CN101237866A

CN101237866A - Use of thiazole derivatives and analogues in the treatment of cancer

Info

Publication number: CN101237866A
Application number: CNA2006800264944A
Authority: CN
Inventors: 雅各布·韦斯特曼; 比约恩·埃里克森; 吉多·库兹; 克里斯琴·赫德伯格
Original assignee: Betagenon AB
Current assignee: Betagenon AB
Priority date: 2005-07-21
Filing date: 2006-07-21
Publication date: 2008-08-06
Also published as: ZA200800399B; CN101277692A; ZA200800243B

Abstract

There is provided a use of a compound of formula (I): wherein X, T, Y5 W, A1, A2, R1, R5 and R6 have meanings given in the description, for the manufacture of a medicament for the treatment of a disorder or condition caused by, linked to, or contributed to by, free fatty acids, such as hyperinsulinemia and associated conditions, including type 2 diabetes and the like.

Description

Use of thiazole derivatives and analogues in diseases caused by free fatty acids

Technical Field

The present invention relates to novel pharmaceutical uses of certain compounds. In particular, the invention relates to the use of such compounds as modulators (e.g. inhibitors) of Free Fatty Acids (FFAs) and thus in the treatment of hyperinsulinemia and related disorders.

Background

Elevated FFAs and hyperinsulinemia (hypersecretion of insulin) represent new targets for the treatment of obesity-related disorders/metabolic syndrome.

Metabolic syndrome is becoming more prevalent and affects about forty-seven million adults in the united states alone. This syndrome is characterized by metabolic risk factors such as central obesity, atherogenic dyslipidemia, hypertension, insulin resistance or glucose intolerance. The syndrome is also characterized by hyperinsulinemia, prothrombotic state in the blood and pro-inflammatory states.

Potential causes of metabolic syndrome include obesity, physiological inactivation, and genetic factors. Patients are at increased risk for coronary heart disease and other diseases associated with arterial wall scarring, such as stroke, peripheral vascular disease, and type II diabetes.

Diabetes is one of the most common metabolic diseases in western countries and is highly prevalent, with over 1 hundred million and 7 million people currently affected by type II diabetes. It is a chronic, currently incurable disease, with patients at high risk of life-threatening complications as the disease worsens. The overall cost to society for diabetes and its complications is enormous.

About 3 million people worldwide suffer from obesity, and at least 10 million people are considered to be out of weight. These problems are associated with elevated FFAs and hyperinsulinemia and may result in increased insulin resistance and, in the worst case, in exacerbations of diabetes (about 80% of adult diabetics are overweight), metabolic syndrome, fatty liver and/or other conditions or diseases.

Thus, to a large extent, obesity, metabolic syndrome and diabetes are related and patients suffering from one or more of these conditions are in great need of better pharmaceutical treatment.

Insulin is a potent hormone and growth factor. In addition to obesity, hyperinsulinemia is evident in conditions such as impaired glucose tolerance, early or intermediate stage type II diabetes, polycystic ovary syndrome, and alzheimer's disease. Evidence has focused on the major role that hyperinsulinemia plays in the exacerbation of these diseases.

High plasma FFAs stimulate pancreatic beta cells and are one of the causes of hyperinsulinemia. Drugs that modulate (e.g. inhibit) the stimulatory effect of FFA on insulin secretion may therefore represent new therapeutic strategies for the treatment or prevention of diseases caused, associated with or caused by hyperinsulinaemia.

Steneberg et al (2005), Cell Metabolism, 1, 245-258, explained a possible mechanism that could potentiate the aetiology of hyperinsulinemia exacerbations after exposure to high plasma FFAs, reported a study under high fat diet conditions and suggested that GPR40 plays a key role in the course of cases leading to diabetes. Mouse mutants lacking the GPR40 receptor may be protected from diabetes. However, no drug which antagonizes FFAs is disclosed in this document.

The other FFA receptor, GPR120, is abundantly expressed in various tissues, especially in the gut. Stimulation of GPR120 by FFAs promotes GLP-1 secretion and increases circulating insulin (see Hirasawa et al (2005), Nature Medicine, 11, 90-94).

There is currently no treatment available to reduce hyperinsulinaemia for different types of diabetes, for example by inhibiting FFA-mediated stimulation of beta-cells:

(a) insulin secretagogues such as sulfonylureas promote only the secretion step of insulin;

(b) metformin acts mainly on glucose production in the liver;

(c) peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists, such as thiazolidinediones, enhance insulin action; and

(d) alpha-glucosidase inhibitors interfere with intestinal glucose production.

All these therapies fail to stop the progression of the disease and, over time, fail to normalize glucose levels and/or stop subsequent complications.

Many of the current therapies for treating type II diabetes have limitations. For example, epstein-barr (exenatide) requires administration by subcutaneous injection and also suffers from storage stability deficiencies.

In addition, existing therapies for treating type II diabetes are known to produce undesirable side effects. For example, insulin secretagogues and insulin injections may cause hypoglycemia and weight gain. Patients may also become unresponsive to insulin secretagogues over time. Metformin and α -glucosidase inhibitors often cause gastrointestinal problems, and PPAR- γ agonists are prone to cause weight gain and edema. Also, epstein-barr is said to cause nausea and vomiting.

With the increasing prevalence of obesity in western society, there is an urgent clinical need to develop new innovative strategies and the goal is to suppress the harmful effects of FFAs and hyperinsulinemia without causing hyperglycemia and diabetes. Furthermore, there is a clear need for new drugs with superior efficacy and/or low side effects.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting about 10% of women of reproductive age. This syndrome is associated with a variety of endocrine and metabolic abnormalities, including insulin resistance (see Ehrmann et al (2006), J Clin Endocrinol Metab, Jan 91(1), 48-53). Patients with PCOS are often hyperinsulinemia and insulin resistance. Hyperinsulinemia can cause androgen hyperactivity and anovulatory dysfunction in a variety of ways. In vitro and in vivo studies have shown that insulin in combination with LH synergistically promotes androgen production by thecal cells. Insulin inhibits hepatic synthesis of sex hormone-binding globulin, thereby increasing the free pool of androgens (Nestler (1997), Hum reprod., Oct 12, Suppl 1, 53-62).

In Alzheimer's Disease (AD), longitudinal studies have identified a strong correlation with hyperinsulinemia. Hyperinsulinemia also involves a significant decrease in cognitive scores associated with memory, but not in other cognitive areas. Hyperinsulinemia is thus associated with a high risk of AD and memory decline.

Insulin degrading enzymes may also build a mechanistic link between hyperinsulinemia and AD (Wei and Folstein (2006), Neurobiology of Aging, 27, 190-. This enzyme degrades insulin and amyloid- β (a β) peptide, which are excess short peptides found in AD brain. Evidence suggests that hyperinsulinemia may elevate a β by competition of insulin with the latter for insulin degrading enzymes. The formation of neurofibrillary tangles, which contain hyperphosphorylated tau (tau), represents a key step in the pathogenesis of neurodegenerative diseases. Enhancement of peripheral insulin stimulation, rapidly increasing insulin receptor tyrosine phosphorylation, activation of mitogen-activated protein kinase and Phosphatidylinositol (PI) 3-kinase pathways, and dose-dependent tau phosphorylation in the central nervous system at Ser (202) in an insulin receptor-dependent manner.

Thus, peripherally injected insulin targets the brain directly and causes rapid brain insulin receptor signaling, revealing another link between hyperinsulinemia and neurodegeneration.

Studies with patients with Systemic Lupus Erythematosus (SLE) have shown significantly higher fasting insulin levels compared to healthy controls. They also present an increased risk of Coronary Heart Disease (CHD), which is not fully explained by the classical CHD risk factors, Magadmi et al (2006) J Rheumatol, Jan 33, 50-56. Hyperinsulinemia may therefore be a manageable risk factor in non-diabetic and diabetic SLE patients. Current studies of metabolic syndrome in patients with chronic kidney disease indicate that insulin resistance and hyperinsulinemia are each associated with an increased prevalence of the disease. Insulin itself can promote the proliferation of mesangial cells and the production of matrix proteins, and also promotes the expression of growth factors such as IGF-1 and TGF- β involved in mitotic and fibrotic processes in renal disease. Insulin also interferes with the system RAS, in particular enhancing the effect of angiotensin II on mesangial cells. Hyperinsulinemia also increases the level of endothelin-1 and is associated with increased oxidative stress. In conclusion, a reduction in high insulin blood levels may be of therapeutic value in patients with progressive renal disease (e.g. chronic renal failure; Sarafidis and Ruilope (2006), Am J Nephrol, 26, 232-.

US1293741 specifically discloses thiazolidinones. However, there is no mention of the use of the compounds of the present invention in the treatment of diabetes.

US 4,103,018 and US 4,665,083 disclose in particular thiazolidinones. However, thiazolidinones substituted in the 5-position are not mentioned or suggested.

WO 2005/051890 specifically discloses thiazolidinones (which are eventually substituted with cyclopropyl) useful for the treatment of diabetes. However, thiazolidinones substituted in position 5 directly or via an alkylene linker by a heterocyclyl, heteroaryl or, in particular, aryl group are not mentioned or suggested.

EP 1559422 discloses a wide range of compounds for use in particular in the treatment of diabetes. However, this document apparently does not relate to thiazolidinone compounds.

US patent application US 2006/0089351 discloses a number of benzothiazole derivatives as neuropeptide Y receptor antagonists and their use in the treatment of eating disorders. International patent application WO2006/020680 discloses a wide range of heterocyclic compounds as modulators of nuclear receptors.

International patent applications WO 2005/075471 and WO 2005/116002 disclose in particular thiazolidinone and oxazolidone compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1. However, there is no teaching that such thiazolidinone or oxazolidone compounds, respectively, are substituted in the 5-position by a heterocyclyl, heteroaryl or especially aryl group, either directly or via an alkylene linker.

We have now surprisingly found compounds capable of modulating (e.g. antagonizing) the stimulatory effect of FFAs on cell proliferation in assays performed using the human breast cancer cell line (MDA-MB-231). The test was performed in the presence of linolenic acid. The compounds may have surprisingly beneficial inhibitory effects and may be useful as FFA modulators.

Disclosure of Invention

According to a first embodiment of the invention there is provided the use of a compound of formula I in the manufacture of a medicament for the treatment of a disease or condition caused, associated or contributed to by FFAs,

wherein

X is alkylene or a bond (e.g. - [ C (R))₈)(R₉)]_n-wherein n is 0, 1, 2 or 3 and R₈And R₉As defined below);

t represents-S-;

y represents-c (o) -or ═ c (h) -;

w represents-NR₇-；

A₁Or A₂One represents a double bond and the other represents a single bond;

when A is₁When represents a single bond, A₂Is a double bond and R₆Is absent;

when A is₂When represents a single bond, A₁Is a double bond and R₇Is absent;

R₁represents heterocyclyl, aryl or heteroaryl (each of which is optionally substituted by one or more groups selected from B⁴、B⁵And B⁶Substituted with a group of (a);

R₅represents hydrogen, alkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl (wherein the last six groups are each optionally substituted by one or more groups selected from B⁷、B⁸、B⁹、B¹⁰、B¹¹And B¹²Substituted with a group of (a);

R₆and R₇Independently represent hydrogen, alkyl, cycloalkyl or benzyl (wherein the last three groups are each optionallyIs one or more selected from B¹³、B¹⁴And B¹⁶Substituted with a group of (a);

B⁴to B¹⁴And B¹⁶If applicable, independently represent cyano, -NO₂Halogen, -OR₁₁、-NR₁₂R₁₃、-SR₁₄、-Si(R₁₅)₃、-C(O)OR₁₆、-C(O)NR_16aR_16b、-S(O)₂NR_16cR_16dAryl or heteroaryl (wherein aryl and heteroaryl are themselves optionally and independently substituted with one or more substituents selected from halogen and R₁₇Substituted with a group of (a); or, alternatively,

B⁴、B⁵、B⁶、B¹⁰、B¹¹、B¹²or B¹⁶Independently (if applicable) represents R₁₇；

R₁₁、R₁₂、R₁₃、R₁₄、R₁₆、R_16a、R_16b、R_16cAnd R_16dIndependently represent H or R₁₇；

In each case when used herein, R₁₅And R₁₇Independently represents C optionally substituted by one or more halogen atoms_1-6An alkyl group, a carboxyl group,

or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically functional derivative thereof.

In the compounds of formula I according to the above first embodiment of the invention, preferably when Y represents-C (O) -R₇Represents H, and:

(i)R₅represents bicyclo [2.2.1]Hept-2-yl, then:

(a) when X represents a bond (e.g. when X represents- [ CR ]₈R₉]_nWhere n represents 0), R₁Does not represent unsubstituted phenyl;

(b) when X represents-CH₂When is, then R₁Does not represent 4-hydroxyphenyl;

(ii)R₅represents a methyl group substituted by a cyclohexyl group (i.e. a partially cyclic C₇Alkyl) and X represents a bond, then R₁Does not represent 2-hydroxyphenyl;

(iii)R₅represents cycloheptyl and X represents-CH₂-, then R₁Does not represent imidazol-4-yl, indol-3-yl, 4-hydroxyphenyl or 3-pyridyl;

(iv)R₅represents cyclooctyl and X represents-CH₂-, then R₁Does not represent 4-hydroxyphenyl;

(v) x represents a bond and R₁Represents 4-tetrahydropyranyl, then R₅Does not represent 2-fluoro-, 2-chloro-or 2-methylphenyl;

(vi) x represents a bond and R₁Represents 3-tetrahydrofuryl, then R₅Does not represent 2-fluoro-or 2-chlorophenyl;

(vii) x represents a bond and R₁Represents tert-butyl-4-piperidinyl-1-carboxylate, then R₅Does not represent 2-chlorophenyl;

(viii) x represents a bond and R₅Represents tricyclo [ 3.3.1.1-3, 7 >]Decyl-1-yl, then R₁Does not represent unsubstituted phenyl;

(ix) x represents a bond and R₅Is represented by B at 1 bit⁷Substituted ethyl radicals in which B is⁷Represents a 4-fluorophenyl group;

(x) X represents-CH₂-and R₅Represents unsubstituted phenyl, then R₁Does not represent benzimidazol-2-yl or 1-methylbenzimidazol-2-yl; and

(xi) X represents-CH₂-and R₅Represents methyl substituted by cyclohexyl, then R₁It does not represent benzimidazol-2-yl.

In the compounds of formula I according to the above-mentioned first embodiment of the invention, it is also preferred that R when Y represents-C (O) -₇Represents H, X represents-CH₂-and:

(a)R₅represents bicyclo [2.2.1]Hept-2-yl, then R₁Does not represent 4-hydroxyphenyl;

(b)R₅represents cycloheptyl, then R₁Does not represent 3, 4-dihydroxyphenyl;

(c)R₁represents [5- (2-chlorophenyl) -1, 3, 4-oxadiazol-2-yl]Then R is₅Do not represent 2-fluorophenyl, tricyclo- [ 3.3.1.0-3, 7 ℃]Nonan-3-yl, 2, 6, 6-trimethylbicyclo [3.1.1]Hept-3-yl or bicyclo [2.2.1]Hept-2-yl;

(d)R₁represents benzimidazol-2-yl, then R₅Not representing cyclohexyl, cycloheptyl or bicyclo- [2.2.1]Hept-2-yl;

(e)R₁represents 1, 3-benzoxazol-2-yl, then R₅Does not represent unsubstituted phenyl or cycloheptyl; and

(f)R₁represents 1, 3-benzothiazol-2-yl, then R₅Not unsubstituted phenyl.

In the compounds of formula I according to the above first embodiment of the invention, preferably when Y represents-C (O) -R₆Represents an unsubstituted benzyl group (or a methyl group substituted by an unsubstituted phenyl group), R₁Represents phenyl and X represents-CH₂-, then R₅Does not represent 2-ethylamino-5-acetylphenyl.

In a second embodiment of the invention, there is provided the use as defined above, wherein the compound is of formula I:

x represents- [ C (R)⁸)(R⁹)]-, where n is 0 or, preferably, 1, 2 or 3;

t represents-S-or-O-;

y represents-S (O)₂-、＝C(R₁₀) -or, preferably, -c (o) -;

w represents-NR₇-、-NR₇C(O)-、-NR₇S(O)₂-、-NR₇C(O)NR₇-or NR₇C(O)O-；

R₁Represents heterocyclyl, aryl or heteroaryl (wherein the last three groups are each optionally substituted by one or more groups selected from B⁴、B⁵And B⁶Substituted with a group of (a);

R₅represents heterocyclyl, aryl or heteroaryl (wherein the last three groups are each optionally substituted by one or more groups selected from B⁹、B¹¹And B¹²Substituted with a group of (a);

R₆and R₇Independently represents hydrogen, alkyl, cycloalkyl, aryl or benzyl (wherein the latter four groups are each optionally substituted by one or more groups selected from B¹³、B¹⁴、B¹⁵And B¹⁶Substituted with a group of (a);

R₈and R₉Independently selected from hydrogen, alkyl and aryl (wherein the latter two groups are each optionally substituted by one or more groups selected from B¹⁷And B¹⁸Substituted with a group of (a);

R₁₀represents hydrogen, alkyl or aryl (wherein the latter two groups are each optionally substituted by one or more groups selected from B¹⁹And B²⁰Substituted with a group of (a);

A₁or A₂One is as defined above and when A₂When represents a single bond, then A₁Is a double bond and one R₇(which α is attached to the desired ring of the compound of formula I) is absent; and

B⁴to B¹⁴And B¹⁶As defined above;

B¹⁵、B¹⁷、B¹⁸、B¹⁹and B²⁰Each independently represents cyano, -NO₂Halogen, -OR₁₁、-nR₁₂R₁₃、-SR₁₄、-Si(R₁₅)₃、-C(O)OR₁₆、-C(O)NR_16aR_16b、-S(O)₂NR_16cR_16dAryl or heteroaryl (wherein aryl and heteroarylAryl is itself optionally and independently substituted by one or more groups selected from halogen and R₁₇Substituted with a group of (a); or, alternatively,

B¹⁵、B¹⁸and B²⁰Represents R₁₇(ii) a And

R₁₁-R₁₇as defined above.

In the compounds of formula I according to the second embodiment of the invention mentioned above, it is preferred that when Y represents-C (O) -, T represents-S-, and W represents-NR₇-，R₇Represents H and:

(i) n represents 0 and:

(a)R₁represents 4-tetrahydropyranyl, then R₅Does not represent 2-fluoro-, 2-chloro-or 2-methylphenyl;

(b)R₁represents 3-tetrahydrofuryl, then R₅Does not represent 2-fluoro-or 2-chlorophenyl;

(c)R₁represents tert-butyl-4-piperidinyl-1-carboxylate, then R₅Does not represent 2-chlorophenyl; and

(ii) x represents-CH₂-and R₅Represents unsubstituted phenyl, then R₁It does not represent benzimidazol-2-yl or 1-methylbenzimidazol-2-yl.

In the compounds of formula I according to the above second embodiment of the invention, it is further preferred when X represents-CH₂-and:

(a)R₅represents unsubstituted phenyl, then R₁Does not represent 1, 3-benzoxazol-2-yl or 1, 3-benzothiazol-2-yl; and

(b)R₅represents 2-fluorophenyl, then R₁Does not represent [5- (2-chlorophenyl) -1, 3, 4-oxadiazol-2-yl]。

In the compounds of formula I according to the above second embodiment of the invention, it is further preferred when Y represents-C (O) -, R₆Represents unsubstituted benzyl (or methyl substituted by unsubstituted phenyl), R₁Represents phenyl and X represents-CH₂-, then R₅Does not represent 2-ethylamino-5-acetylphenyl.

