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

wherein:

R ¹ is hydrogen, -NR ⁶ R ⁷ , -N=CR ¹³ R ¹⁴ , C _1- C ₁₀ alkyl, C _2- C ₁₀ alkenyl, C _2- C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, C ₃ -C ₈ heterocycloalkyl, aryl, aryl Ci-C ₁₀ alkyl, heteroaryl or heteroaryl Q.Cioalkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, C ₃ -C ₆ cycloalkylaryl, aryl Ci-Ci ₀ alkyl, aryl, heteroaryl or heteroaryl Ci.Ci _O alkyl 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-C ₆ alkyl, halo-substituted Ci-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, halo, cyano, nitro, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ , -SR ⁸ , -S(O)R ⁸ , -S(O) ₂ R ⁸ , -NR ⁹ R ¹⁰ , -CONR ⁹ R ¹⁰ , and -SO ₂ NR ⁹ R ¹⁰ ; wherein R ⁶ and R ⁷ are each independently selected from the group consisting of hydrogen, Ci-C ₁₀ alkyl, C _2- Ci ₀ alkenyl, C _2- Ci ₀ alkynyl, C ₃ -C ₈ 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-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, halo, cyano, nitro, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ , -SR ⁸ , -S(O)R ⁸ , -S(O) ₂ R ⁸ , -NR ⁹ R ¹⁰ , -CONR ⁹ R ¹⁰ , and -SO ₂ NR ⁹ R ¹⁰ ; or

R ⁶ and R ⁷ 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;

R ² , R ³ , R ⁴ , and R ⁵ , are each independently selected from the group consisting of hydrogen, nitro, cyano, halo, -C(O)R ⁸ , -C(O)OR ⁸ , -OR ⁸ , -SR ⁸ , -S(O)R ⁸ , -S(O) ₂ R ⁸ , -NR ⁹ R ¹⁰ , -CONR ⁹ R ¹⁰ , -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )C(O)OR ⁸ , -OC(O)NR ⁹ R ¹⁰ , -N(R ⁹ )C(O)NR ⁹ R ¹⁰ , -P(O)(OR ⁸ ) ₂ , -SO ₂ NR ⁹ R ¹⁰ , -N(R ⁹ )SO ₂ R ⁸ , C ₁ -Ci ₀ alkyl, C ₂ -Ci ₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, aryl Ci-Ci ₀ alkyl, heteroaryl and heteroaryl Ci.C ₁₀ alkyl 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-C ₆ alkyl, Q-C ₆ haloalkyl, aryl, heteroaryl, halo, -OR ⁸ , -SR ⁸ , -NR ⁹ R ¹⁰ , cyano, nitro, -C(O)R ⁸ , -C(O)OR ⁸ , -S(O)R ⁸ , -S(O) ₂ R ⁸ , protected -OH, -CONR ⁹ R ¹⁰ , -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )C(O)OR ⁸ , -OC(O)NR ⁹ R ¹⁰ , -N(R ⁹ )C(O)NR ⁹ R ¹⁰ , -P(O)(OR ⁸ ) ₂ , -SO ₂ NR ⁹ R ¹⁰ , -N(R ⁹ )SO ₂ R ⁸ , C ₂ -Ci ₀ alkenyl, C ₂ -Ci ₀ alkynyl, C ₃ -C ₆ cycloalkyl, a 3-6-membered heterocycloalkyl ring, aryl or heteroaryl group; or R ² and R ³ form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N;

R ³ and R ⁴ form a 3-6-membered heterocycloalkyl ring containing 1 or 2 of O, S or N; R ⁴ and R ⁵ 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-C ₁₀ alkyl, C ₂ -C ₁₀ alkeαyl, C ₂ .C, ₀ alkynyl, halo C _1- C ₄ alkyl, -CO(C _r C ₄ alkyl), -CO(aryl), -CO(heteroaryl), -SO ₂ (C ₁ -C ₄ alkyl), C ₃ -Cg cycloalkyl, a 3-8-membered heterocycloalkyl ring, C ₆ -Ci ₄ 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-C ₄ alkyl, halo Ci-C ₄ alkyl, halo, hydroxyl, -0(Ci-C ₄ alkyl), cyano, nitro, -N(Ci-C ₄ alkyl)(C _r C ₄ alkyl), -NH(Q-C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C _r C ₄ alkyl), -CO ₂ H, -C0N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -CONH(Ci-C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(Ci-C ₄ alkyl),-OCON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C _r C ₄ alkyl),-SO ₂ N(Ci-C ₄ alkyl)(C _r C ₄ alkyl), -SO ₂ NH(Ci-C ₄ alkyl), -SO ₂ (Ci-C ₄ alkyl), -CO(Ci-C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, Ci-Qo alkyl, C ₃ -C ₈ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -C0(Q-C ₄ alkyl), -CO(aryl), -CO(heteroaryl), -SO ₂ (Ci-C ₄ alkyl), C ₃ -C ₈ cycloalkyl-Ci-C ₁₀ alkyl, a 3-8-membered heterocycloalkyl ring-Ci-C ₁₀ alkyl, aryl-Q-Cio alkyl or heteroaryl-Q-Qo alkyl group; or R ⁹ and R ¹⁰ 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-C ₄ alkyl, Ci-C ₄ haloalkyl, halo, hydroxyl, -0(Ci-C ₄ alkyl), cyano, nitro,

