HIV integrase inhibitors

Abstract

The present invention describes novel compounds of Formula I which inhibit HIV integrase. The invention also describes compositions and treatments of AIDS or ARC by using these compounds. 1

Description

BACKGROUND OF THE INVENTION

[0001] Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics (UNAIDS: Report on the Global HIV/AIDS Epidemic, December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.

[0002] There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavaridine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Further, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853).

[0003] Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV-1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drug potency, poor compliance to the complicated drug regiment as well as intrinsic pharmacological barriers to exposure provides fertile ground for resistance to emerge. More disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (<50 copies/ml) (Carpenter, C. C. J.; Cooper, D. A.; Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schecter, M.; Schoolery, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 2000, 283,381). Clearly there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further.

[0004] HIV expresses three enzymes, reverse transcriptase, an aspartyl protease and integrase, all of which are potential antiviral targets for the development of drugs for the treatment of AIDS. However, integrase stands out as being the only viral enzyme not targeted by current therapy. The integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is a critical step in the viral life cycle. There are a number of discrete steps involved in this process including processing of the viral cDNA by removal of two bases from each 3′-terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. Therefore, an inhibitor of integrase would be useful as a therapy for AIDS and HIV infection.

[0005] A number of inhibitors of the enzyme have been reported. These include, nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Neamati, N. Expert Opin. Ther. Patents 2002, 12, 709-724). Diketoamide HIV integrase inhibitors have been disclosed (WO 0316266, WO 0335076, WO 0335077, WO 02070486). However, no clinically approved compound has resulted from these leads. Thus, clinically effective inhibitors of HIV integrase would fulfill a therapeutic need.

SUMMARY OF INVENTION

[0006] The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts and solvates thereof 2

Formula I

[0007] wherein R1, R2, R3, and B1 are described as below. The invention includes compositions and methods of treatment using these compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0008] The present invention describes compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof 3

[0009] wherein:

[0010] R1 is

[0011] -phenyl substituted with 1-3 R4,

[0012] -naphthyl, furanyl, thienyl, pyridyl, or imidazolyl unsubtituted or substituted with 1-3 R4,

[0013] —C1-C6 alkyl-aryl unsubtituted or substituted with 1-3 R4, or

[0014] —C1-C5 alkyl-O-aryl unsubtituted or substituted with 1-3 R4;

[0015] R2 is

[0016] —H,

[0017] —C1-C6 alkyl,

[0018] -aryl unsubstituted or substituted with 1-3 R4, or

[0019] —C1-C6 alkyl aryl unsubstituted or substituted with 1-3 R4;

[0020] R3 is

[0021] —H,

[0022] —C1-C6 alkyl,

[0023] —C1-C6 alkyl-aryl unsubstituted or substituted with 1-3 R, or

[0024] —OR9;

[0025] R4 is independently selected from

[0026] -halo,

[0027] —CN,

[0028] —C1-C6 alkyl,

[0029] —C3-C6 cycloalkyl,

[0030] —C1-C6 haloalkyl,

[0031] —OR5,

[0032] —CO2R6,

[0033] —N(R7)(R8),

[0034] —CON(R7)(R8),

[0035] —SR5,

[0036] —SOC1-C6alkyl, and

[0037] —SO2C1-C6alkyl;

[0038] R5 and R6 are independently selected from —H and —C1-C6 alkyl;

[0039] R7 and R8 are independently selected from —H and —C1-C6 alkyl, or NR7R8 is a heterocycle selected from pyrrolidine, piperidine,

[0040] 4-hydroxypiperidine, morpholine, thiomorpholine, piperazine, and

[0041] 4-methylpiperazine;

[0042] R9 is

[0043] —H,

[0044] —C1-C10 alkyl,

[0045] —C1-C6 alkyl-aryl,

[0046] —C2-C10 alkyl-OR5,

[0047] —C1-C10 alkyl-CO2R6,

[0048] —C1-C10 alkyl-N(R7)(R8),

[0049] —C1-C10 alkyl-CON(R7)(R8), or

[0050] —C1-C6 alkyl-heterocycle where the heterocycle is selected from pyrrolidine, piperidine, 4-hydroxypiperidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, and thiazinanedioxide;

[0051] B1 is selected from the group consisting of 4

[0052] R10 is

[0053] —H,

[0054] —C1-C6 alkyl,

[0055] -cycloalkyl,

[0056] —C1-C6 alkyl-aryl,

[0057] -phenyl unsubstituted or substituted with 1-3 R12,

[0058] benzofuran, dihydrobenzofuran, benzodioxane, or

[0059] -heteroaryl selected from furan, thiophene, pyrrole, imidazole, oxazole, thiazole, and pyridine;

[0060] R11 is

[0061] —C1-C6 alkyl,

[0062] -cycloalkyl,

[0063] -aryl unsubstituted or substituted with 1-2 R4,

[0064] —C1-C6 alkyl-aryl unsubstituted or substituted with 1-2 R4,

[0065] —C1-C6 alkyl-heteroaryl where the heteroaryl is selected from furan, thiophene, pyrrole, imidazole, oxazole, thiazole, and pyridine,

[0066] —C1-C6 alkyl-NR7R8,

[0067] —C1-C6 alkyl-OR5,

[0068] —C1-C6 alkyl-P(O)(OR6)2,

[0069] —C1-C6 alkyl-CO2R6, or

[0070] —C1-C6 alkyl-C(O)N(R7)(R8);

[0071] R12 is

[0072] halogen,

[0073] —C1-C6 alkyl,

[0074] —C1-C2 haloalkyl,

[0075] —C1-C3 thioalkyl,

[0076] —OR13,

[0077] tetrahydrofuran,

[0078] dihydropyran,

[0079] —NR7R8,

[0080] —CO2R6,

[0081] —CONR7R8, or

[0082] —CONHCH2Ph where Ph is unsubstituted or substituted with 1-2 R4;

[0083] R13 is

[0084] —H,

[0085] —C1-C6 alkyl,

[0086] —C1-C6 fluoroalkyl,

[0087] allyl,

[0088] propargyl,

[0089] phenyl,

[0090] benzyl,

[0091] —COC1-C6alkyl,

[0092] —CH2CO2R6, or

[0093] —CH2CONR7R8.

[0094] In the present invention, unless otherwise specified the following definitions apply.

[0095] The numbers in the subscript after the symbol “C” define the number of carbon atoms a particular group can contain. For example, “C1-C6” means a substituent containing from one to six carbon atoms.

[0096] As used herein, the term “alkyl” means a saturated, straight chain or branched monovalent hydrocarbon radical having the stated number of carbon atoms. Examples of such alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and, where indicated, higher homologues and isomers such as n-pentyl, n-hexyl, 2-methylpentyl and the like. Haloalkyl refers to an alkyl radical that is substituted with one or more halo radicals, such as trifluoromethyl.

[0097] As used herein, the term “cycloalkyl” means a non-aromatic 3-6 membered ring. Examples include, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0098] Halo means chloro, bromo, iodo or fluoro.

[0099] “Aryl” means an aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and napthyl, indenyl, azulenyl, fluorenyl and anthracenyl.

[0100] The term “heterocyle” refers to a monocyclic saturated heterocyclic nuclei having 3-6 atoms containing 1-3 heteroatoms selected from nitrogen, oxygen or sulfur. Heterocycles include, for example, piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.

[0101] “Heteroaryl” means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl include 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-thienyl, 3-thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl and 1,3,5-trithianyl.

[0102] By virtue of its acidic moiety, where applicable, a compound of Formula I forms salts by the addition of a pharmaceutically acceptable base. Such base addition salts include those derived from inorganic bases which include, for example, alkali metal salts (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium and magnesium), aluminum salts and ammonium salts. In addition, suitable base addition salts include salts of physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, N-benzyl-phenethylamine, dehydroabietylamine, N,N′-bishydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, ethylenediamine, ornithine, choline, N,N′-benzylphenethylamine, chloroprocaine, diethanolamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide and basic amino aids such as lysine, arginine and N-methylglutamine. These salts may be prepared by methods known to those skilled in the art.

[0103] Salts of an amine group may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aryl moiety.

[0104] Compounds of Formula I which are substituted with a basic group may exist as salts formed through acid addition. The acid addition salts are formed from a compound of Formula I and a pharmaceutically acceptable inorganic acid, including but not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or an organic acid such as p-toluenesulfonic, methanesulfonic, acetic, benzoic, citric, malonic, fumaric, maleic, oxalic, succinic, sulfamic, or tartaric. Thus, examples of such pharmaceutically acceptable salts include chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate.

[0105] Certain compounds of Formula I, and their salts, may also exist in the form of solvates with water, for example hydrates, or with organic solvents such as methanol, ethanol or acetonitrile to form, respectively, a methanolate, ethanolate or acetonitrilate. The present invention includes each solvate and mixtures thereof.

[0106] In addition, a compound of Formula I, or its salt or solvate, may exhibit polymorphism. The present invention also encompasses any such polymorphic form.

[0107] Certain compounds of Formula I may contain one or more chiral centers and exist in different optically active forms. When compounds of Formula I contain one chiral center, the compounds exist in two enantiomeric forms. The present invention includes both enantiomers and mixtures of enantiomers such as racemic mixtures. The enantiomers may be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts which may be separated by crystallization, gas-liquid or liquid chromatography, selective reaction of one enantiomer with an enantiomer-specific reagent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by a separation technique, then an additional step is required to form the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0108] Certain compounds of Formula I may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of compounds of Formula I and mixtures thereof.

[0109] Certain compounds of Formula I may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Formula I and mixtures thereof.

[0110] The compounds of this invention can also exist as tautomers; therefore the present invention also includes all tautomeric forms.

[0111] The compounds of Formula I are useful in the inhibition of HIV integrase, the prevention or treatment of infection by the human immunodeficiency virus and the treatment of consequent pathological conditions such as AIDS or ARC. The treatment involves administering to a patient, in need of such treatment, a compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug therefor.

[0112] Treatment extends to prophylaxis as well as established infections or symptoms. This includes initiating treatment pre- and post-exposure to the virus. In addition, the present invention can be administered in conjunction with other anti-HIV agents (HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and HIV-entry inhibitors), immunomodulators, antiinfectives and/or vaccines.

[0113] The compounds of the present invention are also useful in the preparation and execution of screening assays for antiviral compounds. Further, the compounds of the present invention are useful in establishing or determining the binding site of other antiviral compounds to HIV integrase, for example, by competitive inhibition.

[0114] The compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

[0115] This invention also provides a pharmaceutical composition for use in the above described therapeutic method. A pharmaceutical composition of the present invention comprises an effective amount of a compound of Formula I in association with a pharmaceutically acceptable carrier, excipient or diluent.

[0116] The active ingredient in such formulations comprises from 0.1 percent to 99.9 percent by weight of the formulation. By “pharmaceutically acceptable” it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0117] The present pharmaceutical compositions are prepared by known procedures using well known and readily available ingredients. The compositions of this invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, beadlets, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.

[0118] The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.

[0119] When administered orally, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation. For oral administration, the compound is typically formulated with excipients such as binders, fillers, lubricants, extenders, diluents, disintegration agents and the like as are known in the art.

[0120] For parenteral administration, the compound is formulated in pharmaceutically acceptable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, 5 percent dextrose, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0121] A compound of the present invention, or a salt or solvate thereof, can be formulated in unit dosage formulations comprising a dose between about 0.1 mg and about 1000 mg, or more, according to the particular treatment involved. An example of a unit dosage formulation comprises 5 mg of a compound of the present invention in a 10 mL sterile glass ampoule. Another example of a unit dosage formulation comprises about 10 mg of a compound of the present invention as a pharmaceutically acceptable salt in 20 mL of isotonic saline contained in a sterile ampoule.

[0122] The compounds of the present invention can also be administered to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses. One preferred dosage range is 1 to 20 mg/kg body weight orally in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the route of administration, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0123] General methods useful for the synthesis of compounds embodied in this invention are shown below. The preparations shown below are disclosed for the purpose of illustration and are not meant to be interpreted as limiting the processes to make the compounds by any other methods. It will be appreciated by those skilled in the art that a number of methods are available for the preparation of the compounds of the present invention as provided by Formula I.

[0124] Formula I compounds can be prepared by processes which include processes known in the chemical art for the production of structurally analogous compounds or by a novel process described herein. A process for the preparation of a compound of Formula I (or a pharmaceutically acceptable salt thereof) and novel intermediates for the manufacture of a compound of Formula I, as defined above, provide further features of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as defined above, unless otherwise specified. It will be recognized that it may be preferred or necessary to prepare a compound of Formula I in which a functional group is protected using a conventional protecting group, and then to remove the protecting group to provide the compound of Formula I.

[0125] Thus, there is provided a process for preparing a compound of Formula I (or a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions which is selected from any of those described in the examples, including the following.

[0126] The compounds of the present invention can be synthesized according to the following schemes. Schemes I-III represent general methods for the synthesis of the compounds. In Scheme I, an appropriately substituted amine, I-1, can be acylated under standard amide bond forming conditions to yield I-3. Methods for this type of transformation are described, in Jerry March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, 1985. The acetylamide I-3 can be condensed with dimethyl oxalate in the presence of a base such as NaOMe or LiHMDS. In the final step of the sequence, I-5 can be treated with and aldehyde, I-6, and an amine, I-7, to deliver the desired product I-8. 5

[0127] Scheme II illustrates an alternative synthesis. In this route, amine I-1 can be coupled to II-1 using standard amide bond forming methods. The product of this reaction is II-2 which can be converted into I-5 by methanolysis of the dioxalane ring system and the resulting product carried on to the final product in a manner similar to that in Scheme I. In scheme III, compound II-2 can be synthesized as before, but instead of forming intermediate I-5 it can be converted directly to I-8 according to the equation. 67

[0128] In Scheme IV, a substituted benzoic acid derivative can be coupled with amine IV-2 using standard amide bond forming methods to yield IV-3. This intermediate can be reduced to the corresponding benzylic amine, IV-4, which can be coupled to I-2. Intermediate IV-5 can then be condensed with dimethyl oxalate under basic conditions resulting in ketoacid IV-6. The final product can be delivered by treating IV-6 with paraformaldehyde and amine I-7 in acetic acid at elevated temperature. 8

[0129] In Scheme V, (3,4-dichloro-benzyl)-methylamine, V-1, can be coupled to III-B to yield Compound 37-A. This compound can then be treated with paraformaldehyde and amine I-7 resulting in V-2. 9

[0130] In Scheme VI, ketone or aldehyde, VI-1, can be condensed with an alkyl-hydroxylamine, VI-2, to yield the corresponding oxime. This can be then reduced with NaBH3CN to amine VI-4. It will be appreciated by those skilled in the art that this reduction can be carried out with a number of different reducing agents. Intermediate VI-4 can be coupled with III-B to yield VI-5 which can be taken on to VI-7 by two alternative routes. In one, VI-5 can be first treated with methanol to yield the corresponding methyl ester, VI-6, which can be converted to VI-7 as described previously. In the alternative procedure VI-5 can be treated with paraformaldehyde and I-7 as described in Scheme III. 10

[0131] In Scheme VII, amine VII-2 can be attached to an aldehyde-functionalized polystyrene resin (4-formyl-3-methoxy-phenoxymethyl functionalized polystyrene), VII-1, via reductive amination using methodology well known in the art. This intermediate can be coupled to acid, III-A using standard amide bond forming reaction conditions.

[0132] Intermediate VII-4 can be treated with 1-6 and 1-7 to yield VII-5. The final product can be cleaved from the resin under acidic conditions to yield product VII-6. 11

[0133] In Scheme VIII, intermediate carboxylic acid, VIII-1 can be converted to the corresponding acid chloride, VIII-2, under standard conditions. This compound can then be treated with amine VIII-3 under basic conditions to yield amide VIII-4. Amide VIII-4 can be treated with paraformaldehyde and methylamine to provide the final product, VIII-5. 12

[0134] In Scheme IX, compound IX-1 can be synthesized according to the procedure of Heynes R. et al. Bull. Soc. Chim. Fr. (1977) 906-910 and reacted with CH3I or Ac2O to yield intermediates IX-2 and IX-5 respectively. Saponification or hydrogenolysis of the benzyl ester can provide carboxylic acids IX-3 and IX-6 which can be coupled with I-1 under amide bond 10 forming reaction conditions. In the final step of the synthesis the methyl enol of XI-4 and the acetyl enol of IX-7 can be removed to deliver the final product IX-8. 13

[0135] In scheme X, Compound 82-A can be treated with trifluoroacetic acid to effect hydrolysis of the dimethyl-acetal. This then can be reacted with an heterocycle X-1 and a reducing agent such as sodium cyanoborohydride (NaBH3CN) to yield X-2. It will be understood by those skilled in the art that alternative reducing agents exist which can be used to carry out the same transformation. 14

[0136] In scheme XI Compound 24 can be reacted with amines, XI-1 and XI-3, using standard amide bond forming reagents to form compounds XI-2 and XI-4 respectively. 15

[0137] Another method for the synthesis of compounds of the current invention is illustrated in scheme XII. In this scheme Compound 84-A can be reacted with the corresponding acid chloride XII-1, sulfamoyl chloride XII-3 or sulfonyl chloride XII-5 under basic conditions to deliver compounds XII-2, XII-4 and XII-6 respectively. 16

[0138] In still another method to synthesize compounds of formula V-2, amine 1-7 and paraformaldehyde can be reacted in methanol at elevated temperature to form intermediate XIII-1 as shown in scheme XIII. This intermediate is not isolated but added to a methanolic solution of Compound 37-A to yield compounds of formula V-2. 17

[0139] The synthesis of compounds of formula XVI-1 is illustrated in Scheme XIV. In this scheme Compound 93-A can be converted to the corresponding methyl ester, 93-B, as described in the schemes above. Amine 1-7 and paraformaldehyde can be condensed to form intermediate XIII-1 which is reacted with 93-B as before to yield XIV-1. 18

[0140] Compounds of this invention can also be synthesized according to the method illustrated in Scheme XV. In this method 2,4-difluorobenzaldehyde can be treated with thiomethoxide to generate 2-methylthio-4 fluorobenzaldehyde which can be converted to compound XV-1 via reductive amination with amine R3NH2 (IV-2). This intermediate in turn can be acylated with III-B to yield XV-2. Oxidation of the sulfide to the corresponding sulfoxide and sulfone can be carried out under conditions familiar to those skilled in the art. Conversion of XV-3 and XV-4 to the corresponding compounds of formulas XV-5 and XV-6 can be achieved by reaction with amine I-7 and paraformaldehyde as described in previous methods. 19

[0141] In another method Compound 120-B can be treated with 1-7 and paraformaldehyde to yield compounds of formula XVI-1, as illustrated in Scheme XVI. 20

DESCRIPTION OF SPECIFIC EMBODIMENTS

[0142] The specific examples that follow illustrate the syntheses of the compounds of the instant invention, and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variations in order to produce compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different manner will also be evident to one skilled in the art.

[0143] In the following experimental procedures, all temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. In certain cases where the product is isolated as an inseparable mixture of isomers the integration of protons is given in decimal fractions corresponding to the proportion of that particular isomer's protons in the mixture. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). The solvents employed for taking NMR spectra are acetone-d6 (deuterated acetone), DMSO-d6 (perdeuterodimethylsulfoxide), D2O (deuterated water), CDCl3 (deuterochloroform) and other conventional deuterated solvents.

[0144] The abbreviations used herein are conventional abbreviations widely employed in the art. Some of which are: calcd (calculated); DMSO (dimethylsulfoxide); EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride); EtOAc (ethyl acetate); HOBt (1-hydroxybenzotriazole); HPLC (high-pressure liquid chromatography); LC/MS (liquid chromatography, mass spectroscopy); LDA (lithium diisopropyl amide); LiHMDS (lithium bis(trimethylsilyl)amide); MCPBA (3-chloroperoxybenzoic acid) SiO2 (silica gel); THF (tetrahydrofuran), TFA (trifluoroacetic acid), Me (methyl), Et (ethyl), Ph (phenyl), tBuOK (potassium tert-butoxide), NaOMe (sodium methoxide), NaOEt (sodium ethoxide), Boc (tert-butoxycarbonyl), and DEAD (diethylazo dicarboxylate).

Method A

[0145] Compound A-1: (S)-(+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl Ester 21

[0146] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (2.08 g, 11.9 mmol) in dry dichloromethane (20 ml) was treated with triethylamine (1.83 ml, 13.1 mmol) followed by a solution of t-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5 ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reaction mixture was diluted with toluene (250 ml) washed with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (4×12 cm) using a mixture of toluene and ethyl acetate (0-2%) as eluent gave 4.90 g (99% yield) of the title material as a clear oil. 1H NMR (400 MHz, CDCl3) 6:1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79 (dd, 1, J=4, 7), 7.4-7.8 (m, 10).

[0147] Compound A-2: 4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl Ester 22

[0148] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (21.65 g, 52.4 mmol) in carbon tetrachloride (160 ml) was treated with N-bromosuccinimide (9.35 g, 52.4 mmol) and 2,2′-azobisisobutyronitrile (200 mg) and the resulting mixture was heated under reflux (bath temperature 85° C.) while irradiating with a 500 watt lamp. After 10 minutes, the reaction mixture was cooled and the succinimide was filtered. The solvent was evaporated under vacuum to give the title bromide as a light yellow oil (˜26 g) which was used immediately for the next step. 1H NMR (400 MHz, CDCl3) δ: 1.12 (s, 9), 1.41 (s, 3), 1.80 (s, 3), 3.80 (m, 2), 7.3-7.7 (m, 10).

[0149] Compound A-3: (Z)-2,2-Dimethyl-5-(tert-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one 23

[0150] A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (−26 g, 52.4 mmol) in dry tetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5 minutes with 1,8-diazabicyclo [5,4,0] undec-7-ene (12.7 g, 78.8 mmol) and the resulting mixture was stirred at 5° C. for 1.5 hour. The solid formed was filtered and washed with a small amount of tetrahydrofuran. The filtrate was used as such for the next step.

[0151] Alternatively, the reaction mixture can be diluted with toluene, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and ethyl acetate (0-2%) as eluent. The title ester was obtained as an oil in 30-50% yield. 1HNMR (400 MHz, CDCl3) δ: 1.16 (s, 9), 1.76 (s, 6), 5.97 (s, 1), 7.4-7.8 (m, 10).

[0152] Compound III-A: (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic Acid 24

[0153] A solution of pure (Z)-2,2 dimethyl-5-(t-butyldiphenylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (2.80 g, 6.82 mmol) in tetrahydrofuran (40 ml) was treated at 22° C. with acetic acid (2 ml) followed by 6.8 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). The solvent was concentrated under reduced pressure and the residue was triturated with toluene to give 1.00 g (85% yield) of the title compound as a white crystalline material: mp 203-204° C. (dec.). IR (KBr) ν max (cm−1): 1805, 1707 and 1662. 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 6), 5.89 (s, 1). Anal. calcd for C7H8O5: C, 48.84; H, 4.68; Found: C, 48.84; H, 4.65.

[0154] Preparation of (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic Acid from Crude A-3

[0155] A solution of the crude (Z)-2,2-dimethyl-5-(tert-butyldiphenylsilyloxycarbonyl methylene)-1,3-dioxolan-4-one (52.4 mmol) in tetrahydrofuran (200 ml) was treated with acetic acid (13 ml) followed with 50 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue with toluene gave 6.3 g (70% yield for three steps) of the title material as a white solid (>95% pure by 1HNMR).

Method B

[0156] Compound B-1: (+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tertbutyldimethylsilyl Ester 25

[0157] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol) in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 hours. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96% yield) of the title material as a clear oil: Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). 1H NMR (400 MHz, CDCl3) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).

[0158] Compound B-2: 4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tertbutyldimethylsilyl Ester 26

[0159] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, t-butyldimethylsilyl ester (20.9 g, 72.4 mmol) in carbon tetrachloride (200 ml) was treated with N-bromosuccinimide (14.18 g, 79.6 mmol) and 2,2′-azobisisobutyronitrile (0.30 g) and the resulting mixture was heated under reflux while irradiating with a 500 W lamp. After approximately 5 minutes, a mild exothermic reaction was observed and the mixture was heated for an additional 5 minutes. The reaction mixture was then cooled in an ice bath and the floating succinimide was filtered and washed with a small amount of carbon tetrachloride. The filtrate was used immediately as such for the next step. 1H NMR (400 MHz, CDCl3) δ: 0.27 (s, 3), 0.28 (s, 3), 0.94 (s, 9), 1.66 (s, 3), 1.84 (s, 3), 3.62 (m, 2).

[0160] Compound B-3: (Z)-2,2-Dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolane 27

[0161] The solution of crude 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (approximately 220 ml) was cooled to 0-5° C. and treated dropwise over 10 minutes and under vigorous stirring with a solution of 1,8-diazabicyclo (5,4,0) undec-7-ene (12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate was formed which gradually became a granular solid. After 1 h, the solid obtained was filtered and washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a light orange oil which was used as such for the next step.

[0162] Compound III-A: (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic Acid 28

[0163] The crude (Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with acetic acid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate (500 ml), washed with water, brine and dried (anhydrous magnesium sulfate). Evaporation of the solvent under reduced pressure and trituration of the residual solid with toluene (50 ml) gave 7.70 g (62% yield for 3 steps) of the title Z-isomer as a white crystalline solid. Concentration of the mother liquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers. Z-Isomer; 1H NMR (400 MHz, CDCl3) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer: 1H NMR (400 MHz, CDCl3) δ: 1.80 (s, 3), 6.03 (s, 1).

Method C

[0164] Compound III-B (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl Chloride 29

[0165] A mixture of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid (0.50 g, 2.9 mmol) in dry dichloromethane (10 ml) was treated at 22° C. with oxalyl chloride (0.5 ml, 5.8 mmol) followed by a trace (capillary) of N,N-dimethylformamide. After 1 h at 22° C., the clear solution was concentrated in vacuo to give 0.55 g (quantitative) of the title acid chloride as a white crystalline solid.

EXAMPLE 1

[0166] Compound 1-A: 4-Fluoro-N-methyl-benzamide 30

[0167] To a solution of 30 mL MeNH2 (40% wt in H2O) was added 139 mL of 1N NaOH. To this was added 130 mL of CH2Cl2 followed by 4-fluorobenzoyl chloride (22 grams, 139 mmol) while the mixture was rapidly stirred. After 1 hour the organic layer was separated, washed with H2O, dried over Na2SO4 and solvent removed under vacuum to yield 20 grams (94% yield) solid. 1H NMR (500 MHz, DMSO) δ: 2.78 (d, 3, J=5), 7.28 (t, 2, J=9), 7.91 (m, 2), 8.46 (br s, 1). 13C NMR (125 MHz, DMSO) δ: 26.13, 114.95, 115.13, 129.49, 129.56, 130.87, 130.90, 162.67, 164.64, 165.46.

[0168] Compound 1-B: (4-Fluoro-benzyl)-methyl-amine; Hydrochloride 31

[0169] 4-Fluoro-N-methyl-benzamide (18.8 grams, 123 mmol) was dissolved in 180 mL of THF. To this was added BF3.Et2O (5.51 mL, 43 mmol) and the resulting mixture heated to reflux for 15 min. The solution was then cooled to ˜20° C. and BH3.S(CH3)2 (16.5 mL, 174 mmol) added over 10 min. After this the reaction mixture was heated and the solvent removed by distillation for 20 min. The distillation apparatus was replaced with a reflux condenser and the reaction heated to 110° C. for 2 h. After cooling to room temperature 75 mL of 6N HCl was slowly added. After gas evolution had ceased the mixture was heated at reflux for 1 h then allowed to regain room temperature. To this was added 200 mL of 6N NaOH. The mixture was extracted with Et2O. The organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and the solvent removed to yield an oil. The oil was dissolved in Et2O and 30 mL of 4N HCl (dioxane) added resulting in a white ppt. which was filtered to yield 18.9 grams solid (88% yield). 1H NMR (500 MHz, DMSO) δ: 2.48 (s, 3), 4.08 (s, 2), 7.26 (m, 2), 7.63 (m, 2), 9.60 (br s, 2). 13C NMR (125 MHz, DMSO) δ: 31.57, 50.04, 115.24, 115.41, 128.29, 128.32, 132.29, 132.36, 161.24, 163.19.

[0170] Compound 1-C: N-(4-Fluoro-benzyl)-N-methyl-acetamide 32

[0171] 4-Fluoro-benzyl)-methyl-amine; hydrochloride (8.75 grams, 50 mmol) was added to a rapidly stirring mixture of 100 mL CH2Cl2 and 150 mL of 1N NaOH. To this was added acetyl chloride (3.55 mL, 50 mmol) and the resulting mixture stirred overnight. The organic layer was then separated, washed with 1N HCl, dried over Na2SO4, filtered and the solvent removed to yield 2 grams oil (22% yield). HRMS (M+H) calcd for C10H14FNO: 182.0891; found: 182.0979. 1H NMR (500 MHz, DMSO) δ: 2.04 (s), 2.05 (s), 2.77 (s), 2.90 (s), 4.46 (s), 4.53 (s), 7.13-7.28 (m, 4). 13C NMR (125 MHz, DMSO) δ: 21.16, 21.47, 32.85, 35.24, 48.81, 52.40, 114.97, 115.14, 115.30, 115.47, 128.52, 128.59, 129.38, 128.44, 133.58, 133.60, 134.01, 134.03, 160.23, 160.33, 162.16, 162.26, 169.70, 169.84.

[0172] Compound 1-D: 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 33

[0173] N-(4-Fluoro-benzyl)-N-methyl-acetamide (3.6 grams, 20 mmol) was dissolved in 20 mL of THF and cooled to −78° C. To this was added 40 mL of 1M LiHMDS (in THF) and the resulting solution stirred for 30 min. Next dimethyl oxalate (3.5 grams, 30 mmol) dissolved in 8 mL of THF is added and the reaction stirred for 2 h at −78° C., then warmed to 0° C. and stirred an additional 30 min. To this was added 1N HCl and the mixture then extracted with EtOAc. The organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and the solvent removed. The crude product was purified by column chromatography (4×4 cm SiO2, 80:20 Hex/EtOAc) to yield 4.3 grams solid (80% yield). HRMS (M+H) calcd for C13H15NO4F: 268.0985; found: 268.0983. Anal calcd for C13H14NO4F: C, 58.42; H, 5.28; N, 5.24; found: C, 58.48; H, 5.21; N, 5.26. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s), 3.86 (s), 3.89 (s), 4.55 (s), 6.29 (s), 6.31 (s), 7.00-7.24 (overlapping m, 4). 13C NMR δ; 33.43, 34.79, 49.97, 52.63, 52.97, 93.27, 93.55, 115.63, 115.80, 115.95, 116.13, 128.36, 128.42, 129.71, 129.78, 131.32, 132.03, 159.70, 161.40, 163.25, 163.35, 170.93, 171.16.

[0174] Compound 1: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-benzyl)-methyl Amide 34

[0175] To 1.6 mL of ethanol at 60° C. was added paraformaldehyde (46.6 mg, 1.6 mmol. eq. of formaldehyde) and 0.78 mL of 2 M (THF) CH3NH2 and the resulting mixture stirred for 5 min. Compound 1-D (41.5 mg, 1.6 mmol) was added and the reaction stirred for 1 hr. The reaction mixture was then diluted with H2O and extracted with EtOAc. The organic layer was separated, washed with satd NaCl, dried over Na2SO4, filtered and the solvent removed to yield crude product, which was purified by preparative TLC (SiO2, 20% EtOH/CH2Cl2). HRMS [M+H] calcd for C14H16FN2O3: 279.1145. Found: 279.1148. 1H NMR (CDCl3, 500 MHz) δ: 2.99 (s, 3), 3.03 (s, 3), 4.13 (s, 2), 4.60 (s, 2), 6.98-7.23 (overlapping m, 4).

EXAMPLE 2

[0176] Compound 2: 1-[2(4-Chloro-phenyl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl Amide 35

[0177] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(4-chloro-phenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M−H) calcd for C21H19ClFN2O3: 401.1068; found: 401.1080. 1H NMR (500 MHz, CDCl3) δ: 2.90 (t, 2, J=7), 2.95 (s, 3), 3.72 (t, 2, J=7), 3.95 (s, 2), 4.57 (s, 2), 7.03-7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 33.92, 34.45, 44.42, 49.37, 51.46, 108.49, 115.73, 115.91, 128.87, 129.22, 129.98, 131.99, 132.67, 136.60, 154.21, 161.42, 163.37. 164.51, 166.31.

EXAMPLE 3

[0178] Compound 3: 1-[2(Chloro-phenyl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl Amide 36

[0179] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2-chloro-phenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H21ClFN2O3: 403.1225; found: 403.1237. 1H NMR (500 MHz, CDCl3) δ: 2.96 (s, 3), 3.05 (t, 2, J=7), 3.75 (t, 2, J=7), 3.99 (s, 2), 4.58 (s, 2), 7.01-7.34 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 32.37, 34.52, 42.90, 49.36, 51.47, 109.38, 115.66, 115.83, 127.18, 128.37, 129.26, 129.32, 129.67, 130.92, 132.13, 132.15, 134.01, 135.79, 152.71, 161.37, 163.33, 164.91, 166.11.

EXAMPLE 4

[0180] Compound 4: 4-Hydroxy-5-oxo-1-(2-thiophen-2-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl-Amide 37

[0181] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-thiophen-2-yl-ethylamine as described in the preparation of Compound 1. HRMS (M−H) calcd for C19H18FN2O3S: 373.1022; found: 373.1029. 1H NMR (500 MHz, CDCl3) δ: 2.95 (s, 3), 3.14 (t, 2, J=7), 3.76 (t, 2, J=7), 3.97 (s, 2), 4.57 (s, 2), 6.81-7.21 (overlapping m, 7). 13C NMR (125 MHz, CDCl3) δ: 28.76, 34.49, 44.93, 49.46, 51.47, 109.48, 115.65, 115.82, 124.20, 125.59, 127.15, 129.28, 129.34, 132.12, 132.14, 140.34, 152.72, 161.37, 163.33, 164.94, 166.11.

EXAMPLE 5

[0182] Compound 5: 1-[2-(2-Fluoro-phenyl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl-amide 38

[0183] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2-fluoro-phenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H21N2F2O3: 387.1520; found: 387.1525. 1H NMR (500 MHz, CDCl3) δ: 2.96 (overlapping m, 5), 3.75 (t, 2, J=7), 4.02 (s, 2), 4.58 (s, 2), 6.98-7.22 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 28.13, 28.14, 34.55, 43.38, 49.34, 51.52, 109.53, 115.31, 115.48, 115.68, 115.85, 124.38, 124.41, 124.87, 124.99, 128.68, 128.75, 129.29, 129.35, 130.96, 130.99, 131.98, 132.01, 152.46, 160.26, 161.40, 162.21, 163.36, 165.04, 166.09.

EXAMPLE 6

[0184] Compound 6: 1-[2-(2,4-Dichloro-phenyl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-benzyl)-methyl-amide 39

[0185] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(2,4-dichloro-phenyl)-ethylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 2.99 (s, 3), 3.03 (t, 2, J=7), 3.74 (t, J=7), 4.06 (s, 2), 4.60 (s, 2), 7.03-7.37 (overlapping m, 7). 13C NMR (125 MHz, CDCl3) δ: 31.76, 34.67, 42.95, 49.48, 51.61, 109.74, 115.76, 115.93, 127.53, 129.27, 129.32, 129.53, 131.63, 131.78, 131.80, 133.57, 134.14, 134.65, 152.19, 161.44, 163.40, 165.24, 165.98.

EXAMPLE 7

[0186] Compound 7: 4-Hydroxy-5-oxo-1-(2-pyridin-4-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl-amide 40

[0187] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-pyridin-4-yl-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C20H21FN3O3: 370.1567; found: 370.1568. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s, 3), 3.23 (t, 2, J=7), 3.90 (t, 2, J=7), 4.20 (s, 2), 4.60 (s, 2), 7.03 (m, 2), 7.21 (m, 2), 7.80 (d, 2, J=6), 8.73 (d, 2, J=6). 13C NMR (125 MHz, CDCl3) δ: 34.55, 34.63, 42.47, 49.04, 51.55, 109.53, 114.58, 115.74, 115.91, 127.10, 129.30, 129.50, 131.76, 141.92, 153.22, 158.36, 160.92, 161.23, 161.43, 163.40, 165.33, 166.13.

EXAMPLE 8

[0188] Compound 8: 4-Hydroxy-5-oxo-1-phenethyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-benzyl)-methyl-amide 41

[0189] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-phenyl-ethylamine as described in the preparation of Compound 1. HRMS (M+H) calcd for C21H22FN2O3: 369.1615; found: 369.1625. 1H NMR (500 MHz, CDCl3) δ: 2.92 (overlapping m, 5), 3.74 (t, 2, J=7), 3.92 (s, 2), 4.56 (s, 2), 7.01-7.29 (overlapping m, 9). 13C NMR (125 MHz, CDCl3) δ: 34.45, 34.60, 44.70, 49.42, 51.46, 109.12, 115.66, 115.83, 126.75, 128.63, 128.72, 129.26, 129.33, 132.09, 132.11, 138.18, 153.11, 161.38, 163.34, 164.79, 166.18.