There is further provided a novel compound of the second embodiment of the present invention, wherein, when N represents 1, Y represents-C (O) -and W represents-N (R)₇) -, at least one R₈And/or R₉The substituents independently represent an alkyl or aryl group (provided that the latter is not an unsubstituted aryl group), both optionally substituted (if appropriate) as claimed in claims 2 to 21, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, provided that:

(a) when Y represents ═ C (R)₁₀) -, W does not represent-N (R)₇) C (O) -; and

(b) the compound is not:

5-benzyl-4-phenyl-N-p-tolylthiazol-2-amine;

n, 5-dibenzyl-4-phenyl-N-p-tolylthiazol-2-amine;

5-benzyl-4- (4- (diethylamino) phenyl) -N-p-tolylthiazol-2-amine;

3- (5- (2, 6-difluorobenzyl) -2- ((4-carboxybenzyl) amino) thiazol-4-yl) phenol;

2- (5- (2, 6-difluorobenzyl) -2- ((4-carboxybenzyl) amino) thiazol-4-yl) phenol;

2- (5- (2-methoxybenzyl) -2- ((4-carboxybenzyl) amino) thiazol-4-yl) phenol;

2- (5- (2, 3-difluorobenzyl) -2- ((4-carboxybenzyl) amino) thiazol-4-yl) phenol; or

5-benzyl-4-methyl-2- (4-pivaloyloxy) phenylsulfonylaminothiazole.

For the avoidance of doubt, in a second embodiment of the invention when Y represents ═ C (R)₁₀) When, this means a compound of the formula Ia

Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed in conventional manner, for example by reaction of the free acid or free base form of the compound of formula I with one or more equivalents of the appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, the solvent being subsequently removed using standard techniques (for example by vacuum, by lyophilisation or by filtration). Salts may also be prepared by ion exchange of a salt form of a compound of formula I with a counterion of another counterion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable addition salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and arylsulfonic acids.

"pharmaceutically functional derivatives" of compounds of formula I as defined herein include ester derivatives and/or derivatives having or providing the same biological function and/or activity as any of the related compounds. Therefore, for the purposes of the present invention, the term also includes prodrugs of the compounds of formula I.

The term "prodrug" of a related compound of formula I includes any compound that, after oral or parenteral administration, metabolically forms a test detectable amount of the compound within a predetermined time, e.g., administered at 6-24 hour intervals (i.e., 1-4 times per day). For the avoidance of doubt, the term "parenteral" administration includes all forms of administration other than oral administration.

Prodrugs of compounds of formula I may be prepared by modifying functional groups on the compounds in such a way that the modifications are cleaved in vivo when the prodrug is administered to a mammalian subject. Such modifications are typically effected by synthesizing the parent compound with prodrug substituents. Prodrugs include compounds of formula I wherein a hydroxy, amino, thiol, carboxyl or carbonyl group, respectively, in the compound of formula I is bonded to any group that can be cleaved in vivo to form a free hydroxy, amino or thiol group.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives and N-Mannich bases. General information on Prodrugs can be found, for example, in Bundegaard, H. "Design of produgs", pages 1-92, Elesevier, New York-Oxford (1985).

For the sake of simplicity, the compounds of formula I and pharmaceutically acceptable salts, solvates and pharmaceutically functional derivatives of the compounds are hereinafter collectively referred to as "compounds of formula I".

The compounds of formula I may contain double bonds and thus the individual double bonds may be present as e (entgegen) and z (zusammen) geometric isomers. All such isomers and mixtures thereof are within the scope of the present invention.

The compounds of formula I may exist as regioisomers and may also exist as tautomers. All tautomers and mixtures thereof are within the scope of the present invention. Especially, when R is⁶Tautomers exist when representing H. Said compounds having different R's with one or more double bond shifts⁶The attachment site of (a).

The compounds of formula I may also contain one or more asymmetric carbon atoms and may thus have optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, for example chromatography or fractional crystallisation. The different stereoisomers may be separated by separation of a racemic or other mixture of the compounds using conventional techniques, such as fractional crystallisation or HPLC. Alternatively, the desired optical isomer may be prepared by the following reaction: by reaction of the appropriate optically active starting materials under conditions which do not result in racemisation or epimerisation (i.e. a 'chiral pool' process); by reaction of appropriate starting materials with 'chiral auxiliary agents' which are subsequently removable at appropriate stages; by derivatization (i.e. resolution, including dynamic resolution), e.g. reaction with a homochiral acid, followed by separation of the diastereomeric derivatives by conventional means such as chromatography; or by reaction with an appropriate chiral reagent or chiral catalyst under conditions known to those skilled in the art. All stereoisomers and mixtures thereof are within the scope of the invention.

Unless otherwise specified, the term "alkyl" refers to an unbranched or branched, cyclic, saturated or unsaturated (in such form as alkenyl or alkynyl) hydrocarbon group which may be substituted or unsubstituted (by, for example, B)⁷、B⁸、B¹³、B¹⁴、B¹⁷Or B¹⁹Substitution). Wherein when the term "alkyl" refers to an acyclic group, C is preferred_1-10Alkyl and, more preferably, C_1-6Alkyl (e.g., ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., branched or unbranched butyl), pentyl, or more preferably, methyl). When the term "alkyl" is a cyclic group (which may be specified in "cycloalkyl"), C is preferred_3-12Cycloalkyl, more preferably C_5-10(e.g. C)_5-7) A cycloalkyl group.

Alkylene, as used herein, refers to C_1-10(e.g. C)_1-6) Alkylene, preferably C_1-3Alkylene, e.g. pentylene, butylene (branched or unbranched), preferably propylene (n-or isopropylene), ethylene, or, more preferably, methylene (i.e. -CH)₂-). Preferably, X represents an alkylene group (i.e. n represents 1, 2 or 3).

As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.

Heterocyclic groups which may be mentioned include non-aromatic monocyclic heterocyclic groups in which one or more (for example 1 to 4) of the atoms in the ring system is not carbon (i.e. a heteroatom which is preferably selected from N, O and S), and in which the total number of atoms in the ring system is between 3 and 12 (for example between 5 and 10). Furthermore, such heterocycloalkyl groups may be saturated or unsaturated, containing one or more double and/or triple bonds, forming, for example, C_2-qHeterocyclic ringsAlkenyl (wherein q is the upper limit of the range) or C_3-qHeterocycloalkynyl. Mention may be made of C_2-qHeterocycloalkyl radicals include 7-azabicyclo [2.2.1]Heptyl, 6-azabicyclo [3.1.1]Heptyl, 6-azabicyclo [3.2.1]-octyl, 8-azabicyclo [3.2.1]Octyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridinyl, dihydropyrrolyl (including 2, 5-dihydropyrrolyl), dioxolanyl (including 1, 3-dioxolanyl), dioxanyl (including 1, 3-dioxanyl and 1, 4-dioxanyl), dithianyl (including 1, 4-dithianyl), dithianyl (including 1, 3-dithianyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo [2.2.1 ] 1]Heptyl, 6-oxabicyclo [3.2.1]Octyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolane, 3-sulfolene, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl (e.g., 1, 2, 3, 4-tetrahydropyridinyl and 1, 2, 3, 6-tetrahydropyridinyl), thietanyl, thiiranyl, thietanyl, thiomorpholinyl, trithianyl (including 1,3, 5-trithianyl), tropanyl and the like. If appropriate, the substituents on the heterocycloalkyl group can be located at any atom in the ring system, including heteroatoms. The point of attachment of the heterocycloalkyl group may include, if appropriate, a heteroatom (e.g., nitrogen atom) through any atom in the ring system, or may represent an atom in a fused carbocyclic ring that is part of the ring system. Heterocycloalkyl groups may also be in the N-or S-oxidized form. Preferred heterocyclic groups include cyclic amino groups such as pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or cyclic ethers such as tetrahydrofuranyl, monosaccharides.

As used herein, the term "aryl" includes C_6-14(e.g. C)_6-13(e.g. C)_6-10) An aryl group. Such groups may be monocyclic, bicyclic or tricyclic and have 6 to 14 ring carbon atoms, at least one of which is aromatic. The point of attachment of the aryl group may be through any atom of the ring system. However, when the aryl groups are bicyclic or tricyclic, they are aromaticThe loop is attached to the rest of the molecule. C_6-14Aryl groups include phenyl, naphthyl, and the like, such as 1, 2, 3, 4-tetrahydronaphthyl, indanyl, indenyl, and fluorenyl. Most preferred aryl groups include phenyl.

As used herein, the term "heteroaryl" refers to an aromatic group (thereby forming, for example, a mono-, di-or tricyclic heteroaryl group) containing one or more heteroatoms (e.g., 1-4 heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those having 5-14 (e.g., 10) members and can be monocyclic, bicyclic, or tricyclic, provided that at least one ring is aromatic. However, when the heteroaryl groups are bicyclic or tricyclic, they are attached to the rest of the molecule via an aromatic ring. Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2, 1, 3-benzothiadiazolyl), isothiochromanyl, and more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolanyl (benzodioxolyl), benzodioxolyl (including 1, 3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxazolyl (including 2, 1, 3-benzoxazolyl), benzoxazinyl (including 3, 4-dihydro-2H-1, 4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2, 1, 3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, and cinnolinyl, Imidazolyl, imidazo [1, 2-a ] pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl (including 1, 6-naphthyridinyl or, preferably, I, 5-naphthyridinyl and 1, 8-naphthyridinyl), oxadiazolyl (including 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl and 1,3, 4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1, 2, 3, 4-tetrahydroisoquinolinyl and 5, 6, 7, 8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1, 2, 3, 4-tetrahydroquinolinyl and 5, 6, 7, 8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl and 1,3, 4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenenetyl, thienyl, triazolyl (including 1, 2, 3-triazolyl, 1, 2, 4-triazolyl and 1,3, 4-triazolyl), and the like. Substituents on the heteroaryl group, if appropriate, may include heteroatoms at any atom in the ring system. The point of attachment of the heteroaryl group may include, if appropriate, a heteroatom (e.g., nitrogen atom) through any atom in the ring system, or may represent an atom in any fused carbocyclic ring that is part of the ring system. Heteroaryl groups can also be in the form of N-or S-oxides. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, and pteridinyl. Particularly preferred heteroaryl groups include monocyclic heteroaryl groups.

For the avoidance of doubt, where the identity of two or more substituents in a compound of formula I is the same, the actual identity of the individual substituents are not in any way dependent on each other. For example, in which R¹And R²Are all covered by one or more C_1-6In the case of alkyl-substituted aryl, the alkyl groups referred to may be the same or different.

For the avoidance of doubt, when a term such as "B" is used⁴-B¹⁴"as used herein, it is understood by those skilled in the art to mean any (i.e., some or all, if applicable) B is included⁴、B⁵、B⁶、B⁷、B⁸、B⁹、B¹⁰、B¹¹、B¹²、B¹³And B¹⁴。

For the avoidance of doubt, when the 'benzyl' group is substituted, this substituent is preferablyOn the benzene ring of the benzyl group, rather than the methylene group (-CH)₂-) above.

Mention may be made of compounds of formula I according to the first embodiment of the invention, also including those in which:

y preferably represents-C (O) -;

R₁represents-C (O) NR₃R₂、-NR₃R₂、-C(O)OR₂、-NR₄C(O)NR₃R₂、-NR₄C(O)OR₂、-OC(O)NR₃R₂、-NR₄C(O)R₂、-OC(O)R₂、-OR₂、-SR₂H, alkyl, haloalkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl;

R₂and R₅Independently represents hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl;

R₃、R₄、R₆and R₇Independently represents hydrogen, alkyl, haloalkyl, cycloalkyl or benzyl.

Another compound of formula I that may be mentioned includes those wherein:

B⁴-B²⁰(and in particular B)⁴-B¹⁴And B¹⁶) Independently represent halogen, -OR₁₁、-NR₁₂R₁₃、-SR₁₄、-Si(R₁₅)₃、-C(O)OR₁₆Or aryl (wherein aryl itself is optionally substituted by one or more substituents selected from halogen or R₁₇Substituted, or preferably unsubstituted);

R₁₁、R₁₂、R₁₃、R₁₄and R₁₆Independently represent R₁₇Or, more preferably, H.

B⁴-B²⁰(and in particular B)⁴-B¹⁴And B¹⁶) May also independently represent functional groups such as hydroxyl, amineSulfur (sulfide), silyl, carboxylic acids, halogens, aryl groups, and the like.

Compounds of formula I which may be mentioned include those in which:

w represents-NR₇-；

T represents-S-.

Compounds of formula I which may be mentioned include those in which:

when R is₁When represents a heteroaryl group, a monocyclic ring is preferred;

when R is₁When representing a heteroaryl group, preferably containing less than 3 (e.g. 2 or, more preferably, 1) heteroatoms;

R₁aryl groups are preferred.

Preferred compounds of the first embodiment of the invention include those wherein:

R₅do not represent cycloalkyl (e.g. C)_6-10Cycloalkyl groups);

R₁does not represent a heterocyclic group (e.g., tetrahydropyranyl, tetrahydrofuranyl or piperidinyl);

R₅is not represented by B⁷Substituted alkyl radicals in which B is⁷Represents an optionally substituted aryl group;

R₅does not represent a partially cyclic alkyl group (e.g., methyl substituted with cyclohexyl).

Compounds of formula I which may be mentioned include those in which:

R₅does not represent H;

when Y represents-C (O) -R₆Represents H;

when T represents-S-, Y represents-C (O) -and n represents 1 or 2, when X represents- [ CR₈R₉]When, then W represents-CR₇R₇-、-NR₇S(O)₂-、-NR₇C(O)NR₇-or-NR₇C (O) O-or a bond;

when T represents-S-, Y represents-C (O) -, W represents-NR₇When then R is₁represents-C (O) NR₃R₂、-NR₃R₂、-C(O)OR₂、-NR₄C(O)NR₃R₂、-NR₄C(O)OR₂、-OC(O)NR₃R₂、-NR₄C(O)R₂、-OC(O)R₂、-OR₂or-SR₂。

More preferred compounds of formula I include those wherein:

x represents-CH₂-；

Y represents-C (O) -;

R₁and R₂Independently represents an aryl group (e.g. phenyl) as defined above (i.e. R)₁Represents optionally substituted by one or more B⁵Radical-substituted aryl and R₂Represents optionally substituted by one or more B¹¹A group-substituted aryl group);

when R is₁And/or R₂Represents phenyl, which/they are in relation to R₁Or R₂The para position of the point of attachment of the group to X;

B⁵and B¹¹Independently represents halogen; and/or

R₅Represents a heteroaryl group (e.g., pyridyl).

More preferred compounds of formula I include those wherein:

R₁represents a C (O) NHR₂；

R₂Represents an aryl group (e.g., phenyl);

when R is₂In para position (relative to R) when representing phenyl₂The point of attachment of the group to the remainder of the compound of formula I) is substituted (i.e. by B)¹¹Substituent group substitution); and/or

B¹¹Is represented by C₁-C₆An alkyl group.

In another preferred embodiment of the present invention:

R₁is-NHR₂；

R₂Is aryl (e.g., phenyl);

when R is₂When it represents phenyl, it is substituted in the para position (i.e. by B)¹¹Substituent group substitution);

B¹¹is represented by C₁-C₆An alkyl group;

y represents ═ c (h) -;

R₅represents an aryl group (e.g., phenyl); and/or

When R is₅When it represents phenyl, it is unsubstituted or substituted by halogen (i.e. B)¹¹Represents halogen).

In another preferred embodiment of the present invention:

R₅represents an aryl group (e.g., phenyl);

when R is₅Represents phenyl, which is substituted in the para-position (i.e. by B)¹¹Substituent group substitution); and/or

B¹¹Represents R₁₇；

R₁₇Denotes C, preferably substituted by one or more halogen atoms_1-6Alkyl (thereby forming haloalkyl).

In another preferred embodiment of the present invention;

y represents ═ c (h) -;

R₅represents an aryl group (e.g., phenyl);

when R is₅When it represents phenyl, it is substituted in the para position (i.e. by B)¹¹Substituent group substitution);

B¹¹represents halogen or R₁₇(ii) a And/or

In another preferred embodiment of the present invention:

x represents a single bond (i.e., n represents 0);

R₁is-C (O) NHR₂；

R₂Is aryl (e.g., phenyl);

when R is₂Represents phenyl, which is represented by B¹¹Substitution;

B¹¹represents R₁₇(ii) a And/or

R₁₇Is represented by C₁-C₆An alkyl group.

Preferred compounds of formula I (and in particular compounds of the second embodiment of the invention) include those wherein:

t represents-S-;

y represents ═ C (R)₁₀) -, preferably-S (O)₂-or, more preferably-c (o) -;

R₁₀represents an alkyl group (e.g., methyl or trifluoromethyl);

w represents-NR₇C(O)O-、-NR₇C(O)NR₇-、-NR₇S(O)₂-, more preferably-NR₇C (O) -, or especially-NR₇-；

R₁Represents optionally substituted (i.e. by B)⁶Substituted) heteroaryl (e.g., furyl, e.g., furan-2-yl, or thienyl, e.g., thiophen-2-yl) or, more preferably, optionally substituted (i.e., with B)⁵Substituted) aryl (e.g., phenyl);

R₅represents optionally substituted (i.e. by B)¹²Substituted) heteroAryl (e.g. 2-pyridyl) or, preferably, optionally substituted (i.e. by B)¹¹Substituted) aryl (e.g., phenyl);

n represents 0 or, more preferably, 1 or 2;

R₈and R₉Independently represent C_1-3(e.g. C)_1-2) Alkyl (e.g., methyl) or, more preferably, H;

when W represents-NR₇-and R₇Is absent, then R₆Represents an alkyl group such as C_1-6(e.g. C)_1-3) Alkyl (e.g. methyl) or aryl (e.g. phenyl), wherein the latter two radicals may each be substituted by one or more B¹³And B¹⁵Substituted, or more preferably unsubstituted, or, more preferably, R₆Represents H;

when W represents-NR₇-and R₆When not present, then R₇Is represented by C_1-3(e.g. C)_1-2) Alkyl (e.g. methyl), aryl (e.g. phenyl) or benzyl, all of which may be independently substituted by one or more B¹³、B¹⁵And B¹⁶Substituted, or more preferably unsubstituted;

B⁴-B²⁰(if applicable; and in particular B)⁵、B¹¹And B¹²) Independently represent cyano, NO₂Halogen (e.g. chlorine, fluorine OR bromine), -OR₁₁、-C(O)OR₁₆、-C(O)NR_16aR_16bor-S (O)₂NR_16cR_16d(ii) a And/or

B⁴-B⁶、B¹⁰-B¹²、B¹⁵、B¹⁶、B¹⁸And B²⁰(if applicable; and in particular B⁵、B¹¹And B¹²) Represents R₁₇(ii) a And/or

B⁴-B²⁰Independently (if applicable) represents heteroaryl or, preferably, aryl (e.g. phenyl), both of which may be substituted by one or more groups selected from halogen (e.g. fluorine) or R₁₇Substituted with a group of (1);

R₁₁is represented by C_1-3(e.g. C)_1-2) Alkyl (e.g., methyl or ethyl) or H;

R₁₆represents H or C_1-3(e.g. C)_1-2) Alkyl (e.g., ethyl);

R_16a、R_16b、R_16cand R_16dIndependently represent C_1-2Alkyl, or more preferably H;

R₁₇represents C optionally substituted by one or more halogen (e.g. fluorine) atoms_1-4(e.g. C)_1-3) Alkyl (e.g., methyl or isopropyl) (thereby yielding, for example, trifluoromethyl).

