl, -CO(Ci -C4 alkyl), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, aryl Ci.Cio alkyl, and heteroaryl Ci.Cioalkyl; where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, Cg-Ci4 aryl> heteroaryl, -0(C1-C4 alkyl), cyano, -N(Ci-C4-alkyl)(CrC4 alkyl), -NH(Ci-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(CrC4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(Ci-C4 alkyl), -CONH2, -N(Ci-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHC0N(CrC4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(Ci-C4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, and aryl Ci-Ci0 alkyl group in either of the two said instances under R8 is unsubstituted or substituted with one or more of C1-C4 alkyl, halo
Q.Q-alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(C1.C4-alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(Cr C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyiχCrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -C0(CrC4 alkyl), -CO(aryl) and -CO(heteroaryl);
R9 and R10 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(C1-C4 alkyl), C3-C8 cycloalkyl-CrC10 alkyl, a 3-8-membered heterocycloalkyl ring-Ci-C10 alkyl, aryl-CrC10 alkyl or heteroary 1-Ci-Ci0 alkyl group; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulfur, where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, -0(C1-C4 alkyl), cyano,
Figure imgf000013_0001
alkyl), -NH(Ci-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(Ci-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(CrC4 alkyl),
-CONH2, -N(Ci-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(Q-C4 alkyl), -OCON(CrC4 alkyl)(CrC4 alkyl), -OCONH(Ci-C4 alkyl), -CO(Ci-C4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, and aryl-QAo alkyl group in either of the two said instances under R9 and R10 are unsubstituted or substituted with one or more of C1-C4 alkyl, halo C1-C4-alkyl, halo, hydroxyl, -Q(C1-C4 alkyl), cyano, nitro, -N(C1.C4-alkyl)(C1-C4 alkyl), -NH(Ci-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -C0N(CrC4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); R11 is -OR12, or -NR9R10, where R12 is hydrogen, an alkali metal cation or other cationic salt- forming group, or an ester-forming group C1-C10 alkyl wherein the C1-C10 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl and R9, and R10 are the same as defined above; or a pharmaceutically acceptable salt thereof.
A further subset of compounds of interest are those where:
R1 is hydrogen, -NR6R7, -N=CR6R7, Ci-C10 alkyl, cyclohexyl, or phenyl; where the C1-C10 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, -C(O)R8, -C(O)OR8, -NR9R10, and -CONR9R10, C3-C6 cycloalkyl, and a C3-C8heterocyclic ring, and phenyl, biphenyl, 5,6,7,8-tetrahydronaphthalenyl, imidazolyl, 1,3-thiazolyl, isoxazolyl, pyridinyl, quinoxalinyL. or 3-dihydro-2H-isoindolyl, wherein each group is unsubstituted or subsitited with one or more substituents selected from the group consisting of C1-C10 alkyl, halo Q-Qalkyl, halo, cyano, nitro, OR8, -C(O)R8, -C(O)OR8, -NR9R10, and -CONR9R10; wherein R6 and R7 are each independently hydrogen, C1-C10 alkyl, or aryl C1-Ci0 alkyl; R2 is hydrogen, C1-C10 alkyl, -OR8, or halo;
R3 is hydrogen, halo, -OR8, Ci-Ci0 alkyl, halo
Figure imgf000014_0001
nitro, or NR9R10; R4 is hydrogen, -OR8, nitro, NR9R10, halo, Ci-Ci0 alkyl, halo dA-alkyl, -C(O)OR8; or R3 and R4 are combined to form a 3 or 4-membered heterocycloalkyl ring having 2 oxygens;
R5 is hydrogen or halo; where, for R2, R3, and R4, the Ci-Ci0 alkyl group is unsubstituted or substituted or substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, halo, -OR8, -NR9R10, -C(O)R8, -C(O)OR8, protected -OH, -CONR9R10,
-N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10; each R8 is independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, haloCi.Q-alkyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-C14 aryl, heteroaryl, aryl Ci-Ci0 alkyl, and heteroaryl C1-Ci0 alkyl; where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, -0(Ci-C4 alkyl), cyano, -N(C1-C4-alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-C14 aryl, heteroaryl, and aryl-Q.Qo alkyl group in either of the two said instances under R8 is unsubstituted or substituted with one or more of C1-C4 alkyl, halo C1-C4-alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(Ci.C4-alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(CX-C4 alkyl)(Cr C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(C1-C4 alkyl),
-NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl);
R9 and R10 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(C1-C4 alkyl), C3-C8 cycloalkyl-Q-Qo alkyl, a 3-8-membered heterocycloalkyl rmg-Q-Cjo alkyl, aryl-Q-Qo alkyl or heteroaryl-Q-Cio alkyl group; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulfur, where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, C6-C14 aryl, heteroaryl,
-0(C1-C4 alkyl), cyano, -N(C1-C4-alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHC0N(CrC4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(Cj-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-C14 aryl, heteroaryl, and aryl-Q.Qo alkyl group in either of the two said instances under R9 and R10 are unsubstituted or substituted with one or more of C1-C4 alkyl, halo Q.Q-alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(C1.C4-alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); R11 is -OR12, or -NR9R10, where R12 is hydrogen, an alkali metal cation or other cationic salt- forming group, or an ester-forming group C1-C1O alkyl wherein the C1-C10 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl and R9, and R10 are the same as defined above; or a pharmaceutically acceptable salt thereof.
Chemical Background:
The compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention as prepared are given in the examples.
Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts
(1991) Protecting Groups in Organic Synthesis. John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula (T). Those skilled in the art will recognize if a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).
The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic processes. An illustrative method for making these starting compounds and intermediates can be found in a WIPO-published patent application, namely: D. Chai, M. G. Darcy, D. Dhanak, K. J. Duffy, G. A. Erickson, D. M. Fitch, A. T. Gates, V. K. Johnston, R. T. Sarisky, M. J. Sharp, A. N. Shaw, R. Tedesco, K. J. Wiggall, M. N. Zimmerman "Quinolinylthiadiazine dioxides as antiviral agents for treating hepatitis C" PCT Int. Appl. (2002), WO 2002098424 Al
Illustrated Methods of preparation Schemes Included in the present invention is a process according to Schemes 1 and 2 for the synthesis of the compounds:
Scheme 1
Figure imgf000017_0001
a) Diethyl malonate, DBU, 1,4-dioxane, 150 0C, microwave then glycine, 200 0C, microwave.
Scheme 2
Figure imgf000017_0002
Figure imgf000017_0003
a) NaB(OAc)3, AcOH, R1CHO, room temperature; b) CH(CO2Et)3, 1,4-dioxane, 250 0C, microwave; c) NaH, R' CH2X, DMF then diethyl malonate, NaH, 150 0C, microwave; d) glycine, DBU, EtOH, 180 0C, microwave or glycine sodium salt, EtOH, 150-180 0C, microwave.
An appropriately substituted isatoic anhydride derivative may be alkylated with a malonate diester, such as diethyl malonate, in the presence of an appropriate base, such as 1,8- diazabicyclo[5.4.0]undec-7-ene or sodium hydride, either neat or in an appropriate solvent, such as 1,4-dioxane or NN-dimethylformamide, followed by heating under either conventional thermal conditions or by microwave irradiation. Subsequent in situ addition of glycine, followed by further heating under either conventional thermal conditions or by microwave irradiation, provided compounds of formula (I). Alternatively, an appropriately substituted aniline may be reductively alkylated with an appropriate aldehyde or ketone in the presence of an appropriate reducing agent such as sodium triacetoxyborohydride in an appropriate solvent such as acetic acid. Heating of the N- alkylated anilines in the presence of a methanetricarboxylate triester, such as triethyl methanetricarboxylate, under either conventional thermal conditions or by microwave irradiation, provided 4-hydroxy-2-oxo-l,2-dihydro-3-quinolinecarboxylate ester derivatives. Alternatively, an appropriately substituted isatoic anhydride derivative may be N-alkylated with an alkyl halide, such as an appropriately substituted benzyl bromide, in the presence of an appropriate base, such as sodium hydride in an appropriate solvent, such as NN-dimethylformamide, followed by alkylation with a malonate diester, such as diethyl malonate, in the presence of an appropriate base, such as sodium hydride, followed by heating under either conventional thermal conditions or by microwave irradiation to afford 4-hydroxy-2-oxo-l,2-dihydro-3-quinolinec'arboxylate ester derivatives. Compounds of formula (I) are prepared by heating the 4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate ester derivatives in the presence of glycine sodium salt or glycine with an appropriate base, such as l,8-diazabicyclo[5.4.0]undec-7-ene, sodium ethoxide or sodium hydride, in an appropriate solvent, such as ethanol or 1,4-dioxane, under either conventional thermal conditions or by microwave irradiation.
Experinientals
Figure imgf000018_0001
Ν-r("4-Hydroxy-l-methyl-2-oxo-l,2-dihydro-3-quinolinyl')carbonynglvcine A mixture of N-(methyl)isatoic anhydride (0.354 g, 2.0 mmol) and diethylmalonate (0.304 mL, 2.0 mmol) was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (0.598 mL, 4.0 mmol). 1,4- Dioxane (2.0 mL) was added and the solution was heated to 1500C for 20 min. in a Biotage Initiator microwave synthesizer (http://www.biotagexom/DynPage.aspx?id=2929&mnl=1158). Following cooling, glycine (0.225 g, 3.0 mmol) was added and the solution was heated to 2000C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with IM aqueous hydrochloric acid (5.0 mL), filtered, and washed with water and ethyl acetate to give the title compound as a light brown solid (0.082 g; 15%). Following extraction with ethyl acetate, the filtrate was purified via flash column chromatography (50-100% ethyl acetate in hexanes) to provide additional title compound as a beige solid (0.176 g, 32%). 1H NMR (400 MHz, DMSCW6) δ ppm 12.9 (s, 1 H) 10.6 (t, /=5.6 Hz, 1 H) 8.09 (dd, /=8.0, 1.4 Hz, 1 H) 7.82 (ddd, /=8.6, 7.1, 1.5 Hz, 1 H) 7.63 (d, /=8.3 Hz, 1 H) 7.38 (t, /=7.6 Hz, 1 H) 4.14 (d, /=5.6 Hz, 2 H) 3.64 (s, 3 H). MS(ES+) m/e 339 [M+H]+.
Example 2
Figure imgf000018_0002
N-r(4-Hvdroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyllglvcine
A mixture of isatoic anhydride (0.326 g, 2.0 mmol) and diethylmalonate (0.304 mL, 2.0 mmol) was treated with l,8-diazabicyclo[5.4.0]undec-7-ene (0.598 mL, 4.0 mmol). 1,4-Dioxane (2.0 mL) was added and the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Following cooling, glycine (0.225 g, 3.0 mmol) was added and the solution was heated to 200 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous sodium hydroxide (2.0 mL), diluted with water and extracted with diethyl ether. The aqueous layer was then acidified with 6M aqueous hydrochloric acid and extracted twice with ethyl acetate. The organic solution was dried over MgSO4, filtered, concentrated in vacuo, and triturated with ethyl acetate to give the title compound as a light brown solid (0.136 g; 26%). 1H NMR (400 MHz, DMSO-J6) δ ppm 12.9 (s, 1 H) 11.9 (s, 1 H) 10.5 (t, 7=5.3 Hz, 1 H) 7.97 (d, 7=8.1 Hz, 1 H) 7.69 (t, 7=7.6 Hz, 1 H) 7.37 (d, 7=8.3 Hz, 1 H) 7.28 (t, 7=7.6 Hz, 1 H) 4.13 (d, 7=5.6 Hz, 2 H). MS(ES+) m/e 263 [M+H]+.
Example 3
Figure imgf000019_0001
N-I F4-Hvdroxy-l-(3-methylbutyl)-2-oxo-l,2-dihvdro-3-quinolinyllcarbonyl| glycine
Following the procedure of Example 2, except substituting N-(3-methylbutyl)isatoic anhydride (WO 02/098424) for isatoic anhydride, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 12.9 (s, 1 H) 10.6 (t, 7=5.6 Hz, 1 H) 8.11 (dd, 7=8.1, 1.5 Hz, 1 H) 7.83 (ddd, 7=8.9, 7.0, 1.7 Hz, 1 H) 7.59 (d, 7=8.8 Hz, 1 H) 7.37 (t, 7=7.5 Hz, 1 H) 4.22 - 4.30 (m, 2 H) 4.13 (d, 7=5.6 Hz, 2 H) 1.75 (qq, 7=6.8, 6.7 Hz, 1 H) 1.40 - 1.55 (m, 2 H) 0.98 (d, 7=6.6 Hz, 6 H). MS(ES+) m/e 333 [M+H]+. Example 4
Figure imgf000019_0002
N-r^-Hvdroxy^-oxo-l-phenyl-l^-dihvdro-S-quinolinvDcarbonyllglvcine
Following the procedure of Example 2, except substituting N-(phenyl)isatoic anhydride (WO 02/098424) for isatoic anhydride, the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 13.0 (s, 1 H) 10.4 (t, 7=5.2 Hz, 1 H) 8.14 (d, 7=7.1 Hz, 1 H) 7.53 - 7.69 (m, 4 H) 7.39 (d, 7=7.8 Hz, 2 H) 7.35 (d, 7=6.9 Hz, 1 H) 6.57 (d, 7=8.6 Hz, 1 H) 4.10 (d, 7=5.3 Hz, 2 H). MS(ES+) m/e 339 [M+H]+.
Figure imgf000020_0001
N-114-Hvdroxy-2-oxo- 1 -(phenylmethyl)-l ,2-dihydro-3-quinolinyl1carbonyl I glycine
Following the procedure of Example 2, except substituting N-(benzyl)isatoic anhydride for isatoic anhydride, the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 13.0 (s, 1 H) 10.5 (t, 7=5.4 Hz, 1 H) 8.13 (dd, 7=8.1, 1.5 Hz, 1 H) 7.71 (ddd, 7=8.7, 7.1, 1.6 Hz, 1 H) 7.48 (d, 7=8.6 Hz, 1 H) 7.35 (t, 7=7.6 Hz, 1 H) 7.32 (t, 7=7.6 Hz, 2 H) 7.24 (t, 7=7.3 Hz, 1 H) 7.22 (d, 7=6.8 Hz, 2 H) 5.56 (s, 2 H) 4.15 (d, 7=5.6 Hz, 2 H). MS(ES+) m/e 353 [M+H]+.
Alternatively, the compound from Example 5 can be prepared according to the following method:
5a) Ethyl 4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 -quinolinecarboxylate To a mixture of N-(benzyl)isatoic anhydride (5.00 g, 19.7 mmol) and diethyl malonate (3.00 mL, 19.7 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (5.90 mL, 39.5 mmol) dropwise. Following stirring at ambient temperature for 15 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with 6M aqueous hydrochloric acid, diluted with brine, and extracted thrice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (5-40% ethyl acetate in hexanes) to afford the title compound as a white solid (5.13 g, 80%). 1H ΝMR (400 MHz, CHLOROFORM-J) δ ppm 14.4 (s, 1 H), 8.20 (dd, 7=8.1, 1.3 Hz, 1 H), 7.53 (ddd, 7=8.5, 7.1, 1.5 Hz, 1 H), 7.29 (t, 7=7.0 Hz, 2 H), 7.22 (d, 7=8.1 Hz, 2 H), 7.17 - 7.21 (m, 3 H), 5.51 (s, 2 H), 4.52 (q, 7=7.2 Hz, 2 H), 1.49 (t, 7=7.1 Hz, 3 H). MS(ES+) m/e 324 [M+H]+. 5b) N-{r4-Hvdroxy-2-oxo-l-(phenylmethyl)-L2-dihydro-3-qumolinyncarbonyl|glycine A mixture of ethyl 4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinecarboxylate (5.09 g, 15.7 mmol) and glycine sodium salt (2.29 g, 23.6 mmol) in ethanol (10.0 mL) was heated to 200 0C for 2 minutes followed by 150 0C for 5 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with 6M aqueous hydrochloric acid, diluted with water, filtered, washed with water, methanol, and CH2Cl2, and concentrated in vacuo to afford the title compound as a white solid (5.00 g, 90%). 1H ΝMR (400 MHz, DMSO-4) δ ppm 13.0 (s, 1 H), 10.5 (t, 7=5.4 Hz, 1 H), 8.12 (dd, 7=8.1, 1.3 Hz, 1 H), 7.70 (ddd, 7=8.7, 7.1, 1.6 Hz, 1 H), 7.47 (d, 7=8.6 Hz, 1 H), 7.35 (t, 7=7.6 Hz, 1 H), 7.32 (t, 7=7.4 Hz, 2 H), 7.24 (t, 7=7.3 Hz, 1 H), 7.22 (d, 7=7.1 Hz, 2 H), 5.56 (s, 2 H), 4.15 (d, 7=5.6 Hz, 2 H). MS(ES+) m/e 353 [M+H]+.
Alternatively, the compound from Example 5 can be prepared according to the following method: 5 a' ) 1 -(phenylmethyl")-2H-3 , 1 -benzoxazine-2.4f lH)-dione
A suspension of sodium hydride (40.0 g, 60% dispersion in mineral oil, 1.00 mole) in dry tetrahydrofuran (400 mL) was cooled to 10 0C then treated dropwise with a solution of isatoic anhydride (163 g, 1.00 mole) in dry N,N-dimethylacetamide (400 mL) and the mixture stirred for 30 min. after complete addition at 100C. A solution of benzyl bromide (171 g, 1.00 mole) in dry tetrahydrofuran (250 mL) was then added dropwise and the mixture was stirred and allowed to warm to ambient temperature overnight. The mixture was poured into water (1.5 L) and extracted with EtOAc (3 x 1 L), the extracts then dried over sodium sulphate, filtered, and evaporated. The gummy residue was left under high vacuum overnight to give a semi-solid which was then crystallized from toluene (1.2 L) to give the title compound (122.4 g, 48%) as tan needles. A second crop was obtained from the filtrate (14.4 g, 6%). 1H ΝMR (400 MHz, DMSO-^6) δ ppm 8.04 (dd, 7=7.83, 1.5 Hz, 1 H), 7.74 (ddd, 7=8.6, 7.2, 1.6 Hz, 1 H), 7.40 - 7.44 (m, 2 H), 7.26 - 7.37 (m, 5 H), 5.30 (s, 2 H). 5b') Ethyl 4-hvdroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinecarboxylate A suspension of hexanes-washed sodium hydride (23.5 g, 60% dispersion in mineral oil, 0.59 mole) in dry N,N-dimethylacetamide (250 mL) was cooled to 5 0C then treated dropwise with a solution of diethyl malonate (94.1 g, 0.59 mole) in NN-dimethylacetamide (300 mL) and the mixture stirred at 5 0C for 60 min. after complete addition. A solution of l-(phenylmethyl)-2H-3,l-benzoxazine-2,4(lH)- dione (120 g, 0.47 mole) in dry N,N-dimethylacetamide (500 mL) was then added dropwise and the mixture was stirred and heated at 120 0C for 17 h. The heating was then removed and the reaction mixture treated dropwise with glacial acetic acid (40.0 g) and allowed to cool to ambient temperature. The reaction mixture was then poured into water (2.5 L) and extracted with EtOAc (2 x 2 L). The extracts were washed with brine (1 L), dried and evaporated, and the residual semi-solid washed with minimal ethanol (~ 300 mL) and filtered to afford the title compound (125.9 g, 83%) as a cream crystalline material. 1H ΝMR (400 MHz, DMSO-4) δ ppm 13.2 (s, 1 H), 8.09 (d, 7=7.8 Hz, 1 H), 7.64 (t, 7=7.8 Hz, 1 H), 7.37 (d, 7=8.6 Hz, 1 H), 7.23 - 7.33 (m, 4 H), 7.20 (d, 7=7.6 Hz, 2 H), 5.47 (s, 2 H), 4.36 (q, 7=7.1 Hz, 2 H), 1.33 (t, 7=7.1 Hz, 3 H).
5c ' ) N- { r4-Hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3-quinorinyll carbonyl I glycine A mixture of ethyl 4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinecarboxylate (125.9 g, 0.39 mole) and glycine sodium salt (47.2 g, 0.49 mole) in 2-methoxyethanol (1 L) was stirred and heated under reflux for 2 h. The cooled solution was then poured into water (2 L) and acidified by dropwise addition of 6M aqueous hydrochloric acid (100 mL). Filtration afforded the crude product (117 g) as a colorless powder which was crystallized from glacial acetic acid (1.5 L) to afford the title compound (84.0 g, 61%) as colorless needles. 1H ΝMR (400 MHz, DMSO-J6) δ ppm 13.0 (s, 1 H), 10.5 (t, 7=5.4 Hz, 1 H), 8.14 (dd, 7=8.0, 1.4 Hz, 1 H), 7.72 (td, 7=7.8, 1.5 Hz, 1 H), 7.48 (d, 7=8.6 Hz, 1 H), 7.30 - 7.38 (m, 3 H), 7.21 - 7.27 (m, 3 H), 5.57 (s, 2 H), 4.15 (d, 7=5.6 Hz, 2 H). mp. 240-242 0C. C19Hi6N2O5 requires: %C, 64.71; %H, 4.54; %N, 7.95; found: %C, 64.74; %H, 4.14; %N, 7.48. Example 6
Figure imgf000022_0001
N-f 1 l-(CyclohexylmethylV4-hydroxy-2-oxo-l ,2-dihydro-3-quinolinyncarbonyl \ glycine
Following the procedure of Example 2, except substituting N-(cyclohexylmethyl)isatoic anhydride (WO 02/098424) for isatoic anhydride, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 10.7 (t, 7=5.1 Hz, 1 H) 8.20 (d, 7=7.3 Hz, 1 H) 7.76 (ddd, 7=8.7, 7.1, 1.6 Hz, 1 H) 7.56 (d, 7=8.6 Hz, 1 H) 7.34 (t, 7=7.3 Hz, 1 H) 4.12 - 4.31 (m, 4 H) 1.85 - 1.92 (m, 1 H) 1.70 - 1.78 (m, 2 H) 1.59 - 1.70 (m, 7=6.3 Hz, 2 H) 1.13 - 1.28 (m, 4 H) 0.80 - 0.94 (m, 2 H). MS(ES+) m/e 359 [M+H]+. Example 7
Figure imgf000022_0002
N-I r4-Hydroxy-7-(methyloxy)-2-oxo-l-(phenylmethyl)-l ,2-dihydro-3-quinolinyl1carbonyl I glycine
7a) [3 -(Methyloxy )phenyll (phenylmethyl)amine
To a solution of benzaldehyde (0.83 mL, 8.1 mmol) and 3-(methyloxy)aniline (1.0 g, 8.1 mmol) in CH2Cl2 (10.0 mL) was added sodium triacetoxyborohydride (1.88 g, 8.9 mmol) and acetic acid (0.51 mL, 8.9 mmol). The mixture was stirred overnight at ambient temperature, quenched by water, and extracted by CH2Cl2. The organic layer was dried over MgSO4, filtered, concentrated in vacuo and purified via flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow oil (1.2 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 7.35 - 7.44 (m, 4 H) 7.27 - 7.34 (m, 1 H) 7.12 (t, 7=8.1 Hz, 1 H) 6.27 - 6.36 (m, 2 H) 6.24 (t, 7=2.3 Hz, 1 H) 4.35 (m, 2 H) 3.79 (s, 3 H). MS(ES+) m/e 214 [M+H]+.
7b) Ethyl 4-hydroxy-7-(methyloxy V2-oxo- 1 -(phenylmethyl)- 1 ,2-dihvdro-3 - quinolinecarboxylate
A mixture of the compound from Example 7a) (0.760 g, 3.60 mmol) and triethyl methanetricarboxylate (2.30 mL, 10.7 mmol) in 1,4-dioxane (5.0 mL) was heated to 2500C for 30 min. in a Biotage Initiator microwave synthesizer. The mixture was concentrated in vacuo and purified via flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow solid (0.610 g, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 14.4 (s, 1 H) 8.11 (d, 7=9.1 Hz, 1 H) 7.21 - 7.35 (m, 5 H) 6.79 (dd, 7=9.1, 2.3 Hz, 1 H) 6.63 (d, J=2.3 Hz, 1 H) 4.53 (q, 7=7.2 Hz, 2 H) 3.77 (s, 3 H) 1.51 (t, 7=7.2 Hz, 3 H). MS(ES+) m/e 354 [M+H]+.
7c ) N-I r4-Hvdroxy-7-(methyloxy)-2-oxo-l-(phenylmethyl)-1.2-dihydro-3- quinolinyll carbonyl I glycine A mixture of the compound from Example 7b) (0.110 g, 0.310 mmol), glycine (0.350 g, 0.470 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.093 mL, 0.620 mmol) in ethanol (3.0 mL) was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. The mixture was concentrated and purified via flash chromatography (0-10% methanol in CH2Cl2) to afford the title compound as a grey solid (0.095 g, 80%). 1H NMR (400 MHz, DMSOd6) δ ppm 10.5 (t, 7=5.4 Hz, 1 H) 8.03 (d, 7=8.8 Hz, 1 H) 7.29 - 7.38 (m, 2 H) 7.26 (d, 7=7.6 Hz, 3 H) 6.97 (dd, 7=9.0, 2.15 Hz, 1 H) 6.87 (d, 7=2.3 Hz, 1 H) 5.55 (s, 2 H) 4.14 (d, 7=5.6 Hz, 2 H) 3.79 (s, 3 H). MS(ES+) m/e 384 [M+H]+.
Example 8
Figure imgf000023_0001
N-(j4-Hvdroxy-2-oxo-l-(phenylmethyl)-7-r(phenylmethyl)oxy1-l,2-dihydro-3- quinolinyl ) carbonyDglycine
8a) N-(Phenylmethyl)-3-r(phenylmethyl)oxylaniline
Following the procedure of Example 7a), except substituting 3-(benzyloxy)aniline for 3- (methyloxy)aniline, the title compound was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.27 - 7.49 (m, 10 H) 7.08 - 7.15 (m, 1 H) 6.37 - 6.43 (m, 1 H) 6.27 - 6.34 (m, 2 H) 5.04 (s, 2 H) 4.34 (s, 2 H). MS(ES+) m/e 290 [M+H]+.
8b) Ethyl 4-hydroxy-2-oxo- 1 -(phenylmethyl)-7-r(phenylmethyl)oxy1- 1 ,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 7b), except substituting the compound from Example 8a) for the compound from Example 7a), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 14.4 (s, 1 H) 8.12 (d, 7=8.8 Hz, 1 H) 7.13 - 7.45 (m, 10 H) 6.87 (dd, 7=8.8, 2.27 Hz, 1 H) 6.69 (d, 7=2.3 Hz, 1 H) 5.44 (s, 1 H) 5.01 (s, 2 H) 4.53 (q, 7=7.1 Hz, 2 H) 1.50 (t, 7=7.1 Hz, 3 H). MS(ES+) m/e 430 [M+H]+.
8c) N-({4-Hvdroχy-2-oxo-l-(phenylmethyl)-7-r(phenylmethyl)oxyl-l,2-dihvdro-3- quinolinyl )carbonyl)glycine
A mixture of the compound from Example 8b) (0.180 g, 0.430 mmol), glycine (0.048 g, 0.645 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.140 mL, 0.860 mmol) in ethanol (3.0 mL) was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Following concentration in vacuo, the reaction mixture was purified via preparative HPLC chromatography (YMC 75 X 30 mm column, 0.1% TFA in water and 0.1% TFA in acetonitrile) to afford the title compound as a grey solid (0.120 g, 61%). 1H NMR (400 MHz, DMSO-J6) δ ppm 13.0 (s, 1 H), 10.5 (t, /=5.6 Hz, 1 H), 8.05 (d, /=8.8 Hz, 1 H), 7.16 - 7.49 (m, 10 H), 6.88 - 7.13 (m, 2 H), 5.54 (s, 2 H), 5.17 (s, 2 H), 4.14 (d, /=5.6 Hz, 2 H). MS(ES+) m/e 459 [M+H]+.
Example 9
Figure imgf000024_0001
N-ir4-Hvdroxy-7-r(l-methylethyl)oxy1-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3- quinolinylicarbonyl } glycine 9a) 3 -f ( 1 -MethylethyDoxylphenyl I (phenylmethyl)amine
Following the procedure of Example 7a), except substituting 3-(isopropyloxy)aniline for 3- (methyloxy)aniline, the title compound was obtained as a yellow oil. MS(ES+) m/e 242 [M+H]+.
9b) Ethyl 4-hydroxy-7-IYl -methylethyl)oxyl-2-oxo-l -(phenylmethyl)-l ,2-dihydro-3- quinolinecarboxylate Following the procedure of Example 7b), except substituting the compound from Example
9a) for the compound from Example 7a), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 14.4 (s, 1 H) 8.08 (d, /=9.1 Hz, 1 H) 7.14 - 7.40 (m, 5 H) 6.75 (dd, /=9.1, 2.3 Hz, 1 H) 6.58 (d, /=2.0 Hz, 1 H) 5.48 (s, 1 H) 4.39 - 4.59 (m, 3 H) 1.50 (t, /=7.2 Hz, 3 H) 1.24 (d, /=6.1 Hz, 6 H). MS(ES+) m/e 382 [M+HJ+. 9c) N-( r4-Hvdroxy-7-rd-methylethyDoχyl-2-oxo-l-(phenylmethylV1.2-dihvdro-3- qumolinyllcarbonyllglycine
A mixture of the compound from Example 9b) (0.180 g, 0.470 mmol), glycine (0.052 g, 0.710 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.140 mL, 0.940 mmol) in ethanol (3.0 mL) was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. Following concentration in vacuo, the reaction mixture was purified via preparative HPLC chromatography (YMC 75 X 30 mm column, 0.1% TFA in water and 0.1% TFA in acetonitrile) to afford the title compound as a grey solid (0.100 g, 52%). 1H NMR (400 MHz, DMS(W6) δ ppm 13.0 (s, 1 H) 10.5 (t, /=5.6 Hz, 1 H) 8.00 (d, /=9.1 Hz, 1 H) 7.33 (t, /=7.5 Hz, 2 H) 7.21 - 7.28 (m, 3 H) 6.92 (dd, /=8.8, 2.0 Hz, 1 H) 6.78 (d, /=2.0 Hz, 1 H) 5.56 (s, 1 H) 4.68 - 4.79 (m, 1 H) 4.14 (d, /=5.6 Hz, 2 H) 1.17 (d, /=6.1 Hz, 6 H). MS(ES+) m/e 411 [M+H]+.
Figure imgf000025_0001
N-IK-Hvdroxy^-oxo-l-CphenylmethylVT-CplienyloxyVl^-dihvdro-S-quinolinylicarbonyllglvcine
1 Oa) N-("Phenylmethyl)-3 -(phenyloxy)anirine Following the procedure of Example 7a), except substituting 3-(phenyloxy)aniline for 3-
(methyloxy)aniline, the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.29 - 7.42 (m, 7 H) 7.10 - 7.19 (m, 2 H) 7.03 - 7.09 (m, 2 H) 6.38 - 6.46 (m, 2 H) 6.35 (t, 7=2.3 Hz, 1 H) 4.33 (d, J=5.1 Hz, 2 H). MS(ES+) m/e 276 [M+H]+.
IQb) Ethyl 4-hvdroxy-2-oxo-l-(phenylmethyl)-7-(phenyloxy)-l,2-dihydro-3- quinormecarboxylate
Following the procedure of Example 7b), except substituting the compound from Example 10a) for the compound from Example 7a), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 14.4 (s, 1 H) 8.12 (d, J=8.8 Hz, 1 H) 7.34 - 7.43 (m, 2 H) 7.19 - 7.29 (m, 4 H) 7.03 (dd, /=7.2, 2.40 Hz, 2 H) 6.92 - 6.99 (m, 2 H) 6.85 (dd, 7=8.8, 2.3 Hz, 1 H) 5.32 (br. s., 2 H) 4.53 (q, 7=7.1 Hz, 2 H) 1.51 (t, 7=7.1 Hz, 3 H). MS(ES+) m/e 416 [M+H]+.
IQc) N-( r4-Hvdroxy-2-oxo-l-(phenylmethyl)-7-(phenyloxy)-L2-dihydro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 7c), except substituting the compound from Example 10b) for the compound from Example 7b), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H) 10.5 (t, 7=5.4 Hz, 1 H) 8.10 (d, 7=9.6 Hz, 1 H) 7.44 (t, 7=8.0 Hz, 2 H) 7.22 - 7.33 (m, 4 H) 7.01 - 7.10 (m, 4 H) 6.87 - 6.95 (m, 2 H) 5.42 (br. s., 2 H) 4.15 (d, 7=5.6 Hz, 2 H). MS(ES+) m/e 445 [M+H]+.
Example 11
Figure imgf000025_0002
N-rd-Cvclohexyl-4-hydroxy-2-oxo-1.2-dihvdro-3-12qumolinyl)carbonyllglvcine
1 Ia) Ethyl l-cvclohexyl-4-hvdroxy-2-oxo-l,2-dihydro-3-quinolinecarboxylate A mixture of N-cyclohexylaniline (1.0 g, 5.7 mmol) and triethyl methanetricarboxylate (3.63 mL, 17.1 mmol) in 1,4-dioxane (5.0 mL) was heated to 250 0C for 2.5 hours in a Biotage Initiator microwave synthesizer. The mixture was concentrated in vacuo and purified twice via flash column chromatography (0-10% methanol in chloroform, followed by 0-100% ethyl acetate in hexanes) to give the title compound as a yellow solid (0.81 g, 45%). MS(ES+) m/e 316 [M+H]+. llb) N-r(l-Cyclohexyl-4-hydroxy-2-oxo-l,2-dihvdro-3-qumolinyl)carbonyllglvcine A mixture of the compound from Example 1 Ia) (0.03 g, 0.095 mmol) and glycine sodium salt (0.014 g, 0.14 mmol) in ethanol (3.0 iriL) was heated to 180 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, IM aqueous HCl (2.0 mL) was added. The precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as a yellow solid (0.025 g, 76%). 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H) 10.6 (s, 1 H) 8.11 (dd, 7=7.8, 1.5 Hz, 1 H) 7.91 (br. s., 1 H) 7.74 - 7.82 (m, 1 H) 7.36 (t, /=7.7 Hz, 1 H) 4.13 (d, 7=5.6 Hz, 2 H) 2.40 - 2.71 (m, 3 H) 1.85 (d, J=ILl Hz, 2 H) 1.69 (d, 7=11.4 Hz, 3 H) 1.41 - 1.56 (m, 2 H) 1.16 - 1.36 (m, 1 H). MS(ES+) m/e 345 [M+H]+
Example 12
Figure imgf000026_0001
N-{ r4-Hvdroxy- 1 -( 1 -methylethyl)-2-oxo- 1 ,2-dihydro-3-qumorinyll carbonyl I glycine 12a) Ethyl 4-hvdroxy- 1 -( 1 -methylethyl)-2-oxo- 1 ,2-dihvdro-3 -quinolinecarboxylate
Following the procedure of Example Ha), except substituting N-isoproplyaniline for N- cyclohexylaniline, the title compound was obtained as a yellow solid. MS(ES+) m/e 276 [M+H]+. 12b) N-{ r4-Hydroxy-l-(l-methylethyl)-2-oxo-l,2-dihvdro-3-quinolmvncarbonyl}glycine Following the procedure of Example 1 Ib), except substituting the compound from Example 12a) for the compound from Example 1 Ia), the title compound was obtained as a orange solid. 1H
NMR (400 MHz, DMSO-J6) δ ppm 12.9 (s, 1 H) 10.6 (t, 7=5.3 Hz, 1 H) 8.12 (dd, 7=8.1, 1.5 Hz, 1 H) 7.82 - 7.89 (m, 1 H) 7.74 - 7.81 (m, 1 H) 7.36 (t, 7=7.1 Hz, 1 H) 4.13 (d, 7=5.6 Hz, 2 H) 1.58 (d, 7=7.1 Hz, 6 H). MS(ES+) m/e 305 [M+H]+.
Example 13
Figure imgf000026_0002
N-(ri-(2-Cvclopropylethyl)-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyllcarbonyl}glycine
Following the procedure of Example 2, except substituting N-(2-cyclopropylethyl)isatoic anhydride for isatoic anhydride, the title compound was obtained as a light pink solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 12.9 (s, 1 H) 10.6 (t, 7=5.7 Hz, 1 H) 8.11 (dd, 7=8.1, 1.5 Hz, 1 H) 7.81 (ddd, .7=8.7, 7.1, 1.6 Hz, 1 H) 7.69 (d, 7=8.6 Hz, 1 H) 7.37 (t, 7=7.5 Hz, 1 H) 4.29 - 4.42 (m, 2 H) 4.13 (d, 7=5.6 Hz, 2 H) 1.54 (q, 7=7.2 Hz, 2 H) 0.74 - 0.88 (m, 1 H) 0.36 - 0.45 (m, 2 H) 0.02 - 0.10 (m, 2 H). MS(ES+) m/e 331 [M+H]+.
Example 14
Figure imgf000027_0001
N-{ r4-hydroxy-l-(2-methylpropyl)-2-oxo-1.2-dihvdro-3-quinolmyncarbonyllglycine
14a) Ethyl 4-hydroxy- 1 -(2-methylpropyl)-2-oxo- 1 ,2-dihydro-3-quinolinecarboxylate To a solution of isatoic anhydride (0.326 g, 2.0 mmol) and l-bromo-2-methylρropane (0.218 mL, 2.0 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol). Following stirring at ambient temperature for 1.5 h, diethyl malonate (0.304 mL, 2.0 mmol) and sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol) were added. Following stirring at ambient temperature for 5 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with 6M aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (10-40% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (0.090 g, 16%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.20 (dd, J=8.1, 1.3 Hz, 1 H), 7.66 (ddd, J=8.7, 7.1, 1.6 Hz, 1 H), 7.31 (d, J=8.6 Hz, 1 H), 7.24 (ddd, J=8.1, 7.2, 0.9 Hz, 1 H), 4.52 (q, J=7.2 Hz, 2 H), 4.21 (ddd, J=14.3, 7.1, 1.5 Hz, 1 H), 4.13 (q, J=7.1 Hz, 1 H), 2.18 - 2.31 (m, 1 H), 1.48 (t, J=7.2 Hz, 3 H), 0.99 (d, J=6.6 Hz, 6 H). MS(ES+) m/e 290 [M+H]+.
14b) N-I r4-hvdroxy-l-(2-methylpropyl)-2-oxo-l,2-dihydro-3-quinolinvncarbonyl) glycine Following the procedure of Example 1 Ib), except substituting the compound from Example 14a) for the compound from Example 1 Ia), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 10.6 (t, J=5.3 Hz, 1 H), 8.11 (dd, J=8.0, 1.4 Hz, 1 H), 7.80 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.67 (d, J=8.8 Hz, 1 H), 7.37 (t, J=7.6 Hz, 1 H), 4.17 (d, J=6.3 Hz, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 2.08 - 2.22 (m, 1 H), 0.91 (d, J=6.6 Hz, 6 H). MS(ES+) m/e 319 [M+H]+. Example 15
Figure imgf000028_0001
N-( r4-hydroxy-l-methyl-6-(methyloxy')-2-oxo-l,2-dihvdro-3-quinolinyncarbonyl}glycine a') Ethyl 4-hydroxy-l-methyl-6-(methyloxy)-2-oxo-l,2-dihydro-3-quinolmecarboxylate Following the procedure of Example 7b), except substituting N-methyl-4-(methyloxy)aniline for the compound from Example 7a), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 7.43 - 7.61 (m, 2 H), 7.35 - 7.41 (m, 1 H), 4.33 (q, J=7.2 Hz, 2 H), 3.84 (s, 3 H), 3.53 (s, 3 H), 1.30 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 278 [M+H]+. b) N-{ r4-hvdroxy-l-methyl-6-(methyloxy)-2-oxo-l,2-dihydro-3-qumolinyllcarbonyl|glycine Following the procedure of Example 9c), except substituting the compound from Example
15a) for the compound from Example 9b), the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.7 (t, J=5.6 Hz, 1 H), 7.60 (d, J=9.1 Hz, 1 H), 7.43 - 7.51 (m, 2 H), 7.32 - 7.53 (m, 1 H), 4.14 (d, J=5.6 Hz, 1 H), 3.86 (s, 3 H), 3.63 (s, 3 H). MS(ES+) m/e 307 [M+H]+. Example 16
Figure imgf000028_0002
N-({ l-[(2-bromophenyl')methyll-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyllcarbonyl)glycme a) Ethyl l-r(2-bromophenyl)methyll-4-hvdroxy-2-oxo-l,2-dihvdro-3-quinolinecarboxylate To a solution of isatoic anhydride (0.326 g, 2.0 mmol) and 2-bromobenzyl bromide (0.500 g, 2.0 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol). Following stirring at ambient temperature for 1 h, diethyl malonate (0.304 mL, 2.0 mmol) and sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol) were added. Following stirring at ambient temperature for 15 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was poured into water, acidified with 6M aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (5-30% ethyl acetate in hexanes) to afford the title compound as a white solid (0.306 g, 38%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.23 (dd, J=8.1, 1.3 Hz, 1 H), 7.62 (ddd, J=3.5, 2.0 Hz, 1 H), 7.56 (ddd, J=8.7, 7.1, 1.6 Hz, 1 H), 7.25 (ddd, J=8.1, 7.2, 0.8 Hz, 1 H), 7.08 - 7.16 (m, 2 H), 6.99 (d, J=8.6 Hz, 1 H), 6.75 (dd, J=6.6, 2.8 Hz, 1 H), 5.54 (br. s., 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.49 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 402/404 [M+H]+. b) N-( f 1 -r(2-bromophenyl)methyll ^-hydroxy^-oxo- 1 ,2-dihvdro-3 - quinolinyl I carbonyl) glycine Following the procedure of Example 1 Ib), except substituting the compound from Example
16a) for the compound from Example 1 Ia), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.4 (t, J=5.4 Hz, 1 H), 8.17 (dd, J=8.0, 1.4 Hz, 1 H), 7.65 - 7.79 (m, 2 H), 7.39 (t, J=7.5 Hz, 1 H), 7.13 - 7.30 (m, 3 H), 6.62 - 6.70 (m, 1 H), 5.47 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 431/433 [M+H]+. Example 17
Figure imgf000029_0001
N-({ l-r(3-bromophenyl)methyn-4-hydroxy-2-oxo-l,2-dihvdro-3-quinolinyl)carbonyl)glvcine
To a mixture of N-(3-bromobenzyl)isatoic anhydride (WO02/098424) (0.664 g, 2.0 mmol) and diethyl malonate (0.304 mL, 2.0 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (0.598 mL, 4.0 mmol). Following stirring at ambient temperature for 5 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, glycine (0.225 g, 3.0 mmol) and ethanol (2.0 mL) were added and the solution was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with IM aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (20-100% ethyl acetate in hexanes) to afford the title compound as a white solid (0.552 g, 64%). 1H NMR (400 MHz, DMSOd6) 5 ppm 13.0 (s, 1 H), 10.5 (t, J=5.4 Hz, 1 H), 8.14 (dd, J=7.8, 1.0 Hz, 1 H), 7.73 (ddd, J=8.5, 7.0, 1.4 Hz, 1 H), 7.43 - 7.53 (m, 3 H), 7.37 (t, J=7.6 Hz, 1 H), 7.27 (t, J=7.8 Hz, 1 H), 7.17 (d, J=7.6 Hz, 1 H), 5.55 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 431/433 [M+H]+.