-N(Ci-C ₄ alkyl)(Ci-C ₄ alkyl), -NH(C _r C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (Ci-C ₄ alkyl), -CO ₂ H, -CON(Ci-C ₄ alkyl)(Ci-C ₄ alkyl), -CONH(Ci-C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHC0N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C _r C ₄ alkyl), -0C0N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(Ci-C ₄ alkyl),-SO ₂ N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -SO ₂ NH(Ci-C ₄ alkyl), -CO(C ₁ -C ₄ alkyl), -CO(aryl) and -CO(heteroaryl);

R ¹¹ is -OR ¹² , or -NR ⁹ R ¹⁰ , where R ¹² is hydrogen, an alkali metal cation or other cationic salt- forming group, or an ester-forming group exemplified by C _1- C ₁₀ alkyl wherein the C _1- C ₁₀ alky group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C _1- C ₆ alkyl, C ₃ -C ₆ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl, wherein R ⁹ , and R ¹⁰ are the same as defined above;

R ¹³ and R ¹⁴ are each independently selected from the group consisting of hydrogen, C _1- C ₁₀ alkyl, C _2- C ₁₀ alkenyl, C _2- Ci ₀ alkynyl, halo C _1- C ₄ alkyl, -CO(C ₁ -C ₄ alkyl), -CO(aryl), -CO(heteroaryl),

-SO ₂ (Ci-C ₄ alkyl), C ₃ -C ₈ cycloalkyl, a 3-8-membered heterocycloalkyl ring, C ₆ -C ₁₄ aryl, heteroaryl, aryl C _1- Ci ₀ alkyl, and heteroaryl Ci.C ₁₀ alkyl; 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 C ₁ -C ₄ alkyl, halo C _1- C ₄ alkyl, halo, hydroxyl, -0(C ₁ -C ₄ alkyl), cyano, nitro, -N(C _1- C ₄ alkyl)(d-C ₄ alkyl), -NH(C ₁ - C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(d- C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C ₁ -C ₄ alkyl)(C ₁ -C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyl)(d-C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl),-0C0N(d-C ₄ alkyl)(Ci-C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl),-SO2N(d-C ₄ alkyl)(d-C ₄ alkyl), -SO ₂ NH(C ₁ -C ₄ alkyl), -SO ₂ (C ₁ -C ₄ alkyl), -CO(C ₁ -C ₄ 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.C ₄ -alkyl" and "C _1- C ₁₀ 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-C ₄ 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 "C ₃ -C ₈ cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "C ₃ - C ₈ cycloalkyl" groups useful in the present invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term " C ₅ -C ₈ cycloalkenyl" 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: R ¹ is hydrogen, -NR ⁶ R ⁷ , -N=CR ⁶ R ⁷ , Ci-Ci ₀ alkyl, C ₃ -C ₈ cycloalkyl, aryl, aryl Ci-Ci ₀ alkyl,

C ₃ -C ₆ cycloalkylaryl, heteroaryl or heteroaryl Q.Qoalkyl; where the alkyl, cycloalkyl, C ₃ -C ₆ cycloalkylaryl, aryl, aryl Ci-Ci ₀ 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 C _1- C ₆ alkyl, halo, halo-substituted-Ci_C ₆ alkyl, C ₃ -C ₆ cycloalkyl, a

C ₃ -C ₈ heterocyclic ring, aryl, heteroaryl, cyano, nitro, -C(O)R ⁸ , -C(O)OR ⁸ , -NR ⁹ R ¹⁰ , and -CONR ⁹ R ¹⁰ ; wherein R ⁶ and R ⁷ are each independently hydrogen, Ci-Ci ₀ alkyl, or aryl C _1- Ci ₀ alkyl; R ² is hydrogen, Ci-Ci ₀ alkyl, -OR ⁸ , or halo; R ³ is hydrogen, halo, -OR ⁸ , Ci-Ci ₀ alkyl, halo Ci_C ₄ -alkyl, nitro, or NR ⁹ R ¹⁰ ;

R ⁴ is hydrogen, -OR ⁸ , nitro, NR ⁹ R ¹⁰ , halo, Ci-C ₁₀ alkyl, halo Ci.C ₄ -alkyl, -C(O)OR ⁸ ; or R ³ and R ⁴ are combined to form a 3 or 4-membered heterocycloalkyl ring having 2 oxygens;

R ⁵ is hydrogen or halo; where, for R ² , R ³ , and R ⁴ , the C _1- C ₁₀ alkyl group is unsubstituted or substituted or substituted with one or more substituents independently selected from the group consisting of aryl,

heteroaryl, halo, -OR ⁸ , -NR ⁹ R ¹⁰ , -C(O)R ⁸ , -C(O)OR ⁸ , protected -OH, -CONR ⁹ R ¹⁰ , -N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )C(O)OR ⁸ , -OC(O)NR ⁹ R ¹⁰ , -N(R ⁹ )C(O)NR ⁹ R ¹⁰ ; each R ⁸ is independently selected from the group consisting of hydrogen, Ci-Ci ₀ alkyl, haloCi.C ₄ -alkyl, -CO(Ci -C ₄ alkyl), -CO(aryl), -CO(heteroaryl), C ₃ -C ₈ cycloalkyl, a 3-8-membered heterocycloalkyl ring, C ₆ -Ci ₄ 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-Ci ₄ aryl _> heteroaryl, -0(C ₁ -C ₄ alkyl), cyano, -N(Ci-C ₄ -alkyl)(C _r C ₄ alkyl), -NH(Ci-C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C _r C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(Ci-C ₄ alkyl), -CONH ₂ , -N(Ci-C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHC0N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl), -CO(Ci-C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C ₃ -C ₈ cycloalkyl, 3-8-membered heterocycloalkyl ring, C ₆ -Ci ₄ aryl, heteroaryl, and aryl Ci-Ci ₀ alkyl group in either of the two said instances under R ⁸ is unsubstituted or substituted with one or more of C ₁ -C ₄ alkyl, halo