EXAMPLE 9

[0190] Compound 9: 1-[2-(4-Fluoro-phenyl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl amide 42

[0191] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(4-fluoro-phenyl)-ethylamine as described in the preparation of Compound 1. (HRMS (M−H) calcd for C21H19F2N2O3: 385.1364; found: 385.1377. 1H NMR (500 MHz, CDCl3) δ: 2.90 (t, 2, J=7), 2.95 (s, 3), 3.71 (t, 2, J=7), 3.95 (s, 2), 4.57 (s, 2), 6.95-7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 33.74, 34.48, 44.70, 49.41, 51.47, 108.82, 115.49, 115.66, 115.71, 115.77, 115.89, 129.22, 129.27, 130.04, 130.10, 131.97, 133.72, 153.60, 160.81, 161.42, 162.76, 163.38, 164.71, 166.21.

EXAMPLE 10

[0192] Compound 10: 4-Hydroxy-5-oxo-1-(3-phenyl-propyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl-amide 43

[0193] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 3-phenyl-propylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 1.93 (p, 2, J=7), 2.64 (t, 2, J=7), 2.99 (s, 3), 3.53 (t, 2, J=2), 4.10 (s, 2), 4.60 (s, 2), 7.02-7.28 (overlapping m, 9). 13C (125 MHz, CDCl3) δ: 29.77, 33.05, 34.56, 42.81, 48.79, 51.47, 109.25, 115.66, 115.83. 126.14, 128.30, 128.49, 129.34, 129.40, 132.16, 132.79, 140.88, 152.46, 161.39, 163.34, 165.02, 166.08.

EXAMPLE 11

[0194] Compound 11: 4-Hydroxy-1-isopropyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methyl-amide 44

[0195] 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (compound 1-D) was treated with paraformaldehyde and isopropylamine as described in the preparation of Compound 1. 1H NMR (500 MHz, CDCl3) δ: 1.23 (d, 6, J=7), 3.02 (s, 3), 4.10 (s, 2), 4.45 (heptet, 1, J=7), 4.62 (s, 2), 7.03 (m, 2), 7.24 (m, 2). 13C NMR (125 MHz, CDCl3) δ: 20.61, 34.72, 44.09, 44.34, 110.21, 115.57, 115.75, 129.43, 129.50, 132.28, 132.30, 149.92, 161.35, 163.31, 164.76, 165.80.

EXAMPLE 12

[0196] Compound 12-A: N-(3,4-Dichloro-benzyl)-N-methyl-acetamide 45

[0197] A solution of (3,4-dichlorobenzyl)-methylamine (0.50 g, 2.63 mmol) (Shapiro et al. J. Amer. Chem. Soc., (1959) 81, 3725) in a mixture of tetrahydrofuran (20 ml) and 40% aqueous sodium acetate (10 ml) was cooled to 0-5° C. (ice bath) and treated with a solution of acetyl chloride (0.3 g in tetrahydrofuran) added dropwise over 5 min. After 1 h at 0-5° C., the reaction mixture was diluted with ethyl acetate, washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and distillation of the residue in vacuo gave 0.51 g (83% yield) of the title amide as a clear oil: bp 110-120° C./0.2 torr, (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ (ppm), mixture of rotamers: 2.36 and 2.39 (3H, 2 s, COCH3), 3.16 (3H, s, NCH3), 4.70 and 4.75 (2H, 2 s, NCH2), 7.2-7.7 (3H, m, aromatics). Anal. calcd for C10H11Cl2NO: C, 51.74; H, 4.78; N, 6.03. Found: C, 51.70; H, 4.77; N, 6.04.

[0198] Compound 12-B: 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 46

[0199] A solution of N-(3,4-dichlorobenzyl)-N-methyl-acetamide (0.83 g, 3.57 mmol) in tetrahydrofuran (15 ml) was cooled to −78° C. and treated dropwise with 7.1 ml (7.1 mmol) of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran. After 20 min, the mixture was treated dropwise with a solution of dimethyl oxalate (0.63 g, 5.35 mmol) in tetrahydrofuran (3 ml), stirred at −78° C. for 1 h and then at 5° C. for another 45 min. The reaction mixture was then quenched by the addition of 1 N hydrochloric acid and ethyl acetate. The organic phase was washed successively with water, saturated sodium bicarbonate and brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 85:15) gave 0.70 g (61% yield) of the title ester as clear oil. 1HNMR 400 MHz (C6D6) δ (ppm); mixture of rotamers: 2.01 and 2.49 (3H, 2 s, NCH3), 3.43 and 3.5 (3H, 2 s, OCH3), 4.0 and 4.4 (2H, 2 s, NCH2), 6.26 and 6.33 (1H, 2 s, CH), 6.62-7.2 (3H, m, aromatics). Anal. calcd for C13H13Cl2NO4: C, 49.08; H, 4.12; N 4.40. Found: C, 49.38; H, 4.23; N, 4.30.

[0200] Compound 12: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl Amide 47

[0201] A solution of 2 M methylamine in tetrahydrofuran (0.5 ml, 1.0 mmol) was added to a mixture of paraformaldehyde (0.3 g, 1.0 mmol, equivalent of formaldehyde) in anhydrous ethanol (1 ml) and the resulting mixture was heated at 60° C. for 5 min. Then a solution of 3-[(3,4-dichlorobenzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (0.318 g, 1.0 mmol) in ethanol (3 ml) was added all at once and the resulting mixture was maintained at 60° C. for another 20 min. The reaction mixture was then quenched by the addition of ethyl acetate and pH 2 phosphate buffer. The organic phase was washed with brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. Recrystallization of the solid residue from a mixture of ethyl acetate and hexane gave 0.180 g (54% yield) of the title material as a white solid: mp 148-150° C.

EXAMPLE 13

[0202] Compound 13; 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 48

[0203] To 0.5 mL of AcOH at 60° C. was added N-(2-aminoethyl) morpholine (0.066 mL, 0.5 mmol) and paraformaldehyde (15 mg, 0.5 mmol). After stirring for 5 min, 3-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (159 mg, 0.5 mmol) was added and the resulting mixture stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc. The remaining aqueous layer was extracted with CH2Cl2, and dried over Na2SO4. Concentration yielded 51.1 mg (24% yield) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ: 10.52 (bs, 1H), 7.40 (d, 1H, J=10.61), 7.39 (s, 1H), 7.11 (dd, 1H, J=10.24, J=1.83), 4.60 (s, 2H), 4.23 (s, 2H), 3.64 (m, 6H), 3.01 (s, 3H), 2.63 (t, 2H, J=6.22), 2.54, (m, 4H), 2.05 (s, 3H). MS (M+H) calcd for C19H23N3O4Cl2: 427.1; found: 428.11.

EXAMPLE 14

[0204] Compound 14: 1-Cyclopropyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 49

[0205] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and cyclopropylamine as described in the preparation of Compound 12. The title compound was extracted with EtOAc and the organic layer was washed with H2O, and dried over Na2SO4. After concentration, the resulting residue was triturated with EtOAc/Hexane (1:1) to give a white solid (52.7 mg, 30% yield). Mp=163-164° C. 1H NMR (300 MHz, CDCl3) δ: 9.97 (bs, 1H), 7.42, (d, 1H, J=8.42), 7.35 (s, 1H), 7.10 (dd, 1H, J=8.42, J=1.47), 4.60 (s, 2H), 4.09 (s, 2H), 3.02 (s, 3H), 2.81 (m, 1H), 0.86 (m, 4H). HRMS (M+H) calcd for C16H17N2Cl2O3:355.0616; found: 355.0618.

EXAMPLE 15

[0206] Compound 15: 4-Hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 50

[0207] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and methyl-ethane-1,2-diamine as described in the preparation of Compound 12. The title compound was triturated with EtOAc to give a white solid (7.8 mg, 4% yield). 1H NMR (300 MHz, CDCl3) δ: 9.14, (bs, 1H), 7.40, (d, 1H, J=8.05), 7.34 (s, 1H), 7.11 (dd, 1H, J=8.05, J=1.10), 4.58, (s, 2H), 4.34, (s, 2H), 3.94 (m, 2H), 3.25 (m, 2H), 3.03 (s, 3H), 2.78 (s, 3H). HRMS (M+H) calcd for C16H19N3Cl2O3: 372.0881; found: 372.0886.

EXAMPLE 16

[0208] Compound 16: 1-(2,2-Dimethyl-propyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 51

[0209] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2,2-dimethyl-propylamine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (7.9 mg, 4% yield). 1H NMR (500 MHz, DMSO) δ: 7.42 (d, 1H, J=8.24), 7.36 (s, 1H), 7.12 (d, 1H, J=8.24), 4.61 (s, 2H), 4.26 (s, 2H), 3.27 (s, 2H), 3.04 (s, 3H), 0.93 (s, 9H). HRMS (M+H) calcd for C18H23N2Cl2O3: 385.1085; found: 385.1079.

EXAMPLE 17

[0210] Compound 17: 4-Hydroxy-5-oxo-1-[2-(4-sulfamoyl-phenyl)-ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 52

[0211] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(2-amino-ethyl)benzenesulfonamide as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (47.9 mg, 19% yield). Decomposition point=110-113° C. 1H NMR (500 MHz, DMSO) δ: 10.97 (s, 1H), 7.72, (m, 2H), 7.61 (d, 1H, J=8.54), 7.51 (s, 1H), 7.42 (m, 2H), 7.29 (m, 2H), 7.25, (m, 1H), 4.56, (s, 2H), 4.04, (s, 2H), 3.67 (m, 2H), 3.34 (m, 2H), 2.95 (d, 3H, J=6.41). HRMS (M−H) calcd for C21H2OSN3Cl2O5: 496.0500; found: 496.0503.

EXAMPLE 18

[0212] Compound 18: 3-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-propionic Acid 53

[0213] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and β-alanine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber solid (48.5 mg, 25% yield). Mp=183-184° C. 1H NMR (500 MHz, DMSO) δ: 12.34 (s, 2H), 10.79 (s, 1H), 7.61 (d, 1H, J=8.54), 7.51 (s, 1H), 7.24 (bs, 1H), 4.57 (s, 2H), 4.06 (s, 2H), 3.58 (t, 2H, J=6.40), 2.96 (bs, 3H), 2.54 (t, 2H, J=7.02). HRMS (M−H) calcd for C16H15N2Cl2O5: 385.0358; found: 385.0364.

EXAMPLE 19

[0214] Compound 19: 1-(3,4-Dichloro-benzyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 54

[0215] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 3,4 dichloro-benzylamine as described in the preparation of Compound 12. The title compound was isolated as a white foam (155 mg, 66% yield). 1H NMR (500 MHz, CDCl3) δ: 10.70 (bs, 1H), 7.42 (d, 1H, J=3.05), 7.40 (d, 1H, J=3.05), 7.34 (d, 2H, J=1.83), 7.09 (dd, 2H, J=8.24, J=1.83), 4.62 (s, 2H), 4.57 (s, 2H), 4.06 (s, 2H), 3.00 (s, 3H). HRMS (M−H) calcd for C20H15N2Cl4O3: 470.9836; found: 470.9832.

EXAMPLE 20

[0216] Compound 20: {4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-acetic Acid 55

[0217] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and glycine as described in the preparation of Compound 12. The title compound was isolated as a white solid (80 mg, 43% yield). Mp=178-180° C. 1H NMR (300 MHz, DMSO) δ: 12.97 (bs, 1H), 11.07 (s, 1H), 7.62 (d, 1H, J=8.41), 7.53 (s, 1H), 7.25 (d, 1H, J=6.95), 4.59 (s, 2H), 4.15 (s, 2H), 4.10 (s, 2H), 2.98 (s, 3H). HRMS (M−H) calcd for C15H13N2Cl2O5: 371.0201; found: 371.0216.

EXAMPLE 21

[0218] Compound 21: 4-Hydroxy-5-oxo-1-pyridin-4-yl methyl-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 56

[0219] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(amino-methyl)pyridine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a sticky orange solid (10.5 mg, 5% yield). 1H NMR (300 MHz, DMSO) δ: 8.75 (d, 2H, J=6.22), 7.63-7.52 (m, 4H), 7.25 (d, 2H, J=7.31), 4.80 (s, 2H), 4.59 (s, 2H), 4.1 (s, 2H), 2.99 (bs, 3H). HRMS (M−H) calcd for C19H16N3Cl2O3: 404.0568; found: 404.0554.

EXAMPLE 22

[0220] Compound 22: 1-(1-Ethyl-pyrrolidin-2-yl methyl)-4-hydroxy-5-oxo-2,5-dihydro-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 57

[0221] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2-(aminomethyl)-1-ethylpyrrolidine as described in the preparation of Compound 12. The title compound was isolated as an orange solid (18.8 mg, 9% yield). 1H NMR (300 MHz, CDCl3) δ: 12.26 (bs, 1H), 7.43 (d, 1H, J=8.42), 7.36 (s, 1H), 7.13 (dd, 1H, J=8.05, J=1.46), 4.61 (s, 2H), 4.12 (s, 2H), 3.93 (m, 2H), 3.22 (t, 1H, J=8.78), 3.09 (s, 3H), 2.93 (m, 2H), 2.21-1.72 (m, 6H), 1.42 (t, 3H, J=6.95). HRMS (M−H) calcd for C20H24N3Cl2O3: 424.11948; found: 424.1200.

EXAMPLE 23

[0222] Compound 23-A: (2-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-ethyl)-phosphonic Acid Diethyl Ester 58

[0223] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and (2-aminoethyl)phosphonic acid diethylester as described in the preparation of Compound 12. Trituration with CH2Cl2/hexane gave the title compound (106 mg, 44% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (d, 1H, J=8.05), 7.35 (s, 1H), 7.10 (dd, 1H, J=8.05, J=1.47), 4.60 (s, 2H), 4.25 (s, 2H), 4.11 (m, 4H), 3.77 (m, 2H), 3.02 (s, 3H), 2.17 (m, 2H), 1.31 (t, 6H, J=7.32). HRMS (M−H) calcd for C19H24PN2Cl2O6: 477.0749; found: 477.0749.

[0224] Compound 23: (2-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-ethyl)-phosphonic Acid 59

[0225] Compound 23-A (77 mg, 0.16 mmol) was stirred in acetic acid (4 mL) and concentrated HCl (1 mL) at 120° C. 18 hours. Mixture was cooled to room temp and concentrated. Residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to give the title compound as a white powder (4.4 mg, 6.5% yield). 1H NMR (300 MHz, DMSO) δ: 7.61 (d, 1H, J=8.05), 7.52 (s, 1H), 7.24 (d, 1H, J=8.05), 4.58 (s, 2H), 4.09 (s, 2H), 3.55 (m, 2H), 2.96 (bs, 3H), 1.84 (m, 2H). HRMS (M−H) calcd for C15H16PN2Cl2O6: 421.0123; found: 421.0139.

EXAMPLE 24

[0226] Compound 24: 4-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 60

[0227] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and -aminobutyric acid as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (42.1 mg, 21% yield). 1H NMR (300 MHz, CDCl3) δ: 7.42 (d, 1H, J=8.05), 7.36 (s, 1H), 7.11 (dd, 1H, J=8.05, J=1.10), 4.60 (s, 2H), 4.21 (s, 2H), 3.58 (t, 2H, J=6.22), 3.03 (s, 3H), 2.40 (t, 2H, J=6.95), 1.96 (t, 2H, J=6.59). HRMS (M−H) calcd for C17H17N2Cl2O5: 399.0514; found: 399.0509.

EXAMPLE 25

[0228] Compound 25: 2-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-succinamic Acid 61

[0229] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and asparagine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (12 mg, 6% yield). 1H NMR (300 MHz, DMSO) δ: 13.1 (bs, 1H), 11.05 (bs, 1H), 7.62 (d, 1H, J=8.42), 7.53 (s, 1H), 7.51 (s, 1H), 7.25 (bs, 1H), 6.97 (s, 1H), 4.90 (m, 1H), 4.58 (s, 2H), 4.07 (s, 2H), 2.96 (s, 3H), 2.73 (m, 2H). HRMS (M−H) calcd for C17H16N3Cl2O6: 428.0416; found: 428.0415.

EXAMPLE 26

[0230] Compound 26: 4-Hydroxy-5-oxo-1-(2-piperidin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 62

[0231] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 1-(2-aminoethyl)piperidine as described in the preparation of Compound 12. The resulting residue was purified by trituration with CH2Cl2 to yield the title compound as a white solid (81.2 mg, 38% yield). Decomposition point=178-182° C. 1H NMR (300 MHz, DMSO) δ: 10.99 (s, 1H), 7.62 (d, 1H, J=8.25), 7.52 (d, 1H, J=1.46), 7.26 (d, 1H, J=7.68), 4.60 (s, 2H), 4.13 (s, 2H), 3.81 (t, 2H, J=5.85), 3.48 (d, 2H, J=11.34), 3.27 (d, 2H. J=4.76), 3.00 (s, 2H), 2.86 (m, 3H), 1.77 (m, 6H). HRMS (M+H) calcd for C20H26N3Cl2O3: 426.1351; found: 426.1346.

EXAMPLE 27

[0232] Compound 27: 1-(2-Acetylamino-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-5-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 63

[0233] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and N-acetylethylene diamine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (60.8 mg, 30% yield). 1H NMR (500 MHz, CDCl3) δ: 7.44 (d, 1H, J=8.24), 7.36 (s, 1H), 7.11 (dd, 1H, J=9.76, J=7.93), 6.77 (s, 1H), 4.60 (s, 2H), 4.29 (s, 2H), 3.68 (t, 2H, J=5.18), 3.55 (q, 2H, J=5.80), 3.05 (s, 3H), 2.02 (s, 3H). HRMS (M−H) calcd for C17H18N3Cl2O4: 398.0674; found: 398.0682.

EXAMPLE 28

[0234] Compound 28: 7-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-heptanoic Acid 64

[0235] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 7-amino-heptanoic acid as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (11.2 mg, 5% yield). 1H NMR (500 MHz, CDCl3) δ: 11.95 (bs, 1H), 11.00 (s, 1H), 7.61 d, 1H, 1=8.24), 7.52 (s, 1H), 7.25 (s, 1H), 4.58 (s, 2H), 4.04 (s, 2H), 3.36 (m, 2H), 2.98 (s, 3H), 2.18 (t, 2H, J=7.33), 1.48 (m, 4H), 1.26 (m, 4H). HRMS (M+H) calcd for C20H25N2Cl2O5: 443.1140; found: 443.1153.

EXAMPLE 29

[0236] Compound 29: 2-(3-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-propionylamino-3-(3-methyl-3H-imidazol-4-yl)-propionic Acid 65

[0237] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and L-anserine nitrate as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white solid (3.3 mg, 1% yield). 1H NMR (500 MHz, CDCl3) δ: 8.56 (s, 1H), 7.36 (d, 1H, J=8.24) 7.29 (m, 1H), 7.20 (s, 1H), 7.04 (m, 1H), 4.69 (m, 1H), 4.52 (s, 2H), 4.05 (s, 2H), 3.76 (s, 3H), 3.65 (t, 2H, J=5.80), 3.14 (m, 2H), 2.94 (s, 2H), 2.51 (m, 2H). HRMS (M+H) calcd for C23H26N5Cl2O6: 538.1260; found: 538.1280.

EXAMPLE 30

[0238] Compound 30: 4-Hydroxy-1-(3-imidazol-1-yl-propyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 66

[0239] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and N-propylamino imidazole as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber foam (59.1 mg, 28% yield). 1H NMR (300 MHz, DMSO) δ: 14.47 (bs, 1H), 11.05 (bs, 1H), 9.10 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.62 (d, 1H, J=8.05), 7.52 (s, 1H), 7.25 (d, 1H, J=7.32), 4.59 (s, 2H), 4.19 (t, 1H, J=6.95), 4.09 (s, 2H), 3.41 (t, 2H, J=6.59), 2.98 (s, 3H), 2.13 (t, 2H, J=6.59). HRMS (M+H) calcd for C19H21N4Cl2O3: 423.0990; found: 423.0982.

EXAMPLE 31

[0240] Compound 31: 4-Hydroxy-5-oxo-1-thiophen-2-yl methyl-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 67

[0241] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and methylamine thiophene as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (58.7 mg, 28% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (d, 1H, J=8.05), 7.33 (d, 1H, J=1.83), 7.26 (m, 1H), 7.08 (dd, 1H, J=8.05, J=1.83), 6.97 (m, 2H), 4.85 (s, 2H), 4.57 (s, 2H), 4.11 (s, 2H), 3.00 (s, 3H). HRMS (M−H) calcd for C18H15SN2Cl2O3: 409.0180; found: 409.0190.

EXAMPLE 32

[0242] Compound 32-A: (4-Methyl-piperazin-yl)-acetonitrile 68

[0243] A mixture of 1-methyl piperazine (0.55 mL, 5.0 mmol), potassium carbonate (3.49 g, 25 mmol) and chloroacetonitrile (0.34 mL, 5.6 mmol) in acetonitrile (3 mL) was stirred at room temperature 8 h. The mixture was diluted with diethyl ether and filtered and concentrated to yield the title compound as yellow crystals (536.6 mg, 77% yield). 1H NMR (500 MHz, CDCl3) δ: 3.50 (s, 2H), 2.66 (t, 4H, J=4.58), 2.52 (bs, 4H), 2.33 (s, 3H).

[0244] Compound 32-B: 2-(4-Methyl-piperazin-1-yl)-ethylamine 69

[0245] To a suspension of lithium aluminum powder (0.16 g, 4.2 mmol) and diethyl ether (5.0 mL) cooled to 0° C., was added dropwise a solution of the above compound (0.536 g, 3.86 mmol) dissolved in diethyl ether/THF (14 mL, 1:1). The resulting mixture was stirred at room temperature for 5 h. The mixture was cooled to 0° C. and 2N aqueous NaOH added dropwise. The mixture was stirred for 20 min and the precipitate was filtered. The organic solution was concentrated and the resulting oil was dissolved in ethylacetate. A solution of 4N HCl in dioxane (0.97 mL) added and white precipitate filtered to yield the title compound as the HCl salt. 1H NMR (500 MHz, DMSO) δ: 9.48 (s, 2H), 4.18 (m, 6H), 3.75 (m, 2H), 3.68 (m, 2H), 3.26 (m, 2H), 2.82 (s, 3H).

[0246] Compound 32: 4-Hydroxy-1-[2-(4-methyl-piperazin-1-yl)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 70

[0247] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 2-(4-methyl-piperazine-1-yl)-ethyl amine as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber glass (27 mg, 12% yield). 1H NMR (300 MHz, DMSO) δ: 7.63 (d, 1H, J=8.42), 7.52 (s, 1H), 7.25 (d, 1H, J=7.31), 4.59 (s, 2H), 4.24 (m, 10H), 4.11 (s, 2H), 3.58 (s, 2H), 2.98 (s, 3H), 2.78 (s, 3H). HRMS (M−H) calcd for C20H25N4Cl2O3: 439.1303; found: 439.1311.

EXAMPLE 33

[0248] Compound 33: 4-{4-[(3,4-Dihydro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid Methyl Ester 71

[0249] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-aminobutyrate hydrochloride as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (18.9 mg, 9% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (m, 2H), 7.09 (m, 1H), 4.60 (s, 2H), 4.18 (s, 2H), 3.65 (s, 3H), 3.55 (t, 2H, J=7.32), 3.03 (s, 3H), 2.36 (t, 2H, J=7.32), 1.94 (t, 2H, J=6.95). HRMS (M+H) calcd for C18H21N2Cl2O53: 415.0827; found: 415.0831.

EXAMPLE 34

[0250] Compound 34: 3-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-propionic Acid Methyl Ester 72

[0251] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and β-alanine methyl ester as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (34.3 mg, 17% yield). 1H NMR (300 MHz, CDCl3) δ: 7.41 (m, 2H), 7.09 (m, 1H), 4.59 (s, 2H), 4.27 (s, 2H), 3.77 (m, 2H), 3.67 (s, 3H), 3.03 (s, 3H), 2.69 (t, 2H, J=6.22). HRMS (M+H) calcd for C17H19N2C2O5: 401.0671; found: 401.0669.

EXAMPLE 35

[0252] Compound 35: {3-[2-(2-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-acetylamino)-acetylamino]-propionylamino}-acetic Acid 73

[0253] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and H-gly-gly-β-ala-gly-OH as described in the preparation of Compound 12. The reaction mixture was diluted with water and ethylacetate. The white solids were filtered as the title compound (88.2 mg, 32% yield). 1H NMR (300 MHz, DMSO) δ: 8.31 (t, 1H, J=5.49), 8.20 (t, 1H, J=5.49), 7.92 (t, 1H, J=5.49), 7.61 (d, 1H, J=8.42), 7.52 (s, 1H), 7.25 (d, 1H, J=6.59), 4.59 (s, 2H), 4.09 (s, 4H), 3.69 (m, 6H), 2.94 (bs, 3H), 2.30(t, 2H, J=7.31). HRMS (M−H) calcd for C22H24N5Cl2O8: 556.1002; found: 556.0994.

EXAMPLE 36

[0254] Compound 36: 4-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2: oxo-2,5-dihydro-pyrrol-1-yl methyl}-benzoic Acid 74

[0255] 3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and 4-(aminomethyl)benzoic acid as described in the preparation of Compound 12. The resulting residue was triturated with chloroform to give the title compound as a white solid (160 mg, 71% yield). 1H NMR (300 MHz, DMSO) δ: 12.94 (s, 1H), 11.14 (s, 1H), 8.32 (s, 1H), 7.93 (d, 2H, J=8.05), 7.60 (d, 1H, J=8.45), 7.50 (s, 1H), 7.35 (d, 2H, J=7.84), 7.23 (ds, 1H, 1=8.05), 4.66 (s, 2H), 4.57 (s, 2H), 3.99 (s, 2H), 2.97 (s, 3H). HRMS (M+H) calcd for C21H17N2Cl2O5: 447.0515; found: 447.0530.

EXAMPLE 37

[0256] Compound 37-A: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide 75

[0257] To a suspension of (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid, Compound III-A, (4.5 g, 26.2 mmol) in benzene (30 mL) was added oxalyl chloride (15 mL) and the resulting mixture was heated at reflux for 1 h. The mixture was cooled to room temp. and concentrated. The residue was dissolved in methylene chloride (30 mL) and cooled to 0° C. To this was added a suspension of (3,4-dichloro-benzyl)-methyl-amine hydrochloride salt (5.0 g, 22.1 mmol) in methylene chloride (30 mL) and pyridine (18 mL). The resulting mixture was stirred at room temp for 18 h then diluted with 1N HCl. The aqueous phase was saturated with sodium chloride and extracted with methylene chloride (3 times). The organic layers were combined, dried (Na2SO4), and concentrated. The brown oil was purified over silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a pale yellow oil that solidified to a white solid upon standing (6.2 g, 82% yield). 1H NMR (300 MHz, DMSO) δ: 7.44-7.10 (m, 3H), 6.16 (s, 0.66H), 6.08 (s, 0.33H), 4.59 (s, 1.33H), 4.53 (s, 0.67H), 3.02 (s, 2H), 2.97 (s, 1H), 1.74 (s, 4H), 1.69 (s, 2H).

[0258] Compound 37: 3-(3-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2oxo-2,5-dihydro-pyrrol-1-yl}-propionylamino)-propionic Acid 76

[0259] A mixture of paraformaldehyde (0.015 g, 0.5 mmol) and methanol (1.5 mL) was warmed to 55° C. Added to this mixture was H-β-O-Ala-β-ala-OH (0.08 g, 0.5 mmol) and the solution was stirred 5 min. N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo[1,3]dioxolane-4-ylidene)-N-methyl-acetamide (0.1715 g, 0.5 mmol) was added and the mixture was stirred at 55° C. for 45 min. The mixture was concentrated and the resulting residue was triturated with ethylacetate and filtered to give the desired product as a white solid (0.0358 g, 16% yield). 1H NMR (300 MHz, DMSO) δ: 2.35 (t, J=6.7 Hz, 4H), 2.96 (s, 3H), 3.32 (m, 2H), 3.57 (m, 2H), 4.02 (s, 2H), 4.57 (s, 2H), 7.23 (d, J=6.6 Hz, 1H), 7.51 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 8.05 (t, J=10.3 Hz, 1H), 10.97 (s, 1H), 12.19 (s, 1H). HRMS (M+H) calcd for C19H21N3Cl2O6: 456.07292; found: 456.0738.

EXAMPLE 38

[0260] Compound 38: 4-Hydroxy-1-[2-(3-morpholin-4-yl-propionylamino)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 77

[0261] N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and N-(2-amino-ethyl)-3-morpholin-4-yl-propionamide as described in the preparation of Compound 37. The desired product was isolated as a white solid (0.0134 g, 5% yield). 1H NMR (300 MHz, CDCl3) δ: 2.41 (m, 2H), 2.64 (bs, 2H), 2.72 (bs, 2H), 2.98 (m, 2H), 3.03 (s, 3H), 3.51 (t, J=5.6 Hz, 2H), 3.63 (t, J=5.2 Hz, 2H), 3.78 (m, 4H), 4.35 (s, 2H), 4.59 (s, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.35-7.44 (m, 3H), 8.27 (t, 1H). HRMS (M+H) calcd for C22H28N4Cl2O5: 497.13585; found: 497.1377.

EXAMPLE 39

[0262] Compound 39: (3-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-propionylamino)-acetic Acid 78

[0263] N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and H-β-ala-gly-OH as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber powder (0.0158 g, 7% yield). 1H NMR (300 MHz, DMSO) δ: 2.45 (t, J=6.9 Hz, 2H), 2.98 (m, 3H), 3.60 (m, 2H), 3.73 (d, J=5.7 Hz, 2H), 4.06 (s, 2H), 4.57 (s, 2H), 7.23 (d, J=7.2, 1H), 7.65 (d, J=8.4 Hz, 1H), 8.32 (m, 1H), 10.98 (bs, 1H), 12.50 (bs, 1H). HRMS (M−H) calcd for C18H19N3Cl2O6: 442.05727; found: 442.0584.

EXAMPLE 40

[0264] Compound 40: 1-(2-Carbamoyl-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 79

[0265] N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[01,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and β-alaninamide as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber powder (0.0158 g, 7% yield). 1H NMR (300 MHz, CDCl3) δ: 2.68 (t, J=5.9 Hz, 2H), 3.02 (s, 3H), 3.79 (d, J=5.9 Hz, 2H), 4.29 (s, 2H), 4.58 (s, 2H), 6.23 (s, 1H), 6.59 (s, 1H), 7.09 (dd, J=8.4 Hz, J=10.3 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H). HRMS (M−H) calcd for C16H17N3Cl2O4: 384.05179; found: 384.0517.

EXAMPLE 41

[0266] Compound 41: 4-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-ylmethyl}-benzoic Acid Methyl Ester 80

[0267] N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and 4-(aminomethyl)-benzoate hydrochloride salt with 1 equivalent of triethyl amine as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a yellow foam (0.060 g, 26% yield). 1H NMR (300 MHz, CDCl3) δ: 2.98 (s, 3H), 3.91 (s, 3H), 4.05 (s, 2H), 4.56 (s, 2H), 7.07 (dd, J=1.8 Hz, J=8.1 Hz, 1H), 7.30 (m, 3H), 7.40 (m, 1H), 8.00 (d, J=8.1 Hz, 1H). HRMS (M−H) calcd for C22H20N2Cl2O5: 461.0671; found: 461.0690.

EXAMPLE 42

[0268] Compound 42: 1-(2-Cyano-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3 carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 81

[0269] N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and 3-aminopropionitirile with 1 equivalent of triethyl amine as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a yellow foam (0.0819 g, 45% yield). 1H NMR (300 MHz, CDCl3) δ: 2.73 (t, J=6.3 Hz, 2H), 3.04 (s, 3H), 3.78 (t, J=6.3 Hz, 2H), 4.40 (s, 2H), 4.60 (s, 2H), 7.11 (dd, J=1.8 Hz, J=8.1 Hz, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H). HRMS (M−H) calcd for C16H15N3Cl2O3: 366.04122; found: 366.0428.

EXAMPLE 43

[0270] Compound 43: 4-Hydroxy-1-(3-morpholin-4-yl-propyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 82

[0271] N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and N-(3-aminopropyl)morpholine as described in the preparation of Compound 37. The title compound was isolated as a white solid (0.1345 g, 61% yield). 1H NMR (500 MHz, DMSO) δ: 1.69 (t, J=6.4 Hz, 2H), 2.25 (s, 2H), 2.32 (s, 4H), 2.97 (s, 3H), 3.40 (t, J=6.4 Hz, 2H), 3.55 (s, 4H), 4.05 (s, 2H), 4.59 (s, 2H), 7.24 (s, 1H), 7.51 (s, 1H), 7.62 (d, J=8.3 Hz, 1H). HRMS (M−H) calcd for C20H25N3Cl2O4: 442.13005; found: 442.1296.

EXAMPLE 44

[0272] Compound 44-A: 4-Fluoro-benzaldehyde O-methyl-oxime 83

[0273] A solution of methoxylamine hydrochloride (13.4 g, 0.16 mol) in a mixture of water (150 ml) and tetrahydrofuran (50 ml) was treated with sodium acetate (11.2 g, 0.136 mol) followed by 4-fluorobenzaldehyde (11.57 g, 93.2 mmol) and the resulting mixture was stirred at 22° C. for 4 hours. The reaction mixture was then diluted with ether, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave 14.3 g of the crude title material as a clear oil which was used as such for the next step. Distillation of an aliquot in vacuo gave a clear oil; bp 45-50° C./0.5 torr. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.99 (3H, s), 7.09 (2H, m), 7.6 (2H, m), 8.06 (1H, s).

[0274] Compound 44-B: N-(4-Fluoro-benzyl)-O-methyl-hydroxylamine 84

[0275] A solution of 4-fluorobenzaldehyde-O-methyloxime (93.2 mmol) in dichloromethane (150 ml) was treated with sodium cyanoborohydride (9.18 g, 0.146 mol) followed by 120 ml of 2 N hydrochloric acid in methanol added dropwise over 30 minutes. After 96 h at 22° C., the solvent was evaporated under reduced pressure and the residue was slurried with water and the pH was adjusted to 9 with 2 N aqueous sodium hydroxide. The aqueous phase was extracted twice with dichloromethane and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual oil was chromatographed on silica gel (elution toluene-ethyl acetate 0-10% yield) and gave 5.92 g (41% yield) of the title amine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s), 4.01 (2H, s), 5.69 (1H, broad s), 7.01 (2H, m), 7.31 (2H, m). The hydrochloride salt was obtained as a white solid: mp 170-171° C. Anal. calcd for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.31; H, 5.80; N, 7.26

[0276] In an alternative procedure a solution of 4-fluorobenzaldehyde O-methyloxime (0.82 g, 5.35 mmol) in acetic acid (8 ml) was treated at 10° C. with sodium cyanoborohydride (0.67 g, 10.7 mmol) added in small portions over 10 min and the resulting solution was stirred at 25° C. for 18 h. The solvent was evaporated under reduce pressure (co-evaporation with toluene twice) and the residue was slurried with water and the pH was adjusted to 9 with 2 N aqueous sodium hydroxide. The aqueous phase was extracted twice with ether and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual oil was chromatographed on silica gel (elution hexane-ethyl acetate, 8:2) and distilled in vacuo to give 0.62 g (75% yield) of the title amine as a clear oil.

[0277] Compound 44-C: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide 85

[0278] A solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (2.45 g, 12.9 mmol) in dichloromethane (15 ml) was added dropwise over 10 minutes to a cold (0-5° C.) mixture of N-4-fluorobenzyl-O-methyl-hydroxylamine (2.0 g, 12.9 mmol) and pyridine (2.1 ml, 25.7 mmol) in dichloromethane (50 ml). The cooling bath was then removed and the solution was stirred at 22° C. for 30 minutes. The reaction mixture was then quenched by the addition of water and ethyl acetate. The organic phase was washed successively with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (toluence-thyl acetate, 8:2) gave 3.72 g (93% yield) of the title amide as white crystals: mp 111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s), 3.68 (3H, s), 4.79 (2H, s), 6.38 (1H, s), 7.0 (2H, m), 7.34 (2H, m). Anal. calcd for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52; Found: C, 58.33; H, 5.38; N, 4.51.

[0279] Compound 44-D: 3-[(4-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 86

[0280] A solution of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxy-acetamide (0.64 g, 2.07 mmol) in methanol (50 ml), was treated at 22° C. with 0.025 ml of a 4.6 M solution of sodium methoxide in methanol and the resulting mixture was stirred for 2 h at the same temperature. The reaction mixture was then quenched by the addition of 1 ml of 1 N hydrochloric acid and the solvent was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and brine and then dried over anhydrous magnesium sulfate. Evaporation of the solvent and crystallization of the residue from a mixture of ethyl acetate and hexane gave 0.559 g (95% yield) of the title ester as white prisms; mp 71° C. 1HNMR 400 MHz (CDCl3) δ (ppm), mixture of rotamers, major: 3.69 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.80 (2H, s, NCH2), 6.45 (1H, s, CH), 7.03 (2H, m, aromatics), 7.30 (2H, m, aromatics). Anal. calcd for C13H14FNO5: C, 55.12; H, 4.98; N, 4.94. Found: C, 54.95; H, 4.73; N, 4.67.

[0281] Compound 44: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-benzyl)-methoxy-amide 87

[0282] Method 44A: 3-[(4-Fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (48% yield); mp 125° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.1 (3H, s, NCH3), 3.72 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.84 (2H, s, NCH2), 7.04 (2H, m, aromatics), 7.32 (2H, m, aromatics). Anal. calcd for C14H15FN2O4: C, 57.14; H, 5.13; N, 9.52. Found: C, 56.87; H, 5.12; N, 9.42.

