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1. WO2012050500 - 1,2-DIHYDRO-4-HYDROXY-2-OXO-QUINOLINE-3-CARBOXANILIDES AS AHR ACTIVATORS.

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]
1 ,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides as AHR activators.

Field of the invention

The present invention relates to compounds which are 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides, their thieno-pyridone analogs, and prodrugs thereof. This invention specifically relates to such derivatives containing an N-hydrogen in the carboxanilide moiety and which exhibit modulating activity towards the aromatic hydrocarbon receptor (AhR), and, specifically, also to prodrugs thereof . The present invention also relates to use of said compounds as a medicament, and for the treatment of cancer, autoimmune disorders and other disorders with an immunological component, and a pharmaceutical composition comprising one or more of said compounds and a method of treatment.

Background

1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides have been described in the literature since the 1970s (refs 1-4). The most well-known compound in this class, roquinimex (Linomide), was first described by AB Leo as an immuno-stimulating agent (ref 4) but was later also found to have immuno-modulating effects, as well as anti-angiogenetic effects (refs 5a, b). Roquinimex has been claimed beneficial for the treatment of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, diabetes type 1, and psoriasis, as well as for the treatment of cancer (refs 6a-d, 9d and refs therein).



The compound laquinimod (a 5-Cl, N-Et carboxanilide derivative) has been reported by Active Biotech AB to convey a better therapeutic index compared with roquinimex (refs 7a, b) and is currently in phase III clinical studies for the treatment of multiple sclerosis. Laquinimod has also entered clical trials in Crohn's disease and

SLE. Two other compounds in the same class under clinical evaluation are tasquinimod (prostate cancer) and paquinimod (systemic sclerosis). Recently, a molecular target for laquinimod was identified as S100A9 (ref 8).

Fujisawa has reported on similar compounds with inhibitory activity on nephritis and on B16 melanoma metastases (refs 9a-d). Also the closely related thieno-pyridone analogs have been described as immunomodulating compounds with anti-inflammatory properties (ref

10).

Another closely related compound class are the corresponding N-pyridyl-carboxamide derivatives, which have been reported to have antitubercular activity as well as anti-inflammatory properties (ref

11). However, according to litterature (ref 10) these derivatives are less active as immunomodulating agents.

The N-hydrogen 3-carboxanilides ("N-H derivatives") and the N-alkyl 3-carboxanilides ("N-alkyl derivatives"), respectively, are described in the prior art documents relating to inflammation, immunomodulation, and cancer as a homogenous group of compounds in terms of biological effects. Prior art also teaches that the N-alkyl derivatives are the preferred compound derivatives.


In fact, very few studies (refs 4, 9d) of N-hydrogen derivatives, especially in vivo studies, have been reported. Furthermore, no fundamental biological differences between the N-alkyl derivatives and the N-hydrogen derivatives, respectively, have been described.

However, some chemical properties of the N-hydrogen and the N-alkyl derivatives are different (ref 12). N-Alkyl derivatives adopt a twisted 3D-structure, whereas the N-H derivatives are stabilized by intramolecular hydrogen bonds in a planar structure. The N-alkyl derivatives are more soluble in aqueous media, but also inherently unstable towards nucleophiles, such as amines and alcohols (refs 12, 13).

The N-alkyl derivatives roquinimex (N-Me) and laquinimod (N-Et) have been reported to be metabolized in human microsomes to give the corresponding N-hydrogen derivatives, via N-dealkylation catalyzed mainly by CYP3A4 (refs 14a, b).

bHLH-PAS (basic helix-loop-helix Per-Arnt-Sim) proteins constitute a recently descovered protein family functioning as transcripon factors as homo or hetero protein dimers (refs 15a, b). The N-terminal bHLH domain is responsible for DNA binding and contributes to dimerization with other family members. The PAS region (PAS-A and PAS-B) is also involved in protein-protein interactions determining the choice of dimerization partner and the PAS-B domain harbors a potential ligand binding pocket.

The aryl hydrocarbon receptor (AhR or dioxin receptor) and its dimerization partner ARNT (AhR nuclear translocator) were the first mammalian protein members to be identified. AhR is a cytosolic protein in its non-activated form, associated in a protein complex with Hsp90, p23, and XAP2. Upon ligand activation, typically by chlorinated aromatic hydrocarbons like TCDD, the Ahr enters the nucleus and dimerizes with ARNT. The AhR/ARNT dimer recognizes specific xenobiotic response elements (XREs) to regulate TCDD-responsive genes. The ligand binding domain of AhR (AhR-LBD) resides in the PAS-B domain.

Recently, it has been demonstrated that AhR is involved in Thl7 and Treg cell development and AhR has been proposed as a unique target for therapeutic immuno-modulation (refs 16a-c). The AhR ligand TCDD was shown to induce development of Treg (FoxP3+) cells, essential for controlling auto-immunity, and to suppress symptoms in the EAE model. In addition, activation of AhR has been shown essential for the generation of IL-10 producing regulatory Trl cells (ref 16d), and Ahr ligands have also been proven efficacious in other models of auto-immunity, e.g. diabetes type 1, IBD, and uveitis (refs 16e-h). Apart from controlling autoimmune disorders, AhR activation and Treg cell development have been implicated as a therapeutic strategy for other conditions with an immunological component, such as allergic lung inflammation, food allergy, transplant rejection, bone loss, and type 2 diabetes and other metabolic disorders (refs 17a-e).

Apart from its role as a transcription factor, AhR has been reported to function as a ligand-dependent E3 ubiguitin ligase (ref 18), and ligand-induced degradation of β-catenin has been demonstrated to suppress intestinal cancer in mice (ref 19). In addition, activation of AhR has been implicated to play a protective role in prostate cancer (ref 20).

Other members of the bHLH-PAS family are the HIF-α (hypoxia inducible factor alpha) proteins, which also hetero-dimerize with ARNT. In conditions with normal oxygen levels (normoxia), HIF-α proteins are rapidly degraded by the ubiquitin-proteasome system and they are also inactivated by asparagine hydroxylation. Under hypoxic conditions, however, the proteins are active and upregulate genes as a response to the hypoxic state, e.g. genes for erythropoietin and vascular endothelial growth factor (VEGF). VEGF is essential for blood vessel growth (angiogenesis) and is together with HIF-1α considered as interesting targets for anti-angiogenetic tumour theraphy (ref 21). HIF-α proteins can be negatively and indirectly regulated by AhR ligands, which upon binding with AhR reduce the level of the common dimerization partner ARNT. Anti-angiogenetic effects can possibly also be achieved directly by AhR activity via upregulation of thrombospondin-1 (ref 22).

Summary of the invention

The inventor of the present invention has surprisingly found that the N-hydrogen 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides and the N-hydrogen 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides ( thieno-pyridone analogs) are potent activators of AhR. This is in contrast to their corresponding N-alkyl analogs.

The metabolizing enzyme transforming the N-alkyl derivatives to the N-hydrogen AhR activating derivatives is mainly CYP3A4. This enzyme shows a large variability within a general population and is also susceptible to drug-drug interactions with a number of different drugs (ref 14b). Moreover, CYP3A enzymes have been reported to be down-regulated under inflammatory conditions (refs 23a, b). Thus, a person treated with an N-alkyl derivative, such as roquinimex or laquinimod, will be exposed to a varying level of the corresponding N-hydrogen derivative, depending on individual CYP3A4 status and on possible drug-drug interactions, which may lead to inadequate exposure.

The concept of prodrugs is well-known for a person skilled in the art. An ideal prodrug is a biologically inactive compound with optimal physico-chemical properties, e.g. solubility and chemical stability, and which is transformed by the organism in a predictable way to give the biologically active drug (metabolite) compound. This relationship between a prodrug and drug can be likened with the relationship between a drug (parent compound) and its active metabolite.

The N-alkyl derivatives, such as roquinimex and laquinimod, can be considered as prodrugs of the N-hydrogen derivatives. As can be seen, however, there are several liabilities with the N-alkyl derivatives as prodrugs. The N-alkyl derivatives are chemically reactive towards nucleophiles (refs 12, 13) making them unstable in their neutral forms and possibly reactive in a biological environment. They are also biologically transformed in an unpredictable way by CYP enzymes, and, they may have inherent biological activity on their own. In addition, prodrugs that are transformed by hepatic metabolism are not optimal for topical treatment.

The use of the N-hydrogen derivatives as drug compounds may in certain instances also be complicated mainly for two reasons. First, the very low aqueous solubility of N-hydrogen derivatives due to intramolecular hydrogen bonds (ref 12) can complicate e.g. formulation and affect pharmacokinetic properties, such as uptake and bioavailability. Second, some N-hydrogen derivatives are metabolically unstable, e.g. the N-hydrogen metabolite of laquinimod was reported to be rapidly metabolized in the aniline part of the molecule (ref 14b), and as AhR ligands they may induce their own breakdown by CYP1A mediated metabolism causing a transient activity. Blocking such metabolism by aromatic substituents may be important in order to modulate the metabolic stability of the compounds. In some instances, however, e.g. when topical treatment is preferred, a rapid systemic or hepatic clearance may be advantageous.

The inventor of the present invention has found that the properties of the N-hydrogen derivatives as drug compounds can be greatly improved by the introduction of prodrug moieties that break up intramolecular anilide-NH and/or 4-OH hydrogen bonds.

The concept is shown below. Stabilization of a planar structure by intramolecular hydrogen bonds results in very low aqueous solubility. Breaking the H-bond(s) by the introduction of prodrug moieties PM1 and/or PM2, respectively, can improve e.g. the solubility considerably. Also, inherent physical, chemical, or biological properties of selected PM1 and PM2, e.g. polarity, specific affinity, targeting properties, etc., can be exploited in the design of the prodrug compounds.


Conceptually, Ra, Rb, and Rc may independently represent any type of group(s) or substituent(s), e.g. aromatic rings, hetero-aromatic rings, hetero-cyclic or alicyclic rings, or open-chain structures. The prodrug moieties PM1 and PM2, respectively, represent groups susceptible to cleavage in an organism providing the bioactive planar parent compound.

The objective problem of the present invention is to develop new N-hydrogen 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides and N-hydrogen 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides, as activators of the aryl hydrocarbon receptor for the treatment of cancer, autoimmune disorders and other disorders with an immunological component.

Another objective problem of the present invention is to develop new prodrug compounds of said N-hydrogen 1,2-dihydro-4-hydroxy-2-oxo-guinoline-3-carboxanilides and N-hydrogen 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides.

Compounds of the present invention that activate the aryl hydrocarbon receptor are especially useful for the treatment of cancer, such as leukemia, prostate cancer and intestinal cancer, of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, diabetes type 1, and psoriasis, and of other disorders or conditions with an immunological component, such as asthma, allergy, infection, bone loss, atherosclerosis, diabetes type 2, graft-versus-host, and transplant rejection.

Detailed description of the invention

The object of the present invention is to provide novel compounds which are N-hydrogen 1,2-dihydro-4-hydroxy-2-oxo-quinoline-3-carboxanilides or N-hydrogen 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides and prodrugs thereof.

In a first aspect the present invention relates to a compound of the general formula I


wherein

A, B and C are independently chosen from the group comprising H, Me, Et, iso-Pr, tert-Bu, OMe, OEt, O-iso-Pr, SMe, S(O)Me, S(O)2Me, CF3, OCF3, F, Cl, Br, I, and CN, or A and B represents OCH2O and C is H; RN is chosen from the group comprising H, C(O)H, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2H, CO2Me, CO2Et, CO2CH2Ph, C(O)NHMe, C(O)NMe2, C(O)NHEt, C(O)NEt2, C(O)NHPh, C(O)NHCH2Ph, the acyl residues of C5-C20 carboxylic acids optionally containing 1-3 multiple bonds, and the acyl residues of the amino acids glycine, alanine, valine, leucine, iso-leucine, serine, threonine, cysteine, methionine, proline, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylalanine, tyrosine, and tryptophan, and optionally substituted 1-3 times by substituents chosen from the group comprising Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, CI, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2, NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O) (OH)2, and P(O)(OH)2;

R4 is RN, or when RN is H, then R4 is chosen from the group comprising H, P(O)(OH)2, P(O)(OMe)2, P(O)(OEt)2, P(O) (OPh)2, P(O)(OCH2Ph)2, S(O)2OH, S(O)2NH2, S(O)2NMe2, C(O)H, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2H, CO2Me, CO2Et, CO2CH2Ph, C(O)NHMe, C(O)NMe2, C(O)NHEt, C(O)NEt2, C(O)NHPh, C(O)NHCH2Ph, the acyl residues of C5-C20 carboxylic acids optionally containing 1-3 multiple bonds, and the acyl residues of the amino acids glycine, alanine, valine, leucine, iso-leucine, serine, threonine, cysteine, methionine, proline, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylalanine, tyrosine, and tryptophan, and optionally substituted 1-3 times by substituents chosen from the group comprising Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, Cl, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2 , NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O)(OH)2, and P(O)(OH)2;

R5 and R6 are independently chosen from the group comprising H, Me,

Et, iso-Pr, tert-Bu, OMe, OEt, O-iso-Pr, SMe, S(O)Me, S(O)2Me, CF3, OCF3, F, CI, Br, I, and CN, or R5 and R6 represents OCH2O; and

X is -CH=CH-, or S,

or pharmaceutically acceptable salts of the compounds of the general formula I,

with the provisio that compound I is not chosen from the group comprising

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-ethoxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethoxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-bromophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3,4-dichlorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-3-carboxamide,

N-(3,5-dimethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3-methylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3-chlorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3-methoxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3-methylthiophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3-bromophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3,4-methylenedioxo)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-5-fluoro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1,6-dimethyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide, and

N-phenyl-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide.

In one embodiment of the present invention,

A, B and C are independently chosen from the group comprising H, Me, OMe, CF3, OCF3, F, CI, and Br, or A and B represents OCH2O and C is H; and

R5 and R6 are independently chosen from the group comprising H, Me, Et, OMe, SMe, S(O)Me, CF3, OCF3, F, CI, and Br, or R5 and R6 represents OCH2O.

In a further embodiment,

A, B and C are independently chosen from the group comprising Me, OMe, CF3, OCF3, F, and Cl, or A and B represents OCH2O and C is H; and R5 and R6 are independently chosen from the group comprising Me, Et, OMe, SMe, S(O)Me, CF3, F, and Cl, or R5 and R6 represents OCH2O.