Figure imgf000030_0001
N-d l-rf4-bromophenyl')methyn-4-hvdτoxy-2-oxo-l,2-dihvdro-3-qumolinyllcarbonyl)glvcme
To a mixture of N-(4-bromobenzyl)isatoic anhydride (WO02/098424) (0.664 g, 2.0 mmol) and diethyl malonate (0.304 mL, 2.0 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (0.598 mL, 4.0 mmol). Following stirring at ambient temperature for 5 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, glycine (0.225 g, 3.0 mmol) and 1,4-dioxane (2.0 mL) were added and the solution was heated to 2000C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with IM aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (20-100% ethyl acetate in hexanes) to afford the title compound as a beige solid (0.372 g, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.4 Hz, 1 H), 8.13 (dd, J=8.1, 1.0 Hz, 1 H), 7.72 (ddd, J=8.6, 7.2, 1.4 Hz, 1 H), 7.51 (d, J=8.3 Hz, 2 H), 7.46 (d, J=8.6 Hz, 1 H), 7.36 (t, J=7.5 Hz, 1 H), 7.19 (d, J=8.3 Hz, 2 H), 5.53 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 431/433 [MH-H]+.
Example 19
Figure imgf000030_0002
N-[Y 1-1 [4-( 1 , 1 -dimethylethvDphenyllmethyl I ^-hydroxy-Σ-oxo- 1 ,2-dihvdro-3- quinolinyDcarbonyll glycine
Following the procedure of Example 17, except substituting N-(4-tert-butylbenzyl)isatoic anhydride (WO02/098424) for N-(3-bromobenzyl)isatoic anhydride, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.4 Hz, 1 H), 8.13 (dd, J=8.0, 1.4 Hz, 1 H), 7.72 (ddd, J=8.6, 7.2, 1.4 Hz, 1 H), 7.52 (d, J=8.6 Hz, 1 H), 7.35 (t, J=7.4 Hz, 1 H), 7.33 (d, J=8.5 Hz, 2 H), 7.14 (d, J=8.1 Hz, 2 H), 5.52 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 1.22 (s, 9 H). MS(ES+) m/e 409 [MfH]+.
Alternatively, the compound from Example 19 can be prepared according to the following method: 19a) l-{ r4-(l,l-DimethylethvDphenvnmethyl)-2H-3,l-benzoxazine-2.4αH)-dione A suspension of sodium hydride (22.0 g, 60% dispersion in mineral oil, 0.55 mol) in dry tetrahydrofuran (200 mL) was cooled to 5 0C then treated dropwise with a solution of isatoic anhydride (81.5 g, 0.50 mol) in dry N,N-dimethylacetamide (200 mL) and the mixture stirred for 30 min. after complete addition at 5-10 0C. A solution of 4-tert-butylbenzyl bromide (125 g, 0.55 mol) in dry tetrahydrofuran (200 mL) was then added dropwise and the mixture was stirred and allowed to warm to ambient temperature overnight. The mixture was quenched with water (1 L) and filtered to afford a tan powder (160.6 g wet weight) which was crystallized from toluene (1 L) to give the title compound plus a second crop collected after crystallization from the mother liquor as a tan, crystalline solid (65.4 g + 42.5 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (dd, J=7.8, 1.3 Hz, 1 H), 7.76 (ddd, J=7.9, 1.6 Hz, 1 H), 7.16 - 7.48 (m, 6 H), 5.25 (s, 2 H), 1.25 (s, 9 H).
19b) Ethyl l-{[4-(lJ-dimethylethyl)phenvnmethyl|-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinolinecarboxylate
A suspension of hexanes-washed sodium hydride (17.0 g, 60% dispersion in mineral oil, 0.424 mole) in dry N,N-dimethylacetamide (250 mL) was cooled to 10 0C then treated dropwise with a solution of diethyl malonate (67.8 g, 0.424 mole) in N,N-dimethylacetamide (250 mL) and the mixture stirred at < 200C for 30 min. after complete addition. A solution of l-{ [4-(l,l- dimethylethyl)phenyl]methyl}-2H-3,l-benzoxazine-2,4(lH)-dione (105 g, 0.339 mole) in dry N,N- dimethylacetamide (500 mL) was then added dropwise and the mixture was stirred and heated at 120 0C for 16 h. The heating was then removed and the reaction mixture allowed to cool to ~ 60 0C then treated dropwise with glacial acetic acid (50.0 mL) and allowed to cool to ambient temperature. The reaction mixture was then poured into water (2.5 L) and extracted with EtOAc (2 x 1 L). The extracts were washed with brine (300 mL), dried over MgSO4, filtered, and evaporated. The residual semisolid was washed with minimal hexanes (200 mL) and filtered to afford the title compound as a cream crystalline solid (93.6 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.2 (s, 1 H), 8.08 (dd, J=8.1, 1.5 Hz, 1 H), 7.65 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.40 (d, J=8.6 Hz, 1 H), 7.32 (d, J=8.6 Hz, 2 H), 7.25 - 7.30 (m, 1 H), 7.11 (d, J=8.3 Hz, 2 H), 5.42 (s, 2 H), 4.36 (q, J=7.1 Hz, 2 H), 1.32 (t, J=7.2 Hz, 3 H), 1.23 (s, 9 H).
19c) N-F(I-I r4-(lJ-dimethylethyl)phenyllmethyll-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvDcarbonyll glycine
A mixture of ethyl l-{[4-(l,l-dimethylethyl)phenyl]methyl}-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate (93.0 g, 0.245 mole) and glycine sodium salt (47.5 g, 0.45 mole) in 2- methoxyethanol (600 mL) was stirred and heated under reflux for 2 h. The cooled solution was then poured into water (2 L) and acidified by dropwise addition of 6M aqueous hydrochloric acid (100 mL). Filtration and washing with water afforded the crude product (104 g) as a colorless powder which was crystallized from glacial acetic acid (300 mL) to afford the title compound as a colorless, crystalline solid (88.0 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.4 Hz, 1 H), 8.13 (dd, J=8.1, 1.5 Hz, 1 H), 7.68 - 7.78 (m, 1 H), 7.52 (d, J=8.6 Hz, 1 H), 7.28 - 7.41 (m, 3 H), 7.15 (d, J=8.3 Hz, 2 H), 5.52 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). mp. 204-206 0C. C23H24N2O5 requires: %C, 67.33; %H, 5.92; %N, 6.86; found: %C, 67.01; %H, 5.82; %N, 6.64.
Example 20
Figure imgf000032_0001
N-( 14-hydroxy- 1 -r(3-nitxophenyl)methyll -2-oxo-l .2-dihydro-3-quinolinyl lcarbonyl) glycine Following the procedure of Example 17, except substituting N-(3-nitrobenzyl)isatoic anhydride (WO02/098424) for N-(3-bromobenzyl)isatoic anhydride, the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 8.19 (s, 1 H), 8.15 (dd, J=8.2, 1.4 Hz, 1 H), 8.07 - 8.14 (m, 1 H), 7.73 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.58 - 7.64 (m, 2 H), 7.53 (d, J=8.8 Hz, 1 H), 7.38 (t, J=7.6 Hz, 1 H), 5.69 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 398 [M+H]+.
Example 21
Figure imgf000032_0002
N-I rό-fluoro^-hydroxy-l-CS-methylbutyD^-oxo-l^-dihydro-S-quinolinyllcarbonyl) glycine
Following the procedure of Example 17, except substituting N-(3-methylbutyl)-6- (fluoro)isatoic anhydride (WO02/098424) for N-(3-bromobenzyl)isatoic anhydride, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.4 Hz, 1 H), 7.78 (dd, J=8.8, 3.0 Hz, 1 H), 7.72 (ddd, J=8.7, 3.0 Hz, 1 H), 7.65 (dd, J=9.2, 4.1 Hz, 1 H), 4.21 - 4.32 (m, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 1.74 (tq, J=13.3, 6.8, 6.7 Hz, 1 H), 1.42 - 1.54 (m, 2 H), 0.98 (d, J=6.6 Hz, 6 H). MS(ES+) m/e 351 [M+H]+.
Figure imgf000033_0001
N- 1 r4-hydroxy-6-f( 1 -methylethvDoxyl -2-oxo 1 -(phenylmethvD- 1 ,2-dihydro-3 - quinorinvH carbonyl ) glycine 22a) 14-F(I -MethylethvDoxylphenyl I (phenylmethyl)amine
Following the procedure of Example 7a), except substituting 4-(isopropyloxy)aniline for 3- (methyloxy)aniline, the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.35 - 7.44 (m, 4 H), 7.27 - 7.34 (m, 1 H), 6.82 (d, J=7.8 Hz, 2 H), 6.64 (d, J=8.8 Hz, 2 H), 4.40 (qq, J=6.1, 6.1 Hz, 1 H), 4.32 (s, 2 H), 1.33 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 242 [M+H]+.
22b) Ethyl 4-hvdroxy-6-r(l-methylethyl)oxy]-2-oxo-l-(phenylmethyl)-L2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 7b), except substituting the compound from Example 22a) for the compound from Example 7a), the title compound was obtained as a yellow solid. MS(ES+) m/e 382 [M+H]+.
22c) N-ir4-hvdroxy-6-r(l-methylethyl)oxy1-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 9c), except substituting the compound from Example 22b) for the compound from Example 9b), the title compound was obtained as a white solid following purification via preparative HPLC chromatography (YMC 75 X 30 mm column, 0.1% TFA in water and 0.1% TFA in acetonitrile). 1H NMR (400 MHz, DMSOd6) δ ppm 10.6 (t, J=5.4 Hz, 1 H), 7.49 (d, J=2.8 Hz, 1 H), 7.38 - 7.43 (m, 1 H), 7.29 - 7.36 (m, 3 H), 7.18 - 7.27 (m, 3 H), 5.54 (s, 2 H), 4.67 (qq, J=6.1, 6.1 Hz, 1 H), 4.15 (d, J=5.6 Hz, 2 H), 1.28 (d, J=6.1 Hz, 6 H). MS(ES+) m/e 411 [M+H]+.
Figure imgf000034_0001
N-U4-hydro}cy-6-(methyloxyV2-oxo-l-(ρhenylmethylVl,2-dihvdro-3-qmiαolmyl1caτbQnyUglycine
23a) F4-(Methyloxy)phenyl1(phenylmethyl)amine Following the procedure of Example 7a), except substituting 4-(methyloxy)aniIine for 3-
(methyloxy)aniline, the title compound was obtained as a yellow solid. MS(ES+) m/e 214 [M+H]+.
23b) Ethyl 4-hydroxy-6-('methyloxy)-2-oxo-l-('phenylmethyl)-l,2-dihvdro-3- quinolmecarboxylate
Following the procedure of Example 7b), except substituting the compound from Example 23a) for the compound from Example 7a), the title compound was obtained as a yellow solid. 1H
NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=2.0 Hz, 1 H), 7.11 - 7.36 (m, 7 H), 6.75 - 6.93 (m, 1 H), 5.53 (br. s., 2 H), 4.55 (q, J=7.1 Hz, 2 H), 3.88 (s, 3 H), 1.52 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 354 [M+H]+.
23c) N-I [4-hydroxy-6-(methyloxy)-2-oxo4-(phenylmethyiy 1 ,2-dihvdro-3- quinolinyllcarbonyl I glycine
Following the procedure of Example 9c), except substituting the compound from Example 23b) for the compound from Example 9b), the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.6 Hz, 1 H), 7.52 (d, J=2.8 Hz, 1 H), 7.44 (d, J=9.4 Hz, 1 H), 7.29 - 7.38 (m, 3 H), 7.17 - 7.27 (m, 3 H), 5.55 (br. s., 2 H), 4.15 (d, J=5.6 Hz, 2 H), 3.83 (s, 3 H). MS(ES+) m/e 383 [M+H]+.
Example 24
Figure imgf000034_0002
N-f(4-hydrQxy-5-methyl-2-oxo-l,2-dihydro-3-qumolinyl)carbonyllglycine
To a mixture of 5-(methyl)isatoic anhydride (0.100 g, 0.560 mmol) and diethyl malonate (0.086 mL, 0.560 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (0.167 mL, 1.12 mmol).
Following stirring for 10 min. at ambient temperature, the reaction mixture was heated to 1500C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, glycine (0.063 g, 0.840 mmol) and ethanol (5.0 mL) were added and the solution was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with IM aqueous hydrochloric acid (5.0 mL), filtered, and washed with water. The precipitate was collected and purified via preparative HPLC chromatography (YMC 75 X 30 mm column, 0.1% TFA in water and 0.1% TFA in acetonitrile) to afford the title compound as a grey solid (O.OlOg, 6.4%). 1H NMR (400 MHz, OMSO-U6) δ ppm 12.9 (br. s., 1 H), 11.0 (s, 1 H), 10.5 (s, 1 H), 7.86 (d, J=8.1 Hz, 1 H), 7.55 (d, J=7.1 Hz, 1 H), 7.21 (t, J=7.7 Hz, 1 H), 4.15 (d, J=5.8 Hz, 2 H), 2.46 (s, 3 H). MS(ES+) m/e 277 [M+H]+.
Example 25
Figure imgf000035_0001
N-[(4-hvdroxy-6-methyl-2-oxo-l,2-dihydro-3-quinolinyl)carbonyllglvcme
Following the procedure of Example 24, except substituting 6-(methyl)isatoic anhydride for 5-(methyl)isatoic anhydride, the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 11.8 (s, 1 H), 10.5 (t, J=5.7 Hz, 1 H), 7.77 (s, 1 H), 7.53 (dd, J=8.3, 1.8 Hz, 1 H), 7.28 (d, J=8.3 Hz, 1 H), 4.13 (d, J=5.8 Hz, 2 H), 2.38 (s, 3 H). MS(ES+) m/e 277 [M+H]+.
Example 26
Figure imgf000035_0002
3-{f(carboxymethyl)aminolcarbonyl)-4-hydroxy-2-oxo-l,2-dihydro-6-quinolinecarboxylic acid
Following the procedure of Example 24, except substituting 2,4-dioxo-l,4-dihydro-2H-3,l- benzoxazine-6-carboxylic acid for 5-(methyl)isatoic anhydride, the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.1 (s, 1 H), 10.5 (t, J=5.7 Hz, 1 H), 8.07 (d, J=8.3 Hz, 1 H), 7.97 (s, 1 H), 7.77 (d, J=8.6 Hz, 1 H), 4.14 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 307 [M+H]+.
Example 27
Figure imgf000035_0003
N-r(6-bromo-4-hvdroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyllglvcine
Following the procedure of Example 24, except substituting 6-(bromo)isatoic anhydride for 5- (methyl)isatoic anhydride, the title compound was obtained as a purple solid. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 12.0 (s, 1 H), 10.4 (t, J=5.7 Hz, 1 H), 8.03 (d, J=2.3 Hz, 1 H), 7.85 (dd, J=8.8, 2.3 Hz, 1 H), 7.33 (d, J=8.8 Hz, 1 H), 4.13 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 341/343 [M+H]+. Exampie 28
Figure imgf000036_0001
N-r(4,6-dihydroxy-2-oxo-l,2-dihydro-3-quinolm'vDcarbon-yl]glycine
Following the procedure of Example 24, except substituting 6-(hydroxy)isatoic anhydride for 5-(methyϊ)isatoic anhydride, the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 11.7 (s, 1 H), 10.6 (t, J=5.7 Hz, 1 H), 9.73 (s, 1 H), 7.08 - 7.33 (m, 3 H), 4.12 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 279 [M+HJ+.
Example 29
Figure imgf000036_0002
N-r(6-chlorθ'4-hydroxy-2-oxo-l,2-dihydro-3-quinolmyl')carbonvllglycine
Following the procedure of Example 24, except substituting 6-(chloro)isatoic anhydride ione for 5-(methyl)isatoic anhydride, the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 12.0 (s, 1 H), 10.4 (t, J=5.7 Hz, 1 H), 7.89 (d, J=2.3 Hz, 1 H), 7.74 (dd, J=8.8, 2.5 Hz, 1 H), 7.38 (d, J=8.8 Hz, 1 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 297 [M+H]+.
Example 30
Figure imgf000036_0003
N-{r4-hvdroxy-l-C3-methvlbutyl)-5,6-bis(methyloxy)-2-oxo-l,2-dihydiO-3- qumoϋnyHcarbonyl } glycine
Following the procedure of Example 17, except substituting N-(3-methylbutyl)-5,6- dimethoxyisatoic anhydride (WO02/098424) for N-(3-bromobenzyl)isatoic anhydride, the title compound was obtained as a light orange solid. 1HNMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 10.8 (t, J=5.6 Hz, 1 H), 7.61 (d, J=9.3 Hz, 1 H), 7.30 (d, J=9.3 Hz, 1 H), 4.13 - 4.24 (m, 2 H), 4.11 (d, J=5.6 Hz, 2 H), 3.86 (s, 3 H), 3.77 (s, 3 H), 1.67 - 1.77 (m, 1 H), 1.42 - 1.54 (m, 2 H), 0.97 (d, J=6.8 Hz, 6 H). MS(ES+) m/e 393 [M+H]+.
Figure imgf000037_0001
N-(| l-f(3-aminophenyDmethyn-4-hvdroxy-2-oxo-l,2-dihvdro-3-qumolinyπcarbonyDglvcine
To a solution of the compound from Example 20 (0.070 g, 0.176 mmol) in tetrahydrofuran (2.0 rπL) were added stannous chloride dihydrate (0.397 g, 1.76 mmol) and concentrated aqueous hydrochloric acid (1.0 mL). Following stirring at ambient temperature for 3 h, the reaction mixture was treated with 6M aqueous sodium hydroxide, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and triturated with ethyl acetate to give the title compound as a beige solid (0.047 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.0 (br. s., 1 H), 10.5 (t, J=6.1 Hz, 1 H), 8.21 (dd, J=8.0, 1.4 Hz, 1 H), 7.67 (t, J=7.2 Hz, 1 H), 7.44 (d, J=8.3 Hz, 1 H), 7.31 - 7.41 (m, 3 H), 7.17 - 7.27 (m, 1 H), 6.88 - 7.05 (m, 1 H), 5.54 (br. s., 2 H), 4.21 (d, J=5.1 Hz, 2 H). MS(ES+) m/e 368 [M+HJ+.
Example 32
Figure imgf000037_0002
N-( ( 4-hydroxy-2-oxo- 1 -(phenylmethyl)-6-r(phenylmethyl)oxy1 - 1 ,2-dihydro-3- quinolinyl ) carbonvDgly cine
32a) Ethyl 4-hydroxy-2-oxo-l-(phenylmethyl)-6-r(phenylmethyl)oxy]-l,2-dihvdro-3- quinolinecarboxylate
To a solution of 6-hydroxyisatoic anhydride (0.358 g, 2.0 mmol) and benzyl bromide (0.238 mL, 4.0 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (0.160 g, 60% dispersion in mineral oil, 4.0 mmol). Following stirring at ambient temperature for 1 h, diethyl malonate (0.304 mL, 2.0 mmol) and sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol) were added. Following stirring at ambient temperature for 15 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was poured into water, acidified with 6M aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (10-40% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (0.333 g, 39%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.67 (d, J=3.0 Hz, 1 H), 7.40 - 7.43 (m, 2 H), 7.38 (tt, J=7.0, 1.6 Hz, 2 H), 7.31 - 7.34 (m, 1 H), 7.27 - 7.31 (m, 1 H), 7.26 (s, 1 H), 7.21 (d, J=3.0 Hz, 1 H), 7.19 (d, J=3.0 Hz, 1 H), 7.15 - 7.18 (m, 2 H), 7.11 (d, J=9.3 Hz, 1 H), 5.48 (br. s., 2 H), 5.09 (s, 2 H), 4.50 (q, J=7.2 Hz, 2 H), 1.47 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 430 [M+H]+.
32b) N-((4-hvdroxy-2-oxo-l-(phenylmethyl)-6-r(phenylmethyl)oxyl-L2-dihvdro-3- quinolinyl lcarbonyDglycine
Following the procedure of Example lib), except substituting the compound from Example 32a) for the compound from Example 1 Ia), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.2 Hz, 1 H), 7.61 (s, 1 H), 7.46 (d, J=7.0 Hz, 2 H), 7.43 (s, 2 H), 7.39 (t, J=7.3 Hz, 2 H), 7.33 (d, J=7.0 Hz, 1 H), 7.30 (d, J=7.3 Hz, 2 H), 7.24 (d, J=7.3 Hz, 1 H), 7.19 (d, J=7.3 Hz, 2 H), 5.54 (br. s., 2 H), 5.19 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 459 [M+HJ+.
Example 33
Figure imgf000038_0001
N-{[4-hvdroxy-2-oxo-l-(l,3-thiazol-4-ylmethyl*)-l,2-dihydro-3-quinolinvncarbonyl|glycine
33a) Ethyl 4-hydroxy-2-oxo- 1 -( 1 ,3 -thiazol-4-y lmethyl)- 1 ,2-dihydro-3 -quinolinecarboxylate To a solution of isatoic anhydride (0.326 g, 2.0 mmol) and 4-(chloromethyl)-l,3-thiazole hydrochloride (0.340 g, 2.0 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (0.160 g, 60% dispersion in mineral oil, 4.0 mmol). Following stirring at ambient temperature for 1 h, diethyl malonate (0.304 mL, 2.0 mmol) and sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol) were added. Following stirring at ambient temperature for 15 min., the solution was heated to 1500C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was poured into water, acidified with 6M aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (10-50% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (0.033 g, 5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 8.82 (d, J=2.0 Hz, 1 H), 8.19 (dd, J=8.0, 1.1 Hz, 1 H), 7.64 (ddd, J=8.4, 7.0, 1.3 Hz, 1 H), 7.58 (d, J=8.4 Hz, 1 H), 7.27 (d, J=2.0 Hz, 1 H), 7.24 (d, J=7.8 Hz, 1 H), 5.66 (s, 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.49 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 331 [M+H]+. 33b) N-( r4-hvdroxy-2-oxo- l-( 1 ,3-thiazol-4-ylmethvD- 1 ,2-dihvdro-3- quinolinyllcarbonyl I glycine
Following the procedure of Example lib), except substituting the compound from Example 33a) for the compound from Example 1 Ia), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.6 Hz, 1 H), 9.05 (d, J=1.3 Hz, 1 H), 8.12 (dd, J=8.2, 0.9 Hz, 1 H), 7.74 (ddd, J=8.8, 7.2, 1.3 Hz, 1 H), 7.62 (d, J=8.6 Hz, 1 H), 7.48 (d, J=LO Hz, 1 H), 7.36 (t, J=7.1 Hz, 1 H), 5.65 (s, 2 H), 4.14 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 360 [M+EQ+.
Example 34
Figure imgf000039_0001
N-(ri-(2-cvclopropylethyl)-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3-quinolinyllcarbonyllglycine
Following the procedure of Example 17, except substituting N-(2-cyclopropylethyl)-6- (fluoro)isatoic anhydride (WO02/098424) for N-(3-bromobenzyl)isatoic anhydride, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.4 Hz, 1 H), 7.79 (dd, J=8.7, 2.7 Hz, 1 H), 7.76 (dd, J=9.4, 4.3 Hz, 1 H), 7.70 (ddd, J=9.4, 8.1, 3.1 Hz, 1 H), 4.29 - 4.42 (m, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 1.53 (q, J=7.3 Hz, 2 H), 0.74 - 0.86 (m, 1 H), 0.36 - 0.46 (m, 2 H), 0.06 (q, J=4.7 Hz, 2 H). MS(ES+) m/e 349 [M+H]+.
Alternatively, the compound from Example 34 can be prepared according to the following method: 34a) Ethyl l-(2-cvclopropylethyl)-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinolmecarboxylate
A suspension of hexanes-washed sodium hydride (20.1 g, 60% dispersion in mineral oil, 0.50 mole) in dry N,N-dimethylacetamide (250 mL) was cooled to 10 0C then treated drop wise with a solution of diethyl malonate (80.3 g, 0.50 mole) in N,N-dimethylacetamide (300 mL) at such a rate to maintain the temperature < 20 0C. The solution was stirred at ambient temperature for 30 min. then treated dropwise with a solution of the l-(2-cyclopropylethyl)-6-fluoro-2H-3,l-benzoxazine-2,4(lH)- dione (WO02/098424) (100 g, 0.40 mol.) in dry N,N-dimethylacetamide (500 mL) and the mixture was stirred and heated at 120 0C for 20 h. The mixture was allowed to cooled to 60 0C, then acidified with glacial acetic acid (40.0 mL), and poured into water (2.5 L). The mixture was left to stand for Ih, then filtered and dried in vacuo. The solid was then washed with hexanes (1 L) and dried in vacuo to afford the title compound as a cream solid (105.4 g, 83%). 1H NMR (400 MHz, DMSOd6) δ ppm 12.75 (s, 1 H), 7.74 - 7.80 (m, 1 H), 7.62 (s, 1 H), 7.61 (dd, J=4.9, 2.4 Hz, 1 H), 4.30 (q, J=7.1 Hz, 2 H), 4.21 - 4.27 (m, 2 H), 1.44 - 1.51 (m, 2 H), 1.30 (t, 1=1.1 Hz, 3 H), 0.73 - 0.82 (m, 1 H), 0.40 (ddd, J=8.1, 5.7, 4.2 Hz, 2 H), 0.04 - 0.11 (m, 2 H).
34b) N-f [l-(2-cyclopropylethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinylicarbonyl } glycine A mixture of ethyl l-(2-cycloρropylethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate (105.0 g, 0.329 mole) and glycine sodium salt (63.9 g, 0.658 mole) in 2- methoxyethanol (800 mL) was stirred and heated under reflux for 3 h. The cooled solution was then poured into water (2 L) and acidified by drop wise addition of 6M aqueous hydrochloric acid (100 mL). Filtration afforded the crude product (156 g wet weight) as a cream powder which was crystallized from glacial acetic acid (750 mL) to afford the title compound as a cream, crystalline solid (89.0 g, 78%). 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.6 (t, J=5.6 Hz, 1 H), 7.67 - 7.79 (m, 3 H), 4.30 - 4.39 (m, 2 H), 4.13 (d, J=5.8 Hz, 2 H), 1.53 (q, J=7.3 Hz, 2 H), 0.75 - 0.85 (m, 1 H), 0.40 (ddd, J=8.0, 5.6, 4.0 Hz, 2 H), 0.06 (q, J=4.8 Hz, 2 H). mp. 200-2020C. C17H17FN2O5 requires: %C, 58.62; %H, 4.92; %N, 8.04; found: %C, 58.32; %H, 4.96; %N, 7.89. Example 35
Figure imgf000040_0001
N-({4-hydroxy-l-r(2-methyl-4-pyridmyl)methyll-2-oxo-l,2-dihydro-3-quinolinyUcarbonyl)glycine
Following the procedure of Example 17, except substituting N-[(2-methylpyridiN-4- yl)methyl]isatoic anhydride (WO02/098424) for N-(3-bromobenzyl)isatoic anhydride, the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H),
10.4 (t, J=5.2 Hz, 1 H), 8.59 (d, J=6.3 Hz, 1 H), 8.17 (d, J=7.3 Hz, 1 H), 7.72 (ddd, J=8.4, 7.0, 1.3 Hz, 1 H), 7.51 (br. s., 2 H), 7.40 (t, J=7.6 Hz, 2 H), 5.70 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H), 2.58 (s, 3 H). MS(ES+) m/e 368 [M+H]+.
Example 36
Figure imgf000041_0001
N-({ l-f3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)propyll-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl IcarbonvDglycme
Following the procedure of Example 1, except substituting N-[3-(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)propyl isatoic anhydride (WO02/098424) for N-(methyl)isatoic anhydride, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (s, 1 H), 10.5 (t, J=5.6 Hz, 1 H), 8.11 (dd, J=8.0, 1.4 Hz, 1 H), 7.79 - 7.90 (m, 5 H), 7.69 - 7.77 (m, 1 H), 7.39 (t, J=7.5 Hz, 1 H), 4.31 - 4.40 (m, 2 H), 4.10 (d, J=5.6 Hz, 2 H), 3.75 (t, J=7.1 Hz, 2 H), 1.96 - 2.06 (m, 2 H). MS(ES+) m/e 450 [M+H]+.
Example 37
Figure imgf000041_0002
N-r( l-r4-(l,3-dioxo-1.3-dihvdro-2H-isoindol-2-yl')butyll-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinyl ) carbonypglycine
Following the procedure of Example 1, except substituting N-[3-(l,3-dioxo-l,3-dihydro-2H- isoindol-2-yl)butyl isatoic anhydride (WO02/098424) for N-(methyl)isatoic anhydride, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.4 Hz, 1 H), 8.10 (dd, J=8.1, 1.5 Hz, 1 H), 7.77 - 7.88 (m, 5 H), 7.67 - 7.72 (m, 1 H), 7.36 (t, J=7.2 Hz, 1 H), 4.29 (t, J=7.0 Hz, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 3.63 (t, J=6.6 Hz, 2 H), 1.69 - 1.75 (m, 2 H), 1.67 (d, J=8.6 Hz, 2 H). MS(ES+) m/e 464 [M+H]+. Example 38
Figure imgf000042_0001
N-{rϊ-(4-aminobutyl)-4-hydroxy-2-oxo-1.2-dihvdro-3-quinolinyllcarbonyllglycine
A mixture of the compound from example 37 (0.040 g, 0.08 mmol) and hydrazine hydrate (0.100 mL, 2.06 mmol) in ethanol (2.0 mL) were stirred at ambient temperature overnight. While stirring at ambient temperature the product slowly precipitated from the solution. The product was collected via filtration and recrystallized from ethanol:water (4: 1) to yield the title compound as a white crystalline solid (0.0112 g, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.4 (s, 1 H), 10.6 (t, J=5.4 Hz, 1 H), 8.14 (dd, J=8.1, 1.5 Hz, 1 H), 7.79 - 7.88 (m, 1 H), 7.68 - 7.74 (m, 1 H), 7.65 (s, 2 H), 7.40 (t, J=7.6 Hz, 1 H), 4.33 (t, J=6.7 Hz, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 2.78 - 2.91 (m, 2 H), 1.51 - 1.82 (m, 4 H). MS(ES+) m/e 334 [M+HJ+.
Example 39
Figure imgf000042_0002
N-I r 1 -(3-aminopropyl)-4-hydroxy-2-oxo-l ,2-dihvdro-3-quinolinvncarbonyl I glycine
Following the procedure of Example 38, except substituting the compound from example 36 for the compound from example 37, the title compound was obtained as a white solid. MS(ES+) m/e 320 [M+H]+.
Example 40
Figure imgf000042_0003
N- ( F4,6-dihvdroxy-2-oxo- 1 -(phenylmethyD- 1 ,2-dihvdro-3 -quinolinyll carbonyl I glycine
40a 4-r(Phenylmethyl)amino)phenol
Following the procedure of Example 7a), except substituting 4-hydroxyaniline for 3- (methyloxy)aniline, the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-^) δ ppm 7.34 - 7.45 (m, 4 H) 7.29 - 7.33 (m, /=6.82 Hz, 1 H) 6.72 (d, 7=8.59 Hz, 2 H) 6.59 (d, /=8.59 Hz, 2 H) 4.30 (s, 2 H). MS(ES+) m/e 200[M+H]+.
4Qb) Ethyl 4,6-dihydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 -quinolinecarboxylate Following the procedure of Example 7b), except substituting the compound from Example 40a) the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.1 (s, 1 H), 9.72 (s, 1 H), 7.41 (d, J=2.8 Hz, 1 H), 7.31 (t, J=7.3 Hz, 2 H), 7.20 - 7.26 (m, 2 H), 7.17 (d, J=7.1 Hz, 2 H), 7.11 (dd, J=9.1, 2.8 Hz, 1 H), 5.41 (br. s., 2 H), 4.35 (q, J=I. I Hz, 2 H), 1.32 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 340[M+H]+.
40c) N-{ r4,6-dihvdroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quinolinyllcarbonyllglvcine Following the procedure of Example 9c), except substituting the compound from Example
40b) for the compound from Example 9b), the title compound was obtained as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.7 (t, J=5.6 Hz, 1 H), 9.85 (s, 1 H), 7.43 (d, J=3.0 Hz, 1 H), 7.29 - 7.37 (m, 3 H), 7.14 - 7.27 (m, 4 H), 5.51 (br. s., 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 369[M+H]+. Example 41
Figure imgf000043_0001
N- { r6-K2-ammo-2-oxoethyl)oxy1 -4-hy droxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinolinyll carbonyl 1 glycine
41a) Ethyl 6-r(2-amino-2-oxoethyl)oxy 1 -4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihy dro-3- quinolinecarboxylate
To a solution of the compound from Example 40a) (0.150 g, 0.44 mmol) in DMF (5.0 mL) was added sodium hydride (0.053 g, 60% dispersion in mineral oil, 1.32 mmol). After the bubbling stopped, 2-bromoacetamide (0.061 g, 0.44 mmol) was added. The mixture was heated to 150 0C for 2 h in a Biotage Initiator microwave synthesizer. After cooling, the reaction was quenched with ice- water and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow solid (0.102 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.1 (br. s., 1 H), 7.59 (s, 1 H), 7.52 (d, J=2.5 Hz, 1 H), 7.40 (br. s., 1 H), 7.27 - 7.35 (m, 3 H), 7.24 (d, J=7.3 Hz, 1 H), 7.17 (d, J=7.1 Hz, 2 H), 5.45 (br. s., 2 H), 4.49 (s, 2 H), 4.35 (q, J=7.1 Hz, 2 H), 1.32 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 397[M+H]+. 41b) JSH 16-1 (2-ammo-2-oxoethyDoxy1-44iydroxy-2-oxo4-('phenylmethyl)4,2-dihvdro-3- quinolinyllcarbonyl 1 glycine
Following the procedure of Example lib), except substituting the compound from Example 41a) for the compound from Example 1 Ia), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.62 (t, J=5.6 Hz, 1 H), 7.61 (br. s., 1 H), 7.53 (d, J=2.8 Hz, 1 H), 7.43 - 7.49 (m, 1 H), 7.36 - 7.42 (m, 2 H), 7.32 (t, J=7.3 Hz, 2 H), 7.17 - 7.27 (m, 3 H), 5.55 (br. s., 2 H), 4.52 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 426[M+H]+.
Example 42
Figure imgf000044_0001
N-IY4-hy droxy-6-iodo-2-oxo- 1 ,2-dihvdro-3 -quinolinyPcarbonvH glycine
Following the procedure of Example 1, except substituting 6-(iodo)isatoic anhydride (WO02/098424) for N-(methyl)isatoic anhydride, the title compound was obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (s, 1 H), 12.0 (s, 1 H), 10.4 (t, J=5.8 Hz, 1 H), 8.22 (d, J=1.8 Hz, 1 H), 7.98 (dd, J=8.6, 2.0 Hz, 1 H), 7.19 (d, J=8.8 Hz, 1 H), 4.13 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 389 [M+H]+.
Example 43
Figure imgf000044_0002
N- 1 r 1 -(3 -biphenylylmethyl)-4-hydroxy-2-oxo- 1 ,2-dihydro-3-quinolinyll carbonyl I glycine
A solution of the compound from Example 17 (0.100 g, 0.232 mmol), phenylboronic acid (0.028 g, 0.232 mmol), potassium carbonate (0.096 g, 0.696 mmol), and tetrakis(triphenylphosphine)palladium (0.003 g, 0.002 mmol) in 1,4-dioxane (2.0 mL) was heated to 200 0C for 1 h in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with IM aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (20-100% ethyl acetate in hexanes then 0-10% methanol in ethyl acetate) to afford the title compound as an off-white solid (0.081 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.3 (br. s., 1 H), 11.3 (t, J=5.4 Hz, 1 H), 8.25 (dd, J=7.8, 1.0 Hz, 1 H), 7.78 (d, J=6.6 Hz, 2 H), 7.56 - 7.65 (m, 3 H), 7.36 - 7.50 (m, 5 H), 7.06 - 7.15 (m, 2 H), 5.63 (br. s., 2 H), 4.33 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 429 [M+H]+.
Example 44
Figure imgf000045_0001
N-({ l-r(3-cvanophenyl)methyll-4-hvdroxy-2-oxo-l,2-dihvdro-3-quinolinyllcarbonyl)glycine
44a) Ethyl l-[(3-cvanophenyl)methyll-4-hydroxy-2-oxo-l,2-dihvdro-3-quinolinecarboxylate Following the procedure of Example 16a), except substituting 3-cyanobenzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.23 (dd, J=8.1, 1.3 Hz, 1 H), 7.57 (ddd, J=8.5, 7.3, 1.6 Hz, 1 H), 7.53 (d, J=7.3 Hz, 1 H), 7.45 - 7.49 (m, 2 H), 7.41 (t, J=7.7 Hz, 1 H), 7.26 (t, J=7.5 Hz, 1 H), 7.07 (d, J=8.6 Hz, 1 H), 5.51 (br. s., 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 349 [M+H]+.
44b) N-(I l-r(3-cvanophenyl)methvH-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinyl IcarbonyDglvcine Following the procedure of Example 1 Ib), except substituting the compound from Example
44a) for the compound from Example 1 Ia), the title compound was obtained as a peach solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.6 Hz, 1 H), 8.14 (dd, J=8.1, 1.3 Hz, 1 H), 7.78 (s, 1 H), 7.72 - 7.75 (m, 1 H), 7.71 (dd, J=8.9, 1.5 Hz, 1 H), 7.53 (d, J=5.1 Hz, 2 H), 7.46 (d, J=8.6 Hz, 1 H), 7.37 (t, J=7.6 Hz, 1 H), 5.60 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 378 [M+H]+.
Example 45
Figure imgf000045_0002
N N-F(I-I [3-(aminocarbonyl)phenyl1methyl )-4-hvdroxy-2-oxo-1.2-dihydro-3- quinolinyDcarbonyll glycine To a solution of the compound from Example 44b) (0.068 g, 0.180 mmol) in DMSO (0.5 mL) was added potassium carbonate (0.013 g, 0.090 mmol) and 50% aqueous hydrogen peroxide (0.05 mL). Following stirring at ambient temperature overnight, the reaction mixture was treated with IM aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo to afford the title compound as an off-white solid (0.063 g, 88%). 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 10.7 (t, J=3.8 Hz, 1 H), 10.2 (s, 1 H), 8.12 (d, J=7.3 Hz, 1 H), 8.00 (s, 1 H), 7.65 - 7.82 (m, 2 H), 7.57 (t, J=5.5 Hz, 1 H), 7.29 - 7.39 (m, 3 H), 7.24 (t, J=6.4 Hz, 1 H), 5.55 (br. s., 2 H), 3.69 (d, J=3.8 Hz, 2 H). MS(ES+) m/e 396 [M+H]+.
Example 46
Figure imgf000046_0001
N-({4-hydroxy-l-r(2-methyl-l,3-thiazol-4-yl)methyll-2-oxo-l,2-dihydro-3- quinolinyl ) carbonyl) glycine
46a) Ethyl 4-hydroxy-2-oxo-l-r(2-methyl-L3-thiazol-4-yl)methyn-l,2-dihydro-3- quinolinecarboxylate To a solution of isatoic anhydride (0.326 g, 2.0 mmol) and 4-(chloromethyl)-2-methyl-l,3-thiazole hydrochloride (0.368 g, 2.0 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (0.160 g, 60% dispersion in mineral oil, 4.0 mmol). Following stirring at ambient temperature overnight, diethyl malonate (0.304 mL, 2.0 mmol) and sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol) were added. Following stirring at ambient temperature for 15 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was poured into water, acidified with IM aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (20-50% ethyl acetate in hexanes) to afford the title compound as a white solid (0.103 g, 15%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (s, 1 H), 8.18 (dd, J=8.1, 1.3 Hz, 1 H), 7.62 (ddd, J=8.7, 7.1, 1.6 Hz, 1 H), 7.48 (d, J=8.6 Hz, 1 H), 7.24 (ddd, J=8.1, 7.1, 0.8 Hz, 1 H), 6.85 (s, 1 H), 5.56 (br. s., 2 H), 4.51 (q, J=7.1 Hz, 2 H), 2.71 (s, 3 H), 1.48 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 345 [M+H]+.
46b) N-({4-hydroxy-l-r(2-methyl-L3-thiazol-4-yl)methyn-2-oxo-L2-dihydro-3- quinolinyl IcarbonyDglycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 46a) for the compound from Example 1 Ia), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 8.11 (d, J=7.3 Hz, 1 H), 7.74 (t, J=7.2 Hz, 1 H), 7.59 (d, J=8.8 Hz, 1 H), 7.36 (t, J=7.5 Hz, 1 H), 7.17 (s, 1 H), 5.54 (s, 2 H), 4.14 (d, J=5.3 Hz, 2 H), 2.60 (s, 3 H). MS(ES+) m/e 374 [M+H]+. Example 47
Figure imgf000047_0001
N-( { 1 -[(3,5 -dimethyl-4-isoxazoryl)methyll ^-hydroxy^-oxo- 1.2-dihvdro-3 - quinolinvUcarbonyDglvcine 47a) Ethyl l-r(3,5-dimethyl-4-isoxazolyl)methyn-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
To a solution of isatoic anhydride (0.326 g, 2.0 mmol) and 4-(chloromethyl)-3,5- dimethylisoxazole (0.248 mL, 2.0 mmol) in N,N-dimethylformamide (2.0 mL) was added sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol). Following stirring at ambient temperature overnight, diethyl malonate (0.304 mL, 2.0 mmol) and sodium hydride (0.080 g, 60% dispersion in mineral oil, 2.0 mmol) were added. Following stirring at ambient temperature for 15 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was poured into water, acidified with IM aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (20- 50% ethyl acetate in hexanes) to afford the title compound as a white solid (0.349 g, 51%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (s, 1 H), 8.19 (dd, J=8.1, 1.3 Hz, 1 H), 7.58 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.24 (ddd, J=8.1, 7.1, 0.8 Hz, 1 H), 7.04 (d, J=8.6 Hz, 1 H), 5.24 (s, 2 H), 4.50 (q, J=7.2 Hz, 2 H), 2.14 (s, 3 H), 2.11 (s, 3 H), 1.46 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 343 [M+H]+. 47b) N-(I l-r(3,5-dimethyl-4-isoxazolyl)methyn-4-hydroxy-2-oxo-L2-dihvdro-3- quinolinyl I carbonyl) glycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 47a) for the compound from Example 1 Ia), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 10.5 (t, J=5.6 Hz, 1 H), 8.13 (dd, J=8.0, 1.1 Hz, 1 H), 7.79 (ddd, J=8.6, 7.0, 1.3 Hz, 1 H), 7.46 (d, J=8.6 Hz, 1 H), 7.38 (t, J=7.6 Hz, 1 H), 5.34 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H), 2.15 (s, 3 H), 2.05 (s, 3 H). MS(ES+) m/e 372 [M+HJ+. Example 48
Figure imgf000048_0001
N-r(4-hydroxy-l-{ r3-(methyloxy)phenyllmethyl)-2-oxo-l,2-dihydro-3-quinolinyl')carbonyl]glycine
48a) Ethyl 4-hydroxy-l-l r3-(methyloxy)phenyl1methyll-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 3-methoxybenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a clear, colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 8.17 (dd, J=8.1, 1.3 Hz, 1 H), 7.51 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.18 - 7.22 (m, 2 H), 7.17 (d, J=1.8 Hz, 1 H), 6.77 (d, J=7.8 Hz, 1 H), 6.74 (d, J=8.1 Hz, 1 H), 6.72 (d, J=LO Hz, 1 H), 5.47 (br. s., 2 H), 4.51 (q, J=7.1 Hz, 2 H), 3.73 (s, 3 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 354 [M+H]+.
