THIAZOLIDINONE COMPOUNDS AND USE THEREOF

Abstract

A pharmaceutical composition containing a compound of Formula (I) for treating an opioid receptor-associated condition. Also disclosed is a method for treating an opioid receptor-associated condition using such a compound. Further disclosed are two sets of thiazolidinone compounds of formula (I): (i) compounds each having an enantiomeric excess greater than 90% and (ii) compounds each being substituted with deuterium.

Description

BACKGROUND

Opioids are classified as natural opioid (e.g., morphine and codeine noscopine), semi-synthetic opioid (e.g., heroin, oxymorphone, and hydromorphone), synthetic opioid (e.g., methadone, morphinians, and benzamorphans), and peptides opioid (e.g. endorphins, enkephalins and dynorphins).

It is well known in the art that opioids act in both the central and peripheral nervous systems to produce various pharmacological effects, including analgesia, drowsiness, mood changes, respiratory depression, dizziness, mental clouding, dysphoria pruritus, nausea, vomiting, increased pressure in the biliary tract, decreased gastrointestinal motility, and alteration of the endocrine or autonomic nervous systems. They have long been the most potent and effective analgesics available to treat acute pain (such as post-operative pain) and chronic and disabling pain (such as pain from cancer).

Opioids primarily activate three classic subtypes of opioid receptors, namely, mu-opioid receptor (MOR), delta-opioid receptor (DOR), and kappa-opioid receptor (KOR), to exert therapeutic effects. These opioid receptors are all G-protein-coupled receptors. Most opioids clinically used as analgesics produce undesired effects, e.g., respiratory depression. Furthermore, long-term use of opioids for controlling chronic pain develops severe side effects, e.g., tolerance, dependence, and addiction.

There is a need to develop new opioids that modulate opioid receptors with fewer side effects for the treatment of opioid receptor-associated conditions, e.g., pain, immune function, and esophageal reflux.

SUMMARY

The present invention relates to use of an antagonist-to-agonist allosteric modifier of a MOR for treating an opioid receptor-associated condition. Such a modifier combined with a MOR antagonist produces anti-nociceptive effects without developing severe side effects.

In one aspect, this invention relates to a method of treating an opioid receptor-associated condition. The method includes administering to a subject in need thereof a mu-opioid receptor antagonist and an effective amount of the compound of Formula (I):

in which U is C_1-6 alkyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl; V is C_1-6 alkyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, -L-C_6-14 aryl, or -L-C_1-13 heteroaryl, L being a bond, NR, or S(O)₂; X is S, SO₂, CRR′, O, or N; Y is CRR′, O, or N; and W is —C(O)—, —CH═, —CH₂—, N, or O, wherein each of the C_1-6 alkyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, and C_1-13 heteroaryl, independently, either is optionally mono-, di-, or tri-substituted with halo, OH, CN, CF₃, NH₂, NO₂, SO₂, C_1-6 alkyl, C_1-6 haloalkyl, C_2-6 alkenyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_1-6 alkoxy, C_1-6 haloalkoxy, C_1-6 alkylamino, C_2-6 dialkylamino, C_7-12 aralkyl, C_1-12 heteroaralkyl, C_6-14 aryl, C_1-13 heteroaryl, —C(O)OR, —C(O)NRR′, —C(O)R, —C(O)NRS(O)₂R′, —C(O)NRS(O)₂NR′R″, —C(═NH)NRR′, —S(O)₂R, —S(O)₂NRR′, —NRR′, —NRC(O)R′, ˜NRS(O)₂R′, or —NRS(O)₂NR′R″; or is optionally fused with C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl; each of R, R′, and R″, independently, being H, halo, OH, CN, COOH, mono-, di-, or tri-alkylsubstitutes silyl, acetyl, acetamide, dialkylamino, alkylamino, C_1-6 alkyl, C_1-6 multihaloalkyl, C_1-6 alkoxy, C_1-6 multihaloalkoxy, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl; and is either a single bond or a double bond.

The above-described method for treating an opioid receptor-associated condition, in addition to administration of a compound of Formula (I), can further include administration of a MOR antagonist, e.g., naloxone, naltrexone, samidorphan, cyprodime, clocinnamox, and β-FNA. They can be administered jointly (i.e., in one pharmaceutical composition) or separately (i.e., in two pharmaceutical compositions).

This method works via a unique mechanism, namely, opioid antagonist-mediated activation of a MOR to produce anti-nociceptive effects. Unlike using a MOR agonist, the method of this invention uses an allosteric modifier combined with a MOR antagonist to produce anti-nociceptive effects without developing severe side effects, e.g., tolerance, dependence, and addiction.

In another aspect, this invention relates to a compound of formula (I):

in which X is S, Y is —CH₂—, W is —C(O)—, ring A is

U is C₁₄ aryl or C_1-3 heteroaryl, and V is

wherein R₁ is halo, C_1-6 alkyl, or C_2-6 alkenyl; each of R₂, R₄, and R₅, independently, is H, C_1-6 alkyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_1-6 alkoxy, C_6-14 aryl, or C_1-13 heteroaryl; and R₃ is halo, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-13 heteroaryl, —C(O)OR, —C(O)NRR′, —C(O)R, —C(O)NRS(O)₂R′, —C(O)NRS(O)₂NR′R″, —C(═NH)NRR′, —NRC(O)R′, —NRR′, or —NRS(O)₂R′, each of R, R′, and R″, independently, being H, halo, OH, CN, COOH, mono-, di-, or tri-alkylsubstitutes silyl, acetyl, acetamide, dialkylamino, alkylamino, C_1-6 alkyl, C_1-6 multihaloalkyl, C_1-6 alkoxy, C_1-6 multihaloalkoxy, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl; and the compound has an enantiomeric excess of greater than 90%.

In a further aspect, this invention relates to a compound of formula (I):

in which X is S, Y is —CH₂—, W is —C(O)—, ring A is

U is C_6-14 aryl or C_1-3 heteroaryl, and V is

wherein R₁ is halo, C_1-6 alkyl, or C_2-6 alkenyl; each of R₂, R₄, and R₅, independently, is H, C_1-6 alkyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_1-6 alkoxy, C_6-14 aryl, or C_1-13 heteroaryl; R₃ is halo, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-13 heteroaryl, —C(O)OR, C(O)NRR′, —C(O)R, —C(O)NRS(O)₂R′, —C(O)NRS(O)₂NR′R″, —C(═NH)NRR′, —NRC(O)R′, —NRR′, or —NRS(O)₂R′, each of R, R′, and R″, independently, being H, halo, OH, CN, COOH, mono-, di-, or tri-alkylsubstitutes silyl, acetyl, acetamide, dialkylamino, alkylamino, C_1-6 alkyl, C_1-6 multihaloalkyl, C_1-6 alkoxy, C_1-6 multihaloalkoxy, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl; and at least one of R₁, Y, and the carbon U attached to is mono-, di-, or tri-substituted with deuterium.

The term “alkyl” herein refers to a straight or branched hydrocarbon group, containing 1-20 (e.g., 1-10 and 1-6) carbon atoms. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, and t-butyl. The term “haloalkyl” refers to alkyl substituted with one or more halogen (chloro, fluoro, bromo, or iodo) atoms. Examples include trifluoromethyl, bromomethyl, and 4,4,4-trifluorobutyl. The term “alkoxy” refers to an —O-alkyl group. Examples include methoxy, ethoxy, propoxy, and isopropoxy. The term “haloalkoxy” refers to alkoxy substituted with one or more halogen atoms. Examples include —O—CH₂Cl and —O—CHClCH₂Cl.

The term “cycloalkyl” refers to a saturated and partially unsaturated monocyclic, bicyclic, tricyclic, or tetracyclic hydrocarbon group having 3 to 12 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heterocycloalkyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include piperazinyl, imidazolidinyl, azepanyl, pyrrolidinyl, dihydrothiadiazolyl, dioxanyl, morpholinyl, tetrahydropuranyl, and tetrahydrofuranyl.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system, in which each ring may have 1 to 5 substituents. Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The term “aralkyl” refers to alkyl substituted with an aryl group. Examples include benzyl and naphthylmethyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (e.g., O, N, P, and S). Examples include triazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, thiazolyl, and benzothiazolyl. The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl group. Examples include pyridylmethyl and furylmethyl.

The term “halo” refers to a fluoro, chloro, bromo, or iodo radical. The term “amino” refers to a radical derived from amine, which is unsunstituted or mono-/di-substituted with alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. The term “alkylamino” refers to alkyl-NH—. The term “dialkylamino” refers to alkyl-N(alkyl)-.

Alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, aryl, and heteroaryl mentioned herein include both substituted and unsubstituted moieties. Examples of substituents include, but are not limited to, halo, hydroxyl, amino, cyano, nitro, mercapto, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, carbamido, carbamyl, carboxyl, thioureido, thiocyanato, sulfonamido, alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, in which alkyl, alkenyl, alkynyl, alkyloxy, aryl, heteroaryl cycloalkyl, and heterocycloalkyl may further be substituted.

Herein, the term “compound” refers to the compounds of Formula (I) described above, as well as their salts and solvates, if applicable. A salt can be formed between an anion and a positively charged group (e.g., amino) on a compound. Examples of a suitable anion include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumurate, glutamate, glucuronate, lactate, glutarate, and maleate. A salt can also be formed between a cation and a negatively charged group. Examples of a suitable cation include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. A salt further includes those containing quaternary nitrogen atoms. A solvate refers to a complex formed between an active compound and a pharmaceutically acceptable solvent. Examples of a pharmaceutically acceptable solvent include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

Also within the scope of this invention is a pharmaceutical composition for treating an opioid receptor-associated condition. The pharmaceutical composition contains a compound of Formula (I) as described above.

The pharmaceutical composition can further contain a MOR antagonist. Examples of the MOR antagonist include, but are not limited to naloxone, naltrexone, samidorphan, cyprodime, clocinnamox, and β-FNA. Such a composition can be used for treating an opioid receptor-associated condition, e.g., pain, via the above-described mechanism, i.e., an opioid antagonist-mediated activation of a MOR.

This invention also covers use of such a composition for the manufacture of a medicament for treating an opioid receptor-associated condition.

A composition for oral administration can be any orally acceptable dosage form including capsules, tablets, emulsions and aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oily phase combined with emulsifying or suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added. Oral solid dosage forms can be prepared by spray dried techniques; hot melt extrusion strategy, micronization, and nano milling technologies.

A nasal aerosol or inhalation composition can be prepared according to techniques well known in the art of pharmaceutical formulation. For example, such a composition can be prepared as a solution in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. A composition having an active compound can also be administered in the form of suppositories for rectal administration.

The carrier in the pharmaceutical composition must be “acceptable” in the sense that it is compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. One or more solubilizing agents can be utilized as pharmaceutical excipients for delivery of an active compound. Examples of other carriers include colloidal silicon oxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow #10.

The above-described compounds or a pharmaceutical composition containing such a compound can be administered to a subject orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

The term “treating” refers to application or administration of the compound to a subject with the purpose to cure, alleviate, relieve, alter, remedy, improve, or affect the disease, the symptom, or the predisposition. “An effective amount” refers to the amount of the compound which is required to confer the desired effect on the subject. Effective amounts vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments such as use of other active agents.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a variable-temperature ¹HNMR spectra of compound 152 measured at four different temperatures: (a) 25° C.; (b) 40° C.; (c) 60° C.; and (d) 80° C.

DETAILED DESCRIPTION

Disclosed in detail herein is a pharmaceutical composition for treating an opioid receptor-associated condition. The pharmaceutical composition contains a compound of of Formula (I):

Referring to this formula, examples of ring A include, but are not limited to

U can be one of the following moieties:

In one subset, compounds of formula (I) each have V as one of the following moieties:

in which R_v is mono-, di-, or tri-substituted moieties among H, halo, OH, CN, COOH, mono-, di-, or tri-alkylsubstitutes silyl, acetyl, acetamide, dialkylamino, alkylamino, C_1-6 alkyl, C_1-6 multihaloalkyl, C_1-6 alkoxy, C_1-6 multihaloalkoxy, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, and C_1-13 heteroaryl.

In another subset, compounds of formula (I) each have V as one of the following moieties:

in which each of R and R′, independently, is H, halo, OH, CN, COOH, mono-, di-, or tri-alkylsubstitutes silyl, acetyl, acetamide, dialkylamino, alkylamino, C_1-6 alkyl, C_1-6 multihaloalkyl, C_1-6 alkoxy, C_1-6 multihaloalkoxy, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl; n is 1 to 6; X is S, SO₂, CRR′, O, or NR′; and Py is substituted or non-substituted ortho-, meta-, or para-pyridine.

Typically, V is

or C_1-13 heteroaryl, in which R₁ is halo, C_1-6 alkyl, or C_2-6 alkenyl; each of R₂, R₄, and R₅, independently, is H, C_1-6 alkyl, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_1-6 alkoxy, C_6-14 aryl, or C_1-13 heteroaryl; and R₃ is halo, CN, C_1-6 alkyl, C_1-6 alkoxy, C_1-13 heteroaryl, —C(O)OR, —C(O)NRR′, —C(O)R, —C(O)NRS(O)₂R′, —C(O)NRS(O)₂NR′R″, —C(═NH)NRR′, —NRC(O)R′, —NRR′, or —NRS(O)₂R′, each of R, R′, and R″, independently, being H, halo, OH, CN, COOH, mono-, di-, or tri-alkylsubstitutes silyl, acetyl, acetamide, dialkylamino, alkylamino, C_1-6 alkyl, C_1-6 multihaloalkyl, C_1-6 alkoxy, C_1-6 multihaloalkoxy, C_3-8 cycloalkyl, C_2-8 heterocycloalkyl, C_6-14 aryl, or C_1-13 heteroaryl.

Examples of V include, but are not limited to, the following moieties:

in which R_v is

(at any position of the phenyl ring); X is O, S, or NH; and Py is substituted or non-substituted ortho-, meta-, or para-pyridine.

Also within this invention are two sets of thiazolidinone compound of Formula (I):

in which X is S, Y is —CH₂—, W is —C(O)—, ring A is

U is C_6-14 aryl or C_1-13 heteroaryl, and V is

In one set, compounds of formula (I) each have an enantiomeric excess greater than 90%; and in the other set, compounds of formula (I) each have at least one of R₁, Y, and the carbon U attached to mono-, di-, or tri-substituted with deuterium. Typically, in both sets of compounds, R₁ is CH₃ and R₃ is —C(O)OR, —C(O)NRR′, —C(O)R, —C(O)NRS(O)₂R′, or —C(O)NRS(O)₂NR′R″.

Further covered by this invention is a method of treating an opioid receptor-associated condition. The method includes administering to a subject in need thereof a mu-opioid receptor antagonist and an effective amount of the above-described compound of Formula (I).

Typically, the opioid receptor-associated condition is pain, immune disease, esophageal reflux, diarrhea, anxiety, or heroin addiction. The pain can be cancer pain, post operative pain, low back pain, rheumatoid arthritis pain, osteoarthritis pain, neuropathic pain, or fibromyalgia pain.

In an exemplary in vitro screening method for identifying antagonist-to-agonist allosteric modifiers of a MOR, cells that express a MOR are treated with a test compound and a MOR antagonist in a cellular calcium fluorescent assay and fluorescence intensity is then measured to determine whether the MOR is activated. A test compound is identified as an antagonist-to-agonist allosteric modifier of the MOR if the MOR is activated.

Two parameters, i.e., EC₅₀ and AUC, are typically used in such an assay to measure the degree of MOR activation exerted by the test compound. EC₅₀ herein refers to the concentration of a compound that induces a response halfway between the baseline and the maximum after a specified exposure time. AUC refers to the area under the response curve, an indication of the compound's capability of activating a MOR when combined with a MOR antagonist.

In an exemplary in vivo method, a test compound and a MOR antagonist are injected into a mouse pain model (for example, intravenous but not limited), basal latencies are recorded before the treatment and test latencies are recorded at various specified times after the injection, and a time-response curve is recorded and AUC values are calculated to determine whether an analgesic effect is exerted on the mouse. The test compound is confirmed to be an antagonist-to-agonist allosteric modifier of the MOR upon observation of an analgesic effect.

Methods for synthesizing the compounds of Formula (I) are well known in the art. See, for example, R. Larock, Comprehensive Organic Transformations (2^nd Ed., VCH Publishers 1999); P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis (4th Ed., John Wiley and Sons 2007); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2^nd ed., John Wiley and Sons 2009); S. Miyazawa et al., “Benzimidazole Compound” WO 2006112442; M. R. Mautino et al., “IDO Inhibitors” WO2009132238; T. Axenrod et al., “Synthesis and Characterization of 5-Substituted 1,3-Diazacyclohexane Derivatives” J. Org. Chem. 2000, 65, 1200-1206; C. D. Magnusson et al., “Chemoenzymatic Synthesis of Symmetrically Structured Triacylglycerols Possessing Short-chain Fatty Acids” Tetrahedron, 2010, 66, 2728-2731. T. D. Cushing et al., Heterocyclic compounds and their uses. WO 2010151791 A1, Dec. 29, 2010. M. D. H. Bhuiyan et al., “Synthesis of Symmetric Diester-Functionalised Tröger's Base Analogues.” Eur. J. Org. Chem. 2010, 24, 4662-4670. Kelgtenrmans, H. et al., “A Fragment-Based Approach toward Substituted Trioxa[7]helicenes.” Org. Lett. 2012, 14, 5200-5203. Persichetti, R. A.; Harbeson, S. L. Substituted morpholinyl compounds. US20080261983 A1, Oct. 23, 2008. Wang, J.-Z.; Zhou. J.; Xu, C.; Sun, H.; Kürti, L.; Xu, Q.-L. “Symmetry in Cascade Chirality-Transfer Processes: A Catalytic Atroposelective Direct Arylation Approach to BINOL Derivatives.” J. Am. Chem. Soc. 2016, 138, 5202-5205. Plewe, M. B. et al., “Azaindole Hydroxamic Acids are Potent HIV-1 Integrase Inhibitors.” J. Med. Chem. 2009, 52, 7211-7219.

The compounds of Formula (I) thus prepared can be initially screened using in vitro assays, e.g., the FLIPR® calcium assay described in Example 488 below, for their potency in activating a MOR in cells. They can be subsequently evaluated using in vivo assays, e.g., a tail-flick test assay described in Example 489 below, for their efficacy in modulating the conformation of intercellular opioid receptor in a mammal. The selected compounds can be further tested to verify their efficacy in treating an opioid receptor-associated condition. For example, a compound can be co-administered with a MOR antagonist (e.g., naltroxone, naltrexone, samidorphan, cyprodime, clocinnamox, β-FNA, naloxonazine, or nalmefene) to an animal (e.g., a mouse) having an opioid receptor-associated condition and its therapeutic effects are then assessed. Based on the results, an appropriate dosage range and administration route can be determined.

Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications cited herein are incorporated by reference.

Shown in the Table 1 below are the structures and names of 486 exemplary compounds of Formula (I). The methods for preparing these compounds, as well as the analytical data for the compounds thus prepared, are set forth in Examples 1-486 below. The procedures for testing these compounds are described in Examples 488 and 489 also below.

All 486 compounds, when combined with a MOR antagonist, were found to activate a MOR to various degrees as indicated by their EC₅₀ and AUC values included in the following table. -: not available; TBD: to be determined.

TABLE 1
Exemplary compounds and their activities
			FLIPR Ca2+
No.	Structure	Name	EC50 (μM)	AUC
1		2-(3-Fluorophenyl)-3-(2- methoxyphenyl)thiazolidin-4- one	12.4	4897
2		2-(4-Fluorophenyl)-3-(2- methoxyphenyl)thiazolidin-4- one	19.0	10472
3		2-(3,5-Difluorophenyl)-3-(5- fluoro-2- methoxyphenyl)thiazolidin-4- one	—	—
4		2-(3,4-Difluorophenyl)-3-(5- fluoro-2- methoxyphenyl)thiazolidin-4- one	3.3	8199
5		3-(5-Fluoro-2- methoxyphenyl)-2-(3- fluorophenyl)thiazolidin-4- one	5.2	14312
6		3-(5-Fluoro-2- methoxyphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	3.9	9196
7		2-(3,5-Difluorophenyl)-3- (2,4- dimethoxyphenyl)thiazolidin- 4-one	—	—
8		3-(2,4-Dimethoxyphenyl)-2- (4-fluorophenyl)thiazolidin- 4-one	0.3	3020
9		2-(2-Chloro-4-fluorophenyl)- 3-(2,4- dimethoxyphenyl)thiazolidin- 4-one	—	—
10		3-(4,5-Difluoro-2- methoxyphneyl)-2-(4- fluorophenyl)thiazolidin-4- one	2.0	6152
11		3-(3,5-Difluoro-2- methoxyphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	1.6	5451
12		4-[2-(4-fluoro-phenyl)-4-oxo- thiazolidin-3-yl]-3-methoxy- benzoic acid	10.6	12252
14		2-(4-Fluorophenyl)-3-(4- methoxyphenyl)thiazolidin-4- one	3.9	5051
15		3-(3,4-Dimethoxyphenyl)-2- (4-fluorophenyl)thiazolidin- 4-one	10.0	10260
16		2-(4-Fluorophenyl)-3-(3,4,5- trimethoxyphenyl)thiazolidin- 4-one	8.3	10655
17		3-(3-Chloro-4- methoxyphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	—	—
18		3-(3-Chloro-4- (trifluoromethoxy)phenyl)-2- (4-fluorophenyl)thiazolidin- 4-one	—	—
19		3-(3-Chloro-4- (trifluoromethoxy)phenyl)-2- (3,5- difluorophenyl)thiazolidin-4- one	—	—
20		3-(3-Chloro-4-ethoxyphenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	7.3	4633
21		3-(3-Chloro-4-ethoxyphenyl)- 2-(3,5- difluorophenyl)thiazolidin-4- one	—	—
22		2-(3-Chlorophenyl)-3-(3,4- dichlorophenyl)thiazolidin-4- one	—	—
23		2-(3-Bromophenyl)-3-(3,4- dichlorophenyl)thiazolidin-4- one	TBD	TBD
24		2-(2-Bromophenyl)-3-(3,4- dichlorophenyl)thiazolidin-4- one	—	—
25		2-(4-Bromophenyl)-3-(3,4- dichlorophenyl)thiazolidin-4- one	—	—
26		3-(3-Chloro-4-fluorophenyl)- 2-(3- chlorophenyl)thiazolidin-4- one	—	—
27		3-(3-Chloro-4-fluorophenyl)- 2-(3,5- difluorophenyl)thiazolidin-4- one	—	—
28		3-(4-Bromo-3-chlorophenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	—	—
29		3-(4-Bromo-3-fluorophenyl)- 2-(3- bromophenyl)thiazolidin-4- one	—	—
30		3-(4-Bromo-3-fluorophenyl)- 2-(3- chlorophenyl)thiazolidin-4- one	—	—
31		3-(4-Bromo-3-fluorophenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	—	—
32		3-(4-Bromo-3-fluorophenyl)- 2-(3,5- difluorophenyl)thiazolidin-4- one	—	—
33		3-(3-Bromo-4-fluorophenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	—	—
34		3-(3-Bromo-4-fluorophenyl)- 2-(3,5- difluorophenyl)thiazolidin-4- one	—	—
35		2-fluoro-4-[2-(4-fluoro- phenyl)-4-oxo-thiazolidin-3- yl]-benzoic acid methyl ester	—	—
37		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3- yl)benzonitrile	8.2	3288
38		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)benzoic acid	5.4	5620
39		3-(4-Fluorophenyl)-2-(4- methoxyphenyl)thiazolidin-4- one	—	—
40		Methyl 3-fluoro-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]benzoate	—	—
41		3-Fluoro-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]benzoic acid	—	—
42		3-(4-Bromo-2,6- difluorophenyl)-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	—	—
43		3,5-Difluoro-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]benzonitrile	11.2	12926
44		3-Chloro-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]benzoic acid	3.3	13250
46		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzonitrile	10	15394
47		2-(4-Fluorophenyl)-3-(4- methoxy-2- methylphenyl)thiazolidin-4- one	3.3	12268
48		2-(4-Fluorophenyl)-3-(5- methoxy-2-methylphenyl)- 1,3-thiazolidin-4-one	—	—
49		3-(5-Fluoro-4-methoxy-2- methylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	1.8	13102
52		3-(4,5-Dimethoxy-2- methylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	3.6	7780
53		3-(4-(Dimethylamino)-2- methylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	0.5	6407
54		3-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-4- methylbenzoic acid	3.3	8906
55		3-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-4- methylbenzoic acid methyl ester	TBD	TBD
56		4-[2-(4-fluoro-phenyl)-4-oxo- thiazolidin-3-yl]-2-methyl- benzoic acid methyl acid	—	—
58		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	1.1	16361
59		Methyl 4-(2-(4- fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoate	2.6	11534
60		4-(2-(3-Fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	1.1	20700
62		4-(2-(3,4-Difluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	1.6	21586
64		4-(2-(3,5-Difluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	6.0	9368
66		4-(2-(4-Fluoro-2- methylphenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	—	—
68		4-(2-(4-Fluoro-3- methylphenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	6.4	7951
70		4-(2-(3-Fluoro-4- methylphenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	—	—
72		4-(2-(5-Fluoro-2- methylphenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	0.4	3237
74		3-Methyl-4-(4-oxo-2-(3- (trifluoromethyl)phenyl) thiazolidin-3-yl)benzoic acid	4.9	13835
76		3-Methyl-4-(4-oxo-2-(4- (trifluoromethyl)phenyl) thiazolidin-3-yl)benzoic acid	—	—
78		4-[2-(4-methoxy-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid	6.0	9368
80		4-[2-(4-carboxy-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid	—	—
82		4-[2-(4-methanesulfonyl- phenyl)-4-oxo-thiazolidin-3- yl]-3-methyl-benzoic acid	—	—
84		4-[2-(4-chloro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid	7.2	5509
86		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-5- methylphthalic acid	6.6	9544
90		3-(5-Acetyl-2-methylphenyl)- 2-(4-fluorophenyl)-1,3- thiazolidin-4-one	8.4	9401
92		2-(4-Fluorophenyl)-3-[2- methyl-5- (trifluoromethyl)phenyl]-1,3- thiazolidin-4-one	10.0	12278
93		Methyl {4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenoxy}acetate	6.4	11009
95		{4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylphenoxy}acetic acid	—	—
96		Methyl {4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenyl}acetate	10.0	9657
101		{4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylphenyl}acetic acid	7.2	10302
102		3-(2,4-Dimethylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	5.3	9439
103		3-(2,4-Dimethylphenyl)-2-(3- fluorophenyl)thiazolidin-4- one	—	—
104		2-(3,4-Difluorophenyl)-3- (2,4- dimethylphenyl)thiazolidin-4- one	—	—
105		3-(2,5-Dimethylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	TBD	TBD
106		3-(2,5-Dimethylphenyl)-2-(3- fluorophenyl)thiazolidin-4- one	—	—
107		2-(3,4-Difluorophenyl)-3- (2,5- dimethylphenyl)thiazolidin-4- one	—	—
108		3-(2-Fluoro-6-methylphenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	3.3	15782
109		3-(3-Fluoro-2-methylphenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	2.6	9614
110		3-(4-Fluoro-2-methylphenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	3.8	6308
111		3-(4-Bromo-2- methylphenyl)-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	11.0	20920
112		3-(5-Fluoro-2-methylphenyl)- 2-(4- fluorophenyl)thiazolidin-4- one	1.1	8847
113		3-(5-Fluoro-2-methylphenyl)- 2-(3- fluorophenyl)thiazolidin-4- one	1.3	6998
114		3-(5-Fluoro-2-methylphenyl)- 2-(4- (methylsulfonyl)phenyl) thiazolidin-4-one	—	—
115		4-(3-(5-Fluoro-2- methylphenyl)-4- oxothiazolidin-2- yl)benzonitrile	—	—
116		3-[3-(5-fluoro-2-methyl- phenyl)-4-oxo-thiazolidin-2- yl]-benzonitrile	—	—
117		2-(4-ethyl-phenyl)-3-(5- fluoro-2-methyl-phenyl)- thiazolidin-4-one	13.5	7880
118		3-(5-fluoro-2-methyl- phenyl)-2-(4-methylsulfanyl- phenyl)-thiazolidin-4-one	—	—
119		3-(5-Fluoro-2-methylphenyl)- 2-(3-fluoro-4- methylphenyl)thiazolidin-4- one	—	—
120		3-(5-Fluoro-2-methylphenyl)- 2-(4-fluoro-3- methylphenyl)thiazolidin-4- one	—	—
121		2-(3,4-Difluorophenyl)-3-(5- fluoro-2- methylphenyl)thiazolidin-4- one	—	—
122		2-(3,5-Difluorophenyl)-3-(5- fluoro-2- methylphenyl)thiazolidin-4- one	3.6	7010
123		2-(4-Chloro-3-fluorophenyl)- 3-(5-fluoro-2- methylphenyl)thiazolidin-4- one	0.5	4228
124		2-(3-Chloro-4-fluorophenyl)- 3-(5-fluoro-2- methylphenyl)thiazolidin-4- one	3.8	8532
125		2-(4-Fluoro-3-methoxy- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
126		2-(3-Fluoro-4-methoxy- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
127		3-(5-Fluoro-2-methyl- phenyl)-2-(3-fluoro-4- trifluoromethyl-phenyl)- thiazolidin-4-one	—	—
128		3-(5-Fluoro-2-methyl- phenyl)-2-(4-fluoro-3- trifluoromethyl-phenyl)- thiazolidin-4-one	—	—
129		3-(5-Fluoro-2-methyl- phenyl)-2-(3-fluoro-5- trifluoromethyl-phenyl)- thiazolidin-4-one	—	—
130		3-(5-Fluoro-2-methyl- phenyl)-2-(3-fluoro-5- methyl-phenyl)-thiazolidin-4- one	—	—
131		2-(3-Fluoro-4-hydroxy- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
134		2-(2,3-Dihydro- benzo[1,4]dioxin-6-yl)-3-(5- fluoro-2-methyl-phenyl)- thiazolidin-4-one	—	—
135		2-(3-Bromo-5-chloro- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
136		3-(5-Fluoro-2-methyl- phenyl)-2-(3,4,5-trifluoro- phenyl)-thiazolidin-4-one	—	—
137		2-(3,4-Difluoro-5-methyl- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
138		2-(4-Fluoro-3,5-dimethyl- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
139		2-(3-Vhloro-4-ethoxy-5- fluoro-phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
140		2-(3,5-Difluoro-4-methoxy- phenyl)-3-(5-fluoro-2- methyl-phenyl)-thiazolidin-4- one	—	—
141		3-(5-Fluoro-2-methyl- phenyl)-2-(4-hydroxy-3,5- dimethyl-phenyl)-thiazolidin- 4-one	—	—
144		2-(3-Bromo-4-hydroxy-5- methoxy-phenyl)-3-(5-fluoro- 2-methyl-phenyl)- thiazolidin-4-one	—	—
147		3-(5-Chloro-2- methylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	3.2	11516
148		3-(5-Chloro-2- methylphenyl)-2-(3- fluorophenyl)thiazolidin-4- one	—	—
149		3-(5-Bromo-2- methylphenyl)-2-(4- fluorophenyl)thiazolidin-4- one	4.4	4427
150		3-(5-Bromo-2- methylphenyl)-2-(3- fluorophenyl)thiazolidin-4- one	—	—
151		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N- hydroxy-3-methylbenzene carboximidamide	3.4	10591
152		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid ethyl ester	6.3	14743
154		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzoic acid	3.7	15447
156		3-Ethyl-4-[2-(4-fluoro- phenyl)-4-oxo-thiazolidin-3- yl]-benzoic acid ethyl ester	6.2	11998
157		3-Ethenyl-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]benzoic acid	10.0	5903
159		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(methylsulfonyl)- benzamide	1.7	10396
160		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(propylsulfonyl)- benzamide	4.3	13549
162		N-(Ethylsulfonyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	9.1	13767
163		N-(Butylsulfonyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	1.2	11389
165		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(2- propanylsulfonyl)-benzamide	22.6	11927
167		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[(2- methylpropyl)sulfonyl] benzamide	3.4	9905
169		N-(Cyclopropylsulfonyl)-4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	3.0	13189
171		N-(Cyclohexylsulfonyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	3.7	10272
173		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N- sulfamoylbenzamide	5.3	14841
174		N-(Dimethylsulfamoyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	3.8	12074
175		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N- [(trifluoromethyl)sulfonyl] benzamide	1.6	13866
176		N-(Benzylsulfonyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	2.0	10601
177		N-[(3- Fluorobenzyl)sulfonyl]-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	2.2	16276
179		N-[(3,5- Dimethylbenzyl)sulfonyl]-4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	1.1	14442
183		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(phenylsulfonyl)- benzamide	1.9	12230
185		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[(4- methylphenyl)sulfonyl] benzamide	0.6	18048
186		N-[(4-Ethylphenyl)sulfonyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	0.6	18048
187		N-[(4- Cyanophenyl)sulfonyl]-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	3.3	12927
188		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-[(4- methoxyphenyl)sulfonyl]-3- methylbenzamide	0.7	21983
189		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-{[4- (trifluoromethoxy)phenyl] sulfonyl}benzamide	1.1	9544
190		Ethyl 4-({4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoyl}sulfamoyl) benzoate	2.4	16512
192		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[(2,4,6- trimethylphenyl)- sulfonyl]benzamide	1.4	11866
194		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-[(3- fluorophenyl)sulfonyl]-3- methylbenzamide	0.2	19019
196		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-[(4- fluorophenyl)sulfonyl]-3- methylbenzamide	1.1	15620
198		N-[(4- Chlorophenyl)sulfonyl]-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	0.5	13313
200		N-[(4- Bromophenyl)sulfonyl]-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	0.2	12340
202		N-{[4- (Acetylamino)phenyl] sulfonyl}-4-[2-(4- fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzamide	0.6	17087
204		N-[(4-Chloro-2- fluorophenyl)sulfonyl]-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	0.1	15287
206		N-[(2,4- Difluorophenyl)sulfonyl]-4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	0.2	9637
208		N-[(4-Chloro-2,5- dimethylphenyl)sulfonyl]-4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	0.4	13512
210		N-{[5-(Dimethylamino)-1- naphthalenyl]sulfonyl}-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	0.7	9425
211		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(3- pyridinylsulfonyl)- benzamide	0.3	8779
213		N-[(3,5-Dimethyl-1,2-oxazol- 4-yl)sulfonyl]-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	0.9	9005
215		N-Ethoxy-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	4.1	10945
216		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N- methoxy-3-methylbenzamide	4.2	14236
217		N-(Benzyloxy)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	4.1	9543
218		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-phenoxybenzamide	3.6	12768
219		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N- hydroxy-3-methylbenzamide	6.4	14222
220		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzohydrazide	4.9	13871
221		2-(4-Fluorophenyl)-3-[2- methyl-4-(1H-tetrazol-5- yl)phenyl]-1,3-thiazolidin-4- one	0.2	8284
222		2-(4-Fluorophenyl)-3-[2- methyl-4-(3- thiophenyl)phenyl]-1,3- thiazolidin-4-one	—	—
223		2-(4-Fluorophenyl)-3-[2- methyl-4-(2- thiophenyl)phenyl]-1,3- thiazolidin-4-one	—	—
224		2-(4-Fluorophenyl)-3-[4-(2- furanyl)-2-methylphenyl]- 1,3-thiazolidin-4-one	11.7	7384
225		3-[4-(3,5-Dimethyl-1,2- oxazol-4-yl)-2- methylphenyl]-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	—	—
226		2-(4-Fluorophenyl)-3-[2- methyl-4-(1-methyl-1H- pyrazol-4-yl)phenyl]-1,3- thiazolidin-4-one	—	—
227		2-(4-Fluorophenyl)-3-[2- methyl-4-(5-methyl-1,3,4- oxadiazol-2-yl)phenyl]-1,3- thiazolidin-4-one	5.5	15410
228		2-(4-Fluorophenyl)-3-{2- methyl-4-[5- (trifluoromethyl)-1,3,4- oxadiazol-2-yl]phenyl}-1,3- thiazolidin-4-one	8.6	7035
229		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid propyl ester	9.7	13237
230		4-[2-(3,4-Difluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid propyl ester	—	—
231		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid isopropyl ester	2.7	15328
234		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid butyl ester	9.0	10062
235		2-Methyl-2-propanyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	6.8	15203
236		1-Methylcyclopropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	4.7	13348
237		3,3-Dimethylbutyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
238		2-Cyclopropylethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	12.3	15409
239		Cyclopentylmethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	9.4	4342
240		Cyclohexylmethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
241		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid adamantan-1-ylmethyl ester	—	—
242		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-benzoic acid adamantan-1-yl ester	—	—
245		Phenyl 4-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
246		3-Nitrophenyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
247		2-Methoxyphenyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
248		2,3-Dihydro-1H-inden-5-yl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
249		2,3-Dihydro-1H-inden-4-yl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
250		4-(Trifluoromethyl)benzyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
251		1-Phenylethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
252		1-[4- (trifluoromethyl)phenyl]ethyl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
253		3-Phenylpropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	11.2	6717
254		[1-(4- Chlorophenyl)cyclopropyl] methyl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
255		[1-(4- Chlorophenyl)cyclopentyl] methyl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
258		2-(Benzyloxy)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	3.3	6353
259		1,3-Benzodioxol-5-ylmethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
260		2-(2-Chlorophenoxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
261		3-Pyridinylmethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	2.9	11434
262		2-(4-Pyridinyl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
263		3-(2-Pyridinyl)propyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	9.2	14918
264		2,3-Dihydro-1,4- benzodioxin-2-ylmethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
265		2-(3-Thiophenyl)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
266		2-(4-Methyl-1,3-thiazol-5- yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	4.6	12653
267		3-Methoxypropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	6.4	15960
268		2-Oxopropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	3.8	12787
269		2-Cyanoethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	12.3	14183
270		2-(Methylsulfanyl)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	6.4	18775
271		2-(Ethylsulfanyl)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	14.0	11997
272		2-(Acetyloxy)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	2.8	12131
273		[(2,2- Dimethylpropanoyl)oxy] methyl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	5.7	12265
274		Tetrahydro-3-furanyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
275		Tetrahydro-2-furanylmethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	26.9	11236
276		(2,2-Dimethyl-1,3-dioxolan- 4-yl)methyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	6.3	15090
277		2,2-Dimethyl-1,3-dioxan-5-yl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	6.1	14634
278		1,3-Dimethoxy-2-propanyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
279		1-Methoxy-2-propanyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	4.1	10883
280		2-(2-Methoxyethoxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	7.1	15386
281		2-Ethoxyethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	4.5	9792
282		2-(2-Ethoxyethoxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
283		3-Methoxy-3-methylbutyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
284		3-(Trimethylsilyl)propyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
285		1-Butoxy-1-oxo-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
286		2,2,2-Trifluoroethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	9.2	13001
287		2-(Acetylamino)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
288		2-[2- (Acetylamino)ethoxy]ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
290		2-(Dimethylamino)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	10.0	14778
291		3-(Dimethylamino)propyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	1.9	8913
292		2-(Diethylamino)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	3.1	10056
293		2-[Ethyl(phenyl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
294		2-(1-Pyrrolidinyl)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	2.9	14394
295		2-(1-Piperidinyl)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	2.8	10426
296		2-(4-Morpholinyl)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	2.3	14052
297		3-(4-Morpholinyl)propyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	8.1	13753
298		3-(1-Piperidinyl)propyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	1.7	9283
299		2-(1-Acetyl-4- piperidinyl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	5.0	10053
300		1-Methyl-3-pyrrolidinyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	1.6	12918
301		1-Methyl-4-piperidinyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	0.9	9593
302		(1-Methyl-3- piperidinyl)methyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
303		2-(2-Aminoethoxy)ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	7.0	9530
306		2-[2- (Dimethylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	6.2	7531
307		2-[2-(1- Pyrrolidinyl)ethoxy]ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	8.7	14731
309		1,3-Bis(acetylamino)-2- propanyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	TBD	TBD
310		1,3-Bis(acetyloxy)-2- propanyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	3.3	12428
311		(5-Methyl-2-oxo-1,3-dioxol- 4-yl)methyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	4.0	12968
312		1- {[(Cyclohexyloxy)carbonyl] oxy}ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
313		1-[(Ethoxycarbonyl)oxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	5.1	18341
314		{[(2- Propanyloxy)carbonyl]oxy} methyl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	4.5	10852
315		6-O-{4-[2-(4-Fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}-D- glucopyranose	TBD	TBD
319		6-O-{4-[2-(4-Fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}-D- galactopyranose	TBD	TBD
321		3-O-{4-[2-(4-Fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}-D- glucopyranose	TBD	TBD
323		O-{4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}-L-tyrosine	TBD	TBD
326		1-[(3- Pyridinylcarbonyl)amino]-2- propanyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	2.4	12342
328		3-{[2-({4-[2-(4- Fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoyl}oxy)propyl] carbamoyl}-1- methylpyridinium iodide	11.8	9505
329		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzamide	1.7	13749
331		N-Methyl-4-(2-(4- fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzamide	5.7	10998
332		4-(2-(4-Fluorophenyl)-4- oxothiazolidin-3-yl)-N,N,3- trimethylbenzamide	10.0	14442
334		4-[2-(4-Fluoro-phenyl)-4- oxo-thiazolidin-3-yl]-3- methyl-N-propyl-benzamide	5.7	9672
335		N-ethyl-4-[2-(4-Fluoro- phenyl)-4-oxo-thiazolidin-3- yl]-3-methyl-benzamide	4.2	11180
336		N-Cyclopropyl-4-[2-(4- fluoro-phenyl)-4-oxo- thiazolidin-3-yl]-3-methyl- benzamide	11.0	11347
337		N-Cyclobutyl-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	0.3	8936
338		N-Cyclopentyl-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	4.4	9215
339		N-Cyclohexyl-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	10.0	7164
340		N-[2-(Dimethylamino)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	10.0	9445
341		N-(2-(Diethylamino)ethyl)-4- (2-(4-fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzamide	3.3	9983
342		N-[3- (Dimethylamino)propyl]-4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	3.3	16741
343		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-(3- methoxypropyl)-3- methylbenzamide	3.7	11934
344		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[2-(4- morpholinyl)ethyl]benzamide	7.0	12329
345		N-(3-Aminopropyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
347		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[3-(4- morpholinyl)propyl]benzamide	8.2	12967
348		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-[3- (1H-imidazol-1-yl)propyl]-3- methylbenzamide	8.8	13641
349		3-(4-{[(3R)-3- (Dimethylamino)-1- pyrrolidinyl]carbonyl}-2- methylphenyl)-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	10.0	11923
350		4-({4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}amino)-1- piperidinecarboxylate	4.4	12979
351		3-{4-[(3-Amino-1- pyrrolidinyl)carbonyl]-2- methylphenyl}-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	10.0	11205
353		2-(4-Fluorophenyl)-3-{4-[(3- hydroxy-1- piperidinyl)carbonyl]-2- methylphenyl}-1,3- thiazolidin-4-one	7.3	11991
354		2-(4-Fluorophenyl)-3-{4-[(3- hydroxy-1- azetidinyl)carbonyl]-2- methylphenyl}-1,3- thiazolidin-4-one	3.6	14863
355		2-(4-Fluorophenyl)-3-(4- {[(2S)-2-(methoxymethyl)-1- pyrrolidinyl]carbonyl}-2- methylphenyl)-1,3- thiazolidin-4-one	10.0	12691
356		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-(2- methoxyethyl)-N,3- dimethylbenzamide	11.8	9505
357		3-{4-[(4-Amino-1- piperidinyl)carbonyl]-2- methylphenyl}-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	10.0	12663
359		N-(Adamantan-1-yl)-4-(2-(4- fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzamide	—	—
360		N-(Adamantan-1-ylmethyl)- 4-(2-(4-fluorophenyl)-4- oxothiazolidin-3-yl)-3- methylbenzamide	—	—
361		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-phenylbenzamide	8.8	6128
362		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-(4- methoxyphenyl)-3- methylbenzamide	—	—
363		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(4- methylphenyl)benzamide	—	—
364		N-(4-Fluorophenyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
365		N-(4-Chlorophenyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
366		N-(3-Fluorophenyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
367		N-(3-Chlorophenyl)-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
368		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-(3- methoxyphenyl)-3- methylbenzamide	6.7	8915
369		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[4- (trifluoromethyl)phenyl] benzamide	—	—
370		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(3- methylphenyl)benzamide	—	—
371		N-(3,5-Dimethylphenyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
372		N-(2,3-Dihydro-1H-inden-5- yl)-4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzamide	—	—
373		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-(2- methoxyphenyl)-3- methylbenzamide	13.6	12223
374		N-Benzyl-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	5.1	6726
375		N-(4-Chloro-2-fluorobenzyl)- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	3.8	4172
376		N-(2,5-Difluorobenzyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	1.0	8823
377		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-[3- (trifluoromethyl)benzyl] benzamide	12.5	12637
378		N-(3,4-Difluorobenzyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	6.3	15891
379		N-(3,4-Dichlorobenzyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
380		N-(3,5-Dimethoxybenzyl)-4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	8.2	10013
381		N-(3,5-Difluorobenzyl)-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	8.2	6035
382		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(1- naphthalenylmethyl) benzamide	—	—
383		N-[2-(2-Fluorophenyl)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	6.9	5504
384		N-[2-(2-Chlorophenyl)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	6.6	5742
385		N-[2-(3-Fluorophenyl)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	3.9	7501
386		N-[2-(3-Chlorophenyl)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	4.2	5727
387		N-[2-(4-Fluorophenyl)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzamide	4.0	5770
388		N-[2-(4-Chlorophenyl)ethyl]- 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methybenzamide	2.0	2951
389		N-[2-(2,4- Dichlorophenyl)ethyl]-4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	—	—
390		Oxydi-2,1-ethanediyl bis{4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate}	13.9	7399
391		{2-(4-Fluorophenyl)-3-[4- (methoxycarbonyl)-2- methylphenyl]-4-oxo-1,3- thiazolidin-5-yl}acetic acid	—	—
393		Ethyl 4-[5-(2-ethoxy-2- oxoethyl)-2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
394		3-(5-Fluoro-2-methylphenyl)- 2-(4- fluorophenyl)thiazolidin-4- one 1,1-dioxide	—	—
395		3-(3,4-Dimethyl-1,2-oxazol- 5-yl)-2-(4-fluorophenyl)-1,3- thiazolidin-4-one	12.0	7107
396		2-(4-Fluorophenyl)-3-(5- methyl-1,2-oxazol-4-yl)-1,3- thiazolidin-4-one	—	—
397		2-(3,5-Difluorophenyl)-3- (1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)thiazolidin-4- one	—	—
398		2-(2,4-Difluorophenyl)-3- (1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)thiazolidin-4- one\	—	—
399		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(4- (methylthio)phenyl)thiazolidin- 4-one	—	—
400		4-(3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-4- oxothiazolidin-2- yl)benzonitrile	—	—
401		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(4- methoxyphenyl)thiazolidin-4- one	—	—
402		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(4- ethylphenyl)thiazolidin-4-one	—	—
403		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(4- (trifluoromethyl)phenyl) thiazolidin-4-one	—	—
404		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(3- fluorophenyl)thiazolidin-4- one	21.8	7127
405		2-(4-(tert-Butyl)phenyl)-3- (1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)thiazolidin-4- one	—	—
406		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(2- fluorophenyl)thiazolidin-4- one	31.2	9974
407		2-(4-Bromophenyl)-3-(1,5- dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4- yl)thiazolidin-4-one	—	—
408		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2- phenylthiazolidin-4-one	12.7	9281
409		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(4- (dimethylamino)phenyl) thiazolidin-4-one	—	—
410		2-(4-Chlorophenyl)-3-(1,5- dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4- yl)thiazolidin-4-one	—	—
411		3-(1,5-Dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H- pyrazol-4-yl)-2-(4- fluorophenyl)thiazolidin-4- one	20.0	8099
412		Methyl 4-[2-(5-fluoro-2- pyridinyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
413		Methyl 4-(2-cyclohexyl-4- oxo-1,3-thiazolidin-3-yl)-3- methylbenzoate	—	—
414		Methyl 3-methyl-4-[4-oxo-2- (2-pentanyl)-1,3-thiazolidin- 3-yl]benzoate	—	—
415		Methyl 3-methyl-4-[2-(2- methylpropyl)-4-oxo-1,3- thiazolidin-3-yl]benzoate	—	—
416		Methyl 4-[2-(3-furanyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	11.7	6514
417		3-Benzyl-2-(4-fluorophenyl)- 1,3-thiazolidin-4-one	—	—
418		4-{[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3- yl]methyl}benzoic acid	—	—
421		3-[(5-Fluoro-2- methylphenyl)sulfonyl]-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	—	—
423		Methyl 4-{[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3- yl]sulfonyl}benzoate	—	—
424		2-(4-Fluorophenyl)-3-[(2- methylphenyl)sulfonyl]-1,3- thiazolidin-4-one	—	—
425		Methyl 4-{[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]amino}-3- methylbenzoate	—	—
427		3-[(5-Fluoro-2- methylphenyl)amino]-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	—	—
429		(2Z)-3-(5-Fluoro-2- methylphenyl)-2-[(4- fluorophenyl)imino]-1,3- thiazolidin-4-one	—	—
431		Methyl 4-{(2Z)-2-[(4- fluorophenyl)imino]-4-oxo- 1,3-thiazolidin-3-yl}-3- methylbenzoate	—	—
433		(2Z)-2-[(4- Fluorophenyl)imino]-3-(4- methoxyphenyl)-1,3- thiazolidin-4-one	—	—
435		(2Z)-3-(3-Chlorophenyl)-2- [(4-fluorophenyl)imino]-1,3- thiazolidin-4-one	—	—
437		4-[5-(4-Fluorophenyl)-1H- pyrazol-1-yl]-3- methylbenzoic acid	—	—
442		4-[3-(4-Fluorophenyl)-4H- 1,2,4-triazol-4-yl]-3- methylbenzoic acid	—	—
446		2-(2-Hydroxyethoxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
449		2-[2- (Methylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
453		2-[2-(Pyridin-2- ylmethoxy)ethoxy]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
456		2-[2-(Pyridin-3- ylmethoxy)ethoxy]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
458		2-[2-(Pyridin-4- ylmethoxy)ethoxy]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
460		2-[2-(2- Methoxyethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
461		2-[2-(Morpholin-4- yl)ethoxy]ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
463		5-(Morpholin-4-yl)pentyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
465		2-[2-(Acetyloxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
467		2-[2-(Pyrrolidin-2- ylmethoxy)ethoxy]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
471		2-[(2- Methoxyethyl)(methyl)amino] ethyl 4-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
474		Octyl 4-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
475		2-Ethoxy-2-oxoethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
476		(2-Methylcyclopropyl)methyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
477		3,3-Diethoxypropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
478		(1-Methylpiperidin-4- yl)methyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
479		Tetrahydro-2H-pyran-4-yl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
480		3-Methoxybutyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
481		(2-Oxo-1,3-dioxolan-4- yl)methyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
482		1-Ethoxypropan-2-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
483		1-(Morpholin-4-yl)propan-2- yl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
484		2-Phenylpropan-2-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
485		4,4-Dimethyl-2- oxotetrahydrofuran-3-yl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
486		Benzyl 4-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
487		2-Methoxyethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
488		2,3-Dihydroxypropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
489		Oxetan-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
490		(3-Methyloxetan-3-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
491		3-Hydroxy-2- (hydroxymethyl)-2- methylpropyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
492		Cyclobutyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
493		tert-Butyl 4-({4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoyl}oxy)piperidine- 1-carboxylate	—	—
494		Piperidin-4-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
495		2-(4,4-Difluoropiperidin-1- yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
497		2-(3,3-Difluoropyrrolidin-1- yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
499		tert-Butyl 3-({4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoyl}oxy)azetidine- 1-carboxylate	—	—
500		Azetidin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
501		1-Methylazetidin-3-yl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
503		3-{4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}oxy)-1,1- dimethylazetidinium	—	—
504		1-tert-Butylazetidin-3-yl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
505		1-(Oxetan-3-yl)azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
507		2-[(3-Methyloxetan-3- yl)methoxy]-2-oxoethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
508		2-[(3R)-3-Methoxypyrrolidin- 1-yl]ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
510		2-[(3S)-3-Methoxypyrrolidin- 1-yl]ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
512		Octane-1,8-diyl bis{4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate}	—	—
513		1-(Pyridin-3-yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
514		1-(Pyridin-4-yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
515		2-(Pyridin-4-yl)propan-2-yl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
516		Pyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
517		Pyridin-2-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
518		Pyridin-4-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
519		4-Methylpyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
520		6-Methylpyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
521		5-Methylpyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
522		2-Fluoropyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
523		6-Fluoropyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
524		5-Fluoropyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
525		5-Chloropyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
526		6-Chloropyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
527		2-Chloropyridin-3-yl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
528		2-(Morpholin-4- ylmethyl)pyridin-3-yl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
530		5-(Morpholin-4-yl)pyridin-3- yl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
531		6-(Morpholin-4-yl)pyridin-3- yl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
532		2-(Pyridin-2-yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
533		2-({4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}oxy)ethyl pyridine-3-carboxylate	—	—
536		2-({4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}oxy)ethyl pyridine-4-carboxylate	—	—
538		2-({4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}oxy)ethyl pyridine-2-carboxylate	—	—
540		2-(Pyridin-4-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
542		2-(Pyridin-2-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
544		2-(Pyridin-3-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
546		2-(Pyridin-3-yloxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
548		2-(Pyridin-2-yloxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
550		2-(Pyridin-4-yloxy)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
552		5-(Pyridin-2- ylmethoxy)pentyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
556		2-[(Pyridin-3- ylmethyl)sulfanyl]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
558		2-[(Pyridin-2- ylmethyl)sulfanyl]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
560		2-[(Pyridin-4- ylmethyl)sulfanyl]ethyl 4-[2- (4-fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
562		2-(Pyridin-4-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
564		2-(Pyridin-2-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
566		2-(Pyridin-3-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
568		2-(Pyridin-4-ylamino)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
571		2-(Pyridin-2-ylamino)ethyl 4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
574		2-(1-Methyl-1H-imidazol-5- yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
575		2-(1-Methyl-1H-imidazol-2- yl)ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
576		Ethyl 4-[2-(3,4- difluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
578		Methyl 4-{2-[4-fluoro- 2,3,5,6-d4-phenyl]-4-oxo-1,3- thiazolidin-3-yl}-3- methylbenzoate	—	—
579		4-{2-[4-Fluoro-2,3,5,6-d4- phenyl]-4-oxo-1,3- thiazolidin-3-yl}-3- methylbenzoic acid	1.93	14761
580		Ethyl 4-{2-[4-fluoro-2,3,5,6- d4-phenyl]-4-oxo-1,3- thiazolidin-3-yl}-3- methylbenzoate	4.26	14441
581		4-[2-(4-Fluorophenyl)-4-oxo- 2-d1-1,3-thiazolidin-3-yl]-3- methylbenzoic acid	3.31	13703
583		Ethyl 4-[2-(4-fluorophenyl)- 4-oxo-2-d1-1,3-thiazolidin-3- yl]-3-methylbenzoate	4.42	11275
584		6-(Methoxymethyl)pyridin-3- yl 4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoate	—	—
587		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methyl-N-(tetrahydro-2H- pyran-2-yloxy)benzamide	—	—
588		N-Ethoxy-4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzamide	9.27	9986
589		S-Ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzenecarbothioate	—	—
591		2-(2-Methoxyethoxy)ethyl 4- ({4-[2-(4-fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylbenzoyl}sulfamoyl) benzoate	10.3	13033
593		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-[(2- methoxyethyl)sulfonyl]-3- methylbenzamide	2.21	11543
597		4-[2-(4-Fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-N-{[2- (2- methoxyethoxy)ethyl] sulfonyl}-3-methylbenzamide	1.12	10720
600		2-(4-Fluorophenyl)-3-[2- methyl-4-(2,2,2-trifluoro-1- hydroxyethyl)phenyl]-1,3- thiazolidin-4-one	6.75	13110
605		Ethyl {4-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
607		Oxetan-3-yl {4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
608		2-(Morpholin-4-yl)ethyl {4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
609		Propan-2-yl {4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
610		Pyridin-3-ylmethyl {4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
611		2-(Dimethylamino)ethyl {4- [2-(4-fluorophenyl)-4-oxo- 1,3-thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
612		2-(Acetyloxy)ethyl {4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenoxy}acetate	—	—
614		2-(4-Fluorophenyl)-3-(4- hydroxy-2-methylphenyl)- 1,3-thiazolidin-4-one	—	—
615		3-(5-Fluoro-4-hydroxy-2- methylphenyl)-2-(4- fluorophenyl)-1,3-thiazolidin- 4-one	—	—
616		2-(4-Fluorophenyl)-3-[2- methyl-4-(1,3-thiazol-4- ylmethoxy)phenyl]-1,3- thiazolidin-4-one	—	—
617		Ethyl 4-{4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylphenoxy}butanoate	—	—
618		2-(4-Fluorophenyl)-3-{2- methyl-4-[(2-methylprop-2- en-1-yl)oxy]phenyl}-1,3- thiazolidin-4-one	—	—
619		2-(4-Fluorophenyl)-3-[2- methyl-4-(pent-2-yn-1- yloxy)phenyl]-1,3- thiazolidin-4-one	—	—
620		2-(4-Fluorophenyl)-3-{2- methyl-4-[2-(morpholin-4- yl)ethoxy]phenyl}-1,3- thiazolidin-4-one	—	—
621		{4-[2-(4-Fluorophenyl)-4- oxo-1,3-thiazolidin-3-yl]-3- methylphenyl}acetonitrile	—	—
624		2-(4-Fluorophenyl)-3-[2- methyl-4-(1H-tetrazol-5- ylmethyl)phenyl]-1,3- thiazolidin-4-one	—	—
625		2-(4-Fluorophenyl)-3- (pyridin-3-yl)-1,3-thiazolidin- 4-one	—	—
626		2-(4-Fluorophenyl)-3- (pyridin-2-yl)-1,3-thiazolidin- 4-one	—	—
627		2-(4-Fluorophenyl)-3-(6- methoxypyridin-3-yl)-1,3- thiazolidin-4-one	—	—
628		2-(4-Fluorophenyl)-3-(6- methylpyridin-3-yl)-1,3- thiazolidin-4-one	—	—
629		2-(4-Fluorophenyl)-3-(3- methylpyridin-2-yl)-1,3- thiazolidin-4-one	10	4804
630		2-(4-Fluorophenyl)-3- (pyrazin-2-yl)-1,3- thiazolidin-4-one	—	—
631		2-(4-Fluorophenyl)-3- (pyrimidin-2-yl)-1,3- thiazolidin-4-one	—	—
632		2-(4-Fluorophenyl)-3- (pyrimidin-4-yl)-1,3- thiazolidin-4-one	—	—
633		Ethyl 5-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-4- methylpyridine-2-carboxylate	—	—
635		Ethyl 5-[2-(4-fluorophenyl)- 4-oxo-1,3-thiazolidin-3-yl]-6- methylpyridine-2-carboxylate	10.9	9843
639		2-(4-Fluorophenyl)-3-(1,3- thiazol-2-yl)-1,3-thiazolidin- 4-one	—	—
640		3-(5-tert-Butyl-1,2-oxazol-3- yl)-2-(4-fluorophenyl)-1,3- thiazolidin-4-one	14.2	9872
641		2-(4-Fluorophenyl)-3-(1,2- oxazol-3-yl)-1,3-thiazolidin- 4-one	—	—
642		2-(4-Fluorophenyl)-3-(5- methyl-1,3,4-thiadiazol-2-yl)- 1,3-thiazolidin-4-one	—	—
643		2-(4-Fluorophenyl)-3-(4- methyl-1,3-thiazol-2-yl)-1,3- thiazolidin-4-one	—	—
644		Methyl 3-methyl-4-[4-oxo-2- (pyridin-2-yl)-1,3-thiazolidin- 3-yl]benzoate	—	—
645		Methyl 3-methyl-4-[4-oxo-2- (pyridin-3-yl)-1,3-thiazolidin- 3-yl]benzoate	—	—
646		Methyl 3-methyl-4-[4-oxo-2- (1,3-thiazol-2-yl)-1,3- thiazolidin-3-yl]benzoate	—	—
647		Methyl 4-[2-(1-benzofuran-2- yl)-4-oxo-1,3-thiazolidin-3- yl]-3-methylbenzoate	—	—
648		Methyl 3-methyl-4-[4-oxo-2- (thiophen-3-yl)-1,3- thiazolidin-3-yl]benzoate	2.01	9356
649		3-(4-Fluoro-2-methylphenyl)- 2-(thiophen-3-yl)-1,3- thiazolidin-4-one	—	—
650		3-(5-Fluoro-2-methylphenyl)- 2-(thiophen-3-yl)-1,3- thiazolidin-4-one	—	—
651		3-(5-Chloro-2- methylphenyl)-2-(thiophen-3- yl)-1,3-thiazolidin-4-one	—	—
652		Ethyl {3-methyl-4-[4-oxo-2- (thiophen-3-yl)-1,3- thiazolidin-3- yl]phenoxy}acetate	—	—
654		3-(4,5-Dimethoxy-2- methylphenyl)-2-(thiophen-3- yl)-1,3-thiazolidin-4-one	—	—
655		3-(4-Methoxy-2- methylphenyl)-2-(thiophen-3- yl)-1,3-thiazolidin-4-one	—	—
656		1-(5-Fluoro-2-methylphenyl)- 5-(4-fluorophenyl)pyrrolidin- 2-one	—	—
658		Methyl 4-[2-(4- fluorophenyl)-5- oxopyrrolidin-1-yl]-3- methylbenzoate	—	—
660		(−)-Ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—
661		(+)-Ethyl 4-[2-(4- fluorophenyl)-4-oxo-1,3- thiazolidin-3-yl]-3- methylbenzoate	—	—

Shown in Table 2 below are activities of tail-flick test are presented in two ranges, i.e., ++: 25 mg/kg (intravenous) or 50 nmol (intrathecal) active; and +: 100 mg/kg (intravenous) active.

TABLE 2
Compounds' activities of tail-flick test
    Activity of
    tail-flick
No  test
58  ++
152 ++
160 ++
169 ++
174 ++
175 ++
187 ++
196 ++
204 ++
236 +
239 ++
255 +
258 +
260 +
263 +
264 +
265 +
269 ++
270 ++
272 ++
276 +
280 ++
281 +
282 +
286 +
290 +
294 +
296 ++
297 +
299 ++
303 +
310 +
311 +
313 +
446 ++
453 ++
456 ++
458 ++
461 ++
463 ++
465 ++
471 ++
489 ++
495 ++
497 ++
499 ++
504 ++
505 ++
508 ++
510 ++
516 ++
517 ++
519 ++
520 ++
521 ++
522 ++
523 ++
525 ++
526 ++
532 ++
533 ++
538 ++
540 ++
542 ++
546 ++
548 ++
550 ++
556 ++
560 ++
562 ++
564 ++
571 ++
589 ++
605 ++
607 ++

Described below are eleven procedures used to synthesize intermediates of the above-described 661 compounds.

Standard Procedure a for the Preparation of Thazolidinone Derivatives

To a solution of aniline in toluene was added benzaldehyde and Na₂SO₄ anhydrous at room temperature, and it was stirred at room temperature or reflux for 5-20 h to obtain the imine intermediate. Then 2-mercaptoacetic acid was added to the reaction mixture, and it was reflux for 8-22 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10-20% NaOH_(aq), HCl_(aq) or brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified to give the desired product.

Standard Procedure B for the Hydrolysis of Thazolidinone Derivatives

A solution of thazolidinone in 20% NaOH_(aq) and methanol or ethanol was stirred at room temperature for 2-4 h. Methanol or ethanol was removed under reduced pressure. The residue was acidified by 1 N or 2 N HCl_(aq) and extracted with ethyl acetate or CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to afford a residue. The residue was purified to give the desired product.

Standard Procedure C for the Preparation of Thiazolidinyl Sulfonamides

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid in CH₂Cl₂ was added 4-(dimethylamino)pyridine (DMAP), sulfonamide, and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI • HCl) at room temperature. After the reaction mixture was stirred for 16 h-20 h, it was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq) and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified to give the desired products.

Standard Procedure D for the Preparation of Sulfonamides

A solution of sulfonyl chloride in methanol and ammonium hydroxide solution was stirred at 0° C. or room temperature. After the reaction was complete, methanol was removed under reduced pressure. The solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give the desired products without further purification.

Standard Procedure E for the Amide Formation of Thazolidinone Derivatives

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid in CH₂Cl₂ was added triethylamine and ethyl chloroformate at 0° C. After the reaction mixture was stirred at room temperature for 45 min to 1 h, a solution of potassium hydroxide and amine in methanol was added to the reaction mixture. The reaction was stirred for 3-6 h and then concentrated to afford a residue. The residue was purified to give the desired products.

Standard Procedure F for the Preparation of Heteroaryl Thazolidinone Derivatives

A solution of 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one, sodium bicarbonate, and boronic acid in 1,2-dimethoxyethane (DME) and water was degassed with argon for 15 min. Tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) was added and it was further degassed with argon for another 10 min. The reaction mixture was reflux for 3-4 h and cooled to room temperature. The solution was diluted with CH₂Cl₂ and washed with water and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified to give the desired products.

Standard procedure G for the esterification of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]—

3-methylbenzoic acid.

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid in CH₂Cl₂ was added 4-(dimethylamino)pyridine (DMAP), alcohol, and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI • HCl) at room temperature. After the reaction mixture was stirred for 16-20 h, it was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified to give the desired products.

Standard procedure H for the alkylation of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid in DMF was added K₂CO₃ and chloro-substituted derivative at room temperature. The reaction mixture was stirred for 18 h, and then DMF was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography to give the desired products. In one of example, the desired compound was collected by vacuum filtered and washed with water and diethyl ether.

Standard procedure I for the sulfonylation of 2-(4-fluoro-phenyl)-thiazolidin-4-one

To a solution of 2-(4-fluoro-phenyl)-thiazolidin-4-one in CH₂Cl₂ was added triethylamine, DMAP, and sulfonyl chloride derivative at room temperature. After the reaction mixture was stirred for 6-18 h, it was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified to give the desired products.

Standard procedure J for the preparation of phenylimino-thiazolidin-4-one derivatives

To a solution of acetamide in THF (5.0 mL) was added 60% sodium hydride (NaH) in mineral oil at 0° C., and it was stirred for 30 min. Then 4-fluorophenyl isothiocyanate was added to the reaction. The reaction mixture was stirred for 16 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified to give the desired products.

Standard Procedure K for the Amide Formation of Thazolidinone Derivatives

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid in CH₂Cl₂ was added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), various aniline, and triethyl amine at room temperature. After the reaction mixture was stirred for 16-20 h, water was added to the reaction. The reaction mixture was extracted with CH₂Cl₂ or ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified to give the desired products.

Standard procedure L for the alkylation of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid

A solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid, chloro-substituted derivative, and K₂CO₃ in DMF was stirred at 80° C. for 18 h and cooled to room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography to give the desired products.

Example 1

2-(3-Fluorophenyl)-3-(2-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2-methoxylaniline (49.2 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (78.0 mg, 64%). ¹H NMR (CDCl₃, 400 MHz) δ 7.23-7.18 (m, 2H), 7.08 (t, 2H), 6.95-6.87 (m, 3H), 6.82 (t, 1H), 6.07 (s, 1H), 3.95 (d, 1H), 3.88 (d, 1H), 3.84 (s, 3H); LC-MS (ESI) m/z 304.9[M+H]⁺.

Example 2

2-(4-Fluorophenyl)-3-(2-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2-methoxylaniline (49.2 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=2:3) to give the desired product as a yellow viscous liquid (77.0 mg, 63%). 1H NMR (CDCl₃, 400 MHz) δ 7.31 (dd, 2H), 7.22-7.18 (m, 1H), 6.93 (t, 2H), 6.87 (d, 2H), 6.81 (t, 1H), 6.08 (s, 1H), 3.92 (s, 2H), 3.83 (s, 3H); LC-MS (ESI) m/z 304.9 [M+H]⁺.

Example 3

2-(3,5-Difluorophenyl)-3-(5-fluoro-2-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methoxyaniline (56.4 mg, 0.400 mmol), 3,5-difluorobenzaldehyde (56.8 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (63.0 mg, 46%). ¹H NMR (CDCl₃, 400 MHz) δ 6.95 (td, 1H), 6.89-6.82 (m, 3H), 6.75-6.68 (m, 2H), 6.05 (s, 1H), 3.93 (d, 1H), 3.87 (d, 1H), 3.83 (s, 3H); LC-MS (ESI) m/z 340.8 [M+H]⁺.

Example 4

2-(3,4-Difluorophenyl)-3-(5-fluoro-2-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methoxyaniline (56.4 mg, 0.400 mmol), 3,4-difluorobenzaldehyde (56.8 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (82 mg, 61%). ¹H NMR (CDCl₃, 400 MHz) δ 7.21 (t, 1H), 7.08-7.00 (m, 2H), 6.95-6.91 (m, 1H), 6.82 (dd, 1H), 6.69 (dd, 1H), 6.06 (s, 1H), 3.90 (s, 2H), 3.82 (s, 3H); LC-MS (ESI) m/z 340.8 [M+H]⁺.

Example 5

3-(5-Fluoro-2-methoxyphenyl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methoxyaniline (56.4 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (83.0 mg, 64%). ¹H NMR (CDCl₃, 400 MHz) δ 7.23 (dd, 1H), 7.07 (d, 2H), 6.97-6.89 (m, 2H), 6.80 (dd, 1H), 6.70 (dd, 1H), 6.08 (s, 1H), 3.93 (d, 1H), 3.87 (d, 1H), 3.81 (s, 3H); LC-MS (ESI) m/z 322.8 [M+H]⁺.

Example 6

3-(5-Fluoro-2-methoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methoxyaniline (56.4 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.67 mL, 86.5 mg, 0.94 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallized to give the desired product as a yellow solid (57.0 mg, 44%). ¹H NMR (CDCl₃, 300 MHz) δ 7.30 (dd, 1H), 6.95 (t, 3H), 6.89 (dd, 1H), 6.79 (dd, 1H), 6.66 (dd, 1H), 6.09 (s, 1H), 3.90 (s, 2H), 3.80 (s, 3H); LC-MS (ESI) m/z 322.8 [M+H]⁺.