[0283] Method 44B: A solution of 2 M methylamine in tetrahydrofuran (0.58 ml, 1.16 mmol) was added to a mixture of paraformaldehyde (0.35 g, 1.16 mmol, equivalent of formaldehyde) in methanol (3 ml) and the resulting mixture was heated at 60° C. for 5 min. Then solid 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-methoxy-acetamide (0.30 g, 0.97 mmol) was added all at once and the resulting mixture was maintained at 60° C. for another 60 min. The reaction mixture was then quenched by the addition of ethyl acetate and pH 2 phosphate buffer. The organic phase was washed with brine, dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. Recrystallization of the solid residue from a mixture of ethyl acetate and hexane gave 0.181 g (64% yield) of the title material as a white solid.

EXAMPLE 45

[0284] Compound 45: 4-Hydroxy-1-(2-morpholino-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methoxy-amide 88

[0285] 3-[(4-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 44-D) was treated with paraformaldehyde and N-(2-aminoethyl) morphiline as described in the preparation of Compound 13. The reaction mixture was diluted with water and extracted the CH2Cl2. After concentration of the organic phase, the residue was triturated with EtOAc and the solid filtered to yield the title compound as a white solid (0.1444 g, 37% yield). 1H NMR (500 MHz, DMSO) δ: 3.08 (d, J=11.1 Hz, 2H), 3.41 (d, J=5.2 Hz, 2H), 3.51 (d, J=12.2 Hz, 2H), 3.69 (t, J=11.9 Hz, 2H), 3.75 (s, 3H), 3.81 (s, 2H), 3.98 (d, 1=13.2 Hz, 2H), 4.25 (s, 2H), 4.88 (s, 2H), 7.18 (t, J=8.8 Hz, 2H), 7.37 (m, 2H), 10.11 (s, 1H), 11.42 (s, 1H). HRMS (M+H) calcd for C19H24FN3O5: 392.16217; found: 392.1627.

EXAMPLE 46

[0286] Compound 46: 4-Hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-methoxy-amide 89

[0287] 3-[(4-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 44-D) was treated with paraformaldehyde and N-(2-aminoethyl)piperazine as described in the preparation of Compound 13. The mixture was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white powder (0.0110 g, 4.3% yield). 1H NMR (500 MHz, CDCl3) δ: 2.55 (t, J=6.2 Hz, 2H), 2.71 (s, 4H), 2.98 (s, 4H), 3.47 (t, J=5.5 Hz, 2H), 3.57 (s, 3H), 4.03 (s, 2H), 4.68 (s, 2H), 6.87 (s, 2H), 7.17 (m, 2H), 9.72 (bs, 1H), 11.45 (bs, 1H). HRMS (M+H) calcd for C19H25FN4O4: 391.17816; found: 391.1786.

EXAMPLE 47

[0288] Compound 47-A: N-(3,4-Dichloro-benzyl)-O-methyl-hydroxylamine 90

[0289] Reaction of 3,4-dichlorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of Compound 44-A and 44-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.99 (2H, s), 5.74 (1H, broad s), 7.20 (1H, dd, J=2.0 Hz and J=8.1 Hz), 7.40 (1H, d, J=8.1 Hz), 7.47 (1H, d, J=2.0 Hz).

[0290] Compound 47-B: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 91

[0291] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-3,4-dichlorobenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (94% yield): mp 119-120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s), 3.71 (3H, s), 4.72 (2H, s), 6.38 (1H, s), 7.20 (1H, dd, J=2.0 Hz and J=8.5 Hz), 7.40 (1H, d, J=8.5 Hz), 7.46 (1H, d, J=2.0 Hz). Anal. calcd for C15H15C2NO5: C, 50.02; H, 4.20; N, 3.89. Found: C 50.12, H 4.12, N 3.80.

[0292] Compound 47-C: 3-[(3,4-Dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 92

[0293] N-(3,4-Dichlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (95% yield); mp 111° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.46 (1H, s, CH), 7.17 (1H, dd, J=2.0 Hz, J=8.0 Hz, aromatic), 7.42 (1H, d, J=8.0 Hz, aromatic), 7.43 (1H, d, J=2.0 Hz, aromatic). Anal. calcd for C13H13Cl2NO5: C, 46.73; H, 3.92; N 4.19. Found: C, 46.95; H, 3.82; N, 3.97.

[0294] Compound 47: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methoxy-amide 93

[0295] 3-[(3,4-Dichlorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 47-C) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12, yielding the title compound as a white solid (49% yield); mp 149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.82 (2H, s, NCH2), 7.18 (1H, dd, J=2.0 Hz, J=8.2 Hz, aromatic), 7.42 (1H, d, J=8.2 Hz, aromatic), 7.43 (1H, d, J=2.0 Hz, aromatic). Anal. calcd for C14H14Cl2N2O4: C, 48.72; H, 4.09; N, 8.12. Found: C, 48.81; H, 4.04; N, 7.99.

EXAMPLE 48

[0296] Compound 48-A: N-(3-Chloro-4-fluoro-benzyl)-O-methyl-hydroxylamine 94

[0297] Reaction of 3-chloro-4-fluorobenzaldehyde with methoxylamine hydrochloride followed by reduction with sodium cyanoborohydride as described in the preparation of Compound 44-A and 44-B gave the title hydroxylamine as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s), 3.98 (2H, s), 5.72 (1H, broad s), 7.10 (1H, t), 7.22 (1H, m), 7.42 (1H, m).

[0298] Compound 48-B: N-(3-Chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 95

[0299] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-chloro-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (91% yield): mp 110-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s), 3.71 (3H, s), 4.75 (2H, s), 6.38 (1H, s), 7.09 (1H, t, J=8.8 Hz), 7.23 (1H, m), 7.41 (1H, dd, J=2.4 Hz and J=6.8 Hz). Anal. calcd for C15H15ClFNO5: C, 52.41; H, 4.39; N, 4.07. Found: C 52.25, H 4.36, N 3.87.

[0300] Compound 48-C: 3-[(3-Chloro-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 96

[0301] N-(3-Chloro-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (54% yield); mp 97-98° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.45 (1H, s, CH), 7.11 (1H, m, aromatic), 7.2 (1H, m, aromatic), 7.38 (1H, m, aromatic). Anal. calcd for C13H13ClFNO5: C, 49.14; H, 4.12; N, 4.40. Found: C, 48.95; H, 3.96; N, 4.16.

[0302] Compound 48: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3-chloro-4-fluoro-benzyl)-methoxy-amide 97

[0303] 3-[(3-Chloro-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (48-C) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (60% yield); mp 148° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.10 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 7.12 (1H, m, aromatic), 7.22 (1H, m, aromatic), 7.38 (1H, m, aromatic). Anal. calcd for C14H14Cl2N2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 51.19; H, 4.17; N, 8.50.

EXAMPLE 49

[0304] Compound 49-A: N-(3-Fluoro-benzyl)-O-methyl-hydroxylamine 98

[0305] Reduction 3-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compounds 44-A and 44-B gave the title hydroxylamine as a clear oil (60% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.50 (3H, s, OCH3), 4.04 (2H, s, NCH2), 5.75 (1H, broad s, NH), 6.95-7.32 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 130-131° C. (dec.). Anal. calcd for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.10; H, 5.73; N, 7.38.

[0306] Compound 49-B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-benzyl)-N-methoxy-acetamide 99

[0307] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C and gave the title amide as a white solid (94% yield): mp 110-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.82 (2H, s, NCH2), 6.40 (1H, s, CH), 6.96-7.32 (4H, m, aromatics). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.00; H, 5.30; N, 4.49.

[0308] Compound 49-C: 3-[(3-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 100

[0309] N-(3-Fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (53% yield); mp 73-75° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.71 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.82 (2H, s, NCH2), 6.47 (1H, s, CH), 6.98-7.34 (4H, m, aromatics). Anal. calcd for C13H14FNO5: C, 55.12; H, 4.98; N, 4.94. Found: C, 55.18; H, 5.04; N, 5.02.

[0310] Compound 49: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3-fluoro-benzyl)-methoxy-amide 101

[0311] 3-[(3-Fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 49-C) was reacted with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (60% yield); mp 119° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.74 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.87 (2H, s, NCH2), 6.99-7.35 (4H, m, aromatics). Anal. calcd for C14H15FN2O4: C, 57.14; H, 5.14; N, 9.52. Found: C, 57.04; H, 5.02; N, 9.42.

EXAMPLE 50

[0312] Compound 50-A: 2-Fluorobenzaldehyde O-methyloxime 102

[0313] Reaction of 2-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (98% yield). HPLC indicated a 91:9 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.99 (3H, s, OCH3), 7.07 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.34 (1H, m, aromatic), 7.82 (1H, m, aromatic), 8.31 (1H, s, CH).

[0314] Compound 50-B: N-(2-Fluoro-benzyl)-O-methyl-hydroxylamine 103

[0315] Reduction of 2-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (74% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.52 (3H, s, OCH3), 4.11 (2H, s, NCH2), 5.78 (1H, broad s, NH), 7.05 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.38 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 138-143° C. (dec.). Anal. calcd. for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.37; H, 5.71; N, 7.18.

[0316] Compound 50-C: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(2-fluoro-benzyl)-N-methoxy-acetamide 104

[0317] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (84% yield): mp 109-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.92 (2H, s, NCH2), 6.40 (1H, s, CH), 7.03-7.12 (2H, m, aromatics), 7.24-7.30 (1H, m, aromatic), 7.4 (1H, m, aromatic). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.47; H, 5.16; N, 4.66

[0318] Compound 50-D: 3-[(2-Fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 105

[0319] N-(2-Fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white syrup (59% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.93 (2H, s, NCH2), 6.47 (1H, s, CH), 7.05-7.36 (4H, m, aromatics). Anal. calcd for C13H14FNO5: C, 55.12; H, 4.98; N, 4.94. Found: C, 54.91; H, 5.23; N, 4.86.

[0320] Compound 50: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (2-fluoro-benzyl)-methoxy-amide 106

[0321] 3-[(2-Fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 50-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (58% yield); mp 147° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.1 (3H, s, NCH3), 3.76 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.97 (2H, s, NCH2), 7.06-7.39 (4H, m, aromatics). Anal. calcd for C14H15FN2O4: C, 57.14; H, 5.14; N, 9.52. Found: C, 57.00; H, 5.29; N, 9.33.

EXAMPLE 51

[0322] Compound 51-A: N-(4-Chloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 107

[0323] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-chlorobenzyl)-O-methyl-hydroxylamine (Kawase, M. et al., J. Chem. Soc. Perkin Trans. 1, 1979, 643-645) as described in the preparation of compound 1-A gave the title amide as white crystals (95% yield): mp 129-130° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.69 (3H, s, OCH3), 4.79 (2H, s, NCH2), 6.39 (1H, s, CH), 7.4 (4H, s, aromatics). Anal. calcd. for C15H16ClNO5: C, 55.31; H, 4.95; N, 4.30. Found: C, 55.32; H, 4.95; N, 4.27.

[0324] Compound 51-B: 3-[(4-Chloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 108

[0325] N-(4-Chlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white syrup (52% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.80 (2H, s, NCH2), 6.45 (1H, s, CH), 7.25-7.33 (4H, m, aromatics). Anal. calcd for C13H14ClNO5: C, 52.10; H, 4.71; N, 4.67. Found: C, 51.86; H, 4.68; N, 4.45.

[0326] Compound 51: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-chloro-benzyl)-methoxy-amide 109

[0327] 3-[(4-Chlorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 51-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (69% yield); mp 165° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.10 (3H, s, NCH3), 3.72 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.84 (2H, s, NCH2), 7.25-7.34 (4H, m, aromatics). Anal. calcd for C14H15ClN2O4: C, 54.11; H, 4.87; N, 9.02. Found: C, 53.88; H, 4.71; N, 8.78.

EXAMPLE 52

[0328] Compound 52-A: 4-Fluorophenylacetaldehyde O-methyloxime 110

[0329] Reaction of 4-fluorophenylacetaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (43% yield). 1HNMR indicated a 1:1 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.51 (2H, d, J=6.7 Hz, CH2), 3.66 (2H, d, J=5.5 Hz, CH2), 3.88 (3H, s, OCH3), 3.96 (3H, s, OCH3), 6.79 (1H, t, J=5.5 Hz, CH), 7.03 (2H, m, aromatics), 7.19 (2H, m, aromatics), 7.45 (1H, t, J=6.7 Hz, CH).

[0330] Compound 52-B: N-[2-(4-Fluoro-phenyl)-ethyl]-O-methyl-hydroxylamine 111

[0331] Reduction of 4-fluorophenylacetaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (62% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 2.64 (2H, d, J=7.1 Hz, CH2), 2.97 (2H, d, J=7.1 Hz, CH2), 3.53 (3H, s, OCH3), 5.24 (broad, NH), 6.9 (4H, m, aromatics).

[0332] Compound 52-C: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-phenyl)-ethyl]-N-methoxy-acetamide 112

[0333] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[2-(4-fluorophenyl)-ethyl]-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (86% yield): mp 106-107° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 2.95 (2H, m, CH2), 3.72 (3H, s, OCH3), 3.87 (2H, m, NCH2), 6.38 (1H, broad s, CH), 6.99 (2H, m, aromatics), 7.20 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.39; H, 5.43; N, 4.13.

[0334] Compound 52-D: 3{[2-(4-Fluoro-phenyl)-ethyl]-methoxy-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester 113

[0335] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[2-(4-fluorophenyl)-ethyl]-N-methoxy-acetamide was treated with methanol as described in the preparation Compound 44-D and gave the title ester as a clear oil (66% yield). HRMS (MAB N2) calculated for C14H16FNO5:[M]+: 297.101251; found: 297.101514. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.95 (2H, t, J=7.6 Hz, CH2), 3.73 (3H, s, OCH3), 3.89 (2H, t, J=7.6 Hz, CH2), 3.92 (3H, s, OCH3), 6.44 (1H, s, CH), 7.0 (2H, m, aromatics), 7.19 (2H, m, aromatics).

[0336] Compound 52: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-methoxy-amide 114

[0337] 3-{[2-(4-Fluorophenyl)-ethyl]-methoxy-carbamoyl}-2-hydroxy-acrylic acid methyl ester (Compound 52-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (38% yield); mp 157° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.96 (2H, t, J=7.6 Hz, CH2), 3.14 (3H, s, NCH3), 3.71 (3H, s, OCH3), 3.93 (2H, t, J=7.6 Hz, CH2), 4.14 (2H, s, NCH2), 7.01 (2H, m, aromatics), 7.2 (2H, m, aromatics), 11.55 (1H, broad s, OH). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.52; H, 5.66; N, 8.89.

EXAMPLE 53

[0338] Compound 53-A: 4-Fluorobenzaldehyde O-ethyloxime 115

[0339] Reaction of 4-fluorobenzaldehyde with ethoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5) and distillation (58% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.35 (3H, t, J=7.07 Hz, CH3), 4.24 (2H, q, J=7.07 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.07 (1H, s, CH).

[0340] Compound 53-B: O-Ethyl-N-(4-fluoro-benzyl)-hydroxylamine 116

[0341] Reduction of 4-fluorobenzaldehyde O-ethyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography (74% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 1.13 (3H, t, J=7.1 Hz, CH3), 3.70 (2H, q, J=7.1 Hz, OCH2), 3.78 (2H, d, J=5.4 Hz, NCH2), 5.20 (2H, broad t, NH), 6.89 (2H, m, aromatics), 7.09 (2H, m, aromatics). Anal. calcd for C9H12FNO: C, 63.88; H, 7.14; N, 8.27. Found: C, 63.68; H, 7.08; N, 8.46.

[0342] Compound 53-C: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-ethoxy-N-(4-fluoro-benzyl)-acetamide 117

[0343] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-ethyl-N-4-fluorobenzyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (92% yield): mp 95-96° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.07 Hz, CH3), 1.77 (6H, s, CH3), 3.90 (2H, q, J=7.07 Hz, OCH2), 4.81 (2H, s, NCH2), 6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.50; H, 5.60; N, 4.17.

[0344] Compound 53-D: 3-[Ethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 118

[0345] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-ethoxy-N-(4-fluorobenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (84% yield); mp 61-62° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.28 (3H, t, J=7.1 Hz, CH3), 3.91 (3H, s, OCH3), 3.92 (2H, q, J=7.1 Hz, OCH2), 4.82 (2H, s, NCH2), 6.47 (1H, s, CH), 7.05 (2H, m, aromatics), 7.32 (2H, m, aromatics), 13.5 (1H, broad s, OH). Anal. calcd for C14H16FNO5: C, 56.56; H, 5.42; N, 4.71. Found: C, 56.67; H, 5.25; N, 4.64.

[0346] Compound 53: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid ethoxy-(4-fluoro-benzyl)-amide 119

[0347] 3-[Ethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 53-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (50% yield); mp 113-114° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.30 (3H, t, J=7.1 Hz, CH3), 3.12 (3H, s, NCH3), 3.96 (2H, q, J=7.1 Hz, OCH2), 4.16 (2H, s, NCH2), 4.86 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.33 (2H, m, aromatics), 11.65 (1H, broad s, OH). Anal. calcd for C15H17FN2O4: C, 58.43; H, 5.55; N, 9.08. Found: C, 58.30; H, 5.55; N, 9.03.

EXAMPLE 54

[0348] Compound 54-A: 3,4-Difluorobenzaldehyde O-methyloxime 120

[0349] Reaction of 3,4-difluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (100% yield). 1HNMR indicated a 85:15 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.97 (3H, s, OCH3), 7.12-7.26 (2H, m, aromatics), 7.44-7.52 (1H, m, aromatic), 7.97 (1H, s, CH).

[0350] Compound 54-B: N-(3,4-Difluoro-benzyl)-O-methyl-hydroxylamine 121

[0351] Reduction of 3,4-difluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (82% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 3.98 (2H, s, NCH2), 5.73 (1H, broad s, NH), 7.04-7.23 (3H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 139-142° C. (dec.). Anal. calcd. for C8H9F2NO2—HCl: C, 45.83; H, 4.80; N, 6.68. Found: C, 45.96; H, 4.93, N, 6.67.

[0352] Compound 54-C: N-(3,4-Difluoro-benzyl)-2-(2,3-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 122

[0353] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-3,4-difluorobenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (96% yield): mp 110-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.71 (3H, s, OCH3), 4.72 (2H, s, NCH2), 6.38 (1H, s, CH), 7.05-7.22 (3H, m, aromatics). Anal. calcd. for C15H15NO5: C, 55.04; H, 4.62; N, 4.28. Found: C, 54.99; H, 4.55; N, 4.22.

[0354] Compound 54-D: 3-[(3,4-Difluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 123

[0355] N-(3,4-Difluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (53% yield); mp 76-77° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.45 (1H, s, CH), 7.05-7.19 (3H, m, aromatics). Anal. calcd for C13H13F2NO5: C, 51.83; H, 4.35; N, 4.65. Found: C, 51.78; H, 4.28; N, 4.53.

[0356] Compound 54: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-difluoro-benzyl)-methoxy-amide 124

[0357] 3-[(3,4-Difluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 54-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to and gave the title compound as a white solid (53% yield); mp 146-147° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.74 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.79 (2H, s, NCH2), 7.06-7.19 (3H, m, aromatics). Anal. calcd for C14H14F2N2O4: C, 53.84; H, 4.51; N, 8.97. Found: C, 53.82; H, 4.41; N, 8.87.

EXAMPLE 55

[0358] Compound 55-A: 4-Methoxybenzaldehyde O-methyloxime 125

[0359] Reaction of 4-methoxybenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (100% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.83 (3H, s, OCH3), 3.94 (3H, s, OCH3), 6.89 (2H, m, aromatics), 7.52 (2H, m, aromatics), 8.05 (1H, s, CH).

[0360] Compound 55-B: N-(4-Methoxy-benzyl)-O-methyl-hydroxylamine 126

[0361] Reduction of 4-methoxybenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (96% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.98 (2H, s, NCH2), 5.62 (1H, broad s, NH), 6.86 (2H, m, aromatics), 7.25 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 157-158° C. (dec.). Anal. calcd. for C9H13NO2—HCl: C, 53.03; H, 6.92; N, 6.87. Found: C, 53.14; H, 6.76; N, 6.80.

[0362] Compound 55-C: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-(4-methoxy-benzyl)-acetamide 127

[0363] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-methoxybenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (97% yield): mp 113-114° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.66 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.38 (1H, s, CH), 6.85 (2H, m, aromatics), 7.29 (2H, m, aromatics). Anal. calcd. for C16H19NO6: C, 59.80; H, 5.96; N, 4.35. Found: C, 59.87; H, 5.76; N, 4.17.

[0364] Compound 55-D: 2-Hydroxy-3-[methoxy-(4-methoxy-benzyl)-carbamoyl]-acrylic Acid Methyl Ester 128

[0365] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-methoxybenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (56% yield); mp 87-89° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.67 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.44 (1H, s, CH), 6.87 (2H, m, aromatics), 7.26 (2H, m, aromatics). Anal. calcd for C14H17NO6: C, 56.94; H, 5.80; N, 4.74. Found: C, 57.03; H, 5.82; N, 4.68.

[0366] Compound 55: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(4-methoxy-benzyl)-amide 129

[0367] 2-Hydroxy-3-[methoxy-(4-methoxybenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 55-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (58% yield); mp 135-137° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.09 (3H, s, NCH3), 3.71 (3H, s, OCH3), 3.80 (3H, s, OCH3), 4.14 (2H, s, NCH2), 4.82 (2H, s, NCH2), 6.88 (2H, m, aromatics), 7.27 (2H, m, aromatics). Anal. calcd for C15H18N2O5: C, 58.81; H, 5.92; N, 9.14. Found: C, 58.62; H, 5.88; N, 9.12.

EXAMPLE 56

[0368] Compound 56-A: 2-Methylbenzaldehyde O-methyloxime 130

[0369] Reaction of 2-methylbenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (96% yield). HPLC indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.44 (3H, s, CH3), 4.01 (3H, s, OCH3), 7.19-7.28 (3H, m, aromatics), 7.73 (1H, m, aromatic), 8.36 (1H, s, CH).

[0370] Compound 56-B: O-Methyl-N-(2-methyl-benzyl)-hydroxylamine 131

[0371] Reduction of 2-methylbenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (83% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.42 (3H, s, CH3), 3.55 (3H, s, OCH3), 4.11 (2H, s, NCH2), 5.64 (1H, s, NH), 7.19-7.32 (4H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 148-150° C. Anal. calcd. for C9H13NO—HCl: C, 57.60; H, 7.51; N, 7.46. Found: C, 57.59; H, 7.69; N, 7.52.

[0372] Compound 56-C: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-N-(2-methyl-benzyl)-acetamide 132

[0373] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(2-methylbenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (100% yield): mp 96-97° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.78 (6H, s, CH3), 2.4 (3H, s, CH3), 3.59 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.44 (1H, s, CH), 7.2-7.28 (4H, m, aromatics). Anal. calcd. for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.90; H, 6.21; N, 4.52

[0374] Compound 56-D: 2-Hydroxy-3-[methoxy-(2-methyl-benzyl)-carbamoyl]-acrylic Methyl Ester 133

[0375] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(2-methylbenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (61% yield); mp 80-82° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.39 (3H, s, CH3), 3.62 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.5 (1H, s, CH), 7.22-7.28 (4H, m, aromatics), 13.5 (1H, broad s, OH). Anal. calcd for C14H17NO5: C, 60.20; H, 6.13; N, 5.01. Found: C, 60.07; H, 5.88; N, 4.84.

[0376] Compound 56: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(2-methyl-benzyl)-amide 134

[0377] 2-Hydroxy-3-[methoxy-(2-methylbenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 56-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (61% yield); mp 153-154° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.39 (3H, s, CH3), 3.13 (3H, s, NCH3), 3.67 (3H, s, OCH3), 4.19 (2H, s, NCH2), 4.95 (2H, s, NCH2), 7.2-7.3 (4H, m, aromatics), 11.7 (1H, broad s, OH). Anal. calcd for C15H18N2O4: C, 62.05; H, 6.24; N, 9.65. Found: C, 61.79; H, 6.30; N, 9.58.

EXAMPLE 57

[0378] Compound 57-A: 3-Bromo-4-fluorobenzaldehyde O-methyloxime 135

[0379] Reaction of 3-bromo-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (95% yield). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.97 (3H, s, OCH3), 7.12 (1H, m, aromatics), 7.48 (1H, m, aromatic), 7.82 (1H, m, aromatic), 7.97 (1H, s, CH).

[0380] Compound 57-B: N-(3-Bromo-4-fluoro-benzyl)-O-methyl-hydroxylamine 136

[0381] Reduction of 3-bromo-4-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (83% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 3.99 (2H, s, NCH2), 7.08 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.57 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 150-151° C. Anal. calcd. for C8H9BrFNO—HCl: C, 35.52; H, 3.73; N, 5.18. Found: C, 35.54; H, 3.61; N, 5.12.

[0382] Compound 57-C: N-(3-Bromo-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 137

[0383] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-3-bromo-4-fluorobenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (100% yield): mp 117-119° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.71 (3H, s, OCH3), 4.76 (2H, s, NCH2), 6.38 (1H, s, CH), 7.07 (1H, m, aromatic), 7.28 (1H, m, aromatic), 7.56 (1H, m, aromatic). Anal. calcd. for Cl5H15BrFNO5: C, 46.41; H, 3.89; N, 3.61. Found: C, 46.43; H, 4.01; N, 3.53.

[0384] Compound 57-D: 3-[(3-Bromo-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 138

[0385] N-(3-Bromo-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (44% yield); mp 107-108° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.72 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.77 (2H, s, NCH2), 6.45 (1H, s, CH), 7.09 (1H, m, aromatic), 7.25 (1H, m, aromatic), 7.53 (1H, m, aromatic). Anal. calcd for C13H13BrFNO5: C, 43.11; H, 3.62; N, 3.86. Found: C, 43.10; H, 3.54; N, 3.87.

[0386] Compound 57: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3-bromo-4-fluoro-benzyl)-methoxy-amide 139

[0387] 3-[(3-Bromo-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 57-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (35% yield); mp 154-157° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 7.1 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.54 (1H, m, aromatic). Anal. calcd for C14H14BrFN2O4: C, 45.06; H, 3.78; N, 7.50. Found: C, 44.80; H, 3.81; N, 7.33.

EXAMPLE 58

[0388] Compound 58-A: 4-Fluorobenzaldehyde O-isobutyloxime 140

[0389] Reaction of 4-fluorobenzaldehyde with O-isobutyl-hydroxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution toluene-ethyl acetate 95:5), (77% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH3), 2.07 (1H, m, CH), 3.95 (2H, d, J=7.18 Hz, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.08 (1H, s, CH). Anal. calcd for C11H14FNO: C, 67.67; H, 7.22; N, 7.17. Found: C, 67.71; H, 7.32; N, 7.38

[0390] Compound 58-B: N-(4-Fluoro-benzyl)-O-isobutyl-hydroxylamine 141

[0391] Reduction of 4-fluorobenzaldehyde O-isobutyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography (65% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 0.87 (6H, d, J=6.75 Hz, CH3), 1.88 (1H, m, CH), 3.46 (2H, d, J=6.41 Hz, OCH2), 4.05 (2H, s, NCH2), 7.04 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C11H16FNO: C, 66.98; H, 8.17; N, 7.10. Found: C, 66.88; H, 7.97; N, 7.32.

[0392] Compound 58-C: 2-(2.2-Dimethyl-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-isobutoxy-acetamide 142

[0393] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluorobenzyl)-O-isobutyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (91% yield): mp 105-106° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (3H, d, J=6.45 Hz, CH3), 1.77 (6H, s, CH3), 1.95 (1H, m, CH), 3.64 (2H, d, J=6.63 Hz, OCH2), 4.80 (2H, s, NCH2), 6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics). Anal. calcd for C18H22FNO5: C, 61.53; H, 6.31; H, 3.98. Found: C, 61.47; H, 6.39; N, 3.97.

[0394] Compound 58-D: 3-[(4-Fluoro-benzyl)-isobutoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 143

[0395] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-isobutoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (48% yield); mp 55-56° C. 1HNMR 400 MHz (CDCl3) δ (ppm): mixture of rotamers: 0.99 (6H, d, J=7.1 Hz, CH3), 1.96 (1H, m, CH), 3.65 (2H, d, J=6.0 Hz, OCH2), 3.91 (3H, s, OCH3), 4.81 (2H, s, NCH2), 6.49 (1H, s, CH), 7.05 (2H, m, aromatics), 7.33 (2H, m, aromatics), 13.4 (1H, broad s, OH). HRMS (ES+) calculated for C16H21FNO5, [M+H]+: 326.140376; found: 326.139560.

[0396] Compound 58: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-isobutoxy-amide 144

[0397] 3-[(4-Fluorobenzyl)-isobutoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 58-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (40% yield); mp 96-97° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH3), 1.96 (1H, m CH), 3.12 (3H, s, NCH3), 3.69 (2H, d, J=6.4 Hz, OCH2), 4.1 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.33 (2H, m, aromatics), 11.65 (1H, broad s, OH). HRMS (ES+) calculated for C17H??FN2O4, [M+H]+: 337.156361; found: 337.156153.

EXAMPLE 59

[0398] Compound 59-A: 2-Hydroxy-3-[methoxy-(4-methyl-benzyl)-carbamoyl]-acrylic Acid Methyl Ester 145

[0399] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-methylbenzyl)-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-D to give the title ester as white crystals (69% yield); mp 83-84° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.59 (3H, s, CH3), 3.94 (3H, s, OCH3), 4.15 (3H, s, OCH3), 5.05 (2H, s, NCH2), 6.72 (1H, s, CH), 7.41 (2H, d, J=8.1 Hz, aromatics), 7.47 (2H, d, J=8.1 Hz, aromatics), 13.75 (1H, broad s, OH). Anal. calcd for C14H17NO5: C, 60.20; H, 6.13; N, 5.01. Found: C, 60.24; H, 6.09; N, 4.85.

[0400] Compound 59: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(4-methyl-benzyl)-amide 146

[0401] 2-Hydroxy-3-[methoxy-(4-methylbenzyl)-carbamoyl]-acrylic acid methyl ester (Compound 59-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (41% yield); mp 150-152° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.4 (3H, s, CH3), 3.16 (3H, s, NCH3), 3.78 (3H, s, OCH3), 4.21 (2H, s, NCH2), 4.91 (2H, s, NCH2), 7.22 (2H, d, J=8 Hz, aromatics), 7.28 (2H, d, J=8 Hz, aromatics), 11.7 (1H, broad s, OH). Anal. calcd for C15H18N2O4: C, 62.05; H, 6.24; N, 9.65. Found: C, 61.91; H, 6.30; N, 9.56.

EXAMPLE 60

[0402] Compound 60-A: 2,4-Difluorobenzaldehyde O-methyloxime 147

[0403] Reaction of 2,4-difluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil (80% yield). 1HNMR indicated a 95:5 mixture of E- and Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 3.98 (3H, s, OCH3), 6.79-6.91 (2H, m, aromatics), 7.79-7.85 (1H, m, aromatic), 8.24 (1H, s, CH).

[0404] Compound 60-B: N-(2,4-Difluoro-benzyl)-O-methyl-hydroxylamine 148

[0405] Reduction of 2,4-difluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (72% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.51 (3H, s, OCH3), 4.07 (2H, s, NCH2), 6.78-6.88 (2H, m, aromatics), 7.32-7.38 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 154-158° C. (dec.). Anal. calcd. for C8H9NO2—HCl: C, 45.83; H, 4.80; N, 6.68. Found: C, 45.81; H, 4.84; N, 6.59.

[0406] Compound 60-C: N-(2,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 149

[0407] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-2,4-difluorobenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (97% yield): mp 120-125° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.73 (3H, s, OCH3), 4.86 (2H, s, NCH2), 6.38 (1H, s, CH), 6.78-6.87 (2H, m, aromatics), 7.37-7.43 (1H, m, aromatic). Anal. calcd. for C15H15F2NO5: C, 55.04; H, 4.62; N, 4.28. Found: C, 55.03; H, 4.43; N, 4.17.

[0408] Compound 60-D: 3[(2,4-Difluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 150

[0409] N-(2,4-Difluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (55% yield); mp 104-105° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.87 (2H, s, NCH2), 6.45 (1H, s, CH), 6.8-6.9 (2H, m, aromatics), 7.31-7.37 (1H, m, aromatic). Anal. calcd for C13H13F2NO5: C, 51.83; H, 4.35; N, 4.65. Found: C, 51.68; H, 4.27; N, 4.53.

[0410] Compound 60: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (2,4-difluoro-benzyl)-methoxy-amide 151

[0411] 3-[(2,4-Difluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 60-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (55% yield); mp 141-149° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.1 (3H, s, NCH3), 3.77 (3H, s, OCH3), 4.14 (2H, s, NCH2), 4.92 (2H, s, NCH2), 6.8-6.9 (2H, m, aromatics), 7.35-7.41 (1H, m, aromatic).

EXAMPLE 61

[0412] Compound 61-A: 3-Cyano-4-fluorobenzaldehyde O-methyloxime 152

[0413] Reaction of 3-cyano-4-fluorobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8:2) (94% yield). 1HNMR indicated a 93:7 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.26 (1H, m, aromatic), 7.85 (2H, m, aromatics), 8.03 (1H, s, CH).

[0414] Compound 61-B: 2-Fluoro-5-(methoxyamino-methyl)-benzonitrile 153

[0415] Reduction of 3-cyano-4-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil after chromatography on silica gel (elution hexane-ethyl acetate 8: 2) (73% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.46 (3H, s, OCH3), 4.02 (2H, s, NCH2), 7.18 (1H, t, aromatic), 7.58-7.66 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 152-158° C. Anal. calcd for C9H9FN2O—HCl: C, 49.89; H, 4.65; N, 12.93. Found: C, 50.04; H, 4.64; N, 12.84.

[0416] Compound 61-C: N-(3-Cyano-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 154

[0417] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-cyano-4-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (97% yield): mp 119-120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.75 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.36 (1H, s, CH), 7.17 (1H, t, aromatic), 7.58-7.64 (2H, m, aromatics). Anal. calcd for C16H15F2NO5: C, 57.48; H, 4.52; N, 8.38. Found: C, 57.39; H, 4.61; N, 8.32.

[0418] Compound 61-D: 3-[(3-Cyano-4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 155

[0419] N-(3-Cyano-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (47% yield); mp 125-126° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.75 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.81 (2H, s, NCH2), 6.44 (1H, s, CH), 7.18 (1H, m, aromatic), 7.56-7.61 (2H, m, aromatics). Anal. calcd for C14H13FN2O5: C, 54.54; H, 4.25; N, 9.08. Found: C, 54.76; H, 4.29; N, 9.04.

[0420] Compound 61: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3-cyano-4-fluoro-benzyl)-methoxy-amide 156

[0421] 3-[(3-Cyano-4-fluorobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 61-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (69% yield); mp 175° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.78 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.19-7.24 (1H, m, aromatic), 7.59-7.62 (2H, m, aromatics).

EXAMPLE 62

[0422] Compound 62-A: 4-Cyanobenzaldehyde O-methyloxime 157

[0423] Reaction of 4-cyanobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a white solid (96% yield), (Gordon, M. S. et al., J. Org. Chem., 49, 1984,97-100). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 4.02 (3H, s, OCH3), 7.07 (4H, m, aromatics), 8.06 (1H, s, CH).

[0424] Compound 62-B: 4-(Methoxyamino-methyl)-benzonitrile) 158

[0425] Reduction of 4-cyanobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (75% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.48 (3H, s, OCH3), 4.09 (2H, s, NCH2), 7.48 (2H, m, aromatics), 7.63 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 168° C. (dec.). Anal. calcd. for C9H10N2O—HCl: C, 54.41; H, 5.58; N, 14.10. Found: C, 54.44; H, 5.62; N, 13.94.

[0426] Compound 62-C: N-(4-Cyano-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 159

[0427] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-cyanobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (99% yield): mp 148-149° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.72 (3H, s, OCH3), 4.86 (2H, s, NCH2), 6.39 (1H, s, CH), 7.46 (2H, m, aromatics), 7.63 (2H, m, aromatics). Anal. calcd. for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C, 60.60; H, 4.91; N, 8.78.

[0428] Compound 62-D: 3-[(4-Cyano-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 160

[0429] N-(4-Cyanobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D gave the title ester as white crystals (52% yield); mp 110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.73 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.88 (2H, s, NCH2), 6.47 (1H, s, CH), 7.43 (2H, d, J=8.6 Hz, aromatics), 7.64 (2H, d, J=8.6 Hz, aromatics). Anal. calcd for C14H14N2O5: C, 57.93; H, 4.86; N, 9.65. Found: C, 57.87; H, 4.80; N, 9.67.

[0430] Compound 62: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-cyano-benzyl)-methoxy-amide 161

[0431] 3-[(4-Cyanobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 62-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (46% yield); mp 161° C. dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.93 (2H, s, NCH2), 7.44 (2H, d, J=8.2 Hz, aromatics), 7.65 (2H, d, J=8.2 Hz, aromatics). Anal. calcd for C15H15N3O4: C, 59.79; H, 5.01; N, 13.94. Found: C, 59.51; H, 4.90; N, 13.69.

EXAMPLE 63

[0432] Compound 63-A: 4-Acetamidobenzaldehyde O-methyloxime 162

[0433] Reaction of 4-acetamidobenzaldehyde with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether as a white solid (98% yield), (Sakamoto, T. et al., J. Org. Chem., 57, 1992, 3245-3248). 1HNMR indicated a 95:5 mixture of E- to Z-isomers. 1HNMR 400 MHz (CDCl3) δ (ppm): (E-isomer) 2.19 (3H, s, CH3), 3.96 (3H, s, OCH3), 7.22 (1H, broad s, NH), 7.53 (4H, m, aromatics), 8.01 (1H, s, CH).