48b) N-r(4-hydroxy-l-ir3-(methyloxy)phenyllmethyl}-2-oxo-l,2-dihydro-3- quinolinyDcarbonvn glycine
Following the procedure of Example lib), except substituting the compound from Example 48a) for the compound from Example 1 Ia), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=4.9 Hz, 1 H), 8.12 (dd, J=8.0, 1.4 Hz, 1 H), 7.71 (ddd, J=8.7, 7.3, 1.5 Hz, 1 H), 7.47 (d, J=8.6 Hz, 1 H), 7.35 (t, J=7.5 Hz, 1 H), 7.21 (t, J=7.8 Hz, 1 H), 6.84 (s, 1 H), 6.81 (dd, J=8.1, 2.2 Hz, 1 H), 6.70 (d, J=7.6 Hz, 1 H), 5.52 (br. s., 2 H), 4.13 (d, J=5.6 Hz, 2 H), 3.71 (s, 3 H). MS(ES+) m/e 383 [M+HJ+. Example 49
Figure imgf000048_0002
N~r(4-hydroxy-2-oxo-l - 1 r3-(trifluoromethyl)phenynmethyl 1-1 ,2-dihydro-3- quinolmyDcarbonyli glycine
49a) Ethyl 4-hydroxy-2-oxo-l-( r3-(trifluoromethyl)phenyl1methylM.2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 3-(trifluoromethyl)benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.22 (dd, J=8.1, 1.5 Hz, 1 H), 7.56 (ddd, J=8.7, 7.1, 1.6 Hz, 1 H), 7.49 (d, J=1.8 Hz, 2 H), 7.40 (t, J=7.8 Hz, 1 H), 7.34 (d, J=7.6 Hz, 1 H), 7.24 (ddd, J=8.1, 7.3, 1.0 Hz, 1 H), 7.11 (d, J=8.6 Hz, 1 H), 5.55 (br. s., 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 392 [M+H]+. 49b) N-r(4-hydroxy-2-oxo-l-ir3-(trifluoromethvnphenynmethyl|-l,2-dihvdro-3- quinolinvDcarbonvn glycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 49a) for the compound from Example 1 Ia), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.2 Hz, 1 H), 8.14 (d, J=7.3 Hz, 1 H), 7.67 - 7.78 (m, 2 H), 7.62 (d, J=7.9 Hz, 1 H), 7.54 (d, J=7.9 Hz, 1 H), 7.50 (d, J=8.7 Hz, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.37 (t, J=7.6 Hz, 1 H), 5.65 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 421 [M+H]+.
Example 50
Figure imgf000049_0001
N-(j4-hvdroxy-l-r(3-hydroxyphenyl)methvn-2-oxo-L2-dihydro-3-quinolinyl|carbonyl)glycine
To a solution of the compound from Example 48b) (0.080 g, 0.209 mmol) in glacial acetic acid (4.0 mL) was added 48% aqueous hydrobromic acid (1.0 mL) followed by heating to reflux overnight. Upon cooling, the reaction mixture was treated with water (10.0 mL), diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (20-100% ethyl acetate in hexanes) to afford the title compound as an off-white solid (0.032 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.4 Hz, 1 H), 9.35 (s, 1 H), 8.13 (dd, J=8.0, 1.4 Hz, 1 H), 7.72 (ddd, J=8.7, 7.3, 1.5 Hz, 1 H), 7.45 (d, J=8.6 Hz, 1 H), 7.36 (t, J=7.6 Hz, 1 H), 7.11 (t, J=7.8 Hz, 1 H), 6.68 (d, J=7.6 Hz, 1 H), 6.61 (dd, J=8.1, 1.8 Hz, 1 H), 6.52 (s, 1 H), 5.48 (br. s., 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 369 [M+H]+.
Figure imgf000050_0001
N-r(4-hydroxy-7-nitro-2-oxo-1.2-dihydro-3-quinolinyl)carbonvnglycine
51a") Ethyl 4-hvdroxy-7-nitro-2-oxo-l,2-dihydro-3-quinolinecarboxylate To a mixture of 7-(nitro)isatoic anhydride (3.00 g, 14.4 mmol) and diethyl malonate (4.40 mL, 28.8 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (5.39 mL, 36.0 mmol). 1,4-dioxane (2.0 mL) was added and the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was diluted with water (5 mL) and ethyl acetate (10 mL). The organice layer was separated and purified via flash column chromatography (10-100% ethyl acetate in hexanes) to provide the title compound as a brown solid (0.156 g, 4%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.1 (s, 1 H), 8.75 (d, J=2.5 Hz, 1 H), 8.43 (dd, J=9.1, 2.5 Hz, 1 H), 7.43 (d, J=9.1 Hz, 1 H), 4.33 (q, J=7.1 Hz, 2 H), 1.31 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 279 [M+H]+. 51b) N-r(4-hvdroxy-7-nitro-2-oxo-L2-dihvdro-3-quinolmyl)carbonvnglycine To a solution of the compound from Example 51a) (0.075 g, 0.296 mmol) in ethanol (2.0 mL) were added glycine (0.026 g, 0.351 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL, 0.36 mmol) and the solution was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with IM aqueous hydrochloric acid (1.0 mL), and purified via preparative HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)) to afford the title compound as a brown powder (0.0041 g, 5%). MS(ES+) m/e 304 [M+H]+.
Example 52
N-r(7-amino-4-hydroxy-2-oxo-l,2-dihydro-3-qumolinyl)carbonvnglvcine
52a) Ethyl 7-amino-4-hvdroxy-2-oxo-l ,2-dihvdro-3-quinolinecarboxylate To a mixture of 7-(nitro)isatoic anhydride (3.0 g, 14.4 mmol) and diethyl malonate (4.4 mL,
28.8 mmol) was added l,8-diazabicyclo[5.4.0]undec-7-ene (5.39 mL, 36.0 mmol). 1,4-dioxane (2.0 mL) was added and the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was separated and evaporated down to residue. The residue was dissolved in methanol:water (25 mL, 4:1) and 10% palladium on charcoal (0.050 g, 0.047 mmol) was added. The mixture was shaken on a Parr hydrogenator at 45 psi Hydrogen for 2 h. The reaction mixture was filtered and the filtrate evaporated down to residue and used in the next step without further purification. MS(ES+) m/e 249 [M+H]+.
52b) N-r(7-amino-4-hvdroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonvn glycine To a solution of the compound from Example 52a) (0.40Og, 1.61 mmol) in ethanol (2.0 mL) were added glycine (0.145 g, 1.93 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.482 mL, 3.22 mmol) and the solution was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, diluted with water (3 mL) and treated with IM aqueous hydrochloric acid (3.0 mL). The precipitate was collected by filtration and dried in vacuo to afford the title compound (0.080 g, 18%) as a brown powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.5 (s, 1 H), 10.68 (t, J=5.6 Hz, 1 H), 7.09 - 7.14 (m, 1 H), 7.08 (d, J=2.3 Hz, 1 H), 7.01 - 7.05 (m, 1 H), 4.10 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 278 [M+H]+.
Example 53
Figure imgf000051_0001
N-ir4-hydroxy-5-(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quinolinyllcarbonyl}glycine 53a) 5-(Methyloxy)-2H-3,l-benzoxazine-2,4(lH)-dione
To a solution of 2-amino-6-methoxybenzoic acid (1.00 g, 6.00 mmol) in ethyl acetate (15.0 mL) were added potassium carbonate (0.829 g, 6.00 mmol) and triphosgene (0.800 g, 2.70 mmol). Following stirring at ambient temperature for 45 min., the reaction mixture was treated with water, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were concentrated in vacuo and triturated with ethyl acetate to give the title compound as a pale beige solid (1.15 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.6 (s, 1 H), 7.63 (t, J=8.3 Hz, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 6.69 (d, J=8.1 Hz, 1 H), 3.88 (s, 3 H). MS(ES+) m/e 194 [M+H]+.
53b") Ethyl 4-hvdroxy-5-(methyloxy)-2-oxo-l-(phenylmethyl)-L2-dihvdro-3- quinolinecarboxylate Following the procedure of Example 16a), except substituting the compound from Example
53a) for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.8 (br. s., 1 H), 7.38 (t, J=8.6 Hz, 1 H), 7.27 (t, J=7.2 Hz, 2 H), 7.20 (t, J=7.3 Hz, 1 H), 7.17 (d, J=6.8 Hz, 2 H), 6.81 (d, J=8.3 Hz, 1 H), 6.66 (d, J=8.1 Hz, 1 H), 5.47 (br. s., 2 H), 4.48 (q, J=7.2 Hz, 2 H), 3.98 (s, 3 H), 1.45 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 354 [M+H]+.
53c) N-{ r4-hvdroxy-5-(methyloxy)-2-oxo-l-φhenylmethylV1.2-dihvdro-3- quinolinyllcarbonyl I glycine Following the procedure of Example lib), except substituting the compound from Example 53b) for the compound from Example 1 Ia), the title compound was obtained as a peach solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 10.7 (t, J=5.4 Hz, 1 H), 7.58 (t, J=8.5 Hz, 1 H), 7.31 (t, J=7.3 Hz, 2 H), 7.23 (t, J=7.3 Hz, 1 H), 7.18 (d, J=7.1 Hz, 2 H), 6.98 (d, J=8.3 Hz, 1 H), 6.89 (d, J=8.3 Hz, 1 H), 5.53 (br. s., 2 H), 4.12 (d, J=5.6 Hz, 2 H), 3.89 (s, 3 H). MS(ES+) m/e 383 [M+H]+.
Example 54
Figure imgf000052_0001
N-I r4,5-dihydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 -quinolinyll carbonyl I glycine To a refluxing solution of the compound from Example 53c) (0.150 g, 0.392 mmol) in glacial acetic acid (4.0 mL) was added 48% aqueous hydrobromic acid (1.0 mL) followed by stirring at reflux for 2 h. Upon cooling, the reaction mixture was treated with water, producing a precipitate that was filtered, washed with hexanes, and dried in vacuo to afford the title compound as a peach solid (0.140 g, 97%). 1H NMR (400 MHz, DMSOd6) δ ppm 13.1 (br. s., 1 H), 10.7 (t, J=5.6 Hz, 1 H), 7.47 (t, J=8.3 Hz, 1 H), 7.32 (t, J=7.3 Hz, 2 H), 7.25 (t, J=7.1 Hz, 1 H), 7.23 (d, J=8.3 Hz, 2 H), 6.86 (d, J=8.3 Hz, 1 H), 6.66 (d, J=8.1 Hz, 1 H), 5.47 (s, 2 H), 4.22 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 369 [M+H]+.
Example 55
Figure imgf000052_0002
N-{ ri-r(3-cyanophenyl)methyll-4-hvdroxy-5-(methyloxy)-2-oxo-l,2-dihydro-3- quinolinyll carbonyl } glycine
55a) Ethyl l-r(3-cvanophenyl)methyll-4-hydroxy-5-(methyloxy)-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 53a) for isatoic anhydride and 3-cyanobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.2 (br. s., 1 H), 7.53 (d, J=7.3 Hz, 1 H), 7.44 (s, 1 H), 7.44 (t, J=8.4 Hz, 2 H), 7.41 (t, J=7.6 Hz, 1 H), 6.73 (d, J=8.3 Hz, 1 H), 6.68 (d, J=8.6 Hz, 1 H), 5.50 (br. s., 2 H), 4.49 (q, J=7.2 Hz, 2 H), 4.01 (s, 3 H), 1.46 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 379 [MH-H]+.
55b) N-i ri-r(3-cyanophenyl)methyll-4-hvdroxy-5-(methyloxy)-2-oxo-L2-dihvdro-3- quinolinyll carbonyl } glycine Following the procedure of Example 1 Ib), except substituting the compound from Example
55a) for the compound from Example 1 Ia), the title compound was obtained as a light pink solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.3 Hz, 1 H), 7.74 (s, 1 H), 7.73 (d, J=8.2 Hz, 1 H), 7.59 (t, J=8.5 Hz, 1 H), 7.52 (t, J=7.9 Hz, 1 H), 7.48 (d, J=8.2 Hz, 1 H), 6.95 (d, J=8.6 Hz, 1 H), 6.90 (d, J=8.3 Hz, 1 H), 5.56 (s, 2 H), 4.12 (d, J=5.3 Hz, 2 H), 3.89 (s, 3 H). MS(ES+) m/e 408 [M+H]+.
Example 56
Figure imgf000053_0001
N-{ r6-fluoro-4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 -quinolinyll carbonyl } glycine
56a) Ethyl 6-fluoro-4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 -quinolinecarboxylate Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 14.3 (br. s., 1 H), 7.82 (dd, J=8.6, 2.8 Hz, 1 H), 7.28 (t, J=7.2 Hz, 2 H), 7.20 - 7.25 (m, 2 H), 7.17 (d, J=6.8 Hz, 2 H), 7.15 (dd, J=9.2, 4.3 Hz, 1 H), 5.48 (br. s., 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 342 [M+H]+.
56b) N-(r6-fluoro-4-hvdroxy-2-oxo-l-(phenylmethyl)-L2-dihydro-3- quinolinyll carbonyl 1 glycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 56a) for the compound from Example 1 Ia), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 7.81 (dd, J=8.6, 3.0 Hz, 1 H), 7.62 (dt, J=8.7, 3.0 Hz, 1 H), 7.51 (dd, J=9.4, 4.1 Hz, 1 H), 7.32 (t, J=7.2 Hz, 2 H), 7.24 (t, J=7.1 Hz, 1 H), 7.21 (d, J=7.3 Hz, 2 H), 5.56 (s, 2 H), 4.14 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 371 [M+H]+.
Figure imgf000054_0001
N-({ l-rG-cvanophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-L2-dihvdro-3- quinolinyl I carbonyDgrycine
57a) Ethyl l-r(3-cyanophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-L2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 3-cyanobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.86 (dd, J=8.6, 3.0 Hz, 1 H), 7.53 (d, J=7.3 Hz, 1 H), 7.46 (d, J=7.6 Hz, 1 H), 7.44 (s, 1 H), 7.41 (t, J=7.6 Hz, 1 H), 7.29 (ddd, J=9.1, 7.7, 3.0 Hz, 1 H), 7.04 (dd, 1=9.3, 4.0 Hz, 1 H), 5.49 (br. s., 2 H), 4.51 (q, J=7.2 Hz, 2 H), 1.47 (t, 1=7.1 Hz, 3 H). MS(ES+) m/e 367 [M+H]+.
57b) N-({ l-r(3-cyanophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyllcarbonyDglycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 57a) for the compound from Example 1 Ia), the title compound was obtained as a peach solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.6 Hz, 1 H), 7.82 (dd, J=8.7, 2.9 Hz, 1 H), 7.77 (s, 1 H), 7.73 (d, J=3.3 Hz, 1 H), 7.62 (dt, J=8.6, 3.3 Hz, 1 H), 7.53 (d, J=4.8 Hz, 2 H), 7.50 (t, J=4.6 Hz, 1 H), 5.59 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 396 [M+H]+.
Example 58
Figure imgf000054_0002
N-{14-hvdroxy-6J-bisfmethyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3- quinolinyll carbonyl I glycine
58a) 3,4-Bis(methyloxy)-N-(phenylmethyl)aniline
A solution of 3, 4-dimethoxy aniline (2.20 g, 14.4 mmol) and benzaldehyde (1.46 mL, 14.4 mmol) in methanol (20.0 mL) was stirred at ambient temperature for 1 h. Sodium triacetoxyborohydri.de (3.05 g, 14.4 mmol) was added portionwise to the solution at ambient temperature followed by glacial acetic acid (0.82 mL, 14.4 mmol). The resulting mixture was stirred overnight at ambient temperature. The solution was concentrated in vacuo and the residue was taken up in saturated sodium hydrogen carbonate. The aqueous suspension was extracted using ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10% methanol in dichloromethane) afforded the title compound as a yellow oil (2.63 g, 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 - 7.45 (m, 4 H), 7.26 - 7.34 (m, 1 H), 6.77 (d, 1=8.6 Hz, 1 H), 6.30 (d, J=2.8 Hz, 1 H), 6.20 (dd, J=8.5, 2.7 Hz, 1 H), 4.31 (s, 2 H), 3.83 (s, 6 H). MS(ES+) m/e 244 [M+H]+.
58b) Ethyl 4-hvdroxy-6,7-bis(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3- quinolinecarboxylate A solution of the compound from Example 58a) (0.288 g, 1.18 mmol) in 1,4-dioxane (1.0 mL) was treated with triethyl methanetricarboxylate (0.75 mL, 3.55 mmol) and heated to 200 0C for 1 h in a Biotage Initiator microwave synthesizer. The resulting precipitate was filtered and washed with Et2O to afford the title compound as a light yellow solid (0.279 g, 62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.42 (s, 1 H), 7.26 - 7.33 (m, 2 H), 7.17 - 7.26 (m, 3 H), 6.77 (s, 1 H), 5.48 (s, 2 H), 4.35 (q, J=7.0 Hz, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 1.32 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 384 [M+H]+.
58c) N-{r4-hvdroxy-6,7-bis(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3- quinolinylicarbonyl ) glycine
To a solution of the compound from Example 58b) (0.279 g, 0.727 mmol) in ethanol (3.0 mL) was added glycine sodium salt (0.074 g, 0.764 mmol) and the solution was heated to 180 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous hydrochloric acid (5.0 mL), filtered, and washed with water to give the title compound as a pale yellow solid (0.217 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.6 (t, J=5.3 Hz, 1 H), 7.41 (s, 1 H), 7.16 - 7.37 (m, 5 H), 6.92 (s, 1 H), 5.60 (s, 2 H), 4.10 (d, J=5.6 Hz, 2 H), 3.82 (s, 3 H), 3.76 (s, 3 H). MS(ES+) m/e 413 [M+H]+.
Example 59
Figure imgf000055_0001
N-(|4-hydroxy-l-r(5-methyl-3-isoxazolyl)methyll-2-oxo-l,2-dihydro-3-qumolinyl|carbonyl)glycine
59a) Ethyl 4-hydroxy-l-r(5-methyl-3-isoxazolyl)methyl1-2-oxo-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 3-(bromomethyl)-5- methylisoxazole for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 8.13 (dd, J=8.1, 1.5 Hz, 1 H), 7.61 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.53 (d, J=8.3 Hz, 1 H), 7.21 (ddd, J=S.1, 7.2, 1.1 Hz, 1 H), 5.99 (s, 1 H), 5.44 (tar. s., 2 H), 4.50 (q, J=7.1 Hz, 2 H), 2.30 (s, 3 H), 1.47 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 329 [M+H]+.
59b) N-({4-hvdroxy-l-l('5-methyl-3-isoxazolyl)methyll-2-oxo-1.2-dihvdro-3- quinolinyl 1 carbonyl) glycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 59a) for the compound from Example 1 Ia), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 10.4 (t, J=4.7 Hz, 1 H), 8.12 (dd, J=8.0, 1.4 Hz, 1 H), 7.77 (ddd, J=8.6, 7.1, 1.5 Hz, 1 H), 7.58 (d, J=8.6 Hz, 1 H), 7.37 (t, J=7.5 Hz, 1 H), 6.12 (s, 1 H), 5.54 (s, 2 H), 4.06 (d, J=5.3 Hz, 2 H), 2.33 (s, 3 H). MS(ES+) m/e 358 [M+H]+.
Example 60
Figure imgf000056_0001
N-ir4-hydroxy-5,6-bis(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinylicarbonyl I glycine 60a) 5,6-Bis(methyloxy)-2H-3J-benzoxazine-2,4(lH)-dione
To a solution of 6-({ [(l,l-dimethylethyl)oxy]carbonyl}amino)-2,3-bis(methyloxy)benzoic acid (prepared by the method of Bengtsson, S.; Hδgberg, T. J. Org. Chem. 1989, 54, 4549-4553) (11.6 g, 39.1 mmol) in toluene (90.0 mL) was added oxalyl chloride (3.75 mL, 43.0 mmol). The solution was heated to reflux for 2 h, allowed cool to ambient temperature, and concentrated in vacuo. The resulting brick red solid was washed with dichloromethane and filtered to obtain a light beige solid (2.25 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.5 (s, 1 H), 7.52 (d, J=8.8 Hz, 1 H), 6.86 (d, J=8.8 Hz, 1 H), 3.81 (s, 3 H), 3.78 (s, 3 H), 3.43 (s, 1 H). MS(ES+) m/e 224[M+H]+.
60b) Ethyl 4-hydroxy-5 ,6-bis(methyloxy)-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinolinecarboxylate To a solution of the compound from Example 60a) (0.100 g, 0.45 mmol) in N,N- dimethylformamide (2.0 mL) was added sodium hydride (0.018 g, 60 % dispersion in mineral oil, 0.45 mmol) followed by benzyl bromide (0.055 mL, 0.47 mmol). The solution was stirred for 1 h at ambient temperature. Diethyl malonate (0.070 mL, 0.45 mmol) was added to the solution, followed by sodium hydride (0.018 g, 60% dispersion in mineral oil, 0.45 mmol). The solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. The mixture was allowed to cool to ambient temperature, poured into water, acidified with 6M aqueous hydrochloric acid, and extracted twice with ethyl acetate. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (60% ethyl acetate in hexanes) afforded the title compound as a bright yellow solid (0.073 g, 42%). 1H NMR (400 MHz, DMSOd6) δ ppm 7.59 (d, J=2.5 Hz, 1 H), 7.31 (t, J=7.3 Hz, 2 H), 7.19 - 7.26 (m, 1 H), 7.17 (d, J=7.1 Hz, 2 H), 7.12 (d, J=9.3 Hz, 1 H), 5.43 (br. s., 2 H), 4.28 (q, J=7.1 Hz, 2 H), 3.98 (s, 3 H), 3.83 (s, 3 H), 1.29 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 384[M+H]+. 60c) N-ir4-hydroxy-5,6-bis(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyll carbonyl I glycine
To a solution of the compound from Example 60b) (0.073 g, 0.19 mmol) in ethanol (3.0 mL) was added glycine sodium salt (0.020 g, 0.200 mmol) and the solution was heated to 180 0C for 30 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous hydrochloric acid (5.0 mL), filtered, washed with water and triturated with Et2O. Purification via flash column chromatography (60% ethyl acetate in hexanes) afforded the title compound as a pale orange solid (0.023 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.8 (t, J=5.3 Hz, 1 H), 7.49 (d, J=9.6 Hz, 1 H), 7.32 (t, J=7.3 Hz, 2 H), 7.24 (d, J=7.1 Hz, 1 H), 7.17 - 7.22 (m, 3 H), 5.52 (br. s., 1 H), 4.13 (d, J=5.8 Hz, 2 H), 3.81 (s, 3 H), 3.78 (s, 3 H). MS(ES+) m/e 413[M+H]+.
Example 61
Figure imgf000057_0001
N-(11 -r(2-bromophenyl)methvn -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihy dro-3 - quinolinyl I carbonyl) glycine 61a) Ethyl 1 -f(2-bromophenyl)methyll -ό-fluoro^-hydroxy-Σ-oxo- 1 ,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.87 (dd, J=8.5, 2.9 Hz, 1 H), 7.54 - 7.66 (m, 1 H), 7.26 - 7.32 (m, 1 H), 7.07 - 7.16 (m, 2 H), 6.96 (dd, J=9.2, 4.2 Hz5 1 H), 6.69 - 6.75 (m, 1 H), 5.52 (br. s., 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 420/422 [M+HJ+.
61b) N-(f l-r(2-bromophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinolmvUcarbonyDglycine
Following the procedure of Example 1 Ib), except substituting the compound from Example 61a) for the compound from Example 1 Ia), the title compound was obtained as a beige solid. 1H
NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=4.4 Hz, 1 H), 7.86 (dd, J=8.6, 3.0 Hz, 1 H), 7.69 - 7.77 (m, 1 H), 7.64 (ddd, J=8.7, 3.0 Hz, 1 H), 7.30 (dd, J=9.5, 4.2 Hz, 1 H), 7.18 - 7.26 (m, 2 H), 6.66 (t, J=4.8 Hz, 1 H), 5.47 (s, 2 H), 4.13 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 449/451 [M+H]+.
Example 62
Figure imgf000058_0001
N-{ r4-hvdroxy-l-r(l-methyl-lH-imidazol-2-yl)methyll-6,7-bis(methyloxy)-2-oxo-l,2-dihvdro-3- quinolinyll carbonyl I glycine
62a) N-r(l-methyl-lH-imidazol-2-yl)methyll-3,4-bis(methyloxy)aniline Following the procedure of Example 58a), except substituting 1 -methyl- lH-imidazole-2- carbaldehyde for benzaldehyde and dichloromethane for methanol, the title compound was obtained as a pale brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.99 (d, J=I .3 Hz, 1 H), 6.86 (d, J=I.3 Hz, 1 H), 6.77 (d, J=8.3 Hz, 1 H), 6.39 (d, J=2.5 Hz, 1 H), 6.26 (dd, J=8.5, 2.7 Hz, 1 H), 4.32 (s, 2 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 3.68 (s, 3 H). MS(ES+) m/e 248[M+H]+.
62b) Ethyl 4-hydroxy- 1-F(I -methyl- lH-imidazol-2-yl)methyll -6,7-bis(methyloxy)-2-oxo- 1 ,2- dihydro-3 -quinolinecarboxylate Following the procedure from example 58b), except substituting the compound from Example
62a) for the compound from Example 58a), the title compound was obtained as a dark yellow solid. 1H NMR (400 MHz, DMSOd6) δ ppm 7.52 (s, 1 H), 7.39 (s, 1 H), 7.07 (d, J=LO Hz, 1 H), 6.78 (d, J=LO Hz, 1 H), 5.50 (s, 2 H), 4.33 (q, J=7.1 Hz, 2 H), 3.87 (s, 3 H), 3.81 (s, 3 H), 3.67 (s, 3 H), 1.30 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 388[M+H]+. 62c) N-{r4-hydroxy-l-r(l-methyl-lH-imidazol-2-yl)methvn-6,7-bis(methyloxy)-2-oxo-L2- dihydro-3 -quinolinyll carbonyl I glycine
Following the procedure from example 58c), except substituting the compound from Example 62b) for the compound from Example 58b), the title compound was obtained as a cream solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.3 (t, J=4.8 Hz, 1 H), 7.61 (br. s., 1 H), 7.48 (s, 1 H), 7.43 (br. s., 1 H), 7.13 (br. s., 1 H), 5.82 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 3.90 (s, 6 H), 3.87 (s, 3 H). MS(ES+) m/e 417[M+H]+.
Figure imgf000059_0001
N-/ r4-hvdroxy~6,7-bis(methyloxy)-2-oxo-l -( 1 ,3-thiazol-2-ylrαethyl)-l ,2-dihydro-3- quinolinyllcarbonyllglvcme 63a) 34-Bis(methyloxy)-N-Q34Hazol-2-ylmethyl)aniline
Following the procedure of Example 58a), except substituting l,3-thiazole-2-carbaldehyde for benzaldehyde and dichloromethane for methanol, the title compound was obtained as a dark oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.72 (d, J=3.3 Hz, 1 H), 7.24 (d, J=3.3 Hz, 1 H), 6.71 (d, J=8.6 Hz, 1 H), 6.30 (d, J=2.5 Hz, 1 H), 6.17 (dd, J=8.5, 2.7 Hz, 1 H), 3.90 (d, J=3.3 Hz, 1 H), 3.78 (s, 3 H), 3.77 (s, 3 H). MS(ES+) m/e 251[M+H]+.
63b) Ethyl 4-hvdroxy-6,7-bis(methyloxy)-2-oxo-l-q,3-thiazol-2-ylmethyl)-1.2-dihydro-3- quinolinecarboxylate
Following the procedure from example 58b), except substituting the compound from Example 63a) for the compound from Example 58a), the title compound was obtained as a bright yellow solid after washing the residue with ethyl acetate. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.6 (br. s., 1 H), 7.76 (d, J=3.3 Hz, 1 H), 7.68 (d, J=3.3 Hz, 1 H), 7.42 (s, 1 H), 7.22 (s, 1 H), 5.76 (s, 2 H), 4.36 (q, J=7.1 Hz, 2 H), 3.87 (s, 3 H), 3.83 (s, 3 H), 1.33 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 391[M+H]+.
63c) N-{r4-hydroxy-6J-bisfmethyloxy)-2-oxo-l-(l,3-thiazol-2-ylmethyl)-l,2-dihydro-3- quinolinylicarbonyl } glycine Following the procedure from example 58c), except substituting the compound from Example
63b) for the compound from Example 58b), the title compound was obtained as a beige solid after triturating with Et2O. 1H NMR (400 MHz, DMSOd6) δ ppm 10.4 (t, J=5.6 Hz, 1 H), 7.76 (d, J=3.3 Hz, 1 H), 7.69 (d, J=3.3 Hz, 1 H), 7.41 (s, 1 H), 7.30 (s, 1 H), 5.86 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 3.89 (s, 3 H), 3.84 (s, 3 H). MS(ES+) m/e 420[M+H]+. Example 64
N-[Y4-hydroxy- 1 -methyl~6-nitro-2-oxo- 1 ,2-dihydro-3 -quinolinvDcarbonyn glycine
Following the procedures of Examples 7b) and 7c), except substituting N-methyl-4- nitroaniline for the compound from Example 7a), the title compound was obtained as yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.4 (s, 1 H), 8.80 (d, J=2.8 Hz, 1 H), 8.56 (dd, J=9.4, 2.5 Hz, 1 H), 7.85 (d, J=9..4 Hz, 1 H), 4.16 (d, J=5.6 Hz, 2 H), 3.70 (s, 3 H). MS(ES+) m/e 322
[M+H]+.
Example 65
Figure imgf000060_0001
N-I [4.6.7-trihvdroxv-2-oxo-l-Q ,3 -thiazol-2-vlmethvD- 1 ,2-dihvdro-3 -quinolinvllcarbonvl I glycine
Boron tribromide (7.70 mL, 1.0M in dichloromethane, 7.70 mmol) was added to a cooled (-5 0C) solution of the compound from Example 63c) (0.324 g, 0.77 mmol) in dichloromethane (20.0 mL) under a nitrogen atmosphere. After stirring overnight at ambient temperature, the reaction mixture was treated with water and the resulting precipitate was filtered to afford the title compound as a green solid (0.264 g, 88%). 1H NMR (400 MHz, METHANOLS) δ ppm 8.06 (d, J=3.8 Hz, 1 H), 7.91 (d, J=3.5 Hz, 1 H), 7.48 (s, 1 H), 6.94 (s, 1 H), 5.89 (s, 2 H), 4.18 (s, 2 H). MS(ES+) m/e 392 [M+H]+.
Example 66
Figure imgf000060_0002
N-ir4,6,7-trihvdroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolmyncarbonyllglycine
Following the procedure of Example 65, except substituting the compound from Example 58c) for the compound from Example 63c), the title compound was obtained as a light green solid. 1H NMR (400 MHz, DMSOd6) δ ppm 10.6 (t, J=5.6 Hz, 1 H), 7.38 (s, 1 H), 7.33 (t, J=7.3 Hz, 2 H), 7.24 (t, J=7.3 Hz, 1 H), 7.18 (d, J=7.3 Hz, 2 H), 6.75 (s, 1 H), 5.41 (br. s., 2 H), 4.11 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 385 [M+H]+.
Figure imgf000061_0001
N-( { 6-fluoro- 1 -r(2-fluorophenvDmethyl1 -4-hydroxy-2-oxo- 1 ,2-dihy dro-3 - quinolinyl I carbonyl) glycine
67a) Ethyl 6-fluoro-l-r(2-fluorophenyl)methvn-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-fluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.84 (dd, J=8.6, 3.0 Hz, 1 H), 7.29 (ddd, J=9.4, 7.6, 3.0 Hz, 1 H), 7.18 - 7.25 (m, 1 H), 7.14 (dd, J=9.3, 4.0 Hz, 1 H), 7.09 (dt, J=9.3, 0.7 Hz, 1 H), 6.92 - 7.02 (m, 2 H), 5.53 (br. s., 2 H), 4.53 (q, J=7.1 Hz, 2 H), 1.49 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 360 [M+H]+.
67b) N-({6-fluoro-l-l(2-fluorophenyl)methyll-4-hydroxy-2-oxo-L2-dihydro-3- quinormyl)carbonyl)glycme
Following the procedure of Example lib), except substituting the compound from Example 67a) for the compound from Example Ha), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) 5 ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.6 Hz, 1 H), 7.84 (dd, J=8.6, 3.0 Hz, 1 H), 7.65 (dt, J=8.7, 3.0 Hz, 1 H), 7.49 (dd, J=9.3, 4.3 Hz, 1 H), 7.33 (t, J=7.1 Hz, 1 H), 7.27 (t, J=8.8 Hz, 1 H), 7.06 (dt, I=IA, 1.3 Hz, 1 H), 6.84 (t, J=7.6 Hz, 1 H), 5.56 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 389 [M+H]+.
Example 68
Figure imgf000061_0002
N-(l l-r(2-chlorophenyl)methyl1-6-fluoro-4-hydroxy-2-oxo-1.2-dihydro-3- quinolinyl }carbonyl)glycine
68a) Ethyl l-r(2-chlorophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-chlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.86 (dd, J=8.6, 3.0 Hz, 1 H), 7.42 (dd, J=8.0, 1.1 Hz, 1 H), 7.28 (ddd, J=9.3, 7.5, 2.9 Hz, 1 H), 7.18 (dt, J=7.7, 1.5 Hz, 1 H), 7.08 (dt, J=7.6, 1.0 Hz, 1 H), 6.98 (dd, J=9.3, 4.3 Hz, 1 H), 6.76 (d, J=7.8 Hz, 1 H), 5.55 (br. s., 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.48 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 376 [M+H]+. Alternatively, the compound from Example 68a) can be prepared according to the following method:
68a' To a solution of 6-(fluoro)isatoic anhydride (50.0 g, 276 mmol) and 2-chlorobenzyl bromide (35.8 mL, 276 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (11.05 g, 60% dispersion in mineral oil, 276 mmol). Following stirring at ambient temperature for 15 min., the reaction mixture was heated to 100 0C for 20 min. Upon cooling to ambient temperature, diethyl malonate (41.9 mL, 276 mmol) was added and the reaction mixture was cooled to 0 0C, at which point sodium hydride (11.05 g, 60% dispersion in mineral oil, 276 mmol) was added. Following removal of the ice bath, the reaction mixture was stirred at ambient temperature for 30 min., followed by slow heating to 800C. After stirring 20 min. at 80 0C, the reaction mixture was further heated to 150 0C for an additional 20 min. Upon cooling, the reaction mixture was poured into ice-water, acidified with 6M aqueous hydrochloric acid (100 mL), diluted with brine, extracted twice with ethyl acetate, and concentrated in vacuo. Crystallization from methanol afforded the title compound as a white solid (61.5 g, 59%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.88 (dd, J=8.5, 2.9 Hz, 1 H), 7.43 (dd, J=8.0, 1.1 Hz, 1 H), 7.30 (ddd, J=9.3, 7.7, 3.2 Hz, 1 H), 7.20 (dt, J=7.7, 1.8 Hz, 1 H), 7.09 (dt, J=7.6, 1.3 Hz, 1 H), 6.99 (dd, J=9.3, 4.0 Hz, 1 H), 6.77 (dd,
J=7.8, 1.3 Hz, 1 H), 5.57 (s, 2 H), 4.53 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 376 [M+H]+.
68b) N-(( l-r(2-chlorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinyllcarbonyDglycine Following the procedure of Example 1 Ib), except substituting the compound from Example
68a) for the compound from Example 1 Ia), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.8 Hz, 1 H), 7.87 (dd, J=8.6, 3.0 Hz, 1 H), 7.64 (dt, J=8.7, 3.0 Hz, 1 H), 7.56 (dd, J=8.0, 0.9 Hz, 1 H), 7.34 (dd, J=9.6, 3.8 Hz, 1 H), 7.30 (dd, J=7.8, 1.3 Hz, 1 H), 7.18 (dt, J=7.6, 1.0 Hz, 1 H), 6.70 (d, J=7.8 Hz, 1 H), 5.54 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 405 [M+H]+.
Alternatively, the compound from Example 68b) can be prepared according to the following method:
68b') A mixture of the compound from Example 68a) (61.5 g, 163.7 mmole) and glycine sodium salt (31.8 g, 327.3 mole) in 2-methoxyethanol (350 mL) was stirred and heated under reflux for 4 h. The cooled solution was then poured into ice-water and acidified with 6M aqueous hydrochloric acid (100 mL). The reaction mixture was then filtered, washed with water, and dried in vacuo to afford the title compound as a white solid (65.2 g, 98%). IH NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.4 Hz, 1 H), 7.86 (dd, J=8.8, 3.0 Hz, 1 H), 7.64 (ddd, J=9.3, 8.2, 3.0 Hz, 1 H), 7.56 (dd, J=8.0, 1.1 Hz, 1 H), 7.34 (dd, J=9.3, 4.3 Hz, 1 H), 7.31 (dt, J=7.6, 1.6 Hz, 1 H), 7.18 (dt, J=7.6, 1.3 Hz, 1 H), 6.70 (dd, J=7.6, 1.0 Hz, 1 H), 5.53 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 405 [M+H]+.
Example 69
Figure imgf000063_0001
N-(|6-fluoro-4-hvdroxy-l-r(2-methylphenyl')methyll-2-oxo-l,2-dihvdro-3- quinolmyUcarbonvDglvcme
69a) Ethyl 6-fluoro-4-hvdroxy-l-[(2-methylphenyl)methvn-2-oxo-1.2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-methylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.87 (dd, J=8.6, 3.0 Hz, 1 H), 7.25 (ddd, J=9.4, 7.8, 3.0 Hz, 1 H), 7.21 (d, J=7.3 Hz, 1 H), 7.13 (t, J=7.3 Hz, 1 H), 7.00 (t, J=7.5 Hz, 1 H), 6.94 (dd, J=9.3, 4.0 Hz, 1 H), 6.59 (d, J=7.6 Hz, 1 H), 5.41 (br. s., 2 H), 4.50 (q, J=7.2 Hz, 2 H), 2.45 (s, 3 H), 1.47 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 356 [M+H]+.
69b) N-(l6-fluoro-4-hvdroxy-l-r(2-methylphenyl)methyl1-2-oxo-1.2-dihydro-3- quinolinyllcarbonyDglvcine Following the procedure of Example 1 Ib), except substituting the compound from Example
69a) for the compound from Example 1 Ia), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 7.85 (dd, J=8.6, 3.0 Hz, 1 H), 7.61 (dt, J=8.7, 3.0 Hz, 1 H), 7.33 (dd, J=9.3, 4.0 Hz, 1 H), 7.26 (d, J=7.3 Hz, 1 H), 7.14 (t, J=7.3 Hz, 1 H), 7.00 (t, J=7.5 Hz, 1 H), 6.45 (d, J=7.8 Hz, 1 H), 5.46 (s, 2 H), 4.13 (d, J=5.3 Hz, 2 H), 2.46 (s, 3 H). MS(ES+) m/e 385 [M+H]+. Example 70
Figure imgf000064_0001
N-{ [4-hydroxy-2-oxo-l-(l,3-thiazol-2-ylmethylVl,2-dihydro-3-quinolmvncarbonyl|glvcine
70a) N-( 13-tMazol-2-ylmethyl)aniline Following the procedure of Example 58a), except substituting aniline for 3,4- dimethoxy aniline, l,3-thiazole-2-carbaldehyde for benzaldehyde, and dichloromethane for methanol, the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (d, J=3.3 Hz, 1 H), 7.26 (d, J=3.3 Hz, 1 H), 7.17 - 7.23 (m, 2 H), 6.78 (t, 1=1.3, 1.0 Hz, 1 H), 6.66 - 6.71 (m, 2 H), 4.69 (d, J=5.8 Hz, 2 H), 4.54 (br. s., 1 H). MS(ES+) m/e 191 [M+H]+. 70b) Ethyl 4-hvdroxy-2-oxo-l-( 1 ,3-thiazol-2-ylmethylV 1 ,2-dihydro-3-quinolmecarboxylate
A solution of the compound from Example 70a) (1.65 g, 8.67 mmol) in 1,4-dioxane (6.0 mL) was treated with triethyl methanetricarboxylate (5.47 mL, 26.0 mmol) and heated to 200 0C for 45 min. in a Biotage Initiator microwave synthesizer. The homogeneous solution was taken up in water, acidified with IM aqueous hydrochloric acid, and extracted twice with ethyl acetate. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash column chromatography (60% ethyl acetate in hexanes) to afford the title compound as a light yellow oil (0.200 g, 7%). 1H NMR (400 MHz, METHANOLS) δ ppm 6.54 (d, J=8.1 Hz, 1 H), 6.15 (d, J=3.3 Hz, 1 H), 6.07 - 6.13 (m, 1 H), 6.01 - 6.06 (m, 1 H), 5.95 (d, J=3.3 Hz, 1 H), 5.66 - 5.78 (m, 1 H), 4.17 (s, 2 H), 2.92 (q, J=7.1 Hz, 2 H), -0.12 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 331 [M+H]+.
70c) N-ir4-hydroxy-2-oxo-l-(1.3-thiazol-2-ylmethyl)-L2-dihydro-3- quinolinyli carbonyl ) glycine
Following the procedure from example 58c), except substituting the compound from Example 70b) for the compound from Example 58b), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.14 (dd, J=8.0, 1.4 Hz, 1 H), 7.77 - 7.84 (m, 1 H), 7.76 (s, 1 H), 7.75 (d, J=3.3 Hz, 1 H), 7.69 (d, J=3.3 Hz, 1 H), 7.37 - 7.42 (m, 1 H), 5.83 (s, 2 H), 4.16 (d, J=5.8 Hz, 2 H). MS(ES+) m/e 360 [M+H]+. Example 71
Figure imgf000065_0001
N-i rS-fluoro^-hvdroxy^-oxo-l-CphenylmethylVl.Z-dihydro-S-quinolinyllcarbonyl) glycine
7 Ia) 5-Fluoro-2H~3, 1 -benzoxazine-2,4( lH)-dione Following the procedure of Example 53a), except substituting 2-amino-6-fluorobenzoic acid for 2-amino-6-methoxybenzoic acid, the title compound was obtained as a light brown solid. 1H NMR (400 MHz, DMSOd6) 6 ppm 11.9 (s, 1 H), 7.73 (dt, J=8.3, 5.7 Hz, 1 H), 7.05 (ddd, J=10.6, 8.3, 0.8 Hz, 1 H), 6.97 (d, J=8.3 Hz, 1 H). MS(ES+) m/e 182 [M+H]+.