Example 7

2-(3,5-Difluorophenyl)-3-(2,4-dimethoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-dimethoxyaniline (61.3 mg, 0.400 mmol), 3,5-difluorobenzaldehyde (56.8 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.67 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (60.0 mg, 43%). ¹H NMR (CDCl₃, 400 MHz) δ 6.87 (dd, 2H), 6.83 (d, 1H), 6.69 (tt, 1H), 6.44 (d, 1H), 6.36 (dd, 1H), 5.95 (s, 1H), 3.90 (d, 1H), 3.85 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H); LC-MS (ESI) m/z 352.8 [M+H]⁺.

Example 8

3-(2,4-Dimethoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-dimethoxyaniline (61.3 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.67 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=3:4) to give the desired product as a yellow viscous liquid (103 mg, 77%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 2H), 6.95 (t, 2H), 6.73 (d, 1H), 6.41 (d, 1H), 6.31 (dd, 1H), 5.99 (s, 1H), 3.91-3.89 (m, 2H), 3.79 (s, 3H), 3.73 (s, 3H); LC-MS (ESI) m/z 334.9 [M+H]⁺.

Example 9

2-(2-Chloro-4-fluorophenyl)-3-(2,4-dimethoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-dimethoxyaniline (76.0 mg, 0.500 mmol), 2-chloro-4-fluorobenzaldehyde (79.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.042 mL, 54.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (129 mg, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 7.63 (br s, 1H), 7.03-6.93 (br, 2H), 6.86 (d, 1H), 6.56 (br s, 1H), 6.42 (d, 1H), 6.33 (dd, 1H), 3.90 (d, 1H), 3.83 (d, 1H), 3.80 (s, 3H), 3.72 (s, 3H); LC-MS (ESI) m/z 368.8 [M+H]⁺.

Example 10

3-(4,5-Difluoro-2-methoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4,5-difluoro-2-methoxyaniline (63.7 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.500 mL, 64.7 mg, 0.700 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (44.0 mg, 32%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 2H), 6.97 (t, 2H), 6.76-6.66 (m, 2H), 6.02 (s, 1H), 3.89 (s, 2H), 3.80 (s, 3H); LC-MS (ESI) m/z 339.9 [M+H]⁺.

Example 11

3-(3,5-Difluoro-2-methoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,5-difluoro-2-methoxyaniline (63.7 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.500 mL, 64.7 mg, 0.700 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (23.0 mg, 17%). ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (dd, 2H), 6.97 (t, 2H), 6.79-6.73 (m, 1H), 6.46 (dd, 1H), 6.06 (s, 1H), 3.87 (s, 5H); LC-MS (ESI) m/z 340.9 [M+H]⁺.

Example 12

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methoxy-benzoic acid

Step 1. Synthesis of 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methoxy-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methoxybenzoate (181 mg, 1.00 mmol), 4-fluorobenzaldehyde (186 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.130 ml, 168 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (91.0 mg, 25%). ¹H NMR (CDCl₃, 300 MHz) δ 7.53-7.49 (m, 2H), 7.29 (dd, 2H), 6.99 (d, 1H), 6.92 (t, 1H), 6.16 (s, 1H), 3.92 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H); LC-MS (ESI) m/z 362.8 [M+H]⁺.

Step 2. Synthesis of 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methoxy-benzoic acid

The compound was prepared by following the standard procedure B with 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methoxy-benzoic acid methyl ester (70.0 mg, 0.190 mmol) and 20% NaOH_(aq) (0.5 mL, 2.5 mmol) to give the desired product as a white solid (41.0 mg, 61%). ¹H NMR (CDCl₃, 300 MHz) δ 7.60-7.50 (m, 2H), 7.30 (t, 2H), 7.00 (d, 1H), 6.93 (t, 2H), 6.17 (s, 1H), 3.94 (s, 2H), 3.89 (s, 3H); LC-MS (ESI) m/z 348.8 [M+H]⁺.

Example 13

2-(4-Fluorophenyl)-3-(4-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-methoxyaniline (24.6 mg, 0.200 mmol), 4-fluorobenzaldehyde (24.8 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.170 mL, 21.6 mg, 0.230 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a white solid (55.0 mg, 90%). ¹H NMR (CDCl₃, 300 MHz) δ 7.29 (dd, 2H), 7.01-6.95 (m, 4H), 6.79 (d, 2H), 5.98 (s, 1H), 3.97 (d, 1H), 3.88 (d, 1H), 3.73 (s, 3H); LC-MS (ESI) m/z 304.8 [M+H]⁺.

Example 14

3-(3,4-Dimethoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4-dimethoxylaniline (61.2 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=5:4) to give the desired product as a yellow viscous liquid (107 mg, 80%). ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (dd, 2H), 6.98 (t, 2H), 6.73 (d, 1H), 6.61-6.57 (m, 2H), 5.95 (s, 1H), 3.97 (d, 1H), 3.89 (d, 1H), 3.80 (s, 3H), 3.73 (s, 3H); LC-MS (ESI) m/z 334.9 [M+H]⁺.

Example 15

2-(4-Fluorophenyl)-3-(3,4,5-trimethoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4,5-trimethoxyaniline (73.3 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.67 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (52.0 mg, 36%). ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (dd, 2H), 7.01 (t, 2H), 6.25 (s, 2H), 5.94 (s, 1H), 3.98 (d, 1H), 3.89 (d, 1H), 3.77 (s, 3H), 3.70 (s, 6H); LC-MS (ESI) m/z 364.8 [M+H]⁺.

Example 16

3-(3-Chloro-4-methoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-methoxyaniline (63 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (100 mg, 74%). ¹H NMR (CDCl₃, 400 MHz) δ 7.28 (dd, 2H), 7.17 (s, 1H), 6.99 (t, 2H), 6.94 (dd, 1H), 6.80 (d, 1H), 5.98 (s, 1H), 3.96 (d, 1H), 3.87 (d, 1H), 3.83 (s, 3H); LC-MS (ESI) m/z 338.7 [M+H]⁺.

Example 17

3-(3-Chloro-4-(trifluoromethoxy)phenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-(trifluoromethoxy)aniline (42.3 mg, 0.200 mmol), 4-fluorobenzaldehyde (24.8 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.170 mL, 21.6 mg, 0.230 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:7) to give the desired product as a yellow viscous liquid (22.0 mg, 28%). ¹H NMR (CDCl₃, 400 MHz) δ 7.38 (d, 1H), 7.28 (dd, 2H), 7.22 (d, 1H), 7.08 (dd, 1H), 7.02 (t, 2H), 6.07 (s, 1H), 3.96 (d, 1H), 3.87 (d, 1H); LC-MS (ESI) m/z 392.9 [M+H]⁺.

Example 18

3-(3-Chloro-4-(trifluoromethoxy)phenyl)-2-(3,5-difluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-(trifluoromethoxy)aniline (42.3 mg, 0.200 mmol), 3,5-difluorobenzaldehyde (28.4 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.170 mL, 21.6 mg, 0.230 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:5) to give the desired product as a yellow viscous liquid (30.0 mg, 37%). ¹H NMR (CDCl₃, 400 MHz) δ 7.44 (s, 1H), 7.28-7.25 (m, 1H), 7.15-7.11 (m, 1H), 6.82 (dd, 2H), 6.76 (tt, 1H), 6.01 (s, 1H), 3.97 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 409.9 [M+H]⁺.

Example 19

3-(3-Chloro-4-ethoxyphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-ethoxyaniline (34.3 mg, 0.200 mmol), 4-fluorobenzaldehyde (24.8 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:5) to give the desired product as a yellow viscous liquid (63.0 mg, 90%). ¹H NMR (CDCl₃, 400 MHz) δ 7.29-7.26 (m, 2H), 7.15 (s, 1H), 6.99 (t, 2H), 6.91 (dd, 1H), 6.78 (d, 1H), 5.97 (s, 1H), 4.02 (q, 2H), 3.95 (d, 1H), 3.87 (d, 1H), 1.41 (t, 3H); LC-MS (ESI) m/z 352.8 [M+H]⁺.

Example 20

3-(3-Chloro-4-ethoxyphenyl)-2-(3,5-difluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-ethoxyaniline (34.3 mg, 0.200 mmol), 3,5-difluorobenzaldehyde (28.4 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a white solid (40.0 mg, 54%). ¹H NMR (CDCl₃, 400 MHz) δ 7.19 (d, 1H), 6.96 (dd, 1H), 6.82-6.78 (m, 3H), 6.71 (tt, 1H), 5.91 (s, 1H), 4.03 (q, 2H), 3.95 (d, 1H), 3.84 (d, 1H), 1.41 (t, 3H); LC-MS (ESI) m/z 370.7 [M+H]⁺.

Example 21

2-(3-Chlorophenyl)-3-(3,4-dichlorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4-dichloroaniline (40.5 mg, 0.250 mmol), 3-chlorobenzaldehyde (35.0 mg, 0.250 mmol), and 2-mercaptoacetic acid (0.021 mL, 27.0 mg, 0.300 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=1:4) to give the desired product as a yellow viscous liquid (33.0 mg, 37%). ¹H NMR (CDCl₃, 400 MHz) δ 7.40 (d, 1H), 7.36 (d, 1H), 7.29-7.26 (m, 3H), 7.16-7.14 (m, 1H), 7.02 (dd, 1H), 6.01 (s, 1H), 3.97 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 357.8 [M+H]⁺.

Example 22

2-(3-Bromophenyl)-3-(3,4-dichlorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4-dichloroaniline (44.6 mg, 0.280 mmol), 3-bromobenzaldehyde (46.3 mg, 0.250 mmol), and 2-mercaptoacetic acid (0.021 mL, 27.0 mg, 0.300 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=1:5) to give the desired product as a yellow viscous liquid (83.1 mg, 82%). ¹H NMR (CDCl₃, 300 MHz) δ 7.42-7.34 (m, 3H), 7.20 (d, 2H), 7.02 (dd, 1H), 6.00 (s, 1H), 3.97 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 404.7 [M+H]⁺.

Example 23

2-(2-Bromophenyl)-3-(3,4-dichlorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4-dichloroaniline (35.6 mg, 0.220 mmol), 2-bromobenzaldehyde (37.0 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=2:11) to give the desired product as a yellow viscous liquid (40.0 mg, 50%). ¹H NMR (CDCl₃, 400 MHz) δ 7.60 (dd, 1H), 7.56 (d, 1H), 7.35 (d, 1H), 7.33-7.20 (m, 2H), 7.18 (td, 1H), 7.10 (dd, 1H), 6.49 (s, 1H), 3.91 (d, 1H), 3.80 (d, 1H); LC-MS (ESI) m/z 401.5 [M+H]⁺.

Example 24

2-(4-Bromophenyl)-3-(3,4-dichlorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4-dichloroaniline (35.6 mg, 0.220 mmol), 4-bromobenzaldehyde (37.0 mg, 0.200 mmol), and thioglycolic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (49.7 mg, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 7.43 (d, 2H), 7.35 (d, 1H), 7.32 (d, 1H), 7.14 (d, 2H), 6.98 (dd, 1H), 6.01 (s, 1H), 3.93 (d, 1H), 3.84 (d, 1H); LC-MS (ESI) m/z 401.7 [M+H]⁺.

Example 25

3-(3-Chloro-4-fluorophenyl)-2-(3-chlorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-fluoro-3-chloroaniline (32.0 mg, 0.220 mmol), 3-chlorobenzaldehyde (28.1 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (41.6 mg, 60%). ¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.23 (m, 4H), 7.20-7.13 (m, 1H), 7.09-6.98 (m, 2H), 5.97 (s, 1H), 3.98 (d, 1H), 3.86 (d, 1H); LC-MS (ESI) m/z 341.8 [M+H]⁺.

Example 26

3-(3-Chloro-4-fluorophenyl)-2-(3,5-difluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-fluoroaniline (29.1 mg, 0.200 mmol), 3,5-difluorobenzaldehyde (28.4 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (28.0 mg, 41%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 1H), 7.07 (t, 1H), 7.03-6.99 (m, 1H), 6.83-6.75 (m, 2H), 6.73 (tt, 1H), 5.95 (s, 1H), 3.95 (d, 1H), 3.84 (d, 1H); LC-MS (ESI) m/z 344.7 [M+H]⁺.

Example 27

3-(4-Bromo-3-chlorophenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-bromo-3-chloroaniline (41.3 mg, 0.200 mmol), 4-fluorobenzaldehyde (24.8 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.17 mL, 21.6 mg, 0.230 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (27.0 mg, 35%). ¹H NMR (CDCl₃, 400 MHz) δ 7.50 (d, 1H), 7.35 (s, 1H), 7.26 (dd, 2H), 7.01 (t, 2H), 6.92 (dd, 1H), 6.06 (s, 1H), 3.94 (d, 1H), 3.86 (d, 1H); LC-MS (ESI) m/z 385.7 [M+H]⁺.

Example 28

3-4-Bromo-3-fluorophenyl)-2-(3-bromophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-bromo-3-fluoroaniline (29.1 mg, 0.200 mmol), 3-bromobenzaldehyde (37.0 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (58.0 mg, 67%). ¹H NMR (CDCl₃, 400 MHz) δ 7.50-7.40 (m, 3H), 7.22-7.18 (m, 2H), 7.13 (dd, 1H), 6.88 (d, 1H), 6.02 (s, 1H), 3.97 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 429.6 [M+H]⁺.

Example 29

3-(4-Bromo-3-fluorophenyl)-2-(3-chlorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-bromo-3-fluoroaniline (29.1 mg, 0.200 mmol), 3-chlorobenzaldehyde (28.1 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (40.0 mg, 50%). ¹H NMR (CDCl₃, 300 MHz) δ 7.46 (t, 1H), 7.30-7.20 (m, 3H), 7.20-7.10 (m, 2H), 6.88 (dd, 1H), 6.03 (s, 1H), 3.97 (d, 1H), 3.84 (d, 1H); LC-MS (ESI) m/z 385.6 [M+H]⁺.

Example 30

3-(4-Bromo-3-fluorophenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-bromo-3-fluoroaniline (41.8 mg, 0.220 mmol), 4-fluorobenzaldehyde (24.8 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (30.0 mg, 41%). ¹H NMR (CDCl₃, 300 MHz) δ 7.42 (t, 1H), 7.27-7.22 (m, 2H), 7.05 (dd, 1H), 6.99 (t, 2H), 6.83 (dd, 1H), 6.06 (s, 1H), 3.93 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 369.7 [M+H]⁺.

Example 31

3-(4-Bromo-3-fluorophenyl)-2-(3,5-difluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-bromo-3-fluoroaniline (38.0 mg, 0.200 mmol), 3,5-difluorobenzaldehyde (28.4 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (46.0 mg, 60%). ¹H NMR (CDCl₃, 300 MHz) δ 7.48 (dd, 1H), 7.14 (dt, 1H), 6.90 (dd, 1H), 6.84-6.71 (m, 3H), 6.02 (s, 1H), 3.96 (d, 1H), 3.84 (d, 1H); LC-MS (ESI) m/z 387.8 [M+H]⁺.

Example 32

3-(3-Bromo-4-fluorophenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-bromo-4-fluoroaniline (41.3 mg, 0.200 mmol), 4-fluorobenzaldehyde (21.4 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:5) to give the desired product as a yellow viscous liquid (50.0 mg, 70%). ¹H NMR (CDCl₃, 300 MHz) δ 7.39 (d, 1H), 7.30-7.26 (m, 2H), 7.05-6.97 (m, 4H), 6.01 (s, 1H), 3.96 (d, 1H), 3.87 (d, 1H); LC-MS (ESI) m/z 369.8 [M+H]⁺.

Example 33

3-(3-Bromo-4-fluorophenyl)-2-(3,5-difluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-bromo-4-fluoroaniline (41.3 mg, 0.200 mmol), 3,5-difluorobenzaldehyde (28.4 mg, 0.200 mmol), and 2-mercaptoacetic acid (0.017 mL, 20.3 mg, 0.220 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (60.0 mg, 77%). ¹H NMR (CDCl₃, 300 MHz) δ 7.46 (d, 1H), 7.07 (d, 2H), 6.85-6.77 (m, 2H), 6.75 (tt, 1H), 5.97 (s, 1H), 3.97 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 387.6 [M+H]⁺.

Example 34

2-Fluoro-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-benzoic acid methyl ester

Step 1. Synthesis of methyl 4-amino-2-fluorobenzoate

To a solution of 4-amino-2-fluorobenzoic acid (1.00 g, 6.40 mmol) in 15 mL of methanol was treated concentrated HCl (2.0 mL, 24.0 mmol) in one portion at r.t. The reaction mixture was refluxed overnight then directly concentrated to give a crude product, which was partitioned between ethyl acetate (50 mL) and saturated NaHCO_3(aq) (20 mL). The organic layer was washed with brine (10 mL), dried over MgSO₄, and concentrated to give the desired product (932 mg, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 7.77 (t, 1H), 6.42 (d, 1H), 6.34 (d, 1H), 4.18 (br s, 2H), 3.87 (s, 3H).

Step 2. Synthesis of 2-fluoro-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-2-fluorobenzoate (169 mg, 1.00 mmol), 4-fluorobenzaldehyde (186 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.128 ml, 165 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (130 mg, 37%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (t, 1H), 7.27 (dd, 2H), 7.19 (d, 1H), 7.07 (d, 1H), 7.01 (t, 2H), 6.18 (s, 1H), 3.95 (d, 1H), 3.89 (s, 3H), 3.86 (d, 1H); LC-MS (ESI) m/z 349.7 [M+H]⁺.

Example 35

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)benzonitrile

The compound was prepared by following the standard procedure A with 4-aminobenzonitrile (1.18 g, 10.0 mmol), 4-fluorobenzaldehyde (1.24 g, 10.0 mmol), and 2-mercaptoacetic acid (1.25 mL, 1.62 g, 17.5 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (1.18 g, 40%). ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (d, 2H), 7.37 (d, 2H), 7.26 (dd, 2H), 7.00 (t, 2H), 6.18 (s, 1H), 3.95 (d, 1H), 3.87 (d, 1H); LC-MS (ESI) m/z 299.1 [M+H]⁺.

Example 36

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)benzoic acid

To a suspension of 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)benzonitrile (100 mg, 0.340 mmol) in H₂O (2 mL) was added H₂SO_4(conc.) (2 me) in one portion. The reaction mixture was refluxed for 3 h then partitioned between ethyl acetate (30 mL) and H₂O (20 mL). The organic layer was washed with brine, dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography to give the desired product as a yellow liquid (3.50 mg, 3.2%). ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (dd, 2H), 7.36 (dd, 2H), 7.26 (dd, 2H), 7.00 (t, 2H), 6.18 (s, 1H), 3.95 (d, 1H), 3.87 (d, 1H).

Example 37

3-(4-Fluorophenyl)-2-(4-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-fluoroaniline (55.6 mg, 0.500 mmol), p-anisaldehyde (68.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.042 mL, 54.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1 3) to give the desired product as a yellow viscous liquid (100 mg, 66%). ¹H NMR (CDCl₃, 400 MHz) δ 7.19 (d, 2H), 7.07-7.04 (m, 2H), 6.94 (t, 2H), 6.78 (d, 2H), 5.97 (s, 1H), 3.95 (d, 1H), 3.85 (d, 1H), 3.75 (s, 3H); LC-MS (ESI) m/z 304.9 [M+H]⁺.

Example 38

Methyl 3-fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate

Following standard procedure A, methyl 4-amino-3-fluorobenzene carboxylate (0.680 g, 4.02 mmol), 4-fluorobenzaldehyde (1.00 g, 8.04 mmol), Na₂SO₄ (1.14 g, 8.04 mmol), 2-mercaptoacetic acid (0.500 mL, 7.20 mmol), and toluene (10 mL) were used to carry out the reaction. It was reflux 5 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (0.340 g, 24%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.74-7.69 (m, 2H), 7.33 (dd, 2H), 7.16 (dd, 1H), 6.95 (t, 2H), 6.17 (s, 1H), 3.94 (s, 2H), 3.88 (s, 3H); LC-MS (ESI) m/z 350.2 [M+H]⁺.

Example 39

3-Fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid

Following standard procedure B, methyl 3-fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (0.340 g, 0.973 mmol), 20% NaOH_(aq) (0.90 mL), and methanol (8.0 mL) were used to carry out the reaction. After the reaction was stirred for 2 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 3-fluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid (0.213 g, 65%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.78-7.72 (m, 2H), 7.34 (dd, 2H), 7.20 (dd, 1H), 6.96 (t, 2H), 6.18 (s, 1H), 3.95 (s, 2H); LC-MS (ESI) m/z 336.2 [M+H]⁺.

Example 40

3-(4-Bromo-2,6-difluorophenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure A, 4-bromo-2,6-difluoroaniline (0.760 g, 3.65 mmol), 4-fluorobenzaldehyde (0.570 g, 4.59 mmol), Na₂SO₄ (0.520 g, 3.66 mmol), 2-mercaptoacetic acid (0.450 mL, 6.45 mmol), and toluene (11 mL) were used to carry out the reaction. It was reflux 7 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3-(4-bromo-2,6-difluorophenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (358 mg, 25%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.37 (dd, 2H), 7.05 (m, 2H), 6.97 (t, 2H), 6.08 (s, 1H), 3.92 (s, 2H); LC-MS (ESI) m/z 388.1 [M+H]⁺.

Example 41

3,5-Difluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzonitrile

A solution of 3-(4-bromo-2,6-difluorophenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (119 mg, 0.307 mmol) and copper(I) cyanide (82.5 mg, 0.921 mmol) in DMF (1.0 mL) was reflux for 8 h. After the reaction was cooled and quenched with NH₄OH_(aq) (25 mL), the solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) and then recrystallized with CH₂Cl₂/diethyl ether to give 3,5-difluoro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzonitrile (12.8 mg, 12%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.37 (dd, 2H), 7.18 (m, 2H,), 6.97 (t, 2H), 6.17 (s, 1H), 3.94 (s, 2H); LC-MS (ESI) m/z 335.1 [M+H]⁺.

Example 42

3-Chloro-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]benzoic acid

Step 1. Methyl 3-chloro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate

Following standard procedure A, methyl 4-amino-3-chlorobenzene carboxylate (0.522 g, 2.81 mmol), 4-fluorobenzaldehyde (0.999 g, 7.04 mmol), Na₂SO₄ (0.799 g, 5.63 mmol), 2-mercaptoacetic acid (0.400 mL, 5.73 mmol), and toluene (9.0 mL) were used to carry out the reaction. It was reflux 7 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-chloro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (70.5 mg, 7%) as a brown foam. 1H NMR (CDCl₃, 400 MHz) δ 8.07 (s, 1H), 7.78 (dd, 1H), 7.35 (dd, 2H), 6.98-6.94 (m, 3H), 6.13 (s, 1H), 3.96 (s, 2H), 3.89 (s, 3H).

Step 2. 3-Chloro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid

Following standard procedure B, methyl 3-chloro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (0.340 g, 0.973 mmol), 20% NaOH_(aq) (0.25 mL), and methanol (4.0 mL) were used to carry out the reaction. After the reaction was stirred for 2 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 3-chloro-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid (35.2 mg, 37%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.10 (s, 1H), 7.81 (d, 1H), 7.36 (dd, 2H), 6.99-6.94 (m, 3H), 6.15 (s, 1H), 3.97 (s, 2H); LC-MS (ESI) m/z 352.2 [M+H]⁺.

Example 43

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzonitrile

The compound was prepared by following the standard procedure A with 4-amino-3-methylbenzonitrile (200 mg, 1.50 mmol), 4-fluorobenzaldehyde (187 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.190 mL, 246 mg, 2.67 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (51.0 mg, 11%). ¹H NMR (CDCl₃, 300 MHz) δ 7.49 (br s, 1H), 7.38 (br d, 1H), 7.31 (dd, 2H), 6.98 (t, 2H), 5.93 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 313.2 [M+H]⁺.

Example 44

2-(4-Fluorophenyl)-3-(4-methoxy-2-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-methoxy-2-methylaniline (4.00 g, 29.2 mmol), 4-fluorobenzaldehyde (3.60 g, 29.2 mmol), and 2-mercaptoacetic acid (3.00 mL, 3.89 g, 42.1 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography to give the desired product as a brown solid (6.70 g, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (dd, 2H), 6.97 (br s, 2H), 6.80-6.30 (br, 3H), 6.05-5.58 (br, 1H), 4.00 (d, 1H), 3.89 (d, 1H), 3.72 (s, 3H), 2.25 (br s, 3H); LC-MS (ESI) m/z 318.9 [M+H]⁺.

Example 45

2-(4-Fluorophenyl)-3-(5-methoxy-2-methylphenyl)-1,3-thiazolidin-4-one

Following standard procedure A, 5-methoxy-2-methylaniline (0.381 g, 2.78 mmol), 4-fluorobenzaldehyde (0.448 g, 3.61 mmol), Na₂SO₄ (0.395 g, 2.78 mmol), 2-mercaptoacetic acid (0.350 mL, 5.02 mmol), and toluene (8.0 mL) were used to carry out the reaction. It was reflux 2 h for the first step and 18 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) and then (0-5% ethyl acetate in CH₂Cl₂) to give 2-(4-fluorophenyl)-3-(5-methoxy-2-methylphenyl)-1,3-thiazolidin-4-one (149 mg, 17%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.34-7.31 (m, 2H), 7.07 (br s, 1H), 6.96 (br t, 2H), 6.72 (dd, 1H), 6.10-5.60 (br, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.62 (br s, 3H), 2.09 (br s, 3H); LC-MS (ESI) m/z 318.2 [M+H]⁺.

Example 46

3-(5-Fluoro-4-methoxy-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

Step 1. Synthesis of 1-Fluoro-2-methoxy-4-methyl-5-nitrobenzene

To a solution of 2-fluoro-5-methyl-4-nitrophenol (3.10 g, 18.1 mmol) in 30 mL of DMF was added K₂CO_3(s) (3.75 g, 27.2 mmol) and iodomethane (5.60 mL, 12.7 g, 89.9 mmol). The reaction mixture was stirred at 60° C. for overnight then partitioned between ether (80 mL) and H₂O (10 mL). The aqueous layer was washed with ether (50 mL×2). The combined organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give a crude solid (3.20 g) which was recrystallized to give a brown solid (2.18 g, 65%). ¹H NMR (CDCl₃, 300 MHz) δ 7.90 (d, 1H), 6.82 (d, 1H), 3.97 (s, 3H), 2.64 (s, 3H).

Step 2. Synthesis of 5-Fluoro-4-methoxy-2-methylaniline

To a solution of dimethyl 1-fluoro-2-methoxy-4-methyl-5-nitrobenzene (2.04 g, 10.9 mmol) in 30 mL of acetic acid was added zinc dust_(s) (5.27 g, 83.2 mmol) in one portion at r.t. The reaction mixture was stirred at r.t. for 3.5 h then passed through a pad of celite. The filtrate was partitioned between dichloromethane (80 mL) and saturated NaHCO_3(aq) (30 mL). The organic layer was dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (1.30 g, 77%). ¹H NMR (CDCl₃, 400 MHz) δ 6.70 (d, 1H), 6.45 (d, 1H), 3.81 (s, 3H), 3.41 (br s, 2H), 2.12 (s, 3H).

Step 3. Synthesis of 3-(5-Fluoro-4-methoxy-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-4-methoxy-2-methylaniline (1.30 g, 8.30 mmol), 4-fluorobenzaldehyde (1.03 g, 8.30 mmol), and 2-mercaptoacetic acid (0.920 mL, 1.19 g, 12.9 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a brown solid (1.03 g, 37%). ¹H NMR (CDCl₃, 300 MHz) δ 7.40-7.26 (m, 2H), 6.99 (br t, 2H), 6.73 (br s, 2H), 5.80 (br s, 1H), 3.98 (d, 1H), 3.88 (d, 1H), 3.82 (s, 3H), 2.08 (br s, 3H); LC-MS (ESI) m/z 336.9 [M+H]⁺.

Example 47

3-(4,5-Dimethoxy-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4,5-dimethoxy-2-methylaniline (66.9 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=5:4) to give the desired product as a yellow viscous liquid (108 mg, 78%). ¹H NMR (C₆D₆, 300 MHz) δ 6.81 (br s, 2H), 6.52 (t, 2H), 6.28 (br s, 1H), 6.03 (br s, 1H), 5.35 (br s, 1H), 3.54 (d, 1H), 3.44 (d, 1H), 3.25-3.15 (br, 6H), 1.94 (br s, 3H); LC-MS (ESI) m/z 348.9 [M+H]⁺.

Example 48

3-(4-(Dimethylamino)-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with N,N,3-trimethylbenzene-1,4-diamine (120 mg, 0.800 mmol), 4-fluorobenzaldehyde (99.2 mg, 0.800 mmol), and 2-mercaptoacetic acid (0.083 mL, 107 mg, 1.17 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization (ethyl acetate:hexane=1:2) to give the desired product as a yellow solid (110 mg, 42%). ¹H NMR (CDCl₃, 400 MHz) δ 7.31 (dd, 2H), 6.97 (br s, 2H), 6.52 (br s, 1H), 6.30 (br s, 1H), 5.64 (br s, 1H), 4.00 (br d, 1H), 3.88 (d, 1H), 2.88 (s, 6H), 2.24 (br s, 3H); LC-MS (ESI) m/z 331.8 [M+H]⁺.

Example 49

3-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-4-methylbenzoic acid

Step 1. Synthesis of Methyl 3-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-4-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 3-amino-4-methylbenzoate (165 mg, 1.00 mmol), 4-fluorobenzaldehyde (124 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (152 mg, 42%). ¹H NMR (CDCl₃, 300 MHz) δ 7.90-7.88 (br, 2H), 7.32 (dd, 2H), 7.21 (br s, 1H), 6.95 (br s, 2H), 6.22-5.65 (br, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.87 (br s, 3H), 2.45-1.90 (br, 3H).

Step 2. Synthesis of 3-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-4-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 3-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-4-methylbenzoate (152 mg, 0.420 mmol) and 20% NaOH_(aq) (1.00 mL, 5.00 mmol) to give the desired product as a yellow viscous liquid (130 mg, 89%). ¹H NMR (CDCl₃, 400 MHz) δ 7.93-7.80 (br, 2H), 7.34 (dd, 2H), 7.26 (br s, 1H), 6.96 (br s, 2H), 6.20-5.65 (m, 1H), 4.02 (br d, 1H), 3.94 (br d, 1H), 2.45-1.95 (m, 3H); LC-MS (ESI) m/z 332.2 [M+H]⁺.

Example 50

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-2-methyl-benzoic acid methyl ester

Step 1. Synthesis of methyl 4-amino-2-methylbenzoate

To a solution of 4-amino-2-methylbenzoic acid (1.00 g, 6.60 mmol) in 18 mL of methanol was treated concentrated HCl (2.30 mL, 27.6 mmol) in one portion at r.t. The reaction mixture was refluxed overnight then directly concentrated to give a crude product, which was partitioned between ethyl acetate (50 mL) and saturated NaHCO_3(aq) (20 mL). The organic layer was washed with brine (10 mL), dried over MgSO₄ and concentrated to give the desired product (930 mg, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 7.83-7.80 (m, 1H), 6.51-6.48 (m, 2H), 4.15 (br s, 2H), 3.83 (s, 3H), 2.55 (s, 3H).

Step 2. Synthesis of 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-2-methyl-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-2-methylbenzoate (165 mg, 1.00 mmol), 4-fluorobenzaldehyde (186 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.128 mL, 165 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (150 mg, 43%). ¹H NMR (CDCl₃, 300 MHz) δ 7.83 (d, 1H), 7.27 (dd, 2H), 7.13 (s, 1H), 7.03 (d, 1H), 6.98 (t, 2H), 6.15 (s, 1H), 3.96 (d, 1H), 3.86 (d, 1H), 3.84 (s, 3H), 2.52 (s, 3H); LC-MS (ESI) m/z 346.8 [M+H]⁺.

Example 51

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzenecarboxylate (1.50 g, 9.08 mmol), 4-fluorobenzaldehyde (1.20 g, 9.67 mmol), 2-mercaptoacetic acid (1.14 mL, 1.48 g, 16.0 mmol), and toluene (30 mL). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the residue was purified by flash chromatography to give the desired product as yellow viscous liquid (500 mg, 16%). ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.30 (dd, 2H), 6.95 (t, 2H), 5.94 (br s, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.87 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Step 2. Synthesis of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (500 mg, 1.45 mmol), 20% NaOH_(aq) (1.25 mL, 6.25 mmol), and ethanol (5.00 mL). The reaction mixture was stirred for 4 h and work-up to give the desired product (450 mg, 94%). ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (br s, 1H), 7.78 (br s, 1H), 7.31 (dd, 2H), 6.96 (t, 2H), 5.97 (br s, 1H), 4.03 (d, 1H), 3.94 (d, 1H), 2.21 (br s, 3H); LC-MS (ESI) m/z 332.2 [M+H]⁺.

Example 52

4-(2-(3-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(3-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzenecarboxylate (1.65 g, 10.0 mmol), 3-fluorobenzaldehyde (2.48 g, 20.0 mmol), 2-mercaptoacetic acid (1.42 mL, 1.84 g, 20.0 mmol) and toluene (35 mL). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the residue was purified by flash chromatography to give the desired product as a yellow viscous liquid (1.30 g, 38%). ¹H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.74 (br d, 1H), 7.28-7.16 (m, 1H), 7.10-7.04 (m, 2H), 6.97 (br t, 1H), 5.91 (br s, 1H), 4.03 (d, 1H), 3.91 (d, 1H), 3.86 (s, 3H), 2.21 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Step 2. Synthesis of 4-(2-(3-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(3-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (1.23 g, 3.56 mmol), methanol (10 mL), and 20% NaOH_(aq) (3.56 mL, 17.8 mmol). After the reaction mixture was stirred for 5 h and work-up, the residue was purified by flash chromatography to give the desired product (960 mg, 81%). ¹H NMR (CDCl₃, 300 MHz) δ 7.90 (br s, 1H), 7.78 (br d, 1H), 7.27-7.20 (m, 1H), 7.11-7.04 (m, 2H), 6.98 (br t, 1H), 5.93 (br s, 1H), 4.04 (d, 1H), 3.93 (d, 1H), 2.22 (br s, 3H); LC-MS (ESI) m/z 332.2 [M+H]⁺.

Example 53

4-(2-(3,4-Difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(3,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzenecarboxylate (825 mg, 5.00 mmol), 2,4-difluorobenzaldehyde (781 mg, 5.50 mmol), and 2-mercaptoacetic acid (0.63 mL, 921 mg, 10.0 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (480 mg, 26%). ¹H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.76 (br d, 1H), 7.21 (t, 1H), 7.08-6.91 (m, 3H), 5.90 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.87 (s, 3H), 2.20 (br s, 3H); LC-MS (ESI) m/z 364.2 [M+H]⁺.

Step 2. Synthesis of 4-(2-(3,4-Difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the the standard procedure B with methyl 4-(2-(3,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (400 mg, 1.10 mmol), and 20% NaOH_(aq) (1.00 mL, 5.00 mmol). The crude product was directly concentrated to give the desired product as a yellow viscous solid (380 mg, 99%). ¹H NMR (CDCl₃, 400 MHz) δ 7.92 (br s, 1H), 7.80 (br s, 1H), 7.23 (t, 1H), 7.08-6.60 (m, 3H), 5.93 (br s, 1H), 4.02 (d, 1H), 3.93 (d, 1H), 2.22 (br s, 3H); LC-MS (ESI) m/z 350.2 [M+H]⁺.

Example 54

4-(2-(3,5-Difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(3,5-difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 3,5-difluorobenzaldehyde (284 mg, 2.00 mmol), and 2-mercaptoacetic acid (0.21 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. The crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (100 mg, 29%). ¹H NMR (CDCl₃, 400 MHz) δ 7.90 (br s, 1H), 7.78-7.72 (m, 1H), 7.10-6.82 (m, 3H), 6.73 (t, 1H), 5.87 (br s, 1H), 4.01 (d, 1H), 3.90 (d, 1H), 3.87 (s, 3H), 2.30 (br s, 3H).

Step 2. Synthesis of 4-(2-(3,5-Difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(3,5-difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (100 mg, 0.280 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol). The crude product was purified by flash chromatography (ethyl acetate:hexane:acetic acid=50:50:1) to give the desired product as a yellow viscous liquid (25.0 mg, 26%). ¹H NMR (CD₃OD, 400 MHz) δ 7.87 (br s, 1H), 7.77 (br d, 1H), 7.12-7.06 (m, 2H), 6.89 (t, 1H), 6.26 (br s, 1H), 4.12 (d, 1H), 3.94 (d, 1H), 2.21 (br s, 3H); LC-MS (ESI) m/z 350.2 [M+H]⁺.

Example 55

4-(2-(4-Fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(4-fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 4-fluoro-2-methylbenzaldehyde (138 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (29.0 mg, 8%). ¹H NMR (CDCl₃, 400 MHz) δ 7.92 (br s, 1H), 7.72 (d, 1H), 7.61 (br s, 1H), 6.93 (br t, 1H), 6.85 (br s, 1H), 6.71 (d, 1H), 6.21 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.87 (s, 3H), 2.29 (br s, 3H), 2.12 (br s, 3H).

Step 2. Synthesis of 4-(2-(4-Fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(4-fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (29.0 mg, 0.08 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol). The crude product was purified by flash chromatography (ethyl acetate:hexane:acetic acid=40:60:1) to give the desired product as a yellow viscous liquid (10.0 mg, 36%). ¹H NMR (CDCl₃, 400 MHz) δ 7.93 (br s, 1H), 7.75 (br d, 1H), 7.61 (br s, 1H), 6.94 (br t, 1H), 6.88 (br s, 1H), 6.72 (br d, 1H), 6.23 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.30 (br s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 56

4-(2-(4-Fluoro-3-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(4-fluoro-3-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 4-fluoro-3-methylbenzaldehyde (276 mg, 2.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (62.0 mg, 17%). ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.74 (br d, 1H), 7.15 (dd, 1H), 7.11-7.06 (m, 1H), 6.87 (t, 1H), 5.89 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.86 (s, 3H), 2.20 (br s, 6H); LC-MS (ESI) m/z 359.8 [M+H]⁺.

Step 2. Synthesis of 4-(2-(4-Fluoro-3-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(4-fluoro-3-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (52.0 mg, 0.145 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol) to give the desired product as a yellow viscous liquid (50.0 mg, 100%). ¹H NMR (CDCl₃, 300 MHz) δ 7.89 (br s, 1H), 7.76 (br d, 1H), 7.16 (d, 1H), 7.12-7.07 (m, 1H), 6.88 (t, 1H), 5.90 (br s, 1H), 4.03 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 6H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 57

4-(2-(3-Fluoro-4-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(3-fluoro-4-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 4-fluoro-3-methylbenzaldehyde (276 mg, 2.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (70.0 mg, 19%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.74 (br d, 1H), 7.07-7.00 (m, 2H), 6.94 (dd, 1H), 5.88 (br s, 1H), 4.01 (d, 1H), 3.90 (d, 1H), 3.87 (s, 3H), 2.21 (br s, 6H).

Step 2. Synthesis of 4-(2-(3-Fluoro-4-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(3-fluoro-4-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (70.0 mg, 0.190 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol) to give the desired product as a yellow viscous liquid (52.0 mg, 77%). ¹H NMR (CDCl₃, 300 MHz) δ 7.90 (br s, 1H), 7.78 (br d, 1H), 7.09-7.00 (m, 2H), 6.94 (dd, 1H), 5.90 (br s, 1H), 4.03 (d, 1H), 3.92 (d, 1H), 2.21 (br s, 6H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 58

4-(2-(5-Fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

Step 1. Synthesis of Methyl 4-(2-(5-fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 5-fluoro-2-methylbenzaldehyde (138 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (60.0 mg, 17%). ¹H NMR (CDCl₃, 300 MHz) δ 7.91 (br s, 1H), 7.75 (br s, 1H), 7.37-7.28 (m, 1H), 7.00-6.95 (m, 1H), 6.90-6.83 (m, 2H), 6.18 (br s, 1H), 3.98 (d, 1H), 3.88 (d, 1H), 3.87 (s, 3H), 2.30 (br s, 3H), 2.09 (br s, 3H).

Step 2. Synthesis of 4-(2-(5-Fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 4-(2-(5-fluoro-2-methylphenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate (60.0 mg, 0.170 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol). The crude product was purified by flash chromatography (ethyl acetate:hexane=3:2) to give the desired product as a yellow viscous liquid (5.00 mg, 8.7%). ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (br s, 1H), 7.77 (br d, 1H), 7.32 (br s, 1H), 6.99 (dd, 1H), 6.93 (br s, 1H), 6.88 (td, 1H), 6.20 (br s, 1H), 4.03 (d, 1H), 3.91 (d, 1H), 2.32 (br s, 3H), 2.10 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 59

3-Methyl-4-(4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoic acid

Step 1. Synthesis of Methyl 3-methyl-4-(4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 3-(trifluoromethyl)benzaldehyde (174 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (133 mg, 34%). ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.74 (br d, 1H), 7.62 (br s, 1H), 7.54 (br d, 1H), 7.47 (br d, 1H), 7.39 (dd, 1H), 6.94 (br s, 1H), 6.00 (br s, 1H), 4.05 (d, 1H), 3.94 (d, 1H), 3.86 (s, 3H), 2.21 (br s, 3H).

Step 2. Synthesis of 3-Methyl-4-(4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoic acid

The compound was prepared by following the standard procedure B with methyl 3-methyl-4-(4-oxo-2-(3-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoate (133 mg, 0.33 mmol) and 20% NaOH_(aq) (0.200 mL, 1.00 mmol) to give the desired product as a yellow viscous liquid (86.0 mg, 67%). ¹H NMR (CDCl₃, 400 MHz)¹H NMR (CDCl₃, 400 MHz) δ 7.90 (br s, 1H), 7.78 (br s, 1H), 7.63 (br s, 1H), 7.55 (br d, 1H), 7.48 (br d, 1H), 7.41 (br t, 1H), 6.01 (br s, 1H), 4.06 (d, 1H), 3.96 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 382.1 [M+H]⁺.

Example 60

3-Methyl-4-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoic acid

Step 1. Synthesis of Methyl 3-methyl-4-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoate

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 4-(trifluoromethyl)benzaldehyde (174 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (110 mg, 28%). ¹H NMR (CDCl₃, 400 MHz) δ 7.90 (br s, 1H), 7.75 (br d, 1H), 7.55 (d, 2H), 7.45 (d, 2H), 6.95 (br s, 1H), 5.98 (br s, 1H), 4.04 (d, 1H), 3.93 (d, 1H), 3.87 (s, 3H), 2.22 (br s, 3H).

Step 2. Synthesis of 3-Methyl-4-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoic acid

The compound was prepared by following the standard procedure B with methyl 3-methyl-4-(4-oxo-2-(4-(trifluoromethyl)phenyl)thiazolidin-3-yl)benzoate (110 mg, 0.280 mmol) and 20% NaOH_(aq) (0.200 mL, 1.00 mmol) to give the desired product as a yellow viscous liquid (86.0 mg, 81%). ¹H NMR (CDCl₃, 300 MHz) δ 7.91 (br s, 1H), 7.77 (br d, 1H), 7.55 (d, 2H), 7.45 (d, 2H), 6.95 (br s, 1H), 6.00 (br s, 1H), 4.06 (d, 1H), 3.95 (d, 1H), 2.23 (br s, 3H); LC-MS (ESI) m/z 382.1 [M+H]⁺.

Example 61

4-[2-(4-Methoxy-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

Step 1. Synthesis of 4-[2-(4-methoxy-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), p-anisaldehyde (272 mg, 2.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (34.0 mg, 10%). ¹H NMR (CDCl₃, 300 MHz) δ 7.85 (br s, 1H), 7.72 (br d, 1H), 7.23 (d, 2H), 6.76 (d, 2H), 5.93 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 2.20 (br s, 3H).

Step 2. Synthesis of 4-[2-(4-methoxy-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

The compound was prepared by following the standard procedure B with 4-[2-(4-methoxy-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester (34 mg, 0.095 mmol) and 20% NaOH_(aq) (0.300 mL, 1.50 mmol). The crude product was purified by recrystallization to give the desired product as a white solid (20.0 mg, 61%). ¹H NMR (CD₃Cl, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.24 (d, 2H), 6.77 (d, 2H), 5.96 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.75 (s, 3H), 2.21 (br s, 3H); LC-MS (ESI) m/z 344.2 [M+H]⁺.

Example 62

4-[2-(4-Carboxy-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

Step 1. Synthesis of 4-[2-(4-methoxycarbonyl-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), methyl 4-formylbenzenecarboxylate (328 mg, 2.00 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (84.0 mg, 11%). ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (d, 2H), 7.85 (br s, 1H), 7.70 (br s, 1H), 7.39 (d, 2H), 6.91 (br s, 1H), 5.96 (br s, 1H), 4.04 (d, 1H), 3.92 (d, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.24 (br s, 3H); LC-MS (ESI) m/z 385.9 [M+H]⁺.

Step 2. Synthesis of 4-[2-(4-carboxy-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

The compound was prepared by following the standard procedure B with 4-[2-(4-methoxycarbonyl-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester (40.0 mg, 0.100 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol). The crude product was purified by recrystallization to give the desired product as a yellow solid (21.0 mg, 59%). ¹H NMR (CD₃OD, 300 MHz) δ 7.93 (d, 2H), 7.84 (br s, 1H), 7.74 (br s, 1H), 7.54 (d, 2H), 7.20 (br s, 1H), 6.29 (br s, 1H), 4.12 (d, 1H), 3.96 (d, 1H), 2.21 (br s, 3H); LC-MS (ESI) m/z 357.9 [M+H]⁺.

Example 63

4-[2-(4-Methanesulfonyl-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

Step 1. Synthesis of 4-[2-(4-methanesulfonyl-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 4-methylsulphenylbenzaldehyde (202 mg, 1.10 mmol), and 2-mercaptoacetic acid (0.140 mL, 184 mg, 2.00 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:2) to give the desired product as a yellow viscous liquid (104 mg, 26%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88-7.86 (m, 3H), 7.74 (br d, 1H), 7.53 (d, 2H), 6.94 (br s, 1H), 6.00 (br s, 1H), 4.05 (d, 1H), 3.94 (d, 1H), 3.87 (s, 3H), 3.03 (s, 3H), 2.23 (br s, 3H); LC-MS (ESI) m/z 406.7 [M+H]⁺.

Step 2. Synthesis of 4-[2-(4-methanesulfonyl-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

The compound was prepared by following the standard procedure B with 4-[2-(4-Methanesulfonyl-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester (100 mg, 0.250 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol). The crude product was purified by flash chromatography (EA:Hexane:AcOH=50:20:7) to give the desired product as a yellow solid (80.0 mg, 80%). ¹H NMR (CDCl₃, 300 MHz) δ 7.91 (br s, 1H), 7.87 (d, 2H), 7.78 (br d, 1H), 7.54 (d, 2H), 6.96 (br s, 1H), 6.02 (br s, 1H), 4.06 (d, 1H), 3.94 (d, 1H), 3.02 (s, 3H), 2.23 (br s, 3H); LC-MS (ESI) m/z 391.8 [M+H]⁺.

Example 64

4-[2-(4-Chloro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

Step 1. Synthesis of 4-[2-(4-chloro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester

The compound was prepared by following the standard procedure A with methyl 4-amino-3-methylbenzoate (165 mg, 1.00 mmol), 4-chlorobenzaldehyde (168 mg, 1.20 mmol), and 2-mercaptoacetic acid (0.130 mL, 168 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (70.0 mg, 19%). ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br d, 1H), 7.30-7.18 (m, 4H), 6.91 (br s, 1H), 5.91 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.87 (s, 3H), 2.20 (br s, 3H).

Step 2. Synthesis of 4-[2-(4-chloro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid

The compound was prepared by following the standard procedure B with 4-[2-(4-chloro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid methyl ester (65 mg, 0.18 mmol) and 20% NaOH_(aq) (0.500 mL, 2.50 mmol) to give the desired product as a yellow solid (39.0 mg, 62%). ¹H NMR (CD₃OD, 400 MHz) δ 7.85 (br s, 1H), 7.75 (br s, 1H), 7.41 (d, 2H), 7.28 (d, 2H), 6.25 (br s, 1H), 4.07 (d, 1H), 3.95 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 347.8 [M+H]⁺.

Example 65

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-5-methylphthalic acid

Step 1. Synthesis of Dimethyl 4-methyl-5-nitrophthalate

To a solution of 4-methylphthalic anhydride (1.95 g, 12.0 mmol) in 8 mL of concentrated H₂SO₄ was treated with concentrated HNO₃ slowly then added ice water after 5 min. After allowing to warm up to r.t. then extracted with ethyl acetate (120 mL). The organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give a white solid (2.31 g). To the white solid dissolved in 20 mL of methanol was added concentrated HCl in one portion at r.t. The reaction mixture was refluxed overnight then directly concentrated to give a crude product which was partitioned between ethyl acetate (70 mL) and saturated NaHCO_3(aq) (20 mL). The organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give a colorless viscous liquid (700 mg, 23%). ¹H NMR (CDCl₃, 300 MHz) δ 8.41 (s, 1H), 7.61 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.67 (s, 3H).

Step 2. Synthesis of Dimethyl 4-amino-5-methylphthalate

To a solution of dimethyl 4-methyl-5-nitrophthalate (700 mg, 2.76 mmol) in 7.6 mL of acetic acid was added zinc dust_(s) (1.40 g, 22.0 mmol) in one portion at r.t. The reaction mixture was stirred at r.t. for 4 h then passed through a pad of celite. The filtrate was partitioned between ethyl acetate (70 mL) and saturated NaHCO_3(aq) (20 mL). The organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=1:1) to give the desired product as a yellow viscous liquid (310 mg, 50%). ¹H NMR (CDCl₃, 300 MHz) δ 7.58 (s, 1H), 6.75 (s, 1H), 4.05 (br s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 2.16 (s, 3H).

Step 3. Synthesis of Dimethyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-5-methylphthalate

The compound was prepared by following the standard procedure B with dimethyl 4-amino-5-methylphthalate (90.0 mg, 0.400 mmol), 4-fluorobenzaldehyde (60.0 mg, 0.480 mmol), and 2-mercaptoacetic acid (0.084 mL, 109 mg, 1.18 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:1) to give the desired product as a yellow viscous liquid (43.0 mg, 27%). ¹H NMR (CDCl₃, 400 MHz) δ 7.44 (br s, 1H), 7.32 (dd, 2H), 6.97 (t, 2H), 6.00 (br s, 1H), 3.99 (d, 1H), 3.95-3.84 (m, 7H), 2.16 (br s, 3H).

Step 4. Synthesis of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-5-methylphthalic acid

The compound was prepared by following the standard procedure B with dimethyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-5-methylphthalate (43.0 mg, 0.100 mmol) and 20% NaOH_(aq) (0.100 mL, 0.500 mmol). The crude product was purified by flash chromatography (methanol: dichloromethane: acetic acid=20:80:1) to give the desired product as a yellow viscous liquid (14.0 mg, 37%). ¹H NMR (CD₃OD, 400 MHz) δ 7.97 (br s, 1H), 7.49-7.46 (m, 2H), 6.99 (br t, 2H), 6.37 (br s, 1H), 4.05 (br d, 1H), 3.97 (d, 1H), 2.14 (br s, 3H); LC-MS (ESI) m/z 376.2 [M+H]⁺.

Example 66

3-(5-Acetyl-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Step 1. 1-(3-Amino-4-methylphenyl)ethanone

To a solution of 4-methyl-3-nitroacetophenone (1.00 g, 5.58 mmol) in methanol (40 mL) was added tin(II) chloride dehydrate (3.78 g, 16.7 mmol). After the reaction mixture was stirred at 60° C. for 20 h, then cooled to room temperature and concentrated. The crude was treated with CH₂Cl₂, and the undissolved solids were filtered off. The filtrate was washed with saturated NaHCO_3(aq) and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% ethyl acetate in CH₂Cl₂) to give 1-(3-amino-4-methylphenyl)ethanone (0.610 g, 73%) as a dark green solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.34-7.32 (m, 2H), 7.14 (d, 1H), 2.55 (s, 3H), 2.25 (s, 3H).

Step 2. 3-(5-Acetyl-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure A, 1-(3-amino-4-methylphenyl)ethanone (0.284 g, 1.91 mmol), 4-fluorobenzaldehyde (0.354 g, 2.86 mmol), Na₂SO₄ (0.271 g, 1.91 mmol), 2-mercaptoacetic acid (0.270 mL, 3.87 mmol), and toluene (6.0 mL) were used to carry out the reaction. It was reflux 5 h for the first step and 22 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-15% ethyl acetate in CH₂Cl₂) to give 3-(5-acetyl-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (0.125 g, 20%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.74 (br d, 1H), 7.36-7.32 (m, 2H), 6.97 (br s, 3H), 6.15-5.60 (br, 1H), 4.02 (d, 1H), 3.93 (d, 1H), 2.70-1.95 (br, 6H); LC-MS (ESI) m/z 330.2 [M+H]⁺.

Example 67

2-(4-Fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)phenyl]-1,3-thiazolidin-4-one

Following standard procedure A, 2-methyl-5-(trifluoromethyl)aniline (0.372 g, 2.22 mmol), 4-fluorobenzaldehyde (0.343 g, 2.76 mmol), Na₂SO₄ (0.315 g, 2.22 mmol), 2-mercaptoacetic acid (0.280 mL, 4.01 mmol), and toluene (7.0 mL) were used to carry out the reaction. It was reflux 5 h for the first step and 18 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-5-(trifluoromethyl)phenyl]-1,3-thiazolidin-4-one (109 mg, 14%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.41 (d, 1H), 7.34-7.29 (m, 3H), 6.97 (br t, 2H), 6.15-5.70 (br, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 356.2 [M+H]⁺.

Example 68

Methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Step 1. Methyl (4-amino-3-methylphenoxy)acetate

To a solution of 4-amino-m-cresol (1.02 g, 8.28 mmol) in acetone (16 mL) was added potassium carbonate (1.39 g, 10.0 mmol) and methyl chloroacetate (0.880 mL, 10.0 mmol) at room temperature. After the reaction was reflux for 18 h and cooled to room temperature, the reaction mixture was concentrated and quenched with water. The solution was extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by combi-flash column chromatography (0-20% ethyl acetate in CH₂Cl₂) to give methyl (4-amino-3-methylphenoxy)acetate (0.450 g, 28%) as a yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 6.71 (s, 1H), 6.65-6.62 (m, 2H), 4.56 (s, 2H), 3.79 (s, 3H), 2.17 (s, 3H).

Step 2. Methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Following standard procedure A, methyl (4-amino-3-methylphenoxy)acetate (0.311 g, 1.60 mmol), 4-fluorobenzaldehyde (0.257 g, 2.07 mmol), Na₂SO₄ (0.227 g, 1.60 mmol), 2-mercaptoacetic acid (0.200 mL, 2.87 mmol), and toluene (4.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (293 mg, 49%) as a yellow gum. ¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.26 (m, 2H), 6.99 (br t, 2H), 6.90-6.30 (br, 3H), 6.10-5.60 (br, 1H), 4.54 (s, 2H), 4.00 (d, 1H), 3.88 (d, 1H), 3.78 (s, 3H), 2.38-2.00 (br, 3H); LC-MS (ESI) m/z 376.2 [M+H]⁺.

Example 69

{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid

Following standard procedure B, methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (0.198 g, 0.527 mmol), 20% NaOH_(aq) (0.45 mL), and methanol (4.0 mL) were used to carry out the reaction. After the reaction was stirred for 4 h and work-up, the residue was purified by flash column chromatography (20% MeOH in CH₂Cl₂) to give {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (149 mg, 79%) as an orange solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.30 (dd, 2H), 6.97 (br t, 2H), 6.85-6.30 (br, 3H), 6.10-5.60 (br, 1H), 4.52 (s, 2H), 4.01 (d, 1H), 3.90 (d, 1H), 2.40-2.10 (br, 3H); LC-MS (ESI) m/z 362.2 [M+H]⁺.

Example 70

Methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetate

Step 1. Dimethyl (3-methyl-4-nitrophenyl)propanedioate

To a solution of dimethylmalonate (0.960 g, 7.27 mmol) in DMF anhydrous (15 mL) was added 60% sodium hydride in mineral oil (89.5 mg, 7.90 mmol) at 0° C., and the reaction mixture was stirred for 30 min. 4-Fluoro-2-methyl-1-nitrobenzene (1.02 g, 6.58 mmol) was added to the solution, and then stirred at 110° C. for 18 h. The reaction was quenched with water (60 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (30% ethyl acetate in n-hexane) to give dimethyl (3-methyl-4-nitrophenyl)propanedioate (0.550 g, 31%) as a yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.98 (d, 1H), 7.41-7.39 (m, 2H), 4.69 (s, 1H,), 3.78 (s, 6H), 2.61 (s, 3H).

Step 2. (3-Methyl-4-nitrophenyl)acetic acid

To a solution of dimethyl (3-methyl-4-nitrophenyl)propanedioate (0.540 g, 2.02 mmol) in water (10 mL) and methanol (10 mL) was added potassium hydroxide (0.340 g, 6.06 mmol) at room temperature, and it was reflux for 4 h. After the reaction was cooled and acidified by 2 N HCl_(aq) (40 mL), the solution was extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford (3-methyl-4-nitrophenyl)acetic acid (0.480 g, quantitative yield) as an orange solid, which was directly used to next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 7.97 (d, 1H), 7.28-7.26 (m, 2H), 3.71 (s, 2H), 2.61 (s, 3H).

Step 3. Methyl (3-methyl-4-nitrophenyl)acetate

To a solution of (3-methyl-4-nitrophenyl)acetic acid (0.480 g, 2.46 mmol) in methanol (15 mL) was added concentrated HCl_(aq) (1.50 mL). After the reaction mixture was reflux for 20 h and cooled to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer was dried over MgSO_4(s), filtered, and concentrated to give methyl (3-methyl-4-nitrophenyl)acetate (0.410 g, 80%) as a brown oil, which was directly used to next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 7.96 (d, 1H), 7.26 (br s, 2H), 3.72 (s, 3H), 3.67 (s, 2H), 2.60 (s, 3H).

Step 4. Methyl (4-amino-3-methylphenyl)acetate

Tin(II) chloride dehydrate (1.33 g, 5.88 mmol) was added to a solution of methyl (3-methyl-4-nitrophenyl)acetate (0.410 g, 1.96 mmol) in methanol (20 mL). After the reaction mixture was stirred at 60° C. for 20 h, then cooled to room temperature and concentrated. The crude was treated with saturated NaHCO_3(aq) (30 mL) and extracted with CH₂Cl₂ (30 mL×2). The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by flash column chromatography (30% ethyl acetate in n-hexane) to give methyl (4-amino-3-methylphenyl)acetate (0.250 g, 35%) as a brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 6.97-6.94 (m, 2H), 6.66 (d, 1H), 3.67 (s, 3H), 3.50 (s, 2H), 2.17 (s, 3H).

Step 5. Methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetate

Following standard procedure A, methyl (4-amino-3-methylphenyl)acetate (0.200 g, 1.12 mmol), 4-fluorobenzaldehyde (0.180 mL, 1.68 mmol), Na₂SO₄ (0.159 g, 1.12 mmol), 2-mercaptoacetic acid (0.160 mL, 2.29 mmol), and toluene (5.0 mL) were used to carry out the reaction. It was reflux 5 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetate (183 mg, 45%) as a lightly yellow gum. ¹H NMR (CDCl₃, 300 MHz) δ 7.33-7.28 (m, 2H), 7.12 (br s, 1H), 6.97 (br t, 2H), 6.80-6.40 (br, 1H), 6.10-5.60 (br, 1H), 4.01 (d, 1H), 3.89 (d, 1H), 3.66 (s, 3H), 3.51 (s, 2H), 2.16 (br s, 3H); LC-MS (ESI) m/z 382.2 [M+Na]⁺.

Example 71

{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetic acid

Following standard procedure B, methyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetate (0.137 g, 0.382 mmol), 20% NaOH_(aq) (0.50 mL), and methanol (2.0 mL) were used to carry out the reaction. After the reaction was stirred for 4 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetic acid (79.9 mg, 61%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 12.45-12.10 (br, 1H), 7.49-7.45 (m, 2H), 7.12-6.96 (m, 4H), 6.60-6.10 (br, 1H), 4.07 (d, 1H), 3.85 (d, 1H), 3.48 (s, 2H), 2.02 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 72

3-(2,4-Dimethylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-dimethylaniline (48.5 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=1:3) to give the desired product as a yellow viscous liquid (74.2 mg, 62%). ¹H NMR (C₆D₆, 400 MHz) δ 6.80 (br s, 2H), 6.62 (br s, 1H), 6.60-6.40 (m, 4H), 5.38 (br s, 1H), 3.50 (d, 1H), 3.39 (d, 1H), 1.97 (br s, 3H), 1.87 (s, 3H); LC-MS (ESI) m/z 302.9 [M+H]⁺.

Example 73

3-(2,4-Dimethylphenyl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-dimethylaniline (48.5 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=1:3) to give the desired product as a yellow viscous liquid (100 mg, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30-7.20 (br, 1H), 7.08 (d, 2H), 6.98-6.80 (m, 2H), 6.50 (br s, 1H), 5.73 (br s, 1H), 4.02 (d, 1H), 3.88 (d, 1H), 2.50-1.80 (br, 6H); LC-MS (ESI) m/z 302.8 [M+H]⁺.

Example 74

2-(3,4-Difluorophenyl)-3-(2,4-dimethylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-dimethylaniline (48.5 mg, 0.4 mmol), 3,4-difluorobenzaldehyde (56.8 mg, 0.4 mmol), and 2-mercaptoacetic acid (0.67 mL, 86.5 mg, 0.94 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (60 mg, 0.19 mmol, 47%). ¹H NMR (C₆D₆, 400 MHz) δ 6.79 (br s, 1H), 6.61 (br s, 1H), 6.55 (br s, 1H), 6.45-6.30 (m, 3H), 5.25 (br s, 1H), 3.40 (d, 1H), 3.32 (d, 1H), 1.94 (br s, 3H), 1.87 (s, 3H); LC-MS (ESI) m/z 320.9 [M+H]⁺.

Example 75

3-(2,5-Dimethylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,5-dimethylaniline (48.5 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercpatoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=2:3) to give the desired product as a yellow viscous liquid (47.0 mg, 40%). ¹H NMR (C₆D₆, 300 MHz) δ 6.85-6.67 (m, 3H), 6.63 (d, 1H), 6.50 (t, 2H), 6.39 (br s, 1H), 5.39 (br s, 1H), 3.51 (d, 1H), 3.40 (d, 1H), 1.95 (br s, 3H), 1.86 (s, 3H).

Example 76

3-(2,5-Dimethylphenyl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,5-dimethylaniline (48.5 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=1:3) to give the desired product as a yellow viscous liquid (85.0 mg, 71%). ¹H NMR (C₆D₆, 400 MHz) δ 6.85 (br d, 1H), 6.74 (br d, 1H), 6.67-6.56 (m, 3H), 6.50 (br t, 1H), 6.43 (br s, 1H), 5.36 (br s, 1H), 3.46 (d, 1H), 3.35 (d, 1H), 1.97 (s, 3H), 1.84 (br s, 3H); LC-MS (ESI) m/z 302.9 [M+H]⁺.

Example 77

2-(3,4-Difluorophenyl)-3-(2,5-dimethylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,5-dimethylaniline (48.5 mg, 0.400 mmol), 3,4-difluorobenzaldehyde (56.8 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate hexane=3:7) to give the desired product as a yellow viscous liquid (56.0 mg, 44%). 1H NMR (C₆D₆, 400 MHz) δ 6.80-6.70 (m, 2H), 6.62 (d, 1H), 6.43-6.30 (m, 3H), 5.26 (br s, 1H), 3.42 (d, 1H), 3.34 (d, 1H), 1.92 (br s, 3H), 1.85 (br s, 3H); LC-MS (ESI) m/z 320.8 [M+H]⁺.

Example 78

3-(2-Fluoro-6-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2-fluoro-6-methylaniline (50.1 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.7 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (20.0 mg, 16%). ¹H NMR (CDCl₃, 400 MHz) δ 7.34 (dd, 2H), 7.12 (dd, 1H), 6.99 (d, 1H), 6.94 (t, 2H), 6.77 (t, 1H), 5.84 (s, 1H), 4.03 (d, 1H), 3.90 (d, 1H), 2.35 (s, 3H).

Example 79

3-(3-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.500 mL, 64.7 mg, 0.700 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (26.0 mg, 21%). ¹H NMR (C₆D₆, 400 MHz) δ 6.73 (br s, 2H), 6.54-6.40 (m, 4H), 6.25 (br s, 1H), 5.30 (br s, 1H), 3.42 (br d, 1H), 3.31 (d, 1H) 1.95 (s, 3H); LC-MS (ESI) m/z 306.8 [M+H]⁺.

Example 80

3-(4-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.7 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (38.0 mg, 31%). ¹H NMR (CDCl₃, 300 MHz) δ 7.30 (dd, 2H), 7.10-6.30 (br, 5H), 6.20-5.40 (br, 1H), 4.01 (d, 1H), 3.90 (d, 1H), 2.40-1.80 (br, 3H); LC-MS (ESI) m/z 306.8 [M+H]⁺.

Example 81

3-(4-Bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure A, 4-bromo-2-methylaniline (2.51 g, 13.5 mmol), 4-fluorobenzaldehyde (2.01 g, 16.2 mmol), Na₂SO₄ (1.92 g, 13.5 mmol), 2-mercaptoacetic acid (1.70 mL, 24.5 mmol), and toluene (40 mL) were used to carry out the reaction. It was reflux 7 h for the first step and 20 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (1.73 g, 35%) as a white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.48 (dd, 2H), 7.43 (br s, 1H), 7.29 (br d, 1H), 7.11 (t, 2H), 6.50-6.05 (br, 1H), 4.07 (d, 1H), 3.88 (d, 1H), 2.07 (br s, 3H); LC-MS (ESI) m/z 366.1 [M+H]⁺.

Example 82

3-(5-Fluoro-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (2.00 g, 16.0 mmol), 4-fluorobenzaldehyde (2.00 g, 16.0 mmol), and 2-mercaptoacetic acid (1.33 mL, 1.72 g, 18.7 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography to give the desired product as a yellow viscous liquid (1.07 g, 22%). ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (dd, 2H), 7.13 (br s, 1H), 6.98 (t, 2H), 6.88 (td, 1H), 5.87 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 2.10 (br s, 3H); LC-MS (ESI) m/z 306.8 [M+H]⁺.

Example 83

3-(5-Fluoro-2-methylphenyl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (50.0 mg, 41%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30-7.20 (m, 1H), 7.15 (br t, 1H), 7.05 (d, 2H), 7.00 (t, 1H), 6.89 (td, 1H), 6.56 (br s, 1H), 5.83 (br s, 1H), 4.02 (d, 1H), 3.89 (d, 1H), 2.13 (br s, 3H); LC-MS (ESI) m/z 306.9 [M+H]⁺.

Example 84

3-(5-Fluoro-2-methylphenyl)-2-(4-(methylsulfonyl)phenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 4-methylsulfonylbenzaldehyde (73.7 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:2) to give the desired product as a yellow viscous liquid (61.0 mg, 42%). ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (d, 2H), 7.54 (d, 2H), 7.15 (br t, 1H), 6.89 (td, 1H), 6.60 (br s, 1H), 5.94 (br s, 1H), 4.03 (d, 1H), 3.91 (d, 1H), 3.03 (s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 366.6 [M+H]⁺.

Example 85

4-(3-(5-Fluoro-2-methylphenyl)-4-oxothiazolidin-2-yl)benzonitrile

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 4-cyanobenzaldehyde (52.4 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by recrystallization to give the desired product as a yellow solid (28.0 mg, 22%). ¹H NMR (CDCl₃, 400 MHz) δ 7.61 (d, 2H), 7.46 (d, 2H), 7.16 (br t, 1H), 6.91 (td, 1H), 6.60 (br s, 1H), 5.88 (br s, 1H), 4.02 (d, 1H), 3.91 (d, 1H), 2.12 (br s, 3H); LC-MS (ESI) m/z 312.8 [M+H]⁺.

Example 86

3-[3-(5-Fluoro-2-methyl-phenyl)-4-oxo-thiazolidin-2-yl]-benzonitrile

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), 3-cyanobenzaldehyde (97.0 mg, 0.750 mmol), and thioglycolic acid (0.064 mL, 83.0 mg, 0.900 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (95.0 mg, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 7.62-7.59 (m, 3H), 7.45 (br t, 1H), 7.17 (br t, 1H), 6.91 (t, 1H), 6.58 (br s, 1H), 5.88 (br s, 1H), 4.04 (d, 1H), 3.94 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 312.8 [M+H]⁺.

Example 87

2-(4-Ethyl-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), 4-ethylbenzaldehyde (100 mg, 0.750 mmol), and 2-mercaptoacetic acid (0.100 mL, 129 mg, 1.40 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a yellow viscous liquid (49.0 mg, 31%). ¹H NMR (CDCl₃, 400 MHz) δ 7.25 (d, 2H), 7.20-7.10 (m, 3H), 6.87 (t, 1H), 6.55 (br s, 1H), 5.83 (br s, 1H), 4.02 (d, 1H), 3.89 (d, 1H), 2.62 (q, 2H), 2.14 (br s, 3H), 1.21 (t, 3H); LC-MS (ESI) m/z 316.9 [M+H]⁺.

Example 88

3-(5-Fluoro-2-methyl-phenyl)-2-(4-methylsulfanyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-(methylthiol)benzaldehyde (228 mg, 1.50 mmol), 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.128 mL, 166 mg, 1.80 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:5) to give the desired product as a yellow viscous liquid (75.0 mg, 22%). ¹H NMR (CDCl₃, 400 MHz) δ 7.23 (d, 2H), 7.20-7.08 (m, 3H), 6.87 (td, 1H), 6.60 (br s, 1H), 5.83 (br s, 1H), 4.00 (d, 1H), 3.88 (d, 1H), 2.45 (s, 3H), 2.12 (br s, 3H); LC-MS (ESI) m/z 334.6 [M+H]⁺.