In one preferred embodiment,

RN is chosen from the group comprising H, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2Me, CO2Et, and optionally substituted 1-3 times by substituents chosen from the group comprising Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, Cl, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2, NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O) (OH)2, and P(O)(OH)2; and,

R4 is RN, or when RN is H, then R4 is chosen from the group comprising P(O)(OH)2, P(O)(OMe)2, P(O)(OEt)2, P(O)(OPh)2,

P(O) (OCH2Ph)2, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2Me, CO2Et, C(O)NHMe, C(O)NMe2, C(O)NHEt, C(O)NEt2, the acyl residues of C5-C20 carboxylic acids optionally containing 1-3 multiple bonds, and the acyl residues of the amino acids glycine, alanine, valine, leucine, iso-leucine, serine, threonine, cysteine, methionine, proline, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylalanine, tyrosine, and tryptophan, and optionally substituted 1-3 times by substituents chosen from the group comprising Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, Cl, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2, NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O) (OH)2, and P(O) (OH)2;

with the provisio that R4 is not H.

In a further preferred embodiment,

RN is chosen from the group comprising C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, CO2Me, and CO2Et; and R4 is RN.

In onother further preferred embodiment,

RN is H; and

R4 is chosen from the group comprising P(O)(OH)2, P(O)(OMe)2, P(O)(OEt)2, P(O) (OPh)2, P(O)(OCH2Ph)2, C(O)Me, C(O)Et, C(O)Pr, C(O)CH(Me)2, C(O)C(Me)3, C(O)Ph, C(O)CH2Ph, CO2Me, CO2Et, C(O)NHMe, C(O)NMe2, C(O)NHEt, C(O)NEt2, the acyl residues of C5-C20 carboxylic acids optionally containing 1-3 multiple bonds, and the acyl residues of the amino acids glycine, alanine, valine, leucine, iso-leucine, serine, threonine, cysteine, methionine, proline, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylalanine, tyrosine, and tryptophan, and optionally substituted 1-3 times by substituents chosen from the group comprising Me, Et, OMe, OEt, SMe, S(O)Me, S(O)2Me, S(O)2NMe2, CF3, OCF3, F, Cl, OH, CO2H, CO2Me, CO2Et, C(O)NH2, C(O)NMe2, NH2, NH3+, NMe2, NMe3+, NHC(O)Me, NC(=NH)NH2, OS(O)2OH, S(O)2OH, OP(O) (OH)2, and P(O) (OH)2.

In yet onother further preferred embodiment,

RN is H; and

R4 is H.

In another embodiment of the present invention,

X is S.

In a preferred embodiment,

A, B and C are independently chosen from the group comprising H, Me, OMe, CF3, OCF3, F, CI, and Br, or A and B represents OCH2O and C is H; R5 is chosen from the group comprising H, Me, Et, CF3, Cl, and Br; R6 is H; and

X is S.

In yet another embodiment the new compound described above is cosen from the group comprising

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methylphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-methylphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-methylphenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-methylphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-fluorophenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-N-ethoxycarbonyl-4-ethoxycarbonyloxy-1,2-dihydro- 1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-methoxyphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-1-methyl- 2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-trifluoromethylphenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-trifluoromethylphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-trifluoromethoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3,4-difluorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quino1ine-3-carboxamide,

N-acetyl-N-(3,4-difluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3,4-difluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(3,5-di-(trifluoromethyl)phenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylthiophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(3,4-methylenedioxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylenedioxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1,5-dimethyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-diethylphosphoryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-5-1rifluoromethyl-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-5-trifluoromethyl-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-5-trifluoromethyl-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-trifluoromethylphenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-trifluoromethylphenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-trifluoromethylphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide, N-(4-trifluoromethylphenyl)-4-diethylphosphoryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-5-fluoro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-5-fluoro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-diethylphosphoryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylphenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methylphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methylphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-{4-methylphenyl)-5-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-5-bromo-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-5-bromo-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-5-bromo-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-5-methylthio-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-5-methylthio-2-oxo-quino1ine-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-5-methylthio-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-5,6-methylenedioxy-1-methyl-2-oxo-quino1ine-3-carboxamide,

N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-N-phenyl-4-acetoxy-1,2-dihydro-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-5,6-methylenedioxy-1-methyl-2-oxo-quino1ine-3-carboxamide,

N-(4-chlorophenyl)-N-phenyl-4-acetoxy-1,2-dihydro-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-5,6-methylenedioxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1,6-dimethyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1,6-dimethyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-6-trifluoromethyl-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-6-trifluoromethyl-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-6-trifluoromethyl-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-fluorophenyl)-4-ethoxycarbonyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-N-ethoxycarbonyl-4-ethoxycarbonyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-6-trifluoromethoxy-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-6-trifluoromethoxy-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-6-trifluoromethoxy-quinoline-3-carboxamide,

N-phenyl-6-fluoro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-6-fluoro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-6-fluoro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-6-chloro-1,2-dihydro- 1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-diethylphosphoryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl- 2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-n-butyryl-N-(4-fluorophenyl)-4-n-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-6-chloro-1,2-dihydro1-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-fluorophenyl)-6-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-n-butyryl-N-(4-chlorophenyl)-4-n-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-6-chloro-1,2-dihydrol-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-N-ethoxycarbonyl-6-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quino1ine-3-carboxamide,

N-n-butyryl-N-(4-methoxyphenyl)-4-n-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-6-chloro-1,2-dihydrol-methyl-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-(4-methoxyphenyl)-6-chloro-4-ethoxycarbonyloxy- 1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-6-bromo-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-6-bromo-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-6-bromo-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-iso-butyryloxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-benzoyloxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quinoline-3-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-6-methylthio-2-oxo-quino1ine-3-carboxamide,

N-acetyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-6-methylsulfinyl-2-oxo-quinoline-3-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-6-methylsulfinyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-6-methylsulfinyl-2-oxo-quinoline-3-carboxamide,

N-phenyl-6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-6,7-dihydro-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-4-acetoxy-6,7-dihydro-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-benzoyl-N-phenyl-4-benzoyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-4-benzoyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-4-diethylphosphoryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-(4-fluorophenyl)-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-(4-fluorophenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-6,7-dihydro-3,7-dimethyl- 6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-ethoxycarbonyl-N-(4-fluorophenyl)-4-ethoxycarbonyloxy-6,7-dihydro- 3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-(4-chlorophenyl)-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-(4-chlorophenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-(4-methoxyphenyl)-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-(4-methoxyphenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-ethoxycarbonyl-N-(4-methoxyphenyl)-4-ethoxycarbonyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide, N-phenyl-3-ethyl-6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-3-ethyl-6,7-dihydro-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-4-acetoxy-3-ethyl-6,7-dihydro-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide,

N-phenyl-6,7-dihydro-4-hydroxy-7-methyl-6-oxo-3-trifluoromethyl-thieno[2,3-b]pyridine-5-carboxamide,

N-acetyl-N-phenyl-4-acetoxy-6,7-dihydro-7-methyl-6-oxo-3-trifluoromethyl-thieno[2,3-b]pyridine-5-carboxamide, and

N-phenyl-4-acetoxy-6,7-dihydro-7-methyl-6-oxo-3-trifluoromethyl-thieno[2,3-b]pyridine-5-carboxamide .

In a second aspect the present invention relates to a new compound as described above for use as a medicament.

In a third aspect the present invention relates to the use of a new compound as described above for the manufacturing of a medicament for the treatment of cancer, autoimmune disorders, and other disorders with an immunological component.

In one preferred embodiment the cancer is chosen from the group comprising prostate cancer, intestinal cancer, and leukemia.

In another preferred embodiment the autoimmune disorder is chosen from the group comprising rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, diabetes type 1, and psoriasis.

In yet another preferred embodiment the disorder with an immunological component is chosen from the group comprising asthma, allergy, infection, bone loss, atherosclerosis, diabetes type 2, graft-versus-host, and transplant rejection.

In a fourth aspect the present invention relates to a pharmaceutical composition comprising a new compound as described above admixed with one or more pharmaceutically acceptable excipients or carriers.

In one preferred embodiment the excipients are chosen from the group comprising filling agents, lubricants, flavours, colourings, sweetenings, buffers, acidifying agents, diluents and preservatives.

In another prefered embodiment the pharmaceutical composition is administered orally, by oral inhalation, intramuscularly, intravenously, intraperitoneally or subcutaneously, via implants, rectally, intranasally, or transdermally; preferably orally.

In a fifth aspect the present invention relates to a method of treatment comprising administration of a pharmaceutically effective amount of a compound as described above or a pharmaceutical composition as described above to a subject suffering from cancer, autoimmune disorders, or other disorders with an immunological component.

In one embodiment the cancer to be treated is chosen from the group comprising prostate cancer, intestinal cancer, and leukemia.

In another embodiment the autoimmune disorder to be treated is chosen from the group comprising rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, diabetes type 1, and psoriasis.

In yet another embodiment the disorder with an immunological component to be treated is chosen from the group comprising asthma, allergy, infection, bone loss, atherosclerosis, diabetes type 2, graft-versus-host, and transplant rejection.

The compounds of the present invention may be given in doses about 0.01-1000 mg/day, preferably in doses about 0.1-10 mg/day. The compounds of the present invention may be administered orally, by oral inhalation, by injections, e.g. intramuscular, intravenous, intraperitoneal, or subcutaneous, via implants, rectally, intranasally, transdermally, or by any other route suitable to deliver a therapeutically active amount of the compound.

The pharmaceutical composition of the present invention comprises a pharmaceutically effective dose of at least one of the compounds according to the present invention, preferably in admixture with one or more pharmaceutically acceptable excipients, diluents or carriers. The amount administered will vary depending on various factors, e g age, sex, weight, which disorder or condition that is treated and the compound used. Both local and systemic administration is possible.

With "pharmaceutically acceptable" is meant that the excipients, diluents or carriers must be compatible with the other ingredients of the formulation, and not deleterious to the receipient thereof.

The pharmaceutical composition can be prepared according to any of the methods well known by a person skilled in the art of pharmacy. Such methods may include the step of bringing the novel compounds of the present invention in contact with liquid carriers, solid matrices, semi-solid carriers, finely diveded solid carriers or combinations thereof, and then, if necessary, introducing or shaping the product into the desired delivery system.

Embodiments of the present invention

The present invention will now be described in more detail by the following examples, which are included in order to disclose some embodiments of the invention, but not in any way to limit the scope of the invention.

The novel 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxanilide and 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilide compounds according to the invention can be prepared by known methods described in the literature (refs 7b, 9a, 10). Thus, the carboxamides (c) can be formed by reacting acid derivatives (a), activated by e.g. DCC-coupling procedures, with anilines (b), or by reacting ester derivatives (d) or N,N-disubstituted (e.g. N-alkyl-N-aryl) carboxamides (e) with anilines at elevated temperatures (Scheme 1). The N,N-disubstituted carboxamides (e) can be formed analogously from the acid or ester derivatives and the carboxylc acids (a) can be prepared by acidic hydrolysis of the ester derivatives.


Other methods for the preparation of carboxamides (c) are: to react malonic amides (f), as acid chlorides or as esters at elevated temperatures, with anthranilic ester derivatives (g), followed by deprotonation and ring closure to provide the carboxamides (Scheme 2); and, to react malonic amide esters (h) under basic conditions with N-methyl-isatoic anhydrides (i), which can be provided from reacting anthranilic acids (j) with phosgene (Scheme 3).

The preparation of ester derivatives (d) can be performed in various ways starting from anthranilic esters (g), N-methyl-isatoic anhydrides (i) as well as from N-methyl-aniline derivatives (j) (Scheme 4). Reacting anthranilic esters (g) with alkylmalonic acidchloride or with dialkylmalonate at elevated temperatures provides amide intermediate (k), wich can be reacted further under basic conditions to give the ester derivative (d). Similarly as described above, N-methyl-isatoic anhydrides react with dialkylmalonate under basic conditions to provide the ester derivative (d). Another method to prepare esters (d) is to react N-methyl-anilines (j) with trialkylmethanecarboxylate at high temperatures, typically at 180-230 °C in inert high-boiling solvents such as diphenylether.


In the preparations of esters (d) described above, the N-methyl group may be included in the starting materials as shown, or alternatively, it may be introduced in a last step, e.g. using Mel under basic conditions. The basic conditions referred to in the above reactions are typically a strong non-nucleophilic base, such as NaH, in an aprotic solvent, such as DMF, at temperatures 20-120 °C.

Preparation of the 4-acyloxy (l) and the N-acyl-4-acyloxy (m) prodrug compounds can be performed using activated acid derivatives, such as acid chlorides or anhydrides and a non-nucleophilic base, such as trialkylamine, in non-nucleophilic solvents, such as CH2Cl2 (Scheme 5).


The mono- and the di-acylated products, (l) and (m), respectively, can be separated, e.g. by silica column chromatography. The N-acyl-4-acyloxy compounds (m) can selectively be prepared using an excess of the acylation reagents.

The mono-acylated 4-acyloxy compounds (1) can be prepared from the N-acyl-4-acyloxy compounds (m) by regioselective hydrolysis of the N-acyl group, using e.g. a solution of NaOH in MeOH, optionally with a co-solvent like THF.

An alternative method for the selective introduction of the prodrug moiety R4 is to use a protecting group at the amide nitrogen. Blocking the amide nitrogen will also disrupt intramolecular hydrogen bonding and give a twisted structure with enhanced reactivity at the 4-hydroxy group. The protecting group can be introduced during the preparation of the disubstituted amides (see Scheme 1), e.g. from the acid (a) or the ester (d) derivatives, using N-protected anilines as starting materials. The resulting protected amides (o) can be reacted at the 4-hydroxy group to give compounds (p), followed by deprotection providing the 4-hydroxy derivatized prodrug compounds (q) (Scheme 6).


One such protecting group is the 2,4-dimethoxybenzyl, which can be cleaved under acidic or oxidative conditions, e.g. by the use of cerium (IV) ammoniumnitrate in aqueous solvents. This protecting group can be introduced by preparation of the N-(2,4-dimethoxybenzyl)-aniline derivative (r), e.g. by reductive amination using NaBH4 in MeOH, followed by reaction with an acid (a) or an ester (d) derivative providing the N-(2,4-dimethoxybenzyl) protected compound (s) (Scheme 7).


In the preparative examples column chromatography separations were performed using Merck SiO2 60 (0.040-0.063 mm) silica gel. NMN spectra were recorded on Varian Mercury (400 MHz) or on Bruker UltraShield (300 MHz) machines with CDCl3 as solvent if not otherwise stated.

The following starting materials were prepared as described in the literature (refs 7b, 10):

Ethyl 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate


1H NMR: 1.48 (t, 3H), 3.65 (s, 3H), 4.50 (q, 2H), 7.26 (t, 1H), 7.31 (d, 1H), 7.68 (ddd, 1H), 8.18 (dd, 1H), 14.21 (s, 1H).