7 Ib) Ethyl 5 -fluoro-4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 -quinolinecarboxylate Following the procedure of Example 16a), except substituting the compound from Example
71a) for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.8 (s, 1 H), 7.43 (dt, J=8.5, 5.6 Hz, 1 H), 7.29 (t, J=7.2 Hz, 2 H), 7.23 (d, J=7.3 Hz, 1 H), 7.18 (d, J=7.3 Hz, 2 H), 6.98 (d, J=8.8 Hz, 1 H), 6.86 (dd, J=I 1.4, 8.3 Hz, 1 H), 5.49 (br. s., 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.48 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 342 [M+H]+
71c) N-{r5-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3- quinolinyll carbonyl } glycine
Following the procedure of Example lib), except substituting the compound from Example 71b) for the compound from Example 1 Ia), the title compound was obtained as a pale yellow solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.6 (t, J=5.4 Hz, 1 H), 7.67 (dt, J=8.5, 5.8 Hz, 1 H), 7.32 (t, J=7.2 Hz, 2 H), 7.27 (d, J=8.6 Hz, 1 H), 7.26 (t, J=6.6 Hz, 1 H), 7.21 (d, J=7.3 Hz, 2 H), 7.11 (dd, J=11.9, 8.1 Hz, 1 H), 5.54 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 371 [M+H]+.
Example 72
Figure imgf000065_0002
N-i r7-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinyl1carbonyl)glycine
72a) 7-Fluoro-2H-3J-benzoxazine-2.4(lH)-dione
Following the procedure of Example 53a), except substituting 2-amino-4-fluorobenzoic acid for 2-amino-6-methoxybenzoic acid, the title compound was obtained as a cream solid. 1H NMR (400 MHz, DMSOd6) δ ppm 11.9 (s, 1 H), 8.00 (dd, J=8.8, 6.1 Hz, 1 H), 7.11 (dt, J=8.7, 2.5 Hz, 1 H), 6.88 (dd, J=9.7, 2.4 Hz, 1 H). MS(ES+) m/e 182 [M+H]+.
72b) Ethyl 7-fluoro-4-hvdroxy-2-oxo-l-(phenylmethyl)-L2-dihvdro-3-quinolinecarboxylate Following the procedure of Example 16a), except substituting the compound from Example 72a) for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.18 (dd, J=9.1, 6.3 Hz, 1 H), 7.30 (t, J=7.2 Hz, 2 H), 7.25 (dd, 1=6.1, 5.4 Hz, 1 H), 7.20 (d, J=7.1 Hz, 2 H), 6.91 (ddd, J=8.8, 8.1, 2.2 Hz, 1 H), 6.87 (dd, J=ILO, 2.1 Hz, 1 H), 5.44 (br. s., 2 H), 4.51 (q, J=7.2 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 342 [M+H]+. 72c) N-{r7-fluoro-4-hydroxy-2-oxo-l-(phenylmethylVl,2-dihydro-3- quinolinyll carbonyl I glycine
Following the procedure of Example lib), except substituting the compound from Example 72b) for the compound from Example lla), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.2 (br. s., 1 H), 10.4 (t, J=5.3 Hz, 1 H), 8.17 (dd, J=8.6, 6.6 Hz, 1 H), 7.35 (d, J=3.3 Hz, 1 H), 7.31 (d, J=7.6 Hz, 2 H), 7.18 - 7.27 (m, 4 H), 5.53 (s, 2 H), 4.11 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 371 [M+H]+.
Example 73
Figure imgf000066_0001
N-{ r9-hvdroxy-7-oxo-6-(phenylmethyl)-2,3,6,7-tetrahydrori,41dioxinor2,3-g:lquinolin-8- yli carbonyl I glycine
73a) N-(phenylmethyl)-2,3-dihydro-l .4-benzodioxin-6-amine
To a solution of benzaldehyde (1.00 mL, 9.90 mmol) and 3, 4-ethylenedioxy aniline (1.50 g, 9.90 mmol) in CH2Cl2 (25.0 mL) was added sodium triacetoxyborohydride (2.30 g, 10.9 mmol) and glacial acetic acid (0.50 mL, 9.90 mmol). The mixture was stirred 2 h at ambient temperature, quenched with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over MgSU4, filtered, and concentrated in vacuo to afford the title compound as a dark oil (2.40 g, 99%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.30 - 7.35 (m, 2 H), 7.23 - 7.30 (m, 2 H), 7.15 - 7.23 (m, 1 H), 6.58 (d, J=8.6 Hz, 1 H), 6.19 (d, J=2.5 Hz, 1 H), 6.16 (q, J=2.6 Hz, 1 H), 4.19 (s, 2 H), 4.10 - 4.14 (m, 2 H), 4.05 - 4.09 (m, 2 H). MS(ES+) m/e 242 [M+H]+. 73b) Ethyl 9-hvdroxy-7-oxo-6-(phenylmethylV2.3.6.7-tetrahvdrori.41dioxinor2.3- giquinoline-8-carboxylate
Following the procedure from example 58b), except substituting the compound from Example 73a) for the compound from Example 58a), the title compound was obtained as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 13.4 (br. s., 1 H), 7.45 (s, 1 H), 7.28 - 7.34 (m, 2 H), 7.20 - 7.26 (m, 1 H), 7.17 (d, J=7.1 Hz, 2Η), 6.78 (s, 1 H), 5.38 (br. s., 2 H), 4.34 (q, J=7.1 Hz, 2 H), 4.28 - 4.32 (m, 2 H), 4.22 - 4.28 (m, 2 H), 1.31 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 382 [M+H]+.
73c) N-{ r9-hvdroxy-7-oxo-6-(phenylmethyl)-2,3,6,7-tetrahvdrorL41dioxinor2,3-glquinolin- 8-yllcarbonyl } glycine
A mixture of the compound from Example 73b) (0.59 g, 1.55 mmol) and glycine sodium salt (0.16 g, 1.63 mmol) in ethanol (5.0 mL) was heated to 1800C for 30 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was concentrated in vacuo and the residue washed with DMSO. The precipitate was filtered and dried in vacuo to afford the title compound as a white solid (0.183 g, 29%). 1H NMR (400 MHz, DMSOd6) δ ppm 10.5 (t, J=4.9 Hz, 1 H), 7.45 (s, 1 H), 7.32 (t, J=7.3 Hz, 2 H), 7.25 (d, J=7.3 Hz, 1 H), 7.20 (t, J=6.3 Hz, 2 H), 6.89 (s, 1 H), 5.47 (s, 2 H), 4.30 - 4.35 (m, 2 H), 4.25 - 4.29 (m, 2 H), 4.10 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 411 [M+H]+.
Example 74
Figure imgf000067_0001
N-{r8-hydroxy-6-oxo-5-(phenybxιethyl)-5,6-dihvdrorL31dioxolor4,5-g1quinolin-7- ylicarbonyl } glycine
74a) N-(phenylmethyl)-l,3-benzodioxol-5-amine
Following the procedure of Example 73a), except substituting 3,4-methylenedioxyaniline for 3,4-ethylenedioxyaniline, the title compound was obtained as a brown oil after purification via flash column chromatography (60% ethyl acetate in hexanes). 1H NMR (400 MHz, METHANOL-d4) 6 ppm 7.31 - 7.37 (m, 2 H), 7.24 - 7.31 (m, 2 H), 7.15 - 7.23 (m, 1 H), 6.56 (d, J=8.3 Hz, 1 H), 6.27 (d, J=2.3 Hz, 1 H), 6.07 (dd, J=8.3, 2.3 Hz, 1 H), 5.75 (s, 2 H), 4.21 (s, 2 H). MS(ES+) m/e 228 [M+H]+.
74b) Ethyl 8-hvdroxy-6-oxo-5-(phenylmethyl)-5,6-dihydrori31dioxolof4,5-glquinoline-7- carboxylate Following the procedure from example 58b), except substituting the compound from Example
74a) for the compound from Example 58a), the title compound was obtained as an orange solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.5 (br. s., 1 H), 7.41 (s, 1 H), 7.31 (t, J=7.3 Hz, 2 H), 7.20 - 7.26 (m, 1 H), 7.17 (d, J=7.1 Hz, 2 H), 6.96 (s, 1 H), 6.13 (s, 2 H), 5.44 (s, 2 H), 4.35 (q, J=7.2 Hz, 2 H), 1.31 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 368 [M+H]+. 74c) N-{ r8-hvdroxy-6-oxo-5-(phenylmethyl)-5,6-dihvdron,31dioxolor4.5-e1quinolin-7- ylicarbonyl } glycine
To a solution of the compound from Example 74b) (1.60 g, 4.35 mmol) in ethanol (2.0 mL) was added glycine sodium salt (0.40 g, 4.57 mmol) and the solution was heated to 180 0C for 30 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous hydrochloric acid (5.0 mL), and filtered to obtain a yellow solid, which in turn was washed with methanol, ethyl acetate, and DMSO to afford the title compound as a light yellow solid (0.070 g, 4%). 1H NMR (400 MHz, DMSOd6) δ ppm 10.5 (t, J=5.3 Hz, 1 H), 7.43 (s, 1 H), 7.32 (t, J=7.3 Hz, 2 H), 7.25 (d, J=7.6 Hz, 1 H), 7.21 (t, J=6.4 Hz, 2 H), 7.08 (s, 1 H), 6.15 (br. s., 2 H), 5.53 (br. s., 2 H), 4.12 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 397 [M+H]+.
Example 75
Figure imgf000068_0001
N-{r6,7-difluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quinolinyncarbonyl)glycine 75a^ 6,7-Difluoro-2H-3.1-benzoxazine-2,4(lH)-dione
Following the procedure of Example 53a), except substituting 2-amino-4,5-difluorobenzoic acid for 2-amino-6-methoxybenzoic acid, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 11.9 (s, 1 H), 8.00 (dd, J=9.9, 8.3 Hz, 1 H), 7.11 (dd, J=10.9, 6.6 Hz, 1 H). MS(ES+) m/e 200 [M+H]+. 75b) Ethyl 6,7-difluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 75a) for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.95 (t, J=9.4 Hz, 1 H), 7.31 (t, J=7.1 Hz, 2 H), 7.24 (t, J=7.4 Hz, 1 H), 7.19 (d, J=7.3 Hz, 2 H), 6.99 (dd, J=12.0, 6.4 Hz, 1 H), 5.43 (s, 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 360 [M+H]+.
75c) N-i r6,7-difluoro-4-hvdroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyli carbonyl \ glycine A mixture of the compound from Example 75b) (0.387 g, 1.08 mmol) and glycine sodium salt
(0.157 g, 1.62 mmol) in ethanol (2.0 mL) was heated to 160 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with water and acidified with 6M aqueous hydrochloric acid. Following stirring at ambient temperature for 5 min., the precipitate was filtered, washed with water, and dried in vacuo to afford the title compound as a white solid (0.385 g, 92%). 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.07 (dd, J=10.2, 9.2 Hz, 1 H), 7.64 (dd, J=12.8, 6.7 Hz, 1 H), 7.33 (t, J=7.5 Hz, 2 H), 7.27 (t, J=7.3 Hz, 1 H), 7.23 (d, J=7.1 Hz, 2 H), 5.53 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 389 [M+H]+.
Figure imgf000069_0001
N-{r4-hydroxy-6-methyl-2-oxo-l-('phenylmethyl)-l,2-dihvdro-3-quinolinvncarbonvUelvcine
76a) 6-Methyl-2H-3,l-benzoxazine-2,4(lH)-dione Following the procedure of Example 53a), except substituting 2-amino-5-methylbenzoic acid for 2-amino-6-methoxybenzoic acid, the title compound was obtained as a peach solid. 1H NMR (400 MHz, DMSOd6) δ ppm 11.7 (s, 1 H), 7.72 (s, 1 H), 7.56 (dd, J=8.3, 1.5 Hz, 1 H), 7.07 (d, J=8.3 Hz, 1 H), 2.33 (s, 3 H). MS(ES+) m/e 178 [M+H]+.
76b) Ethyl 4-hydroxy-6-methyl-2-oxo-l-(phenylmethyl)-L2-dihvdro-3-quinolinecarboxylate Following the procedure of Example 16a), except substituting the compound from Example
76a) for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.98 (d, J=1.0 Hz, 1 H), 7.34 (dd, J=8.6, 1.8 Hz, 1 H), 7.27 (tt, J=7.0, 1.3 Hz, 2 H), 7.21 (dd, J=9.7, 1.4 Hz, 2 H), 7.19 (d, J=10.8 Hz, 1 H), 7.09 (d, J=8.6 Hz, 1 H), 5.49 (br. s., 2 H), 4.52 (q, J=7.1 Hz, 2 H), 2.38 (s, 3 H), 1.49 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 338 [M+H]+.
76c) N-i r4-hvdroxy-6-methyl-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 75c), except substituting the compound from Example 76b) for the compound from Example 75b), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.6 (t, J=5.4 Hz, 1 H), 7.92 (s, 1 H), 7.53 (d, J=7.6 Hz, 1 H), 7.38 (d, J=8.8 Hz, 1 H), 7.31 (t, J=7.3 Hz, 2 H), 7.24 (d, J=7.1 Hz, 1 H), 7.19 (d, J=7.6 Hz, 2 H), 5.54 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H), 2.37 (s, 3 H). MS(ES+) m/e 367 [M+H]+.
Example 77
Figure imgf000070_0001
N-F(I-I \4-( 1.1-dimethylethvDphenyllmethyl I -6-fluoro-4-hvdroxy-2-oxo-l .2-dihvdro-3- quinolinyPcarbonyl] glycine 77a) Ethyl 1-1 r4-(l,l-dimethylethyl')phenyllmethyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-
3 -quinorinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (s, 1 H), 7.84 (d, J=8.1 Hz, 1 H), 7.30 (d, J=7.1 Hz, 2 H), 7.24 - 7.28 (m, 1 H), 7.21 (dd, J=9.1, 3.8 Hz, 1 H), 7.12 (d, J=7.6 Hz, 2 H), 5.46 (br. s., 2 H), 4.52 (q, J=7.0 Hz, 2 H), 1.48 (t, J=7.1 Hz, 3 H), 1.26 (s, 9 H). MS(ES+) m/e 398 [M+H]+.
77b) N-F(I-I F4-(l. l-dimethylethyl)phenvnmethyl}-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvDcarbonyll glycine Following the procedure of Example 75c), except substituting the compound from Example
77a) for the compound from Example 75b), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.1 Hz, 1 H), 7.82 (dd, J=8.6, 3.0 Hz, 1 H), 7.64 (dt, J=8.7, 3.0 Hz, 1 H), 7.56 (dd, J=9.5, 4.3 Hz, 1 H), 7.33 (d, J=8.3 Hz, 2 H), 7.13 (d, J=8.1 Hz, 2 H), 5.51 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 427 [M+H]+.
Example 78
Figure imgf000071_0001
N-Clό-fluoro^-hydroxy-Z-oxo-l-rfS.S.δ.δ-tetramethyl-S^J^-tetrahvdro-Σ-naphthalenvDmethyll-l^- dihvdro-3-quinolmyl|carbonyl)grycine 78a) Ethyl ό-fluoro^-hvdroxy-l-oxo-l-rCS^.δ.S-tetramethyl-S.όJ^-tetrahydro-Σ- naphthalenyDmethyll -1 ,2-dihydro-3-quinolme carboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 6-(bromomethyl)-l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene for 2- bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 14.3 (s, 1 H), 7.84 (dd, J=8.6, 2.8 Hz, 1 H), 7.28 (dt, J=9.3, 2.6 Hz, 1 H), 7.23 (dd, J=9.3, 4.3 Hz, 1 H), 7.16 (d, J=7.5 Hz, 1 H), 7.15 (s, 1 H), 6.82 (d, J=8.1 Hz, 1 H), 5.44 (br. s., 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.64 (s, 4 H), 1.48 (t, J=7.2 Hz, 3 H), 1.22 (s, 6 H), 1.21 (s, 6 H). MS(ES+) m/e 452 [M+H]+.
78b) N-({6-fluoro-4-hvdroxy-2-oxo-l-r(5,5,8,8-tetramethyl-5.6.7,8-tetrahydro-2- naphthalenyl)methyll-l,2-dihydro-3-quinolinyl)carbonyl)glycine
Following the procedure of Example 75c), except substituting the compound from Example 78a) for the compound from Example 75b), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 7.82 (dd, J=8.6, 2.5 Hz, 1 H), 7.65 (dt, J=8.8, 3.0 Hz, 1 H), 7.60 (dd, 3=9.2, 4.2 Hz, 1 H), 7.31 (s, 1 H), 7.21 (d, J=8.3 Hz, 1 H), 6.78 (d, J=7.6 Hz, 1 H), 5.48 (br. s., 2 H), 4.13 (d, J=5.3 Hz, 2 H), 1.60 (s, 4 H), 1.19 (s, 6 H), 1.17 (s, 6 H). MS(ES+) m/e 481 [M+H]+.
Example 79
Figure imgf000072_0001
N-r(6-fluoro-4-hvdroxy-2-oxo- 1 - ( r4-(trifluoromethyl)phenyll methyl 1-1.2-dihvdro-3- quinolinyDcarbonyn glycine
79a) Ethyl 6-fluoro-4-hvdroxy-2-oxo-l-{ r4-(trifluoromethyl)phenyllmethyl)4,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-trifluoromethylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.86 (dd, J=8.6, 3.0 Hz, 1 H), 7.55 (d, J=8.1 Hz, 2 H), 7.30 (d, J=8.1 Hz, 2 H), 7.25 - 7.30 (m, 1 H), 7.07 (dd, J=9.2, 4.2 Hz, 1 H), 5.54 (br. s., 2 H), 4.52 (q, 1=1.1 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 410 [M+H]+.
79b) N-r(6-fluoro-4-hydroxy-2-oxo-l-{ r4-(trifluoromethyl)phenyllmethyl|-L2-dihydro-3- quinolinyDcarbonyll glycine
Following the procedure of Example 75c), except substituting the compound from Example 79a) for the compound from Example 75b), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 7.84 (dd, J=8.6, 3.0 Hz, 1 H), 7.69 (d, J=8.3 Hz, 2 H), 7.63 (dt, J=8.7, 2.7 Hz, 1 H), 7.51 (dd, J=9.5, 4.2 Hz, 1 H), 7.43 (d, J=8.1 Hz, 2 H), 5.65 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 439 [M+H]+.
Example 80
Figure imgf000072_0002
N-r(l-{ r2-bromo-4-(l,l-dimethylethyl)phenynmethyll-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvDcarbonyll glycine
80a) Ethyl 1-1 r2-bromo-4-(l J-dimethylethyl)phenyllmethyll-6-fluoro-4-hvdroxy-2-oxo-l,2- dihvdro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-bromo-4-tert-butylbenzyl bromide (prepared by the method of Doherty, E. M.; Fotsch, C; Bo, Y.; Chakrabarti, P. P.; Chen, N.; Gavva, N.; Han, N.; Kelly, M. G.; Kincaid, J.; Klionsky, L.; Liu, Q.; Ognyanov, V. I.; Tamir, R.; Wang, X.; Zhu, J.; Norman, M. H.; Treanor, J. J. S. J. Med. Chem. 2005, 48, 71-90) for 2-bromobenzyl bromide, the title compound was obtained as an orange solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.86 (dd, J=8.6, 3.0 Hz, 1 H), 7.59 (d, J=2.0 Hz, 1 H), 7.26 - 7.30 (m, 1 H), 7.12 (dd, J=8.1, 2.0 Hz, 1 H), 7.00 (dd, J=9.3, 4.0 Hz, 1 H), 6.63 (d, J=8.1 Hz, 1 H), 5.47 (br. s., 2 H), 4.51 (q, J=7.2 Hz, 2 H), 1.47 (t, J=I .1 Hz, 3 H), 1.25 (s, 9 H). MS(ES+) m/e 476/478 [M+H]+.
80b) N-rα-l r2-bromo-4-q, l-dimethylethyDphenylimethyl }-6-fluoro-4-hvdroxy-2-oxo-1.2- dihydro-3 -quinolinvDcarbonyli glycine Following the procedure of Example 75c), except substituting the compound from Example
80a) for the compound from Example 75b), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=4.9 Hz, 1 H), 7.86 (dd, J=8.8, 3.0 Hz, 1 H), 7.67 (d, J=I.8 Hz, 1 H), 7.64 (dt, J=8.8, 3.3 Hz, 1 H), 7.34 (dd, J=9.5, 4.2 Hz, 1 H), 7.24 (dd, J=8.2, 1.9 Hz, 1 H), 6.56 (d, J=8.1 Hz, 1 H), 5.43 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 505/507 [M+H]+.
Example 81
Figure imgf000073_0001
N-r(l-{ r3-(l.l-dimethylethyl)phenyllmethyll-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvDcarbonyll glycine 81a) Ethyl 1-1 r3-(l.l-dimethylethvDphenyllmethyll-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-
3-quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 3-tert-butylbenzyl bromide (prepared by the method of Kagechika, H.; Himi, T.;
Namikawa, K.; Kawachi, E.; Hashimoto, Y.; Shudo, K. J. Med. Chem. 1989, 32, 1098-1108) for 2- bromobenzyl bromide, the title compound was obtained as a light orange solid. 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 14.3 (s, 1 H), 7.85 (dd, J=8.6, 2.8 Hz, 1 H), 7.23 - 7.30 (m, 3 H), 7.15 -
7.22 (m, 2 H), 6.87 (d, J=7.3 Hz, 1 H), 5.50 (br. s., 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.48 (t, J=7.1 Hz, 3
H), 1.27 (s, 9 H). MS(ES+) m/e 398 [M+H]+. 81b~) N-rri-( r3-rLl-dimethylethyl)phenvnmethyl}-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvDcarbonyll glycine
Following the procedure of Example 75c), except substituting the compound from Example 81a) for the compound from Example 75b), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.2 Hz, 1 H), 7.81 (dd, J=8.6, 3.0 Hz, 1 H), 7.64 (dt, J=8.7, 3.0 Hz, 1 H), 7.55 (dd, J=9.2, 4.4 Hz, 1 H), 7.41 (s, 1 H), 7.27 (d, J=8.1 Hz, 1 H), 7.19 (t, J=7.7 Hz, 1 H), 6.82 (d, J=7.8 Hz, 1 H), 5.55 (br. s., 2 H), 4.15 (d, J=5.6 Hz, 2 H), 1.25 (s, 9 H). MS(ES+) m/e 427 [M+H]+.
Example 82
Figure imgf000074_0001
N-(l l-r(2,4-dimethyl-L3-thiazol-5-yl)methyll-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl ) carbonyl) glycine
82a) 2.4-Dimethyl-N-phenyl-l,3-thiazole-5-carboxamide
Aniline (0.23 mL, 2.54 mmol), 2,4-dimethylthiazole-5-carboxylic acid (0.40 g, 2.54 mmol), (benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (1.32 g, 2.54 mmol) and
N,N-diisopropylethyI amine (1.11 mL, 6.36 mmol) were combined as a solution in dichloromethane (15.0 mL) and stirred at ambient temperature for 18 h. The reaction mixture was then poured into IM aqueous hydrochloric acid, diluted with brine, and extracted thrice with ethyl acetate. The combined organic portions were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (60% ethyl acetate in hexanes) to afford the title compound as an amber oil (0.306 g, 52%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.59 (dd, J=8.7, 1.1 Hz, 2 H), 7.33 (tt, J=8.3, 2.0 Hz, 2 H), 7.13 (tt, J=7.1, 1.3 Hz, 1 H), 2.66 (s, 3 H), 2.59 (s, 3 H). MS(ES+) m/e 233 [M+H]+.
82b) N-rf 2,4-dirnethyl-l .3-thiazol-5-yl)rnethyl1aniline To a solution of the compound from Example 82a) (0.306 g, 1.31 mmol) in tetrahydrofuran
(5.0 mL) was added lithium aluminum hydride (2.63 mL, IM solution in Et20, 2.63 mmol). The resulting turbid yellow solution was stirred at ambient temperature for 18 h. The solution was then treated with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, concentrated in vacuo, and purified via flash column chromatography (40% ethyl acetate in hexanes) to afford the title compound as a brown oil (0.150 g, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07 (dd, J=8.6, 7.3 Hz, 2 H), 6.49 - 6.65 (m, 3 H), 6.14 (t, J=5.8 Hz, 1 H), 4.30 (d, J=5.8 Hz, 2 H), 2.51 (s, 3 H), 2.31 (s, 3 H). MS(ES+) m/e 219 [M+HJ+. 82c) Ethyl l-r(2,4-dimethyl-13-thiazol-5-ynmethyll-4-hvdroxy-2-oxo-L2-dihvdro-3- quinolinecarboxylate
To a solution of the compound from Example 82b) (0.150 g, 0.69 mmol) in 1,4-dioxane (5.0 mL) was added triethyl methanetricarboxylate (0.43 mL, 2.06 mmol). The solution was heated to 220 0C for 2 h in a Biotage Initiator microwave synthesizer. The reaction mixture was cooled and concentrated in vacuo. Purification via flash column chromatography (60% ethyl acetate in hexanes) afforded the title compound as a yellow solid (0.050 g, 20%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.22 (dd, J=8.1, 1.5 Hz, 1 H), 7.77 (tt, J=5.6, 1.5 Hz, 1 H), 7.48 (d, J=8.6 Hz, 1 H), 7.35 (t, J=7.6 Hz, 1 H), 5.57 (s, 2 H), 4.49 (q, J=7.1 Hz, 2 H), 2.54 (s, 3 H), 2.52 (s, 3 H), 1.43 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 359 [M+H]+.
82d>) N-(( l-r(2.4-dimethyl-L3-thiazol-5-vDmethvn-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinoliny 1 ) carbonyl) glycine
To a solution of the compound from Example 82c) (0.050 g, 0.140 mmol) in ethanol (1.0 mL) was added glycine sodium salt (0.014g, 0.146 mmol). The solution was heated to 1600C for 25 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was poured into water and then acidified with IM aqueous hydrochloric acid. The clear solution was stirred for 18 h and the resulting precipitate was filtered and washed with Et2O to afford the title compound as a pale yellow solid (0.017 g, 32%). 1H NMR (400 MHz, DMSOd6) δ ppm 10.4 (t, J=5.4 Hz, 1 H), 8.14 (dd, J=8.1, 1.5 Hz, 1 H), 7.84 (tt, J=7.3, 1.5 Hz, 1 H), 7.59 (d, J=8.6 Hz, 1 H), 7.41 (t, J=7.6 Hz, 1 H), 5.60 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 3.17 (s, 3 H), 2.47 (s, 3 H). MS(ES+) m/e 388 [M+H]+.
Example 83
Figure imgf000075_0001
N-U4-hydroxy-5,6,7-tris(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyll carbonyl } glycine 83a) (Phenylmethyl)r3,4,5-tris(methyloxy')ρhenyllamine
Following the procedure of Example 58a), except substituting 3,4,5-tris(methyloxy)aniline for
3, 4-dimethoxy aniline and dichloromethane for methanol, the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 - 7.42 (m, 5 H), 5.91 (s, 2 H), 4.31 (s, 2 H),
3.79 (s, 6 H), 3.77 (s, 3 H). MS(ES+) m/e 274 [M+H]+. 83b) Ethyl 4-hydroxy-2-oxo-l-(phenylmethyl)-7-(phenyloxy)-1.2-dihvdro-3- quinolinecarboxylate
To a solution of the compound from Example 83a) (0.540 g, 1.98 mmol) in 1,4-dioxane (4.0 mL) was added triethyl methanetricarboxylate (1.25 mL, 5.93 mmol). The solution was heated to 250 0C for 1.5 h in a Biotage Initiator microwave synthesizer. The reaction mixture was cooled and concentrated in vacuo. Purification via flash column chromatography (40-60% ethyl acetate in hexanes) afforded the title compound as an amber oil (0.740 g, 90%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30 - 7.36 (m, 3 H), 7.23 - 7.28 (m, 2 H), 6.47 (s, 1 H), 5.25 (br. s., 2 H), 4.53 (q, J=7.1 Hz, 2 H), 3.99 (s, 3 H), 3.85 (s, 3 H), 3.73 (s, 3 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 414 [M+H]+.
83c) N-f r4-hydroxy-5,6,7-tris(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyll carbonyl ) glycine
To a solution of the compound from Example 83b) (0.740 g, 1.79 mmol) in ethanol (6.0 mL) was added glycine sodium salt (0.347 g, 3.58 mmol) and the solution was heated to 160 0C for 20 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was then cooled, treated with 6M aqueous hydrochloric acid (5.0 mL), filtered, washed with water, and triturated with Et2O. Purification via flash column chromatography (60% ethyl acetate in hexanes) afforded an orange solid which was in turn washed with ethyl acetate to afford the title compound as a light orange solid (0.029 g, 3%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 10.7 (t, J=5.4 Hz, 1 H), 7.19 - 7.38 (m, 5 H), 6.73 (s, 1 H), 5.58 (br. s., 2 H), 4.13 (d, J=5.6 Hz, 2 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 3.71 (s, 3 H). MS(ES+) m/e 443 [M+H]+.
Example 84
Figure imgf000076_0001
N-I r6-fluoro-4-hvdroxy-2-oxo-l-(5-quinoxalinylmethyl)-l ,2-dihydro-3-quinolinyllcarbonyl I glycine 84a) 4-Fluoro-N-(5-quinoxalinylmethyl)anirme
Following the procedure of Example 73a), except substituting 4-fluoroaniline for 3,4- ethylenedioxy aniline and quinoxaline-5-carbaldehyde for benzaldehyde, the title compound was obtained as a yellow-orange oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.90 (d, J=I.8 Hz, 1 H), 8.87 (d, J=1.8 Hz, 1 H), 8.04 (dd, J=8.3, 1.5 Hz, 1 H), 7.75 - 7.84 (m, 1 H), 7.68 - 7.76 (m, 1 H), 6.83 - 6.90 (m, 2 H), 6.66 - 6.72 (m, 2 H), 4.96 (s, 2 H). MS(ES+) m/e 254 [M+H]+.
84b") Ethyl 6-fluoro-4-hydroxy-2-oxo-l-(5-quinoxalinylmethylVl,2-dihvdro-3- quinolinecarboxylate .
Following the procedure of Example 70b), except substituting the compound from Example 84a) for the compound from Example 70a), the title compound was obtained as a light orange solid.
1H NMR (400 MHz, METHANOL-d4) δ ppm 9.04 (d, J=1.8 Hz, 1 H), 8.98 (d, J=1.8 Hz, 1 H), 8.01 (d, J=7.8 Hz, 1 H), 7.91 (dd, J=8.7, 2.7 Hz, 1 H), 7.62 - 7.73 (m, 1 H), 7.23 - 7.37 (m, 3 H), 6.22 (s, 2 H), 4.50 (q, J=7.2 Hz, 2 H), 1.43 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 394 [M+H]+.
84c) N-{ r6-fluoro-4-hvdroxy-2-oxo-l-r5-quinoxalinylmethyl)-1.2-dihvdro-3- ' quinolinylicarbonyl I glycine Following the procedure of Example 82d), except substituting the compound from Example
84b) for the compound from Example 82c), the title compound was obtained as a light orange solid after washing with ethyl acetate. 1H NMR (400 MHz, DMSOd6) δ ppm 10.5 (t, J=5.6 Hz, 1 H), 9.10 (dd, J=7.8, 1.8 Hz, 2 H), 8.02 (d, J=8.3 Hz, 1 H), 7.86 (dd, J=8.7, 2.9 Hz, 1 H), 7.64 - 7.76 (m, 1 H), 7.54 (dd, J=8.3, 3.0 Hz, 1 H), 7.39 (dd, J=9.5, 4.2 Hz, 1 H), 7.18 (d, J=6.6 Hz, 1 H), 6.14 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 423 [M+H]+.
Example 85
Figure imgf000077_0001
N- { r6-fluoro-4-hydroxy-2-oxo- 1 -(6-quinoxalinylmethyl)- 1 ,2-dihydro-3-quinolinyn carbonyl I glycine 85a) 4-Fluoro-N-(6-qumoxalmylmethyl)aniline Following the procedure of Example 73a), except substituting 4-fluoroanaline for 3,4- ethylenedioxyaniline and quinoxaline-6-carbaldehyde for benzaldehyde, the title compound was obtained as a yellow orange oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 - 8.85 (m, 2 H), 8.06 - 8.14 (m, 2 H), 7.80 (dd, J=8.6, 2.0 Hz, 1 H), 6.82 - 6.93 (m, 2 H), 6.55 - 6.61 (m, 2 H), 4.58 (s, 2 H). MS(ES+) m/e 254 [M+H]+. 85b) Ethyl 6-fluoro-4-hydroxy-2-oxo- 1 -(6-qumoxalmylmethyl)- 1 ,2-dihydro-3- quinolinecarboxylate
A solution of the compound from Example 85a) (0.280 g, 1.10 mmol) in 1,4-dioxane (2.0 mL) was treated with triethyl methanetricarboxylate (0.690 mL, 3.31 mmol) and heated to 240 0C for 20 min. followed by 200 0C for 30 min. followed by 220 0C for 1 h in a Biotage Initiator microwave synthesizer. The homogeneous solution was concentrated in vacuo and the residue was purified via flash column chromatography (40% ethyl acetate in hexanes) to afford the title compound as a light orange solid (0.097 g, 23%). 1H NMR (400 MHz, MeOD) δ ppm 8.87 (d, J=1.8 Hz, 1 H), 8.85 (d, J=1.8 Hz, 1 H), 8.12 (d, J=8.6 Hz, 1 H), 7.93 (dd, J=8.6, 2.8 Hz, 1 H), 7.82 - 7.86 (m, 1 H), 7.81 (s, 1 H), 7.40 - 7.53 (m, 2 H), 5.84 (br. s., 1 H), 4.53 (q, J=7.1 Hz, 2 H), 1.45 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 394 [M+H]+. 85c) N-( r6-fluoro-4-hydroxy-2-oxo-l-(6-quinoxalinylmethyl')-1.2-dihydro-3- quinolinyll carbonyl } glycine
Following the procedure of Example 82d), except substituting the compound from Example 85b) for the compound from Example 82c), the title compound was obtained as a pale beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 10.5 (t, J=5.4 Hz, 1 H), 8.91 (q, J=1.9 Hz, 2 H), 8.09 (d, J=8.8 Hz, 1 H), 7.80 - 7.88 (m, 2 H), 7.77 (dd, J=8.6, 2.0 Hz, 1 H), 7.57 - 7.66 (m, 2 H), 5.82 (s, 2 H), 4.16 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 423 [M+H]+.
Example 86
Figure imgf000078_0001
N-{ ri-ir4-(lJ-dimethylethyl)phenyllmethyl}-4-hvdroxy-5-(methyloxy)-2-oxo-l,2-dihydro-3- quinolinyll carbonyl } glycine
86a) Ethyl 1-1 r4-(l,l-dimethylethyl)phenyllmethyll-4-hydroxy-5-(methyloxy)-2-oxo-l,2- dihydro-3-quinormecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 53a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 13.6 (br. s., 1 H), 7.42 (t, J=8.5 Hz, 1 H), 7.28 (d, J=8.3 Hz, 2 H), 7.11 (d, J=8.3 Hz, 2 H), 6.88 (d, J=8.6 Hz, 1
H), 6.67 (d, J=8.3 Hz, 1 H), 5.45 (br. s., 2 H), 4.48 (q, J=7.2 Hz, 2 H), 3.99 (s, 3 H), 1.45 (t, J=7.1 Hz,
3 H), 1.26 (s, 9 H). MS(ES+) m/e 410 [M+H]+. 86b) N-f π-( r4-α.l-dimethylethyl)phenyllmethyll-4-hvdroxy-5-rmethyloxy)-2-oxo-l,2- dihydro-3-quinolinyllcarbonyllglycine
Following the procedure of Example 75c), except substituting the compound from Example
86a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H
NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.7 (t, J=5.6 Hz, 1 H), 7.59 (t, J=8.5 Hz, 1 H), 7.32 (d, J=8.6 Hz, 2 H), 7.09 (d, J=8.6 Hz, 2 H), 7.01 (d, J=8.6 Hz, 1 H), 6.88 (d, J=8.3 Hz, 1 H), 5.48 (br. s., 2 H), 4.12 (d, J=5.6 Hz, 2 H), 3.88 (s, 3 H), 1.22 (s, 9 H). MS(ES+) m/e 439 [M+H]+. Example 87
Figure imgf000079_0001
N-r(l-{r4-qj-dimethylethyl)phenvnmethyl)-4,5-dihydroxy-2-oxo-l,2-dihydro-3- quinolinyPcarbonyH glycine
Following the procedure of Example 54, except substituting the compound from Example 86b) for the compound from Example 53c), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 14.0 (br. s., 1 H), 13.1 (br. s., 1 H), 10.7 (s, 1 H), 7.48 (t, J=8.3 Hz, 1 H), 7.34 (d, J=8.1 Hz, 2 H), 7.15 (d, J=8.1 Hz, 2 H), 6.89 (d, J=8.3 Hz, 1 H), 6.66 (d, J=8.1 Hz, 1 H), 5.43 (s, 2 H), 4.21 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 425 [M+H]+.
Example 88
Figure imgf000079_0002
N-(( l-[(2,6-dichlorophenyl)methvn-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinyl I carbonvD glycine
88a) Ethyl l-r(2,6-dichlorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,6-dichlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.82 (dd, J=8.7, 2.9 Hz, 1 H), 7.28 (d, J=7.7 Hz, 2 H), 7.21 (ddd, J=9.3, 7.8, 2.9 Hz, 1 H), 7.14 (dd, J=8.4, 7.7 Hz, 1 H), 7.00 (dd, J=9.3, 4.0 Hz, 1 H), 5.85 (s, 2 H), 4.53 (q, J=7.2 Hz, 2 H), 1.49 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 410/412 [M+H]+.
88b) N-(I l-r(2,6-dichlorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl)carbonyl)glycine
Following the procedure of Example 75c), except substituting the compound from Example 88a) for the compound from Example 75b), the title compound was obtained as a peach solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (s, 1 H), 10.3 (t, J=5.6 Hz, 1 H), 7.82 (dd, J=8.7, 2.9 Hz, 1 H), 7.67 (dt, J=8.7, 3.0 Hz, 1 H), 7.52 (dd, 3=9.6, 4.3 Hz, 1 H), 7.45 (d, J=7.9 Hz, 2 H), 7.33 (dd, J=8.6, 7.6 Hz, 1 H), 5.76 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 439/441 [M+H]+.
Example 89
Figure imgf000080_0001
N-IY 1-1 T4-( 1 J-dimethylethyl)phenyllmethyll-6,7-difluoro-4-hvdroxy-2-oxo-l ,2-dihvdro-3- quinolmyDcarbonyll glycine
89a) Ethyl 1-1 r4-d.l-dimethylethvDphenyllmethyll-6.7-difluoro-4-hvdroxy-2-oxo-L2- dihydro-3-qumolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 75a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.95 (dd, J=IO.1, 8.8 Hz, 1 H), 7.32 (d, J=8.3 Hz, 2 H), 7.12 (d, J=8.3 Hz, 2 H), 7.04 (dd, J=12.0, 6.4 Hz, 1 H), 5.39 (br. s., 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.48 (t, 3=1.1 Hz, 3 H), 1.27 (s, 9 H). MS(ES+) m/e 416 [M+H]+. 89b) N-[( 1 - { r4-α .1 -dimethylethvDphenyllmethyl I -6 J-difluoro^-hvdroxy-2-oxo- 1.2- dihydro-3-quinolinyl)carbonyllglycine
Following the procedure of Example 75c), except substituting the compound from Example 89a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.06 (dd, J=10.2, 9.0 Hz, 1 H), 7.70 (dd, J=12.6, 6.6 Hz, 1 H), 7.34 (d, J=8.3 Hz, 2 H), 7.15 (d, J=8.3 Hz, 2 H), 5.48 (br. s., 2 H), 4.14 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 445 [M+H]+.
Example 90
Figure imgf000081_0001
quinolinvDcarbonyll glycine 90a) Ethyl 1-1 ri-bromo^-d.l-dimethylethvDphenyllmethyD-βJ-difluoro^-hvdroxy^-oxo- l,2-dihydro-3-qumolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 75 a) for isatoic anhydride and 2-bromo-4-tert-butylbenzyl bromide (prepared by the method of Doherty, E. M.; et al. J. Med. Chem. 2005, 48, 71-90) for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.98 (dd, J=10.1, 8.6 Hz, 1 H), 7.60 (d, J=2.0 Hz, 1 H), 7.14 (dd, J=8.2, 1.9 Hz, 1 H), 6.84 (dd, J=I 1.7, 6.4 Hz, 1 H), 6.64 (d, J=8.1 Hz, 1 H), 5.41 (br. s., 2 H), 4.51 (q, J=7.1 Hz, 2 H), 1.47 (t, J=7.1 Hz, 3 H), 1.26 (s, 9 H). MS(ES+) m/e 494/496 [M+H]+.
90b) N-F(I-I r2-bromo-4-( 1 „ 1 -dimethylethyDphenyllmethyl I -6 J-difluoro-4-hydroxy-2-oxo- L2-dihvdro-3-quinolmyl)carbonyl1 glycine
Following the procedure of Example 75c), except substituting the compound from Example 90a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.3 (t, J=6.1 Hz, 1 H), 8.11 (dd, J=10.1, 9.1 Hz, 1 H), 7.66 (d, J=1.8 Hz, 1 H), 7.62 (dd, J=12.8, 6.7 Hz, 1 H), 7.24 (dd, J=8.2, 1.6 Hz, 1 H), 6.57 (d, J=8.1 Hz, 1 H), 5.40 (s, 2 H), 4.10 (d, J=5.3 Hz, 2 H), 1.24 (s, 9 H). MS(ES+) m/e 523/525 [M+H]+.
Example 91
Figure imgf000082_0001
N-r(l-ir4-q,l-dimethylethyl')phenvnmethyll-7-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyDcarbonyll glycine
91a*) Ethyl 1-1 r4-(l.l-dimethylethyl')phenyllmethyll-7-fluoro-4-hydroxy-2-oxo-l,2-dihydro- 3-quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 72a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.18 (dd, J=9.5, 6.4 Hz, 1 H), 7.31 (d, J=8.3 Hz, 2 H), 7.13 (d, J=8.3 Hz, 2 H), 6.92 - 6.95 (m, 1 H), 6.91 (dd, J=4.8, 2.3 Hz, 1 H), 5.40 (br. s., 2 H), 4.51 (q, J=7.2 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H), 1.27 (s, 9 H). MS(ES+) m/e 398 [M+H]+.