Q.Q-alkyl, halo, hydroxyl, -0(C ₁ -C ₄ alkyl), cyano, nitro, -N(C ₁ .C ₄ -alkyl)(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyiχC _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl), -C0(C _r C ₄ alkyl), -CO(aryl) and -CO(heteroaryl);

R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(C ₁ -C ₄ alkyl), -CO(aryl), -CO(heteroaryl), -SO ₂ (C ₁ -C ₄ alkyl), C ₃ -C ₈ cycloalkyl-C _r C ₁₀ alkyl, a 3-8-membered heterocycloalkyl ring-Ci-C ₁₀ alkyl, aryl-C _r C ₁₀ alkyl or heteroary 1-Ci-Ci ₀ alkyl group; or R ⁹ and R ¹⁰ 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, C ₆ -Ci ₄ aryl, heteroaryl, -0(C ₁ -C ₄ alkyl), cyano, alkyl), -NH(Ci-C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (Ci-C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C _r C ₄ alkyl),

-CONH ₂ , -N(Ci-C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(Q-C ₄ alkyl), -OCON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(Ci-C ₄ alkyl), -CO(Ci-C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C ₃ -C ₈ cycloalkyl, 3-8-membered heterocycloalkyl ring, C ₆ -Ci ₄ aryl, heteroaryl, and aryl-QAo alkyl group in either of the two said instances under R ⁹ and R ¹⁰ are unsubstituted or substituted with one or more of C ₁ -C ₄ alkyl, halo C _1- C ₄ -alkyl, halo, hydroxyl, -Q(C ₁ -C ₄ alkyl), cyano, nitro, -N(C ₁ .C ₄ -alkyl)(C ₁ -C ₄

alkyl), -NH(Ci-C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -C0N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl), -CO(C ₁ -C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); R ¹¹ is -OR ¹² , or -NR ⁹ R ¹⁰ , where R ¹² is hydrogen, an alkali metal cation or other cationic salt- forming group, or an ester-forming group C _1- C ₁₀ alkyl wherein the C _1- C ₁₀ alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C ₃ -C ₆ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl and R ⁹ , and R ¹⁰ are the same as defined above; or a pharmaceutically acceptable salt thereof.

A further subset of compounds of interest are those where:

R ¹ is hydrogen, -NR ⁶ R ⁷ , -N=CR ⁶ R ⁷ , Ci-C ₁₀ alkyl, cyclohexyl, or phenyl; where the C _1- C ₁₀ alkyl is unsubstituted or substituted with one or more substituents selected from the group consisting of halo, cyano, -C(O)R ⁸ , -C(O)OR ⁸ , -NR ⁹ R ¹⁰ , and -CONR ⁹ R ¹⁰ , C ₃ -C ₆ cycloalkyl, and a C ₃ -C ₈ heterocyclic 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 C _1- C ₁₀ alkyl, halo Q-Qalkyl, halo, cyano, nitro, OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ , -NR ⁹ R ¹⁰ , and -CONR ⁹ R ¹⁰ ; wherein R ⁶ and R ⁷ are each independently hydrogen, C _1- C ₁₀ alkyl, or aryl C _1- Ci ₀ alkyl; R ² is hydrogen, C _1- C ₁₀ alkyl, -OR ⁸ , or halo;

R ³ is hydrogen, halo, -OR ⁸ , Ci-Ci ₀ alkyl, halo nitro, or NR ⁹ R ¹⁰ ; R ⁴ is hydrogen, -OR ⁸ , nitro, NR ⁹ R ¹⁰ , halo, Ci-Ci ₀ alkyl, halo dA-alkyl, -C(O)OR ⁸ ; or R ³ and R ⁴ are combined to form a 3 or 4-membered heterocycloalkyl ring having 2 oxygens;

R ⁵ is hydrogen or halo; where, for R ² , R ³ , and R ⁴ , the Ci-Ci ₀ alkyl group is unsubstituted or substituted or substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, halo, -OR ⁸ , -NR ⁹ R ¹⁰ , -C(O)R ⁸ , -C(O)OR ⁸ , protected -OH, -CONR ⁹ R ¹⁰ ,

-N(R ⁹ )C(O)R ⁸ , -N(R ⁹ )C(O)OR ⁸ , -OC(O)NR ⁹ R ¹⁰ , -N(R ⁹ )C(O)NR ⁹ R ¹⁰ ; each R ⁸ is independently selected from the group consisting of hydrogen, Ci-Ci ₀ alkyl, haloCi.Q-alkyl, -CO(C ₁ -C ₄ alkyl), -CO(aryl), -CO(heteroaryl), C ₃ -C ₈ cycloalkyl, a 3-8-membered heterocycloalkyl ring, C ₆ -C ₁₄ aryl, heteroaryl, aryl Ci-Ci ₀ alkyl, and heteroaryl C _1- Ci ₀ 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, C ₆ -Ci ₄ aryl, heteroaryl, -0(Ci-C ₄ alkyl), cyano, -N(C _1- C ₄ -alkyl)(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH ₂ , aryl,

heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl), -CO(C ₁ -C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C ₃ -C ₈ cycloalkyl, 3-8-membered heterocycloalkyl ring, C ₆ -C ₁₄ aryl, heteroaryl, and aryl-Q.Qo alkyl group in either of the two said instances under R ⁸ is unsubstituted or substituted with one or more of C ₁ -C ₄ alkyl, halo C _1- C ₄ -alkyl, halo, hydroxyl, -0(C ₁ -C ₄ alkyl), cyano, nitro, -N(Ci.C ₄ -alkyl)(C _r C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -CON(C _X -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C ₁ -C ₄ alkyl),

-NHCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl), -CO(C ₁ -C ₄ alkyl), -CO(aryl) and -CO(heteroaryl);

R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, heteroaryl, -CO(C ₁ -C ₄ alkyl), -CO(aryl), -CO(heteroaryl), -SO ₂ (C ₁ -C ₄ alkyl), C ₃ -C ₈ cycloalkyl-Q-Qo alkyl, a 3-8-membered heterocycloalkyl rmg-Q-Cjo alkyl, aryl-Q-Qo alkyl or heteroaryl-Q-Cio alkyl group; or R ⁹ and R ¹⁰ 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, C ₆ -C ₁₄ aryl, heteroaryl,

-0(C ₁ -C ₄ alkyl), cyano, -N(C _1- C ₄ -alkyl)(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHC0N(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(Cj-C ₄ alkyl), -CO(C ₁ -C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); and the -CO(aryl), -CO(heteroaryl), C ₃ -C ₈ cycloalkyl, 3-8-membered heterocycloalkyl ring, C ₆ -C ₁₄ aryl, heteroaryl, and aryl-Q.Qo alkyl group in either of the two said instances under R ⁹ and R ¹⁰ are unsubstituted or substituted with one or more of C ₁ -C ₄ alkyl, halo Q.Q-alkyl, halo, hydroxyl, -0(C ₁ -C ₄ alkyl), cyano, nitro, -N(C ₁ .C ₄ -alkyl)(C ₁ -C ₄ alkyl), -NH(C ₁ -C ₄ alkyl), -NH ₂ , aryl, heteroaryl, -CO ₂ (C ₁ -C ₄ alkyl), -CO ₂ H, -CON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -CONH(C ₁ -C ₄ alkyl), -CONH ₂ , -N(C ₁ -C ₄ alkyl)CON(C _r C ₄ alkyl)(C _r C ₄ alkyl), -NHCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -NHCONH(C ₁ -C ₄ alkyl), -OCON(C ₁ -C ₄ alkyl)(C _r C ₄ alkyl), -OCONH(C ₁ -C ₄ alkyl), -CO(C ₁ -C ₄ alkyl), -CO(aryl) and -CO(heteroaryl); R ¹¹ is -OR ¹² , or -NR ⁹ R ¹⁰ , where R ¹² is hydrogen, an alkali metal cation or other cationic salt- forming group, or an ester-forming group C _1- C _1O alkyl wherein the C _1- C ₁₀ alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of

C ₃ -C ₆ cycloalkyl, a 3-8-membered heterocycloalkyl ring, aryl, or heteroaryl and R ⁹ , and R ¹⁰ 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

a) Diethyl malonate, DBU, 1,4-dioxane, 150 ⁰ C, microwave then glycine, 200 ⁰ C, microwave.

Scheme 2

a) NaB(OAc) ₃ , AcOH, R ¹ CHO, room temperature; b) CH(CO ₂ Et) ₃ , 1,4-dioxane, 250 ⁰ C, microwave; c) NaH, R' CH ₂ X, DMF then diethyl malonate, NaH, 150 ⁰ C, microwave; d) glycine, DBU, EtOH, 180 ⁰ C, microwave or glycine sodium salt, EtOH, 150-180 ⁰ C, 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

ν-r( ^" 4-Hydroxy-l-methyl-2-oxo-l,2-dihydro-3-quinolinyl')carbonyng lvcine 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 150 ⁰ C 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 200 ⁰ C 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%). ¹ H NMR (400 MHz, DMSCW ₆ ) 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

N-r(4-Hvdroxy-2-oxo-l,2-dihydro-3-quinolinyl)carbonyllglvcin e

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 ⁰ C 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 ⁰ C 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 MgSO ₄ , filtered, concentrated in vacuo, and triturated with ethyl acetate to give the title compound as a light brown solid (0.136 g; 26%). ¹ H NMR (400 MHz, DMSO-J ₆ ) 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

N-I F4-Hvdroxy-l-(3-methylbutyl)-2-oxo-l,2-dihvdro-3-quinolinyll carbonyl| 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. ¹ H NMR (400 MHz, DMSO-J ₆ ) 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

N-r^-Hvdroxy^-oxo-l-phenyl-l^-dihvdro-S-quinolinvDcarbony llglvcine

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. ¹ H NMR (400 MHz, DMSO-J ₆ ) 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]+.