Preferred compounds of formula I (and in particular the compounds of the first embodiment of the invention) include those wherein:

n represents 0 or, more preferably, 1 or 2;

R₁represents optionally substituted (i.e. by B)⁵Substituted) aryl;

R₅represents a benzyl group, which group is optionally substituted (i.e. by B)¹⁰Substituted), or more preferably unsubstituted; or

R₅Represents optionally substituted (i.e. by B)⁷Substituted) alkyl (e.g. methyl or isopropyl) or cycloalkyl (e.g. cyclohexyl), which is optionally substituted (i.e. by B)⁸Substituted) or, more preferably, unsubstituted;

B⁴-B²⁰e.g. B⁴-B¹⁴And B¹⁶(and in particular B)⁷And B¹⁰) Represents halogen or aryl (e.g. phenyl), wherein the latter group is optionally substituted by halogen.

Preferred compounds of formula I include those wherein:

R¹⁰does not represent H;

when Y represents ═ C (R)¹⁰) When W does not represent-N (R)₇)C(O)-；

When X represents a single bond (i.e. n represents 0) and R₁When represents an optionally substituted alkyl group, it is preferably saturated;

when X does not represent a single bond (i.e. n does not represent 0), then R₁Does not represent-NR₃R₂、-OR₂、-SR₃、-NR₄C(O)R₂、-NR₄C(O)NR₃R₂or-NR₄C(O)OR₂；

When X represents-CH₂-，R₁Represents an optionally substituted aryl group, and W represents-NR₇-then:

(i)R₅do not represent alkyl or cycloalkyl; or

(ii)R₅Does not represent hydrogen;

when X represents a single bond (i.e. n represents 0) and R₅When represents an optionally substituted aryl group, then R₁Does not represent optionally substituted alkyl or hydrogen;

when X represents-CH₂-and R₅When represents an optionally substituted aryl group, then R₁Does not represent-C (O) NR₃R₂；

When X represents-CH₂-and R₅When represents an optionally substituted alkyl or aryl group, then R₁Does not represent-C (O) NR₃R₂。

More preferred compounds of formula I include those described below by way of example and, in particular:

5- (4-fluorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one;

5- (p-methylbenzyl) -2- (4-chlorophenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (4-chlorophenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (4-isopropylphenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (4-methoxyphenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (phenylimino) thiazolidin-4-one;

2- (3, 4-dichlorophenylimino) -5- (3- (trifluoromethyl) benzyl) thiazolidin-4-one;

2- (2, 4-dichlorophenylimino) -5- (3- (trifluoromethyl) benzyl) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) -3-methylthiazolidin-4-one;

n- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidene) -4-chlorobenzamide;

5- (3- (trifluoromethyl) benzyl) -2- (4-chlorophenyl) sulfonyliminothiazolidin-4-one; and

5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidenecarbamic acid phenyl ester.

Particularly preferred compounds of formula I include:

5- (4-fluorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (4-chlorophenylimino) thiazolidin-4-one; and

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one.

The compounds of formula I may be known and/or may be commercially available. Other compounds of formula I (e.g., not commercially available) may be prepared according to techniques well known to those skilled in the art, for example as described below.

According to another aspect of the present invention there is provided a process for the preparation of a compound of formula I, which process comprises:

(i) for compounds in which Y represents-C (O) -, W represents-NR₇And A₁Represents a double bond (and R₇Thus absent) of the formula I, the reaction being either:

(A) a compound of the formula (II),

(B) a compound of the formula (III),

wherein R is^aIs represented by C_1-6Alkyl (e.g. ethyl; ester groups formed thereby), L¹Represents a suitable leaving group such as a halogen (e.g. bromine or chlorine) or a sulphonic acid group (e.g. a methanesulphonic acid group, or preferably a toluenesulphonic acid group); or

(C) A compound of the formula IV,

wherein, in all cases, X and R₁As defined above, in each case with a compound of the formula V,

wherein T is^aRepresents S or O and R₆As defined above, under reaction conditions known to those skilled in the art, for exampleSuch as those described for reaction (A) above, for example, Blanchet et al, Tetrahedron Letters, 2004, 45, 4449-4452; for the above reaction (B), conditions are, for example, those of St.Laurent et al, Tetrahedron Letters, 2004, 45, 1907-; K.Arakawa et al, chem.pharm.Bull.1997, 45, 1984-1993; mustafa, w.musker, a.f.a.m.shalaby, a.h.harhash, r.daguer, Tetrahedron 1964, 20; 25-31; or P.Herold, A.F.Indolese, M.studer, H.P.Jalett, U.S. Siegrist, H.U.Blaser, Tetrahedron2000, 56, 6497-;

(ii) wherein Y represents-S (O)₂-, W represents-NR₇And A and₁represents a double bond (and R₇Thus absent), X represents a bond (i.e. - [ R ]₈R₉]_n-wherein n represents 0) and R₁Represents H, and the compound of formula VI,

wherein L is²Represents a suitable leaving group, such as halogen (e.g. chloro), with a compound of formula VII,

R₅-N＝C＝T^a VII

wherein T is^aAs defined above, but preferably S and R₅As defined above, under conditions known to the person skilled in the art, such as those described by Zbirovsky and Seifert, Coll. Czech. chem. Commun.1977, 42, 2672-2679 or Von Zaki El-Heweri, Franz Runge, Journal of Urrapaktische Chemie, 4, Band 16, 1962, for example in the presence of a base (for example an aqueous solution of NaOH) in a suitable solvent (for example acetone), for example at elevated temperature (for example 50 ℃);

(iii) for compounds of formula I wherein A₁Represents a double bond (and R₇Thus absent), X represents an alkylene group (e.g. - [ R ]₈R₉]_n-wherein n represents 1, 2 or 3) and R₁As defined above, and preferably Y represents-S (O)₂-and/or W represents-NR₇Wherein X represents a bond (i.e. n represents 0) and R₁Reacting a compound of formula I, representing hydrogen, with a compound of formula VIII,

R_1a-X^a-L³ VIII

wherein X^aRepresents an alkylene group (e.g. - [ R ]₈R₉]_n-wherein n represents 1, 2 or 3) and R_1aRepresents R as defined above₁Or n represents 0 and R_1aRepresents R as defined above₁Provided that it does not represent hydrogen, aryl or heteroaryl, and L³Represents a suitable leaving group (e.g. halogen or sulfonic acid group) under reaction conditions known to those skilled in the art, e.g. in the presence of a suitable base (e.g. an organometallic base (e.g. organolithium), an alkali metal base (e.g. sodium hydride) or an amide salt (e.g. (Me)₃Si)₂NNa), etc.) and in a suitable solvent (e.g., tetrahydrofuran, dimethylformamide, dimethylsulfoxide, etc.) at or below room temperature (e.g., at sub-zero temperatures (e.g., -78 ℃). For example, for a compound in which Y represents-S (O)₂-and/or W represents-NR₇The reaction conditions for the synthesis of the compounds of formula (I) include those disclosed in the journal literature as mentioned in step (ii) of the above process.

(iv) For compounds of formula I wherein X represents a bond (i.e. n represents 0) and R₁Represents an optional substitution as defined above (i.e. by B)¹Substituted) alkenyl, in which one double bond of the alkenyl group is directly attached to the desired ring of the formula I, or R₁Represents an alkyl group substituted by an-OH group which is alpha to the point of attachment of the alkyl group to the desired ring of formula I, which alkyl group is further optionally substituted, and in both cases W represents-NR₇C(O)-、-NR₇S(O)₂-、-NR₇C(O)NR₇-、-NR₇C (O) O-or-NR₇In which X represents a bond (i.e. n represents 0) and R₁Reaction of a corresponding compound of formula I, representing H, with a compound of formula IX,

R_1b＝O IX

wherein R is_1bIs represented by B¹Optionally substituted alkyl, wherein B¹Having a general formula B as defined above⁷The same definition, under reaction conditions known to those skilled in the art. For example for wherein R is as defined above¹The preparation of compounds representing alkenyl groups is carried out under standard dehydration conditions, for example in the presence of a suitable base (for example NaOAc or a suitable base as described in process step (vii) below) in the presence of a suitable solvent (for example glacial acetic acid), for example as described in a.mustafa, w.musker, a.f.a.m.shalaby, a.h.harhash, r.daguer, Tetrahedron 1964, 20, 25-31. For R in the formula₁The preparation of a compound as defined above, representing an alkyl group substituted by-OH, is carried out in the presence of a suitable base, for example lithium diisopropylamide or another suitable base as described in method step (vii) below, in the presence of a suitable solvent, for example anhydrous THF, at or below room temperature, for example about 0 ℃ in an inert atmosphere. Those skilled in the art will understand that the preparation of R wherein₁Compounds as defined above which represent optionally substituted alkenyl groups may include intermediates to compounds of formula I above in which R is₁As defined above represents an alkyl group substituted by-OH (which intermediate may be isolatable), which intermediate may need to be converted to an alkenyl group alone, for example by conversion of-OH to a better leaving group, for example by reaction with trifluoroacetic anhydride or the like, optionally in the presence of a suitable base (e.g. triethylamine) and a catalyst (e.g. DMAP), in a suitable solvent (e.g. dichloromethane) at below room temperature (e.g. about 0 ℃), for example using the conditions described for Zbirovsky and Seifert, col, czech, chem, commu.1977, 42, 2672-2679;

(v) for compounds in which X represents a bond (i.e. n represents 0) and R₁Denotes saturated optional substitution (i.e. by B)₁Substituted) alkyl as defined above, Y represents-S (O)₂Or preferably-C (o) -or ═ C (R)₁₀) -a compound of formula I as defined above, reduction of which R₁Compounds of the corresponding formula I, representing an optionally substituted unsaturated alkyl group, under standard reaction conditions, e.g. in the presence of a suitable (e.g. chemo-selective) reducing agent such as LiBH₄In the presence of, optionally in a suitable solvent such as THF or pyridine (or mixtures thereof), for example r.g. giles, n.j.lewis, j.k.quick, m.j.sasse, m.w.j.urquhart, l.youssef, Tetrahedron 2000; 56, 4531 and 4537. To achieve the desired selectivity of selective reduction, one skilled in the art will appreciate that the choice of reducing agent is important (i.e., while not reducing other functional groups, such as the carbonyl group in the compound of formula I). Other methods include hydrogenation reduction under standard conditions, for example, in the presence of hydrogen or nascent hydrogen, in a suitable solvent (e.g., an alcoholic solvent) and a catalyst (e.g., Pd/C);

(vi) for compounds of formula I wherein R₆Is alkyl, cycloalkyl or benzyl, all of which are optionally substituted as defined above, wherein R is₆Reacting a compound of formula I representing H with a compound of formula X,

R_6aL₄ X

wherein R is_6aRepresents alkyl, cycloalkyl or benzyl (for example each of which is optionally substituted by one or more groups selected from B¹³、B¹⁴Or B¹⁶Substituted with groups) and L⁴Represents a suitable leaving group such as a halogen (e.g. iodine or bromine) or a sulfonic acid group, under standard reaction conditions, e.g. at about room temperature, in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, sodium hydroxide or mixtures thereof) in a suitable solvent (e.g., pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, triethylamine, dimethylsulfoxide, water, or mixtures thereof) and, in the case of biphasic reaction conditions, optionally in the presence of a phase transfer catalyst;

(vii) for compounds represented by-C (O) NR_16aR_16bB of a radical⁴-B²⁰At least one substituted compound of the formula I, in which B⁴-B²⁰The substituents represent-C (O) OR₁₆With a compound of formula XI or a protected derivative (e.g. salt) thereof,

HNR_16aR_16b XI

wherein R is_16aAnd R_16bAs defined above, for example under standard coupling reaction conditions. For example, in which R₁₆In the case of H, the compound is reacted with a suitable coupling agent (e.g., 1 ' -carbonyldiimidazole, N ' -dicyclohexylcarbodiimide, 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide (or hydrochloride thereof), N ' -disuccinimidyl carbonate, benzotriazol-1-yloxytris (dimethylamino) - * hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris-pyrrolidino * hexafluorophosphate, bromo-trispyrrolidino * hexafluorophosphate, 2- (1H-benzotriazol-1-yl) -1, 1,3, 3-tetramethyluronium tetrafluoroborate or 1-cyclohexylcarbodiimide-3-propoxymethylpolystyrene) in the presence of a suitable base (e.g., sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, sodium hydroxide, N-ethyldiisopropylamine, N- (methylpolystyrene) -4- (methylamino) pyridine, potassium bis (trimethylsilyl) -amide, sodium bis (trimethylsilyl) amide, potassium tert-butoxide, lithium diisopropylamide, lithium 2, 2, 6, 6-tetramethylpiperidine, or a mixture thereof), and a suitable solvent (e.g., tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, or dimethylformamide). Or, for example, in which R₁₆In the case where it is not H (i.e., -C (O) OR)₁₆Representing an ester group), which reaction can be carried out in the presence of a suitable reagent (e.g. trimethylaluminum), in the presence of a suitable solvent (e.g. benzene), for example at elevated temperature (e.g. about 60 ℃), for example Hwang, k. — j.; o' Neil, J. -P.; katzenllenbogen, J.A.J.org.chem.1992, 57, 1262 as described in (2);

(viii) for where W represents-NR₇C(O)-、-NR₇S(O)₂-、-NR₇C(O)NR₇-or-NR₇C (O) O-wherein W represents-NR₇-and R₅The corresponding compound of formula I, representing H, is reacted with a compound of formula XII,

L⁵W^xR₅ XII

wherein W^xrepresents-C (O) -, -S (O)₂、-C(O)NR₇or-C (O) O-, L⁵Represents a suitable leaving group such as halogen (e.g. chloro) and R⁵As defined above, under reaction conditions known to the person skilled in the art, for example in the presence of a suitable base (e.g. NaH, NaOH, triethylamine, pyridine, another suitable base mentioned in the above process step (vii) or a mixture thereof) and a solvent (e.g. pyridine (which acts as a base and a solvent) DMF or dichloromethane (e.g. further in the presence of water and optionally a phase transfer catalyst)), for example at room temperature, for example according to Hurst, d.t.; stacey, a.d., Nethercleft, m., Rahim, a., harden, m.r.aust.j.chem.1998, 41, 1221; or

(ix) For where W represents-NR₇C (O) NH-of the formula I, wherein W represents-NR₇And R₅The corresponding compound of formula I, representing H, is reacted with a compound of formula XIII,

R₅-N＝C＝O XIII

wherein R is₅As defined above, under standard conditions, e.g. in the presence of a suitable solvent (e.g. a polar aprotic solvent such as toluene) and at elevated temperature (e.g. reflux), e.g. as described in the journal articles mentioned above in method (viii).

The compounds of formula II can be prepared by reacting a compound of formula XIV,

R₁-X-C(O)H XIV

wherein R is₁And X is as defined above, with trichloroacetic acid under standard conditions known to those skilled in the art, for example those described in the journal literature referred to above in connection with process step (i) (part (A)).

Compounds of formula III are commercially available, prepared under standard conditions, or for those in which X represents-CH₂-、R₁Represents an optionally substituted aryl or heteroaryl group as defined above and L¹A compound representing halogen, reacting a compound of formula XV,

R_1cNH₂ XV

wherein R is_1cRepresents aryl or heteroaryl (e.g. optionally substituted by B)⁵And B⁶Substitution) to form the corresponding diazonium salt (e.g., by reaction with sodium nitrite at low temperature, e.g., about 0 ℃), followed by reaction of the compound of formula XVI,

R^a-OC(O)CH＝CH₂ XVI

wherein R is^aAs defined above, the hydrohalic acid is preferably concentrated (e.g., in which L is¹In the case of chlorine, concentrated hydrochloric acid), optionally in the presence of a reagent that facilitates the Michael addition of the halide on the acrylate/enone, such as cuprous oxide.

Wherein L is¹Compounds of formula III which represent sulfonic acid groups (e.g. p-toluenesulfonate or methanesulfonate) may be prepared by reacting the corresponding compound of formula III but wherein L is¹Compounds representing-OH are prepared by reaction with the appropriate sulfonyl chloride (e.g., tosyl chloride or mesyl chloride) under standard conditions known to those skilled in the art, such as those described above for the preparation of compounds of formula I (method step (vi) above).

The compounds of formula VI can be prepared by reacting a compound of formula XVII,

wherein L is⁶Represents a suitable leaving group such as halogen (e.g. chloro) and L²As defined above, with ammonia (e.g. in gaseous or other form), for example under conditions standard to those skilled in the art, such as those described above in the preparation of compounds of formula I (process step (vi) above), or preferably, at low temperatures (e.g. about 0 ℃) in the presence of diethyl ether, wherein the skilled person will understand that ammonia also acts as a base.

The compounds of formulae IV, V, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI and XVII (and certain compounds of formulae I, II, III and VI) are either commercially available or known in the literature or can be obtained according to analogous methods described herein (or as described in the references included herein) or by conventional synthetic methods using appropriate reagents and reaction conditions from available starting materials according to standard techniques.

Substituents such as R in the final compounds of formula I or related intermediates₁、R₅、R₆X, W and Y can be modified 1 or more times after or during the above methods by methods well known to those skilled in the art. Examples of such processes include substitution, reduction, oxidation, alkylation, acylation, hydrolysis, esterification, and etherification. The precursor groups may be converted to different such groups or to groups as defined in formula I at any time during the reaction.

The compounds of formula I may be isolated from their reaction mixtures using conventional techniques.

It will be appreciated by those skilled in the art that in the above and following processes, the functional groups of the intermediate compounds may need to be protected with protecting groups.

The protection and deprotection of the functional groups can be performed before or after the reaction of the above scheme.

Protecting groups may be removed according to techniques well known to those skilled in the art and described hereinafter. For example, the protected compounds/intermediates described herein can be chemically converted to the unprotected compounds using standard deprotection techniques.

The chemistry involved in this type refers to the requirements and type of protecting groups and the order in which the synthesis is performed.

The use of protecting Groups is fully disclosed in "Protective Groups in Organic Chemistry", edited by J WF McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3 rd edition, T.W.Greene & P.G.M.Wutz, Wiley-Interscience (1999).

The term "functional group" as used herein refers to a hydroxyl-, thiol-, amino-functional group, carboxylic acid, in the case of an unprotected functional group, and refers to a lower alkoxy, N-, O-, S-acetyl, carboxylic acid ester, in the case of a protected functional group.

The term "diseases or conditions caused by, associated with or predominating by FFAs" is understood by the person skilled in the art to include hyperinsulinemia and related conditions, such as type II diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinemia in children, hypercholesterolemia, hypertension, obesity, fatty liver conditions, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular diseases such as stroke, systemic lupus erythematosus, neurodegenerative diseases such as alzheimer's disease, and polycystic ovary syndrome. Other disease states include progressive renal disease such as chronic renal failure.

Preferred diseases include hyperinsulinemia, particularly type II diabetes.

According to another aspect of the present invention there is provided a method of treating a disease or condition caused, associated or predominated by FFAs, which method comprises administering to a patient in need of such treatment an effective amount of a compound of formula I.

For the avoidance of doubt, throughout the present invention, the terms "treatment", "treating" and "therapy" include therapeutic and/or palliative treatment of a patient in need thereof, as well as prophylactic treatment and/or diagnosis of a patient susceptible to a disease or condition caused, associated or predominated by FFAs.

"patient" includes mammalian (including human) patients.

The term "effective amount" refers to an amount of a compound that produces a therapeutic effect in the patient being treated (e.g., sufficient to treat or prevent the disease). The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication or feels an effect).

The novel compounds of the formula I as defined above are useful as medicaments and are therefore indicated for use as medicaments.

According to the present invention, the compounds of formula I may be administered alone, but are preferably administered orally, intravenously, intramuscularly, intradermally, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermally, nasally, pulmonarily (e.g. tracheally or bronchially), topically, by any other parenteral route, in the form of a pharmaceutical formulation containing said compounds, in a pharmaceutically acceptable dosage form. Preferred modes of administration include oral, intravenous, intradermal or subcutaneous, nasal, intramuscular or intraperitoneal administration.