[0434] Compound 63-B: N-[4-(Methoxyamino-methyl)-phenyl]-acetamide 163

[0435] Reduction of 4-acetamidobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a waxy solid (100% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.16 (3H, s, CH3), 3.49 (3H, s, OCH3), 4.00 (2H, s, NCH2), 7.26 (1H, broad s, NH), 7.29 (2H, m, aromatics), 7.46 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 186-188° C. (dec.). Anal. calcd. for C10H14N2O2—HCl-H2O: C, 50.87; H, 6.66; N, 11.87. Found: C, 50.77; H, 6.44; N, 12.16.

[0436] Compound 63-C: N-(4-Acetylamino-benzyl)-2(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide 164

[0437] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-acetamidobenzyl)-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (92% yield): mp 212-215° C. (dec.) (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.73 (6H, s, CH3), 2.16 (3H, s, CH3), 3.67 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.39 (1H, s, CH), 7.32 (3H, m, aromatics and NH), 7.45 (2H, m, aromatics). Anal. calcd. for C17H20N2O6: C, 57.87; H, 5.86; N, 7.94. Found: C, 57.76; H, 5.68; N, 8.51.

[0438] Compound 63-D: 3-[(4-Acetylamino-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 165

[0439] N-(4-Acetylaminobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (35% yield); mp 125° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.18 (3H, s, COCH3), 3.68 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.79 (2H, s, NCH2), 6.46 (1H, s, CH), 7.16 (1H broad s, NH), 7.29 (2H, d, J=8.6 Hz, aromatics), 7.48 (2H, d, J=8.6 Hz, aromatics). Anal. Calcd for C15H18N2O6: C, 55.89; H, 5.62; N, 8.69. Found: C, 55.95; H, 5.70; N, 8.59.

[0440] Compound 63: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-acetylamino-benzyl)-methoxy-amide 166

[0441] 3-[(4-Acetylaminobenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 63-D) was treated with paraformaldehyde and methylamine as described in the preparation Compound 12 to give the title compound as a white solid (43% yield); mp 110° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.18 (3H, s, COCH3), 3.1 (3H, s, NCH3), 3.71 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.83 (2H, s, NCH2), 7.29 (2H, d, J=8.6 Hz, aromatics), 7.34 (1H, broad s, NH), 7.50 (2H, d, J=8.6 Hz, aromatics). HRMS (ES+) calculated for C16H20N3O5:[M+H]+: 334.140296; found: 334.139137.

EXAMPLE 64

[0442] Compound 64-A: 3-[(4-Fluoro-3-methyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 167

[0443] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluoro-3-methylbenzyl)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-C and gave the title ester as white crystals (32% yield); mp 60-62° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, broad s, CH3), 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.76 (2H, s, NCH2), 6.46 (1H, s, CH), 6.96 (1H, m, aromatic), 7.12 (2H, m, aromatics). Anal. calcd for C14H16FNO5: C, 56.56; H, 5.42; N, 4.71. Found: C, 56.36; H, 5.44; N, 4.54.

[0444] Compound 64: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-3-methyl-benzyl)-methoxy-amide 168

[0445] 3-[(4-Fluoro-3-methylbenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 64-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as white crystals (76% yield); mp 160-164° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.27 (3H, s, CH3), 3.10 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.15 (2H, s, NCH2), 4.81 (2H, s, NCH2), 6.97 (1H, m, aromatic), 7.12 (2H, m, aromatics). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.41; H, 5.61; N, 8.90.

EXAMPLE 65

[0446] Compound 65-A: 3-[(3-Fluoro-4-methyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 169

[0447] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(3-fluoro-4-methylbenzyl)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-C and gave the title ester as white crystals (49% yield); mp 88° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.25 (3H, d, J=1.5 Hz, CH3), 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.78 (2H, s, NCH2), 6.47 (1H, s, CH), 6.96 (2H, m, aromatics), 7.26 (1H, m, aromatic). HRMS (MAB N2) calculated for C14H16FNO5, [M]+: 297.101251; found: 297.101261.

[0448] Compound 65: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3-fluoro-4-methyl-benzyl)-methoxy-amide 170

[0449] 3-[(3-Fluoro-4-methylbenzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 65-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as white crystals (54% yield); mp 145° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.26 (3H, broad s, CH3), 3.11 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.83 (2H, s, NCH2), 6.99 (2H, m, aromatics), 7.16 (1H, m, aromatic). Anal. calcd for C15H17FN2O4: C, 58.44; H, 5.56; N, 9.09. Found: C, 58.16; H, 5.44; N, 8.88.

EXAMPLE 66

[0450] Compound 66-A: 2-Hydroxy-3-[(2-isopropoxy-benzyl)-methoxy-carbamoyl]-acrylic Acid Methyl Ester 171

[0451] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(2-isopropoxybenzyl)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white syrup (62% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (6H, d, J=6 Hz, CH3), 3.68 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.59 (1H, m, CH), 4.9 (2H, s, NCH2), 6.50 (1H, s, CH), 6.88 (2H, m, aromatics), 7.24 (2H, m, aromatics). HRMS (MAB N2) calculated for C16H21NO6, [M]+: 323.136888; found: 323.136700.

[0452] Compound 66: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (2-isopropoxy)-methoxy-amide 172

[0453] 2-Hydroxy-3-[(2-isopropoxybenzyl)-methoxy-carbamoyl]-acrylic acid methyl ester (Compound 66-A) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a tan solid (22% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 1.26 (6H, d, J=6.2 Hz, CH3), 2.91 (3H, s, NCH3), 3.57 (3H, s, OCH3), 4.03 (2H, s, NCH2), 4.60 (1H, m, CH), 4.71 (2H, s, NCH2), 6.66 (1H, m, aromatic), 6.95 (1H, m, aromatic), 7.15 (2H, m, aromatics). HRMS (ES+) calculated for C17H23N2O5, [M+H]+: 335.160697; found: 335.161171.

EXAMPLE 67

[0454] Compound 67-A: 4-Carbomethoxybenzaldehyde O-methyloxime 173

[0455] Reaction of methyl 4-formylbenzoate with methoxylamine hydrochloride as described in the preparation of Compound 44-A gave the title oxime ether (96% yield) as a white solid (mixture of E- and Z-isomers). The E-isomer was obtained as white crystals from hexane; mp 66-67° C. (Lit. mp 65-66° C., Cooks, Org. Mass Spectrum., 5, 1971, 687). 1HNMR 400 MHz (DMSO-d6) δ (ppm): (E-isomer) 3.86 (3H, s, OCH3), 3.93 (3H, s, OCH3), 7.75 (2H, d, aromatics), 7.98 (2H, d, aromatics), 8.32 (1H, s, CH).

[0456] Compound 67-B: 4-(Methoxyamino-methyl)-benzoic Acid Methyl Ester 174

[0457] Reduction of 4-carbomethoxybenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as an oil (53% yield). The hydrochloride salt was obtained as a white solid: mp 166-169° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.75 (3H, s, OCH3), 3.86 (3H, s, OCH3), 4.39 (2H, s, NCH2), 7.65 (2H, d, aromatics), 7.97 (2H, d, aromatics). Anal. calcd for C10H13NO3—HCl: C, 51.84; H, 6.09; N, 6.04. Found: C, 51.74; H, 6.01; N, 5.50.

[0458] Compound 67-C: 4-({[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-benzoic Acid Methyl Ester 175

[0459] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-4-carbomethoxybenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (83% yield): mp 120° C. (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.67 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.88 (2H, s, NCH2), 6.40 (1H, s, CH), 7.42 (2H, d, aromatics), 8.0 (2H, d, aromatics). Anal. calcd for C17H19NO7: C, 58.45; H, 5.48; N, 4.01. Found: C, 58.54; H, 5.55; N, 3.61.

[0460] Compound 67-D: 4{[(3-Hydroxy-3-methoxycarbonyl-acryloyl)-methoxy-amino]-methyl}-benzoic Acid Methyl Ester 176

[0461] 4-({[2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-methoxyamino}-methyl)-benzoic acid methyl ester was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.70 (3H, s, OCH3), 3.90 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.89 (2H, s, NCH2), 6.5 (1H, s, CH), 7.39 (2H, d, J=8.1 Hz, aromatics), 8.02 (2H, d, J=8.1 Hz, aromatics). HRMS (ES+) calculated for C15H18NO7, [M+H]+: 324.108327; found: 324.109066.

[0462] Compound 67: 4-{[(4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-methoxy-amino]-methyl}-benzoic Acid Methyl Ester 177

[0463] 4-{[(3-Hydroxy-3-[methoxycarbonyl-acryloyl)-methoxyamino]-methyl}-benzoic acid methyl ester (Compound 67-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a tan solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.73 (3H, s, OCH3), 3.92 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.93 (2H, s, NCH2), 7.4 (2H, d, J=8.1 Hz, aromatics), 8.02 (2H, d, J=8.1 Hz, aromatics), 11.54 (1H, broad s, OH). HRMS (ES+) calculated for C16H19N2O6, [M+H]+: 335.1249; found: 335.1243.

EXAMPLE 68

[0464] Compound 68-A: 4-{[(4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-methoxy-amino]-methyl}-benzoic Acid Tert-Butyl Ester 178

[0465] 4-({[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-methoxyamino}-methyl)-benzoic acid tert-butyl ester, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (40% yield); mp 157-160° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (9H, s, t-Bu), 3.11 (3H, s, NCH3), 3.72 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.92 (2H, s, NCH2), 7.37 (2H, d, J=8 Hz, aromatics), 7.97 (2H, d, J=8 Hz, aromatics), 11.55 (1H, broad s, OH).

[0466] Compound 68: 4-{[(4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-methoxy-amino]-methyl}-benzoic Acid 179

[0467] A solution of 4-{[(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-methoxyamino]-methyl}-benzoic acid tert-butyl ester (0.062 g, 0.16 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (0.6 ml) and stirred at 25° C. for 2 h. The solvent was then evaporated in vacuo and the residue was triturated with acetonitrile to give 0.041 g (80% yield) of the title material as a white solid; mp 196-197° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.97 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.19 (2H, s, NCH2), 4.96 (2H, s, NCH2), 7.42 (2H, d, J=8.3 Hz, aromatics), 7.91 (2H, d, J=8.3 Hz, aromatics), 11.4 (1H, broad s, OH), 12.9 (1H, broad s, OH). Anal. calcd for C15H16N2O6.H2O: C, 53.25; H, 5.36; N, 8.28. Found: C, 53.59; H, 4.79; N, 8.19.

EXAMPLE 69

[0468] Compound 69: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid [1-(4-fluoro-phenyl)-ethyl]-methoxy-amide 180

[0469] 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[1-(4-fluorophenyl)-ethyl]-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation Compound 12 to give the title compound as a white solid (47% yield); mp 136-138° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.68 (3H, d, J=7.1 Hz, CH3), 3.1 (3H, s, NCH3), 3.49 (3H, s, OCH3), 4.13 (2H, AB system, JAB=18.2 Hz, Av=45.7 Hz, NCH2), 5.75 (1H, q, J=7.1 Hz, CH), 7.06 (2H, m, aromatics), 7.42 (2H, m, aromatics). Anal. calcd for C15H17FN2O4: C, 58.43; H, 5.55; N, 9.08. Found: C, 58.40; H, 5.38; N, 9.01.

EXAMPLE 70

[0470] Compound 70-A: (4-Fluorobenzylideneaminooxy)-acetic Acid Tert-Butyl Ester 181

[0471] Condensation of 4-fluorobenzaldehyde with hydroxylamine hydrochloride using the same procedure as Compound 44-A followed by reaction with tert-butyl bromoacetate gave the title oxime ether as a clear oil (84% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.52 (9H, s, t-Bu), 4.61 (2H, s, OCH2), 7.08 (2H, m, aromatics), 7.59 (2H, m, aromatics), 8.19 (1H, s, CH).

[0472] Compound 70-B: [N-(4-Fluoro-benzyl)aminooxy]-acetic Acid Tert-Butyl Ester 182

[0473] Reduction of (4-fluorobenzylideneaminooxy)-acetic acid tert-butyl ester as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (65% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 1.43 (9H, s, t-Bu), 3.84 (2H, d, J=5.6 Hz, NCH2), 4.17 (2H, s, OCH2), 6.39 (1H, broad t, NH), 6.86 (2H, m, aromatics), 7.05 (2H, m, aromatics).

[0474] Compound 70-C: [[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-(4-fluoro-benzyl)-aminooxy]-acetic Acid Tert Butyl Ester 183

[0475] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with [N-(4-fluorobenzyl)aminooxy]-acetic acid tert-butyl ester as described in the preparation of compound 1-A gave the title amide as white crystals (85% yield): mp 119-120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.48 (9H, s, t-Bu), 1.74 (6H, s, CH3), 4.30 (2H, s, CH2), 4.88 (2H, s, CH2), 6.48 (1H, s, CH), 7.0 (2H, m, aromatics), 7.38 (2H, m, aromatics). Anal. calcd for C20H24FNO7: C, 58.67; H, 5.91; N, 3.42. Found: C, 58.83; H, 5.92; N, 3.31.

[0476] Compound 70-D: 3-[tert-Butoxycarbonylmethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 184

[0477] [[2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid tert-butyl ester was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a clear oil (69% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.50 (9H, s, t-Bu), 3.92 (3H, s, OCH3), 4.35 (2H, s, CH2), 4.94 (2H, s, CH2), 6.55 (1H, s, CH), 7.05 (2H, m, aromatics), 7.39 (2H, m, aromatics), 13.35 (1H, broad s, OH). HRMS (ES+) calculated for C18H23FNO7, [M+H]+: 384.145856; found: 384.146214.

[0478] Compound 70: [(4-Fluoro-benzyl)-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-3-carbonyl)-aminooxy-acetic Acid Tert-Butyl Ester 185

[0479] 3-[tert-Butoxycarbonylmethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 70-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (30% yield); mp 128-130° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.48 (9H, s, t-Bu), 3.1 (3H, s, NCH3), 4.22 (2H, s, CH2), 4.35 (2H, s, CH2), 4.93 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.38 (2H, m, aromatics), 11.55 (1H, broad s, OH). HRMS (ES+) calculated for C19H24FN2O6, [M+H]+: 395.161840; found: 395.161599.

EXAMPLE 71

[0480] Compound 71: [(4-Fluoro-benzyl)-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-aminooxy]-acetic Acid 186

[0481] A solution of [(4-fluorobenzyl)-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-aminooxy]-acetic acid tert-butyl ester (0.041 g, 0.104 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at 22° C. for 2 h. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and hexane to give 0.027 g (80% yield) of the tittle material as white crystals; mp 147-150° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.95 (3H, s, NCH3), 4.14 (2H, s, CH2), 4.62 (2H, s, CH2), 4.92 (2H, s, CH2), 7.17 (2H, m, aromatics), 7.36 (2H, m, aromatics), 11.4 (1H, broad s, OH), 13.1 (1H, broad s, OH). HRMS (ES+) calculated for C15H16FN2O6, [M+H]+: 339.099240; found: 339.100624.

EXAMPLE 72

[0482] Compound 72-A: N-Dimethylcarbamoylmethoxy-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide 187

[0483] A solution of [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid (0.681 g, 1.93 mmol) in dichloromethane (20 ml) was treated at 22° C. with oxalyl chloride (0.34 ml, 3.9 mmol) and a trace of N,N-dimethylformamide and the resulting mixture was stirred for 1 h. The solvent and excess reagent were then evaporated in vacuo. The residual material was dissolved in dry dichloromethane (10 ml) and added dropwise to a cold (0° C.) solution of dimethylamine (0.18 g, 4.0 mmol) and pyridine (0.25 ml, 3.2 mmol) in dichloromethane. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo and crystallisation of the residue from a mixture of ethyl acetate and hexane gave 0.370 g (50% yield) of the title material as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.77 (6H, s, CH3), 2.91 (3H, s, CH3), 2.97 (3H, s, CH3), 4.53 (2H, s, CH2), 4.93 (2H, s, CH2), 6.43 (1H, s, CH), 7.03 (2H, m, aromatics), 7.41 (2H, m, aromatics).

[0484] Compound 72-B: 3-[Dimethylcarbamoylmethoxy-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 188

[0485] N-Dimethylcarbamoylmethoxy-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (54% yield); mp 133-135° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.9 (3H, s, NCH3), 2.98 (3H, s, NCH3), 3.91 (3H, s, OCH3), 4.54 (2H, s, CH2), 4.96 (2H, s, CH2), 6.52 (1H, s, CH), 7.06 (2H, m, aromatics), 7.39 (2H, m, aromatics), 13.38 (1H, broad s, OH). Anal. calcd for Cl6H19FN2O6: C, 54.24; H, 5.40; N, 7.90. Found: C, 53.62; H, 5.40; N, 7.79.

[0486] Compound 72: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid dimethylcarbamoylmethoxy-(4-fluoro-benzyl)-amide 189

[0487] 3-[Dimethylcarbamoylmethoxy-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 72-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (25% yield); mp 147-149° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.79 (3H, s, NCH3), 2.96 (3H, s, NCH3), 3.11 (3H, s, NCH3), 4.25 (2H, s, CH2), 4.51 (2H, s, CH2), 4.96 (2H, s, CH2), 7.06 (2H, m, aromatics), 7.38 (2H, m, aromatics), 11.54 (1H, broad s, OH). HRMS (ES+) calculated for C17H21FN3O5, [M+H]+: 366.146524; found: 366.146176.

EXAMPLE 73

[0488] Compound 73: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid [bis-(4-fluoro-phenyl)-methyl]-methoxy-amide 190

[0489] N-[Bis-(4-fluorophenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 44, Method 44B, to give the title compound as a tan solid (42% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.9 (3H, broad s, NCH3), 3.1 (3H, broad s, OCH3), 4.2 (2H, broad, NCH2), 6.9 (1H, broad s, CH), 7.0-7.4 (8H, m, aromatics). HRMS (ES+) calculated for C20H22F2N3O4, [M+NH4]+: 406.157838; found: 406.158046.

EXAMPLE 74

[0490] Compound 74: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (2-chloro-4-fluoro-benzyl)-methoxy-amide 191

[0491] N-(2-Chloro-4-fluorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 44, Method 44B, to give the title compound as white crystals (55% yield); mp 152-155° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 5.01 (2H, s, NCH2), 6.99 (1H, m, aromatic), 7.15 (1H, dd, J=2.5 Hz, J=8.0 Hz, aromatic), 7.36 (1H, dd, J=5.7 Hz, J=8.8 Hz, aromatic). Anal. calcd for C14H14ClFN2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 50.62; H, 4.18; N, 8.40.

EXAMPLE 75

[0492] Compound 75: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid [1-(4-chloro-benzyl)-2-(4-chloro-phenyl)-ethyl]-methyl-amide 192

[0493] N-[1-(4-Chloro-benzyl)-2-(4-chloro-phenyl)-ethyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 44, Method 44B, to give the title compound as white crystals (56% yield); mp 152-154° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): mixture of rotamers: 2.7-3.0 (4H, m, CH2), 2.84 (3H, s, NCH3), 2.9 (3H, broad s, NCH3), 3.4 and 3.7 (2H, two broad s, NCH2), 4.16 and 4.9 (1H, broad m, CH), 7.15-7.34 (8H, m, aromatics), 10.7 and 11.0 (1H, two s, OH). HRMS (MAB N2) calculated for C22H22Cl2N2O3: [M]+: 432.100748; found: 432.100835.

EXAMPLE 76

[0494] Compound 76-A: 4-Fluoro-N-(4-fluoro-benzyl)-benzamide 193

[0495] 4-Flourobenzyl amine (27 grams, 0.22 mole) was dissolved in 200 mL of CH2Cl2. To this was added 400 mL of 1N NaOH and the resulting mixture cooled to 0° C. 4-Fluorobenzoyl chloride (33 grams, 0.21 mole) was added dropwise with stirring. The reaction was allowed to proceed for 20 min after which the organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 47 grams (92% yield) of 4-fluoro-N-(4-fluoro-benzyl)-benzamide as a solid. MS (M−H) calcd for C14H10F2NO: 246.1; found: 246.0. Anal. Calcd for C14H11F2NO; C, 68.01; H, 4.48; N, 5.66; found: C, 67.76; H, 4.54; N, 5.45. 1H NMR (500 MHz, DMSO) δ: 4.45 (d, 2, J=6), 7.15 (m, 2), 7.34 (overlapping m, 4), 7.97 (m, 2), 9.09 (t, 1, J=6). 13C NMR (125 MHz, DMSO) δ: 41.88, 114.81, 114.98, 115.06, 115.23, 129.08, 129.15, 129.76, 129.83, 130.60, 130.62, 135.66, 135.68, 160.10, 162.03, 162.83, 164.81, 165.04.

[0496] Compound 76-B: Bis-(4-fluoro-benzyl)-amine Hydrochloride 194

[0497] 4-Fluoro-N-(4-fluoro-benzyl)-benzamide (40.0 grams, 0.16 mole) was dissolved in 240 mL of THF. To this was added BF3.Et2O (7.4 mL. 0.06 mole) and the resulting mixture heated to reflux for 15 min. After cooling to −30° C., BH3.SMe2 (22.3 mL, 0.24 mole) was added using a dropping funnel. The reaction was allowed to warm to room temperature. The reaction flask was fitted with a distillation condenser and solvent removed under reflux for 25 min The distillation apparatus was replaced with a reflux condenser and the reaction heated to 110° C. for 2 h. After cooling to 0° C., 100 mL of 6N HCl was added and the mixture heated to reflux for 1 hr to yield a thick slurry. 300 mL of 6N NaOH was slowly added at room temperature with intermittent cooling using an ice bath. After all the solid has dissolved Et2O was added and the mixture transferred to a separatory funnel. The organic layer was separated, dried over Na2SO4, filtered and the solvent removed under vacuum to yield an oil. The oil was dissolved in 50 mL of Et2O and 4N HCl (dioxane) added resulting in the formation of a white precipitate which was isolated by filtration to yield 40 grams (93% yield) of bis-(4-fluoro-benzyl)-amine hydrochloride. MS (M+H) calcd for C14H14F2N: 234.1; found: 234.0. Anal. calcd for C14H14F2NCl: C, 62.34; H, 5.23; N, 5.19; found: C, 61.89; H, 5.15; N, 5.27. 1H NMR (500 MHz, DMSO) δ: 4.12 (br s, 4), 7.26 (m, 4), 7.65 (m, 4), 9.91 (br s, 2).

[0498] Compound 76-C: N,N-Bis-(4-fluoro-benzyl)-acetamide 195

[0499] Bis-(4-fluoro-benzyl)-amine hydrochloride (43 grams, 0.16 mole) was suspended in 200 mL of CH2Cl2. To this was added 730 mL of 1N NaOH. The reaction mixture was stirred vigorously while AcCl (20 mL, 0.28 mole) was slowly added. The reaction was stirred for 0.5 h, then the organic layer separated, washed with 1N HCl, dried over Na2SO4, filtered and the solvent removed under vacuum to yield 24 grams (55% yield) of N,N-bis-(4-fluoro-benzyl)-acetamide as an oil. MS (M+H) calcd for C16H16F2NO: 276.1; found: 276.0. Anal. calcd for C16H15F2NO: C, 69.80; H, 5.49; N, 5.08; found: C, 69.53; H, 5.41; N, 5.06. 1H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.50 (s, 2), 7.11-7.27 (overlapping m, 8). 13C NMR (125 MHz, DMSO) δ: 21.34, 50.04, 54.80, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.27, 170.22.

[0500] Compound 76-D: 3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 196

[0501] N,N-Bis-(4-fluoro-benzyl)-acetamide (15.0 grams, 54.5 mmol) and dimethyloxalate (9.6 grams, 81.3 mmol) were dissolved in 54 mL of THF. After cooling to 0° C. 108 mL of 1N LIHMDS (THF) was added dropwise. The reaction mixture was stirred 1 hr then quenched with 1N HCl. The resulting mixture was extracted with CH2Cl2, dried over Na2SO4, filtered and the solvent removed under vacuum. The product was purified by flash column chromatography (SiO2, 80:20 hexanes/EtOAc) to yield 10 grams (53% yield) of 3-[bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a solid. Mp=118-120° C. Anal. calcd for C19H17F2NO4: C, 63.15; H, 4.74; N, 3.87; found: C, 62.97; H, 4.72; N, 3.81. 1H NMR (500 MHz, CDCl3) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s, 2), 6.32 (s, 1), 7.00-7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 47.34, 49.35, 53.03, 93.34, 115.66, 115.83, 116.00, 116.18, 128.45, 128.52, 130.03, 130.10, 131.09, 131.93, 131.95, 160.29, 161.44, 161.51, 163.10, 163.41, 163.47, 171.36.

[0502] Compound 76: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid bis-(4-fluoro-benzyl)-amide 197

[0503] To 2 mL of AcOH at 60° C. was added 1 mL 2M MeNH2 (THF) and 60 mg paraformaldehyde. After stirring for 5 min 3-[bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (723 mg, 2.0 mmol) was added and the resulting solution stirred at 60° C. for 2 h. The reaction mixture was then cooled to room temperature and transferred to a separatory funnel. The solution was extracted with EtOAc, the organic layer separated, washed with H2O, satd NaCl, then dried over Na2SO4. After filtration the solvent was removed to isolate 500 mg (67% yield) of 4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid bis-(4-fluoro-benzyl)-amide as an orange solid. MS (M+H) calcd for C20H19F2N2O3: 373.1; found: 373.0. 1H NMR (500 MHz, DMSO) δ: 2.94 (s, 3), 4.01 (s, 2), 4.46 (br s, 2), 4.55 (br s, 2), 7.13-7.22 (overlapping m, 8).

EXAMPLE 77

[0504] Compound 77-A: (4-Chloro-benzyl)-(3,4-dichloro-benzyl)-amine 198

[0505] From N-(4-chlorobenzyl)-3,4-dichlorobenzamide (Borgma et al. Farmaco Ed. Sci. 1977, 32, 813). 1HNMR 400 MHz (C6D6) δ (ppm): 3.22 (2H, s, NCH2), 3.31 (2H, s, NCH2), 6.78 (1H, d, J=8.5 Hz, aromatic), 6.99 (2H, d, J=8.1 Hz, aromatics), 7.15 (2H, d, J=8.1 Hz, aromatics), 7.24-7.31 (3H, m, aromatics).

[0506] Compound 77-B: N-(4-Chloro-benzyl)-N-(3,4-dichloro-benzyl)-acetamide 199

[0507] 4-(Chlorobenzyl)-(3,4-dichlorobenzyl)-amine was acetylated as described in the preparation of Compound 76-C and gave the title amide as a clear oil (78% yield). 1HNMR 400 MHz (C6D6) δ (ppm), mixture of rotamers: 1.77 and 1.78 (3H, 2 s, COCH3), 3.6 and 3.66 (2H, 2 s, NCH2), 4.26.and 4.33 (2H, 2 s, NCH2), 6.37-7.2 (7H, m, aromatics). Anal. calcd for C16H14Cl3NO: C, 56.08; H, 4.12; N, 4.09. Found: C, 56.13; H, 4.07; N, 4.08.

[0508] Compound 77-C: 3-[(4-Chloro-benzyl)-(3,4-dichloro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 200

[0509] N-(4-Chlorobenzyl)-N-(3,4-dichlorobenzyl)-acetamide was reacted with dimethyl oxalate as described in the preparation of Compound 76-D and gave the title methyl ester as a clear oil (40% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): mixture of rotamers: 3.9 (3H, s, OCH3), 4.47, 4.5, 4.58 and 4.62 (2×2H, 4 s, NCH2), 6.27 and 6.33 (1H, 2 s, CH), 7.0-7.48 (7H, m, aromatics), 14.33 and 14.37 (1H, 2 s, OH).

[0510] Compound 77: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-chloro-benzyl)-(3,4-dichloro-benzyl)-amide 201

[0511] 3-[(4-Chlorobenzyl)-(3,4-dichlorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester was reacted with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (39% yield); mp 165° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.09 (3H, s, NCH3), 4.09, 4.55 and 4.56 (3×2H, 3 s, NCH2), 7.05-7.45 (7H, m, aromatics), 10.3 (1H, broad, OH).

EXAMPLE 78

[0512] Compound 78-A: N-(3,4-Dichloro-phenyl)-N-(4-fluoro-benzyl)-acetamide 202

[0513] 3,4-(Dichlorophenyl)-(4-fluorobenzyl)-amine was acetylated as described in the preparation of Compound 76-C and gave the title amide as a clear oil (89% yield). 1HNMR 400 MHz (C6D6) δ (ppm): 1.59 (3H, s, COCH3), 4.56 (2H, s, NCH2), 6.04 (1H, broad s, aromatic), 6.71-6.98 (6H, m, aromatics). Anal. calcd for C15H12Cl2FNO: C, 57.71; H, 3.87; N, 4.48. Found: C, 57.85; H, 3.89; N, 4.49.

[0514] Compound 78-B: 3-[(3,4-Dichloro-phenyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 203

[0515] N-(3,4-Dichlorophenyl)-N-(4-fluorobenzyl)-acetamide was reacted with dimethyl oxalate as described in the preparation of Compound 76-D and gave the title methyl ester as a clear oil (40% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.84 (3H, s, OCH3), 4.90 (2H, s, NCH2), 5.69 (1H, s, CH), 6.83 (1H, dd, J=2.0 Hz and J=8.5 Hz, aromatic), 7.02 (2H, m, aromatic), 7.19 (3H, m, aromatic), 7.47 (1H, d, J=8.5 Hz, aromatic), 13.83 (1H, s, OH).

[0516] Compound 78: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-phenyl)-(4-fluoro-benzyl)-amide 204

[0517] 3-[(3,4-Dichlorophenyl)-(4-fluorobenzyl)-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 78-B) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (68% yield); mp 195° C., dec. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.9 (3H, s, NCH3), 3.03 (2H, s, NCH2), 4.90 (2H, s, NCH2), 6.87 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.02 (2H, m, aromatics), 7.2 (2H, m, aromatics), 7.22 (1H, d, J=2.5 Hz, aromatic), 7.49 (1H, d, J=8.6 Hz, aromatic), 11.9 (1H, broad, OH). Anal. calcd for C19H15Cl2FN2O3: C, 55.76; H, 3.69; N, 6.84. Found: C, 55.53; H, 3.61; N, 6.75.

EXAMPLE 79

[0518] Compound 79-A: N-Benzyl-N-methyl-acetamide 205

[0519] Compound 79-A was prepared using methods described in the previous examples. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 2.20 (s), 2.95 (s), 2.97 (s), 4.56 (s), 4.62 (s), 7.19-7.41 (overlapping m). 13C NMR (125 MHz, CDCl3) δ: 21.42, 21.80, 33.82, 35.58, 50.68, 54.29, 126.33, 127.41, 127.70, 128.07, 128.63, 128.99, 136.46, 137.26, 170.88, 171.19.

[0520] Compound 79-B: 3-(Benzyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester 206

[0521] Compound 79-B was prepared using methods described in the previous examples. 1H NMR shows a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 3.02 (s), 3.86 (s), 3.90 (s), 4.60 (s), 4.66 (s), 6.31 (s), 6.34 (s), 7.18-7.40 (overlapping m).

[0522] Compound 79: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid Benzyl-Methyl-Amide 207

[0523] Compound 79 was prepared using methods described in the previous examples. HRMS (M−H) calcd for C14H15N2O3: 259.10827; found 259.1082. 1H NMR (500 MHz, CDCl3) δ: 3.03 (s, 3), 3.09 (s, 3), 4.15 (s, 2), 4.65 (s, 2), 7.23-7.37 (m, 5). 13C NMR (125 MHz, CDCl3 8: 29.95, 34.67, 50.80, 52.28, 108.72, 127.38, 127.86, 128.94, 136.12, 154.15, 165.10, 166.46.

EXAMPLE 80

[0524] Method for the Preparation of Compounds 80-724

[0525] PL-FMP resin (4-formyl-3-methoxy-phenoxymethyl functionalized polystyrene), VII-1 in Scheme VII or similar aldehyde derivatized resin (approximately 40 mg, 0.048 meq.) was suspended in 2 ml of anhydrous DMF, anhydrous trimethylorthoformate and acetic acid mixture in 7:3:1 ratio. To this mixture was added a primary amine, VII-2 in scheme VII, (0.72 mmol) followed by sodium triacetoxy borohydride (0.72 mmol). The resulting mixture was agitated for 72 h at room temperature using a shaker. The resin was filtered, washed successively with (DMF, THF and DCM, 3×2 ml each), dried and used as is in the next step.

[0526] The resin (VII-3 in Scheme VII) was suspended in anhydrous dichloromethane (1 mL) and to this was added, 2,2-dimethyl-5-(carboxymethylene)-1,3-dioxalan-4-one (Compound III-A) (16.5 mg, 0.096 mmol), Pybop (50 mg, 0.096 mmol) and iPr2NEt (24.8 mg, 0.192 mmol). The resulting mixture was agitated for 48 h at room temperature using a shaker. Resin was filtered, washed successively (DMF, THF and DCM, 3×2 ml each), dried and used in the next step.

[0527] Next the resin, VII-4 in Scheme VII, was suspended in 1 ml anhydrous N-methyl-2-pyrrolidinone (NMP). To this mixture was added a preformed imine mixture (preformed by heating aldehyde (18 mg, 0.55 mmol), and amine (0.5 mmol) and 0.25 ml methanol, at 70° C. for 2 h) and the resulting mixture was heated with agitation in a sealed container at 70-80° C. for 72 h. Resin was filtered, washed successively with (DMF, DMF/MeOH (1:1), THF and DCM, 3×2 ml each), dried.

[0528] The final product, VII-6 in Scheme VII, was cleaved from the resin by treating with 1.5 ml of 1:1 mixture of trifluoroacetic acid and dichloromethane for 1 h. TFA solution was filtered and the solvent was evaporated to give the required product.