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. ¹ H NMR (400 MHz, DMSO-J ₆ ) 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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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-qumolinync arbonyl|glycine A mixture of ethyl 4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quinolinecarb oxylate (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 ⁰ C for 2 minutes followed by 150 ⁰ C 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 CH ₂ Cl ₂ , and concentrated in vacuo to afford the title compound as a white solid (5.00 g, 90%). ¹ H 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 ⁰ C 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 10 ⁰ C. 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%). ¹ H 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-quinolinecarb oxylate 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 ⁰ C 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 ⁰ C 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 ⁰ C 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. ¹ H 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-quinolinecarb oxylate (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. ¹ H νMR (400 MHz, DMSO-J ₆ ) 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 ⁰ C. C ₁₉ Hi ₆ N ₂ O ₅ requires: %C, 64.71; %H, 4.54; %N, 7.95; found: %C, 64.74; %H, 4.14; %N, 7.48.

Example 6

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. ¹ H 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

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 CH ₂ Cl ₂ (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 CH ₂ Cl ₂ . The organic layer was dried over MgSO ₄ , 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%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 250 ⁰ C 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%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 ⁰ C for 20 min. in a Biotage Initiator microwave synthesizer. The mixture was concentrated and purified via flash chromatography (0-10% methanol in CH ₂ Cl ₂ ) to afford the title compound as a grey solid (0.095 g, 80%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H NMR (400 MHz, CDCl ₃ ) 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. ¹ H NMR (400 MHz, CDCl ₃ ) 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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSO-J ₆ ) 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

N-ir4-Hvdroxy-7-r(l-methylethyl)oxy1-2-oxo-l-(phenylmethy l)-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. ¹ H NMR (400 MHz, CDCl ₃ ) 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-d ihvdro-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 ⁰ C 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%). ¹ H NMR (400 MHz, DMS(W ₆ ) 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] ⁺ .

N-IK-Hvdroxy^-oxo-l-CphenylmethylVT-CplienyloxyVl^-dihvdr o-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. ¹ H NMR (400 MHz, CDCl ₃ ) 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. ¹ H NMR (400 MHz, CDCl ₃ ) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-rd-Cvclohexyl-4-hydroxy-2-oxo-1.2-dihvdro-3-12qumolinyl)ca rbonyllglvcine

1 Ia) Ethyl l-cvclohexyl-4-hvdroxy-2-oxo-l,2-dihydro-3-quinolinecarboxyl ate 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 ⁰ C 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)car bonyllglvcine 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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-quinolmvnca rbonyl}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. ¹ H

NMR (400 MHz, DMSO-J ₆ ) 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

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. ¹ H NMR (400 MHz, DMSO-J ₆ ) 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

N-{ r4-hydroxy-l-(2-methylpropyl)-2-oxo-1.2-dihvdro-3-quinolmync arbonyllglycine

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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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-quinolinvn carbonyl) 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-( r4-hydroxy-l-methyl-6-(methyloxy')-2-oxo-l,2-dihvdro-3-quino linyncarbonyl}glycine a') Ethyl 4-hydroxy-l-methyl-6-(methyloxy)-2-oxo-l,2-dihydro-3-quinolm ecarboxylate 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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-qumoli nyllcarbonyl|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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-({ l-[(2-bromophenyl ^' )methyll-4-hydroxy-2-oxo-l,2-dihydro-3-quinolinyllcarbonyl)g lycme a) Ethyl l-r(2-bromophenyl)methyll-4-hvdroxy-2-oxo-l,2-dihvdro-3-quin olinecarboxylate 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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-({ l-r(3-bromophenyl)methyn-4-hydroxy-2-oxo-l,2-dihvdro-3-quino linyl)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 ⁰ C 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 ⁰ C 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

N-d l-rf4-bromophenyl ^' )methyn-4-hvdτoxy-2-oxo-l,2-dihvdro-3-qumolinyllcarbonyl)gl vcme

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 ⁰ C 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 200 ⁰ C 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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 ⁰ C 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 ⁰ C. 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-di hvdro-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 ⁰ C 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 < 20 ⁰ C for 30 min. after complete addition. A solution of l-{ [4-(l,l- dimethylethyl)phenyl]methyl}-2H-3,l-benzoxazine-2,4(lH)-dion e (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 ⁰ C for 16 h. The heating was then removed and the reaction mixture allowed to cool to ~ 60 ⁰ C 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-dihv dro-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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ⁰ C. C ₂₃ H ₂₄ N ₂ O ₅ requires: %C, 67.33; %H, 5.92; %N, 6.86; found: %C, 67.01; %H, 5.82; %N, 6.64.

Example 20

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-I rό-fluoro^-hydroxy-l-CS-methylbutyD^-oxo-l^-dihydro-S-quino linyllcarbonyl) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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. ¹ H 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-d ihydro-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). ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

N-U4-hydro}cy-6-(methyloxyV2-oxo-l-(ρhenylmethylVl,2-dih vdro-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. ¹ H

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-f(4-hydrQxy-5-methyl-2-oxo-l,2-dihydro-3-qumolinyl)carb onyllglycine

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 150 ⁰ C 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 ⁰ C 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%). ¹ H NMR (400 MHz, OMSO-U ₆ ) 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

N-[(4-hvdroxy-6-methyl-2-oxo-l,2-dihydro-3-quinolinyl)car bonyllglvcme

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

3-{f(carboxymethyl)aminolcarbonyl)-4-hydroxy-2-oxo-l,2-di hydro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-r(6-bromo-4-hvdroxy-2-oxo-l,2-dihydro-3-quinolinyl)carb onyllglvcine

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ HNMR (400 MHz, DMSOd ₆ ) 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]+.