Ethyl 6-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate

1H NMR: 1.27 (t, 3H), 1.47 (t, 3H), 2.72 (q, 2H), 3.63 (s, 3H), 4.49 (q, 2H), 7.22 (d, 1H), 7.52 (dd, 1H), 7.97 (d, 1H), 14.20 (s, 1H).

Ethyl 6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate


1H NMR: 1.48 (t, 3H), 3.64 (s, 3H), 4.51 (q, 2H), 7.26 (d, 1H), 7.62 (dd, 1H), 8.15 (d, 1H), 14.22 (s, 1H).

Ethyl 1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxylate


1H NMR: 1.49 (t, 3H), 3.65 (s, 3H), 3.90 (s, 3H), 4.51 (q, 2H), 7.26 (d, 1H), 7.31 (dd, 1H), 7.58 (d, 1H), 14.24 (s, 1H).

Ethyl 6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxylate


1H NMR: 1.45 (t, 3H), 2.49 (d, 1H), 3.55 (s, 3H), 4.45 (q, 2H), 6.46 (q, 1H), 14.23 (s, 1H).

N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.00 (bs, 3H), 3.50 (s, 3H), 7.15-7.30 (m, 7H), 7.60 (ddd, 1H), 8.14 (dd, 1H), 12.48 (s, 1H).

N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.22 (t, 3H), 1.30 (t, 3H), 3.22-3.29 (m, 5H), 4.00 (q, 2H), 7.03 (t, 2H), 7.11-7.25 (m, 5H), 7.44 (dd, 1H), 13.16 (bs, 1H).

N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 1.22 (t, 3H), 3.30 (s, 3H), 3.99 (q, 2H), 7.10-7.27 (m, 7H), 7.42 (dd, 1H), 12.63 (bs, 1H).

N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-5-methoxy-2-oxo-quinoline-3-carboxamide


1H NMR: 1.24 (t, 3H), 3.49 (s, 3H), 3.95 (q, 2H), 4.01 (s, 3H), 6.63 (d, 1H), 6.87 (d, 1H), 7.11-7.23 (m, 3H), 7.34-7.43 (m, 3H), 9.78 (s, 1H).

Example 1

N-(4-fluorophenyl ) - 1 , 2 -dihydro-4-hydroxy-1-methyl-2 -oxo-quinoline-3 -carboxamide


A solution of N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (15 mg, 0.050 mmol) and 4-fluoro-aniline (0.100 mmol) in toluene (0.5 mL) was stirred at 100 °C for 1 h. Heptane (1.5 mL) was added and the solution was allowed to cool to room temperature. The crystallized product was separated from the solution and washed with heptane to give the title compound (12 mg, 79%).

1H NMR: 3.74 (s, 3H), 7.07 (t, 2H), 7.34 (t, 1H), 7.40 (d, 1H), 7.65 (m, 2H), 7.73 (ddd, 1H), 8.26 (dd, 1H), 12.52 (s, 1H), 16.62 (s, 1H).

The following compounds were prepared by the same method in 70-95 % yields:

Example 2

N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.33 (t, 1H), 7.41 (d, 1H), 7.62 (d, 2H), 7.73 (ddd, 1H), 7.82 (d, 2H), 8.26 (dd, 1H), 12.81 (s, 1H), 16.35 (s, 1H).

Example 3

N-(4-ethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 1.24 (t, 3H), 2.65 (q, 2H), 3.74 (s, 3H), 7.22 (d, 2H), 7.34 (t, 1H), 7.40 (d, 1H), 7.60 (d, 2H), 7.72 (ddd, 1H), 8.26 (dd, 1H), 12.44 (s, 1H), 16.87 (s, 1H).

Example 4

N-(4-tert-butylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.33 (s, 9H), 3.74 (s, 3H), 7.34 (t, 1H), 7.40 (2d, 3H), 7.61 (d, 2H), 7.72 (ddd, 1H), 8.26 (dd, 1H), 12.43 (s, 1H), 16.88 (s, 1H).

Example 5

N-(4-iodophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.73 (s, 3H), 7.34 (t, 1H), 7.40 (d, 1H), 7.48 (d, 2H), 7.67 (d, 2H), 7.73 (ddd, 1H), 8.25 (dd, 1H), 12.60 (s, 1H), 16.49 (s, 1H).

Example 6

N-(4-methylthiophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 2.49 (s, 3H), 3.73 (s, 3H), 7.28 (d, 2H), 7.33 (t, 1H), 7.39 (d, 1H), 7.63 (d, 2H), 7.71 (ddd, 1H), 8.24 (dd, 1H), 12.51 (s, 1H), 16.69 (s, 1H).

Example 7

N-(3-methylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 2.38 (s, 3H), 3.74 (s, 3H), 6.99 (d, 1H), 7.27 (t, 1H), 7.34 (t, 1H), 7.40 (d, 1H), 7.51 (m, 2H), 7.72 (ddd, 1H), 8.26 (dd, 1H), 12.49 (s, 1H), 16.79 (s, 1H).

Example 8

N-(3,5-di(trifluoromethyl)phenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.76 (s, 3H), 7.38 (t, 1H), 7.44 (d, 1H), 7.65 (bs, 1H), 7.77 (ddd, 1H), 8.22 (bs, 2H), 8.29 (dd, 1H), 13.10 (s, 1H), 16.00 (s, 1H).

Example 9

N-(3,4-difluorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.15 (m, 1H), 7.25-7.30 (m, 1H), 7.35 (t, 1H), 7.41 (d, 1H), 7.74 (ddd, 1H), 7.79 (m, 1H), 8.26 (dd, 1H), 12.65 (s, 1H), 16.36 (s, 1H).

The same method, with stirring for 2 h, and using N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-5-methoxy-2-oxo-quinoline-3-carboxamide, N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide, or N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide, as starting material, was used to prepare the following compounds:

Example 10

N-phenyl-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.71 (s, 3H), 4.01 (s, 3H), 6.79 (d, 1H), 6.99 (d, 1H), 7.15 (t, 1H), 7.37 (dd, 1H), 7.60 (t, 1H), 7.68 (d, 1H), 12.69 (s, 1H), 17.68 (s, 1H).

Example 11

N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.72 (s, 3H), 4.02 (s, 3H), 6.81 (d, 1H), 7.00 (d, 1H), 7.59-7.65 (m, 3H), 7.81 (d, 2H), 12.99 (s, 1H).

Example 12

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.71 (s, 3H), 4.02 (s, 3H), 6.80 (d, 1H), 7.00 (d, 1H), 7.06 (t, 2H), 7.59-7.68 (m, 3H), 12.69 (s, 1H), 17.55 (s, 1H).

Example 13

N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


The product was crystallized from abs. EtOH.

1H NMR: 1.31 (t, 3H), 3.32 (q, 2H), 3.73 (s, 3H), 7.13 (d, 1H), 7.16 (tt, 1H), 7.28 (dd, 1H),7.38 (t, 2H), 7.58 (dd, 1H), 7.69 (m,

2H),12.78 (bs, 1H), 17.55 (s, 1H).

Example 14

N-(4-chlorophenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.31 (t, 3H), 3.31 (q, 2H), 3.73 (s, 3H), 7.14 (d, 1H), 7.29 (d, 1H), 7.34 (d, 2H), 7.59 (dd, 1H), 7.65 (d, 2H), 12.87 (bs, 1H), 17.43 (s, 1H).

N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylation reactions.


1H NMR : 3.73 (s, 3H), 7.18 (t, 1H), 7.31-7.42 (m, 4H), 7.54 (dd, 1H), 7.68 (d, 2H), 12.58 (s, 1H), 17.91 (s, 1H).

Example 15

N-(4-methylphenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 2.36 (s, 3H), 3.71 (s, 3H), 7.19 (d, 2H), 7.34 (m, 2H), 7.52-7.59 (m, 3H), 12.52 (s, 1H), 18.00 (s, 1H).

Example 16

N-(4-chlorophenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.31-7.39 (m, 4H), 7.56 (t, 1H), 7.64 (d, 2H), 12.70 (s, 1H), 17.68 (s, 1H).

Example 17

N-(4-methoxyphenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 3.83 (s, 3H), 6.93 (d, 2H), 7.32-7.38 (m, 2H), 7.51-7.62 (m, 3H), 12.48 (bs, 1H), 18.05 (s, 1H).

N-(4-methylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylation reactions.


A solution of ethyl 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate (247 mg, 1.00 mmol) and 4-Me-aniline (133 mg, 1.25 mmol) in heptane (20 mL) was stirred at 100 °C for 8 h in a sealed vial, with occasional opening letting formed EtOH to evaporate.

After cooling the product crystallized from the solution and was collected by filtration. Recrystallization from heptane gave the title compound (229 mg, 74 %).

1H NMR: 2.35 (s, 3H), 3.74 (s, 3H), 7.19 (d, 2H), 7.34 (t, 1H), 7.40 (d, 1H), 7.57 (d, 2H), 7.72 (ddd, 1H), 8.26 (dd, 1H), 12.43 (s, 1H), 16.86 (s, 1H).

The following compounds were prepared by essentially the same method in 71-99% yields starting from the corresponding Et-ester starting materials, in scales ranging from 0.10 to 40 mmol. Recrystallizations if needed were performed from heptane or from heptane-EtOAc mixtures:

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylation reactions.


1H NMR: 3.74 (s, 3H), 7.17 (t, 1H), 7.34 (t, 1H), 7.39 (t, 2H), 7.40 (d, 1H), 7.70 (d, 2H), 7.72 (ddd, 1H), 8.26 (dd, 1H), 12.53 (s, 1H), 16.75 (s, 1H).

N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylation reactions.


1H NMR: 3.74 (s, 3H), 3.82 (s, 3H), 6.92 (d, 2H), 7.34 (t, 1H), 7.40 (d, 1H), 7.60 (d, 2H), 7.72 (ddd, 1H), 8.26 (dd, 1H), 12.37 (s, 1H), 16.88 (s, 1H)

Example 18 (same compound as Example 1)

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.07 (t, 2H), 7.34 (t, 1H), 7.40 (d, 1H), 7.65 (m, 2H), 7.73 (ddd, 1H), 8.26 (dd, 1H), 12.52 (s, 1H), 16.62 (s,

1H).

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylation reactions.


1H NMR: 3.73 (s, 3H), 7.33 (d, 2H), 7.34 (t, 1H), 7.40 (d, 1H), 7.65 (d, 2H), 7.72 (ddd, 1H), 8.25 (dd, 1H), 12.60 (s, 1H), 16.52 (s, 1H).

Example 19 (same compound as Example 2)

N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.33 (t, 1H), 7.41 (d, 1H), 7.62 (d, 2H), 7.73 (ddd, 1H), 7.82 (dd, 2H), 8.26 (d, 1H), 12.81 (s, 1H), 16.35 (s, 1H).

Example 20

N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 1.30 (t, 3H), 2.77 (q, 2H), 3.72 (s, 3H), 7.17 (t, 1H), 7.33 (d, 1H), 7.39 (t, 2H), 7.57 (dd, 1H), 7.70 (d, 2H), 8.07 (d, 1H), 12.58 (s, 1H), 16.74 (s, 1H).

Example 21

N-(4-ethylphenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 1.24 (t, 3H), 1.30 (t, 3H), 2.64 (q, 2H), 2.77 (q, 2H), 3.72 (s, 3H), 7.22 (d, 2H), 7.33 (d, 1H), 7.57 (dd, 1H), 7.60 (d, 2H), 8.07 (d, 1H), 12.49 (s, 1H), 16.85 (s, 1H).

Example 22

N-phenyl-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide


1H NMR: 2.55 (s, 3H), 3.65 (s, 3H), 6.54 (s, 1H), 7.15 (t, 1H), 7.38 (t, 2H), 7.67 (d, 2H), 12.39 (s, 1H), 16.65 (s, 1H).

Example 23

N-(4-methoxyphenyl)-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide


1H NMR: 2.55 (s, 3H), 3.65 (s, 3H), 3.82 (s, 3H), 6.54 (s, 1H), 6.92 (d, 2H), 7.58 (d, 2H), 12.24 (s, 1H), 16.74 (s, 1H).

Example 24

N-(4-fluorophenyl)-6,7-dihydro-4-hydroxy-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide


1H NMR: 2.55 (s, 3H), 3.65 (s, 3H), 6.54 (s, 1H), 7.07 (dd, 2H), 7.63 (m, 2H), 12.39 (s, 1H), 16.52 (s, 1H).

N-phenyl-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylation reactions. Purified by silica column chromatography (CHCl3) and recrystallized from heptane-CHCl3.


1H NMR: 3.73 (s, 3H), 3.93 (s, 3H), 7.18 (t, 1H), 7.34 (bs, 2H), 7.39 (t, 2H), 7.64 (bs, 1H), 7.70 (d, 2H), 12.65 (s, 1H), 16.78 (s, 1H).

Example 25

N-(4-fluorophenyl)-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

Purified by silica column chromatography (CHCl3) and recrystallized from heptane-CHCl3.


1H NMR: 3.73 (s, 3H), 3.92 (s, 3H), 7.08 (t, 2H), 7.34 (d, 2H), 7.61-7.70 (m, 3H), 12.64 (s, 1H), 16.65 (s, 1H).

Example 26

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

Purified by silica column chromatography (CHCl3) and recrystalliz from heptane-CHCl3.


1H NMR: 3.72 (s, 3H), 3.92 (s, 3H), 7.31-7.37 (m, 4H), 7.61-7.69 (m 3H), 12.73 (s, 1H), 16.65 (s, 1H).

N-phenyl-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Not according to invention. Prepared as precursor for acylatioi reactions. Purified by silica column chromatography (CHCl3) am recrystallized from heptane-CHCl3.


2H NMR: 3.73 (s, 3H), 7.18 (t, 1H), 7.34 (d, 1H), 7.39 (t, 2H), 7.65 (dd, 1H), 7.69 (d, 2H), 8.22 (d, 1H), 12.44 (s, 1H), 16.85 (s, 1H).

Example 27

N-(4-fluorophenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo- quinoline-3-carboxamide

Purified by silica column chromatography (CHCl3) and recrystallized from heptane-CHCl3.

1H NMR: 3.72 (s, 3H), 7.08 (t, 2H), 7.34 (d, 1H), 7.60-7.68 (m, 3H), 8.20 (d, 1H), 12.42 (s, 1H), 16.70 (s, 1H).

Example 28

N-(4-chlorophenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo- quinoline-3-carboxamide

Purif ied by silica column chromatography (CHCl3) and recrystallized from heptane-CHCl3.