The compounds of formula I are generally administered as pharmaceutical formulations in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers can be chemically inert to the active compound and can be free of deleterious side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations can be found, for example, in Remington The Science and Practice of Pharmacy, 19th ed., Mack printing company, Easton, Pennsylvania (1995). For parenteral administration, parenterally acceptable aqueous solutions may be used, which are pyrogen-free and have the desired pH, isotonicity, and stability. Suitable solutions are well known to those skilled in the art and have been reported in the literature in a number of ways. A general description of the method of administration can also be found, for example, in Langer, Science 249, 1527 (1990).

Additionally, the preparation of suitable formulations may be non-inventively achieved by those skilled in the art using routine techniques and/or in accordance with standard and/or acceptable pharmaceutical practice.

Another aspect of the invention includes pharmaceutical compositions comprising a therapeutically effective amount of a novel compound of formula I as defined above and a pharmaceutically acceptable excipient such as an adjuvant, diluent or carrier.

The amount of the compound of formula I in the formulation will depend on the severity of the condition, the patient to be treated, and the compound used, but can be determined non-inventively by those skilled in the art.

Depending on the disease and the patient to be treated, and the route of administration, the compounds of formula I may be administered to a patient in need thereof at varying therapeutically effective doses.

However, the dosage administered to a mammal, particularly a human, should be sufficient in the present invention to produce a therapeutic response in the mammal within a reasonable time frame. Those skilled in the art will appreciate that the precise dosage and composition selected and the most suitable dosage regimen will be specifically influenced by the pharmacological properties of the formulation, the nature and severity of the condition being treated, the physical condition and mental sensitivity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient being treated, and the stage and severity of the disease.

Administration may be continuous or intermittent (e.g., by bolus injection). The dosage may also be determined by the timing and number of administrations. In the case of oral or parenteral administration, the dosage may vary from about 0.01mg to about 1000mg per day of a compound of formula I (or, if used, a corresponding amount of a pharmaceutically acceptable salt or prodrug thereof).

In any event, the medical practitioner, or other skilled person, should be able to routinely determine the actual dosage which should be most appropriate for the individual patient. The above dosages are exemplary of the general case; it is obvious that in individual cases it may be higher or lower than the stated dosage range, but this also falls within the scope of the present invention.

The compounds of formula I may be administered or used in combination therapy with one or more other drugs effective in the treatment of diseases or conditions caused by, associated with or predominating by FFAs, such as hyperinsulinemia and type II diabetes.

According to another aspect of the present invention, there is provided a combination product comprising:

(A) a compound of formula I; and

(B) another therapeutic agent effective in treating a disease or condition caused by, associated with, or predominating by FFAs,

wherein each of components (A) and (B) is formulated in admixture with pharmaceutically acceptable adjuvants, diluents and carriers.

Such combination products provide for the co-administration of a compound of formula I with other therapeutic agents, and thus may be provided as separate formulations, wherein at least one of those formulations contains a compound of formula I and at least one contains the other therapeutic agent, or may be provided (i.e. formulated) as a combined formulation (i.e. provided as a single formulation including a compound of formula I and the other therapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation comprising a compound of formula I; another therapeutic agent effective in treating a disease or condition caused by, associated with, or predominating by FFAs; and pharmaceutically acceptable adjuvants, diluents and carriers; and

(2) a kit of parts comprising the components:

(a) pharmaceutical formulations comprising a compound of formula I in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation comprising a mixture of another therapeutic agent effective in the treatment of a disease or condition caused, associated or predominated by FFAs, together with pharmaceutically acceptable adjuvants, diluents and carriers,

wherein components (a) and (b) are each provided in a form suitable for administration in combination with the other.

The components (a) and (b) of the kit of parts described herein may be administered simultaneously or sequentially.

Other therapeutic agents effective in the treatment of diseases or conditions caused, associated or dominated by FFAs, such as hyperinsulinemia and type II diabetes, are well known to those skilled in the art and include insulin, insulin secretagogues, such as sulfonylureas, metformin, Peroxisome Proliferator Activated Receptor (PPAR) agonists, such as thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, elsinand, inhibitors of type 1 11-beta hydroxysteroid dehydrogenase (11 beta-HSD 1), such as AMG221 developed by Amgen and BVT83370 developed by Biovitrum AB, enzymes associated with the conversion of corticosterone to cortisol in the liver and adipose tissue.

In a preferred embodiment, the other therapeutic agent may also comprise GLP-1 or a biologically active fragment, variant, fusion or derivative thereof. For example, the pharmaceutical agent may be selected from Exendin-4 (Essentid; Byetta), Essentid extended release (LAR), Essentid derivatives (e.g., ZP10 developed by Zealand pharmaceuticals), native GLP-1, human GLP-1 derivatives (e.g., BIM51077(Ipsen and Roche)), anti-DPP-IV GLP-1 analogs (e.g., LY315902 and LY30761 SR (Lilly)), extended GLP-1 derivatives (e.g., NN2211(Novo Nordisk)) and complexing proteins (e.g., GLP-1-albumin complex CJC-1131).

In another preferred embodiment, the additional therapeutic agent may comprise a dipeptidyl peptidase IV (DPP-IV) inhibitor. For example, the agent may be selected from Vildagliptin (LAF237), MK-0431-Sitagliptin and Saxagliptin.

In another preferred embodiment, the additional therapeutic agent may comprise a Gastric Inhibitory Polypeptide (GIP), or a biologically active fragment, variant, fusion or derivative thereof. GIP, also known as glucose-dependent insulinotropic polypeptide, is a 42-amino acid peptide hormone synthesized and secreted by K cells of intestinal epithelial cells. An important determinant of GIP action is the N-terminal cleavage of the peptide to produce inactive GIP (3-42). The enzyme DPP-4, which also cleaves GLP-1 and GLP-2, rapidly inactivates GIP in vitro and in vivo. Therefore, it may be desirable to administer GIP in combination with a DPP-4 inhibitor.

Certain compounds of formula I may also have the additional advantage that they exhibit partial agonist activity and are therefore useful in conditions such as late type II diabetes, where stimulation of insulin production is required. By "agonist activity" we include both direct and indirect acting agonists.

The methods/uses of the present invention also have the advantage of being more convenient for the physician and/or patient, more effective, less toxic, more potent, less toxic than prior art similar methods (treatments) for treating ffa-caused, related or predominant diseases or conditions, or may have other useful pharmacological properties in the treatment of FFAs-caused, related or predominant diseases or conditions.

According to the present invention, there is also provided a method of screening for:

(i) an inhibitor; and/or

(ii) (Co-) stimulating factor

FFA induces cell proliferation. The breast cancer cell line MDA-MB-231 results in an increased proliferation rate in response to FFA stimulation (Hardy et al (2005) j.biol.chem., 280, 13285. we have found that:

(a) by simultaneously exposing the cells to FFA and the compound to be screened for activity; and

(b) assaying for proliferation, e.g., by cell cycle analysis³H]Thymidine incorporation, metabolic or intracellular signaling markers,

for example, as described below, active compounds can be identified.

Therefore, according to two further aspects of the invention, there are provided:

(1) a method of screening for an inhibitor of FFA-induced cell proliferation comprising subjecting a cell and FFA to known conditions to give FFA-induced cell proliferation, providing a test compound to the cell, and assessing whether FFA-induced cell proliferation is inhibited, wherein the finding of inhibition confirms that the test compound is an inhibitor of FFA-induced cell proliferation; and

(2) a method of screening for a co-stimulator of FFA-induced cell proliferation comprising subjecting a cell and FFA to known conditions to give a specified amount of FFA-induced cell proliferation, providing a test compound to the cell, and assessing whether FFA-induced cell proliferation is enhanced, wherein the finding of enhanced FFA-induced cell proliferation confirms that the test compound is a co-stimulator of FFA-induced cell proliferation. The enhancement of FFA-induced cell proliferation may be an increase in the rate, extent and duration of FFA-induced cell proliferation.

The invention is illustrated by the following examples in which the error bars represent the SEM and the following abbreviations are used:

LA-linolenic acid

DMSO-dimethyl sulfoxide.

FIGS. 1a-1e are representative examples of cell cycles analyzed using flow cytometry. The cells were cultured for 24 hours in the presence or absence of linolenic acid and the compound of example 95 (compound X). The histogram shows the cumulative behavior as measured by the intensity of PI staining (FL3) and its distribution in the cell cycle. (a) Untreated, (b) LA 100. mu.M, (c) LA 100. mu.M + Compound X10. mu.M, (d) Compound X10. mu.M, (e) DMSO 0.2%.

Figure 2A is a histogram summarizing 4 assays in which one compound was identified and confirmed as an FFA antagonist. Cells were cultured for 24 hours at the indicated concentrations in the presence or absence of linolenic acid and compound X. The cells of the S-phase of the untreated sample were set to 100% in each experiment.

Fig. 2B and 2C are histograms in which compounds were identified and confirmed as FFA antagonists. The cells were cultured for 24 hours in the presence or absence of linolenic acid and the compounds of examples 4 and 6 (compound Z and compound Y) and at the indicated concentrations. The S-phase cells of the untreated sample were set to 100% (n-2) in each experiment.

FIG. 3 is a histogram showing serum insulin levels in Ob/Ob mice fasted for 4 hours after 2 weeks, i.e., intraperitoneal injections of 1mg/kg of Compound Z or vehicle control, respectively, per day. n-9 (VC)10 (compound Z).

Examples

When a preparative route is not included, the relevant examples are commercially available (e.g., from Chemical university, San Diego, Calif., USA or other commercial sources).

Example 1

5-benzyl-2- (phenylimino) thiazolidin-4-one

Example 2

5- (4-methylbenzyl) -2- (4-chlorophenylimino) thiazolidin-4-one

Example 3

5- (4-chlorobenzyl) -2- (4-chlorophenylimino) thiazolidin-4-one

Example 4

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one

(a) 2-chloro-3- (3- (trifluoromethyl) phenyl) propionic acid methyl ester

A solution of sodium nitrite (0.47g, 6.82mmol) in water (1.4mL) was added dropwise to a solution of 3-trifluoromethylaniline (0.77mL, 6.21mmol) in concentrated hydrochloric acid and acetone (14mL), the latter solution mixture being cooled in an ice-water bath beforehand. The mixture was stirred at 0 ℃ for 10 minutes. After addition of methyl acrylate (3.37mL, 37.4mmol), cuprous oxide (40mg) was added to the mixture in portions at 40 ℃. The mixture was stirred at 35 ℃ for 20 minutes and then washed 2 times with equal amounts of water and ethyl acetate (50 mL). The organic layer was MgSO₄Drying, filtering and concentrating. The crude oil was purified by chromatography on silica gel using chloroform as eluent to give the sub-title compound (1.22g, 4.58mmol, 74%) as a yellow oil. ES-MS m/z 289.1(MNa +).¹HNMR：δ(CDCl₃)：3.24(dd，1H)，3.43(dd，1H)，3.76(s，3H)，4.46(dd，1H)，7.4-7.6(m，4H)。

(b)5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one

A mixture of methyl 2-chloro-3- (3- (trifluoromethyl) phenyl) propanoate (0.61g, 2.29 mmol; see step (a) above), N- (p-methylphenyl) thiourea (698mg, 4.2mmol) and sodium acetate (212mg, 2.54mmol) in ethanol (5.0mL) was refluxed for 8 hours and then concentrated. The crude product was purified by chromatography on silica gel with toluene: ethyl acetate (3: 2) as eluent followed by recrystallization from hot methanol to give the title compound (170mg, 0.47mmol, 21%) as a white solid. LC-MS (A) t_R: 6.26 min, m/z365.2(MH +).¹HNMR：δ(DMSO-d₆)：2.27(s，3H)，3.14(nr，1H)，3.46(dd，1H)，4.75(nr，1H)，6.80(nr，1H)，7.12(m，2H)，7.56(m，5H)。

Example 5

5- (3- (trifluoromethyl) benzyl) -2- (4-isopropylphenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 167mg of the title compound as a white solid. LC-MS (A) t_R: 7.03 min, m/z 393.4(MH +).¹H NMR：δ(DMSO-d₆)：1.15(d，6H)，2.83(m，1H)，3.15(m，1H)，3.45(ddd，1H)，4.75(m，1H)，6.83(d，1H)，7.30(dd，2H)，7.45-7.65(m，5H)。

Example 6

5- (3- (trifluoromethyl) benzyl) -2- (4-chlorophenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 271mg of the title compound as a white solid. LC-MS (A) t_R: 6.9 min, m/z 385.4(MH +).¹HNMR：δ(DMSO-d₆): 3.2(m, 1H), 3.6 (large HDO signal), 4.8(nr, 1H), 6.85(d, 1H), 7.4(dd, 2H), 7.5-7.7(m, 6H).

Example 7

5- (3- (trifluoromethyl) benzyl) -2- (4-methoxyphenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 137mg of the title compound as a white solid. LC-MS (A) t_R: 6.25 min, m/z 381.2(MH +).¹HNMR：δ(DMSO-d₆)：3.12(dd，1H)，3.45(ddd，1H)，4.74(dd，1H)，6.86-6.95(m，3H)，7.50-7.63(m，5H)。

Example 8

5- (3- (trifluoromethyl) benzyl) -2- (phenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. TheThe title compound was purified by flash chromatography and recrystallized from hot methanol to give 289mg of the title compound as a white solid. LC-MS (A) t_R: 6.42 min, m/z 351.4(MH +).¹HNMR：δ(DMSO-d₆)：3.1-3.5(m，2H)，4.76(dd，1H)，6.86(d，1H)，7.11(m，1H)，7.23(m，2H)，7.57(m，5H)。

Example 9

5- (4-fluorobenzyl) -2- (phenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 181mg of the title compound as a white solid. LC-MS (B) t_R: 1.57 min, m/z 301.3(MH +).¹H NMR：δ(DMSO-d₆)：3.00(dd，1H)，3.15-3.40(m，2H)，4.69(dd，1H)，6.90(nr，1H)，7.11(m，3H)，7.30(m，4H)，7.62(d，1H)。

Example 10

5- (4-fluorobenzyl) -2- (p-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 144mg of the title compound as a white solid. LC-MS (B) t_R: 1.62 min, m/z 315.2(MH +).¹H NMR：δ(DMSO-d₆)：2.23(s，3H)，2.99(m，1H)，3.12-3.41(m，2H)，4.65(m，1H)，6.80(m，1H)，7.11(m，4H)，7.25(m，2H)，7.49(d，1H)。

Example 11

2- (4-chlorophenylimino) -5- (4-fluorobenzyl) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and reconstituted from hot methanolCrystallization gave 175mg of the title compound as a white solid. LC-MS (B) t_R: 1.75 min, m/z 335.2(MH +).¹H NMR：δ(DMSO-d₆)：3.0(dd，1H)，3.3(nr，1H，HDO)，4.7(dd，1H)，6.9-7.7(m，8H)。

Example 12

5- (4-fluorobenzyl) -2- (4-methoxyphenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 166mg of the title compound as a white solid. LC-MS (B) t_R: 1.51 min, m/z331.1(MH +).¹H NMR：δ(DMSO-d₆)：2.99(dd，1H)，3.36(nr，1H，HDO)，3.72(s，3H)，4.65(b，1H)，6.90(m，3H)，7.10(m，2H)，7.25(m，2H)，7.40(d，1H)。

Example 13

5- (4-fluorobenzyl) -2- (4-isopropylphenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 55mg of the title compound as a white solid. LC-MS (A) t_R: 7.30 min, m/z 343.2(MH +).¹HNMR：δ(DMSO-d₆)：1.18(d，6H)，2.82(m，1H)，3.10(m，1H)，3.15-3.41(m，1H)，4.66(dd，1H)，6.83(m，1H)，7.1-7.3(m，6H)，7.51(d，1H)。

Example 14

5- (4- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 242mg of the title compound, which was purified by flash chromatographyAs a white solid. LC-MS (A) t_R: 7.50 min, m/z365.2(MH +).¹H NMR：δ(DMSO-d₆)：2.25(s，3H)，3.10(m，1H)，3.36(m，1H)，4.72(m，1H)，6.80(m，1H)，7.12(dd，2H)，7.46(m，3H)，7.63(m，2H)。

Example 15

5- (4-methoxybenzyl) -2- (p-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 282mg of the title compound as a white solid. LC-MS (A) t_R: 6.45 min, m/z 327.4(MH +).¹H NMR：δ(DMSO-d₆)：2.25(s，3H)，2.90(dd，1H)，3.33(m，1H)，3.70(s，3H)，4.60(dd，1H)，6.83(m，3H)，7.12(m，4H)，7.50(d，1H)。

Example 16

5-benzyl-2- (phenylimino) thiazolidin-4-one

The title compound was prepared according to examples 26 and 65 below. The title compound was purified by flash chromatography to yield 27mg of the title compound. LCMS (A) t_R: 8.50 minutes. ES-MSm/z: 283.2(MH +).¹HNMR：δ(DMSO-d₆)：3.00(dd，1H)，3.40(m，1H)，4.75(dd，1H)，6.90(d，1H)，7.05-7.45(m，8H)，7.65(d，1H)。

Example 17

5- (3- (trifluoromethyl) benzyl) -2- (4-fluorophenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to yield 78mg of the title compound as a white powder. LC-MS (A) t_R: 9.14 minutes. ES-MS m/z: 369.0(MH+).¹HNMR：δ(DMSO-d₆)：3.10-3.25(m，1H)，3.45(ddd，1H)，4.80(m，1H)，6.9(m，1H)，7.10-7.30(m，2H)，7.50-7.75(m，5H)。

Example 18

5- (3- (trifluoromethyl) benzyl) -2- (4-bromophenylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 803mg of the title compound as an off-white powder. LC-MS (A) t_R: 9.38 minutes. ES-MS m/z: 431.2(MH +).¹HNMR：δ(DMSO-d₆)：3.20(m，1H)，3.40(dd，1H)，4.75(m，1H)，7.40-7.60(m，7H)。

Example 19

2- (3, 4-dichlorophenylimino) -5- (3- (trifluoromethyl) benzyl) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to yield 67mg of the title compound as a white powder. LC-MS (A) t_R: 9.14 minutes. ES-MS m/z: 369.0(MH +).¹HNMR：δ(DMSO-d₆)：3.15(app.t，1H)，3.45(m，1H)，4.80(m，1H)，6.85(d，1H)，7.10(s，1H)，7.50-7.70(5H)，8.10(m，1H)。

Example 20

2- (2, 4-dichlorophenylimino) -5- (3- (trifluoromethyl) benzyl) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 68mg of the title compound as a beige powder. LC-MS (A) t_R: 9.52 minutes. ES-MS m/z: 419.0(MH +).¹HNMR：δ(DMSO-d₆)：3.20(m，1H)，3.40(dd，1H)，4.80(dd，1H)，6.95(d，1H)，7.35(d，1H)，7.50-7.65(m，4H)。

Example 21

4- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylideneamino) benzonitrile

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 45mg of the title compound as a white powder. LC-MS (A) t_R: 8.98 minutes. ES-MS m/z: 376.2(MH +).¹HNMR：δ(DMSO-d₆)：3.20(dd，1H)，3.50(bs，1H)，4.85(bs，1H)，7.00(bs，1H)，7.50-8.00(m，7H)。

Example 22

4- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylideneamino) benzoic acid ethyl ester

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot ethyl acetate to give 560mg of the title compound as white crystals. LC-MS (A) t_R: 8.77 minutes. ES-MS m/z 423.2(MH +).¹HNMR：δ(400 MHz)(CDCl₃)：1.50(t，3H)，3.31(dd，1H)，3.67(dd，1H)，4.48(q，2H)，4.58(dd，1H)，7.17-7.23(m，2H)，7.48-7.69(m，4H)，8.14(d，2H)ppm。