N-(| l-f(3-aminophenyDmethyn-4-hvdroxy-2-oxo-l,2-dihvdro-3-qumoli nyπcarbonyDglvcine

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 MgSO ₄ , filtered, concentrated in vacuo, and triturated with ethyl acetate to give the title compound as a beige solid (0.047 g, 73%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-d ihvdro-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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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-L 2-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 150 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-(ri-(2-cvclopropylethyl)-6-fluoro-4-hvdroxy-2-oxo-l,2-d ihydro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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 ⁰ C 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 ⁰ C. 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 ⁰ C for 20 h. The mixture was allowed to cooled to 60 ⁰ C, 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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. 200-202 ⁰ C. C ₁₇ H ₁₇ FN ₂ O ₅ requires: %C, 58.62; %H, 4.92; %N, 8.04; found: %C, 58.32; %H, 4.96; %N, 7.89. Example 35

N-({4-hydroxy-l-r(2-methyl-4-pyridmyl)methyll-2-oxo-l,2-d ihydro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-({ l-f3-(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)propyll-4-hydro xy-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-r( l-r4-(l,3-dioxo-1.3-dihvdro-2H-isoindol-2-yl')butyll-4-hvdro xy-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-{rϊ-(4-aminobutyl)-4-hydroxy-2-oxo-1.2-dihvdro-3-quino linyllcarbonyllglycine

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). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-quinolin yllcarbonyllglvcine 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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 ⁰ C 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-d ihvdro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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 ⁰ C 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-({ l-r(3-cvanophenyl)methyll-4-hvdroxy-2-oxo-l,2-dihvdro-3-quin olinyllcarbonyl)glycine

44a) Ethyl l-[(3-cvanophenyl)methyll-4-hydroxy-2-oxo-l,2-dihvdro-3-quin olinecarboxylate Following the procedure of Example 16a), except substituting 3-cyanobenzyl bromide for 2- bromobenzyl bromide, the title compound was obtained as a white solid. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 MgSO ₄ , filtered, concentrated in vacuo to afford the title compound as an off-white solid (0.063 g, 88%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-dihy dro-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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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-d ihydro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-dih ydro-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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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-dihv dro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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-dihy dro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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]+.

N-r(4-hydroxy-7-nitro-2-oxo-1.2-dihydro-3-quinolinyl)carb onvnglycine

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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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)carbonvng lycine 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 ⁰ C 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)carbo nvnglvcine

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 ⁰ C 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)carbonv n 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 ⁰ C 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-ir4-hydroxy-5-(methyloxy)-2-oxo-l-(phenylmethyl)-l,2-di hvdro-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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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-dihydr o-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. ¹ H 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-dihyd ro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 MgSO ₄ , 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%). ¹ H 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-dihv dro-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 ⁰ C for 1 h in a Biotage Initiator microwave synthesizer. The resulting precipitate was filtered and washed with Et ₂ O to afford the title compound as a light yellow solid (0.279 g, 62%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-dihvdr o-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. ¹ H 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-d ihvdro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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)be nzoic 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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 ⁰ C 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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 ⁰ C 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 Et ₂ O. Purification via flash column chromatography (60% ethyl acetate in hexanes) afforded the title compound as a pale orange solid (0.023 g, 30%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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 Hz ₅ 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-dihvd ro-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. ¹ H

NMR (400 MHz, DMSOd ₆ ) 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

N-{ r4-hvdroxy-l-r(l-methyl-lH-imidazol-2-yl)methyll-6,7-bis(met hyloxy)-2-oxo-l,2-dihvdro-3- quinolinyll carbonyl I glycine

62a) N-r(l-methyl-lH-imidazol-2-yl)methyll-3,4-bis(methyloxy)anil ine 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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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(m ethyloxy)-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-ylmet hyl)-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 Et ₂ O. ¹ H NMR (400 MHz, DMSOd ₆ ) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 ⁰ C) 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%). ¹ H 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

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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-dihyd ro-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. ¹ H 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-d ihydro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-(l l-r(2-chlorophenyl)methyl1-6-fluoro-4-hydroxy-2-oxo-1.2-dihy dro-3- quinolinyl }carbonyl)glycine

68a) Ethyl l-r(2-chlorophenyl)methyll-6-fluoro-4-hvdroxy-2-oxo-l,2-dihv dro-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. ¹ H 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 ⁰ C 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 ⁰ C, 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 80 ⁰ C. After stirring 20 min. at 80 ⁰ C, the reaction mixture was further heated to 150 ⁰ C 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%). ¹ H 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-dihv dro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-d ₆ ) 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

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-dihyd ro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-{ [4-hydroxy-2-oxo-l-(l,3-thiazol-2-ylmethylVl,2-dihydro-3-qui nolmvncarbonyl|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. ¹ H 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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-i rS-fluoro^-hvdroxy^-oxo-l-CphenylmethylVl.Z-dihydro-S-quinol inyllcarbonyl) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-i r7-fluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-qui nolinyl1carbonyl)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. ¹ H NMR (400