1H NMR : 3.72 (s, 3H), 7.32-7.38 (m, 3H), 7.62-7.69 (m, 3H), 8.23 (d, 1H), 12.52 (s, 1H), 16.62 (s, 1H).

Example 29

N-(4-methoxyphenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

Purified by silica column chromatography (CHCl3) and recrystallized from heptane-CHCl3.


1H NMR: 3.70 (s, 3H), 3.82 (s, 3H), 6.92 (d, 2H), 7.32 (d, 1H), 7.58 (d, 2H), 7.62 (dd, 1H), 8.19 (d, 1H), 12.27 (s, 1H), 16.96 (s, 1H).

Example 30

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


and

Example 31

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


A solution of acetylchloride (447 mg, 5.69 mmol) in CH2Cl2 (3.0 mL) was added to a solution of N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (864 mg, 2.94 mmol), EtNiPr2 (1.31 g, 10.1 mmol) and DMAP (49 mg, 0.40 mmol) in CH2Cl2 (10 mL). The reaction mixture ws stirred for 30 min, then additional EtNiPr2 (1.31 g, 10.1 mmol) and acetylchloride (447 mg, 5.69 mmol) was added. The reaction mixture was stirred for another 60 min and concentrated at reduced pressure. The residue was purified by silica column

chromatography (heptane : EtOAc 2:1, 1:1, 1:2) to give the title compounds.

For N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (129 mg, 13 %):

1H NMR : 2.57 (s, 3H), 3.82 (s, 3H), 7.12 (tt, 1H), 7.31-7.41 (m, 3H), 7.48 (d, 1H), 7.67-7.78 (m, 3H), 7.94 (dd, 1H), 11.85 (s, 1H).

For N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (280 mg, 25 %):

1H NMR: 2.11 (s, 3H), 2.39 (s, 3H), 3.68 (s, 3H), 7.27 (t, 1H), 7.35-7.48 (m, 6H), 7.58-7.65 (m, 2H).

Example 32 (same compound as Example 30)

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

A solution of AcCl (6.28 g, 80.0 mmol) in CH2Cl2 (10 mL) was added in portions during 1 h to a solution of N-phenyl-1,2-dihydro-4-hydroxy-1,5-dimethyl-2-oxo-quinoline-3-carboxamide (6.40 g, 22.0 mmol) and EtNiPr2 (12.92 g, 100.0 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred for another 30 min and was then partitioned between EtOAc and 1 M HCl (aq. ). The organic phase was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was purified by silica column chromatography (CHCl3, CHCl3-EtOAc 10:1) and recrystallized from EtOAc-heptane to give the title compound (5.57 g, 68 %).

Examples 33-112

A library of di-acylated compounds was prepared by reacting starting materials (1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxanilides and 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides) with acylchlorides (acetylchloride, n-butyrylchloride, iso-butyrylchloride, benzoylchloride, and ethylchloroformate) according to the following general procedure: A solution of the acylchloride (0.40 mmol) in CH2Cl2 (0.2 mL) was added to a solution of the starting material (0.10 mmol) and EtNiPr2 (2.0 mmol) in CH2Cl2 (1.0 mL). The reaction mixture was shaken in a sealed vial for 30 min. A second portion of the acyl chloride (0.40 mmol) was added and shaking was continued for between 30 min and 24 h depending on the reactivity and solubility of the starting

material. The reaction mixture was analyzed by TLC (silica, heptane-EtOAc, 1:1) and purified by silica column chromatography (heptane-EtOAc, 1:1) followed by crystallization from heptane-EtOAc to give the diacylated compound.

Example 33

N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.30 (s, 3H), 2.33 (s, 3H), 3.63 (s, 3H), 3.90 (s, 3H), 6.72 (d, 1H), 6.98 (d, 1H), 7.50 (d, 2H), 7.52 (t, 1H), 7.67 (d, 2H).

Example 34

N-ethoxycarbonyl-N-(4-trifluoromethylphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.05 (t, 3H), 1.37 (t, 3H), 3.74 (s, 3H), 3.92 (s, 3H), 4.10 (q, 2H), 4.32 (q, 2H), 6.76 (d, 1H), 7.05 (d, 1H), 7.49 (d, 2H), 7.56 (t, 1H), 7.72 (d, 2H).

Example 35

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.33 (s, 3H), 2.34 (s, 3H), 3.63 (s, 3H), 3.89 (s, 3H), 6.70 (d, 1H), 6.96 (d, 1H), 7.07 (t, 2H), 7.34 (m, 2H), 7.51 (t, 1H).

Example 36

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.17 (d, 6H), 1.33 (d, 6H), 2.85 (m, 1H), 3.09 (bm, 1H), 3.62 (s, 3H), 3.85 (s, 3H), 6.68 (d, 1H), 6.95 (d, 1H), 7.06 (t, 2H), 7.33 (m, 2H), 7.49 (t, 1H).

Example 37

N-acetyl-N-phenyl-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.28 (t, 3H), 2.16 (s, 3H), 2.34 (s, 3H), 2.99 (q, 2H), 3.70 (s, 3H), 7.10 (d, 1H), 7.28 (d, 1H), 7.35-7.55 (m, 6H).

Example 38

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.06 (t, 3H), 1.29 (t, 3H), 1.36 (t, 3H), 3.04 (bm, 2H), 3.76 (s, 3H), 4.10 (q, 2H), 4.34 (q, 2H), 7.14 (d, 1H), 7.31-7.50 (m, 6H), 7.54 (t, 1H).

Example 39

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.28 (t, 3H), 2.20 (s, 3H), 2.34 (s, 3H), 2.99 (q, 2H), 3.69 (s, 3H), 7.11 (d, 1H), 7.27-7.46 (m, 5H), 7.52 (dd, 1H).

Example 40

N-acetyl-N-phenyl-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.11 (s, 3H), 2.32 (s, 3H), 2.35 (d, 3H), 3.62 (s, 3H), 6.59 (q, 1H), 7.31-7.53 (m, 5H).

Example 41

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.11 (d, 6H), 1.30 (d, 6H), 2.32 (d, 3H), 2.75 (m, 1H), 2.83 (m, 1H), 3.61 (s, 3H), 6.56 (q, 1H), 7.34-7.48 (m, 5H).

Example 42

N-benzoyl-N-phenyl-4-benzoyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR : 2.26 (d, 3H), 3.62 (s, 3H), 6.57 (q, 1H), 7.13-7.38 (m, 8H), 7.51 (t, 2H), 7.65 (t, 1H), 7.77 (d, 2H), 8.19 (d, 2H).

Example 43

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.09 (t, 3H), 1.35 (t, 3H), 2.39 (d, 3H), 3.68 (s, 3H), 4.11 (q, 2H), 4.34 (q, 2H), 6.61 (q, 1H), 7.31-7.48 (m, 5H).

Example 44

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.10 (d, 6H), 1.30 (d, 6H), 2.32 (d, 3H), 2.73-2.89 (m, 2H), 3.60 (s, 3H), 3.83 (s, 3H), 6.56 (q, 1H), 6.93 (d, 2H), 7.27 (d, 2H).

Example 45

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-6,7-dihydro-3,7-dimethyI-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.26 (d, 3H), 3.60 (s, 3H), 3.72 (s, 3H), 6.57 (q, 1H), 6.77 (d, 2H), 7.17 (d, 2H), 7.23-7.39 (m, 3H), 7.51 (t, 2H), 7.65 (t, 1H), 7.79 (d, 2H), 8.19 (d, 2H).

Example 46

N-ethoxycarbonyl-N-(4-methoxyphenyl)-4-ethoxycarbonyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.10 (t, 3H), 1.36 (t, 3H), 2.39 (d, 3H), 3.67 (s, 3H), 3.84 (s, 3H), 4.11 (q, 2H), 4.33 (q, 2H), 6.61 (q, 1H), 6.95 (d, 2H), 7.25 (d, 2H).

Example 47

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.16 (s, 3H), 2.33 (s, 3H), 2.35 (d, 3H), 3.62 (s, 3H), 6.61 (q, 1H), 7.12 (t, 2H), 7.36 (m, 2H).

Example 48

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.13 (d, 6H), 1.31 (d, 6H), 2.33 (d, 3H), 2.76-2.90 (m, 2H), 3.60 (s, 3H), 6.57 (q, 1H), 7.11 (t, 2H), 7.34 (m, 2H).

Example 49

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.25 (d, 3H), 3.61 (s, 3H), 6.59 (q, 1H), 6.95 (t, 2H), 7.20-7.41 (m, 5H), 7.51 (t, 2H), 7.66 (t, 1H), 7.77 (d, 2H), 8.19 (d, 2H).

Example 50

N-ethoxycarbonyl-N-(4-fluorophenyl)-4-ethoxycarbonyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.09 (t, 3H), 1.36 (t, 3H), 2.39 (d, 3H), 3.67 (s, 3H), 4.11 (q, 2H), 4.33 (q, 2H), 6.62 (q, 1H), 7.12 (t, 2H), 7.32 (m, 2H).

Example 51 (same compound as Examples 30 and 32)

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.11 (s, 3H), 2.39 (s, 3H), 3.68 (s, 3H), 7.27 (t, 1H), 7.35-7.48 (m, 6H), 7.58-7.65 (m, 2H).

Example 52

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.10 (d, 6H), 1.37 (d, 6H), 2.74 (m, 1H), 2.92 (m, 1H), 3.69 (s, 3H), 7.25 (t, 1H), 7.35-7.50 (m, 6H), 7.56-7.65 (m, 2H).

Example 53

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.68 (s, 3H), 7.16-7.42 (m, 10H), 7.52 (t, 2H), 7.61-7.72 (m, 3H), 7.76 (d, 2H), 8.25 (d, 2H).

Example 54

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.06 (t, 3H), 1.38 (t, 3H), 3.75 (s, 3H), 4.11 (q, 2H), 4.35 (q, 2H), 7.31 (t, 2H), 7.34-7.50 (m, 6H), 7.66 (ddd, 1H), 7.77 (dd, 1H).

Example 55

N-acetyl-N-(4-methylphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.11 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 3.70 (s, 3H), 7.24-7.31 (m, 5H), 7.39 (dd, 1H), 7.60-7.66 (m, 2H).

Example 56

N-iso-butyryl-N-(4-methylphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.09 (d, 6H), 1.36 (d, 6H), 2.39 (s, 3H), 2.73 (m, 1H), 2.92

(m, 1H), 3.69 (s, 3H), 7.22-7.28 (m, 5H), 7.37 (d, 1H), 7.56-7.64

(m, 2H).

Example 57

N-benzoyl-N-(4-methylphenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.26 (s, 3H), 3.68 (s, 3H), 7.06 (d, 2H), 7.15 (d, 2H), 7.20- 7.40 (m, 5H), 7.54 (t, 2H), 7.58-7.71 (m, 3H), 7.78 (d, 2H), 8.25 (d, 2H).

Example 58

N-ethoxycarbonyl-N-(4-methylphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.07 (t, 3H), 1.37 (t, 3H), 2.40 (s, 3H), 3.75 (s, 3H), 4.11 (q, 2H), 4.34 (q, 2H), 7.21-7.27 (m, 4H), 7.31 (t, 1H), 7.42 (d, 2H), 7.65 (ddd, 1H), 7.76 (dd, 1H).

Example 59

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.15 (s, 3H), 2.40 (s, 3H), 3.69 (s, 3H), 3.82 (s, 3H), 6.95 (d, 2H), 7.24-7.32 (m, 3H), 7.38 (d, 1H), 7.59-7.66 (m, 2H).

Example 60

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.11 (d, 6H), 1.37 (d, 6H), 2.81 (m, 1H), 2.92 (m, 1H), 3.68 (s, 3H), 3.82 (s, 3H), 6.95 (d, 2H), 7.21-7.31 (m, 3H), 7.37 (d, 1H), 7.54-7.63 (m, 2H).

Example 61

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.68 (s, 3H), 3.72 (s, 3H), 6.77 (d, 2H), 7.16-7.41 (m, 7H), 7.54 (t, 2H), 7.59-7.73 (m, 3H), 7.79 (d, 2H), 8.25 (d, 2H).

Example 62

N-ethoxycarbonyl-N-(4-methoxyphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.07 (t, 3H), 1.38 (t, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 4.11 (q, 2H), 4.35 (q, 2H), 6.96 (d, 2H), 7.23-7.34 (m, 3H), 7.42 (d, 1H), 7.66 (ddd, 1H), 7.76 (dd, 1H).

Example 63

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 2.17 ( s , 3H), 2.41 (s, 3H), 3.69 (s, 3H), 7.13 (t, 2H), 7.25-7.42 (m, 4H), 7.61-7.68 (m, 2H).

Example 64

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.12 (d, 6H), 1.37 (d, 6H), 2.82 (m, 1H), 2.94 (m, 1H), 3.68 (s, 3H), 7.12 (dd, 2H), 7.26 (ddd, 1H), 7.31-7.40 (m, 3H), 7.56-7.65 (m, 2H).

Example 65

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.68 (s, 3H), 6.96 (t, 2H), 7.22-7.41 (m, 7H), 7.55 (t, 2H), 7.60-7.73 (m, 3H), 7.77 (d, 2H), 8.25 (d, 2H).

Example 66

N-ethoxycarbonyl-N-(4-fluorophenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.04 (t, 3H), 1.38 (t, 3H), 3.74 (s, 3H), 4.10 (q, 2H), 4.35 (q, 2H), 7.14 (t, 2H), 7.26-7.38 (m, 5H), 7.43 (d, 1H), 7.66 (t, 1H), 7.78 (d, 1H).

Example 67

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.17 (s, 3H), 2.41 (s, 3H), 3.69 (s, 3H), 7.28-7.44 (m, 6H), 7.61-7.68 (m, 2H).

Example 68

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.12 (d, 6H), 1.37 (d, 6H), 2.79 (m, 1H), 2.92 (m, 1H), 3.68 (s, 3H), 7.26 (ddd, 1H), 7.31 (d, 2H), 7.38 (d, 1H), 7.41 (d, 2H), 7.59 (dd, 1H), 7.62 (ddd, 1H).

Example 69

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.67 (s, 3H), 7.18-7.42 (m, 9H), 7.54 (t, 2H), 7.61-7.73 (m, 3H), 7.78 (d, 2H), 8.25 (d, 2H).

Example 70

N-(4-chlorophenyl)-N-ethoxycarbonyl-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.07 (t, 3H), 1.38 (t, 3H), 3.75 (s, 3H), 4.11 (q, 2H), 4.35 (q, 2H), 7.26-7.35 (m, 3H), 7.40-7.46 (m, 3H), 7.66 (ddd, 1H), 7.79 (dd, 1H).