208
					LC
Compd	X1	X2	X3	MS obsd	RT (min)
80	209	X2-H	X3-CH3	261.1	1.3
81	210	X2-H	X3-CH3	289.2	1.5
82	211	X2-H	X3-CH3	317.0	1.5
83	212	X2-H	X3-CH3	315.1	1.4
84	213	X2-H	X3-CH3	265.1	1.1
85	214	X2-H	X3-CH3	321.1	1.3
86	215	X2-H	X3-CH3	275.2	1.4
87	216	X2-H	X3-CH3	311.2	1.6
88	217	X2-H	X3-CH3	275.3	1.3
89	218	X2-H	X3-CH3	329.0	1.6
90	219	X2-H	X3-CH3	279.1	1.4
91	220	X2-H	X3-CH3	279.1	1.4
92	221	X2-H	X3-CH3	347.1	1.6
93	222	X2-H	X3-CH3	307.4	1.1
94	223	X2-H	X3-CH3	277.4	1.2
95	224	X2-H	X3-CH3	297.3	1.5
96	225	X2-H	X3-CH3	275.4	1.5
97	226	X2-H	X3-CH3	287.4	1.5
98	227	X2-H	228	435.3	1.6
99	229	X2-H	230	428.3	1.2
100	231	X2-H	232	456.3	1.6
101	233	X2-H	234	412.4	1.2
102	235	X2-H	236	435.3	1.6
103	237	X2-H	238	373.3	1.5
104	239	X2-H	240	359.3	1.4
105	241	X2-H	242	357.3	1.6
106	243	X2-H	244	359.3	1.4
107	245	X2-H	246	389.3	1.3
108	247	X2-H	248	386.4	1.2
109	249	X2-H	250	359.3	1.4
110	251	X2-H	252	472.3	1.4
111	253	X2-H	254	409.3	1.2
112	255	X2-H	256	373.3	1.5
113	257	X2-H	258	406.3	1.2
114	259	X2-H	260	446.3	1.2
115	261	X2-H	262	421.3	1.7
116	263	X2-H	264	414.4	1.1
117	265	266	X3-CH3	397.3	1.8
118	267	268	X3-CH3	391.3	1.7
119	269	270	X3-CH3	409.3	1.7
120	271	272	X3-CH3	421.3	1.8
121	273	274	X3-CH3	451.3	1.7
122	275	276	X3-CH3	435.3	1.8
123	277	278	X3-CH3	416.3	1.6
124	279	280	X3-CH3	439.3	1.6
125	281	282	X3-CH3	421.3	1.7
126	283	284	X3-CH3	416.3	1.6
127	285	286	X3-CH3	434.3	1.3
128	287	288	X3-CH3	421.3	1.7
129	289	290	X3-CH3	463.3	2.0
130	291	292	X3-CH3	443.2	1.8
131	293	294	X3-CH3	406.3	1.3
132	295	296	X3-CH3	392.3	1.2
133	297	298	X3-CH3	449.3	1.6
134	299	300	X3-CH3	435.3	1.5
135	301	302	X3-CH3	405.3	1.7
136	303	304	X3-CH3	419.3	1.8
137	305	306	X3-CH3	357.3	1.6
138	307	308	X3-CH3	371.3	1.7
139	309	310	X3-CH3	449.3	1.6
140	311	312	X3-CH3	381.3	1.6
141	313	314	X3-CH3	451.3	1.7
142	315	316	X3-CH3	492.4	1.3
143	317	318	X3-CH3	355.3	1.6
144	319	320	X3-CH3	465.3	1.5
145	321	322	X3-CH3	435.3	1.7
146	323	324	X3-CH3	469.2	1.7
147	325	326	X3-CH3	447.3	2.0
148	327	328	X3-CH3	533.2	2.0
149	329	330	331	455.4	1.17
150	332	333	334	441.1	1.05
151	335	336	337	472.3	0.75
152	338	339	340	365.2	1.57
153	341	342	343	375.2	1.32
154	344	345	346	415.2	1.48
155	347	348	349	471.2	1.05
156	350	351	352	403.3	1.37
157	353	354	355	478.2	1.19
158	356	357	358	488.6	1.41
159	359	360	361	497.1	1.13
160	362	363	364	447.2	1.10
161	365	366	367	457.5	1.03
162	368	369	370	497.1	1.05
163	371	372	373	429.3	1.38
164	374	375	376	439.1	1.03
165	377	378	379	361.2	1.41
166	380	381	382	411.1	1.53
167	383	384	385	453.2	1.50
168	386	387	388	576.2	1.59
169	389	390	391	536.2	2.03
170	392	393	394	429.1	1.23
171	395	396	397	439.2	1.25
172	398	399	400	467.2	1.35
173	401	402	403	507.3	1.33
174	404	405	406	620.4	1.07
175	407	408	409	592.1	1.21
176	410	411	412	511.2	0.94
177	413	414	415	561.1	1.00
178	416	417	418	475.1	1.62
179	419	420	421	425.1	1.24
180	422	423	424	435.3	2.18
181	425	426	427	598.2	1.45
182	428	429	430	525.1	1.04
183	431	432	433	429.1	1.26
184	434	435	436	425.4	1.27
185	437	438	439	453.2	1.41
186	440	441	442	578.2	1.24
187	443	444	445	528.5	0.27
188	446	447	448	536.2	1.20
189	449	450	451	578.1	1.26
190	452	453	454	507.2	1.03
191	455	456	457	547.1	1.04
192	458	459	460	461.1	1.72
193	461	462	463	489.2	1.03
194	464	465	466	411.2	1.37
195	467	468	469	421.2	1.45
196	470	471	472	461.1	1.77
197	473	474	475	566.3	1.35
198	476	477	478	568.2	1.23
199	479	480	481	479.3	1.36
200	482	483	484	439.2	1.39
201	485	486	487	537.1	1.14
202	488	489	490	469.4	1.19
203	491	492	493	509.1	1.31
204	494	495	496	565.1	1.11
205	497	498	499	622.1	1.23
206	500	501	502	582.3	1.34
207	503	504	505	591.1	1.04
208	506	507	508	483.2	1.22
209	509	510	511	533.1	1.05
210	512	513	514	455.1	1.31
211	515	516	517	465.2	1.42
212	518	519	520	505.1	1.58
213	521	522	523	467.1	1.30
214	524	525	526	479.3	0.94
215	527	528	529	419.2	1.39
216	530	531	532	453.1	1.30
217	533	534	535	616.2	1.30
218	536	537	538	461.2	1.38
219	539	540	541	413.2	1.68
220	542	543	544	427.1	1.50
221	545	546	547	349.1	1.11
222	548	549	550	399.1	1.32
223	551	552	553	427.1	1.43
224	554	555	556	377.3	1.28
225	557	558	559	387.3	1.30
226	560	561	562	462.2	1.10
227	563	564	565	512.1	1.22
228	566	567	568	481.1	1.02
229	569	570	571	431.2	1.01
230	572	573	574	441.3	0.96
231	575	576	577	481.1	1.04
232	578	579	580	361.1	0.97
233	581	582	583	423.0	1.00
234	584	585	586	345.2	1.41
235	587	588	589	355.2	1.37
236	590	591	592	395.1	1.54
237	593	594	595	588.4	1.46
238	596	597	598	541.1	1.57
239	599	600	601	501.2	1.84
240	602	603	604	541.1	1.86
241	605	606	607	529.4	1.55
242	608	609	610	654.2	1.39
243	611	612	613	604.2	1.43
244	614	615	616	614.3	1.31
245	617	618	619	654.2	1.36
246	620	621	622	573.3	1.06
247	623	624	625	583.2	1.14
248	626	627	628	505.2	1.41
249	629	630	631	515.3	1.51
250	632	633	634	565.1	1.04
251	635	636	637	497.2	1.68
252	638	639	640	519.2	1.59
253	641	642	643	523.1	1.10
254	644	645	646	551.2	1.73
255	647	648	649	664.2	1.05
256	650	651	652	596.6	1.30
257	653	654	655	636.2	1.41
258	656	657	658	469.2	1.61
259	659	660	661	519.1	1.85
260	662	X2-H	663	387.2	1.02
261	664	X2-H	665	309.1	1.05
262	666	X2-H	667	319.1	1.13
263	668	X2-H	669	347.2	1.31
264	670	X2-H	671	387.1	1.24
265	672	673	674	538.3	1.35
266	675	676	677	507.4	1.02
267	678	679	680	429.4	1.34
268	681	682	683	479.1	1.52
269	684	685	686	507.2	1.59
270	687	688	689	457.2	1.36
271	690	691	692	542.2	1.15
272	693	694	695	552.2	1.25
273	696	697	698	592.5	1.48
274	699	700	701	561.2	1.59
275	702	703	704	443.2	1.30
276	705	706	707	493.2	1.40
277	708	709	710	503.1	1.04
278	711	712	713	425.2	1.91
279	714	715	716	435.5	1.46
280	717	718	719	467.3	1.39
281	720	721	722	507.2	1.46
282	723	724	725	469.5	1.31
283	726	X2-H	727	406.2	1.12
284	728	X2-H	729	416.2	1.12
285	730	X2-H	731	416.2	1.21
286	732	X2-H	733	323.2	1.07
287	734	X2-H	735	333.2	1.29
288	736	X2-H	737	289.1	1.16
289	738	X2-H	739	387.3	1.29
290	740	X2-H	741	337.1	1.11
291	742	X2-H	743	434.2	0.93
292	744	X2-H	745	432.2	0.53
293	746	X2-H	747	391.2	0.70
294	748	X2-H	749	336.0	1.22
295	750	X2-H	751	348.0	1.38
296	752	X2-H	753	386.0	1.56
297	754	755	756	397.2	1.31
298	757	758	759	407.2	1.32
299	760	761	762	383.2	1.19
300	763	764	765	381.1	1.23
301	766	767	768	421.1	1.40
302	769	770	771	447.3	1.23
303	772	773	774	435.4	1.65
304	775	776	777	385.2	1.26
305	778	779	780	395.0	1.25
306	781	782	783	395.2	1.35
307	784	785	786	463.1	1.05
308	787	788	789	427.2	1.23
309	790	791	792	493.1	1.17
310	793	794	795	493.2	1.40
311	796	797	798	443.2	1.27
312	799	800	801	455.2	1.59
313	802	803	804	493.1	1.41
314	805	806	807	497.3	0.94
315	808	809	810	509.2	0.94
316	811	812	813	547.1	1.05
317	814	815	816	429.1	1.26
318	817	818	819	441.2	1.23
319	820	821	822	439.3	1.82
320	823	824	825	479.1	1.75
321	826	827	828	423.2	1.36
322	829	830	831	493.0	1.51
323	832	833	834	443.0	1.22
324	835	836	837	455.0	1.17
325	838	839	840	451.0	1.25
326	841	842	843	493.0	1.56
327	844	845	846	456.7	1.17
328	847	848	849	493.7	1.57
329	850	851	852	491.1	1.28
330	853	854	855	491.1	1.58
331	856	857	858	563.8	1.01
332	859	860	861	590.0	1.45
333	862	863	864	415.1	1.28
334	865	866	867	491.1	1.03
335	868	869	870	507.1	1.04
336	871	872	873	459.1	1.15
337	874	875	876	572.1	1.17
338	877	878	879	584.0	1.15
339	880	881	882	616.7	1.13
340	883	884	885	549.0	1.00
341	886	887	888	485.0	1.36
342	889	890	891	497.0	1.26
343	892	893	894	500.0	1.17
344	895	896	897	461.1	1.46
345	898	899	900	411.1	1.27
346	901	902	903	421.2	1.37
347	904	905	906	461.1	1.47
348	907	908	909	487.4	1.03
349	910	911	912	562.2	1.01
350	913	914	915	521.6	1.04
351	916	917	918	385.2	1.28
352	919	920	921	397.2	1.23
353	922	923	924	395.4	1.41
354	925	926	927	463.1	1.01
355	928	929	930	449.1	1.43
356	931	932	933	409.2	1.44
357	934	935	936	449.1	1.64
358	937	938	939	477.2	1.04
359	940	941	942	441.2	1.29
360	943	944	945	479.1	1.47
361	946	947	948	469.2	1.36
362	949	950	951	554.3	2.12
363	952	953	954	592.1	1.26
364	955	956	957	523.2	0.96
365	958	959	960	521.2	1.12
366	961	962	963	561.2	1.07
367	964	965	966	455.2	1.30
368	967	968	969	453.2	1.38
369	970	971	972	493.2	1.45
370	973	974	975	475.1	1.59
371	976	977	978	437.2	1.32
372	979	980	981	533.0	1.08
373	982	983	984	506.0	1.37
374	985	986	987	461.1	1.29
375	988	989	990	451.0	1.52
376	991	992	993	521.0	1.20
377	994	995	996	447.1	1.12
378	997	998	999	397.1	1.04
379	1000	1001	1002	479.1	1.46
380	1003	1004	1005	504.6	1.65
381	1006	1007	1008	521.3	1.24
382	1009	1010	1011	561.1	1.10
383	1012	1013	1014	475.1	1.30
384	1015	1016	1017	425.4	1.22
385	1018	1019	1020	435.2	1.28
386	1021	1022	1023	501.0	1.03
387	1024	1025	1026	468.0	1.18
388	1027	1028	1029	466.0	1.38
389	1030	1031	1032	506.0	1.57
390	1033	1034	1035	435.3	1.30
391	1036	1037	1038	483.0	1.64
392	1039	1040	1041	518.0	2.20
393	1042	1043	1044	431.2	1.37
394	1045	1046	1047	471.0	1.94
395	1048	1049	1050	503.4	1.39
396	1051	1052	1053	465.4	1.28
397	1054	1055	1056	463.2	1.34
398	1057	1058	1059	531.1	1.00
399	1060	1061	1062	531.1	1.61
400	1063	1064	1065	491.2	1.40
401	1066	1067	1068	531.1	1.58
402	1069	1070	1071	566.1	1.18
403	1072	1073	1074	576.2	1.25
404	1075	1076	1077	641.7	1.14
405	1078	1079	1080	585.2	1.03
406	1081	1082	1083	517.1	2.03
407	1084	1085	1086	475.0	1.37
408	1087	1088	1089	459.2	1.70
409	1090	1091	1092	497.0	2.02
410	1093	1094	1095	525.1	1.05
411	1096	1097	1098	492.0	1.26
412	1099	1100	1101	357.4	1.34
413	1102	1103	1104	397.1	1.49
414	1105	1106	1107	470.1	1.16
415	1108	1109	1110	429.2	1.44
416	1111	1112	1113	389.2	1.37
417	1114	1115	1116	429.2	1.48
418	1117	1118	1119	331.2	1.30
419	1120	1121	1122	371.1	1.36
420	1123	1124	1125	385.2	1.42
421	1126	1127	1128	345.2	1.40
422	1129	1130	1131	385.1	1.43
423	1132	1133	1134	413.1	1.05
424	1135	1136	1137	377.2	1.23
425	1138	1139	1140	415.1	1.45
426	1141	1142	1143	443.1	1.51
427	1144	1145	1146	405.2	1.28
428	1147	1148	1149	528.1	1.23
429	1150	1151	1152	488.3	1.20
430	1153	1154	1155	556.2	1.07
431	1156	1157	1158	429.2	1.44
432	1159	1160	1161	379.2	1.22
433	1162	1163	1164	391.2	1.23
434	1165	1166	1167	389.2	1.34
435	1168	1169	1170	373.2	1.34
436	1171	1172	1173	381.1	1.35
437	1174	1175	1176	331.1	1.14
438	1177	1178	1179	341.2	1.25
439	1180	1181	1182	381.1	1.38
440	1183	1184	1185	409.0	1.23
441	1186	1187	1188	414.2	1.02
442	1189	1190	1191	363.1	1.19
443	1192	1193	1194	375.3	1.82
444	1195	1196	1197	439.1	1.03
445	1198	1199	1200	317.2	1.79
446	1201	1202	1203	315.2	1.42
447	1204	1205	1206	369.2	1.33
448	1207	1208	1209	361.2	1.11
449	1210	1211	1212	359.2	1.23
450	1213	1214	1215	423.2	1.33
451	1216	1217	1218	546.1	1.06
452	1219	1220	1221	615.0	2.14
453	1222	1223	1224	397.2	1.31
454	1225	1226	1227	409.2	1.26
455	1228	1229	1230	447.1	1.59
456	1231	1232	1233	475.1	1.03
457	1234	1235	1236	461.1	1.42
458	1237	1238	1239	411.2	1.33
459	1240	1241	1242	423.1	1.29
460	1243	1244	1245	421.2	1.45
461	1246	1247	1248	489.1	1.05
462	1249	1250	1251	491.1	1.41
463	1252	1253	1254	441.2	1.32
464	1255	1256	1257	451.2	1.43
465	1258	1259	1260	491.1	1.66
466	1261	1262	1263	519.2	1.54
467	1264	1265	1266	481.2	1.40
468	1267	1268	1269	479.3	1.50
469	1270	1271	1272	519.5	1.49
470	1273	1274	1275	547.2	1.02
471	1276	1277	1278	554.2	1.21
472	1279	1280	1281	566.2	1.41
473	1282	1283	1284	564.3	1.27
474	1285	1286	1287	632.1	1.05
475	1288	1289	1290	523.2	1.00
476	1291	1292	1293	535.2	1.13
477	1294	1295	1296	533.6	1.27
478	1297	1298	1299	573.1	1.12
479	1300	1301	1302	601.1	1.03
480	1303	1304	1305	505.1	1.61
481	1306	1307	1308	467.2	1.33
482	1309	1310	1311	465.2	1.41
483	1312	1313	1314	505.1	1.45
484	1315	1316	1317	533.2	1.03
485	1318	1319	1320	487.1	1.78
486	1321	1322	1323	437.2	1.38
487	1324	1325	1326	449.2	1.42
488	1327	1328	1329	447.3	1.50
489	1330	1331	1332	487.2	1.61
490	1333	1334	1335	480.0	1.38
491	1336	1337	1338	518.0	1.57
492	1339	1340	1341	473.2	1.78
493	1342	1343	1344	485.5	1.37
494	1345	1346	1347	483.2	1.58
495	1348	1349	1350	551.1	1.04
496	1351	1352	1353	583.0	0.99
497	1354	1355	1356	497.4	1.47
498	1357	1358	1359	447.2	1.36
499	1360	1361	1362	459.2	1.49
500	1363	1364	1365	457.2	1.50
501	1366	1367	1368	497.4	1.52
502	1369	1370	1371	525.2	1.02
503	1372	1373	1374	473.3	1.40
504	1375	1376	1377	471.2	1.57
505	1378	1379	1380	511.2	1.61
506	1381	1382	1383	539.1	1.03
507	1384	1385	1386	503.2	1.42
508	1387	1388	1389	531.3	1.43
509	1390	1391	1392	597.2	1.02
510	1393	1394	1395	616.3	1.25
511	1396	1397	1398	682.2	1.04
512	1399	1400	1401	623.2	1.15
513	1402	1403	1404	585.2	1.09
514	1405	1406	1407	623.5	1.14
515	1408	1409	1410	517.3	1.39
516	1411	1412	1413	555.2	1.62
517	1414	1415	1416	583.1	1.06
518	1417	1418	1419	537.1	1.69
519	1420	1421	1422	499.2	1.69
520	1423	1424	1425	537.2	1.75
521	1426	1427	1428	569.2	1.04
522	1429	1430	1431	570.0	1.50
523	1432	1433	1434	461.1	1.30
524	1435	1436	1437	411.4	1.33
525	1438	1439	1440	423.1	1.21
526	1441	1442	1443	421.2	1.34
527	1444	1445	1446	461.1	1.35
528	1447	1448	1449	489.1	1.05
529	1450	1451	1452	576.1	1.73
530	1453	1454	1455	493.1	1.37
531	1456	1457	1458	443.1	1.24
532	1459	1460	1461	455.2	1.26
533	1462	1463	1464	385.1	1.12
534	1465	1466	1467	395.5	0.97
535	1468	1469	1470	395.2	2.06
536	1471	1472	1473	449.1	1.34
537	1474	1475	1476	411.1	1.22
538	1477	1478	1479	449.1	1.65
539	1480	1481	1482	477.1	1.01
540	1483	1484	1485	479.1	1.34
541	1486	1487	1488	439.5	1.68
542	1489	1490	1491	457.1	1.24
543	1492	1493	1494	469.1	1.20
544	1495	1496	1497	507.1	1.42
545	1498	1499	1500	550.0	1.14
546	1501	1502	1503	592.1	1.23
547	1504	1505	1506	523.2	1.04
548	1507	1508	1509	561.2	1.43
549	1510	1511	1512	443.1	1.23
550	1513	1514	1515	455.1	1.22
551	1516	1517	1518	493.1	1.39
552	1519	1520	1521	437.4	2.03
553	1522	1523	1524	508.0	1.56
554	1525	1526	1527	533.0	1.04
555	1528	1529	1530	499.4	0.93
556	1531	1532	1533	565.0	1.00
557	1534	1535	1536	429.2	1.40
558	1537	1538	1539	441.5	2.09
559	1540	1541	1542	439.2	1.72
560	1543	1544	1545	479.1	1.67
561	1546	1547	1548	507.0	1.07
562	1549	1550	1551	493.1	1.64
563	1552	1553	1554	441.0	0.83
564	1555	1556	1557	455.2	1.51
565	1558	1559	1560	453.5	1.52
566	1561	1562	1563	523.1	1.07
567	1564	1565	1566	553.0	1.04
568	1567	1568	1569	598.2	1.73
569	1570	1571	1572	563.0	2.02
570	1573	1574	1575	537.2	1.70
571	1576	1577	1578	487.2	1.63
572	1579	1580	1581	495.7	1.82
573	1582	1583	1584	537.2	1.69
574	1585	1586	1587	564.8	1.02
575	1588	1589	1590	479.2	1.80
576	1591	1592	1593	548.6	1.92
577	1594	1595	1596	500.0	1.22
578	1597	1598	1599	550.0	1.56
579	1600	1601	1602	445.2	2.08
580	1603	1604	1605	443.2	1.43
581	1606	1607	1608	482.6	1.56
582	1609	1610	1611	511.1	1.05
583	1612	1613	1614	516.3	1.10
584	1615	1616	1617	546.7	1.15
585	1618	1619	1620	513.0	0.42
586	1621	1622	1623	407.1	1.26
587	1624	1625	1626	419.1	1.23
588	1627	1628	1629	417.2	1.32
589	1630	1631	1632	457.1	1.45
590	1633	1634	1635	471.4	1.39
591	1636	1637	1638	433.4	1.27
592	1639	1640	1641	431.2	1.44
593	1642	1643	1644	471.1	1.43
594	1645	1646	1647	501.1	1.41
595	1648	1649	1650	451.1	1.26
596	1651	1652	1653	461.2	1.39
597	1654	1655	1656	501.2	1.42
598	1657	1658	1659	489.0	1.29
599	1660	1661	1662	611.6	1.19
600	1663	1664	1665	564.1	1.18
601	1666	1667	1668	576.2	1.17
602	1669	1670	1671	574.2	1.25
603	1672	1673	1674	614.1	1.31
604	1675	1676	1677	642.2	1.20
605	1678	1679	1680	583.1	1.10
606	1681	1682	1683	533.2	1.00
607	1684	1685	1686	543.3	1.02
608	1687	1688	1689	475.2	1.41
609	1690	1691	1692	515.1	1.42
610	1693	1694	1695	447.2	1.31
611	1696	1697	1698	459.2	1.53
612	1699	1700	1701	457.2	1.46
613	1702	1703	1704	496.6	1.67
614	1705	1706	1707	489.0	1.33
615	1708	1709	1710	528.0	1.51
616	1711	1712	1713	478.0	1.22
617	1714	X2-H	1715	414.0	1.10
618	1716	X2-H	1717	456.1	1.39
619	1718	X2-H	1719	335.1	1.15
620	1720	X2-H	1721	373.1	1.33
621	1722	X2-H	1723	329.0	1.26
622	1724	X2-H	1725	279.1	1.13
623	1726	X2-H	1727	291.1	1.11
624	1728	X2-H	1729	329.0	1.33
625	1730	X2-H	1731	323.1	1.14
626	1732	X2-H	1733	333.1	1.20
627	1734	X2-H	1735	305.1	1.23
628	1736	1737	1738	447.1	1.49
629	1739	1740	1741	447.1	1.55
630	1742	1743	1744	470.1	1.11
631	1745	1746	1747	482.1	1.06
632	1748	1749	1750	480.1	1.14
633	1751	1752	1753	562.2	1.50
634	1754	1755	1756	512.2	1.40
635	1757	1758	1759	524.2	1.37
636	1760	1761	1762	441.2	1.33
637	1763	1764	1765	465.1	1.44
638	1766	1767	1768	564.0	1.18
639	1769	1770	1771	483.2	1.32
640	1772	1773	1774	537.1	1.38
641	1775	1776	1777	537.1	1.50
642	1778	1779	1780	591.1	1.09
643	1781	1782	1783	541.1	1.00
644	1784	1785	1786	553.2	0.99
645	1787	1788	1789	551.2	1.07
646	1790	1791	1792	523.1	1.37
647	1793	1794	1795	534.1	1.23
648	1796	1797	1798	496.2	1.13
649	1799	1800	1801	494.2	1.17
650	1802	1803	1804	534.1	1.25
651	1805	1806	1807	526.2	1.45
652	1808	1809	1810	536.3	1.52
653	1811	1812	1813	493.1	1.59
654	1814	1815	1816	443.2	1.42
655	1817	1818	1819	423.1	1.25
656	1820	1821	1822	534.0	1.16

[0529]

					LC
Compd	X1	X2	X3	MS obsd	RT (min)
657	1823	1824	1825	494.2	1.14
658	1826	1827	1828	534.0	1.16
659	1829	1830	1831	397.1	1.21
660	1832	1833	1834	429.1	1.25
661	1835	1836	1837	441.1	1.25
662	1838	1839	1840	439.2	1.33
663	1841	1842	1843	479.1	1.38
664	1844	1845	1846	511.1	1.00
665	1847	1848	1849	493.1	1.41
666	1850	1851	1852	437.2	1.34
667	1853	1854	1855	485.1	1.58
668	1856	1857	1858	447.1	1.38
669	1859	1860	1861	467.2	1.47
670	1862	1863	1864	467.2	1.47
671	1865	1866	1867	449.1	1.52
672	1868	1869	1870	430.2	1.16
673	1871	1872	1873	474.3	1.38
674	1874	1875	1876	512.2	1.64
675	1877	1878	1879	404.1	1.05
676	1880	1881	1882	454.1	1.12
677	1883	1884	1885	446.2	1.32
678	1886	1887	1888	458.2	1.30
679	1889	1890	1891	456.2	1.36
680	1892	1893	1894	496.1	1.47
681	1895	1896	1897	373.2	1.36
682	1898	1899	1900	305.1	1.22
683	1901	1902	1903	369.1	1.40
684	1904	1905	1906	319.1	1.28
685	1907	1908	1909	331.1	1.25
686	1910	1911	1912	397.1	1.35
687	1913	1914	1915	427.1	1.45
688	1916	1917	1918	389.1	1.28
689	1919	1920	1921	413.1	1.36
690	1922	1923	1924	375.1	1.24
691	1925	1926	1927	395.1	1.55
692	1928	1929	1930	473.1	1.59
693	1931	1932	1933	435.2	1.40
694	1934	1935	1936	473.1	1.61
695	1937	1938	1939	496.1	1.12
696	1940	1941	1942	508.2	1.15
697	1943	1944	1945	546.1	1.28
698	1946	1947	1948	588.1	1.60
699	1949	1950	1951	550.3	1.43
700	1952	1953	1954	505.1	1.62
701	1955	1956	1957	455.2	1.43
702	1958	1959	1960	573.1	1.11
703	1961	1962	1963	523.1	1.71
704	1964	1965	1966	523.1	1.76
705	1967	1968	1969	596.1	1.30
706	1970	1971	1972	546.1	1.19
707	1973	1974	1975	558.3	1.19
708	1976	1977	1978	638.2	1.76
709	1979	1980	1981	517.2	1.52
710	1982	1983	1984	555.1	1.81
711	1985	1986	1987	534.0	1.19
712	1988	1989	1990	494.1	1.15
713	1991	1992	1993	534.0	1.18
714	1994	1995	1996	538.2	1.31
715	1997	1998	1999	453.2	1.44
716	2000	2001	2002	493.1	1.49
717	2003	2004	2005	435.1	1.42
718	2006	2007	2008	493.1	1.43
719	2009	2010	2011	578.1	1.33
720	2012	2013	2014	528.1	1.24
721	2015	2016	2017	556.0	1.24
722	2018	2019	2020	560.2	1.44
723	2021	2022	2023	583.1	1.13
724	2024	2025	2026	497.1	1.67

EXAMPLE 81

[0530] Method for the Preparation of Compounds 725-746

[0531] Compounds 81-A to 81-V were synthesized from [[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetic acid according to Scheme VIII. Amines VIII-3 (0.165 mmol) in 1,2-dichloroethane (1 ml) were treated at 5° C. with 2-(2-pyridyl)ethyl functionalized silica gel (0.38 mmol) followed by a solution of [[2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetyl]-(4-fluorobenzyl)-aminooxy]-acetyl chloride, VIII-2, (0.165 mmol) in 1,2-dichloroethane (1 ml). After one hour at 25° C., the reaction mixtures were filtered and purified on a Shimadzu automated preparative HPLC system (column Waters X Terra C-8, 5μ, 19×100 mm, elution H2O 5 mM NH4OAc—acetonitrile). The collected compounds were analysed using the following LC/MS conditions.

Column:              X Terra 5μ C-8, 4.6 × 30 mm
Solvent:             Solvent A: 10% CH3CN—90% H2O, 5 mM
                     NH4OAc
                     Solvent B: 90% CH3CN—10% H2O, 5 mM
                     NH4OAc
Gradient:            100% solvent A/0% solvent B to 0% solvent A/
                     100% solvent B
Gradient time:       2 minutes, hold time 1 minute.
Flow rate:           4 ml/min.
Detector wavelenght: 220 nm.

[0532] Spectrometry (MS) data were determined with a Micromass ZMD Platform TSQ 7000 LC/MS in positive electrospray mode.

2027
		HPLC
		Retention time	MS Data
Compound	X1	(min)	(M + H)+
81-A	2028	1.34	423
81-B	2029	1.95	602
81-C	2030	1.69	457
81-D	2031	1.68	461
81-E	2032	1.75	477
81-F	2033	1.64	473
81-G	2034	1.71	457
81-H	2035	1.79	511
81-I	2036	1.72	475
81-J	2037	2.08	643
81-K	2038	1.87	499
81-L	2039	1.72	449
81-M	2040	1.53	451
81-N	2041	1.48	455
81-O	2042	1.81	465
81-P	2043	2.08	521
81-Q	2044	1.53	453
81-R	2045	1.47	472
81-S	2046	1.49	469
81-T	2047	1.31	478
81-U	2048	1.43	381
81-V	2049	1.59	409

[0533] According to the method illustrated in Scheme VIII, the dioxolanes 81-A to 81-V, VIII-4 in the scheme, (approximately 0.06 mmol) were treated with a solution of formaldehyde-methyl amine adduct (0.12 mmol) in methanol (1 ml) as described in the preparation of Compound 44 (Method 44B) and the resulting mixtures were heated at 50° C. for 45 min. The reaction mixture was then diluted with acetonitrile (1 ml) and purified on a Shimadzu automated preparative HPLC system (column Waters X Terra C-8, 5μ, 19×100 mm, elution water 0.05% TFA—acetonitrile). The collected compounds were analysed using the following LC/MS conditions.

Column:              X Terra 5μ C-8, 4.6 × 30 mm
Solvent:             Solvent A: 10% CH3CN—90% H2O, 0.05% TFA
                     Solvent B: 90% CH3CN—10% H2O, 0.05% TFA
Gradient:            100% solvent A/0% solvent B to 0% solvent A/
                     100% solvent B
Gradient time:       2 minutes, hold time 1 minute.
Flow rate:           4 ml/min.
Detector wavelenght: 220 nm.

[0534] Spectrometry (MS) data were determined with a Micromass ZMD Platform TSQ 7000 LC/MS in positive electrospray mode.

2050
		HPLC
		Retention time	MS Data
Compound	X1	(min)	(M + H)+
725	2051	1.12	408
726	2052	1.77	587
727	2053	1.48	442
728	2054	1.47	446
729	2055	1.54	462
730	2056	1.43	458
731	2057	1.51	442
732	2058	1.60	496
733	2059	1.52	460
734	2060	1.93	628
735	2061	1.68	484
736	2062	1.51	434
737	2063	1.27	436
738	2064	1.23	440
739	2065	1.62	450
740	2066	1.93	506
741	2067	1.29	438
742	2068	0.98	457
743	2069	1.26	454
744	2070	1.11	463
745	2071	1.16	366
746	2072	1.35	394

EXAMPLE 82

[0535] Method for the Preparation of Compounds 747-750

[0536] The general method for the synthesis of compounds 747-750 is outlined in Scheme X.

[0537] Compound 82-A: 1-(2,2-Dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2073

[0538] To a solution of 2-aminoacetaldehyde dimethylacetal (0.526 g mL, 5.0 mmol) and paraformaldehyde 90.15 g, 5 mmol) in MeOH (10 mL) at 55° C. was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (1.715 g, 5.0 mmol). After 45 min, the reaction mixture was cooled and purified by preparative HPLC on a C18 reverse phase column using acetonitrile (40-50%)/water (0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to yield the title compound as an amber oil (0.68 g, 34% yield). 1H NMR (300 MHz, CDCl3) δ: 10.81 (bs, 1H), 7.42 (d, 1H, J=8.1), 7.35 (d, 1H, J=1.8), 7.10 (dd, 1H, J=8.1, J=1.8), 4.59 (s, 2H), 4.47 (t, 1H, J=5.1), 4.27 (s, 2H), 3.59 (d, 2H, J=5.1), 3.38 (s, 6H), 3.02 (s, 3H). HRMS (M+Na) calcd for C17H20N2Cl2O5Na: 425.0647; found: 425.0647.

[0539] Compound 747: 4-Hydroxy-5-oxo-1-[2-(4-pyridin-4-yl-piperazine-1-yl)-ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2074

[0540] A solution of 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (0.29 g, 0.71 mmol) in acetonitrile/water (10 mL, 2.5:1) was stirred with trifluoroacetic acid (1 mL) overnight at room temp. The mixture was concentrated then dissolved in MeOH (3 mL). 1-(4-pyridyl)-piperazine (0.42 g, 2.6 mmol) was added and the resulting mixture was stirred at room temp 30 min. Sodium cyanoborohydride (0.013 g, 0.2 mmol) was added and the mixture was stirred an additional 5 h at room temp. The crude product was purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber foam (0.0042 g, 12% yield). HRMS (M+H) calcd for C24H28N5Cl2O3: 504.15693; found: 504.1564.

[0541] Compound 748: 1-{2-[4-(4-Fluoro-phenyl)piperazine-1-yl]-ethyl}-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2075

[0542] Compound 748 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 1-(4-fluoro-phenyl)-piperazine using the method described for compound 747. The title compound was isolated as an amber foam (0.009 g, 25% yield). HRMS (M+H) calcd for C24H28N4Cl2O3F: 521.15226; found: 521.1531.

[0543] Compound 749: 1-[2-(4-Benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2076

[0544] Compound 749 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 1-benzo[1,3]dioxol-5-ylmethyl-piperazine using the method described for compound 747. The title compound was isolated as a white solid (0.0068 g, 17% yield). HRMS (M+H) calcd for C27H31N4Cl2O5: 561.16716; found: 561.1674.

[0545] Compound 750: 1-[2-(2.6-Dimethyl-morpholin-4-yl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2077

[0546] Compound 750 was prepared from 1-(2,2-dimethoxy-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 2,6-dimethyl-morpholine using the method described for compound 747. The title compound was isolated as a pale yellow powder (0.014 g, 14% yield). HRMS (M+H) calcd for C21H28N3Cl2O4: 456.14570; found: 456.1472.

EXAMPLE 83

[0547] Method for the Preparation of Compounds 751-758

[0548] The general method for the synthesis of compounds 751-758 is outlined in Scheme XI.

[0549] Compound 751: 1-(3-Dimethylcarbamoyl-propyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2078

[0550] To a solution of 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid, Compound 24, (0.06 g, 0.15 mmol) in dichloromethane (1 mL) was added EDC (0.057 g, 0.3 mmol), HOBT (0.0020 g, 0.015 mmol) and dimethyl amine (0.15 mL, 2 M solution in THF, 0.30 mmol). The mixture was stirred at room temp for 6 h then concentrated and the crude product purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber oil (0.0147 g, 23% yield). HRMS (M+H) calcd for C19H24N3Cl2O4: 428.11440; found: 428.1143.

[0551] Compound 752: 4-Hydroxy-1-(4-morpholin-4-yl-4-oxo-butyl)-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2079

[0552] Compound 752 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and morpholine using the method described for compound 751. The title compound was isolated as an amber oil (0.0148 g, 21% yield). HRMS (M+H) calcd for C21H26N3Cl2O5: 470.12496; found: 470.1256.

[0553] Compound 753: 4-Hydroxy-1-[4-(4-methyl-piperazin-1-yl)-4-oxo-butyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2080

[0554] Compound 753 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 4-methyl-piperazine using the method described for compound 751. The title compound was isolated as a white powder (0.0508 g, 42% yield). HRMS (M+H) calcd for C22H29N4Cl2O4: 483.1566; found: 483.1581.

[0555] Compound 754: 4-Hydroxy-1-(3-methylcarbamoyl-propyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2081

[0556] Compound 754 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and methylamine using the method described for compound 751. The title compound was isolated as a white powder (0.0192 g, 18% yield). HRMS (M+H) calcd for C18H22N3Cl2O4: 414.09875; found: 414.0969.

[0557] Compound 755: 4-Hydroxy-1-(4-methanesulfonylamino-4-oxo-butyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2082

[0558] Compound 755 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and methane sulfonamide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30%-40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0158 g, 13% yield). HRMS (M−H) calcd for C18H20N3Cl2O6S: 476.04499; found: 476.0431.

[0559] Compound 756: 1-[4-(3,5-Dimethyl-isoxazole-4-sulfonylamino)-4-oxo-butyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2083

[0560] Compound 756 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 3,5-dimethyl-isoxazole-4-sulfonic acid amide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0296 g, 21% yield). HRMS (M−H) calcd for C22H23N4Cl2O7S: 557.06645; found: 557.0663.

[0561] Compound 757: 4-Hydroxy-5-oxo-1-[4-oxo-4-(1-phenyl-cyclopropanesulfonylamino)-butyl]-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2084

[0562] Compound 757 was prepared from 4-{4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric acid and 1-phenyl-cyclopropanesulfonic acid amide using the method described for compound 751. The title compound was purified by preparative HPLC (C18, ODS-A, S-751 μm, 50% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0026 g, 3% yield). HRMS (M−H) calcd for C26H30N3Cl2O6S: 582.12324; found: 582.1215.

[0563] Compound 758: 4-Hydroxy-1-(2-morpholin-4-yl-2-oxo-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2085

[0564] Compound 758 was prepared from {4-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-acetic acid, Compound 20, and morpholine using the method described for compound 751. The title compound was isolated as a white powder (0.0088 g, 20% yield). HRMS (M+H) calcd for C19H22N3Cl2O5: 442.09366; found: 442.0951.

EXAMPLE 84

[0565] Method for the Preparation of Compounds 759-765

[0566] The general method for the synthesis of compounds 759-765 is outlined in Scheme XII.

[0567] Compound 84-A: 4-Hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2086

[0568] Compound 84-A was prepared from N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide and 2-piperazin-1-yl-ethylamine using the method described for compound 37. The title compound was isolated as a white solid (0.183 g, 86% yield). HRMS (M+H) calcd for C19H25N3Cl2O4: 427.13038; found: 427.1307.

[0569] Compound 759: 1-[2-(4-Benzoyl-piperazin-1-yl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2087

[0570] To a solution of benzoyl chloride (0.023 mL, 0.23 mmol) in dichloromethane (1 mL) cooled to 0° C. was added dropwise a solution of 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (00.10 g, 0.20 mmol) in pyridine/dichloromethane (4 mL, 1:1). The resulting mixture was stirred at room temp 18 h and quenched with 1N HCl. The organic phase was washed with 1N HCl (3 times). The aqueous washings were combined and purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% TFA) to give the title compound as a white powder (0.0215 g, 20% yield). HRMS (M+H) calcd for C26H29N4Cl2O4: 531.1566; found: 531.1563.

[0571] Compound 760: 1-{2-[4-(4-Fluoro-benzoyl)-piperazin-1-yl]-ethyl}-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2088

[0572] Compound 760 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 4-fluoro-benzoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0098 g, 2% yield). HRMS (M−H) calcd for C26H26N4Cl2O4F: 547.13151; found: 547.1310.

