HK1077068B

HK1077068B - Azolidinone-vinyl fused-benzene derivatives

Info

Publication number: HK1077068B
Application number: HK05111691.4A
Authority: HK
Inventors: T‧吕克利克; 江旭亮; P‧盖拉德; D‧丘奇; T‧瓦乐顿
Original assignee: 默克雪兰诺有限公司
Priority date: 2002-07-10
Filing date: 2003-07-10
Publication date: 2010-10-22

Description

Oxazolidinone-vinyl fused-benzene derivatives

Technical Field

The present invention relates to oxazolidinone (azolidinone) -vinyl fused-benzene derivatives of formula (I) for use in the treatment and/or prevention of autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplant rejection or lung injuries. The present invention specifically relates to substituted oxazolidinone (azolidinone) -vinyl fused-benzene derivatives useful for modulating the activity or function of, inter alia, the phosphoinositide-3' OH kinase family (PI3K), particularly PI3K γ.

Background

The cytoplasmic membrane of a cell can be seen as a reservoir of large second messengers that can participate in a variety of signaling pathways. With respect to the function and regulation of effector enzymes in the phospholipid signaling pathway, these enzymes produce second messengers from the membrane phospholipid pool (class I PI3 kinases, such as PI3K γ)) which are dual specific kinases, meaning that they exhibit both phospholipid kinase activity (phosphorylation of phosphoinositides) and protein kinase activity, enabling phosphorylation of other protein substrates, including autophosphorylation as an intramolecular regulatory mechanism. These phospholipid-signaling enzymes are activated in response to various extracellular signals such as growth factors, mitogens, integrins (cell-cell interaction) hormones, cytokines, viruses and neurotransmitters (as shown in figure 1 below), and also by intracellular cross-regulation (cross-talk) by other signaling molecules such as small molecules of gtpase, kinases or phosphatases, where the original signal activates certain parallel pathways that in a second step transmit signals to PI3K through intracellular signaling events.

The inositol phospholipid (phosphoinositide) intracellular signaling pathway begins with the binding of signaling molecules (extracellular ligands, stimuli, receptor dimerization, transactivation by heterologous receptors such as receptor tyrosine kinases) to G-protein coupled transmembrane receptors integrated in the cytoplasmic membrane. PI3K converts the membrane phospholipid PIP (4, 5)2 into PIP (3, 4, 5)3, which in turn can be further converted by 5 ' -specific phosphoinositide phosphatase into another 3 ' -phosphorylated form, so that the enzymatic activity of PI3K leads directly or indirectly to the production of two 3 ' -phosphoinositide isoforms which function as second messengers in intracellular signaling (Vanhaaesebroeck B, et al, Trends Biochem Sci.22(7) p.267-72 (1977); Leslie NR, et al, chem. Rev.101(8) p.2365-80 (2001); Katso R.Annu Rev Cell Dev biol.17p.615-75 (2001); Toker A.et al, Cell Mol Life Sci.59(5) p.2002-79, PI3 isoforms are regulated by their respective functional subunits, their regulation of signal expression by the subunit-specific subunit, their regulation of intracellular signaling (p.110-3K, PI) and their respective subunit regulation, β, δ and γ), performing this enzyme-catalyzed reaction (vanhaes ebroeck b. expcell res.25(1) p.239-54 (1999); kasto R, et al, Annu Rev Cell Dev biol.17p.615-75 (2001)).

The evolutionarily conserved isoforms p110 α and β are ubiquitously expressed, whereas δ and γ are specifically expressed in hematopoietic cell systems, smooth muscle cells, muscle cells and endothelial cells (Vanhaaesebroeck B et al trends biochem. Sci.22(7) p.267-72 (1997). their expression can also be regulated in an inducible manner, depending on the cell-, tissue type and stimulation and disease status. currently, eight mammalian PI3K have been identified, divided into three major classes (I, II, III) PI3K, which phosphorylate Phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PIP), phosphatidylinositol-4, 5-diphosphate (PIP2), producing phosphatidylinositol-3-phosphate (PIP), respectively, Phosphatidylinositol-3, 4-bisphosphate and phosphatidylinositol-3, 4, 5-triphosphate. Class II PI3K phosphorylates PI and phosphatidylinositol-4-phosphate. Class III PI3K only phosphorylates PI (VanhaaesebroeckB et al, Exp Cell Res.25(1) p.239-54 (1999); Vanhaaesebroeck B, Trends Biochem Sci.22(7) p.267-72 (1997); Leslie NR et al, chem. Rev.101(8) p.2365-80 (2001)). G-protein coupled receptors mediate phosphoinositide 3' OH-kinase activation by small molecule gtpases such as G β γ and Ras, and therefore PI3K signaling plays a central role in establishing and coordinating cellular polarity and the dynamic organization of the cytoskeleton (which together provide the driving force for cellular motility).

Scheme 1

Inositol phosphate 3 as illustrated in scheme 1The kinase (PI3K) is involved in the phosphorylation of phosphatidylinositol (PtdIns) at the third carbon of the inositol ring. Phosphorylation of PtdIns to 3, 4, 5-triphosphate (PtdIns (3, 4, 5) P₃)、PtdIns(3，4)P₂And PtdIns (3) P, which act as second messengers for a variety of signaling pathways, including those for cell proliferation, cell differentiation, cell growth, cell volume, cell survival, apoptosis, adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeletal rearrangement, cell shape modification, vesicle transport and metabolism pathways (Katso et al, Annu RevCell Dev biol.17p.615-75 (2001); Stein RC, Mol Med Today 6(9) p.347-57 (2000)). Chemotaxis-directed movement of cells towards a gradient of chemoattractant (also known as chemokine) concentration is associated with a number of important diseases such as inflammation/autoimmunity, neurodegeneration, angiogenesis, invasion/metastasis and wound healing (Wyman NP et al, Immunol Today 21 (6)) p.260-4(2000), Hirsh et al, Science 287(5455) p.1049-53(2000), Hirsh et al, FASEB J15 (11) p.2019-21(2001), Gerard C et al, Nat Immunol.2(2) p.108-15 (2001)).

Recent advances in the use of genetic methods and pharmacological tools have provided us with an insight into signaling and molecular pathways that mediate chemotaxis of chemoattractants. Activated G-protein coupled receptor PI 3-kinase (associated with the production of these phosphorylation signal products) was originally identified as an activity associated with viral oncoprotein and growth factor receptor tyrosine kinase, which phosphorylates Phosphatidylinositol (PI) and its derivatives phosphorylated at the 3' -hydroxyl group of the inositol ring (Panayotou et al, Trends Cell biol.2p.358-60 (1992)), however, more recent biochemical studies revealed that class I PI3 kinases (such as class IB isoform PI3K γ) are dual-specific kinases, meaning that they exhibit lipid kinase (phosphorylation of phosphoinositides) and protein kinase activity, capable of phosphorylating other protein substrates, including autophosphorylation as an intramolecular regulatory mechanism.