Example 71

N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.16 (s, 3H), 2.41 (s, 3H), 3.70 (s, 3H), 7.30 (t, 1H), 7.40 (d, 1H), 7.53 (d, 2H), 7.60-7.70 (m, 2H), 7.72 (d, 2H).

Example 72

N-benzoyl-N-(4-trifluoromethylphenyl)-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.67 (s, 3H), 7.22-7.42 (m, 7H), 7.50-7.58 (m, 4H), 7.61-7.72 (m, 2H), 7.76 (d, 2H), 8.25 (d, 2H).

Example 73

N-ethoxycarbonyl-N-(4-trifluoromethylphenyl)-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.07 (t, 3H), 1.38 (t, 3H), 3.76 (s, 3H), 4.12 (q, 2H), 4.35 (q, 2H), 7.33 (t, 1H), 7.44 (d, 1H), 7.50 (d, 2H), 7.68 (ddd, 1H), 7.73 (d, 2H), 7.80 (dd, 2H).

Example 74

N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.16 (s, 3H), 2.35 (s, 3H), 3.70 (s, 3H), 7.29 (dd, 1H), 7.32-7.51 (m, 7H).

Example 75

N-n-butyryl-N-phenyl-4-n-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 0.84 (t, 3H), 1.02 (t, 3H), 1.57 (m, 2H), 1.76 (m, 2H), 2.31 (bt, 2H), 2.60 (t, 2H), 3.72 (s, 3H), 7.28-7.51 (m, 7H).

Example 76

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.11 (d, 6H), 1.30 (d, 6H), 2.77 (bm, 1H), 2.87 (m, 1H), 3.69 (s, 3H), 7.26 (dd, 1H), 7.33-7.50 (m, 6H).

Example 77

N-benzoyl-N-phenyl-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.70 (s, 3H), 7.16-7.38 (m, 10H), 7.45-7.56 (m, 3H), 7.65 (tt, 1H), 7.71 (bd, 2H), 8.22 (d, 2H).

Example 78

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.07 (t, 3H), 1.36 (t, 3H), 3.76 (s, 3H), 4.10 (q, 2H), 4.34 (q, 2H), 7.30-7.55 (m, 8H).

Example 79

N-ethoxycarbonyl-N-(4-methylphenyl)-5-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

2H NMR: 1.08 (t, 3H), 1.36 (t, 3H), 2.40 (s, 3H), 3.76 (s, 3H), 4.10 (q, 2H), 4.33 (q, 2H), 7.20-7.30 (m, 4H), 7.32 (d, 1H), 7.38 (d, 1H), 7.51 (t, 1H).

Example 80

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.20 (s, 3H), 2.35 (s, 3H), 3.69 (s, 3H), 7.28-7.34 (m, 4H), 7.43 (d, 2H), 7.50 (t, 1H).

Example 81

N-n-butyryl-N-(4-chlorophenyl)-4-n-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 0.87 (t, 3H), 1.01 (t, 3H), 1.59 (m, 2H), 1.73 (m, 2H), 2.35 (bm, 2H), 2.60 (t, 2H), 3.69 (s, 3H), 7.27-7.52 (m, 7H).

Example 82

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.18 (s, 3H), 2.34 (s, 3H), 3.70 (s, 3H), 3.82 (s, 3H), 6.95 (d, 2H), 7.24-7.41 (m, 4H), 7.48 (t( 1H).

Example 83

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.11 (d, 6H), 1.30 (d, 6H), 2.85 (bm, 1H), 2.87 (m, 1H), 3.69 (s, 3H), 3.83 (s, 3H), 6.94 (d, 2H), 7.24-7.30 (m, 3H), 7.32 (dd, 1H), 7.46 (dd, 1H).

Example 84

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.12 (s, 3H), 2.40 (s, 3H), 3.68 (s, 3H), 3.86 (s, 3H), 7.02 (d, 1H), 7.24 (dd, 1H), 7.32 (d, 1H), 7.36-7.50 (m, 5H).

Example 85

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.11 (d, 6H), 1.38 (d, 6H), 2.75 (m, 1H), 2.93 (m, 1H), 3.67 (s, 3H), 3.83 (s, 3H), 6.99 (d, 1H), 7.21 (dd, 1H), 7.31 (d, 1H), 7.35-7.49 (m, 5H).

Example 86

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.66 (m, 1H), 3.76 (s, 3H), 7.05 (d, 1H), 7.15-7.38 (m, 9H), 7.54 (t, 2H), 7.68 (tt, 1H), 7.77 (d, 2H), 8.25 (d, 2H).

Example 87

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.06 (t, 3H), 1.38 (t, 3H), 3.73 (s, 3H), 3.87 (s, 3H), 4.10 (q, 2H), 4.35 (q, 2H), 7.16 (d, 1H), 7.26 (dd, 1H), 7.33-7.50 (m, 6H).

Example 88

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.17 (s, 3H), 2.40 (s, 3H), 3.66 (s, 3H), 3.85 (s, 3H), 7.02 (d, 1H), 7.12 (t, 2H), 7.24 (dd, 1H), 7.32 (d, 1H), 7.36 (m, 2H).

Example 89

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.12 (d, 6H), 1.38 (d, 6H), 2.83 (m, 1H), 2.93 (m, 1H), 3.66 (S, 3H), 3.83 (S, 3H), 6.98 (d, 1H), 7.12 (t, 2H), 7.22 (dd, 1H), 7.31 (d, 1H), 7.36 (m, 2H).

Example 90

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.66 (s, 3H), 3.76 (s, 3H), 6.95 (t, 2H), 7.04 (d, 1H), 7.22-7.41 (m, 8H), 7.55 (t, 2H), 7.69 (tt, 1H), 7.77 (d, 2H), 8.25 (d, 2H).

Example 91

N-ethoxycarbonyl-N-(4-fluorophenyl)-4-ethoxycarbonyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.06 (t, 3H), 1.39 (t, 3H), 3.73 (s, 3H), 3.87 (s, 3H), 4.10 (q, 2H), 4.35 (q, 2H), 7.13 (t, 2H), 7.17 (d, 1H), 7.27 (dd, 1H), 7.31-7.39 (m, 3H).

Example 92

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.12 (d, 6H), 1.38 (d, 6H), 2.81 (m, 1H), 2.93 (m, 1H), 3.66 (s, 3H), 3.84 (s, 3H), 6.99 (d, 1H), 7.23 (dd, 1H), 7.30-7.35 (m, 3H), 7.41 (d, 2H).

Example 93

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.66 (s, 3H), 3.76 (s, 3H), 7.05 (d, 1H), 7.19-7.41 (m, 9H), 7.54 (t, 2H), 7.69 (tt, 1H), 7.77 (d, 2H), 8.24 (d, 2H).

Example 94

N-(4-chlorophenyl)-N-ethoxycarbonyl-4-ethoxycarbonyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.07 (t, 3H), 1.38 (t, 3H), 3.73 (s, 3H), 3.88 (s, 3H), 4.11 (q, 2H), 4.35 (q, 2H), 7.17 (d, 1H), 7.25-7.33 (m, 3H), 7.37 (d, 1H), 7.43 (d, 2H).

Example 95

N-acetyl-N-phenyl-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.09 (s, 3H), 2.41 (s, 3H), 3.68 (s, 3H), 7.32 (d, 1H), 7.35-7.51 (m, 5H), 7.55-7.60 (m, 2H).

Example 96

N-n-butyryl-N-phenyl-4-n-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 0.83 (t, 3H), 1.06 (t, 3H), 1.56 (m, 2H), 1.82 (m, 2H), 2.25 (bt, 2H), 2.66 (t, 2H), 3.68 (s, 3H), 7.30-7.52 (m, 6H), 7.54-7.59 (m, 2H).

Example 97

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.10 (d, 6H), 1.37 (d, 6H), 2.68 (m, 1H), 2.98 (m, 1H), 3.67 (s, 3H), 7.31 (d, 1H), 7.35-7.51 (m, 5H), 7.52-7.58 (m, 2H).

Example 98

N-benzoyl-N-phenyl-4-benzoyloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.65 (s, 3H), 7.16-7.38 (m, 9H), 7.51-7.61 (m, 4H), 7.66-7.76 (m, 3H), 8.25 (d, 2H).

Example 99

N-ethoxycarbonyl-N-phenyl-4-ethoxycarbonyloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.08 (t, 3H), 1.389 (t, 3H), 3.73 (s, 3H), 4.11 (q, 2H), 4.37 (q, 2H), 7.33-7.50 (m, 6H), 7.59 (dd, 1H), 7.74 (d, 1H).

Example 100

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.12 (s, 3H), 2.41 (s, 3H), 3.67 (s, 3H), 7.15 (dd, 2H), 7.30-7.39 (m, 3H), 7.55-7.60 (m, 2H).

Example 101

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.10 (d, 6H), 1.37 (d, 6H), 2.73 (m, 1H), 2.93 (m, 1H), 3.67 (s, 3H), 7.14 (dd, 2H), 7.30-7. 38 (m, 3H), 7.52-7.58 (m, 2H).

Example 102

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-6-chloro-1,2-dihydro1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.66 (s, 3H), 6.95 (dd, 2H), 7.18-7.40 (m, 6H), 7.52-7.62 (m, 4H), 7.67-7.75 (m, 3H), 8.24 (d, 2H).

Example 103

N-ethoxycarbonyl-N-(4-fluorophenyl)-6-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.08 (t, 3H), 1.39 (t, 3H), 3.73 (s, 3H), 4.11 (q, 2H), 4.36 (q, 2H), 7.14 (t, 2H), 7.33 (m, 2H), 7.36 (d, 1H), 7.60 (dd, 1H), 7.75 (d, 1H).

Example 104

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 2.13 (s, 3H), 2.41 (s, 3H), 3.68 (s, 3H), 7.29-7.36 (m, 3H), 7.44 (d, 2H), 7.56-7.61 (m, 2H).

Example 105

N-n-butyryl-N-(4-chlorophenyl)-4-n-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 0.85 (t, 3H), 1.06 (t, 3H), 1.57 (m, 2H), 1.81 (m, 2H), 2.27 (bt, 2H), 2.65 (t, 2H), 3.66 (s, 3H), 7.27-7.35 (m, 3H), 7.45 (d, 2H), 7.54-7.59 (m, 2H).

Example 106

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.10 (d, 6H), 1.36 (d, 6H), 2.71 (m, 1H), 2.92 (m, 1H), 3.67 (s, 3H), 7.28-7.35 (m, 2H), 7.44 (d, 2H), 7.53-7.59 (m, 2H).

Example 107

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-6-chloro-1,2-dihydrol-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.66 (s, 3H), 7.16-7.40 (m, 8H), 7.52-7.62 (m, 4H), 7.67-7.75 (m, 3H), 8.23 (d, 2H).

Example 108

N-(4-chlorophenyl)-N-ethoxycarbonyl-6-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.08 (t, 3H), 1.39 (t, 3H), 3.72 (s, 3H), 4.11 (q, 2H), 4.36 (q, 2H), 7.29 (d, 2H), 7.36 (d, 1H), 7.45 (d, 2H), 7.60 (dd, 1H), 7.75 (d, 1H).

Example 109

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

*H NMR: 2.12 (s, 3H), 2.41 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H), 6.96 (d, 2H), 7.28 (bd, 2H), 7.32 (d, 1H), 7.54-7.59 (m, 2H).

Example 110

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.09 (d, 6H), 1.37 (d, 6H), 2.75 (bm, 1H), 2.92 (m, 1H), 3.67 (s, 3H), 3.83 (s, 3H), 6.96 (d, 2H), 7.27 (d, 2H), 7.31 (d, 1H), 7.50-7.58 (m, 2H).

Example 111

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-6-chloro-1,2-dihydrol-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.67 (s, 3H), 3.72 (s, 3H), 6.77 (d, 2H), 7.17 (d, 2H), 7.23-7.40 (m, 4H), 7.51-7.61 (m, 4H), 7.66-7.78 (m, 3H), 8.24 (d, 2H).

Example 112

N-ethoxycarbonyl-N-(4-methoxyphenyl)-6-chloro-4-ethoxycarbonyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.08 (t, 3H), 1.39 (t, 3H), 3.72 (s, 3H), 3.84 (s, 3H), 4.10 (q, 2H), 4.36 (q, 2H), 6.96 (d, 2H), 7.26 (d, 2H), 7.35 (d, 1H), 7.59 (dd, 1H), 7.73 (d, 1H).

Example 113 (same compound as Example 31)

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


A solution of NaOH in MeOH (0.50 mL, 0.20 M, 0.10 mmol) was added to a solution of N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (38 mg, 0.10 mmol) in MeOH (1.0 mL) and THF (0.5 mL). After stirring for 3 min, the solution was neutralized with aq. HCl (0.2 mL, 0.5 M) and further diluted with water (ca 10 mL). The precipitated product (29 mg, 86 %) was collected by filtration and washed with water.

The following compounds were prepared by the same method:

Example 114

N-(4-fluorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo- quinoline-3-carboxamide

Yield: 39 mg (quant.).

1H NMR: 2.57 (s, 3H), 3.81 (s, 3H), 7.04 (t, 2H), 7.42 (d, 1H), 7 (m, 2H), 7.69 (dd, 1H), 7.89 (d, 1H), 11.77 (s, 1H).

Example 115

N-(4-chlorophenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo- quinoline-3-carboxamide

Yield: (40 mg, 98 %).

1H NMR : 2.58 (s, 3H), 3.81 (s, 3H), 7.31 (d, 2H), 7.42 (d, 1H), 7. (d, 2H), 7.69 (dd, 1H), 7.89 (d, 1H), 11.87 (s, 1H).

Example 116

N-(4-methoxyphenyl)-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


Yield: (38 mg, 95 %).

1H NMR: 2.57 (s, 3H), 3.80 (s, 3H), 3.81 (s, 3H), 6.89 (d, 2H), 7.41 (d, 1H), 7.59 (d, 2H), 7.67 (dd, 1H), 7.88 (d, 1H), 11.59 (s, 1H).

Example 117

N-phenyl-4-dibenzylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

N-(2,4-dimethoxybenzyl)-aniline


Trifluoroaceticacid (10 drops) was added to a solution of 2,4-dimethoxybenzaldehyde (16.62 g, 100 mmol) and aniline (9.31 g, 100 mmol) in toluene (100 mL). The reaction mixture was stirred at reflux temperature and toluene/water was distilled off during 1.5 h. After cooling the reaction mixture was concentrated at reduced pressure and the residue was dissolved in MeOH (200 mL). NaBH4 (2.0 g, 54 mmol) was added in portions during 20 min and the reaction mixture was then stirred for 1 h. The product (22.16 g, 91%) crystallized from the reaction mixture and was isolated by filtration.