Example 89

3-(5-Fluoro-2-methylphenyl)-2-(3-fluoro-4-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 3-fluoro-4-methylbenzaldehyde (55.2 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.500 mL, 64.7 mg, 0.700 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (80.0 mg, 63%). ¹H NMR (CDCl₃, 300 MHz) δ 7.19-6.95 (m, 4H), 6.89 (td, 1H), 6.57 (br s, 1H), 5.79 (br s, 1H), 4.00 (d, 1H), 3.87 (d, 1H), 2.23 (s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 320.9 [M+H]⁺.

Example 90

3-(5-Fluoro-2-methylphenyl)-2-(4-fluoro-3-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 4-fluoro-3-methylbenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (32.0 mg, 25%). ¹H NMR (CDCl₃, 400 MHz) δ 7.17-7.08 (m, 3H), 6.95-6.83 (m, 2H), 6.55 (br s, 1H), 5.81 (br s, 1H), 4.00 (d, 1H), 3.89 (d, 1H), 2.22 (s, 3H), 2.12 (br s, 3H); LC-MS (ESI) m/z 320.8 [M+H]⁺.

Example 91

2-(3,4-Difluorophenyl)-3-(5-fluoro-2-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 3,4-difluorobenzaldehyde (56.8 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:5) to give the desired product as a yellow viscous liquid (58.0 mg, 44%). ¹H NMR (CDCl₃, 300 MHz) δ 7.22-7.00 (m, 4H), 6.91 (td, 1H), 6.56 (br s, 1H), 5.83 (br s, 1H), 4.00 (d, 1H), 3.89 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 324.9 [M+H]⁺.

Example 92

2-(3,5-Difluorophenyl)-3-(5-fluoro-2-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 3,5-difluorobenzaldehyde (56.8 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.067 mL, 81.2 mg, 0.880 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (78.0 mg, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 7.17 (br t, 1H), 6.92 (td, 1H), 6.87 (d, 2H), 6.75 (br t, 1H), 6.60 (br s, 1H), 5.78 (br s, 1H), 4.01 (d, 1H), 3.88 (d, 1H), 2.13 (br s, 3H); LC-MS (ESI) m/z 324.7 [M+H]⁺.

Example 93

2-(4-Chloro-3-fluorophenyl)-3-(5-fluoro-2-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 4-chloro-3-fluorobenzaldehyde (63.4 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:7) to give the desired product as a yellow viscous liquid (60.0 mg, 44%). ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (t, 1H), 7.20-7.10 (m, 2H), 7.04 (d, 1H), 6.91 (td, 1H), 6.60 (br s, 1H), 5.82 (br s, 1H), 4.00 (d, 1H), 3.89 (d, 1H), 2.12 (br s, 3H); LC-MS (ESI) m/z 339.9 [M+H]⁺.

Example 94

2-(3-Chloro-4-fluorophenyl)-3-(5-fluoro-2-methylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (50.0 mg, 0.400 mmol), 3-chloro-4-fluorobenzaldehyde (63.4 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=2:5) to give the desired product as a yellow viscous liquid (51.0 mg, 38%). ¹H NMR (CDCl₃, 300 MHz) δ 7.42 (br d, 1H), 7.21-7.13 (m, 2H), 7.05 (t, 1H), 6.90 (td, 1H), 6.59 (br s, 1H), 5.82 (br s, 1H), 4.00 (d, 1H), 3.89 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 340.8 [M+H]⁺.

Example 95

2-(4-Fluoro-3-methoxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), 4-fluoro-3-methoxybenzaldehyde (231 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.128 mL, 165 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (100 mg, 30%). ¹H NMR (CDCl₃, 400 MHz) δ 7.15 (br t, 1H), 7.00-6.94 (m, 2H), 6.90 (t, 1H), 6.85-6.80 (m, 1H), 5.87 (br s, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 3.85 (s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 336.7 [M+H]⁺.

Example 96

2-(3-Fluoro-4-methoxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), 3-fluoro-4-methoxybenzaldehyde (231 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.128 mL, 165 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (100 mg, 30%). ¹H NMR (CDCl₃, 400 MHz) δ 7.20-7.15 (m, 2H), 6.98 (d, 1H), 6.89 (t, 1H), 6.83 (t, 1H), 6.60 (br s, 1H), 5.81 (br s, 1H), 3.99 (d, 1H), 3.89 (d, 1H), 3.86 (s, 3H), 2.12 (br s, 3H); LC-MS (ESI) m/z 335.8. [M+H]⁺.

Example 97

3-(5-Fluoro-2-methyl-phenyl)-2-(3-fluoro-4-trifluoromethyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), 3-fluoro-4-(trifluoromethyl)benzaldehyde (288 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.128 mL, 165 mg, 1.80 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (261 mg, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (t, 1H), 7.26-7.17 (m, 3H), 6.93 (t, 1H), 6.62 (br s, 1H), 5.88 (br s, 1H), 4.03 (d, 1H), 3.91 (d, 1H), 2.14 (br s, 3H); LC-MS (ESI) m/z 373.7 [M+H]⁺.

Example 98

3-(5-Fluoro-2-methyl-phenyl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), 4-fluoro-3-(trifluoromethyl)benzaldehyde (144 mg, 0.750 mmol), and 2-mercpatoacetic acid (0.064 mL, 83.0 mg, 0.900 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (130 mg, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 7.59 (br s, 1H), 7.55-7.51 (m, 1H), 7.20-7.10 (m, 2H), 6.91 (t, 1H), 6.60 (br s, 1H), 5.92 (br s, 1H), 4.01 (d, 1H), 3.93 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 374.7 [M+H]⁺.

Example 99

3-(5-Fluoro-2-methyl-phenyl)-2-(3-fluoro-5-trifluoromethyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-fluoro-5-(trifluoromethyl)benzaldehyde (144 mg, 0.750 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.063 mL, 83.0 mg, 0.900 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:11) to give the desired product as a yellow viscous liquid (110 mg, 59%). ¹H NMR (CDCl₃, 400 MHz) δ 7.37 (s, 1H), 7.26 (d, 2H), 7.18 (br s, 1H), 6.92 (td, 1H), 6.60 (br s, 1H), 5.89 (br s, 1H), 4.03 (d, 1H), 3.92 (d, 1H), 2.13 (br s, 3H); LC-MS (ESI) m/z 373.7 [M+H]⁺.

Example 100

3-(5-Fluoro-2-methyl-phenyl)-2-(3-fluoro-5-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-fluoro-5-methylbenzaldehyde (103 mg, 0.750 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.100 mL, 129 mg, 1.40 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (73.0 mg, 46%). ¹H NMR (CDCl₃, 300 MHz) δ 7.16 (br t, 1H), 6.93-6.79 (m, 4H), 6.57 (br s, 1H), 5.77 (br s, 1H), 4.02 (d, 1H), 3.87 (d, 1H), 2.30 (s, 3H), 2.14 (br s, 3H); LC-MS (ESI) m/z 320.9 [M+H]⁺.

Example 101

2-(3-Fluoro-4-hydroxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

Step 1. Synthesis of 4-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-benzaldehyde

To a solution of 3-fluoro-4-hydroxybenzaldehyde (560 mg, 4.00 mmol) and TBDMSCl (900 mg, 6.00 mmol) in 10 mL of CH₂Cl₂ was added imidazole (544 mg, 8.00 mmol) in one portion at 0° C. The reaction mixture was stirred at room temperature for 4.5 h then partitioned between CH₂Cl₂ (50 mL) and H₂O (20 mL). The organic layer was dried over MgSO₄ then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=1:8) to give the desired product as a colorless viscous liquid (750 mg, 75%). ¹H NMR (CDCl₃, 400 MHz) δ 9.85 (s, 1H), 7.59 (d, 1H), 7.56 (dd, 1H), 7.03 (t, 1H), 1.01 (s, 9H), 0.23 (s, 6H).

Step 2. Synthesis of 2-[4-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-phenyl]-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-benzalde hyde (305 mg, 1.20 mmol), and 2-mercaptoacetic acid (0.130 mL, 165 mg, 1.80 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a yellow viscous liquid (93.0 mg, 21%). ¹H NMR (CDCl₃, 400 MHz) δ 7.18-7.06 (m, 2H), 6.95-6.85 (m, 2H), 6.79 (br t, 1H), 5.78 (br s, 1H), 3.98 (d, 1H), 3.88 (d, 1H), 2.09 (br s, 3H), 0.96 (s, 9H), 0.16 (s, 6H).

Step 3. Synthesis of 2-(3-fluoro-4-hydroxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

To a solution of 2-[4-(tert-butyl-dimethyl-silanyloxy)-3-fluoro-phenyl]-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one (93.0 mg, 0.210 mmol) in 2 mL of THF was added 75% TBAF_(aq) (0.150 mL, 0.420 mmol) in one portion and stirred at room temperature for 1.5 h. The reaction mixture was directly concentrated to give a crude product which was partitioned between ethyl acetate (30 mL) and H₂O (10 mL). The organic layer was washed with brine (10 mL) dried over MgSO₄ then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (68.0 mg, 100%). ¹H NMR (CDCl₃, 400 MHz) δ 7.13 (d, 2H), 6.96 (d, 1H), 6.89 (t, 2H), 6.54 (br s, 1H), 5.79 (br s, 1H), 5.26 (s, 1H), 3.98 (d, 1H), 3.88 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 322.9 [M+H]⁺.

Example 102

2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 1,4-benzodioxane-6-carboxaldehyde (123 mg, 0.750 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.063 mL, 83.0 mg, 0.900 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (36.0 mg, 21%). ¹H NMR (CDCl₃, 400 MHz) δ 7.15 (br t, 1H), 6.89 (td, 1H), 6.87 (s, 1H), 6.83-6.77 (m, 2H), 6.59 (br s, 1H), 5.75 (br s, 1H), 4.23 (s, 4H), 3.99 (d, 1H), 3.86 (d, 1H), 2.14 (br s, 3H); LC-MS (ESI) m/z 346.8 [M+H]⁺.

Example 103

2-(3-Bromo-5-chloro-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-bromo-5-chlorobenzaldehyde (131 mg, 0.600 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.100 mL, 129 mg, 1.40 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a yellow viscous liquid (136 mg, 68%). ¹H NMR (CDCl₃, 300 MHz) δ 7.45 (s, 1H), 7.36 (s, 1H), 7.25 (s, 1H), 7.18 (br t, 1H), 6.93 (td, 1H), 6.59 (br s, 1H), 5.74 (br s, 1H), 4.02 (d, 1H), 3.88 (d, 1H), 2.14 (br s, 3H); LC-MS (ESI) m/z 401.7 [M+H]⁺.

Example 104

3-(5-Fluoro-2-methyl-phenyl)-2-(3,4,5-trifluoro-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4,5-trifluorobenzaldehyde (120 mg, 0.750 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.100 mL, 129 mg, 1.40 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a yellow viscous liquid (120 mg, 71%). ¹H NMR (CDCl₃, 400 MHz) δ 7.19 (br t, 1H), 6.99 (t, 2H), 6.93 (td, 1H), 6.60 (br s, 1H), 5.78 (br s, 1H), 3.99 (d, 1H), 3.89 (d, 1H), 2.12 (br s, 3H); LC-MS (ESI) m/z 341.8 [M+H]⁺.

Example 105

2-(3,4-Difluoro-5-methyl-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,4-difluoro-5-methylbenzaldehyde (117 mg, 0.750 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.100 mL, 129 mg, 1.40 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (71.0 mg, 42%). ¹H NMR (CDCl₃, 300 MHz) δ 7.16 (br t, 1H), 7.10-6.98 (m, 1H), 6.95-6.84 (m, 2H), 6.58 (br s, 1H), 5.77 (br s, 1H), 3.99 (d, 1H), 3.87 (d, 1H), 2.24 (s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 338.9 [M+H]⁺.

Example 106

2-(4-Fluoro-3,5-dimethyl-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-fluoro-3,5-dimethylbenzaldehyde (114 mg, 0.750 mmol), 5-fluoro-2-methylaniline (63.0 mg, 0.500 mmol), and 2-mercaptoacetic acid (0.100 mL, 129 mg, 1.40 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (40.0 mg, 24%). ¹H NMR (CDCl₃, 300 MHz) δ 7.15 (br t, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.87 (td, 1H), 6.55 (br s, 1H), 5.75 (br s, 1H), 4.00 (d, 1H), 3.87 (d, 1H), 2.20 (s, 6H), 2.14 (br s, 3H); LC-MS (ESI) m/z 334.9 [M+H]⁺.

Example 107

2-(3-Chloro-4-ethoxy-5-fluoro-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-chloro-4-ethoxy-5-fluorobenzaldehyde (303 mg, 1.50 mmol), 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.128 mL, 166 mg, 1.80 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (140 mg, 37%). ¹H NMR (CDCl₃, 300 MHz) δ 7.17 (br t, 1H), 7.12 (s, 1H), 7.01 (d, 1H), 6.93 (br t, 1H), 6.59 (br s, 1H), 5.74 (br s, 1H), 4.17 (q, 2H), 4.00 (d, 1H), 3.87 (d, 1H), 2.12 (br s, 3H), 1.39 (t, 3H); LC-MS (ESI) m/z 384.9 [M+H]⁺.

Example 108

2-(3,5-Difluoro-4-methoxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,5-difluoro-4-methoxybenzaldehyde (206 mg, 1.20 mmol), 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), and 2-mercaptoacetic acid (0.128 mL, 166 mg, 1.80 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (123 mg, 35%). ¹H NMR (CDCl₃, 300 MHz) δ 7.18 (br t, 1H), 6.95-6.85 (m, 3H), 6.60 (br s, 1H), 5.75 (br s, 1H), 4.02-3.95 (m, 4H), 3.87 (d, 1H), 2.13 (br s, 3H); LC-MS (ESI) m/z 354.9 [M+H]⁺.

Example 109

3-(5-Fluoro-2-methyl-phenyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-thiazolidin-4-one

Step 1. Synthesis of 4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-benzaldehyde

To a solution of 3,5-dimethyl-4-hydroxybenzaldehyde (600 mg, 4.00 mmol) and TBDMSCl (900 mg, 6.00 mmol) in 10 mL of CH₂Cl₂ was added imidazole (544 mg, 8.00 mmol) in one portion at 0° C. The reaction mixture was stirred at room temperature for 4.5 h then partitioned between CH₂Cl₂ (50 mL) and H₂O (20 mL). The organic layer was dried over MgSO₄ then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=1:8) to give the desired product as a colorless viscous liquid (600 mg, 60%). ¹H NMR (CDCl₃, 300 MHz) δ 9.83 (s, 1H), 7.53 (s, 2H), 2.27 (s, 6H), 1.03 (s, 9H), 0.23 (s, 6H).

Step 2. Synthesis of 2-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-benzaldehyde (317 mg, 1.20 mmol), and 2-mercaptoacetic acid (0.128 mL, 165 mg, 1.80 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:5) to give the desired product as a yellow viscous liquid (36.0 mg, 8%). ¹H NMR (CDCl₃, 300 MHz) δ 7.12 (br t, 1H), 6.95-6.80 (m, 3H), 6.50 (br s, 1H), 5.71 (br s, 1H), 4.00 (d, 1H), 3.87 (d, 1H), 2.14 (br s, 9H), 0.98 (s, 9H), 0.16 (s, 6H).

Step 3. Synthesis of 3-(5-Fluoro-2-methyl-phenyl)-2-(4-hydroxy-3,5-dimethyl-phenyl)-thiazolidin-4-one

To a solution of 2-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one (36.0 mg, 0.08 mmol) in 1 mL of THF was added 75% TBAF_(aq) (0.06 mL, 0.160 mmol) in one portion and stirred at room temperature for 4 h. The reaction mixture was directly concentrated to give a crude product which was partitioned between ethyl acetate (20 mL) and H₂O (10 mL). The organic layer was washed with brine (10 mL) dried over MgSO₄ then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=2:3) to give the desired product as a yellow viscous liquid (10.0 mg, 38%). ¹H NMR (CDCl₃, 300 MHz) δ 7.16 (br t, 1H), 6.96 (s, 2H), 6.88 (br t, 1H), 6.55 (br s, 1H), 5.75 (br s, 1H), 5.14 (br s, 1H), 4.01 (d, 1H), 3.86 (d, 1H), 2.20-2.00 (m, 9H); LC-MS (ESI) m/z 332.7 [M+H]⁺.

Example 110

2-(3-Bromo-4-hydroxy-5-methoxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

Step 1. Synthesis of 3-bromo-4-(tert-butyl-dimethyl-silanyloxy)-5-methoxy-benzaldehyde

To a solution of 5-bromovanillin (924 mg, 4.00 mmol) and TBDMSCl (900 mg, 6.00 mmol) in 10 mL of CH₂Cl₂ was added imidazole (817 mg, 12.0 mmol) in one portion at 0° C. The reaction mixture was stirred at room temperature for 5.5 h then partitioned between CH₂Cl₂ (60 mL) and H₂O (30 mL). The organic layer was dried over MgSO₄ then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a colorless viscous liquid (760 mg, 55%). ¹H NMR (CDCl₃, 300 MHz) δ 9.79 (s, 1H), 7.64 (s, 1H), 7.33 (s, 1H), 3.87 (s, 3H), 1.04 (s, 9H), 0.25 (s, 6H).

Step 2. Synthesis of 2-[3-bromo-4-(tert-butyl-dimethyl-silanyloxy)-5-methoxy-phenyl]-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-fluoro-2-methylaniline (125 mg, 1.00 mmol), 3-bromo-4-(tert-butyl-dimethyl-silanyloxy)-5-methoxybenzaldehyde (518 mg, 1.50 mmol), and 2-mercaptoacetic acid (0.130 mL, 165 mg, 1.80 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (110 mg, 21%). ¹H NMR (CDCl₃, 300 MHz) δ 7.14 (br d, 1H), 7.08 (s, 1H), 6.89 (t, 1H), 6.72 (s, 1H), 5.77 (br s, 1H), 3.98 (d, 1H), 3.88 (d, 1H), 3.72 (s, 3H), 2.11 (br s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).

Step 3. Synthesis of 2-(3-bromo-4-hydroxy-5-methoxy-phenyl)-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one

To a solution of 2-[3-bromo-4-(tert-butyl-dimethyl-silanyloxy)-5-methoxy-phenyl]-3-(5-fluoro-2-methyl-phenyl)-thiazolidin-4-one (110 mg, 0.210 mmol) in 2 mL of THF was added 75% TBAF_(aq) (0.150 mL, 0.420 mmol) in one portion and stirred at room temperature for 2.5 h. The reaction mixture was directly concentrated to give a crude product which was partitioned between ethyl acetate (30 mL) and H₂O (10 mL). The organic layer was washed with brine (10 mL), dried over MgSO₄, then concentrated to give a crude product. The crude product was purified by flash chromatography (ethyl acetate:hexane=3:4) to give the desired product as a yellow viscous liquid (69.0 mg, 80%). ¹H NMR (CDCl₃, 400 MHz) δ 7.16 (br s, 1H), 7.06 (br s, 1H), 6.90 (td, 1H), 6.79 (s, 1H), 6.60 (br s, 1H), 5.97 (br s, 1H), 5.78 (br s, 1H), 4.00-3.80 (m, 5H), 2.13 (br s, 3H); LC-MS (ESI) m/z 411.6 [M+H]⁺.

Example 111

3-(5-Chloro-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-chloro-2-methylaniline (56.4 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (48.0 mg, 37%). ¹H NMR (CDCl₃, 400 MHz) δ 7.32 (dd, 2H), 7.14-7.05 (m, 2H), 6.99 (br t, 2H), 5.89 (br s, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 2.08 (br s, 3H); LC-MS (ESI) m/z 322.7 [M+H]⁺.

Example 112

3-(5-Chloro-2-methylphenyl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-chloro-2-methylaniline (56.4 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (77.0 mg, 60%). ¹H NMR (CD₃OD, 400 MHz) δ 7.38-7.25 (br, 1H), 7.24-7.21 (m, 2H), 7.17 (br s, 2H), 7.03 (br t, 1H), 6.21 (br s, 1H), 4.07 (br d, 1H), 3.93 (d, 1H), 2.10 (br s, 3H); LC-MS (ESI) m/z 322.9 [M+H]⁺.

Example 113

3-5-Bromo-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-bromo-2-methylaniline (74.4 mg, 0.400 mmol), 4-fluorobenzaldehyde (49.6 mg, 0.400 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethyl acetate:hexane=3:1:5) to give the desired product as a yellow viscous liquid (47.0 mg, 32%). ¹H NMR (CD₃CN, 300 MHz) δ 7.49 (dd, 2H), 7.33 (d, 1H), 7.14 (br s, 1H), 7.06 (t, 2H), 6.12 (br s, 1H), 3.97 (d, 1H), 3.87 (d, 1H), 2.10 (br s, 3H); LC-MS (ESI) m/z 365.7 [M+H]⁺.

Example 114

3-(5-Bromo-2-methylphenyl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 5-bromo-2-methylaniline (74.4 mg, 0.400 mmol), 3-fluorobenzaldehyde (49.6 mg, 0.4 mmol), and 2-mercaptoacetic acid (0.670 mL, 86.5 mg, 0.940 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a yellow viscous liquid (72.0 mg, 49%). ¹H NMR (CDCl₃, 300 MHz) δ 7.35-7.20 (m, 2H), 7.15-6.80 (m, 5H), 5.83 (br s, 1H), 4.01 (d, 1H), 3.88 (d, 1H), 2.09 (br s, 3H); LC-MS (ESI) m/z 365.7 [M+H]⁺.

Example 115

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-hydroxy-3-methylbenzene carboximidamide

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzonitrile (61.8 mg, 0.198 mmol) in ethanol (2.0 mL) and water (0.40 mL) was added sodium carbonate (44.1 mg, 0.356 mmol) and hydroxylamine hydrochloride (24.7 mg, 0.356 mmol) at room temperature, and the reaction mixture was stirred at 70° C. for 18 h. After the reaction was cooled and quenched with water, the solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-100% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-hydroxy-3-methylbenzene carboximidamide (30.2 mg, 44%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.64 (br s, 1H), 7.50-7.25 (m, 4H), 7.10 (br t, 2H), 6.60-6.20 (br, 1H), 5.77 (br s, 1H), 4.08 (d, 1H), 3.88 (d, 1H), 2.09 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 116

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid ethyl ester

Step 1. Synthesis of 4-amino-3-methyl-benzoic acid ethyl ester

To a solution of ethyl 3-methyl-4-nitrobenzoate (1.26 g, 6.00 mmol) in 12.0 mL of acetic acid was added zinc dust_(s) (1.90 g, 30.0 mmol) in one portion at r.t. The reaction mixture was stirred at r.t. for 4 h then passed through a pad of celite. The filtrate was partitioned between ethyl acetate (100 mL) and saturated NaHCO_3(aq) (50 mL). The organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a white solid (540 mg, 50%). ¹H NMR (CDCl₃, 400 MHz) δ 7.77-7.74 (m, 2H), 6.69 (d, 1H), 4.49 (br s, 2H), 4.32 (q, 2H), 2.21 (s, 3H), 1.36 (t, 3H).

Step 2. Synthesis of 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid ethyl ester

The compound was prepared by following the standard procedure A with ethyl 4-amino-3-methylbenzoate (358 mg, 2.00 mmol), 4-fluorobenzaldehyde (273 mg, 2.20 mmol), and 2-mercaptoacetic acid (0.260 mL, 331 mg, 3.60 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (140 mg, 20%). ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.30 (dd, 2H), 6.94 (br t, 2H), 5.94 (br s, 1H), 4.31 (q, 2H), 3.99 (d, 1H), 3.90 (d, 1H), 2.18 (br s, 3H), 1.34 (t, 3H); LC-MS (ESI) m/z 360.9 [M+H]⁺.

Example 117

3-Ethyl-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-benzoic acid

Step 1. Synthesis of 3-Ethyl-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-benzoic acid ethyl ester

The compound was prepared by following the standard procedure A with methyl 3-amino-4-ethylbenzoate (268 mg, 1.50 mmol), 4-fluorobenzaldehyde (242 mg, 1.95 mmol), and 2-mercaptoacetic acid (0.192 mL, 248 mg, 2.70 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (58.0 mg, 11%). ¹H NMR (CDCl₃, 400 MHz) δ 8.00-7.60 (m, 2H), 7.32-7.26 (m, 2H), 6.95 (br s, 2H), 6.55 (br s, 1H), 6.20-5.60 (m, 1H), 4.02 (br d, 1H), 3.92 (d, 1H), 3.88 (s, 3H), 2.64 (br s, 2H), 1.40-0.85 (m, 3H); LC-MS (ESI) m/z 360.9 [M+H]⁺.

Step 2. Synthesis of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-ethylbenzoic acid

The compound was prepared by following the standard procedure B with methyl 3-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-4-ethylbenzoate (58.0 mg, 0.160 mmol) and 20% NaOH_(aq) (1.00 mL, 5.00 mmol) to give the desired product as a yellow solid (54.0 mg, 100%). ¹H NMR (CDCl₃, 400 MHz) δ 7.98 (br s, 1H), 7.72 (br d, 1H), 7.40-7.26 (m, 2H), 6.97 (br s, 2H), 6.61 (br s, 1H), 6.20-5.60 (m, 1H), 4.03 (br d, 1H), 3.93 (d, 1H), 2.64 (br s, 2H), 1.40-1.00 (m, 3H); LC-MS (ESI) m/z 346.0 [M+H]⁺.

Example 118

3-Ethyl-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-benzoic acid ethyl ester

The compound was prepared by following the standard procedure C with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-ethylbenzoic acid (50.0 mg, 0.145 mmol), EDCI • HCl (40.0 mg, 0.210 mmol), ethanol (0.5 mL) and DMAP (25.0 mg, 0.210 mmol). The desired product is a orange viscous liquid (24.0 mg, 44%). ¹H NMR (CDCl₃, 400 MHz) δ 8.00-7.85 (m, 1H), 7.66 (br s, 1H), 7.31-7.28 (m, 2H), 6.96 (br s, 2H), 6.56 (br s, 1H), 6.20-5.60 (br, 1H), 4.34 (q, 2H), 4.02 (br d, 1H), 3.92 (d, 1H), 2.63 (br s, 2H), 1.45-1.00 (m, 6H); LC-MS (ESI) m/z 374.8 [M+H]⁺.

Example 119

3-Ethenyl-4-[2-(4 fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid

Step 1. Methyl 3-ethenyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate

Following standard procedure A, methyl 4-amino-3-ethenylbenzoate (0.231 g, 1.30 mmol), 4-fluorobenzaldehyde (0.210 mL, 1.95 mmol), Na₂SO₄ (0.185 g, 1.30 mmol), 2-mercaptoacetic acid (0.160 mL, 2.29 mmol), and toluene (5.0 mL) were used to carry out the reaction. It was reflux 22 h for the first step and 8 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-ethenyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (28.9 mg, 6%) as a yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 8.19 (s, 1H), 7.79 (d, 1H), 7.28-7.22 (m, 2H), 6.95 (t, 2H), 6.70 (dd, 1H), 5.94 (s, 1H), 5.83 (d, 1H), 5.48 (d, 1H), 3.99-3.88 (m, 5H).

Step 2. 3-Ethenyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid

Following standard procedure B, methyl 3-ethenyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (28.7 mg, 8.03×10⁻⁵ mmol), 20% NaOH_(aq) (0.10 mL), and methanol (0.50 mL) were used to carry out the reaction. After the reaction was stirred for 4 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 3-ethenyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]benzoic acid (15.7 mg, 57%) as a brown gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (s, 1H), 7.83 (d, 1H), 7.28-7.22 (m, 2H), 6.96-6.91 (m, 3H), 6.71 (dd, 1H), 5.96 (s, 1H), 5.84 (d, 1H), 5.50 (d, 1H), 4.03 (d, 1H), 3.95 (d, 1H); LC-MS (ESI) m/z 344.2 [M+H]⁺.

Example 120

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(methylsulfonyl)-benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (86.9 mg, 0.262 mmol), DMAP (80.0 mg, 0.655 mmol), EDCI • HCl (101 mg, 0.524 mmol), methanesulfonamide (29.9 mg, 0.314 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(methylsulfonyl)benzamide (85.1 mg, 80%) as a beige solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.06 (br s, 1H), 7.60-7.40 (br, 2H), 7.33-7.26 (m, 2H), 6.95 (t, 2H), 6.10-5.80 (br, 1H), 4.10-3.95 (m, 2H), 3.34 (s, 3H), 2.18 (br s, 3H); LC-MS (ESI) m/z 409.2 [M+H]⁺.

Example 121

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(propylsulfonyl)-benzamide

Step 1. 1-Propanesulfonamide

Following standard procedure D, 1-propanesulfonyl chloride (1.00 mL, 8.92 mmol), methanol (4.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at 0° C. for 1 h and room temperature for 2 h, 1-propanesulfonamide (0.610 g, 55%) was obtained as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 4.70 (br s, 2H), 3.13-3.08 (m, 2H), 1.90 (sextet, 2H), 1.08 (t, 3H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methyl-N-(propylsulfonyl)benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (71.2 mg, 0.215 mmol), DMAP (65.7 mg, 0.538 mmol), EDCI • HCl (82.4 mg, 0.430 mmol), 1-propanesulfonamide (35.4 mg, 0.258 mmol), and CH₂Cl₂ (4.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by column chromatography (5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(propylsulfonyl)-benzamide (54.8 mg, 58%) as a beige solid. 1H NMR (CDCl₃, 300 MHz) δ 9.01 (br s, 1H), 7.61-7.45 (br, 2H), 7.33-7.28 (m, 2H), 6.95 (br t, 2H), 5.97 (br s, 1H), 4.00 (s, 2H), 3.49-3.44 (m, 2H), 2.17 (br s, 3H), 1.86 (sextet, 2H), 1.09 (t, 3H); LC-MS (ESI) m/z 437.2 [M+H]⁺.

Example 122

N-(Ethylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (88.3 mg, 0.266 mmol), DMAP (81.3 mg, 0.665 mmol), EDCI • HCl (102 mg, 0.532 mmol), 1-ethanesulfonamide (34.9 mg, 0.320 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-4% MeOH in CH₂Cl₂) to give N-(ethylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (99.8 mg, 89%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 9.10-8.60 (br, 1H), 7.56 (br s, 1H), 7.48 (br d, 1H), 7.33-7.29 (m, 2H), 6.95 (t, 2H), 6.10-5.90 (br, 1H), 4.07-3.96 (m, 2H), 3.52 (q, 2H), 2.18 (br s, 3H), 1.39 (t, 3H); LC-MS (ESI) m/z 423.2 [M+H]⁺.

Example 123

N-(Butylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 1-Butanesulfonamide

Following standard procedure D, 1-butanesulfonyl chloride (2.11 g, 13.5 mmol), methanol (10 mL), and ammonium hydroxide solution (30 mL) were used to carry out the reaction. After the reaction was stirred at 0° C. for 1 h and room temperature for 3 h, 1-butanesulfonamide (0.730 g, 39%) was obtained as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 4.70 (br s, 2H), 3.14-3.10 (m, 2H), 1.84 (quint, 2H), 1.48 (sextet, 2H), 0.96 (t, 3H).

Step 2. N-(Butylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (83.4 mg, 0.252 mmol), DMAP (76.9 mg, 0.630 mmol), EDCI • HCl (96.6 mg, 0.504 mmol), 1-butanesulfonamide (41.4 mg, 0.302 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-(butylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (70.9 mg, 62%) as a beige solid. 1H NMR (DMSO-d₆, 400 MHz) δ 7.72 (br s, 1H), 7.61 (br s, 1H), 7.50-7.46 (m, 2H), 7.09 (t, 2H), 6.60-6.10 (br, 1H), 4.06 (d, 1H), 3.90 (d, 1H), 2.13 (br s, 3H), 1.62 (quint, 2H), 1.36 (sextet, 2H), 0.85 (t, 3H); LC-MS (ESI) m/z 451.2 [M+H]⁺.

Example 124

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(2-propanylsulfonyl)-benzamide

Step 1. 2-Propanesulfonamide

Following standard procedure D, 2-propanesulfonyl chloride (1.00 mL, 8.91 mmol), methanol (5.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at 0° C. for 1 h and room temperature for 2 h, 2-propanesulfonamide (0.260 g, 24%) was obtained as a brown solid. 1H NMR (CDCl₃, 400 MHz) δ 4.60-4.40 (br, 2H), 3.22 (heptet, 1H), 1.41 (d, 6H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methyl-N-(2-propanylsulfonyl)-benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.5 mg, 0.249 mmol), DMAP (76.1 mg, 0.623 mmol), EDCI • HCl (95.5 mg, 0.498 mmol), 2-propanesulfonamide (36.8 mg, 0.299 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(2-propanylsulfonyl)benzamide (97.1 mg, 89%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 9.00-8.70 (br, 1H), 7.56 (br s, 1H), 7.52 (br s, 1H), 7.33-7.29 (m, 2H), 6.95 (t, 2H), 6.20-5.80 (br, 1H), 4.05-3.88 (m, 3H), 2.17 (br s, 3H), 1.44-1.39 (m, 6H); LC-MS (ESI) m/z 437.2 [M+H]⁺.

Example 125

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2-methylpropyl)sulfonyl]benzamide

Step 1. 2-Methyl-propanesulfonamide

Following standard procedure D, isobutanesulfonyl chloride (1.00 g, 6.38 mmol), methanol (5.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at 0° C. for 1 h and room temperature for 2 h, 2-methyl-propanesulfonamide (0.330 g, 38%) was obtained as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 4.87 (br s, 2H), 3.04 (d, 2H), 2.29 (heptet, 1H), 1.12 (d, 6H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2-methylpropyl)sulfonyl]benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.7 mg, 0.250 mmol), DMAP (76.4 mg, 0.625 mmol), EDCI • HCl (95.9 mg, 0.500 mmol), 2-methyl-propanesulfonamide (41.1 mg, 0.299 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by column chromatography (10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2-methylpropyl) sulfonyl]benzamide (29.6 mg, 26%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 12.00 (br s, 1H), 7.74 (br s, 1H), 7.61 (br, 1H), 7.51-7.48 (m, 2H), 7.10 (t, 2H), 6.60-6.20 (br, 1H), 4.09 (d, 1H), 3.92 (d, 1H), 3.38 (d, 2H), 2.20-2.05 (m, 4H), 1.00 (d, 6H); LC-MS (ESI) m/z 451.2 [M+H]⁺.

Example 126

N-(Cyclopropylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. Cyclopropanesulfonamide

Following standard procedure D, cyclopropanesulfonyl chloride (0.400 mL, 3.95 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work up, cyclopropanesulfonamide (0.249 g, 52%) was obtained as a white solid. 1H NMR (DMSO-d₆, 300 MHz) δ 6.78 (br s, 2H), 2.50-2.46 (m, 1H), 0.89-0.86 (m, 4H).

Step 2. N-(cyclopropylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methyl-benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (72.7 mg, 0.219 mmol), DMAP (66.9 mg, 0.548 mmol), EDCI • HCl (83.9 mg, 0.438 mmol), cycloproanesulfonamide (26.6 mg, 0.219 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by column chromatography (0-5% MeOH in CH₂Cl₂) to give N-(cyclopropylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (50.9 mg, 53%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 9.08 (br s, 1H), 7.60-7.40 (br, 2H), 7.33-7.27 (m, 2H), 6.94 (br t, 2H), 6.00 (br s, 1H), 4.05-3.94 (m, 2H), 3.06-2.98 (m, 1H), 2.16 (br s, 3H), 1.43-1.35 (br, 2H), 1.10 (d, 2H); LC-MS (ESI) m/z 435.2 [M+H]⁺.

Example 127

N-(Cyclohexylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. Cyclohexanesulfonamide

Following standard procedure D, 1-cyclohexanesulfonyl chloride (0.570 g, 3.12 mmol), methanol (3.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 7 h and work up, cyclohexanesulfonamide (0.143 g, 28%) was obtained as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 4.45 (br s, 2H), 2.95-2.88 (m, 1H), 2.27-2.23 (m, 2H), 1.94-1.90 (m, 2H), 1.74-1.71 (m, 1H), 1.56-1.46 (m, 2H), 1.36-1.17 (m, 3H).

Step 2. N-(Cyclohexylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (76.9 mg, 0.232 mmol), DMAP (70.9 mg, 0.580 mmol), EDCI • HCl (88.9 mg, 0.464 mmol), cyclohexanesulfonamide (37.9 mg, 0.232 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-(cyclohexylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (62.4 mg, 56%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.58 (br s, 1H), 7.57 (br s, 1H), 7.52 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.20-5.80 (br, 1H), 4.03-3.94 (m, 2H), 3.67-3.61 (m, 1H), 2.19-2.04 (br, 5H), 1.92-1.88 (m, 2H), 1.72-1.50 (m, 3H), 1.35-1.18 (m, 3H); LC-MS (ESI) m/z 477.2 [M+H]⁺.

Example 128

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-sulfamoylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (86.9 mg, 0.262 mmol), DMAP (48.0 mg, 0.393 mmol), EDCI • HCl (55.2 mg, 0.288 mmol), sulfamide (27.7 mg, 0.288 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-3% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-sulfamoylbenzamide (18.1 mg, 17%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 7.48 (br s, 1H), 7.40 (br s, 1H), 7.30 (dd, 2H), 6.94 (br t, 2H), 6.10-5.80 (br, 1H), 5.63 (br s, 2H), 4.04-3.93 (m, 2H), 2.09 (br s, 3H); LC-MS (ESI) m/z 410.2 [M+H]⁺.

Example 129

N-(Dimethylsulfamoyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (84.5 mg, 0.255 mmol), DMAP (62.3 mg, 0.510 mmol), EDCI • HCl (73.3 mg, 0.382 mmol), N,N-dmethylsulfamide (37.9 mg, 0.306 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% MeOH in CH₂Cl₂) and recrystallized with CH₂Cl₂/diethyl ether to give N-(dimethylsulfamoyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (58.5 mg, 52%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 11.71 (br s, 1H), 7.73 (br s, 1H), 7.60 (br s, 1H), 7.49 (dd, 2H), 7.10 (t, 2H), 6.60-6.10 (br, 1H), 4.08 (d, 1H), 3.90 (d, 1H), 2.83 (s, 6H), 2.14 (br s, 3H); LC-MS (ESI) m/z 438.2 [M+H]⁺.

Example 130

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(trifluoromethyl)sulfonyl]benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.8 mg, 0.250 mmol), DMAP (76.3 mg, 0.625 mmol), EDCI • HCl (95.8 mg, 0.500 mmol), trifluoromethanesulfonamide (37.3 mg, 0.250 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(trifluoromethyl)sulfonyl]benzamide (20.2 mg, 17%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 7.67 (br s, 1H), 7.57 (br s, 1H), 7.48-7.45 (m, 2H), 7.09 (t, 2H), 6.60-6.10 (br, 1H), 4.08 (d, 1H), 3.90 (d, 1H), 2.06 (br s, 3H); LC-MS (ESI) m/z 463.2 [M+H]⁺.

Example 131

N-(Benzylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (72.8 mg, 0.220 mmol), DMAP (67.2 mg, 0.550 mmol), EDCI • HCl (84.2 mg, 0.439 mmol), α-toluenesulfonamide (41.4 mg, 0.242 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-4% MeOH in CH₂Cl₂) to give N-(benzylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (77.8 mg, 73%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 11.93 (br s, 1H), 7.70 (br s, 1H), 7.57 (br s, 1H), 7.48 (dd, 2H), 7.34-7.27 (m, 6H), 7.10 (t, 2H), 6.60-6.10 (br, 1H), 4.79 (s, 2H), 4.08 (d, 1H), 3.91 (d, 1H), 2.12 (br s, 3H); LC-MS (ESI) m/z 485.2 [M+H]⁺.

Example 132

N-[(3-Fluorobenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 1-(3-Fluorophenyl)methanesulfonamide

Following standard procedure D, 3-fluorobenzylsulfonyl chloride (0.251 mg, 1.20 mmol), methanol (1.0 mL), and ammonium hydroxide solution (5.0 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 3 h and work-up, 1-(3-fluorophenyl)methanesulfonamide (0.169 g, 74%) was obtained as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.38 (dd, 1H), 7.22-7.08 (m, 3H), 4.54 (br s, 2H), 4.32 (s, 2H).

Step 2. N-[(3-Fluorobenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (70.8 mg, 0.214 mmol), DMAP (65.4 mg, 0.535 mmol), EDCI • HCl (82.0 mg, 0.428 mmol), 1-(3-fluorophenyl)methanesulfonamide (40.4 mg, 0.214 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-[(3-fluorobenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (84.6 mg, 79%) as a white solid. 1H NMR (DMSO-d₆, 300 MHz) δ 11.98 (br s, 1H), 7.69 (s, 1H), 7.57 (br d, 1H), 7.48 (dd, 2H), 7.42-7.31 (m, 1H), 7.28-7.07 (m, 6H), 6.38 (br s, 1H), 4.84 (s, 2H), 4.08 (d, 1H), 3.91 (d, 1H), 2.12 (br s, 3H); LC-MS (ESI) m/z 503.2 [M+H]⁺.

Example 133

N-[(3,5-Dimethylbenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. Sodium (3,5-dimethylphenyl)methanesulfonate

A solution of 3,5-dimethyl benzyl bromide (1.03 g, 5.17 mmol) and sodium sulfite (0.850 g, 0.674 mmol) in water (8.0 mL) was reflux for 18 h and cooled in ice bath. The white solid was collected by vacuum filtration and washed with cold water to give sodium (3,5-dimethylphenyl)methanesulfonate (0.890 g, 77%). ¹H NMR (DMSO-d₆, 400 MHz) δ 6.87 (s, 2H), 6.81 (s, 1H), 3.59 (s, 2H), 2.21 (s, 6H).

Step 2. (3,5-Dimethylphenyl)methanesulfonyl chloride

A solution of sodium (3,5-dimethylphenyl)methanesulfonate (0.590 g, 0.265 mmol) and phosphorus pentachloride (0.55 g, 0.265 mmol) in phosphoryl chloride (3.0 mL) was stirred at 60° C. for 6 h and cooled to room temperature. The solution was quenched with water and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give (3,5-dimethylphenyl)methanesulfonyl chloride (0.304 g, 52%) as a brown solid. 1H NMR (CDCl₃, 400 MHz) δ 7.10 (s, 1H), 7.08 (s, 2H), 4.80 (s, 2H), 2.35 (s, 6H).

Step 3. 1-(3,5-Dimethylphenyl)methanesulfonamide

Following standard procedure D, (3,5-dimethylphenyl)methanesulfonyl chloride (0.251 g, 1.20 mmol), methanol (10 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work up, 1-(3,5-dimethylphenyl)methanesulfonamide (0.121 g, 46%) was obtained as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.03-7.01 (m, 3H), 4.50 (br s, 2H), 4.26 (s, 2H), 2.33 (s, 6H).

Step 4. N-[(3,5-Dimethylbenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (77.1 mg, 0.233 mmol), DMAP (56.9 mg, 0.465 mmol), EDCI • HCl (89.2 mg, 0.465 mmol), 1-(3,5-dimethylphenyl)methanesulfonamide (40.4 mg, 0.214 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-[(3,5-Dimethylbenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (59.8 mg, 50%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 8.60 (br s, 1H), 7.55-7.39 (br, 2H), 7.31-7.25 (m, 2H), 6.98-6.90 (m, 5H), 5.94 (br s, 1H), 4.67 (d, 1H), 4.62 (d, 1H), 3.88 (s, 2H), 2.21 (s, 6H), 2.04 (br s, 3H); LC-MS (ESI) m/z 513.3 [M+H]⁺.

Example 134

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methyl-N-(phenylsulfonyl)-benzamide

Step 1. Benzenesulfonamide

Following standard procedure D, benzenesulfonyl chloride (0.920 g, 5.21 mmol), methanol (8.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 3 h and work-up, benzenesulfonamide (0.550 g, 67%) was obtained as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.93 (d, 2H), 7.62-7.51 (m, 3H), 4.81 (br s, 2H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(phenylsulfonyl)benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.5 mg, 0.249 mmol), DMAP (76.1 mg, 0.623 mmol), EDCI • HCl (95.5 mg, 0.498 mmol), benzenesulfonamide (39.1 mg, 0.249 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(phenylsulfonyl)benzamide (91.7 mg, 83%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 12.60-12.30 (br, 1H), 7.95 (d, 2H), 7.71-7.68 (m, 2H), 7.61 (dd, 2H), 7.58-7.52 (br, 1H), 7.47 (dd, 2H), 7.08 (t, 2H), 6.50-6.10 (br, 1H), 4.07 (d, 1H), 3.90 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 471.2 [M+H]⁺.

Example 135

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(4-methylphenyl)sulfonyl]benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (80.9 mg, 0.244 mmol), DMAP (74.5 mg, 0.610 mmol), EDCI • HCl (93.5 mg, 0.488 mmol), p-toluenesulfonamide (41.8 mg, 0.244 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(4-methylphenyl)sulfonyl]benzamide (96.2 mg, 81%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 12.38 (br s, 1H), 7.83 (d, 2H), 7.67 (br s, 1H), 7.53 (br s, 1H), 7.49-7.45 (m, 2H), 7.41 (d, 2H), 7.08 (t, 2H), 6.50-6.20 (br, 1H), 4.07 (d, 1H), 3.90 (d, 1H), 2.37 (s, 3H), 2.11 (br s, 3H); LC-MS (ESI) m/z 485.2 [M+H]⁺.

Example 136

N-[(4-Ethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (80.3 mg, 0.242 mmol), DMAP (73.9 mg, 0.605 mmol), EDCI • HCl (92.9 mg, 0.485 mmol), 4-ethylbenzenesulfonamide (44.9 mg, 0.242 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-4% MeOH in CH₂Cl₂) to give N-[(4-ethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (103 mg, 85%) as a lightly yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.32 (br s, 1H), 7.99 (d, 2H), 7.35-7.26 (m, 6H), 6.91 (br t, 2H), 6.20-5.80 (br, 1H), 4.05 (br s, 2H), 2.70 (q, 2H), 2.04 (br s, 3H), 1.24 (t, 3H); LC-MS (ESI) m/z 499.2 [M+H]⁺.

Example 137

N-[(4-Cyanophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (80.5 mg, 0.243 mmol), DMAP (74.2 mg, 0.608 mmol), EDCI • HCl (93.1 mg, 0.486 mmol), 4-cyanobenzenesulfonamide (44.3 mg, 0.243 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-[(4-cyanophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (105 mg, 87%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 8.09 (s, 4H), 7.68 (br s, 1H), 7.55 (br d, 1H), 7.49-7.46 (m, 2H), 7.08 (t, 2H), 6.50-6.10 (br, 1H), 4.07 (d, 1H), 3.90 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 496.2 [M+H]⁺.

Example 138

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-N-[(4-methoxyphenyl)sulfonyl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (80.9 mg, 0.244 mmol), DMAP (74.5 mg, 0.610 mmol), EDCI • HCl (93.6 mg, 0.488 mmol), 4-methoxybenzenesulfonamide (45.7 mg, 0.244 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(4-methoxyphenyl)sulfonyl]-3-methylbenzamide (116 mg, 85%) as a yellow solid. 1H NMR (DMSO-d₆, 300 MHz) δ 12.30 (br s, 1H), 7.87 (d, 2H), 7.66 (br s, 1H), 7.53 (br d, 1H), 7.46 (dd, 2H), 7.11-7.04 (m. 4H), 6.50-6.10 (br, 1H), 4.07 (d, 1H), 3.89 (d, 1H), 3.82 (s, 3H), 2.10 (br s, 3H); LC-MS (ESI) m/z 501.2 [M+H]⁺.

Example 139

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-{[4-(trifluoromethoxy)phenyl]sulfonyl}benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (81.2 mg, 0.245 mmol), DMAP (74.8 mg, 0.613 mmol), EDCI • HCl (94.0 mg, 0.490 mmol), 4-(trifluoromethoxy)-benzenesulfonamide (59.1 mg, 0.245 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-{[4-(trifluoromethoxy)phenyl]sulfonyl}benzamide (107 mg, 79%) as a white foam. 1H NMR (DMSO-d₆, 400 MHz) δ 8.08 (d, 2H), 7.69 (br s, 1H), 7.61 (d, 2H), 7.57 (br s, 1H), 7.47 (dd, 2H), 7.08 (t, 2H), 6.60-6.20 (br, 1H), 4.07 (d, 1H), 3.90 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 555.2 [M+H]⁺.

Example 140

Ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl) benzoate

Step 1. Ethyl 4-sulfamoylbenzoate

A solution of 4-aminosulfonylbenzoic acid (0.590 g, 0.265 mmol) in ethanol (3.0 mL) and concentrated HCl_(aq) was reflux for 20 h and cooled to room temperature. After ethanol was removed under reduced pressure, the residue was partitioned between saturated NaHCO_3(aq) and ethyl acetate. The organic layer was washed with brine, dried over MgSO_4(s), filtered, and concentrated to give ethyl 4-sulfamoylbenzoate (0.304 g, 52%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 8.18 (d, 2H), 7.99 (d, 2H), 4.93 (br s, 2H), 4.42 (q, 2H), 1.42 (t, 3H).

Step 2. Ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl)benzoate

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (71.2 mg, 0.215 mmol), DMAP (65.7 mg, 0.538 mmol), EDCI • HCl (82.4 mg, 0.430 mmol), ethyl 4-sulfamoylbenzoate (49.3 mg, 0.215 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl)benzoate (10.7 mg, 9%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 9.80-9.30 (br, 1H), 8.15-7.80 (br, 4H), 7.60-7.20 (br, 4H), 6.90 (br s, 2H), 6.20-5.60 (br, 1H), 4.39 (q, 2H), 4.01 (br s, 2H), 2.11 (br s, 3H), 1.38 (t, 3H); LC-MS (ESI) m/z 543.2 [M+H]⁺.

Example 141

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methyl-N-[(2,4,6-trimethylphenyl)-sulfonyl]benzamide

Step 1. 2,4,6-Trimethylbenzenesulfonamide

Following standard procedure D, 2-mesitylenesulfonyl chloride (0.890 g, 4.07 mmol), methanol (8.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 5 h and work-up, 2,4,6-trimethylbenzenesulfonamide (0.241 g, 30%) was obtained as a beige solid. 1H NMR (CDCl₃, 400 MHz) δ 6.96 (s, 2H), 4.81 (br s, 2H), 2.65 (s, 6H), 2.30 (s, 3H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2,4,6-trimethylphenyl)-sulfonyl]benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (80.6 mg, 0.243 mmol), DMAP (74.2 mg, 0.608 mmol), EDCI • HCl (93.3 mg, 0.486 mmol), 2,4,6-trimethylbenzenesulfonamide (48.5 mg, 0.243 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-6.5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2,4,6-trimethylphenyl)-sulfonyl]benzamide (78.2 mg, 63%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 9.40 (br s, 1H), 7.50-7.35 (br, 2H), 7.31-7.27 (m, 2H), 7.00-6.85 (m, 4H), 6.20-5.80 (br, 1H), 4.04 (br s, 2H), 2.71 (s, 6H), 2.28 (s, 3H), 2.14 (br s, 3H); LC-MS (ESI) m/z 513.3 [M+H]⁺.

Example 142

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(3-fluorophenyl)sulfonyl]-3-methylbenzamide

Step 1. 3-Fluorobenzenesulfonamide

Following standard procedure D, 3-fluorobenzenesulfonyl chloride (0.590 g, 3.03 mmol), methanol (3.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 5 h, the solid was collected by vacuum filtration and washed with water to give 3-fluorobenzenesulfonamide (0.310 g, 58%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.73 (d, 1H), 7.65-7.62 (m, 1H), 7.55-7.50 (m, 1H), 7.32-7.27 (m, 1H), 4.87 (br s, 2H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(3-fluorophenyl)sulfonyl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (78.6 mg, 0.237 mmol), DMAP (58.0 mg, 0.474 mmol), EDCI • HCl (90.9 mg, 0.474 mmol), 3-fluorobenzenesulfonamide (41.6 mg, 0.237 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(3-fluorophenyl)sulfonyl]-3-methylbenzamide (82.2 mg, 71%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 9.60-9.20 (br, 1H), 7.90 (d, 1H), 7.79 (br d, 1H), 7.54-7.50 (m, 1H), 7.50-7.26 (m, 5H), 6.92 (br t, 2H), 6.20-5.80 (br, 1H), 4.04 (br s, 2H), 2.14 (br s, 3H); LC-MS (ESI) m/z 489.2 [M+H]⁺.

Example 143

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(4-fluorophenyl)sulfonyl]-3-methylbenzamide

Step 1. 4-Fluorobenzenesulfonamide

Following standard procedure D, 4-fluorobenzenesulfonyl chloride (0.580 g, 2.98 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 5 h, the solid was collected by vacuum filtration and washed with water to give 4-fluorobenzenesulfonamide (0.390 g, 75%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 7.88-7.84 (m, 2H), 7.43-7.38 (m, 4H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(4-fluorophenyl)sulfonyl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (75.8 mg, 0.229 mmol), DMAP (69.9 mg, 0.573 mmol), EDCI • HCl (87.7 mg, 0.458 mmol), 4-fluorobenzenesulfonamide (40.1 mg, 0.229 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(4-fluorophenyl)sulfonyl]-3-methylbenzamide (71.5 mg, 64%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 9.30 (br s, 1H), 8.12 (dd, 2H), 7.43 (br s, 2H), 7.30-7.26 (m, 2H), 7.19 (t, 2H), 6.92 (br t, 2H), 6.20-5.70 (br, 1H), 4.03 (s, 2H), 2.13 (br s, 3H); LC-MS (ESI) m/z 489.2 [M+H]⁺.

Example 144

N-[(4-Chlorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 4-Chlorobenzenesulfonamide

Following standard procedure D, 4-chlorobenzenesulfonyl chloride (0.650 g, 3.08 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h, the solid was collected by vacuum filtration and washed with water to give 4-chlorobenzenesulfonamide (0.430 g, 73%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 7.81 (d, 2H), 7.65 (d, 2H), 7.48 (br s, 2H).

Step 2. N-[(4-Chlorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (75.9 mg, 0.229 mmol), DMAP (69.9 mg, 0.573 mmol), EDCI • HCl (87.8 mg, 0.458 mmol), 4-chlorobenzenesulfonamide (43.9 mg, 0.229 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-[(4-chlorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (88.5 mg, 77%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 9.39 (br s, 1H), 8.03 (d, 2H), 7.49 (d, 2H), 7.42 (br s, 2H), 7.30-7.26 (m, 2H), 6.92 (br t, 2H), 6.20-5.70 (br, 1H), 4.03 (br s, 2H), 2.13 (br s, 3H); LC-MS (ESI) m/z 505.2 [M+H]⁺.

Example 145

N-[(4-Bromophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 4-Bromobenzenesulfonamide

Following standard procedure D, 4-bromobenzenesulfonyl chloride (0.650 g, 2.54 mmol), methanol (5.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, 4-bromobenzenesulfonamide (0.370 g, 62%) was obtained as a white solid. 1H NMR (DMSO-d₆, 300 MHz) δ 7.79 (d, 2H), 7.73 (d, 2H), 7.46 (br s, 2H).

Step 2. N-[(4-Bromophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (76.8 mg, 0.232 mmol), DMAP (70.9 mg, 0.580 mmol), EDCI • HCl (88.9 mg, 0.464 mmol), 4-bromobenzenesulfonamide (54.7 mg, 0.232 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-[(4-bromophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (87.1 mg, 68%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 9.44 (br s, 1H), 7.95 (d, 2H), 7.66 (d, 2H), 7.40 (br s, 2H), 7.31-7.26 (m, 2H), 6.92 (br t, 2H), 6.20-5.80 (br, 1H), 4.04 (br s, 2H), 2.12 (br s, 3H); LC-MS (ESI) m/z 549.1 [M+H]⁺.

Example 146

N-{[4-(Acetylamino)phenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. N-(4-Sulfamoylphenyl)acetamide

Following standard procedure D, N-acetylsulfanilyl chloride (0.651 g, 2.79 mmol), methanol (5.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 5 h and work-up, N-(4-sulfamoylphenyl)acetamide (0.340 g, 57%) was obtained as a white solid. 1H NMR (CDCl₃+CD₃OD, 400 MHz) δ 7.78 (d, 2H), 7.65 (d, 2H), 2.12 (s, 3H).

Step 2. N-{[4-(Acetylamino)phenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (80.1 mg, 0.242 mmol), DMAP (73.9 mg, 0.605 mmol), EDCI • HCl (92.8 mg, 0.484 mmol), N-(4-sulfamoylphenyl)acetamide (51.8 mg, 0.242 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-{[4-(acetylamino)phenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (51.1 mg, 40%) as a white solid. 1H NMR (DMSO-d₆, 300 MHz) δ 12.36 (br s, 1H), 10.39 (br s, 1H), 7.87 (d, 2H), 7.75 (d, 2H), 7.66 (br s, 1H), 7.52 (br d, 1H), 7.46 (dd, 2H), 7.08 (t, 2H), 6.40 (br s, 1H), 4.07 (d, 1H), 3.89 (d, 1H), 2.20-2.00 (m, 6H); LC-MS (ESI) m/z 528.2 [M+H]⁺.

Example 147

N-[(4-Chloro-2-fluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 4-Chloro-2-fluorobenzenesulfonamide

Following standard procedure D, 4-chloro-2-fluorobenzenesulfonyl chloride (0.450 g, 1.96 mmol), methanol (2.0 mL), and ammonium hydroxide solution (10 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, 4-chloro-2-fluorobenzenesulfonamide (0.360 g, 88%) was obtained as a white solid. 1H NMR (CDCl₃+CD₃OD, 400 MHz) δ 7.78 (t, 1H), 7.22 (d, 2H).

Step 2. N-[(4-Chloro-2-fluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (72.3 mg, 0.218 mmol), DMAP (66.6 mg, 0.545 mmol), EDCI • HCl (83.7 mg, 0.436 mmol), 4-chloro-2-fluorobenzenesulfonamide (45.7 mg, 0.218 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-[(4-chloro-2-fluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (77.4 mg, 68%) as a beige solid. ¹H NMR (CDCl₃, 300 MHz) δ 8.07 (t, 1H), 7.51 (br s, 1H), 7.43 (br d, 1H), 7.34-7.26 (m, 3H), 7.20 (d, 1H), 6.94 (br t, 2H), 6.10-5.80 (br, 1H), 4.10-3.90 (m, 2H), 2.14 (br s, 3H); LC-MS (ESI) m/z 523.2 [M+H]⁺.

Example 148

N-[(2,4-Difluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 2,4-Difluorobenzenesulfonamide

Following standard procedure D, 2,4-difluorobenzenesulfonyl chloride (0.470 g, 2.21 mmol), methanol (3.0 mL), and ammonium hydroxide solution (20 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h, methanol was removed under reduce pressure. The solid was collected by vacuum filtration and washed with water to give 2,4-difluorobenzenesulfonamide (0.390 g, 91%) as a white solid. 1H NMR (DMSO-d₆, 300 MHz) δ 7.88-7.82 (m, 1H), 7.70 (br s, 2H), 7.54-7.47 (m, 1H), 7.28-7.21 (m, 1H).

Step 2. N-[(2,4-Difluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (81.6 mg, 0.247 mmol), DMAP (75.4 mg, 0.618 mmol), EDCI • HCl (94.6 mg, 0.494 mmol), 2,4-difluorobenzenesulfonamide (47.7 mg, 0.247 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-6% MeOH in CH₂Cl₂) to give N-[(2,4-difluorophenyl) sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (73.7 mg, 59%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 8.04-7.99 (m, 1H), 7.69 (br s, 1H), 7.56 (br d, 1H), 7.49-7.45 (m, 3H), 7.38-7.31 (m, 1H), 7.08 (t, 2H), 6.60-6.20 (br, 1H), 4.07 (d, 1H), 3.90 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 507.2 [M+H]⁺.

Example 149

N-[(4-Chloro-2,5-dimethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 4-Chloro-2,5-dimethylbenzenesulfonamide

Following standard procedure D, 4-chloro-2,5-dimethylbenzenesulfonyl chloride (0.620 g, 2.59 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h, methanol was removed under reduce pressure. The solid was collected by vacuum filtration and washed with water to give 4-chloro-2,5-dimethylbenzenesulfonamide (0.366 g, 64%) as a white solid. 1H NMR (DMSO-d₆, 300 MHz) δ 7.76 (s, 1H), 7.45 (s, 1H), 7.42 (br s, 2H), 2.50 (s, 3H), 2.32 (s, 3H).

Step 2. N-[(4-Chloro-2,5-dimethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (75.8 mg, 0.229 mmol), DMAP (69.9 mg, 0.573 mmol), EDCI • HCl (87.8 mg, 0.458 mmol), 4-chloro-2,5-dimethylbenzenesulfonamide (50.3 mg, 0.229 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-[(4-chloro-2,5-dimethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (86.7 mg, 71%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 9.48 (br s, 1H), 8.05 (s, 1H), 7.50-7.38 (br, 2H), 7.32-7.24 (m, 3H), 6.90 (br t, 2H), 6.20-5.80 (br, 1H), 4.03 (br s, 2H), 2.57 (s, 3H), 2.40 (s, 3H), 2.15 (br s, 3H); LC-MS (ESI) m/z 533.2 [M+H]⁺.

Example 150

N-{[5-(Dimethylamino)-1-naphthalenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (78.6 mg, 0.237 mmol), DMAP (72.4 mg, 0.593 mmol), EDCI • HCl (90.9 mg, 0.474 mmol), 1-(dimethylamino)-5-naphthalene sulfonamide (54.9 mg, 0.237 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-{[5-(dimethylamino)-1-naphthalenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (63.6 mg, 48%) as a yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 10.00-9.40 (br, 1H), 8.53 (br s, 2H), 8.40-8.23 (br, 1H), 7.70-7.30 (br, 3H), 7.30-7.20 (br, 2H), 7.12 (br d, 1H), 7.00-6.60 (br, 4H), 6.20-5.70 (br, 1H), 4.05 (br s, 2H), 2.84 (s, 6H), 2.09 (br s, 3H); LC-MS (ESI) m/z 564.3 [M+H]⁺.

Example 151

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(3-pyridinylsulfonyl)-benzamide

Step 1. 3-Pyridinesulfonamide

Following standard procedure D, pyridine-3-sulfonyl chloride (0.450 g, 2.53 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 20 h and work-up, 3-pyridinesulfonamide (35.7 mg, 9%) was obtained as a green solid. 1H NMR (DMSO-d₆, 400 MHz) δ 8.96 (s, 1H), 8.78 (d, 1H), 8.19-8.16 (m, 1H), 7.64-7.60 (m, 3H).

Step 2. 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(3-pyridinylsulfonyl)-benzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (70.2 mg, 0.212 mmol), DMAP (64.8 mg, 0.530 mmol), EDCI • HCl (81.3 mg, 0.424 mmol), 3-pyridinesulfonamide (33.5 mg, 0.212 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(3-pyridinylsulfonyl)-benzamide (64.3 mg, 64%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 9.07 (d, 1H), 8.85 (d, 1H), 8.32 (dd, 1H), 7.68 (br s, 1H), 7.66 (dd, 1H), 7.55 (br d, 1H), 7.47 (dd, 2H), 7.08 (t, 2H), 6.50-6.10 (br, 1H), 4.07 (d, 1H), 3.90 (d, 1H), 2.11 (br s, 3H); LC-MS (ESI) m/z 472.2 [M+H]⁺.

Example 152

N-[(3, 5-Dimethyl-1, 2-oxazol-4-yl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. 3,5-Dimethyl-1,2-oxazole-4-sulfonamide

Following standard procedure D, 3,5-dimethylisoxazole-4-sulfonyl chloride (0.399 g, 2.04 mmol), methanol (3.0 mL), and ammonium hydroxide solution (12 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h, methanol was removed under reduce pressure. The solid was collected by vacuum filtration and washed with water to give 3,5-dimethyl-1,2-oxazole-4-sulfonamide (0.271 g, 75%) as a white solid. 1H NMR (DMSO-d₆, 400 MHz) δ 7.60 (br s, 2H), 2.54 (s, 3H), 2.32 (s, 3H).

Step 2. N-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid 0 (80.9 mg, 0.244 mmol), DMAP (74.5 mg, 0.610 mmol), EDCI • HCl (93.6 mg, 0.488 mmol), 3,5-dimethyl-1,2-oxazole-4-sulfonamide (43.0 mg, 0.244 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give N-[(3,5-dimethyl-1,2-oxazol-4-yl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (92.2 mg, 77%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 9.70-9.50 (br, 1H), 7.50-7.30 (br, 2H), 7.30 (dd, 2H), 6.94 (br t, 2H), 6.20-5.80 (br, 1H), 4.10-3.95 (m, 2H), 2.76 (s, 3H), 2.44 (s, 3H), 2.17 (br s, 3H); LC-MS (ESI) m/z 490.2 [M+H]⁺.

Example 153

N-Ethoxy-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (89.7 mg, 0.271 mmol), triethylamine (46.0 μL, 0.332 mmol), ethyl chloroformate (35.3 mg, 0.325 mmol), CH₂Cl₂ (4.0 mL), potassium hydroxide (23.0 mg, 0.332 mmol), O-ethylhydroxylamine hydrochloride (40.0 mg, 0.410 mmol), and methanol (4.0 mL) were used to carry out the reaction. It was stirred for 1 h for the first step and 5 h for the second step. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give N-ethoxy-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (46.3 mg, 46%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.80-8.40 (br, 1H), 7.52 (br s, 1H), 7.40 (br s, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 6.20-5.70 (br, 1H), 4.04 (q, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.17 (br s, 3H), 1.30 (t, 3H); LC-MS (ESI) m/z 375.2 [M+H]⁺.

Example 154

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-methoxy-3-methylbenzamide

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (90.5 mg, 0.273 mmol), triethylamine (46.0 μL, 0.332 mmol), ethyl chloroformate (35.6 mg, 0.328 mmol), CH₂Cl₂ (4.0 mL), potassium hydroxide (23.0 mg, 0.332 mmol), O-methylhydroxylamine hydrochloride (34.2 mg, 0.410 mmol), and methanol (7.0 mL) were used to carry out the reaction. It was stirred for 1 h for the first step and 6 h for the second step. The residue was purified by Isco Combi-Flash Companion column chromatography (0-4% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-methoxy-3-methylbenzamide (66.3 mg, 67%) as a lightly yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 8.85 (br s, 1H), 7.51 (br s, 1H), 7.37 (br s, 1H), 7.33-7.27 (m, 2H), 6.95 (t, 2H), 5.91 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.83 (s, 3H), 2.14 (br s, 3H); LC-MS (ESI) m/z 361.2 [M+H]⁺.

Example 155

N-(Benzyloxy)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.6 mg, 0.249 mmol), triethylamine (42.0 μL, 0.302 mmol), ethyl chloroformate (32.5 mg, 0.299 mmol), CH₂Cl₂ (5.0 mL), potassium hydroxide (15.4 mg, 0.274 mmol), O-benzylhydroxylamine hydrochloride (43.7 mg, 0.274 mmol), and methanol (8.0 mL) were used to carry out the reaction. It was stirred for 45 min for the first step and 6 h for the second step. The residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give N-(benzyloxy)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (71.2 mg, 66%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.40 (br s, 1H), 7.50-7.35 (m, 6H), 7.33-7.20 (m, 3H), 6.95 (br t, 2H), 6.10-5.70 (br, 1H), 5.12 (s, 2H), 3.99 (d, 1H), 3.90 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 437.3 [M+H]⁺.

Example 156

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-phenoxybenzamide

A solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.1 mg, 0.248 mmol) in thionyl chloride (0.80 mL) was reflux for 1 h and cooled to room temperature. Thionyl chloride was removed under reduced pressure completely. The benzoyl chloride intermediate was dissolved in THF (4.0 mL), and a solution of triethylamine (0.100 mL, 0.714 mmol) and N-phenylhydroxylamine (60.3 mg, 0.414 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 h and then concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-55% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-phenoxybenzamide (15.7 mg, 13%) as a yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 9.02 (br s, 1H), 7.63 (br s, 1H), 7.52 (br s, 1H), 7.36-7.24 (m, 5H), 7.11-7.04 (m, 2H), 6.97 (t, 2H), 6.05-5.85 (br, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 423.2 [M+H]⁺.

Example 157

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-hydroxy-3-methylbenzamide

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (126 mg, 0.380 mmol), triethylamine (68.3 μL, 0.493 mmol), ethyl chloroformate (49.4 mg, 0.455 mmol), CH₂Cl₂ (3.0 mL), potassium hydroxide (15.4 mg, 0.274 mmol), hydroxylamine hydrochloride (34.1 mg, 0.607 mmol), and methanol (6.0 mL) were used to carry out the reaction. It was stirred for 1 h for the first step and 3 h for the second step. The residue was purified by Isco Combi-Flash Companion column chromatography (0-100% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-hydroxy-3-methylbenzamide (71.9 mg, 55%) as a yellow solid. 1H NMR (DMSO-d₆, 400 MHz) δ 11.13 (br s, 1H), 9.02 (br s, 1H), 7.54-7.43 (m, 4H), 7.10 (t, 2H), 6.60-6.10 (br, 1H), 4.08 (d, 1H), 3.90 (d, 1H), 2.13 (br s, 3H); LC-MS (ESI) m/z 347.2 [M+H]⁺.

Example 158

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzohydrazide

A solution of methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (158 mg, 0.458 mmol) in hydrazine monohydrate (0.30 mL) and methanol (3.0 mL) was reflux for 2.5 h and cooled to room temperature. Methanol was removed under reduced pressure. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzohydrazide (107 mg, 67%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.55 (br s, 1H), 7.41 (br s, 1H), 7.32-7.28 (m, 2H), 7.24 (br s, 1H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.20-3.88 (m, 4H), 2.18 (br s, 3H); LC-MS (ESI) m/z 346.2 [M+H]⁺.