Thus, PI 3-kinase is believed to be involved in several cellular responses including cell growth, differentiation and apoptosis (Parker et al, Current Biology, 5p.577-99 (1995); Yao et al, Science, 267p.2003-05 (1995)). PI 3-kinase appears to be involved in many aspects of leukocyte activation. It has been shown that a p 85-related PI 3-kinase activity is physically associated with the cytoplasmic domain of CD28, which is an important costimulatory molecule in the activation of T-cells in response to antigens (Pages et al, Nature, 369p.327-29 (1994); Rudd, Immunity, 4p.527-34 (1996)). Activation of T cells by CD28 lowers the threshold for activation by antigens, increasing the magnitude and duration of the proliferative response. These effects are associated with increased transcription of several genes, including interleukin-2 (IL2), an important T cell growth factor (Fraser et al, Science, 251p.313-16 (1991)). Mutation of CD28 (to allow it to interact with PI 3-kinase for longer periods of time) resulted in the inability to trigger IL2 production, suggesting a critical role for PI 3-kinase in T-cell activation. PI3K γ has been identified as a mediator of the G β γ -dependent regulation of JNK activity, whereas G β γ is a subunit of heterotrimeric G protein (j.biol.chem., 273(5) p.2505-8 (1998)). The cellular processes in which PI3K plays an essential role include inhibition of apoptosis, reorganization of the actin skeleton, cardiomyocyte growth, stimulation of glycogen synthase by insulin production, TNF α -mediated neutrophil activation and superoxide production, and leukocyte migration and adhesion to endothelial cells. Recently, it has been described in Immunity16(3) p.441-51(2002) that p.441-51(2002) PI3K transduces inflammatory signals through various g (i) -coupled receptors, which signals mast cell function, stimulation of leukocytes, central points of immunology including, for example, cytokines, chemokines, adenosine, antibodies, integrins, aggregations, growth factors, viruses or hormones (lawler MA et al, j.cell sci.114(Pt 16) p.2903-10 (2001); lafague m.et al, Immunity16(3) p.441-51 (2002); and Stephens l.et al, curr. opinion Cell biol.14(2) p.203-13 (2002)).

Specific inhibitors against individual members of the enzyme family provide invaluable tools for deciphering the function of each enzyme. Two compounds, LY294002 and wortmannin (see below), have been widely used as PI 3-kinase inhibitors. These compounds are non-specificBecause they do not distinguish between the four members of class I PI 3-kinases. For example, the IC of wortmannin for each class I PI 3-kinase₅₀Values ranged from 1-10 nM. Similarly, IC of LY294002 on these PI 3-kinases₅₀Values of about 15-20 μ M (Fruman et al, an. Rev. biochem.67, p.481-507(1998)), and inhibitory activity against CK2 protein kinase and against some phospholipases are also 5-10 μ M. Wortmannin is a fungal metabolite that irreversibly inhibits PI3K activity by covalently binding to the catalytic domain of the enzyme. Inhibition of PI3K activity by wortmannin abrogates subsequent cellular responses to extracellular factors. For example, neutrophils stimulate PI3K and synthesize PtdIns (3, 4, 5) P₃The responsive chemokine is fMet-Leu-Phe (fMLP). This synthesis is associated with the activation of ventilator rupture, which is involved in the destruction of neutrophils by invading microorganisms. Treatment of neutrophils with wortmannin prevented fMLP-induced ventilator disruption responses (Thelenet al pnas 91p.4960-64 (1994)). Indeed, these experiments with wortmannin, as well as other experimental evidence, suggest that PI3K activity in hematopoietic cell lineages, particularly in neutrophils, monocytes, and other types of leukocytes, is associated with a number of non-memory immune responses associated with acute and chronic inflammation.

Based on studies with wortmannin, there is evidence that certain aspects of leukocyte signaling through G-protein coupled receptors also require PI 3-kinase function (Thelen et al, proc.natl.acad.sci.usa, 91p.4960-64 (1994)). Furthermore, it has been shown that wortmannin and LY294002 block neutrophil migration and superoxide release. However, since these compounds do not distinguish between the individual isoforms of PI3K, it remains unclear which specific PI3K isoform or isoforms are involved in these phenomena.

Oxazolidinone-vinylbenzene derivatives having the requisite benzimidazole group are described in WO 02/051490. Such compounds are said to inhibit telomerase and are said to be useful in the treatment of cancer.

Disclosure of Invention

The invention relates to oxazolidinone-vinyl fused-benzene derivatives of formula (I)

Wherein, A, X, Y, Z, n, R¹And R²As will be described in detail below, and the use of pharmaceutically acceptable salts thereof for the preparation of a pharmaceutical composition for the treatment and/or prevention of: autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation complications, graft rejection or lung injuries. The compounds of the present invention are inhibitors of phosphoinositide 3-kinase (PI3K), particularly phosphoinositide-kinase gamma (PI3K gamma).

Detailed Description

It has been found that the compounds of the present invention are modulators of phosphoinositide 3-kinase (PI3K), in particular phosphoinositide 3-kinase gamma (PI3K gamma). When phosphoinositide 3-kinase (PI3K) is inhibited by the compounds of the invention, PI3K is unable to exert its enzymatic biological and/or pharmacological effects. The compounds of the invention are therefore useful for the treatment and prevention of autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation complications, graft rejection or lung injuries.

The following paragraphs provide definitions of the various chemical groups that make up the compounds of the present invention and are intended to be used throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

“C₁-C₆-alkyl "refers to a monovalent alkyl group having 1 to 6 carbon atoms. The term can be exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

"aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl groups include phenyl, naphthyl, phenanthryl, and the like.

“C₁-C₆-alkylaryl "refers to a C having an aryl substituent₁-C₆Alkyl groups including benzyl, phenethyl and the like.

"heteroaryl" refers to a monocyclic heteroaromatic or a bicyclic or tricyclic fused ring heteroaromatic group. Specific examples of heteroaryl groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2-a ] pyridyl, benzothiazolyl, benzoxazolyl, thienyl, etc, Quinolizinyl, quinazolinyl, 2, 3-diazanaphthyl, quinoxalinyl, cinnolinyl, 1, 5-diazanaphthyl, pyrido [3, 4-b ] pyridyl, pyrido [3, 2-b ] pyridyl, pyrido [4, 3-b ] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5, 6, 7, 8-tetrahydroquinolyl, 5, 6, 7, 8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

“C₁-C₆-Alkylheteroaryl "refers to a C having a heteroaryl substituent₁-C₆Alkyl radicals, packagesIncluding 2-furyl methyl, 2-thienyl methyl, 2- (1H-indol-3-yl) ethyl, and the like.