9 Ib) N-IT 1 - ( T4-( 1.1 -dimethylethvDphenyll methyl I -7-fluoro-4-hvdroxy-2-oxo- 1.2-dihvdro-3- quinolmyDcarbonyll glycine
Following the procedure of Example 75c), except substituting the compound from Example 91a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.4 Hz, 1 H), 8.18 (dd, J=8.8, 6.6 Hz, 1 H), 7.40 (dd, J=I 1.6, 2.3 Hz, 1 H), 7.34 (d, J=8.6 Hz, 2 H), 7.23 (dt, J=8.6, 2.3 Hz, 1 H), 7.15 (d, J=8.3 Hz, 2 H), 5.49 (br. s., 2 H), 4.14 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 427 [M+H]+.
Example 92
Figure imgf000082_0002
N-rCl-i r2-bromo-4-(l,l-dimethylethyl)phenynmethyll-7-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvDcarbonyll glycine
92a) Ethyl l-{ r2-bromo-4-(l J-dimethylethyl)phenvnmethyl)-7-fluoro-4-hydroxy-2-oxo-l,2- di h vdro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 72a) for isatoic anhydride and 2-bromo-4-tert-butylbenzyl bromide (prepared by the method of Doherty, E. M.; et al; J. Med. Chem. 2005, 48, 71-90) for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5 (br. s., 1 H), 8.21 (dd, J=8.8, 6.3 Hz, 1 H), 7.60 (d, J=2.0 Hz, 1 H), 7.13 (dd, J=8.2, 1.9 Hz, 1 H), 6.95 (ddd, J=9.0, 8.1, 2.3 Hz, 1 H), 6.72 (dd, J=10.7, 2.1 Hz, 1 H), 6.65 (d, J=8.1 Hz, 1 H), 5.42 (br. s., 2 H), 4.50 (q, J=7.1 Hz, 2 H), 1.47 (t, J=7.1 Hz, 3 H), 1.26 (s, 9 H). MS(ES+) m/e 476/478 [M+H]+.
92b) N-r(l-{r2-bromo-4-d.l-dimethylethvDphenyllmethyl)-7-fluoro-4-hvdroxy-2-oxo-l,2- dihvdro-3-quinolinyl)carbonynglycine
Following the procedure of Example 75c), except substituting the compound from Example 92a) for the compound from Example 75b), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) 6 ppm 13.0 (br. s., 1 H), 10.3 (t, J=5.3 Hz, 1 H), 8.22 (dd, J=9.0, 6.4 Hz, 1 H), 7.67 (d, J=1.8 Hz, 1 H), 7.21 - 7.31 (m, 3 H), 6.57 (d, J=8.1 Hz, 1 H), 5.41 (s, 2 H), 4.11 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 505/507 [M+H]+.
Example 93
Figure imgf000083_0001
N-i ri-(2-cvclopentylethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyllcarbonyllg:lvcine 93a) 2-Cyclopentyl-N-(4-fluorophenyl)acetamide
A solution of 4-fluoroaniline (0.629 g, 4.29 mmol), cyclopentylacetyl chloride (0.370 mL, 3.90 mmol) and triethylamine (0.890 mL, 6.44 mmol) in dichloromethane (12.0 mL) was stirred for 15 min. at 0 0C, then at ambient temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed succesively with 10% aqueous hydrochloric acid, water, and brine. The organic portion was dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an off-white solid (0.838 g, 97%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.49 - 7.58 (m, 2 H), 6.99 - 7.08 (m, 2 H), 2.33 - 2.39 (m, 2 H), 1.76 - 1.91 (m, 3 H), 1.50 - 1.75 (m, 6 H). MS(ES+) m/e 222 [M+H]+. 93b) N-(2-cvclopentylethyl)-4-fluoroaniline
To a solution of the compound from Example 93a) (0.838 g, 3.78 mmol) in tetrahydrofuran (20.0 mL) was added lithium aluminum hydride (5.68 mL, IM solution in Et2O, 5.68 mmol). The resulting turbid yellow solution was stirred overnight at ambient temperature. Additional lithium aluminum hydride (3.78 mL, IM solution in Et2O, 3.78 mmol) was added and the reaction mixture was stirred 3 h at ambient temperature. The solution was then treated with water and extracted thrice with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a clear yellow oil (0.650 g, 83%). 1H NMR (400 MHz, METHANOLS) δ ppm 6.84 (t, J=8.8 Hz, 2 H), 6.60 (dd, J=8.8, 4.5 Hz, 2 H), 3.02 (m, 2 H), 1.63- 1.53 (m, 10 H), 1.15-1.10 (m, 3 H). MS(ES+) m/e 208 [M+H]+.
93c) Ethyl 1 -(2-cvclopentylethyl)-6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3- quinolinecarboxylate Following the procedure of Example 85b), except substituting the compound from Example
93b) for the compound from Example 85a), the title compound was obtained as a clear yellow oil. MS(ES+) m/e 348 [M+H]+.
93d) N-I r l-(2-cvclopentylethyl)-6-fluoro-4-hvdroxy-2-oxo-l ,2-dihvdro-3- quinolinyll carbonyl } glycine To a solution of the compound from Example 93c) (0.705 g, 2.03 mmol) in ethanol (2.0 mL) was added glycine sodium salt (0.197 g, 2.03 mmol). The solution was heated to 1500C for 15 min. in a Biotage Initiator microwave synthesizer. The reaction mixture was poured into water and then acidified with IM aqueous hydrochloric acid. Following filtration, the filtrate was concentrated and purified via flash column chromatoghraphy (60% ethyl acetate in hexanes) to afford the title compound as a light yellow solid (0.004 g, 1%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=4.8 Hz, 1 H), 7.80 (dd, J=8.7, 2.7 Hz, 1 H), 7.65 - 7.76 (m, 2 H), 4.22 - 4.30 (m, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 1.87 - 1.97 (m, 1 H), 1.75 - 1.87 (m, 2 H), 1.43 - 1.68 (m, 6 H), 1.12 - 1.26 (m, 2 H). MS(ES+) m/e 377 [M+H]+.
Example 94
Figure imgf000084_0001
N-(ri-(2-cvclohexylethyl)-6-fluoro-4-hydroxy-2-oxo-1.2-dihydro-3-qumolinvncarbonyl}glycine 94a) Ethyl 2-r(2-cyclohexylethyl)aminol-5-fluorobenzoate A solution of 2-ammo-5-fluorobenzoic acid (0.428 g, 2.76 mmol) and 2- cyclohexylethylbromide (0.43 mL, 2.76 mmol) in ethanol (2.0 mL) was heated to 150 0C for 30 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was diluted with ethanol (25.0 mL), treated with concentrated sulfuric acid (5.0 mL), and refluxed overnight. The reaction mixture was cooled, neutralized with 6M aqueous sodium hydroxide, and extracted thrice with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, concentrated in vacuo and purified via flash column chromatography (60% ethyl acetate in hexanes) to afford the title compound as a light yellow oil (0.310 g, 38%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.62 (ddd, J=9.9, 3.0, 1.3 Hz, 1 H), 7.47 (br. s., 1 H), 7.07 - 7.17 (m, 1 H), 6.61 (dd, J=9.3, 4.5 Hz, 1 H), 4.33 (q, J=7.1 Hz, 2 H), 3.12 - 3.26 (m, 2 H), 1.64 - 1.73 (m, 4 H), 1.42 - 1.54 (m, 1 H), 1.08 - 1.31 (m, 5 H), 0.84 - 1.07 (m, 3 H). MS(ES+) m/e 294 [M+H]+.
94b) Ethyl l-(2-cvclohexylethyl)-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinecarboxylate To a solution of the compound from Example 94a) (0.310 g, 1.06 mmol) in dichloromethane
(25.0 mL) was added triethylamine (0.300 mL, 2.16 mmol) followed by ethyl malonylchloride (0.270 mL, 2.16 mmol). The reaction mixture was stirred for 3 days at ambient temperature followed by concentration in vacuo. The residue was diluted with ethanol (25.0 mL), treated with sodium ethoxide (0.850 mL, 21 wt % in ethanol, 2.16 mmol), and stirred at ambient temperature for 2 h. The resulting solution was concentrated in vacuo, redissolved in ethyl acetate and treated with 6M aqueous hydrochloric acid. The aqueous phase was extracted twice with ethyl acetate, dried over MgSO4, filtered, concentrated in vacuo and purified via flash column chromatography (40% ethyl acetate in hexanes) to afford the title compound as a yellow oil (0.167 g, 43%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.2 (br. s., 1 H), 7.81 (dd, J=8.6, 3.0 Hz, 1 H), 7.33 - 7.43 (m, 1 H), 7.23 (dd, J=9.3, 4.0 Hz, 1 H), 4.50 (q, J=7.1 Hz, 2 H), 4.15 - 4.25 (m, 2 H), 1.77 - 1.87 (m, 2 H), 1.63 - 1.77 (m, 4 H), 1.52 - 1.62 (m, 3 H), 1.47 (t, J=7.1 Hz, 3 H), 0.98 - 1.17 (m, 4 H). MS(ES+) m/e 362 [M+H]+.
94c) N-f ri-(2-cyclohexylethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyllcarbonyllglycine Following the procedure of Example 82d), except substituting the compound from Example
94b) for the compound from Example 82c), the title compound was obtained as a pale beige solid. 1H NMR (400 MHz, DMSOd6) 5 ppm 10.6 (t, J=5.7 Hz, 1 H), 7.77 (dd, J=8.7, 2.9 Hz, 1 H), 7.67 - 7.74 (m, 1 H), 7.59 - 7.66 (m, 1 H), 4.25 (t, J=6.8 Hz, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 1.79 (d, J=I 1.4 Hz, 2 H), 1.56 - 1.74 (m, 3 H), 1.38 - 1.55 (m, 3 H), 1.11 - 1.32 (m, 3 H), 0.91 - 1.03 (m, 2 H). MS(ES+) m/e 391 [M+H]+.
Example 95
Figure imgf000085_0001
N-{ri-(2-cvclohexylethyl)-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl]carbonyl)glvcine
95a) Methyl 2-r(2-cvclohexylethyl)amino1benzoate A solution of methyl 2-aminobenzoate (0.400 g, 2.65 mmol) and 2-cyclohexylethylbromide
(0.410 mL, 2.65 mmol) in ethanol (2.0 mL) was heated to 1500C for 30 min. in a Biotage Initiator microwave synthesizer. The resulting solution was concentrated in vacuo and the residue was purified via flash column chromatography (60% ethyl acetate in hexanes) to afford the title compound as a clear oil (0.603 g, 87%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.89 (d, J=8.1 Hz, 1 H), 6.36 (t, J=8.1 Hz, 1 H), 5.67 - 5.77 (m, 1 H), 5.57 (t, J=7.5 Hz, 1 H), 2.85 (s, 3 H), 2.13 - 2.30 (m, 2 H), 0.64 - 0.85 (m, 4 H), 0.58 (q, J=6.6 Hz, 1 H), 0.42 - 0.53 (m, 2 H), 0.26 - 0.36 (m, 3 H), -0.16 - 0.10 (m, 3 H). MS(ES+) m/e 262 [M+H]+.
95b) Ethyl l-(2-cyclohexylethyl)-4-hydroxy-2-oxo-L2-dihvdro-3-qumolinecarboxylate Following the procedure of Example 94b), except substituting the compound from Example 95a) for the compound from Example 94a), the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (dd, J=8.1, 1.5 Hz, 1 H), 7.55 - 7.64 (m, 1 H), 7.20 (d, J=8.6 Hz, 1 H), 7.10 - 7.18 (m, 1 H), 4.42 (q, 3=7.1 Hz, 2 H), 1.71 - 1.81 (m, 2 H), 1.55 - 1.69 (m, 2 H), 1.45 - 1.55 (m, 2 H), 1.39 (t, J=7.1 Hz, 3 H), 0.93 - 1.00 (m, 4 H), 0.75 - 0.82 (m, 5 H). MS(ES+) m/e 344 [M+H]+.
95c") N-I r 1 -(2-cvclohexylethyl)-4-hydroxy-2-oxo- 1 ,2-dihydro-3-quinolmyllcarbonyl ) glycine Following the procedure of Example 82d), except substituting the compound from Example 95b) for the compound from Example 82c), the title compound was obtained as a red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.6 (t, J=5.6 Hz, 1 H), 8.11 (dd, J=8.1, 1.5 Hz, 1 H), 7.76 - 7.87 (m, 1 H), 7.58 (d, J=8.6 Hz, 1 H), 7.37 (t, J=7.6 Hz, 1 H), 4.22 - 4.33 (m, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 1.81 (d, J=I 1.6 Hz, 2 H), 1.58 - 1.74 (m, 3 H), 1.35 - 1.56 (m, 3 H), 1.12 - 1.30 (m, 4 H), 0.90 - 1.06 (m, 2 H). MS(ES+) m/e 373 [M+H]+. Example 96
Figure imgf000086_0001
N-(f l-r(2-chlorophenyl)methyll-7-fluoro-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinyllcarbonyDglycine
96a) Ethyl l-[(2-chlorophenyl)methvn-7-fluoro-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example
72a) for isatoic anhydride and 2-chlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5
(br. s., 1 H), 8.21 (dd, J=8.8, 6.3 Hz, 1 H), 7.43 (dd, J=8.0, 1.1 Hz, 1 H), 7.19 (dt, 3=7.7, 1.5 Hz, 1 H), 7.09 (dt, 3=7.6, 1.0 Hz, 1 H), 6.95 (ddd, J=8.9, 7.9, 2.0 Hz, 1 H), 6.78 (dd, 3=7.6, 1.0 Hz, 1 H), 6.70
(dd, J=10.7, 2.1 Hz, 1 H), 5.50 (br. s., 2 H), 4.51 (q, J=7.2 Hz, 2 H), 1.47 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 376 [M+H]+. 96tri N-(11 -r(2-chlorophenvDmethyll ^-fluoro^-hvdroxy-^-oxo- 1 ,2-dihvdro-3- quinolinyl ) carbonyDglycine
Following the procedure of Example 75c), except substituting the compound from Example 96a) for the compound from Example 75b), the title compound was obtained as a beige solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.3 (t, J=5.4 Hz, 1 H), 8.23 (dd, J=8.6, 6.6 Hz, 1 H), 7.56 (dd, J=8.0, 0.9 Hz, 1 H), 7.32 (dd, J=7.3, 1.5 Hz, 1 H), 7.23 - 7.30 (m, 2 H), 7.19 (t, J=Zl Hz, 1 H), 6.71 (d, J=7.1 Hz, 1 H), 5.51 (s, 2 H), 4.11 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 405 [M+H]+.
Example 97
Figure imgf000087_0001
N-( { 1 -r(2,6-dichlorophenyl)methyll -7-fluoro-4-hydroxy-2-oxo-l ,2-dihydro-3- quinolinyUcarbonyDglycine
97a) Ethyl l-r(2,6-dichlorophenyl)methyn-7-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 72a) for isatoic anhydride and 2,6-dichlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.16 (dd, J=9.0, 6.4 Hz, 1 H), 7.29 (d, J=8.1 Hz, 2 H), 7.15 (dd, J=8.3, 7.7 Hz, 1 H), 6.89 (ddd, J=8.8, 7.8, 2.3 Hz, 1 H), 6.75 (dd, J=ILl, 2.3 Hz, 1 H), 5.80 (s, 2 H), 4.52 (q, J=7.2 Hz, 2 H), 1.48 (t, J=Zl Hz, 3 H). MS(ES+) m/e 410/412 [M+H]+. 97b> N-(( l-r(2,6-dichlorophenyl)methyl1-7-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolmyllcarbonyDglycine
Following the procedure of Example 75c), except substituting the compound from Example 97a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (s, 1 H), 10.2 (t, J=5.6 Hz, 1 H), 8.18 (dd, J=8.8, 6.6 Hz, 1 H), 7.46 (d, J=8.1 Hz, 2 H), 7.41 - 7.46 (m, 1 H), 7.33 (dd, J=8.3, 7.6 Hz, 1 H), 7.24 (dt, J=8.6, 2.0 Hz, 1 H), 5.70 (s, 2 H), 4.10 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 439/441 [M+H]+. Example 98
Figure imgf000088_0001
N-r(7-chloro-l-i r4-α,l-dimethylethyl)phenyllmethyπ-4-hydroxy-2-oxo-L2-dihvdro-3- quinolinvDcarbonyl] glycine 98a) 7-Chloro-2H-3 J-benzoxazine-2.4dBD-dione
Following the procedure of Example 53a), except substituting 2-amino-4-chlorobenzoic acid for 2-amino-6-methoxybenzoic acid, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 11.9 (s, 1 H), 7.92 (d, J=8.3 Hz, 1 H), 7.30 (dd, J=8.6, 2.0 Hz, 1 H), 7.15 (d, J=1.8 Hz, 1 H). MS(ES+) m/e 198 [M+H]+. 98b) Ethyl 7-chloro-l-l [4-(l J-dimethylethyl)phenyllmethyl|-4-hydroxy-2-oxo-l,2-dihydro-
3-qumormecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 98a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.11 (d, J=8.6 Hz, 1 H), 7.32 (d, J=8.6 Hz, 2 H), 7.26 (d, J=1.8 Hz, 1 H), 7.18 (dd, J=8.6, 1.8 Hz, 1 H), 7.14 (d, J=8.6 Hz, 2 H), 5.41 (br. s., 2 H), 4.51 (q, J=7.1 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H), 1.28 (s, 9 H). MS(ES+) m/e 414 [M+H]+.
98c) N-r(7-chloro-l-ir4-(lJ-dimethylethyDphenvnmethyll-4-hvdroxy-2-oxo-L2-dihydro-3- quinolinyDcarbonyl] glycine Following the procedure of Example 75c), except substituting the compound from Example
98b) for the compound from Example 75b), the title compound was obtained as a cream solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.1 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.11 (d, J=8.6 Hz, 1 H), 7.61 (d, J=1.5 Hz, 1 H), 7.40 (dd, J=8.6, 1.8 Hz, 1 H), 7.34 (d, J=8.3 Hz, 2 H), 7.13 (d, J=8.1 Hz, 2 H), 5.51 (br. s., 2 H), 4.12 (d, J=5.3 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 443 [M+H]+. Example 99
Figure imgf000089_0001
N-i r4-hvdroxy-7-nitro-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinvncarbonyl}glycine
99a) Ethyl 4-hydroxy-7-nitro-2-oxo-l-(phenylmethγlVL2-dihvdro-3-quinolmecarboxylate Following the procedure of Example 16a), except substituting 7-(nitro)isatoic anhydride for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 369 [M+H]+.
99b) N-( r4-hydroxy-7-nitro-2-oxo-l-(phenylmethyl)-L2-dihvdro-3- quinolinyll carbonyl } glycine Following the procedure of Example 75c), except substituting the compound from Example
99a) for the compound from Example 75b), the title compound was obtained as a yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.3 (t, J=4.9 Hz, 1 H), 8.83 (d, J=2.8 Hz, 1 H), 8.47 (dd, J=9.4, 2.8 Hz, 1 H), 7.69 (d, J=9.4 Hz, 1 H), 7.31 - 7.37 (m, 3 H), 7.23 - 7.29 (m, 3 H), 5.62 (s, 2 H), 4.17 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 398 [M+H]+. Example 100
Figure imgf000089_0002
N-(f4-hydroxy-2-oxo-l-r(phenylmethyl)aminol-l,2-dihvdro-3-quinolinyl)carbonyl)glycine
1 OQa) Ethyl 4-hydroxy-2-oxo- 1 -[(phenylmethyDaminol - 1 ,2-dihydro-3 -quinolinecarboxylate To a solution of ethyl 4-hydroxy-2-oxo-l-{ [(lE)-phenylmethylidene]amino}-l,2-dihydro-3- quinolinecarboxylate (prepared by the method of Pratt, J. K.; et al.; Bioorg. Med. Chem. Lett. 2005, 15, 1577-1582) (0.100 g, 0.297 mmol) in tetrahydrofuran (5.0 mL) was added 10% palladium on charcoal (0.032 g, 0.030 mmol) followed by evacuation of the reaction vessel and purging with 1 atmosphere of hydrogen. Following stirring at ambient temperature for 30 min., the reaction mixture was filtered through Celite®, washed through with methanol, and concentrated in vacuo to afford the title compound as a light yellow solid (0.100 g, 99%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (s, 1 H), 8.14 (dd, J=8.0, 0.9 Hz, 1 H), 7.91 (d, J=8.6 Hz, 1 H), 7.67 (ddd, J=8.3, 7.1, 1.4 Hz, 1 H), 7.51 (d, J=7.1 Hz, 2 H), 7.37 (t, J=7.2 Hz, 2 H), 7.31 (t, J=7.1 Hz, 1 H), 7.23 (t, J=7.6 Hz, 1 H), 5.91 (t, J=7.1 Hz, 1 H), 4.54 (q, J=7.1 Hz, 2 H), 4.15 (br. s., 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 339 [M+H]+.
100b) N-({4-hvdroxy-2-oxo-l-r('phenylmethyl)aminol-l,2-dihydro-3- quinolinyl } carbonyDglycine A mixture of the compound from Example 100a) (0.100 g, 0.296 mmol) and glycine sodium salt (0.032 g, 0.325 mmol) in ethanol (2.0 mL) was heated to 160 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with water, acidified with 6M aqueous hydrochloric acid, diluted with brine, and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo to afford the title compound as a pale yellow solid (0.100 g, 92%). 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 10.4 (t, J=4.7 Hz, 1 H), 8.07 (d, J=8.1 Hz, 1 H), 7.96 (d, J=8.3 Hz, 1 H), 7.78 (t, J=7.5 Hz, 1 H), 7.47 (d, J=7.1 Hz, 2 H), 7.35 (d, J=7.1 Hz, 2 H), 7.25 - 7.40 (m, 2 H)5 6.53 (t, J=6.2 Hz, 1 H), 4.17 (d, J=5.1 Hz, 2 H), 4.07 (br. s., 2 H). MS(ES+) m/e 368 [M+H]+.
Example 101
Figure imgf000090_0001
N-rd-amino^-hydroxy^-oxo-l^-dihydro-S-qumolinvDcarbonyllglycme
A mixture of ethyl 4-hydroxy-2-oxo-l-{[(lE)-phenylmethylidene]amino}-l,2-dihydro-3- quinolinecarboxylate (prepared by the method of Pratt, J. K.;et al; Bioorg. Med. Chem. Lett. 2005, 15, 1577-1582) (0.200 g, 0.595 mmol) and glycine sodium salt (0.115 g, 1.19 mmol) in ethanol (2.0 mL) was heated to 160 0C for 20 minutes in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was diluted with hexanes, filtered, and washed with hexanes. The residue was dissolved in 1:1 methanol/water, acidified with IM aqueous hydrochloric acid, filtered, and washed with hexanes to afford the title compound as a white solid (0.110 g, 67%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.2 Hz, 1 H), 8.07 (d, J=7.8 Hz, 1 H), 8.00 (d, J=8.6 Hz, 1 H), 7.82 (t, J=7.8 Hz, 1 H), 7.35 (t, J=7.6 Hz, 1 H), 5.71 (s, 2 H), 4.16 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 278 [M+HJ+.
Figure imgf000091_0001
N-r(4-hvdroxy-2-oxo-l-ir(lE')-phenylmethylidenelamino|-l,2-dihvdro-3-quinolinyl')caibonyllglvcine
Following the procedure of Example 75c), except substituting ethyl 4-hydroxy-2-oxo-l- { [(lE)-phenylmethylidene]amino}-l,2-dihydro-3-quinolinecarboxylate (prepared by the method of Pratt, J. K.; et al; Bioorg. Med. Chem. Lett. 2005, 15, 1577-1582) for the compound from Example 75b), the title compound was obtained as a pale yellow solid solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.8 Hz, 1 H), 9.02 (s, 1 H), 8.15 (dd, J=8.3, 1.5 Hz, 1 H), 8.01 - 8.05 (m, J=8.3, 1.5 Hz, 2 H), 7.80 (ddd, J=8.7, 7.1, 1.4 Hz, 1 H), 7.66 (tt, J=7.3, 1.5 Hz, 1 H), 7.61 (d, J=7.6 Hz, 2 H), 7.57 - 7.61 (m, 1 H), 7.44 (ddd, J=8.0, 7.1, 1.0 Hz, 1 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 366 [M+H]+.
Example 103
Figure imgf000091_0002
N-(14-hvdroxy- 1 -F(I -methylethylidene)amino1 -2-oxo- 1 ,2-dihvdro-3-quinolinyl ) carbonyl) glycine A solution of the compound from Example 101 (0.214g, 0.772 mmol) in methanol (5.0 mL) and acetone (5.0 mL) was stirred at ambient temperature for 30 min. followed by concentration in vacuo to afford the title compound as a beige solid (0.244 g, 100%). 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.12 (dd, J=8.1, 1.3 Hz, 1 H), 7.77 (ddd, J=8.7, 7.3, 1.5 Hz, 1 H), 7.40 (ddd, J=8.1, 7.2, 0.9 Hz, 1 H), 7.30 (d, J=8.1 Hz, 1 H), 4.13 (dd, J=5.6, 1.3 Hz, 2 H), 2.34 (s, 3 H), 1.76 (s, 3 H). MS(ES+) m/e 318 [M+H]+. Example 104
Figure imgf000092_0001
N-( { 4-hydroxy- 1 -IY 1 -methylethvDaminol -2-oxo-l ,2-dihydro-3 -quinolinyl ) carbonyDgly cine
To a solution of the compound from Example 103 (0.050 g, 0.158 mmol) in methanol (5.0 mL) was added sodium cyanoborohydri.de (0.015 g, 0.236 mmol). Following stirring at ambient temperature for 2 h, the reaction mixture was diluted with brine and extracted thrice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a white solid (0.046 g, 91%). 1H NMR (400 MHz, DMSOd6) 5 ppm 13.0 (br. s., 1 H), 10.4 (t, J=4.6 Hz, 1 H), 8.06 (d, J=4.5 Hz, 2 H), 7.78 (t, J=7.6 Hz, 1 H), 7.34 (t, J=7.2 Hz, 1 H), 6.10 (s, 1 H), 4.12 (d, J=4.5 Hz, 2 H), 3.45 - 3.60 (m, 1 H), 1.10 (br. s., 3 H), 0.90 (br. s., 3 H). MS(ES+) m/e 320 [M+H]+.
Example 105
Figure imgf000092_0002
N-F(I-I f4-(l,l-dimethylethyl)phenyllmethyll-4-hydroxy-7-methyl-2-oxo-l,2-dihvdro-3- quinolinyDcarbonyll glycine
105a) 7-Methyl-2H-3,l-benzoxazine-2,4(lH)-dione
To a solution of 2-amino-4-methylbenzoic acid (1.00 g, 6.62 mmol) in ethyl acetate (15.0 mL) were added potassium carbonate (0.914 g, 6.62 mmol) and triphosgene (0.883 g, 2.98 mmol). Following stirring at ambient temperature for 15 min., the reaction mixture was treated with water, filtered, washed with water and hexanes, and dried in vacuo to afford the title compound as an off- white solid (1.16 g, 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.7 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.08 (dd, J=8.0, 0.9 Hz, 1 H), 6.93 (s, 1 H), 2.38 (s, 3 H). MS(ES+) m/e 178 [M+H]+
105b) Ethyl l-{ r4-(l,l-dimethylethyl)ρhenyllmethyll-4-hvdroxy-7-methyl-2-oxo-1.2- dihvdro-3-quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 105a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.2 (br. s., 1 H), 8.05 (d, J=8.1 Hz, 1 H), 7.30 (d, J=8.3 Hz, 2 H), 7.15 (d, J=8.3 Hz, 2 H), 7.06 (s, 1 H), 7.02 (d, J=8.3 Hz, 1 H), 5.44 (br. s., 2 H), 4.50 (q, J=7.1 Hz, 2 H), 2.38 (s, 3 H), 1.47 (t, J=7.1 Hz, 3 H), 1.27 (s, 9 H). MS(ES+) m/e 394 [M+H]+.
105c) N-rd-U4-(l,l-dimethylethyl)phenyllmethyl>-4-hvdroxy-7-methyl-2-oxo-1.2-dihvdro- 3-quinolmyl)carbonyll glycine Following the procedure of Example 75c), except substituting the compound from Example
105b) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.5 (t, J=5.6 Hz, 1 H), 8.01 (d, J=8.1 Hz, 1 H), 7.40 (s, 1 H), 7.33 (d, J=8.3 Hz, 2 H), 7.19 (d, J=8.1 Hz, 1 H), 7.14 (d, J=8.3 Hz, 2 H), 5.49 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 2.40 (s, 3 H), 1.23 (s, 9 H). MS(ES+) m/e 423 [M+H]+. Example 106
Figure imgf000093_0001
N-{r8-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinyl1carbonyl)glycine 106a) Ethyl 3-fluoro-2-r(phenylmethyl)aminolbenzoate To a solution of 2-chloro-3-fluorobenzoic acid (0.500 g, 2.86 mmol) and benzylamine (0.620 mL, 5.72 mmol) in tetrahydrofuran (25.0 mL) were added potassium carbonate (0.870 g, 6.29 mmol) and copper (II) bromide (0.050 g, 0.215 mmol). The resulting solution was stirred for 18 h under reflux. The solution was allowed to cool to ambient temperature and then was poured into IM aqueous sodium hydroxide. The solids were filtered and washed with tetrahydrofuran. The filtrate was acidified to pH 5 with IM aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to afford a peach solid. The solid was dissolved in ethanol (30.0 mL) and treated with concentrated sulfuric acid (3.0 mL). The solution was refluxed for 18 h, cooled to ambient temperature, neutralized with 6M aqueous sodium hydroxide, and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as an amber oil (0.125 g, 16%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.76 (dq, J=8.1, 1.0, 0.8 Hz, 1 H), 7.33 - 7.43 (m, 5 H), 7.28 (t, J=6.8 Hz, 1 H), 7.11 (qd, J=6.1, 1.8 Hz, 1 H), 6.53 - 6.65 (m, 1 H), 4.69 (d, J=3.3 Hz, 2 H), 4.35 (q, J=7.1 Hz, 2 H), 1.40 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 274 [M+H]+.
106b) Ethyl 8-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quinolinecarboxylate Following the procedure of Example 94b), except substituting the compound from Example 106a) for the compound from Example 94a), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 8.06 (d, J=7.3 Hz, 1 H), 7.25 - 7.36 (m, 3 H), 7.15 - 7.25 (m, 4 H), 5.70 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 342 [M+H]+. 106c) N-I rδ-fluoro^-hvdroxy-l-oxo-l-CphenylmethvD-l^-dihydro-S- quinolinyll carbonyl I glycine
Following the procedure of Example 82d), except substituting the compound from Example 106b) for the compound from Example 82c), the title compound was obtained as a yellow solid. 1H NMR (400 MHz, DMSOd6) δ ppm 10.4 (t, J=5.4 Hz, 1 H), 8.01 (d, J=8.1 Hz, 1 H), 7.60 (ddd, J=8.1, 1.3 Hz, 1 H), 7.36 (td, J=8.0, 4.2 Hz, 1 H), 7.30 (t, J=7.3 Hz, 2 H), 7.22 (t, J=7.3 Hz, 1 H), 7.13 (d, J=7.3 Hz, 2 H), 5.60 (br. s., 1 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 371 [M+H]+.
Example 107
Figure imgf000094_0001
N-f r 1 -I F4-( 1 , 1 -dimethylethvDphenylimethyl I -4-hvdroxy-2-oxo-7-(trifluoromethyl)- 1 ,2-dihvdro-3 - quinolinyll carbonyl I glycine
107a) 7-(Trifluoromethyl)-2H-3J-benzoxazine-2.4(lH)-dione Following the procedure of Example 105a), except substituting 2-amino-4- trifluoromethylbenzoic acid for 2-amino-4-methylbenzoic acid, the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.0 (s, 1 H), 8.12 (d, J=8.1 Hz, 1 H), 7.56 (dd, J=8.2, 1.1 Hz, 1 H), 7.40 (s, 1 H). MS(ES+) m/e 232 [M+H]+.
107b) Ethyl 1-1 r4-(l.l-dimethylethvDphenyllmethyll-4-hvdroxy-2-oxo-7-(trifluoromethylV 1.2-dihvdro-3-qumolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 107a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.30 (d, J=8.1 Hz, 1 H), 7.55 (s, 1 H), 7.43 (d, J=8.6 Hz, 1 H), 7.32 (d, J=8.6 Hz, 2 H), 7.18 (d, J=8.3 Hz, 2 H), 5.47 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.49 (t, J=7.1 Hz, 3 H), 1.27 (s, 9 H). MS(ES+) m/e 448 [M+H]+. 107c) N-iri-(r4-(lJ-dimethylethyl)phenyllmethyl)-4-hvdroxy-2-oxo-7-(trifluoromethyl)-
1.2-dihydro-3 -quinolinyll carbonyl } glycine
Following the procedure of Example 75c), except substituting the compound from Example 107b) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.6 Hz, 1 H), 8.32 (d, J=8.3 Hz, 1 H), 7.82 (s, 1 H), 7.66 (d, J=8.6 Hz, 1 H), 7.34 (d, J=8.6 Hz, 2 H), 7.17 (d, J=8.3 Hz, 2 H), 5.60 (s, 2 H), 4.16 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 477 [M+H]+.
Figure imgf000095_0001
N-I ri-CS^-dimethylhexyD-ό-fluoro^-hydroxy-l-oxo-l.l-dihvdro-S-qumolinvncarbonyl) glycine
108a) N-(4-fluorophenyr)-5 ,5-dimethylhexanamide A solution of 4-fluoroaniline (0.303 niL, 3.16 mmol) and 5,5-dimethylhexanoic acid (0.500 mL, 3.16 mmol) in dichloromethane (15.0 mL) was treated with l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.605 g, 3.16 mmol) and 4- (dimethylamino)pyridine (0.386 g, 0.316 mmol) and stirred at ambient temperature for 24 h. The reaction mixture was diluted with dichloromethane and washed successively using 10% aqueous hydrochloric acid, water, and 20% aqueous sodium hydroxide. The organic phase was dried over
MgSO4, filtered and concentrated in vacuo to afford the title compound as a clear yellow oil (0.750 g, 100%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (br. s., 1 H), 7.43 - 7.57 (m, 2 H), 6.98 (t, J=8.6 Hz, 2 H), 2.33 (t, J=7.6 Hz, 2 H), 1.60 - 1.76 (m, 2 H), 1.17 - 1.26 (m, 2 H), 0.89 (s, 9 H). MS(ES+) m/e 238 [M+H]+. 108b) N-(5,5-dimethylhexyl)-4-fluoroaniline
To a solution of the compound from Example 108a) (0.750 g, 3.16 mmol) in tetrahydrofuran (5.0 mL) was added lithium aluminum hydride (4.74 mL, IM solution in Et2O, 4.74 mmol) at ambient temperature. The resulting turbid yellow solution was stirred at ambient temperature for 10 min. The solution was then cooled to 0 0C and treated with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a yellow oil (0.563 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.88 (t, J=8.8 Hz, 2 H), 6.52 - 6.57 (m, 2 H), 3.07 (t, J=7.2 Hz, 2 H), 1.51 - 1.65 (m, 2 H), 1.31 - 1.42 (m, 2 H), 1.19 - 1.25 (m, 2 H), 0.90 (s, 9 H). MS(ES+) m/e 224 [M+H]+. 108c) Ethyl l-(5.5-dimethylhexyl)-6-fluoro-4-hvdroxy-2-oxo-L2-dihvdro-3- quinolinecarboxylate
A mixture of the compound from Example 108b) (0.563 g, 2.52 mmol) and triethyl methanetricarboxylate (1.59 mL, 7.56 mmol) in 1,4-dioxane (3.0 mL) was heated to 2200C for 1 h min. in a Biotage Initiator microwave synthesizer. The mixture was cooled and concentrated in vacuo. The residue was purified via flash column chromatography (60% ethyl acetate in hexanes) to afford a mixture of compounds of which the title compound represented 37%. MS(ES+) m/e 364 [M+H]+.
108d') N-(ri-f5.5-dimethylhexylV6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinylicarbonyl I glycine Following the procedure of Example 83c), except substituting the compound from Example
108c) for the compound from Example 83b), the title compound was obtained as a light brown solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.3 Hz, 1 H), 7.63 - 7.79 (m, 3 H), 4.22 (t, J=7.6 Hz, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 1.50 - 1.64 (m, 2 H), 1.29 - 1.45 (m, 2 H), 1.09 - 1.25 (m, 2 H), 0.87 (s, 9 H). MS(ES+) m/e 393 [M+H]+. Example 109
Figure imgf000096_0001
N-ir6-fluoro-4-hvdroxy-2-oxo-l-(3-phenylpropyl)-1.2-dihvdro-3-quinolinyllcarbonyl|glycine 109a) (4-Fluorophenyl) (3-phenylpropyl)amine
Following the procedure of Example 73a), except substituting 4-fluoroaniline for 3,4- ethylenedioxyaniline and phenylpropionaldehyde for benzaldehyde, the title compound was obtained as an amber oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.36 - 7.45 (m, 2 H), 7.28 - 7.35 (m, 3 H), 6.95 - 7.01 (m, 2 H), 6.52 - 6.62 (m, 2 H), 3.54 (br. s., 1 H), 3.18 (t, 7=7.1 Hz, 2 H), 2.82 (t, 7=7.8 Hz, 2 H), 1.96 - 2.09 (m, 2 H). MS(ES+) m/e 230 [M+H]+.
109b) Ethyl 6-fluoro-4-hydroxy-2-oxo-l-(3-phenylpropyl)-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 108c), except substituting the compound from Example 109a) for the compound from Example 108b), the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-**) δ ppm 14.2 (br. s., 1 H), 7.81 (dd, J=8.6, 3.0 Hz, 1 H), 7.26 - 7.36 (m, 3 H), 7.19 - 7.26 (m, 3 H), 6.96 (dd, 7=9.3, 4.3 Hz, 1 H), 4.51 (q, 7=7.1 Hz, 2 H), 4.16 - 4.24 (m, 2 H), 2.78 (t, 7=7.5 Hz, 2 H), 1.93 - 2.04 (m, 2 H), 1.49 (t, 7=7.1 Hz, 3 H). MS(ES+) m/e 370
109c) N-(r6-fluoro-4-hvdroxy-2-oxo-l-(3-phenylpropyl)-l,2-dihydro-3- quinolinyll carbonyl I glycine
To a solution of the compound from Example 109b) (0.050 g, 0.130 mmol) in ethanol (1.0 mL) was added glycine sodium salt (0.013g, 0.136 mmol). The solution was heated to 150 0C for 15 min. in a Biotage Initiator microwave synthesizer. The resulting solid was filtered, washed with ethyl acetate, dissolved in water and treated with 6M aqueous hydrochloric acid. The resulting solid was filtered, washed with hexanes, and dried in vacuo to afford the title compound as a pale orange solid (0.013 g, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.4 Hz, 1 H), 7.74 (dd, J=8.7, 1.6 Hz, 1 H), 7.59 - 7.68 (m, 2 H), 7.20 - 7.32 (m, 4 H), 7.13 - 7.20 (m, 1 H), 4.27 (t, J=7.3 Hz, 2 H), 4.12 (d, J=5.6 Hz, 2 H), 2.73 (t, J=7.7 Hz, 2 H), 1.84 - 1.96 (m, 2 H). MS(ES+) m/e 399 [M+H]+-
Example 110
Figure imgf000097_0001
N-i r6-fluoro-4-hvdroxy-2-oxo-l-(2-phenylethyl)-l,2-dihydro-3-quinolinyllcarbonyllglycine 110a) (4-Fluorophenyl) (2-phenylethyl)amine Following the procedure of Example 73a), except substituting 4-fluoroaniline for 3,4- ethylenedioxyaniline and phenylacetaldehyde for benzaldehyde, the title compound was obtained as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 (t, J=7.2 Hz, 2 H), 7.21 - 7.32 (m, 3 H), 6.93 (t, J=8.8 Hz, 2 H), 6.59 (dd, J=4.6 Hz, 2 H), 3.40 (t, J=7.1 Hz, 2 H), 2.95 (t, J=6.9 Hz, 2 H). MS(ES+) m/e 216 [M+H]+. 1 IQb) Ethyl 6-fluoro-4-hydroxy-2-oxo-l-(2-phenylethyl)-l,2-dihydro-3-quinolmecarboxylate
A mixture of the compound from Example 110a) (0.275 g, 1.28 mmol) and triethyl methanetricarboxylate (0.810 mL, 3.83 mmol) in 1,4-dioxane (3.0 mL) was heated to 250 0C for 1 h in a Biotage Initiator microwave synthesizer. The mixture was cooled and concentrated in vacuo. The residue was purified via flash column chromatography (60% ethyl acetate in hexanes) to afford the title compound as a dark oil (0.220 g, 48%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.84 (dd, J=8.6, 2.8 Hz, 1 H), 7.14 - 7.44 (m, 5 H), 6.96 - 7.09 (m, 2 H), 4.53 (q, J=7.1 Hz, 2 H), 4.34 - 4.45 (m, 2 H), 2.93 - 3.04 (m, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 356 [M+H]+.
1 IQc) N-I r6-fluoro-4-hvdroxy-2-oxo4-(2-phenylethyl)-l,2-dihvdro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 60c), except substituting the compound from Example 110b) for the compound from Example 60b), the title compound was obtained as a pale beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.6 (t, J=6.4 Hz, 1 H), 7.80 (td, J=8.3, 3.4 Hz, 2 H), 7.70 (td, J=8.7, 3.0 Hz, 1 H), 7.28 - 7.41 (m, 4 H), 7.24 (tt, J=5.3, 2.5 Hz, 1 H), 4.46 (t, J=6.3 Hz, 2 H), 4.14 (d, J=5.6 Hz, 2 H), 2.92 (t, J=7.6 Hz, 2 H). MS(ES+) m/e 385 [M+H]+.
Figure imgf000098_0001
N- 111 -(3 ,3 -dimethylbutyl)-6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3 -quinolinylicarbonyl ) glycine
11 Ia) N-(4-fluorophenvD-3,3-dimethylbutanamide Following the procedure of Example 108a), except substituting 3,3-dimethylbutanoic acid for
5,5-dimethylhexanoic acid, the title compound was obtained as a yellowish powder. 1H NMR (400
MHz, CHLOROFORM-d) δ ppm 7.46 (dd, J=9.1, 4.8 Hz, 2 H), 7.12 (br. s., 1 H), 7.01 (t, J=8.7 Hz, 2
H), 2.22 (s, 2 H), 1.11 (s, 9 H). MS(ES+) m/e 210 [MH-H]+.