MHz, DMSOd ₆ ) 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-quino linecarboxylate 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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-{ r9-hvdroxy-7-oxo-6-(phenylmethyl)-2,3,6,7-tetrahydrori,41dio xinor2,3-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 CH ₂ Cl ₂ (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 MgSU ₄ , filtered, and concentrated in vacuo to afford the title compound as a dark oil (2.40 g, 99%). ¹ H NMR (400 MHz, METHANOL-d ₄ ) 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 ⁾ Eth ^y l 9-hvdroxy-7-oxo-6-(phenylmethylV2.3.6.7-tetrahvdrori.41dioxi nor2.3- 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.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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-tetrahvdrorL41diox inor2,3-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 180 ⁰ C 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-{r8-hydroxy-6-oxo-5-(phenybxιethyl)-5,6-dihvdrorL31dioxol or4,5-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). ¹ H NMR (400 MHz, METHANOL-d ₄ ) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-{r6,7-difluoro-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dih vdro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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. ¹ H 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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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-quino linecarboxylate 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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-o xo-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. ¹ H 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-d ihvdro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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^-tetr ahydro-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-tetrahydronaphth alene for 2- bromobenzyl bromide, the title compound was obtained as a light orange solid. ¹ H 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)glyci ne

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-r(l-{ r2-bromo-4-(l,l-dimethylethyl)phenynmethyll-6-fluoro-4-hvdro xy-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-r(l-{ r3-(l.l-dimethylethyl)phenyllmethyll-6-fluoro-4-hvdroxy-2-ox o-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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, METHANOL-d ₄ ) 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 Et ₂ 0, 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 MgSO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-d ihvdro-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 ⁰ C 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%). ¹ H NMR (400 MHz, METHANOL-d ₄ ) 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-d ihvdro-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 160 ⁰ C 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 Et ₂ O to afford the title compound as a pale yellow solid (0.017 g, 32%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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

⁰ C 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%). ¹ H 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 ⁰ C 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 Et ₂ O. 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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.

¹ H NMR (400 MHz, METHANOL-d ₄ ) 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-dihvd ro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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 ⁰ C for 20 min. followed by 200 ⁰ C for 30 min. followed by 220 ⁰ C 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-{ ri-ir4-(lJ-dimethylethyl)phenyllmethyl}-4-hvdroxy-5-(methylo xy)-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. ¹ H 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. ¹ H

NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-(( l-[(2,6-dichlorophenyl)methvn-6-fluoro-4-hvdroxy-2-oxo-l,2-d ihydro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

quinolinvDcarbonyll glycine 90a) Ethyl 1-1 ri-bromo^-d.l-dimethylethvDphenyllmethyD-βJ-difluoro^-hvdro xy^-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-r(l-ir4-q,l-dimethylethyl')phenvnmethyll-7-fluoro-4-hyd roxy-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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-rCl-i r2-bromo-4-(l,l-dimethylethyl)phenynmethyll-7-fluoro-4-hvdro xy-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 ⁰ C, 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 MgSO ₄ , filtered, and concentrated in vacuo to afford the title compound as an off-white solid (0.838 g, 97%). ¹ H NMR (400 MHz, METHANOL-d ₄ ) 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 Et ₂ O, 5.68 mmol). The resulting turbid yellow solution was stirred overnight at ambient temperature. Additional lithium aluminum hydride (3.78 mL, IM solution in Et ₂ O, 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 MgSO ₄ , filtered, and concentrated in vacuo to afford the title compound as a clear yellow oil (0.650 g, 83%). ¹ H 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 150 ⁰ C 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-(ri-(2-cvclohexylethyl)-6-fluoro-4-hydroxy-2-oxo-1.2-dihyd ro-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 ⁰ C 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 MgSO ₄ , 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%). ¹ H 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 MgSO ₄ , 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-{ri-(2-cvclohexylethyl)-4-hydroxy-2-oxo-l,2-dihydro-3-q uinolinyl]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 150 ⁰ C 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%). ¹ H NMR (400 MHz, METHANOL-d ₄ ) 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-qumolinec arboxylate 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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-(f l-r(2-chlorophenyl)methyll-7-fluoro-4-hydroxy-2-oxo-l,2-dihv dro-3- quinolinyllcarbonyDglycine

96a) Ethyl l-[(2-chlorophenyl)methvn-7-fluoro-4-hydroxy-2-oxo-l,2-dihvd ro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-d ihydro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-r(7-chloro-l-i r4-α,l-dimethylethyl)phenyllmethyπ-4-hydroxy-2-oxo-L2-dihv dro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-i r4-hvdroxy-7-nitro-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quin olinvncarbonyl}glycine

99a) Ethyl 4-hydroxy-7-nitro-2-oxo-l-(phenylmethγlVL2-dihvdro-3-quinol mecarboxylate 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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%). ¹ H 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 ⁰ C 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 MgSO ₄ , filtered, concentrated in vacuo to afford the title compound as a pale yellow solid (0.100 g, 92%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-rd-amino^-hydroxy^-oxo-l^-dihydro-S-qumolinvDcarbonyllg lycme

A mixture of ethyl 4-hydroxy-2-oxo-l-{[(lE)-phenylmethylidene]amino}-l,2-dihydr o-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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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+.

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-quinolinecarbox ylate (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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 MgSO ₄ , filtered, and concentrated in vacuo to afford the title compound as a white solid (0.046 g, 91%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-F(I-I f4-(l,l-dimethylethyl)phenyllmethyll-4-hydroxy-7-methyl-2-ox o-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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-o xo-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. ¹ H 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-met hyl-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 MgSO ₄ , 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 MgSO ₄ , filtered, and concentrated in vacuo to afford the title compound as an amber oil (0.125 g, 16%). ¹ H 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-quin olinecarboxylate 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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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-(trifl uoromethylV 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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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

MgSO ₄ , filtered and concentrated in vacuo to afford the title compound as a clear yellow oil (0.750 g, 100%). ¹ H 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 Et ₂ O, 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 ⁰ C and treated with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate. The combined organic phases were dried over MgSO ₄ , filtered, and concentrated in vacuo to afford the title compound as a yellow oil (0.563 g, 80%). ¹ H 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 220 ⁰ C 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-dihvdr o-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-ir6-fluoro-4-hvdroxy-2-oxo-l-(3-phenylpropyl)-1.2-dihvd ro-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. ¹ H 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. ¹ H 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 ⁰ C 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-i r6-fluoro-4-hvdroxy-2-oxo-l-(2-phenylethyl)-l,2-dihydro-3-qu inolinyllcarbonyllglycine 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. ¹ H 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-qui nolmecarboxylate

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 ⁰ C 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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]+.