Example 23

4- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylideneamino) benzoic acid

Ethyl 4- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylideneamino) benzoate (100mg, 0.24 mmol; see example 22) was dissolved in a dioxane/water mixture (4: 1, 5mL) and 1.0MLiOH aqueous solution (0.5mL) was added. The reaction mixture was refluxed for 6 hours and then usedAcidification with 1.0M aqueous HCl. The precipitate formed was filtered to give 93mg (0.24mmol, 99%) of the title compound as a white solid. LC-MS (A) t_R: 8.32 minutes. ES-MS m/z 395.0(MH +).¹H NMR：δ(400MHz)(DMSO-d₆)：3.26-3.62(m，2H)，4.87-4.95(m，1H)，6.97-7.08(m，2H)，7.61-8.09(m，6H)ppm。

Example 24

4- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylideneamino) benzamide

To NH at 0 DEG C₄To a solution of Cl (324mg, 6.00mmol) in dry benzene (6ml) was added a 25% solution of trimethylaluminum in hexane (3.0ml, 6.00 mmol). After removal of the ice bath, the reaction mixture was stirred for 1.5 hours until no gas evolution was observed. To this aluminum reagent was added a solution of ethyl 4- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylideneamino) benzoate (393mg, 1.00 mmol; see example 23) in benzene (2ml) at room temperature. The yellow solution was stirred at 60 ℃ for 1.5 hours, cooled to room temperature, and CH was added₂Cl₂And water. The organic phase is MgSO₄Dried, filtered and concentrated in vacuo. The crude product is purified by chromatography on silica gel with a gradient of petroleum ether/EtOAc (10-50%) as eluent to give 56mg (0.14mmol, yield 14%) of the title compound as a white solid. LC-MS (A) t_R: 8.32 minutes. ES-MS m/z 394.2(MH +).¹HNMR：δ(400MHz)(DMSO-d₆)：3.20-3.35(m，1H)，3.44-3.66(m，1H)，4.87-4.98(m，1H)，6.94-7.05(m，1H)，7.29-7.43(m，1H)，7.58-8.09(m，8H)ppm。

Example 25

5- (3- (trifluoromethyl) benzyl) -2- (m-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to give 220mg of the title compoundThe product was a white powder. LC-MS (A) t_R: 9.52 minutes. ES-MS m/z: 365(MH +).¹HNMR：δ(DMSO-d₆)：7.10-7.61(m，8H)，3.86(t，1H)，3.56(m，1H)，3.30(m，1H)，2.35(s，3H)。

Example 26

2- (4-chlorophenylimino) -5- (4-fluoro-3- (trifluoromethyl) benzyl) thiazolidin-4-one

(a)2- (4-chlorophenylimino) thiazolidin-4-one

A mixture of ethyl 2-bromoacetate (0.25mL, 2.29mmol), N- (4-chlorophenyl) thiourea (2.29mmol) and sodium acetate (212mg, 2.54mmol) in ethanol (5mL) was refluxed overnight. The mixture was concentrated, diluted with dichloromethane and washed with water. The organic layer was MgSO₄Drying, filtering and concentrating. The crude product is purified by chromatography on silica gel with toluene: ethyl acetate (2: 1) as eluent (441mg) and recrystallisation from methanol gave 178mg (0.86mmol, 38%) of the sub-title compound. LC-MS (A) t_R: 4.68 min, m/z 207.2(MH +).¹HNMR：δ(DMSO-d₆)：2.26(s，3H)，3.84(d，2H)，6.69(d，1H)，7.16(d，2H)，7.57(d，1H)。

(b)2- (4-chlorophenylimino) -5- (4-fluoro-3- (trifluoromethyl) -benzylidene) thiazolidin-4-one

A mixture of 2- (4-chlorophenylimino) thiazolidin-4-one (0.48 mmol; see step (a) above), benzaldehyde (0.73mmol) and NaOAc (62mg, 0.75mmol) in 2mL of glacial AcOH was refluxed for 21 hours. The solvent was evaporated and the crude product was purified by chromatography on silica gel with toluene: acetone 3: 1 as eluent to give 120mg (78%) of the sub-title compound as a brown powder. LC-MS (A) t_R: 9.30 minutes. ES-MS m/z: 323(MH +).

(c)2- (4-chlorophenylimino) -5- (4-fluoro-3- (trifluoromethyl) benzyl) thiazolidin-4-one

2- (4-chlorophenylimino) -5- (4-fluoro-3- (trifluoromethyl) benzylidene)A mixture of thiazolidin-4-one (61.7mg, 0.154 mmol; see step (b) above) and pyridine (0.5mL) in THF (0.4mL) was heated in a closed screw-capped tube at 70 ℃ for 2 h. LC-MS monitoring showed no trace of the desired product. Sodium borohydride (40mg, 1.06mmol) was added and the mixture was heated overnight. The reaction was quenched with acetic acid (2mL), diluted with ethyl acetate, washed with water and concentrated in vacuo. The crude product (126.4mg) was purified by chromatography on silica gel using petroleum ether: ethyl acetate (2: 1) as eluent followed by 2 precipitations of the impurity with ethyl acetate/petroleum ether to give 30mg (0.074mmol, 48% yield) of the title compound as an oil. LC-MS (A) t_R: 10.88 minutes. (B) t is t_R: 0.68 minutes. m/z 403.3/405.3(MH +).

Example 27

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) -3-methylthiazolidin-4-one

A mixture of 5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one (250mg, 0.686mmol), sodium carbonate (145mg, 1,37mmol) and iodomethane (127. mu.L, 1.37mmol) in DMF (2.5mL) was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with water. The organic layer was MgSO₄Drying, filtering and concentrating. The crude product was purified by chromatography on silica gel using toluene: ethyl acetate (2: 1) as eluent to give the title compound (99mg, 0.262mmol, 38%). LC-MS (B) t_R: 0.98 min (256 nm).¹HNMR：δ(DMSO-d₆)：2.42(s，3H)，3.11(d，1H)，3.28(s，3H)，3.33(dd，2H)，7.20-7.33(m，6H)，7.38(t，1H)，7.53(d，1H)。

Example 28

5- (3- (trifluoromethyl) benzyl) -2- (N-methyl-N-phenylamino) thiazol-4 (5H) -one

The title compound was prepared according to example 4. The title compound was purified by flash chromatography and recrystallized from hot methanol to yield 237mg of the title compoundThe title compound was a white powder. LC-MS (A) t_R：8.82min.ES-MS m/z：365(MH+).¹HNMR：δ(DMSO-d₆)：7.61-7.10(m，6H)，7.30-7.10(m，3H)，4.4(t，1H)，3.55(m，1H)，3.15(m，1H)，2.35(s，3H)。

Example 29

5- (3- (trifluoromethyl) benzyl) -2- (N-methyl-N-p-tolylamino) thiazol-4 (5H) -oneThe title compound was prepared according to the methods described herein.

Example 30

5- (4-Fluorobenzyl) -2- (N-methyl-N- (pyridin-2-yl) amino) thiazol-4 (5H) -one

The title compound was prepared according to the methods described herein.

Example 31

2- (2- (N-methyl-N-p-tolylamino) -4, 5-dihydro-4-oxothiazol-5-yl) -N-p-tolyl-N Acetamide

The title compound was prepared according to the methods described herein.

Example 32

5- (3- (trifluoromethyl) benzyl) -2- (N-benzyl-N-p-tolylamino) thiazol-4 (5H) -oneThe title compound was prepared according to the methods described herein.

Example 33

5- (4-Fluorobenzyl) -2- (N-benzyl-N- (pyridin-2-yl) amino) thiazol-4 (5H) -oneThe title compound was prepared according to the methods described herein.

Example 34

2-(2- (N-benzyl-N-p-tolylamino) -4, 5-dihydro-4-oxi-thiazol-5-yl) -N-p-tolyl Acetamide

The title compound was prepared according to the methods described herein.

Example 35

5- (3- (trifluoromethyl) benzyl) -2- (N-phenyl-N-p-tolylamino) thiazol-4 (5H) -oneThe title compound was prepared according to the methods described herein.

Example 36

5- (4-Fluorobenzyl) -2- (N-phenyl-N- (pyridin-2-yl) amino) thiazol-4 (5H) -oneThe title compound was prepared according to the methods described herein.

Example 37

2- (2- (N-phenyl-N-p-tolylamino) -4, 5-dihydro-4-oxothiazol-5-yl) -N-p-tolyl-N Acetamide

The title compound was prepared according to the methods described herein.

Example 38

5- (3- (trifluoromethyl) benzylidene) -2- (phenylimino) thiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered off, washed with AcOH and toluene and dried in vacuo to give 50mg of the title compound as a yellow powder. LC-MS (A) t_R: 9.46 minutes. ES-MS m/z: 349.4(MH +).¹HNMR：δ(DMSO-d₆)：7.05(d，1H)，7.22(t，1H)，7.40(m，2H)，7.70-8.00(m，5H)。

Example 39

5- (3- (trifluoromethyl) benzylidene) -2- (p-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered off, washed with AcOH and toluene and dried in vacuo to give 47mg of the title compound as a yellow powder. LC-MS (A) t_R: 9.32 minutes. ES-MS m/z: 363.2(MH +).¹HNMR：δ(DMSO-d₆)：2.30(s，3H)，6.95(m，1H)，7.25(t，2H)，7.60-7.85(m，4H)，7.95(m，2H)。

Example 40

5- (4-Fluorobenzylidene) -2- (phenylimino) thiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered off, washed with AcOH and toluene and dried in vacuo to give 39mg of the title compound as a yellow powder. LC-MS (A) t_R: 9.14 minutes. ES-MS m/z: 299.0(MH +).¹HNMR：δ(DMSO-d₆)：7.05(d，1H)，7.20(t，1H)，7.30-7.50(m，4H)，7.55-7.80(m，3H)。

EXAMPLE 41

5- (4-Fluorobenzylidene) -2- (p-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered off, washed with AcOH and toluene and dried in vacuo to give 49mg of the title compound as a yellow powder.¹HNMR：δ(DMSO-d₆)：2.35(s，3H)，7.00(app.s，1H)，7.25(t，2H)，7.35(t，1H)，7.45(t，1H)，7.60(t，1H)，7.65(t，1H)，7.65-7.75(m，3H)。

Example 42

5-benzylidene-2- (phenylimino) aminesYl) Thiazolidin-4-ones

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered, recrystallized from acetic acid (2 ×), washed with toluene and dried in vacuo to give 442mg of the title compound.¹HNMR：δ(CD₃CN-d₃)：7.03(d，2H)，7.19(t，2H)，7.44(m，2H)，7.63(m，2H)，7.71(s，1H)，7.78(d，2H)。

Example 43

2- (p-tolylimino) -5-benzylidenethiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product that precipitated from the reaction mixture was filtered off, washed with AcOH and toluene and dried in vacuo to give 43mg of the title compound as a yellow powder.¹HNMR：δ(DMSO-d₆)：2.40(s，3H)，7.95(d，1H)，7.25(t，2H)，7.37-7.75(6H)。

Example 44

5- (3- (trifluoromethyl) benzylidene) -2- (4-chlorophenylimino) thiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b).

Example 45

2- (4-chlorophenylimino) -5-benzylidenethiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered off, washed with AcOH and toluene and dried in vacuo to give 83mg of the title compound as a yellow powder. LC-MS (A) t_R: 9.46 minutes. ES-MS m/z: 314.8(MH +).¹HNMR：δ(DMSO-d₆)：7.05(d，2H)，7.40-7.60(m，4H)，7.65(m，2H)，7.70(s，1H)，8.80(d，1H)。

Example 46

2- (4-chlorophenylimino) -5- (4-fluoro-3- (trifluoromethyl) benzylidene) thiazolidin-4-one

The title compound was prepared according to example 26 and 65 steps (a) and (b). The product precipitated from the reaction mixture was filtered off and recrystallized from acetic acid to yield 83mg of the title compound. LC-MS (A) t_R: 11.03 minutes. (B) t is t_R: 0.82 minute. m/z 401.3/403.2(MH +).

Example 47

2- (4-methylbenzyl) -5- (3-trifluoromethyl-benzyl) -thiazol-4-one

The title compound was prepared according to the methods described herein.

Example 48

5- (4-Fluorobenzyl) -2-pyridin-2-ylmethyl-thiazol-4-one

The title compound was prepared according to the methods described herein.

Example 49

2- [2- (4-methylbenzyl) -4-oxo-4, 5-dihydrothiazol-5-yl]-N-p-tolyl-acetamide The title compound was prepared according to the methods described herein.

Example 50

2- (1-p-tolylethyl) -5- (3-trifluoromethylbenzyl) -thiazol-4-one

The title compound was prepared according to the methods described herein.

Example 51

5- (4-Fluorobenzyl) -2- (1-pyridin-2-Yl-Ethyl) Thiazol-4-one

The title compound was prepared according to the methods described herein.

Example 52

2- [ 4-oxo-2- (1-p-tolylethyl) -4, 5-dihydro-thiazol-5-yl]-N-p-tolylacetamide

The title compound was prepared according to the methods described herein.

Example 53

2-phenyl-5- (3-trifluoromethylbenzyl) thiazol-4-one

The title compound was prepared according to the methods described herein.

Example 54

5- (4-Fluorobenzyl) -2-pyridin-2-Yl-Thiazol-4-one

The title compound was prepared according to the methods described herein.

Example 55

2- (4-oxo-2-phenyl-4, 5-dihydrothiazol-5-yl) -N-p-tolylacetamide

The title compound was prepared according to the methods described herein.

Example 56

2-p-tolylimino-5- [1- (3-trifluoromethylphenyl) ethyl]Thiazolidin-4-ones

The title compound was prepared according to the methods described herein.

Example 57

5- [1- (4-fluorophenyl) ethyl group]-2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 58

5- [ 1-methyl-1- (3-trifluoromethylphenyl) ethyl]-2-p-tolylimino thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 59

5- [1- (4-fluorophenyl) -1-methylethyl]-2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 60

5- (4-methoxyphenylethyl) -2- (p-tolylimino) thiazolidin-4-one

(a) 2-hydroxy-4- (4-methoxyphenyl) -4-oxobutanoic acid ethyl ester

Ethyl glyoxylate (50% in toluene, 6mL, 29.39mmol) and 4-methoxyacetophenone (4400mg, 29.39mmol) were stirred in an open flask at 135 ℃ for 20 h. The crude reaction mixture was purified by chromatography on silica gel with toluene: EtOAc 2: 1 as eluent to give the title compound as a viscous pale yellow oil which solidified upon standing (4000mg, 54%).¹HNMR：δ(CDCl₃)：1.40(t，3H)，3.45(dt，2H)，3.90(s，3H)，4.25(q，2H)，4.65(t，1H)，6.95(d，2H)，7.95(d，2H)。

(b)2-hydroxy-4- (4-methoxyphenyl) butanoic acid ethyl ester

To a solution of ethyl 2-hydroxy-4- (4-methoxyphenyl) -4-oxobutanoate (500mg, 1.98 mmol; see step (a) above) in HCl ethanol (1M, 20mL) was added 10% Pd/C (40 mg). Using H₂Gas-filled balloon H₂The reaction mixture was purged with gas and hydrogenated at 1atm for 6 hours. After stirring for 6 hours, the palladium catalyst was filtered off and the solvent and HCl were evaporated to give the sub-title compound (470mg, 100%) which was used without purification.¹HNMR：δ(CDCl₃)：1.30(t，3H)，1.95(m，1H)，2.10(m，1H)，2.75(m，2H)，3.80(s，3H)，4.25(q，2H)，6.85(d，2H)，7.15(d，2H)。

(c)1- (ethoxycarbonyl) -3- (4-methoxyphenyl) propyl 4-methylbenzenesulfonate

To a solution of ethyl 2-hydroxy-4- (4-methoxyphenyl) butanoate (470mg, 2.0 mmol; see step (b) above) in pyridine (5mL) was added tosyl chloride (497mg, 2.6mmol) portionwise at room temperature. The reaction mixture was stirred overnight, diluted with toluene and washed with water (3 ×). The organic phase was dried (MgSO)₄) And concentrated, and the crude product was purified by chromatography on silica gel with toluene: EtOAc 20: 1 as the eluent to give the sub-title compound as a pale red oil (322mg, 41%).¹HNMR：δ(CDCl₃)：1.20(t，3H)，2.15(m，1H)，2.45(s，3H)，2.55-2.70(m，2H)，8.85(S，3H)，4.15(t，2H)，5.90(m，1H)，6.85(d，2H)，7.10(d，2H)，7.40(d，2H)，7.90(d，2H)。

(d)5- (4-methoxyphenylethyl) -2- (p-tolylimino) thiazolidin-4-one

1- (ethoxycarbonyl) -3- (4-methoxyphenyl) propyl 4-methylbenzenesulfonate (155mg, 0.40 mmol; see step (c) above), p-tolylthiourea (67mg, 0.40mmol) and NaOAc (36mg, 0.44mmol) were dissolved in 1.0mL 95% EtOH. The reaction mixture was refluxed for 16 h, concentrated in vacuo and partitioned between EtOAc and water. After 3 extractions with EtOAc, the combined organic phases were dried (MgSO)₄) And concentrated, the crude product purified by chromatography on silica gel with toluene: EtOAc2: 1 as eluent. Further purification by recrystallization from hot MeOH afforded the title compound as a tan powder (42mg, 31%). LC-MS (A) t_R: 8.50 minutes. ES-MS m/z: 341.2(MH +).¹HNMR：δ(DMSO-d₆): 1.80-2.00(m, 1H), 2.20-2.40(s, 3H overlaps with m, 1H), 2.60(m, 1H), 2.75(m, 1H), 3.70(s, 3H), 4.15-4.25(m, 1H), 6.80-6.90(m, 2H), 6.95(m, 1H), 7.05-7.20(m, 4H), 7.60(d, 1H).

Example 61

5- (4-methoxyphenylethyl) -2- (phenylimino) thiazolidin-4-one

The title compound was prepared according to example 60, purified by flash chromatography and recrystallized from hot methanol to give 35mg of the title compound as a beige powder. LC-MS (A) t_R: 8.58 minutes. ES-MS m/z: 327.0(MH +).¹HNMR：δ(DMSO-d₆)：1.95(m，1H)，2.20-2.40(m，1H)，2.65(m，1H)，2.70(m，1H)，3.70(s，3H)，4.25(m，1H)，6.85(m，2H)，6.95-7.20(m，4H)，7.40(m，2H)，7.70(d，1H)。

Example 62

2- (p-tolylimino) -5-phenethylthiazolidin-4-one

The title compound was prepared according to example 60, purified by flash chromatography and recrystallized from hot methanol to yield 96mg of the title compound. LC-MS (B) t_R: 1.75 min, m/z 310.9(MH +).¹HNMR：δ(DMSO-d₆)：2.00(m，1H)，2.30(s，3H)，2.36(m，1H)，2.61(m，1H)，2.75(m，1H)，4.21(dm，1H)，6.91(m，1H)，7.19(m，5H)，7.29(m，2H)，7.58(d，2H)。

Example 63

2-p-tolylimino-5- [2- (3-trifluoromethyl-phenyl) -ethyl]Thiazolidin-4-ones

The title compound was prepared according to the methods described herein.

Example 64

5- [2- (4-fluorophenyl) -ethyl]-2- (pyridin-2-ylimino) -thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 65

2- (p-tolylimino) -5- (3-phenylpropyl) thiazolidin-4-one

The following procedure is similar to that described in example 26 above.