[0573] Compound 761: 4-Hydroxy-1-{2-[4-(4-methyl-benzoyl)-piperazin-1-yl]-ethyl}-5-oxo-2,5-dihydro-1H-pyrrole-3 carboxylic acid (3,4-dichloro-benxyl)-methyl-amide 2089

[0574] Compound 761 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and 4-methyl-benzoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30%-40% acetonitrile/water/0.5% TFA) and isolated as a white powder (0.0210 g, 17% yield). HRMS (M+H) calcd for C27H31N4Cl2O4: 545.17225; found: 545.1720.

[0575] Compound 762: 4-Hydroxy-5-oxo-1-{2-[4-(pyridine-2-carbonyl)-piperazin-1-yl]-ethyl}-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2090

[0576] Compound 762 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and pyridine-2-carbonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%-20%-30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0476 g, 39% yield). HRMS (M+H) calcd for C25H28N4Cl2O5: 532.15184; found: 532.1514.

[0577] Compound 763: 4-Hydroxy-1-{2-[4-(isoxazole-5-carbonyl)-piperazin-1-yl]-ethyl}-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2091

[0578] Compound 763 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and isoxazole-5-carbonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%-20%-30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0268 g, 22% yield). HRMS (M+H) calcd for C23H26N5Cl2O5: 522.13111; found: 522.1312.

[0579] Compound 764: 4-Hydroxy-1-[2-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2092

[0580] Compound 764 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and methanesulfonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%-20%-30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0140 g, 12% yield). HRMS (M+H) calcd for C20H27N4Cl2O5S: 505.10793; found: 505.1095.

[0581] Compound 765: 1-[2-(4-Dimethylsulfamoyl-piperazin-1-yl)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2093

[0582] Compound 765 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and dimethylsulfamoyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0231 g, 19% yield). HRMS (M+H) calcd for C21H30N5Cl2O5S: 534.13448; found: 534.1322.

EXAMPLE 85

[0583] Compound 766: 4-Hydroxy-5-oxo-1-[2-(4-oxy-morpholin-4-yl)-ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2094

[0584] To a solution of 4-hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (0.069 g, 0.16 mmol) in dichloromethane (1 mL), was added meta-chloro-peroxy-benzoic acid (MCPBA) (0.036 g, 0.21 mmol). The mixture was stirred for 24 h then concentrated. Purification using preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% HCl) gave the title compound as a white solid (0.03 g, 94% yield). HRMS (M+H) calcd for C19H24N3Cl2O5: 444.10931; found: 444.1073.

EXAMPLE 86

[0585] Method for the Preparation of Compounds 767-777

[0586] The general method for the preparation of compounds 767-777 is outlined in Scheme XIII.

[0587] Compound 86-A: 2-Methyleneamino-ethanol 2095

[0588] 2-Aminoethanol (0.061 g, 1.0 mmol) and paraformaldehyde (0.03 g, 1.0 mmol) were stirred in methanol (10 mL) at 55° C. until the solids dissolved (approximately 20 min). The solution was cooled and used without further purification

[0589] Compound 767: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5 dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2096

[0590] To a solution of 2-methyleneamino-ethanol (1 mL, 0.1 mmol) in MeOH (1 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (0.036 g, 0.1 mmol). The mixture was stirred at 55° C. for 1 h, cooled and purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA). The title compound was isolated as a white foam (0.018 g, 49% yield). HRMS (M−H) calcd for C15H15N2Cl2O4: 357.04089; found: 357.0396.

[0591] Compound 768: 4-Hydroxy-1-[1-hydroxymethyl-2-(1H-indol-3-yl)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2097

[0592] Compound 768 was prepared from N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide, paraformaldehyde and 2-amino-3-(1H-indol-3-yl)-propan-1-ol according to the procedures described for compound 86-A and compound 767. The title compound was isolated as a yellow solid (0.0038 g, 8% yield). 1HNMR (300 MHz, CDCl3) δ: 7.52 (1H, d, J=8.05 Hz), 7.36-7.29 (3H, m), 7.14-6.98 (4H, m), 4.46 (2H, s), 4.40-4.36 (1H, m), 3.99 (2H, s), 3.81-3.78 (2H, m), 3.11-3.08 (3H, m), 2.85 (3H, s).

[0593] Compounds 769-777

[0594] As illustrated in Scheme XII, compounds 769-777 were prepared from N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide, paraformaldehyde and an amine, I-7, according to the procedures described for compound 86-A and compound 767.

2098
		LC/MS
		Retention
		time	MS calcd
Compound	X1	(min)	(M + H)	MS found
769	2099	1.5	451.3	433.3
770	2100	1.4	373.2	373.3
771	2101	1.6	401.3	401.3
772	2102	1.4	389.2	389.3
773	2103	1.6	413.3	413.3
774	2104	1.4	417.3	417.3
775	2105	1.4	373.2	373.3
776	2106	1.3	389.2	389.3
777	2107	1.4	373.2	373.3

EXAMPLE 87

[0595] Method for the Preparation of Compounds 778-781

[0596] Compound 87-A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-N-naphthalen-1-ylmethyl-acetamide 2108

[0597] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with methyl-naphthalen-1-yl-methyl-amine as described in the preparation of Compound 44-C gave the title amide as a, pale yellow oil (0.4931 g, 26% yield). 1HNMR (300 MHz, CDCl3) δ: 8.18 (0.6H, d), 7.88-7.80 (2.4H, m), 7.54-7.38 (4H, m), 6.17 (0.6H, s), 6.08 (0.4H, s), 5.13 (1.2H, s), 5.06 (0.8H, s), 3.08 (1.2H, s), 2.90 (1.8H, s), 1.73 (3.6H, s), 1.67 (2.4H, s).

[0598] Compound 87-B: 2-Hydroxy-3-(methyl-naphthalen-1-ylmethyl-carbamoyl-acrylic Acid Methyl Ester 2109

[0599] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-N-naphthalen-1-ylmethyl-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a colorless oil (0.04 g, 33% yield). 1HNMR (300 MHz, CDCl3) δ: 14.65 (1H, bs), 7.89-7.82 (3H, m), 7.57-7.20 (4H, m), 6.31 (0.6H, s), 6.21, (0.4H, s), 5.15 (1.2H, s), 5.07 (0.8H, s), 3.89 (1.8H, s), 3.80 (1.2H, s), 3.11 (1.2H, s), 2.94 (1.8H, s).

[0600] Compounds 778-781

[0601] 2-Hydroxy-3-(methyl-naphthalen-1-ylmethyl-carbamoyl)-acrylic acid methyl ester was treated with paraformaldehyde and an amine according to the procedure described in the preparation of compound 12 to yield compounds 778-781.

2110
		LC/MS
		retention	MS
		time	calculated	MS
Compound	X1	(min)	(M + H)	found
778	2111	1.4	325.4	325.4
779	2112	1.1	410.5	410.4
780	2113	1.3	341.4	341.4
781	2114	1.2	371.4	371.4

EXAMPLE 88

[0602] Compound 782: 4-[3-Hydroxy-4-(methyl-naphthalen-1-ylmethyl-carbamoyl)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric Acid 2115

[0603] 2-Hydroxy-3-(methyl-naphthalen-1-ylmethyl-carbamoyl)-acrylic acid methyl ester was treated with paraformaldehyde and 4-amino-butyric acid according to the procedure described in the preparation of compound 12 to give the title compound as a white powder (0.0210 g, 55% yield).). 1HNMR (300 MHz, CDCl3) δ: 7.93-7.81 (2H, m), 7.55-7.42 (4H, m), 7.42-7.28 (1H, m), 5.13 (2H, s), 4.14 (2H, s), 3.52-3.50 (2H, m), 2.36-2.29 (2H, m), 1.90-1.87 (2H, m).

EXAMPLE 89

[0604] Method for the Preparation of Compounds 783-791

[0605] The general method for the preparation of compounds 783-791 is illustrated in Scheme XV.

[0606] Compound 89-A: (4-Fluoro-2-methylsulfanyl-benzyl)-methyl-amine 2116

[0607] A suspension of 2,4-difluorobenzaldehyde (16 mL, 146 mmol) and sodium thiomethoxide (14 g, 200 mmol) in toluene (200 mL) was stirred at 80° C. for 7 h and 14 h at room temperature. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL), saturated aqueous NaHCO3 (100 mL) and brine (50 mL). The aqueous layers were combined and extracted with ether (2×100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to give a viscous oil. This viscous oil was dissolved in ether/hexanes (1:1, v/v) and slowly concentrated on under vacuum. The precipitated white solid was separated by filteration and dried to give 2-methylthio-4-fluorobenzaldehyde (18.7 g, 75% yield). 1HNMR (500 MHz, CDCl3) δ: 10.11 (1H, s), 7.78 (1H, dd, J=8.55, 6.11 Hz), 6.97 (1H, dd, J=10.07, 2.44 Hz), 6.91 (1H, td, J=8.54, 2.44 Hz), 2.45 (3H, s). MS calcd for C8H7FOS (M+H): 171.2; found: 171.6.

[0608] A solution of 2-methylthio-4-fluorobenzaldehyde (2.04 g, 12 mmol) and 2M methylamine in methanol (24 mL, 48 mmol) was stirred at room temperature for 2 h. To this was added a solution of ZnCl2 (0.818 g, 6 mmol) and NaCNBH3 (0.754 g, 12 mmol) in methanol (30 mL). After stirring for 20 h, the reaction mixture was concentrated and the resulting residue was taken up in aqueous NaOH (0.5 M, 20 mL), extracted with CH2Cl2 (5×50 mL). The combined organic layers were concentrated and the resulting residue was taken up in 1N HCl (25 mL). This solution was extracted with ethyl acetate (3×25 mL). The organic layers were discarded and aqueous layer was brought to pH 9 by adding Na2CO3 and extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 layers were dried over MgSO4, filtered and concentrated to give the desired benzylamine as a viscous pale yellow oil (1.4 g, 60% pure).

[0609] Compound 89-B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide 2117

[0610] To a stirred solution of (4-fluoro-2-methylsulfanyl-benzyl)-methyl-amine (1.3 g) and diisopropylethylamine (1.74 mL, 10 mmol) in CH2Cl2 (60 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (1.1 g, 6 mmol). After 1 h, the reaction mixture was concentrated and the resulting residue was taken up in ether (100 mL), washed with 1N HCl (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a viscous yellow oil. Flash chromatography on a silica gel column with 3:2 hexanes/EtOAc followed by 2:3 hexanes/EtOAc gave the desired product as a 1:1 mixture of E and Z isomers 1.8123 g, 89% yield). 1HNMR (500 MHz, CDCl3) o: 7.17 (0.5H, dd, J=8.54, 6.11 Hz), 7.00 (0.5H, dd, J=8.55, 5.8 Hz), 6.94-6.89 (1H, m), 6.83-6.77 (1H, m), 6.17 (0.5H, s), 6.04 (0.5H, s), 4.68 (1H, s), 4.51 (1H, s), 2.98 (1.5H, s), 2.97 (1.5H, s), 2.48 (1.5H, s), 2.45 (1.5H, s), 1.72 (3H, s), 1.67 (3H, s). MS calcd for C16H19FNO4S (M+H): 340.1; found: 340.3.

[0611] Compound 89-C: 2-(2,2-Dimethyl-5-oxo-[1,2]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methoxy-acetamide 2118

[0612] To a stirred solution of 4-fluoro-2-methylsulfanylbenzaldehyde (9.7 g, 57 mmol) in CH2Cl2 (300 mL) was added in small portions m-chloroperbenzoic acid (60%, 20.71 g, 120 mmol) over 20 minutes. After 24 h, 5 mL of dimethylsulfoxide followed by saturated NaHCO3 (100 mL) was added and stirred for additional 2 h. The organic layer separated and washed with saturated NaHCO3 (2×100 mL). The combined aqueous layers were saturated with NaCl and extracted with CH2Cl2 (2×100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give a viscous yellow oil. This residue was purified by flash chromatography on a silica gel column using hexanes/ether/ethyl acetate (gradient elution). The fractions containing the desired product are combined and concentrated to give 4-fluoro-2-methylsulfonylbenzaldehyde (3.85 g, 33%) and 4-fluoro-2-methylsulfinylbenzaldehyde (5.61 g, 53% yield) as a white solid. 4-fluoro-2-methylsulfonylbenzaldehyde: 1HNMR (500 MHz, CDCl3) δ: 10.41 (1H, s), 8.08-8.06 (1H, M), 7.85-7.71 (2H, m), 3.09 (3H, s). HRMS calcd for C8H6FO3S (M−H): 201.0022; found: 201.0025. 4-fluoro-2-methylsulfinyl-benzaldehyde: 1HNMR (500 MHz, CDCl3) δ: 9.97 (1H, s), 8.07-8.05 (1H, M), 7.99-7.94 (1H, m), 7.36-7.33 (1H, m), 2.80 (3H, s). MS calcd for C8H8FO2S (M+H): 187.02; found: 187.02.

[0613] To a stirred solution of 4-fluoro-2-methylsulfinylbenzaldehyde (2.234 g, 12 mmol) in 2M methylamine in methanol (24 mL, 48 mmol) was added a solution of ZnCl2 (0.818 g, 6 mmol) and NaCNBH3 (0.754 g, 12 mmol) in methanol (30 mL). After stirring for 16 h an additional methyl amine (1 equiv) and NaCNBH3 (1 equiv) every 24 h for 5 days. After seven days, the reaction mixture was concentrated and the resulting residue was taken up into aqueous NaOH (1 M, 100 mL), extracted with CH2Cl2 (5×50 mL). The combined organic layers were concentrated to give a yellow oil which was a mixture of aldehyde and the desired (4-Fluoro-2-methanesulfinyl-benzyl)-methyl-amine. This material was used in the next step without further purification.

[0614] To a stirred solution of above amine and diisopropylethylamine (1.75 mL, 10 mmol) in CH2Cl2 (30 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.95 g, 5 mmol). After 1 h, the reaction mixture was concentrated and the resulting residue was taken up into ether (150 mL), washed with 1N HCl (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give a yellow residue which was purified by flash column chromatography on silica gel column using 1:1 v/v hexanes/ethyl acetate, ethyl acetate and 2-5% methanol/ethyl acetate. The fractions containing the compound were combined and concentrated to give the product (1.65 g, 93% yield based on acid chloride used). 1HNMR (500 MHz, CDCl3) δ: 7.76-7.72 (1H, m), 7.28 (1H, dd, J=8.3, 5.0 Hz), 7.13 (1H, td, J=8.2, 2.7 Hz), 6.14 (1H, s), 4.88 (1H, d, J=15.3 Hz), 4.46 (1H, d, J=15.3 Hz), 3.03 (3H, s), 2.71 (3H, s), 1.72 (6H, s). HRMS calcd for C16H19FNO5S (M+H): 356.1; found: 356.3.

[0615] Compound 89-D: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methyl-acetamide 2119

[0616] To a solution of 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide (0.5 g, 1.475 mmol) in CH2Cl2 (10 mL) was added 50% m-chloroperbenzoic acid (1.035 g, 3 mmol) and the resulting mixture stirred at room temperature for 4 h, then, taken up into EtOAc, washed successively with saturated NaHSO4, saturated NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated and the residue purified on a silica gel column using hexanes/EtOAc (0-75%) to afford the desired product as a mixture of E/Z isomers (0.4977 g, 91%). 1HNMR (300 MHz, CDCl3) δ: 7.76 (1H, dd, J=8.2, 2.7 Hz), 7.38-7.27 (2H, m), 6.21 (0.8H, s), 5.93 (0.2H, s), 5.05 (1.6H, s), 5.01 (0.4H, s), 3.19 (2.4H, s), 3.16 (2.4H, s), 3.11 (0.6H, s), 3.03 (0.6H, s), 1.72 (4.8H, s), 1.69 (1.2H, s). HRMS calcd for C16H19FNO6S (M+H): 372; found: 372.

[0617] Compound 783: 4-{4-[(4-Fluoro-2-methylsulfanyl-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2120

[0618] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 4-amino-butyric acid as described in Method 44B to give the title compound as a white solid (0.05 g, 49% yield). 1 (300 MHz, CDCl3) δ: 7.11 (1H, dd, J=8.42, 5.85 Hz), 6.91 (1H, dd, J=9.52, 2.57 Hz), 6.82 (1H, td, J=8.41, 2.56 Hz), 4.64 (2H, s), 4.15 (2H, s), 3.55 (2H, t, J=6.96 Hz), 2.98 (3H, s), 2.47 (3H, s), 2.38 (2H, t, J=6.95 Hz), 1.96-1.88 (2H, m).

[0619] Compound 784: 4-{4-[(4-Fluoro-2-methanesulfinyl-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2121

[0620] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 4-amino-butyric acid as described in Method 44B to give the title compound as a colorless oil (0.015 g, 18% yield). 1HNMR (300 MHz, CDCl3) δ: 7.76 (1H, dd, J=8.05, 2.20 Hz), 7.34 (1H, dd, J=8.41, 5.12 Hz), 7.19 (1H, td, J=8.05, 2.56 Hz), 4.85 (2H, d, J=15.01 Hz), 4.18 (2H, s), 3.58 (2H, t, J=5.86), 3.01 (3H, s), 2.76 (3H, s), 2.39 (2H, t, J=5.86 Hz), 1.95 (2H, t, J=6.22 Hz).

[0621] Compound 785: 4-{4-[(4-Fluoro-2-methanesulfonyl-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2122

[0622] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 4-amino-butyric acid as described in Method 44B to give the title compound as a colorless oil (0.01 g, 9% yield). 1HNMR (300 MHz, CDCl3) δ: 7.78 (1H, dd, J=8.06, 2.57 Hz), 7.43 (1H, dd, J=8.60, 4.94 Hz), 7.36-7.30 (1H, m), 5.08 (2H, s), 4.20 (2H, s), 3.58 (2H, t, J=5.85 Hz), 3.16 (6H, s), 2.42 (2H, t, J=6.22 Hz), 1.95 (2H, t, J=6.59).

[0623] Compound 786: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-2-methylsulfanyl-benzyl)-methyl-amide 2123

[0624] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine as described in Method 44B to give the title compound as a white solid (0.032 g, 76% yield). 1HNMR (300 MHz, CDCl3) δ: 7.07 (1H, dd, J=9.52, 6.23 Hz), 6.92 (1H, dd, J=9.52, 2.56 Hz), 6.82 (1H, td, J=8.06, 2.57 Hz), 4.61 (2H, s), 4.27 (2H, s), 3.95-3.90 (8H, m), 3.76-3.72 (2H, m), 3.39 (2H, t, J=5.85 Hz), 2.97 (3H, s), 2.47 (3H, s).

[0625] Compound 787: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methylsulfanyl-benzyl)-methyl-amide 2124

[0626] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and amino-ethanol as described in Method 44 B to give the title compound as a white solid (0.28 g, 79% yield). 1HNMR (300 MHz, MeOD) δ: 7.21 (1H, dd, J=8.42, 5.86 Hz), 7.06 (1H, dd, J=9.88, 2.57 Hz), 6.88 (1H, td, J=8.41, 2.56 Hz), 4.69 (2H, s), 4.23 (2H, s), 3.72 (2H, t, J=10.24, 5.12H), 3.61-3.57 (2H, m), 3.02 (3H, s), 2.50 (3H, s).

[0627] Compound 788: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-2-methanesulfinyl-benzyl)-methyl-amide 2125

[0628] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine as described in Method 44 B to give the title compound as a yellow solid (0.04 g, 88% yield). 1HNMR (300 MHz, MeOD) δ: 7.72 (1H, dd, J=8.42, 2.56 Hz), 7.49 (1H, dd, J=8.79, 5.13 Hz), 7.32-7.26 (1H, m), 4.19 (2H, s), 4.09-3.46 (10H, m), 3.30-3.21 (2H, m), 3.12 (3H, s), 2.81 (3H, s).

[0629] Compound 789: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methylsulfinyl-benzyl)-methyl-amide 2126

[0630] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and amino-ethanol as described in Method 44B to give the title compound as a colorless oil (0.015 g, 40% yield). 1HNMR (300 MHz, MeOD) δ: 7.71 (1H dd, J=8.42, 2.56 Hz), 7.47 (1H, dd, J=8.42, 5.12 Hz), 7.31 (1H, td, J=8.41, 2.56 Hz), 4.95 (2H, s), 4.23 (2H, s), 3.73 (2H, t, J=5.12 Hz), 3.59 (2H, t, J=4.76 Hz), 3.11 (3H, s), 2.80 (3H, s).

[0631] Compound 790: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-2-methanesulfonyl-benzyl)-methyl-amide 2127

[0632] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine as described in Method 44B to give the title compound as a white solid (0.032 g, 69% yield). 1HNMR (300 MHz, DMSO) δ: 9.65 (1H, bs), 7.74 (1H, dd, J=8.41, 2.56 Hz), 7.64-7.59 (1H, m), 7.43-7.38 (1H, m), 4.99 (2H, s), 4.15 (2H, s), 4.00-3.53 (10H, m), 3.43 (2H, s), 3.38 (3H, s), 3.11 (3H, s).

[0633] Compound 791: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methylsulfonyl-benzyl)-methyl-amide 2128

[0634] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and amino-ethanol as described in Method 44 B to give the title compound as a colorless oil (0.02 g, 41% yield). 1HNMR (300 MHz, MeOD) 8:7.77 (1H, dd, J=8.42, 2.57 Hz), 7.56-7.45 (2H, m), 5.10 (2H, s), 4.26 (2H, s), 3.73 (2H, bs), 3.59 (2H, bs), 3.23 (6H, s).

EXAMPLE 90

[0635] Method for the Preparation of Compounds 792-808

[0636] Compound 90-A: N-(3,4-dichloro-benzyl)-O-methyl-hydroxylamine 2129

[0637] To methoxylamine hydrochloride (20 g, 0.24 mol) in water (200 mL) and THF (74 mL) was added sodium acetate (16.3 g, 0.2 mol) followed by 3,4-dichlorobenzaldehyde (25 g, 0.14 mol). The mixture was stirred at room temp for 6 h and diluted with diethyl ether. The aqueous phase was extracted with ethyl acetate, dried (sodium sulfate) and concentrated to give a colorless oil. The oil was dissolved in glacial acetic acid (200 mL) and cooled to 0° C. Sodium cyanoborohydride (18.8 g, 0.26 mol) was added over 30 min. The mixture was stirred at room temp for 4 days, cooled to 0° C. and made basic with 10 N NaOH. The mixture was extracted with EtOAc (3×'s) and the combined organic extracts were washed with water and brine and concentrated to give an oil that solidifies upon standing. This residue was stirred in diethyl ether and the resulting title compound was filtered as a white solid (9.61 g, 33% yield). 1HNMR (300 MHz, DMSO) δ: 10.12 (1H, bs), 7.74 (1H, s), 7.67 (1H, d, J=8.42 Hz), 7.44 (1H, d, J=8.05 Hz), 4.21 (2H, s), 3.59 (3H, s).

[0638] Compound 90-B: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolane-4-ylidene)-N-methoxy-acetamide 2130

[0639] A suspension of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid (4.37 g, 25.4 mmol) in benzene (30 mL) was refluxed for 1 h with oxalyl chloride (15 mL). The resulting solution was cooled and concentrated. The residue was dissolved in dichloromethane (30 mL) and cooled to 0° C. and N-(3,4-dichloro-benzyl)-O-methyl-hydroxylamine (5.3 g, 22 mmol) in dichloromethane (30 mL) and pyridine (18 mL) was added dropwise. The resulting mixture was stirred at room temp for 18 h. The mixture was diluted with 1N HCl and extracted with EtOAc. The organic phase was washed with 1N HCl, dried (sodium sulfate) and concentrated to give the title compound as a yellow solid (7.59 g, 83% yield). 1HNMR (300 MHz, CDCl3) δ: 7.44 (1H, s), 7.39 (2H, d, J=8.05 Hz), 7.19 (2H, d, J=8.05 Hz), 6.37 (1H, s), 4.75 (2H, s), 3.70 (3H, s), 1.74 (6H, s).

[0640] Compound 90-C: 3-[(3,4-Dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester 2131

[0641] A mixture of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolane-4-ylidene)-N-methoxy-acetamide (1.0 g, 2.8 mmol) and potassium carbonate (0.39 g, 2.8 mmol) in MeOH (20 mL) was stirred at room temp for 1 h. The suspension was diluted with EtOAc and washed with 1N HCl followed by brine. The organic phase was dried (sodium sulfate) and concentrated. The title compound was purified by flash chromatography eluting with 100% hexane followed by 25% EtOAc/hexane to give a white solid (0.3107 g, 33% yield). 1HNMR (300 MHz, CDCl3) δ: 13.28 (1H, s), 7.41 (2H, m), 7.15 (1H, dd, J=9.52, 1.47 Hz), 6.45 (1H, s), 4.77 (2H, s), 3.89 (3H, s), 3.72 (3H, s).

[0642] Compounds 792-808:

[0643] Amine (0.1 mmol) was reacted with paraformaldehyde according to the method described for the preparation of compound 86-A. This was combined with 3-[(3,4-dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (0.036 g, 0.1 mmol), in MeOH (1.0 mL) and the resulting mixture stirred at 55° C. for 1 h. The resulting solution was cooled and purified by preparative HPLC (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to give the title compounds. Compounds were evaluated by LC/MS (Waters XTERRA, 4.6 mm×30 mm, MeOH/H2O/0.1% TFA, 10%-90% MeOH, 2 min gradient, 5 mL/min flow rate; ESI+).

2132
		LC/MS	MS
		retention	calcd
Compound	X1	time (min)	(M + H)	MS found
792	2133	1.6	514.1	514.2
793	2134	1.50	375.2	375.2
794	2135	1.3	443.3	443.3
795	2136	1.3	471.4	471.3
796	2137	1.3	458.3	458.3
797	2138	1.8	486.4	486.3
798	2139	1.7	443.3	443.3
799	2140	1.3	460.4	460.3
800	2141	1.3	388.3	388.2
801	2142	1.7	359.2	359.3
802	2143	1.4	495.3	495.3
803	2144	1.5	389.2	389.3
804	2145	1.7	417.3	417.3
805	2146	1.4	405.2	405.3
806	2147	1.5	433.2	433.3
807	2148	1.5	389.2	389.3
808	2149	1.4	405.2	405.3

EXAMPLE 91

[0644] Compound 809: 4-Hydroxy-1-(4-hydroxy-butyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methoxy-amide 2150

[0645] 3-[(3,4-Dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester, paraformaldehyde and 4-amino-butanol were reacted according to the method described for compounds 792-808 to give the tile compound as a yellow oil (0.015 g, 36% yield). 1HNMR (300 MHz, CDCl3) δ: 7.43-7.40 (2H, m), 7.18 (1H, dd, J=8.42, 1.83 Hz), 4.81 (2H, s), 4.14 (2H, s), 3.74 (3H, s), 3.63 (2H, t, J=6.40 Hz), 3.51 (2H, t, J=4.01 Hz), 1.68-1.53 (4H, M), 1.43-1.33 (2H, m).

EXAMPLE 92

[0646] Compound 810: 4-{4-[(3,4-Dichloro-benzyl)-methoxy-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2151

[0647] To a solution of 4-amino butyric acid (0.093 g, 0.90 mmol) in acetic acid (0.5 mL) at 55° C. was added paraformaldehyde (0.027 g, 0.90 mmol). After stirring for 10 min, 3-[(3,4-dichloro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (0.2978 g, 0.89 mmol) was added and the mixture was stirred at 55° C. for 1 h. The clear yellow solution was cooled, concentrated and purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%-40% acetonitrile/water/0.5% HCl) to give the title compound as a yellow foam (0.129 g, 34% yield). HRMS (M+H) calcd for C17H19N2Cl2O6: 417.06203; found: 417.0607.

EXAMPLE 93

[0648] Method for the Preparation of Compounds 811-814

[0649] The general method for the synthesis of compounds 811-814 is illustrated in Scheme XIV.

[0650] Compound 93-A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolane-4-ylidene)-N-methoxy-N-naphthalen-1-ylmethyl-acetamide 2152

[0651] O-Methyl-N-naphthalen-1-ylmethyl-hydroxylamine was reacted with (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid according to the method described for the preparation of compound 90-B to give the title compound as a pale yellow solid (0.826 g, 56% yield). 1HNMR (300 MHz, CDCl3) δ: 8.18 (1H, d, J=8.05 Hz), 7.85 (2H, t, J=9.15 Hz), 7.56-7.41 (4H, m), 6.40 (1H, s), 5.30 (2H, s), 3.43 (3H, s), 1.77 (6H, s).

[0652] Compound 93-B: 2-Hydroxy-3-(methoxy-naphthalen-1-ylmethyl-carbamoyl)-acrylic Acid Methyl Ester 2153

[0653] Compound 93-B was prepared using the same procedure described for the preparation of compound 90-C and isolated as an orange powder (0.022 g, 45% yield). 1HNMR (300 MHz, CDCl3) δ: 8.09 (1H, d, J=8.05 Hz), 7.87 (2H, t, J=7.68 Hz), 7.57-7.41 (4H, m), 5.35 (2H, s), 4.16 (2H, s), 3.56 (3H, s), 3.54 (2H, t, J=6.33 Hz), 2.38 (2H, t, J=6.58 Hz), 1.91 (2H, t, J=6.22 Hz).

[0654] Compounds 811-814

[0655] As illustrated in Scheme XIV, compounds 811-814 were prepared from 2-hydroxy-3-(methoxy-naphthalen-1-ylmethyl-carbamoyl)-acrylic acid methyl ester, paraformaldehyde and an amine, I-7 using the same method described for the preparation of compounds 792-808.

2154
		LC/MS
		retention	MS calcd	MS
Compound	X1	time (min)	(M + H)	found
811	2155	1.5	341.4	341.4
812	2156	1.2	426.5	426.4
813	2157	1.4	357.4	357.3
814	2158	1.3	387.4	387.3

EXAMPLE 94

[0656] Compound 815: 4-[3-Hydroxy-4(methoxy-naphthalen-1-yl methyl-carbamoyl)-2-oxo-2,5-dihydro-pyrrol-1-yl]-butyric Acid 2159

[0657] 2-Hydroxy-3-(methoxy-naphthalen-1-ylmethyl-carbamoyl)-acrylic acid methyl ester, paraformaldehyde and 4-amino-butyric acid were reacted using the method described for the synthesis of Compound 810 to give the title compound as an orange powder (0.0217 g, 45% yield). 1HNMR (300 MHz, CDCl3) δ: 8.09 (1H, d, J=8.05 Hz), 7.87 (2H, t, J=768 Hz), 7.57-7.41 (4H, m), 5.35 (2H, s), 4.16 (2H, s), 3.56 (3H, s), 3.54 (2H, t, J=6.33 Hz), 2.38 (2H, t, J=6.58 Hz) 1.91 (2H, t, J=6.22 Hz).

EXAMPLE 95

[0658] Compound 95-A: N-(4-fluoro-2-methylsulfanyl-benzyl)-O-methyl-hydroxylamine Hydrochloride 2160

[0659] A 250 mL round bottom flask was charged with 4-fluoro-2-methylsulfanylbenzaldehyde (5.106 g, 30 mmol), O-methylhydroxylamine hydrochloride (3.758 g, 45 mmol), sodium acetate (6.124 g, 45 mmol), water (50 mL) and THF (75 mL). The reaction mixture was stirred at room temperature for 4 h and taken up into ether (300 mL), washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give 4-fluoro-2-methylsulfanyl-benzaldehyde-O-methyl-oxime (5.892 g, 99%) as a white solid.

[0660] To a stirred solution of 4-fluoro-2-methylsulfanyl-benzaldehyde-O-methyl-oxime (5.982 g, 29.58 mmol) in CH2Cl2 (30 mL) was added trifluoroacetic acid (30 mL) followed by triethylsilane (14 mL, 90 mmol). After stirring for 6 h, the reaction mixture was concentrated and the resulting residue was taken up in saturated aqueous NaHCO3 (100 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to give a viscous oil. The crude product was re-dissolved in anhydrous ether and 2M HCl/ether w (18 mL) was added. The resulting white solid was filtered and dried to yield the desired product as the HCl salt (6.666 g, 93% yield). 1HNMR (500 MHz, DMSO-d6) δ: 11.44 (1H, br s), 7.66-7.59 (1H, m), 7.24 (1H, dd, J=10.1, 2.1 Hz), 7.08 (1H, td, J=8.6, 2.4 Hz), 4.85 (2H, s), 3.82 (3H, s), 2.53 (3H, s). MS calcd for C9H13FNOS (M+H): 202.07; found: 202.07.

[0661] Compound 95-B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide 2161

[0662] To a stirred solution of N-(4-fluoro-2-methylsulfanyl-benzyl)-O-methyl-hydroxylamine hydrochloride (1.19 g, 5 mmol) and (2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.953 g, 5 mmol) in CH2Cl2 (20 mL) was added diisopropyethylamine (1.9 mL, 11 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was taken up into ether (150 mL), washed with 1N HCl (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give product as a white solid (1.77 g, 99%). 1HNMR (300 MHz, CDCl3) δ: 7.28-7.23 (1H, m), 6.90 (1H, dd, J=9.5, 2.6 Hz), 6.78 (1H, td, J=8.4, 2.6 Hz), 6.37 (1H, s), 4.88 (2H, s), 3.62 (3H, s), 2.44 (3H, s), 1.71 (6H, s). MS calcd for C16H18FNO5S Na (M+Na): 378.078; found: 378.18.

[0663] Compound 816: 4-{4-[(4-Fluoro-2-methylsulfanyl-benzyl)-methoxy-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2162

[0664] 2(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide was reacted with methanol to give 3-[(4-fluoro-2-methylsulfanyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a white sticky solid (0.0807 g, 88% yield). This was then reacted with paraformaldehyde and 4-amino butyric acid following the procedure described for Compound 810 to give the title compound as an orange solid (0.0360 g, 64% yield). 1HNMR (300 MHz, DMSO) δ: 12.10 (1H, bs), 11.35 (1H, bs), 7.30 (1H, m), 7.14 (1H, dd, J=12.44, 2.20 Hz), 6.97 (1H, td, J=8.41, 2.65 Hz), 4.86 (2H, s), 4.18 (2H, s), 3.69 (3H, s), 3.42 (2H, t, J=6.73 Hz), 2.50 (3H, t, J=1.83 Hz), 2.22 (2H, t, J=6.73 Hz), 1.78 (2H, m).

EXAMPLE 96

[0665] Compound 96-A: 2-(2,2-Dimethyl-5-oxo-[1,2]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methoxy-acetamide 2163

[0666] MCPBA (0.49 g, 1.41 mmol) was added to a solution of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide (0.50 g, 1.41 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temp for 4 h. After diluting with EtOAc and washing with saturated NaHSO4, NaHCO3 and brine, the organic phase was dried (sodium sulfate) and concentrated. The title compound was purified by flash chromatography eluting with 100% hexane to 100% EtOAc to give a white foamy solid (0.4789 g, 92% yield). 1HNMR (300 MHz, CDCl3) δ: 7.75 (1H, dd, J=8.42, 2.92 Hz), 7.49 (1H, dd, J=8.42, 5.12 Hz), 7.15 (1H, td, J=8.42, 2.93 Hz), 6.34 (1H, s), 4.88 (2H, d, J=8.05 Hz), 3.70 (3H, s), 2.76 (3H, s), 1.74 (6H, s).

[0667] Compound 817: 4-{4-[(4-Fluoro-2-methanesulfinyl-benzyl)-methoxy-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2164

[0668] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methoxy-acetamide was reacted with methanol using the procedure described for the synthesis of compound 90-C to yield 3-[(4-fluoro-2-methanesulfinyl-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a white sticky solid (0.1020 g, 100% yield). This crude was reacted with paraformaldehyde and 4-amino-butyric acid using the procedure described for Compound 810 to give the title compound as an orange solid (0.0360 g, 64% yield). 1HNMR (300 MHz, CDCl3) δ: 7.75 (1H, dd, J=8.05, 2.56 Hz), 7.48 (1H, dd, J=8.42, 4.76 Hz), 7.21 (1H, td, J=8.05, 2.56 Hz), 4.96 (2H, q), 4.19 (2H, s), 3.78 (3H, s), 3.58 (2H, td, J=6.95, 1.83 Hz), 2.82 (3H, s), 2.39 (2H, t, J=6.95 Hz), 1.97-1.92 (2H, m).

EXAMPLE 97

[0669] Compound 97-A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide 2165

[0670] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide was reacted with 2 equivalents of MCPBA using the method described for the synthesis of Compound 96-A to give the title compound as a white solid (0.263 g, 48% yield). 1HNMR (300 MHz, CDCl3) δ: 7.74 (1H, dd, J=8.06, 2.57 Hz), 7.60 (1H, dd, J=8.78, 5.12 Hz), 7.27 (1H, td, 7.68, 2.56 Hz), 6.45 (1H, s), 5.26 (2H, s), 3.81 (3H, s), 3.22 (3H, s), 1.74 (6H, s).

[0671] Compound 818: 4-{4-[(4-Fluoro-2-methanesulfonyl-benzyl)-methoxy-carbamoyl-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-butyric Acid 2166

[0672] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide was reacted with methanol using the procedure described for the synthesis of compound 90-C to yield 3-[(4-fluoro-benzyl)-methoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester as a white sticky solid (0.102 g, 100% yield). This was reacted with paraformaldehyde and 4-amino-butyric acid using the procedure described for Compound 810 to give the title compound as an orange solid (0.018 g, 14% yield). 1HNMR (300 MHz, CDCl3) δ: 7.78 (1H, dd, J=8.05, 2.56 Hz), 7.59-7.54 (1H, m), 7.36-7.29 (1H, m), 5.35 (2H, s), 4.25 (2H, s), 3.83 (3H, s), 3.60 (2H, t, J=6.95 Hz), 3.22 (3H, s), 2.43 (2H, t, J=6.95 Hz), 2.00-1.96 (2H, m).