Example 159

2-(4-Fluorophenyl)-3-[2-methyl-4-(1H-tetrazol-5-yl)phenyl]-1,3-thiazolidin-4-one

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzonitrile (59.4 mg, 0.190 mmol) in DMF (0.60 mL) was added silver nitrate (4.9 mg, 0.286 mmol) and sodium azide (30.9 mg, 0.475 mmol), and it was stirred at 120° C. for 18 h. Another 0.15 equivalent of silver nitrate and 2.5 equivalent of sodium azide were added to the reaction, and the solution was continued stirred at 140° C. for 8 h and cooled to room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-20% MeOH in CH₂Cl₂) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(1H-tetrazol-5-yl)phenyl]-1,3-thiazolidin-4-one (31.1 mg, 46%) as a yellow solid. 1H NMR (DMSO-d₆, 400 MHz) δ 7.84 (br, 1H), 7.73 (br, 1H), 7.51 (dd, 2H), 7.11 (t, 2H), 6.60-6.20 (br, 1H), 4.10 (d, 1H), 3.93 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 356.1 [M+H]⁺.

Example 160

2-(4-Fluorophenyl)-3-[2-methyl-4-(3-thiophenyl)phenyl]-1,3-thiazolidin-4-one

Following standard procedure F, 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (136 mg, 0.372 mmol), sodium bicarbonate (77.8 mg, 0.926 mmol), 3-thiophene boronic acid (94.7 mg, 0.740 mmol), Pd(PPh₃)₄ (21.4 mg, 0.0185 mmol), DME (4.0 mL), and water (2.0 mL) were used to carry out the reaction. After the reaction mixture was reflux for 4 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(3-thiophenyl)phenyl]-1,3-thiazolidin-4-one (101 mg, 74%) as an orange solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.38-7.24 (m, 7H), 6.97 (br t, 2H), 6.10-5.60 (br, 1H), 4.03 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 370.2 [M+H]⁺.

Example 161

2-(4-Fluorophenyl)-3-[2-methyl-4-(2-thiophenyl)phenyl]-1,3-thiazolidin-4-one

Following standard procedure F, 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (141 mg, 0.386 mmol), sodium bicarbonate (80.6 mg, 0.959 mmol), 2-thiophene boronic acid (98.2 mg, 0.767 mmol), Pd(PPh₃)₄ (22.2 mg, 0.0192 mmol), toluene (4.0 mL), and water (2.0 mL) were used to carry out the reaction. After the reaction mixture was reflux for 3.5 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(2-thiophenyl)phenyl]-1,3-thiazolidin-4-one (65.4 mg, 46%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 7.42 (br s, 1H), 7.36-7.31 (m, 3H), 7.26-7.23 (m, 2H), 7.04 (dd, 1H), 6.98 (br t, 2H), 6.10-5.60 (br, 1H), 4.03 (d, 1H), 3.91 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 370.2 [M+H]⁺.

Example 162

2-(4-Fluorophenyl)-3-[4-(2-furanyl)-2-methylphenyl]-1,3-thiazolidin-4-one

Following standard procedure F, 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (131 mg, 0.359 mmol), sodium bicarbonate (75.3 mg, 0.896 mmol), 2-furan boronic acid (80.3 mg, 0.718 mmol), Pd(PPh₃)₄ (20.7 mg, 0.0179 mmol), DME (4.0 mL), and water (2.0 mL) were used to carry out the reaction. After the reaction mixture was reflux for 3 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[4-(2-furanyl)-2-methylphenyl]-1,3-thiazolidin-4-one (102 mg, 80%) as a yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 7.48 (br s, 1H), 7.42 (d, 1H), 7.35-7.31 (m, 3H), 6.96 (br t, 2H), 6.59 (d, 1H), 6.43 (dd, 1H), 6.10-5.70 (br, 1H), 4.02 (d, 1H), 3.91 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 354.2 [M+H]⁺.

Example 163

3-[4-(3,5-Dimethyl-1,2-oxazol-4-yl)-2-methylphenyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure F, 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (101 mg, 0.276 mmol), sodium bicarbonate (58.1 mg, 0.691 mmol), 3,5-dimethylisoxazole-4-boronic acid pinacol ester (123 mg, 0.553 mmol), Pd(PPh₃)₄ (16.0 mg, 0.0138 mmol), DME (4.0 mL), and water (2.0 mL) were used to carry out the reaction. After the reaction mixture was reflux for 4 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 3-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-methylphenyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (69.1 mg, 65%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.36-7.33 (m, 2H), 7.07 (br s, 2H), 6.99 (br t, 2H), 6.10-5.60 (br, 1H), 4.04 (d, 1H), 3.92 (d, 1H), 2.35 (s, 3H), 2.30-2.00 (br, 6H); LC-MS (ESI) m/z 383.3 [M+H]⁺.

Example 164

2-(4-Fluorophenyl)-3-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1,3-thiazolidin-4-one

Following standard procedure F, 3-(4-bromo-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (101 mg, 0.276 mmol), sodium bicarbonate (57.8 mg, 0.688 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (115 mg, 0.551 mmol), Pd(PPh₃)₄ (15.9 mg, 0.0138 mmol), DME (4.0 mL), and water (2.0 mL) were used to carry out the reaction. After the reaction mixture was reflux for 3 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-1,3-thiazolidin-4-one (53.5 mg, 53%) as a yellow gum. 1H NMR (CDCl₃, 400 MHz) δ 7.69-7.64 (m, 2H), 7.57-7.45 (m, 3H), 7.33 (dd, 2H), 6.97 (br t, 2H), 6.20-5.60 (br, 1H), 4.02 (d, 1H), 3.93-3.89 (m, 4H), 2.20-2.00 (br, 3H); LC-MS (ESI) m/z 368.3 [M+H]⁺.

Example 165

2-(4-Fluorophenyl)-3-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1,3-thiazolidin-4-one

A solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzohydrazide (199 mg, 0.575 mmol) in triethyl orthoacetate (1.5 mL) was stirred at 90° C. for 20 h and cooled to room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1,3-thiazolidin-4-one (38.2 mg, 18%) as a yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.73 (br s, 1H), 7.32 (dd, 2H), 6.96 (t, 2H), 5.95 (br s, 1H), 4.02 (d, 1H), 3.93 (d, 1H), 2.58 (s, 3H), 2.23 (br s, 3H); LC-MS (ESI) m/z 370.2 [M+H]⁺.

Example 166

2-(4-Fluorophenyl)-3-{2-methyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}-1,3-thiazolidin-4-one

A solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (159 mg, 0.478 mmol), trifluoroacetic acid hydrazide (61.3 mg, 0.478 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 218 mg, 0.574 mmol), and N,N-diisopropylethylamine (0.170 mL, 0.980 mmol) in THF (4.0 mL) was stirred at room temperature for 45 min. Burgess reagent (285 mg, 1.20 mmol) was added to the reaction mixture, and it was stirred for 2 h. The crude was directly purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-{2-methyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}-1,3-thiazolidin-4-one (68.9 mg, 34%) as a solid. 1H NMR (CDCl₃, 400 MHz) δ 7.93 (br s, 1H), 7.90-7.70 (br, 1H), 7.35-7.31 (m, 2H), 6.96 (br t, 2H), 6.15-5.70 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.24 (br s, 3H).

Example 167

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid propyl ester

The compound was prepared by following the standard procedure C with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol), EDCI • HCl (43.0 mg, 0.230 mmol), n-propanol (0.5 mL) and DMAP (28.0 mg, 0.230 mmol). After the reaction was stirred for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate hexane=1:3) to give the desired product as a white solid (44.0 mg, 79%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 5.94 (br s, 1H), 4.24 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.76 (sextet, 2H), 1.00 (t, 3H); LC-MS (ESI) m/z 374.0 [M+H]⁺.

Example 168

4-[2-(3,4-difluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid propyl ester

The compound was prepared by following the standard procedure C with 4-(2-(3,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (52.0 mg, 0.150 mmol), EDCI • HCl (43.0 mg, 0.230 mmol), n-propanol (0.5 mL) and DMAP (28.0 mg, 0.230 mmol). After the reaction was stirred for 18 h and work-up, the residue was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a white solid (50.0 mg, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.77 (br d, 1H), 7.22 (t, 1H), 7.10-6.90 (m, 3H), 5.89 (br s, 1H), 4.24 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.21 (br s, 3H), 1.75 (sextet, 2H), 1.00 (t, 3H); LC-MS (ESI) m/z 392.9 [M+H]⁺.

Example 169

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid isopropyl ester

Step 1. Synthesis of 3-methyl-4-nitro-benzoic acid isopropyl ester

Fine powered Na₂CO_3(s) (1.17 g, 11.0 mmol) was mixed with the SOCl₂ (0.800 mL, 11.0 mmol) and 4-nitro-3-methylbenzenecarboxylic acid (1.81 g, 10.0 mmol) in 20 mL of isopropanol. The reaction mixture was refluxed for 3.5 h. On completion of the reaction, the reaction mixture was poured into dilute solution of 10% NaHCO_3(aq) untile the pH value of the reaction solution reached 9 and extracted with CH₂Cl₂ (80 mL). The organic layer was dried over MgSO₄ and concentrated to give the product (1.86 g, 83%). ¹H NMR (CDCl₃, 300 MHz) δ 8.01-7.96 (m, 3H), 5.27 (septet, 1H), 2.63 (s, 3H), 1.39 (d, 6H).

Step 2. Synthesis of 4-amino-3-methyl-benzoic acid isopropyl ester

To a solution of 3-methyl-4-nitro-benzoic acid isopropyl ester (1.86 g, 8.30 mmol) and SnCl₂ (7.90 g, 41.7 mmol) in 40.0 mL of EtOH at 80° C. was added a solution of NaBH_4(s) (157 mg, 4.15 mmol) in 10 mL of EtOH over 15 minutes with stirring. After being stirred for further 2 h, the mixture was partitioned between ethyl acetate (80 mL) and saturated NaHCO_3(aq) (20 mL). The organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give the product (1.54 g, 96%). ¹H NMR (CDCl₃, 400 MHz) δ 7.75-7.72 (m, 2H), 6.64 (d, 1H), 5.20 (septet, 1H), 4.00 (br s, 2H), 2.18 (s, 3H), 1.33 (d, 6H).

Step 3. Synthesis of 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid isopropyl ester

The compound was prepared by following the standard procedure A with 4-amino-3-methyl-benzoic acid isopropyl ester (386 mg, 2.00 mmol), 4-fluorobenzaldehyde (496 mg, 4.00 mmol), and 2-mercaptoacetic acid (0.260 mL, 331 mg, 3.60 mmol). It was stirred at room temperature 5 for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (26.0 mg, 4%). ¹H NMR (CDCl₃, 300 MHz) δ 7.85 (br s, 1H), 7.74 (br s, 1H), 7.31 (dd, 2H), 6.95 (br t, 2H), 5.94 (br s, 1H), 5.19 (septet, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H), 1.33 (d, 6H); LC-MS (ESI) m/z 373.9 [M+H]⁺.

Example 170

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid butyl ester

The compound was prepared by following the standard procedure C with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (45.0 mg, 0.135 mmol), EDCI • HCl (40.0 mg, 0.210 mmol), n-butanol (0.500 mL) and DMAP (25.0 mg, 0.210 mmol). After the reaction was stirred for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate hexane=1:3) to give the desired product as a yellow viscous liquid (45.0 mg, 86%). ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 5.94 (br s, 1H), 4.27 (t, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H), 1.71 (quint, 2H), 1.43 (sextet, 2H), 0.95 (t, 3H); LC-MS (ESI) m/z 388.9 [M+H]⁺.

Example 171

2-Methyl-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (185 mg, 0.560 mmol), DMAP (171 mg, 1.40 mmol), EDCI • HCl (215 mg, 1.12 mmol), tert-butanol (0.50 mL), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-25% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (124 mg, 57%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.80 (br s, 1H), 7.69 (br s, 1H), 7.32-7.29 (m, 2H), 6.96 (br t, 2H), 6.10-5.70 (br, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.18 (br s, 3H), 1.54 (s, 9H); LC-MS (ESI) m/z 388.3 [M+H]⁺.

Example 172

1-Methylcyclopropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (162 mg, 0.490 mmol), DMAP (120 mg, 0.980 mmol), EDCI • HCl (141 mg, 0.735 mmol), 1-methylcyclopropanol (42.4 mg, 0.588 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-25% ethyl acetate in n-hexane) to give 1-methylcyclopropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (148 mg, 78%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 7.81 (br s, 1H), 7.71 (br d, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.18 (br s, 3H), 1.59 (s, 3H), 1.00-0.90 (m, 2H), 0.80-0.68 (m, 2H); LC-MS (ESI) m/z 386.2 [M+H]⁺.

Example 173

3,3-Dimethylbutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (158 mg, 0.477 mmol), DMAP (146 mg, 1.19 mmol), EDCI • HCl (183 mg, 0.954 mmol), 3,3-dimethyl-1-butanol (88.0 μL, 0.727 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3,3-dimethylbutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (146 mg, 74%) as a lightly yellow foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.32 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H), 1.66 (t, 2H), 0.97 (s, 9H); LC-MS (ESI) m/z 416.3 [M+H]⁺.

Example 174

2-Cyclopropylethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (166 mg, 0.501 mmol), DMAP (153 mg, 1.25 mmol), EDCI • HCl (192 mg, 1.00 mmol), 2-cyclopropylethanol (51.8 mg, 0.601 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-cyclopropylethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (88.3 mg, 44%) as a colorless gum. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.33 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.19 (br s, 3H), 1.62 (q, 2H), 0.79-0.75 (m, 1H), 0.48-0.45 (m, 2H), 0.12-0.08 (m, 2H); LC-MS (ESI) m/z 400.3 [M+H]⁺.

Example 175

Cyclopentylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), cyclopentylmethanol (0.110 g, 0.725 mmol), EDCI • HCl (0.139 g, 0.725 mmol), DMAP (0.110 g, 0.906 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give cyclopentylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (97.4 mg, 65%). 1H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.33-7.26 (m, 2H), 6.96 (t, 2H), 5.98 (br s, 1H), 4.16 (d, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 2.35-2.20 (m, 4H), 1.82-1.78 (m, 2H), 1.64-1.57 (m, 2H), 1.34-1.25 (m, 4H); LC-MS (ACPI) m/z 414.5 [M+H]⁺.

Example 176

Cyclohexylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), cyclohexylmethanol (0.130 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give cyclohexylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 86%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br, 1H), 7.31 (dd, 2H), 6.96 (t, 2H), 5.95 (br s, 1H), 4.12-4.04 (m, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.79-1.67 (m, 5H), 1.31-1.13 (m, 4H), 1.06-0.98 (m, 2H); LC-MS (ACPI) m/z 428.8 [M+H]⁺.

Example 177

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid adamantan-1-ylmethyl ester

The compound was prepared by following the standard procedure C with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (70.0 mg, 0.210 mmol), EDCI • HCl (48.3 mg, 0.250 mmol), 1-adamantanemethanol (70.0 mg, 0.42 mmol), DMAP (38.0 mg, 0.310 mmol), and CH₂Cl₂ (3.0 mL). After the reaction was stirred for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a white solid (54.0 mg, 54%). ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.75 (br d, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 5.94 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.89 (d, 1H), 3.84 (d, 1H), 2.21 (br s, 3H), 2.07-1.95 (m, 3H), 1.80-1.50 (m, 12H); LC-MS (ESI) m/z 480.1 [M+H]⁺.

Example 178

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid adamantan-1-yl ester

Step 1. Synthesis of 3-methyl-4-nitro-benzoic acid adamantan-1-yl ester

The compound was prepared by following the standard procedure C with 3-methyl-4-nitrobenzoic acid (2.00 g, 11.0 mmol), EDCI • HCl (2.32 g, 12.1 mmol), 1-adamantanol (3.35 g, 22.0 mmol), and DMAP (1.08 g, 8.80 mmol). After the reaction was stirred for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a white solid (770 mg, 22%). ¹H NMR (CDCl₃, 300 MHz) δ 7.96-7.92 (m, 3H), 2.61 (s, 3H), 2.25 (br s, 9H), 1.72 (br s, 6H).

Step 2. Synthesis of 4-amino-3-methyl-benzoic acid adamantan-1-yl ester

To a solution of 3-methyl-4-nitro-benzoic acid adamantan-1-yl ester (770 mg, 2.44 mmol) in 8.0 mL of acetic acid was added zinc dust_(s) (1.55 g, 24.4 mmol) in one portion at r.t. The reaction mixture was stirred at r.t. for 4 h then passed through a pad of celite. The filtrate was partitioned between ethyl acetate (120 mL) and saturated NaHCO_3(aq) (30 mL). The organic layer was washed with brine (20 mL), dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=1:4) to give the desired product as a white solid (440 mg, 63%). ¹H NMR (CDCl₃, 400 MHz) δ 7.70-7.68 (m, 2H), 6.64 (d, 1H), 4.19 (br s, 2H), 2.24 (br s, 3H), 2.24-2.18 (m, 9H), 1.80-1.60 (m, 6H).

Step 3. Synthesis of 4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid adamantan-1-yl ester

The compound was prepared by following the standard procedure A with 4-amino-3-methyl-benzoic acid adamantan-1-yl ester (285.4 mg, 1.00 mmol), 4-fluorobenzaldehyde (248 mg, 2.0 mmol), and 2-mercaptoacetic acid (0.210 mL, 272 mg, 2.95 mmol). It was stirred at room temperature 5 h for the first step and 16 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=1:3) to give the desired product as a white solid (120 mg, 26%). ¹H NMR (CDCl₃, 300 MHz) δ 7.79 (br s, 1H), 7.69 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 5.92 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.40-2.00 (m, 12H), 1.80-1.60 (m, 6H).

Example 179

Phenyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (168 mg, 0.507 mmol), DMAP (124 mg, 1.01 mmol), EDCI • HCl (146 mg, 0.761 mmol), phenol (47.7 mg, 0.507 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give phenyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (177 mg, 86%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.03 (br s, 1H), 7.92 (br s, 1H), 7.41 (t, 2H), 7.34 (dd, 2H), 7.28-7.24 (m, 1H), 7.15 (d, 2H), 6.98 (br t, 2H), 6.10-5.80 (br, 1H), 4.02 (d, 1H), 3.93 (d, 1H), 2.25 (br s, 3H); LC-MS (ESI) m/z 408.2 [M+H]⁺.

Example 180

3-Nitrophenyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (142 mg, 0.427 mmol), DMAP (131 mg, 1.07 mmol), EDCI • HCl (164 mg, 0.855 mmol), 3-nitrophenol (63.1 mg, 0.453 mmol), and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-35% ethyl acetate in n-hexane) to give 3-nitrophenyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (144 mg, 74%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.16 (ddd, 1H), 8.07 (t, 1H), 8.03 (br s, 1H), 7.91 (br d, 1H), 7.60 (t, 1H), 7.53 (ddd, 1H), 7.34 (dd, 2H), 6.99 (t, 2H), 6.10-5.90 (br, 1H), 4.03 (d, 1H), 3.95 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 453.2 [M+H]⁺.

Example 181

2-Methoxyphenyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (173 mg, 0.522 mmol), DMAP (128 mg, 1.04 mmol), EDCI • HCl (150 mg, 0.782 mmol), guaiacol (71.3 mg, 0.574 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-25% ethyl acetate in n-hexane) to give 2-methoxyphenyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (142 mg, 63%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.05 (br s, 1H), 7.93 (br s, 1H), 7.36-7.27 (m, 2H), 7.25-7.21 (m, 1H), 7.09 (dd, 1H), 7.01-6.95 (m, 4H), 6.10-5.80 (br, 1H), 4.03 (d, 1H), 3.93 (d, 1H), 3.79 (s, 3H), 2.24 (br s, 3H); LC-MS (ESI) m/z 438.2 [M+H]⁺.

Example 182

2,3-Dihydro-1H-inden-5-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (186 mg, 0.561 mmol), DMAP (171 mg, 1.40 mmol), EDCI•HCl (215 mg, 1.12 mmol), 5-indanol (82.6 mg, 0.616 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction was stirred for 17 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (10-20% ethyl acetate in n-hexane) to give 2,3-dihydro-1H-inden-5-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl benzoate (211 mg, 84%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 8.02 (br s, 1H), 7.90 (br d, 1H), 7.36-7.30 (m, 2H), 7.23-7.21 (m, 1H), 7.11-6.95 (m, 3H), 6.91-6.86 (m, 1H), 6.00 (br s, 1H), 4.03 (d, 1H), 3.94 (d, 1H), 2.91 (dd, 4H), 2.24 (br s, 3H), 2.11 (quint, 2H); LC-MS (ESI) m/z 448.3 [M+H]⁺.

Example 183

2,3-Dihydro-1H-inden-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (150 mg, 0.453 mmol), DMAP (111 mg, 0.906 mmol), EDCI • HCl (130 mg, 0.680 mmol), 4-indanol (60.7 mg, 0.453 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2,3-dihydro-1H-inden-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl benzoate (157 mg, 77%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 8.03 (br s, 1H), 7.91 (br s, 1H), 7.34 (dd, 2H), 7.20-7.12 (m, 2H), 6.99 (br t, 2H), 6.90 (d, 1H), 6.10-5.80 (br, 1H), 4.03 (d, 1H), 3.94 (d, 1H), 2.97 (t, 2H), 2.78 (t, 2H), 2.25 (br s, 3H), 2.05 (quint, 2H); LC-MS (ESI) m/z 448.3 [M+H]⁺.

Example 184

4-(Trifluoromethyl)benzyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 4-(trifluoromethyl)benzyl alcohol (0.150 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 4-(trifluoromethyl)benzyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.250 g, 94%). 1H NMR (CDCl₃, 300 MHz) δ 7.89 (br s, 1H), 7.78 (br d, 1H), 7.63 (d, 2H), 7.51 (d, 2H), 7.33-7.26 (m, 2H), 6.95 (t, 2H), 5.97 (br s, 1H), 5.36 (s, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H); LC-MS (ACPI) m/z 490.6 [M+H]⁺.

Example 185

1-Phenylethyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (148 mg, 0.447 mmol), DMAP (126 mg, 1.03 mmol), EDCI • HCl (154 mg, 0.805 mmol), 1-phenylethanol (54.6 mg, 0.447 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-25% ethyl acetate in n-hexane) to give 1-phenylethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (157 mg, 81%) as a white foam. 1H NMR (CDCl₃, 400 MHz) δ 7.89 (br s, 1H), 7.78 (br s, 1H), 7.41-7.27 (m, 7H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 6.07 (q, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H), 1.63 (d, 3H); LC-MS (ESI) m/z 436.1 [M+H]⁺.

Example 186

1-[4-(Trifluoromethyl)phenyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (148 mg, 0.447 mmol), DMAP (126 mg, 1.03 mmol), EDCI • HCl (154 mg, 0.805 mmol), 1-[4-(trifluoromethyl)phenyl]ethanol (85.0 mg, 0.447 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-25% ethyl acetate in n-hexane) to give 1-[4-(trifluoromethyl)phenyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (192 mg, 85%) as a lightly yellow foam. 1H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.77 (br d, 1H), 7.61 (d, 2H), 7.49 (d, 2H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 6.08 (q, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H), 1.64 (d, 3H); LC-MS (ESI) m/z 504.1 [M+H]⁺.

Example 187

3-Phenylpropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 3-phenyl-1-propanol (0.150 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3-phenylpropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.160 g, 66%). 1H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.73 (br s, 1H), 7.33-7.28 (m, 4H), 7.20-7.17 (m, 3H), 6.96 (t, 2H), 5.97 (br s, 1H), 4.29 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.75 (t, 2H), 2.20 (br s, 3H), 2.07 (quint, 2H); LC-MS (ACPI) m/z 450.7 [M+H]⁺.

Example 188

[1-(4-Chlorophenyl)cyclopropyl]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (164 mg, 0.495 mmol), DMAP (151 mg, 1.24 mmol), EDCI • HCl (189 mg, 0.990 mmol), 1-(4-chlorophenyl)-1-cyclopropanemethanol (94.9 mg, 0.520 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give [1-(4-chlorophenyl)cyclopropyl]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (206 mg, 86%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.79 (br s, 1H), 7.66 (br s, 1H), 7.32-7.24 (m, 6H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.36-4.28 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H), 1.01-0.92 (m, 4H); LC-MS (ESI) m/z 518.1 [M+Na]⁺.

Example 189

[1-(4-Chlorophenyl)cyclopentyl]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Methyl 1-(4-chlorophenyl)cyclopentanecarboxylate

To a solution of 1-(4-chlorophenyl)-1-cyclopentane carboxylic acid (1.01 g, 4.50 mmol) in methanol (20 mL) was added thionyl chloride (0.660 mL, 9.10 mmol) slowly in ice-bath. The solution was stirred at room temperature for 5 h and concentrated to afford a residue. The residue was treated with CH₂Cl₂ (60 mL) and washed with saturated NaHCO_3(aq) (40 mL). The organic layer was dried over MgSO_4(s), filtered, concentrated, and dried under vacuum to obtain methyl 1-(4-chlorophenyl)cyclopentanecarboxylate (0.864 g, 81%) as a brown oil. 1H NMR (CDCl₃, 400 MHz) δ 7.31-7.25 (m, 4H), 3.62 (s, 3H), 2.65-2.59 (m, 2H), 1.91-1.83 (m, 2H), 1.75-1.71 (m, 4H).

Step 2. [1-(4-Chlorophenyl)cyclopentyl]methanol

To a solution of methyl 1-(4-chlorophenyl)cyclopentanecarboxylate (0.748 g, 3.13 mmol) in THF (20 mL) was added lithium aluminium hydride (0.297 g, 7.83 mmol) in small portion in ice-bath. The reaction was warm up to room temperature and then reflux for 6 h. After the solution was cooled to room temperature, it was quenched with saturated Na₂SO_4(aq) and 10% NaOH_(aq), and diluted with diethyl ether. The undissolved solids were filtered off and washed with diethyl ether. The filtrate was dried over MgSO_4(s), filtered, concentrated, and dried under vacuum to obtain [1-(4-chlorophenyl)cyclopentyl]methanol (0.614 g, 93%) as a lightly yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.34-7.23 (m, 4H), 3.53 (s, 2H), 2.04-1.98 (m, 2H), 1.90-1.80 (m, 2H), 1.77-1.71 (m, 4H).

Step 3. [1-(4-Chlorophenyl)cyclopentyl]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (158 mg, 0.477 mmol), DMAP (146 mg, 1.19 mmol), EDCI • HCl (183 mg, 0.954 mmol), [1-(4-chlorophenyl)cyclopentyl]methanol (106 mg, 0.501 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give [1-(4-chlorophenyl)cyclopentyl]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (202 mg, 83%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.71 (br s, 1H), 7.60 (br s, 1H), 7.36-7.27 (m, 6H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.27-4.20 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.17 (br s, 3H), 2.05-1.92 (m, 4H), 1.79-1.76 (m, 4H); LC-MS (ESI) m/z 546.3 [M+Na]⁺.

Example 190

2-(Benzyloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 2-phenylmethoxyethanol (0.150 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-(benzyloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.140 g, 52%). 1H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.75 (br s, 1H), 7.32-7.29 (m, 8H), 6.96 (t, 2H), 5.98 (br s, 1H), 4.58 (s, 2H), 4.45 (dd, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.77-3.75 (m, 2H), 2.20 (br s, 3H); LC-MS (ACPI) m/z 466.8 [M+H]⁺.

Example 191

1,3-Benzodioxol-5-ylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (165 mg, 0.498 mmol), DMAP (152 mg, 1.25 mmol), EDCI • HCl (191 mg, 0.996 mmol), helioalcohol (79.6 mg, 0.523 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 1,3-benzodioxol-5-ylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (175 mg, 75%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.31-7.28 (m, 2H), 6.95 (br t, 2H), 6.89-6.87 (m, 2H), 6.79 (d, 1H), 6.05-5.85 (br, 3H), 5.20 (s, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.18 (br s, 3H); LC-MS (ESI) m/z 466.2 [M+H]⁺.

Example 192

2-(2-Chlorophenoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (136 mg, 0.410 mmol), DMAP (100 mg, 0.820 mmol), EDCI • HCl (118 mg, 0.615 mmol), 2-(2-chlorophenoxy)ethanol (70.8 mg, 0.410 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-35% ethyl acetate in n-hexane) to give 2-(2-chlorophenoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (152 mg, 76%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.36 (dd, 1H), 7.32-7.28 (m, 2H), 7.22-7.18 (m, 1H), 6.97-6.90 (m, 4H), 6.10-5.80 (br, 1H), 4.65 (t, 2H), 4.34 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.18 (br s, 3H); LC-MS (ESI) m/z 486.2 [M+H]⁺.

Example 193

3-Pyridinylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.150 g, 0.453 mmol), nicotinyl alcohol (88.0 μL, 0.906 mmol), EDCI • HCl (0.170 g, 0.906 mmol), DMAP (0.140 g, 1.13 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 3-pyridinylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.106 g, 69%). 1H NMR (CDCl₃, 400 MHz) δ 8.68 (s, 1H), 8.59 (d, 1H), 7.87 (br s, 1H), 7.81-7.73 (m, 2H), 7.33-7.28 (m, 3H), 6.95 (t, 2H), 5.93 (br s, 1H), 5.33 (s, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H); LC-MS (APCI) m/z 423.7 [M+H]⁺.

Example 194

2-(4-Pyridinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 4-pyridineethanol (0.120 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (3% MeOH in CH₂Cl₂) to give 2-(4-pyridinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.210 g, 89%). 1H NMR (CDCl₃, 300 MHz) δ 8.53 (d, 2H), 7.80 (br s, 1H), 7.67 (br d, 1H), 7.33-7.28 (m, 2H), 7.19 (d, 2H), 6.95 (t, 2H), 5.96 (br s, 1H), 4.52 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.04 (t, 2H), 2.19 (br s, 3H); LC-MS (ACPI) m/z 437.6 [M+H]⁺.

Example 195

3-(2-Pyridinyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), 2-pyridinepropanol (94.0 μL, 0.725 mmol), EDCI • HCl (0.139 g, 0.725 mmol), DMAP (0.110 g, 0.906 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 3-(2-pyridinyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (70.5 mg, 43%). 1H NMR (CDCl₃, 300 MHz) δ 8.52 (d, 1H), 7.83 (br s, 1H), 7.72 (br d, 1H), 7.58 (td, 1H), 7.33-7.27 (m, 2H), 7.14-7.08 (m, 2H), 6.96 (t, 2H), 5.97 (br s, 1H), 4.33 (t, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 2.92 (dd, 2H), 2.25-2.16 (m, 5H); LC-MS (ACPI) m/z 451.6 [M+H]⁺.

Example 196

2,3-Dihydro-1,4-benzodioxin-2-ylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), 2-hydroxymethyl-1,4-benzodioxan (0.120 g, 0.725 mmol), EDCI • HCl (0.139 g, 0.725 mmol), DMAP (0.110 g, 0.906 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 2,3-dihydro-1,4-benzodioxin-2-ylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (80.5 mg, 46%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.75 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (t, 2H), 6.92-6.83 (m, 4H), 5.98 (br s, 1H), 4.58-4.47 (m, 3H), 4.33 (dd, 1H), 4.12 (dd, 1H), 4.00 (d, 1H), 3.94 (d, 1H), 2.20 (br s, 3H); LC-MS (APCI) m/z 480.5 [M+H]⁺.

Example 197

2-(3-Thiophenyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), 2-Thiopheneethanol (79.0 μL, 0.725 mmol), EDCI • HCl (0.139 g, 0.725 mmol), DMAP (0.110 g, 0.906 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 2-(3-thiophenyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (79.2 mg, 50%). 1H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br d, 1H), 7.33-7.28 (m, 2H), 7.16 (dd, 1H), 6.99-6.88 (m, 4H), 5.96 (br s, 1H), 4.49 (t, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 3.25 (t, 2H), 2.20 (br s, 3H); LC-MS (ACPI) m/z 442.4 [M+H]⁺.

Example 198

2-(4-Methyl-1,3-thiazol-5-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (133 mg, 0.401 mmol), DMAP (73.5 mg, 0.602 mmol), EDCI • HCl (115 mg, 0.602 mmol), 4-methyl-5-thiazole ethanol (63.2 mg, 0.441 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-65% ethyl acetate in n-hexane) to give 2-(4-methyl-1,3-thiazol-5-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (71.5 mg, 39%) as a yellow gum. 1H NMR (CDCl₃, 400 MHz) δ 8.61 (s, 1H), 7.85 (br s, 1H), 7.72 (br s, 1H), 7.32-7.29 (m, 2H), 6.96 (br t, 2H), 6.10-5.85 (br, 1H), 4.44 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.20 (t, 2H), 2.42 (s, 3H), 2.20 (br s, 3H); LC-MS (ESI) m/z 457.2 [M+H]⁺.

Example 199

3-Methoxypropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (158 mg, 0.477 mmol), DMAP (109 mg, 0.892 mmol), EDCI • HCl (129 mg, 0.671 mmol), 3-methoxy-1-propanol (48.3 mg, 0.536 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 3-methoxypropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (100 mg, 56%) as a colorless gum. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.36 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.49 (t, 2H), 3.34 (s, 3H), 2.20 (br s, 3H), 1.99 (quint, 2H); LC-MS (ESI) m/z 404.2 [M+H]⁺.

Example 200

2-Oxopropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (149 mg, 0.450 mmol), DMAP (110 mg, 0.900 mmol), EDCI • HCl (129 mg, 0.671 mmol), hydroxyacetone (40.0 mg, 0.540 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-oxopropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (122 mg, 70%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.92 (br s, 1H), 7.80 (br s, 1H), 7.33-7.30 (m, 2H), 6.97 (br t, 2H), 6.10-5.80 (br, 1H), 4.84 (s, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.30-2.10 (br, 6H); LC-MS (ESI) m/z 388.2 [M+H]⁺.

Example 201

2-Cyanoethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid 0 (158 mg, 0.477 mmol), DMAP (117 mg, 0.954 mmol), EDCI • HCl (140 mg, 0.730 mmol), 3-hydroxypropionitrile (50.0 μL, 0.732 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-cyanoethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (143 mg, 77%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.77 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.48 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.80 (t, 2H), 2.21 (br s, 3H); LC-MS (ESI) m/z 385.2 [M+H]⁺.

Example 202

2-(Methylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (158 mg, 0.477 mmol), DMAP (117 mg, 0.954 mmol), EDCI • HCl (140 mg, 0.730 mmol), 2-(methylthio)ethanol (51.0 μL, 0.569 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-(methylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (140 mg, 73%) as a colorless gum. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.44 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.81 (t, 2H), 2.30-2.10 (br, 6H); LC-MS (ESI) m/z 428.2 [M+Na]⁺.

Example 203

2-(Ethylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 2-(ethylthio)ethanol (0.120 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-(ethylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 88%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.33-7.28 (m, 2H), 6.98 (t, 2H), 5.93 (br s, 1H), 4.42 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.84 (t, 2H), 2.61 (q, 2H), 2.20 (br s, 3H), 1.26 (t, 3H); LC-MS (ESI) m/z 442.4 [M+Na]⁺.

Example 204

2-(Acetyloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (135 mg, 0.408 mmol), DMAP (74.8 mg, 0.612 mmol), EDCI • HCl (117 mg, 0.612 mmol), 2-hydroxyethyl acetate (42.5 mg, 0.408 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-45% ethyl acetate in n-hexane) to give 2-(acetyloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (115 mg, 77%) as a colorless gum. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.76 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.50-4.45 (m, 2H), 4.38-4.35 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.23 (br s, 3H), 2.06 (s, 3H); LC-MS (ESI) m/z 440.2 [M+Na]⁺.

Example 205

[(2,2-Dimethylpropanoyl)oxy]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (190 mg, 0.573 mmol) was dissolved in DMF (2.0 mL) and chloromethyl pivalate (0.100 mL, 0.690 mmol) was added followed by triethylamine (0.120 mL, 0.861 mmol) and sodium iodide (94.4 mg, 0.630 mmol). The reaction was heated to 50° C. for 10 h, and then DMF was removed under reduced pressure. The crude was dissolved in ethyl acetate and washed with saturated NaHCO_3(aq) and brine, dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-35% ethyl acetate in n-hexane) to give [(2,2-dimethylpropanoyl)oxy]methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (201 mg, 79%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 7.89 (br s, 1H), 7.77 (br d, 1H), 7.33-7.28 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 3H), 4.01 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H), 1.20 (s, 9H); LC-MS (ESI) m/z 468.2 [M+Na]⁺.

Example 206

Tetrahydro-3-furanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 3-hydroxytetrahydrofuran (88.0 μL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give tetrahydro-3-furanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 92%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.74 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (t, 2H), 5.95 (br s, 1H), 5.51-5.47 (m, 1H), 4.02-3.86 (m, 6H), 2.30-2.07 (m, 5H); LC-MS (ACPI) m/z 402.9 [M+H]⁺.

Example 207

Tetrahydro-2-furanylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), tetrahydrofuryl alcohol (0.110 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give tetrahydro-2-furanylmethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.180 g, 80%). 1H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.76 (br d, 1H), 7.32-7.28 (m, 3H), 6.95 (t, 2H), 5.93 (br s, 1H), 4.36-4.29 (m, 1H), 4.23-4.18 (m, 2H), 4.03-3.77 (m, 4H), 2.18 (br s, 3H), 2.10-1.97 (m, 1H), 1.95-1.90 (m, 2H), 1.71-1.65 (m, 1H); LC-MS (ACPI) m/z 416.7 [M+H]⁺.

Example 208

(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (186 mg, 0.563 mmol), DMAP (137 mg, 1.13 mmol), EDCI • HCl (162 mg, 0.844 mmol), (±)-2,2-dimethyl-1,3-dioxolane-4-methanol (81.8 mg, 0.619 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give (2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (171 mg, 68%) as a yellow gum. 1H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br d, 1H), 7.32-7.28 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.43-4.30 (m, 3H), 4.11 (dd, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.81 (dd, 1H), 2.20 (br s, 3H), 1.43 (s, 3H), 1.37 (s, 3H); LC-MS (ESI) m/z 406.2 [M+H]⁺ (deprotection of dimethylacetal to terminal diol compound by using 0.1% formic acid in H₂O and CH₃CN as the eluent of LC).

Example 209

2,2-Dimethyl-1,3-dioxan-5-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (169 mg, 0.510 mmol), DMAP (156 mg, 1.28 mmol), EDCI • HCl (196 mg, 1.02 mmol), 2,2-dimethyl-1,3-dioxan-5-ol (80.9 mg, 0.612 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2,2-dimethyl-1,3-dioxan-5-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (169 mg, 74%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.91 (br s, 1H), 7.80 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.95 (br s, 1H), 4.89 (quint, 1H), 4.16 (dd, 2H), 4.05-3.88 (m, 4H), 2.20 (br s, 3H), 1.46 (s, 3H), 1.45 (s, 3H); LC-MS (ESI) m/z 406.2 [M+H]⁺ (deprotection of dimethylacetal to terminal diol compound by using 0.1% formic acid in H₂O and CH₃CN as the eluent of LC).

Example 210

1,3-Dimethoxy-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (195 mg, 0.588 mmol), DMAP (144 mg, 1.18 mmol), EDCI • HCl (169 mg, 0.882 mmol), 1,3-dimethoxypropan-2-ol (84.8 mg, 0.706 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 1,3-dimethoxy-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (129 mg, 51%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.77 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 5.33 (quint, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.66-3.53 (m, 4H), 3.36 (s, 6H), 2.19 (br s, 3H); LC-MS (ESI) m/z 434.3 [M+H]⁺.

Example 211

1-Methoxy-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 1-methoxy-2-propanol (0.110 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 1-methoxy-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.190 g, 87%). 1H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.74 (br, 1H), 7.33-7.28 (m, 2H), 6.96 (t, 2H), 5.95 (br s, 1H), 5.33-5.23 (m, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.55 (dd, 1H), 3.47 (dd, 1H), 3.37 (s, 3H). 2.19 (br s, 3H), 1.31 (d, 3H).

Example 212

2-(2-Methoxyethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (190 mg, 0.573 mmol), DMAP (178 mg, 1.43 mmol), EDCI • HCl (220 mg, 1.15 mmol), diethylene glycol monomethyl ether (0.50 mL), and CH₂Cl₂ (8.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 2-(2-methoxyethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (119 mg, 48%) as a colorless gum. 1H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.75 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.46-4.42 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.80-3.78 (m, 2H), 3.67-3.65 (m, 2H), 3.55-3.53 (m, 2H), 3.37 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 456.2 [M+Na]⁺.

Example 213

2-Ethoxyethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 2-ethoxyethanol (0.110 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-ethoxyethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.170 g, 78%). 1H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.76 (br d, 1H), 7.33-7.28 (m, 2H), 6.95 (t, 2H), 5.94 (br s, 1H), 4.42 (dd, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.72 (dd, 2H), 3.55 (q, 2H), 2.19 (br s, 3H), 1.21 (t, 3H); LC-MS (ACPI) m/z 404.7 [M+H]⁺.

Example 214

2-(2-Ethoxyethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 2-(2-ethoxyethoxy)ethanol (0.150 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (30% ethyl acetate in n-hexane) to give 2-(2-ethoxyethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 82%). 1H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.76 (br s, 1H), 7.30 (dd, 2H), 6.95 (t, 2H), 5.96 (br s, 1H), 4.44-4.42 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.81-3.78 (m, 2H), 3.69-3.64 (m, 2H), 3.61-3.57 (m, 2H), 3.55-3.48 (m, 2H), 2.19 (br s, 3H), 1.20-1.16 (m, 3H); LC-MS (ACPI) m/z 448.7 [M+H]⁺.

Example 215

3-Methoxy-3-methylbutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 3-methoxy-3-methyl-1-butanol (0.140 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 3-methoxy-3-methylbutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.170 g, 72%). 1H NMR (CDCl₃, 300 MHz) δ 7.85 (br s, 1H), 7.75 (br d, 1H), 7.33-7.28 (m, 2H), 6.95 (t, 2H), 5.95 (br, 1H), 4.37 (t, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 3.21 (s, 3H), 2.19 (br s, 3H), 1.92 (t, 2H), 1.23 (s, 6H); LC-MS (ESI) m/z 454.3 [M+Na]⁺.

Example 216

3-(Trimethylsilyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 3-(trimethylsilyl)-1-propanol (0.170 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3-(trimethylsilyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.180 g, 74%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (t, 2H), 5.96 (br s, 1H), 4.22 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H), 1.74-1.66 (m, 2H), 0.55-0.51 (m, 2H), 0.00 (s, 9H); LC-MS (ESI) m/z 446.2 [M+H].

Example 217

1-Butoxy-1-oxo-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), butyl lactate (0.160 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 1-butoxy-1-oxo-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.230 g, 92%). 1H NMR (CDCl₃, 400 MHz) δ 7.90 (br s, 1H), 7.79 (br s, 1H), 7.32-7.28 (m, 2H), 6.98 (t, 2H), 5.93 (br s, 1H), 5.26 (q, 1H), 4.18 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.64-1.57 (m, 5H), 1.35 (sextet, 2H), 0.90 (t, 3H); LC-MS (ACPI) m/z 460.5 [M+H]⁺.

Example 218

2,2,2-Trifluoroethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), 2,2,2-trifluoroethanol (52.0 μL, 0.725 mmol), EDCI • HCl (139 mg, 0.725 mmol), DMAP (110 mg, 0.906 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 2,2,2-trifluoroethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (86.1 mg, 58%). 1H NMR (CDCl₃, 300 MHz) δ 7.90 (br s, 1H), 7.78 (br d, 1H), 7.31 (dd, 2H), 6.97 (t, 2H), 5.98 (br s, 1H), 4.65 (q, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.22 (br s, 3H); LC-MS (APCI) m/z 414.9 [M+H]⁺.

Example 219

2-(Acetylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), N-acetylethanolamine (0.100 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (3% MeOH in CH₂Cl₂) to give 2-(acetylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.180 g, 80%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (t, 2H), 5.93 (br s, 1H), 5.79 (br s, 1H), 4.38-4.35 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.61 (q, 2H), 2.21 (br s, 3H), 1.98 (s, 3H); LC-MS (ACPI) m/z 417.7 [M+H]⁺.

Example 220

2-[2-(Acetylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of N-[2-(2-hydroxyethoxy)ethyl]acetamide

To a solution of 2-(2-aminoethoxy)ethanol (0.480 mL, 4.76 mmol) and acetic anhydride (0.450 mL, 4.76 mmol) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 5 h. The reaction mixture was extracted with CH₂Cl₂. The water layer was concentrated. The residue was used directly for next step without further purification. 1H NMR (CDCl₃, 400 MHz) δ 6.25 (br s, 1H), 3.74 (dd, 2H), 3.58-3.55 (m, 4H), 3.47-3.43 (m, 2H), 1.98 (s, 3H).

Step 2. Synthesis of 2-[2-(acetylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), N-[2-(2-hydroxyethoxy)ethyl]acetamide (0.160 g, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (3% MeOH in CH₂Cl₂) to give 2-[2-(acetylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.230 g, 92%). 1H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br d, 1H), 7.32-7.28 (m, 2H), 6.96 (t, 2H), 5.88 (br s, 1H), 4.44 (dd, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.77-3.74 (m, 2H), 3.57 (dd, 2H), 3.46-3.40 (m, 2H), 2.20 (br s, 3H), 1.92 (s, 3H); LC-MS (ACPI) m/z 461.7 [M+H]⁺.

Example 221

2-(Dimethylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (139 mg, 0.421 mmol) in CH₂Cl₂ (5.0 mL) was added 2-(dimethylamino)ethanol (84.0 μL, 0.840 mmol) and EDCI • HCl (121 mg, 0.631 mmol) at room temperature. After the reaction mixture was stirred for 20 h, it was diluted with CH₂Cl₂ and washed with water. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-20% MeOH in CH₂Cl₂) to give 2-(dimethylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (63.6 mg, 38%) as a colorless gum. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.29 (dd, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.37 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.67 (t, 2H), 2.30 (s, 6H), 2.17 (br s, 3H); LC-MS (ESI) m/z 403.3 [M+H]⁺.

Example 222

3-(Dimethylamino)propyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), 3-(dimethylamino)propan-1-ol (39.0 μL, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.0 μL, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (5% MeOH in CH₂Cl₂) to give 3-(dimethylamino)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (81.2 mg, 65%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (t, 2H), 5.97 (br s, 1H), 4.31 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.40 (dd, 2H), 2.24 (s, 6H), 2.20 (br s, 3H), 1.90 (quint, 2H); LC-MS (ESI) m/z 417.1 [M+H]⁺.

Example 223

2-(Diethylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), 2-(diethylamino)ethan-1-ol (65.0 μL, 0.604 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 2-(diethylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (40.1 mg, 31%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 6.95 (t, 2H), 5.96 (br s, 1H), 4.34 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.80 (t, 2H), 2.60 (q, 4H), 2.19 (br s, 3H), 1.04 (t, 6H); LC-MS (APCI) m/z 431.8 [M+H]⁺.

Example 224

2-[Ethyl(phenyl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 2-(N-ethylanilino)ethanol (0.180 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-[ethyl(phenyl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.260 g, 99%). 1H NMR (CDCl₃, 300 MHz) δ 7.82 (br s, 1H), 7.71 (br d, 1H), 7.33-7.28 (m, 2H), 7.22 (t, 2H), 6.96 (t, 2H), 6.80-6.74 (m, 2H), 6.68 (t, 1H), 5.95 (br s, 1H), 4.42 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.65 (t, 2H), 3.42 (q, 2H), 2.18 (br s, 3H), 1.17 (t, 3H); LC-MS (ACPI) m/z 479.7 [M+H].

Example 225

2-(1-Pyrrolidinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), 2-(pyrrolidin-1-yl)ethan-1-ol (38.0 mg, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.6 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (5% MeOH in CH₂Cl₂) to give 2-(1-pyrrolidinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (33.0 mg, 26%). 1H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.80-7.70 (br, 1H), 7.32-7.28 (m, 2H), 7.15-6.92 (m, 3H), 5.94 (br s, 1H), 4.41 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.83 (t, 2H), 2.68-2.55 (m, 4H), 2.19 (br s, 3H), 1.84-1.76 (br, 4H); LC-MS (APCI) m/z 428.9 [M+H]⁺.

Example 226

2-(1-Piperidinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.362 mmol), 2-(piperidin-1-yl)ethan-1-ol (96.0 μL, 0.725 mmol), HBTU (210 mg, 0.544 mmol), triethylamine (0.11 mL, 0.797 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 2-(1-piperidinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (9.9 mg, 6%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.74 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (t, 2H), 5.93 (br s, 1H), 4.40 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.71 (t, 2H), 2.55-2.42 (br, 4H), 2.20 (br s, 3H), 1.61-1.55 (m, 4H), 1.45-1.42 (m, 2H); LC-MS (APCI) m/z 443.7 [M+H]⁺.

Example 227

2-(4-Morpholinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), 2-morpholinoethanol (89.0 μL, 0.398 mmol), EDCI • HCl (86.8 mg, 0.453 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 2-(4-morpholinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (12.0 mg, 9%). 1H NMR (CDCl₃, 300 MHz) δ 7.85 (br s, 1H), 7.80-7.70 (br, 1H), 7.33-7.26 (m, 2H), 6.98-6.93 (m, 3H), 5.94 (br s, 1H), 4.40 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.75-3.62 (m, 4H), 2.72 (t, 2H), 2.59-2.47 (m, 4H), 2.20 (br s, 3H); LC-MS (APCI) m/z 445.8 [M+H]⁺.

Example 228

3-(4-Morpholinyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (191 mg, 0.576 mmol) in CH₂Cl₂ (5.0 mL) was added 3-(4-morpholinyl)-1-propanol (200 μL, 1.44 mmol) and EDCI • HCl (166 mg, 0.866 mmol) at room temperature. After the reaction mixture was stirred for 18 h, it was diluted with CH₂Cl₂ and washed with water. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 3-(4-morpholinyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (105 mg, 40%) as a lightly yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.36-4.32 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.81 (br s, 4H), 2.61 (br s, 6H), 2.19 (br s, 3H), 2.05 (br s, 2H); LC-MS (ESI) m/z 459.3 [M+H]⁺.

Example 229

3-(1-Piperidinyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (191 mg, 0.576 mmol) in CH₂Cl₂ (5.0 mL) was added 1-piperidinepropanol (210 μL, 1.39 mmol) and EDCI • HCl (160 mg, 0.832 mmol) at room temperature. After the reaction mixture was stirred for 20 h, it was diluted with CH₂Cl₂ and washed with water. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 3-(1-piperidinyl)propyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (102 mg, 40%) as a yellow gum. 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.72 (br s, 1H), 7.32-7.28 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.32-4.29 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.43-2.38 (m, 6H), 2.20 (br s, 3H), 1.92 (quint, 2H), 1.65-1.54 (m, 4H), 1.45-1.41 (m, 2H); LC-MS (ESI) m/z 457.3 [M+H]⁺.

Example 230

2-(1-Acetyl-4-piperidinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (136 mg, 0.410 mmol), DMAP (75.1 mg, 0.615 mmol), EDCI • HCl (118 mg, 0.614 mmol), 1-[4-(2-hydroxyethyl)-1-piperidinyl]-ethanone (84.2 mg, 0.492 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 2-(1-acetyl-4-piperidinyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (71.5 mg, 36%) as a colorless gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.73 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.36-4.30 (m, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.00-2.60 (br, 2H), 2.30-2.00 (m, 9H), 1.82-1.76 (m, 2H), 1.72-1.68 (m, 2H), 1.23-1.14 (m, 2H); LC-MS (ESI) m/z 507.1 [M+Na]⁺.

Example 231

1-Methyl-3-pyrrolidinyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), 1-methylpyrrolidin-3-ol (66.0 μL, 0.604 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 1-methyl-3-pyrrolidinyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (10.8 mg, 8%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.31-7.28 (m, 2H), 6.94 (t, 2H), 5.96 (br s, 1H), 5.36 (br, 1H), 3.99 (d, 1H), 3.91 (d, 1H), 2.87-2.72 (m, 3H), 2.40-2.30 (m, 4H), 2.17 (br s, 3H), 2.00-1.92 (m, 2H); LC-MS (APCI) m/z 415.9 [M+H]⁺.

Example 232

1-Methyl-4-piperidinyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), 1-methylpiperidin-4-ol (38.0 mg, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.0 μL, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (5% MeOH in CH₂Cl₂) to give 1-methyl-4-piperidinyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (48.1 mg, 37%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.74 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.98 (br s, 1H), 5.01-4.99 (m, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.69 (br s, 2H), 2.36 (br s, 2H), 2.32 (s, 3H), 2.20 (br s, 3H), 2.00-1.96 (m, 2H), 1.87-1.79 (m, 2H); LC-MS (ESI) m/z 429.1 [M+H]⁺.

Example 233

(1-Methyl-3-piperidinyl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 3-(hydroxymethyl)-1-methylpiperidine (0.150 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give (1-methyl-3-piperidinyl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.240 g, 99%). 1H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.72 (br s, 1H), 7.34-7.31 (m, 2H), 6.97 (t, 2H), 5.98 (br s, 1H), 4.28-4.13 (m, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.35 (br, 2H), 2.68 (br s, 3H), 2.58-2.30 (br, 3H), 2.21 (br s, 3H), 1.91 (t, 2H), 1.27-1.20 (m, 2H); LC-MS (ESI) m/z 443.4 [M+H]⁺.

Example 234

2-(2-Aminoethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-methyl-2-propanyl [2-(2-hydroxyethoxy)ethyl]carbamate

To a solution of diethylene glycolamine (0.480 mL, 4.76 mmol) and di-tert-butyl dicarbonate (1.04 g, 4.76 mmol) in CH₂Cl₂ (5.0 mL) was stirred at room temperature for 2 h. The result mixture was extracted with CH₂Cl₂, dried over MgSO_4(s), filtered, and concentrated. The residue was used directly for next step without further purification. 1H NMR (CDCl₃, 400 MHz) δ 5.03 (br s, 1H), 3.72 (br, 2H), 3.58-3.52 (m, 4H), 3.33-3.31 (br, 2H), 1.44 (s, 9H).

Step 2. Synthesis of 2-[2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.200 g, 0.604 mmol), 2-methyl-2-propanyl [2-(2-hydroxyethoxy)ethyl]carbamate (0.250 g, 1.21 mmol), EDCI • HCl (0.230 g, 1.21 mmol), DMAP (0.160 g, 1.33 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-[2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.300 g, 96%). 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.76 (br s, 1H), 7.33-7.28 (m, 2H), 6.95 (t, 2H), 5.94 (br s, 1H), 4.89 (br s, 1H), 4.45-4.40 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.74 (t, 2H), 3.58-3.54 (m, 4H), 2.20 (br s, 3H), 1.43 (s, 9H).

Step 3. Synthesis of 2-(2-aminoethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

To a solution of 2-[2-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.350 g) and TFA (0.250 mL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 3 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH value to above 8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 2-(2-aminoethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (32.7 mg, 12%). 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.73 (br s, 1H), 7.33-7.29 (m, 2H), 6.95 (t, 2H), 6.81 (br s, 1H), 5.98 (br s, 1H), 4.44 (dd, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.78-3.76 (m, 2H), 3.65-3.59 (m, 2H), 3.55 (quint, 2H), 2.21 (br s, 3H).

Example 235

2-[2-(Dimethylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.540 mmol), 2-[2-(dimethylamino)ethoxy]ethanol (0.150 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-[2-(dimethylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (85.4 mg, 36%). 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.76 (br s, 1H), 7.31 (dd, 2H), 6.95 (t, 2H), 5.98 (br s, 1H), 4.43 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.76-3.74 (m, 2H), 3.62 (t, 2H), 2.55 (t, 2H), 2.28 (s, 6H), 2.20 (br s, 3H); LC-MS (ESI) m/z 447.4 [M+H]⁺.

Example 236

2-[2-(1-Pyrrolidinyl)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[2-(1-pyrrolidinyl)ethoxy]ethanol

To a solution of pyrrolidine (0.350 mL, 4.01 mmol) and 2-(2-chloroethoxy)ethanol (0.450 mL, 4.01 mmol) in CH₂Cl₂ (7.0 mL) was stirred at room temperature for 5 h. The reaction mixture was extracted with CH₂Cl₂. The water layer was concentrated. The residue was used directly for next step without further purification. 1H NMR (CDCl₃, 400 MHz) δ 3.83-3.80 (m, 2H), 3.79-3.70 (m, 2H), 3.68-3.58 (m, 2H), 3.33-3.29 (m, 6H), 2.15-2.03 (m, 3H), 1.97 (br s, 1H).

Step 2. Synthesis of 2-[2-(1-pyrrolidinyl)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (275 mg, 1.06 mmol), 2-[2-(1-pyrrolidinyl)ethoxy]ethanol (260 mg, 1.66 mmol), HBTU (470 mg, 1.24 mmol), triethylamine (0.250 mL, 1.83 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 2-[2-(1-pyrrolidinyl)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.130 g, 33%). 1H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.77 (br s, 1H), 7.33 (dd, 2H), 6.95 (t, 2H), 5.99 (br s, 1H), 4.51-4.42 (m, 2H), 4.00 (d, 1H), 3.94-3.81 (m, 3H), 3.35 (br s, 2H), 3.32-3.29 (m, 2H), 2.20 (br s, 3H), 2.07-1.98 (m, 4H), 1.80-1.49 (br, 4H); LC-MS (ESI) m/z 473.3 [M+H]⁺.

Example 237

1,3-Bis(acetylamino)-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.303 mmol), DMAP (92.5 mg, 0.757 mmol), EDCI • HCl (116 mg, 0.605 mmol), 1,3-diacetaminopropan-2-ol (52.8 mg, 0.303 mmol), and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in ethyl acetate) to give 1,3-bis(acetylamino)-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl benzoate (96.8 mg, 66%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.83 (br s, 1H), 7.72 (br, 1H), 7.31 (dd, 2H), 6.97 (br t, 2H), 6.30 (br s, 2H), 6.10-5.80 (br, 1H), 5.01 (quint, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.64-3.58 (m, 2H), 3.45-3.38 (m, 2H), 2.17 (br s, 3H), 2.00 (s, 6H); LC-MS (ESI) m/z 488.3 [M+H]⁺.

Example 238

1,3-Bis(acetyloxy)-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (101 mg, 0.304 mmol), DMAP (92.8 mg, 0.760 mmol), EDCI • HCl (117 mg, 0.608 mmol), 1,3-diacetylglycerol (58.9 mg, 0.334 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 1,3-bis(acetyloxy)-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (115 mg, 77%) as a gum. 1H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.32 (dd, 2H), 6.97 (br t, 2H), 5.95 (br s, 1H), 5.45 (quint, 1H), 4.38-4.24 (m, 4H), 4.01 (d, 1H), 3.91 (d, 1H), 2.21 (br s, 3H), 2.05 (s, 6H); LC-MS (ESI) m/z 512.2 [M+Na]⁺.

Example 239

(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure H, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (159 mg, 0.480 mmol), K₂CO₃ (133 mg, 0.960 mmol), 4-chloromethyl-5-methyl-1,3-dioxal-2-one (74.8 mg, 0.504 mmol), and DMF (1.0 mL) were used to carry out the reaction. The desird product was collected by filtered and washed with water and diethyl ether to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (145 mg, 68%) as a beige solid. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 5.03 (s, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.30-2.10 (br, 6H); LC-MS (ESI) m/z 466.2 [M+Na]⁺.

Example 240

1-{[(Cyclohexyloxy)carbonyl]oxy}ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure H, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (167 mg, 0.504 mmol), K₂CO₃ (139 mg, 1.01 mmol), 1-chloroethyl cyclohexyl carbonate (0.102 mL, 0.554 mmol), and DMF (1.0 mL) were used to carry out the reaction. The residue was purified by column chromatography (0-25% ethyl acetate in n-hexane) to give 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (214 mg, 85%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.30 (dd, 2H), 6.98-6.94 (m, 3H), 6.10-5.80 (br, 1H), 4.62 (quint, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H), 1.93-1.90 (m, 2H), 1.75-1.72 (m, 2H), 1.60 (d, 3H), 1.53-1.42 (m, 2H), 1.38-1.22 (m, 4H); LC-MS (ESI) m/z 524.3 [M+Na]⁺.

Example 241

1-[(Ethoxycarbonyl)oxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure H, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (163 mg, 0.492 mmol), K₂CO₃ (136 mg, 0.984 mmol), 1-chlorodiethyl carbonate (80.0 μL, 0.597 mmol), and DMF (1.0 mL) were used to carry out the reaction. The residue was purified by column chromatography (0-25% ethyl acetate in n-hexane) to give 1-[(ethoxycarbonyl)oxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (178 mg, 81%) as a lightly yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.76 (br s, 1H), 7.30 (dd, 2H), 6.99-6.94 (m, 3H), 6.10-5.80 (br, 1H), 4.21 (q, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H), 1.60 (d, 3H), 1.30 (t, 3H); LC-MS (ESI) m/z 470.2 [M+Na]⁺.

Example 242

{[(2-Propanyloxy)carbonyl]oxy}methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure H, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (168 mg, 0.507 mmol), K₂CO₃ (140 mg, 1.01 mmol), carbonic acid chloromethyl isopropyl ether (80.0 μL, 0.599 mmol), and DMF (1.0 mL) were used to carry out the reaction. The residue was purified by column chromatography (0-30% ethyl acetate in n-hexane) to give {[(2-propanyloxy)carbonyl]oxy}methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (169 mg, 74%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.90 (br s, 1H), 7.77 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 3H), 4.92 (septet, 1H), 4.00 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.31 (d, 6H); LC-MS (ESI) m/z 470.2 [M+Na]⁺.

Example 243

6-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-glucopyranose

Step 1. 1,2,3,4,6-Penta-O-trimethylsilyl-β-D-glucopyranose

To a solution of D-glucose (1.01 g, 4.50 mmol) in DMF (10 mL) was added chlorotrimethylsilane (4.50 mL, 35.5 mmol) and triethylamine (4.90 mL, 35.3 mmol) in ice-bath. After the solution was stirred at room temperature for 5 h, crushed ice and n-hexane were added to the reaction. The aqueous layer was extracted with n-hexane. The combined organic layers were dried over MgSO_4(s), filtered, concentrated, and dried under vacuum to obtain 1,2,3,4,6-penta-O-trimethylsilyl-3-D-glucopyranose (2.89 g, 91%) as a yellow oil. 1H NMR (CDCl₃, 400 MHz) δ 5.00 (d, 1H), 3.77 (t, 1H), 3.73-3.65 (m, 3H), 3.39 (t, 1H), 3.33 (dd, 1H), 0.19-0.09 (m, 45H).

Step 2. 1,2,3,4-Tetra-O-trmethylsilyl-β-D-glucopyranose

To a solution of 1,2,3,4,6-penta-O-trimethylsilyl-3-D-glucopyranose (1.43 g, 2.64 mmol) in methanol (10 mL) and CH₂Cl₂ (10 mL) was added ammonium acetate (0.410 g, 5.32 mmol). After the solution was stirred at room temperature for 30 h, the solvent was removed under reduced pressure. The residue was dissolved in n-hexane and washed with water. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The crude was purified by column chromatography (0-100% ethyl acetate in n-hexane) to give 1,2,3,4-tetra-O-trimethylsilyl-3-D-glucopyranose (0.730 g, 59%) as a yellow oil. 1H NMR (CDCl₃, 400 MHz) δ 5.00 (d, 1H), 3.81-3.67 (m, 4H), 3.44 (t, 1H), 3.33 (dd, 1H), 0.22-0.10 (m, 36H).

Step 3. 6-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,3,4-tetrakis-O-(trimethylsilyl)-D-glucopyranose

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (147 mg, 0.442 mmol), DMAP (135 mg, 1.11 mmol), EDCI • HCl (170 mg, 0.884 mmol), 1,2,3,4-tetra-O-trimethylsilyl-β-D-glucopyranose (228 mg, 0.486 mmol), and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-15% ethyl acetate in n-hexane) to give 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,3,4-tetrakis-O-(trimethylsilyl)-D-glucopyranose (289 mg, 84%) as a white foam. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.31-7.27 (m, 2H), 6.94 (br t, 2H), 6.10-5.80 (br, 1H), 5.00 (d, 1H), 4.55 (ddd, 1H), 4.23 (dt, 1H), 4.03-3.95 (m, 2H), 3.83-3.67 (m, 2H), 3.51-3.42 (m, 1H), 3.40-3.32 (m, 1H), 2.17 (br s, 3H), 0.22-0.06 (m, 36H).

Step 4. 6-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-glucopyranose

To a solution of 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,3,4-tetrakis-O-(trimethylsilyl)-D-glucopyranose (285 mg, 0.365 mmol) in CH₂Cl₂ (5.0 mL) was added trifluoroacetic acid (1.50 mL). After the solution was stirred at room temperature for 5 h, the solvent was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% methanol in CH₂Cl₂) to give 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-glucopyranose (104 mg, 58%) as a beige solid. 1H NMR (Acetone-d₆, 400 MHz) δ 7.81 (br s, 1H), 7.72 (br d, 1H), 7.55 (dd, 2H), 7.05 (t, 2H), 6.50-6.20 (br, 1H), 5.80-5.70 (br, 1H), 5.55 (br s, 1H), 5.09 (br s, 1H), 4.59-4.49 (m, 1H), 4.42-4.34 (m, 1H), 4.30 (br s, 1H), 4.10-4.05 (m, 2H), 4.02 (d, 1H), 3.89 (d, 1H), 3.69 (t, 1H), 3.42-3.30 (m, 2H), 2.19 (br s, 3H); LC-MS (ESI) m/z 516.2 [M+Na]⁺.

Example 244

6-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-galactopyranose

Step 1. 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,3,4-di-O-isopropylidene-D-galactopyranose

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (140 mg, 0.421 mmol), DMAP (129 mg, 1.05 mmol), EDCI • HCl (161 mg, 0.840 mmol), 1,2,3,4-di-O-isopropylidene-t-D-galactopyranose (121 mg, 0.463 mmol), and CH₂Cl₂ (2.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,3,4-di-O-isopropylidene-D-galactopyranose (174 mg, 72%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 6.10-5.70 (br, 1H), 5.54 (d, 1H), 4.63 (dd, 1H), 4.48 (dt, 1H), 4.39-4.32 (m, 2H), 4.28 (dd, 1H), 4.13 (t, 1H), 4.00 (d, 1H), 3.92 (d, 1H), 2.19 (br s, 3H), 1.46 (s, 3H), 1.43 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H).

Step 2. 6-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-galactopyranose

A solution of 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,3,4-di-O-isopropylidene-D-galactopyranose (172 mg, 0.299 mmol) in CH₂Cl₂ (2.0 mL) and trifluoroacetic acid (1.0 mL) was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-15% methanol in CH₂Cl₂) to give 6-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-galactopyranose (63.2 mg, 43%) as a beige solid. 1H NMR (CD₃OD-d₄, 300 MHz) δ 7.84 (br s, 1H), 7.76 (br s, 1H), 7.48-7.43 (m, 2H), 7.40-7.10 (br, 1H), 7.00 (br t, 2H), 6.50-6.10 (br, 1H), 5.14 (d, 1H), 4.46-4.31 (m, 3H), 4.08-3.75 (m, 4H), 3.49-3.47 (m, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 516.2 [M+Na]⁺.

Example 245

3-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-glucopyranose

Step 1. 3-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,5,6-di-O-isopropylidene-D-glucopyranose

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (174 mg, 0.526 mmol), DMAP (161 mg, 1.32 mmol), EDCI • HCl (202 mg, 1.052 mmol), 1,2,5,6-di-O-isopropylidene-α-D-glucofuranose (151 mg, 0.579 mmol), and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 3-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,5,6-di-O-isopropylidene-D-glucopyranose (214 mg, 71%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.83 (br s, 1H), 7.72 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (m, 2H), 5.44 (s, 1H), 4.55 (d, 1H), 4.28-4.27 (m, 2H), 4.13-4.03 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.21 (br s, 3H), 1.55 (s, 3H), 1.40 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H).

Step 2. 3-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-glucopyranose

A solution of 3-O-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-1,2,5,6-di-O-isopropylidene-D-glucopyranose (210 mg, 0.366 mmol) in CH₂Cl₂ (1.0 mL) and trifluoroacetic acid (1.0 mL) was stirred at room temperature for 48 h. The solvent was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% methanol in CH₂Cl₂) to give 3-O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-D-glucopyranose (90.6 mg, 51%) as a beige solid. 1H NMR (CD₃OD-d₄, 400 MHz) δ 7.89 (br s, 1H), 7.81 (br s, 1H), 7.45 (dd, 2H), 6.99 (br t, 2H), 6.50-6.10 (br, 1H), 5.41 (t, 1H), 5.20-5.10 (m, 1H), 4.05 (d, 1H), 3.97 (d, 1H), 3.91-3.54 (m, 4H), 3.42-3.38 (m, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 516.2 [M+Na]⁺.

Example 246

O-[4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl]-L-tyrosine

Step 1. 2-Methyl-2-propanyl N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate

To a solution of L-tyrosine tert-butyl ester (1.43 g, 2.64 mmol) in CH₂Cl₂ (5.0 mL) was added triethylamine (0.320 mL, 2.31 mmol) and di-tert-butyldicarbonate (0.303 g, 1.39 mmol) at 0° C. After the solution was stirred at room temperature for 18 h, the solution was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate (299 mg, 77%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.02 (d, 2H), 6.73 (d, 2H), 5.59 (br s, 1H), 5.00 (br d, 1H), 4.39 (q, 1H), 3.01-2.92 (m, 2H), 1.42 (s, 9H), 1.41 (s, 9H). Step 2. 2-Methyl-2-propanyl O-[4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl]-N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (164 mg, 0.496 mmol), DMAP (151 mg, 1.24 mmol), EDCI • HCl (190 mg, 0.991 mmol), 2-methyl-2-propanyl N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate (167 mg, 0.496 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl 0-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate (232 mg, 72%) as a beige solid. 1H NMR (CDCl₃, 400 MHz) δ 8.01 (br s, 1H), 7.89 (br s, 1H), 7.35-7.32 (m, 2H), 7.21 (d, 2H), 7.07 (d, 2H), 6.98 (t, 2H), 6.10-5.80 (br, 1H), 5.02 (d, 1H), 4.44 (q, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 3.06 (d, 2H), 2.23 (br s, 3H), 1.43 (s, 9H), 1.40 (s, 9H).