(a)2- (p-tolylimino) thiazolidin-4-one

A mixture of ethyl 2-bromoacetate (0.25mL, 2.29mmol), N- (4-methylphenyl) thiourea (381mg, 2.29mmol) and sodium acetate (212mg, 2.54mmol) in ethanol (5mL) was refluxed overnight. The mixture was concentrated, diluted with dichloromethane and washed with water. The organic layer was MgSO₄Drying, filtering and concentrating. The crude product is purified by chromatography on silica gel with toluene/ethyl acetate (2: 1) as eluent (441mg) and recrystallisation from methanol gave 178mg (0.86mmol, 38%) of the sub-title compound. LC-MS (A) t_R: 4.68 min, m/z 207.2(MH +).¹HNMR：δ(DMSO-d₆)：2.26(s，3H)，3.84(d，2H)，6.69(d，1H)，7.16(d，2H)，7.57(d，1H)。

(b)2- (p-tolylimino) -5- (3-phenylpropylene) thiazolidin-4-one

A mixture of 2- (p-tolylimino) thiazolidin-4-one (100mg, 0.48 mmol; see step (a) above), 3-phenylpropionaldehyde (72mg, 0.73mmol) and NaOAc (62mg, 0.75mmol) in 2mL glacial AcOH was refluxed for 21 hours. The solvent was evaporated and the crude product was purified by chromatography on silica gel with toluene: acetone 3: 1 as eluent to give 120mg (78)%) as a brown powder. LC-MS (A) t_R: 9.30 minutes. ES-MS m/z: 323(MH +).

(c)2- (p-tolylimino) -5- (3-phenylpropyl) thiazolidin-4-one

To a solution of 2- (p-tolylimino) -5- (3-phenylpropylidene) thiazolidin-4-one (220mg, 0.68 mmol; see step (b) above) in pyridine (0.55mL) and THF (0.50mL) was slowly added LiBH at room temperature₄(2M in THF, 0.75mL, 1.50mmol) and the resulting mixture refluxed for 5 hours. The mixture was allowed to reach room temperature and the reaction was quenched by the addition of 1M HCl. Water was added and the mixture was extracted 3 times with EtOAc. The combined organic phases were separated by MgSO₄Drying, filtering and concentrating. The crude product was purified by chromatography on silica gel using toluene: EtOAc 2: 1 as eluent to give 23mg (10%) of the title compound. LC-MS (A) t_R: 9.14 minutes. ES-MS m/z: 325.4(MH +).

Example 66

2-p-tolylimino-5- [3- (3-trifluoromethylphenyl) propyl group]Thiazolidine-4-one

The title compound was prepared according to the methods described herein.

Example 67

5- [3- (4-fluorophenyl) propyl group]-2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 68

5- (3-Phenylallylidene) -2- (phenylimino) thiazolidin-4-ones

A solution of 2- (phenylimino) thiazolidin-4-one (100mg, 0.52mmol), cinnamaldehyde (171mg, 0.78mmol) and NaOAc (66mg, 0.80mmol) in 2mL of glacial AcOH was returnedFlow for 18 hours while precipitating the product. The suspension was brought to room temperature, diluted with 2mL of AcOH, transferred to a tube and centrifuged. The mother liquor was removed and another 4mL of AcOH was added and the tube was centrifuged again. The washing process was repeated with 2X 4mL of toluene. The residue was dried in vacuo to give the title compound (135mg, 85%) as a yellow powder. LC-MS (A) t_R: 9.46 minutes. ES-MS m/z: 307.0(MH +).

Example 69

2-p-tolylimino-5- [ (3-trifluoromethylphenylamino) methyl group]Thiazolidine-4-oneThe title compound was prepared according to the methods described herein.

Example 70

5- [ (4-fluorophenylamino) methyl group]-2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 71

5- { [ methyl- (3-trifluoromethylphenyl) amino]Methyl } -2-p-tolylimino-thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 72

5- { [ 4-fluorophenyl) methylamino]Methyl } -2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 73

2-p-tolylimino-5- (3-trifluoromethyl-phenoxymethyl) -thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 74

5- (4-fluorophenoxymethyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 75

2-p-tolylimino-5- (3-trifluoromethylphenylthiomethyl) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 76

5- (4-fluorophenylthiomethyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 77

2-p-tolylimino-5- [ (3-trifluoromethylbenzylamino) methyl group]Thiazolidine-4-one

The title compound was prepared according to the methods described herein.

Example 78

5- [ (4-Fluorobenzylamino) methyl group]-2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 79

5- { [ methyl- (3-trifluoromethylbenzyl) amino]Methyl } -2-p-tolylimino-thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 80

5- { [ 4-Fluorobenzyl) methylamino]Methyl } -2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared according to the methods described herein.

Example 81

N- (4-oxo-2-p-tolylimino-thiazolidin-5-ylmethyl) -3-trifluoromethyl-benzamide

The title compound was prepared according to the methods described herein.

Example 82

4-fluoro-N- [ 4-oxo-2- (pyridin-2-ylimino) thiazolidin-5-ylmethyl]Benzamide derivatives

The title compound was prepared according to the methods described herein.

Example 83

N-methyl-N- (4-oxo-2-p-tolylimino-thiazolidin-5-ylmethyl) -3-trifluoromethyl-benzene Carboxamides

The title compound was prepared according to the methods described herein.

Example 84

4-fluoro-N-methyl-N- [ 4-oxo-2- (pyridin-2-ylimino) thiazolidin-5-ylmethyl]-benzoyl Amines as pesticides

The title compound was prepared according to the methods described herein.

Example 85

N- (4-oxo-2-p-tolylimino-thiazolidin-5-ylmethyl) -2- (3-trifluoromethyl-phenyl) - Acetamide

The title compound was prepared according to the methods described herein.

Example 86

2- (4-fluorophenyl) -N- [ 4-oxo-2- (pyridin-2-ylimino) thiazolidin-5-ylmethyl]-acetamide

The title compound was prepared according to the methods described herein.

Example 87

1- (4-oxo-2-p-tolylimino thiazolidin-5-ylmethyl) -3- (3-trifluoromethylphenyl) urea

The title compound was prepared according to the methods described herein.

Example 88

1- (4-fluorophenyl) -3- [ 4-oxo-2- (pyridin-2-ylimino) thiazolidin-5-ylmethyl]Urea

The title compound was prepared according to the methods described herein.

Example 89

(4-oxo-2-p-tolylimino thiazolidin-5-ylmethyl) -carbamic acid 3-trifluoromethyl-phenyl Esters

The title compound was prepared according to the methods described herein.

Example 90

[ 4-oxo-2- (pyridin-2-ylimino) thiazolidin-5-ylmethyl]Carbamic acid 4-fluorophenyl ester

The title compound was prepared according to the methods described herein.

Example 91

(3-trifluoromethylphenyl) carbamic acid 4-oxo-2-p-tolyliminothiazolidin-5-ylmethyl Esters

The title compound was prepared according to the methods described herein.

Example 92

(4-fluorophenyl) carbamic acid 4-oxo-2- (pyridin-2-ylimino) thiazolidin-5-ylmethyl ester

The title compound was prepared according to the methods described herein.

Example 93

5- (4-chlorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 94

5- (4-methoxybenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 95

5- (4-fluorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 96

5- (2-methylbenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 97

5- (4-methylbenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 98

5- (2, 3-dichlorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 99

5- (4-bromobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

Example 100

5- (3- (trifluoromethyl) benzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one

The title compound was prepared as described in example 4, purified by flash chromatography and purified from ThermoA

Recrystallization of the alcohol gave 94mg of the title compound. LC-MS (B) t_R: 0.73 min, m/z 352.4(MH +).¹HNMR：δ(DMSO-d₆)：3.15(m，1H)，3.45(dd，1H)，4.60(nr，1H)，7.19(m，2H)，7.5-7.6(m，4H)，7.78(m，1H)，8.30(nr，1H)。

Example 101

5- (4-Fluorobenzyl) -2- (benzylamino) thiazol-4 (5H) -one

The title compound was prepared according to example 4, purified by flash chromatography and recrystallized from hot methanol to give 322mg of the title compound. LC-MS (B) t_R: 1.45 min, m/z 315.1(MH +).

¹HNMR：δ(DMSO-d₆)：2.95(dd，1H)，3.30(nr，1H，HDO)，4.48-4.62(m，3H)，7.05-7.33(m，9H)。

Example 102

5- (3- (trifluoromethyl) benzyl) -2- (benzylimino) thiazolidin-4-one

The title compound was prepared according to example 4, purified by flash chromatography and recrystallized from hot methanol to yield 133mg of the title compound. LC-MS (A) t_R: 6.08 min, m/z 365.4(MH +).

¹HNMR：δ(DMSO-d₆)：3.11(dd，1H)，3.42(dd，1H)，4.50(d，1H)，4.59(d，1H)，4.69(dd，1H)，7.13(d，2H)，7.29(m，4H)，7.5-7.6(m，4H)。

Example 103

2- ((pyridin-2-yl) methylamino) -5- (4-fluorobenzyl) thiazol-4 (5H) -one

The title compound was prepared according to the methods described herein.

Example 104

N- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidene) benzamide

To 5- (3- (trifluoromethyl) benzyl) -2-aminothiazol-4 (5H) -one (100mg, 0.36mmol, prepared as described in example 4) and triethylamine (76uL, 0.55mmol) in CH₂Cl₂To the suspension in (3ml) was added dropwise benzoyl chloride (50uL, 0.40 mmol). The reaction mixture was stirred at room temperature overnight and poured into NaHCO₃Is added to the saturated aqueous solution of (1). CH for the aqueous phase₂Cl₂Extracting, and collecting organic phase with MgSO₄Dried, filtered and concentrated in vacuo. Purification of the crude product by column chromatography with CH₂Cl₂A gradient (0-1%) of MeOH as eluent gave 38mg (0.10mmol, 28%) of the title compound as a colorless oil. From CH₂Cl₂Recrystallization from isohexane gave 22mg of the title compound as a white solidAnd (3) a body. LC-MS (A) t_R: 8.72 minutes. ES-MS m/z 379.0(MH +).¹HNMR：δ(400MHz)(CDCl₃)：3.23(dd，1H)，3.64(dd，1H)，4.34(dd，1H)，7.46-7.61(m，7H)，8.12(d，2H)ppm。

Example 105

N- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidene) -4-chlorobenzamide

The title compound was prepared as described in example 104, purified by flash chromatography (83mg, colorless oil) and purified from CH₂Cl₂Recrystallization from isohexane gave 72mg of the title compound as a white solid. LC-MS (A) t_R: 8.92 minutes. ES-MS m/z 413.2(MH +).¹HNMR：δ(400MHz)(CDCl₃)：3.22(dd，1H)，3.61(dd，1H)，4.34(dd，1H)，7.42-7.49(m，4H)，7.52-7.59(m，2H)，8.12(d，2H)ppm。

Example 106

N- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidene) -4-methylbenzamide

The title compound was prepared as described in example 104, purified by flash chromatography (32mg, colorless oil) and purified from CH₂Cl₂Recrystallization from isohexane gave 10mg of the title compound as a white solid. LC-MS (A) t_R: 8.73 minutes. ES-MS m/z 393.0(MH +).¹HNMR：δ(400MHz)(CDCl₃)：2.54(s，3H)，3.30(dd，1H)，3.74(dd，1H)，4.41(dd，1H)，7.35-7.42(m，2H)，7.52-7.71(m，3H)，7.78(d，1H)，8.12(d，2H)ppm。

Example 107

N- (5- (4-fluorobenzyl) -4, 5-dihydro-4-oxothiazol-2-yl) picolinamide

The title compound was prepared according to the methods described herein.

Example 108

5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidenecarbamic acid phenyl ester

The title compound was prepared as described in example 104, purified by flash chromatography (88mg, colorless oil) and purified from CH₂Cl₂Recrystallization from isohexane gave 74mg of the title compound as a white solid. LC-MS (A) t_R: 8.73 minutes. ES-MS m/z 395.0(MH +).¹HNMR：δ(400MHz).CDCl₃)：3.22(dd，1H)，3.61(dd，1H)，4.37(dd，1H)，7.21-7.28(m，3H)，7.37-7.58(m，6H)ppm。

Example 109

5- (4-Fluorobenzyl) -4, 5-dihydro-4-oxothiazol-2-ylcarbamic acid pyridin-2-yl esterThe title compound was prepared according to the methods described herein.

Example 110

1- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidene) -3-phenylurea

5- (3- (trifluoromethyl) benzyl) -2-aminothiazol-4 (5H) -one (100mg, 0.36mmol, prepared as in example 4) was dissolved in toluene (3mL) and phenyl isocyanate (44uL, 0.40mmol) was added dropwise. The reaction mixture was heated to reflux for 3 hours. The precipitate which had formed was filtered, washed with toluene and dried in vacuo to give 137mg (0.35mmol, 97%) of the title compound as a white solid.¹HNMR：δ(400MHz)(DMSO-d₆)：3.21(dd，1H)，3.46(dd，1H)，4.64(dd，1H)，6.98-7.02(m，1H)，7.23-7.28(m，2H)，7.56-7.68(m，6H)，9.79(br.s，1H)ppm。

Example 111

1- (5- (3- (trifluoromethyl) benzyl) -4-oxoThiazolidine-2-ylidene) -3-p-tolylurea

The title compound was prepared according to example 110 to give 126mg of the title compound as a white solid.¹HNMR：δ(400MHz)(DMSO-d₆)：2.20(s，3H)，3.21(dd，1H)，3.46(dd，1H)，4.63(dd，1H)，7.04(d，2H)，7.44-7.66(m，6H)，9.71(br.s，1H)ppm。

Example 112

1- (5- (3- (trifluoromethyl) benzyl) -4-oxothiazolidin-2-ylidene) -3- (4-chlorophenyl) -urea

The title compound was prepared according to the method described for example 110 to give 161mg of the title compound as a white solid.¹HNMR：δ(400MHz)(DMSO-d₆)：3.19(dd，1H)，3.43(dd，1H)，4.64(dd，1H)，7.28(d，2H)，7.58-7.69(m，6H)，9.95(br.s，1H)ppm。

Example 113

1- (5- (4-fluorobenzyl) -4, 5-dihydro-4-oxothiazol-2-yl) -3- (pyridin-2-yl) ureaThe title compound was prepared according to the methods described herein.

Example 114

5- (3- (trifluoromethyl) benzyl) -2-tosyliminothiazolidin-4-one

5- (3- (trifluoromethyl) benzyl) -2-aminothiazol-4 (5H) -one (100mg, 0.36mmol, prepared as in example 4) was dissolved in pyridine (3mL) and p-toluenesulfonyl chloride (77mg, 0.40mmol) was added. The reaction mixture was stirred at room temperature overnight and poured into NaHCO₃Saturated solution in water. CH for the aqueous phase₂Cl₂Extracting, and collecting organic phase with MgSO₄Dried, filtered and concentrated in vacuo. Purification of the crude product by column chromatography with CH₂Cl₂Gradient of/MeOH (0-1%) as eluent gave 55mg (0.13 mmol)36%) as a colorless oil. From CH₂Cl₂Recrystallization from isohexane gave 34mg of a white solid. LC-MS (A) t_R: 8.53 minutes. ES-MS m/z 429.2(MH +).¹HNMR：δ(400MHz)(CDCl₃)：2.44(s，3H)，3.22(dd，1H)，3.5 8(dd，1H)，4.40(dd，1H)，7.33(d，2H)，7.42-7.51(m，3H)，7.58(d，1H)，7.78(d，2H)ppm。

Example 115

5- (3- (trifluoromethyl) benzyl) -2-phenylsulfonyliminothiazolidin-4-one

The title compound was prepared according to example 114, purified by flash chromatography (49mg, colorless oil) and purified from CH₂Cl₂Recrystallization from isohexane gave 29mg of the title compound as a white solid. LC-MS (A) t_R: 8.37 minutes. ES-MS m/z 415.0(MH +).¹HNMR：δ(400MHz)(CDCl₃)：3.24(dd，1H)，3.57(dd，1H)，4.40(dd，1H)，7.44-7.67(m，7H)，7.91(d，2H)ppm。

Example 116

5- (3- (trifluoromethyl) benzyl) -2- (4-chlorophenyl) sulfonyliminothiazolidin-4-one

The title compound was prepared according to example 114, purified by flash chromatography (43mg, colorless oil) and purified from CH₂Cl₂Recrystallization from isohexane gave 20mg of the title compound as a white solid. LC-MS (A) t_R: 8.78 minutes. ES-MS m/z 449.2(MH +).¹HNMR：δ(400MHz)(CDCl₃)：3.35(dd，1H)，3.57(dd，1H)，4.40(dd，1H)，7.41-7.45(m，5H)，7.59(d，1H)，7.83(d，2H)ppm。

Example 117

5- (4-Fluorobenzyl) -2- (2-pyridylsulfonylamino) thiazol-4 (5H) -one

The title compound was prepared according to the methods described herein.

Example 118

5- (3- (trifluoromethyl) benzyl) -2- (isopropylamino) thiazol-4 (5H) -one

The title compound was prepared according to example 4 and purified by flash chromatography and preparative HPLC to give 170mg of the title compound as a beige powder. LC-MS (A) t_R: 7.08 minutes. ES-MSm/z: 317.0(MH +).¹HNMR：δ(DMSO-d₆)：1.05(d，3H)，1.15(d，3H)，3.10(dd，1H)，3.45(dd，1H)，4.00(m，1H)，4.65(dd，1H)，7.50-7.65(m，4H)，9.00(d，1H)。

Example 119

5- (3- (trifluoromethyl) benzyl) -2- (cyclohexylamino) thiazol-4 (5H) -one

The title compound was prepared according to example 4 and purified by flash chromatography and preparative HPLC to give 120mg of the title compound as a beige powder. LC-MS (A) t_R9.08 minutes. ES-MS m/z357.2(MH +).¹HNMR：δ(DMSO-d₆)：1.00-1.40(m，5H)，1.54(d，1H)，1.60-1.90(m，4H)，3.05(dd，1H)，3.40(dd，1H)，3.65(m，1H)，4.55(dd，1H)，7.45-7.65(m，4H)，9.05(d，1H)。

Example 120

5- (3- (trifluoromethyl) benzyl) -2- (methylamino) thiazol-4 (5H) -one

The title compound was prepared according to example 4 and purified by flash chromatography to give 240mg of the title compound as an oil. LC-MS (A) t_R: 4.74 min, m/z 289.2(MH +).