“C₂-C₆-alkenyl "means an alkenyl group preferably having 2 to 6 carbon atoms and having at least 1 to 2 alkenyl unsaturations. Preferred alkenyl groups include vinyl (-CH ═ CH)₂) N-2-propenyl (allyl, -CH)₂CH＝CH₂) And the like.

“C₂-C₆-alkenylaryl "means C with an aryl substituent₂-C₆Alkenyl groups including 2-phenylvinyl and the like.

“C₂-C₆-alkenylheteroaryl "means C having a heteroaryl substituent₂-C₆Alkenyl groups including 2- (3-pyridyl) vinyl and the like.

“C₂-C₆-alkynyl "means an alkynyl group preferably having 2 to 6 carbon atoms and having at least 1 to 2 alkynyl unsaturated bonds. Preferred alkynyl groups include ethynyl (-CH.ident.CH), propynyl (-CH)₂C.ident.CH) and the like.

“C₂-C₆-alkynylaryl "means C with an aryl substituent₂-C₆Alkynyl groups include phenylethynyl and the like.

“C₂-C₆-alkynylheteroaryl "refers to C with a heteroaryl substituent₂-C₆Alkynyl groups, including 2-thienylethynyl and the like.

“C₃-C₈-cycloalkyl "refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl groups include cyclopentyl, cyclohexyl, norbornyl, and the like.

"Heterocycloalkyl" means C as defined above₃-C₈Cycloalkyl in which up to 3 carbon atoms are substituted by a heteroatom selected from O, S, NR, R being defined as hydrogen or methyl. Preferred heterocycloalkyl groups include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine and the like.

“C₁-C₆-alkylcycloalkyl "denotes C with a cycloalkyl substituent₁-C₆Alkyl groups including cyclohexylmethyl, cyclopentylpropyl and the like.

“C₁-C₆-Alkylheterocycloalkyl "means a C having a heterocycloalkyl substituent₁-C₆Alkyl groups including 2- (1-pyrrolidinyl) ethyl, 4-morpholinylmethyl, (1-methyl-4-piperidinyl) methyl, and the like.

"carboxy" refers to the group-C (O) OH.

“C₁-C₆-Alkylcarboxy "means C having a carboxy substituent₁-C₆Alkyl groups including 2-carboxyethyl and the like.

"acyl" refers to the group-C (O) R, wherein R includes "C₁-C₆-alkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl ".

“C₁-C₆-Alkylacyl "means C having an acyl substituent₁-C₆Alkyl groups including 2-acetylethyl and the like.

"Arylacyl" refers to an aryl group having an acyl substituent, including 2-acetylphenyl and the like.

"heteroarylacyl" refers to heteroaryl groups having an acyl substituent, including 2-acetylpyridyl, and the like.

“C₃-C₈(hetero) cycloalkylacyl "refers to a 3-8 membered cycloalkyl or heterocycloalkyl group having an acyl substituent.

"acyloxy" refers to the group-OC (O) R, where R includes H, "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkyl radicalAryl "or" C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-Alkylacyloxy "means C having an acyloxy substituent₁-C₆Alkyl groups including 2- (acetoxy) ethyl and the like.

"alkoxy" refers to the group-O-R, where R includes "C₁-C₆-alkyl "or" aryl "or" heteroaryl "or" C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl ". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy and the like.

“C₁-C₆-Alkylalkoxy "means C with an alkoxy substituent₁-C₆Alkyl groups including 2-ethoxyethyl and the like.

"alkoxycarbonyl" refers to the group-C (O) OR, where R includes H, "C₁-C₆-alkyl ", or" aryl "or" heteroaryl "or" C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl ".

“C₁-C₆Alkylalkoxycarbonyl "refers to a C group having an alkoxycarbonyl substituent₁-C₆Alkyl groups including 2- (benzyloxycarbonyl) ethyl and the like.

"aminocarbonyl" refers to the group-C (O) NRR 'where R, R' independently includes hydrogen or C₁-C₆-alkyl or aryl or heteroaryl or "C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl ".

“C₁-C₆-alkylaminocarbonyl "meansC having aminocarbonyl substituent₁-C₆Alkyl groups including 2- (dimethylaminocarbonyl) ethyl and the like.

"acylamino" refers to the group-NRC (O) R ', wherein each R, R' is independently hydrogen, "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-Alkylacylamino "means C having an acylamino substituent₁-C₆Alkyl groups including 2- (propionylamino) ethyl and the like.

"ureido" means a radical-NRC (O) NR 'R "where R, R', R" are independently hydrogen, "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ", and wherein R' and R" together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

“C₁-C₆-Alkylureido "means a C group having a ureido substituent₁-C₆Alkyl groups including 2- (N' -methylureido) ethyl and the like.

"Carbamate" refers to the group-NRC (O) OR ', wherein R, R' is independently hydrogen, "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

"amino" refers to the group-NRR 'where R, R' is independently hydrogen or "C₁-C₆-alkyl "," aryl "," heteroaryl "or" C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl "or" cycloalkyl "or" heterocycloalkyl ", and wherein R' and R" together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

“C₁-C₆-alkylamino "means C having an amino substituent₁-C₆Alkyl groups including 2- (1-pyrrolidinyl) ethyl and the like.

"ammonium" refers to a positively charged group-N⁺RR 'R' where R, R ', R' are independently "C₁-C₆-alkyl "or" C₁-C₆-alkylaryl "or" C₁-C₆-alkylheteroaryl "or" cycloalkyl "or" heterocycloalkyl ", and R', together with the nitrogen atom to which they are attached, may optionally form a 3-8 membered heterocycloalkyl ring.

“C₁-C₆-alkylammonium "means C with an ammonium substituent₁-C₆Alkyl groups including 2- (1-pyrrolidinyl) ethyl and the like.

"halogen" means a fluorine, chlorine, bromine, iodine atom.

"Sulfonyloxy" refers to the group-OSO₂R, wherein R is selected from H and C₁-C₆-alkyl ", halogen-substituted" C₁-C₆Alkyl radicals "e.g. -OSO₂CF₃、“C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-Alkylsulfonyloxy "means C having a sulfonyloxy substituent₁-C₆Alkyl groups including 2- (methylsulfonyloxy) ethyl and the like.

"Sulfonyl" refers to the group-SO₂R, wherein R is selected from H, "aryl", "heteroaryl", "C₁-C₆-alkyl ", halogen-substituted" C₁-C₆Alkyl radicals "such as-SO₂CF₃、“C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-alkylsulfonyl "means C with a sulfonyl substituent₁-C₆Alkyl groups including 2- (methylsulfonyl) ethyl and the like.