11 Ib) N-(3,3-dimethylbutyl)-4-fluoroaniline To a solution of the compound from Example 11 Ia) (0.831 g, 3.97 mmol) in tetrahydrofuran
(20.0 mL) was added lithium aluminum hydride (8.73 mL, IM solution in Et2O, 8.73 mmol) at 0 0C.
The resulting solution was stirred for 4 days at ambient temperature. The solution was then treated with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a clear oil (0.658 g, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.89 (t,
J=8.8 Hz, 2 H), 6.54 (dd, J=9.1, 4.3 Hz, 2 H), 3.24 (br. s., 1 H), 3.01 - 3.13 (m, 2 H), 1.48 - 1.56 (m, 2
H), 0.98 (s, 9 H). MS(ES+) m/e 196 [M+H}+.
111c) Ethyl l-(3,3-dimethylbutyl)-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinecarboxylate A mixture of the compound from Example 11 Ib) (0.658 g, 3.37 mmol) and triethyl methanetricarboxylate (2.13 mL, 10.11 mmol) in 1,4-dioxane (4.0 mL) was heated to 250 0C for 2 h in a Biotage Initiator microwave synthesizer. The mixture was cooled and concentrated in vacuo.
The residue was purified via flash column chromatography (60-80% ethyl acetate in hexanes) to afford an amber oil of which the title compound represented 20%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.78 (dd, /=8.8, 3.0 Hz, 1 H), 7.33 - 7.42 (m, 1 H), 7.21 (dd, 7=9.3, 4.0
Hz, 1 H), 4.48 (q, 7=7.1 Hz, 2 H), 4.18 - 4.26 (m, 2 H), 1.53 (dd, 7=9.7, 7.7 Hz, 2 H), 1.43 (t, 7=7.1
Hz, 3 H), 1.02 (s, 9 H) MS(ES+) m/e 336 [M+H]+.
11 Id) N-I ri-(3.3-dimethylbutyl)-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinolinylicarbonyll glycine . To a solution of the compound from Example 11 Ic) (0.900 g, 2.68 mmol) in ethanol (3.0 mL) was added glycine sodium salt (0.274 g, 2.82 mmol) and the solution was heated to 150 0C for 15 min. in a Biotage Initiator microwave synthesizer. The resulting solution was dissolved in water, acidified with IM aqueous hydrochloric acid, and extrated with ethyl acetate. The organic portion was dried over MgSC>4, filtered, concentrated in vacuo, and purified via flash column chromatography (60% ethyl acetate in hexanes) to afford the title compound as a pale pink solid (0.037 g, 4%, 2 steps). 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (br. s., 1 H), 10.55 (t, J=5.4 Hz, 1 H), 7.69 - 7.85 (m, 2 H), 7.56 (dd, J=9.5, 4.2 Hz, 1 H), 4.21 - 4.33 (m, 2 H), 4.14 (d, J=5.6 Hz, 2 H), 1.50 (t, J=8.6 Hz, 2 H), 1.04 (s, 9H). MS(ES+) m/e 365 [M+H]+.
Example 112
Figure imgf000099_0001
N-( 11 -r(2-chloro-4-fluorophenyl)methyll -6-fluoro-4-hydroxy-2-oxo-l .2-dihvdro-3- quinolinyl)carbonyl)glvcine
112a) Ethyl l-r^-chloro^-fluorophenvDmethyll-ό-fluoro^-hydroxy^-oxo-l^-dihydro-S- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-chloro-4-fluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.89 (dd, J=8.6, 3.0 Hz, 1 H), 7.31 (ddd, 1=93, 7.6, 3.0 Hz, 1 H), 7.20 (dd, J=8.2, 2.4 Hz, 1 H), 6.97 (dd, J=9.3, 4.0 Hz, 1 H), 6.83 (dt, J=8.2, 2.5 Hz, 1 H), 6.76 (dd, J=8.6, 5.8 Hz, 1 H), 5.51 (s, 2 H), 4.53 (q, J=7.2 Hz, 2 H), 1.50 (t, 1=1.1 Hz, 3 H). MS(ES+) m/e 394 [M+H]+.
112b) N-(I l-[(2-chloro-4-fluorophenyl)methyn-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinvUcarbonvDglvcine
Following the procedure of Example 75c), except substituting the compound from Example 112a) for the compound from Example 75b), the title compound was obtained as an off-white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.86 (dd, J=8.6, 3.0 Hz, 1 H), 7.64 (ddd, 1=93, 8.6, 3.0 Hz, 1 H), 7.58 (dd, J=8.7, 2.7 Hz, 1 H), 7.36 (dd, 1=9.6, 4.0 Hz, 1 H), 7.05 (dt, J=8.3, 2.8 Hz, 1 H), 6.76 (dd, J=8.6, 6.3 Hz, 1 H), 5.49 (s, 2 H), 4.13 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 423 [M+H]+. Example 113
Figure imgf000100_0001
N-({ l-r(2-chloro-5-fluorophenyl)methyn-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } earbonyDglycine 113a) Ethyl l-r(2-chloro-5-fluorophenvDmethyl1-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinecaiboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-chloro-5-fluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.90 (dd, J=8.6, 3.0 Hz, 1 H), 7.40 (dd, J=8.8, 5.1 Hz, 1 H), 7.32 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 6.96 (dd, J=9.3, 4.3 Hz, 1 H), 6.92 (dt, J=8.5, 2.4 Hz, 1 H), 6.49 (dd, J=9.1, 3.0 Hz, 1 H), 5.52 (br. s., 2 H), 4.54 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 394 [M+H]+.
113b) N-(I l-r(2-chloro-5-fluorophenyl)methyn-6-fluoro-4-hydroxy-2-oxo-L2-dihvdro-3- quinolinyl ) earbonvDglycine Following the procedure of Example 75c), except substituting the compound from Example
113a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.86 (dd, J=8.5, 2.9 Hz, 1 H), 7.62 - 7.68 (m, 1 H), 7.62 (dd, J=10.9, 5.3 Hz, 1 H), 7.35 (dd, J=9.3, 4.0 Hz, 1 H), 7.19 (dt, J=8.3, 2.8 Hz, 1 H), 6.64 (dd, J=9.5, 2.9 Hz, 1 H), 5.50 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 423 [M+H]+.
Example 114
Figure imgf000100_0002
N-C( l-r(2.5-dichlorophenyl)methvn-6-fluoro-4-hydroxy-2-oxo-L2-dihvdro-3- quinolinyllcarbonvDglvcine 114a) Ethyl l-r(2,5-dichlorophenyl)methyn-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,5-dichlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 14.5 (s, 1 H), 7.91 (dd, J=8.5, 2.9 Hz, 1 H), 7.38 (d, J=8.6 Hz, 1 H), 7.32 (ddd, J=9.3, 7.8, 3.0 Hz, 1 H), 7.19 (dd, J=8.6, 2.3 Hz, 1 H), 6.94 (dd, J=9.2, 4.2 Hz, 1 H), 6.73 (d, J=2.3 Hz, 1 H), 5.52 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 410/412 [MH-H]+. 114b) N-(I l-r(2,5-dichlorophenyl)metb.yll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinolinyl IcarbonyDglycine
Following the procedure of Example 75c), except substituting the compound from Example 114a) for the compound from Example 75b), the title compound was obtained as a white solid. IH NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.86 (dd, J=8.8, 3.0 Hz, 1 H), 7.64 (dt, J=9.1, 2.8 Hz, 1 H), 7.61 (d, J=8.6 Hz, 1 H), 7.40 (dd, J=8.6, 2.5 Hz, 1 H), 7.36 (dd, J=9.5, 4.2 Hz, 1 H), 6.80 (d, J=2.3 Hz, 1 H), 5.49 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 439/441 [MH-H]+.
Example 115
Figure imgf000101_0001
N-i r7-amino-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quinolinyllcarbonyl|glycme
To a solution of the compound from Example 99b) (0.180 g, 0.453 mmol) in ethyl acetate (5 mL) and methanol (5 mL) was added 10% palladium on charcoal (0.100 g, 0.094 mmol). The mixture was shaken on a Parr hydrogenator at 45 psi Hydrogen for 2 h. The reaction mixture was filtered and the filtrate evaporated down to residue and resuspended in DMSO. The fluorescent solution was purified via preparative HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)) to afford the title compound (0.0061 g, 4%) as a brown powder. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.7 (t, J=5.3 Hz, 1 H), 7.41 (d, J=2.3 Hz, 1 H), 7.26 - 7.36 (m, 4 H), 7.24 (d, 3=1.1 Hz, 1 H), 7.20 (d, J=7.3 Hz, 3 H), 7.13 (dd, J=9.1, 2.5 Hz, 1 H), 5.50 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 368 [MH-H]+
Figure imgf000102_0001
N-iri-^^-dimethylpentvD-β-fluoro^-hydroxy^-oxo-L∑-dihvdro-S-quinolinyllcarbonyllglvcme
116a) N-(4-fluorophenyl*)-4,4-dimethylpentanamide Following the procedure of Example 108a), except substituting 4,4-dimethylpentanoic acid for 5,5-dimethylhexanoic acid, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (br. s., 1 H), 7.44 - 7.56 (m, 2 H), 6.98 (t, J=8.6 Hz, 2 H), 2.25 - 2.39 (m, 2 H), 1.60 - 1.71 (m, 2 H), 0.92 (s, 9 H). MS(ES+) m/e 224 [M+H]+.
116b) N-(4,4-dimethylpentvD-4-fluoroaniline Following the procedure of Example 11 Ib), except substituting the compound from Example
116a) for the compound from Example 11 Ia), the title compound was obtained as a clear oil following purification via flash column chromatography (10% ethyl acetate in hexanes). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.92 (t, J=8.8 Hz, 2 H), 6.52 - 6.60 (m, 2 H), 3.53 (br. s., 1 H), 3.06 (t, J=7.1 Hz, 2 H), 1.54 - 1.68 (m, 2 H), 1.27 - 1.34 (m, 2 H), 0.94 (s, 9 H). MS(ES+) m/e 210
116c) Ethyl l-(4,4-dimethylpentyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
A mixture of the compound from Example 116b) (0.082 g, 0.390 mmol) and triethyl methanetricarboxylate (0.250 mL, 1.18 mmol) in 1,4-dioxane (2.0 mL) was heated to 220 0C for 30 min. followed by 240 0C for 30 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with IM aqueous hydrochloric acid, extracted with ethyl acetate, concentrated in vacuo, and purified via flash column chromatography (30% ethyl acetate in hexanes) to afford the title compound as a yellow oil (0.087 g, 64%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (dd, 7=8.8, 3.0 Hz, 1 H), 7.35 - 7.45 (m, 1 H), 7.21 (dd, 7=9.3, 4.3 Hz, 1 H), 4.48 (q, 7=7.1 Hz, 2 H), 4.08 - 4.15 (m, 2 H), 1.56 - 1.70 (m, 2 H), 1.45 (t, 7=7.2 Hz, 3 H), 1.19 - 1.25 (m, 2 H), 0.85
(s, 9 H) MS(ES+) m/e 350 [M+H]+.
116d) N-I ri-(4,4-dimethylpentyl)-6-fluoro-4-hvdroxy-2-oxo-1.2-dihydro-3- quinolmylicarbonyl I elvcine
Following the procedure of Example 11 Id), except substituting the compound from Example 116c) for the compound from Example 11 Ic), the title compound was obtained as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.6 (t, J=5.4 Hz, 1 H), 7.79 (d, J=8.8 Hz, 1 H), 7.72 (d, J=4.8 Hz, 2 H), 4.17 - 4.26 (m, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 1.51 - 1.65 (m, 2 H), 1.26 1.35 (m, 2 H), 0.86 (s, 9 H). MS(ES+) m/e 379 [M+H]+.
Example 117
Figure imgf000103_0001
N-( I 1 -r(2,3-difluorophenyl)methyll -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3- qumolinyllcarbonyl)glvcme
117a) Ethyl l-r(2,3-difluorophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinormecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,3-difluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.88 (dd, J=8.5, 2.9 Hz, 1 H), 7.34 (ddd, J=9.3, 7.8, 3.0 Hz, 1 H), 7.12 (dd, J=9.3, 4.3 Hz, 1 H), 7.03 - 7.09 (m, 1 H), 6.90 - 6.98 (m, 1 H), 6.73 (t, J=7.1 Hz, 1 H), 5.56 (s, 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 378 [M+H]+. 117b) N-(I l-r(23-difluorophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinyl ) carbony 1) glycine
Following the procedure of Example 75c), except substituting the compound from Example 117a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=4.9 Hz, 1 H), 7.84 (dd, J=8.6, 2.8 Hz, 1 H), 7.66 (dt, J=9.1, 3.0 Hz, 1 H), 7.54 (dd, J=9.3, 4.0 Hz, 1 H), 7.35 (q, J=8.3 Hz, 1 H), 7.07 (dd, J=12.6, 7.6 Hz, 1 H), 6.66 (t, J=6.8 Hz, 1 H), 5.60 (s, 2 H), 4.13 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 407 [M+H]+.
Figure imgf000104_0001
N-dό-fluoro^-hvdroxy^-oxo-l-rCΣ.S^-trifluorophenvDmethyll-l^-dihvdro-S- quinolinyl I carbonyDglycine
118a) Ethyl 6-fluoro-4-hvdroxy-2-oxo-l-r(2,3,4-trifluorophenyDmethyll-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,3,4-trifiuorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.89 (dd, J=8.6, 3.0 Hz, 1 H), 7.35 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.11 (dd, J=9.3, 4.0 Hz, 1 H), 6.80 - 6.89 (m, 1 H), 6.69 - 6.77 (m, 1 H), 5.51 (s, 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 396 [M+H]+.
118b) N-({6-fluoro-4-hydroxy-2-oxo-l-r(2,3,4-trifluorophenyl)methvn-l,2-dihydro-3- quinolinyl I carbonyl) glycine
Following the procedure of Example 75c), except substituting the compound from Example 118a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.3 Hz, 1 H), 7.84 (dd, J=8.6, 2.8 Hz, 1 H), 7.66 (dt, J=8.7, 2.8 Hz, 1 H), 7.55 (dd, J=9.3, 4.0 Hz, 1 H), 7.16 (q, J=8.8 Hz, 1 H), 6.73 (q, J=6.1 Hz, 1 H), 5.56 (s, 2 H), 4.13 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 425 [M+H]+.
Example 119
Figure imgf000104_0002
N-lϊό-chloro-l -I [4-( 1 , 1 -dimethylethvDphenyllmethyl \ -4-hvdroxy-2-oxo-l ,2-dihvdro-3- quinolinyDcarbonyll glycine
119a) Ethyl 6-chloro-l-f T4-(l J-dimethylethyl)phenv11methvU-4-hvdroxy-2-oxo-1.2- dihydro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(chloro)isatoic anhydride for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 8.13 (d, J=2.5 Hz, 1 H), 7.45 (dd, J=9.0, 2.4 Hz, 1 H), 7.30 (d, J=8.3 Hz, 2 H), 7.18 (d, J=9.1 Hz, 1 H), 7.11 (d, J=8.3 Hz, 2 H), 5.45 (br. s., 2 H), 4.53 (q, J=7.2 Hz, 2 H), 1.49 (t, J=7.1 Hz, 3 H), 1.27 (s, 9 H). MS(ES+) m/e 414 [M+H]+. 119b) N-IYά-chloro-l-f F4-(l J-dimethylemvDphenylimemylM^iydroxy^-oxo-l^-dihvdro-
S-qumolmyDcarbonyri glycine
Following the procedure of Example 75c), except substituting the compound from Example 119a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 8.05 (d, J=2.5 Hz, 1 H), 7.77 (dd, J=9.1, 2.5 Hz, 1 H), 7.54 (d, J=9.1 Hz, 1 H), 7.33 (d, J=8.6 Hz, 2 H), 7.12 (d, J=8.3 Hz, 2 H), 5.50 (br. s., 2 H), 4.15 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 443 [M+H]+.
Example 120
Figure imgf000105_0001
N-({6-chloro-14(2-chlorophenyl)methyl1-4-hydroxy-2-oxo4,2-dihydro-3- quinolinyl)carbonyl)glvcine
120a) Ethyl 6-chloro-l-r(2-chlorophenyl)methyll-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(chloro)isatoic anhydride for isatoic anhydride and 2-chlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 8.19 (d, J=2.5 Hz, 1 H), 7.49 (dd, J=9.0, 2.4 Hz, 1 H), 7.43 (dd, J=8.0, 1.1 Hz, 1 H), 7.20 (dt, J=7.6, 1.6 Hz, 1 H), 7.09 (dt, J=7.6, 1.0 Hz, 1 H), 6.96 (d, J=9.1 Hz, 1 H), 6.76 (d, J=7.1 Hz, 1 H), 5.55 (br. s., 2 H), 4.53 (q, J=7.1 Hz, 2 H), 1.49 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 392 [M+EQ+.
120b) N-((6-chloro-l-r(2-chlorophenyl)methyll-4-hydroxy-2-oxo-L2-dihydro-3- quinolinyllcarbonyDglycine
Following the procedure of Example 75c), except substituting the compound from Example 120a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.3 Hz, 1 H), 8.08 (d, J=2.5 Hz, 1 H), 7.76 (dd, J=9.1, 2.3 Hz, 1 H), 7.56 (d, J=8.1 Hz, 1 H), 7.32 (d, J=8.8 Hz, 1 H), 7.31 (t, J=7.3 Hz, 1 H), 7.18 (t, J=7.3 Hz, 1 H), 6.70 (d, J=7.3 Hz, 1 H), 5.51 (s, 2 H), 4.12 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 421 [M+H]+.
Figure imgf000106_0001
N-("{ l-r("2,6-difluorophenyl)methyn-6-fluoro-4-hydτoxy-2-oxo-L2-dihydro-3- quinolinyl ) carbonyDgrycine
121a) Ethyl l-rfZ.β-difluorophenvDmethvn-ό-fluoro^-hydroxy^-oxo-l.l-dihvdro-B- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,6-difluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.84 (dd, J=8.6, 3.0 Hz, 1 H), 7.31 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.17 - 7.26 (m, 2 H), 6.85 (t, J=8.3 Hz, 2 H), 5.66 (s, 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 378 [M+H]+.
121b) N-(I l-r(2.6-difluorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinyl } carbonvDglycine
Following the procedure of Example 75c), except substituting the compound from Example 121a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.4 (t, J=4.8 Hz, 1 H), 7.82 (d, J=7.8 Hz, 1 H), 7.70 (d, J=4.8 Hz, 2 H), 7.38 (ddd, J=14.8, 7.2, 6.8 Hz, 1 H), 7.06 (t, J=8.0 Hz, 2 H), 5.62 (s, 2 H), 4.13 (d, J=4.8 Hz, 2 H). MS(ES+) m/e 407 [M+H]+.
Example 122
Figure imgf000106_0002
N-( { 6-fluoro-4-hvdroxy-2-oxo-l -F(2 A6-trifluorophenyl)rnethyll - 1 ,2-dihvdro-3- quinolinyl } carbonyl) glycine
122a) Ethyl 6-fluoro-4-hydroxy-2-oxo-l-r(2,4,6-trifluorophenyl)methyll-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,4,6-trifluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.85 (dd, J=8.6, 3.0 Hz, 1 H), 7.33 (ddd, J=9.3, 7.8, 3.0 Hz, 1 H), 7.18 (dd, J=9.3, 4.0 Hz, 1 H), 6.64 (t, J=8.3 Hz, 2 H), 5.59 (s, 2 H), 4.53 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 396 [MH-H]+.
122b) N-d6-fluoro-4-hydroxy-2-oxo-l-r('2,4,6-trifluorophenyl)methyn-L2-dihvdro-3- quinolinvUcarbonyDglvcine Following the procedure of Example 75c), except substituting the compound from Example
122a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.9 (br. s., 1 H), 10.4 (t, J=4.9 Hz, 1 H), 7.82 (dd, J=8.7, 1.6 Hz, 1 H), 7.73 (d, J=4.5 Hz, 1 H), 7.61 - 7.78 (m, 1 H), 7.17 (t, J=9.0 Hz, 2 H), 5.56 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 425 [MH-H]+. Example 123
Figure imgf000107_0001
N-(( l-r(2-chloro-6-fluorophenyl)methyn-6-fluoro-4-hydroxy-2-oxo-L2-dihydro-3- qumolinyllcarbonyDglycme
123a) Ethyl l-r(2-chloro-6-fluorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-chloro-6-fluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.84 (dd, J=8.6, 3.0 Hz, 1 H), 7.28 (ddd, J=9.3, 7.8, 3.0 Hz, 1 H), 7.23 (d, J=7.6 Hz, 1 H), 7.18 (dt, J=8.0, 5.4 Hz, 1 H), 7.09 (dd, J=9.2, 4.2 Hz, 1 H), 6.87 (ddd, J=10.6, 7.8, 1.5 Hz, 1 H), 5.74 (s, 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 394 [MH-H]+.
123b) N-(I l-r(2-chloro-6-fluorophenyl)methyn-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinyl I carbonyl) glycine
Following the procedure of Example 75c), except substituting the compound from Example 123a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.79 (d, J=6.6 Hz, 1 H), 7.67 (t, J=6.6 Hz, 1 H), 7.56 (d, J=8.3 Hz, 1 H), 7.29 - 7.42 (m, 2 H), 7.10 (t, J=7.6 Hz, 1 H), 5.66 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 423 [MH-H]+.
Figure imgf000108_0001
N-(| l-r(4-chloro-2-fluorophenyl)methyn-6-fluoro-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinyl I carbonyl) glycine 124a") Ethyl l-r(4-chloro-2-fluorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-chloro-2-fluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.87 (dd, J=8.6, 3.0 Hz, 1 H), 7.33 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.15 (dd, J=9.9, 2.0 Hz, 1 H), 7.11 (dd, J=9.3, 4.3 Hz, 1 H), 7.00 (dd, J=8.6, 1.8 Hz, 1 H), 6.93 (t, J=8.2 Hz, 1 H), 5.49 (s, 2 H), 4.54 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 394 [M+BQ+.
124b) N-(I l-r(4-chloro-2-fluorophenyl)methvn-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl ) carbonyDglycine Following the procedure of Example 75c), except substituting the compound from Example
124a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.84 (dd, J=8.8, 3.0 Hz, 1 H), 7.65 (td, J=8.7, 3.0 Hz, 1 H), 7.52 (dd, J=8.1, 2.3 Hz, 1 H), 7.49 (dd, J=9.1, 4.3 Hz, 1 H), 7.14 (dd, J=8.3, 1.5 Hz, 1 H), 6.88 (t, J=8.5 Hz, 1 H), 5.53 (s, 2 H), 4.11 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 423 [M+H]+.
Example 125
Figure imgf000108_0002
N- 1 r4-hydroxy-6-(4-methyl- 1 -piperazinyl)-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihy dro-3- quinolinyll carbonyl I glycine 125 a) Ethyl 4-hvdroxy-6-(4-methyl- 1 -piperazinyl)-2-oxo- 1 -(phenylmethvD- 1 ,2-dihydro-3 - quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(4-methyl-l-piperazinyl)-2H- 3,l'benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and benzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 422 [M+H]+.
125b) N- 1 r4-hydroxy-6-(4-methyl- 1 -piperazmylV2-oxo- 1 -(phenylmethyl)- 1 ,2-dihvdro-3- quinolinyllcarbonyl } glycine Following the procedure of Example 75c), except substituting the compound from Example
125a) for the compound from Example 75b), the title compound was obtained as a light brown powder. 1H NMR (400 MHz, DMSOd6) δ ppm 11.0 - 11.5 (m, 2 H), 7.67 (dd, J= 14.8, 2.9 Hz, 1 H), 7.02 - 7.41 (m, 7 H), 5.45 (s, 2 H), 4.08 (dd, J=15.5, 5.2 Hz, 2 H), 2.98 - 3.19 (m, 4 H), 2.48 (s, 4 H), 2.24 (s, 3 H). MS(ES+) m/e 451 [M+H]+. Example 126
Figure imgf000109_0001
N-(16-fluoro-4-hvdroxy- 1 -r(4-methylphenyl")methyll -2-oxo- 1 ,2-dihydro-3 - quinolinyllcarbonyDglycine
126a) Ethyl 6-fluoro-4-hydroxy-l-r(4-methylphenyl)methyll-2-oxo-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-methylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.85 (dd, J=8.7, 2.9 Hz, 1 H), 7.27 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.19 (dd, J=9.3, 4.3 Hz, 1 H), 7.07 - 7.13 (m, 4 H), 5.46 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 2.30 (s, 3 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 356 [M+H]+.
126b) N-(f6-fluoro-4-hvdroxy-l-r(4-methylphenyl)methyl1-2-oxo-1.2-dihvdro-3- quinolinyl I carbony 1) glycine
Following the procedure of Example 75c), except substituting the compound from Example 126a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.6 Hz, 1 H), 7.78 (dd, J=8.3, 2.5 Hz, 1 H), 7.60 (dt, J=8.8, 2.8 Hz, 1 H), 7.49 (dd, J=9.3, 4.0 Hz, 1 H), 7.11 (s, 4 H), 5.49 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 2.24 (s, 3 H). MS(ES+) m/e 385 [M+H]+. Example 127
Figure imgf000110_0001
N-({ l-r(2,4-dimethylphenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3- quinoliny 11 carbonyl) glycine
127a) Ethyl l-r(2,4-dimethylphenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l ,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,4-dimethylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 14.4 (br. s., 1 H), 7.88 (dd, J=8.6, 3.0 Hz, 1 H), 7.26 (ddd, J=9.3, 7.8, 3.0 Hz, 1 H), 7.04 (s, 1 H), 6.96 (dd, J=9.3, 4.0 Hz, 1 H), 6.81 (d, J=7.6 Hz, 1 H), 6.49 (d, J=8.1 Hz, 1 H), 5.39 (s, 2 H), 4.52 (q, J=7.2 Hz, 2 H), 2.42 (s, 3 H), 2.26 (s, 3 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 370 [M+H]+.
127b) N-(I l-r(2.4-dimethylphenyl)methvn-6-fluoro-4-hvdiOxy-2-oxo-l,2-dihvdro-3- quinoliny 11 carbonyl) glycine
Following the procedure of Example 75c), except substituting the compound from Example 127a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) 5 ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.2 Hz, 1 H), 7.83 (dd, J=8.6, 3.0 Hz, 1 H), 7.60 (dt, J=8.8, 3.0 Hz, 1 H), 7.28 (dd, J=9.3, 4.3 Hz, 1 H), 7.07 (s, 1 H), 6.80 (d, J=7.3 Hz, 1 H), 6.33 (d, J=7.6 Hz, 1 H), 5.41 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 2.41 (s, 3 H), 2.21 (s, 3 H). MS(ES+) m/e 399 [M+H]+.
Example 128
Figure imgf000110_0002
N-(I l -IY2.5 -difluorophenyDmethyli -ό-fluoro^-hvdroxy^-oxo- 1 ,2-dihydro-3 - quinoliny 11 carbonyl) glycine
128a) Ethyl l-r(2.5-difluorophenyl)methvn-6-fluoro-4-hvdroxy-2-oxo-1.2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fiuoro)isatoic anhydride for isatoic anhydride and 2,5-difluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.89 (dd, J=8.6, 3.0 Hz, 1 H), 7.33 (ddd, 3=9.2, 7.7, 3.0 Hz, 1 H), 7.12 (dd, J=9.3, 4.0 Hz, 1 H), 7.08 (dt, 3=9 A, 4.6 Hz, 1 H), 6.92 (ddd, J=12.1, 7.8, 3.5 Hz, 1 H), 6.67 (ddd, J=8.8, 5.7, 3.2 Hz, 1 H), 5.51 (s, 2 H), 4.55 (q, J=7.1 Hz, 2 H), 1.51 (t, 3=7.1 Hz, 3 H). MS(ES+) m/e 378 [M+H]+. 128b) N-(I l-r(2,5-difluorophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-L2-dihydro-3- quinolinyl I carbonyl) glycine
Following the procedure of Example 75c), except substituting the compound from Example 128a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.1 Hz, 1 H), 7.84 (dd, J=8.6, 2.0 Hz, 1 H), 7.66 (t, J=7.1 Hz, 1 H), 7.50 (dd, J=9.0, 3.7 Hz, 1 H), 7.34 (dt, J=9.0, 4.8 Hz, 1 H), 7.11 - 7.23 (m, 1 H), 6.70 - 6.81 (m, 1 H), 5.54 (s, 2 H), 4.13 (d, J=5.1 Hz, 2 H). MS(ES+) m/e 407 [M+H]+.
Example 129
Figure imgf000111_0001
N-F(I-I r3,5-bis(trifluoromethyl)phenyllmethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinvDcarbonyl] glycine
129a) Ethyl 1-1 r3,5-bis(trifluoromethyl)phenyllmethyll-6-fluoro-4-hvdroxy-2-oxo-l,2- dihydro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 3,5-bis(trifluoromethyl)benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5 (br. s., 1 H), 7.92 (dd, J=8.5, 2.9 Hz, 1 H), 7.79 (s, 1 H), 7.63 (s, 2 H), 7.34 (ddd, J=9.2, 7.5, 3.0 Hz, 1 H), 7.04 (dd, 3=9.3, 4.0 Hz, 1 H), 5.59 (br. s., 2 H), 4.55 (q, 3=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 478 [M+H]+.
129b) N-IY 1 -I r3.5-bis(trifluoromethvDphenyl1methyl I -6-fluoro-4-hvdroxy-2-oxo- 1 ,2- dihydro-3-quinolinyl)carbonyri glycine
Following the procedure of Example 75c), except substituting the compound from Example 129a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 8.03 (s, 1 H), 7.95 (s, 2 H), 7.84 (dd, J=8.6, 3.0 Hz, 1 H), 7.65 (dt, J=8.7, 2.9 Hz, 1 H), 7.58 (dd, 3=9.3, 4.0 Hz, 1 H), 5.71 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 507 [M+H]+. Example 130
Figure imgf000112_0001
N-{[6-(dimethylamino)-4-hydroxy-2-oxo-l-(phenylmethyl)-L2-dihydro-3- quinolinyll carbonyl I glycine
130a) Ethyl 6-(dimethylaroinoV4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(dimethylamino)-2H-3,l- benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and benzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a yellow crystalline powder. 1H NMR (400 MHz, DMSOd6) δ ppm 13.2 (s, 1 H), 7.30 (t, J=7.3 Hz, 2 H), 7.15 - 7.25 (m, 6 H), 5.43 (s, 2 H), 4.36 (q, J=7.2 Hz, 2 H), 2.91 (s, 6 H), 1.32 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 367 [M+H]+.
130b) N- { r6-(dimethylamino)-4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihvdro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 75c), except substituting the compound from Example 130a) for the compound from Example 75b), the title compound was obtained as a yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 10.7 (t, J=5.3 Hz, 1 H), 7.00 - 7.54 (m, 8 H), 5.53 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 2.93 (s, 6 H). MS(ES+) m/e 396 [M+H]+.
Example 131
Figure imgf000112_0002
N- 1 r4-hydroxy-6-(4-morpholinyl)-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinoliny 11 carbonyl ) glycine
13 Ia) Ethyl 4-hydroxy-6-(4-morpholrnyl)-2-oxo-l-(phenylmethyl)-1.2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(4-morpholinyl)-2H-3,l- benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and benzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 13.1 (s, 1 H), 7.44 (d, J=2.8 Hz, 1 H), 7.27 - 7.36 (m, 5 H), 7.17 (d, J=7.1 Hz, 2 H), 5.44 (s, 2 H), 4.35 (q, J=7.2 Hz, 2 H), 3.72 - 3.77 (m, 4 H), 3.06 - 3.14 (m, 4 H), 1.32 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 409 [M+H]+.
131b) N-I r4-hvdroxy-6-(4-morpholinyl)-2-oxo-l-(phenylmethyl)-L2-dihydro-3- quinolinyli carbonyl I glycine Following the procedure of Example 75c), except substituting the compound from Example
131a) for the compound from Example 75b), the title compound was obtained as a light brown powder. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.7 (t, J=5.4 Hz, 1 H), 6.99 - 7.83 (m, 8 H), 5.54 (s, 2 H), 4.15 (d, J=5.3 Hz, 2 H), 3.64 - 3.88 (m, 4 H), 3.03 - 3.24 (m, 4 H), 2.55 (s, 3 H). MS(ES+) m/e 438 [M+HJ+. Example 132
Figure imgf000113_0001
N-(| l-r(4-bromophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl) glycine
132a) Ethyl 1 -r(4-bromophenyl)methy 11 -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-bromobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.87 (dd, J=8.6, 3.0 Hz, 1 H), 7.43 (d, J=8.3 Hz, 2 H), 7.29 (ddd, J=9.3, 7.8, 3.0 Hz, 1 H), 7.11 (dd, J=9.3, 4.0 Hz, 1 H), 7.08 (d, J=8.6 Hz, 2 H), 5.44 (br. s., 2 H), 4.54 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 420/422 [M+H]+.
132b) N-(I l-r(4-bromophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-1.2-dihydro-3- quinolinyl 1 carbonyl) glycine
Following the procedure of Example 75c), except substituting the compound from Example 132a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.5 (t, J=5.6 Hz, 1 H), 7.81 (dd, J=8.6, 2.8 Hz, 1 H), 7.63 (dt, J=8.7, 2.8 Hz, 1 H), 7.51 (d, J=8.1 Hz, 2 H), 7.46 - 7.50 (m, 1 H), 7.18 (d, J=8.1 Hz, 2 H), 5.52 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 449/451 [M+H]+. Example 133
Figure imgf000114_0001
N-I ri-(4-biphenylylmethylV6-fluoro-4-hvdroxy-2-oxo-l,2-dihvdro-3-quinolinyllcarbonyl) glycine
133a) Ethyl l-(4-biphenylylmethyl)-6-fluoro-4-hydroxy-2-oxo4.2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-(bromomethyl)biphenyl for 2-bromobenzyl bromide, the title compound was obtained as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.3 (br. s., 1 H), 7.87 (dd, J=8.6, 3.0 Hz, 1 H), 7.54 (d, J=7.1 Hz, 2 H), 7.53 (d, J=8.1 Hz, 2 H), 7.42 (t, J=7.6 Hz, 2 H), 7.34 (d, J=7.3 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.27 (d, J=8.1 Hz, 2 H), 7.23 (dd, J=9.1, 4.0 Hz, 1 H), 5.54 (br. s., 2 H), 4.55 (q, J=7.2 Hz, 2 H), 1.51 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 418 [M+H]+.
133b) N-I ri-(4-biphenylylmethyl)-6-fluoro-4-hydroxy-2-oxo-L2-dihydro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 75c), except substituting the compound from Example 133a) for the compound from Example 75b), the title compound was obtained as a beige solid. 1H
NMR (400 MHz, DMSOd6) δ ppm 13.2 (br. s., 1 H), 10.6 (t, J=5.1 Hz, 1 H), 7.83 (dd, J=8.7, 2.9 Hz, 1 H), 7.65 (dd, J=9.3, 3.0 Hz, 1 H), 7.61 (d, J=7.8 Hz, 4 H), 7.54 - 7.60 (m, 1 H), 7.44 (t, J=7.6 Hz, 2 H), 7.35 (d, J=7.3 Hz, 1 H), 7.31 (d, J=8.3 Hz, 2 H), 5.60 (s, 2 H), 4.12 (d, J=5.1 Hz, 2 H). MS(ES+) m/e 447 [M+H]+.
Example 134
Figure imgf000115_0001
N-({ l-r(3,4-difluorophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinyl I carbonyl) glycine 134a) Ethyl l-r(3,4-difluorophenvDmethyn-6-fluoro-4-hvdroxy-2-oxo-L2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 3,4-difluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.88 (dd, J=8.6, 3.0 Hz, 1 H), 7.32 (ddd, J=9.2, 7.7, 3.0 Hz, 1 H), 7.11 (dd, J=13.9, 4.5 Hz, 1 H), 7.09 (dd,
J=9.9, 8.1 Hz, 1 H), 7.01 (ddd, J=10.6, 7.6, 2.0 Hz, 1 H), 6.92 - 6.98 (m, 1 H), 5.44 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 378 [M+BQ+.
134b) N-({ l-r(3,4-difluorophenyl)methyn-6-fluoro-4-hydroxy-2-oxo-L2-dihydro-3- quinolinyl ) carbonyl) glycine Following the procedure of Example 75c), except substituting the compound from Example
134a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.3 Hz, 1 H), 7.82 (dd, J=8.6, 2.8 Hz, 1 H), 7.64 (dt, J=8.6, 2.8 Hz, 1 H), 7.53 (dd, J=9.3, 4.3 Hz, 1 H), 7.39 (d, J=8.8 Hz, 1 H), 7.36 (dd, J=10.1, 9.1 Hz, 1 H), 7.00 - 7.09 (m, 1 H), 5.53 (s, 2 H), 4.15 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 407 [M+H]+.
Example 135
Figure imgf000116_0001
N-d l-rO.S-difluorophenvDmethyll-ό-fluoro^-hvdroxy^-oxo-l^-dihydro-S- quinolinyl 1 carbonyl) glycine
135a) Ethyl l-rO.S-difluorophenyπmethyll-ό-fluoro^-hvdroxy^-oxo-l^-dihvdro-B- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 3,5-difluorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.89 (dd, J=8.5, 2.9 Hz, 1 H), 7.32 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.07 (dd, J=9.3, 4.0 Hz, 1 H), 6.71 (d, J=8.1 Hz, 2 H), 6.64 - 6.74 (m, 1 H), 5.46 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 378 [M+H]+.
135b) N-( { 1 -r(3,5-difluorophenyl)methyll -6-fluoro-4-hydroxy-2-oxo-l ,2-dihydro-3- quinolinyllcarbonyDglycine
Following the procedure of Example 75c), except substituting the compound from Example 135a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.5 (t, J=5.2 Hz, 1 H), 7.83 (dd, J=8.6, 3.0 Hz, 1 H), 7.64 (dt, J=8.7, 3.0 Hz, 1 H), 7.50 (dd, J=9.5, 4.2 Hz, 1 H), 7.13 (tt, J=9.3, 2.0 Hz, 1 H), 6.98 (d, J=6.6 Hz, 2 H), 5.56 (s, 2 H), 4.15 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 407 [M+HJ+.
Example 136
Figure imgf000116_0002
N-[(6-fluoro-4-hvdroxy-2-oxo-l-ir2-(trifluoromethyl)phenyllmethyll-l,2-dihydro-3- quinolinyDcarbonyll glycine
136a) Ethyl 6-fluoro-4-hvdroxy-2-oxo-l-( r2-(trifluoromethyl)phenyllmethyl}-l,2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-trifluoromethylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (br. s., 1 H), 7.87 (dd, J=8.6, 3.0 Hz, 1 H), 7.73 (dd, J=5.3, 3.8 Hz, 1 H), 7.32 - 7.38 (m, 2 H), 7.26 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 6.95 (dd, J=9.2, 4.2 Hz, 1 H), 6.83 (dd, J=5.1, 3.5 Hz, 1 H), 5.68 (br. s., 2 H), 4.52 (q, J=7.1 Hz, 2 H), 1.48 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 410 [M+H]+. 136bN) N-r(6-fluoro-4-hvdroxy-2-oxo-l-( r2-(trifluoromethyl)phenyllmethvU-1.2-dihvdro-3- quinolmyDcarbonyli glycine
Following the procedure of Example 75c), except substituting the compound from Example 136a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.2 Hz, 1 H), 7.88 (dd, J=8.8, 3.0 Hz, 1 H), 7.84 (dd, J=6.3, 4.0 Hz, 1 H), 7.64 (dt, J=8.7, 3.0 Hz, 1 H), 7.47 - 7.53 (m, 2 H), 7.26 (dd, J=9.3, 4.0 Hz, 1 H), 6.84 (t, J=4.3 Hz, 1 H), 5.65 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 439 [M+H]+.
Example 137
Figure imgf000117_0001
N-F(I-I r2,4-bis(trifluoromethyl)phenyllmethvπ-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinvDcarbonyll glycine
137a) Ethyl 1-1 [2,4-bis(trifluoromethyl)phenyllmethyl)-6-fluoro-4-hydroxy-2-oxo-l,2- dihvdro-3-qumolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2,4-bis(trifluoromethyl)benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5 (br. s., 1 H), 8.00 (s, 1 H), 7.92 (dd, J=8.6, 3.0 Hz, 1 H), 7.62 (d, J=8.1 Hz, 1 H), 7.30 (ddd, J=9.3, 7.6, 3.0
Hz, 1 H), 6.99 (d, J=8.1 Hz, 1 H), 6.90 (dd, J=9.3, 4.0 Hz, 1 H), 5.72 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2
H), 1.49 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 478 [M+H]+. 137fr) N-r(l-l r2.4-bis(trifluoromethyl)phenyllmethvn-6-fluoro-4-hvdroxy-2-oxo-1.2- dihvdro-3-quinolmyl)carbonvi1grycme
Following the procedure of Example 75c), except substituting the compound from Example
137a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H
NMR (400 MHz, DMSO-d6) δ ppm 13.0 (br. s., 1 H), 10.3 (t, J=5.3 Hz, 1 H), 8.14 (s, 1 H), 7.87 (d, J=8.3 Hz, 2 H), 7.64 (dt, J=8.8, 2.5 Hz, 1 H), 7.35 (dd, J=9.3, 3.8 Hz, 1 H), 7.12 (d, J=8.1 Hz, 1 H),
5.69 (s, 2 H), 4.11 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 507 [M+H]+.
Figure imgf000118_0001
N-rCβ-fluoro-l-irS-fluoro^-CtrifluoromethyDphenyllmethyll^-hvdroxy^-oxo-l^-dihydro-S- quinolinvDcarbonyll glycine 137a) Ethyl 6-fluoro-l-{ r3-fluoro-4-(trifluoromethyDphenyllmethyll-4-hvdroxy-2-oxo-l,2- dihydro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 3-fluoro-4-trifluoromethylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.4 (s, 1 H), 7.91 (dd, J=8.6, 3.0 Hz, 1 H), 7.55 (t, J=7.7 Hz, 1 H), 7.33 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.10 (d, J=8.3 Hz, 1 H), 7.05 (dd, 3=9.3, 4.0 Hz, 1 H), 7.01 (d, J=10.6 Hz, 1 H), 5.52 (br. s., 2 H), 4.54 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H). MS(ES+) m/e 428 [M+H]+.
137b) N-r(6-fluoro-l-{ r3-fluoro-4-(trifluoromethyl)phenyllmethyl|-4-hydroxy-2-oxo-l,2- dihydro-3 -quinolinyDcarbonyll glycine Following the procedure of Example 75c), except substituting the compound from Example
138a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.84 (dd, J=8.7, 2.9 Hz, 1 H), 7.72 (t, J=7.8 Hz, 1 H), 7.64 (ddd, J=9.3, 8.3, 2.9 Hz, 1 H), 7.50 (dd, J=9.5, 4.2 Hz, 1 H), 7.45 (d, J=11.6 Hz, 1 H), 7.19 (d, J=8.1 Hz, 1 H), 5.64 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 457 [M+H]+.