Example 121

2- (p-tolylimino) -5-methylthiazolidin-4-one

The title compound was prepared according to example 4, purified by flash chromatography and recrystallized from methanol to yield 149mg of the title compound. LC-MS (A) t_R: 5.57 min, m/z 221.2(MH +).¹HNMR：δ(DMSO-d₆)：1.47(dd，3H)，2.25(s，3H)，3.50(dd，1H)，4.23(q，1H)，6.89(t，1H)，6.88(d，1H)，7.16(m，2H)，7.57(d，1H)。

Example 122

2- (p-tolylimino) thiazolidin-4-one

The title compound was prepared according to example 4, purified by flash chromatography and recrystallized from methanol to yield 178mg of the title compound. LC-MS (A) t_R: 4.68 min, m/z 207.2(MH +).¹HNMR：δ(DMSO-d₆)：2.26(s，3H)，3.84(d，2H)，6.69(d，1H)，7.16(d，2H)，7.57(d，1H)。

Example 123

5- (3- (trifluoromethyl) benzyl) -2-aminothiazol-4 (5H) -one

The title compound was prepared according to example 4. The reaction mixture was concentrated and partitioned between dichloromethane and water. The solid was filtered to give 1.22g of the title compound. The organic layer was dried (MgSO₄) And concentrated and the residue triturated with isohexane to give a further 1.02g of the title compound (ca. 2.24g)_R: 5.3 min, m/z 275.2(MH +).¹HNMR：δ(DMSO-d₆)：3.05(dd，1H)，3.45(dd，1H)，4.63(dd，1H)，7.56(m，4H)，8.80(b，2H)。

Example 124

2- (2- (4-carboxyphenylimino) -4-oxothiazolidin-5-yl) -N- (3-methoxyphenyl) -acetamide

Example 125

2- (2- (4-hydroxyphenylimino) -4-oxothiazolidin-5-yl) -N- (4-bromophenyl) -acetamide

Example 126

2- (2- (4-ethoxyphenylimino) -4-oxothiazolidin-5-yl) -N- (4-bromophenyl) acetamide

Example 127

2- (2- (3-hydroxyphenylimino) -4-oxothiazolidin-5-yl) -N- (4-bromophenyl) -acetamide

Example 128

2- (2- (4-hydroxyphenylimino) -4-oxothiazolidin-5-yl) -N-phenylacetamide

Example 129

2- (2- (4-hydroxyphenylimino) -4-oxothiazolidin-5-yl) -N- (4-fluorophenyl) -acetamide

Example 130

2- (2- (p-tolylimino) -4-oxothiazolidin-5-yl) -N-p-tolylacetamide

Example 131

2- (2- (4-methoxyphenylimino) -4-oxothiazolidin-5-yl) -N- (4-methoxyphenyl) -acetyl Amines as pesticides

Example 132

2- (2- (4-ethoxyphenylimino) -4-oxothiazolidin-5-yl) -N-Phenylacetamides

Example 133

4- (2- (2- (4-ethoxyphenylimino) -4-oxothiazolidin-5-yl) acetamido) benzoic acid ethyl ester Esters

Example 134

2- (2- (3- (trifluoromethyl) phenylimino) -4-oxothiazolidin-5-yl) acetic acid

Example 135

N- (2, 4-dimethylphenyl) -2- (4-oxo-2- (phenylimino) thiazolidin-5-yl) acetamide

Example 136

N- (2, 4-Dimethoxyphenyl) -2- (4-oxo-2- (phenylimino) thiazolidin-5-yl) acetamide

Example 137

2- (4-oxo-2- (4-sulfonamido (phenylamino) phenylimino) thiazolidin-5-yl) -N-pair Tolylacetamide

Example 138

N- (4-fluorophenyl) -2- (4-oxo-2- (phenylimino) thiazolidin-5-yl) acetamide

Example 139

2- (2- (m-tolylimino) -4-oxothiazolidin-5-yl) -N- (2-chlorophenyl) acetamide

Example 140

2- (2- (2, 5-dimethyl)Phenylimino) -4-oxothiazolidin-5-yl-N- (2, 4-dichlorophenyl) -ethyl Amides of carboxylic acids

Example 141

2- (4-oxo-3-phenyl-2- (phenylimino) thiazolidin-5-yl) -N-p-tolylacetamide

Example 142

2- (2- (cyclohexylimino) -4-oxothiazolidin-5-yl) -N-phenylacetamide

Example 143

2- (2- (methylimino) -4-oxothiazolidin-5-yl) -N- (2, 4-dimethylphenyl) acetamide

Example 144

N-ethyl-2- (2- (methylimino) -4-oxothiazolidin-5-yl) acetamide

Example 145

2- (2- (allylimino) -4-oxothiazolidin-5-yl) -N- (2-nitrophenyl) acetamide

Example 146

1, 1-dioxo-1. lamda⁶-[1，4，2]Dithiazolidin-3-ylidene]P-tolyl-amine

(a)2-chloromethanesulfonamide

Ammonia gas was bubbled through chloromethanesulfonyl chloride (5.0g, 34mmol) in Et at 0 deg.C₂O (50 mL). The reaction mixture was stirred at room temperature for 2 hours. The precipitate was filtered (ammonium chloride) and washed with EtOAc (3 ×). The combined organic phases were dried (Na)₂SO₄) And concentrated to give 2.96g (67%) of the crude subtitle compound as a white solid. The compound was used without further purification.¹HNMR：δ(DMSO-d₆)：5.74(s，2H)，7.33(s，2H)。

(b)1, 1-dioxo-1. lamda⁶-[1，4，2]Dithiazolidin-3-ylidene]P-tolyl-amine

An aqueous solution of NaOH (18M, 1.38mL, 25mmol) was added over 30 minutes to a solution of crude 2-chloromethanesulfonamide (2.96g,. about.23 mmol) and 4-methylphenyl isothiocyanate (3.75g, 24.0mmol) in acetone (14mL) at 50 ℃. The resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified with hydrochloric acid (1M) and the organic solvent was evaporated in vacuo. Water and EtOAc were added and the aqueous phase was extracted with EtOAc (× 3). The combined organic phases were dried (Na)₂SO₄) And concentrated, and the crude product purified by silica gel column chromatography (toluene/EtOAc 4: 1-2: 1) to give 3.46g (63%) of the title compound as a white solid. LC-MS (A) t_R: 7.70 minutes. ES-MS m/z: 243.0(MH +).¹HNMR：δ(DMSO-d₆)：2.28(s，3H)，4.75(s，2H)，7.22(d，2H)，7.45(d，2H)。

Example 147

[1, 1-dioxo-5- (3- (trifluoromethyl) phenyl) (hydroxy) methyl) -1. lamda⁶-[1，4，2]Dithiazolidin-3-ylidene]P-tolyl-amine

LDA (1.8M, 2.1mL, 3.72mmol) was added to the 1, 1-dioxo-1. lambda. in a nitrogen atmosphere at 0 ℃ over 20 minutes⁶-[1，4，2]Dithiazolidin-3-ylidene]-p-tolyl-amine (300mg, 1.24mmol) in dry THF (2 mL). The reaction mixture was allowed to reach room temperature over 1 hour and stirring was continued at room temperature for 3 hours. After the reaction mixture was cooled to 0 ℃ again, a solution of 3- (trifluoromethyl) benzaldehyde (420. mu.L, 3.1mmol) in anhydrous THF (0.5mL) was added dropwise. The reaction temperature slowly reached room temperature and the resulting mixture was left overnight. Hydrochloric acid and EtOAc were added, and the aqueous phase was extracted with EtOAc (× 3). The combined organic phases were dried (Na)₂SO₄) And the solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (toluene/EtOAc 100)0-2: 1) to yield 364mg (70%) of the title compound as a 1: 1 mixture of diastereomers. LC-MS (A) t_R: 10.02 minutes. ES-MS m/z: 417.2(MH +).¹HNMR (1: 1 diastereoisomeric mixture): delta (CD)₃CN-d₃)：2.31(s，3H)，2.34(s，3H)，5.13(m，2H)，5.27(d，1H)，5.55(d，1H)，7.19(d，2H)，7.22(d，2H)，7.31(m，2H)，7.40(m，2H)，7.58(m，2H)，7.66(m，2H)，7.74(m，2H)，7.81(m，2H)。

Example 148

[1, 1-dioxo-5- (3- (trifluoromethyl) benzylidene) -1. lambda⁶-[1，4，2]Dithiazolidin-3-ylidene]P-tolyl-amine

Trifluoroacetic anhydride (136 μ L, 0.99mmol) was added to a solution of the compound from example 147 (370mg, 0.89mmol), 4- (dimethylamino) pyridine (27mg, 0.22mmol) and Et3N (370 μ L, 2.67mmol) in DCM (2.5mL) at 0 deg.C under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 hours. Hydrochloric acid (1M) and EtOAc were added and the aqueous phase was extracted with EtOAc (× 3). The combined organic phases were dried (Na)₂SO₄) And concentrated and the crude product purified by column chromatography on silica gel (toluene/EtOAc 100: 0-2: 1) to give 293mg (84%) of the title compound as an off-white solid. LC-MS (A) t_R: 9.57 minutes. ES-MS m/z: 399.2(MH +).¹HNMR：δ(DMSO-d₆)：2.33(s，3H)，7.28(d，2H)，7.53(d，2H)，7.86(m，4H)，7.92(s，1H)。

Example 149

[1, 1-dioxo-5- (3-trifluoromethylbenzyl) -1. lambda⁶-[1，4，2]Dithiazolidin-3-ylidene]-p-tolylamine

The title compound was prepared according to the methods described herein.

Example 150

[1, 1-dioxo-5- (4- (fluoro) phenyl) (hydroxy) methyl) -1. lamda⁶-[1，4，2]Dithiazolidin-3-ylidene]P-tolyl-amine

The title compound was prepared according to the methods described for examples 146 and 147 and was purified by flash chromatography to give 312mg of the title compound as a 1: 1 mixture of diastereomers. LC-MS (A) t_R: 9.10 minutes. ES-MS m/z: 367.2(MH +).¹HNMR (1: 1 diastereoisomeric mixture): delta (CD)₃CN-d₃)：5.09(m，2H)，5.21(d，1H)，5.39(d，1H)，7.13(m，4H)，7.20(m，4H)，7.38-7.45(m，4H)，7.54(m，4H)。

Example 151

[1, 1-dioxo-5- (4- (fluoro) benzylidene) -1. lambda⁶-[1，4，2]Dithiazolidin-3-ylidene]P-tolyl-amine

The title compound was prepared as described in example 146-148 and purified by flash chromatography to give 176mg of the title compound as an off-white solid. LC-MS (A) t_R: 10.14 minutes. ES-MS m/z: 349.4(MH +).¹HNMR：δDMSO-d₆)：2.35(s，3H)，7.32(d，2H)，7.45(d，2H)，7.57(m，2H)，7.70(m，2H)，7.79(s，1H)。

Example 152

[1, 1-dioxo-5- (3- (trifluoromethyl) phenyl) (hydroxy) methyl) -1. lamda⁶-[1，4，2]Dithiazolidin-3-ylidene]-4-chlorophenyl-amine

The title compound was prepared according to the methods described for examples 146 and 147 and was purified by flash chromatography to give 0.5g of the title compound as a 1: 1 mixture of diastereomers. LC-MS (A) t_R: 9.54 minutes. ES-MS m/z: 437.2(MH +).¹H NMR (1: 1 diastereomeric mixture): delta (CD)₃CN-d₃)：5.28(m，2H)，5.40(d，1H)，5.68(d，1H)，7.51(m，4H)，7.60(d，2H)，7.71(m，2H)，7.80(m，2H)，7.58(m，2H)，7.85(m，2H)，7.96(m，2H)。

Example 153

[5- (4-fluoro-benzyl) -1, 1-dioxo-1. lamda. -)⁶-[1，4，2]Dithiazolidin-3-ylidene]-pyridin-2-yl-amine the title compound was prepared according to the methods described herein.

Example 154

2- (1, 1-dioxo-3-p-tolylimino-1. lambda⁶-[1，4，2]Dithiazol-5-yl) -N-p-tolyl-acetamide

The title compound was prepared according to the methods described herein.

Example 155

5- (3- (trifluoromethyl) benzyl) -4-methyl-N-p-tolylthiazol-2-amine

The title compound was prepared according to the methods described herein.

Example 156

N- (5- (4-fluorobenzyl) -4-methylthiazol-2-yl) pyridin-2-amine

The title compound was prepared according to the methods described herein.

Example 157

5- (3- (trifluoromethyl) benzyl) -4- (trifluoromethyl) -N-p-tolylthiazol-2-amine

The title compound was prepared according to the methods described herein.

Example 158

N- (5- (4-fluorobenzyl) -4- (trifluoromethyl) thiazol-2-yl) pyridin-2-amine

The title compound was prepared according to the methods described herein.

Example 159

2- (4-chlorophenylimino) -5- ((5-methylfuran-2-yl) methylene) thiazolidin-4-one

The title compound was prepared according to examples 26 and 65. The product precipitated from the reaction mixture was filtered off and recrystallized from acetic acid to yield 139mg of the title compound. LC-MS t_R: 1.6 minutes. m/z 319.2/321.2(MH +). The main tautomer:¹HNMR(400MHz，CDCl₃δ ppm: 2.38(s, 3H), 6.20(d, J ═ 3.32Hz, 1H), 6.73(d, J ═ 3.53Hz, 1H), 7.42(d, J ═ 8.57Hz, 2H), 7.17(d, J ═ 8.30Hz, 2H), 7.52(s, 1H) (total 10H). Minor tautomer (about 20% relative to the major tautomer): 2.47(s, 0.64H), 6.25(d, J ═ 3.20Hz, 0.20H), 6.82(d, J ═ 3.46Hz, 0.20H), 7.24(s, 0.29H), 7.49(d, J ═ 8.65Hz, 0.46H), 7.66(s, 0.18H) (total 1.97H).

Example 160

2- (4-chlorophenylimino) -5- ((5-methylfuran-2-yl) methyl) thiazolidin-4-one

A mixture of 2- (4-chlorophenylimino) -5- ((5-methylfuran-2-yl) methylene) -thiazolidin-4-one (66.5mg, 0.209 mmol; see example 160) and sodium borohydride (26.5mg, 0.701mmol) in THF (0.8mL) was heated overnight at 70 ℃ in a sealed screw-capped tube. The reaction was quenched with methanol (1mL) and acetic acid (1mL), diluted with ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated, and the crude product is purified by chromatography on silica gel using petroleum ether ethyl acetate (2: 1) as eluent to give 52mg of the title compound. LC-MS (B) t_R: 1.5 minutes. m/z 321.3/323.2(MH +).¹HNMR：δCDCl₃)：8.26(b，1H)，7.33(d，J＝8.63Hz，2H)，7.12(d，J＝8.55Hz，2H)，5.97(d，J＝3.00Hz，1H)，5.85(d，J＝2.13Hz，1H)，4.42(dd，J＝10.41，3.49Hz，1H)，3.54(dd，J＝15.37，3.38Hz，1H)，3.02(dd，J＝15.46，10.43Hz，1H)，2.22(s，3H)。

Example 161

2- (4-chlorophenylimino) -5- ((5-methylthiophen-2-yl) methylene) thiazolidin-4-one

The title compound was prepared according to examples 26 and 65. The product precipitated from the reaction mixture was filtered off, and recrystallized from acetic acid to yield 106mg of the title compound. LC-MS (B) t_R: 2.05 minutes. 335.85(MH +).

Example 162

2- (4-chlorophenylimino) -5- ((5-methylthiophen-2-yl) methyl) thiazolidin-4-one

A mixture of 2- (4-chlorophenylimino) -5- ((5-methylthiophen-2-yl) methylene) -thiazolidin-4-one (33mg, 0.0985 mmol; see example 61) and sodium borohydride (13mg, 0.343mmol) in THF (0.8mL) was refluxed overnight. The reaction was quenched with acetic acid (2mL), diluted with ethyl acetate and washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated, and the crude product is purified by column chromatography on silica gel using petroleum ether ethyl acetate (2: 1) as eluent to give 20mg of the title compound as a yellow solid. LC-MS (B) t_R: 1.77 minutes. m/z 337(MH +).¹HNMR：δ(DMSO-d₆): 3.25(s, 3H), 3.25(ddd, 1H), 3.80(ddd, 1H), 4.4(dd, 1H), 4.56(dd, 1H), 6.60(d, 1H), 6.70(d, 1H) tautomers, 7.20(d, 2H), 7.50(d, 2H).

Example 163

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino)Oxazolidin-4-ones

A solution of ethyl 2-chloro-3- (3- (trifluoromethyl) phenyl) propionate (610mg, 2.17mmol), p-methylphenyl urea (337mg, 2.25mmol) and NaOAc (212mg, 2.53mmol) in 5.0mL 95% EtOH was refluxed for 72 hours and then concentrated.The residue was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc (3 ×). With MgSO₄The combined organic phases were dried, filtered and concentrated, and the crude product was purified by silica gel column chromatography with toluene: EtOAc 2: 1 as eluent. Subsequent recrystallization from MeOH yielded 493mg of the title compound as a white powder. LC-MS (A) t_R: 10.42 minutes. ES-MSm/z: 349.4(MH +).¹HNMR：δ(DMSO-d₆)：3.1(s，3H)，3.4(m，1H)，3.6(m，1H)，3.8(m，1H)，4.0(m，1H)，4.25-4.35(ddd，1H)，7.19(m，4H)，7.55(m，2H)，7.7(m，2H)。

Example 164

[5- (3-trifluoromethylbenzyl) -1, 1-dioxo-1. lamda. -)⁶-[1，4，2]Dithiazolidin-3-ylidene]- (4-chloro) phenyl-2-amines

Sodium bis (trimethylsilyl) amide (0.6M, 1.06mL, 0.63mmol) was added dropwise to 1, 1-dioxo-1. lambda. under nitrogen at-78 deg.C⁶-[1，4，2]Dithiazolidin-3-ylidene]-p-chlorophenyl-amine (33mg, 0.12mmol) in anhydrous THF (2 mL). The reaction mixture was stirred at this temperature for 1 hour, after which a solution of 3-trifluorobenzyl bromide (75 μ L, 0.63mmol) in anhydrous THF (0.5mL) was added dropwise. The temperature was maintained at-78 ℃ for 5h and the reaction was stopped by addition of hydrochloric acid and EtOAc. The aqueous phase was extracted with EtOAc (× 3) and the combined organic phases were extracted with Na₂SO₄Drying, filtering and concentrating. The crude product was purified by silica gel. Delta (DMSO-d)₆): 3.2(dd, 1H), 3.6(dd, 1H), 5.5(dd, 1H), 7.4-7.5.(m, 2H), 7.6-7.7. (m, column chromatography (toluene: EtOAc 100: 0-2: 1) gives 15mg of the title compound LC-MS (A) t_R: 10.89 minutes. ES-MS m/z: 421.2(MH +).¹HNMR：4H)，7.7-7.8(d，1H)，7.8(s，1H)。

Example 165

[5- (3-trifluoromethylbenzyl) -1, 1-dioxo-1. lamda. -)⁶-[1，4，2]Dithiazolidin-3-ylidene]-2-benzamides

The above compounds are prepared according to the methods described herein.

Example 166

5- (3- (trifluoromethyl) benzyl) -4-methyl-N- (4-chlorophenyl) thiazol-2-amine

(a)3-chloro-4- (3- (trifluoromethyl) phenyl) butan-2-one

A solution of sodium nitrite (0.31g, 4.42mmol) in water (0.9ml) was added dropwise to a solution of 3-trifluoromethylaniline (0.50ml, 4.02mmol) in concentrated hydrochloric acid (1.0ml) and acetone (9.0ml) with cooling in an ice-water bath. The mixture was stirred at 0 ℃ for 20 minutes. Methyl vinyl ketone (2.00ml, 24.11mmol) and Cu were added₂After O (26mg), the mixture was stirred at 40 ℃ for 40 minutes. The reaction mixture was cooled to room temperature and poured into saturated NaHCO₃An aqueous solution. Using CH as the aqueous phase₂Cl₂Extracting, and collecting organic phase with MgSO₄Dried and concentrated in vacuo to give a brown oil. The crude product was purified by chromatography on silica gel using petroleum ether/EtOAc (0-5%) as eluent to give 605mg of the title compound as a yellow oil.¹H NMR：

400MHz)(CDCl₃)：2.34(s，3H)，3.12(dd，1H)，3.41(dd，1H)，4.40(m，1H)，7.42-7.57(m，4H)ppm。

(b)5- (3- (trifluoromethyl) benzyl) -4-methyl-N- (4-chlorophenyl) thiazol-2-amine

3-chloro-4- (3- (trifluoromethyl) phenyl) butan-2-one (200mg, 0.80 mmol; see step (a) above), 4-chlorophenylthiourea (149mg, 0.80mmol) and NaOAc (72mg, 0.88mmol) were suspended in 95% EtOH (2 ml). The reaction mixture was refluxed for 72 hours and the solvent was evaporated. The crude product was dissolved in EtOAc and extracted with water. The aqueous phase was washed with EtOAc and the organic phases were combined and MgSO₄Dry and evaporate the solvent. The crude product was purified by column chromatography on silica gel using a gradient of petroleum ether/EtOAc (0-30%) as eluent and recrystallisation from hot methanol gave 157mg of the crude productThe title compound as white crystals. LC-MS (A) t_R: 10.68 minutes. ES-MS m/z 383.4(MH +).¹HNMR：

400MHz).DMSO-d₆)：2.19(s，3H)，4.08(s，2H)，7.29-7.31(m，2H)，7.50-7.61(m，6H)ppm。

Biological assay

Test A

Cell proliferation assay

Reagent

Dulbecco's modified Eagle's Medium (D-MEM) +1000mg/L glucose + GlutaMAX^TM1+ Pyruvate (Pyruvate) (Gibco #21885-

V/V fetal bovine serum (Gibco 10500-

PEST (100U/ml penicillin, 100ug/ml streptomycin, Gibco 15140-

CyStain PI absolute T kit (Partec #05-5023)

Linolenic acid 99%, L2376 from Sigma Aldrich

Dimethyl sulfoxide (DMSO)

Instrument for measuring the position of a moving object

Cytomics^TMFC500 flow cytometer with CXP software (Beckman Coulter)

MDA-MB-231 cells

MDA-MB-231 cells were cultured in D-MEM +1000mg/L glucose + GlutaMAX^TM1+ pyruvate and propagation medium supplemented with 10% V/V fetal bovine serum and PEST (100U/mL penicillin, 100. mu.g/mL streptomycin). Cells were seeded in 6-well plates to a density of 300000 cells/well in propagation medium. After 24 hours, the medium was replaced with serum-free D-MEM medium.