EXAMPLE 98

[0673] Compound 819: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methylsulfanyl-benzyl)-methoxy-amide 2167

[0674] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine using the method described for the preparation of Compound 767 to give the title compound as a white solid (0.012 g, 18% yield). 1HNMR (300 MHz, CDCl3) δ: 7.27-7.22 (1H, m), 6.94 (1H, dd, J=9.51, 2.56 Hz), 6.83 (1H, td, J=8.42, 2.56 Hz), 4.95 (2H, s), 4.28 (2H, s), 3.97-3.75 (8H, m), 3.68 (3H, s), 3.40 (2H, t, J=5.85 Hz), 2.95 (2H, bs), 2.49 (3H, s).

EXAMPLE 99

[0675] Compound 820: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-benzyl)-methoxy-amide 2168

[0676] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and amino-ethanol using the method described for the synthesis of Compound 767 to give the title compound as a yellow oil (0.021 g, 56% yield). 1HNMR (300 MHz, MeOD) δ: 7.35-7.29 (1H, m), 7.08 (1H, d, J=8.05 Hz), 6.92-6.84 (1H, m), 4.99 (2H, s), 4.39 (2H, s), 3.76-3.70 (5H, m), 3.63-360 (2H, m), 2.51 (3H, s).

EXAMPLE 100

[0677] Compound 821: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methanesulfinyl-benzyl)-methoxy-amide 2169

[0678] 2-(2,2-Dimethyl-5-oxo-[1,2]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfinyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine using the method described for the preparation of Compound 767 to give the title compound as a yellow solid (0.045 g, 99% yield). 1HNMR (300 MHz, MeOD) δ: 7.27 (1H, dd, J=8.42, 2.56 Hz), 7.62 (1H, dd, J=8.79, 5.49 Hz), 7.32 (1H, td, J=8.41, 2.93 Hz), 5.06 (2H, s), 4.03-3.92 (4H, m), 3.83 (3H, s), 3.80-3.63 (4H, m), 3.51-3.46 (2H, m), 3.19 (2H, bs), 2.84 (3H, s).

EXAMPLE 101

[0679] Compound 822: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methanesulfinyl-benzyl)-methoxy-amide 2170

[0680] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and amino-ethanol using the method described for the preparation of compound 767 to give the title compound as a colorless oil (0.015 g, 40% yield). 1HNMR (300 MHz, MeOD) δ: 7.71 (1H, dd, J=8.78, 2.93 Hz), 7.61 (1H, dd, J=8.78, 5.12 Hz), 7.31 (1H, td, J=8.42, 2.56 Hz), 5.05 (2H, d, J=9.15 Hz), 4.38 (2H, s), 3.81 (3H, s), 3.74 (2H, t, J=5.12 Hz), 3.60 (2H, t, J=5.49 Hz), 2.84 (3H, s).

EXAMPLE 102

[0681] Compound 823: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-methanesulfonyl-benzyl)-methoxy-amide 2171

[0682] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and 2-morpholin-4-yl-ethylamine using the method described for the preparation of compound 767 to give the title compound as a white solid (0.021 g, 45% yield). 1HNMR (300 MHz, MeOD) δ: 7.75 (1H, dd, J=8.78, 2.93 Hz), 7.63-7.54 (2H, m), 5.34 (2H, s), 4.29 (2H, s), 4.01-3.99 (2H, m), 3.84-3.81 (2H, m), 3.77 (3H, s), 3.63-3.45 (6H, m), 3.39 (3H, s), 3.16-3.08 (2H, m).

EXAMPLE 103

[0683] Compound 824: 4-Hydroxy-1-(2-hydroxy-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-2-methanesulfonyl-benzyl)-methoxy-amide 2172

[0684] 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methanesulfonyl-benzyl)-N-methoxy-acetamide was reacted with paraformaldehyde and amino-ethanol using the method described for the preparation of compound 767 to give the title compound as a colorless oil (0.100 g, 25% yield). 1HNMR (300 MHz, MeOD) δ: 7.77 (1H, dd, J=8.42, 2.56 Hz), 7.66 (1H, dd, J=8.79, 5.13 Hz), 7.45 (1H td, J=8.42, 2.93 Hz), 5.41 (2H, s), 4.46 (2H, s), 3.84 (3H, s), 3.76 (2H, t, J=5.12 Hz), 3.63 (2H, t, J=5.13 Hz), 3.28 (3H, s).

EXAMPLE 104

[0685] Compound 104-A: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide 2173

[0686] To a stirred suspension of 3,4-dichlorobenzylamine (17.6 mg, 0.1 mmol) and resin bound morpholine (100 mg, 2.5-4.0 mmol/1 g) in CH2Cl2 (2 mL) was added (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (20 mg, 0.11 mmol) and the mixture stirred for 1 h. The mixture filtered and the filtrate concentrated to give the product as a white solid (33 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.39 (2H, m), 7.15 (1H, m), 6.60 (1H, s), 5.89 (1H, s), 4.50 (2H, d, J=6.0 Hz), 1.74 (6H, s). MS calcd for C14H14Cl2NO4 [M+H]+: 330.03; found: 330.1

[0687] Compound 104-B: Methylene-(2-morpholin-4-yl-ethyl)-amine 2174

[0688] 2-Aminoethanol (0.8712 g, 10.0 mmol) and paraformaldehyde (0.3 g, 10.0 mmol) were stirred in methanol (50 mL) at 55° C. until the solids dissolved (approximately 20 min). The solution was cooled and used without further purification

[0689] Compound 825: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid 3,4-dichloro-benzylamide 2175

[0690] A mixture of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (66 mg, 0.2 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.5 mL, 0.3 mmol) was heated at 70° C. for 1.5 h. The reaction mixture was then cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as eluent. The fractions containing the product were combined and concentrated to give a white powder (23.3 mg, 22% yield). 1H NMR (500 MHz, DMSO) δ: 9.50 (1H, br s), 8.08 (1H, t, J=6.2 Hz), 7.59 (1H, d, J=8.2 Hz), 7.53 (1H, d, J=1.8 Hz), 7.28 (1H, dd, J=8.2, 1.8 Hz), 4.42 (2H, d, J=6.1 Hz), 4.04 (2H, s), 4.02-3.95 (2H, m), 3.81-3.77 (2H, m), 3.73-3.37 (6H, m), 3.15-3.06 (2H, m). HRMS calcd for C18H22Cl2N3O4 (M+H): 414.09875; found: 414.0987.

EXAMPLE 105

[0691] Compound 105-A: N-(3,5-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide 2176

[0692] To a stirred suspension of 3,4-difluorobenzylamine (0.43 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5-4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture stirred for 1 h. The mixture was filtered and the filtrate concentrated to give the product as a white solid (85 mg, 95% yield). MS calcd for C14H13F2NO4Na (M+Na): 320.29; found: 320.27.

[0693] Compound 826: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid 3,5-difluoro-benzylamide 2177

[0694] A mixture of N-(3,5-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (60 mg, 0.2 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.25 mL, 0.25 mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a white powder (22 mg, 22% yield). 1H NMR (500 MHz, DMSO) δ: 11.95 (1H, br s), 9.54 (1H, br s), 8.08 (1H, t, J=6.1 Hz), 7.12-7.08 (1H, m), 7.00-6.94 (2H, m), 4.45 (2H, d, J=6.1 Hz), 4.05 (2H, s), 4.02-3.94 (2H, m), 3.83-3.77 (2H, m), 3.69-3.38 (6H, m), 3.16-3.05 (2H, m). HRMS calcd for C18H20F2N3O4 (M−H): 380.1422; found: 380.1422.

EXAMPLE 106

[0695] Compound 106-A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide 2178

[0696] To a stirred suspension of 4-fluorobenzylamine (37.5 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5-4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture shaken for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (84.4 mg, 100% yield). MS calc for C14H14FNO4 (M+Na): 302.29; found: 302.29.

[0697] Compound 827: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid 4-fluoro-benzylamide 2179

[0698] A mixture of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide (77 mg, 0.275 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.5 mL, 0. mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a pale yellow powder (42 mg, 32% yield). 1H NMR (500 MHz, DMSO) δ: 11.92 (1H, br s), 9.48 (1H, br s), 7.95 (1H, t, J=4.9 Hz), 7.34-7.31 (2H, m), 7.17-7.13 (2H, m), 4.42 (2H, d, J=4.9 Hz), 4.04 (2H, s), 4.01-3.95 (2H, m), 3.80-3.77 (2H, m), 3.66-3.39 (6H, m), 3.15-3.06 (2H, m). HRMS calcd for C18H21FN3O4 (M+H): 362.1516; found: 362.1505.

EXAMPLE 107

[0699] Compound 107-A: N-(3,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide 2180

[0700] To a stirred suspension of 3,4-difluorobenzylamine (0.43 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5-4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2C2 (3 mL) and the mixture stirred for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (81.8 mg, 92% yield). MS calcd for C14H13F2NO4Na (M+Na): 320.29; found: 320.27.

[0701] Compound 828: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid 3,4-difluoro-benzylamide 2181

[0702] A mixture of N-(3,4-difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide (58 mg, 0.195 mmol) and a 0.2 mmol solution of methylene-(2-morpholin-4-yl-ethyl)-amine in methanol (1.1 mL, 0.22 mmol) was heated at 70° C. for 1 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC using methanol/water (0.1% TFA) as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a hydroscopic yellow powder (30 mg, 31% yield). 1H NMR (500 MHz, DMSO) δ: 11.95 (1H, br s), 9.56 (1H, br s), 8.03 (1H, t, J=6.1 Hz), 7.41-7.30 (2H, m), 7.15-7.12 (1H, m), 4.41 (2H, d, J=6.1 Hz), 4.04 (2H, s), 4.02-3.93 (2H, m), 3.82-3.77 (2H, m), 3.65-3.51 (4H, m), 3.45-3.41 (2H, m), 3.15-3.06 (2H, m). HRMS calcd for C18H20F2N3O4 (M+H): 380.1422; found: 380.1424.

EXAMPLE 108

[0703] Compound 108-A: (3,4-Dichloro-benzyl)-isopropyl-amine; Compound Hydrochloride 2182

[0704] To a stirred solution of 3,4-dichlorobenzaldehyde (3.50 g, 20 mmol) and isopropylamine (2.40 g, 40 mmol) in methanol (20 mL) was added a freshly prepared solution zinc chloride (1.36 g, 10 mmol) and sodium cyanoborohydride (1.25 g, 20 mmol) in methanol (50 mL) at room temperature. The resulting clear reaction mixture was stirred overnight, then concentrated. The residue was taken up into aq NaOH (0.2N, 100 mL), extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give viscous yellow oil. The residue was dissolved into ether and converted to hydrochloride salt (4.75 g, 93% yield). 1H NMR (500 MHz, DMSO) δ: 9.54 (2H, s), 8.00 (1H, d, J=2 Hz), 7.70 (1H, d, J=8 Hz), 7.65 (1H, m), 4.13 (2H, t, J=6 Hz), 3.25-3.22 (1H, m), 1.30 (3H, d, J=6.5 Hz). MS calcd for C10H14Cl2N (M+H): 218.04; found: 218.04.

[0705] Compound 108-B: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-isopropyl-acetamide 2183

[0706] To a stirred mixture of (3,4-dichloro-benzyl)-isopropyl-amine; compound hydrochloride (260 mg, 1.024 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (190 mg, 1.0 mmol) in CH2Cl2 (20 mL) at room temperature was added diisopropylethylamine (350 μL, 2.0 mmol). After 30 min, the reaction mixture was diluted with ethyl acetate (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give viscous yellow oil. Purification on a silica gel column using hexanes/ethyl acetate (3:2) gave pure product as a viscous yellow oil (372 mg, 93% yield). 1H NMR (500 MHz, CDCl3) δ: 7.41-7.30 (2H, m), 7.11 (0.67H, d, J=10.1 Hz), 7.10 (0.33H, d, J=10.1 Hz), 6.22 (0.67H, s), 5.87 (0.33H, s), 4.87-4.81 (0.33H, m), 4.51 (1.34H, s), 4.47 (0.66H, s), 4.30-4.24 (0.67H, m), 1.73 (4H, s), 1.71 (2H, s), 1.21 (4H, d, J=6.2 Hz), 1.11 (2H, d, J=6.7 Hz). MS calcd for C17H20Cl2NO4 (M+H): 372.24; found: 372.18.

[0707] Compound 829: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-isopropyl-amide 2184

[0708] Compound 829 was prepared according to the methods described in the previous examples to yield 217 mg (47% yield) of the title compound as the corresponding TFA salt. 1H NMR (300 MHz, DMSO) δ: 11.02 (1H, s), 9.62 (1H, br s), 7.57 (1H, d, J=8.1 Hz), 7.48 (1H, s), 7.22 (1H, d, J=7.7 Hz), 4.55 (2H, s), 4.33-4.24 (1H, br m), 4.11 (2H, s), 4.02-3.96 (2H, br m), 3.77 (2H, s), 3.64-3.54 (4H, m), 3.42 (2H, br s), 3.19-3.04 (2H, br m), 1.12 (6H, d, J=6.6 Hz). HRMS calcd for C21H28Cl2N3O4 (M+H): 456.1457; found: 456.1470

EXAMPLE 109

[0709] Compound 109-A: (3,4-Dichloro-benzyl)-(3-phenyl-propyl)-amine; Hydrochloride 2185

[0710] To a stirred solution of 3,4-dichlorobenzaldehyde (3.50 g, 20 mmol) and 3-phenylpropylamine (5.40 g, 40 mmol) in methanol (20 mL) was added a freshly prepared solution of zinc chloride (1.36 g, 10 mmol) and sodium cyanoborohydride (1.25 g, 20 mmol) in methanol (50 mL) at room temperature. The resulting clear reaction mixture was stirred overnight, then concentrated. The residue was taken up into aq NaOH (0.2N, 100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a viscous yellow oil. The residue was purified on silica gel column using 30-40% ethyl acetate in hexanes. The product was dissolved in Et2O and treated with HCl (in ether) to form the corresponding hydrochloride salt as a precipitate which was isolated by filtration (5.40 g, 98% yield). 1H NMR (500 MHz, DMSO) δ: 9.66 (2H, s), 7.94 (1H, d, J=2.0 Hz), 7.69 (1H, d, J=8.5 Hz), 7.59 (1H, m), 7.30-7.18 (5H, m), 4.13 (2H, s), 2.89-2.5 (2H, br s), 2.65 (2H, t, J=7.5 Hz), 1.99 (2H, m). MS calcd for C16H17C2N (M+1): 294.08; found: 294.08.

[0711] Compound 109-B: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-phenyl-propyl)-acetamide 2186

[0712] To a stirred mixture of (3,4-dichloro-benzyl)-(3-phenyl-propyl)-amine; hydrochloride (330 mg, 1.0 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (206 mg, 1.08 mmol) in CH2Cl2 (10 mL) at room temperature was added diisopropylethylamine (386 μL, 2.2 mmol). After 30 min, the reaction mixture was diluted with ether (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the desired amide (447 mg, 100% yield) as a viscous oil. 1H NMR (300 MHz, CDCl3) δ: 7.41-6.94 (8H, m), 6.08 (0.66H, s), 6.01 (0.34H, s), 4.53 (1.33H, s), 4.48 (0.67H, s), 3.41 (0.67H, t, J=7.5 Hz), 3.26 (1.33H, t, J=7.8 Hz), 2.61 (2H, t, J=7.3 Hz), 1.95-1.85 (2H, m), 1.71 (6H, s). MS calcd for C23H23Cl2NO4Na (M+Na): 470.09. Found: 470.09

[0713] Compound 830: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-(3-phenyl-propyl)-amide 2187

[0714] Compound 830 was prepared according to the methods described in the previous examples to yield 207 mg (38% yield) of the title compound as the corresponding TFA salt. 1HNMR (500 MHz, DMSO-d6) δ: 11.04 (1H, s), 9.64 (1H, s), 7.59 (1H, d, J=8.2 Hz), 7.50 (1H, s), 7.28-7.21 (3H, m), 7.17-7.11 (3H, m), 4.63 (2H, s), 4.07 (2H, s), 4.04-3.96 (2H, br s), 3.79-3.73 (2H, br s), 3.68-3.51 (4H, br m), 3.46-3.35 (4H, br m), 3.28 (1H, br s), 3.16-3.05 (2H, br s), 1.88-1.71 (2H, br s). HRMS calcd for C27H32Cl2N3O4 (M+H): 532.1770; found: 532.1758.

EXAMPLE 110

[0715] Compound 110-A: (3,4-Dichloro-benzyl)-(3-methyl-butyl)-amine Hydrochloride 2188

[0716] To a stirred solution of 3,4-dichlorobenzaldehyde (3.50 g, 20 mmol) and 3-methylbutylamine (2.62 g, 40 mmol) in methanol (20 mL) was added a freshly prepared solution zinc chloride (1.36 g, 10 mmol) and sodium cyanoborohydride (1.25 g, 20 mmol) in methanol (50 mL) at room temperature. The resulting clear reaction mixture was stirred overnight, then concentrated. The residue was taken up into aq NaOH (0.2N, 100 mL), extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give viscous yellow oil. The residue was purified on silica gel column using 1:4, 3:7 and 2:3 ethyl acetate/hexanes as eluent. The product was dissolved in Et2O and treated with HCl (in ether) to form the corresponding hydrochloride salt as a precipitate which was isolated by filtration (4.924 g, 73% yield). 1H NMR (500 MHz, DMSO) δ: 9.57 (2H, s), 7.95 (1H, d, J=2 Hz), 7.70 (1H, d, J=8.5 Hz), 7.60 (1H, m), 4.13 (2H, s), 2.87-2.85 (2H, br m), 1.63-1.54 (3H, m), 0.86 (6H, d, J=6.5 Hz). MS calcd for C12H18Cl2N (M+H): 246.08; found: 246.31.

[0717] Compound 110-B: N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-methyl-butyl)-acetamide 2189

[0718] To a stirred mixture of (3,4-dichloro-benzyl)-(3-methyl-butyl)-amine hydrochloride (283 mg, 1.0 mmol) and (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (206 mg, 1.08 mmol) in CH2Cl2 (10 mL) at room temperature was added diisopropylethylamine (386 μL, 2.2 mmol). After 30 min, the reaction mixture was diluted with ether (50 mL), washed with dilute aqueous HCl (1×5 mL), water (1×10 mL), and saturated aq. NaCl (1×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give viscous yellow oil. Purification on a Silica gel column using hexanes/ethyl acetate (20-40% EtOAc) as the eluent gave the title compound as a viscous yellow oil (400 mg, 100% yield). 1H NMR (500 MHz, CDCl3) δ: 7.42-7.26 (2H, m), 7.11 (0.67H, d, J=8.2 Hz), 7.01 (0.33H, d, J=8.2 Hz), 6.14 (0.67H, s), 6.00 (0.33H, s), 4.56 (1.34H, s), 4.52 (0.66H, s), 3.39-3.36 (0.67H, m), 3.29-3.26 (1.33H, m), 1.74 (4H, s), 1.70 (2H, s), 1.59-1.50 (1H, m), 1.47-1.42 (2H, m), 0.90-0.88 (6H, m). MS calcd for C19H24Cl2NO4 (M+H): 400.1; found: 400.07.

[0719] Compound 831: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-(3-methyl-butyl)-amide 2190

[0720] Compound 831 was prepared according to the methods described in the previous examples to yield 213 mg (38% yield) of the title compound as the corresponding TFA salt. 1HNMR (500 MHz, DMSO-d6) δ: 11.08 (1H, s), 9.73 (1H, s), 7.61 (1H, d, J=8.2 Hz), 7.52 (1H, s), 7.25 (1H, br s), 4.61 (2H, s), 4.11 (2H, s), 4.05-3.95 (2H, br m), 3.78 (2H, br s), 3.70-3.48 (4H, m), 3.46-3.31 (4H, br m), 3.26 (1H, br s), 3.17-3.02 (2H, br m), 1.57-1.27 (3H, br m), 0.80 (6H, br s). HRMS calcd for C23H32Cl2N3O4 (M+H): 484.177; found: 484.1793.

EXAMPLE 111

[0721] Compound 832: 4-Hydroxy-5-oxo-1-[2-(tetrahydro-pyran-4-yl)-ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2191

[0722] A mixture of paraformaldehyde (18 mg, 0.563 mmol) and 4-(2-aminoethyl)tetrahydropyran (65 mg, 0.5 mmol) in anhydrous methanol (3 mL) was warmed to 60° C. To the resulting clear homogeneous solution was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (172 mg, 0.5 mmol) and stirring continued for 18 h at 60° C. and an additional 6 h at room temperature. The crude reaction mixture was purified by preparative HPLC on a C18 column using water/methanol (0.1% TFA) as the eluent. The fractions containing the desired product were combined, the methanol removed under vacuum and the remaining aqueous solution extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as a white solid (164 mg, 77% yield).

[0723] 1 HNMR (500 MHz, CDCl3) δ: 10.15 (1H, br s), 7.41 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.60 (2H, s), 4.13 (2H, s), 3.93 (2H, dd, J=11, 3.7 Hz), 3.54 (2H, t, J=7.1 Hz), 3.34 (2H, t, J=11.9 Hz), 3.03 (3H, s), 1.65-1.24 (7H, m). HRMS calcd for C20H25Cl2N2O4 (M+H): 427.1191; found: 427.1179.

EXAMPLE 112

[0724] Compound 833: 4-Hydroxy-5-oxo-1-(2-thiomorpholin-4-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2192

[0725] A mixture of paraformaldehyde (56 mg, 1.75 mmol) and 1-(2-aminoethyl)thiomorpholine (219 mg, 1.5 mmol) in anhydrous methanol (5 mL) was warmed to 60° C. To the resulting clear homogeneous solution was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (516 mg, 1.5 mmol) and stirring continued for 18 h at 60° C. and an additional 6 h at room temperature. The crude reaction mixture was purified on C18 column using water/acetonitrile (contains 0.05% TFA) as the eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the corresponding TFA salt of the title compound as a white solid (555 mg, 66% yield). 1HNMR (500 MHz, DMSO-d6) δ: 11.10 (1H, s), 9.53 (1H, br s), 7.62 (1H, d, J=8.2 Hz), 7.50 (1H, s), 7.28-7.20 (1H, br s), 4.59 (2H, s), 4.12 (2H, s), 3.85-3.73 (4H, m), 3.45-3.37 (2H, br s), 3.25-3.14 (2H, br m), 3.02-2.95 (2H, br m), 2.94-2.85 (4H, br m). HRMS calcd for C19H24Cl2N3O3S: 444.0915; found: 444.0909.

EXAMPLE 113

[0726] Compound 834: 4-Hydroxy-1-[2-(2-hydroxy-ethylamino)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2193

[0727] A mixture of paraformaldehyde (18 mg, 0.563 mmol) and 2-(2-aminoethylamino)ethanol (54 mg, 0.5 mmol) in anhydrous methanol (3 mL) was warmed to 60° C. To the resulting clear homogeneous solution was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (175 mg, 0.5 mmol) and the mixture stirred for 30 min at 60° C. The crude product was purified by preparative HPLC on a C18 column using water/methanol (0.1% TFA) as the eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the corresponding TFA salt of the title compound as a white powder (156 mg, 61%. yield). 1HNMR (500 MHz, CDCl3) δ: 9.08 (2H, br s), 7.39 (1H, d, J=8.2 Hz), 7.32 (1H, s), 7.08 (1H, d, J=8.2 Hz), 4.55 (2H, s), 4.24 (2H, s), 3.93-3.80 (5H, br m), 3.40 (2H, br s), 3.21 (2H, br s), 2.98 (3H, s). HRMS calcd for C17H22C2N3O4 (M+H): 402.0987; found: 402.1311

EXAMPLE 114

[0728] Compound 835: 4-Hydroxy-5-oxo-1-[2-(1-oxo-1λ4-thiomorpholin-4-yl)-ethyl]-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2194

[0729] To a stirred solution of 4-hydroxy-5-oxo-1-(2-thiomorpholin-4-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (108 mg, 0.243 mmol) in water (20 mL) was added 30% hydrogen peroxide (0.3 mL). After stirring overnight the reaction mixture was lyophilized to give the title compound as a white powder. 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.5 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.59 (2H, s), 4.28 (2H, s), 3.89 (2H, t, J=5.8 Hz), 3.74-3.70 (2H, m), 3.63 (2H, t, J=11.9 Hz), 3.29-3.24 (2H, m), 3.18 (2H, t, J=11.9 Hz), 3.07-2.99 (2H, m), 3.01 (3H, s). HRMS calcd for C19H24Cl2N3O4S (M+H): 460.0865; found: 460.0884.

EXAMPLE 115

[0730] Compound 836: [(2-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-ethyl)-(2-hydroxy-ethyl)-amino]-acetic Acid Methyl Ester 2195

[0731] To a stirred warm (approximately 60° C.) solution of 2-(2-aminoethylamino)ethanol (104 mg, 1.0 mmol) and paraformaldehyde (32 mg, 1.0 mmol) in anhydrous methanol was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (344 mg, 1 mmol). After 30 min, the mixture was cooled to room temperature and methyl bromoacetate (104 μL, 1.1 mmol) followed by K2CO3 was added. The resulting suspension was stirred overnight at 40° C., then filtered and purified by preparative HPLC on a C18 column using water/methanol (0.1% TFA) as the eluent. The fractions containing the desired product were combined, concentrated and lyophilized to yield the corresponding TFA salt of the title compound as a white powder (248 mg, 42% yield). 1HNMR (500 MHz, CDCl3) δ: 7.38 (1H, d, J=8.2 Hz), 7.32 (1H, s), 7.07 (1H, d, J=8 Hz), 4.56 (3H, s), 4.20 (2H, s), 4.01 (2H, s), 3.86-3.78 (4H, m), 3.59-2.55 (2H, m), 3.38-3.34 (2H, m), 3.01-2.94 (4H, m), 2.73 (3H, s). HRMS calcd for C20H26Cl2N3O5 (M+H): 474.1199; found: 474.1295.

EXAMPLE 116

[0732] Compound 837: 4-{4-[(3,4-Dichloro-benzyl)-methyl-carbamoyl]-3-hydroxy-2-oxo-2,5-dihydro-pyrrol-1-yl}-piperidine-1-carboxylic Acid Ethyl Ester 2196

[0733] To a stirred warm (60° C.) solution of ethyl 4-amino-1-piperidinecarboxylate (86.1 mg, 0.5 mmol) and paraformaldehyde (16 mg, 0.5 mmol) in methanol (2 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (175 mg, 0.5 mmol). After 2 h, the reaction mixture was cooled and purified using preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as the eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (64 mg, 27% yield). 1HNMR (500 MHz, CDCl3) δ: 10.16 (2H, br s), 7.40 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.10 (1H, d, J=8.0 Hz), 4.59 (2H, s), 4.34-4.18 (3H, m), 4.13 (2H, q, J=7.0 Hz), 4.09 (2H, s), 2.06 (2H, s), 2.87-2.80 (2H, br m), 1.82-1.76 (2H, br m), 1.63-1.55 (2H, m), 1.25 (3H, t, J=7.0 Hz). MS calcd for C21H26Cl2N3O5 (M+H): 470.36; found: 470.02.

EXAMPLE 117

[0734] Compound 838: 4-Hydroxy-5-oxo-1-piperidin-3-yl-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2197

[0735] To a stirred warm (60° C.) solution of 3-aminopiperidine dihydrochloride (150 mg, 0.867 mmol), paraformaldehyde (34 mg, 1.04 mmol) and triethylamine (0.3 mL, 2.14 mmol) in methanol (5 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (300 mg, 0.872 mmol). After 1 h, the reaction mixture was cooled and purified by preparative HPLC using a C18 column and water/methanol (0.001 mM HCl) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the corresponding hydrochloride salt of the title compound as a white powder (162 mg, 43% yield). 1HNMR (500 MHz, DMSO-d6) δ: 11.06 (1H, br s), 9.35 (1H, d, J=10.1 Hz), 9.10-8.99 (1H, m), 7.62 (1H, d, J=8.2 Hz), 7.52 (1H, s), 7.29-7.20 (1H, br s), 4.59 (2H, d, JAB=15.7 Hz), 4.34-3.88 (4H, m), 3.40-2.73 (6H, m), 1.90-1.74 (4H, m). HRMS calcd for C18H22Cl2N3O3 (M+H): 398.1038; found: 398.1042.

EXAMPLE 118

[0736] Compound 839: 4-Hydroxy-5-oxo-1-(2,2,2-trifluoro-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2198

[0737] To a stirred warm (60° C.) solution of 2,2,2-trifluoroethylamine hydrochloride (100 mg, 1.0 mmol) paraformaldehyde (32 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) in methanol (5 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (344 mg, 1.0 mmol). After 24 h, the reaction mixture was cooled and purified by preparative HPLC using a C18 column and water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (81.4 mg, 21% yield). 1HNMR (500 MHz, CDCl3) δ: 10.05 (1H, br s), 7.42 (1H, d, J=8.2 Hz), 7.36 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.60 (2H, s), 4.32 (2H, s), 4.10 (2H, q, 8.9 Hz), 3.04 (3H, s). HRMS calcd for C15H12Cl2F3N2O3 (M−H): 395.0177; found: 395.0192.

EXAMPLE 119

[0738] Compound 840: 4-Hydroxy-5-oxo-1-piperidin-4-yl-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2199

[0739] To a stirred warm (60° C.) solution of 4-aminopiperidine (36 mg, 0.25 mmol) and paraformaldehyde (8 mg, 0.25 mmol) in methanol (1.5 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (93 mg, 0.27 mmol). After 1 h, the reaction mixture was cooled and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as the eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the corresponding TFA salt of the title compound as white powder (46.3 mg, 36% yield). 1HNMR (300 MHz, CDCl3) δ: 9.65 (1H, br s), 9.17 (1H, br s), 7.42 (1H, d, J=8.1 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8.1 Hz), 4.60 (2H, s), 4.40-4.29 (1H, m), 4.20 (2H, s), 3.65-3.52 (2H, m), 3.10-2.82 (2H, m), 3.04 (3H, s), 2.43-1.97 (4H, m). HRMS calcd for C18H?Cl2N3O3 (M+H): 398.1038; found: 398.1044.

EXAMPLE 120

[0740] Method for the Preparation of Compounds 857-862

[0741] The general method for the preparation of compounds 857-862 is illustrated in Scheme XVI.

[0742] Compound 120-A: 3,5-Dichlorobenzyl-methyl Amine Hydrochloride 2200

[0743] To a stirred solution of 3,5-dichlorobenzaldehyde (9.0 g, 51 mmol) in methanol (100 mL) was added methanolic methylamine (2M, 100 mL, 200 mmol) and the resulting mixture stirred for 2 h at room temperature. To this was added a solution of ZnCl2 (3.402 g, 25 mmol) slowly and NaCNBH3 (3.142 g, 50 mmol) in methanol (100 mL). After 24 h, the reaction mixture was concentrated, and the resulting residue taken up in dilute aq NaOH (0.5 N, 200 mL) and extracted with CH2Cl2 (5×50 mL). The combined CH2Cl2 extracts were dried over anhydrous Na2SO4, filtered and concentrated to give a yellow viscous liquid. The crude product was dissolved in ether (200 mL) to which was added 29 mL of 2N HCl (in ether). The resulting white 3,5-dichlorobenzyl-methylamine hydrochloride salt was filtered and dried under vacuum to give 11.20 g (97% yield) of product. 1HNMR (300 MHz, DMSO-d6) δ: 9.48 (2H, s), 7.68 (3H, s), 4.13 (2H, s), 2.50 (3H, s). MS calcd for C8H10C12N (M+H): 190.02; found: 190.05.

[0744] Compound 120-B: N-(3,5-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide 2201

[0745] To a stirred solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.96 g, 5 mmol) in CH2Cl2 (20 mL) was added a solution of 3, 5-dichlorobenzyl-methylamine hydrochloride (1.133 g, 5 mmol) and Et3N (2 mL) in CH2Cl2 (25 mL). The addition flask was rinsed with CH2Cl2 (5 mL) and added to the reaction mixture. After 2 h, the reaction mixture was concentrated and the resulting residue was triturated with ether (100 mL), filtered and concentrated to give the desired product as a viscous brown oil (1.70 g, 100% yield). 1HNMR (300 MHz, CDCl3) δ: 7.30-7.27 (1H, m), 7.16 (1.5H, br s), 7.06 (0.5H, s), 6.17 (0.66H, s), 6.07 (0.34H, s), 4.59 (1.33H, s), 4.53 (0.67H, s), 3.03 (2H, s), 2.97 (1H, s), 1.74 (4H, s), 1.70 (2H, s).

[0746] General Procedure for the Preparation of Compounds 857-862

[0747] As illustrated in Scheme XVI, a 0.2 mM solution of amine, 1-7, and paraformaldehyde in methanol (1 mL) are added to 0.1 mM solution of N-(3,5-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide in methanol (2 mL). The mixture is warmed to 60° C. and kept at this temperature until the reaction is complete (1-24 h). The reaction mixture is purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized.

[0748] Compound 841: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide 2202

[0749] Reaction time 1 h. Obtained 47 mg (53% yield). 1HNMR (500 MHz, CDCl3) δ: 7.29 (1H, s), 7.13 (2H, s), 4.59 (2H, s), 4.16 (2H, s), 3.11 (3H, s), 3.03 (3H, s). HRMS calcd for C14H15Cl2N2O3 (M+H): 329.04598; found: 329.0456.

[0750] Compound 842: 1-Ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,5-dichloro-benzyl)-methyl-amide 2203

[0751] Reaction time 1 h. Obtained 39.8 mg (44% yield). 1HNMR (500 MHz, CDCl3) δ: 7.29 (1H, s), 7.14 (2H, s), 4.60 (2H, s), 4.17 (2H, s), 3.36 (2H, q, J=7.3 Hz), 3.04 (3H, s), 1.22 (3H, t, J=7.3 Hz). HRMS calcd for C15H17Cl2N2O3 (M+H): 343.0616; found: 343.0609.

[0752] Compound 843:1-(2-Fluoro-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,5-dichloro-benzyl)-methyl-amide 2204

[0753] Reaction time 24 h. Obtained 13.6 mg (14% yield). 1HNMR (500 MHz, CDCl3) δ: 7.29 (1H, s), 7.14 (2H, s), 4.65 (1H, t, J=4.6 Hz), 4.59 (2H, s), 4.56 (1H, t, J=4.6 Hz), 4.33 (2H, s), 3.84 (1H, t, J=4.6 Hz), 3.78 (1H, t, J=4.6 Hz), 3.04 (3H, s). HRMS calcd for C15H14Cl2FN2O3 (M−H): 359.0366; found: 359.0374.

[0754] Compound 844: 4-Hydroxy-5-oxo-1-piperidin-4-yl-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,5-dichloro-benzyl)-methyl-amide 2205

[0755] Reaction time 1 h. Obtained 42.3 mg (41% yield) as the corresponding TFA salt. 1HNMR (500 MHz, CDCl3) δ: 9.66 (1H, s), 9.17 (1H, s), 7.30 (1H, s), 7.14 (2H, s), 4.60 (2H, s), 4.37 (1H, m), 4.21 (2H, s), 3.56-3.53 (2H, m), 3.08-3.03 (2H, m), 3.06 (3H, s), 2.27-2.19 (2H, m), 2.03-1.97 (2H, m). HRMS calcd for C18H22Cl2N3O3 (M+H): 398.1038; found: 398.1040.

[0756] Compound 845: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide 2206

[0757] Reaction time 1 h. Obtained 61.1 mg (56% yield) as the corresponding TFA salt. 1HNMR (500 MHz, CDCl3) δ: 9.15 (1H, br s), 7.29 (1H, s), 7.12 (2H, s), 4.57 (2H, s), 4.28 (2H, s), 4.06-3.72 (8H, m), 3.45-3.37 (2H, br s), 3.00 (3H, s), 2.98-2.91 (2H, m). HRMS calcd for C19H24Cl2N3O4 (M+H): 428.1144; found: 428.1135.

[0758] Compound 846: 1-(2-Amino-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,5-dichloro-benzyl)-methyl-amide 2207

[0759] 1 HNMR (500 MHz, DMSO-d6) δ: 11.01 (1H, s), 7.53 (1H, s), 7.32 (2H, s), 4.60 (2H, s), 4.10 (2H, s), 3.64 (2H, t, J=5.35 Hz), 3.43 (3H, br s), 3.07-3.00 (4H, m). HRMS calcd for C15H18Cl2N3O3 (M+H): 358.0725; found: 358.0719.

EXAMPLE 121

[0760] Compound 847: 4-Hydroxy-1-(2-(dimethylsulfamidoyl-methyl-amino)-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2208

[0761] To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (150 mg, 0.367 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by dimethylsulfamoyl chloride (53 μL, 0.5 mmol) at room temperature. After 4 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white solid (134.3 mg, 62% yield). 1HNMR (500 MHz, CDCl3) δ: 10.38 (1H, br s), 7.42 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.58 (2H, s), 4.29 (2H, s), 3.69 (2H, t, J=5.8 Hz), 3.43 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.81 (3H, s), 2.73 (6H, s). HRMS calcd for C18 H25Cl2N4O5S (M+H): 479.0923; found: 479.0941.