Example 139
Figure imgf000119_0001
N-Kό-fluoro- 1 - { r4-fluoro-2-(trifluoromethyl)pheny llmethyl 1 ^-hvdroxy-^-oxo- 1 ,2-dihydro3 - quinolinvDcarbonyll glycine 139a) Ethyl 6-fluoro-l-(r4-fluoro-2-(trifluoromethyl)phenvnmethyl)-4-hydroxy-2-oxo-l,2- dihvdro-3-qumolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 4-fluoro-2-trifluoromethylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5 (s, 1 H), 7.90 (dd, J=8.6, 2.8 Hz, 1 H), 7.46 (dd, J=8.3, 2.5 Hz, 1 H), 7.32 (ddd, J=9.3, 7.6, 3.0 Hz, 1 H), 7.03 - 7.10 (m, 1 H), 6.94 (dd, J=9.1, 4.3 Hz, 1 H), 6.83 (dd, J=9.0, 4.8 Hz, 1 H), 5.64 (br. s., 2 H), 4.53 (q, J=7.2 Hz, 2 H), 1.49 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 428 [M+H]+.
139b) N-r(6-fluoro-l-{r4-fluoro-2-(trifluoromethyl)phenyllmethyl)-4-hvdroxy-2-oxo-1.2- dihvdro-3-quinolmyl)carbonyri glycine Following the procedure of Example 75c), except substituting the compound from Example
139a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (br. s., 1 H), 10.4 (t, J=5.6 Hz, 1 H), 7.88 (dd, J=8.7, 2.9 Hz, 1 H), 7.77 (dd, J=8.8, 2.3 Hz, 1 H), 7.65 (ddd, J=9.4, 8.2, 2.8 Hz, 1 H), 7.35 (dt, J=8.1, 1.9 Hz, 1 H), 7.29 (dd, J=9.3, 4.0 Hz, 1 H), 6.90 (dd, J=8.5, 5.7 Hz, 1 H), 5.61 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 457 [M+H]+.
Example 140
Figure imgf000119_0002
N-iri-r(2-chloroρhenyl)methyll-4-hvdroxy-2-oxo-7-('trifluoromethyl)-l,2-dihvdro-3- quinolinyll carbonyl I glycine 140a) Ethyl l-r(2-chlorophenyl)methyll-4-hvdroxy-2-oxo-7-(trifluoromethylV1.2-dihydro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 107a) for isatoic anhydride and 2-chlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 14.5 (s, 1 H), 8.34 (d, J=8.3 Hz, 1 H), 7.42 - 7.50 (m, 2 H), 7.33 (s, 1 H), 7.21 (dt, J=7.6, 1.4 Hz, 1 H), 7.11 (dt, J=7.6, 1.0 Hz, 1 H), 6.85 (dd, J=7.6, 1.0 Hz, 1 H), 5.61 (s, 2 H), 4.55 (q, J=7.1 Hz, 2 H), 1.51 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 426 [M+H]+. 140b) N-I ri-r(2-chlorophenyl)methvn-4-hvdroxy-2-oxo-7-(trifluoromethyl)-l,2-dihydro-3- quinolinylicarbonyl I glycine
Following the procedure of Example 75c), except substituting the compound from Example 140a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 13.0 (br. s., 1 H), 10.4 (t, J=4.8 Hz, 1 H), 8.36 (d, J=8.1 Hz, 1 H), 7.70 (d, J=8.1 Hz, 1 H), 7.61 (s, 1 H), 7.57 (d, J=7.8 Hz, 1 H), 7.31 (t, J=7.3 Hz, 1 H), 7.19 (t, J=7.5 Hz, 1 H), 6.80 (d, J=7.6 Hz, 1 H), 5.63 (s, 2 H), 4.14 (d, J=4.8 Hz, 2 H). MS(ES+) m/e 455 [M+H]+.
Example 141
Figure imgf000120_0001
N-f r 1 - ( F4-( 1.1 -dimethylethyDphenylimethyl 1 -4-hydroxy-6-(4-morpholinyl)-2-oxo- 1 ,2-dihydro-3- quinolinyll carbonyl I glycine
141a) Ethyl 1-1 r4-(lJ-dimethylethyl)phenyl1methyll-4-hydroxy-6-(4-morpholinyl)-2-oxo- 1 ,2-dihydro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(4-morpholinyl)-2H-3,l- benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 465 [M+H]+.
141b) N-(Il-I r4-α.l-dimethylethyl)Dhenyllmethvn-4-hvdroxy-6-(4-morpholinylV2-oxo-L2- dihvdro-3-quinolmyllcarbonyl)glycine
Following the procedure of Example 75c), except substituting the compound from Example 141a) for the compound from Example 75b), the title compound was obtained as a yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.7 (t, J=5.4 Hz, 1 H), 6.84 - 7.67 (m, 7 H), 5.50 (s, 2 H), 4.15 (d, J=5.6 Hz, 2 H), 3.70 - 3.80 (m, 4 H), 3.09 - 3.19 (m, 4 H), 1.23 (s, 9 H). MS(ES+) m/e 494 [M+H]+.
Figure imgf000121_0001
N-(fl-r(2-chlorophenyl')methvπ-4-hydroxy-6-(4-morpholmyl)-2-oxo-1.2-dihvdro-3- quinolinyl] carbonyl I glycine 142a) Ethyl l-r('2-chlorophenyl)methyn-4-hvdroxy-6-(4-morpholinyl')-2-oxo-l ,2-dihvdro-3- quinolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(4-morpholinyl)-2H-3,l- benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and 2-chlorobenzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 443 [M+H]+.
142b) N-I ri-r("2-chlorophenyl)methyll-4-hvdroxy-6-(4-morpholinyl)-2-oxo-l,2-dihvdro-3- quinolinyll carbonyl ) glycine
Following the procedure of Example 75c), except substituting the compound from Example 142a) for the compound from Example 75b), the title compound was obtained as a bright yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.5 (t, J=5.6 Hz, 1 H), 7.56 (dd, J=8.0, 1.1 Hz, 1 H), 7.45 - 7.52 (m, 2 H), 7.25 - 7.35 (m, 1 H), 7.19 (t, J=7.6 Hz, 2 H), 6.65 (d, J=7.6 Hz, 1 H), 5.51 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 3.70 - 3.83 (m, 4 H), 3.10 - 3.20 (m, 4 H). MS(ES+) m/e 472 [M+H]+.
Example 143
Figure imgf000121_0002
N-(ri-[(2-chlorophenyl)methyll-6-(dimethylamino)-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinyll carbonyl I glycine
143a) Ethyl l-r(2-chlorophenyl)methyll- 6-(dimethylamino)-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate Following the procedure of Example 16a), except substituting 6-(dimethylamino)-2H-3,l- benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and 2-chlorobenzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 401
[M+H]+. 143b) N-I ri-r("2-chlorophenyl')methyll-6-('dimethylamino)-4-hvdroxy-2-oxo-L2-dihydro-3- quinolinyll carbonyl I glycine
Following the procedure of Example 75c), except substituting the compound from Example 143a) for the compound from Example 75b), the title compound was obtained as a yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.6 (t, J=5.4 Hz, 1 H), 7.56 (dd, J=7.8, 1.0 Hz, 1 H), 7.25 - 7.35 (m, 3 H), 7.10 - 7.24 (m, 2 H), 6.65 (d, J=7.6 Hz, 1 H), 5.51 (s, 2 H), 4.13 (d, J=5.6 Hz, 2 H), 2.95 (s, 6 H). MS(ES+) m/e 430 [M+H]+.
Example 144
Figure imgf000122_0001
N-r(6-(dimethylamino)-l-{ r4-(U-dimethylethyl)phenyllmethyll-4-hydroxy-2-oxo-L2-dihvdro-3- quinormvDcarbonyll glycine
144a) Ethyl 6-(dimethylammo)-l- 1 [4-(l J-dimethylethvDphenylimethylM-hvdroxy-Σ-oxo- l^-dihydro-θ-qumolinecarboxylate
Following the procedure of Example 16a), except substituting 6-(dimethylamino)-2H-3,l- benzoxazine-2,4(lH)-dione (WO05/009969) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 423 [M+H]+.
144b N-r(6-(dimethylamino)- 1-{ [4-( 1 , 1 -dimethylethvDphenylimethyl I -4-hvdroxy-2-oxo-l ,2- dihvdro-3-quinolmyl)carbonyri glycine Following the procedure of Example 75c), except substituting the compound from Example
144a) for the compound from Example 75b), the title compound was obtained as a yellow powder. 1H NMR (400 MHz, DMSOd6) δ ppm 12.9 (s, 1 H), 10.7 (t, J=5.3 Hz, 1 H), 7.39 (d, J=9.4 Hz, 1 H), 7.26 - 7.35 (m, 3 H), 7.22 (d, J=3.0 Hz, 1 H), 7.12 (d, J=8.3 Hz, 2 H), 5.48 (s, 2 H), 4.15 (d, J=5.3 Hz, 2 H), 2.93 (s, 6 H), 1.23 (s, 9 H). MS(ES+) m/e 452 [M+H]+. Example 145
Figure imgf000123_0001
N- ( r 1 - ( F4-( 1 , 1 -dimemylethyl)phenyllmethyl I -4-hydroxy-2-oxo-6-(trifluoromethyr)- 1 ,2-dihydro-3 - quinolinyll carbonyl 1 glycine 145a) 6-(Trifluoromethyl)-2H-3,l-benzoxazine-2,4(lH)-dione
To a suspension of 2-({[(l,l-dimethylethyl)oxy]carbonyl}amino)-5-(trifluoromethyl)benzoic acid (prepared by the method of Jδnsson, S.; Andersson, G.; Fex, T.; Fristedt, T.; Hedlund, G.; Jansson, K.; Abramo, L.; Fritzson, L; Pekarski, O.; Runstrδm, A.; Sandin, H.; Thuvesson, L; Bjδrk, A. J. Med. Chem. 2004, 47, 2075-2088) (2.0 g, 6.55 mmol) in toluene (15.0 mL) was added oxalyl chloride (0.629 mL, 7.21 mmol). The reaction mixture was heated to reflux for 1 h, concentrated in vacuo, washed with hexanes, filtered, and dried in vacuo to afford the title compound as a white solid (1.36 g, 90%). 1H NMR (400 MHz, DMSOd6) δ ppm 12.1 (s, 1 H), 8.14 (d, J=LO Hz, 1 H), 8.07 (dd, J=8.7, 1.9 Hz, 1 H), 7.32 (d, J=8.6 Hz, 1 H). MS(ES+) m/e 232 [M+H]+.
145b) Ethyl 1-1 r4-(l,l-dimethylethyl)phenyl1methyl|-4-hvdroxy-2-oxo-6-(trifluoromethyl)- 1 ,2-dihydro-3 -quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 145a) for isatoic anhydride and 4-tert-butylbenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5 (s, 1 H), 8.47 (d, J=1.3 Hz, 1 H), 7.75 (dd, J=9.0, 1.9 Hz, 1 H), 7.35 (d, J=9.1 Hz, 1 H), 7.32 (d, J=8.3 Hz, 2 H), 7.13 (d, J=8.3 Hz, 2 H), 5.49 (br. s., 2 H), 4.54 (q, J=7.1 Hz, 2 H), 1.50 (t, J=7.1 Hz, 3 H), 1.28 (s, 9 H). MS(ES+) m/e 448 [M+H]+.
145c) N-in-l F4-(Ll-dimethylethyl)phenyllmethyll-4-hydroxy-2-oxo-6-(trifluoromethyl)- 1 ,2-dihydro-3 -quinolinyll carbonyl 1 glycine
Following the procedure of Example 75c), except substituting the compound from Example 145b) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.4 (t, J=5.2 Hz, 1 H), 8.34 (d, J=1.8 Hz, 1 H), 8.04 (dd, J=9.0, 1.9 Hz, 1 H), 7.70 (d, J=9.1 Hz, 1 H), 7.34 (d, J=8.3 Hz, 2 H), 7.14 (d, J=8.3 Hz, 2 H), 5.55 (s, 2 H), 4.16 (d, J=5.6 Hz, 2 H), 1.23 (s, 9 H). MS(ES+) m/e 477 [M+H]+.
Figure imgf000124_0001
N-I Fl-f('2-chlorophenyl')methyll-4-hvdroxy-2-oxo-6-('trifluoromethyl)-l,2-dihydro-3- quinolinyli carbonyl 1 glycine
146a) Ethyl 1 -r(2-chlorophenyl)methvn -4-hvdroxy-2-oxo-6-(trifluoromethyl)- 1 ,2-dihvdro-3 - quinolinecarboxylate
Following the procedure of Example 16a), except substituting the compound from Example 145a) for isatoic anhydride and 2-chlorobenzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 14.5 (s, 1 H), 8.51 (d, J=LO Hz, 1 H), 7.77 (dd, J=9.0, 2.1 Hz, 1 H), 7.45 (d, J=6.8 Hz, 1 H), 7.21 (dt, J=8.1, 1.8 Hz, 1 H), 7.12 (d, J=9.1 Hz, 1 H), 7.11 (dt, J=7.6, 1.0 Hz, 1 H), 6.77 (dd, J=7.3, 1.0 Hz, 1 H), 5.60 (s, 2 H), 4.54 (q, J=7.2 Hz, 2 H), 1.50 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 426 [M+H]+.
146b) N- ( r 1 -r(2-chlorophenyl)methyll -4-hvdroxy-2-oxo-6-(trifluoromethyl)- 1 ,2-dihydro-3 - quinolinyll carbonyl I glycine
Following the procedure of Example 75c), except substituting the compound from Example 146a) for the compound from Example 75b), the title compound was obtained as a white solid. 1H NMR (400 MHz, DMSOd6) δ ppm 13.0 (s, 1 H), 10.3 (t, J=5.3 Hz, 1 H), 8.38 (d, J=1.3 Hz, 1 H), 8.04 (dd, J=9.1, 2.0 Hz, 1 H), 7.57 (dd, J=8.0, 0.9 Hz, 1 H), 7.50 (d, J=9.1 Hz, 1 H), 7.32 (dt, J=7.7, 1.3 Hz, 1 H), 7.18 (dt, J=7.5, 0.9 Hz, 1 H), 6.75 (dd, J=8.0, 0.9 Hz, 1 H), 5.56 (s, 2 H), 4.13 (d, J=5.3 Hz, 2 H). MS(ES+) m/e 455 [M+H]+.
Example 147
Figure imgf000124_0002
N-(2-amino-2-oxoethyl)-4-hydroxy-2-oxo-l-(phenylmethyl)-1.2-dihvdro-3-quinolinecarboxamide
To a solution of N-(benzyl)isatoic anhydride (0.253 g, 1.00 mmol) and diethyl malonate (0.152 mL, 1.00 mmol) in 1,4-dioxane (2.0 mL) was added sodium hydride (0.050 g, 60% dispersion in mineral oil, 1.25 mmol). Following stirring at ambient temperature for 5 min., the solution was heated to 150 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, glycinamide hydrochloride (0.166 g, 1.50 mmol) was added and the solution was heated to 200 0C for 20 min. in a Biotage Initiator microwave synthesizer. Upon cooling, the reaction mixture was treated with 6M aqueous sodium hydroxide, and the precipitate that was formed was filtered, washed with water and Et2O, and dried in vacuo to afford the title compound as an off-white solid (0.295 g, 84%). 1H NMR (400 MHz, DMSOd6) δ ppm 10.6 (t, J=5.1 Hz, 1 H), 8.12 (dd, J=8.1, 1.3 Hz, 1 H), 7.70 (ddd, J=8.5, 7.1, 1.5 Hz, 1 H), 7.60 (s, 1 H), 7.46 (d, J=8.6 Hz, 1 H), 7.35 (d, J=7.8 Hz, 1 H), 7.33 (d, J=4.0 Hz, 1 H), 7.31 (d, J=7.3 Hz, 1 H), 7.24 (s, 2 H), 7.22 (d, J=8.4 Hz, 2 H), 5.56 (s, 2 H), 4.03 (d, J=5.1 Hz, 2 H). MS(ES+) m/e 352 [M+H]+.
Example 148
Figure imgf000125_0001
N-I r4-hydroxy-6-nitro-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quinolinyllcarbonyl) glycine
148a) Ethyl 4-hydroxy-6-nitro-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinecarboxylate Following the procedure of Example 16a), except substituting 6-(nitro)isatoic anhydride
(WO05/009969) for isatoic anhydride and benzyl bromide for 2-bromobenzyl bromide, the title compound was obtained as a yellow powder. MS(ES+) m/e 369 [M+H]+.
148b) N-{r4-hydroxy-6-nitro-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyll carbonyl ) glycine
Following the procedure of Example 75c), except substituting the compound from Example
148a) for the compound from Example 75b), the title compound was obtained as a brown powder. 1H
NMR (400 MHz, DMSO-d6) δ ppm 12.9 (s, 1 H), 10.3 (t, J=4.7 Hz, 1 H), 8.82 (d, J=2.8 Hz, 1 H),
8.46 (dd, J=9.4, 2.8 Hz, 1 H), 7.68 (d, J=9.4 Hz, 1 H), 7.01 - 7.54 (m, 5 H), 5.61 (s, 2 H), 4.17 (d,
J=5.6 Hz, 2 H). MS(ES+) m/e 398 [M+HJ+.
Example 149
Figure imgf000125_0002
N-(r6-amino-4-hvdroxy-2-oxo-l-(phenylmethyl)-L2-dihydro-3-quinolinyllcarbonyl)glvcine To the compound from Example 148b) (1.00 g, 2.51 mmol) in ethyl acetate (25.0 mL) was added 10% palladium on charcoal (0.100 g, 0.094 mmol). The mixture was shaken on a Parr hydrogenator at 45 psi hydrogen for 4 h. The reaction mixture was filtered and the filtrate evaporated down to residue and resuspended in DMSO. The fluorescent solution was purified via preparative HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)) to afford the title compound as a pale brown powder (0.400 g, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.7 (t, J=5.4 Hz, 1 H), 7.14 - 7.39 (m, 9 H), 7.08 (dd, J=9.0, 2.7 Hz, 1 H), 5.49 (s, 2 H), 4.14 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 368 [M+H]+.
Example 150
Figure imgf000126_0001
N-I [6-fluoro-4-hvdroxy-2-oxo- 1 -(2-oxo-2-phenylethyl)- 1 ,2-dihvdro-3 -quinolinyll carbonyl ) glycine 150a) Ethyl l-(3,3-dimethyl-2-oxobutyl)-6-fluoro-4-hvdroxy-2-oxo-l,2-dihydro-3- quinolinecarboxylate Following the procedure of Example 16a), except substituting 6-(fluoro)isatoic anhydride for isatoic anhydride and 2-bromoacetophenone for 2-bromobenzyl bromide, the title compound was obtained as a pale pink solid after washing the residue with hexanes, followed by ethyl acetate. 1H
NMR (400 MHz, DMSOd6) δ ppm 7.39 - 7.47 (m, 2 H), 7.14 (dd, J=8.8, 3.0 Hz, 1 H), 7.01 (tt, J=IA,
1.3, 1.1 Hz, 1 H), 6.89 (t, J=7.7 Hz, 2 H), 6.71 - 6.83 (m, 1 H), 6.67 (dd, J=9.3, 4.3 Hz, 1 H), 5.13 (s, 2 H), 3.69 (q, J=7.3 Hz, 2 H), 0.63 (t, J=7.2 Hz, 3 H). MS(ES+) m/e 370 [M+H]+.
150b) N-( r6-fluoro-4-hydroxy-2-oxo-l-(2-oxo-2-phenylethyl)-L2-dihvdro-3- qumolinvncarbonyl } glycine
Following the procedure of Example 60c), except substituting the compound from Example
150a) for the compound from Example 60b), the title compound was obtained as a tan solid. 1H NMR (400 MHz, DMSOd6) δ ppm 10.4 (t, J=5.6 Hz, 1 H), 8.15 (d, J=7.3 Hz, 1 H), 7.81 - 7.91 (m, 1 H),
7.76 (t, J=7.3 Hz, 1 H), 7.56 - 7.70 (m, 5 H), 5.96 (s, 2 H), 4.12 (d, J=5.6 Hz, 2 H). MS(ES+) m/e 399
[M+H]+.
Biological Background: The following references set out information about the target enzymes, pyrolyl hydroxylases, and methods and materials for measuring inhibition of same by small molecules.
M. Hirsila, P. Koivunen, V. Gunzler, K. I. Kivirikko, and J. Myllyharju "Characterization of the Human Prolyl 4-Hydroxylases That Modify the Hypoxia-inducible Factor" J. Biol. Chem., 2003, 278, 30772-30780. C. Willam, L. G. Nicholls, P. J. Ratcliffe, C. W. Pugh, P. H. Maxwell "The prolyl hydroxylase enzymes that act as oxygen sensors regulating destruction of hypoxia-inducible factor α" Advan. Enzyme Regul., 2004, 44, 75-92
M. S. Wiesener, J. S. Jϋrgensen, C. Rosenberger, C. K. Scholze, J. H. Hδrstrup, C. Warnecke, S. Mandriota, I. Bechmann, U. A. Frei, C. W. Pugh, P. J. Ratcliffe, S. Bachmann, P. H. Maxwell, and K.-U. Eckardt "Widespread hypoxia-inducible expression of HIF-2HΓ in distinct cell populations of different organs" FASEB J., 2003, 17, 271-273.
S. J. Klaus, C. J. Molineaux, T. B. Neff, V. Guenzler-Pukall, I. Lansetmo Parobok, T. W. Seeley, R. C. Stephenson "Use of hypoxia-inducible factor α (HDFα) stabilizers for enhancing erythropoiesis" PCT Int Appl. (2004), WO 2004108121 Al
C. Warnecke, Z. Zaborowska, J. Kurreck, V. A. Erdmann, U. Frei, M. Wiesener, and K.-U. Eckardt "Differentiating the functional role of hypoxia-inducible factor (BQF)-Ia and HIF-2α (EPAS- 1) by the use of RNA interference: erythropoietin is a HIF-2α target gene in Hep3B and Kelly cells" FASEB J., 2004, 18, 1462-1464. For the expression ofEGLN3 see:
R. K. Bruick and S. L. McKnight "A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF" Science, 2001, 294, 1337-1340.
For the expression ofHIF2a-CODD see: a) P. Jaakkola, D. R. Mole, Y.-M. Tian, M. I. Wilson, J. Gielbert,.S. J. Gaskell, A. von Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P, J. Ratcliffe "Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation" Science, 2001, 292, 468-472. b) M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J. M. Asara, W. S. Lane, W. G. Kaelin Jr. "HTFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing" Science, 2001, 292, 464-468.
For the expression of VHL, elongin b and elongin c see:
A. Pause, S. Lee, R. A. Worrell, D. Y. T. Chen, W. H. Burgess, W. M. Linehan, R. D. Klausner "The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins" Proc. Natl. Acad. Sd. USA, 1997, 94, 2156-2161.
Biological Assay(s)
EGLN3 Assay Materials: His-MBP-EGLN3 (6HisMBPAttB 1EGLN3( 1-239)) was expressed in E. CoIi and purified from an amylase affinity column. Biotin-VBC [6HisSumoCysVHL(2-213), 6HisSumoElonginB(l- 118), and 6ffisSumoElonginC(l-112)] and His-GBl-HIF2α-CODD (6HisGB ltevHIF2A(467-572)) were expressed from E. CoIi.
Method: Cy5-labelled H3F2α CODD, and a biotin-labeled VBC complex were used to determine
EGLN3 inhibition. EGLN3 hydroxylation of the Cy5CODD substrate results in its recognition by the biotin-VBC. Addition of a Europium/streptavidin (Eu/SA) chelate results in proximity of Eu to Cy5 in the product, allowing for detection by energy transfer. A ratio of Cy5 to Eu emission (LANCE Ratio) is the ultimate readout, as this normalized parameter has significantly less variance than the Cy5 emission alone.
5OnL of inhibitors in DMSO (or DMSO controls) were stamped into a 384-well low volume Corning NBS plate, followed by addition of 2.5 μL of enzyme [50 mL buffer (50 mM HEPES/50 mM KCl) + 1 mL of a 10 mg/mL BSA in buffer + 6.25 μL of a lOmg/mL FeCl2 solution in water + 100 μL of a 200 mM solution of ascorbic acid in water + 15.63 μL EGLN3] or control [50 mL buffer + 1 mL of a 10 mg/mL BSA in buffer + 6.25 μL of a lOmg/mL FeCl2 solution in water + 100 μL of a 200 mM solution of ascorbic acid in water]. Following a 3 minutes incubation, 2.5 μL of substrate [5OmL Buffer + 68.6 μL biotin-VBC + 70.4 μL Eu (at 710 μg/mL stock) + 91.6 μL Cy5CODD + 50 μL of a 20 mM solution of 2-oxoglutaric acid in water 4- 0.3mM CHAPS] was added and incubated for 30 minutes. The plate was loaded into a PerkinElmer Viewlux for imaging. For dose response experiments, normalized data were fit by ABASE/XC50 using the equation y = a + (b- a)/(l+(10Λx/10Λc)Λd), where a is the minimum % activity, b is the maximum % activity, c is the pIC50, and d is the Hill slope.
The IC50 for exemplar compounds in the EGLN3 assay ranged from approximately 20 - 1000 nanomolar. This range represents the data accumulated as of the time of the filing of this initial application. Later testing may show variations in IC50 data due to variations in reagents, conditions and variations in the method(s) used from those given herein above. So this range is to be viewed as illustrative, and not a absolute set of numbers.
Measure Epo protein produced by Hep3B cell line using ELISA method. Hep3B cells obtained from the American Type Culture Collection (ATCC) are seeded at 2xlOΛ4 cells/well in Dulbecco's Modified Eagle Medium (DMEM) + 10% FBS in 96-well plates. Cells are incubated at 37degC/5% CO2/90% humidity (standard cell culture incubation conditions). After overnight adherence, medium is removed and replaced with DMEM without serum containing test compound or DMSO negative control. Following 48 hours incubation, cell culture medium is collected and assayed by ELISA to quantitate Epo protein.
The EC50 for exemplar compounds in the Hep3B ELISA assay ranged from approximately 1 - 20 micromolar using the reagents and under the conditions outlined herein above. This range represents the data accumulated as of the time of the filing of this initial application. Later testing may show variations in EC50 data due to variations in reagents, conditions and variations in the method(s) used from those given herein above. So this range is to be viewed as illustrative, and not a absolute set of numbers.
The foregoing examples and assay have been set forth to illustrate the invention, not limit it. What is reserved to the inventors is to be determined by reference to the claims.

Claims

What is claimed is:
1. A compound of formula (I)
Figure imgf000130_0001
wherein: R1 is hydrogen, -NR6R7, -N=CR13R14, C1-C10 alkyl, C2.Cω alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C3-C8 heterocycloalkyl, aryl, aryl Ci-Ci0 alkyl, heteroaryl or heteroaryl Ci.CiOalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, C3-C6 cycloalkylaryl, aryl Ci-Ci0 alkyl, aryl, heteroaryl or heteroaryl Q.Cioalkyl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, halo-substituted Ci-C6 alkyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, halo, cyano, nitro, -OR8, -C(O)R8, -C(O)OR8, -SR8, -S(O)R8, -S(O)2R8, -NR9R10, -CONR9R10, and -SO2NR9R10; wherein R6 and R7 are each independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl or heteroaryl group where the alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, a 3-8- membered heterocycloalkyl ring, aryl, heteroaryl, halo, cyano, nitro, -OR8, -C(O)R8, - C(O)OR8, -SR8, -S(O)R8, -S(O)2R8, -NR9R10, -CONR9R10, and -SO2NR9R10; or
R6 and R7 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen or sulphur;
R2, R3, R , and R5, are each independently selected from the group consisting of hydrogen, nitro, cyano, halo, -C(O)R8, -C(O)OR8, -OR8, -SR8, -S(O)R8, -S(O)2R8, -NR9R10, -CONR9R10, -N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10, -P(O)(OR8)2, -SO2NR9R10, -N(R9)SO2R8, Ci-Ci0 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, aryl CrCio alkyl, heteroaryl and heteroaryl Q.Cioalkyl group; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, halo, -OR8, -SR8, -NR9R10, cyano, nitro, -C(O)R8, -C(O)OR8, -S(O)R8, -S(O)2R8, protected -OH, -CONR9R10, -N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10, -P(O)(OR8)2, -SO2NR9R10, -N(R9)SO2R8, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, a 3-6- membered heterocycloalkyl ring, aryl or heteroaryl group; or
R2 and R3 form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N; R3 and R4 form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N; R4 and R5 form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N; each R8 is independently selected from the group consisting of hydrogen, C1-Ci0 alkyl,
C2-C10 alkenyl, C2-C10 alkynyl, halo C1-C4 alkyl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(C1-C4 alkyl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, aryl Ci-Ci0 alkyl, and heteroaryl C1-Cloalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of Q-C4 alkyl, halo Ci-C4 alkyl, halo, hydroxyl, -O(Cr C4 alkyl), cyano, nitro, -N(d.C4 alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(Ci-C4 alkyl)(Ci-C4 alkyl), -NHCONH(Ci-C4 alkyl),-OCON(CrC4 alkyl)(CrC4 alkyl), -OCONH(Ci-C4 alkyl),-SO2N(Ci-C4 alkyl)(CrC4 alkyl), -SO2NH(C1-C4 alkyl), -SO2(Cj-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl);
R9 and R10 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(C1-C4 alkyl), C3-C8 cycloalkyl-CrC10 alkyl, a 3-8-membered heterocycloalkyl ring-Q-Qo alkyl, aryl-CrC10 alkyl or heteroaryl-Ci-Ci0 alkyl group; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulfur, where the alkyl, cycloalkyl, heterocycloalkyl, aryl , heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl or heteroarylalkyl group or 5- or 6-membered ring is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(Ci-C4 alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl),
-CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(Ci-C4 alkyl), -NHCONH(C1- C4 alkyl), -OCON(CrC4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl),-SO2N(CrC4 alkyl)(C!-C4 alkyl), -SO2NH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); R11 is -OR12, or -NR9R10, where R12 is hydrogen, an alkali metal cation or other cationic salt-forming group, or an ester-forming group exemplified by Ci-Ci0 alkyl wherein the Ci-Ci0 alky group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl, wherein R9, and R10 are the same as defined above;
R13 and R14 are each independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, halo C1-C4 alkyl, -CO(Ci-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(Ci-C4 alkyl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6- Ci4 aryl, heteroaryl, aryl Ci-Ci0 alkyl, and heteroaryl Ci.CiOalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl group is unsubstituted or substituted on the alkyl group or the aromatic group, particularly on the aromatic group, with one or more substituents independently selected from the group consisting of C1-C4 alkyl, halo C1-C4 alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(C1-C4 alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H,
-CON(C1-C4 alkyl)(d-C4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(d-C4 alkyl)(C1-C4 alkyl), -NHCON(C1-C4 alkyl)(Ci-C4 alkyl), -NHCONH(Ci-C4 alkyl),-OCON(CrC4 alkyl)(d-C4 alkyl), -OCONH(C1-C4 alkyl),-SO2N(d-C4 alkyl)(d-C4 alkyl), -SO2NH(C1-C4 alkyl), -SO2(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein
R1 is hydrogen, -NR6R7, -N=CR6R7, Ci-Ci0 alkyl, C3-C8 cycloalkyl, aryl, aryl Ci-Ci0 alkyl, C3-C6 cycloalkylaryl, heteroaryl or heteroaryl Ci.CiOalkyl; where the alkyl, cycloalkyl, C3-C6 cycloalkylaryl, aryl, aryl Ci-C10 alkyl, heteroaryl or heteroaryl Q.Cioalky group is unsubstituted, or substituted on the alkyl group, or on the aromatic group, with one or more substituents independently selected from the group consisting of Ci-C6 alkyl, halo, halo-substituted-Ci_C6 alkyl, C3-C6 cycloalkyl, a C3-C8heterocyclic ring, aryl, heteroaryl, cyano, nitro, -C(O)R8, -C(O)OR8, -NR9R10, and -CONR9R10; wherein R6 and R7 are each independently hydrogen, Ci.Cio alkyl, or aryl Ci-Ci0 alkyl; R2 is hydrogen, C1-Ci0 alkyl, -OR8, or halo;
R3 is hydrogen, halo, -OR8, Ci-Ci0 alkyl, halo d.C4-alkyl, nitro, or NR9R10; R4 is hydrogen, -OR8, nitro, NR9R10, halo, Ci-C10 alkyl, halo Ci.C4-alkyl, -C(O)OR8; or R3 and R4 are combined to form a 3 or 4-membered heterocycloalkyl ring having 2 oxygens; R5 is hydrogen or halo; where, for R2, R3, and R4, the Ci-Ci0 alkyl group is unsubstituted or substituted or substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, halo, -OR8, -NR9R10, -C(O)R8, -C(O)OR8, protected -OH, -CONR9R10, -N(R9)C(0)R\ -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10; each R8 is independently selected from the group consisting of hydrogen, C1-Ci0 alkyl, haloCi.C4-alkyl, -CO(CrC4 alkyl), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, aryl Ci-Ci0 alkyl, and heteroaryl Ci.CiOalkyl; where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, -0(Ci-C4 alkyl), cyano, -N(Ci-C4-alkyl)(CI-C4 alkyl), -NH(Q-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(CrC4 alkyl), -CO2H, -CON(CrC4 alkyl)(CrC4 alkyl), -CONH(CrC4 alkyl), -CONH2, -N(Cx-C4 alkyl)CON(C!-C4 alkyl)(Q-C4 alkyl), -NHCON(Ci-C4 alkyl)(Ci-C4 alkyl), -NHCONH(Ci-C4 alkyl), -OCON(Ci-C4 alkyl)(Q-C4 alkyl), -OCONH(Ci-C4 alkyl), -C0(CrC4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, and aryl Ci-Ci0 alkyl group in either of the two said instances under R8 is unsubstituted or substituted with one or more of Ci-C4 alkyl, halo Ci.Gt-alkyl, halo, hydroxyl, -0(CrC4 alkyl), cyano, nitro, -N(Ci.C4-alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(Ci-C4 alkyl), -CO2H, -CON(CJ-C4 alkyl)(Ci-C4 alkyl), -CONH(CrC4 alkyl), -CONH2, -N(Q-C4 alkyl)CON(Q-C4 alkyl)(Q-
C4 alkyl), -NHCON(Q-C4 alkyl)(Q-C4 alkyl), -NHCONH(Q-C4 alkyl), -OCON(Q-C4 alkyl)(Q-C4 alkyl), -OCONH(Q-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); R9 and R10 are each independently selected from the group consisting of hydrogen, C1-Ci0 alkyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(C1-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(Q-C4 alkyl), C3-C8 cycloalkyl-Q-Q0 alkyl, a 3-8-membered heterocycloalkyl ring-Q-Qo alkyl, aryl-Ci-Cio alkyl or heteroaryl-Ci-Cio alkyl group; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulfur, where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, Ce-Ci4 aryl, heteroaryl,
-0(C1-C4 alkyl), cyano, -N(C1.C4-alkyl)(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(Ci-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(CrC4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, and aryl-Q.Qo alkyl group in either of the two said instances under R9 and R10 are unsubstituted or substituted with one or more of C1-C4 alkyl, halo C1.C4-alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(C1-C4- alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H,
-CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(Cr C4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHCONH(C1-C4 alkyl), -OCON(C1-C4 alkyl)(CrC4 alkyl), -OCONH(C1-C4 alkyl), -CO(C1-C4 alkyl), -CO(aryl) and -CO(heteroaryl); R11 is -OR12, or -NR9R10, where R12 is hydrogen, an alkali metal cation or other cationic salt-forming group, or an ester-forming group Ci-C10 alkyl wherein the Ci-C10 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl and R9, and R10 are the same as defined above; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 wherein
R1 is hydrogen, -NR6R7, -N=CR6R7, C1-C10 alkyl, cyclohexyl, or phenyl; where the C1-C10 alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, -C(O)R8, -C(O)OR8, -NR9R10, and
-CONR9R10, C3-C6 cycloalkyl, and a C3-C8heterocyclic ring, and phenyl, biphenyl, 5,6,7,8-tetrahydronaphthalenyl, imidazolyl, 1,3-thiazolyl, isoxazolyl, pyridinyl, quinoxalinyl^ or 3-dihydro-2H-isoindolyl, wherein each group is unsubstituted or subsitited with one or more substituents selected from the group consisting of C1-C10 alkyl, halo Q-Qalkyl, halo, cyano, nitro, OR8, -C(O)R8, -C(O)OR8, -NR9R10, and
-CONR9R10; wherein R6 and R7 are each independently hydrogen, Ci-Ci0 alkyl, or aryl Ci-Ci0 alkyl;
R2 is hydrogen, Ci-Ci0 alkyl, -OR8, or halo;
R3 is hydrogen, halo, -OR8, Ci-Ci0 alkyl, halo C-|.C4-alkyl, nitro, or NR9R10; R4 is hydrogen, -OR8, nitro, NR9R10, halo, Ci-Ci0 alkyl, halo C1-C4-alkyl, -C(O)OR8; or R3 and R4 are combined to form a 3 or 4-membered heterocycloalkyl ring having 2 oxygens;
R5 is hydrogen or halo; where, for R2, R3, and R4, the Ci-Ci0 alkyl group is unsubstituted or substituted or substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, halo, -OR8, -NR9R10, -C(O)R8, -C(O)OR8, protected -OH, -CONR9R10, -N(R9)C(O)R8, -N(R9)C(O)OR8, -OC(O)NR9R10, -N(R9)C(O)NR9R10; each R8 is independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, haloCi.C4-alkyl, -CO(CrC4 alkyl), -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, aryl Ci-Ci0 alkyl, and heteroaryl Ci-Ci0 alkyl; where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, C6-C]4 aryl, heteroaryl, -0(Ci-C4 alkyl), cyano, -N(Ci.C4-alkyl)(Ci-C4 alkyl), -NH(Ci-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(CrC4 alkyl), -CO2H, -CON(CrC4 alkyl)(CrC4 alkyl), -C0NH(CrC4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(CrC4 alkyl)(CrC4 alkyl), -NHC0N(CrC4 alkyl)(Ci-C4 alkyl), -NHCONH(Ci-C4 alkyl), -OCON(Ci-C4 alkyl)(CrC4 alkyl), -OCONH(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl* heteroaryl, and aryl-Ci.Cio alkyl group in either of the two said instances under R8 is unsubstituted or substituted with one or more of Ci-C4 alkyl, halo Ci.C4-alkyl, halo, hydroxyl, -0(Q-C4 alkyl), cyano, nitro, -N(Ci-C4-alkyl)(CrC4 alkyl), -NH(Ci-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(Ci-C4 alkyl), -CO2H, -CON(CrC4 alkyl)(Ci-C4 alkyl), -C0NH(CrC4 alkyl), -CONH2, -N(Ci-C4 alkyl)CON(CrC4 alkyl)(Cr C4 alkyl), -NHC0N(CrC4 alkyl)(CrC4 alkyl), -NHCONH(Ci-C4 alkyl), -OCON(Ci-C4 alkyl)(Ci-C4 alkyl), -0C0NH(CrC4 alkyl), -CO(CrC4 alkyl), -CO(aryl) and
-CO(heteroaryl);
R9 and R10 are each independently selected from the group consisting of hydrogen, Ci-Ci0 alkyl, C3-C8 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(Ci-C4 alkyl), -CO(aryl), -CO(heteroaryl), -SO2(CrC4 alkyl), C3-C8 cycloalkyl-CrCi0 alkyl, a 3-8-membered heterocycloalkyl ring-Ci-Ci0 alkyl, aryl-Ci-Qo alkyl or heteroaryl-Ci-Ci0 alkyl group; or R9 and R10 taken together with the nitrogen to which they are attached represent a 5- or 6-membered saturated ring optionally containing one other heteroatom selected from oxygen, nitrogen and sulfur, where the alkyl group is unsubstituted or substituted with one or more substituents selected from the group consisting of a 3-8-membered heterocycloalkyl ring, Ce-Ci4 aryl, heteroaryl, -0(Ci-C4 alkyl), cyano, -NCQ.GralkylXCi-Ct alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(Ci-C4 alkyl), -CO2H, -C0N(CrC4 alkyl)(CrC4 alkyl), -CONH(CrC4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(Q-C4 alkyl)(CrC4 alkyl), -NHC0N(CrC4 alkyl)(C!-C4 alkyl), -NHC0NH(CrC4 alkyl), -OCON(CrC4 alkyl)(CrC4 alkyl), -OCONH(Ci-C4 alkyl), -CO(CrC4 alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C3-C8 cycloalkyl, 3-8-membered heterocycloalkyl ring, C6-Ci4 aryl, heteroaryl, and aryl-Q.Cio alkyl group in either of the two said instances under R9 and R10 are unsubstituted or substituted with one or more of C1-C4 alkyl, halo Ci.C4-alkyl, halo, hydroxyl, -0(C1-C4 alkyl), cyano, nitro, -N(C1-C4- alkyl)(CrC4 alkyl), -NH(C1-C4 alkyl), -NH2, aryl, heteroaryl, -CO2(C1-C4 alkyl), -CO2H, -CON(C1-C4 alkyl)(CrC4 alkyl), -CONH(C1-C4 alkyl), -CONH2, -N(C1-C4 alkyl)CON(Cr
C4 alkyl)(CrC4 alkyl), -NHCON(C1-C4 alkyl)(CrC4 alkyl), -NHC0NH(CrC4 alkyl), -OCON(C1-C4 alkyl)(Ci-C4 alkyl), -0C0NH(CrC4 alkyl), -CO(Cj-C4 alkyl), -CO(aryl) and -CO(heteroaryl);
R11 is -OR12, or -NR9R10, where R12 is hydrogen, an alkali metal cation or other cationic salt-forming group, or an ester-forming group C1-Ci0 alkyl wherein the C1-C10 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting Of C3-C6 cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl and R9, and R10 are the same as defined above; or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 which is
N-[(4-hydroxy-l-methyl-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine; N~[(4-hydroxy-2-oxo- 1 ,2-dihydro-3 -quinolinyl)carbonyl] glycine; N-{[4-hydroxy-l-(3-methylbutyl)-2-oxo-l,2-dihydro-3-quinolinyl]carbonyl}glycine; N-[(4-hydroxy-2-oxo-l-phenyl-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-{[4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinyl]carbonyl}glycine; N-{[l-(cyclohexylmethyl)-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl]carbonyl}glycine; N-{[4-hydroxy-7-(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl] carbony 1 } glycine; N-({4-hydroxy-2-oxo-l-(phenylmethyl)-7-[(phenylmethyl)oxy]-l,2-dihydro-3- quinolinyl } carbony l)glycine; N-{ [4-hydroxy-7-[(l-methylethyl)oxy]-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl } glycine;
N-{ [4-hydroxy-2-oxo-l-(phenylmethyl)-7-(phenyloxy)-l,2-dihydro-3- quinolinyl]carbonyl}glycine; N-[( l-cyclohexyl-4-hydroxy-2-oxo-l ,2-dihydro-3-12quinolinyl)carbonyl]glycine;
N- { [4-hydroxy- 1 -( 1 -methylethyl)-2-oxo- 1 ,2-dihydro-3-quinolinyl] carbonyl } glycine;
N- { [ 1 -(2-cy clopropylethyl)-4-hydroxy-2-oxo- 1 ,2-dihydro-3 -quinolinyl] carbonyl } glycine;
N-{ [4-hydroxy-l-(2-methylpropyl)-2-oxo-l,2-dihydro-3-quinolinyl]carbonyl}glycme;