"sulfinyl" refers to the group-S (O) R, wherein R is selected from H, "C₁-C₆-alkyl ", halogen-substituted" C₁-C₆Alkyl radicals "e.g. -SOCF₃、“C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-alkylsulfinyl "means C having a sulfinyl substituent₁-C₆Alkyl groups including 2- (methylsulfinyl) ethyl and the like.

"Thioalkyl" refers to the group-SR, where R is selected from H, "C₁-C₆-alkyl ", halogen-substituted" C₁-C₆Alkyl radicals "e.g. -SOCF₃、“C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylarylBase "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

“C₁-C₆-Alkylsulfanyl "means a C group having a sulfanyl substituent₁-C₆Alkyl groups including 2- (ethylsulfanyl) ethyl and the like.

"Sulfonylamino" refers to the group-NRSO₂R ', wherein each R, R' independently comprises H, "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-alkylsulfonylamino "means C having a sulfonylamino substituent₁-C₆Alkyl groups including 2- (ethylsulfonylamino) ethyl and the like.

"aminosulfonyl" refers to the group-SO₂NRR 'wherein each R, R' is independently selected from H, "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," C₃-C₈-cycloalkyl "," heterocycloalkyl "," aryl "," heteroaryl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₂-C₆-alkenylaryl group "," C₂-C₆-alkenylheteroaryl "," C₂-C₆-alkynylaryl "," C₂-C₆-alkynylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl ".

“C₁-C₆-alkylaminosulfonyl "refers to C having an aminosulfonyl substituent₁-C₆Alkyl groups including 2- (cyclohexylaminosulfonyl) ethyl and the like.

"substituted or unsubstituted": unless otherwise limited by the definition of each substituent, the groups described above, such as "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl", may be optionally substituted with 1 to 5 substituents selected from: "C₁-C₆-alkyl group "," C₂-C₆-alkenyl "," C₂-C₆-alkynyl "," cycloalkyl "," heterocycloalkyl "," C₁-C₆-alkylaryl group "," C₁-C₆-alkylheteroaryl "," C₁-C₆-alkylcycloalkyl "," C₁-C₆-alkylheterocycloalkyl "," amino "," ammonium "," acyl "," acyloxy "," acylamino "," aminocarbonyl "," alkoxycarbonyl "," ureido "," aryl "," carbamate "," heteroaryl "," sulfinyl "," sulfonyl "," alkoxy "," sulfanyl "," halogen "," carboxy ", trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. Alternatively, said substitution may also comprise the case where adjacent substituents undergo cyclization, in particular when adjacent functional substituents are involved, thus forming, for example, lactams, lactones, cyclic anhydrides, but also acetals, thioacetals, aldolamines formed by ring closure as, for example, protecting groups.

"pharmaceutically acceptable cationic salts or complexes" is used to define such salts: alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as calcium or magnesium), aluminum salts, ammonium salts and salts with organic amines such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, morpholine, N-Me-D-glucamine, N '-bis (phenylmethyl) -1, 2-ethylenediamine, ethanolamine, diethanolamine, ethylenediamine, N-methylmorpholine, piperidine, benztropine (N, N' -dibenzylethylenediamine), choline, ethylenediamine, meglumine (N-methylglucamine), benzphetamine (N-benzylphenethylamine), diethylamine, piperazine, tributanolamine (2-amino-2-hydroxymethyl-1, 3-propanediol), procaine and amines of the formula-NRR 'R' wherein R, R, R', R "are independently hydrogen, alkyl or benzyl. Particularly preferred salts are sodium and potassium salts.

"pharmaceutically acceptable salt or complex" refers to a salt or complex of a compound of the invention, as defined below, which retains the desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; acid addition salts with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, 4' -methylenebis (3-hydroxy-2-naphthoic acid), alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known in the art, including in particular those of the formula-NRR' R "⁺Z^-The quaternary ammonium salt shown, wherein R, R 'and R' are independently hydrogen, alkyl or benzyl, C₁-C₆Alkyl radical, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆Alkyl aryl radical, C₁-C₆-alkylheteroaryl, cycloalkyl, heterocycloalkyl, Z is a counterion, including chloride, bromide, iodide, -O-alkyl, p-toluenesulfonate, methanesulfonate, sulfonate, phosphate, or carboxylate (e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamate, mandelate, and diphenylacetate).

"pharmaceutically active derivative" refers to any compound that, when administered to a recipient, is capable of providing, directly or indirectly, the activity disclosed herein.

"enantiomeric excess" (ee) refers to the product obtained by asymmetric synthesis, i.e. synthesis involving non-racemic starting materials and/or reagents or comprising at least one enantioselective step, wherein the excess of one enantiomer is at least 52% ee.

The general formula (I) of the present invention also includes tautomers thereof, geometrical isomers thereof, optically active forms thereof such as enantiomers, diastereomers and racemic forms thereof, and pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts of the invention are acid addition salts with pharmaceutically acceptable acids such as the hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulphonate, benzenesulphonate and p-toluenesulphonate salts.

The compounds of the invention may be obtained as mixtures of E/Z isomers or as substantially pure E-or Z-isomers. The E/Z isomerism preferably refers to a vinyl group linking a phenyl group to an oxazolidinone moiety. In a particular embodiment, the compound of formula (I) is the Z-isomer.

A first aspect of the invention comprises compounds of formula (I)

And geometric isomers, enantiomers, diastereomers and racemates thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, in the preparation of medicaments for treating and/or preventing autoimmune diseases and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplant complications caused by rejection, transplant rejection or lung injury.

In a preferred embodiment, these compounds are useful for the treatment and/or prevention of autoimmune or inflammatory diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, pulmonary inflammation, thrombosis, or brain infection/inflammation (e.g., meningitis or encephalitis).

In another preferred embodiment, these compounds are useful for the treatment and/or prevention of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Huntington's disease, CNS trauma, stroke or ischemic diseases.

In a particularly preferred embodiment of the invention, these compounds are useful for the treatment and/or prophylaxis of cardiovascular diseases, such as arteriosclerosis, cardiac hypertrophy, cardiac myocyte insufficiency, elevated blood pressure or vasoconstriction.

In another particularly preferred embodiment of the invention, these compounds are useful for the treatment and/or prevention of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic diseases, ischemia-reperfusion, platelet aggregation/activation, skeletal muscle atrophy/hypertrophy, self cell aggregation in cancer tissues, angiogenesis, invasive metastasis, in particular melanoma, Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplant complications due to rejection, transplant rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial injuries in the lung or general lung airway inflammation.

The substituents in formula (I) are defined as follows:

a is an unsubstituted or substituted 5-8 membered heterocyclic group or an unsubstituted or substituted carbocyclic group.

The carbocyclic group may be fused to an unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted heterocycloalkyl.