Step 3. 0-{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-L-tyrosine

A solution of 2-methyl-2-propanyl 0-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-N-{[(2-methyl-2-propanyl)oxy]carbonyl}-L-tyrosinate (119 mg, 0.182 mmol) in CH₂Cl₂ (3.0 mL) and trifluoroacetic acid (3.0 mL) was stirred at room temperature for 6 h. The solvent was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-20% methanol in CH₂Cl₂) to give O-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-L-tyrosine (67.7 mg, 75%) as a white solid. 1H NMR (CD₃OD-d₄, 400 MHz) δ 7.98 (br s, 1H), 7.89 (br s, 1H), 7.51-7.47 (m, 2H), 7.38 (d, 2H), 7.17 (d, 2H), 7.02 (t, 2H), 6.50-6.10 (br, 1H), 4.07 (d, 1H), 3.99 (d, 1H), 3.79 (dd, 1H), 3.35 (dd, 1H), 3.03 (dd, 1H), 2.22 (br s, 3H); LC-MS (ESI) m/z 495.3 [M+H]⁺.

Example 247

1-[(3-Pyridinylcarbonyl)amino]-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. N-(2-Hydroxypropyl)-3-pyridinecarboxamide

A solution of methyl nicotinate (1.03 g, 7.51 mmol) and DL-1-amino-2-propanol (0.590 mL, 7.54 mmol) in ethanol (8.0 mL) was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and ethanol was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-(2-hydroxypropyl)-3-pyridinecarboxamide (889 mg, 66%) as a lightly yellow oil. 1H NMR (CDCl₃, 400 MHz) δ 8.98 (d, 1H), 8.66 (dd, 1H), 8.13-8.09 (m, 1H), 7.35 (dd, 1H), 7.20 (br t, 1H), 4.04 (br quint, 1H), 3.70-3.62 (m, 1H), 3.59 (br s, 1H), 3.33-3.24 (m, 1H), 1.25 (d, 3H).

Step 2. 1-[(3-Pyridinylcarbonyl)amino]-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (485 mg, 1.46 mmol), DMAP (179 mg, 1.46 mmol), EDCI • HCl (421 mg, 2.20 mmol), N-(2-hydroxypropyl)-3-pyridinecarboxamide (277 mg, 1.54 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 20 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% methanol in CH₂Cl₂) to give 1-[(3-pyridinylcarbonyl)amino]-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (650 mg, 90%) as a lightly yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 8.93 (s, 1H), 8.70 (d, 1H), 8.05 (dt, 1H), 7.84 (br s, 1H), 7.73 (br s, 1H), 7.37-7.34 (m, 1H), 7.31 (dd, 2H), 6.95 (br t, 2H), 6.83 (br t, 1H), 5.95 (br, 1H), 5.33 (sextet, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 3.81-3.74 (m, 1H), 3.69-3.61 (m, 1H), 2.18 (br s, 3H), 1.35 (d, 3H); LC-MS (ESI) m/z 494.3 [M+H]⁺.

Example 248

3-{{2-([4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)propyl]carbamoyl}-1-methylpyridinium iodide

A solution of 1-[(3-pyridinylcarbonyl)amino]-2-propanyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.310 g, 0.628 mmol) and methyl iodide (0.140 mL, 2.25 mmol) in CH₂Cl₂ (6.0 mL) and acetonitrile (2.0 mL) was stirred in a closed system at room temperature for 24 h. Another portion of methyl iodide (0.140 mL, 2.25 mmol) was added to the reaction mixture and the reaction mixture was continually stirred for 48 h. The solvent was removed under reduced pressure and dried under high vacuum to give 3-{[2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)propyl]carbamoyl}-1-methylpyridinium iodide (399 mg, quantitative yield) as a yellow solid. 1H NMR (DMSO-d₆, 300 MHz) δ 9.35-9.20 (m, 2H), 9.01 (d, 1H), 8.79 (d, 1H), 8.16 (dd, 1H), 7.75 (br s, 1H), 7.68 (br s, 1H), 7.47 (dd, 2H), 7.09 (br t, 2H), 6.60-6.10 (br s, 1H), 5.20-5.16 (m, 1H), 4.34 (s, 3H), 4.06 (d, 1H), 3.90 (d, 1H), 2.13 (br s, 3H), 1.28 (d, 3H); LC-MS (ESI) m/z 508.3 [M]⁺.

Example 249

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzamide

Step 1. Synthesis of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoyl azide

To a solution of 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (200 mg, 0.58 mmol) and diphenylphosphorous azide (220 mg, 0.800 mmol) in THF (3 mL) was treated DIPEA (0.140 mL, 103.4 mg, 0.800 mmol) in one portion. The reaction mixture was stirred at r.t. for overnight then directly concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (150 mg, 73%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br d, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 5.96 (br s, 1H), 4.00 (d, 1H), 3.92 (d, 1H) 2.00 (br s, 3H).

Step 2. Synthesis of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzamide

To a solution of 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoyl azide (120 mg, 0.34 mmol) in 2 mL of co-solvent (ethanol: H₂O=3:1) was added zinc dust_(s) (39 mg, 0.6 mmol) in one portion at r.t. The reaction mixture was stirred at r.t. overnight then passed through a pad of celite. The filtrate was partitioned between ethyl acetate (50 mL) and H₂O (10 mL). The organic layer was washed with brine (10 mL), dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=6:1) to give the desired product as a yellow viscous liquid (45 mg, 0.14 mmol, 40%). ¹H NMR (CDCl₃, 400 MHz) δ 7.62 (br s, 1H), 7.47 (br s, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 6.03-5.80 (br, 2H), 5.67 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.18 (br s, 3H); LC-MS (ESI) m/z 331.9 [M+H]⁺.

Example 250

N-Methyl-4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzamide

The compound was prepared by following the standard procedure K with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol), HBTU (85.3 mg, 0.225 mmol), methylamine (40% in methanol, 0.500 mL), and DIPEA (0.052 mL, 38.7 mg, 0.300 mmol). After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by flash chromatography (dichloromethane:methanol=9:1) to give the desired product as a yellow viscous liquid (20.0 mg, 40%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.76 (br s, 1H), 7.31 (dd, 2H), 7.07-6.60 (br, 3H), 5.95 (br s, 1H), 5.88 (br s, 1H), 4.01 (d, 1H), 3.93 (d, 1H), 2.99 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 345.7 [M+H]⁺.

Example 251

4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-N,N,3-trimethylbenzamide

Step 1. Synthesis of 4-Amino-N,N,3-trimethylbenzamide

To a solution of 4-amino-3-methylbenzoic acid (1.00 g, 6.60 mmol), EDCI • HCl (1.89 g, 9.90 mmol), HOBt (1.34 g, 9.90 mmol), and dimethylamine hydrochloride (0.650 g, 7.90 mmol) in THF (12 mL) was treated DIPEA (4.00 mL, 2.89 g, 23.1 mmol) in one portion. The reaction mixture was stirred at r.t. overnight then partitioned between ethyl acetate (60 mL) and 5N NaOH (10 mL). The organic layer was washed with brine (10 mL) dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography to give the desired product as a brown viscous liquid (1.08 g, 92%). ¹H NMR (CDCl₃, 300 MHz) δ 7.19 (s, 1H), 7.14 (d, 1H), 6.63 (d, 1H), 3.77 (br s, 2H), 3.05 (s, 6H), 2.16 (s, 3H).

Step 2. Synthesis of 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-N,N,3-trimethylbenzamide

The compound was prepared by following the standard procedure A with 4-amino-N,N-trimethylbenzamide (200 mg, 1.12 mmol), 4-fluorobenzaldehyde (153 mg, 1.24 mmol), and 2-mercaptoacetic acid (0.140 mL, 181 mg, 1.97 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate) to give the desired product as a yellow viscous liquid (90.0 mg, 23%). ¹H NMR (CDCl₃, 300 MHz) δ 7.36-7.26 (m, 3H), 7.11 (br s, 1H), 6.96 (br t, 2H), 5.90 (br s, 1H), 4.02 (d, 1H), 3.90 (d, 1H), 3.10-2.83 (br, 6H), 2.17 (br s, 3H); LC-MS (ESI) m/z 359.2 [M+H]⁺.

Example 252

4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-N-propyl-benzamide

The compound was prepared by following the standard procedure K with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol), HBTU (85.3 mg, 0.225 mmol), propylamine (0.300 mmol, 17.7 mg), DIPEA (52.0 μL, 38.7 mg, 0.300 mmol), and CH₂Cl₂ (2.0 mL). After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate:hexane=2:1) to give the desired product as a yellow viscous liquid (36.0 mg, 64%). ¹H NMR (CDCl₃, 400 MHz) δ 7.55 (br s, 1H), 7.40 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.12 (br s, 1H), 5.88 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.35 (q, 2H), 2.16 (br s, 3H), 1.59 (sextet, 2H), 0.95 (t, 3H); LC-MS (ESI) m/z 373.9 [M+H]⁺.

Example 253

N-Ethyl-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzamide

To a solution of 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol) and ethylchloroformate (19.7 mg, 0.180 mmol) in tetrahydrofuran (0.5 mL) was treated DIPEA (34.0 μL, 25.0 mg, 0.195 mmol) in one portion. The reaction mixture was stirred at rt for 40 min then treated the solution of ethylamine (1.0 mL, 2 M) at room temperature. The reaction mixture was stirred at room temperature for 5 h then partitioned between CH₂Cl₂ (30 mL) and 2N HCl (10 mL). The organic layer was dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=5:2) to give the desired product as a yellow viscous liquid (39.0 mg, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 7.57 (br s, 1H), 7.40 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 5.96 (br s, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.44 (quint, 2H), 2.18 (br s, 3H), 1.23 (t, 3H); LC-MS (ESI) m/z 359.9 [M+H]⁺.

Example 254

N-Cyclopropyl-4-[2-(4-fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzamide

The compound was prepared by following the standard procedure K with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol), HBTU (85.3 mg, 0.225 mmol), cyclopropylamine (0.225 mmol, 12.8 mg), DIPEA (0.052 mL, 38.7 mg, 0.300 mmol), and CH₂Cl₂ (3.0 mL). After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate:hexane=2:1) to give the desired product as a yellow viscous liquid (50.0 mg, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 7.52 (br s, 1H), 7.39 (br s, 1H), 7.29 (dd, 2H), 6.94 (br t, 2H), 6.19 (br s, 1H), 5.90 (br s, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 2.85-2.75 (m, 1H), 2.16 (br s, 3H), 0.86-0.80 (m, 2H), 0.58-0.53 (m, 2H).

Example 255

N-Cyclobutyl-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.300 mmol), cyclobutanamine (28.0 μL, 0.330 mmol), HBTU (172 mg, 0.450 mmol), triethylamine (90.0 μL, 0.660 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane) to give N-cyclobutyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (87.0 mg, 75%). 1H NMR (CDCl₃, 400 MHz) δ 7.55 (br s, 1H), 7.43 (br s, 1H), 7.31-7.28 (m, 2H), 6.95 (dd, 2H), 6.14 (d, 1H), 5.98 (br s, 1H), 4.52 (sextet, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.43-2.36 (m, 2H), 2.20 (br s, 3H), 1.90 (quint, 2H), 1.78-1.67 (m, 2H); LC-MS (ACPI) m/z 385.6 [M+H]⁺.

Example 256

N-Cyclopentyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), cyclopentanamine (38.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give N-cyclopentyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (84.0 mg, 58%). 1H NMR (CDCl₃, 400 MHz) δ 7.53 (br s, 1H), 7.41 (br s, 1H), 7.29 (dd, 2H), 6.94 (dd, 2H), 6.10-5.80 (m, 2H), 4.32 (sextet, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 2.17 (br s, 3H), 2.10-2.01 (m, 2H), 1.75-1.55 (m, 4H), 1.50-1.38 (m, 2H); LC-MS (APCI) m/z 399.6 [M+H]⁺.

Example 257

N-Cyclohexyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), cyclohexanamine (45.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give N-cyclohexyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (70.0 mg, 47%). 1H NMR (CDCl₃, 400 MHz) δ 7.60-7.35 (m, 2H), 7.35-7.28 (m, 2H), 6.95 (dd, 2H), 6.10-5.80 (m, 2H), 4.00 (d, 1H), 3.91-3.87 (m, 2H), 2.23 (br s, 3H), 2.05-1.95 (m, 2H), 1.80-1.58 (m, 4H), 1.50-1.14 (m, 4H); LC-MS (ESI) m/z 413.8 [M+H]⁺.

Example 258

N-[2-(Dimethylamino)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), N,N-dimethylethane-1,2-diamine (36.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-[2-(dimethylamino)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (43.7 mg, 36%). 1H NMR (CDCl₃, 300 MHz) δ 7.62 (br s, 1H), 7.48 (br s, 1H), 7.32-7.26 (m, 2H), 6.95 (br s, 3H), 5.93 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.52-3.47 (m, 2H), 2.52 (t, 2H), 2.26 (br s, 6H), 2.19 (br s, 3H); LC-MS (ESI) m/z 402.1 [M+H]⁺.

Example 259

N-(2-(Diethylamino)ethyl)-4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzamide

To a solution of 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (87.0 mg, 0.260 mmol), EDCI (99.0 mg, 0.520 mmol), HOBt (35.0 mg, 0.260 mmol), and N,N-diethylethylenediamine (0.048 mL, 40.0 mg, 0.340 mmol) in CH₂Cl₂ (2.0 mL) was treated DIPEA (90.0 μL, 67.2 mg, 0.520 mmol) in one portion. The reaction mixture was stirred at r.t. for 5.5 h then partitioned between ethyl acetate (80 mL) and saturated NH₄Cl_(aq) (10 mL). The organic layer was washed with brine (10 mL) dried over MgSO₄ and concentrated to give a crude product which was purified by PLC (Alumium oxide) (eluent: ethyl acetate) to give the desired product as a yellow viscous liquid (29.0 mg, 26%). ¹H NMR (CD₃OD, 400 MHz) δ 7.62 (br s, 1H), 7.56 (br s, 1H), 7.46 (dd, 2H), 6.99 (br t, 2H), 6.19 (br s, 1H), 4.05 (br d, 1H), 3.96 (d, 1H), 3.44 (dd, 2H), 2.67-2.58 (m, 6H), 2.16 (br s, 3H), 1.06 (t, 6H); LC-MS (ESI) m/z 429.9 [M+H]⁺.

Example 260

N-[3-(Dimethylamino)propyl]-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), N,N-dimethylpropane-1,3-diamine (42.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give N-[3-(dimethylamino)propyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (21.7 mg, 17%). 1H NMR (CDCl₃, 400 MHz) δ 8.38 (br s, 1H), 7.63 (br s, 1H), 7.50 (br s, 1H), 7.31-7.27 (m, 2H), 6.94 (t, 2H), 5.90 (br s, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 3.49 (q, 2H), 2.58 (t, 2H), 2.35 (s, 6H), 2.18 (br s, 3H), 1.79 (quint, 2H); LC-MS (APCI) m/z 416.5 [M+H]⁺.

Example 261

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(3-methoxypropyl)-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), 3-methoxypropan-1-amine (34.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(3-methoxypropyl)-3-methylbenzamide (29.5 mg, 24%). 1H NMR (CDCl₃, 400 MHz) δ 7.56 (br s, 1H), 7.42 (br s, 1H), 7.31-7.27 (m, 2H), 6.94 (br t, 2H), 6.88 (br s, 1H), 5.95 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.57-3.48 (m, 4H), 3.34 (s, 3H), 2.16 (br s, 3H), 1.84 (quint, 2H); LC-MS (APCI) m/z 403.7 [M+H]⁺.

Example 262

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[2-(4-morpholinyl)ethyl]benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), 2-morpholinoethan-1-amine (44.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[2-(4-morpholinyl)ethyl]benzamide (28.5 mg, 21%). 1H NMR (CDCl₃, 400 MHz) δ 7.58 (br s, 1H), 7.52 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 6.71 (br s, 1H), 5.95 (br s, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.72-3.69 (m, 4H), 3.49 (br q, 2H), 2.56 (t, 2H), 2.48 (br s, 4H), 2.20 (br s, 3H); LC-MS (APCI) m/z 444.7 [M+H]⁺.

Example 263

N-(3-Aminopropyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Step 1. Synthesis of 2-methyl-2-propanyl [3-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}amino)propyl]carbamate

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.200 g, 0.604 mmol), ethyl carbonochloridate (64.0 μL, 0.665 mmol), triethylamine (0.170 mL, 1.21 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction was stirred for 1 h, tert-butyl (3-aminopropyl)carbamate (0.120 mL, 0.665 mmol) was added and then stirred at room temperature for 22 h and work up. The residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl [3-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}amino)propyl]carbamate (0.204 g, 69%). 1H NMR (CDCl₃, 400 MHz) δ 7.69 (br s, 1H), 7.52 (br s, 1H), 7.32-7.28 (m, 2H), 7.24 (br s, 1H), 6.95 (br t, 2H), 4.86 (br s, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.44 (q, 2H), 3.20 (br q, 2H), 2.20 (br s, 3H), 1.70-1.67 (m, 2H), 1.43 (s, 9H).

Step 2. Synthesis of N-(3-aminopropyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

The solution of 2-methyl-2-propanyl [3-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}amino)propyl]carbamate (0.150 g) and TFA (3.00 μL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 3 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH value to above 8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give N-(3-Aminopropyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (70.0 mg, 60%). 1H NMR (CDCl₃, 400 MHz) δ 7.57 (br s, 1H), 7.46 (br s, 1H), 7.30-7.28 (m, 3H), 6.91, (br s, 2H), 3.96 (d, 1H), 3.88 (d, 1H), 3.37-3.32 (m, 2H), 2.84 (t, 2H), 2.30-2.00 (br, 3H), 1.81 (quint, 2H); LC-MS (ESI) m/z 388.1 [M+H]⁺.

Example 264

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[3-(4-morpholinyl)propyl]benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), 3-morpholinopropan-1-amine (32.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[3-(4-morpholinyl)propyl]benzamide (21.4 mg, 16%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.63 (br s, 1H), 7.50 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.67 (br s, 4H), 3.50 (q, 2H), 2.55-2.50 (m, 6H), 2.19 (br s, 3H), 1.76 (quint, 2H); LC-MS (APCI) m/z 458.8 [M+H]⁺.

Example 265

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[3-(1H-imidazol-1-yl)propyl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), 3-(1H-imidazol-1-yl)propan-1-amine (40.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[3-(1H-imidazol-1-yl)propyl]-3-methylbenzamide (26.1 mg, 20%). 1H NMR (CDCl₃, 300 MHz) δ 7.54 (br s, 1H), 7.44-7.40 (m, 2H), 7.30 (dd, 2H), 7.01 (s, 1H), 7.00-6.90 (m, 3H), 6.73 (t, 1H), 5.90 (br s, 1H), 4.02-3.96 (m, 3H), 3.88 (d, 1H), 3.37 (q, 2H), 2.15 (br s, 3H), 2.09-2.03 (m, 2H); LC-MS (APCI) m/z 439.6 [M+H]⁺.

Example 266

3-(4-{[(3R)-3-(Dimethylamino)-1-pyrrolidinyl]carbonyl}-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.302 mmol), (R)—N,N-dimethylpyrrolidin-3-amine (41.0 μL, 0.332 mmol), HBTU (0.170 g, 0.453 mmol), triethylamine (93.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 3-(4-{[(3R)-3-(dimethylamino)-1-pyrrolidinyl]carbonyl}-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (97.3 mg, 75%). 1H NMR (CDCl₃, 400 MHz) δ 7.34 (br s, 0.4H), 7.31-7.28 (m, 2H), 7.20 (br s, 1.6H), 6.99 (br, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 3.87-3.72 (m, 1H), 3.60-3.49 (m, 1.5H), 3.43-3.35 (m, 1H), 3.26-3.21 (m, 0.5H), 2.78-2.58 (m, 1H), 2.29 (s, 3H), 2.25-2.17 (m, 6H), 2.20-2.03 (m, 1H), 1.84-1.76 (m, 1H); LC-MS (APCI) m/z 428.8 [M+H]⁺.

Example 267

Ethyl

4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}amino)-1-piperidinecarboxylate

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), ethyl 4-aminopiperidine-1-carboxylate (68.0 mg, 0.398 mmol), HBTU (0.210 g, 0.544 mmol), triethylamine (0.11 mL, 0.800 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}amino)-1-piperidinecarboxylate (90.0 mg, 51%). 1H NMR (CDCl₃, 400 MHz) δ 7.55 (br s, 1H), 7.47 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.12 (d, 1H), 5.95 (br s, 1H), 4.22-4.05 (m, 5H), 3.99 (d, 1H), 3.89 (d, 1H), 2.91 (br t, 2H), 2.17 (br s, 3H), 2.00-1.90 (m, 2H), 1.34 (qd, 2H), 1.25 (t, 3H); LC-MS (APCI) m/z 486.7 [M+H]⁺.

Example 268

3-[4-[(3-Amino-1-pyrrolidinyl)carbonyl]-2-methylphenyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Step 1. Synthesis of 2-methyl-2-propanyl (1-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-3-pyrrolidinyl)carbamate

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), triethylamine (84.0 μL, 0.604 mmol), ethyl chloroformate (36.0 mg, 0.332 mmol), CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction was stirred for 1 h, tert-butyl pyrrolidin-3-ylcarbamate (61.9 mg, 0.332 mmol) was added and then stirred at room temperature for 16 h and work up. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl (1-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-3-pyrrolidinyl)carbamate (33.6 mg, 22%). 1H NMR (CDCl₃, 400 MHz) δ 7.34 (br s, 1H), 7.31-7.27 (m, 2H), 7.26-7.40 (br, 2H), 6.96 (br t, 2H), 4.62-4.55 (br, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.78-3.63 (m, 2H), 3.49-3.41 (m, 2H), 3.26-3.20 (m, 1H), 2.22 (br s, 3H), 1.86 (br s, 1H), 1.45-1.41 (m, 9H).

Step 2. Synthesis of 3-[4-[(3-Amino-1-pyrrolidinyl)carbonyl]-2-methylphenyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

To a solution of 2-methyl-2-propanyl (1-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-3-pyrrolidinyl)carbamate (33.6 mg) and TFA (5.00 μL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 2 h. The reaction mixture was added saturated NaHCO_3(aq) to adjust the pH value to above 8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated. It was purified by Isco Combi-Flash Companion column chromatography (10% MeOH in CH₂Cl₂) to give 3-{4-[(3-amino-1-pyrrolidinyl)carbonyl]-2-methylphenyl}-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (17.6 mg, 66%). 1H NMR (CDCl₃, 400 MHz) δ 7.35 (br s, 0.4H), 7.29 (dd, 2H), 7.25-7.03 (br, 1.6H), 6.99 (br, 2H), 4.01 (d, 1H), 3.90 (d, 1H), 3.79-3.74 (m, 2H), 3.64-3.54 (m, 2H), 3.40-3.32 (m, 1.5H), 3.20-3.10 (br, 0.5H), 2.20-2.00 (br, 4H); LC-MS (APCI) m/z 400.6 [M+H]⁺.

Example 269

2-(4-Fluorophenyl)-3-[4-[(3-hydroxy-1-piperidinyl)carbonyl]-2-methylphenyl]-1,3-thiazolidin-4-one

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), piperidin-3-ol (33.6 mg, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-{4-[(3-hydroxy-1-piperidinyl)carbonyl]-2-methylphenyl}-1,3-thiazolidin-4-one (40.0 mg, 32%). 1H NMR (CDCl₃, 400 MHz) δ 7.31-7.28 (m, 3H), 7.10 (br s, 1H), 6.96 (br, 2H), 5.80 (br s, 1H), 4.02 (d, 1H), 3.92-3.88 (m, 2H), 3.70 (br s, 1H), 3.60-3.10 (br, 3H), 2.30-2.20 (br, 4H), 1.89 (br s, 2H), 1.74 (br s, 1H); LC-MS (APCI) m/z 415.7 [M+H]⁺.

Example 270

2-(4-Fluorophenyl)-3-[4-[(3-hydroxy-1-azetidinyl)carbonyl]-2-methylphenyl]-1,3-thiazolidin-4-one

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), azetidin-3-ol (25.6 mg, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.0 μL, 0.664 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-{4-[(3-hydroxy-1-azetidinyl)carbonyl]-2-methylphenyl}-1,3-thiazolidin-4-one (24.0 mg, 21%). 1H NMR (CDCl₃, 400 MHz) δ 7.52-7.41 (m, 2H), 7.31-7.27 (m, 3H), 6.95 (br t, 2H), 4.68 (br s, 1H), 4.42-4.38 (m, 2H), 4.14-4.09 (m, 1H), 4.03-3.99 (m, 2H), 3.91 (d, 1H), 2.20 (br s, 3H); LC-MS (APCI) m/z 387.8 [M+H]⁺.

Example 271

2-(4-Fluorophenyl)-3-(4-{[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}-2-methylphenyl)-1,3-thiazolidin-4-one

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), (S)-2-(methoxymethyl)pyrrolidine (41.0 μL, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.0 μL, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(4-{[(2S)-2-(methoxymethyl)-1-pyrrolidinyl]carbonyl}-2-methylphenyl)-1,3-thiazolidin-4-one (17.6 mg, 14%). 1H NMR (CDCl₃, 400 MHz) δ 7.38-7.20 (m, 5H), 6.96 (br, 2H), 4.38 (br s, 1H), 4.01 (d, 1H), 3.90 (d, 1H), 3.59 (br s, 2H), 3.37 (br s, 3H), 2.16 (br s, 3H), 2.05-1.85 (br, 4H), 1.75-1.52 (m, 2H); LC-MS (APCI) m/z 429.7 [M+H]⁺.

Example 272

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-N-(2-methoxyethyl)-N,3-dimethylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.302 mmol), 2-methoxy-N-methylethan-1-amine (36.0 μL, 0.332 mmol), HBTU (170 mg, 0.453 mmol), triethylamine (92.0 μL, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(2-methoxyethyl)-N,3-dimethylbenzamide (15.0 mg, 12%). 1H NMR (CDCl₃, 400 MHz) δ 7.31-7.27 (m, 3H), 7.16 (br s, 1H), 6.97-6.90 (br, 2H), 5.81 (br s, 1H), 4.01 (d, 1H), 3.89 (d, 1H), 3.70-3.60 (br, 2H), 3.42-3.30 (br, 4H), 3.24 (br s, 1H), 3.10-2.97 (br, 3H), 2.15 (br s, 3H); LC-MS (APCI) m/z 403.8 [M+H]⁺.

Example 273

3-[4-[(4-Amino-1-piperidinyl)carbonyl]-2-methylphenyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Step 1. Synthesis of 2-methyl-2-propanyl (1-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-4-piperidinyl)carbamate

Following standard procedure E, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (130 mg, 0.393 mmol), triethylamine (0.110 mL, 0.785 mmol), ethyl chloroformate (46.0 mg, 0.431 mmol), CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction was stirred for 1 h, tert-butyl piperidin-4-ylcarbamate (87.0 mg, 0.431 mmol) was added and then stirred at room temperature for 16 h and work up. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-methyl-2-propanyl (1-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-4-piperidinyl)carbamate (96.0 mg, 48%). 1H NMR (CDCl₃, 400 MHz) δ 7.31-7.27 (m, 2H), 7.21-7.19 (br, 1H), 7.12-7.09 (br, 1H), 7.03-6.96 (m, 2H), 4.51-4.46 (m, 4H), 4.06 (d, 1H), 3.94 (d, 1H), 3.78-3.64 (m, 4H), 3.03-2.91 (br, 1H), 2.20 (br s, 3H), 1.44 (s, 9H).

Step 2. Synthesis of 3-[4-[(4-amino-1-piperidinyl)carbonyl]-2-methylphenyl]-2-(4-fluorophenyl)-1, 3-thiazolidin-4-one

The solution of (1-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}-4-piperidinyl)carbamate (90.0 mg) and TFA (5.00 μL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 2 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH value to above 8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (15% MeOH in CH₂Cl₂) to give 3-{4-[(4-amino-1-piperidinyl)carbonyl]-2-methylphenyl}-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (6.80 mg, 9%). 1H NMR (CDCl₃, 400 MHz) δ 7.31-7.28 (m, 2H), 7.22 (br s, 1H), 7.08 (br s, 1H), 6.95 (br s, 2H), 4.51 (br s, 1H), 3.95 (d, 1H), 3.89 (d, 1H), 3.64 (br s, 1H), 3.06-2.97 (br, 2H), 2.84 (br s, 1H), 2.24 (br s, 5H), 1.92 (br s, 2H), 1.76 (br s, 2H); LC-MS (ACPI) m/z 414.5 [M+H]⁺.

Example 274

N-(Adamantan-1-yl)-4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzamide

The compound was prepared by following the standard procedure K with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol), HBTU (85.3 mg, 0.225 mmol), 1-adamantamine (27.2 mg, 0.180 mmol), DIPEA (52.0 μL, 38.7 mg, 0.300 mmol), and CH₂Cl₂ (3.0 mL). After the reaction mixture was stirred for 16 h and work-up, the residue was purified by recrystallization to give the desired product as a white solid (50.0 mg, 72%). 1H NMR (CDCl₃, 300 MHz) δ 7.51 (br s, 1H), 7.38 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 5.90 (br s, 1H), 5.66 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 2.28-2.00 (br, 9H), 1.80 (br s, 3H), 1.70 (br s, 6H); LC-MS (ESI) m/z 465.9 [M+H]⁺.

Example 275

N-(Adamantan-1-ylmethyl)-4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzamide

The compound was prepared by following the standard procedure K with 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (50.0 mg, 0.150 mmol), HBTU (85.3 mg, 0.225 mmol), 1-adamantanemethylamine (24.9 mg, 0.150 mmol), DIPEA (52.0 μL, 38.7 mg, 0.300 mmol), and CH₂Cl₂ (9.0 mL). After the reaction mixture was stirred for 16 h and work-up, the residue was purified by flash chromatography (ethyl acetate:hexane=1:1) to give the desired product as a yellow viscous liquid (48.0 mg, 67%). ¹H NMR (CDCl₃, 400 MHz) δ 7.56 (br s, 1H), 7.43 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.20-5.70 (br, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.20-3.00 (m, 2H), 2.19 (br s, 3H), 1.98 (br s, 3H), 1.73-1.58 (m, 6H), 1.51 (s, 6H); LC-MS (ESI) m/z 479.9 [M+H]⁺.

Example 276

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-phenylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (85.3 mg, 0.257 mmol), aniline (26.3 mg, 0.283 mmol), triethylamine (80.0 μL, 0.569 mmol), HBTU (146 mg, 0.386 mmol), and CH₂Cl₂ (6.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 15 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-phenylbenzamide (40.5 mg, 39%) as a beige solid. 1H NMR (CDCl₃, 400 MHz) δ 7.77 (s, 1H), 7.70-7.45 (m, 4H), 7.39-7.32 (m, 4H), 7.16 (t, 1H), 7.01-6.96 (m, 3H), 6.10-5.70 (br, 1H), 4.04 (d, 1H), 3.95 (d, 1H), 2.22 (br s, 3H); LC-MS (ESI) m/z 407.3 [M+H]⁺.

Example 277

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-N-(4-methoxyphenyl)-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (150 mg, 0.450 mmol), 4-methoxyaniline (60.0 mg, 0.490 mmol), HBTU (260 mg, 0.680 mmol), triethylamine (0.300 mL, 1.00 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the resulting residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(4-methoxyphenyl)-3-methylbenzamide (73.0 mg, 37%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (s, 1H), 7.60 (br s, 1H), 7.56-7.51 (m, 3H), 7.32-7.27 (m, 2H), 6.98 (t, 2H), 6.88-6.85 (m, 2H), 5.99 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.80 (s, 3H), 2.17 (br s, 3H); LC-MS (APCI) m/z 437.8 [M+H]⁺.

Example 278

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(4-methylphenyl)benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (110 mg, 0.330 mmol), p-toluidine (39.0 mg, 0.370 mmol), HBTU (189 mg, 0.500 mmol), triethylamine (0.100 mL, 0.730 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(4-methylphenyl)benzamide (46.0 mg, 33%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 8.15 (br s, 1H), 7.53 (br s, 1H), 7.47 (d, 2H), 7.43-7.39 (m, 2H), 7.27 (t, 2H), 7.12 (d, 2H), 6.93 (t, 2H), 5.95 (br s, 1H), 3.99 (d, 1H), 3.89 (d, 1H), 2.31 (s, 3H), 2.09 (br s, 3H); LC-MS (APCI) m/z 421.6 [M+H]⁺.

Example 279

N-(4-Fluorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (150 mg, 0.450 mmol), 4-fluoroaniline (48.0 μL, 0.500 mmol), HBTU (260 mg, 0.680 mmol), triethylamine (0.140 mL, 1.00 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(4-fluorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (190 mg, 98%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.95 (br s, 1H), 7.60-7.50 (m, 2H), 7.46 (br s, 1H), 7.30 (dd, 2H), 7.07-7.01 (m, 2H), 6.96 (t, 2H), 5.95 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.07 (br s, 3H); LC-MS (APCI) m/z 425.7 [M+H]⁺.

Example 280

N-(4-Chlorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (150 mg, 0.450 mmol), 4-chloroaniline (63.0 μL, 0.500 mmol), HBTU (260 mg, 0.680 mmol), triethylamine (0.140 mL, 0.100 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(4-chlorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (193 mg, 78%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.98 (s, 1H), 7.57-7.51 (m, 2H), 7.45 (br s, 1H), 7.31-7.28 (m, 4H), 6.96 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.13 (br s, 3H); LC-MS (APCI) m/z 441.9 [M+H]⁺.

Example 281

N-(3-Fluorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 3-fluoroaniline (48.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(3-fluorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (33.0 mg, 21%). 1H NMR (CDCl₃, 400 MHz) δ 7.99 (s, 1H), 7.58 (br s, 1H), 7.54 (dd, 1H), 7.46 (br s, 1H), 7.35-7.22 (m, 4H), 6.96 (t, 2H), 6.84 (t, 1H), 5.97 (br s, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 2.16 (br s, 3H); LC-MS (APCI) m/z 425.6 [M+H]⁺.

Example 282

N-(3-Chlorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 3-chloroaniline (42.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give N-(3-chlorophenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (13.0 mg, 8%). 1H NMR (CDCl₃, 400 MHz) δ 7.98 (s, 1H), 7.68 (d, 1H), 7.57 (br s, 1H), 7.48 (d, 1H), 7.40-7.22 (m, 4H), 7.11 (d, 1H), 6.96 (t, 2H), 5.99 (br s, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 2.15 (br s, 3H); LC-MS (APCI) m/z 441.5 [M+H]⁺.

Example 283

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-N-(3-methoxyphenyl)-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 3-methoxyaniline (44.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(3-methoxyphenyl)-3-methylbenzamide (82.0 mg, 52%). 1H NMR (CDCl₃, 400 MHz) δ 7.90 (br s, 1H), 7.60 (br s, 1H), 7.48 (br s, 1H), 7.36 (t, 1H), 7.30 (dd, 2H), 7.26-7.20 (m, 1H), 7.06 (dd, 1H), 6.96 (dd, 2H), 6.67 (dd, 1H), 5.95 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.80 (s, 3H), 2.17 (br s, 3H); LC-MS (ESI) m/z 437.6 [M+H]⁺.

Example 284

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[4-(trifluoromethyl)phenyl]benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 4-(trifluoromethyl)aniline (50.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[4-(trifluoromethyl)phenyl]benzamide (21.0 mg, 12%). 1H NMR (CDCl₃, 400 MHz) δ 8.43 (s, 1H), 7.74 (d, 2H), 7.58 (d, 2H), 7.52 (br s, 1H), 7.41 (br s, 1H), 7.28 (dd, 2H), 6.94 (dd, 2H), 5.95 (br s, 1H), 4.01 (d, 1H), 3.91 (d, 1H), 2.07 (br s, 3H); LC-MS (APCI) m/z 475.8 [M+H]⁺.

Example 285

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(3-methylphenyl)benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), m-toluidine (43.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(3-methylphenyl)benzamide (88.0 mg, 58%). 1H NMR (CDCl₃, 400 MHz) δ 7.76 (br s, 1H), 7.63 (br s, 1H), 7.49 (br s, 1H), 7.43 (s, 1H), 7.37-7.30 (m, 3H), 7.25-7.20 (m, 2H), 7.03-6.95 (m, 3H), 5.95 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.35 (s, 3H), 2.20 (br s, 3H); LC-MS (ACPI) m/z 421.7 [M+H]⁺.

Example 286

N-(3,5-Dimethylphenyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.300 mmol), 3,5-dimethylaniline (40.0 μL, 0.330 mmol), HBTU (172 mg, 0.450 mmol), triethylamine (90.0 μL, 0.660 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give N-(3,5-dimethylphenyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (62.0 mg, 47%). 1H NMR (CDCl₃, 400 MHz) δ 7.98 (br s, 1H), 7.56 (br s, 1H), 7.45 (br s, 1H), 7.30-7.26 (m, 2H), 6.95 (dd, 2H), 6.77 (br s, 1H), 5.97 (br s, 1H), 3.99 (d, 1H), 3.89 (d, 1H), 2.28 (s, 6H), 2.12 (br s, 3H); LC-MS (ACPI) m/z 435.7 [M+H]⁺.

Example 287

N-(2,3-Dihydro-1H-inden-5-yl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.300 mmol), 2,3-dihydro-1H-inden-5-amine (44.0 mg, 0.330 mmol), HBTU (172 mg, 0.450 mmol), and triethylamine (90.0 μL, 0.660 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane) to give N-(2,3-dihydro-1H-inden-5-yl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (39.0 mg, 40%). 1H NMR (CDCl₃, 400 MHz) δ 7.73 (s, 1H), 7.63 (br s, 1H), 7.52 (s, 1H), 7.33-7.29 (m, 2H), 7.23 (dd, 1H), 7.17 (d, 1H), 6.97 (t, 2H), 6.20-5.70 (br, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 2.92-2.84 (m, 4H), 2.21 (br s, 3H), 2.10-2.04 (m, 2H); LC-MS (ACPI) m/z 447.6 [M+H]⁺.

Example 288

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(2-methoxyphenyl)-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (100 mg, 0.300 mmol) was added 2-methoxyaniline (44.0 mg, 0.330 mmol), HBTU (172 mg, 0.450 mmol), triethylamine (90.0 μL, 0.660 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-(2-methoxyphenyl)-3-methylbenzamide (39.0 mg, 40%). 1H NMR (CDCl₃, 400 MHz) δ 8.43 (d, 1H), 8.39 (s, 1H), 7.69 (br s, 1H), 7.59 (br s, 1H), 7.35-7.30 (m, 2H), 7.07 (dd, 1H), 7.03-6.95 (m, 3H), 6.89 (d, 1H), 5.95 (br s, 1H), 4.02 (d, 1H), 3.92-3.84 (m, 4H), 2.20 (br s, 3H); LC-MS (ACPI) m/z 437.8 [M+H]⁺.

Example 289

N-Benzyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (82.1 mg, 0.248 mmol), benzyl amine (30.0 μL, 0.274 mmol), diisopropylethylamine (64.1 mg, 0.496 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 141 mg, 0.372 mmol), and CH₂Cl₂ (6.0 mL) were use to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-90% ethyl acetate in n-hexane) to give N-benzyl-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (47.9 mg, 46%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.65-7.40 (br, 2H), 7.37-7.28 (m, 8H), 6.95 (br t, 2H), 6.26 (br t, 1H), 6.20-5.80 (br, 1H), 4.60 (d, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 421.3 [M+H]⁺.

Example 290

N-(4-Chloro-2-fluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), (4-chloro-2-fluorophenyl)methanamine (50.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane, 5% MeOH in CH₂Cl₂) to give N-(4-chloro-2-fluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (977 mg, 57%). 1H NMR (CDCl₃, 400 MHz) δ 7.57 (br s, 1H), 7.45 (br s, 1H), 7.34-7.25 (m, 3H), 7.11-7.07 (m, 3H), 6.95 (t, 2H), 6.44 (br s, 1H), 5.93 (br s, 1H), 4.58 (d, 2H), 3.99 (d, 1H), 3.90 (d, 1H), 2.17 (br s, 3H); LC-MS (APCI) m/z 473.6 [M+H]⁺.

Example 291

N-(2,5-Difluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), (2,5-difluorophenyl)methanamine (40.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane, 5% MeOH in CH₂Cl₂) to give N-(2,5-difluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (0.120 g, 73%). 1H NMR (CDCl₃, 400 MHz) δ 7.58 (br s, 1H), 7.45 (br s, 1H), 7.30-7.28 (m, 2H), 7.10-6.85 (m, 6H), 6.56 (br s, 1H), 5.91 (br s, 1H), 4.58 (d, 2H), 3.99 (d, 1H), 3.90 (d, 1H), 2.17 (br s, 3H); LC-MS (APCI) m/z 457.7 [M+H]⁺.

Example 292

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[3-(trifluoromethyl)benzyl]benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 3-(trifluoromethyl)benzylamine (69.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[3-(trifluoromethyl)benzyl]benzamide (120 mg, 79%). 1H NMR (CDCl₃, 400 MHz) δ 7.60-7.37 (m, 7H), 7.29-7.26 (m, 2H), 6.93 (t, 2H), 6.84 (t, 1H), 5.90 (br s, 1H), 4.56 (d, 2H), 3.97 (d, 1H), 3.87 (d, 1H), 2.10 (br s, 3H); LC-MS (ACPI) m/z 489.7 [M+H]⁺.

Example 293

N-(3,4-Difluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), (3,4-difluorophenyl)methanamine (57.0 mg, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(3,4-difluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (100 mg, 60%). 1H NMR (CDCl₃, 400 MHz) δ 7.58 (br s, 1H), 7.46 (br s, 1H), 7.31-7.26 (m, 2H), 7.12 (dd, 3H), 7.03 (br s, 1H), 6.95 (t, 2H), 6.44 (br s, 1H), 5.92 (br s, 1H), 4.52 (d, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.18 (br s, 3H); LC-MS (ACPI) m/z 457.8 [M+H]⁺.

Example 294

N-(3,4-Dichlorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), (3,4-dichlorophenyl)methanamine (53.0 mg, 0.400 mmol), HBTU (210 mg, 0.540 mmol), and triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(3,4-dichlorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (130 mg, 73%). 1H NMR (CDCl₃, 400 MHz) δ 7.51 (br s, 1H), 7.43-7.32 (m, 3H), 7.28-7.25 (m, 2H), 7.14-7.07 (m, 2H), 6.98 (t, 1H), 6.92 (t, 2H), 5.90 (br s, 1H), 4.42 (d, 2H), 3.96 (d, 1H), 3.86 (d, 1H), 2.07 (br s, 3H); LC-MS (ACPI) m/z 490.6 [M+H]⁺.

Example 295

N-(3,5-Dimethoxybenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), (3,5-dimethoxyphenyl)methanamine (60.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(3,5-dimethoxybenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (110 mg, 63%). 1H NMR (CDCl₃, 400 MHz) δ 7.59 (br s, 1H), 7.46 (br s, 1H), 7.31-7.27 (m, 2H), 6.95 (t, 2H), 6.45 (d, 2H), 6.38 (t, 1H), 6.29 (t, 1H), 5.95 (br s, 1H), 4.52 (d, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.78 (s, 6H), 2.18 (br s, 3H); LC-MS (ACPI) m/z 481.6 [M+H]⁺.

Example 296

N-(3,5-Difluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), (3,5-difluorophenyl)methanamine (57.0 mg, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-(3,5-difluorobenzyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (120 mg, 73%). 1H NMR (CDCl₃, 300 MHz) δ 7.60 (br s, 1H), 7.48 (br, 1H), 7.32-7.27 (m, 2H), 6.96 (t, 2H), 6.88-6.79 (m, 2H), 6.75-6.64 (m, 1H), 6.50 (t, 1H), 5.93 (br s, 1H), 4.57 (d, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.18 (br s, 3H); LC-MS (ACPI) m/z 457.7 [M+H]⁺.

Example 297

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methyl-N-(1-naphthalenylmethyl)benzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 1-naphthalenemethylamine (60.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane, 5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(1-naphthalenylmethyl)benzamide (60.0 mg, 31%). 1H NMR (CDCl₃, 400 MHz) δ 8.03 (d, 1H), 7.89 (dd, 1H), 7.84 (d, 1H), 7.56-7.49 (m, 3H), 7.48-7.42 (m, 2H), 7.30-7.22 (m, 3H), 6.93 (t, 2H), 6.26 (br s, 1H), 5.92 (br s, 1H), 5.03 (d, 2H), 3.97 (d, 1H), 3.88 (d, 1H), 2.14 (br s, 3H); LC-MS (APCI) m/z 471.6 [M+H]⁺.

Example 298

N-[2-(2-Fluorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 2-(2-fluorophenyl)ethanamine (50.0 mg, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-[2-(2-fluorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (120 mg, 73%). 1H NMR (CDCl₃, 400 MHz) δ 7.51 (br s, 1H), 7.38 (br s, 1H), 7.30-7.27 (m, 2H), 7.23-7.19 (m, 2H), 7.09-7.01 (m, 2H), 6.95 (t, 2H), 6.14 (br s, 1H), 5.90 (br s, 1H), 3.99 (d, 1H), 3.90 (d, 1H), 3.65 (q, 2H), 2.93 (t, 2H), 2.16 (br s, 3H); LC-MS (ACPI) m/z 453.8 [M+H]⁺.

Example 299

N-[2-(2-Chlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 2-(2-chlorophenyl)ethanamine (62.0 mg, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-[2-(2-chlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (110 mg, 65%). 1H NMR (CDCl₃, 400 MHz) δ 7.52 (br s, 1H), 7.40-7.38 (m, 2H), 7.35-7.27 (m, 2H), 7.25-7.16 (m, 3H), 6.95 (t, 2H), 6.12 (br s, 1H), 5.90 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.68 (q, 2H), 3.04 (t, 2H), 2.17 (br s, 3H); LC-MS (ACPI) m/z 469.6 [M+H]⁺.

Example 300

N-[2-(3-Fluorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 2-(3-fluorophenyl)ethanamine (52.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give N-[2-(3-fluorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (93.0 mg, 57%). 1H NMR (CDCl₃, 400 MHz) δ 7.50 (br s, 1H), 7.36 (br s, 1H), 7.31-7.24 (m, 4H), 6.98-6.90 (m, 4H), 6.03 (br s, 1H), 5.95 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.65 (q, 2H), 2.89 (t, 2H), 2.17 (br s, 3H); LC-MS (ACPI) m/z 453.7 [M+H]⁺.

Example 301

N-[2-(3-Chlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 2-(3-chlorophenyl)ethanamine (55.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-[2-(3-chlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (55.0 mg, 33%). 1H NMR (CDCl₃, 400 MHz) δ 7.50 (br s, 1H), 7.39 (br s, 1H), 7.32-7.27 (m, 2H), 7.24-7.20 (m, 3H), 7.08 (dt, 1H), 6.95 (t, 2H), 6.05 (br t, 1H), 5.95 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 3.63 (q, 2H), 2.86 (t, 2H), 2.17 (br s, 3H); LC-MS (APCI) m/z 469.6 [M+H]⁺.

Example 302

N-[2-(4-Fluorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.360 mmol), 2-(4-fluorophenyl)ethan-1-amine (52.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give N-[2-(4-fluorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (25.0 mg, 15%). 1H NMR (CDCl₃, 400 MHz) δ 7.48 (br s, 1H), 7.40-7.26 (m, 3H), 7.17-7.12 (m, 2H), 7.00-6.92 (m, 4H), 6.18 (br t, 1H), 5.90 (br s, 1H), 3.98 (d, 1H), 3.89 (d, 1H), 3.60 (q, 2H), 2.84 (t, 2H), 2.14 (br s, 3H); LC-MS (APCI) m/z 453.8 [M+H]⁺.

Example 303

N-[2-(4-Chlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.300 mmol), 2-(4-chlorophenyl)ethan-1-amine (46.0 μL, 0.330 mmol), HBTU (0.170 g, 0.450 mmol), triethylamine (93.0 μL, 0.670 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give N-[2-(4-chlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (72.0 mg, 51%). 1H NMR (CDCl₃, 400 MHz) δ 7.48 (br s, 1H), 7.40-7.25 (m, 5H), 7.11 (d, 2H), 6.94 (t, 2H), 6.17 (br t, 1H), 5.95 (br s, 1H), 3.98 (d, 1H), 3.89 (d, 1H), 3.59 (q, 2H), 2.84 (t, 2H), 2.15 (br s, 3H); LC-MS (APCI) m/z 469.6 [M+H]⁺.

Example 304

N-[2-(2, 4-Dichlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide

Following standard procedure K, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (120 mg, 0.360 mmol), 1-(2,4-dichloro-phenyl)-ethylamine (60.0 μL, 0.400 mmol), HBTU (210 mg, 0.540 mmol), triethylamine (0.110 mL, 0.790 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (5% MeOH in CH₂Cl₂) to give N-[2-(2,4-dichlorophenyl)ethyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (14.0 mg, 8%). 1H NMR (CDCl₃, 400 MHz) δ 7.52 (br s, 1H), 7.38 (s, 2H), 7.30 (dd, 2H), 7.20-7.14 (m, 2H), 6.97 (t, 2H), 6.08 (br s, 1H), 5.91 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.65 (q, 2H), 3.01 (t, 2H), 2.17 (br s, 3H); LC-MS (APCI) m/z 504.7 [M+H]⁺.

Example 305

Oxydi-2,1-ethanediyl bis{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate}

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (270 mg, 0.815 mmol), DMAP (398 mg, 3.26 mmol), EDCI • HCl (469 mg, 2.45 mmol), diethylene glycol (43.2 mg, 0.408 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-65% ethyl acetate in n-hexane) to give oxydi-2,1-ethanediyl bis {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate} (137 mg, 46%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 2H), 7.71 (br d, 2H), 7.30 (dd, 4H), 6.94 (br t, 4H), 6.10-5.80 (br, 2H), 4.43-4.41 (m, 4H), 4.01 (d, 2H), 3.93 (d, 2H), 3.82-3.79 (m, 4H), 2.17 (br s, 6H); LC-MS (ESI) m/z 755.3 [M+Na]⁺.

Example 306

{2-(4-Fluorophenyl)-3-[4-(methoxycarbonyl)-2-methylphenyl]-4-oxo-1,3-thiazolidin-5-yl}acetic acid

Step 1. Methyl 4-{[(E)-(4-fluorophenyl)methylidene]amino}-3-methylbenzoate

A solution of methyl 4-amino-3-methylbenzene carboxylate (1.68 g, 10.2 mmol) and 4-fluorobenzaldehyde (1.39 g, 11.2 mmol) in ethanol (12 mL) was reflux for 20 h. Ethanol was removed under reduced pressure and dried under high vacuum. The crude solids were washed with n-hexane to give methyl 4-{[(E)-(4-fluorophenyl)methylidene]amino}-3-methylbenzoate (2.77 g, 100%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 8.31 (s, 1H), 7.95-7.91 (m, 3H), 7.18 (t, 2H), 6.91 (d, 1H), 3.91 (s, 3H), 2.36 (s, 3H).

Step 2. [2-(4-fluorophenyl)-3-[4-(methoxycarbonyl)-2-methylphenyl]-4-oxo-1, 3-thiazolidin-5-yl]acetic acid

To a solution of methyl 4-{[(E)-(4-fluorophenyl)methylidene]amino}-3-methylbenzoate (1.43 g, 2.64 mmol) in toluene (5.0 mL) was added DL-mercaptosuccinic acid (0.320 mL, 2.31 mmol). The solution was reflux for 16 h and cooled to room temperature. The solution was diluted with ethyl acetate and washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% methanol in CH₂Cl₂) to give {2-(4-fluorophenyl)-3-[4-(methoxycarbonyl)-2-methylphenyl]-4-oxo-1,3-thiazolidin-5-yl}acetic acid (206 mg, 44%) as a white solid. 1H NMR (CDCl₃, 300 MHz) δ 7.84 (br s, 1H), 7.77 (br s, 1H), 7.33-7.27 (m, 2H), 6.94 (br t, 2H), 6.00 (br s, 1H), 4.60-4.42 (br, 1H), 3.90 (s, 3H), 3.30-3.00 (br, 2H), 2.15 (br s, 3H); LC-MS (ESI) m/z 404.2 [M+H]⁺.

Example 307

Ethyl 4-[5-(2-ethoxy-2-oxoethyl)-2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

A solution of {2-(4-fluorophenyl)-3-[4-(methoxycarbonyl)-2-methylphenyl]-4-oxo-1,3-thiazolidin-5-yl}acetic acid (1.43 g, 2.64 mmol) in concentrated HCl_(aq) (0.50 mL) and ethanol (4.0 mL) was reflux for 16 h and cooled to room temperature. Ethanol was removed under reduced pressure. The residue was treated with water and extracted with ethyl acetate. The organic layers were washed with water and brine, dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-25% ethyl acetate in n-hexane) to give ethyl 4-[5-(2-ethoxy-2-oxoethyl)-2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (47.9 mg, 47%) as a colorless gum. 1H NMR (CDCl₃, 300 MHz) δ 7.90-7.70 (br, 2H), 7.32 (dd, 2H), 6.93 (t, 2H), 6.20-5.90 (br, 1H), 4.55-4.42 (br, 1H), 4.32 (q, 2H), 4.23 (q, 2H), 3.15 (br s, 2H), 2.14 (br s, 3H), 1.37-1.25 (m, 6H); LC-MS (ESI) m/z 446.3 [M+H]⁺.

Example 308

3-(5-Fluoro-2-methyphenylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one 1,1-dioxide

To a solution of 3-(5-fluoro-2-methylphenyl)-2-(4-fluorophenyl)thiazolidin-4-one (60.0 mg, 0.200 mmol) in 1 mL of acetic acid was added H₂O_2(aq) (30%) (0.300 mL, 2.60 mmol) in one portion at r.t. The reaction mixture was stirred at 65° C. overweekend then partitioned between ethyl acetate (20 mL) and saturated NaHCO_3(aq) (10 mL). The organic layer was washed with brine (5 mL), dried over MgSO₄ and concentrated to give a crude product which was purified by flash chromatography (ethyl acetate:hexane=1:2) to give the desired product as a yellow viscous liquid (47.0 mg, 69%). ¹H NMR (CDCl₃, 400 MHz) δ 7.38 (dd, 2H), 7.24 (dd, 1H), 7.17 (br t, 2H), 6.96 (td, 1H), 6.67 (dd, 1H), 5.75 (br s, 1H), 4.13-4.00 (m, 2H), 2.31 (s, 3H).

Example 309

3-(3,4-Dimethyl-1,2-oxazol-5-yl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure A, 5-amino-3,4-dimethylisoxazole (0.254 g, 2.26 mmol), 4-fluorobenzaldehyde (0.562 g, 4.53 mmol), Na₂SO₄ (0.321 g, 2.26 mmol), 2-mercaptoacetic acid (0.320 mL, 4.58 mmol), and toluene (6.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. After work-up, the residue was purified by column chromatography (40% ethyl acetate in n-hexane) to give 3-(3,4-dimethyl-1,2-oxazol-5-yl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (44.3 mg, 7%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.37 (dd, 2H), 7.00 (t, 2H), 6.16 (s, 1H), 3.90 (s, 2H), 2.11 (s, 3H), 1.75 (s, 3H); LC-MS (ESI) m/z 293.2 [M+H]⁺.

Example 310

2-(4-Fluorophenyl)-3-(5-methyl-1,2-oxazol-4-yl)-1,3-thiazolidin-4-one

Following standard procedure A, 5-methylisoxazol-3-amine (0.500 g, 5.20 mmol), 4-fluorobenzaldehyde (0.840 mL, 7.80 mmol), Na₂SO₄ (0.730 g, 5.20 mmol), 2-mercaptoacetic acid (0.730 mL, 10.4 mmol) and toluene (10.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. The reaction mixture was treated with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(5-methyl-1,2-oxazol-4-yl)-1,3-thiazolidin-4-one (0.420 g, 29%). 1H NMR (DMSO-d₆, 400 MHz) δ 7.42-7.37 (m, 2H), 7.13 (dd, 2H), 6.79 (s, 1H), 6.40 (s, 1H), 4.10 (d, 1H), 3.83 (d, 1H), 2.33 (s, 3H); LC-MS (APCI) m/z 279.0 [M+H]⁺.

Example 311

2-(3,5-Difluorophenyl)-3-(1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3,5-difluorobenzaldehyde (35.5 mg, 0.25 mmol), 4-aminoantipyrine (55.8 mg, 0.280 mmol), and 2-mercaptoacetic acid (21.0 μL, 27.0 mg, 0.300 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a yellow viscous liquid (48.9 mg, 49%). ¹H NMR (CDCl₃, 400 MHz) δ 7.43 (t, 2H), 7.30 (t, 1H), 7.24-7.21 (m, 2H), 6.97-6.92 (m, 2H), 6.73 (tt, 1H), 6.45 (s, 1H), 3.85 (s, 2H), 3.02 (s, 3H), 2.02 (s, 3H); LC-MS (ESI) m/z 402.8 [M+H]⁺.

Example 312

2-(2,4-Difluorophenyl)-3-(1, 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2,4-difluorobenzaldehyde (71.0 mg, 0.500 mmol), 4-aminoantipyrine (102 mg, 0.500 mmol), and 2-mercaptoacetic acid (42.0 μL, 55.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a yellow viscous liquid (179 mg, 89%). ¹H NMR (CDCl₃, 400 MHz) δ 7.41 (t, 2H), 7.36-7.26 (m, 2H), 7.23 (d, 2H), 6.81-6.75 (m, 2H), 6.56 (s, 1H), 3.93 (d, 1H), 3.79 (d, 1H), 3.02 (s, 3H), 2.03 (s, 3H); LC-MS (ESI) m/z 402.9 [M+H]⁺.

Example 313

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-(methylthi)phenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-methylthiobenzaldehyde (76.0 mg, 0.500 mmol), 4-aminoantipyrine (102 mg, 0.500 mmol), and 2-mercaptoacetic acid (42.0 μL, 55.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a yellow viscous liquid (153 mg, 75%). ¹H NMR (CDCl₃, 400 MHz) δ 7.41 (t, 2H), 7.33-7.20 (m, 5H), 7.13 (d, 2H), 6.41 (s, 1H), 3.88 (d, 1H), 3.82 (d, 1H), 2.99 (s, 3H), 2.45 (s, 3H), 1.97 (s, 3H); LC-MS (ESI) m/z 412.8 [M+H]⁺.

Example 314

4-(3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxothiazolidin-2-yl)benzonitrile

The compound was prepared by following the standard procedure A with 4-cyanobenzaldehyde (65.6 mg, 0.500 mmol), 4-aminoantipyrine (102 mg, 0.500 mmol), and 2-mercaptoacetic acid (42.0 μL, 55.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane ethanol=30:1) to give the desired product as a yellow viscous liquid (149 mg, 76%). ¹H NMR (CDCl₃, 300 MHz) δ 7.58 (d, 2H), 7.52 (d, 2H), 7.42 (t, 2H), 7.30 (t, 1H), 7.21 (d, 2H), 6.54 (s, 1H), 3.92-3.80 (m, 2H), 3.01 (s, 3H), 2.02 (s, 3H); LC-MS (ESI) m/z 391.9 [M+H]⁺.

Example 315

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-methoxyphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-methoxybenzaldehyde (68.0 mg, 0.500 mmol), 4-aminoantipyrine (102 mg, 0.500 mmol), and 2-mercaptoacetic acid (42.0 μL, 55.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a yellow viscous liquid (108 mg, 55%). ¹H NMR (CDCl₃, 400 MHz) δ 7.41 (t, 2H), 7.33 (d, 2H), 7.28 (t, 1H), 7.21 (d, 2H), 6.79 (dd, 2H), 6.37 (s, 1H), 3.88 (d, 1H), 3.81 (d, 1H), 3.77 (s, 3H), 2.97 (s, 3H), 1.94 (s, 3H); LC-MS (ESI) m/z 396.9 [M+H]⁺.

Example 316

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-ethylphenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-ethybenzaldehyde (67.0 mg, 0.500 mmol), 4-aminoantipyrine (102 mg, 0.500 mmol), and 2-mercaptoacetic acid (42.0 μL, 55.0 mg, 0.600 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane ethanol=30:1) to give the desired product as a yellow viscous liquid (153 mg, 78%). ¹H NMR (CDCl₃, 300 MHz) δ 7.41 (t, 2H), 7.32-7.27 (m, 3H), 7.24-7.20 (m, 2H), 7.10 (d, 2H), 6.39 (s, 1H), 3.92-3.80 (m, 2H), 2.96 (s, 3H), 2.60 (q, 2H), 1.95 (s, 3H), 1.19 (t, 3H); LC-MS (ESI) m/z 394.9 [M+H]⁺.

Example 317

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-(trifluoromethyl)phenyl)thiazolidin-4-on

The compound was prepared by following the standard procedure A with 4-trifluoromethylbenzaldehyde (174 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a yellow viscous liquid (300 mg, 69%). ¹H NMR (CDCl₃, 300 MHz) δ 7.57-7.51 (m, 4H), 7.42 (t, 2H), 7.30 (t, 1H), 7.19 (d, 2H), 6.55 (s, 1H), 3.92-3.80 (m, 2H), 3.00 (s, 3H), 2.01 (s, 3H); LC-MS (ESI) m/z 434.9 [M+H]⁺.

Example 318

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 3-fluorobenzaldehyde (124 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a white solid (310 mg, 81%). ¹H NMR (CDCl₃, 400 MHz) δ 7.42 (t, 2H), 7.29 (t, 1H), 7.25-7.16 (m, 4H), 7.15 (dd, 1H), 6.98 (td, 1H), 6.43 (s, 1H), 3.88 (d, 1H), 3.84 (d, 1H), 2.99 (s, 3H), 1.99 (s, 3H); LC-MS (ESI) m/z 384.9 [M+H]⁺.

Example 319

2-(4-(tert-butyl)phenyl)-3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-tert-butlybenzaldehyde (162 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a yellow viscous liquid (330 mg, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 7.43 (t, 2H), 7.34-7.27 (m, 5H), 7.23 (dd, 2H), 6.40 (s, 1H), 3.88 (s, 2H), 2.98 (s, 3H), 1.96 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 422.9 [M+H]⁺.

Example 320

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 2-fluorobenzaldehyde (124 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=30:1) to give the desired product as a white viscous liquid (212 mg, 55%). ¹H NMR (CDCl₃, 400 MHz) δ 7.41 (t, 2H), 7.33 (td, 1H), 7.31-7.22 (m, 4H), 7.07-7.00 (m, 2H), 6.58 (s, 1H), 3.96 (d, 1H), 3.79 (d, 1H), 3.00 (s, 3H), 2.02 (s, 3H); LC-MS (ESI) m/z 384.9 [M+H]⁺.

Example 321

2-(4-Bromophenyl)-3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-bromobenzaldehyde (185 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:2) to give the desired product as a white viscous liquid (404 mg, 91%). ¹H NMR (CDCl₃, 400 MHz) δ 7.44-7.39 (m, 4H), 7.32-7.27 (m, 3H), 7.21 (d, 2H), 6.43 (s, 1H), 3.88 (d, 1H), 3.82 (d, 1H), 3.00 (s, 3H), 1.99 (s, 3H); LC-MS (ESI) m/z 444.8 [M+H]⁺.

Example 322

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-phenylthiazolidin-4-one

The compound was prepared by following the standard procedure A with benzaldehyde (106 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:2) to give the desired product as a white viscous liquid (292 mg, 80%). ¹H NMR (CDCl₃, 400 MHz) δ 7.43-7.38 (m, 4H), 7.30-7.26 (m, 4H), 7.20 (d, 2H), 6.42 (s, 1H), 3.89 (d, 1H), 3.85 (d, 1H), 2.95 (s, 3H), 1.95 (s, 3H); LC-MS (ESI) m/z 366.9 [M+H]⁺.

Example 323

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-(dimethylamino)phenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-dimethylbenzaldehyde (149 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (ethyl acetate:hexane=3:2) to give the desired product as a yellow viscous liquid (230 mg, 56%). ¹H NMR (CDCl₃, 400 MHz) δ 7.41 (t, 2H), 7.29-7.22 (m, 5H), 6.59 (d, 2H), 6.32 (s, 1H), 3.87 (d, 1H), 3.81 (d, 1H), 2.96 (s, 3H), 2.92 (s, 6H), 1.95 (s, 3H); LC-MS (ESI) m/z 409.9 [M+H]⁺.

Example 324

2-(4-Chlorophenyl)-3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-chlorobenzaldehyde (141 mg, 1.00 mmol), 4-aminoantipyrine (203 mg, 1.00 mmol), and 2-mercaptoacetic acid (83.0 μL, 110 mg, 1.20 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane:ethanol=20:1) to give the desired product as a white solid (160 mg, 40%). ¹H NMR (CDCl₃, 300 MHz) δ 7.42 (t, 2H), 7.39-7.19 (m, 7H), 6.44 (s, 1H), 3.94-3.78 (m, 2H), 2.99 (s, 3H), 1.98 (s, 3H); LC-MS (ESI) m/z 400.9 [M+H]⁺.

Example 325

3-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(4-fluorophenyl)thiazolidin-4-one

The compound was prepared by following the standard procedure A with 4-fluorobenzaldehyde (122 mg, 0.980 mmol), 4-aminoantipyrine (200 mg, 0.980 mmol), and 2-mercaptoacetic acid (70.0 μL, 92.8 mg, 1.00 mmol). It was reflux 6 h for the first step and 18 h for the second step. After work-up, the crude product was purified by flash chromatography (dichloromethane ethanol=8:1) to give the desired product as a white solid (246 mg, 64%). ¹H NMR (CDCl₃, 400 MHz) δ 7.44-7.38 (m, 4H), 7.29 (t, 1H), 7.20 (d, 2H), 6.96 (t, 2H), 6.44 (s, 1H), 3.89 (d, 1H), 3.82 (d, 1H), 2.98 (s, 3H), 1.96 (s, 3H); LC-MS (ESI) m/z 384.9 [M+H]⁺.

Example 326

Methyl 4-[2-(5-fluoro-2-pyridinyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure A, 5-methylisoxazol-3-amine (0.330 g, 1.99 mmol), 5-fluoropicolinaldehyde (0.500 mL, 2.99 mmol), Na₂SO₄ (0.280 g, 1.99 mmol), 2-mercaptoacetic acid (0.280 mL, 3.99 mmol) and toluene (15.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. The reaction mixture was treated with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 4-[2-(5-fluoro-2-pyridinyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.226 g, 33%). 1H NMR (CDCl₃, 400 MHz) δ 8.41 (br s, 1H), 7.89 (br s, 1H), 7.72 (br d, 1H), 7.32 (td, 1H), 7.21 (dd, 1H), 6.91 (br s, 1H), 5.89 (br s, 1H), 4.16 (d, 1H), 3.86 (s, 3H), 3.80 (d, 1H), 2.29 (br s, 3H); LC-MS (APCI) m/z 347.9 [M+H]⁺.

Example 327

Methyl 4-(2-cyclohexyl-4-oxo-1,3-thiazolidin-3-yl)-3-methylbenzoate

Following standard procedure A, methyl 4-amino-3-methylbenzoate (0.500 g, 3.03 mmol), cyclohexanecarbaldehyde (0.550 mL, 4.54 mmol), Na₂SO₄ (0.450 g, 3.03 mmol), 2-mercaptoacetic acid (0.420 mL, 6.05 mmol) and toluene (10.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. The reaction mixture was treated with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane and 20% acetone in n-hexane) to give methyl 4-(2-cyclohexyl-4-oxo-1,3-thiazolidin-3-yl)-3-methylbenzoate (10.3 mg, 33%). 1H NMR (CDCl₃, 400 MHz) δ 7.99 (br s, 1H), 7.93-7.91 (m, 1H), 7.16 (br s, 1H), 4.64 (br s, 1H), 3.91 (s, 3H), 3.71 (d, 1H), 3.58 (d, 1H), 2.30 (s, 3H), 1.85-1.34 (m, 9H), 1.27-1.23 (m, 2H); LC-MS (APCI) m/z 334.9 [M+H]⁺.

Example 328

Methyl 3-methyl-4-[4-oxo-2-(2-pentanyl)-1,3-thiazolidin-3-yl]benzoate

Following standard procedure A, methyl 4-amino-3-methylbenzoate (0.500 g, 3.03 mmol), 2-methylpentanal (0.550 mL, 4.54 mmol), Na₂SO₄ (0.450 g, 3.03 mmol), 2-mercaptoacetic acid (0.420 mL, 6.05 mmol) and toluene (10.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. The reaction mixture was treated with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (100% n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(2-pentanyl)-1,3-thiazolidin-3-yl]benzoate (76.1 mg, 8%). 1H NMR (CDCl₃, 300 MHz) δ 7.99 (br s, 1H), 7.91 (d, 1H), 7.25-7.10 (m, 1H), 4.80-4.70 (br d, 1H), 3.90 (s, 3H), 3.72 (d, 1H), 3.61 (d, 1H), 2.30 (s, 3H), 1.78 (br s, 1H), 1.53-1.06 (m, 4H), 1.00-0.78 (m, 6H); LC-MS (APCI) m/z 322.8 [M+H]⁺.

Example 329

Methyl 3-methyl-4-[2-(2-methylpropyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate

Following standard procedure A, methyl 4-amino-3-methylbenzoate (0.500 g, 3.03 mmol), 3-methylbutanal (0.490 mL, 4.54 mmol), Na₂SO₄ (0.450 g, 3.03 mmol), 2-mercaptoacetic acid (0.420 mL, 6.05 mmol) and toluene (10.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. The reaction mixture was treated with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (30% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[2-(2-methylpropyl)-4-oxo-1,3-thiazolidin-3-yl]benzoate (0.100 g, 11%). 1H NMR (CDCl₃, 400 MHz) δ 7.99 (d, 1H), 7.91 (dd, 1H), 7.18 (d, 1H), 5.19 (br s, 0.6H), 4.82 (br s, 0.4H), 3.91 (s, 3H), 3.73-3.70 (m, 2H), 2.15 (s, 3H), 1.76-1.40 (m, 3H), 0.90-0.82 (m, 3H), 0.76 (d, 3H); LC-MS (ESI) m/z 308.1 [M+H]⁺.