1H NMR: 3.80 (s, 3H), 3.84 (s, 3H), 4.05 (bs, 1H), 4.26 (s, 2H), 6.44 (dd, 1H), 6.47 (d, 1H), 6.66 (m, 2H), 6.70 (tt, 1H), 7.17 (m, 2H), 7.21 (d, 1H).

N-(2,4-dimethoxybenzyl)-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


A solution of ethyl 1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxylate (9.25 g, 37.4 mmol) and N-(2,4-dimethoxybenzyl)-aniline (9.10 g, 37.4 mmol) in heptane (200 mL) was stirred at 110 °C under a flow of N2 for 6 h letting the EtOH evaporate from the reaction mixture. The product started to precipitate and some extra heptane was added. The reaction mixture was then stirred at 100 °C overnight, still under a gentle flow of N2. The product (12.21 g, 73 %) crystallized from the reaction mixture and was collected by filtration while still warm (ca 50 °C).

1H NMR: 3.30 (bs, 3H), 3.69 (s, 3H), 3.77 (s, 3H), 5.09 (s, 2H), 6.39 (d, 1H), 6.46 (bd, 1H), 7.07-7.19 (m, 5H), 7.20 (bd, 1H), 7.24 (t, 1H), 7.47 (bs, 1H), 7.59 (ddd, 1H), 8.12 (dd, 1H), 12.09 (bs, 1H).

N-(2,4-dimethoxybenzyl)-N-phenyl-4-dibenzylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


CCl4 (154 mg, 1.00 mmol) was added to a solution of EtNiPr2 (52 mg, 0.40 mmol), DMAP (5 mg, 0.04 mmol) and (PhCH2O)2POH (79 mg, 0.30 mmol) in dry MeCN (1.5 mL). The reaction mixture was stirred for 3 min and was then added to a slurry of N-(2,4-dimethoxybenzyl)-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (44 mg, 0.10 mmol) in dry MeCN (0.5 mL). The reaction mixture was stirred at room temperature for 20 min and was then concentrated at reduced pressure. The residue was purified by silica column chromatography (heptane-EtOAc, 1:2, then EtOAc) to give the title compound (62 mg, 88%).

1H NMR: 3.54 (s, 3H), 3.55 (s, 3H), 3.73 (s, 3H), 4.78 (d, 1H), 5.12-5.29 (m, 5H), 6.29 (d, 1H), 6.44 (dd, 1H), 6.91-7.05 (m, 3H), 7.12 (t, 1H), 7.14-7.42 (m, 5H), 7.48 (ddd, 1H), 7.61 (d, 1H), 7.89 (dd, 1H).

N-phenyl-4-dibenzylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-guinoline-3-carboxamide


N-(2,4-dimethoxybenzyl)-N-phenyl-4-dibenzylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (116 mg, 0.165 mmol) was added to a solution of cerium ammonium nitrate (CAN, 226 mg, 0.412 mmol, 2.5 eq.) in aq. MeCN (95%, 8.0 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated at reduced pressure, and then partitioned between EtOAc and water. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by silica column chromatography (heptane-EtOAc, 1:1, then 1:2) to give the title compound (61 mg, 67%).

1H NMR: 3.78 (s, 3H), 5.20 (m, 4H), 7.11 (t, 1H), 7.21 (d, 1H), 7.25-7.31 (m, 10H), 7.33 (t, 2H), 7.41 (d, 1H), 7.69 (t, 1H), 7.72 (d, 2H), 8.16 (d, 1H), 10.52 (s, 1H).

Example 118

N-phenyl-4-phosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide di-sodium salt


N-phenyl-4-dibenzylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (14 mg, 0.025 mmol) was hydrogenated at 1 atm. H2 at room temperature for 30 min in methanol (2 mL) in the presence of Na2CO3 (10 mg, 0.10 mmol) using Pd/C (10%, 8 mg) as catalyst. The reaction mixture was filtered and concentrated at reduced pressure to give the title compound.

1H NMR (CD3OD) : 3.73 (s, 3H), 7.07 (t, 1H), 7.27-7.34 (m, 3H), 7.51 (d, 1H), 7.64 (ddd, 1H), 7.92 (d, 2H), 8.69 (dd, 1H).

Example 119

N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

N-(2,4-dimethoxybenzyl)-N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


Diethylphosphorylchloride (150 mg, 0.87 mmol)was added to a solution of EtNiPr2 (129 mg, 1.00 mmol), DMAP (10 mg, 0.08 mmol) and N-(2,4-dimethoxybenzyl)-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (222 mg, 050 mmol) in CH2Cl2 (3.0 mL). The reaction mixture was stirred for 30 min and was then concentrated at reduced pressure. The residue was purified by silica column chromatography (EtOAc) to give the title compound (196 mg, 68%).

1H NMR: 1.31 (t, 3H), 1.45 (t, 3H), 3.59 (s, 3H), 3.59 (s, 3H), 3.78 (s, 3H), 4.20-4.43 (m, 4H), 4.83 (d, 1H), 5.35 (d, 1H), 6.33 (d, 1H), 6.54 (dd, 1H), 7.00-7.44 (m, 7H), 7.54 (ddd, 1H), 7.66 (d, 1H), 7.99 (dd, 1H).

N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide


N-(2,4-dimethoxybenzyl)-N-phenyl-4-diethylphosphoryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (125 mg, 0.22 mmol) was added to a solution of cerium ammonium nitrate in 95% aq. MeCN (0.50 mmol, 0.1 M, 5.0 mL). The reaction mixture was stirred at room temperature for 1 h, concentrated at reduced pressure, and then partitioned between EtOAc and water. The organic phase was washed with water and brine, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by silica column chromatography (EtOAc) to give the title compound (45 mg, 49%).

1H NMR: 1.33 (dt, 6H), 3.79 (s, 3H), 4.30 (m, 4H), 7.12 (tt, 1H), 7.31-7.41 (m, 3H), 7.44 (d, 1H), 7.68-7.75 (m, 3H), 8.20 (dd, 1H), 10.35 (s, 1H).

Examples 120-126 were prepared by methods as described for Example 1 and Example 18.

Example 120

N-(4-fluorophenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.09 (t, 2H), 7.35 (dd, 1H), 7.36 (dd, 1H), 7.56 (t, 1H), 7.65 (m, 2H), 12.62 (s, 1H).

Example 121

N-(4-trifluoromethylphenyl)-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.74 (s, 3H), 7.34 (dd, 1H), 7.35 (dd, 1H), 7.56 (t, 1H), 7.63 (d, 2H), 7.80 (d, 2H), 12.90 (s, 1H).

Example 122

N-(4-fluorophenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.31 (t, 3H), 3.32 (q, 2H), 3.74 (s, 3H), 7.08 (t, 2H), 7.14 (d, 1H), 7.29 (d, 1H), 7.59 (dd, 1H), 7.66 (m, 2H), 12.79 (s, 1H).

Example 123

N-(4-trifluoromethylphenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.32 (t, 3H), 3.32 (q, 2H), 3.73 (s, 3H), 7.14 (d, 1H), 7.29 (d, 1H), 7.60 (dd, 1H), 7.63 (d, 2H), 7.82 (d, 2H), 13.09 (s, 1H).

Example 124

N-(4-methoxyphenyl)-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 1.31 (t, 3H), 3.32 (q, 2H), 3.73 (s, 3H), 3.83 (s, 3H), 6.93 (d, 2H), 7.13 (d, 1H), 7.28 (d, 1H), 7.58 (dd, 1H), 7.60 (d, 2H), 12.63 (s, 1H).

Example 125

N-(4-chlorophenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide


1H NMR: 3.71 (s, 3H), 4.03 (s, 3H), 6.80 (d, 1H), 7.00 (d, 1H), 7. (d, 2H), 7.62 (t, 1H), 7.64 (d, 2H), 12.79 (s, 1H).

Example 126

N-(4-methoxyphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-5-carboxamide


1H NMR: 3.71 (s, 3H), 3.82 (s, 3H), 4.02 (s, 3H), 6.79 (d, 1H), 6.92 (d, 2H), 6.99 (d, 1H), 7.59 (d, 2H), 7.60 (t, 1H), 12.54 (s, 1H).

Examples 127-163

A library of di-acylated compounds was prepared by reacting starting materials (1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3- carboxanilides and 6,7-dihydro-4-hydroxy-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides) with acylchlorides (acetylchloride, iso-butyrylchloride, and benzoylchloride according to the following general procedure:

The acyl chloride (0.80 mmol) was added in portions during 1-4 h to a solution of the starting material (0.20 mmol) and EtNiPr2 (1.00 mmol) in CH2Cl2 (1-2 mL). The reaction mixture was shaken in a sealed vial at 50 °C for 4-48 h. The reaction mixture was analyzed by TLC (silica, heptane-EtOAc, 1:1) and the product was purified by silica column chromatography (heptane-EtOAc 2:1, 1:1, 0:1) followed by crystallization from heptane-EtOAc to give the diacylated compound.

Example 127

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.23 (s, 3H), 2.33 (s, 3H), 3.65 (s, 3H), 3.90 (s, 3H), 6.71 (d, 1H), 6.98 (d, 1H), 7.31-7.48 (m, 5H), 7.51 (t, 1H).

Example 128

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.14 (d, 6H), 1.33 (d, 6H), 2.85 (m, 1H), 2.93 (broad m, 1H), 3.64 (s, 3H), 3.85 (s, 3H), 6.68 (d, 1H), 6.97 (d, 1H), 7.33-7.46 (m, 5H), 7.48 (t, 1H).

Example 129

N-benzoyl-N-phenyl-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.50 (s, 3H), 3.65 (s, 3H), 6.64 (d, 1H), 6.96 (d, 1H), 7.17-7.40 (m, 8H), 7.46-7.58 (m, 3H), 7.66 (tt, 1H), 7.82 (broad d, 2H), 8.22 (d, 2H).

Example 130

N-iso-butyryl-N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.17 (d, 6H), 1.33 (d, 6H), 2.86 (m, 1H), 2.98 (broad m, 1H), 3.64 (s, 3H), 3.87 (s, 3H), 6.70 (d, 1H), 6.97 (d, 1H), 7.46-7.54 (m, 3H), 7.68 (d, 2H).

Example 131

N-benzoyl-N-(4-trifluoromethylphenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.50 (s, 3H), 3.64 (s, 3H), 6.65 (d, 1H), 6.97 (d, 1H), 7.29 (t, 2H), 7.39 (tt, 1H), 7.42 (d, 2H), 7.49-7.59 (m, 5H), 7.67 (tt, 1H), 7.80 (broad d, 2H), 8.21 (d, 2H).

Example 132

N-benzoy1-N-(4-fluorophenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.50 (s, 3H), 3.65 (s, 3H), 6.64 (d, 1H), 6.97 (d, 1H), 6.97 (t, 2H), 7.24-7.34 (m, 4H), 7.39 (tt, 1H), 7.51 (t, 2H), 7.51-7.59 (m, 2H), 7.67 (tt, 1H), 7.83 (broad d, 2H), 8.21 (d, 2H).

Example 133

N-iso-butyryl-N-phenyl-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.13 (d, 6H), 1.26 (t, 3H), 1.32 (d, 6H), 2.84 (m, 1H), 2.85 (broad m, 1H), 2.97 (q, 2H), 3.69 (s, 3H), 7.08 (d, 1H), 7.27 (d, 1H), 7.34-7.44 (m, 5H), 7.49 (dd, 1H).

Example 134

N-benzoyl-N-phenyl-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.21 (t, 3H), 2.92 (q, 2H), 3.70 (s, 3H), 7.08 (d, 1H), 7.15-7.39 (m, 9H), 7.48-7.58 (m, 3H), 7.68 (tt, 1H), 7.80 (broad d, 2H), 8.21 (d, 2H).

Example 135

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.14 (d, 6H), 1.26 (t, 3H), 1.32 (d, 6H), 2.84 (m, 1H), 2.88 (broad m, 1H), 2.98 (q, 2H), 3.69 (s, 3H), 7.09 (d, 1H), 7.28 (d, 1H), 7.32 (d, 2H), 7.40 (d, 2H), 7.51 (dd, 1H).

Example 136

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.21 (t, 3H), 2.92 (q, 2H), 3.69 (s, 3H), 7.09 (d, 1H), 7.20-7.33 (m, 7H), 7.38 (tt, 1H), 7.49-7.58 (m, 3H), 7.68 (tt, 1H), 7.79 (broad d, 2H), 8.20 (d, 2H).

Example 137

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.15 (s, 3H), 2.33 (s, 3H), 2.36 (d, 3H), 3.62 (s, 3H), 3.83 (s, 3H), 6.59 (d, 1H), 6.95 (d, 2H), 7.28 (d, 2H).

Example 138

N-iso-butyryl-N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.13 (d, 6H), 1.38 (d, 6H), 2.71 (m, 1H), 2.93 (m, 1H), 3.69 (s, 3H), 7.28 (ddd, 1H), 7.39 (d, 1H), 7.53 (d, 2H), 7.59-7.67 (m, 2H), 7.73 (d, 2H).

Example 139

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.13 (d, 6H), 1.31 (d, 6H), 2.85 (broad m, 1H), 2.88 (m, 1H), 3.69 (s, 3H), 7.26-7.36 (m, 4H), 7.43 (d, 2H), 7.48 (dd, 1H).

Example 140

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.71 (s, 3H), 7.15-7.40 (m, 9H), 7.48-7.57 (m, 3H), 7.67 (tt, 1H), 7.71 (broad d, 2H), 8.21 (d, 1H).

Example 141

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.68 (s, 3H), 3.71 (s, 3H), 6.77 (d, 2H), 7.17 (broad d, 2H), 7.21-7.41 (m, 5H), 7.44-7.56 (m, 3H), 7.66 (tt, 1H), 7.74 (broad d, 2H), 8.21 (d, 1H).

Example 142

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.18 (s, 3H), 2.41 (s, 3H), 3.67 (s, 3H), 3.87 (s, 3H), 7.03 (d, 1H), 7.26 (dd, 1H), 7.31-7.36 (m, 3H), 7.42 (d, 2H).

Example 143

N-acetyl-N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.32 (s, 3H), 2.33 (s, 3H), 3.63 (s, 3H), 3.89 (s, 3H), 6.71 (d, 1H), 6.97 (d, 1H), 7.30 (d, 2H), 7.37 (d, 2H), 7.52 (t, 1H).