Such heterocyclic or carbocyclic groups include aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups including phenyl, phenanthryl, cyclopentyl, cyclohexyl, norbornyl, pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-triazinyl, 1, 2, 3-triazinyl, benzofuranyl, [2, 3-dihydro ] benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, Indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo [1, 2-a ] pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, 2, 3-naphthyridinyl, quinoxalinyl, cinnolinyl, 1, 5-naphthyridinyl, pyrido [3, 4-b ] pyridyl, pyrido [3, 2-b ] pyridyl, pyrido [4, 3-b ] pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5, 6, 7, 8-tetrahydroquinolinyl, 5, 6, 7, 8-tetrahydroisoquinolinyl, purinyl, pteridinyl, carbazolyl, xanthenyl, or benzoquinolinyl.

Other examples of heterocyclic or carbocyclic groups a include unsubstituted or substituted dioxolyl, unsubstituted or substituted dioxinyl, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (dihydro) furanyl, unsubstituted or substituted (dihydro) oxazinyl, unsubstituted or substituted pyridyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted (dihydro) naphthyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted oxadiazolyl.

X is S, O, or NH, preferably S.

Y¹And Y²Each independently S, O, or-NH, preferably O.

Z is S, O, preferably O.

R¹Selected from H, CN, carboxyl, acyl, C₁-C₆Alkoxy, halogen, hydroxy, acyloxy, unsubstituted or substituted C₁-C₆-alkylcarboxy, unsubstituted or substituted C₁-C₆-an alkanoyloxy group, unsubstituted or substituted C₁-C₆Alkyl alkoxy, alkoxycarbonyl, unsubstituted or substituted C₁-C₆Alkyl alkoxycarbonyl, aminocarbonyl, unsubstituted or substituted C₁-C₆Alkylaminocarbonyl, acylamino, unsubstituted or substituted C₁-C₆Alkylacylamino, ureido, unsubstituted or substituted C₁-C₆-alkylureido, amino, unsubstituted or substituted C₁-C₆Alkylamino, ammonium, sulfonyloxy, unsubstituted or substituted C₁-C₆-alkylsulfonyloxy, sulfonyl, unsubstituted or substituted C₁-C₆-alkylsulfonyl, sulfinyl, unsubstituted or substituted C₁-C₆-alkylsulfinyl, sulfanyl, unsubstituted or substituted C₁-C₆Alkylsulfanyl, sulfonylamino, unsubstituted or substituted C₁-C₆-alkylsulfonylamino or carbamate. In a particular embodiment R¹Is H.

R²Selected from H, halogen, acyl, amino, unsubstituted or substituted C₁-C₆Alkyl, unsubstituted or substituted C₂-C₆-alkenyl, unsubstituted or substituted C₂-C₆-alkynyl, unsubstituted or substituted C₁-C₆-alkylcarboxy, unsubstituted or substituted C₁-C₆Alkanoyl, unsubstituted or substituted C₁-C₆Alkyl alkoxycarbonyl, unsubstituted or substituted C₁-C₆Alkylaminocarbonyl, unsubstituted or substituted C₁-C₆-an alkanoyloxy group, unsubstituted or substituted C₁-C₆Alkylacylamino, unsubstituted or substituted C₁-C₆-alkylureido, unsubstituted or substituted C₁-C₆Alkyl carbamates, unsubstituted or substituted C₁-C₆Alkylamino, unsubstituted or substituted C₁-C₆Alkyl alkoxy, unsubstituted or substituted C₁-C₆Alkyl sulfanyl, unsubstituted or substituted C₁-C₆-alkylsulfinyl, unsubstituted or substituted C₁-C₆-alkylsulfonyl, unsubstituted or substituted C₁-C₆-alkylsulfonylaminoaryl, unsubstituted or substituted aryl, unsubstituted or substituted C₃-C₈Cycloalkyl or heterocycloalkyl, unsubstituted or substituted C₁-C₆Alkylaryl, unsubstituted or substituted C₂-C₆Alkenylaryl, unsubstituted or substituted C₂-C₆Alkynylaryl, carboxyl, cyano, hydroxyl, C₁-C₆-alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl or sulfonyl.

n is an integer 0, 1 or 2, preferably n is 0 or 1. Most preferably n is 0.

According to a particular embodiment of the invention, R¹And R²Are all H.

In a further embodiment of the invention, X is S, Y¹And Y²Are all O, R¹And R²As defined above, n is 0.

Yet another particularly preferred aspect of the present invention relates to the use of thiazolidinedione-vinyl fused-benzene derivatives of formula (Ia), (Ib), (Ic) and (Id) for the preparation of medicaments for the treatment and/or prevention of: autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation complications, graft rejection or lung injuries:

in the formula (Ia), R¹、R²、Y¹Z and n are as defined above.

G in formula (Ia) is unsubstituted or substituted C₁-C₅Alkylene (e.g. methylene, ethylene, propylene, etc.) or unsubstituted or substituted C₁-C₅Alkenylene (e.g. methine (-CH), -CH ═ CH-yl, propenylene, etc.).

In formula (Ia), W and V are each independently selected from O, S, -NR³Wherein R is³Is H or unsubstituted or substituted C₁-C₆Alkyl, m and o are each independently 0 or 1; o is an integer of 1 to 4 and q is an integer of 0 to 4.

More preferred compounds of formula (Ia) are those wherein G is C₁-C₄Alkylene, thus giving a compound of formula (Ib) (i.e. p ═ 1, 2, 3, or 4, preferably 1 or 2).

A particular subgroup of formula (Ib) are compounds of formula (Ic) wherein W, R¹、Y¹As defined above; in particular R¹C which may be unsubstituted or substituted₁-C₄-alkyl or unsubstituted or substituted C₂-C₆Alkenyl, carboxyl, cyano, C₁-C₄Alkoxy, nitro, acylamino, ureido.

Another particular subgroup of formula (Ia) are compounds in which V, W, Y¹Are both O, thus providing the compound of formula (Id).

In a preferred embodiment of formula (Ia), (Ib) or (Id), n is 0, m is 1, p is 1 or 2, o is 0, q is 1, R is¹And R²As defined above.

In another specific embodiment of formula (Ia), (Ib) or (Id), m is 1, n is 0, p is 1 or 2, q is 0, o is 1, R¹And R²As defined above, R is more preferred¹Is a halogen or hydrogen atom.

In yet another specific embodiment of formula (Ia), (Ib) or (Id), p is 1 or 2, q is 0, m is 0, n is 1, R¹And R²As defined above.

The compounds of the invention are useful for modulating, primarily inhibiting, the activity of phosphoinositide 3-kinases (PI3K), particularly phosphoinositide 3-kinase (PI3K γ). It is therefore believed that the compounds of the invention are also particularly useful in the treatment and/or prevention of disorders mediated by PI3K, in particular PI3K γ. The treatment involves modulation, in particular inhibition or down-regulation, of phosphoinositide 3-kinase.