Example 330

Methyl 4-[2-(3-furanyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure A, methyl 4-amino-3-methylbenzoate (0.500 g, 3.03 mmol), furan-3-carbaldehyde (0.390 mL, 4.54 mmol), Na₂SO₄ (0.450 g, 3.03 mmol), 2-mercaptoacetic acid (0.420 mL, 6.05 mmol) and toluene (10.0 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. The reaction mixture was treated with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane) to give methyl 4-[2-(3-furanyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (13.0 mg, 1%). 1H NMR (CDCl₃, 300 MHz) δ 7.91 (br s, 1H), 7.81 (d, 1H), 7.33 (br s, 1H), 7.27 (s, 1H), 7.02 (br s, 1H), 6.37 (br s, 1H), 5.97 (br s, 1H), 4.00-3.84 (m, 5H), 2.20 (br s, 3H); LC-MS (APCI) m/z 318.8 [M+H]⁺.

Example 331

3-Benzyl-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

To a solution of 4-fluorobenzaldehyde (0.530 mL, 4.90 mmol) in CH₂Cl₂ (10.0 mL) was added phenylmethanamine (0.500 g, 4.67 mmol), 2-mercaptoacetic acid (0.650 mL, 9.33 mmol) and silica gel (2.30 g) at room temperature, and it was stirred for 16 h. After the reaction was quenched with water and extracted with ethyl acetate, the combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3-benzyl-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (0.880 g, 66%). 1H NMR (CDCl₃, 400 MHz) δ 7.29-7.25 (m, 3H), 7.22-7.18 (m, 2H), 7.13-7.03 (m, 4H), 5.38 (d, 1H), 5.12 (d, 1H), 3.90 (d, 1H), 3.77 (d, 1H), 3.53 (d, 1H); LC-MS (ACPI) m/z 288.8 [M+H]⁺.

Example 332

4-{[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]methyl}benzoic acid

Step 1. Synthesis of methyl 4-(aminomethyl)benzoate

To a solution of 4-(aminomethyl)benzoic acid (0.500 g, 3.31 mmol) in methanol (15.0 mL) was added concentrated HCl_(aq) (0.8 mL). After the reaction mixture was reflux for overnight and cooled to room temperature, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO_4(s), filtered, and concentrated to give a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (100% ethyl acetate and 15% MeOH in CH₂Cl₂) to give methyl 4-(aminomethyl)benzoate (200 mg, 37%). 1H NMR (CDCl₃, 400 MHz) δ 7.98 (d, 2H), 7.36 (d, 2H), 3.91 (s, 2H), 3.88 (s, 3H).

Step 2. Synthesis of methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]methyl}benzoate

To a solution of 4-fluorobenzaldehyde (0.140 mL, 1.27 mmol) in CH₂Cl₂ (5.0 mL) was added methyl 4-(aminomethyl)benzoate (200 mg, 1.20 mmol), thiogly acid (0.160 mL, 2.42 mmol) and silica gel (0.600 g) at room temperature, and it was stirred for 16 h. After the reaction was quenched with water and extracted with ethyl acetate, the combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]methyl}benzoate (170 mg, 31%). 1H NMR (CDCl₃, 400 MHz) δ 7.95 (dd, 2H), 7.21-7.16 (m, 2H), 7.12 (d, 2H), 7.08-7.03 (m, 2H), 5.36 (s, 1H), 5.09 (d, 1H), 3.95-3.88 (m, 4H), 3.81 (d, 1H), 3.64 (d, 1H).

Step 3. 4-{[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]methyl}benzoic acid

Following standard procedure B, methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]methyl}benzoate (180 mg) in methanol (5.0 mL) and 20% NaOH_(aq) (2.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 2 h and work-up. The residue purified by Isco Combi-Flash Companion column chromatography (4% MeOH in CH₂Cl₂) to give 4-{[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]methyl}benzoic acid (90.0 mg, 53%). 1H NMR (CDCl₃, 400 MHz) δ 8.04 (d, 2H), 7.23-7.17 (m, 4H), 7.09-7.05 (m, 2H), 5.39 (s, 1H), 5.13 (d, 1H), 3.93 (d, 1H), 3.82 (d, 1H), 3.68 (d, 1H); LC-MS (ESI) m/z 332.9 [M+H]⁺.

Example 333

3-[(5-Fluoro-2-methylphenyl)sulfonyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Step 1. 2-(4-Fluorophenyl)-1,3-thiazolidin-4-one

A solution of 4-fluorobenzaldehyde (0.680 g, 5.48 mmol), 2-mercaptoacetic acid (0.480 mL, 7.10 mmol), and ammonium carbonate (2.74 g, 28.5 mmol) in toluene (18 mL) was reflux for 18 h and cooled to room temperature. Toluene was removed under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-1,3-thiazolidin-4-one (0.520 g, 48%) as a lightly yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.41-7.38 (m, 2H), 7.07 (t, 2H), 6.93 (br s, 1H), 5.77 (s, 1H), 3.67 (s, 2H).

Step 2. 3-[(5-Fluoro-2-methylphenyl)sulfonyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Following standard procedure I, 2-(4-fluorophenyl)-1,3-thiazolidin-4-one (110 mg, 0.559 mmol), triethylamine (0.120 mL, 0.866 mmol), DMAP (6.8 mg, 0.557 mmol), and 5-fluoro-2-methyl benzene sulfonyl chloride (175 mg, 0.839 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3-[(5-fluoro-2-methylphenyl)sulfonyl]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (58.7 mg, 28%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.74 (dd, 1H), 7.41 (dd, 2H), 7.31-7.21 (m, 2H), 7.11 (t, 2H), 6.29 (s, 1H), 3.86 (d, 1H), 3.51 (d, 1H), 2.60 (s, 3H); LC-MS (ESI) m/z 370.1 [M+H]⁺.

Example 334

Methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]sulfonyl}benzoate

Following standard procedure I, 2-(4-fluorophenyl)-1,3-thiazolidin-4-one (111 mg, 0.564 mmol), triethylamine (0.120 mL, 0.866 mmol), DMAP (6.9 mg, 0.564 mmol), and methyl 4-(chlorosulfonyl)benzene (132 mg, 0.564 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred for 6 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]sulfonyl}benzoate (8.5 mg, 4%) as a beige solid. 1H NMR (CDCl₃, 300 MHz) δ 8.05 (d, 2H), 7.70 (d, 2H), 7.26-7.20 (m, 2H), 7.02 (t, 2H), 6.28 (s, 1H), 3.96 (s, 3H), 3.86 (d, 1H), 3.70 (d, 1H); LC-MS (ESI) m/z 396.1 [M+H]⁺.

Example 335

2-(4-Fluorophenyl)-3-[(2-methylphenyl)sulfonyl]-1,3-thiazolidin-4-one

Following standard procedure I, 2-(4-fluorophenyl)-1,3-thiazolidin-4-one (119 mg, 0.603 mmol), triethylamine (0.125 mL, 0.902 mmol), DMAP (7.4 mg, 0.603 mmol), and O-toluenesulfonyl chloride (127 mg, 0.664 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred for 6 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-100% CH₂Cl₂ in n-hexane) to give 2-(4-fluorophenyl)-3-[(2-methylphenyl)sulfonyl]-1,3-thiazolidin-4-one (67.5 mg, 32%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.07 (d, 1H), 7.54 (td, 1H), 7.44-7.31 (m, 4H), 7.10 (t, 2H), 6.32 (s, 1H), 3.84 (d, 1H), 3.48 (d, 1H), 2.65 (s, 3H); LC-MS (ESI) m/z 374.1 [M+Na]⁺.

Example 336

Methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]amino}-3-methylbenzoate

Step 1. Methyl 4-hydrazinyl-3-methylbenzoate hydrochloride

To a solution of methyl 4-amino-3-methylbenzene carboxylate (1.02 g, 6.17 mmol) in concentrated HCl_(aq) (6.0 mL) and water (2.0 mL) was added a solution of sodium nitrite (0.640 g, 9.28 mmol) in water (2.0 mL) slowly at 0° C. After the reaction mixture was stirred at 0° C. for 1 h, a solution of tin(II) chloride (3.51 g, 18.5 mmol) in concentrated HCl_(aq) (3.0 mL) was added. The solution was stirred for another 3 h at room temperature. The solids were collected by filtration and washed with cold water and n-hexane to give methyl 4-hydrazinyl-3-methylbenzoate hydrochloride (0.980 g, 73%) as a lightly yellow solid. 1H NMR (DMSO-d₆, 300 MHz) δ 8.50-8.10 (br, 1H), 7.77 (d, 1H), 7.69 (s, 1H), 6.90 (d, 1H), 3.76 (s, 3H), 2.18 (s, 3H).

Step 2. Methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]amino}-3-methylbenzoate

A solution of methyl 4-hydrazinyl-3-methylbenzoate hydrochloride (0.190 g, 1.06 mmol), 4-fluorobenzaldehyde (0.140 mL, 1.30 mmol), and Na₂SO₄ (0.150 g, 1.06 mmol) in toluene (3.0 mL) was reflux for 18 h. The solution was filtered off, and the filtrate was concentrated to obtain methyl 4-[2-(4-fluorobenzylidene)hydrazinyl]-3-methylbenzoate. A solution of previously prepared compound in 2-mercaptoacetic acid (1.0 mL) was stirred at 60° C. for 3 h and cooled to room temperature. The solution was quenched with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-{[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]amino}-3-methylbenzoate (16.2 mg, 4%) as a yellow gum. 1H NMR (CDCl₃, 400 MHz) δ 7.84 (d, 1H), 7.74 (s, 1H), 7.32 (dd, 2H), 7.08 (t, 2H), 6.69 (d, 1H), 5.72 (s, 1H), 3.96-3.80 (m, 5H), 1.99 (s, 3H); LC-MS (ESI) m/z 361.2 [M+H]⁺.

Example 337

3-[(5-Fluoro-2-methylphenyl)amino]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

Step 1. (5-Fluoro-2-methylphenyl)hydrazine hydrochloride

To a solution of 2-methyl-5-fluoroaniline (1.31 g, 10.5 mmol) in concentrated HCl_(aq) (12 mL) was added a solution of sodium nitrite (1.08 g, 15.7 mmol) in water (4.0 mL) slowly at 0° C. After the reaction mixture was stirred at 0° C. for 1 h, a solution of tin(II) chloride (5.97 g, 31.5 mmol) in concentrated HCl_(aq) (6.0 mL) was added. The solution was stirred for another 2 h at room temperature. The solids were collected by filtration and washed with cold water and n-hexane to give (5-fluoro-2-methylphenyl)hydrazine hydrochloride (1.34 g, 72%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 10.26 (br s, 2H), 8.06 (br s, 1H), 7.11 (dd, 1H), 6.75 (dd, 1H), 6.66 (ddd, 1H), 2.11 (s, 3H).

Step 2. 3-[(5-Fluoro-2-methylphenyl)amino]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

To a solution of (5-fluoro-2-methylphenyl)hydrazine hydrochloride (0.410 g, 2.93 mmol) in toluene (4.0 mL) was added 4-fluorobenzaldehyde (0.380 mL, 3.52 mmol) and Na₂SO₄ (0.420 g, 2.93 mmol). The reaction was stirred at 70° C. for 2 h. The solvent was removed to obtain N-(4-fluoro-benzylidene)-N′-(5-fluoro-2-methylphenyl)hydrazine. A solution of previously prepared compound in 2-mercaptoacetic acid (3.0 mL) was stirred at 60° C. for 5 h and cooled to room temperature. The solution was quenched with saturated NaHCO_3(aq) and extracted with ethyl acetate. The organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 3-[(5-fluoro-2-methylphenyl)amino]-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (195 mg, 21%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.34-7.30 (m, 2H), 7.08 (t, 2H), 6.97 (dd, 1H), 6.58-6.53 (m, 1H), 6.42 (dd, 1H), 5.71 (s, 1H), 5.59 (br s, 1H), 3.87 (d, 1H), 3.81 (d, 1H), 1.91 (s, 3H); LC-MS (ESI) m/z 321.2 [M+H]⁺.

Example 338

(2Z)-3-(5-Fluoro-2-methylphenyl)-2-[(4-fluorophenyl)imino]-1, 3-thiazolidin-4-one

Step 1. 2-Chloro-N-(5-fluoro-2-methylphenyl) acetamide

A solution of 2-methyl-5-fluoroaniline (0.880 g, 7.03 mmol) and chloroacetyl chloride (1.12 mL, 14.1 mmol) in THF (10 mL) was stirred at room temperature for 20 h. The solvent was concentrated and dried under high vacuum to give 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide (1.46 g, 100%) as a gray solid. 1H NMR (CDCl₃, 400 MHz) δ 8.30 (br s, 1H), 7.86 (dd, 1H), 7.14 (dd, 1H), 6.81 (td, 1H), 4.24 (s, 2H), 2.27 (s, 3H); LC-MS (ESI) m/z 224.0 [M+Na]⁺.

Step 2. (2Z)-3-(5-Fluoro-2-methylphenyl)-2-[(4-fluorophenyl)imino]-1, 3-thiazolidin-4-one

Following standard procedure J, 2-chloro-N-(5-fluoro-2-methylphenyl)acetamide (271 mg, 1.35 mmol), 60% NaH in mineral oil (59.2 mg, 1.48 mmol), and 4-fluorophenyl isothiocyanate (217 mg, 1.41 mmol) were used to carry out the reaction. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give (2Z)-3-(5-fluoro-2-methylphenyl)-2-[(4-fluorophenyl)imino]-1,3-thiazolidin-4-one (211 mg, 49%) as an orange solid. 1H NMR (CDCl₃, 400 MHz) δ 7.32 (dd, 1H), 7.09 (td, 1H), 7.03-6.98 (m, 3H), 6.86 (dd, 2H), 4.02 (s, 2H), 2.23 (s, 3H); LC-MS (ESI) m/z 319.0 [M+H]⁺.

Example 339

Methyl 4-{(2Z)-2-[(4-fluorophenyl)imino]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate

Step 1. Methyl 4-[(chloroacetyl)amino]-3-methylbenzoate

A solution of methyl 4-amino-3-methylbenzene carboxylate (1.01 g, 6.11 mmol) and chloroacetyl chloride (0.980 mL, 6.11 mmol) in THF (10 mL) was stirred at room temperature for 20 h. The solvent was concentrated and dried under high vacuum to give methyl 4-[(chloroacetyl)amino]-3-methylbenzoate (1.48 g, 100%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.42 (br s, 1H), 8.19 (d, 1H), 7.94-7.91 (m, 2H), 4.26 (s, 2H), 3.91 (s, 3H), 2.37 (s, 3H); LC-MS (ESI) m/z 264.0 [M+Na]⁺.

Step 2. Methyl 4-{(2Z)-2-[(4-fluorophenyl)imino]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate

Following standard procedure J, methyl 4-[(chloroacetyl)amino]-3-methylbenzoate (282 mg, 1.17 mmol), 60% NaH in mineral oil (51.6 mg, 1.29 mmol), and 4-fluorophenyl isothiocyanate (188 mg, 1.23 mmol) were used to carry out the reaction. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-{(2Z)-2-[(4-fluorophenyl)imino]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate (244 mg, 55%) as a yellow solid. 1H NMR (CDCl₃, 300 MHz) δ 8.06 (s, 1H), 8.01 (dd, 1H), 7.32 (d, 1H), 7.00 (t, 2H), 6.88-6.83 (m, 2H), 4.04 (s, 2H), 3.92 (s, 3H), 2.32 (s, 3H); LC-MS (ESI) m/z 359.2 [M+H]⁺.

Example 340

(2Z)-2-[(4-Fluorophenyl)imino]-3-(4-methoxyphenyl)-1,3-thiazolidin-4-one

Step 1. 2-Chloro-N-(4-methoxyphenyl)acetamide

A solution of para-anisidine (1.01 g, 6.11 mmol) and chloroacetyl chloride (0.980 mL, 6.11 mmol) in THF (10 mL) was stirred at room temperature for 18 h. The solvent was concentrated and dried under high vacuum to give 2-chloro-N-(4-methoxyphenyl)acetamide (1.68 g, 100%) as a purple solid. 1H NMR (CDCl₃, 400 MHz) δ 8.14 (br s, 1H), 7.44 (d, 2H), 6.89 (d, 2H), 4.22 (s, 2H), 3.80 (s, 3H).

Step 2. (2Z)-2-[(4-Fluorophenyl)imino]-3-(4-methoxyphenyl)-1,3-thiazolidin-4-one

Following standard procedure J, 2-chloro-N-(4-methoxyphenyl)acetamide (243 mg, 1.22 mmol), 60% NaH in mineral oil (58.6 mg, 1.47 mmol), and 4-fluorophenyl isothiocyanate (196 mg, 1.28 mmol) were used to carry out the reaction. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give (2Z)-2-[(4-fluorophenyl)imino]-3-(4-methoxyphenyl)-1,3-thiazolidin-4-one (208 mg, 54%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.28 (d, 2H), 7.04-6.98 (m, 4H), 6.89-6.85 (m, 2H), 3.98 (s, 2H), 3.83 (s, 3H); LC-MS (ESI) m/z 317.2 [M+H]⁺.

Example 341

(2Z)-3-(3-Chlorophenyl)-2-[(4-fluorophenyl)imino]-1,3-thiazolidin-4-one

Step 1. 2-Chloro-N-(3-chlorophenyl)acetamide

A solution of 2-chloroaniline (0.500 mL, 4.74 mmol) and chloroacetyl chloride (0.570 mL, 7.16 mmol) in THF (10 mL) was stirred at room temperature for 18 h. The solvent was concentrated and dried under high vacuum to give 2-chloro-N-(3-chlorophenyl)acetamide (0.976 g, 100%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.23 (br s, 1H), 7.67 (s, 1H), 7.40 (ddd, 1H), 7.28 (t, 1H), 7.15 (ddd, 1H), 4.20 (s, 2H).

Step 2. (2Z)-3-(3-Chlorophenyl)-2-[(4-fluorophenyl)imino]-1,3-thiazolidin-4-one

Following standard procedure J, 2-chloro-N-(3-chlorophenyl)acetamide (259 mg, 1.27 mmol), 60% NaH in mineral oil (61.0 mg, 1.53 mmol), and 4-fluorophenyl isothiocyanate (204 mg, 1.33 mmol) were used to carry out the reaction. After work-up, the residue was purified by column chromatography (25% ethyl acetate in n-hexane) to give (2Z)-3-(3-chlorophenyl)-2-[(4-fluorophenyl)imino]-1,3-thiazolidin-4-one (88.7 mg, 22%) as a yellow solid. 1H NMR (CDCl₃, 400 MHz) δ 7.48-7.40 (m, 3H), 7.29 (dt, 1H), 7.02 (dd, 2H), 6.88 (dd, 2H), 4.00 (s, 2H); LC-MS (ESI) m/z 321.1 [M+H]⁺.

Example 342

4-[5-(4-Fluorophenyl)-1H-pyrazol-1-yl]-3-methylbenzoic acid

Step 1. Synthesis of methyl 4-hydrazinyl-3-methylbenzoate hydrochloride

A solution of methyl 4-amino-3-methylbenzoate (1.00 g, 6.06 mmol) in concentrated HCl_(aq) (2.7 mL) and sodium nitrite (0.460 g, 6.67 mmol) in water (2.2 mL) were used to carry out the reaction at 0° C. for 1 h. To the above mixture, a solution of SnCl₂ (3.45 g, 6.67 mmol) in concentrated HCl_(aq) (4.4 mL) was added. After the reaction was stirred at room temperature for 3 h, the white solid was collected by vacuum filtration and washed with ethyl acetate to give methyl 4-hydrazinyl-3-methylbenzoate hydrochloride (0.250 g, 19%). 1H NMR (DMSO-d₆, 400 MHz) δ 10.38 (br s, 2H), 8.39 (br s, 1H), 7.77 (dd, 1H), 7.70 (d, 1H), 6.96 (d, 1H), 3.78 (s, 3H), 2.20 (s, 3H).

Step 2. Synthesis of (2E)-3-(Dimethylamino)-1-(4-fluorophenyl)-2-propen-1-one

A solution of 1-(4-fluorophenyl)ethanone (0.875 mL, 7.24 mmol) in toluene (5.0 mL) and N,N-dimethylformamide dimethyl acetal (DIFDA, 1.35 mL, 10.1 mmol) were used to carry out the reaction. After the reaction was reflux for 4 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give (2E)-3-(dimethylamino)-1-(4-fluorophenyl)-2-propen-1-one (0.987 g, 71%). 1H NMR (CDCl₃, 400 MHz) δ 7.91 (dd, 2H), 7.80 (d, 1H), 7.07 (dd, 2H), 5.67 (d, 1H), 3.15 (br s, 3H), 2.93 (br s, 3H).

Step 3. Synthesis of methyl 4-[5-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-methylbenzoate

A solution of 2-(E)-3-(Dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (24.0 mg, 0.130 mmol) in MeOH (5.0 mL) and water (1.0 mL), methyl 4-hydrazinyl-3-methylbenzoate hydrochloride (30.0 mg, 0.140 mmol) and sodium carbonate (9.00 mg, 0.0900 mmol) were added and then to the above mixture, acetic acid was added to adjust the pH value to above 4. After the reaction mixture was stirred at 135° C. for 2 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give methyl 4-[5-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-methylbenzoate (38.0 mg, 99%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 7.94 (s, 1H), 7.89 (d, 1H), 7.74 (s, 1H), 7.28 (d, 1H), 7.13-7.08 (m, 2H), 6.96-6.90 (m, 2H), 6.53 (s, 1H), 3.92 (s, 3H), 2.02 (s, 3H). LC-MS (ESI) m/z 311.1 [M+H]⁺.

Step 4. Synthesis of 4-[5-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-methylbenzoic acid

Following standard procedure B, 4-[5-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-methylbenzoate (38.0 mg) in methanol (5.0 mL) and 20% NaOH_(aq) (1.0 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 3 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[5-(4-fluorophenyl)-1H-pyrazol-1-yl]-3-methylbenzoic acid (4.00 mg, 13%) as a white solid. 1H NMR (CDCl₃, 400 MHz) δ 8.00 (s, 1H), 7.96 (d, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.14-7.11 (m, 2H), 6.95 (dd, 2H), 6.55 (s, 1H), 2.05 (s, 3H); LC-MS (APCI) m/z 297.9 [M+H]⁺.

Example 343

4-[3-(4-Fluorophenyl)-4H-1,2,4-triazol-4-yl]-3-methylbenzoic acid

Step 1. Synthesis of methyl 4-[(4-fluorobenzoyl)amino]-3-methylbenzoate

Following standard procedure, 4-fluorobenzoic acid (0.510 g, 3.63 mmol), methyl 4-amino-3-methylbenzoate (0.500 g, 3.03 mmol), EDCI • HCl (1.16 g, 6.06 mmol), DMAP (0.930 g, 7.57 mmol) and CH₂Cl₂ (7.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 4-[(4-fluorobenzoyl)amino]-3-methylbenzoate (0.380 g, 44%). ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 1H), 7.96-7.88 (m, 4H), 7.75 (br s, 1H), 7.20 (td, 2H), 3.91 (s, 3H), 2.39 (s, 3H).

Step 2. Synthesis of methyl 4-{[(Z)-(4-fluorophenyl)(hydrazinyl)methylidene]amino}-3-methylbenzoate

The solution of methyl 4-[(4-fluorobenzoyl)amino]-3-methylbenzoate (0.140 g, 0.490 mmol) and PCl₅ (0.110 g, 0.540 mmol) in benzene (10.0 mL) was reflux for 4 h. To the mixture was added a solution of N₂H₄.H₂O (0.240 g, 4.87 mmol) in THF (5.0 mL). After stirring at room temperature for 1 h, the reaction mixture was extracted with ethyl acetate, dried over MgSO_4(s), filtered and concentrated. The residue was used directly for next step without further purification. 1H NMR (CDCl₃, 300 MHz) δ 7.85 (s, 1H), 7.65 (dd, 1H), 7.47 (dd, 2H), 6.99 (dd, 2H), 6.33 (d, 1H), 3.84 (s, 3H), 2.37 (s, 3H).

Step 3. Synthesis of methyl 4-[3-(4-fluorophenyl)-4H-1,2,4-triazol-4-yl]-3-methylbenzoate

To a solution of methyl 4-{[(Z)-(4-fluorophenyl)(hydrazinyl)methylidene]amino}-3-methylbenzoate (0.190 g, 0.630 mmol) was added p-toluenesulfonic acid (PTSA, 54.0 mg, 0.320 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.110 mL, 0.820 mmol) in toluene (5.0 mL). After the reaction was reflux for 3 h, the reaction mixture was extracted with ethyl acetate, dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give methyl 4-[3-(4-fluorophenyl)-4H-1,2,4-triazol-4-yl]-3-methylbenzoate (0.110 g, 56%). 1H NMR (CDCl₃, 400 MHz) δ 8.22 (s, 1H), 8.01-7.98 (m, 2H), 7.42-7.38 (m, 2H), 7.32 (d, 1H), 6.99-6.94 (m, 2H), 3.94 (s, 3H), 1.98 (s, 3H).

Step 4. Synthesis of 4-[3-(4-fluorophenyl)-4H-1,2,4-triazol-4-yl]-3-methylbenzoic acid

Following standard procedure B, methyl 4-[3-(4-fluorophenyl)-4H-1,2,4-triazol-4-yl]-3-methylbenzoate (0.110 g) in methanol (10.0 mL) and 20% NaOH_(aq) (3.0 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 3 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[3-(4-fluorophenyl)-4H-1,2,4-triazol-4-yl]-3-methylbenzoic acid (88.0 mg, 84%). 1H NMR (CDCl₃, 400 MHz) δ 8.25 (s, 1H), 7.99-7.97 (m, 2H), 7.38-7.34 (m, 2H), 7.28 (d, 1H), 6.96 (dd, 2H), 1.95 (s, 3H); LC-MS (APCI) m/z 298.8 [M+H]⁺.

Example 344

2-(2-Hydroxyethoxy)ethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of tert-butyl[2-(2-chloroethoxy)ethoxy]dimethylsilane

To a solution of 2-(2-chloroethoxy)ethanol (3.00 mL, 28.4 mmol) in THF (120 mL) was added tert-butyldimethylsilyl chloride (5.56 g, 36.9 mmol) and imidazole (2.90 g, 42.6 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated. The residue was treated with 1.0 N HCl_(aq) and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give tert-butyl[2-(2-chloroethoxy)ethoxy]dimethylsilane (6.75 g, 99%) as colorless oil which was directly used to next step without further purification. ¹H NMR (CDCl₃, 300 MHz) δ 3.79-3.74 (m, 4H), 3.64-3.57 (m, 4H), 0.89 (s, 9H), 0.07 (s, 6H).

Step 2. Synthesis of 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (158 mg, 0.477 mmol), K₂CO₃ (79.1 mg, 0.572 mmol), tert-butyl[2-(2-chloroethoxy)ethoxy]dimethylsilane (137 mg, 0.572 mmol) and DMF (1.0 mL) were used to carry out the reaction. After work-up, we got 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (255 mg, 0.477 mmol) which was directly used to next step without further purification. ¹H NMR (CDCl₃, 300 MHz) δ 7.88 (s, 1H), 7.76 (br d, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.05-5.80 (br, 1H), 4.41 (dd, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.80-3.72 (m, 4H), 3.64-3.56 (m, 2H), 2.19 (br s, 3H), 0.87 (s, 9H), 0.04 (s, 6H).

Step 3. Synthesis of 2-(2-hydroxyethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

To a solution of 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (255 mg, 0.477 mmol) in THF (4.0 mL) was added 1.0 M tetra-n-butylammonium fluoride in THF solution (0.80 mL, 0.80 mmol) at room temperature. The reaction mixture was stirred for 1 h and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-(2-hydroxyethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (161 mg, 81%) as a colorless gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (s, 1H), 7.76 (br s, 1H), 7.31 (dd, 2H), 6.96 (dd, 2H), 6.10-5.80 (br, 1H), 4.44 (dd, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.79 (dd, 2H), 3.74 (dd, 2H), 3.62 (dd, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 442.1 [M+Na]⁺.

Example 345

2-[2-(Methylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of ethyl {2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}acetate

A solution of ethyl 2-diazoacetate (0.900 mL, 8.56 mmol), tert-butyl (2-hydroxyethyl)(methyl)carbamate (1.50 g, 8.56 mmol) and rhodium(II) acetate dimer (0.380 g, 0.856 mmol) in CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% ethyl acetate in n-hexane) to give ethyl {2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}acetate (0.690 g, 31%). ¹H NMR (CDCl₃, 300 MHz) δ 4.28-4.18 (m, 2H), 4.07 (br s, 2H), 3.65 (br s, 2H), 3.42 (br s, 2H), 2.93-2.92 (m, 3H), 1.45-1.44 (m, 9H), 1.25 (br t, 3H).

Step 2. Synthesis of tert-butyl [2-(2-hydroxyethoxy)ethyl]methylcarbamate

A solution of ethyl {2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}acetate (0.688 g, 2.63 mmol) in methanol (10.0 mL) and sodium borohydride (0.120 g, 3.16 mmol) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give tert-butyl [2-(2-hydroxyethoxy)ethyl]methylcarbamate (0.167 g, 29%). ¹H NMR (CDCl₃, 300 MHz) δ 3.70 (br s, 2H), 3.57 (br s, 4H), 3.40 (br s, 2H), 2.89 (br s, 3H), 1.44 (s, 9H).

Step 3. Synthesis of 2-{2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.250 g, 0.760 mmol), tert-butyl [2-(2-hydroxyethoxy)ethyl]methylcarbamate (0.167 mg, 0.760 mmol), EDCI • HCl (0.290 g, 1.51 mmol), DMAP (0.200 g, 1.66 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-{2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.370 g, 92%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 6.96 (br t, 2H), 6.10-5.70 (br, 1H), 4.41-4.39 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.73 (br t, 2H), 3.60 (br s, 2H), 3.38 (br s, 2H), 2.88 (br s, 3H), 2.20 (br s, 3H), 1.46 (s, 9H).

Step 4. Synthesis of 2-[2-(methylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

The solution of 2-{2-[(tert-butoxycarbonyl)(methyl)amino]ethoxy}ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.350 g) and TFA (5.0 mL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 3 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH value>8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-[2-(methylamino)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.180 g, 63%). 1H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33-7.28 (m, 2H), 6.96 (br t. 2H), 5.99 (br s, 1H), 4.41 (br t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.78-3.75 (m, 4H), 3.11 (t, 2H), 2.66 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 433.2 [M+H]⁺.

Example 346

2-[2-(Pyridin-2-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate

A solution of 2-(2-chloroethoxy)ethanol (2.50 mL, 23.7 mmol), DMAP (289 mg, 2.36 mmol), p-toluenesulfonyl chloride (4.51 g, 23.7 mmol), and pyridine (1.90 mL, 23.6 mmol) in CH₂Cl₂ (50 mL) was stirred at room temperature for 5 h. The solution was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq), 5% NaOH_(aq), and water. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate (245 mg, 37%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 7.80 (d, 2H), 7.35 (d, 2H), 4.17 (dd, 2H), 3.72-3.66 (m, 4H), 3.54 (t, 2H), 2.45 (s, 3H).

Step 2. Synthesis of 2-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine

To a solution of pyridine-2-methanol (231 mg, 2.11 mmol) in THF (15 mL) was added 60% NaH in mineral oil (127 mg, 3.17 mmol) at 0° C., and it was stirred for 30 min. Then a solution of 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate (765 mg, 2.75 mmol) in THF (3.0 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 20 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-35% ethyl acetate in n-hexane) to give 2-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine (285 mg, 63%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (d, 1H), 7.69 (dd, 1H), 7.47 (d, 1H), 7.18 (dd, 1H), 4.69 (s, 2H), 3.79-3.74 (m, 4H), 3.66-3.63 (m, 2H).

Step 3. Synthesis of 2-[2-(pyridin-2-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (149 mg, 0.450 mmol), 2-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine (116 mg, 0.540 mmol), K₂CO₃ (93.3 mg, 0.675 mmol), and DMF (1.0 mL) were used to carry out the reaction. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-[2-(pyridin-2-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (183 mg, 80%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.53 (d, 1H), 7.87 (br s, 1H), 7.76 (br s, 1H), 7.64 (dd, 1H), 7.44 (d, 1H), 7.31-7.28 (m, 2H), 7.17 (dd, 1H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.68 (s, 2H), 4.44 (dd, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.81 (dd, 2H), 3.73 (s, 4H), 2.17 (br s, 3H); LC-MS (ESI) m/z 511.2 [M+H]⁺.

Example 347

2-[2-(Pyridin-3-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 3-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine

To a solution of 3-(hydroxymethyl)pyridine (231 mg, 2.11 mmol) in THF (15 mL) was added 60% NaH in mineral oil (127 mg, 3.17 mmol) at 0° C., and it was stirred for 30 min. Then a solution of 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate (833 mg, 2.99 mmol) in THF (3.0 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 16 h and 60° C. for 8 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 3-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine (129 mg, 26%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.58 (d, 1H), 8.53 (dd, 1H), 7.70 (dd, 1H), 7.28 (dd, 1H), 4.60 (s, 2H), 3.78-3.62 (m, 8H).

Step 2. Synthesis of 2-[2-(pyridin-3-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (165 mg, 0.498 mmol), 3-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine (129 mg, 0.598 mmol), K₂CO₃ (103 mg, 0.747 mmol), and DMF (1.0 mL) were used to carry out the reaction. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-[2-(pyridin-3-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (183 mg, 80%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.56 (d, 1H), 8.53 (dd, 1H), 7.87 (br s, 1H), 7.75 (br s, 1H), 7.67 (d, 1H), 7.32-7.27 (m, 3H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.57 (s, 2H), 4.43 (dd, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.80 (dd, 2H), 3.71-3.64 (m, 4H), 2.18 (br s, 3H); LC-MS (ESI) m/z 511.2 [M+H]⁺.

Example 348

2-[2-(Pyridin-4-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 4-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine

To a solution of 4-(hydroxymethyl)pyridine (251 mg, 2.30 mmol) in THF (15 mL) was added 60% NaH in mineral oil (138 mg, 3.45 mmol) at 0° C., and it was stirred for 30 min. Then a solution of 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate (833 mg, 2.99 mmol) in THF (3.0 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 16 h and 60° C. for 8 h. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 4-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine (202 mg, 41%) as a lightly brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.56 (d, 2H), 7.27 (d, 2H), 4.60 (s, 2H), 3.79-3.63 (m, 8H).

Step 2. Synthesis of 2-[2-(pyridin-4-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (195 mg, 0.587 mmol), 4-{[2-(2-chloroethoxy)ethoxy]methyl}pyridine (152 mg, 0.705 mmol), K₂CO₃ (122 mg, 0.881 mmol), and DMF (1.0 mL) were used to carry out the reaction. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-[2-(pyridin-4-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (224 mg, 75%) as a lightly yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (d, 2H), 7.87 (br s, 1H), 7.75 (br s, 1H), 7.32-7.28 (m, 2H), 7.24 (d, 2H), 6.94 (br t, 2H), 6.10-5.80 (br, 1H), 4.57 (s, 2H), 4.45 (dd, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.81 (dd, 2H), 3.73-3.66 (m, 4H), 2.17 (br s, 3H); LC-MS (ESI) m/z 511.2 [M+H]⁺.

Example 349

2-[2-(2-Methoxyethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (168 mg, 0.507 mmol), DMAP (155 mg, 1.27 mmol), EDCI • HCl (175 mg, 0.913 mmol), triethylene glycol monomethyl ether (87.4 mg, 0.532 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 2-[2-(2-methoxyethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (198 mg, 82%) as a lightly yellow gum. ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br d, 1H), 7.32-7.27 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.42 (dd, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 3.79 (dd, 2H), 3.70-3.61 (m, 6H), 3.54-3.50 (m, 2H), 3.37 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 500.2 [M+Na]⁺.

Example 350

2-[2-(Morpholin-4-yl)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[2-(morpholin-4-yl)ethoxy]ethanol

To the solution of morpholine (1.00 mL, 11.5 mmol) in DMF (5.0 mL), 2-(2-chloroethoxy)ethanol (1.10 mL, 10.4 mmol) and K₂CO₃ (1.59 g, 11.5 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (50% ethyl acetate in n-hexane) to give 2-(2-morpholinoethoxy)ethanol (0.130 g, 8%); ¹H NMR (CDCl₃, 400 MHz) δ 3.74-3.60 (m, 10H), 2.59-2.57 (m, 3H), 2.55-2.52 (br, 3H).

Step 2. Synthesis of 2-[2-(morpholin-4-yl)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.240 g, 0.740 mmol), 2-[2-(morpholin-4-yl)ethoxy]ethanol (0.130 g, 0.740 mmol), EDCI • HCl (0.280 g, 1.48 mmol), DMAP (0.190 g, 1.59 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-[2-(morpholin-4-yl)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.210 g, 59%). ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.75 (br d, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 4.45-4.39 (m, 2H), 4.01 (d, 1H), 3.91 (d, 1H), 3.75-3.71 (m, 8H), 2.75-2.50 (br, 6H), 2.20 (br s, 3H); LC-MS (ESI) m/z 489.2 [M+H]⁺.

Example 351

5-(Morpholin-4-yl)pentyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 5-(morpholin-4-yl)pentan-1-ol

To the solution of 5-bromopentanol (0.720 mL, 5.99 mmol) in DMF (5.0 mL), morpholine (0.520 mL, 5.99 mmol) and K₂CO₃ (0.900 g, 6.59 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was used directly for next step without further purification. (0.300 g, crude yield 29%). ¹H NMR (CDCl₃, 300 MHz) δ 3.71-3.66 (m, 4H), 3.63 (br t, 2H), 2.50-2.40 (br, 4H), 2.34 (br t, 2H), 1.61-1.23 (m, 6H).

Step 2. Synthesis of 5-morpholinopentyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 5-(morpholin-4-yl)pentan-1-ol (0.100 g, 0.598 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 5-(morpholin-4-yl)pentyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 76%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33-7.28 (m, 2H), 6.96 (br t, 2H), 4.31-4.25 (m, 2H), 4.03-3.90 (m, 6H), 3.00-2.60 (br, 4H), 2.20 (br s, 3H), 1.81-1.74 (m, 4H), 1.49-1.41 (m, 2H); LC-MS (ESI) m/z 487.2 [M+H]⁺.

Example 352

2-[2-(Acetyloxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(2-chloroethoxy)ethyl acetate

To the solution of 2-(2-chloroethoxy)ethyl acetate (0.510 mL, 4.82 mmol) and acetic anhydride (0.500 mL, 5.29 mmol) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, the residue was used directly for next step without further purification. (0.79 g, crude yield 98%). ¹H NMR (CDCl₃, 300 MHz) δ 4.23 (dd, 2H), 3.77-3.70 (m, 4H), 3.63 (t, 2H), 2.08 (s, 3H).

Step 2. Synthesis of 2-[2-(acetyloxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(2-chloroethoxy)ethyl acetate (90.0 mg, 0.544 mmol) and K₂CO₃ (83.0 g, 0.598 mmol) and DMF (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-[2-(acetyloxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.220 g, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.76 (br s, 1H), 7.31 (dd, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.43 (m, 2H), 4.22 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.79 (m, 2H), 3.71 (m, 2H), 2.19 (br s, 3H), 2.05 (s, 3H); LC-MS (ESI) m/z 484.6 [M+Na]⁺.

Example 353

2-[2-(Pyrrolidin-2-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate

A solution of 2-pyrrolidinemethanol (0.300 g, 1.98 mmol) in CH₂Cl₂ (5.0 mL) and di-tert-butyl dicarbonate (0.650 g, 1.98 mmol) were used to carry out the reaction. After the reaction was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.590 g, 98%). ¹H NMR (CDCl₃, 300 MHz) δ 4.78 (br d, 1H), 4.05-3.90 (br, 1H), 3.67-3.53 (m, 2H), 3.49-3.41 (m, 1H), 3.34-3.26 (m, 1H), 2.00 (dddd, 1H), 1.85-1.72 (m, 2H), 1.60-1.50 (m, 1H), 1.46 (s, 9H).

Step 2. Synthesis of tert-butyl 2-((2-(2-chloroethoxy)ethoxy)methyl)pyrrolidine-1-carboxylate

A solution of 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate (0.990 g, 3.58 mmol) in DMF (10.0 mL), tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.600 g, 2.98 mmol) and sodium hydride (0.140 g, 3.58 mmol) were used to carry out the reaction. After the reaction was stirred at 80° C. for 16 h and work-up, the residue was used directly for next step without further purification. (0.240 g, crude yield 26%). ¹H NMR (CDCl₃, 300 MHz) δ 3.80-3.63 (br, 1H), 3.63-3.44 (br, 8H), 3.31 (br s, 4H), 1.98-1.65 (br, 4H), 1.44 (br s, 9H).

Step 3. Synthesis of tert-butyl 2-({2-[2-([4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethoxy]ethoxy]methyl)pyrrolidine-1-carboxylate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.258 g, 0.780 mmol), tert-butyl 2-((2-(2-chloroethoxy)ethoxy)methyl)pyrrolidine-1-carboxylate (0.240 mg, 0.780 mmol) and K₂CO₃ (0.120 g, 0.857 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give tert-butyl 2-({2-[2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethoxy]ethoxy}methyl)pyrrolidine-1-carboxylate (0.192 g, 41%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.76 (br s, 1H), 7.32-7.28 (m, 2H), 6.97 (br t, 2H), 6.10-5.80 (br, 1H), 4.42 (br t, 2H), 4.02-3.93 (m, 3H), 3.79 (dd, 2H), 3.64-3.55 (m, 5H), 3.37-3.28 (m, 3H), 2.20 (br s, 3H), 1.92-1.74 (m, 4H), 1.45 (s, 9H).

Step 4. Synthesis of 2-[2-(pyrrolidin-2-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

The solution of tert-butyl 2-({2-[2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethoxy]ethoxy}methyl)pyrrolidine-1-carboxylate (0.192 g) and TFA (5.00 mL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 3 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH>8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-[2-(pyrrolidin-2-ylmethoxy)ethoxy]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (76.7 mg, 48%). ¹H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.76 (br d, 1H), 7.33-7.28 (m, 2H), 6.95 (br t, 2H), 4.44-4.41 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.82-3.75 (m, 2H), 3.68-3.60 (m, 4H), 3.52-3.41 (m, 1H), 3.40-3.30 (m, 2H), 3.02-2.87 (m, 2H), 2.19 (br s, 3H), 1.88-1.67 (m, 4H); LC-MS (ESI) m/z 503.2 [M+H]⁺.

Example 354

2-[(2-Methoxyethyl)(methyl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of ethyl N-(2-methoxyethyl)-N-methylglycinate

A solution of N-(2-methoxyethyl)methyl amine (0.698 g, 5.81 mmol), triethylamine (1.00 mL, 7.17 mmol), ethyl bromoacetate (0.800 mL, 7.21 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature for 8 h. The solution was diluted with CH₂Cl₂ and washed with saturated NaHCO_3(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated to give ethyl N-(2-methoxyethyl)-N-methylglycinate (0.952 g, 92%) as a yellow liquid. ¹H NMR (CDCl₃, 400 MHz) δ 4.17 (q, 2H), 3.49 (t, 2H), 3.35 (s, 2H), 3.34 (s, 3H), 2.77 (t, 2H), 2.44 (s, 3H), 1.26 (t, 3H).

Step 2. Synthesis of 2-[(2-methoxyethyl)(methyl)amino]ethanol

To a solution of ethyl N-(2-methoxyethyl)-N-methylglycinate (0.952 g, 5.91 mmol) in THF (30 mL) was added lithium aluminium hydride (0.355 g, 9.35 mmol) at 0° C. slowly. The solution was stirred at room temperature for 16 h and quenched with saturated Na₂SO_4(aq) and 10% NaOH_(aq). The mixture was diluted with diethyl ether and filtered off. The filtrate was dried over over MgSO_4(s), filtered, and concentrated to give 2-[(2-methoxyethyl)(methyl)amino]ethanol (657 mg, 93%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 3.58 (dd, 2H), 3.47 (t, 2H), 3.35 (s, 3H), 2.63 (t, 2H), 2.57 (dd, 2H), 2.32 (s, 3H).

Step 3. Synthesis of 2-[(2-methoxyethyl)(methyl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (151 mg, 0.456 mmol), 2-[(2-methoxyethyl)(methyl)amino]ethanol (81.5 mg, 0.684 mmol), EDCI • HCl (131 mg, 0.684 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-[(2-methoxyethyl)(methyl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (54.8 mg, 27%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.32-7.28 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.38 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.47 (t, 2H), 3.33 (s, 3H), 2.81 (t, 2H), 2.67 (t, 2H), 2.37 (s, 3H), 2.20 (br s, 3H); LC-MS (ESI) m/z 447.3 [M+H]⁺.

Example 355

Octyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (152 mg, 0.459 mmol), 1-octanol (65.7 mg, 0.725 mmol), EDCI • HCl (0.158 g, 0.826 mmol), DMAP (0.140 g, 1.15 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-22% ethyl acetate in n-hexane) to give octyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (135 mg, 66%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 6.10-5.70 (br s, 1H) 4.25 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.71 (quint, 2H), 1.40-1.20 (m, 10H), 0.87 (t, 3H); LC-MS (ESI) m/z 444.2 [M+H]⁺.

Example 356

2-Ethoxy-2-oxoethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure H, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (173 mg, 0.783 mmol), chloroacetic acid ethyl ester (70.4 mg, 0.574 mmol), K₂CO₃ (108 mg, 0.881 mmol), and DMF (1.0 mL) were used to carry out the reaction. The solution was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-35% ethyl acetate in n-hexane) to give 2-ethoxy-2-oxoethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (181 mg, 83%) as a lightly yellow foam. ¹H NMR (CDCl₃, 300 MHz) δ 7.92 (br s, 1H), 7.80 (br d, 1H), 7.33-7.27 (m, 2H), 6.96 (br t, 2H), 5.95 (br s, 1H), 4.79 (s, 2H), 4.23 (q, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.28 (t, 3H); LC-MS (ESI) m/z 440.1 [M+Na]⁺.

Example 357

(2-Methylcyclopropyl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-methylcyclopropanemethanol (80.0 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.210 g, 1.08 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give (2-methylcyclopropyl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.210 g, 97%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.77 (br s, 1H), 7.32 (dd, 2H), 6.95 (br t, 2H), 5.99 (br s, 1H), 4.16-4.06 (m, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.07 (d, 3H), 0.98-0.83 (m, 1H), 0.81-0.71 (m, 1H), 0.50-0.46 (m, 1H), 0.36-0.31 (m, 1H); LC-MS (ESI) m/z 400.2 [M+H]⁺.

Example 358

3,3-Diethoxypropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3,3-diethoxy-1-propanol (0.130 mL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mm ol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 3,3-diethoxypropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.240 g, 96%). ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.77 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 5.98 (br s, 1H), 4.69-4.64 (m, 1H), 4.35 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.71-3.62 (m, 2H), 3.55-3.46 (m, 2H), 2.19 (br s, 3H), 2.04 (q, 2H), 1.24-1.17 (m, 6H).

Example 359

(1-Methylpiperidin-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), (1-methylpiperidin-4-yl)methanol (0.110 mL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give (1-methylpiperidin-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.160 g, 67%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.98 (br s, 1H), 4.22-4.17 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.37-3.34 (br, 2H), 2.64 (s, 3H), 2.54 (br t, 2H), 2.21 (br s, 3H), 2.04-1.89 (m, 5H); LC-MS (ESI) m/z 443.6 [M+H]⁺.

Example 360

Tetrahydro-2H-pyran-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), tetrahydro-2H-pyran-4-ol (80.0 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give tetrahydro-2H-pyran-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 89%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.78 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 5.96 (br s, 1H), 5.15 (quint, 1H), 4.03-3.90 (m, 4H), 3.59 (td, 2H), 2.20 (br s, 3H), 2.04-1.97 (m, 2H), 1.81-1.73 (m, 2H); LC-MS (ESI) m/z 416.7 [M+H]⁺.

Example 361

3-Methoxybutyl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3-methoxy-1-butanol (90.0 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 3-methoxybutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.190 g, 84%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33-7.28 (m, 2H), 6.96 (br t, 2H), 5.99 (br s, 1H), 4.40-4.33 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.46 (quint, 1H), 3.31 (s, 3H), 2.20 (br s, 3H), 1.93-1.81 (m, 2H), 1.18 (d, 3H); LC-MS (ESI) m/z 418.7 [M+H]⁺.

Example 362

(2-Oxo-1,3-dioxolan-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 4-(hydroxymethyl)-1,3-dioxolan-2-one (70.0 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give (2-oxo-1,3-dioxolan-4-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.220 g, 94%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33-7.30 (m, 2H), 6.97 (br t, 2H), 5.03-5.01 (br, 1H), 4.63-4.33 (m, 4H), 4.00 (d, 1H), 3.92 (d, 1H), 2.21 (br s, 3H); LC-MS (ESI) m/z 432.6 [M+H]⁺.

Example 363

1-Ethoxypropan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 1-ethoxy-2-propanol (95.0 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 1-ethoxypropan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.150 g, 66%). ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.75 (br d, 1H), 7.33-7.28 (m, 2H), 6.96 (br t, 2H), 5.99 (br s, 1H), 5.29-5.23 (m, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 3.61-3.46 (m, 4H), 2.19 (br s, 3H), 1.31 (d, 3H), 1.17 (t, 3H); LC-MS (ESI) m/z 418.1 [M+H]⁺.

Example 364

1-(Morpholin-4-yl)propan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(morpholin-4-yl)ethanol (90.0 μL, 0.652 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 1-(morpholin-4-yl)propan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.110 g, 44%). ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.72 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 5.31-5.26 (m, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.65-3.62 (m, 4H), 2.61 (dd, 1H), 2.56-2.51 (m, 2H), 2.47-2.41 (m, 3H), 2.20 (br s, 3H), 1.31 (d, 3H); LC-MS (ESI) m/z 459.2 [M+H]⁺.

Example 365

2-Phenylpropan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), α,α-dimethylbenzenemethanol (74.0 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-phenylpropan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (56.8 mg, 23%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.74 (br s, 1H), 7.39-7.30 (m, 6H), 7.25-7.22 (m, 2H), 6.97 (br t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.86 (s, 6H); LC-MS (ESI) m/z 472.1 [M+Na]⁺.

Example 366

4,4-Dimethyl-2-oxotetrahydrofuran-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3-hydroxy-4,4-dimethyldihydrofuran-2 (3H)-one (0.140 mL, 1.09 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.160 g, 1.36 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 4,4-dimethyl-2-oxotetrahydrofuran-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 7.91 (br s, 1H), 7.81 (br s, 1H), 7.33-7.27 (m, 2H), 6.97 (br t, 2H), 5.96 (br s, 1H), 5.56 (s, 1H), 4.15-4.06 (m, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.22 (br s, 3H), 1.25 (s, 3H), 1.18 (s, 3H); LC-MS (ESI) m/z 444.2 [M+H]⁺.

Example 367

Benzyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), benzyl alcohol (56.0 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give benzyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.200 g, 91%). ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (br s, 1H), 7.77 (br s, 1H), 7.42-7.27 (m, 8H), 6.95 (br t, 2H), 5.31 (s, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H); LC-MS (ESI) m/z 422.2 [M+H]⁺.

Example 368

2-Methoxyethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-methoxyethanol (42.8 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-methoxyethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.190 g, 90%). ¹H NMR (CDCl₃, 300 MHz) δ 7.88 (br s, 1H), 7.77 (br d, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.42 (dd, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.69-3.65 (m, 2H), 3.40 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 412.1 [M+Na]⁺.

Example 369

2,3-Dihydroxypropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (188 mg, 0.567 mmol), 2,2-dimethyl-1,3-dioxolane-4-methanol (82.5 mg, 0.624 mmol), EDCI • HCl (163 mg, 0.851 mmol), DMAP (139 mg, 1.13 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by column chromatography (80% ethyl acetate in n-hexane) to give 2,3-dihydroxypropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (124 mg, 54%) as a yellow gum. ¹H NMR (CDCl₃, 300 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.33-7.27 (m, 2H), 6.96 (t, 2H), 6.10-5.85 (br, 1H), 4.51-4.38 (m, 4H), 4.36-4.26 (m, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 406.1 [M+H]⁺.

Example 370

Oxetan-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3-oxetanol (34.0 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give oxetan-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.190 g, 90%). ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (br s, 1H), 7.77 (br s, 1H), 7.34-7.29 (m, 2H), 6.96 (br t, 2H), 5.97 (br s, 1H), 5.61 (quint, 1H), 4.97 (dd, 2H), 4.73 (dd, 2H), 4.01 (d, 1H), 3.93 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 388.6 [M+H]⁺.

Example 371

(3-Methyloxetan-3-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3-methyl-3-oxetanemethanol (54.0 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give (3-methyloxetan-3-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.210 g, 98%). ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.94 (br s, 1H), 4.59 (d, 2H), 4.43 (d, 2H), 4.34 (s, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.21 (br s, 3H), 1.39 (s, 3H); LC-MS (APCI) m/z 416.7 [M+H]⁺.

Example 372

3-Hydroxy-2-(hydroxymethyl)-2-methylpropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

To the solution of (3-methyloxetan-3-yl)methyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (50.0 mg, 0.120 mmol) in CH₂Cl₂ (5.0 mL) and boron trifluoride diethyl etherate were used to carry out the reaction. After the reaction mixture was stirred at 0° C.-−10° C. for 3 h and work-up, trimethylamine (4.50 μL) was added and then work-up. The residue was extracted with ethyl acetate, dried over MgSO_4(s), filtered and concentrated to yield 3-hydroxy-2-(hydroxymethyl)-2-methylpropyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate as a white solid. (16.0 mg, 31%). ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.41 (d, 1H), 4.36 (d, 1H), 4.00 (d, 1H), 3.92 (d, 1H), 3.61 (d, 2H), 3.55 (d, 2H), 2.21 (br s, 3H), 0.86 (s, 3H); LC-MS (ESI) m/z 434.2 [M+H]⁺.

Example 373

Cyclobutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), cyclobutanol (43.0 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give cyclobutyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.180 g, 86%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.74 (br s, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 5.94 (br s, 1H), 5.16 (quint, 1H), 4.01 (d, 1H), 3.93 (d, 1H), 2.45-2.38 (m, 3H), 2.38-2.10 (m, 4H), 1.87-1.80 (m, 1H), 1.73-1.61 (m, 1H); LC-MS (ESI) m/z 386.2 [M+H]⁺.

Example 374

tert-Butyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)piperidine-1-carboxylate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.200 g, 0.604 mmol), 1-Boc-4-hydroxypiperidine (0.120 g, 0.604 mmol), EDCI • HCl (0.230 g, 1.33 mmol), DMAP (0.160 g, 1.33 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give tert-butyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)piperidine-1-carboxylate (0.290 g, 93%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.75 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 5.16-5.10 (m, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.78-3.72 (br, 2H), 3.34-3.28 (m, 2H), 2.22 (br s, 3H), 1.94-1.89 (m, 2H), 1.73-1.62 (m, 2H), 1.46 (s, 9H); LC-MS (ESI) m/z 537.3 [M+Na]⁺.

Example 375

Piperidin-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

The solution of tert-butyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)piperidine-1-carboxylate (0.230 g) and TFA (5.00 mL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 3 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH>8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated to give pure piperidin-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.170 g, 92%). ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.75 (br s, 1H), 7.32 (dd, 2H), 6.97 (br t. 2H), 5.96 (br s, 1H), 5.18-5.14 (m, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.22-3.19 (m, 2H), 3.01-2.97 (m, 2H), 2.22 (br s, 3H), 2.17-2.07 (m, 2H), 1.89-1.85 (m, 2H); LC-MS (ESI) m/z 415.2 [M+H]⁺.

Example 376

2-(4,4-Difluoropiperidin-1-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(4,4-difluoropiperidin-1-yl)ethanol

To the solution of 2-chloroethanol (0.190 mL, 2.86 mmol) in acetonitrile (5.0 mL), 4,4-difluoropiperidine (0.300 g, 1.90 mmol) and K₂CO₃ (0.290 g, 2.09 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was used directly for next step without further purification. (59.0 mg, crude yield 19%). ¹H NMR (CDCl₃, 400 MHz) δ 3.70 (dd, 2H), 2.77-2.75 (m, 4H), 2.73-2.68 (m, 2H), 2.15-2.06 (m, 4H).

Step 2. Synthesis of 2-(4,4-difluoropiperidin-1-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.110 g, 0.357 mmol), 2-(4,4-difluoropiperidin-1-yl)ethanol (59.0 mg, 0.357 mmol), EDCI • HCl (0.130 g, 0.660 mmol), DMAP (89.3 mg, 0.730 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-90% ethyl acetate in n-hexane) to give trace 2-(4,4-difluoropiperidin-1-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate. ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.73 (br s, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 6.05-5.83 (br, 1H), 4.43-4.37 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.77 (t, 2H), 2.65-2.62 (m, 4H), 2.21 (br s, 3H), 2.02-1.92 (m, 4H); LC-MS (ESI) m/z 479.6 [M+H]⁺.

Example 377

2-(3,3-Difluoropyrrolidin-1-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(3, 3-difluoropyrrolidin-1-yl)ethanol

To the solution of 2-chloroethanol (0.420 mL, 6.27 mmol) in DMF (5 mL), 3,3-difluoropyrrolidine (0.300 g, 2.09 mmol) and K₂CO₃ (0.320 g, 2.30 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was used directly for next step without further purification. (0.220 g, crude yield 70%). ¹H NMR (CDCl₃, 400 MHz) δ 3.83-3.60 (m, 4H), 3.24-3.14 (m, 1H), 3.10-3.00 (m, 1H), 2.90-2.80 (m, 1H), 2.50-2.30 (m, 3H).

Step 2. Synthesis of 2-(3,3-difluoropyrrolidin-1-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(3,3-difluoropyrrolidin-1-yl)ethanol (98.6 mg, 0.652 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(3,3-difluoropyrrolidin-1-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (73.6 mg, 29%). ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.73 (br s, 1H), 7.33-7.29 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.41-4.37 (m, 2H), 4.00 (d, 1H), 3.96 (d, 1H), 3.02 (t, 2H), 2.87-2.83 (m, 4H), 2.32-2.19 (m, 5H); LC-MS (ESI) m/z 465.1 [M+H]⁺.

Example 378

tert-Butyl 3-({4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)azetidine-1-carboxylate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (94.1 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give tert-butyl 3-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)azetidine-1-carboxylate (0.240 g, 91%). ¹H NMR (CDCl₃, 300 MHz) δ 7.87 (br s, 1H), 7.75 (br d, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 6.05-5.93 (br, 1H), 5.34-5.27 (m, 1H), 4.34-4.28 (m, 2H), 4.04-3.89 (m, 4H), 2.21 (br s, 3H), 1.44 (s, 9H); LC-MS (ESI) m/z 509.2 [M+Na]⁺.

Example 379

Azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

The solution of tert-butyl 3-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)azetidine-1-carboxylate (0.310 g) and TFA (5.0 mL) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 3 h. To the reaction mixture was added saturated NaHCO_3(aq) to adjust the pH>8 and extracted with CH₂Cl₂. The organic layers were dried over MgSO_4(s), filtered and concentrated to give pure azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.220 g, 89%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.77 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.47-5.42 (m, 1H), 4.03-3.90 (m, 4H), 3.79-3.75 (m, 2H), 2.18 (br s, 3H); LC-MS (ESI) m/z 387.2 [M+H]⁺.

Example 380

1-Methylazetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 1-methylazetidin-3-ol

To a solution of methylamine (0.700 mL, 0.0160 mmol) in MeOH (5.0 mL), 2-(chloromethyl)oxirane (1.26 mL, 0.0160 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. After removed the solvent, the residue was used directly for next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 3.96-3.91 (m, 1H), 3.63-3.53 (m, 2H), 2.61-2.54 (m, 2H), 2.39 (s, 3H).

Step 2. Synthesis of 1-methylazetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), 1-methylazetidin-3-ol (34.7 mg, 0.398 mmol), EDCI • HCl (0.140 g, 0.604 mmol), DMAP (97.3 mg, 0.797 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, CH₂Cl₂:ethyl acetate:n-hexane=1:1:2) to give 1-methylazetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (57.7 g, 40%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s. 1H), 7.75 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.95 (br s, 1H), 5.31 (s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.80-3.70 (m, 2H), 2.87-2.71 (m, 2H), 2.36 (s, 3H), 2.21 (br s, 3H); LC-MS (ESI) m/z 423.1 [M+Na]⁺.

Example 381

3-({4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)-1,1-dimethylazetidinium

To the solution of azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (80.0 mg, 0.207 mmol) in CH₂Cl₂ (5.0 mL), iodomethane (14.0 μL, 0.228 mmol) and N,N-diisopropylethylamine (38.0 μL, 0.228 mmol) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 4 h and work-up, the residue was had no further purification to give 3-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)-1,1-dimethylazetidinium (8.20 mg, 10%). ¹H NMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.76 (br s, 1H), 7.35-7.29 (m, 2H), 6.97-6.93 (m, 2H), 5.68-5.63 (m, 1H), 5.18-5.14 (m, 2H), 4.63-4.58 (m, 2H), 4.02-3.89 (m, 2H), 3.58-3.56 (m, 6H), 2.20 (br s, 3H). LC-MS (ESI) m/z 416.1 [M+H]⁺.

Example 382

1-tert-Butylazetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 1-tert-butylazetidin-3-ol (77.2 mg, 0.598 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.20 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 1-tert-butylazetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.220 g, 92%). ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 1H), 7.74 (br d, 1H), 7.31-7.27 (m, 2H), 6.96 (br t, 2H), 5.30-5.28 (m, 1H), 4.02-3.86 (m, 4H), 3.54 (br s, 2H), 2.20 (br s, 3H), 1.15 (s, 9H); LC-MS (ESI) m/z 443.7 [M+H]⁺.

Example 383

1-(Oxetan-3-yl)azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 1-(oxetan-3-yl)azetidin-3-ol

A mixture of azetidin-3-ol hydrochloride salt (0.200 g, 1.83 mmol), 3-oxetanone (71.0 μL, 1.22 mmol) and 4A molecular sieves (0.600 g) in CH₂Cl₂ (10.0 mL) was stirred at room temperature for 4 h. To the above reaction, NaBH(OAc)₃ (0.520 g, 2.43 mmol) was added. After the reaction mixture was stirred at room temperature for 16 h, the precipitate was filtered through a pad of celite and the filtrate was diluted with ethyl acetate and filtered again. The residue was used directly for next step without further purification (0.115 g, crude yield 49%). ¹H NMR (CDCl₃, 400 MHz) δ 4.76-4.69 (m, 2H), 4.52-4.46 (m, 3H), 3.81 (quint, 1H), 3.66 (dd, 2H), 3.17 (dd, 2H).

Step 2. Synthesis of 1-(oxetan-3-yl)azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.260 g, 0.809 mmol), 1-(oxetan-3-yl)azetidin-3-ol (0.115 g, 0.891 mmol), EDCI • HCl (0.300 g, 1.57 mmol), DMAP (0.210 g, 1.73 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 10% MeOH in CH₂Cl₂) to give 1-(oxetan-3-yl)azetidin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.160 g, 46%). ¹H NMR (CDCl₃, 400 MHz) δ 7.87 (br s, 1H), 7.75 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 5.30-5.27 (m, 1H), 4.71 (t, 2H), 4.53 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.86-3.79 (m, 3H), 3.29 (dd, 2H), 2.11 (br s, 3H); LC-MS (ESI) m/z 443.1 [M+H]⁺.

Example 384

2-[(3-Methyloxetan-3-yl)methoxy]-2-oxoethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.499 mmol), (3-methyloxetan-3-yl)methanol (50.0 μL, 0.499 mmol), EDCI • HCl (0.190 g, 0.990 mmol), DMAP (0.130 g, 1.09 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-[(3-methyloxetan-3-yl)methoxy]-2-oxoethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.160 g, 72%). ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (dd, 2H), 6.97 (br s, 2H), 6.80-6.18 (br, 3H), 6.08-5.45 (br, 1H), 4.60 (s, 2H), 4.51 (d, 2H), 4.39 (d, 2H), 4.27 (s, 2H), 3.99 (d, 1H), 3.88 (d, 1H), 2.33-1.81 (br, 3H), 1.26 (s, 3H).

Example 385

2-[(3R)-3-Methoxypyrrolidin-1-yl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[(3R)-3-methoxypyrrolidin-1-yl]ethanol

A solution of (3R)-3-methoxypyrrolidine hydrochloride (282 mg, 2.05 mmol), 2-bromoethanol (0.145 mL, 2.05 mmol), and potassium carbonate (566 mg, 4.10 mmol) in CH₃CN (8.0 mL) was stirred at room temperature for 18 h. The solution was filtered off and washed with CH₂Cl₂. The filtrate was concentrated and dried under high vacuum to give 2-[(3R)-3-methoxypyrrolidin-1-yl]ethanol (308 mg, quantitative yield) as a colorless oil which was directly used to next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 3.95-3.90 (m, 1H), 3.63 (dd, 2H), 3.27 (s, 3H), 2.80-2.72 (m, 2H), 2.67-2.63 (m, 3H), 2.56-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.85-1.79 (m, 1H).

Step 2. Synthesis of 2-[(3R)-3-methoxypyrrolidin-1-yl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (189 mg, 0.572 mmol), 2-[(3R)-3-methoxypyrrolidin-1-yl]ethanol (83.1 mg, 0.572 mmol), DMAP (105 mg, 0.858 mmol), EDCI • HCl (164 mg, 0.858 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and concentrated, the residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 5% methanol in ethyl acetate) to give 2-[(3R)-3-methoxypyrrolidin-1-yl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (134 mg, 51%) as a lightly yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.80-7.70 (br, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.41 (t, 2H), 4.00 (d, 1H), 3.93-3.89 (m, 2H), 3.28 (s, 3H), 2.83-2.77 (m, 4H), 2.68 (dd, 1H), 2.54 (dd, 1H), 2.19 (br s, 3H), 2.08-2.03 (m, 1H), 1.84-1.78 (m, 1H); LC-MS (ESI) m/z 459.3 [M+H]⁺.

Example 386

2-[(3S)-3-Methoxypyrrolidin-1-yl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[(3S)-3-methoxypyrrolidin-1-yl]ethanol

A solution of (3S)-3-methoxypyrrolidine hydrochloride (282 mg, 2.05 mmol), 2-bromoethanol (0.145 mL, 2.05 mmol), and potassium carbonate (566 mg, 4.10 mmol) in CH₃CN (8.0 mL) was stirred at room temperature for 18 h. The solution was filtered off and washed with CH₂Cl₂. The filtrate was concentrated and dried under high vacuum to give 2-[(3S)-3-methoxypyrrolidin-1-yl]ethanol (313 mg, quantitative yield) as a colorless oil which was directly used to next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 3.95-3.90 (m, 1H), 3.63 (dd, 2H), 3.27 (s, 3H), 2.80-2.72 (m, 2H), 2.67-2.63 (m, 3H), 2.56-2.50 (m, 1H), 2.11-2.02 (m, 1H), 1.85-1.79 (m, 1H); LC-MS (ESI) m/z 146.2 [M+H]⁺.

Step 2. Synthesis of 2-[(3S)-3-methoxypyrrolidin-1-yl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (189 mg, 0.572 mmol), 2-[(3S)-3-methoxypyrrolidin-1-yl]ethanol (83.1 mg, 0.572 mmol), DMAP (105 mg, 0.858 mmol), EDCI • HCl (164 mg, 0.858 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and concentrated, the residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 5% methanol in ethyl acetate) to give 2-[(3S)-3-methoxypyrrolidin-1-yl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (117 mg, 45%) as a lightly yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.30 (dd, 2H), 6.96 (br t, 2H), 6.10-5.80 (br, 1H), 4.41 (t, 2H), 4.00 (d, 1H), 3.94-3.90 (m, 2H), 3.28 (s, 3H), 2.85-2.76 (m, 4H), 2.67 (dd, 1H), 2.55 (dd, 1H), 2.20 (br s, 3H), 2.10-2.01 (m, 1H), 1.86-1.78 (m, 1H); LC-MS (ESI) m/z 459.3 [M+H]⁺.

Example 387

Octane-1,8-diyl bis{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate}

To a solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (289 mg, 0.872 mmol) in DMF (1.0 mL) was added K₂CO₃ (145 mg, 1.05 mmol) and 1,6-dibromohexane (106 mg, 0.436 mmol). The solution was stirred at 60° C. for 20 h and cooled to room temperature. The solution was quenched with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40% 0-80% ethyl acetate in n-hexane) to give octane-1,8-diyl bis {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate} (269 mg, 40%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.85 (br s, 2H), 7.74 (br s, 2H), 7.31 (dd, 4H), 6.95 (br t, 4H), 6.10-5.70 (br, 2H), 4.25 (t, 4H), 4.01 (d, 2H), 3.92 (d, 2H), 2.19 (br s, 6H), 1.73-1.68 (m, 4H), 1.36-1.26 (m, 8H); LC-MS (ESI) m/z 773.3 [M+H]⁺.

Example 388

1-(Pyridin-3-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3-pyridylmethylcarbinol (93.0 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 1-(pyridin-3-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.220 g, 95%). ¹H NMR (CDCl₃, 300 MHz) δ 8.68 (s, 1H), 8.56 (br s, 1H), 7.87 (s, 1H), 7.76 (br d, 1H), 7.71 (d, 1H), 7.33-7.28 (m, 4H), 6.95 (br t, 2H), 6.09 (q, 1H), 5.94 (br s, 1H), 4.00 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H), 1.66 (d, 3H); LC-MS (ESI) m/z 437.1 [M+H]⁺.

Example 389

1-(Pyridin-4-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol),4-pyridylmethylcarbinol (80.4 μL, 0.816 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 1-(pyridin-4-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.190 g, 80%). ¹H NMR (CDCl₃, 300 MHz) δ 8.59 (br d, 2H), 7.90 (br s, 1H), 7.79 (br d, 1H), 7.34-7.28 (m, 5H), 6.96 (br t, 2H), 6.02 (q, 1H), 5.96 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 2.22 (br s, 3H), 1.61 (d, 3H); LC-MS (ESI) m/z 437.1 [M+H]⁺.

Example 390

2-(Pyridin-4-yl)propan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(4-pyridyl)-2-propanol (74.6 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 2-(pyridin-4-yl)propan-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (83.5 mg, 34%). ¹H NMR (CDCl₃, 400 MHz) δ 8.56 (d, 2H), 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33 (dd, 2H), 7.29-7.24 (m, 2H), 6.98 (br t, 2H), 6.10-5.80 (br, 1H), 4.02 (d, 1H), 3.92 (d, 1H), 2.21 (br s, 3H), 1.83 (s, 6H); LC-MS (ESI) m/z 451.1 [M+H]⁺.