N-{ [4-hydroxy-l-methyl-6-(methyloxy)-2-oxo-l,2-dihydro-3-quinolinyl]carbonyl}glycine; N-({ l-[(2-bromophenyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-({ l-[(3-bromophenyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-( { 1 -[(4-bromophenyl)methyl]-4-hydroxy-2-oxo- 1 ,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-[( 1 -{ [4-( 1 , 1 -dimethylethyl)phenyl]methyl } -4-hydroxy-2-oxo-l ,2-dihydro-3- quinolinyl)carbonyl] glycine;
N-( { 4-hydroxy- 1 -[(3-nitrophenyl)methyl] -2-oxo- 1 ,2-dihydro-3 - quinolinyl }carbonyl)glycine; N-{[6-fluoro-4-hydroxy-l-(3-methylbutyl)-2-oxo-l,2-dihydro-3- quinolinyl]carbonyl}glycine;
N- { [4-hydroxy-6-[( 1 -methylethyl)oxy] -2-oxo-l -(phenylmethyl)- 1 ,2-dihydro-3- quinolinyl]carbonyl Jglycine;
N-{ [4-hydroxy-6-(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl}glycine;
N-[(4-hydroxy-5-methyl-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-[(4-hydroxy-6-methyl-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
3-{ [(carboxymethyl)amino]carbonyl}-4-hydroxy-2-oxo-l,2-dihydro-6-quinolinecarboxylic acid; N-[(6-bromo-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-[(4,6-dihydroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-[(6-chloro-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-{[4-hydroxy-l-(3-methylbutyl)-5,6-bis(methyloxy)-2-oxo-l,2-dihydro-3- quinolinyl] carbonyl } glycine; N-({ l-[(3-aminophenyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine; N-({4-hydroxy-2-oxo-l-(phenylmethyl)-6-[(phenylmethyl)oxy]-l,2-dihydro-3- quinolinyl}carbonyl)glycine;
N-{[4-hydroxy-2-oxo-l-(l,3-thiazol-4-ylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl } glycine; N- { [ 1 -(2-cyclopropylethyl)-6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3 - quinolinyl] carbony 1 } glycine;
N-( { 4-hydroxy- 1 -[(2-methyl-4-pyridinyl)methyl] -2-oxo- 1 ,2-dihydro-3 - quinolinyl}carbonyl)glycine;
N-d l-tS-Cl.S-dioxo-l^-dihydro^h-isoindol^-yDpropyU^-hydroxy^-oxo-l^-dihydro-S- quinolinyl }carbonyl)glycine;
N-({ l-[4-(l,3-dioxo-l,3-dihydro-2h-isoindol-2-yl)butyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbony l)glycine;
N-{ [ 1 -(4-aminobutyl)-4-hydroxy-2-oxo-l ,2-dihydro-3-quinolinyl]carbonyl } glycine;
N-Jtl-CS-aminopropyO^-hydroxy^-oxo-l^-dihydro-S-quinolinylJcarbonylJglycine; N-{ [4,6-dihydroxy-2-oxo-l-(phenylmethyl)-l ,2-dihydro-3 -quinolinyl] carbony 1 } glycine;
N-{[6-[(2-amino-2-oxoethyl)oxy]-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl] carbonyl } glycine;
N-[(4-hydroxy-6-iodo-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-{ [ 1 -(3-biphenylylmethyl)-4-hydroxy-2-oxo- 1 ,2-dihydro-3 -quinolinyl] carbonyl } glycine; N-({ l-[(3-cyanophenyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine; '
N-[(l-{ [3-(aminocarbonyl)phenyl]methyl}-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl)carbonyl]glycine;
N-({4-hydroxy-l-[(2-methyl-l,3-thiazol-4-yl)methyl]-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine;
N-({ l-[(3,5-dimethyl-4-isoxazolyl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-[(4-hydroxy-l-{ [3-(methyloxy)phenyl]methyl } -2-oxo-l ,2-dihydro-3- quinolinyl)carbonyl]glycine; N-[(4-hydroxy-2-oxo-l-{[3-(trifluoromethyl)phenyl]methyl}-l,2-dihydro-3- quinolinyl)carbonyl]glycme;
N-({4-hydroxy-l-[(3-hydroxyphenyl)methyl]-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-[(4-hydroxy-7-nitro-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine; N-[(7-amino-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycme; N- { [4-hydroxy-5 -(methyloxy)-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3- quinolinyl]carbonyl Jglycine;
N-l^^-dihydroxy-Z-oxo-l-Cphenylmethy^-l^-dihydro-S-quinolinyycarbonylJglycine;
N-{[l-[(3-cyanophenyl)methyl]-4-hydroxy-5-(methyloxy)-2-oxo-l,2-dihydro-3- quinolinyl]carbonyl}glycine;
N-{ [6-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl] carbonyl } glycine;
N-( { 1 -[(3-cy anophenyl)methyl] -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3 - quinolinyl }carbonyl)glycine; N-{ [4-hydroxy-6,7-bis(methyloxy)-2-oxo-l-(phenylmethyl)-l ,2-dihydro-3- quinolinyl] carbonyl Jglycine;
N-({4-hydroxy-l-[(5-methyl-3-isoxazolyl)methyl]-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-{[4-hydroxy-5,6-bis(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl}glycine;
N-( { 1 -[(2-bromophenyl)methyl] -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-{[4-hydroxy-l-[(l-methyl-lh-imidazol-2-yl)methyl]-6,7-bis(methyloxy)-2-oxo-l,2- dihydro-3-quinolinyl]carbonyl}glycine; N-{[4-hydroxy-6,7-bis(methyloxy)-2-oxo-l-(l,3-thiazol-2-ylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl}glycine;
N-[(4-hydroxy-l-methyl-6-nitro-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-{[4,6,7-trihydroxy-2-oxo-l-(l,3-thiazol-2-ylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl Iglycine; N-I^^J-trihydroxy^-oxo-l-Cphenylmethy^-l^-dihydro-S-quinolinyllcarbonylJglycine;
N-( { 6-fluoro- 1 -[(2-fluorophenyl)methyl] -4-hydroxy-2-oxo- 1 ,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-({ l-[(2-chlorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine; N-({6-fluoro-4-hydroxy-l-[(2-methylphenyl)methyl]-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-{ [4-hydroxy-2-oxo-l-(l,3-thiazol-2-ylmethyl)-l,2-dihydro-3- quinolinyl] carbonyl Jglycine;
N-{ [5 -fluoro-4-hy droxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinolinyl]carbonyl}glycine; N-{ [7-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl Jglycine;
N-{[9-hydroxy-7-oxo-6-(phenylmethyl)-2,3,6,7-tetrahydro[l,4]dioxino[2,3-g]quinolm-8- yl]carbonyl Jglycine; N-ICδ-hydroxy-ό-oxo-S-Cphenylmethy^-S.ό-dihydrotl^ldioxolo^^-gjqumolin^- yl]carbonyl}glycine;
N-{[6,7-difluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl}glycine;
N-{[4-hydroxy-6-methyl-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl] carbony 1 } glycine;
N-tCl-l^-ClJ-dimethylethyOphenylJmethylJ-ό-fluoro^-hydroxy^-oxo-l^-dihydro-S- quinolinyl)carbonyl]glycine;
N-dό-fluoro^-hydroxy^-oxo-l-CCS.S^^-tetramethyl-S^J.S-tetrahydro-Z- naphthalenyl)methyl] - 1 ,2-dihydro-3 -quinolinyl } carbonyl)glycine; N-[(6-fluoro-4-hydroxy-2-oxo-l-{ [4-(trifluoromethyl)phenyl]methyl}-l,2-dihydro-3- quinolinyl)carbonyl]glycine;
N-[( 1 -{ [2-bromo-4-( 1 , 1 -dimethylethyl)phenyl] methyl } -ό-fluoro^-hydroxy^-oxo- 1 ,2- dihydro-3-qumolinyl)carbonyl]glycine;
N-ECl-itS-Cl.l-dimethylethyOphenyUmethylJ-β-fluoro^-hydroxy^-oxo-l^-dihydro-S- quinolinyl)carbonyl]glycine;
N-({ l-[(2,4-dimethyl-l,3-thiazol-5-yl)methyl]-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-{[4-hydroxy-5,6,7-tris(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl Jglycine; N-{[6-fluoro-4-hydroxy-2-oxo-l-(5-qumoxalinylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl } glycine;
N- { [6-fluoro-4-hydroxy-2-oxo- 1 -(6-quinoxalinylmethyl)- 1 ,2-dihydro-3- quinolinyl] carbonyl } glycine;
N-{[l-{[4-(l,l-dimethylethyl)phenyl]methyl}-4-hydroxy-5-(methyloxy)-2-oxo-l,2- dihydro-3 -quinolinyl] carbonyl } glycine;
N-[(l-{ [4-(l,l-dimethylethyl)phenyl]methyl}-4,5-dihydroxy-2-oxo-l,2-dihydro-3- quinolinyl)carbonyl] glycine;
N-( { 1 -[(2,6-dichlorophenyl)methyl] -ό-fluoro^-hydroxy^-oxo- 1 ,2-dihydro-3 - quinolinyl } carbony l)glycine; N-[(l-{[4-(l,l-dimethylethyl)phenyl]methyl}-6,7-difluoro-4-hydroxy-2-oxo-l,2-dihydro-
3-quinolinyl)carbonyl]glycine; N-[( 1 -{ [2-bromo-4-( 1 , 1 -dimethy lethyl)phenyl]methy 1 } -6,7-difluoro-4-hydroxy-2-oxo- 1,2- dihydro-3-quinolinyl)carbonyl]glycine;
N-[( 1 - { [4-( 1 , 1 -dimethylethyl)phenyl]methyl } ^-fluoro^-hydroxy^-oxo- 1 ,2-dihy dro-3- quinolinyl)carbonyl]glycine; N-[(l-{[2-bromo-4-(l,l-dimethylethyl)phenyl]methyl}-7-fluoro-4-hydroxy-2-oxo-l,2- dihydro-3-quinolinyl)carbonyl]glycine;
N-{ [l-(2-cyclopentylethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl]carbonyl } glycine;
N-{[l-(2-cyclohexylethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl]carbonyl } glycine;
N-{[l-(2-cyclohexylethyl)-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl]caxbonyl}glycine;
N-({ l-[(2-chlorophenyl)methyl]-7-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-({ l-[(2,6-dichlorophenyl)methyl]-7-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolmyl}carbonyl)glycme;
N-[(7-chloro- 1 -{ [4-( 1 , 1 -dimethy lethyl)phenyl]methyl } -4-hydroxy-2-oxo- 1 ,2-dihy dro-3 - quinolinyl)carbonyl] glycine;
N-{[4-hydroxy-7-nitro-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl] carbonyl } glycine; N-( { 4-hydroxy-2-oxo-l -[(phenylmethyl)amino] - 1 ,2-dihy dro-3 - quinolinyl }carbonyl)glycine;
N-[(l-amino-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyl]glycine;
N-[(4-hydroxy-2-oxo 1 - { [( lE)-phenylmethylidene] amino } - 1 ,2-dihy dro-3- quinolinyl)carbonyl]glycine; N-( { 4-hydroxy- 1 -[( 1 -methylethylidene)amino] -2-oxo- 1 ,2-dihy dro-3 - quinolinyl}carbonyl)glycme;
N-( { 4-hydroxy- 1 -[( 1 -methylethyl)amino] -2-oxo-l ,2-dihy dro-3- quinolinyl}carbonyl)glycine;
N-[( 1 -{ [4-( 1 , l-dimethylethyl)phenyl]methyl }-4-hydroxy-7-methyl-2-oxo-l ,2-dihydro-3- quinolmyl)carbonyl]glycine;
N- { [8-fluoro-4-hydroxy-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinolinyl] carbonyl } glycine;
N-{[l-{ [4-(l,l-dimethylethyl)phenyl]methyl}-4-hydroxy-2-oxo-7-(trifluoromethyl)-l,2- dihydro-3-quinolinyl]carbonyl}glycine; N-{ [l-(5,5-dimethylhexyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl] carbonyl } glycine; N-{[6-fluoro-4-hydroxy-2-oxo-l-(3-phenylpropyl)-l,2-dihydro-3- quinolinyl]carbonyl }glycine;
N-{[6-fluoro-4-hydroxy-2-oxo-l-(2-phenylethyl)-l,2-dihydro-3- quinolinyl]carbonyl}glycine; N-lfl-CS^-dimethylbuty^-o-fluoro^-hydroxy^-oxo-l^-dihydro-S- quinolinyl]carbonyl } glycine;
N-({ l-[(2-chloro-4-fluorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-( { 1 -[(2-chloro-5 -fluorophenyl)methyl] -β-fluoro^-hydroxy^-oxo- 1 ,2-dihydro-3- quinolinyl } carbonyl)gly cine;
N-({ l-[(2,5-dichlorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-{ [7-amino-4-hydroxy-2-oxo-l-(phenylmethyl)-l ,2-dihydro-3- quinolinyl] carbonyl } glycine; N-{ [l-(4,4-dimethylpentyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl]carbony 1 } glycine;
N-({ l-[(2,3-difluorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine;
N-({6-fluoro-4-hydroxy-2-oxo-l-[(2,3,4-trifluorophenyl)methyl]-l,2-dihydro-3- quinolinyl }carbonyl)glycine;
N-[(6-chloro-l -{ [4-( 1 , 1 -dimethylethyl)phenyl]methyl } -4-hydroxy-2-oxo-l ,2-dihydro-3- quinolinyl)carbony 1] glycine;
N-( { 6-chloro- 1 -[(2-chlorophenyl)methyl] -4-hydroxy-2-oxo- 1 ,2-dihydro-3- quinolinyl }carbonyl)glycine; N-({ l-[(2,6-difluorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-( { 6-fluoro-4-hydroxy-2-oxo-l -[(2,4,6-trifluorophenyl)methyl] -1 ,2-dihydro-3- quinolinyl}carbonyl)glycine;
N-({l-[(2-chloro-6-fluorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine;
N-({ l-[(4-chloro-2-fluorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine;
N-{ [4-hydroxy-6-(4-methyl- 1 -ρiperazinyl)-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinolinyl] carbonyl } glycine; N-({6-fluoro-4-hydroxy-l-[(4-methylphenyl)methyl]-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine; N-Cl l-fCZ^-dimethylpheny^methylJ-ό-fluoro^-hydroxy-l-oxo-l^-dihydro-S- quinolinyl } carbonyl)glycine;
N-({ l-[(2,5-difluorophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl}carbonyl)glycine; N-[(l-{[3,5 -bis(trifluoromethyl)phenyl]methyl } -ό-fluoro^-hydroxy^-oxo- 1 ,2-dihydro-3 - quinolinyl)carbonyl] glycine;
N-{[6-(dimethylamino)-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl }glycine;
N- { [4-hydroxy-6-(4-morpholinyl)-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihy dro-3 - quinolinyl]carbonyl}glycine;
N-({ l-[(4-bromophenyl)methyl]-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl } carbonyl)glycine;
N-{[l-(4-biphenylylmethyl)-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl] carbonyl } glycine; N-( { 1 -[(3 ,4-difluorophenyl)methyl] -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihydro-3 - quinolinyl } carbonyl)glycine;
N-( { 1 -[(3 ,5-difluorophenyl)methyl] -6-fluoro-4-hydroxy-2-oxo- 1 ,2-dihy dro-3 - quinolinyl } carbonyl)glycine;
N-[(6-fluoro-4-hy droxy-2-oxo- 1 - { [2-(trifluoromethyl)phenyl]methyl } - 1 ,2-dihy dro-3 - quinolinyl)carbonyl]glycine;
N-[(l-{[2,4-bis(trifluoromethyl)phenyl]methyl}-6-fluoro-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl)carbonyl]glycine;
N-tCό-fluoro-l-lfS-fluoro^-Ctrifluoromethy^phenyymethylJ^-hydroxy^-oxo-l^- dihydro-3-quinolinyl)caxbonyl]glycine; N-[(6-fluoro-l -{ [4-fluoro-2-(trifluoromethyl)phenyl]methyl } -4-hydroxy-2-oxo- 1 ,2- dihydro-3 -quinolinyl)carbonyl] glycine;
N-{[l-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-7-(trifluoromethyl)-l,2-dihydro-3- quinolinyl] carbonyl } glycine;
N- { [ 1 -{ [4-( 1 , 1 -dimethylethyl)phenyl]methyl } -4-hydroxy-6-(4-morpholinyl)-2-oxo-l ,2- dihydro-3 -quinolinyl] carbonyl } glycine;
N-{[l-[(2-chlorophenyl)methyl]-4-hydroxy-6-(4-morpholinyl)-2-oxo-l,2-dihydro-3- quinolinyl]carbonyl } glycine;
N-{[l-[(2-chlorophenyl)methyl]-6-(dimethylamino)-4-hydroxy-2-oxo-l,2-dihydro-3- quinolinyl]carbonyl } glycine; N-[(6-(dimethylamino)-l-{ [4-(l,l-dimethylethyl)phenyl]methyl}-4-hydroxy-2-oxo-l,2- dihydro-3-quinolinyl)carbonyl]glycine; N-{ [ 1 - { [4-( 1 , 1 -dimethylethyl)phenyl]methyl } -4-hydroxy-2-oxo-6-(trifluoromethyl)- 1,2- dihydro-3-quinolinyl]carbonyl}glycine;
N-{[l-[(2-chlorophenyl)methyl]-4-hydroxy-2-oxo-6-(trifluoromethyl)-l,2-dihydro-3- quinolinyl]carbonyl Jglycine; N-(2-amino-2-oxoethyl)-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinecarboxamide;
N- { [4-hydroxy-6-nitro-2-oxo- 1 -(phenylmethyl)- 1 ,2-dihydro-3 - quinolinyl] carbonyl } glycine;
N-{[6-amino-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3- quinolinyl]carbonyl } glycine;
N-{[6-fluoro-4-hydroxy-2-oxo-l-(2-oxo-2-phenylethyl)-l,2-dihydro-3- qumolinyl]carbonyl}glycine; or a pharmaceutically acceptable salt or solvate thereof.
5. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
6. A method for treating anemia comprising administering a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof, neat or admixed with a pharmaceutically acceptable excipient, in an amount sufficient to increase production of Epo.
7. A method for preparing compounds of formula (I) according to claim 1, comprising the steps of heating a mixture of an isatoic anhydride derivative with a malonate diester in the presence of an appropriate base, such as l,8-diazabicyclo[5.4.0]undec-7-ene or sodium hydride, under either conventional thermal conditions or by microwave irradiation, followed by the addition of glycine and further heating.
8. A method for preparing compounds of formula (I) according to claim 1, comprising the step of heating a solution of a 4-hydroxy-2-oxo-l,2-dihydro-3-quinolinecarboxylate ester derivative and glycine sodium salt or glycine with an_appropriate base, such as l,8-diazabicyclo[5.4.0]undec- 7-ene, sodium ethoxide or sodium hydride, under either conventional thermal conditions or by microwave irradiation.
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Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007070359A3 (en) * 2005-12-09 2008-04-03 Amgen Inc Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
WO2008062859A1 (en) * 2006-11-22 2008-05-29 Ajinomoto Co., Inc. Process for production of phenylalanine derivatives having quinazolinedione skeletons and intermediates for the production
WO2008130600A3 (en) * 2007-04-18 2009-02-19 Amgen Inc Quinolones and azaquinolones that inhibit prolyl hydroxylase
WO2008137084A3 (en) * 2007-05-04 2009-02-26 Amgen Inc Diazaquinolones that inhibit prolyl hydroxylase activity
WO2009041072A1 (en) 2007-09-27 2009-04-02 Kowa Company, Ltd. Prophylactic and/or therapeutic agent for anemia, comprising tetrahydroquinoline compound as active ingredient
WO2009073669A1 (en) 2007-12-03 2009-06-11 Fibrogen, Inc. Isoxazolopyridine derivatives for use in the treatment of hif-mediated conditions
US7569726B2 (en) 2007-04-18 2009-08-04 Amgen Inc. Indanone derivatives that inhibit prolyl hydroxylase
WO2009100250A1 (en) * 2008-02-05 2009-08-13 Fibrogen, Inc. Chromene derivatives and use thereof as hif hydroxylase activity inhibitors
US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
EP2136810A1 (en) * 2007-04-18 2009-12-30 Merck & Co., Inc. Novel 1,8-naphthyridine compounds
WO2010022307A3 (en) * 2008-08-21 2010-04-22 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
WO2010056767A1 (en) * 2008-11-14 2010-05-20 Fibrogen, Inc. Thiochromene derivatives as hip hydroxylase inhibitors
WO2010113498A1 (en) 2009-03-31 2010-10-07 興和株式会社 Prophylactic and/or therapeutic agent for anemia comprising tetrahydroquinoline compound as active ingredient
US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
EP2240178A1 (en) * 2007-12-19 2010-10-20 GlaxoSmithKline LLC Prolyl hydroxylase inhibitors
JP2011513221A (en) * 2008-02-25 2011-04-28 メルク・シャープ・エンド・ドーム・コーポレイション Tetrahydroflopyridone
CN102164905A (en) * 2009-07-15 2011-08-24 北京贝美拓新药研发有限公司 Compounds as hypoxia mimetics, and compositions, and uses thereof
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8217043B2 (en) 2008-08-20 2012-07-10 Fibrogen, Inc. Compounds and methods for their use
KR20120088711A (en) 2009-10-21 2012-08-08 다이이찌 산쿄 가부시키가이샤 5-hydroxypyrimidine-4-carboxamide derivative
WO2012106472A1 (en) 2011-02-02 2012-08-09 Fibrogen, Inc. Naphthyridine derivatives as inhibitors of hypoxia inducible factor (hif) hydroxylase
WO2012110789A1 (en) 2011-02-15 2012-08-23 Isis Innovation Limited Method for assaying ogfod1 activity
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
WO2013014449A1 (en) 2011-07-28 2013-01-31 Isis Innovation Limited Assay for histidinyl hydroxylase activity
US8372857B2 (en) 2009-06-30 2013-02-12 Merck Sharp & Dohme Corp. Substituted 4-hydroxypyrimidine-5-carboxamides
CN102964301A (en) * 2012-11-26 2013-03-13 盛世泰科生物医药技术(苏州)有限公司 Method for synthesizing IOX2
WO2014021281A1 (en) 2012-07-30 2014-02-06 大正製薬株式会社 Partially saturated nitrogen-containing heterocyclic compound
US8759345B2 (en) 2008-04-28 2014-06-24 Janssen Pharmaceutica Nv Benzoimidazoles as prolyl hydroxylase inhibitors
WO2014102818A1 (en) * 2012-12-24 2014-07-03 Cadila Healthcare Limited Novel quinolone derivatives
US8815865B2 (en) 2009-06-30 2014-08-26 Merck Sharp & Dohme Corp. Substituted 4-hydroxypyrimidine-5-carboxamides
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US8952160B2 (en) 2008-01-11 2015-02-10 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
US8962598B2 (en) 2010-10-14 2015-02-24 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators
US9034851B2 (en) 2011-09-23 2015-05-19 Merck Sharp & Dohme Corp. Substituted pyrimidines
US9079930B2 (en) 2011-09-23 2015-07-14 Merck Sharp & Dohme Corp. Substituted pyrimidines
CN105294648A (en) * 2015-11-30 2016-02-03 山东罗欣药业集团股份有限公司 Preparation method of sitafloxacin
US9273034B2 (en) 2011-10-25 2016-03-01 Janssen Pharmaceutica Nv Meglumine salt formulations of 1-(5,6-dichloro-1H-benzo[D]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid
CN105384687A (en) * 2014-09-02 2016-03-09 广东东阳光药业有限公司 Quinolinone compound and application thereof in drugs
WO2016045127A1 (en) * 2014-09-28 2016-03-31 Merck Sharp & Dohme Corp. Inhibitors of hif prolyl hydroxylase
CN108069952A (en) * 2016-11-08 2018-05-25 广东东阳光药业有限公司 It quinolinones compound and its is applied in drug
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10000501B2 (en) * 2014-09-28 2018-06-19 Merck Sharp & Dohme Corp. Inhibitors of HIF prolyl hydroxylase
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
CN111269177A (en) * 2019-11-28 2020-06-12 南北兄弟药业投资有限公司 Crystal forms of quinolinone compounds
CN112851581A (en) * 2019-11-28 2021-05-28 广东东阳光药业有限公司 Crystal form of quinolinone compound and application thereof
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
CN115010664A (en) * 2021-03-05 2022-09-06 广东东阳光药业有限公司 Crystal form of quinolinone compound and application thereof
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4738971A (en) * 1981-03-03 1988-04-19 Aktiebolaset Leo N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamides
US20030153503A1 (en) * 2001-12-06 2003-08-14 Klaus Stephen J. Methods of increasing endogenous erythropoietin (EPO)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4738971A (en) * 1981-03-03 1988-04-19 Aktiebolaset Leo N-aryl-1,2-dihydro-4-substituted-1-alkyl-2-oxo-quinoline-3-carboxamides
US20030153503A1 (en) * 2001-12-06 2003-08-14 Klaus Stephen J. Methods of increasing endogenous erythropoietin (EPO)

Cited By (130)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006326662B2 (en) * 2005-12-09 2011-07-28 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
WO2007070359A3 (en) * 2005-12-09 2008-04-03 Amgen Inc Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
US8012968B2 (en) 2005-12-09 2011-09-06 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
JP2009519249A (en) * 2005-12-09 2009-05-14 アムジエン・インコーポレーテツド Quinolone-based compounds exhibiting prolyl hydroxylase inhibitory activity, and compositions thereof and uses thereof
US7728130B2 (en) 2005-12-09 2010-06-01 Amgen Inc. Quinolone based compounds exhibiting prolyl hydroxylase inhibitory activity
US8017626B2 (en) 2005-12-09 2011-09-13 Amgen Inc. Quinolone based compounds exhibiting, prolyl hydroxylase inhibitory activity, and compositions, and uses thereof
US8050873B2 (en) 2006-03-07 2011-11-01 Warner Chilcott Company Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US8512972B2 (en) 2006-03-07 2013-08-20 Akebia Therapeutics, Inc. Crystal of hypoxia inducible factor 1 alpha prolyl hydroxylase
US11883386B2 (en) 2006-06-26 2024-01-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US9598370B2 (en) 2006-06-26 2017-03-21 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8343952B2 (en) 2006-06-26 2013-01-01 Akebia Therapeutics Inc. Prolyl hydroxylase inhibitors and methods of use
US11426393B2 (en) 2006-06-26 2022-08-30 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US10729681B2 (en) 2006-06-26 2020-08-04 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8940773B2 (en) 2006-06-26 2015-01-27 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8722895B2 (en) 2006-06-26 2014-05-13 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and method of use
USRE47437E1 (en) 2006-06-26 2019-06-18 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US7811595B2 (en) 2006-06-26 2010-10-12 Warner Chilcott Company, Llc Prolyl hydroxylase inhibitors and methods of use
US8598210B2 (en) 2006-06-26 2013-12-03 Akebia Therapeutics, Inc. Prolyl hydroxylase inhibitors and methods of use
US8323671B2 (en) 2006-06-26 2012-12-04 Akebia Therapeutics Inc. Prolyl hydroxylase inhibitors and methods of use
US8058432B2 (en) 2006-11-22 2011-11-15 Ajinomoto Co., Inc. Method for preparing phenylalanine derivatives having quinazoline-dione skeleton and intermediates for use in the preparation of derivatives
WO2008062859A1 (en) * 2006-11-22 2008-05-29 Ajinomoto Co., Inc. Process for production of phenylalanine derivatives having quinazolinedione skeletons and intermediates for the production
US8546610B2 (en) 2006-11-22 2013-10-01 Ajinomoto Co., Inc. Method for preparing phenylalanine derivatives having quinazoline-dione skeleton and intermediates for use in the preparation of the derivatives
US7928139B2 (en) 2006-12-18 2011-04-19 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US8048892B2 (en) 2006-12-18 2011-11-01 Amgen Inc. Azaquinolone based compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
US7635715B2 (en) 2006-12-18 2009-12-22 Amgen Inc. Naphthalenone compounds exhibiting prolyl hydroxylase inhibitory activity, compositions, and uses thereof
JP2010524935A (en) * 2007-04-18 2010-07-22 メルク・シャープ・エンド・ドーム・コーポレイション Novel 1,8-naphthyridine compounds
US8349868B2 (en) 2007-04-18 2013-01-08 Amgen Inc. Azaquinolones that inhibit prolyl hydroxylase
EP2136810A1 (en) * 2007-04-18 2009-12-30 Merck & Co., Inc. Novel 1,8-naphthyridine compounds
US8048894B2 (en) 2007-04-18 2011-11-01 Amgen Inc. Quinolones and azaquinolones that inhibit prolyl hydroxylase
AU2008241483B2 (en) * 2007-04-18 2011-03-24 Amgen Inc. Quinolones and azaquinolones that inhibit prolyl hydroxylase
US7569726B2 (en) 2007-04-18 2009-08-04 Amgen Inc. Indanone derivatives that inhibit prolyl hydroxylase
WO2008130600A3 (en) * 2007-04-18 2009-02-19 Amgen Inc Quinolones and azaquinolones that inhibit prolyl hydroxylase
EP2136810A4 (en) * 2007-04-18 2012-01-04 Merck Sharp & Dohme Novel 1,8-naphthyridine compounds
US8030346B2 (en) 2007-05-04 2011-10-04 Amgen Inc. Heterocyclic quinolone derivatives that inhibit prolyl hydroxylase activity
WO2008137084A3 (en) * 2007-05-04 2009-02-26 Amgen Inc Diazaquinolones that inhibit prolyl hydroxylase activity
US8097620B2 (en) 2007-05-04 2012-01-17 Amgen Inc. Diazaquinolones that inhibit prolyl hydroxylase activity
WO2009041072A1 (en) 2007-09-27 2009-04-02 Kowa Company, Ltd. Prophylactic and/or therapeutic agent for anemia, comprising tetrahydroquinoline compound as active ingredient
WO2009073669A1 (en) 2007-12-03 2009-06-11 Fibrogen, Inc. Isoxazolopyridine derivatives for use in the treatment of hif-mediated conditions
EP2240178A4 (en) * 2007-12-19 2011-10-26 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
EP2240178A1 (en) * 2007-12-19 2010-10-20 GlaxoSmithKline LLC Prolyl hydroxylase inhibitors
US8952160B2 (en) 2008-01-11 2015-02-10 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
US9387200B2 (en) 2008-01-11 2016-07-12 Fibrogen, Inc. Isothiazole-pyridine derivatives as modulators of HIF (hypoxia inducible factor) activity
US8324405B2 (en) 2008-02-05 2012-12-04 Fibrogen, Inc. Chromene derivatives and use thereof as HIF hydroxylase activity inhibitors
WO2009100250A1 (en) * 2008-02-05 2009-08-13 Fibrogen, Inc. Chromene derivatives and use thereof as hif hydroxylase activity inhibitors
JP2011513221A (en) * 2008-02-25 2011-04-28 メルク・シャープ・エンド・ドーム・コーポレイション Tetrahydroflopyridone
US10851083B2 (en) 2008-04-28 2020-12-01 Janssen Pharmaceutica Nv Benzoimidazoles as prolyl hydroxylase inhibitors
US9073923B2 (en) 2008-04-28 2015-07-07 Janssen Pharmaceutica Nv Benzoimidazoles as prolyl hydroxylase inhibitors
US8865713B2 (en) 2008-04-28 2014-10-21 Janssen Pharmaceutica Nv Benzoimidazoles as prolyl hydroxylase inhibitors
US11618744B2 (en) 2008-04-28 2023-04-04 Janssen Pharmaceutica Nv Benzoimidazoles as prolyl hydroxylase inhibitors
US8759345B2 (en) 2008-04-28 2014-06-24 Janssen Pharmaceutica Nv Benzoimidazoles as prolyl hydroxylase inhibitors
US8217043B2 (en) 2008-08-20 2012-07-10 Fibrogen, Inc. Compounds and methods for their use
WO2010022307A3 (en) * 2008-08-21 2010-04-22 Glaxosmithkline Llc Prolyl hydroxylase inhibitors
CN102272117A (en) * 2008-11-14 2011-12-07 菲布罗根有限公司 Thiochromene derivatives as hip hydroxylase inhibitors
WO2010056767A1 (en) * 2008-11-14 2010-05-20 Fibrogen, Inc. Thiochromene derivatives as hip hydroxylase inhibitors
AU2009314155B2 (en) * 2008-11-14 2015-10-08 Fibrogen, Inc. Thiochromene derivatives as HIF hydroxylase inhibitors
CN105037323A (en) * 2008-11-14 2015-11-11 菲布罗根有限公司 Thiochromene derivatives as HIF hydroxylase inhibitors
WO2010113498A1 (en) 2009-03-31 2010-10-07 興和株式会社 Prophylactic and/or therapeutic agent for anemia comprising tetrahydroquinoline compound as active ingredient
US8791090B2 (en) 2009-03-31 2014-07-29 Kowa Company, Ltd. Prophylactic and/or therapeutic agent for anemia comprising tetrahydroquinoline compound as active ingredient
JP5572154B2 (en) * 2009-03-31 2014-08-13 興和株式会社 A prophylactic and / or therapeutic agent for anemia comprising a tetrahydroquinoline compound as an active ingredient
US9045423B2 (en) 2009-03-31 2015-06-02 Kowa Company, Ltd. Prophylactic and/or therapeutic agent for anemia comprising tetrahydroquinoline compound as active ingredient
US8815865B2 (en) 2009-06-30 2014-08-26 Merck Sharp & Dohme Corp. Substituted 4-hydroxypyrimidine-5-carboxamides
US8372857B2 (en) 2009-06-30 2013-02-12 Merck Sharp & Dohme Corp. Substituted 4-hydroxypyrimidine-5-carboxamides
CN102164905B (en) * 2009-07-15 2014-04-30 北京贝美拓新药研发有限公司 Compounds as hypoxia mimetics, and compositions, and uses thereof
CN102164905A (en) * 2009-07-15 2011-08-24 北京贝美拓新药研发有限公司 Compounds as hypoxia mimetics, and compositions, and uses thereof
US8785462B2 (en) 2009-10-21 2014-07-22 Daiichi Sankyo Company, Limited 5-hydroxypyrimidine-4-carboxamide derivative
KR20120088711A (en) 2009-10-21 2012-08-08 다이이찌 산쿄 가부시키가이샤 5-hydroxypyrimidine-4-carboxamide derivative
US8536181B2 (en) 2009-11-06 2013-09-17 Aerpio Therapeutics Inc. Prolyl hydroxylase inhibitors
US9540326B2 (en) 2009-11-06 2017-01-10 Aerpio Therapeutics, Inc. Prolyl hydroxylase inhibitors
US8309537B2 (en) 2009-11-06 2012-11-13 Aerpio Therapeutics Inc. Compositions and methods for treating colitis
US9045495B2 (en) 2009-11-06 2015-06-02 Aerpio Therapeutics Inc. Prolyl hydroxylase inhibitors
US8999971B2 (en) 2009-11-06 2015-04-07 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US10562854B2 (en) 2009-11-06 2020-02-18 Aerpio Therapeutics, Inc. Prolyl hydroxylase inhibitors
US8883774B2 (en) 2009-11-06 2014-11-11 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US9278930B2 (en) 2009-11-06 2016-03-08 Aerpio Therapeutics, Inc. Methods for increasing the stabilization of hypoxia inducible factor-α
US8778412B2 (en) 2009-11-06 2014-07-15 Aerpio Therapeutics Inc. Methods for increasing the stabilization of hypoxia inducible factor-1 alpha
US8962598B2 (en) 2010-10-14 2015-02-24 Immunahr Ab 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators
WO2012106472A1 (en) 2011-02-02 2012-08-09 Fibrogen, Inc. Naphthyridine derivatives as inhibitors of hypoxia inducible factor (hif) hydroxylase
WO2012110789A1 (en) 2011-02-15 2012-08-23 Isis Innovation Limited Method for assaying ogfod1 activity
US8865748B2 (en) 2011-06-06 2014-10-21 Akebia Therapeutics Inc. Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer
US10738010B2 (en) 2011-06-06 2020-08-11 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US10246416B2 (en) 2011-06-06 2019-04-02 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino] alkanoic acids, esters and amides
US11267785B2 (en) 2011-06-06 2022-03-08 Akebia Therapeutics, Inc. Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
WO2013014449A1 (en) 2011-07-28 2013-01-31 Isis Innovation Limited Assay for histidinyl hydroxylase activity
US9079930B2 (en) 2011-09-23 2015-07-14 Merck Sharp & Dohme Corp. Substituted pyrimidines
US9034851B2 (en) 2011-09-23 2015-05-19 Merck Sharp & Dohme Corp. Substituted pyrimidines
US9273034B2 (en) 2011-10-25 2016-03-01 Janssen Pharmaceutica Nv Meglumine salt formulations of 1-(5,6-dichloro-1H-benzo[D]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid
US10807969B2 (en) 2011-10-25 2020-10-20 Janssen Pharmaceutica Nv Meglumine salt formulations of 1-(5,6-dichloro-1h-benzo[d]imidazol-2-yl)-1h-pyrazole-4-carboxylic acid
US9708298B2 (en) 2011-10-25 2017-07-18 Janssen Pharmaceutica Nv Meglumine salt formulations of 1-(5,6-dichloro-1H-benzo[D]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid
US9422240B2 (en) 2012-07-30 2016-08-23 Taisho Pharmaceutical Co., Ltd Partially saturated nitrogen-containing heterocyclic compound
KR20150036219A (en) 2012-07-30 2015-04-07 다이쇼 세이야꾸 가부시끼가이샤 Partially saturated nitrogen-containing heterocyclic compound
WO2014021281A1 (en) 2012-07-30 2014-02-06 大正製薬株式会社 Partially saturated nitrogen-containing heterocyclic compound
CN102964301A (en) * 2012-11-26 2013-03-13 盛世泰科生物医药技术(苏州)有限公司 Method for synthesizing IOX2
CN104903295B (en) * 2012-12-24 2017-09-01 卡迪拉保健有限公司 Carbostyril derivative
TWI598339B (en) * 2012-12-24 2017-09-11 卡地拉保健有限公司 Novel quinolone derivatives
EA028402B1 (en) * 2012-12-24 2017-11-30 Кадила Хелзкэр Лимитед Quinolone derivatives
JP2016503052A (en) * 2012-12-24 2016-02-01 カディラ・ヘルスケア・リミテッド New quinolone derivatives
AU2013368843B2 (en) * 2012-12-24 2016-02-25 Zydus Lifesciences Limited Novel quinolone derivatives
US9394300B2 (en) 2012-12-24 2016-07-19 Cadila Healthcare Limited Quinolone derivatives
KR101733901B1 (en) 2012-12-24 2017-05-08 카딜라 핼쓰캐어 리미티드 Novel quinolone derivatives
WO2014102818A1 (en) * 2012-12-24 2014-07-03 Cadila Healthcare Limited Novel quinolone derivatives
CN104903295A (en) * 2012-12-24 2015-09-09 卡迪拉保健有限公司 Novel quinolone derivatives
US11857543B2 (en) 2013-06-13 2024-01-02 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US9987262B2 (en) 2013-11-15 2018-06-05 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11065237B2 (en) 2013-11-15 2021-07-20 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10149842B2 (en) 2013-11-15 2018-12-11 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US11690836B2 (en) 2013-11-15 2023-07-04 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10596158B2 (en) 2013-11-15 2020-03-24 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid, compositions, and uses thereof
US10065928B2 (en) * 2014-09-02 2018-09-04 Sunshine Lake Pharma Co., Ltd. Quinolinone compound and use thereof
WO2016034108A1 (en) * 2014-09-02 2016-03-10 广东东阳光药业有限公司 Quinolinone compound and use thereof
CN105384687A (en) * 2014-09-02 2016-03-09 广东东阳光药业有限公司 Quinolinone compound and application thereof in drugs
AU2015311333B2 (en) * 2014-09-02 2017-11-16 Sunshine Lake Pharma Co., Ltd. Quinolinone compound and use thereof
JP2017525737A (en) * 2014-09-02 2017-09-07 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Quinolinone compounds and their use in drugs
US10000501B2 (en) * 2014-09-28 2018-06-19 Merck Sharp & Dohme Corp. Inhibitors of HIF prolyl hydroxylase
WO2016045127A1 (en) * 2014-09-28 2016-03-31 Merck Sharp & Dohme Corp. Inhibitors of hif prolyl hydroxylase
US10961200B2 (en) 2014-12-29 2021-03-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US11247971B2 (en) 2014-12-29 2022-02-15 The Trustees Of The University Of Pennsylvania Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US10150734B2 (en) 2015-01-23 2018-12-11 Akebia Therapeutics, Inc. Solid forms of 2-(5-(3-fluorophenyl)-3-hydroxypicolinamido)acetic acid, compositions, and uses thereof
US11324734B2 (en) 2015-04-01 2022-05-10 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
US11844756B2 (en) 2015-04-01 2023-12-19 Akebia Therapeutics, Inc. Compositions and methods for treating anemia
CN105294648A (en) * 2015-11-30 2016-02-03 山东罗欣药业集团股份有限公司 Preparation method of sitafloxacin
CN108069952A (en) * 2016-11-08 2018-05-25 广东东阳光药业有限公司 It quinolinones compound and its is applied in drug
CN108069952B (en) * 2016-11-08 2022-09-27 广东东阳光药业有限公司 Quinolinone compound and application thereof in medicines
US11713298B2 (en) 2018-05-09 2023-08-01 Akebia Therapeutics, Inc. Process for preparing 2-[[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino]acetic acid
US11524939B2 (en) 2019-11-13 2022-12-13 Akebia Therapeutics, Inc. Solid forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino} acetic acid
CN112851581A (en) * 2019-11-28 2021-05-28 广东东阳光药业有限公司 Crystal form of quinolinone compound and application thereof
CN111269177B (en) * 2019-11-28 2023-05-09 广东东阳光药业有限公司 Crystal forms of quinolinone compounds
CN112851581B (en) * 2019-11-28 2022-08-12 广东东阳光药业有限公司 Crystal form of quinolinone compound and application thereof
CN111269177A (en) * 2019-11-28 2020-06-12 南北兄弟药业投资有限公司 Crystal forms of quinolinone compounds
CN115010664A (en) * 2021-03-05 2022-09-06 广东东阳光药业有限公司 Crystal form of quinolinone compound and application thereof

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