EXAMPLE 122

[0762] Compound 848: 4-Hydroxy-1-[2-(methanesulfonyl-methyl-amino)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2209

[0763] To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (150 mg, 0.367 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by methanesulfonyl chloride (38 μL, 0.5 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (21.3 mg, 13% yield). 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.58 (2H, s), 4.29 (2H, s), 3.71 (2H, t, J=5.8 Hz), 3.38 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.89 (3H, s), 2.78 (3H, s). HRMS calcd for C17H22Cl2N3O5S (M+H): 450.0657; found: 450.0658.

EXAMPLE 123

[0764] Compound 849: 1-[2-(1,3-Dimethyl-ureido)-ethyl]-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2210

[0765] To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (155 mg, 0.379 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by methyl isocyanate (29 μL, 0.5 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol (0.1% TFA) as eluent. The fractions containing the product were combined, concentrated and lyophilized to give the title compound as a white powder (107.6 mg, 52% yield). 1HNMR (500 MHz, CDCl3) δ: 11.56 (1H, br s), 7.41 (1H, d, J=8.2 Hz), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.66 (1H, br s), 4.57 (2H, s), 4.28 (2H, s), 3.62 (2H, t, J=5.8 Hz), 3.56 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.89 (3H, s), 2.70 (3H, s). HRMS calcd for C18H23Cl2N4O4 (M+H): 429.1096; found: 429.1082.

EXAMPLE 124

[0766] Compound 850: 4-Hydroxy-1-[2-(1-methyl-ureido)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2211

[0767] To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (153 mg, 0.374 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by trimethylsilyl isocyanate (68 μL, 0.5 mmol) at room temperature. After 2 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the product were combined, concentrated and lyophilized to yield the title compound as a white powder (120 mg, 61% yield). 1HNMR (500 MHz, CDCl3) δ: 10.37 (1H, br s), 7.41 (1H, d, J=8.2H), 7.34 (1H, s), 7.10 (1H, d, J=8.2 Hz), 5.78 (2H, br s), 4.56 (2H, s), 4.22 (2H, s), 3.64 (2H, t, J=5.2 Hz), 3.55 (2H, t, J=5.2 Hz), 2.99 (3H, s), 2.94 (3H, s). HRMS calcd for C17H21Cl2N4O4 (M+H): 415.094; found: 415.0941.

EXAMPLE 125

[0768] Compound 851: 4-Hydroxy-1-[2-(2-((N-tert-butylcarbamoyl-sulfamidoyl)-methyl-amino)-ethyl]-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide 2212

[0769] To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (110 mg, 0.269 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by a freshly prepared solution of t-butanol and chlorosulfonyl isocyanate (concentration=0.2 mM, 2 mL, 0.4 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the product were combined, concentrated and lyophilized to give the title compound as a white powder (77 mg, 43% yield). 1HNMR (500 MHz, CDCl3) δ: 7.68 (1H, s), 7.41 (1H d, J=8.2 Hz), 7.35 (1H, s), 7.10 (1H, d, J=8.2 Hz), 4.57 (2H, s), 4.26 (2H, s), 3.68 (2H, t, J=5.2 Hz), 3.54 (2H, t, J=5.2 Hz), 3.00 (3H, s), 2.92 (3H, s), 1.45 (9H, s). HRMS calcd for C21H27Cl2N4O7S (M+H): 549.0978; found: 549.0988.

EXAMPLE 126

[0770] Compound 852: 1-(2-Amino-ethyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2213

[0771] Compound 852 was prepared according to the methods described in the previous examples. 1HNMR (500 MHz, DMSO-d6) δ: 10.98 (1H, br s), 7.62 (1H, d, J=8.24 Hz), 7.52 (1H, d, J=2.14 Hz), 7.25 (1H, d, J=7.33 Hz), 4.59 (2H, s), 4.10 (2H, s), 3.64 (5H, br s), 3.06-3.00 (4H, m). HRMS calcd for C15H18Cl2N3O3 (M+H): 358.0725; found: 358.0717.

EXAMPLE 127

[0772] Compound 853: 4-Hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,5-dichloro-benzyl)-methyl-amide 2214

[0773] Compound 853 was prepared according to the methods described in the previous examples. 1HNMR (500 MHz, CDCl3) δ: 11.96 (1H, br s), 8.92 (2H, s), 7.53 (1H, s), 7.31 (2H, s), 4.60 (2H, s), 4.11 (2H, s), 3.89 (3H, br s), 3.70 (2H, br s), 3.15 (2H, m), 2.55 (3H, t, J=5.19 Hz). HRMS calcd for C16H20Cl2N3O3 (M+H): 372.0882; found: 372.0884.

EXAMPLE 128

[0774] Compound 854: 4-Hydroxy-1-(2-(dimethylsulfamidoyl-methyl-amino)-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide 2215

[0775] To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,5-dichloro-benzyl)-methyl-amide (82 mg, 0.2 mmol) and Et3N (0.084 mL, 0.6 mmol) in CH2Cl2 (3 mL) was added dimethylsulfamoyl chloride (0.028 mL, 0.26 mmol). After stirring for 2 h at room temperature, the reaction mixture was concentrated and purified by preparative HPLC using MeOH/Water as the eluent. The fractions containing the product were combined and concentrated to give the title compound as a paste (70 mg, 59% yield). 1HNMR (500 MHz, CDCl3) δ: 10.68 (1H, br s), 7.27 (1H, s), 7.13 (2H, s), 4.58 (2H, s), 4.29 (2H, s), 3.71-3.65 (2H, m), 3.45-3.40 (2H, m), 3.02 (3H, s), 2.80 (3H, s), 2.71 (6H, s). HRMS calcd for C18H25Cl2N4O5S (M+H): 479.0923; found: 479.0918.

EXAMPLE 129

[0776] Compound 855: 1-Carbamoylmethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-methyl-amide 2216

[0777] Compound 855 was prepared according to the methods described in the previous examples. 1HNMR (500 MHz, CDCl3) δ: 7.84 (1H, d, J=8.24 Hz), 7.28 (1H, br s), 7.05-7.01 (1H, m), 4.52 (2H, s), 4.17 (2H, s), 4.03 (2H, s), 3.43 (3H, br s), 2.94 (3H, s). HRMS calcd for C15H14Cl2N3O4 (M−H): 370.0361; found: 370.0361.

EXAMPLE 130

[0778] Compound 856: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(4-methylbenzyl)-amide 2217

[0779] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-methylbenzyl)-acetamide (0.30 g, 0.98 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.17 g (45% yield) of the title compound as a solid. 1HNMR 400 MHz (CDCl3) δ (ppm); 2.35 (3H, s, CH3), 2.47 (4H, m, 2×NCH2), 2.56 (2H, t, J=6.2 Hz, NCH2), 3.62 (2H, t, J=6.2 Hz, NCH2), 3.66 (4H, m, 2×OCH2), 3.71 (3H, s, OCH3), 4.27 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.14-7.24 (4H, m, aromatics). HRMS (FAB+) calculated for C20H28N3O5:[M+H]+: 390.202896; found: 390.203567.

EXAMPLE 131

[0780] Compound 857: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methyl-(4-trifluoromethyl-benzyl)-amide 2218

[0781] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methyl-N-(4-trifluoromethylbenzyl)-acetamide (0.50 g, 1.45 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.31 g (64% yield) of the title compound as white crystals; mp 126-128° C. (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 3.07 (3H, s, NCH3), 3.13 (3H, s, NCH3), 4.18 (2H, s, NCH2), 4.74 (2H, s, NCH2), 7.41 (2H, d, J=8.1 Hz, aromatics), 7.64 (2H, d, J=8.1 Hz, aromatics), 10.56 (1H, broad, OH). Anal. Calcd for C15H15F3N2O3: C, 54.88; H, 4.61; N, 8.53. Found: C, 54.93; H, 4.57; N, 8.44.

EXAMPLE 132

[0782] Compound 858: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methyl-(4-trifluoromethyl-benzyl)-amide 2219

[0783] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methyl-N-(4-trifluoromethyl-benzyl)-acetamide (0.36 g, 1.05 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.16 g (35% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 2.46 (4H, m, 2×NCH2), 2.57 (2H, t, J=6.1 Hz, NCH2), 3.04 (3H, s, NCH3), 3.6 (6H, m, 2×OCH2 and NCH2), 4.25 (2H, s, NCH2), 4.72 (2H, s, NCH2), 7.41 (2H, d, J=8.0 Hz, aromatics), 7.62 (2H, d, J=8.0 Hz, aromatics). HRMS (FAB+) calculated for C20H25F3N3O4:[M+H]+: 428.179716; found: 428.179157.

EXAMPLE 133

[0784] Compound 859: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(4-trifluoromethyl-benzyl)-amide 2220

[0785] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-trifluoromethylbenzyl)-acetamide (0.20 g, 0.56 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.10 g (52% yield) of the title compound as white crystals; mp 145° C. (dec) (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 3.11 (3H, s, NCH3), 3.75 (3H, s, OCH3), 4.17 (2H, s, NCH2), 4.94 (2H, s, NCH2), 7.45 (2H, d, J=8.1 Hz, aromatics), 7.61 (2H, d, J=8.1 Hz, aromatics). Anal. Calcd for C15H15F3N2O4: C, 52.33; H, 4.39; N, 8.13. Found: C, 52.17; H, 4.34; N, 7.98.

EXAMPLE 134

[0786] Compound 860: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(4-trifluoromethyl-benzyl)-amide 2221

[0787] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-N-(4-trifluoromethyl-benzyl)-acetamide (0.41 g, 1.13 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.38 g (75% yield) of the title compound as crystals after chromatography on reversed phase silica gel; mp 119° C. (dec) (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 2.48 (4H, m, 2×NCH2), 2.58 (2H, t, J=6.3 Hz, NCH2), 3.64 (2H, t, J=6.3 Hz, NCH2), 3.67 (4H, m, 2×OCH2), 3.75 (3H, s, OCH3), 4.31 (2H, s, NCH2), 4.94 (2H, s, NCH2), 7.47 (2H, d, J=8.1 Hz, aromatics), 7.63 (2H, d, J=8.1 Hz, aromatics). Anal. Calcd for C20H24F3N3O5: C, 54.17; H, 5.46; N, 9.48. Found: C, 54.12; H, 5.57; N, 9.52.

EXAMPLE 135

[0788] Compound 861: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid methoxy-(4-methylcarbamoyl-benzyl)-amide 2222

[0789] Reaction 4-({[2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methoxy-amino}-methyl)-N-methyl-benzamide (0.053 g, 0.15 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.034 g (41% yield) of the title compound as a white solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); (TFA salt) 2.77 (3H, d, J=4.65 Hz, NCH3), 3.1 (2H, broad m, NCH2), 3.4-3.8 (8H, broad m, 2×NCH2 and 2×OCH2), 3.75 (3H, s, OCH2), 3.98 (2H, broad, NCH2), 4.24 (2H, s, NCH2), 4.94 (2H, s, NCH2), 7.39 (2H, d, J=8.4 Hz, aromatics), 7.80 (2H, d, J=8.4 Hz, aromatic), 8.41 (1H, q, J=4.5 Hz, NH). HRMS (FAB+) calculated for C21H29N4O6:[M+H]+: 433.208710; found: 433.209419.

EXAMPLE 136

[0790] Compound 862: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichlorobenzyl)-methoxy-amide 2223

[0791] Reaction of N-(3,4-dichlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.20 g, 0.56 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.071 g (28% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 2.39 (4H, broad, 2×NCH2), 2.47 (2H, t, J=6.3 Hz, NCH2), 3.49 (2H, t, J=6.3 Hz, NCH2), 3.53 (4H, broad, 2×OCH2), 3.66 (3H, s, OCH3), 4.16 (2H, s, NCH2), 4.89 (2H, s, NCH2), 7.33 (1H, dd, J=1.8 Hz and J=8.1 Hz, aromatic), 7.60 (1H, d, J=8.1 Hz, aromatic), 7.63 (1H, d, J=1.8 Hz, aromatic). HRMS (MAB/N2) calculated for C19H23C2N3O5:[M+]: 443.101477; found: 443.103002.

EXAMPLE 137

[0792] Compound 863: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-trifluoromethyl-benzyl)-methoxy-amide 2224

[0793] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluoro-2-trifluoromethylbenzyl)-N-methoxy-acetamide (0.14 g, 0.37 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.056 g (42% yield) of the title compound as white crystals; mp 167° C. (dec) (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 3.13 (3H, s, NCH3), 3.71 (3H, s, OCH3), 4.21 (2H, s, NCH2), 5.09 (2H, s, NCH2), 7.22-7.27 (1H, m, aromatic), 7.39-7.46 (2H, m, aromatics). Anal. Calcd for C15H14F4N2O4: C, 49.73; H, 3.89; N, 7.73. Found: C, 49.74; H, 3.92; N, 7.70.

EXAMPLE 138

[0794] Compound 864: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-2-trifluoromethyl-benzyl)-methoxy-amide 2225

[0795] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluoro-2-trifluoromethyl-benzyl)-N-methoxy-acetamide (0.21 g, 0.55 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.13 g (50% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 2.51 (4H, m, 2×NCH2), 2.60 (2H, t, J=6.1 Hz, NCH2), 3.65 (6H, m, 2×OCH2 and NCH2), 3.71 (3H, s, OCH3), 4.32 (2H, s, NCH2), 5.09 (2H, s, NCH2), 7.23-7.27 (2H, m, aromatics), 7.39-7.48 (2H, m, aromatics). MS (ESI+) calculated for C20H24F4N3O5:[M+H]+: 462; found: 462.

EXAMPLE 139

[0796] Compound 865: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid [3-(3,4-dichlorophenyl)-propyl]-amide 2226

[0797] Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-acetamide (0.432 g, 1.20 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.232 g (56% yield) of the title compound as white crystals; mp 157-158° C. (dec) (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 1.81 (2H, m, CH2), 2.57 (2H, t, J=7.5 Hz, CH2), 3.05 (3H, s, NCH3), 3.33 (2H, m, NCH2), 3.98 (2H, s, NCH2), 6.95 (1H, broad t, NH), 7.05 (1H, broad dd, aromatic), 7.21 (1H, d, J=2 Hz, aromatic), 7.26 (1H, d, J=8.1 Hz, aromatic), 10.13 (1H, broad, OH). Anal. Calcd for C5H16Cl2N2O3: C, 52.49; H, 4.70; N, 8.16. Found: C, 52.39; H, 4.80; N, 7.89.

EXAMPLE 140

[0798] Compound 866: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid [3-(4-fluorophenyl)-propyl]-methyl-amide 2227

[0799] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methyl-acetamide (0.20 g, 0.62 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.11 g (56% yield) of the title compound as white crystals; mp 129° C. (dec) (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 1.91 (2H, m, CH2), 2.63 (2H, t, J=7.6 Hz, CH2), 3.04 (3H, s, NCH3), 3.05 (3H, s, NCH3), 3.40 (2H, broad t, J=7.5 Hz, NCH2), 3.90 (2H, broad s, NCH2), 6.99 (2H, m, aromatics), 7.14 (2H, m, aromatics). Anal. Calcd for C16H19FN2O3: C, 62.73; H, 6.25; N, 9.14. Found: C, 62.75; H, 6.23; N, 9.11.

EXAMPLE 141

[0800] Compound 867: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid [3-(4-fluorophenyl)-propyl]-methyl-amide 2228

[0801] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methyl-acetamide (0.245 g, 0.76 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.103 g (33% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.92 (2H, m, CH2), 2.47 (4H, broad, 2×NCH2), 2.54 (2H, broad t, NCH2), 2.63 (2H, t, J=7.5 Hz, CH2), 3.04 (3H, s, NCH3), 3.42 (2H, broad t, NCH2), 3.58 (2H, broad, NCH2), 3.66 (4H, broad, 2×OCH2), 4.12 (2H, broad s, NCH2), 6.97 (2H, m, aromatics), 7.14 (2H, m, aromatics). HRMS (FAB+) calculated for C21H29FN3O4:[M+H]+: 406.214210; found: 406.214016.

EXAMPLE 142

[0802] Compound 868: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid [3-(3,4-dichlorophenyl)-propyl]-methyl-amide 2229

[0803] Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methyl-acetamide (0.570 g, 1.53 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.287 g (52% yield) of the title compound as white crystals; mp 138-140° C. (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 1.80 (2H, m, CH2), 2.49 (2H, t, J=7.6 Hz, CH2), 2.92 (3H, s, NCH3), 2.95 (3H, s, NCH3), 3.31 (2H, broad t, J=7.3 Hz, NCH2), 3.87 (2H, broad s, NCH2), 6.91 (1H, dd, J=2.0 Hz and J=8.1 Hz, aromatic), 7.16 (1H, d, J=2.0 Hz, aromatic), 7.23 (1H, d, J=8.1 Hz, aromatic), 10.94 (1H, broad s, OH). Anal. Calcd for C6H18Cl2N2O3: C, 53.80; H, 5.08; N, 7.84. Found: C, 53.90; H, 5.17; N, 7.83.

EXAMPLE 143

[0804] Compound 869: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid [3-(4-fluorophenyl)-propyl]-methoxy-amide 2230

[0805] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methoxy-acetamide (0.560 g, 1.66 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.446 g (63% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 1.84 (2H, m, CH2), 2.40 (4H, broad, 2×NCH2), 2.46 (2H, t, J=6.5 Hz, CH2), 2.56 (2H, t, J=8.1 Hz, CH2), 3.46 (2H, t, J=6.5 Hz, NCH2), 3.52 (3H, s, OCH3), 3.55 (4H, broad, 2×OCH2), 3.67 (2H, t, J=7.1 Hz, NCH2), 3.95 (2H, s, NCH2), 7.09 (2H, m, aromatics), 7.23 (2H, m, aromatics). HRMS (FAB+) calculated for C21H29FN3O5:[M+H]+: 422.209125; found: 422.208679.

EXAMPLE 144

[0806] Compound 870: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid [3-(3,4-dichlorophenyl)-propyl]-methoxy-amide 2231

[0807] Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.480 g, 1.16 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.250 g (58% yield) of the title compound as white crystals; mp 106-108° C. (ethyl acetate—hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 2.01 (2H, m, CH2), 2.65 (2H, t, J=7.6 Hz, CH2), 3.14 (3H, s, NCH3), 3.73 (3H, s, OCH3), 3.77 (2H, t, J=7.0 Hz, NCH2), 4.11 (2H, s, NCH2), 7.04 (1H, dd, J=2.0 Hz and J=8.1 Hz, aromatic), 7.30 (1H, d, J=2.0 Hz, aromatic), 7.36 (1H, d, J=8.1 Hz, aromatic), 11.67 (1H, broad s, OH). Anal. Calcd for C16H18Cl2N2O4: C, 51.49; H, 4.86; N, 7.51. Found: C, 51.65; H, 4.90; N, 7.45.

EXAMPLE 145

[0808] Compound 871: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid [3-(3,4-dichlorophenyl)-propyl]-methoxy-amide 2232

[0809] Reaction of N-[3-(3,4-dichlorophenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide (0.378 g, 0.97 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.196 g (42% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.98 (2H, m, CH2), 2.49 (4H, broad, 2×NCH2), 2.58 (2H, t, J=6.2 Hz, CH2), 2.63 (2H, t, J=7.5 Hz, CH2), 3.63 (2H, t, J=6.2 Hz, NCH2), 3.68 (4H, broad, 2×OCH2), 3.71 (3H, s, OCH3), 3.74 (2H, t, J=7.0 Hz, NCH2), 4.23 (2H, s, NCH2), 7.02 (1H, dd, J=2.0 Hz and J=8.2 Hz, aromatic), 7.28 (1H, d, J=2.0 Hz, aromatic), 7.34 (1H, d, J=8.2 Hz, aromatic). HRMS (FAB+) calculated for C21H28Cl2N3O5:[M+H]+: 472.140602; found: 472.138651.

EXAMPLE 146

[0810] Compound 146-A: 4-Fluorobenzaldehyde O-(3-chloropropyl)-oxime 2233

[0811] A suspension of sodium hydride (73.0 mmol, 3.0 g of a 60% suspension in mineral oil) was washed twice with hexane and then suspended in dry tetrahydrofuran (40 ml). The reaction mixture was then treated at 25° C. with 1-bromo-3-chloropropane (10 ml, 97.5 mmol) followed by a solution of 4-fluorobenzaldehyde oxime (6.78 g, 48.7 mmol) in tetrahydrofuran (30 ml) added dropwise over 10 min. The resulting mixture was then heated under reflux for 16 h. The cooled mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution hexane—ethyl acetate, 9: 1) gave 8.52 g (81%) of the title oxime as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.23 (2H, m, CH2), 3.74 (2H, t, J=6.5 Hz, CH2), 4.36 (2H, t, J=5.8 Hz, CH2), 7.13 (2H, m, aromatics), 7.63 (2H, m, aromatics), 8.11 (1H, s, CH). Anal. Calcd for C10H11ClFNO: C, 55.69; H, 5.14; N, 6.49. Found: C, 55.44; H, 5.12; N, 6.41.

[0812] Compound 146-B: 4-Fluorobenzaldehyde O-(3-morpholin-4-yl-propyl)-oxime 2234

[0813] A mixture of 4-fluorobenzaldehyde O-(3-chloropropyl)-oxime (0.430 g, 2.0 mmol), morpholine (0.70 g, 8.0 mmol), sodium iodide (0.1 g) and potassium carbonate (0.55 g) in acetone (10 ml) was sealed and heated at 80° C. for 34 h. The cooled mixture was concentrated, diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (elution ethyl acetate—acetone, 8:2) gave 0.376 g (70%) of the title oxime as a clear oil. 1HNMR 400 MHz (C6D6) δ (ppm): 1.94 (2H, m, CH2), 2.27 (4H, m, NCH2), 2.38 (2H, t, J=7.1 Hz, NCH2), 3.69 (4H, m, OCH2), 4.40 (2H, t, J=6.5 Hz, OCH2), 6.76 (2H, m, aromatics), 7.33 (2H, m, aromatics), 8.03 (1H, s, CH).

[0814] Compound 146-C: N-(4-Fluorobenzyl)-O-(3-morpholin-4-yl-propyl)-hydroxylamine 2235

[0815] Reduction of 4-fluorobenzaldehyde O-(3-morpholin-4-yl-propyl)-oxime (0.330 g, 1.24 mmol) with sodium cyanoborohydride in acetic acid as described in the preparation of compound 44-B gave 0.330 (100% yield) of the crude title hydroxylamine as a light yellow oil which was used as such for the acylation step. 1HNMR 400 MHz (C6D6) δ (ppm): 1.69 (2H, m, CH2), 2.22 (4H, m, NCH2), 2.27 (2H, t, J=7.0 Hz, NCH2), 3.63 (4H, m, OCH2), 3.74 (2H, t, J=6.3 Hz, OCH2), 3.79 (2H, s, NCH2), 6.91 (2H, m, aromatics), 7.12 (2H, m, aromatics).

[0816] Compound 146-D: 2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-N-(3-morpholin-4-yl-propoxy)-acetamide 2236

[0817] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (1.0 mmol) with N-(4-fluorobenzyl)-O-(3-morpholin-4-yl-propyl)-hydroxylamine (0.268 g, mmol) as described in the preparation of compound 44-C (acid wash was skipped in this case) gave 0.200 g (47% yield) of the title amide as a clear oil after chromatography on silica gel. 1HNMR 400 MHz (C6D6) δ (ppm): 1.10 (6H, s, CH3), 1.50 (2H, m, CH2), 2.19 (2H, t, J=6.6 Hz, NCH2), 2.20 (4H, m, NCH2), 3.70 (2H, t, J=6.2 Hz, OCH2), 3.71 (4H, m, OCH2), 4.73 (2H, s, NCH2), 6.85 (3H, m, CH and aromatics), 7.22 (2H, m, aromatics). HRMS (MAB N2) calculated for C21H27FN2O6 [M+]: 422.185315: found: 422.185246.

[0818] Compound 872: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-(3-morpholin-4-yl-propoxy)-amide 2237

[0819] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.080 g, 0.18 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.027 g (35% yield) of the title compound as a white solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 1.61 (2H, m, CH2), 2.23 (2H, t, J=7.0 Hz, NCH2), 2.28 (4H, broad, 2×NCH2), 2.93 (3H, s, NCH3), 3.54 (4H, broad, 2×OCH2), 3.76 (2H, broad t, OCH2), 3.97 (2H, s, NCH2), 4.88 (2H, s, NCH2), 7.13 (2H, m, aromatics), 7.40 (2H, m, aromatics). HRMS (MAB N2) calculated for C20H26FN3O5: [M]+: 407.185650; found: 407.184331.

EXAMPLE 147

[0820] Compound 873: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (4-fluoro-benzyl)-(3-morpholin-4-yl-propoxy)-amide 2238

[0821] Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.080 g, 0.19 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.019 g (20% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.65 (2H, m, CH2), 2.25 (2H, t, J=7.3 Hz, NCH2), 2.29 (4H, broad, 2×NCH2), 2.39 (4H, broad, 2×NCH2), 2.46 (2H, t, J=6.6 Hz, CH2), 3.50 (2H, t, J=6.6 Hz, NCH2), 3.68 (8H, broad, 4×OCH2), 3.84 (2H, t, J=7.0 Hz, OCH2), 4.11 (2H, s, NCH2), 4.87 (2H, s, NCH2), 7.16 (2H, m, aromatics), 7.40 (2H, m, aromatics). HRMS (MAB N2) calculated for C25H35FN4O6: [M]+: 506.254064; found: 506.254892.

EXAMPLE 148

[0822] Compound 148-A: 3,4-Dichlorobenzaldehyde O-(3-chloropropyl)-oxime 2239

[0823] Reaction of 3,4-dichlorobenzaldehyde oxime (2.5 g, 13.15 mmol) with 1-bromo-3-chloropropane (2.6 ml, 26.3 mmol) as described in the preparation of Compound 146-A gave 2.60 g (74% yield) of the title oxime as a clear oil after chromatography on silica gel (elution hexane—ethyl acetate, 9:1). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.21 (2H, m, CH2), 3.69 (2H, t, J=6.5 Hz, CH2), 4.34 (2H, t, J=5.8 Hz, OCH2), 7.41 (1H, dd, J=2 Hz and J=8 Hz, aromatic), 7.47 (1H, d, J=8 Hz, aromatic), 7.71 (1H, d, J=2 Hz, aromatic), 8.01 (1H, s, CH).

[0824] Compound 148-B: 3,4-Dichlorobenzaldehyde O-(3-morpholin-4-yl-propyl)-oxime 2240

[0825] Reaction of 3,4-dichlorobenzaldehyde O-(3-chloropropyl)-oxime (2.6 g, 9.75 mmol) with morpholine (3.4 ml) as described in the preparation of compound 146-B gave 2.25 g (72% yield) the title oxime as a clear oil after chromatography on silica gel (elution ethyl acetate—acetone, 8: 2). 1HNMR 400 MHz (C6D6) δ (ppm): 1.89 (2H, m, CH2), 2.25 (4H, m, NCH2), 2.35 (2H, t, J=7.1 Hz, NCH2), 3.69 (4H, m, OCH2), 4.35 (2H, t, J=6.5 Hz, OCH2), 6.98 (1H, d, J=8.5 Hz, aromatic), 7.02 (1H, dd, J=1.9 Hz and J=8.5 Hz, aromatic), 7.50 (1H, d, J=1.9 Hz, aromatic), 7.77 (1H, s, CH). Anal. Calcd for C14H18Cl2N2O2: C, 53.01; H, 5.71; N, 8.83. Found: C, 52.99; H, 5.69; N, 8.75.

[0826] Compound 148-C: N-(3,4-Dichlorobenzyl)-O-(3-morpholin-4-yl-propyl)-hydroxylamine 2241

[0827] A solution of 3,4-dichlorobenzaldehyde O-(3-morpholin-4-yl-propyl)-oxime (0.160 g, 0.5 mmol) in a mixture of dichloromethane (2 ml) and acetic acid (1 ml) was treated with borane-pyridine complex (0.17 ml, 1.36 mmol) and the resulting mixture was heated under reflux (bath temperature 60° C.) for 4 h. The solvent was then evaporated under reduced pressure and the residue was treated with 10% aqueous hydrochloric acid (3 ml). The reaction mixture was then basified with solid sodium carbonate and extracted with ethyl acetate. The organic phase was then washed with brine, dried (anhydrous magnesium sulfate) and concentrated to give 0.150 g (93% yield) of the crude title hydroxylamine as a light yellow oil which was used as such for the acylation step. 1HNMR 400 MHz (C6D6) δ (ppm): 1.66 (2H, m, CH2), 2.22 (2H, t, J=7.1 Hz, NCH2), 2.24 (4H, m, NCH2), 3.56 (2H, s, NCH2), 3.69 (4H, m, OCH2), 3.70 (2H, t, J=6.5 Hz, OCH2), 5.2 (1H, broad, NH), 6.82 (1H, dd, J=1.9 Hz and J=8.5 Hz, aromatic), 7.13 (1H, d, J=8.5 Hz, aromatic), 7.33 (1H, d, J=1.9 Hz, aromatic).

[0828] Compound 148-D: N-(3,4-Dichlorobenzyl)-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(3-morpholin-4-yl-propoxy)-acetamide 2242

[0829] Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.49 mmol) with N-(3,4-dichlorobenzyl)-O-(3-morpholin-4-yl-propyl)-hydroxylamine (0.150 g, 0.49 mmol) as described in the preparation of compound 44-C gave 0.150 g (65% yield) of the title amide as white crystals after chromatography on silica gel: mp 77-78° C. (ether—hexane). 1HNMR 400 MHz (C6D6) δ (ppm): 1.09 (6H, s, CH3), 1.47 (2H, m, CH2), 2.17 (2H, t, J=6.5 Hz, NCH2), 2.22 (4H, m, NCH2), 3.66 (2H, t, J=6.0 Hz, OCH2), 3.73 (4H, m, OCH2), 4.56 (2H, s, NCH2), 6.82 (1H, s, CH), 6.98 (1H, dd, J=2.0 Hz and J=8.0 Hz, aromatic), 7.06 (1H, d, J=8.0 Hz, aromatic), 7.40 (1H, d, J=2.0 Hz, aromatic). Anal. Calcd for C21H26Cl2N2O6: C, 53.28; H, 5.53; N, 5.91. Found: C, 53.31; H, 5.67; N, 5.77.

[0830] Compound 874: 4-Hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-(3-morpholin-4-yl-propoxy)-amide 2243

[0831] Reaction of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.200 g, 0.42 mmol) with the paraformaldehyde—methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.090 g (47% yield) of the title compound as a white amorphous solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (DMSO-d6) δ (ppm); 1.66 (2H, m, CH2), 2.27 (2H, t, J=7.1 Hz, NCH2), 2.32 (4H, broad, 2×NCH2), 2.95 (3H, s, NCH3), 3.55 (4H, broad, 2×OCH2), 3.86 (2H, broad t, OCH2), 4.06 (2H, s, NCH2), 4.88 (2H, s, NCH2), 7.35 (1H, dd, J=2 Hz and J=8.1 Hz, aromatic), 7.61 (1H, d, J=8.1 Hz, aromatic), 7.65 (1H, d, J=2 Hz, aromatic). HRMS (FAB+) calculated for C20H26Cl2N3O5: [M+H]+: 458.124952; found: 458.123753.

EXAMPLE 149

[0832] Compound 875: 4-Hydroxy-1-(2-morpholin-4-yl-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic Acid (3,4-dichloro-benzyl)-(3-morpholin-4-yl-propoxy)-amide 2244

[0833] Reaction of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.200 g, 0.42 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.160 g (68% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.56 (2H, m, CH2), 2.18 (2H, t, J=7.1 Hz, NCH2), 2.25 (4H, broad, 2×NCH2), 2.39 (4H, broad, 2×NCH2), 2.46 (2H, t, J=6.1 Hz, CH2), 3.50 (2H, t, J=6.1 Hz, NCH2), 3.54 (8H, broad, 4×OCH2), 3.71 (2H, broad t, OCH2), 3.99 (2H, s, NCH2), 4.87 (2H, s, NCH2), 7.40 (1H, broad d, aromatic), 7.58 (1H, d, J=8.1 Hz, aromatic), 7.73 (1H, broad s, aromatic). HRMS (FAB+) calculated for C25H35Cl2N4O6: [M+H]+: 557.193366; found: 557.192134

BIOLOGICAL ACTIVITY

[0834] For each reaction, 5 pmole of biotin labeled substrate DNA was bound to 100 ug of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech). 0.26 ng of recombinant integrase was incubated with the beads for 90 min at 37C. Unbound enzyme was removed by washing the complex followed by addition of inhibitors and 0.1 fmol of P33 labeled target DNA. Reaction was stopped by adding EDTA to a final concentration of 10 mM. Sampled were counted in TopCountNXT (Packard) and the CPM was used as a measure of integration. Reaction condition was as described in A. Engelman and R. Craigie, J. Virol. 69, 5908-5911 (1995). The sequences of substrate and target DNA were described in Nucleic Acid Research 2,1121-1122 (1994). Using this assay, representative examples were found to have IC50=0.01 to 50 μM. The table below shows the percent inhibition of HIV-integrase in the presence of 20 μM of compounds 1-79.

Compound % Inhibition @ 20 μM
1        99.9
2        99.9
3        99.9
4        99.9
5        99.8
6        99.9
7        99.9
8        99.9
9        99.9
10       99.9
11       99.9
12       99.9
13       99.9
14       99.7
15       99.7
16       99.9
17       99.9
18       99.9
19       99.9
20       99.9
21       99.9
22       99.9
23-A     99.9
23       99.9
24       99.9
25       99.9
26       99.9
27       99.9
28       99.9
29       99.9
30       99.9
31       99.9
32       99.9
33       99.9
34       99.9
35       99.9
36       92
37       99.9
38       99.9
39       99.9
40       99.9
41       99.9
42       99.9
43       99.9
45       99.5
46       99.3
47       99.9
49       98.5
50       92
51       99.9
52       86
53       99
54       99.9
55       99.9
56       88
57       99.9
58       99.5
59       99.9
60       99.7
61       99.3
62       97.7
63       12
64       99.7
65       99.9
66       99
67       96.5
68-A     4.5
68       12
69       97
70       99.8
71       99.9
72       98.8
73       10
74       97.8
75       96.5
76       96
77       99.8
78       99.9
79       92.4

[0835] Inhibition of HIV Replication

[0836] Cell culture assays were performed using a single cycle, recombinant HIV virus expressing Renella luciferase. Anti-viral activity was evaluated by measuring the production of luciferase in the infected cells 5 days post-infection. Susceptibility of the virus to compounds was determined by incubation in the presence of the serially-diluted compound. The 50% effective concentration (EC50) was calculated by using the exponential form of the median effect equation where (Fa)=1/[1+(ED50/drug conc.)m].

[0837] Representative compounds of this invention tested in this assay have EC50's of approximately 0.01 to 150 μM.

Claims

1. A compound of Formula I, or pharmaceutically acceptable salts or solvates thereof

2. A compound of claim 1 where R1 is phenyl substituted with 1-3 R4 or C1-C6 alkylaryl unsubstituted or substituted with 1-3 R4, R2 is H, and R4 is halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, OR5, CO2R6, or NR7R8.

3. A compound of claim 2 where R10 is H or phenyl unsubstituted or substituted with 1-3 R4.

4. A compound of claim 3 where R12 is OR13.

5. A compound of claim 3 where R11 is C1-C6 alkyl or C1-C6-alkyl-heterocycle where the heterocycle is selected from pyrrolidine, piperidine, 4-hydroxypiperidine, morpholine, thiomorpholine, piperazine, 4-methylpiperazine, and thiazinanedioxide.

6. A compound of claim 1 selected from the group consisting of 4-hydroxy-5-oxo-1-(2-[4-methylpiperazin-1-yl]ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichlorobenzyl)-methyl-amide; 4-hydroxy-5-oxo-1-(2-[morpholin-1-yl]ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichlorobenzyl)-methyl-amide; 4-hydroxy-5-oxo-1-(2-[morpholin-1-yl]ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dimethylbenzyl)-methyoxy-amide; 4-hydroxy-5-oxo-1-(2-[morpholin-1-yl]ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid 3-(4-fluorophenyl)prop-1-yl-methyoxy-amide; 4-hydroxy-5-oxo-1-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichlorobenzyl)-methyl-amide; 4-hydroxy-5-oxo-1-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichlorobenzyl)-methoxy-amide; 4-hydroxy-5-oxo-1-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dimethylbenzyl)-methoxy-amide; 4-hydroxy-5-oxo-1-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (4-fluoro-3-methylbenzyl)-methoxy-amide; and 4-hydroxy-5-oxo-1-methyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3-fluoro-4-methylbenzyl)-methoxy-amide.

7. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7, further comprising a therapeutically effective amount of one or more other HIV treatment agent selected from (a) an HIV protease inhibitor; (b) a nucleoside reverse transcriptase inhibitor; (c) a non-nucleoside reverse transcriptase inhibitor; (d) an HIV-entry inhibitor; (e) an immunomodulator; (f) or a combination thereof.

9. A method of inhibiting HIV integrase which comprises administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a mammal in need of such treatment.

10. A method of treating an HIV infection in a patient in need thereof, comprising the administration of a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof to the patient.

11. A method of therapeutically treating AIDS or ARC in a patient in need thereof, comprising the administration of a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, to the patient.