Example 391

Pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 3-pyridinol (51.7 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.206 g, 93%). ¹H NMR (CDCl₃, 400 MHz) δ 8.53-8.50 (m, 2H), 8.04 (br s, 1H), 7.91 (br s, 1H), 7.55 (d, 1H), 7.39-7.32 (m, 3H), 6.98 (br t, 2H), 4.02 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 408.9 [M+H]⁺.

Example 392

Pyridin-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-pyridinol (51.7 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give pyridin-2-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (93.8 mg, 42%). ¹H NMR (CDCl₃, 400 MHz) δ 8.44 (d, 1H), 8.05 (br s, 1H), 7.94 (br s, 1H), 7.83 (t, 1H), 7.32 (dd, 2H), 7.28-7.25 (m, 1H), 7.17 (d, 1H), 6.97 (br t, 2H), 4.02 (d, 1H), 3.94 (d, 1H), 2.23 (br s, 3H); LC-MS (ESI) m/z 409.2 [M+H]⁺.

Example 393

Pyridin-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.174 g, 0.530 mmol), 2-pyridinol (50.0 mg, 0.530 mmol), EDCI • HCl (0.200 g, 1.05 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give pyridin-4-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.129 g, 60%). ¹H NMR (CDCl₃, 400 MHz) δ 8.66 (d, 2H), 8.01 (br s, 1H), 7.91 (br s, 1H), 7.34 (dd, 2H), 7.19 (d, 2H), 6.98 (br t, 2H), 4.02 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 409.3 [M+H]⁺.

Example 394

4-Methylpyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (126 mg, 0.380 mmol), 3-hydroxy-4-methylpyridine (41.5 mg, 0.380 mmol), EDCI • HCl (109 mg, 0.570 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 4-methylpyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (102 mg, 63%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.39 (d, 1H), 8.35 (s, 1H), 8.05 (br s, 1H), 7.93 (br d, 1H), 7.35 (dd, 2H), 7.22 (d, 1H), 6.99 (t, 2H), 6.10-5.90 (br, 1H), 4.03 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H), 2.23 (s, 3H); LC-MS (ESI) m/z 423.1 [M+H]⁺.

Example 395

6-Methylpyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (122 mg, 0.368 mmol), 5-hydroxy-2-methylpyridine (40.2 mg, 0.368 mmol), EDCI • HCl (106 mg, 0.552 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 6-methylpyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (114 mg, 74%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 8.02 (br s, 1H), 7.91 (br d, 1H), 7.43 (dd, 1H), 7.34 (dd, 2H), 7.21 (d, 1H), 6.98 (t, 2H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.58 (s, 3H), 2.25 (br s, 3H); LC-MS (ESI) m/z 423.2 [M+H]⁺.

Example 396

5-Methylpyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (126 mg, 0.380 mmol), 3-hydroxy-5-methylpyridine (41.5 mg, 0.380 mmol), DMAP (69.6 mg, 0.570 mmol), EDCI • HCl (109 mg, 0.570 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 5-methylpyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (104 mg, 65%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 8.35 (s, 1H), 8.30 (d, 1H), 8.02 (br s, 1H), 7.90 (br d, 1H), 7.36-7.32 (m, 3H), 6.98 (t, 2H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.38 (s, 3H), 2.25 (br s, 3H); LC-MS (ESI) m/z 423.2 [M+H]⁺.

Example 397

2-Fluoropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (124 mg, 0.374 mmol), 2-fluoro-3-hydroxypyridine (42.3 mg, 0.374 mmol), DMAP (68.5 mg, 0.561 mmol), EDCI • HCl (108 mg, 0.561 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 2-fluoropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (108 mg, 68%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.11 (d, 1H), 8.03 (br s, 1H), 7.90 (br d, 1H), 7.67 (dd, 1H), 7.34 (dd, 2H), 7.27-7.24 (m, 1H), 6.99 (br t, 2H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 449.2 [M+Na]⁺.

Example 398

6-Fluoropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (124 mg, 0.374 mmol), 6-fluoro-3-hydroxypyridine (42.3 mg, 0.374 mmol), DMAP (68.5 mg, 0.561 mmol), EDCI • HCl (108 mg, 0.561 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 6-fluoropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (87.5 mg, 55%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 8.09 (s, 1H), 8.02 (br s, 1H), 7.90 (br d, 1H), 7.67-7.62 (m, 1H), 7.34 (dd, 2H), 7.01-6.96 (m, 3H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 449.1 [M+Na]⁺.

Example 399

5-Fluoropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (115 mg, 0.347 mmol), 3-fluoro-5-hydroxypyridine (39.2 mg, 0.347 mmol), DMAP (63.6 mg, 0.521 mmol), EDCI • HCl (99.8 mg, 0.521 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 5-fluoropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (89.5 mg, 60%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.42 (d, 1H), 8.37 (s, 1H), 8.02 (br s, 1H), 7.90 (br d, 1H), 7.40-7.32 (m, 3H), 6.98 (t, 2H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 427.2 [M+H]⁺.

Example 400

5-Chloropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (97.4 mg, 0.294 mmol), 5-chloro-3-hydroxypyridine (38.1 mg, 0.294 mmol), EDCI • HCl (84.5 mg, 0.441 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 50% ethyl acetate in n-hexane) to give 5-chloropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (46.1 mg, 35%) as a colorless gum. ¹H NMR (CDCl₃, 300 MHz) δ 8.50 (d, 1H), 8.41 (d, 1H), 8.01 (br s, 1H), 7.90 (br d, 1H), 7.62 (s, 1H), 7.36-7.32 (m, 2H), 6.98 (t, 2H), 6.10-5.90 (br, 1H), 4.03 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 443.2 [M+H]⁺.

Example 401

6-Chloropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (112 mg, 0.338 mmol), 2-chloro-5-hydroxypyridine (43.8 mg, 0.338 mmol), DMAP (41.3 mg, 0.338 mmol), EDCI • HCl (97.2 mg, 0.507 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 40% ethyl acetate in n-hexane) to give 6-chloropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (93.1 mg, 62%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 8.29 (d, 1H), 8.02 (br s, 1H), 7.89 (br d, 1H), 7.54 (dd, 1H), 7.39 (d, 1H), 7.34 (dd, 2H), 6.98 (t, 2H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.26 (br s, 3H); LC-MS (ESI) m/z 465.1 [M+Na]⁺.

Example 402

2-Chloropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (135 mg, 0.407 mmol), 2-chloro-3-hydroxypyridine (52.8 mg, 0.407 mmol), DMAP (74.6 mg, 0.611 mmol), EDCI • HCl (116 mg, 0.611 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 50% ethyl acetate in n-hexane) to give 2-chloropyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (89.4 mg, 50%) as a lightly beige solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.33 (dd, 1H), 8.06 (br s, 1H), 7.94 (br d, 1H), 7.61 (dd, 1H), 7.37-7.31 (m, 3H), 6.99 (t, 2H), 6.10-5.90 (br, 1H), 4.03 (d, 1H), 3.94 (d, 1H), 2.27 (br s, 3H); LC-MS (ESI) m/z 443.1 [M+H]⁺.

Example 403

2-(Morpholin-4-ylmethyl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(morpholin-4-ylmethyl)pyridin-3-ol

To the solution of 3-pyridinol (0.500 g, 5.26 mmol) in benzene (40.0 mL), morpholine (0.550 mL, 6.31 mmol) and paraformaldehyde (0.440 mL, 6.31 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-(morpholin-4-ylmethyl)pyridin-3-ol (0.950 g, 93%). ¹H NMR (CDCl₃, 400 MHz) δ 8.02 (d, 1H), 7.13-7.07 (m, 2H), 3.92 (s, 2H), 3.77 (br s, 4H), 2.63 (br s, 4H).

Step 2. Synthesis of 2-(morpholin-4-ylmethyl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(morpholin-4-ylmethyl)pyridin-3-ol (0.110 g, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-75% ethyl acetate in n-hexane) to give 2-(morpholin-4-ylmethyl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (68.7 mg, 25%). ¹H NMR (CDCl₃, 400 MHz) δ 8.49 (dd, 1H), 8.03 (br s, 1H), 7.92 (br d, 1H), 7.47 (dd, 1H), 7.37-7.30 (m, 3H), 6.98 (br t, 2H), 4.02 (d, 1H), 3.95 (d, 1H), 3.65 (s, 2H), 3.34 (br s, 4H), 2.34-2.20 (m, 7H); LC-MS (ESI) m/z 508.2 [M+H]⁺.

Example 404

5-(Morpholin-4-yl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (110 mg, 0.332 mmol), 5-(morpholin-4-yl)pyridin-3-ol (59.8 mg, 0.332 mmol), EDCI • HCl (95.5 mg, 0.498 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 20% ethyl acetate in CH₂Cl₂) to give 5-(morpholin-4-yl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (57.4 mg, 35%) as a lightly yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.06 (s, 1H), 8.02 (br s, 1H), 7.89 (br s, 1H), 7.37-7.32 (m, 3H), 6.98 (t, 2H), 6.66 (d, 1H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 3.83 (dd, 4H), 3.49 (dd, 4H), 2.24 (br s, 3H); LC-MS (ESI) m/z 494.1 [M+H]⁺.

Example 405

6-(Morpholin-4-yl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (121 mg, 0.365 mmol), 6-(morpholin-4-yl)pyridin-3-ol (65.8 mg, 0.365 mmol), DMAP (66.9 mg, 0.548 mmol), EDCI • HCl (105 mg, 0.548 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 70% ethyl acetate in n-hexane) to give 6-(morpholin-4-yl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (48.2 mg, 27%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.20 (d, 1H), 8.02-8.00 (m, 2H), 7.90 (br s, 1H), 7.34 (dd, 2H), 7.00-6.96 (m, 3H), 6.10-5.90 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 3.86 (dd, 4H), 3.21 (dd, 4H), 2.25 (br s, 3H); LC-MS (ESI) m/z 494.2 [M+H]⁺.

Example 406

2-(Pyridin-2-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-pyridineethanol (61.0 μL, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(pyridin-2-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.190 g, 80%). ¹H NMR (CDCl₃, 300 MHz) δ 8.55 (d, 1H), 7.80 (br s, 1H), 7.68 (br s, 1H), 7.61 (t, 1H), 7.32-7.27 (m, 2H), 7.21-7.13 (m, 2H), 6.95 (t, 2H), 4.66 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.21 (t, 2H), 2.17 (br s, 3H); LC-MS (ESI) m/z 437.1 [M+H]⁺.

Example 407

2-({4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-3-carboxylate

Step 1. Synthesis of pyridine-3-carbonyl chloride

A solution of nicotinic acid (0.220 g) in SOCl₂ (5.0 mL) was carried out the reaction. After the reaction was stirred at 55° C. for 3 h and work-up, the residue was used directly for next step without further purification. (0.300 g, crude yield 99%). ¹H NMR (DMSO-d₆, 400 MHz) δ 9.17 (s, 1H), 8.96 (d, 1H), 8.64 (d, 1H), 7.91-7.87 (m, 1H).

Step 2. Synthesis of 2-chloroethyl pyridine-3-carboxylate

A solution of pyridine-3-carbonyl chloride (0.280 g, 1.57 mmol) in pyridine (10.0 mL) and 2-chloroehtanol (0.210 mL, 3.15 mmol) were used to carry out the reaction. After the reaction was stirred at 100° C. for 3 h and work-up, the residue was used directly for next step without further purification. (82.8 mg, crude yield 29%). ¹H NMR (CDCl₃, 400 MHz) δ 9.29 (s, 1H), 8.87-8.86 (m, 1H), 8.50 (br d, 1H), 7.59 (dd, 1H), 4.65-4.62 (m, 2H), 3.85-3.82 (m, 2H).

Step 3. Synthesis of 2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-3-carboxylate

Following standard procedure L, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.148 g, 0.450 mmol), 2-chloroethyl pyridine-3-carboxylate (82.8 mg, 0.450 mmol), K₂CO₃ (68.0 g, 0.490 mmol) and DMF (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-3-carboxylate (0.110 g, 51%). ¹H NMR (CDCl₃, 400 MHz) δ 9.22 (s, 1H), 8.79-8.78 (m, 1H), 8.29 (d, 1H), 7.87 (br s, 1H), 7.75 (br s, 1H), 7.42-7.38 (m, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.66-4.62 (m, 4H), 4.00 (d, 1H), 3.91 (d, 1H), 2.19 (br s, 3H); LC-MS (ESI) m/z 481.1[M+H]⁺.

Example 408

2-({4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-4-carboxylate

Step 1. Synthesis of 2-hydroxyethyl pyridine-4-carboxylate

To the solution of 2-bromoethanol (0.380 mL, 5.36 mmol) in DMF (10.0 mL), isonicotinic acid (0.600 g, 4.87 mmol) and K₂CO₃ (0.740 g, 5.36 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 60° C. for 16 h and work-up, the residue was used directly for next step without further purification. (0.350 g, crude yield 43%). ¹H NMR (CDCl₃, 300 MHz) δ 8.80-8.77 (m, 2H), 7.87-7.84 (m, 2H), 4.52-4.49 (m, 4H), 3.99 (dd, 1H).

Step 2. Synthesis of 2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-4-carboxylate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-hydroxyethyl pyridine-4-carboxylate (90.8 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-4-carboxylate (0.168 g, 64%). ¹H NMR (CDCl₃, 400 MHz) δ 8.78 (dd, 2H), 7.86 (br s, 1H), 7.83 (dd, 2H), 7.75 (br s, 1H), 7.32-7.27 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.67-4.61 (m, 4H), 4.00 (d, 1H), 3.92 (d, 1H), 2.19 (br s, 3H); LC-MS (ESI) m/z 481.1 [M+H]⁺.

Example 409

2-({4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-2-carboxylate

Step 1. Synthesis of 2-hydroxyethyl pyridine-2-carboxylate

To the solution of 2-bromoethanol (0.380 mL, 5.36 mmol) in DMF (10.0 mL), picolinic acid (0.600 g, 4.87 mmol) and K₂CO₃ (0.740 g, 5.36 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 60° C. for 16 h and work-up, the residue was used directly for next step without further purification. (0.160 g, curde yield 20%). ¹H NMR (CDCl₃, 400 MHz) δ 8.73 (d, 1H), 8.17 (d, 1H), 7.87 (t, 1H), 7.53-7.47 (m, 1H), 4.53-4.52 (m, 2H), 4.01-3.99 (m, 2H).

Step 2. Synthesis of 2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-2-carboxylate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-hydroxyethyl pyridine-2-carboxylate (90.8 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 2-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}oxy)ethyl pyridine-2-carboxylate (0.106 g, 46%). ¹H NMR (CDCl₃, 300 MHz) δ 8.77 (br d, 1H), 8.12 (d, 1H), 7.87-7.82 (m, 2H), 7.75 (br s, 1H), 7.50 (dd, 1H), 7.31-7.25 (m, 3H), 6.94 (br t, 2H), 4.75-4.72 (m, 2H), 4.65-4.62 (m, 2H), 3.99 (d, 1H), 3.91 (d, 1H), 2.17 (br s, 3H); LC-MS (ESI) m/z 503.1 [M+Na]⁺.

Example 410

2-(Pyridin-4-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-4-ylmethoxy)ethanol

To the solution of ethylene glycol (0.490 g, 7.91 mmol) in THF (10.0 mL), 4-(bromomethyl)pyridine (0.200 g, 0.790 mmol) and sodium hydride (47.4 mg, 1.19 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-100% ethyl acetate in n-hexane) to give 2-(pyridin-4-ylmethoxy)ethanol (42.6 mg, 35%). ¹H NMR (CDCl₃, 300 MHz) δ 8.58 (br s, 2H), 7.28 (br s, 2H), 4.59 (br s, 2H), 3.83-3.81 (m, 2H), 3.66-3.64 (m, 2H).

Step 2. Synthesis of 2-(pyridin-4-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (92.1 mg, 0.278 mmol), 2-(pyridin-4-ylmethoxy)ethanol (42.6 mg, 0.278 mmol), EDCI • HCl (0.110 g, 0.556 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-90% ethyl acetate in n-hexane) to give 2-(pyridin-4-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (10.5 mg, 8%). ¹H NMR (CDCl₃, 400 MHz) δ 8.55 (br s, 2H), 7.88 (br s, 1H), 7.76 (br s, 1H), 7.33-7.30 (m, 2H), 7.29-7.30 (m, 2H), 6.97 (br t, 2H), 4.59 (s, 2H), 4.48 (br s, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.80 (br s, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 467.1 [M+H]⁺.

Example 411

2-(Pyridin-2-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-2-ylmethoxy)ethanol

To the solution of ethylene glycol (0.130 mL, 2.37 mmol) in THF (5.0 mL), 2-(bromomethyl)pyridine (0.300 g, 1.19 mmol) and sodium hydride (71.1 mg, 1.78 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 2-(pyridin-2-ylmethoxy)ethanol (0.110 g, 61/%). ¹H NMR (CDCl₃, 400 MHz) δ 8.57 (d, 1H), 7.70 (t, 1H), 7.36 (d, 1H), 7.24-7.20 (m, 1H), 4.71 (s, 2H), 3.82-3.79 (m, 2H), 3.76-3.73 (m, 2H).

Step 2. Synthesis of 2-(pyridin-2-ylmethoxy)ethyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.21 g, 0.653 mmol), 2-(pyridin-2-ylmethoxy)ethanol (0.110 g, 0.719 mmol), EDCI • HCl (0.240 g, 1.27 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 2-(pyridin-2-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (38.2 mg, 13%). ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (d, 1H), 7.87 (br s, 1H), 7.77 (br s, 1H), 7.63 (t, 1H), 7.42 (d, 1H), 7.32-7.29 (m, 2H), 7.18 (dd, 1H), 6.95 (br t, 2H), 5.96 (br s, 1H), 4.71 (s, 2H), 4.49-4.47 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.89-3.85 (m, 2H), 2.19 (br s, 3H); LC-MS (APCI) m/z 467.7 [M+H]⁺.

Example 412

2-(Pyridin-3-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-3-ylmethoxy)ethanol

To the solution of ethylene glycol (0.130 mL, 2.37 mmol) in THF (10.0 mL), 3-(bromomethyl)pyridine (0.300 g, 1.18 mmol) and sodium hydride (71.1 mg, 1.78 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-100% ethyl acetate in n-hexane) to give 2-(pyridin-3-ylmethoxy)ethanol (61.3 mg, 19%). ¹H NMR (CDCl₃, 300 MHz) δ 8.58 (s, 1H), 8.55 (d, 1H), 7.70 (d, 1H), 7.30 (dd, 1H), 4.58 (s, 2H), 3.80-3.77 (m, 2H), 3.64-3.61 (m, 2H).

Step 2. Synthesis of 2-(pyridin-3-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.130 g, 0.393 mmol), 2-(pyridin-3-ylmethoxy)ethanol (61.3 mg, 0.393 mmol), EDCI • HCl (0.150 g, 0.785 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-90% ethyl acetate in n-hexane) to give less 2-(pyridin-3-ylmethoxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate. ¹H NMR (CDCl₃, 400 MHz) δ 8.58 (s, 1H), 8.54 (br d, 1H), 7.87 (br s, 1H), 7.75 (br s, 1H), 7.67 (d, 1H), 7.31 (dd, 2H), 7.26-7.23 (m, 1H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 4.59 (s, 2H), 4.46 (dd, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.79 (dd, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 467.2 [M+H]⁺.

Example 413

2-(Pyridin-3-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-3-yloxy)ethanol

To the solution of ethylene glycol (1.90 mL, 3.41 mmol), 3-bromopyridine (0.180 mL, 1.90 mmol), CuCl₂ (12.8 mg, 0.0900 mmol) and K₂CO₃ (0.790 g, 5.70 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 130° C. for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 10% MeOH in CH₂Cl₂) to give 2-(pyridin-3-yloxy)ethanol (67.7 mg, 26%). ¹H NMR (CDCl₃, 300 MHz) δ 8.33 (br s, 1H), 8.24 (br t, 1H), 7.24-7.22 (m, 2H), 4.14 (dd, 2H), 3.99 (dd, 2H).

Step 2. Synthesis of 2-(pyridin-3-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.160 g, 0.487 mmol), 2-(pyridin-3-yloxy)ethanol (67.7 mg, 0.487 mmol), EDCI • HCl (0.190 g, 0.967 mmol), DMAP (0.130 g, 1.06 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 50% ethyl acetate in n-hexane) to give 2-(pyridin-3-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.168 g, 77%). ¹H NMR (CDCl₃, 400 MHz) δ 8.35 (br s, 1H), 8.25 (br s, 1H), 7.86 (br s, 1H), 7.76 (br s, 1H), 7.30 (dd, 2H), 7.24-7.20 (m, 2H), 6.95 (br t, 2H), 5.94 (br s, 1H), 4.67-4.62 (m, 2H), 4.33-4.31 (m, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 453.2 [M+H]⁺.

Example 414

2-(Pyridin-2-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-2-yloxy)ethanol

To the solution of ethylene glycol (3.80 mL, 6.84 mmol), 2-bromopyridine (0.360 mL, 3.80 mmol), CuCl₂ (25.5 mg, 0.190 mmol) and K₂CO₃ (1.57 g, 11.4 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 130° C. for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 10% MeOH in CH₂Cl₂) to give 2-(pyridin-2-yloxy)ethanol (60.6 mg, 12%). ¹H NMR (CDCl₃, 300 MHz) δ 8.11 (d, 1H), 7.60 (dd, 1H), 6.90 (dd, 1H), 6.80 (d, 1H), 4.48-4.45 (m, 2H), 3.96-3.93 (m, 2H), 3.84 (br s, 1H).

Step 2. Synthesis of 2-(pyridin-2-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.140 g, 0.436 mmol), 2-(pyridin-2-yloxy)ethanol (60.6 mg, 0.436 mmol), EDCI • HCl (0.170 g, 0.871 mmol), DMAP (0.120 g, 0.950 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(pyridin-2-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.168 g, 88%). ¹H NMR (CDCl₃, 400 MHz) δ 8.12 (br d, 1H), 7.85 (br s, 1H), 7.74 (br s, 1H), 7.58 (dd, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 6.87 (dd, 1H), 6.76 (d, 1H), 6.10-5.80 (br s, 1H), 4.64-4.62 (br, 4H), 4.00 (d, 1H), 3.91 (d, 1H), 2.18 (br s, 3H); LC-MS (ESI) m/z 453.2 [M+H]⁺.

Example 415

2-(Pyridin-4-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-4-yloxy)ethanol

To the solution of ethylene glycol (3.80 mL, 6.84 mmol), 4-bromopyridine (0.360 mL, 3.80 mmol), CuCl₂ (20.7 mg, 0.150 mmol) and K₂CO₃ (1.28 g, 9.26 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 130° C. for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 10% MeOH in CH₂Cl₂) to give 2-(pyridin-4-yloxy)ethanol (26.9 mg, 6%). 1H NMR (CDCl₃, 300 MHz) δ 8.43 (d, 2H), 6.83 (d, 2H), 4.14 (t, 2H), 4.00 (t, 2H).

Step 2. Synthesis of 2-(pyridin-4-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (64.0 mg, 0.193 mmol), 2-(pyridin-4-yloxy)ethanol (26.9 mg, 0.193 mmol), EDCI • HCl (74.2 mg, 0.387 mmol), DMAP (52.0 mg, 0.426 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 50% ethyl acetate in n-hexane) to give 2-(pyridin-4-yloxy)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (46.7 mg, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.44 (d, 2H), 7.86 (br s, 1H), 7.75 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 6.83 (d, 2H), 6.10-5.82 (br, 1H), 4.67-4.62 (m, 2H), 4.32 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 453.1 [M+H]⁺.

Example 416

5-(Pyridin-2-ylmethoxy)pentyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of [(5-bromopentyl)oxy](tert-butyl)dimethylsilane

A solution of 5-bromo-1-pentanol (0.80 mL, 6.64 mmol), tert-butyldimethylsilyl chloride (1.20 g, 7.97 mmol) and imidazole (0.542 g, 7.97 mmol) in CH₂Cl₂ (30 mL) was stirred at room temperature for 18 h. The solution was washed with 1 N HCl_(aq), dried over MgSO_4(s), filtered, and concentrated to give [(5-bromopentyl)oxy](tert-butyl)dimethylsilane (1.62 g, 87%) as a colorless oil. ¹H NMR (CDCl₃, 400 MHz) δ 3.61 (t, 2H), 3.41 (t, 2H), 1.87 (quint, 2H), 1.57-1.48 (m, 4H), 0.88 (s, 9H), 0.05 (s, 6H).

Step 2. Synthesis of 2-{[(5-{[tert-butyl(dimethyl)silyl]oxy}pentyl)oxy]methyl}pyridine

To a solution of pyridine-2-methanol (194 mg, 1.78 mmol) in THF (10 mL) was added 60% NaH in mineral oil (85.4 mg, 2.14 mmol) at 0° C., and it was stirred for 30 min. Then a solution of [(5-bromopentyl)oxy](tert-butyl)dimethylsilane (550 mg, 1.96 mmol) in THF (3.0 mL) was added to the reaction mixture. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 2-{[(5-{[tert-butyl(dimethyl)silyl]oxy}pentyl)oxy]methyl}pyridine (428 mg, 78%) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ 8.54 (dd, 1H), 7.69 (td, 1H), 7.44 (d, 1H), 7.19-7.15 (m, 1H), 4.62 (s, 2H), 3.63-3.54 (m, 2H), 3.41 (t, 2H), 1.70-1.44 (m, 6H), 0.88 (s, 9H), 0.04 (s, 6H).

Step 3. Synthesis of 5-(pyridin-2-ylmethoxy)pentan-1-ol

A solution of 2-{[(5-{[tert-butyl(dimethyl)silyl]oxy}pentyl)oxy]methyl}pyridine (0.428 g, 1.38 mmol) in ethanol (5.0 mL) and 12 M HCl_(aq) (0.50 mL) was stirred at room temperature for 3 h and then concentrated. The residue was treated with saturated NaHCO_3(aq) and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The crude product was purified by Isco Combi-Flash Companion column chromatography (0-5% methanol in CH₂Cl₂) to give 5-(pyridin-2-ylmethoxy)pentan-1-ol (116 mg, 51%) as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ 8.53 (d, 1H), 7.69 (td, 1H), 7.43 (d, 1H), 7.19-7.15 (m, 1H), 4.62 (s, 2H), 3.65 (t, 2H), 3.57 (t, 2H), 1.73-1.44 (m, 6H).

Step 4. Synthesis of 5-(pyridin-2-ylmethoxy)pentyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (175 mg, 0.528 mmol), 5-(pyridin-2-ylmethoxy)pentan-1-ol (103 mg, 0.528 mmol), EDCI • HCl (152 mg, 0.791 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 5-(pyridin-2-ylmethoxy)pentyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (72.7 mg, 27%) as a lightly yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.54 (d, 1H), 7.85 (br s, 1H), 7.74 (br s, 1H), 7.67 (td, 1H), 7.42 (d, 1H), 7.32-7.29 (m, 2H), 7.18 (dd, 1H), 6.95 (br t, 2H), 6.05-5.80 (br, 1H), 4.62 (s, 2H), 4.28 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.57 (t, 2H), 2.19 (br s, 3H), 1.80-1.67 (m, 4H), 1.56-1.48 (m, 2H); LC-MS (ESI) m/z 509.3 [M+H]⁺.

Example 417

2-[(Pyridin-3-ylmethyl)sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[(pyridin-3-ylmethyl)sulfanyl]ethanol

To the solution of 2-mercaptoethanol (0.143 mL, 2.08 mmol) in DMF (5.0 mL), 3-(bromomethyl)pyridine (0.500 g, 1.98 mmol) and Cs₂CO₃ (0.680 g, 2.08 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 60° C. for 4 h, 6 h at room temperature and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 75% ethyl acetate in n-hexane) to give 2-[(pyridin-3-ylmethyl)sulfanyl]ethanol (50.0 mg, 17%). ¹H NMR (CDCl₃, 400 MHz) δ 8.51 (s, 1H), 8.49-8.47 (m, 1H), 7.70-7.68 (m, 1H), 7.28-7.25 (m, 1H), 3.73-3.70 (m, 4H), 2.67-2.61 (m, 2H).

Step 2. Synthesis of 2-[(pyridin-3-ylmethyl)sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.100 g, 0.297 mmol), 2-[(pyridin-3-ylmethyl)sulfanyl]ethanol (50.0 mg, 0.327 mmol), EDCI • HCl (0.120 g, 0.604 mmol), DMAP (81.2 mg, 0.664 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-[(pyridin-3-ylmethyl) sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (93.3 mg, 64%). ¹H NMR (CDCl₃, 400 MHz) δ 8.55 (s, 1H), 8.50 (dd, 1H), 7.85 (br s, 1H), 7.74 (br d, 1H), 7.69 (dd, 2H), 7.33-7.28 (m, 2H), 7.27-7.21 (m, 1H), 6.97 (br t, 2H), 6.10-5.80 (br, 1H), 4.39 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.78 (s, 2H), 2.74 (t, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 483.6 [M+H]⁺.

Example 418

2-[(Pyridin-2-ylmethyl)sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[(pyridin-2-ylmethyl)sulfanyl]ethanol

To the solution of 2-mercaptoethanol (0.150 mL, 2.08 mmol) in DMF (5.0 mL), 2-(bromomethyl)pyridine (0.500 g, 1.98 mmol) and Cs₂CO₃ (0.680 g, 2.08 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 60° C. for 4 h, 6 h at room temperature and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 75% ethyl acetate in n-hexane) to give 2-[(pyridin-2-ylmethyl)sulfanyl]ethanol (91.5 mg, 30%). ¹H NMR (CDCl₃, 400 MHz) δ 8.53 (dd, 1H), 7.67 (t, 1H), 7.29-7.25 (m, 1H), 7.19 (dd, 1H), 3.91 (s, 2H), 3.86-3.82 (m, 2H), 2.80-2.77 (m, 2H).

Step 2. Synthesis of 2-[(pyridin-2-ylmethyl)sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-[(pyridin-2-ylmethyl)sulfanyl]ethanol (91.5 mg, 0.598 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 2-[(pyridin-2-ylmethyl) sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.148 g, 57%). ¹H NMR (CDCl₃, 400 MHz) δ 8.52 (dd, 1H), 7.86 (br s, 1H), 7.74 (br s, 1H), 7.64 (t, 1H), 7.36 (d, 1H), 7.32-7.28 (m, 2H), 7.16 (dd, 1H), 6.95 (br t, 2H), 4.38 (t, 2H), 4.00 (d, 1H), 3.94-3.85 (m, 3H), 2.84 (t, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 483.6 [M+H]⁺.

Example 419

2-[(Pyridin-4-ylmethyl)sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-[(pyridin-4-ylmethyl)sulfanyl]ethanol

To the solution of 2-mercaptoethanol (0.150 mL, 2.08 mmol) in DMF (5.0 mL), 4-(bromomethyl)pyridine (0.500 g, 1.98 mmol) and Cs₂CO₃ (0.680 g, 2.08 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 60° C. for 4 h, 6 h at room temperature and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 80% ethyl acetate in n-hexane) to give 2-[(pyridin-4-ylmethyl)sulfanyl]ethanol (61.0 mg, 20%). ¹H NMR (CDCl₃, 400 MHz) δ 8.55 (dd, 2H), 7.27-7.26 (m, 2H), 3.73-3.70 (m, 4H), 2.63 (t, 2H).

Step 2. Synthesis of 2-[(pyridin-4-ylmethyl)sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.120 g, 0.362 mmol), 2-[(pyridin-4-ylmethyl)sulfanyl]ethanol (61.0 mg, 0.398 mmol), EDCI • HCl (0.140 g, 0.725 mmol), DMAP (97.4 mg, 0.797 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 50% ethyl acetate in n-hexane) to give 2-[(pyridin-4-ylmethyl) sulfanyl]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (92.2 mg, 53%). ¹H NMR (CDCl₃, 400 MHz) δ 8.55 (dd, 2H), 7.85 (br s, 1H), 7.73 (br s, 1H), 7.33-7.28 (m, 2H), 7.27-7.26 (m, 2H), 6.95 (br t, 2H), 6.08-5.80 (br, 1H), 4.39 (t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 3.72 (s, 2H), 2.73 (t, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 483.5 [M+H]⁺.

Example 420

2-(Pyridin-4-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-4-ylsulfanyl)ethanol

To the solution of 4-mercaptopyridine (0.300 g, 2.70 mmol) in H₂O (30.0 mL), 2-chloroethanol (0.200 mL, 2.97 mmol) and sodium hydride (0.300 g, 8.10 mmol) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 1 h and work-up, the residue was used directly for next step without further purification (0.310 g, curde yield 74%). ¹H NMR (CDCl₃, 400 MHz) δ 8.42-8.38 (m, 2H), 7.17-7.14 (m, 2H), 3.90-3.87 (m, 2H), 3.22-3.19 (m, 2H).

Step 2. Synthesis of 2-(pyridin-4-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(pyridin-4-ylsulfanyl)ethanol (84.0 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 60% ethyl acetate in n-hexane) to give 2-(pyridin-4-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.180 g, 71%). ¹H NMR (CDCl₃, 400 MHz) δ 8.41 (d, 2H), 7.81 (br s, 1H), 7.68 (br d, 1H), 7.31 (dd, 2H), 7.20 (d, 2H), 6.96 (br t, 2H), 4.53-4.47 (m, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.32 (t, 2H), 2.19 (br s, 3H); LC-MS (ESI) m/z 469.6 [M+H]⁺.

Example 421

2-(Pyridin-2-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 2-(pyridin-2-ylsulfanyl)ethanol

To the solution of 2-mercaptopyridine (0.300 g, 2.70 mmol) in H₂O (30.0 mL), 2-chloroethanol (0.200 mL, 2.97 mmol) and sodium hydride (0.300 g, 8.10 mmol) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 1 h and work-up, the residue was used directly for next step without further purification (0.360 g, crude yield 86%). ¹H NMR (CDCl₃, 400 MHz) δ 8.38-8.37 (m, 1H), 7.51 (t, 1H), 7.29 (d, 1H), 7.04 (dd, 1H), 3.97 (t, 2H), 3.32 (t, 2H).

Step 2. Synthesis of 2-(pyridin-2-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 2-(pyridin-2-ylsulfanyl)ethanol (92.7 mg, 0.598 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-(pyridin-2-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.120 g, 47%). ¹H NMR (CDCl₃, 400 MHz) δ 8.39 (d, 2H), 7.82 (br s, 1H), 7.70 (br d, 1H), 7.46 (dd, 1H), 7.33-7.28 (m, 2H), 7.22-7.17 (m, 1H), 7.04-6.93 (m, 3H), 5.95 (br s, 1H), 4.50 (t, 2H), 4.00 (d, 1H), 3.93 (d, 1H), 3.54 (t, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 469.5 [M+H]⁺.

Example 422

2-(Pyridin-3-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step. Synthesis of 2-(pyridin-3-ylsulfanyl)ethanol

To the solution of 3-mercaptopyridine (39.0 mg, 0.350 mmol) in H₂O (5.0 mL), 2-chloroethanol (26.0 μL, 0.386 mmol) and sodium hydride (42.0 mg, 1.05 mmol) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 1 h and work-up, the residue was used directly for next step without further purification (5.00 mg, crude yield 9%). ¹H NMR (CDCl₃, 400 MHz) δ 8.63 (s, 1H), 8.46 (d, 1H), 7.73 (dd, 1H), 7.25-7.22 (m, 1H), 3.80-3.76 (m, 2H), 3.13 (t, 2H).

Step 2. Synthesis of 2-(pyridin-3-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (10.7 mg, 0.0320 mmol), 2-(pyridin-3-ylsulfanyl)ethanol (5.00 mg, 0.0320 mmol), EDCI • HCl (12.4 mg, 0.0640 mmol), DMAP (8.70 mg, 0.0710 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give 2-(pyridin-3-ylsulfanyl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (15.0 mg, 99%). ¹H NMR (CDCl₃, 400 MHz) δ 8.65 (br s, 1H), 8.42 (br d, 1H), 7.77 (br s, 1H), 7.72 (br d, 1H), 7.67 (br s, 1H), 7.33-7.28 (m, 2H), 7.20-7.17 (m, 1H), 6.98-6.94 (m, 2H), 5.95 (br s, 1H), 4.48-4.42 (m, 2H), 3.99 (d, 1H), 3.92 (d, 1H), 3.28-3.23 (m, 2H), 2.20 (br s, 3H); LC-MS (ESI) m/z 469.1 [M+H]⁺.

Example 423

2-(Pyridin-4-ylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of tert-butyl (2-hydroxyethyl)pyridin-4-ylcarbamate

A solution of 2-[(pyridine-4-yl)amino]ethan-1-ol (352 mg, 2.55 mmol) and di-tert-butyl dicarbonate (429 mg, 2.55 mmol) in ethanol (6.0 mL) was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure. The residue was purified by Isco Combi-Flash Companion column chromatography (0-10% methanol in CH₂Cl₂) to give tert-butyl (2-hydroxyethyl)pyridin-4-ylcarbamate (209 mg, 34%) as a colorless gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.21 (d, 2H), 6.46 (d, 2H), 4.54 (br s, 1H), 4.27 (t, 2H), 3.46 (q, 2H), 1.49 (s, 9H).

Step 2. Synthesis of 2-[(tert-butoxycarbonyl)(pyridin-4-yl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (163 mg, 0.492 mmol), tert-butyl (2-hydroxyethyl)pyridin-4-ylcarbamate (117 mg, 0.492 mmol), EDCI • HCl (141 mg, 0.738 mmol) and CH₂Cl₂ (2.0 mL) were used to carry out the reaction. After the reaction mixture was treated with CH₂Cl₂ and washed with H₂O. The organic layer was dried over MgSO_4(s), filtered, and concentrated to give 2-[(tert-butoxycarbonyl)(pyridin-4-yl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate which was directly used to next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 8.38 (d, 2H), 7.22 (dd, 2H), 6.94 (t, 2H), 6.87 (d, 2H), 6.00-5.80 (br, 1H), 4.35 (t, 2H), 4.14 (t, 2H), 3.94 (d, 1H), 3.86 (d, 1H), 2.05 (br s, 3H), 1.41 (s, 9H); LC-MS (ESI) m/z 552.2 [M+H]⁺.

Step 3. Synthesis of 2-(pyridin-4-ylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

A solution of 2-[(tert-butoxycarbonyl)(pyridin-4-yl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.492 mmol) in trifluoroacetic acid (2.50 mL) and CH₂Cl₂ (8.0 mL) was stirred at room temperature for 8 h. The solution was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 8% methanol in CH₂Cl₂) to give 2-(pyridin-4-ylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (126 mg, 57% by two steps) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.19 (d, 2H), 7.83 (br s, 1H), 7.72 (br s, 1H), 7.33-7.29 (m, 2H), 6.96 (br t, 2H), 6.49 (d, 2H), 6.10-5.80 (br, 1H), 4.65 (br s, 1H), 4.48 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.55 (q, 2H), 2.19 (br s, 3H); LC-MS (ESI) m/z 452.2 [M+H]⁺.

Example 424

2-(Pyridin-2-ylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of tert-butyl (2-hydroxyethyl)pyridin-2-ylcarbamate

A solution of 2-[(pyridine-2-yl)amino]ethan-1-ol (256 mg, 1.87 mmol), triethylamine (0.260 mL, 1.87 mmol), and di-tert-butyl dicarbonate (556 mg, 1.97 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature for 16 h. The solution was diluted with CH₂Cl₂ and washed with H₂O and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated to give tert-butyl (2-hydroxyethyl)pyridin-2-ylcarbamate (347 mg, 78%) as a colorless oil which was directly used to next step without further purification. ¹H NMR (CDCl₃, 400 MHz) δ 8.08 (dd, 1H), 7.42-7.37 (m, 1H), 6.59-6.57 (m, 1H), 6.41 (dd, 1H), 4.74 (br s, 1H), 4.26 (t, 2H), 3.63 (q, 2H), 1.48 (s, 9H).

Step 2. Synthesis of 2-[(tert-butoxycarbonyl)(pyridin-2-yl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

A solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (178 mg, 0.537 mmol) in thionyl chloride (2.0 mL) was stirred at 80° C. for 40 min. Thionyl chloride was removed under reduced pressure to afford a acyl chloride intermediate which was directly used to next step without further purification. To a solution of acyl chloride (0.537 mmol) in CH₂Cl₂ (5.0 mL) was added triethylamine (75.0 μL, 0.537 mmol) and tert-butyl (2-hydroxyethyl)pyridin-2-ylcarbamate (128 mg, 0.537 mmol), and the solution was stirred at room temperature for 8 h. After the reaction mixture was concentrated, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 70% ethyl acetate in n-hexane) to give 2-[(tert-butoxycarbonyl)(pyridin-2-yl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (189 mg, 64% by two steps) as a lightly brown solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 7.36 (dd, 1H), 7.24-7.20 (m, 4H), 7.03-7.00 (m, 1H), 6.92 (t, 2H), 6.67 (d, 1H), 6.00-5.70 (br, 1H), 4.37-4.31 (m, 4H), 3.94 (d, 1H), 3.86 (d, 1H), 2.04 (br s, 3H), 1.40 (s, 9H).

Step 3. Synthesis of 2-(pyridin-2-ylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

A solution of 2-[(tert-butoxycarbonyl)(pyridin-2-yl)amino]ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (189 mg, 0.343 mmol) in trifluoroacetic acid (2.0 mL) and CH₂Cl₂ (8.0 mL) was stirred at room temperature for 5 h. The solution was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 5% methanol in CH₂Cl₂) to give 2-(pyridin-2-ylamino)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (132 mg, 85%) as a yellow foam. ¹H NMR (CDCl₃, 400 MHz) δ 8.07 (d, 1H), 7.84 (br s, 1H), 7.74 (br s, 1H), 7.41 (dd, 1H), 7.32-7.29 (m, 2H), 6.96 (br t, 2H), 6.59 (dd, 1H), 6.44 (d, 1H), 6.10-5.80 (br, 1H), 4.86 (br s, 1H), 4.47 (t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.70 (q, 2H), 2.17 (br s, 3H); LC-MS (ESI) m/z 452.2 [M+H]⁺.

Example 425

2-(1-Methyl-1H-imidazol-5-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (147 mg, 0.444 mmol), 2-(1-methyl-1H-imidzol-5-yl)ethan-1-ol (56.0 mg, 0.444 mmol), EDCI • HCl (128 mg, 0.665 mmol), triethylamine (0.124 mL, 0.890 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 18 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-(1-methyl-1H-imidazol-5-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (74.3 mg, 38%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.83 (br s, 1H), 7.72 (br s, 1H), 7.41 (s, 1H), 7.32-7.28 (m, 2H), 6.95 (br t, 2H), 6.89 (s, 1H), 6.10-5.80 (br, 1H), 4.48 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.58 (s, 3H), 2.99 (t, 2H), 2.19 (br s, 3H); LC-MS (ESI) m/z 440.2 [M+H]⁺.

Example 426

2-(1-Methyl-1H-imidazol-2-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (158 mg, 0.477 mmol), 2-(1-methyl-1H-imidazol-2-yl)ethan-1-ol (60.2 mg, 0.477 mmol), EDCI • HCl (119 mg, 0.621 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-(1-methyl-1H-imidazol-2-yl)ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (116 mg, 55%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (br s, 1H), 7.71 (br s, 1H), 7.32-7.28 (m, 2H), 6.97-6.93 (m, 3H), 6.81 (s, 1H), 6.10-5.80 (br, 1H), 4.64 (t, 2H), 4.00 (d, 1H), 3.91 (d, 1H), 3.60 (s, 3H), 3.11 (t, 2H), 2.17 (br s, 3H); LC-MS (ESI) m/z 440.2 [M+H]⁺.

Example 427

Ethyl 4-[2-(3,4-difluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of ethyl 4-{[(3,4-difluorophenyl)methylidene]amino}-3-methylbenzoate

A solution of ethyl 4-amino-3-methylbenzoate (0.706 g, 3.94 mmol) and 3,4-difluorobenzaldehye (1.00 mL, 9.08 mmol) in ethanol (10 mL) was stirred at reflux for 18 h and cooled to room temperature. The crude was washed with diethyl ether/n-hexane (1:20) to give ethyl 4-{[(3,4-difluorophenyl)methylidene]amino}-3-methylbenzoate (0.986 g, 83%) as an orange solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.28 (s, 1H), 7.91-7.81 (m, 3H), 7.62-7.59 (m, 1H), 7.31-7.27 (m, 1H), 6.91 (d, 1H), 4.38 (q, 2H), 2.36 (s, 3H), 1.40 (t, 3H).

Step 2. Synthesis of ethyl 4-[2-(3,4-difluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

A solution of ethyl 4-{[(3,4-difluorophenyl)methylidene]amino}-3-methylbenzoate (511 mg, 1.68 mmol) and 2-mercaptoacetic acid (0.150 mL, 2.15 mmol) in toluene (15 mL) was stirred at 100° C. for 18 h. The solution was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 10% NaOH_(aq) and 2N HCl_(aq), dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give ethyl 4-[2-(3,4-difluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (137 mg, 22%) as a yellow gum. ¹HNMR (CDCl₃, 400 MHz) δ 7.88 (br s, 1H), 7.77 (br s, 1H), 7.22 (t, 1H), 7.07-6.99 (m, 2H), 6.10-5.80 (br, 1H), 4.33 (q, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.20 (br s, 3H), 1.37 (t, 3H); LC-MS (ESI) m/z 378.2 [M+H]⁺.

Example 428

Methyl 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate

A solution of methyl 4-amino-3-methylbenzoate (0.846 g, 5.12 mmol), Na₂SO₄ anhydrous (1.46 g, 10.2 mmol), and 4-fluorobenzaldehyde-2,3,5,6-d₄ (0.722 g, 5.63 mmol) in toluene (30 mL) was reflux for 24 h. Then 2-mercaptoacetic acid (0.840 mL, 12.0 mmol) was added to the reaction mixture, and it was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq) and 3 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate (0.503 g, 29%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.10-6.80 (br, 1H), 6.10-5.80 (br, 1H), 4.01 (d, 1H), 3.93 (d, 1H), 3.87 (s, 3H), 2.17 (br s, 3H); LC-MS (ESI) m/z 350.1 [M+H]⁺.

Example 429

4-{2-[4-Fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoic acid

A solution of methyl 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate (0.498 g, 1.43 mmol) in 10% NaOH_(aq) (8.0 mL) and methanol (25 mL) was stirred at room temperature for 2 h. Methanol was removed under reduced pressure. The residue was acidified by 2 N HCl_(aq) and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated give 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoic acid (0.407 g, 85%) as a gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.89 (br s, 1H), 7.77 (br s, 1H), 7.10-6.80 (br, 1H), 6.10-5.80 (br, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 2.21 (br s, 3H); LC-MS (ESI) m/z 336.2 [M+H]⁺.

Example 430

Ethyl 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate

Following standard procedure G, 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoic acid (187 mg, 0.558 mmol), ethanol (0.50 mL), DMAP (136 mg, 1.12 mmol), EDCI • HCl (160 mg, 0.836 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and concentrated, the residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give ethyl 4-{2-[4-fluoro-2,3,5,6-d₄-phenyl]-4-oxo-1,3-thiazolidin-3-yl}-3-methylbenzoate (153 mg, 75%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br d, 1H), 7.10-6.70 (br, 1H), 6.10-5.80 (br, 1H), 4.32 (q, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.17 (br s, 3H), 1.35 (t, 2H); LC-MS (ESI) m/z 364.2 [M+H]⁺.

Example 431

4-[2-(4-Fluorophenyl)-4-oxo-2-d₁-1,3-thiazolidin-3-yl]-3-methylbenzoic acid

Step 1. Synthesis of methyl 4-[2-(4-fluorophenyl)-4-oxo-2-dl-1,3-thiazolidin-3-yl]-3-methylbenzoate

A solution of methyl 4-amino-3-methylbenzoate (390 mg, 2.36 mmol), Na₂SO₄ anhydrous (503 mg, 3.54 mmol), and 4-fluorobenaldehyde-d₁ (325 mg, 2.60 mmol) in toluene (10 mL) was reflux for 18 h. Then 2-mercaptoacetic acid (0.296 mL, 4.24 mmol) was added to the reaction mixture, and it was stirred at 90-100° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-[2-(4-fluorophenyl)-4-oxo-2-d-1,3-thiazolidin-3-yl]-3-methylbenzoate (152 mg, 19%) as a lightly yellow foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.73 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 3.87 (s, 3H), 2.19 (br s, 3H); LC-MS (ESI) m/z 347.1 [M+H]⁺.

Step 2. Synthesis of 4-[2-(4-fluorophenyl)-4-oxo-2-d₁-1,3-thiazolidin-3-yl]-3-methylbenzoic acid

A solution of methyl 4-[2-(4-fluorophenyl)-4-oxo-2-di-1,3-thiazolidin-3-yl]-3-methylbenzoate (125 mg, 0.361 mmol) in 10% NaOH_(aq) (1.0 mL) and methanol (5.0 mL) was stirred at room temperature for 2 h. Methanol was removed under reduced pressure. The residue was acidified by 2 N HCl_(aq) and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 100% ethyl acetate) to give 4-[2-(4-fluorophenyl)-4-oxo-2-di-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (101 mg, 84%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.30 (dd, 2H), 6.95 (br t, 2H), 4.01 (d, 1H), 3.92 (d, 1H), 2.18 (br s, 3H); LC-MS (ESI) m/z 355.1 [M+Na]⁺.

Example 432

Ethyl 4-[2-(4-fluorophenyl)-4-oxo-2-d₁-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-2-d₁-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (90.0 mg, 0.271 mmol), ethanol (0.20 mL), DMAP (59.6 mg, 0.488 mmol), EDCI • HCl (77.9 mg, 0.406 mmol) and CH₂Cl₂ (3.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 8 h and concentrated, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give ethyl 4-[2-(4-fluorophenyl)-4-oxo-2-d₁-1,3-thiazolidin-3-yl]-3-methylbenzoate (69.5 mg, 71%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (br s, 1H), 7.74 (br s, 1H), 7.32-7.29 (m, 2H), 6.95 (br t, 2H), 4.33 (q, 2H), 4.00 (d, 1H), 3.92 (d, 1H), 2.19 (br s, 3H), 1.35 (t, 3H); LC-MS (ESI) m/z 361.2 [M+H]⁺.

Example 433

6-(Methoxymethyl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Step 1. Synthesis of 5-(benzyloxy)-2-(methoxymethyl)pyridine

To a solution of (5-(benzyloxy)pyridin-2-yl)methanol (0.300 g, 1.39 mmol) in THF (10.0 mL), sodium hydride (40.0 mg, 1.67 mmol) was added. The reaction mixture was stirred at 0° C. for 3 mins, followed by adding methyl iodide (96.0 μL, 1.53 mmol) and stirred at room temperature for 3 h. The result mixture was extracted with ethyl acetate, dried over MgSO_4(s), filtered and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 5-(benzyloxy)-2-(methoxymethyl)pyridine (0.270 g, 85%). ¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 7.44-7.31 (m, 6H), 7.27-7.25 (m, 1H), 5.10 (s, 2H), 4.52 (s, 2H), 3.44 (s, 3H).

Step 2. Synthesis of 6-(methoxymethyl)pyridin-3-ol

10% palladium on carbon was added to a MeOH (20.0 mL) of 5-(benzyloxy)-2-(methoxymethyl)pyridine (0.270 g), and the mixture was stirred at room temperature for 1 h under hydrogen atmosphere. After reaction, the solution was filtered and concentrated to yield product which was used directly for next step without further purification (0.160 g, crude yield 96%). ¹H NMR (CDCl₃, 400 MHz) δ 8.22 (br s, 1H), 7.34 (d, 1H), 7.27 (d, 1H), 4.53 (s, 2H), 3.44 (s, 3H).

Step 3. Synthesis of 6-(methoxymethyl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

Following standard procedure G, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), 6-(methoxymethyl)pyridin-3-ol (75.7 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.19 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 6-(methoxymethyl)pyridin-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.172 g, 70%). ¹H NMR (CDCl₃, 400 MHz) δ 8.43 (s, 1H), 8.03 (br s, 1H), 7.91 (br d, 1H), 7.56 (d, 1H), 7.49 (d, 1H), 7.36-7.32 (m, 2H), 6.98 (br t, 2H), 4.60 (s, 2H), 4.02 (d, 1H), 3.94 (d, 1H), 3.49 (s, 3H), 2.25 (br s, 3H); LC-MS (ESI) m/z 453.2 [M+H]⁺.

Example 434

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(tetrahydro-2H-pyran-2-yloxy)benzamide

To the solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (63.6 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.09 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (0.210 g, 90%). ¹H NMR (CDCl₃, 400 MHz) δ 8.74 (s, 1H), 7.56 (br s, 1H), 7.43 (br s, 1H), 7.32-7.28 (m, 2H), 6.96 (br t, 2H), 5.93 (br s, 1H), 5.02 (br s, 1H), 4.02-3.89 (m, 4H), 2.20 (br s, 3H), 1.89-1.77 (m, 4H), 1.69-1.59 (m, 2H); LC-MS (ESI) m/z 453.2 [M+Na]⁺.

Example 435

N-ethoxy-4-[2-(4-fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-3-methylbenzamide

To the solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.180 g, 0.544 mmol), O-ethylhydroxylamine (53.0 mg, 0.544 mmol), EDCI • HCl (0.210 g, 1.09 mmol), DMAP (0.150 g, 1.09 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give N-ethoxy-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide (0.177 g, 87%). ¹H NMR (CDCl₃, 400 MHz) δ 9.13 (br s, 1H), 7.46 (br s, 1H), 7.30-7.27 (m, 3H), 6.94 (br t, 2H), 6.10-5.73 (br, 1H), 4.02-3.97 (m, 3H), 3.90 (d, 1H), 2.15 (br s, 3H), 1.27 (t, 3H); LC-MS (ESI) m/z 375.2 [M+H]⁺.

Example 436

S-Ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzenecarbothioate

Step 1. Synthesis of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl chloride

A solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (0.200 g) in CH₂Cl₂ (10.0 mL) and SOCl₂ (8.0 mL) were carried out the reaction. After the reaction was stirred at room temperature for 1 h and work-up, the residue was used directly for next step without further purification. (0.210 g, crude yield 99%).

Step 2. Synthesis of S-ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzenecarbothioate

To the solution of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl chloride (0.210 g, 0.602 mmol), ethanethiol (30.0 μL, 0.401 mmol), 1-methylimidazole (50.0 μL, 0.620 mmol), K₂CO₃ (0.100 g, 0.720 mmol) and acetonitrile (10.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give S-ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzenecarbothioate (0.160 g, 71%). ¹H NMR (CDCl₃, 400 MHz) δ 7.77 (br s, 1H), 7.66 (br d, 1H), 7.31 (dd, 2H), 6.96 (br t, 2H), 5.94 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.03 (q, 2H), 2.21 (br s, 3H), 1.25 (t, 3H); LC-MS (ESI) m/z 376.1 [M+H]⁺.

Example 437

2-(2-Methoxyethoxy)ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl)benzoate

Step 1. Synthesis of 2-(2-methoxyethoxy)ethyl 4-sulfamoylbenzoate

A solution of 4-aminosulfonylbenzoic acid (558 mg, 2.77 mmol) in concentrated HCl_(aq) (0.50 mL) and diethylene glycol methyl ether (3.0 mL) was stirred at 100° C. for 20 h and cooled to room temperature. It was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-(2-methoxyethoxy)ethyl 4-sulfamoylbenzoate (199 mg, 24%) as a colorless gum. ¹H NMR (CDCl₃, 400 MHz) δ 8.18 (d, 2H), 7.99 (d, 2H), 5.01 (s, 2H), 4.52 (dd, 2H), 3.85 (dd, 2H), 3.69 (dd, 2H), 3.58 (dd, 2H), 3.38 (s, 3H).

Step 2. Synthesis of 2-(2-methoxyethoxy)ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl)benzoate

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (156 mg, 0.471 mmol), DMAP (115 mg, 0.942 mmol), EDCI • HCl (135 mg, 0.706 mmol), 2-(2-methoxyethoxy)ethyl 4-sulfamoylbenzoate (143 mg, 0.471 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 2-(2-methoxyethoxy)ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl)benzoate (228 mg, 79%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 9.50 (br s, 1H), 8.20-8.13 (m, 4H), 7.42 (br, 2H), 7.31-7.28 (m, 2H), 6.91 (br t, 2H), 6.10-5.70 (br, 1H), 4.51 (dd, 2H), 4.10 (br s, 2H), 3.82 (dd, 2H), 3.69-3.66 (m, 2H), 3.57-3.54 (m, 2H), 3.34 (s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 617.2 [M+H]⁺.

Example 438

4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(2-methoxyethyl)sulfonyl]-3-methylbenzamide

Step 1. Synthesis of sodium 2-methoxyethanesulfonate

A solution of 2-chloroethyl methyl ether (1.01 g, 10.7 mmol) and Na₂SO₃ (1.42 g, 11.2 mmol) in H₂O (5.0 mL) was stirred at reflux for 20 h. The solution was cooled to room temperature and concentrated to give sodium 2-methoxyethanesulfonate (2.33 g, quantitative yield) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 3.53 (t, 2H), 3.37 (s, 3H), 2.70 (t, 2H).

Step 2. Synthesis of 2-methoxyethanesulfonyl chloride

A solution of sodium 2-methoxyethanesulfonate (0.998 g, 2.11 mmol) in POCl₃ (3.0 mL) was stirred at 110° C. for 8 h and room temperature for 16 h. The solution was poured into ice warer and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 2-methoxyethanesulfonyl chloride (2.13 g, quantitative yield) as a colorless oil. ¹H NMR (CDCl₃, 300 MHz) δ 3.97-3.95 (m, 4H), 3.43 (s, 3H).

Step 3. Synthesis of 2-methoxyethanesulfonamide

A solution of 2-methoxyethanesulfonyl chloride (2.13 g, 2.11 mmol) in H₂O (15 mL) and 28% NH_3(aq) (10 mL) was stirred at room temperature for 5 h. The solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 2-methoxyethanesulfonamide (65.9 mg, 8%) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ 4.89 (br s, 2H), 3.85 (t, 2H), 3.41 (s, 3H), 3.36 (t, 2H).

Step 4. Synthesis of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(2-methoxyethyl)sulfonyl]-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (134 mg, 0.405 mmol), DMAP (124 mg, 1.01 mmol), EDCI • HCl (140 mg, 0.729 mmol), 2-methoxyethanesulfonamide (56.4 mg, 0.405 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-5% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(2-methoxyethyl)sulfonyl]-3-methylbenzamide (142 mg, 77%) as a white solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.02 (br s, 1H), 7.71 (br s, 1H), 7.59 (br s, 1H), 7.48 (dd, 2H), 7.09 (br t, 2H), 6.60-6.10 (br s, 1H), 4.07 (d, 1H), 3.91 (d, 1H), 3.71 (br s, 4H), 3.10 (s, 3H), 2.13 (br s, 3H); LC-MS (ESI) m/z 475.2 [M+Na]⁺.

Example 439

4-[2-(4-Fluorophenyl)-4-oxo-1, 3-thiazolidin-3-yl]-N-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-methylbenzamide

Step 1. Synthesis of 1-bromo-2-(2-methoxyethoxy)ethane

To a solution of diethylene glycol monomethyl ether (0.698 g, 5.81 mmol) in THF (10 mL) was added triphenylphosphine (1.53 g, 5.83 mol) and carbon tetrabromide (1.93 g, 5.81 mol) at 0° C. After the solution was stirred at room temperature for 16 h, it was quenched with saturated NaHCO_3(aq) and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by flash chromatography (20% ethyl acetate in n-hexane) to give 1-bromo-2-(2-methoxyethoxy)ethane as a yellow liquid. ¹H NMR (CDCl₃, 300 MHz) δ 3.81 (t, 2H), 3.68-3.65 (m, 2H), 3.57-3.54 (m, 2H), 3.48 (t, 2H), 3.39 (s, 3H).

Step 2. Synthesis of 2-(2-methoxyethoxy)ethanesulfonamide

A solution of 1-bromo-2-(2-methoxyethoxy)ethane (0.520 g, 2.86 mmol) and Na₂SO₃ (360 g, 2.86 mmol) in H₂O (3.0 mL) was stirred at reflux for 20 h. The solution was cooled to room temperature and concentrated to give sodium 2-(2-methoxyethoxy)ethanesulfonate as a yellow solid. A solution of sodium 2-(2-methoxyethoxy)ethanesulfonate (0.998 g, 2.11 mmol) in POCl₃ (3.0 mL) was stirred at 110° C. for 6 h and room temperature for 16 h. The solution was slowly poured into ice-salt warer and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 2-(2-methoxyethoxy)ethanesulfonyl chloride as a brown oil. Then 2-(2-methoxyethoxy)ethanesulfonyl chloride was stirred in H₂O (10 mL) and 28% NH_3(aq) (10 mL) was at room temperature for 8 h and concentrated. The residue was treated with H₂O and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 2-(2-methoxyethoxy)ethanesulfonamide (118 mg, 23%) as a brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 5.21 (br s, 2H), 3.97 (dd, 2H), 3.69-3.67 (m, 2H), 3.56-3.54 (m, 2H), 3.38 (s, 3H), 3.34 (dd, 2H).

Step 3. Synthesis of 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-methylbenzamide

Following standard procedure C, 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoic acid (127 mg, 0.383 mmol), DMAP (93.6 mg, 0.766 mmol), EDCI • HCl (117 mg, 0.610 mmol), 2-(2-methoxyethoxy)ethanesulfonamide (70.2 mg, 0.383 mmol), and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction was stirred for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-10% MeOH in CH₂Cl₂) to give 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-{[2-(2-methoxyethoxy)ethyl]sulfonyl}-3-methylbenzamide (163 mg, 54%) as a beige solid. ¹H NMR (CDCl₃, 400 MHz) δ 9.90-9.40 (br, 1H), 7.69 (br s, 1H), 7.56 (br s, 1H), 7.32-7.27 (m, 2H), 6.95 (br t, 2H), 6.10-5.80 (br, 1H), 3.99 (d, 1H), 3.94-3.89 (m, 3H), 3.68 (br t, 2H), 3.53 (br t, 2H), 3.32 (br t, 2H), 3.13 (s, 3H), 2.20 (br s, 3H); LC-MS (ESI) m/z 519.2 [M+Na]⁺.

Example 440

2-(4-Fluorophenyl)-3-[2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1,3-thiazolidin-4-one

Step 1. Synthesis of 2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanone

To a solution of ethyl 3-methyl-4-nitrobenzoate (1.58 g, 7.55 mmol) in CH₂Cl₂ (30 mL) was added (trifluoromethyl)trimethylsilane (1.56 mL, 10.6 mmol) and 1.0 M tetrabutylammonium fluoride (0.22 mL, 0.22 mmol) at −78° C. After the solution was slowly warm to room temperature and stirred for 18 h, it was washed with H₂O and brine, dried over MgSO_4(s), filtered, and concentrated to give a residue. Then the crude ether was stirred in 1,4-dioxane (6.0 mL) and 12 M HCl_(aq) (3.0 mL) for 4 h. The solution was treated with H₂O and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanone (0.665 g, 37%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.05-8.04 (m, 3H), 2.67 (s, 3H).

Step 2. Synthesis of 1-(4-amino-3-methylphenyl)-2, 2,2-trifluoroethanone

To a solution of 2,2,2-trifluoro-1-(3-methyl-4-nitrophenyl)ethanone (0.647 g, 2.78 mmol) in ethanol (12 mL) was added iron powder (0.775 g, 13.9 mmol) and acetic acid (5.0 mL) at room temperature. After the solution was stirred at reflux for 18 h and cooled to room temperature, the reaction mixture was filtration through celite. The filtrate was concentrated under reduce pressure to afford a residue, The residue was treated with saturated NaHCO_3(aq) and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 1-(4-amino-3-methylphenyl)-2,2,2-trifluoroethanone (0.447 g, 79%) as a yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.81-7.78 (m, 2H), 6.67 (d, 1H), 4.38 (br s, 2H), 2.20 (s, 3H).

Step 3. Synthesis of 1-(4-amino-3-methylphenyl)-2, 2,2-trifluoroethanol

To a solution of 1-(4-amino-3-methylphenyl)-2,2,2-trifluoroethanone (0.200 g, 0.985 mmol) in 2-propanol (3.0 mL) was added sodium borohydride (56.2 mg, 1.49 mmol) at room temperature. After the solution was stirred for 6 h, it was quenched by saturated NaHCO_3(aq) and extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated to give 1-(4-amino-3-methylphenyl)-2,2,2-trifluoroethanol (0.193 g, 96%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.14-7.11 (m, 2H), 6.68 (d, 1H), 4.87 (q, 1H), 3.73 (br s, 2H), 2.45 (br s, 1H), 2.18 (s, 3H).

Step 4. Synthesis of 2,2,2-trifluoro-1-(4-{[(4-fluorophenyl)methylidene]amino}-3-methylphenyl)ethanol

A solution of 1-(4-amino-3-methylphenyl)-2,2,2-trifluoroethanol (0.193 g, 0.941 mmol) and 4-fluorobenzaldehye (0.111 mL, 1.04 mmol) in toluene (6.0 mL) was stirred at reflux for 8 h and then concentrated to give a 2,2,2-trifluoro-1-(4-{[(4-fluorophenyl)methylidene]amino}-3-methylphenyl)ethanol (0.255 g, 87%) as a solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.32 (s, 1H), 7.94-7.90 (m, 2H), 7.32-7.30 (m, 2H), 7.17 (t, 2H), 6.92 (d, 1H), 5.00 (q, 1H), 2.75-2.60 (br, 1H), 2.36 (s, 3H).

Step 5. Synthesis of 2-(4-fluorophenyl)-3-[2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1,3-thiazolidin-4-one

A solution of 2,2,2-trifluoro-1-(4-{[(4-fluorophenyl)methylidene]amino}-3-methylphenyl)ethanol (234 mg, 0.752 mmol) and 2-mercaptoacetic acid (68.0 μL, 0.974 mmol) in toluene (10 mL) was stirred at 100° C. for 18 h. The solution was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with 10% NaOH_(aq), dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-70% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]-1,3-thiazolidin-4-one (48.3 mg, 17%) as a yellow foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.32-7.25 (m, 3H), 7.25-7.00 (br, 1H), 6.97 (br t, 2H), 6.10-5.70 (br, 1H), 4.92-4.89 (m, 1H), 4.02 (d, 1H), 3.91 (d, 1H), 2.70 (br s, 1H), 2.20 (br s, 3H); LC-MS (ESI) m/z 408.1 [M+Na]⁺.

Example 441

Ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Step 1. Synthesis of ethyl (4-amino-3-methylphenoxy)acetate.

A solution of 4-amino-m-cresol (1.40 g, 11.4 mmol), potassium carbonate (1.73 g, 12.5 mmol), and ethyl bromoacetate (2.09 g, 12.5 mmol) in acetone (20 mL) was stirred at reflux for 3 h and cooled to room temperature. The reaction mixture was concentrated and treated with water. The solution was extracted with CH₂Cl₂. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by combi-flash column chromatography (0-30% ethyl acetate in n-hexane) to give ethyl (4-amino-3-methylphenoxy)acetate (0.256 g, 12%) as a brown oil. ¹H NMR (CDCl₃, 400 MHz) δ 6.70 (d, 1H), 6.65-6.58 (m, 2H), 4.53 (s, 2H), 4.26 (q, 2H), 3.39 (br s, 2H), 2.14 (s, 3H), 1.28 (t, 3H).

Step 2. Synthesis of ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Following standard procedure A, ethyl (4-amino-3-methylphenoxy)acetate (0.256 g, 1.33 mmol), 4-fluorobenzaldehyde (0.220 mL, 2.06 mmol), Na₂SO₄ (0.188 g, 1.33 mmol), 2-mercaptoacetic acid (0.170 mL, 2.44 mmol), and toluene (15 mL) were used to carry out the reaction. It was reflux 4 h for the first step and 18 h for the second step. After work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (0.201 g, 37%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.28 (m, 2H), 6.97 (br s, 2H), 6.90-6.30 (br, 3H), 6.10-5.60 (br, 1H), 4.52 (s, 2H), 4.24 (q, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.30-1.80 (br, 3H), 1.26 (t, 3H); LC-MS (ESI) m/z 412.2 [M+Na]⁺.

Example 442

Oxetan-3-yl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

To a solution of {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (139 mg, 0.385 mmol) in CH₂Cl₂ (5.0 mL) was added DMAP (70.6 mg, 0.578 mmol), 3-hydroxyoxetane (36 μL, 0.578 mmol), and EDCI • HCl (111 mg, 0.578 mmol) at room temperature. After the reaction mixture was stirred for 18 h, it was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give oxetan-3-yl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (114 mg, 71%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 2H), 6.97 (br t, 2H), 6.90-6.30 (br, 3H), 6.10-5.60 (br, 1H), 5.53 (quint, 1H), 4.90 (t, 2H), 4.64-4.60 (m, 2H), 4.59 (s, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.40-1.80 (br, 3H); LC-MS (ESI) m/z 440.1 [M+Na]⁺.

Example 443

2-(Morpholin-4-yl)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

To a solution of {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (135 mg, 0.374 mmol) in CH₂Cl₂ (5.0 mL) was added DMAP (68.7 mg, 0.563 mmol), 4-(2-hydroxyethyl)morpholine (58.8 mg, 0.448 mmol), and EDCI • HCl (108 mg, 0.563 mmol) at room temperature. After the reaction mixture was stirred for 18 h, it was concentrated to afford a residue. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 8% methanol in CH₂Cl₂) to give 2-(morpholin-4-yl)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (117 mg, 66%) as a colorless gum. ¹H NMR (CDCl₃, 300 MHz) δ 7.30 (dd, 2H), 6.97 (br t, 2H), 6.90-6.20 (br, 3H), 6.10-5.50 (br, 1H), 4.55 (s, 2H), 4.31 (t, 2H), 4.00 (d, 1H), 3.88 (d, 1H), 3.68-3.62 (m, 4H), 2.61 (t, 2H), 2.46 (dd, 4H), 2.40-1.80 (br, 3H); LC-MS (ESI) m/z 475.2 [M+H]⁺.