The following compounds are not included in formula (I):

R¹is lower alkyl or aralkyl, R²Is H or halogen, the compound TE is disclosed as an intermediate in JP 55045648,without any biological activity, JA is described in Journal of Medicinal Chemistry (1998), 41(18), 3515-3529 and is inactive in the paw swelling test.

The compounds of the invention include in particular the following:

5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (1, 3-benzodioxol-5-ylmethylene) -2-thioxo-1, 3-thiazolidin-4-one

5- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (2, 3-dihydro-1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- [ (7-methoxy-1, 3-benzodioxol-5-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- [ (9, 10-dioxo-9, 10-dihydroanthracen-2-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

(5- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

(5Z) -5- (1, 3-dihydro-2-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- [ (4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- (1, 3-benzodioxol-5-ylmethylene-2-imino-1, 3-thiazolidin-4-one

5-quinolin-6-ylmethylene-thiazolidine-2, 4-diones

5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

5- (3-methyl-benzo [ d ] isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

5- [ (4-amino-quinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- [ (4-piperidin-1-ylquinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- [ (4-morpholin-4-ylquinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- { [4- (benzylamino) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- { [4- (diethylamino) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- ({4- [ (pyridin-2-ylmethyl) amino ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({4- [ (pyridin-3-ylmethyl) amino ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

1- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] quinazolin-4-yl } piperidine-3-carboxylic acid ethyl ester

1- {6- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] quinazolin-4-yl } piperidine-4-carboxylic acid ethyl ester

1- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] quinazolin-4-yl } -L-proline tert-butyl ester

5- { [4- (4-methylpiperazin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- { [4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- ({4- [4- (4-fluorophenyl) piperidin-1-yl ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- { [4- (4-benzylpiperidin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- ({4- [4- (2-phenylethyl) piperidin-1-yl ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- { [4- (4-methylpiperidin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- { [4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

1- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) quinazolin-4-yl ] -piperidine-4-carboxylic acid

1- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) quinazolin-4-yl ] -piperidine-3-carboxylic acid

1- [6- (2, 4-dioxo-thiazolidin-5-ylmethyl) quinazolin-4-yl ] -pyrrolidine-2-carboxylic acid

5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

2-imino-5- (4-piperidinyl-quinazolin-6-ylmethylene) -thiazolidin-4-one

2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

5- (2-methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-ethyl-3H-benzimidazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- { [1- (4-phenylbutyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- [ (1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- [ (1- {2- [4- (trifluoromethyl) phenyl ] ethyl } -1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- ({1- [2- (4-hydroxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

4- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1H-benzimidazol-1-yl } cyclohexanecarboxylic acid methyl ester

5- ({1- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({1- [ (1-methyl-1H-pyrazol-4-yl) methyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({1- [2- (3, 4-Dimethoxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({1- [2- (4-phenoxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({1- [4- (trifluoromethyl) benzyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

4- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1H-benzimidazol-1-yl } cyclohexanecarboxylic acid

5- [ (1-isobutyl-1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- ({1- [2- (1, 3-benzodioxol-4-yl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({1- [2- (2-phenoxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- { [1- (3, 3-diphenylpropyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- { [1- (2-methoxybenzyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- { [1- (3-Furanylmethyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- [1- (1-propyl-1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5-quinoxalin-6-ylmethylene-thiazolidine-2, 4-dione

5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-ones

2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-ones

5-benzothiazol-6-ylmethylene-thiazolidine-2, 4-diones

5- (3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5- (2-bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-bromo-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -acrylic acid ethyl ester

3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -acrylic acid

5- [3- (3-oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene ] -thiazolidine-2, 4-dione

1- ((3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -prop-2-enoyl) proline methyl ester

1- ((3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -prop-2-enoyl) -D-proline methyl ester

(5- ({3- [ (3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl) -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- ({3- [ 3-morpholin-4-yl-3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

1- (3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -prop-2-enoyl) -L-proline methyl ester

N-cyclohexyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N-methylacrylamide

3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N-ethyl-N- (2-hydroxyethyl) acrylamide

N-cyclobutyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -acrylamide

5- ({3- [ 3-azetidin-1-yl-3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

5- ({3- [3- (1, 3-dihydro-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione

5- ({3- [ 3-azepan-1-yl-3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N-piperidin-1-ylacrylamide

3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N- (pyridin-3-ylmethyl) acrylamide

N-cyclohexyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1-benzofuran-3-yl } acrylamide

5- ({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

N-cycloheptyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } acrylamide

5- ({3- [3- (2, 5-dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione

N-cyclopentyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1-benzofuran-3-yl } acrylamide

3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -propionic acid ethyl ester

3- [5- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -benzofuran-3-yl ] -propionic acid

5- [3- (3-oxo-piperidin-1-yl-propyl) -benzofuran-5-yl ] methylene ] -thiazolidine-2, 4-dione

6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -2, 3-dihydro-benzo [1, 4] oxazine-4-carboxylic acid tert-butyl ester

5- (3, 4-2H-dihydro-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-benzoyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-acetyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

6- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzo [1, 4] oxazine-4-carboxylic acid tert-butyl ester

[6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] oxazin-4-yl ] acetic acid methyl ester N-benzyl-2- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] oxazin-4-yl ] -acetamide

5- (4-butyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (2-chloro-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-amino-benzo [ d ] isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5-benzo [1, 2, 5] thiadiazol-5-ylmethylene-thiazolidine-2, 4-diones

5-benzo [1, 2, 5] oxadiazol-5-ylmethylene-thiazolidine-2, 4-dione

5- (2-methyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

5- (3-bromo-2-fluoro-2, 3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

5- (2-fluoro-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

Another aspect of the present invention is a novel thiazolidinedione-vinyl fused-benzene derivative represented by formula (IIa).

A is selected from: unsubstituted or substituted dioxole, unsubstituted or substituted dioxin, unsubstituted or substituted dihydrofuran, unsubstituted or substituted (dihydro) furyl, unsubstituted or substituted (dihydro) oxazinyl, unsubstituted or substituted pyridyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted (dihydro) naphthyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted triazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted oxadiazolyl.