Example 144

N-iso-butyryl-N-(4-chlorophenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.17 (d, 6H), 1.33 (d, 6H), 2.85 (m, 1H), 3.05 (broad m, 1H), 3.63 (s, 3H), 3.86 (s, 3H), 6.69 (d, 1H), 6.97 (d, 1H), 7.29 (d, 2H), 7.37 (d, 2H), 7.50 (t, 1H).

Example 145

N-benzoyl-N-(4-chlorophenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.50 (s, 3H), 3.65 (s, 3H), 6.64 (d, 1H), 6.97 (d, 1H), 7.20-7.34 (m, 6H), 7.40 (tt, 1H), 7.48-7.59 (m, 3H), 7.67 (tt, 1H), 7.82 (broad d, 2H), 8.20 (d, 2H).

Example 146

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-5-carboxamide

1H NMR : 2.28 (s, 3H), 2.33 (s, 3H), 3.64 (s, 3H), 3.80 (s, 3H), 3.89 (s, 3H), 6.70 (d, 1H), 6.91 (d, 2H), 6.97 (d, 1H), 7.27 (broad d, 2H), 7.51 (t, 1H).

Example 147

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.14 (d, 6H), 1.33 (d, 6H), 2.85 (m, 1H), 3.01 (broad m, 1H), 3.64 (s, 3H), 3.81 (s, 3H), 3.85 (s, 3H), 6.68 (d, 1H), 6.91 (d, 2H), 6.97 (d, 1H), 7.27 (d, 2H), 7.48 (t, 1H).

Example 148

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.49 (s, 3H), 3.64 (s, 3H), 3.72 (s, 3H), 6.63 (d, 1H), 6.79 (d, 2H), 6.95 (d, 1H), 7.19-7.32 (m, 4H), 7.37 (t, 1H), 7.48 (t, 1H), 7.54 (t, 2H), 7.66 (tt, 1H), 7.83 (broad d, 2H), 8.21 (d, 2H).

Example 149

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.29 (t, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 2.99 (q, 2H), 3.70 (s, 3H), 7.07-7.15 (m, 3H), 7.29 (d, 1H), 7.37 (m, 2H), 7.53 (dd, 1H).

Example 150

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.14 (d, 6H), 1.26 (t, 3H), 1.33 (d, 6H), 2.84 (m, 1H), 2.94 (broad m, 1H), 2.97 (q, 2H), 3.68 (s, 3H), 7.06-7.14 (m, 3H), 7.28 (d, 1H), 7.36 (m, 2H), 7.50 (dd, 1H).

Example 151

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.21 (t, 3H), 2.92 (q, 2H), 3.70 (s, 3H), 6.95 (t, 2H), 7.09 (d, 1H), 7.24-7.33 (m, 5H), 7.37 (tt, 1H), 7.50-7.58 (m, 3H), 7.69 (tt, 1H), 7.80 (broad d, 2H), 8.20 (d, 2H).

Example 152

N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.29 (t, 3H), 2.17 (s, 3H), 2.35 (s, 3H), 3.00 (q, 2H), 3.69 (s, 3H), 7.12 (d, 1H), 7.29 (d, 1H), 7.49-7.57 (m, 3H), 7.72 (d, 2H).

Example 153

N-iso-butyryl-N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.14 (d, 6H), 1.27 (t, 3H), 1.32 (d, 6H), 2.79 (broad m, 1H), 2.84 (m, 1H), 2.99 (q, 2H), 3.69 (s, 3H), 7.10 (d, 1H), 7.29 (d, 1H), 7.47-7.56 (m, 3H), 7.71 (d, 2H).

Example 154

N-benzoyl-N-(4-trifluoromethylphenyl)-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 1.22 (t, 3H), 2.93 (broad q, 2H), 3.69 (s, 3H), 7.11 (d, 1H), 7.25-7.43 (m, 6H), 7.50-7.58 (m, 5H), 7.68 (t, 1H), 7.77 (broad d, 2H), 8.21 (d, 2H).

Example 155

N-acetyl-N-(4-methoxyphenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.28 (t, 3H), 2.20 (s, 3H), 2.35 (s, 3H), 2.99 (q, 2H), 3.70 (s, 3H), 3.81 (s, 3H), 6.93 (d, 2H), 7.10 (d, 1H), 7.26-7.35 (m, 3H), 7.51 (dd, 2H).

Example 156

N-iso-butyryl-N-(4-methoxyphenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.13 (d, 6H), 1.26 (t, 3H), 1.33 (d, 6H), 2.84 (m, 1H), 2.89-3.03 (m, 3H), 3.69 (s, 3H), 3.81 (s, 3H), 6.92 (d, 2H), 7.08 (d, 1H), 7.25-7.32 (m, 3H), 7.49 (dd, 1H).

Example 157

N-benzoyl-N-(4-methoxyphenyl)-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.20 (t, 3H), 2.91 (broad q, 2H), 3.69 (s, 3H), 3.71 (s, 3H), 6.77 (d, 2H), 7.07 (d, 1H), 7.18-7.32 (m, 5H), 7.47-7.58 (m, 3H), 7.68 (tt, 1H), 7.83 (broad d, 2H), 8.21 (d, 2H).

Example 158

N-acetyl-N-(4-fluorophenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.20 (s, 3H), 2.36 (s, 3H), 3.69 (s, 3H), 7.14 (t, 2H), 7.30 (dd, 1H), 7.32-7.40 (m, 3H), 7.50 (dd, 1H).

Example 159

N-iso-butyryl-N-(4-fluorophenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.13 (d, 6H), 1.31 (d, 6H), 2.87 (broad m, 1H), 2.88 (m, 1H), 3.68 (s, 3H), 7.13 (t, 2H), 7.27 (dd, 1H), 7.30-7.39 (m, 3H), 7.44 (dd, 2H).

Example 160

N-benzoyl-N-(4-fluorophenyl)-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 3.70 (s, 3H), 6.96 (t, 2H), 7.19-7.42 (m, 7H), 7.46-7.57 (m, 3H), 7.67 (tt, 1H), 7.72 (broad d, 2H), 8.21 (d, 1H).

Example 161

N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.17 (s, 3H), 2.36 (s, 3H), 3.69 (s, 3H), 7.31 (dd, 1H), 7.35 (dd, 1H), 7.47-7.55 (m, 3H), 7.74 (d, 2H).

Example 162

N-iso-butyryl-N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.13 (d, 6H), 1.31 (d, 6H), 2.75 (broad m, 1H), 2.88 (m, 1H), 3.70 (s, 3H), 7.29 (dd, 1H), 7.34 (dd, 1H), 7.49 (dd, 1H), 7.51 (d, 2H), 7.74 (d, 2H).

Example 163

N-benzoyl-N-(4-trifluoromethylphenyl)-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.70 (s, 3H), 7.24-7.42 (m, 7H), 7.48-7.57 (m, 5H), 7.67 (tt, 1H), 7.70 (broad d, 2H), 8.21 (d, 1H).

Examples 164-208

A library of 4-O-mono-acylated compounds (4-acyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxanilides and 4-acyloxy-6,7-dihydro-7-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxanilides) was prepared by basic cleavage of the corresponding di-acylated starting materials according to the following general procedure:

A solution of NaOH in MeOH (0.10 mL, 0.020 mmol, 0.20 M) was added to a solution of the di-acylated starting material (0.020 mmol) in THF (0.2 mL) and MeOH (0.2 mL). The reaction mixture was stirred for 5 min, then aq. HCl (0.10 mL, 0.020 mmol, 0.20 M) was added followed by water (3-5 mL) to precipitate the product. After centrifugation, removal of water, and drying, the product was dissolved in CH2Cl2 and purified by silica column chromatography (heptane-EtOAc 2:1, 1:1, 0:1).

Example 164

N-phenyl-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.46 (s, 3H), 3.80 (s, 3H), 3.95 (s, 3H), 6.79 (d, 1H), 7.07 (d, 1H), 7.11 (tt, 1H), 7.35 (t, 2H), 7.62 (t, 1H), 7.69 (d, 2H), 11.20 (s, 1H).

Example 165

N-phenyl-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 3.58 (s, 3H), 3.83 (s, 3H), 6.73 (d, 1H), 7.06 (tt, 1H), 7.08 (d, 1H), 7.28 (t, 2H), 7.54 (t, 2H), 7.58-7.70 (m, 4H), 8.27 (d, 2H), 10.87 (s, 1H).

Example 166

N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR : 2.47 (s, 3H), 3.80 (s, 3H), 3.97 (s, 3H), 6.80 (d, 1H), 7.08 (d, 1H), 7.59 (d, 2H), 7.65 (t, 1H), 7.82 (d, 2H), 11.74 (s, 1H).

Example 167

N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.41 (d, 6H), 3.03 (m, 1H), 3.75 (s, 3H), 3.93 (s, 3H), 6.80 (d, 1H), 7.05 (d, 1H), 7.56 (d, 2H), 7.63 (t, 1H), 7.79 (d, 2H), 11.31 (s, 1H).

Example 168

N-(4-trifluoromethylphenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.59 (s, 3H), 3.82 (s, 3H), 6.75 (d, 1H), 7.09 (d, 1H), 7.51 (d, 2H), 7.56 (t, 2H), 7.64 (t, 1H), 7.68 (tt, 1H), 7.75 (d, 2H), 8.27 (d, 2H), 11.49 (s, 1H).

Example 169

N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.45 (s, 3H), 3.79 (s, 3H), 3.95 (s, 3H), 6.79 (d, 1H), 7.03 (t, 2H), 7.07 (d, 1H), 7.62 (t, 1H), 7.65 (m, 2H), 11.33 (s, 1H).

Example 170

N-(4-fluorophenyl)-4-iso-butyryloxy-1,2-dihydro-5-methoxy-1-methyl- 2-oxo-quinoline-3-carboxamide

1H NMR: 1.40 (d, 6H), 3.02 (m, 1H), 3.77 (s, 3H), 3.92 (s, 3H), 6.78

(d, 1H), 7.02 (t, 2H), 7.05 (d, 1H), 7.61 (t, 1H), 7.64 (m, 2H), 10.85 (s, 1H).

Example 171

N-phenyl-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.35 (t, 3H), 2.54 (s, 3H), 3.16 (q, 2H), 3.85 (s, 3H), 7.12 (tt, 1H), 7.19 (d, 1H), 7.36 (t, 2H), 7.38 (d, 1H), 7.62 (dd, 1H), 7.69 (d, 2H), 11.75 (s, 1H).

Example 172

N-phenyl-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.32 (t, 3H), 1.44 (d, 6H), 3.08 (m, 1H), 3.16 (q, 2H), 3.84 (s, 3H), 7.11 (tt, 1H), 7.19 (d, 1H), 7.35 (t, 2H), 7.38 (d, 1H), 7.61 (dd, 1H), 7.68 (d, 2H), 11.26 (s, 1H).

Example 173

N-phenyl-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline- 3-carboxamide

1H NMR: 1.20 (t, 3H), 3.08 (broad m, 2H), 3.88 (s, 3H), 7.05 (tt, 1H), 7.18 (d, 1H), 7.27 (t, 2H), 7.42 (d, 1H), 7.53-7.67 (m, 5H), 7.71 (tt, 1H), 8.30 (d, 2H), 11.51 (s, 1H).

Example 174

N-(4-chlorophenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

2H NMR: 1.34 (t, 3H), 2.53 (s, 3H), 3.16 (q, 2H), 3.84 (s, 3H), 7.21 (d, 1H), 7.31 (d, 2H), 7.39 (d, 1H), 7.63 (dd, 1H), 7.65 (d, 2H), 11.94 (s, 1H).

Example 175

N-(4-chlorophenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.32 (t, 3H), 1.44 (d, 6H), 3.07 (m, 1H), 3.17 (q, 2H), 3.84 (s, 3H), 7.20 (d, 1H), 7.30 (d, 2H), 7.38 (d, 1H), 7.59-7.67 (m, 3H), 11.50 (s, 1H).

Example 176

N-phenyl-4-acetoxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.46 (d, 3H), 2.51 (s, 3H), 3.77 (s, 3H), 6.77 (q, 1H), 7.10 (tt, 1H), 7.34 (t, 2H), 7.69 (d, 2H), 11.87 (s, 1H).

Example 177

N-phenyl-4-iso-butyryloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 1.43 (d, 6H), 2.45 (d, 3H), 3.12 (m, 1H), 3.77 (s, 3H), 6.65 (q, 1H), 7.09 (tt, 1H), 7.33 (t, 2H), 7.69 (d, 2H), 11.73 (s, 1H).

Example 178

N-(4-fluorophenyl)-4-benzoyloxy-6,7-dihydro-3,7-dimethyl-6-oxo-thieno[2,3-b]pyridine-5-carboxamide

1H NMR: 2.37 (d, 3H), 3.81 (s, 3H), 6.67 (q, 1H), 6.95 (t, 2H), 7.52-7.60 (m, 4H), 7.70 (tt, 1H), 8.28 (d, 2H), 11.84 (s, 1H).

Example 179

N-phenyl-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

*H NMR: 1.49 (d, 6H), 3.18 (m, 1H), 3.84 (s, 3H), 7.11 (tt, 1H), 7.31-7.41 (m, 3H), 7.48 (d, 1H), 7.70 (d, 2H), 7.75 (ddd, 1H), 7.90 (dd, 1H), 11.67 (s, 1H).

Example 180

N-phenyl-4-benzoyloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.88 (s, 3H), 7.07 (tt, 1H), 7.29 (t, 2H), 7.35 (t, 1H), 7.52 (d, 1H), 7.59 (t, 2H), 7.64 (d, 2H), 7.72 (tt, 1H), 7.76 (tt, 1H), 7.97 (dd, 1H), 8.34 (d, 2H), 11.73 (s, 1H).

Example 181

N-(4-methoxyphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.57 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 6.90 (d, 2H), 7.38 (t, 1H), 7.48 (d, 1H), 7.61 (d, 2H), 7.75 (ddd, 1H), 7.95 (dd, 1H), 11.72 (s, 1H).

Example 182

N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.59 (s, 3H), 3.85 (s, 3H), 7.41 (t, 1H), 7.50 (d, 1H), 7.60 (d, 2H), 7.78 (ddd, 1H), 7.83 (d, 2H), 7.97 (dd, 1H), 12.23 (s, 1H).

Example 183

N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.50 (d, 6H), 3.18 (m, 1H), 3.85 (s, 3H), 7.39 (tt, 1H), 7.50 (d, 1H), 7.60 (d, 2H), 7.77 (ddd, 1H), 7.82 (d, 2H), 7.91 (dd, 1H), 12.08 (s, 1H).