Example 444

Propan-2-yl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

To a solution of {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (118 mg, 0.327 mmol) in CH₂Cl₂ (5.0 mL) was added DMAP (59.8 mg, 0.490 mmol), 2-propanol (0.50 mL), and EDCI • HCl (93.9 mg, 0.490 mmol) at room temperature. After the reaction mixture was stirred for 16 h, it was diluted with CH₂Cl₂ and washed with 2 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 40% ethyl acetate in n-hexane) to give propan-2-yl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (93.4 mg, 71%) as a colorless gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.28 (m, 2H), 6.96 (br s, 2H), 6.90-6.30 (br, 3H), 6.10-5.60 (br, 1H), 5.10 (quint, 1H), 4.49 (s, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.35-1.80 (br, 3H), 1.24 (d, 6H); LC-MS (ESI) m/z 426.2 [M+Na]⁺.

Example 445

Pyridin-3-ylmethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

To a solution of {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (128 mg, 0.354 mmol) in CH₂Cl₂ (5.0 mL) was added DMAP (64.9 mg, 0.531 mmol), 3-(hydroxymethyl)pyridine (38.7 mg, 0.354 mmol), and EDCI • HCl (102 mg, 0.531 mmol) at room temperature. After the reaction mixture was stirred for 16 h, it was diluted with CH₂Cl₂ and washed with H₂O. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 90% ethyl acetate in n-hexane) to give pyridin-3-ylmethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (112 mg, 70%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 8.60-8.59 (m, 2H), 7.63 (d, 1H), 7.31-7.28 (m, 3H), 6.97 (br s, 2H), 6.90-6.30 (br, 3H), 6.10-5.50 (br, 1H), 5.23 (s, 2H), 4.58 (s, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.30-1.80 (br, 3H); LC-MS (ESI) m/z 453.2 [M+H]⁺.

Example 446

2-(Dimethylamino)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Following standard procedure G, {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (0.180 g, 0.499 mmol), 2-(dimethylamino)ethanol (50.0 μL, 0.499 mmol), EDCI • HCl (0.190 g, 1.00 mmol), DMAP (0.130 g, 1.09 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-20% MeOH in CH₂Cl₂) to give 2-(dimethylamino)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (24.0 mg, 11%). ¹H NMR (CDCl₃, 300 MHz) δ 7.29 (dd, 2H), 6.96 (br t, 2H), 6.83-6.23 (br, 2H), 6.17-5.51 (br, 1H), 4.55 (s, 2H), 4.27 (t, 2H), 3.99 (d, 1H), 3.87 (d, 1H), 2.55 (t, 2H), 2.40-1.75 (br, 9H); LC-MS (ESI) m/z 433.2 [M+H]⁺.

Example 447

2-(Acetyloxy)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Step 1. Synthesis of 2-hydroxyethyl acetate

To a solution of acetic acid (0.140 mL, 2.42 mmol), ethylene glycol (0.270 mL, 4.83 mmol) and catalyst of H₂SO₄ were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h, the residue was extracted with ethyl acetate, dried over MgSO_4(s), filtered and concentrated to give 2-hydroxyethyl acetate which was used directly for next step without further purification (0.120 g, crude yield 47%). ¹H NMR (CDCl₃, 400 MHz) δ 4.21-4.19 (m, 2H), 3.82 (br t, 2H), 2.10 (s, 3H).

Step 2. Synthesis of 2-(acetyloxy)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate

Following standard procedure G, {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetic acid (0.370 g, 1.05 mmol), 2-hydroxyethyl acetate (0.120 g, 1.15 mmol), EDCI • HCl (0.390 g, 2.05 mmol), DMAP (0.280 g, 2.25 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(acetyloxy)ethyl {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}acetate (0.250 g, 55%). ¹H NMR (CDCl₃, 300 MHz) δ 7.32-7.27 (m, 2H), 6.97 (br t, 2H), 6.91-6.27 (br, 2H), 6.11-5.50 (br, 1H), 4.56 (s, 2H), 4.40-4.31 (m, 2H), 4.29-4.26 (m, 2H), 4.00 (d, 1H), 3.88 (d, 1H), 2.40-1.80 (m, 6H); LC-MS (ESI) m/z 448.3 [M+H]⁺.

Example 448

2-(4-Fluorophenyl)-3-(4-hydroxy-2-methylphenyl)-1,3-thiazolidin-4-one

A solution of 4-amino-3-methylphenol (0.658 g, 5.34 mmol), Na₂SO₄ anhydrous (0.912 g, 6.42 mmol), and 4-fluorobenzaldehyde (0.688 mL, 6.42 mmol) in toluene (20 mL) was stirred at 70° C. for 3 h. Then 2-mercaptoacetic acid (0.670 mL, 9.60 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with saturated NaHCO_3(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(4-hydroxy-2-methylphenyl)-1,3-thiazolidin-4-one (0.812 g, 50%) as a lightly brown solid. ¹H NMR (DMSO-d₆, 400 MHz) δ 9.41 (br s, 1H), 7.44 (br s, 2H), 7.10 (br s, 2H), 6.70-6.10 (br, 3H), 5.90-5.80 (br, 1H), 4.03 (d, 1H), 3.82 (d, 1H), 2.20-1.70 (br, 3H); LC-MS (ESI) m/z 304.1 [M+H]⁺.

Example 449

3-(5-Fluoro-4-hydroxy-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

A solution of 4-amino-2-fluoro-5-methylphenol (0.219 g, 1.55 mmol), Na₂SO₄ anhydrous (0.330 g, 2.33 mmol), and 4-fluorobenzaldehyde (0.183 mL, 1.71 mmol) in toluene (10 mL) was stirred at 70° C. for 3 h. Then 2-mercaptoacetic acid (0.200 mL, 2.87 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with saturated NaHCO_3(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 50% ethyl acetate in n-hexane) to give 3-(5-fluoro-4-hydroxy-2-methylphenyl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (0.181 g, 36%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.27 (m, 2H), 6.99 (br s, 2H), 6.69 (br s, 1H), 6.20-5.60 (br, 1H), 5.78 (br s, 1H), 4.00 (d, 1H), 3.90 (d, 1H), 2.20-1.70 (br, 3H); LC-MS (ESI) m/z 322.1 [M+H]⁺.

Example 450

2-(4-Fluorophenyl)-3-[2-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]-1,3-thiazolidin-4-one

To the solution of 2-(4-fluorophenyl)-3-(4-hydroxy-2-methylphenyl)thiazolidin-4-one (80.0 mg, 0.267 mmol) in DMF (5.0 mL), 4-(chloromethyl)thiazole (56.1 mg, 0.267 mmol) and K₂CO₃ (50.0 mg, 0.290 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 100° C. for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(1,3-thiazol-4-ylmethoxy)phenyl]-1,3-thiazolidin-4-one (34.0 mg, 32%). ¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 7.34 (s, 1H), 7.32-7.28 (m, 2H), 7.17-6.20 (br, 4H), 6.11-5.49 (br, 1H), 5.17 (s, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.38-1.80 (br, 3H). LC-MS (ESI) m/z 401.1 [M+H]⁺.

Example 451

Ethyl 4-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}butanoate

Following standard procedure L, 2-(4-fluorophenyl)-3-(4-hydroxy-2-methylphenyl)-1,3-thiazolidin-4-one (80.0 mg, 0.264 mmol), ethyl 4-bromobutanoate (31.0 μL, 0.290 mmol) and K₂CO₃ (40.1 mg, 0.290 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give ethyl 4-{4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenoxy}butanoate (81.7 mg, 74%). ¹H NMR (CDCl₃, 400 MHz) δ 7.32-7.28 (m, 2H), 6.97 (br s, 2H), 6.79-6.21 (m, 2H), 6.10-5.50 (br, 1H), 4.12 (q, 2H), 3.99 (d, 1H), 3.94-3.86 (m, 3H), 2.45 (t, 2H), 2.30-1.70 (m, 5H), 1.24 (t, 3H); LC-MS (ESI) m/z 418.2 [M+H]⁺.

Example 452

2-(4-Fluorophenyl)-3-[2-methyl-4-[(2-methylprop-2-en-1-yl)oxy]phenyl]-1,3-thiazolidin-4-one

Following standard procedure L, 2-(4-fluorophenyl)-3-(4-hydroxy-2-methylphenyl)-1,3-thiazolidin-4-one (80.0 mg, 0.264 mmol), 3-bromo-2-methylprop-1-ene (32.0 μL, 0.316 mmol) and K₂CO₃ (40.1 mg, 0.290 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-{2-methyl-4-[(2-methylprop-2-en-1-yl)oxy]phenyl}-1,3-thiazolidin-4-one (65.1 mg, 69%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 2H), 6.97 (br s, 2H), 6.82-6.21 (br, 2H), 6.13-5.52 (br, 1H), 5.03 (s, 1H), 4.95 (s, 1H), 4.32 (s, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.30-1.58 (m, 6H); LC-MS (ESI) m/z 358.2 [M+H]⁺.

Example 453

2-(4-Fluorophenyl)-3-[2-methyl-4-(pent-2-yn-1-yloxy)phenyl]-1,3-thiazolidin-4-one

Following standard procedure L, 2-(4-fluorophenyl)-3-(4-hydroxy-2-methylphenyl)-1,3-thiazolidin-4-one (80.0 mg, 0.264 mmol), 1-bromopent-2-yne (32.0 μL, 0.316 mmol) and K₂CO₃ (40.1 mg, 0.290 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 80° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(pent-2-yn-1-yloxy)phenyl]-1,3-thiazolidin-4-one (58.9 mg, 61%). ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 2H), 6.97 (br s, 2H), 6.85-6.22 (br, 3H), 6.18-5.50 (br, 1H), 4.56 (s, 2H), 4.00 (d, 1H), 3.89 (d, 1H), 2.37-1.80 (m, 5H), 1.12 (t, 3H); LC-MS (ESI) m/z 370.2 [M+H]⁺.

Example 454

2-(4-Fluorophenyl)-3-[2-methyl-4-[2-(morpholin-4-yl)ethoxy]phenyl]-1,3-thiazolidin-4-one

A solution of 2-(4-fluorophenyl)-3-(4-hydroxy-2-methylphenyl)-1,3-thiazolidin-4-one (88.9 mg, 0.293 mmol), 4-(2-chloroethyl)morpholine hydrochloride (60.0 mg, 0.322 mmol), and cesium carbonate (210 mg, 0.645 mmol) in DMF (1.0 mL) was stirred at 50° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 100% ethyl acetate) to give 2-(4-fluorophenyl)-3-{2-methyl-4-[2-(morpholin-4-yl)ethoxy]phenyl}-1,3-thiazolidin-4-one (80.7 mg, 66%) as a white foam. ¹H NMR (CDCl₃, 400 MHz) δ 7.30 (dd, 2H), 7.00 (br s, 2H), 6.80-6.30 (br, 2H), 6.10-5.60 (br, 1H), 4.02-3.98 (m, 3H), 3.89 (d, 1H), 3.71 (dd, 4H), 2.74 (t, 2H), 2.54 (dd, 4H), 2.30-1.80 (br, 3H); LC-MS (ESI) m/z 417.2 [M+H]⁺.

Example 455

{4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetonitrile

Step 1. Synthesis of (3-methyl-4-nitrophenyl)acetonitrile

To a solution of ethyl carbonocyanidate (0.470 mL, 7.46 mmol) and potassium hydroxide (0.300 g, 7.46 mmol) in DMSO (1.0 mL) was stirred at room temperature for 1 h, followed by addition of 4-fluoro-2-methyl-1-nitrobenzene (0.690 mL, 5.74 mmol) in one portion. After the reaction mixture was stirred at room temperature for 7 h, a solution of 37% HCl_(aq)(1.40 mL) and AcOH (1.60 mL) was added and the reaction mixture is heated for 3 h at reflux, then quenched with H₂O, extracted with diethylether. The organic layers are washed with brine, dried over MgSO_4(s), filtered and concentrated to give the residue which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to yield (3-methyl-4-nitrophenyl)acetonitrile (0.440 g, 57%). ¹H NMR (CDCl₃, 300 MHz) δ 8.00 (d, 1H), 7.34-7.30 (m, 2H), 3.81 (s, 2H), 2.62 (s, 3H).

Step 2. Synthesis of (4-amino-3-methylphenyl)acetonitrile

Palladium on carbon was added to a MeOH (20.0 mL) of (3-methyl-4-nitrophenyl)acetonitrile (0.440 g), and the mixture was stirred at room temperature for 2 h under hydrogen atmosphere. After reaction, the solution was filtered and concentrated to yield product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to yield (4-amino-3-methylphenyl)acetonitrile (0.315 g, 86%). ¹H NMR (CDCl₃, 400 MHz) δ 7.00 (s, 1H), 6.96 (d, 1H), 6.65 (d, 1H), 3.50 (br s, 1H), 3.61 (s, 2H), 2.16 (s, 3H).

Step 3. Synthesis of 2-(4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylphenyl)acetonitrile

To a solution of (4-amino-3-methylphenyl)acetonitrile (0.300 g, 2.05 mmol), Na₂SO₄ (0.350 g, 2.46 mmol) and 4-fluorobenzaldehyde (0.330 mL, 3.08 mmol) in toluene (10.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.220 mL, 3.28 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylphenyl)acetonitrile (0.130 g, 19%). ¹H NMR (CDCl₃, 300 MHz) δ 7.34-7.28 (m, 2H), 7.16 (br s, 1H), 7.10-6.95 (m, 3H), 4.01 (d, 1H), 3.90 (d, 1H), 3.65 (s, 2H), 2.17 (br s, 3H); LC-MS (ESI) m/z 349.1 [M+Na]⁺.

Example 456

2-(4-Fluorophenyl)-3-[2-methyl-4-(1H-tetrazol-5-ylmethyl)phenyl]-1,3-thiazolidin-4-one

A solution of {4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylphenyl}acetonitrile (52.4 mg, 0.161 mmol), sodium azide (15.7 g, 0.241 mmol), and ammonium acetate (18.6 mg, 0.241 mmol) in DMF (1.0 mL) was stirred at 120° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated. The residue was was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 10% methanol in CH₂Cl₂) to give 2-(4-fluorophenyl)-3-[2-methyl-4-(1H-tetrazol-5-ylmethyl)phenyl]-1,3-thiazolidin-4-one (13.9 mg, 23%) as a lightly brown solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.38-7.30 (m, 2H), 6.98 (br s, 3H), 6.80-6.30 (br, 2H), 6.20-5.60 (br, 2H), 4.11-4.06 (m, 3H), 3.93 (d, 1H), 2.23 (br s, 3H); LC-MS (ESI) m/z 392.2 [M+Na]⁺.

Example 457

2-(4-Fluorophenyl)-3-(pyridin-3-yl)-1,3-thiazolidin-4-one

A solution of 3-aminopyridine (0.953 g, 10.1 mmol), Na₂SO₄ anhydrous (1.43 g, 10.1 mmol), and 4-fluorobenzaldehyde (1.26 g, 10.1 mmol) in toluene (20 mL) was stirred at 60° C. for 36 h. Then 2-mercaptoacetic acid (1.27 mL, 18.2 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq) and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-80% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(pyridin-3-yl)-1,3-thiazolidin-4-one (0.985 g, 36%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.42-8.39 (m, 2H), 7.57-7.54 (m, 1H), 7.31-7.22 (m, 3H), 6.99 (t, 2H), 6.14 (s, 1H), 3.98 (d, 1H), 3.90 (d, 1H); LC-MS (ESI) m/z 275.5 [M+H]⁺.

Example 458

2-(4-Fluorophenyl)-3-(pyridin-2-yl)-1,3-thiazolidin-4-one

A solution of 2-aminopyridine (0.411 g, 4.54 mmol), Na₂SO₄ anhydrous (0.760 g, 5.35 mmol), and 4-fluorobenzaldehyde (0.579 mL, 5.35 mmol) in toluene (15 mL) was stirred at 60° C. for 16 h. Then 2-mercaptoacetic acid (0.570 mL, 8.17 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-100% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(pyridin-2-yl)-1,3-thiazolidin-4-one (0.484 g, 40%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.23 (d, 1H), 8.03 (d, 1H), 7.69 (dd, 1H), 7.31-7.27 (m, 2H), 7.03-7.00 (m, 1H), 6.95 (t, 2H), 6.85 (s, 1H), 4.01 (d, 1H), 3.83 (d, 1H); LC-MS (ESI) m/z 297.1 [M+Na]⁺.

Example 459

2-(4-Fluorophenyl)-3-(6-methoxypyridin-3-yl)-1,3-thiazolidin-4-one

A solution of 5-amino-2-methoxypyridine (0.878 g, 7.07 mmol), Na₂SO₄ anhydrous (1.00 g, 7.07 mmol), and 4-fluorobenzaldehyde (0.760 mL, 7.09 mmol) in toluene (15 mL) was stirred at 50° C. for 8 h. Then 2-mercaptoacetic acid (0.890 mL, 12.8 mmol) was added to the reaction mixture, and it was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq) and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(6-methoxypyridin-3-yl)-1,3-thiazolidin-4-one (1.37 g, 64%) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (d, 1H), 7.34-7.28 (m, 3H), 7.00 (t, 2H), 6.66 (d, 1H), 5.97 (s, 1H), 3.97 (d, 1H), 3.89 (d, 1H), 3.86 (s, 3H); LC-MS (ESI) m/z 305.1 [M+H]⁺.

Example 460

2-(4-Fluorophenyl)-3-(6-methylpyridin-3-yl)-1,3-thiazolidin-4-one

A solution of 5-amino-2-picoline (0.345 g, 3.19 mmol), Na₂SO₄ anhydrous (0.542 g, 3.82 mmol), and 4-fluorobenzaldehyde (0.410 mL, 3.82 mmol) in toluene (15 mL) was stirred at 60° C. for 6 h. Then 2-mercaptoacetic acid (0.445 mL, 6.38 mmol) was added to the reaction mixture, and it was stirred at 100° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-90% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(6-methylpyridin-3-yl)-1,3-thiazolidin-4-one (0.428 g, 47%) as a lightly yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 8.25 (d, 1H), 7.40 (dd, 1H), 7.29 (dd, 2H), 7.08 (d, 1H), 6.99 (t, 2H), 6.08 (s, 1H), 3.97 (d, 1H), 3.89 (d, 1H), 2.47 (s, 3H); LC-MS (ESI) m/z 289.2 [M+H]⁺.

Example 461

2-(4-Fluorophenyl)-3-(3-methylpyridin-2-yl)-1,3-thiazolidin-4-one

To a solution of 3-methylpyridin-2-amine (0.300 g, 2.77 mmol), Na₂SO₄ (0.470 g, 3.33 mmol) and 4-fluorobenzaldehyde (0.450 mL, 4.16 mmol) in toluene (5.0 mL) was stirred at 110° C. for 16 h, followed by addition of thioglycolic acid (0.310 mL, 4.44 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(3-methylpyridin-2-yl)-1,3-thiazolidin-4-one (0.230 g, 29%). ¹H NMR (CDCl₃, 300 MHz) δ 8.22 (d, 1H), 7.44 (d, 1H), 7.42-7.35 (m, 2H), 7.04 (dd, 1H), 6.89 (t, 2H), 6.59 (s, 1H), 4.00-3.92 (m, 2H), 2.15 (s, 3H); LC-MS (ESI) m/z 289.1 [M+H]⁺.

Example 462

2-(4-Fluorophenyl)-3-(pyrazin-2-yl)-1,3-thiazolidin-4-one

To a solution of pyrazin-2-amine (0.300 g, 3.15 mmol), Na₂SO₄ (0.540 g, 3.79 mmol) and 4-fluorobenzaldehyde (0.510 mL, 4.73 mmol) in toluene (5.0 mL) was stirred at 110° C. for 16 h, followed by addition of thioglycolic acid (0.350 mL, 5.05 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(pyrazin-2-yl)-1,3-thiazolidin-4-one (0.330 g, 38%). ¹H NMR (CDCl₃, 300 MHz) δ 9.43 (s, 1H), 8.30 (d, 1H), 8.20 (dd, 1H), 7.33-7.25 (m, 2H), 6.97 (t, 2H), 6.71 (s, 1H), 4.04 (d, 1H), 3.84 (d, 1H); LC-MS (ESI) m/z 276.1 [M+H]⁺.

Example 463

2-(4-Fluorophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-4-one

To a solution of pyrimidin-2-amine (0.300 g, 3.15 mmol), Na₂SO₄ (0.540 g, 3.79 mmol) and 4-fluorobenzaldehyde (0.510 mL, 4.73 mmol) in toluene (5.0 mL) was stirred at 110° C. for 16 h, followed by addition of thioglycolic acid (0.350 mL, 5.05 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-60% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-4-one (24.0 mg, 3%). ¹H NMR (CDCl₃, 400 MHz) δ 8.61 (d, 2H), 7.37-7.32 (m, 2H), 7.03 (t, 1H), 6.95 (t, 2H), 6.66 (s, 1H), 4.00 (d, 1H), 3.85 (d, 1H); LC-MS (ESI) m/z 276.1 [M+H]⁺.

Example 464

2-(4-Fluorophenyl)-3-(pyrimidin-4-yl)-1,3-thiazolidin-4-one

To a solution of pyrimidin-4-amine (0.300 g, 3.15 mmol), Na₂SO₄ (0.540 g, 3.79 mmol) and 4-fluorobenzaldehyde (0.510 mL, 4.73 mmol) in toluene (5.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.350 mL, 5.05 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(pyrimidin-4-yl)-1,3-thiazolidin-4-one (0.150 g, 18%). ¹H NMR (CDCl₃, 400 MHz) δ 8.81 (s, 1H), 8.65 (d, 1H), 8.33 (d, 1H), 7.27-7.24 (m, 2H), 7.03-6.97 (m, 2H), 6.80 (s, 1H), 4.02 (d, 1H), 3.78 (d, 1H); LC-MS (ESI) m/z 276.1 [M+H]⁺.

Example 465

Ethyl 5-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-4-methylpyridine-2-carboxylate

Step 1. Synthesis of ethyl 5-amino-4-methylpyridine-2-carboxylate

To a solution of ethyl 4-methyl-5-nitropyridine-2-carboxylate (0.665 g, 3.16 mmol) in THF (20 mL) was added palladium on carbon (70 mg) at room temperature under H_2(g) (1 atm). The reaction mixture was stirred at room temperature for 18 h and then filtered through celite and washed with CH₂Cl₂. The filtrate was concentrated and dried under high vacuum to give ethyl 5-amino-4-methylpyridine-2-carboxylate (0.580 g, quantitative yield) as a green solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.08 (s, 1H), 7.86 (s, 1H), 4.42 (q, 2H), 4.04 (br s, 2H), 2.20 (s, 3H), 1.41 (t, 3H).

Step 2. Synthesis of ethyl 5-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-4-methylpyridine-2-carboxylate

Following standard procedure A, ethyl 5-amino-4-methylpyridine-2-carboxylate (0.285 g, 1.58 mmol), 4-fluorobenzaldehyde (0.200 mL, 1.87 mmol), Na₂SO₄ (0.336 g, 2.37 mmol), 2-mercaptoacetic acid (0.200 mL, 2.86 mmol), and toluene (5.0 mL) were used to carry out the reaction. It was reflux 24 h for the first step and 18 h for the second step. After work-up, the residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 70% ethyl acetate in n-hexane) to give ethyl 5-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-4-methylpyridine-2-carboxylate (28.1 mg, 5%) as a red solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (br s, 1H), 7.34-7.31 (m, 2H), 6.97 (t, 2H), 6.10-5.90 (br, 1H), 4.42 (q, 2H), 4.00 (d, 1H), 3.95 (d, 1H), 2.22 (br s, 3H), 1.40 (t, 3H); LC-MS (ESI) m/z 361.2 [M+H]⁺.

Example 466

Ethyl 5-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-6-methylpyridine-2-carboxylate

Step 1. Synthesis of 6-methyl-5-nitropyridine-2-carbonitrile

A solution of 6-bromo-2-methyl-3-nitropyridine (2.85 g, 13.1 mmol), zinc cyanide (2.16 g, 18.4 mmol), and Pd(PPh₃)₄ (0.759 g, 0.607 mmol) in DMF (20 mL) was stirred at 80° C. for 20 h. The reaction mixture was cooled to room temperature, and DMF was removed under reduced pressure. The crude was treated with ethyl acetate and saturated NaHCO_3(aq). The organic layer was washed with H₂O and brine, dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 6-methyl-5-nitropyridine-2-carbonitrile (1.75 g, 82%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.38 (d, 1H), 7.76 (d, 1H), 2.90 (s, 3H).

Step 2. Synthesis of ethyl 6-methyl-5-nitropyridine-2-carboxylate

A solution of 6-methyl-5-nitropyridine-2-carbonitrile (0.680 g, 4.17 mmol) in H₂O (50 μL) and 1.25 M hydrogen chloride in ethanol solution (6.0 mL) was reflux for 34 h. The reaction mixture was cooled to room temperature and concentrated to give ethyl 6-methyl-5-nitropyridine-2-carboxylate (0.676 g, 77%) as a yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 8.36 (d, 1H), 8.12 (d, 1H), 4.51 (q, 2H), 2.93 (s, 3H), 1.45 (t, 2H).

Step 3. Synthesis of ethyl 6-Methyl-5-aminopyridine-2-carboxylate

To a solution of ethyl 6-methyl-5-nitropyridine-2-carboxylate (0.676 g, 3.22 mmol) in THF (20 mL) was added palladium on carbon (70 mg) at room temperature under H_2(g) (1 atm). The reaction mixture was stirred at room temperature for 18 h and then filtered through celite and washed with CH₂Cl₂. The filtrate was concentrated and dried under high vacuum to give ethyl 6-methyl-5-aminopyridine-2-carboxylate (0.584 g, quantitative yield) as a yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.86 (d, 1H), 6.93 (d, 1H), 4.42 (q, 2H), 4.04 (br s, 2H), 2.48 (s, 3H), 1.40 (t, 3H),

Step 4. Synthesis of ethyl 5-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-6-methylpyridine-2-carboxylate

Following standard procedure A, ethyl 6-methyl-5-aminopyridine-2-carboxylate (0.280 g, 1.55 mmol), 4-fluorobenzaldehyde (0.200 mL, 1.87 mmol), Na₂SO₄ (0.330 g, 2.33 mmol), 2-mercaptoacetic acid (0.200 mL, 2.86 mmol), and toluene (5.0 mL) were used to carry out the reaction. It was reflux 24 h for the first step and 18 h for the second step. After work-up, the residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 70% ethyl acetate in n-hexane) to give ethyl 5-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-6-methylpyridine-2-carboxylate (37.3 mg, 7%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (d, 1H), 7.32-7.27 (m, 3H), 6.97 (dd, 2H), 5.94 (br s, 1H), 4.43 (q, 2H), 4.01 (d, 1H), 3.93 (d, 1H), 2.52 (br s, 3H), 1.39 (t, 3H); LC-MS (ESI) m/z 361.2 [M+H]⁺.

Example 467

2-(4-Fluorophenyl)-3-(1,3-thiazol-2-yl)-1,3-thiazolidin-4-one

A solution of 2-aminothiazole (0.457 g, 4.56 mmol), Na₂SO₄ anhydrous (0.768 g, 5.41 mmol), and 4-fluorobenzaldehyde (0.580 mL, 5.41 mmol) in toluene (15 mL) was stirred at 60° C. for 16 h. Then 2-mercaptoacetic acid (0.570 mL, 8.17 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-35% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(1,3-thiazol-2-yl)-1,3-thiazolidin-4-one (0.455 g, 36%) as a lightly yellow solid. ¹H NMR (CDCl₃, 400 MHz) δ 7.39 (d, 1H), 7.27-7.24 (m, 2H), 7.03-6.99 (m, 3H), 6.67 (s, 1H), 4.08 (d, 1H), 3.83 (d, 1H); LC-MS (ESI) m/z 303.0 [M+Na]⁺.

Example 468

3-(5-tert-Butyl-1,2-oxazol-3-yl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one

To a solution of 5-(tert-butyl)isoxazol-3-amine (0.300 g, 2.14 mmol), Na₂SO₄ (0.360 g, 2.57 mmol) and 4-fluorobenzaldehyde (0.350 mL, 3.21 mmol) in toluene (5.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.240 mL, 3.42 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 3-(5-tert-butyl-1,2-oxazol-3-yl)-2-(4-fluorophenyl)-1,3-thiazolidin-4-one (0.620 g, 91%). ¹H NMR (CDCl₃, 400 MHz) δ 7.31-7.27 (m, 2H), 7.05-7.01 (m, 2H), 6.78 (s, 1H), 6.29 (s, 1H), 3.97 (d, 1H), 3.72 (d, 1H), 1.30 (s, 9H); LC-MS (ESI) m/z 321.1 [M+H]⁺.

Example 469

2-(4-Fluorophenyl)-3-(1,2-oxazol-3-yl)-1,3-thiazolidin-4-one

To a solution of 3-aminoisoxazole (0.300 g, 3.57 mmol), Na₂SO₄ (0.610 g, 4.28 mmol) and 4-fluorobenzaldehyde (0.580 mL, 5.35 mmol) in toluene (5.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.400 mL, 5.71 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(1,2-oxazol-3-yl)-1,3-thiazolidin-4-one (0.940 g, 99%). ¹H NMR (CDCl₃, 400 MHz) δ 8.28 (d, 1H), 7.31-7.27 (m, 2H), 7.17 (d, 1H), 7.05-7.00 (m, 2H), 6.34 (s, 1H), 3.99 (d, 1H), 3.76 (d, 1H); LC-MS (ESI) m/z 287.1 [M+Na]⁺.

Example 470

2-(4-Fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1,3-thiazolidin-4-one

To a solution of 5-methyl-1,3,4-thiadiazol-2-amine (0.300 g, 2.61 mmol), Na₂SO₄ (0.440 g, 3.13 mmol) and 4-fluorobenzaldehyde (0.420 mL, 3.91 mmol) in toluene (5.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.290 mL, 4.17 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1,3-thiazolidin-4-one (0.600 g, 78%). ¹H NMR (CDCl₃, 400 MHz) δ 7.33-7.29 (m, 2H), 7.02 (t, 2H), 6.66 (s, 1H), 4.11 (d, 1H), 3.86 (d, 1H), 2.67 (s, 3H); LC-MS (ESI) m/z 318.0 [M+Na]⁺.

Example 471

2-(4-Fluorophenyl)-3-(4-methyl-1,3-thiazol-2-yl)-1,3-thiazolidin-4-one

To a solution of 2-amino-4-methylthiazole (0.300 g, 2.63 mmol), Na₂SO₄ (0.450 g, 3.15 mmol) and 4-fluorobenzaldehyde (0.420 mL, 3.94 mmol) in toluene (10.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.290 mL, 4.20 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-20% ethyl acetate in n-hexane) to give 2-(4-fluorophenyl)-3-(4-methyl-1,3-thiazol-2-yl)-1,3-thiazolidin-4-one (0.160 g, 21%). ¹H NMR (CDCl₃, 400 MHz) δ 7.29-7.25 (m, 2H), 7.03-6.97 (m, 2H), 6.66 (s, 1H), 6.55 (s, 1H), 4.06 (d, 1H), 3.81 (d, 1H), 2.22 (s, 3H); LC-MS (ESI) m/z 317.1 [M+Na]⁺.

Example 472

Methyl 3-methyl-4-[4-oxo-2-(pyridin-2-yl)-1,3-thiazolidin-3-yl]benzoate

To a solution of methyl 4-amino-3-methylbenzenecarboxylate (0.300 g, 1.82 mmol), Na₂SO₄ (0.260 g, 1.82 mmol) and pyridine-2-carbaldehyde (0.260 mL, 2.73 mmol) in toluene (10.0 mL) was stirred at 110° C. for 6 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(pyridin-2-yl)-1,3-thiazolidin-3-yl]benzoate (75.0 mg, 13%). ¹H NMR (CDCl₃, 400 MHz) δ 8.56 (br d, 1H), 7.88 (br s, 1H), 7.70 (br d, 1H), 7.61 (t, 1H), 7.22-7.18 (m, 2H), 6.95 (br s, 1H), 5.85 (br s, 1H), 4.19 (d, 1H), 3.85 (s, 3H), 3.79 (d, 1H), 2.30 (br s, 3H); LC-MS (ESI) m/z 329.2 [M+H]⁺.

Example 473

Methyl 3-methyl-4-[4-oxo-2-(pyridin-3-yl)-1,3-thiazolidin-3-yl]benzoate

To a solution of methyl 4-amino-3-methylbenzenecarboxylate (0.300 g, 1.82 mmol), Na₂SO₄ (0.260 g, 1.82 mmol) and nicotinaldehyde (0.290 mL, 2.73 mmol) in toluene (10.0 mL) was stirred at 110° C. for 24 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(pyridin-3-yl)-1,3-thiazolidin-3-yl]benzoate (0.115 g, 19%). ¹H NMR (CDCl₃, 400 MHz) δ 8.50 (br d, 1H), 8.45 (s, 1H), 7.84 (br s, 1H), 7.74-7.71 (m, 2H), 7.25-7.21 (m, 1H), 7.18-6.60 (br, 1H), 5.99 (br s, 1H), 4.01 (d, 1H), 3.92 (d, 1H), 3.84 (s, 3H), 2.29-1.85 (br, 3H); LC-MS (ESI) m/z 329.1 [M+H]⁺.

Example 474

Methyl 3-methyl-4-[4-oxo-2-(1,3-thiazol-2-yl)-1,3-thiazolidin-3-yl]benzoate

To a solution of methyl 4-amino-3-methylbenzenecarboxylate (0.300 g, 1.82 mmol), Na₂SO₄ (0.260 g, 1.82 mmol) and thiazole-2-carbaldehyde (0.240 mL, 2.73 mmol) in toluene (5.0 mL) was stirred at 110° C. for 16 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(1,3-thiazol-2-yl)-1,3-thiazolidin-3-yl]benzoate (0.130 g, 21%). ¹H NMR (CDCl₃, 400 MHz) δ 7.92 (br s, 1H), 7.82-7.76 (m, 1H), 7.64 (d, 1H), 7.36 (d, 1H), 7.04 (br s, 1H), 6.23 (br s, 1H), 4.11 (d, 1H), 3.88-3.84 (m, 4H), 2.23 (br s, 3H); LC-MS (ESI) m/z 357.1 [M+Na]⁺.

Example 475

Methyl 4-[2-(1-benzofuran-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate

To a solution of methyl 4-amino-3-methylbenzenecarboxylate (0.300 g, 1.82 mmol), Na₂SO₄ (0.310 g, 2.18 mmol) and benzofuran-2-carbaldehyde (0.330 mL, 2.73 mmol) in toluene (10.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give methyl 4-[2-(1-benzofuran-2-yl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (0.115 g, 17%). ¹H NMR (CDCl₃, 400 MHz) δ 7.91 (br s. 1H), 7.74 (br d, 1H), 7.52-7.46 (m, 2H), 7.33 (t, 1H), 7.24-7.20 (m, 1H), 6.95 (br s, 1H), 6.54 (s, 1H), 5.92 (br s, 1H), 4.23 (d, 1H), 3.93-3.81 (m, 4H), 2.32 (br s, 3H); LC-MS (ESI) m/z 368.2 [M+H]⁺.

Example 476

Methyl 3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]benzoate

To a solution of methyl 4-amino-3-methylbenzenecarboxylate (0.300 g, 1.82 mmol), Na₂SO₄ (0.260 g, 1.82 mmol) and thiophene-3-carbaldehyde (0.240 mL, 2.73 mmol) in toluene (5.0 mL) was stirred at 110° C. for 16 h, followed by addition of thioglycolic acid (0.250 mL, 3.63 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give methyl 3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]benzoate (0.134 g, 22%). ¹H NMR (CDCl₃, 300 MHz) δ 7.88 (s, 1H), 7.77 (br d, 1H), 7.26-7.25 (m, 1H), 7.12-7.08 (m, 2H), 6.93 (br s, 1H), 6.03 (br s, 1H), 3.99 (d, 1H), 3.96-3.85 (m, 4H), 2.17 (br s, 3H); LC-MS (ESI) m/z 334.1 [M+H]⁺.

Example 477

3-(4-Fluoro-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one

A solution of 4-fluoro-2-methylaniline (259 mg, 2.07 mmol), Na₂SO₄ anhydrous (441 mg, 3.11 mmol), and thiophene-3-carboxaldehyde (255 mg, 2.28 mmol) in toluene (10 mL) was stirred at 70° C. for 10 h. Then 2-mercaptoacetic acid (0.296 mL, 4.24 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give 3-(4-fluoro-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one (136 mg, 22%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (br s, 1H), 7.11 (br s, 2H), 6.91 (br s, 1H), 6.77 (br s, 1H), 6.70-6.30 (br, 1H), 6.20-5.60 (br, 1H), 3.98 (d, 1H), 3.87 (d, 1H), 2.20-1.80 (br, 3H); LC-MS (ESI) m/z 294.2 [M+H]⁺.

Example 478

3-(5-Fluoro-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one

A solution of 5-fluoro-2-methylaniline (218 mg, 1.74 mmol), Na₂SO₄ anhydrous (371 mg, 2.61 mmol), and thiophene-3-carboxaldehyde (195 mg, 1.74 mmol) in toluene (10 mL) was stirred at 70° C. for 10 h. Then 2-mercaptoacetic acid (0.220 mL, 3.15 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 25% ethyl acetate in n-hexane) to give 3-(5-fluoro-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one (63.8 mg, 12%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (br s, 1H), 7.21-7.11 (m, 3H), 6.92 (ddd, 1H), 6.58 (br s, 1H), 5.96 (br s, 1H), 3.98 (d, 1H), 3.87 (d, 1H), 2.09 (br s, 3H); LC-MS (ESI) m/z 294.4 [M+H]⁺.

Example 479

3-(5-Chloro-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one

A solution of 5-chloro-2-methylaniline (229 mg, 1.62 mmol), Na₂SO₄ anhydrous (345 mg, 2.43 mmol), and thiophene-3-carboxaldehyde (181 mg, 1.62 mmol) in toluene (10 mL) was stirred at 80° C. for 18 h. Then 2-mercaptoacetic acid (0.200 mL, 2.87 mmol) was added to the reaction mixture, and it was stirred at 90° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with 10% NaOH_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by preparative thin layer chromatography plates (2.0 mm of silica gel on glass support, 30% ethyl acetate in n-hexane) to give 3-(5-chloro-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one (48.9 mg, 10%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.29 (br s, 1H), 7.17-7.11 (m, 4H), 5.97 (br s, 1H), 3.97 (d, 1H), 3.87 (d, 1H), 2.07 (br s, 3H); LC-MS (ESI) m/z 310.1 [M+H]⁺.

Example 480

Ethyl {3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]phenoxy}acetate

Step 1. Synthesis of ethyl ethyl (4-amino-3-methylphenoxy)acetate

To the solution of 4-amino-3-methylphenol (1.00 g, 8.12 mmol) in acetone (10.0 mL), ethyl 2-chloroacetate (1.04 mL, 9.74 mmol) and K₂CO₃ (1.23 g, 8.93 mmol) were used to carry out the reaction. After the reaction mixture was stirred at 50° C. for 16 h and work-up, the residue was purified by Isco Combi-Flash Companion column chromatography (0-40% ethyl acetate in n-hexane) to give ethyl (4-amino-3-methylphenoxy)acetate (0.480 g, 28%). ¹H NMR (CDCl₃, 400 MHz) δ 6.70 (s, 1H), 6.65-6.58 (m, 2H), 4.53 (s, 2H), 4.25 (q, 2H), 3.39 (br s, 2H), 2.17 (s, 3H), 1.28 (t, 3H).

Step 2. Synthesis of ethyl {3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]phenoxy}acetate

To a solution of ethyl (4-amino-3-methylphenoxy)acetate (0.300 g, 1.43 mmol), Na₂SO₄ (0.200 g, 1.43 mmol) and thiophene-3-carbaldehyde (0.190 mL, 2.15 mmol) in toluene (10.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.200 mL, 2.87 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO₄ (s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane, 0-2% MeOH in CH₂Cl₂) to give ethyl {3-methyl-4-[4-oxo-2-(thiophen-3-yl)-1,3-thiazolidin-3-yl]phenoxy}acetate (0.200 g, 37%). ¹H NMR (CDCl₃, 400 MHz) δ 7.21-7.17 (br, 2H), 7.10 (br s, 2H), 6.83-6.43 (br, 1H), 5.92-5.62 (br, 1H), 4.54 (s, 2H), 4.25 (q, 2H), 3.98 (d, 1H), 3.86 (d, 1H), 2.34-1.72 (br, 3H), 1.28 (t, 3H); LC-MS (ESI) m/z 400.1 [M+Na]⁺.

Example 481

3-(4,5-Dimethoxy-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one

To a solution of 4,5-dimethoxy-2-methylaniline (0.300 g, 1.79 mmol), Na₂SO₄ (0.250 g, 1.79 mmol) and thiophene-3-carbaldehyde (0.240 mL, 2.69 mmol) in toluene (10.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.250 mL, 3.59 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-50% ethyl acetate in n-hexane) to give 3-(4,5-dimethoxy-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one (0.350 g, 58%). ¹H NMR (CDCl₃, 400 MHz) δ 7.52 (br s, 1H), 7.31-7.16 (br, 2H), 6.68 (br s, 1H), 6.00-5.65 (br, 1H), 3.99 (d, 1H), 3.88 (d, 1H), 3.83 (s, 3H), 3.52 (br s, 3H), 2.18 (br s, 3H); LC-MS (ESI) m/z 336.1 [M+H]⁺.

Example 482

3-(4-Methoxy-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one

To a solution of 4-methoxy-2-methylaniline (0.280 mL, 2.19 mmol), Na₂SO₄ (0.310 g, 2.19 mmol) and thiophene-3-carbaldehyde (0.280 mL, 3.28 mmol) in toluene (10.0 mL) was stirred at 110° C. for 7 h, followed by addition of thioglycolic acid (0.250 mL, 3.59 mmol) in one portion. The reaction mixture was refluxed overnight, then partitioned between ethyl acetate and H₂O. The organic layer was dried over MgSO_4(s) and concentrated to give a crude product which was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give 3-(4-methoxy-2-methylphenyl)-2-(thiophen-3-yl)-1,3-thiazolidin-4-one (0.420 g, 63%). ¹H NMR (CDCl₃, 400 MHz) δ 7.28 (br s, 1H), 7.10 (br s, 2H), 6.81-6.29 (br, 2H), 6.19-5.64 (br, 1H), 3.98 (d, 1H), 3.86 (d, 1H), 3.73 (s, 3H), 2.30-1.63 (br, 3H); LC-MS (ESI) m/z 328.1 [M+Na]⁺.

Example 483

1-(5-Fluoro-2-methylphenyl)-5-(4-fluorophenyl)pyrrolidin-2-one

Step 1. Synthesis of N-(5-fluoro-2-methylphenyl)-4-(4-fluorophenyl)-4-oxobutanamide

To a solution of 5-fluoro-2-methylaniline (0.701 g, 5.60 mmol), 3-(4-fluorobenzoyl)propionic acid (1.10 g, 5.60 mmol), and DMAP (1.37 g, 11.2 mmol) in CH₂Cl₂ (20 mL) was added EDCI□HCl (1.93 g, 10.1 mmol) at room temperature. The reaction mixture was stirred for 16 h and diluted with CH₂Cl₂. The solution was washed with 2 N HCl_(aq) and brine. The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-30% ethyl acetate in n-hexane) to give N-(5-fluoro-2-methylphenyl)-4-(4-fluorophenyl)-4-oxobutanamide (1.06 g, 62%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 8.03 (dd, 2H), 7.82 (br d, 1H), 7.62 (br s, 1H), 7.19-7.07 (m, 3H), 6.74 (br t, 1H), 3.44 (dd, 2H), 2.85 (dd, 2H), 2.27 (s, 3H).

Step 2. Synthesis of 1-(5-fluoro-2-methylphenyl)-5-(4-fluorophenyl)pyrrolidin-2-one

To a solution of N-(5-fluoro-2-methylphenyl)-4-(4-fluorophenyl)-4-oxobutanamide (0.282 g, 0.929 mmol) in CH₃CN (4.0 mL) was added triethylsilane (0.300 mL, 1.88 mmol) and aluminum triflate (0.441 g, 0.929 mmol) at room temperature, and the reaction mixture was reflux for 3 h. The solution was treated with H₂O and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-100% ethyl acetate in n-hexane) to give 1-(5-fluoro-2-methylphenyl)-5-(4-fluorophenyl)pyrrolidin-2-one (56.8 mg, 21%) as a yellow solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.20-7.16 (m, 2H), 7.11 (dd, 1H), 7.00-6.94 (m, 2H), 6.81 (ddd, 1H), 6.61 (d, 1H), 4.99 (dd, 1H), 2.84-2.63 (m, 3H), 2.23-2.20 (m, 1H), 2.18 (s, 3H); LC-MS (ESI) m/z 288.2 [M+H]⁺.

Example 484

Methyl 4-[2-(4-fluorophenyl)-5-oxopyrrolidin-1-yl]-3-methylbenzoate

Step 1. Synthesis of methyl 4-{[4-(4-fluorophenyl)-4-oxobutanoyl]amino}-3-methylbenzoate

To a solution of methyl 4-amino-3-methylbenzene carboxylate (0.814 g, 4.93 mmol), 3-(4-fluorobenzoyl)propionic acid (0.966 g, 4.93 mmol), and DMAP (1.20 g, 9.86 mmol) in CH₂Cl₂ (15 mL) was added EDCI□HCl (1.89 g, 9.86 mmol) at room temperature. The reaction mixture was stirred for 16 h and diluted with CH₂Cl₂. The solution was washed with 2 N HCl_(aq). The organic layer was dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-45% ethyl acetate in n-hexane) to give methyl 4-{[4-(4-fluorophenyl)-4-oxobutanoyl]amino}-3-methylbenzoate (1.08 g, 64%) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 8.13 (br d, 1H), 8.04 (dd, 2H), 7.88-7.87 (m, 2H), 7.79 (br s, 1H), 7.15 (t, 2H), 3.88 (s, 3H), 3.45 (dd, 2H), 2.87 (dd, 2H), 2.36 (s, 3H).

Step 2. Synthesis of methyl 4-[2-(4-fluorophenyl)-5-oxopyrrolidin-1-yl]-3-methylbenzoate

To a solution of methyl 4-{[4-(4-fluorophenyl)-4-oxobutanoyl]amino}-3-methylbenzoate (0.402 g, 1.17 mmol) in CH₃CN (4.0 mL) was added triethylsilane (0.380 mL, 2.30 mmol) and aluminum triflate (0.554 g, 1.17 mmol) at room temperature, and the reaction mixture was reflux for 5 h. The solution was treated with H₂O and extracted with ethyl acetate. The combined organic layers were dried over MgSO_4(s), filtered, and concentrated. The residue was purified by Isco Combi-Flash Companion column chromatography (0-65% ethyl acetate in n-hexane) to give methyl 4-[2-(4-fluorophenyl)-5-oxopyrrolidin-1-yl]-3-methylbenzoate (97.1 mg, 18%) as a yellow gum. ¹H NMR (CDCl₃, 400 MHz) δ 7.84 (s, 1H), 7.71 (d, 1H), 7.16 (dd, 2H), 6.97-6.92 (m, 3H), 5.07 (dd, 1H), 3.85 (s, 3H), 2.84-2.65 (m, 3H), 2.26 (s, 3H), 2.24-2.17 (m, 1H); LC-MS (ESI) m/z 328.2 [M+H]⁺.

Example 485

Synthesis of (−)-Ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (Compound 660)

Following standard procedure G, (−)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl benzoic acid (90.0 mg, 0.272 mmol), ethanol (17.0 μL, 0.299 mmol), EDCI • HCl (0.100 g, 0.544 mmol), DMAP (73.1 mg, 0.598 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 20% ethyl acetate in n-hexane) to give (−)-ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (83.4 mg, 85%). [α]_D²⁰=−138.50° (c=0.1, CHCl₃).

Example 486

Synthesis of (+)-Ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (Compound 661)

Following standard procedure G, (+)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl benzoic acid (90.0 mg, 0.272 mmol), ethanol (17.0 μL, 0.299 mmol), EDCI • HCl (0.100 g, 0.544 mmol), DMAP (73.1 mg, 0.598 mmol) and CH₂Cl₂ (5.0 mL) were used to carry out the reaction. After the reaction mixture was stirred at room temperature for 16 h and work-up, the residue was purified by preparative thin layer chromatography plates (1.0 mm of silica gel on glass support, 20% ethyl acetate in n-hexane) to give (+)-ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate (81.0 mg, 83%). [α]_D²⁰=142.20° (c=0.1, CHCl₃).

Example 487

Variable-Temperature 1H NMR Spectroscopy Experiment

Chemical shifts of resonances obtained in the NMR spectra are used for structure identification and characterization of organic compounds. The 1H NMR spectrum of thiazolidine derivatives at room temperature showed broadening of signals owing to the restriction of bond rotation. Compound 152 was used to perform and study variable-temperature experiments by NMR spectroscopy. This compound was dissolved in dimethylsulfoxide-d₆ and chemical shifts (δ) were obtained in ppm using the center of the dimethylsulfoxide-d₆ quintet (δ 2.49 ppm) as the internal reference. ¹H NMR data were acquired at 25-80° C. on a VARIAN VNMRS-700 NMR spectrometer. The chemical shift of the proton of C6′ on the benzoate ring was invisible at room temperature. The proton signals of C2, C7′, C2′, and C6′ showed line broadening (FIG. 1a). ¹H NMR experiments are often recorded at high temperatures to overcome the rotation energy barrier in rigid structures. For compound 152, an improvement on resolution of the 1H NMR spectrum was observed at 80° C. (FIG. 1d). The hydrogen signals at δ 2.16 (s, C7′-H), 6.30 (s, C2-H), and 7.76 (s, C2′-H) became sharper, and the signal for the aromatic hydrogen of C6′ at 7.66 ppm appeared as a doublet. The proton peak of C5′ was recorded at 7.18 ppm and was broadened. When 1H NMR spectra were measured at 60° C., not all aromatic hydrogen signals could be clearly distinguished.

Example 488

The exemplary compounds prepared in Examples 1-486 above were tested for modulating opioid receptor activities.

Cell Culture

Human embryonic kidney 293 (HEK-293) cells constitutively expressing MOR (HEK-MOR) and DOR (HEK-DOR) (kindly provided by Dr. Ping-Yee Law, University of Minnesota, USA) were cultured in high-glucose Dulbecco's modified Eagle's medium (DMEM, GIBCO) supplemented with 400 μg/mL G418 (Sigma), 2 mM L-glutamine and P/S/F (100 units/mL penicillin, 100 μg/mL streptomycin, 10% fetal bovine serum). Chinese hamster ovary (CHO)-K1 cells, stably expressing hMOR and Gα15 (CHO-K1/MOR/Gα15), were cultured in F12 medium (GIBCO) supplemented with 10 μg/mL Hygromycin B (Invivogen), 20 μg/mL Zeocin (Invivogen) P/S/F (100 units/mL penicillin, 100 μg/mL streptomycin, 10% fetal bovine serum). The cultures were incubated at 37° C. in a humidified 5% CO₂ incubator.

FLIPR® Calcium Assay

One day before the assay, CORNING® black with clear flat bottom 96-well assay plates were coated with a 0.1 mg/mL Poly-L-Lysine solution. CHO-K1/MOR/Gα15 cells were suspended in the F12 medium and plated at a density of ˜8×10⁴ cells/well in 200 μL medium. Cells were incubated in a humidified atmosphere of 10% CO₂ at 37° C. overnight so as to reach an 80-90% confluent cell monolayer before assay. At the day of assay, 150 μL medium/well was removed from plate. To each well, 50 μL FLIPR® calcium assay reagent dissolved in 1× assay buffer (HBSS: KCl 5 mM, KH₂PO₄ 0.3 mM, NaCl 138 mM, NaHCO₃ 4 mM, Na₂HPO4 0.3 mM, d-glucose 5.6 mM, with additional 20 mM HEPES and 13 mM CaCl₂, pH 7.4), with 2.5 mM probenecid was added and the plate was incubated at 37° C. for 1 h. Compounds and other reagents were dissolved in the assay buffer. Using a FlexStationIII (Molecular Devices Corp.), the [Ca²⁺]_i fluorescence increases after robotic injections of compounds or other reagents were monitored every 1.52 s interval with excitation wavelength at 485 nm and with emission wavelength at 525 nm. The [Ca²⁺]_i fluorescence was measured up to 90 s after agonist injection. The fluorescence intensity from 6 to 12 wells of cells were averaged and the relative amount of [Ca²⁺]_i release was determined by integrating the AUC of the [Ca²⁺]_i fluorescence averages.

Among the tested compounds, compounds 4-6, 8, 10, 11, 14-16, 20, 37, 38, 44, 46, 47, 49, 52-55, 58-60, 62, 64, 68, 72, 74, 78, 84, 86, 90, 92, 93, 96, 101, 102, 108-110, 112, 113, 122-124, 147, 149, 151, 152, 154, 156, 157, 159, 160, 162, 163, 167, 169, 171, 173-177, 179, 183, 185-190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 211, 213, 215-221, 227-229, 231, 234-236, 239, 258, 261, 263, 266-268, 270, 272, 273, 276, 277, 279-281, 286, 290-292, 294-301, 303, 306, 307, 310, 311, 313, 314, 326, 329, 331, 332, 334, 335, 337, 338, 339-344, 347-351, 353-355, 357, 361, 368, 374-376, 378, 380, 381, 383-388, 579-581, 583, 588, 593, 597, 600, and 648 each showed an EC₅₀ value less than 10 μM.

Among the tested compounds, compounds 2, 4-6, 10-12, 14-16, 38, 43, 44, 46, 47, 49, 52-55, 58-60, 62, 64, 68, 74, 78, 84, 86, 90, 92, 93, 96, 101, 102, 108-113, 117, 122, 124, 147, 151, 152, 154, 156, 157, 159, 160, 162, 163, 165, 167, 169, 171, 173-177, 179, 183, 185-190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 211, 213, 215-221, 224, 227-229, 231, 234-236, 238, 253, 258, 261, 263, 266-273, 275-277, 279-281, 286, 290-292, 294-301, 303, 306, 307, 310, 311, 313, 314, 326, 328, 329, 331, 332, 334-344, 347-351, 353-357, 361, 368, 373, 374, 376-378, 380, 381, 383-387, 390, 395, 404, 406, 408, 411, 416, 579-581, 583, 588, 591, 593, 597, 600, 635, 640, and 648 each showed an AUC value more than 5000.

cAMP Assay

Briefly, 2000 HEK-MOR cells or HEK-DOR cells were plated in 10 μL/well of DMEM in 96-well solid bottom white plates and 10 μL/well compound in HBSS in the presence with 1 μM forskolin and 100 μM 3-isobutyl-1-methylxanthine (IBMX). After 30 minutes of incubation at room temperature, 10 μL/well of labeled d2-cAMP and 10 μL/well of anti-cAMP antibody (both diluted in lysis buffer) were added to each well. Two hours later, plates were measured using the FlexStationIII (Molecular Devices Corp.) with excitation at 330 nm and emissions of 620 nm and 665 nm.

Tail-Flick Test

Male wild-type (WT) B6 mice (25-30 g) were kept in a temperature-controlled animal room with a 12-h light/dark cycle. The protocol has been approved by the Institutional Animal Care and Use Committee of the National Health Research Institutes, Taiwan. Animal experiments were carried out in accordance with the Policies on the Use of Animals in Neuroscience Research and the ethical guidelines for investigations of experimental pain in conscious animals, International Association for the Study of Pain. Tail-Flick Analgesia Meter (Columbia Instruments) was used to measure the tail-flick latencies of mice. The cut-off time for each measurement was 10 s to avoid tissue damage. Basal latencies were recorded before treatment and test latencies were recorded 30, 60, 90, 120 and 180 min after an intravenous injection of drugs. A time-response curve was calculated for antinociceptive effects (test latency—basal latency) occurring during 0 to 180 min, and the AUC value was calculated. ED₅₀ values were determined by the up-and-down method reported in Crocker et al., Pharmacol Biochem Behav, 1984, 21, 133-136.

Example 489

Identification of μ-Opioid Receptor Antagonist to Agonist Allosteric Modifiers (AAMs) by Using Calcium Assay System

A CHO-K1 cell line, expressing a MOR and Gα15 (GenScript), was used to set up a sensitive high-throughput screen (HTS) system. In a FLIPR® calcium assay using CHO-K1/MOR/Gα15 cells, activation of MOR elicits an intracellular calcium release leading to an increase in the relative fluorescence units (FRU). In this assay, the EC₅₀ value of D-ala2-nmephe4-gly-ol-enkephalin (DAMGO), a MOR-specific agonist, was determined to be 0.67 nM. The HTS was performed in the absence or presence of an opioid antagonist, naloxone (25 nM), to identify antagonist to agonist allosteric modifiers (AAM). Compounds 112 and 58 were identified as opioid receptor AAMs. Both compounds 112 and 58 did not show responses on their own, but induced a significant calcium release in the presence of naloxone. Upon co-administrated with naloxone (20 nM), compound 58 induced calcium release in a dose dependent manner, exhibiting an EC₅₀ value of 1.3 μM.

Furthermore, concentration-response curves (CRCs) of naloxone in presence of compound 58 at different concentrations were determined by a calcium assay. Magnitudes of the increase in naloxone efficacy produced by each concentration of compound 58 were recorded. It was observed that both E_max and potency of naloxone were altered by varying concentrations of compound 58. Similar to naloxone, compound 58 also worked as an AAM of naltrexone, with similar potency but a higher magnitude of efficacy. Probe dependence (effect of allosteric modifier can only be observed when combine with certain ligands) is a unique character in allosteric modifiers. Compared a combination of compounds and naloxone, no activity was observed in CHO-K1/MOR/Gα15 cells treated with a combination of peptide MOR antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and compound 58. Thus, compound showed marked antagonist probe dependence as it produced highly selective AAM property with alkaloid antagonist over peptide antagonist.

To characterize of novel opioid receptor AAMs, the activity and selectivity of compound 58 were tested by inhibiting adenylyl cyclase activity (i.e., cAMP assay).

Opoid receptors inhibit adenylyl cyclase activity through Gi/o family of heterotrimeric G proteins. A cAMP-accumulation assay was performed to determine whether opioid receptor AAMs affect a G protein-dependent signaling pathway. The cAMP-inhibition response produced by an opioid agonist, DAMGO, [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) in HEK-MOR or HEK-DOR were 90% and 60% of forskolin-stimulated (1 μM) cAMP assumulation, with EC₅₀ values of 5.5 nM and 0.5 nM, respectively. The combination of compound 58 and naloxone (20 nM) significantly inhibited adenylyl cyclase activity in HEK-MOR cells, with an EC₅₀ value of 3 μM. By contrast, compound 58 produced no effect in the presence of naloxone (20 nM) in HEK-DOR cells. Thus, compound 58 was determined to be selective for mu-over delta-opioid receptors.

Traditional allosteric modifiers are classified by mode of target protein activity modulated by compounds. Positive allosteric modifiers (PAMs) enhance the binding affinity or efficacy of the orthosteric agonist when they bind to the receptor; negative allosteric modifiers (NAMs) inhibit the binding affinity or efficacy of the orthosteric agonist. Studies were performed to evaluate whether μ-opioid receptor AAMs also showed other properties of traditional allosteric modifiers. Concentration-response curves (CRCs) of morphine, a partial agonist of opioid receptor with high structure similarity of naloxone, were determined by a FLIPR calcium assay in the presence or absence of compound 58 at various concentrations.

It was observed that neither E_max nor potency of morphine was significantly altered by compound 58 at any tested concentration. Morphine produced similar E_max as compared to the combination of morphine and compound 58 at concentrations of 30, 10, 3.3 μM. These results indicate that compound 58 modulates the action of opiate antagonist without any PAM or NAM effect of mu-opioid receptor.

Naloxone Produced Antinociceptive Effects in Mice Injected with Compound 58

An in vivo study, i.e., tail-flick test, was performed to investigate whether AAMs could change innate character of μ-opioid receptor in the presence of naloxone. Compound 58 alone groups (50, 25, 12.5 and 6.25 nmole; i.t.) didn't exhibit any antinociceptive effects in B6 mice. On the other hand, significant inhibition of the tail-flick response was observed in mice co-injected with both naloxone (10 mg/kg; s.c.) and compound 58 (50, 25, and 12.5 nmole; i.t.), with area under the curve (AUC) values of 649.8±123.3, 560.6±96.5, and 241.5±111.3 (min×s), respectively. In mice injected with naloxone (10 mg/kg; s.c.), the ED₅₀ value of compound 58 in inhibition of the tail-flick response was determined to be 23.1±7.1 nmole. In mice injected with saline, no antinociception effect was observed with the highest dose of compound 58 tested (50 nmole; i.t.).

These results indicate that compound 58 worked in vivo as a unique AAM.

Example 490

Activation of μ-Opioid Receptor with Compound 58 Combined with a μ-Opioid Receptor Antagonist

A CHO-K1 cell line, expressing a MOR and Gα15 (GenScript), was used to set up a sensitive assay system for detecting μ-opioid receptor activation. A FLIPR® calcium assay using CHO-K1/MOR/Gα15 cells, in which activation of MOR elicits intracellular calcium release leading to an increase in the relative fluorescence units (FRU), was conducted and the EC₅₀ value of D-ala2-nmephe4-gly-ol-enkephalin (DAMGO), a MOR-specific agonist, was determined to be 0.67 nM. The assay was performed in the presence of an opioid antagonist, i.e., naloxone (25 nM), naltrexone (20 nM), samidorphan (10 nM), naloxonazine dihydrochloride (20 nM), β-funaltrexamine hydrochloride (20 nM), cyprodime hydrochloride (500 nM), or nalmefene (20 nM), in combination with compound 58, an antagonist to agonist allosteric modifier (AAM), to identify activation of the μ-opioid receptor. Compound 58 did not elicit any response on its own, but induced significant calcium release in the presence of an antagonist. Co-administrated with one of the opioid antagonists listed above, compound 58 induced calcium release in a dose dependent manner, exhibiting EC₅₀ values and AUC values shown in Table 3 below.

TABLE 3
Effect of compound 58 combined with an
opioid antagonist on calcium release
	Concentration
Opioid antagonist	(nM)	EC50 (μM)	AUC
Naloxonazine dihydrochloride	20	0.642 ± 1.939	11819.33
β-Funaltrexamine hydrochloride	20	0.346 ± 0.209	8553.5
Cyprodime hydrochloride	500	5.123 ± 2.521	7893
Naltrexone	20	0.630 ± 0.217	12980.33
Samidorphan	10	5.525	13179
Samidorphan	20	5.273	14094
Nalmefene	20	—	8506

These results indicate that compound 58 combined with an opioid antagonist unexpectedly exhibited high activities in μ-opioid receptor activation.

Other Embodiments

All of the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.

From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. For example, compounds structurally analogous to the compounds of this invention also can be made, screened for their modulating activities to opioid receptor and treating opioid receptor associated conditions. Thus, other embodiments are also within the claims.

Claims

1. A pharmaceutical composition for treating an opioid receptor-associated condition, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I):

2. The pharmaceutical composition of claim 1, wherein ring A is

3. The pharmaceutical composition of claim 2, wherein ring A is

4. The pharmaceutical composition of claim 1, wherein U is one of the following moieties:

5. The pharmaceutical composition of claim 1, wherein V is

6. The pharmaceutical composition of claim 5, wherein V is one of the following moieties:

7. The pharmaceutical composition of claim 1, wherein V is one of the following moieties:

8. The pharmaceutical composition of claim 1, wherein V is one of the following moieties:

9. The pharmaceutical composition of claim 3, wherein U is one of the following moieties:

10. The pharmaceutical composition of claim 9, wherein V is

11. The pharmaceutical composition of claim 1, wherein the compound is one of Compounds 4-6, 10, 11, 14-16, 38, 44, 46, 47, 49, 52-55, 58-60, 62, 64, 68, 74, 78, 84, 86, 90, 92, 93, 95, 96, 101, 102, 108-110, 112, 113, 122, 124, 147, 151, 152, 154, 156, 159, 160, 162, 163, 167, 169, 171, 173-177, 179, 183, 185-190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 211, 213, 215-221, 227-229, 231, 234-236, 239, 247, 250, 252, 258, 260, 261, 263-265, 268-272, 276, 280-282, 284-286, 290, 291, 294-301, 303, 310, 311, 312-314, 329, 331, 332, 334, 335, 337, 338, 341-344, 347-351, 353-355, 357, 361, 368, 374, 376, 378, 380, 381, 383-387, 390, 404, 406, 408, 411, 416, 446, 453, 456, 458, 461, 463, 465, 489, 495, 497, 499, 504, 505, 508, 510, 516, 517, 519-521, 525, 526, 532, 533, 538, 540, 542, 546, 548, 550, 556, 560, 562, 564, 571, 579-581, 583, 588, 589, 591, 593, 597, 600, 605, 607, 629, 635, 640, 648, 660, and 661.

12. The pharmaceutical composition of claim 3, wherein the compound is one of Compounds 44, 53, 54, 58, 59, 93, 95, 101, 112, 152, 160, 169, 174, 175, 187, 196, 204, 206, 236, 239, 261, 269, 270, 272, 280, 296, 299, 313, 390, 453, 465, 489, 495, 497, 499, 504, 505, 508, 510, 516, 517, 519-521, 532, 533, 538, 540, 542, 546, 548, 550, 556, 560, 562, 564, 571, 579-581, 583, 588, 589, 591, 593, 597, 600, 605, 607, 619-621, 629, 635, 640, 648, 660, and 661.

13. The pharmaceutical composition of claim 1, further comprising a second therapeutic agent for treating pain.

14. The pharmaceutical composition of claim 13, wherein the second therapeutic agent is a mu-opioid receptor antagonist.

15. The pharmaceutical composition of claim 14, wherein the mu-opioid receptor antagonist is naloxone, naltrexone, samidorphan, cyprodime, clocinnamox, β-FNA, naloxonazine, or nalmefene.

16. The pharmaceutical composition of claim 15, wherein the compound is one of Compounds 10, 11, 44, 46, 49, 53, 54, 58-60, 62, 64, 74, 86, 90, 92, 93, 95, 96, 101, 109, 112, 113, 152, 159, 160, 169, 174-176, 185, 187, 188, 190, 194, 196, 198, 202, 204, 206, 208, 211, 213, 219-221, 227, 236, 239, 247, 250, 252, 258, 260, 261, 263-265, 268-270, 272, 276, 280-282, 286, 290, 294, 296, 297, 299, 301, 303, 310, 311, 313, 331, 337, 361, 376, 386, 387, 390, 446, 453, 456, 458, 461, 463, 465, 489, 495, 497, 499, 504, 505, 508, 510, 516, 517, 519-521, 525, 526, 532, 533, 538, 540, 542, 546, 548, 550, 556, 560, 562, 564, 571, 589, 605, 607, 660, and 661.

17. The pharmaceutical composition of claim 16, wherein the compound is one of Compounds 44, 53, 54, 58, 59, 93, 95, 101, 112, 152, 160, 169, 174, 175, 187, 196, 204, 206, 236, 239, 261, 269, 270, 272, 280, 296, 299, 313, 390, 453, 465, 489, 495, 497, 499, 504, 505, 508, 510, 516, 517, 519-521, 532, 533, 538, 540, 542, 546, 548, 550, 556, 560, 562, 564, 571, 579-581, 583, 588, 589, 591, 593, 597, 600, 605, 607, 619-621, 629, 635, 640, 648, 660, and 661.

18. A compound of formula (I):

19. The compound of claim 18, wherein R1 is CH3 and R3 is —C(O)OR, —C(O)NRR′, —C(O)R, —C(O)NRS(O)2R′, or —C(O)NRS(O)2NR′R″.

20. A compound of formula (I):

21. The compound of claim 20, wherein R1 is CH3 and R3 is —C(O)OR, —C(O)NRR′, —C(O)R, —C(O)NRS(O)2R′, or —C(O)NRS(O)2NR′R″.

22. A method of treating an opioid receptor-associated condition, the method comprising administering to a subject in need thereof a mu-opioid receptor antagonist and an effective amount of a compound of Formula (I):

23. The method of claim 22, wherein the mu-opioid receptor antagonist is naloxone, naltrexone, samidorphan, cyprodime, clocinnamox, β-FNA, naloxonazine, or nalmefene.

24. The method of claim 22, wherein the opioid receptor-associated condition is pain, immune disease, esophageal reflux, diarrhea, anxiety, or heroin addiction.

25. The method of claim 24, wherein the opioid receptor-associated condition is pain.

26. The method of claim 25, wherein the pain is cancer pain, post operative pain, low back pain, rheumatoid arthritis pain, osteoarthritis pain, neuropathic pain, or fibromyalgia pain.

27. The method of claim 25, wherein the compound is Compound 10, 11, 44, 46, 49, 53, 54, 58-60, 62, 64, 74, 86, 90, 92, 93, 95, 96, 101, 109, 112, 113, 152, 159, 160, 169, 174-176, 185, 187, 188, 190, 194, 196, 198, 202, 204, 206, 208, 211, 213, 219-221, 227, 236, 239, 247, 250, 252, 258, 260, 261, 263-265, 268-270, 272, 276, 280-282, 286, 290, 294, 296, 297, 299, 301, 303, 310, 311, 313, 331, 337, 361, 376, 386, 387, 390, 446, 453, 456, 458, 461, 463, 465, 489, 495, 497, 499, 504, 505, 508, 510, 516, 517, 519-521, 525, 526, 532, 533, 538, 540, 542, 546, 548, 550, 556, 560, 562, 564, 571, 589, 605, 607, 660, or 661.

28. The method of claim 27, wherein the compound is Compound 44, 53, 54, 58, 59, 93, 95, 101, 112, 152, 160, 169, 174, 175, 187, 196, 204, 206, 236, 239, 261, 269, 270, 272, 280, 296, 299, 313, 390, 453, 465, 489, 495, 497, 499, 504, 505, 508, 510, 516, 517, 519-521, 532, 533, 538, 540, 542, 546, 548, 550, 556, 560, 562, 564, 571, 579-581, 583, 588, 589, 591, 593, 597, 600, 605, 607, 619-621, 629, 635, 640, 648, 660, or 661.