R²Selected from H, halogen, acyl, amino, unsubstituted or substituted C₁-C₆Alkyl, unsubstituted or substituted C₂-C₆-alkenyl, unsubstituted or substituted C₂-C₆Alkynyl, unsubstituted or substituted C₁-C₆-alkylcarboxy, unsubstituted or substituted C₁-C₆Alkanoyl, unsubstituted or substituted C₁-C₆Alkyl alkoxycarbonyl, unsubstituted or substituted C₁-C₆Alkylaminocarbonyl, unsubstituted or substituted C₁-C₆-an alkanoyloxy group, unsubstituted or substituted C₁-C₆Alkylacylamino, unsubstituted or substituted C₁-C₆-alkylureido, unsubstituted or substituted C₁-C₆Alkyl carbamates, unsubstituted or substituted C₁-C₆Alkylamino, unsubstituted or substituted C₁-C₆Alkyl alkoxy, unsubstituted or substituted C₁-C₆Alkyl sulfanyl, unsubstituted or substituted C₁-C₆-alkylsulfinyl, unsubstituted or substituted C₁-C₆-alkyl sulfonic acidAcyl, unsubstituted or substituted C₁-C₆-alkylsulfonylaminoaryl, unsubstituted or substituted aryl, unsubstituted or substituted C₃-C₈Cycloalkyl or heterocycloalkyl, unsubstituted or substituted C₁-C₆Alkylaryl, unsubstituted or substituted C₂-C₆Alkenylaryl, unsubstituted or substituted C₂-C₆Alkynylaryl, carboxyl, cyano, hydroxyl, C₁-C₆-alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl.

More specifically, novel thiazolidinone-vinyl fused-benzene derivatives of formula (II)

And geometric isomers thereof, optically active forms thereof as enantiomers, diastereomers and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein Y is¹、Z、R¹、R²As defined above, n is 0 or 1.

In a particular embodiment, R¹Is unsubstituted or substituted C₁-C₆Alkyl, unsubstituted or substituted C₁-C₆Alkylaryl, unsubstituted or substituted aryl, unsubstituted or substituted C₃-C₈Cycloalkyl or heterocycloalkyl, unsubstituted or substituted C₁-C₆Alkylaryl, unsubstituted or substituted C₂-C₆Alkenylaryl, unsubstituted or substituted C₂-C₆-alkynylaryl.

In another preferred embodiment of the present invention, Y is¹Is 0.

In still another aspect of the present invention are novel thiazolidinone-vinyl fused-benzene derivatives represented by formula (III)

And geometric isomers thereof, optically active forms thereof as enantiomers, diastereomers and racemic forms thereof, and pharmaceutically acceptable salts and pharmaceutically active derivatives thereof, wherein R is¹And R²As defined above (the dotted line represents the optional presence of a double bond).

Yet another embodiment comprises compounds of formulae (IV), (V), and (VI):

R¹selected from hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆Alkoxy, acyl, alkoxycarbonyl, R²As defined above. In a particular embodiment, R²Is an amino group.

Another aspect of the invention is the use of a compound of formula (II), (IIa), (III), (IV), (V) or (VI) as a medicament.

Yet another aspect of the present invention is a pharmaceutical composition comprising at least one thiazolidinone-vinyl fused-benzene derivative of formula (II), (III), (IV), (V) or (VI) and a pharmaceutically acceptable carrier, diluent or excipient therefor.

A further aspect of the invention is the use of a compound of formula (II), (III), (IV), (V) or (VI) in the manufacture of a medicament for the prevention and/or treatment of diseases mediated by PI3 kinase, in particular PI3 kinase gamma.

Specific diseases include: autoimmune and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplant complications resulting from rejection, transplant rejection or lung injuries.

In another particularly preferred embodiment of the invention, these compounds are useful for the treatment and/or prevention of chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic diseases, ischemia-reperfusion, platelet aggregation/activation, skeletal muscle atrophy/hypertrophy, leukocyte aggregation in cancer tissues, angiogenesis, invasive metastasis (especially melanoma), Kaposi's sarcoma, acute and chronic bacterial and viral infections, sepsis, transplant complications from rejection, transplant rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial injury in the lung or general lung airway inflammation.

According to the invention, the compounds of formula (II), (IIa), (III), (IV), (V) or (VI) are suitable for modulating, in particular inhibiting, PI3 kinase activity, more in particular PI3 kinase gamma activity.

Another object of the present invention is a process for the preparation of oxazolidinone-vinyl fused-benzene derivatives of formula (I), (Ia), (Ib), (Ic) or (Id) and for the preparation of thiazolidinone-vinyl fused-benzene derivatives of formula (II), (II-a), (III), (IV), (V) or (VI).

The oxazolidinone-vinyl fused-benzene derivatives exemplified in the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be recognized that while typical or preferred experimental conditions (i.e., reaction temperatures, times, moles of reagents, solvents, etc.) are given, other experimental conditions may be used unless otherwise indicated. Optimum reaction conditions will vary with the particular reagents or solvents used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

In the methods set forth in the following schemes, R¹、R²、G、V、W、Y¹、Y²Z, m, n, o, p and q are as defined in the above specification.

In general, the oxazolidinone-vinyl fused-benzene derivatives of formula (I) can be obtained by several synthetic methods using solution phase and solid phase chemistry schemes (Brummond et al, JOC, 64, 1723-one 1726(1999)) or by conventional methods or by microwave assisted techniques.

Scheme 1

Scheme 2

In the first step, approximately equimolar amounts of aldehyde reactant P1(P1a) and compound 2 (especially thiazolidinedione or rhodanine P3) are heated in the presence of a preferably weak base to produce the corresponding alkene of formula (Ia). In this first step, P1a may be replaced by precursors P1b and P1c, in order to obtain the final compounds (Ib) and (Ic), respectively, as explained above.

Particularly preferred processes of the present invention are illustrated by the following schemes 3 and 4, wherein the compounds of formula (II) and (III) can be obtained by the same reactions as described above, respectively.

Scheme 3

Scheme 4

Although this step can be carried out in the absence of a solvent at a temperature sufficiently high to at least partially melt the reaction mixture, it is preferably carried out in the presence of an inert solvent. The preferred temperature range is from about 100 ℃ to 250 ℃, particularly preferably from 120 ℃ to 200 ℃. Examples of the solvent for the above reaction include solvents such as dimethoxymethane, xylene, toluene, o-chlorobenzene and the like. Examples of suitable weak bases for the above reaction include weak acids (e.g., (C)₁-C₁₂) -alkyl carboxylic acids and benzoic acids), alkali metal and alkaline earth metal salts, alkali metal and alkaline earth metal carbonates and bicarbonates (e.g. calcium carbonate, magnesium carbonate, potassium bicarbonate) and secondary amines (e.g. piperidine, morpholine) and tertiary amines (e.g. pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-ethylpiperidine, N-methylmorpholine)Piperidine, etc.). Particularly preferred weak bases are sodium acetate or piperidine because they are economical and efficient.