Example 184

N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.52 (s, 3H), 3.84 (s, 3H), 7.13 (tt, 1H), 7.32-7.45 (m, 4H), 7.59 (dd, 1H), 7.68 (d, 2H), 11.16 (s, 1H).

Example 185

N-phenyl-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.40 (d, 6H), 3.06 (m, 1H), 3.82 (s, 3H), 7.12 (tt, 1H), 7.35 (t, 2H), 7.38 (dd, 1H), 7.41 (dd, 1H), 7.57 (dd, 1H), 7.66 (d, 2H), 10.43 (s, 1H).

Example 186

N-phenyl-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

2H NMR: 3.87 (s, 3H), 7.07 (tt, 1H), 7.27 (t, 2H), 7.38 (dd, 1H), 7.45 (dd, 1H), 7.52-7.62 (m, 5H), 7.68 (tt, 1H), 8.29 (d, 2H), 10.80 (s, 1H).

Example 187

N-(4-chlorophenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.52 (s, 3H), 3.83 (s, 3H), 7.31 (d, 2H), 7.41 (dd, 1H), 7.44 (dd, 1H), 7.60 (dd, 1H), 7.64 (d, 2H), 11.41 (s, 1H).

Example 188

N-(4-methoxyphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.51 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 6.90 (d, 2H), 7.38-7.45 (m, 2H), 7.55-7.62 (m, 3H), 11.03 (s, 1H).

Example 189

N-(4-methoxyphenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.39 (d, 6H), 3.05 (m, 1H), 3.81 (s, 3H), 3.81 (s, 3H), 6.88 (d, 2H), 7.37 (dd, 1H), 7.40 (dd, 1H), 7.53-7.61 (m, 3H), 10.27 (s, 1H).

Example 190

N-phenyl-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.59 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 7.12 (tt, 1H), 7.30 (d, 1H), 7.32-7.39 (m, 3H), 7.43 (d, 1H), 7.71 (d, 2H), 12.00 (s, 1H).

Example 191

N-phenyl-4-iso-butyryloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.49 (d, 6H), 3.19 (m, 1H), 3.83 (s, 3H), 3.89 (s, 3H), 7.11 (tt, 1H), 7.26 (d, 1H), 7.35 (t, 2H), 7.35 (dd, 1H), 7.42 (d, 1H), 7.70 (d, 2H), 11.83 (s, 1H).

Example 192

N-(4-fluorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.58 (s, 3H), 3.83 (s, 3H), 3.92 (s, 3H), 7.04 (t, 2H), 7.30 (d, 1H), 7.38 (dd, 1H), 7.44 (dd, 1H), 7.67 (m, 2H), 12.05 (s, 1H).

Example 193

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.58 (s, 3H), 3.83 (s, 3H), 3.92 (s, 3H), 7.30 (d, 1H), 7.31 (d, 2H), 7.38 (dd, 1H), 7.44 (d, 1H), 7.66 (d, 2H), 12.15 (s, 1H).

Example 194

N-(4-chlorophenyl)-4-benzoyloxy-1,2-dihydro-6-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.82 (s, 3H), 3.86 (s, 3H), 7.23 (d, 2H), 7.32 (d, 1H), 7.38 (dd, 1H), 7.47 (d, 1H), 7.59 (d, 2H), 7.60 (t, 2H), 7.73 (tt, 1H), 8.33 (d, 2H), 12.04 (s, 1H).

Example 195

N-phenyl-4-acetoxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.59 (s, 3H), 3.82 (s, 3H), 7.13 (tt, 1H), 7.36 (t, 2H), 7.43 (d, 1H), 7.66-7.72 (m, 3H), 7.89 (d, 1H), 11.73 (s, 1H).

Example 196

N-(4-fluorophenyl)-4-iso-butyryloxy-6-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.49 (d, 6H), 3.16 (m, 1H), 3.82 (s, 3H), 7.04 (t, 2H), 7.43 (d, 1H), 7.65 (m, 2H), 7.69 (dd, 1H), 7.83 (d, 1H), 11.60 (s, 1H).

Example 197

N-(4-chlorophenyl)-4-benzoyloxy-6-chloro- 1 , 2 -dihydro-1-methyl-2 -oxo-quinoline-3 -carboxamide

1H NMR: 3.85 (s, 3H), 7.24 (d, 2H), 7.46 (d, 1H), 7.57 (d, 2H), 7.61 (t, 2H), 7.70 (dd, 1H), 7.74 (tt, 1H), 7.91 (d, 1H), 8.32 (d, 2H), 11.78 (s, 1H).

Example 198

N-(4-chlorophenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.46 (s, 3H), 3.80 (s, 3H), 3.96 (s, 3H), 6.80 (d, 1H), 7.08 (d, 1H), 7.30 (d, 2H), 7.62 (t, 1H), 7.66 (d, 2H), 11.48 (s, 1H).

Example 199

N-(4-methoxyphenyl)-4-benzoyloxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.57 (s, 3H), 3.77 (s, 3H), 3.82 (s, 3H), 6.72 (d, 1H), 6.82 (d, 2H), 7.08 (d, 1H), 7.50-7.69 (m, 6H), 8.26 (d, 2H), 10.69 (s, 1H).

Example 200

N-(4-fluorophenyl)-4-benzoyloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.20 (t, 3H), 3.08 (broad m, 2H), 3.88 (s, 3H), 6.95 (t, 2H), 7.19 (d, 1H), 7.42 (d, 1H), 7.54 (m, 2H), 7.58 (t, 2H), 7.63 (dd, 1H), 7.71 (tt, 1H), 8.29 (d, 2H), 11.62 (s, 1H).

Example 201

N-(4-trifluoromethylphenyl)-4-acetoxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

*H NMR : 1.35 (t, 3H), 2.55 (s, 3H), 3.17 (q, 2H), 3.86 (s, 3H), 7.22 (d, 1H), 7.40 (d, 1H), 7.60 (d, 2H), 7.65 (dd, 1H), 7.82 (d, 2H), 12.18 (s, 1H).

Example 202

N-(4-trifluoromethylphenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.33 (t, 3H), 1.45 (d, 6H), 3.08 (m, 1H), 3.17 (q, 2H), 3.83 (s, 3H), 7.21 (d, 1H), 7.38 (d, 1H), 7.59 (d, 2H), 7.63 (dd, 1H), 7.80 (d, 2H), 11.77 (s, 1H).

Example 203

N-(4-methoxyphenyl)-4-iso-butyryloxy-5-ethyl-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.32 (t, 3H), 1.43 (d, 6H), 3.07 (m, 1H), 3.16 (q, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.89 (d, 2H), 7.18 (d, 1H), 7.37 (d, 1H), 7.60 (d, 2H), 7.60 (t, 1H), 11.11 (s, 1H).

Example 204

N-(4-fluorophenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.51 (s, 3H), 3.83 (s, 3H), 7.05 (t, 2H), 7.41 (dd, 1H), 7.43 (dd, 1H), 7.59 (dd, 1H), 7.64 (m, 2H), 11.29 (s, 1H).

Example 205

N-(4-fluorophenyl)-4-iso-butyryloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 1.40 (d, 6H), 3.05 (m, 1H), 3.80 (s, 3H), 7.03 (t, 2H), 7.38 (dd, 1H), 7.41 (dd, 1H), 7.58 (dd, 1H), 7.63 (m, 2H), 11.61 (s, 1H).

Example 206

N-(4-fluorophenyl)-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.86 (s, 3H), 6.96 (t, 2H), 7.38 (dd, 1H), 7.46 (dd, 1H), 7.50-7.59 (m, 4H), 7.60 (dd, 1H), 7.68 (tt, 1H), 8.29 (d, 2H), 10.97 (s, 1H).

Example 207

N-(4-trifluoromethylphenyl)-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 2.53 (s, 3H), 3.84 (s, 3H), 7.42 (dd, 1H), 7.45 (dd, 1H), 7.60 (d, 2H), 7.61 (dd, 1H), 7.81 (d, 2H), 11.67 (s, 1H).

Example 208

N-(4-trifluoromethylphenyl)-4-benzoyloxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide

1H NMR: 3.87 (s, 3H), 7.40 (dd, 1H), 7.46 (dd, 1H), 7.52 (d, 2H), 7.57 (t, 2H), 7.62 (dd, 1H), 7.66-7.74 (m, 3H), 8.29 (d, 2H), 11.41 (s, 1H).

Example 209

Solubility measurements

Solubilities of a di- and a mono-acylated compound were measured in 0.2 M phosphate buffer pH 7.4 and compared with the solubility of the corresponding non-acylated compound.

Saturated compound solutions were prepared by mixing the compounds and the buffer solution at ambient temperature for 24 h followed by separation of the aqueous solution by centrifugation. Standard solutions of compounds (1.00 mg/mL) were prepared in DMSO.

The compound concentrations were measured by HPLC-MS/UV (Waters Alliance 2790 Separations Module / 996 PDA detector / Micromass

Quattro Micro) after approprite dilutions of the aqueous saturated solutions (1/10 and 1/100) and the standard solutions (1/100, 1/200, and 1/1000), respectively, with mobile phase solvent.

The following compounds were tested:

Compound 1

N-acetyl-N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (Example 30)

Compound 2

N-phenyl-4-acetoxy-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide (Example 31)

Compound 3

N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (N-hydrogen amide derivative of Roquinimex)

Results (from two dilutions):

Compound 1: 21 and 38 mg/L

Compound 2: 186 and 221 mg/L

Compound 3 : <1 mg/L

The results show that acylation of N-hydrogen-4-hydroxy-carboxanilides to give acylated prodrugs can enhance the aqueous solubility considerably.

Example 210

Activation of the aryl-hydrocarbon receptor

Activation of the aryl hydrocarbon receptor can be measured in cell-based reporter-gene assays, which consist of cell lines containing the aryl hydrocarbon recptor and transfected with a reporter gene regulated by activated Ahr via an XRE (xenobiotic response element). AhR activation will thus result in an enhanced expression of the reporter protein (e.g. luciferase) which functional activity can be measured.

Commercial reporter-gene assays for this purpose are e.g. the GeneBLAzer® CYP1A1-bla LS-180 cell line (Invitrogen) which involves an XRE of a CYP1A1 promotor and a beta-lactamase reporter gene, the XDS-CALUXR® assay (Xenobiotic Detection Systems) developed in a mouse hepatoma cell-line using the luciferase reporter gene, and the Cignal XRE Reporter (SABiosciences) also with a luciferase reporter gene. Such reporter-gene assays can also be constructed by a person skilled in the art.

Activation of human AhR was measured in the GeneBLAzer® CYP1A1-bla LS-180 cell line (Invitrogen Corporation, Madison, www.invitrogen.com/drugdiscovery) using a beta-lactamase reporter gene (.bla) combined with a FRET-enabled substrate sensitive to bla expression.

CYPlAl-bla LS-180 cells are harvested and suspended in Assay Media (OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM Sodium Pyruvate, 100 U/mL/100 μg/mL Pen/Strep) to a concentration of 625,000 cells/mL. 32 μL of cell suspension (20,000 cells) is added to each well of a 384-well Poly-D-Lysine assay plate. Cells in assay media are incubated for 16-24 hours in the plate at 37-C/5% CO2 in a humidified incubator. 4 μL of a 10X serial dilution of beta-naphthoflavone (control activator starting concentration, 100,000 nM) or compounds are added to appropriate wells. 4 μL of Assay Media is added to all wells to bring the final assay volume to 40 μL. The plate is incubated for 16 hours at 37C/5% CO2 in a humidified incubator. 8 μL of 1 μΜ Substrate solution is added to each well and the plate is incubated for 1.5 hours at room temperature. The plate is read on a fluorescence plate reader.

Test Compounds

The compounds tested in duplicates are serially diluted in 100% DMSO to 1000 x test concentrations. An aliquot of the serial dilution is diluted 1:100 in assay media and then added to the assay plate where the addition of other assay reagents dilute the compounds to the final test concentration in the assay with a DMSO concentration of 0.1%.

The following compounds were tested:

Compound 4

N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (Laquinimod, an N-alkyl amide reference compound)

Compound 5

N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide (N-hydrogen amide derivative of Laquinimod)

Compound 6

N-(4-trifluoromethylphenyl)-1,2-dihydro-4-hydroxy-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide (Example 11)

Compound 7

N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3- carboxamide (Example 13)

Compound 8

N-(4-fluorophenyl)-6-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo- quinoline-3-carboxamide (Example 27)

The results shown in the table below are presented as % activation at different compound concentrations (nM) where 100% activation represents the maximum activation by the assay reference compound beta-naphthoflavone (EC50 2090 nM).

The results show that the N-hydrogen-carboxanilide derivatives, contrary to the N-alkyl-carboxanilides, are potent activators of the aryl hydrocarbon receptor.

Example 211

In vivo activity in the MS model Experimental Autoimmune Encephalomyelitis (EAE) in rats

EAE was induced day 0 in female Dark Agouti (DA) rats with subcutaneous injection of spinal cord homogenate (SCH, approximately 2 mg, from naive rats) emulsified in incomplete Freunds adjuvant (IFA, total volume 100 ul per rat) at the base of the tail. Disease was evaluated daily from day 5 until the end of the experiment (day

22) according to following criteria: 0 = healthy, 1 = tail weakness, 2 = tail paralysis, 3 = tail paralysis and mild waddle, 4 = tail paralysis and severe waddle, 5 = tail paralysis and paralysis of one limb, 6 = tail paralysis and paralysis of both hind limbs, 7 = tetraparesis or paralysis of three limbs, and 8 = premorbid or dead.

Statistical analysis was performed using Prism 5 for Mac OS X (GraphPad Software, San Diego, CA, USA).

Experimental groups and treatment

Treatment was initiated day 0 after EAE induction with following treatment injections administered day 3, 6, and 9. The dose was administered as a 500 uL corn oil solution subcutaneously at the lower back. Treatment groups were mixed in all cages to avoid cage effects.

Groups:

Control (vehicle, corn oil, Sigma Aldrich), 11 animals

Cyclosporin A (positive control, Sigma Aldrich), 10 mg/kg, first dissolved in 70% EtOH to 50 mg/mL, 11 animals

Compound 9 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide, Example 74), 1 mg/kg, 10 animals

Results in the graph below show that administration of Compound 9 (1 mg/kg day 0, 3, 6, and 9) efficiently prevented EAE development. After discontinuation of treatment the severity of the first disease period was lower than for vehicle control treated animals.


References

1. Derivatives of 6,7 or 8 cycloalkyl 4-oxo quinoline 3 carboxyl acid. Ferrini, P. G. et al., US3960868A (Jun 1, 1976, Ciba-Gei Corporation).

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