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. ¹ H 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 Et ₂ O, 8.73 mmol) at 0 ⁰ C.

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 MgSO ₄ , filtered, and concentrated in vacuo to afford the title compound as a clear oil (0.658 g, 85%). ¹ H 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 ⁰ C 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%. ¹ H 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 ⁰ C 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). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-C( l-r(2.5-dichlorophenyl)methvn-6-fluoro-4-hydroxy-2-oxo-L2-di hvdro-3- quinolinyllcarbonvDglvcine 114a) Ethyl l-r(2,5-dichlorophenyl)methyn-6-fluoro-4-hvdroxy-2-oxo-1.2-d ihvdro-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. ¹ H 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, DMSOd ₆ ) 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

N-i r7-amino-4-hydroxy-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quin olinyllcarbonyl|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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺

N-iri-^^-dimethylpentvD-β-fluoro^-hydroxy^-oxo-L∑-dihv dro-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. ¹ H 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). ¹ H 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 ⁰ C for 30 min. followed by 240 ⁰ C 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%). ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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-d ihydro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

N-dό-fluoro^-hvdroxy^-oxo-l-rCσ.S^-trifluorophenvDmethy ll-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. ¹ H 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)methv n-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-dihy dro-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. ¹ H 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-d ihydro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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]+.

N-( ^" { l-r( ^" 2,6-difluorophenyl)methyn-6-fluoro-4-hydτoxy-2-oxo-L2-dihyd ro-3- quinolinyl ) carbonyDgrycine

121a) Ethyl l-rfZ.β-difluorophenvDmethvn-ό-fluoro^-hydroxy^-oxo-l.l-di hvdro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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] ⁺ .

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-dihv dro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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-d ihvdro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-d ihvdro-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. ¹ H 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-d ihydro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-dihvd ro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-dihvd ro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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-dihyd ro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-(| l-r(4-bromophenyl)methyll-6-fluoro-4-hydroxy-2-oxo-l,2-dihyd ro-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. ¹ H 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-dihyd ro-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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. ¹ H 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. ¹ H

NMR (400 MHz, DMSOd ₆ ) 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

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-dih ydro-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. ¹ H 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-di hydro-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-d l-rO.S-difluorophenvDmethyll-ό-fluoro^-hvdroxy^-oxo-l^-dihy dro-S- quinolinyl 1 carbonyl) glycine

135a) Ethyl l-rO.S-difluorophenyπmethyll-ό-fluoro^-hvdroxy^-oxo-l^-dih vdro-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-[(6-fluoro-4-hvdroxy-2-oxo-l-ir2-(trifluoromethyl)pheny llmethyll-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. ¹ H 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]+. 136b ^N ) 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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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. ¹ H 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. ¹ H

NMR (400 MHz, DMSO-d ₆ ) 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]+.

N-rCβ-fluoro-l-irS-fluoro^-CtrifluoromethyDphenyllmethyl l^-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-hyd roxy-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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-(trifluoromethy lV1.2-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. ¹ H 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-(trifluoromethy l)-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. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-morpholin yl)-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-morpholin ylV2-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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] ⁺ .

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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-(ri-[(2-chlorophenyl)methyll-6-(dimethylamino)-4-hvdrox y-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-r(6-(dimethylamino)-l-{ r4-(U-dimethylethyl)phenyllmethyll-4-hydroxy-2-oxo-L2-dihvdr o-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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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-(trifluorometh yl)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%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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-(trif luoromethyl)- 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. ¹ H 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-(trifl uoromethyl)- 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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]+.

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. ¹ H 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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

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 ⁰ C 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 ⁰ C 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 Et ₂ O, and dried in vacuo to afford the title compound as an off-white solid (0.295 g, 84%). ¹ H NMR (400 MHz, DMSOd ₆ ) 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

N-I r4-hydroxy-6-nitro-2-oxo-l-(phenylmethyl)-l,2-dihvdro-3-quin olinyllcarbonyl) glycine

148a) Ethyl 4-hydroxy-6-nitro-2-oxo-l-(phenylmethyl)-l,2-dihydro-3-quino linecarboxylate 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. ¹ H

NMR (400 MHz, DMSO-d ₆ ) 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

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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

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-dih ydro-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. ¹ H

NMR (400 MHz, DMSOd ₆ ) 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. ¹ H NMR (400 MHz, DMSOd ₆ ) 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 O ₂ -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 O ₂ 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 FeCl ₂ 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 FeCl ₂ 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+(10 ^λ x/10 ^λ c) ^λ d), where a is the minimum % activity, b is the maximum % activity, c is the pIC ₅₀ , and d is the Hill slope.

The IC ₅₀ 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 IC ₅₀ 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 2xlO ^λ 4 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 EC ₅₀ 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 EC ₅₀ 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.