Linolenic acid was diluted in DMSO to a concentration of 100mM and added to the medium to a final concentration of 100. mu.M.

The compounds were dissolved in DMSO to concentrations of 10mM (compounds of examples 95 and 6 (compound X and compound Y, respectively)) and 40mM (compound of example 4 (compound Z)) and added to the medium to final concentrations of 10. mu.M (X and Y) and 40. mu.M (Z), respectively.

After 24 hours in serum-free medium DMEM, linolenic acid (final concentration of 10. mu.M) and the compound to be screened for activity were added to a final concentration of 10. mu.M (compounds X and Y) and 40. mu.M (compound Z), respectively. The final DMSO concentration remained at 0.2% in all wells. After 24 hours of stimulation, cells were harvested and stained with propidium iodide (propidium iodide) using the CyStain PI Absolute T kit according to the manufacturer's instructions. Followed by Cytomics with CXP software^TMFC500 flow cytometer (Beckman Coulter) analyzes cell cycle distribution of cells. Cells were cultured for 24 hours in the presence or absence of Linolenic Acid (LA) and compounds X, Y and Z at the indicated concentrations. The cells of the S-phase of the untreated sample were set to 100% in each experiment.

Results

The method was shown to have the sensitivity required to detect free fatty acid stimulated antagonists. The determination of DNA synthesis for quantitative analysis of cell proliferation minimizes the inherent error of several other assays.

FFA stimulation of MDA-MB-231 cells was observed to result in increased proliferation, as demonstrated in FIGS. 1a and 1b, where the proportion of cells in the S phase of the cell cycle was increased by b versus a, as determined by the incorporation of propidium iodide. The stimulatory effect of FFA can be attenuated by the action of compound X at a 10: 1 molar ratio (FIG. 1 c). However, this compound did not have any detectable effect on the basal proliferation of MDA-MB-231 cells (FIG. 1 d). These results indicate that compound X is able to antagonize free fatty acid-stimulated cell proliferation.

This experiment was repeated 4 times and the results are summarized in fig. 2A. Compounds Z and Y are also able to antagonize free fatty acid-stimulated cell proliferation, as shown in fig. 2B and 2C, respectively.

Therefore, the related compounds attenuated FFA-induced cell proliferation in human breast cancer cell lines. The ability of compounds X, Y and Z to inhibit such proliferative effects can be expressed as percent antagonist activity as follows:

compound X-is 70% at a concentration of 10. mu.M

Compound Y-is 100% at a concentration of 10. mu.M

Compound Z-was 50% at a concentration of 10. mu.M.

Similar tests were carried out in the compounds of the above examples, in which it was also found that at a concentration of 10 μ M it had a percent antagonistic activity of at least 20%.

Test B

Insulin determination study in diabetic Ob/Ob mice

Reagent

The ultrasensitive rat insulin ELISA kit (Crystal Chen inc) was according to the manufacturer's instructions.

Serum insulin assays were performed on 4-hour fasted Ob/Ob mice (Taconnic) of 8-9 weeks of age. Mice were divided into Vehicle Control (VC) or compound Z treated groups so that the average s-insulin was the same between groups. Groups of 1mg/kg body weight of compound Z and VC in PBS/1% v/v DMSO were injected intraperitoneally 1 time daily for 2 weeks, after which the fasting serum insulin levels were determined for 4 hours as described above.

Results

Compound Z attenuated hyperinsulinemia in Ob/Ob mice (see figure 3). Hyperinsulinemia observed in Ob/Ob mice is generally thought to be the result of obesity and disturbed lipid metabolism. From the results obtained in test A above, we explain the activity of the test compound in Ob/Ob mice as interfering with the action of lipids as a signaling molecule.

Test C

Determination of glucose in diabetic FRID mice and intraperitoneal glucose tolerance test study

Reagents and methods

FRID mouse (Hart, et al, Nature, 408, 864(2000)

Research Diets#D12309

Dimethyl sulfoxide (DMSO)

14 male FRID mice were analyzed by fasting blood glucose assay and intra-peritoneal glucose tolerance test (IPGTT) after 12 hours of fasting.

Mice were divided into two matched groups of 7 mice each. On the first day of the experiment, all mice received high fat feed (study feed # D12309) and were injected intraperitoneally 1 time per day with a formulation containing compound of example 95 (compound X) (1mg/kg body weight) or a control Vehicle (VC) for 7 consecutive days. On day 8, after 12 hours of fasting, the mice were analyzed for fasting blood glucose measurements and IPGTT.

Compound preparation

Test compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and diluted to 0.2mg/ml with Phosphate Buffered Saline (PBS). The solution was brought to a final DMSO concentration of 0.9%. PBS containing 0.9% DMSO was used as a vehicle control.

Glucose measurement/IPGTT

Mice were fasted for 12 hours and blood glucose was analyzed after intraperitoneal injection of 2 grams of glucose/kg body weight, and blood glucose analysis was repeated at 30, 60 and 120 minutes post injection. Blood glucose concentration was determined by tail prick blood sampling and analysis of the resulting blood drops with an Ascesia Elit XL (Bayer Diagnostic) hand-assisted glucometer.

Results

FRID mouse models have a rapid pathogenesis leading to overt diabetes, which is caused by a High Fat Diet (HFD). The test compounds partially inhibit HFD-induced diabetes.

Claims

1. The use of a compound of formula I or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, in the manufacture of a medicament for the treatment of a disease or condition caused, associated or predominated by free fatty acids,

wherein

X is alkylene or a bond;

t represents-S-;

y represents-c (o) -or ═ c (h) -;

w represents-NR₇-；

A₁Or A₂One represents a double bond and the other represents a single bond;

when A is₁Represents a single bond, A₂Is a double bond and R₆Is absent;

when A is₂Represents a single bond, A₁Is a double bond and R₇Is absent;

R₁represents heterocyclyl, aryl or heteroaryl (each of which is optionally substituted by one or more groups selected from B₄、B₅And B₆Substituted with a group of (a);

R₅represents hydrogen, alkyl, cycloalkyl, heterocyclyl, benzyl, aryl or heteroaryl (wherein the latter 6 groups are each optionally substituted by one or more groups selected from B⁷、B⁸、B⁹、B¹⁰、B¹¹And B¹²Substituted with a group of (a);

R₆and R₇Independently represents hydrogen, alkyl, cycloalkyl or benzyl (wherein the last 3 groups are each optionally substituted by one or more groups selected from B¹³、B¹⁴And B¹⁶Substituted with a group of (a);

B⁴to B¹⁴And B¹⁶If applicable, independently represent cyano, -NO₂Halogen, -OR₁₁、-NR₁₂R₁₃、-SR₁₄、-Si(R₁₅)₃、-C(O)OR₁₆、-C(O)NR_16aR_16b、-S(O)₂NR_16cR_16dAryl or heteroaryl (said aryl and heteroaryl being themselves optionally and independently substituted by one or more groups selected from halogen and R₁₇Substituted with a group of (a); or,

B⁴、B⁵、B⁶、B¹⁰、B¹¹、B¹²or B¹⁶Independently (if applicable) represents R¹⁷；

R₁₅And R₁₇Independently represents C optionally substituted by one or more halogen atoms_1-6An alkyl group.

2. The use of a compound of formula I according to claim 1, wherein in the compound:

x represents- [ C (R)⁸)(R⁹)]_n-, where n is 0, 1, 2 or 3;

t represents-S-or-O-;

y represents-S (O)₂-、＝C(R₁₀) -or-c (o) -;

w represents-NR₇-、-NR₇C(O)-、-NR₇S(O)₂-、-NR₇C(O)NR⁷-or NR₇C(O)O-；

R₁Represents heterocyclyl, aryl or heteroaryl (wherein the latter 3 groups are each optionally substituted by one or more groups selected from B⁴、B⁵And B⁶Substituted with a group of (a);

R₅represents heterocyclyl, aryl or heteroaryl (wherein the latter 3 groups are each optionally substituted by one or more groups selected from B⁹、B¹¹And B¹²Substituted with a group of (a);

R₆and R₇Independently represent hydrogen, alkyl, cycloalkyl, aryl or benzyl (wherein the latter 4 groups are each optionally substituted by one or more groups selected from B¹³、B¹⁴、B¹⁵And B¹⁶Substituted with a group of (a);

R₈and R₉Independently selected from hydrogen, alkyl and aryl (wherein the latter 2 groups are each optionally substituted by one or more groups selected from B¹⁷And B¹⁸Substituted with a group of (a);

R₁₀represents hydrogen, alkyl or aryl (wherein the latter 2 groups are each optionally substituted by one or more groups selected from B¹⁹And B²⁰Substituted with a group of (a);

A₁or A₂One is as defined above, and when A₂When represents a single bond, then A₁Is a double bond and one R₇(wherein α is attached to the desired ring of the compound of formula I) is absent; and

B⁴to B¹⁴And B¹⁶As defined in claim 1;

B¹⁵、B¹⁷、B¹⁸、B¹⁹and B²⁰Independently represent cyano, -NO₂Halogen, -OR₁₁、-NR₁₂R₁₃、-SR₁₄、-Si(R₁₅)₃、-C(O)OR₁₆、-C(O)NR_16aR_16b、-S(O)₂NR_16cR_16dAryl or heteroaryl (the aryl and heteroaryl groups themselves are optionally and independently substituted by one or more groups selected from halogen and R₁₇Substituted with a group of (a); or,

B¹⁵、B¹⁸and B²⁰Represents R₁₇(ii) a And

R₁₁to R₁₇As defined in claim 1.

3. Use according to claim 1 or claim 2, wherein, in the compound of formula I, T represents-S-.

4. Use as claimed in any one of the preceding claims wherein, in the compound of formula I, Y represents-c (o) -.

5. Use as claimed in claim 2 or claim 3, wherein, in the compound of formula I, when Y represents ═ C (R)₁₀)-，R₁₀Represents an alkyl group.

6. Use as claimed in any one of claims 2 to 5 wherein, in the compound of formula I, W represents-NR₇C (O) -or-NR₇-。

7. The use as claimed in claim 6, wherein W represents-NR₇-。

8. The use as claimed in any one of the preceding claims, wherein, in the compound of formula I, R₁And R₅Independently represents an optionally substituted heteroaryl or an optionally substituted aryl.

9. The use as claimed in claim 8, wherein, at R₁In the case of (a), the heteroaryl group is furyl or thienyl.

10. The use as claimed in claim 8, wherein, at R₅In the case of (3), the heteroaryl group is a 2-pyridyl group.

11. The use of claim 8, wherein R₁And/or R₅If appropriate phenyl.

12. Use according to any one of claims 2 to 10 wherein, in the compound of formula I, n represents 1 or 2.

13. The use as claimed in any one of the preceding claims, wherein, in the compound of formula I, R₈And R₉Independently represent C_1-3Alkyl or H.

14. The use of claim 13, wherein R₈And R₉Are all H.

15. Use as claimed in any one of the preceding claims, wherein, in the compound of formula I, when W represents-NR₇-and R₇When not present, then R₆Representation H, C_1-6Alkyl or phenyl, whereinThe 2 groups may each be substituted by one or more B¹³And B¹⁵And (4) substitution.

16. The use of claim 15, wherein R₆Is H.

17. Use as claimed in any one of the preceding claims, wherein, in the compound of formula I, when W represents-NR₇-and R₆When not present, then R₇Is represented by C_1-3Alkyl, phenyl or benzyl, each of which may be independently substituted by one or more B¹³、B¹⁵And B¹⁶And (4) substitution.

18. Use according to any one of the preceding claims, wherein, in the compound of formula I, B⁴To B²⁰Independently represent cyano, NO₂Halogen, -OR₁₁、-C(O)OR₁₆、-C(O)NR_16aR_16bor-S (O)₂NR_16cR_16dAnd/or B₄To B₆、B₁₀To B₁₂、B₁₅、B₁₆、B₁₈And B₂₀Independently represent R₁₇(ii) a And/or B⁴To B²⁰Independently represents heteroaryl or phenyl, both of which may be substituted by one or more substituents selected from halogen or R₁₇Is substituted with a group (b).

19. The use as claimed in any one of the preceding claims, wherein, in the compound of formula I, R₁₁And/or R₁₆Independently represent C_1-3Alkyl or H.

20. The use as claimed in any one of the preceding claims, wherein, in the compound of formula I, R_16a、R_16b、R_16cAnd R_16dIndependently represent C_1-2Alkyl or H.

21. The use as claimed in any one of the preceding claims, wherein, in the compound of formula I, R₁₇Represents C optionally substituted by one or more halogen atoms_1-4An alkyl group.

22. The use according to any one of claims 1, 3-9 or 11-21, wherein, in the compound of formula I, R₅Represents a benzyl group, which group is an optionally substituted or optionally substituted alkyl or cycloalkyl group, wherein the latter group is optionally substituted.

23. The use as claimed in any one of the preceding claims, wherein the compound is selected from:

5- (4-fluorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one;

5- (p-methylbenzyl) -2- (4-chlorophenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (4-chlorophenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (4-methoxyphenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (phenylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) -3-methylthiazolidin-4-one;

24. The use of claim 23, wherein the compound is selected from the group consisting of:

5- (4-fluorobenzyl) -2- (pyridin-2-ylimino) thiazolidin-4-one;

5- (3- (trifluoromethyl) benzyl) -2- (p-tolylimino) thiazolidin-4-one.

25. The use according to any one of the preceding claims, wherein the disease or condition is hyperinsulinaemia or a related condition.

26. The use of claim 25, wherein the disorder is selected from the group consisting of hyperinsulinemia, type II diabetes, glucose intolerance, insulin resistance, metabolic syndrome, dyslipidemia, hyperinsulinemia in children, hypercholesterolemia, hypertension, obesity, fatty liver disease, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, cardiovascular disease, atherosclerosis, cerebrovascular disorder, stroke, systemic lupus erythematosus, neurodegenerative disease, alzheimer's disease, polycystic ovary syndrome, progressive renal disease, and chronic renal failure.

27. The use according to claim 27, wherein the condition is hyperinsulinemia or type II diabetes.

28. A compound according to any one of claims 2 to 22, provided that, when N represents 1, Y represents-c (o) -and W represents-N (R)₇) -, at least one R₈And/or R₉The substituents independently represent an alkyl or aryl group (provided that the latter is not an unsubstituted aryl group), both of which are optionally substituted (if appropriate) as defined in claims 2 to 21, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, provided that:

(a) when Y represents ═ C (R)₁₀) When W does not represent-N (R)₇) C (O) -; and

(b) the compound is not:

5-benzyl-4-phenyl-N-p-tolylthiazol-2-amine;

n, 5-dibenzyl-4-phenyl-N-p-tolylthiazol-2-amine;

5-benzyl-4- (4- (diethylamino) phenyl) -N-p-tolylthiazol-2-amine;

2- (5- (2-methoxybenzyl) -2- ((4-carboxybenzyl) amino) thiazol-4-yl) phenol;

5-benzyl-4-methyl-2- (4-pivaloyloxy) phenylsulfonylaminothiazole.

29. A compound as defined in claim 28, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, for use as a medicament.

30. A pharmaceutical formulation including a compound as defined in claim 28, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

31. A method of treatment of a disease or condition caused, associated or dominated by free fatty acids, which method comprises administering an effective amount of a compound of formula I as defined in any one of claims 1 to 24 or 28, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof, to a patient in need of such treatment.

32. A combination product, comprising:

(A) a compound of formula I as defined in any one of claims 1 to 24 or 28, or a pharmaceutically acceptable salt or solvate, or a pharmaceutically functional derivative thereof; and

(B) another therapeutic agent effective in treating a disease or condition caused by, associated with, or predominating by free fatty acids,

wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

33. A combination product as claimed in claim 32, which comprises a pharmaceutical formulation comprising a compound of formula I as defined in any one of claims 1 to 24 or 28, or a pharmaceutically acceptable salt or solvate, or pharmaceutically functional derivative thereof; another therapeutic agent effective in treating a disease or condition caused by, associated with, or predominating by free fatty acids; and a pharmaceutically acceptable adjuvant, diluent or carrier.

34. A combination product as claimed in claim 32, which comprises a kit of parts comprising the components:

(a) a pharmaceutical formulation including a compound of formula I as defined in any one of claims 1 to 24 or 28, or a pharmaceutically acceptable salt or solvate or pharmaceutically functional derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(b) a pharmaceutical formulation including, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, another therapeutic agent effective in the treatment of a disease or condition mediated, associated or predominated by free fatty acids,

the components (a) and (b) are each provided in a form suitable for administration in combination with the other component.

35. A combination product as defined in any of claims 32 to 34, wherein the further therapeutic agent is selected from insulin, insulin secretagogues, metformin, peroxisome proliferator activated receptor agonists, α -glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, elsinants, inhibitors of the 11- β hydroxysteroid dehydrogenase type 1, enzymes associated with the conversion of corticosterone to cortisol in the liver and adipose tissue, and GLP-1 or gastric inhibitory polypeptides, or biologically active fragments, variants, fusions or derivatives of any of these peptides.

36. A method of screening for an inhibitor of free fatty acid-induced cell proliferation, comprising providing a cell and a free fatty acid under conditions known to result in free fatty acid-induced cell proliferation, providing a test compound to the cell, and assessing whether free fatty acid-induced cell proliferation is inhibited, wherein the finding of inhibition confirms that the test compound is an inhibitor of free fatty acid-induced cell proliferation.

37. A method of screening for a co-stimulator of free fatty acid-induced cell proliferation, comprising providing a cell and free fatty acid under conditions known to result in a specified amount of free fatty acid-induced cell proliferation, providing a test compound to the cell, and assessing whether the free fatty acid-induced cell proliferation is increased, wherein the finding that the increase in free fatty acid-induced cell proliferation confirms that the test compound is a co-stimulator of free fatty acid-induced cell proliferation.

38. The method of claim 37, wherein an increase in free fatty acid-induced cell proliferation is an increase in the rate, extent, or duration of free fatty acid-induced cell proliferation.

39. The method of any one of claims 36-38, wherein the cells are obtained from the breast cancer cell line MDA-MB-231.

40. The method of any one of claims 36-39, wherein the evaluating comprises a cell cycle assay, [2 ]³H]An assay for thymidine incorporation, an assay for metabolic markers, or an assay for intracellular signaling markers.