In a typical such reaction (Yietze et al, "The Knoevenagel reaction", p.341 ff., Pergamon Press, Oxford 1991, eds.: Trost BM, Fleming I.), approximately equimolar amounts of The aldehyde starting material P1a and The other starting compound (e.g., thiazolidinedione) P3 and 0.5-1 equivalent of piperidine are mixed in dimethoxymethane or a similar solvent and heated at 120-. The desired alkene of the formula (Ia), if precipitated from the reaction mixture after cooling, can be isolated by filtration or, for example, can be obtained as a crude product by mixing with water and then filtration, and if desired can be purified, for example, by crystallization or standard chromatography.

Alternatively, an equimolar amount of thiazolidinedione P3 may be mixed with the aldehyde P1a and a molar excess (preferably 2-4 fold excess) of anhydrous sodium acetate, the mixture being heated at a temperature sufficiently high to melt the mixture, at which temperature the reaction is substantially complete within 5 to 60 minutes to obtain the compound of formula (Ia).

Preferably, the above reaction is carried out in an acidic medium (e.g., acetic acid) in the presence of sodium acetate or beta-alanine.

The above reaction can also be carried out under the condition of microwave as a heat source. Generally, the starting materials aldehyde P1a and thiazolidinedione P3 are mixed in approximately equimolar amounts with 0.5 to 1 equivalent of piperidine in dimethoxymethane or similar solvent and heated at 140 ℃ to 240 ℃ at which temperature the reaction is substantially complete within 3 to 10 min.

Pharmaceutically acceptable cationic salts of the compounds of the invention can be readily prepared by reacting the acid form with an appropriate base (typically 1 equivalent) in a co-solvent. Common bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium hydroxide, potassium methoxide, magnesium hydroxide, calcium hydroxide, dibenzylethylenediamine, choline, diethanolamine, ethylenediamine, meglumine, benzphetamine, diethylamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by addition of a non-solvent. In some cases, salts may be prepared by mixing a solution of the acid with a solution of the cation (sodium ethylhexanoate, magnesium oleate) using a solvent in which the desired cationic salt precipitates, or the salt may be isolated by concentration and addition of a non-solvent.

The 2, 4-oxazolidinone derivative P3 is commercially available from a variety of commercial sources. The aldehyde of formula P1a can be prepared by various known methods, for example from the corresponding alkyl carboxylate or carboxylic acid by oxidation-reduction using standard techniques to reduce the alkyl carboxylate or carboxylic acid to the benzyl alcohol using lithium aluminium hydride, diisopropylaluminium etc. and finally by mild oxidation using for example manganese dioxide, chromic acid, Dess-Martin reagent or Swern or by oxidation of the corresponding benzyl alcohol to the corresponding aldehyde under known conditions for the production of aldehydes from primary alcohols. Yet another approach is to directly reduce the corresponding alkyl or carboxylic acid carboxylate to the aldehyde using DIBAL at low temperatures or by other methods known in the art.

Scheme 5

Another method for preparing a suitable aldehyde is to selectively reduce the nitrile moiety to the corresponding aldehyde using known methods (e.g., DIBAL, etc.). Another way of obtaining the aldehyde P1a is the selective reduction of the corresponding acid chloride with, for example, lithium tri-tert-butoxyaluminum hydride (ChaJS, Brown HC, JOC 1993, 58, p.4732-34). Another method for producing suitable aldehydes is to subject the corresponding benzene derivatives to a Friedel-Crafts type reaction in which the substrate P4 shown in scheme 5 above is reacted with 1, 1-dichloromethyl methyl ether in the presence of a Lewis acid such as titanium tetrachloride or aluminum trichloride or any other Lewis acid suitable for the reaction.

According to a more preferred method of the invention, reactant P2 may be obtained by reaction with 1, 1-dichloromethyl ether as described above starting from P5, as described in the literature (Petrov OI, Kalcheva VB, Antonova AT, Collection, Czech, chem. Commun, 62, p.494-7(1997)) and in scheme 6 below.

Scheme 6

According to another more preferred process of the invention, starting from P7, the reactant P6 may be obtained by reaction with DMF in the presence of magnesium or n-butyllithium, as described in scheme 7 below, or by any other method known to the person skilled in the art.

Scheme 7

According to another more preferred method of the invention, as illustrated in scheme 8 below, starting from P9, by reacting in a suitable electrophile R¹Reaction of n-butyllithium or LDA in the presence of-X, or by other methods known to those skilled in the art, affords reactant P6. The process can be repeated with P8 to give the corresponding P6.

Scheme 8

Likewise, P9 and a suitable electrophile R may be used¹-X and R²X gives saturated precursor P6 in a one-pot reaction, as shown in scheme 9.

Scheme 9

If the general synthetic methods described above are not yet available to give compounds of formula (I) and/or intermediates required for the synthesis of compounds of formula (I), suitable preparative methods known to those skilled in the art should be used. In general, the synthetic route for each particular compound of formula (I) depends on the particular substituents per molecule and on whether the desired intermediate is readily available; these factors are well known to those skilled in the art.

For protection and deprotection methods see Philip J.Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W.Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3^rd Edition 1999。

The compounds of the invention associated with the solvent molecules can be isolated by crystallization from evaporation of a suitable solvent. Pharmaceutically acceptable acid addition salts of the compounds of the invention containing a base centre may be prepared by conventional methods. For example, a solution of the free base can be treated with a suitable acid (either neat or dissolved in a suitable solvent) and the resulting salt isolated by filtration or evaporation of the reaction solvent in vacuo. Pharmaceutically acceptable base addition salts can likewise be obtained by treating the compounds of the invention with a suitable base. The two types of salts may be formed or interconverted with ion exchange resins.

When used as a medicament, the oxazolidinedione-vinyl fused-benzene derivatives of the present invention are generally administered in the form of a pharmaceutical composition. Accordingly, pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient are also within the scope of the invention. Those skilled in the art are aware of all such carriers, diluents or excipients which are suitable for formulating pharmaceutical compositions.

The compounds of the present invention may be incorporated in the dosage form of pharmaceutical compositions and unit doses thereof, which may be in solid form (e.g., tablets or filled capsules), or in liquid form (e.g., solutions, suspensions, emulsions, elixirs, or capsules filled with these) for oral use, together with conventional adjuvants, carriers, diluents, or excipients; or a sterile injectable solution for parenteral administration (including subcutaneous administration). Such pharmaceutical compositions and unit dosage forms may contain the ingredients in conventional proportions, with or without other active ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

Pharmaceutical compositions containing the oxazolidinedione-vinyl fused-benzene derivatives of the invention may be prepared by methods well known in the pharmaceutical industry, and comprise at least one active compound. Generally, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response per patient, severity of the patient's symptoms, and the like.

The pharmaceutical compositions of the present invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Compositions for oral administration may take the form of large liquid solutions or suspensions, or large powders. More typically, however, the compositions will be presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to physically discrete units suitable for use as unitary dosages by humans or other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-metered ampoules or injections of liquid compositions, or pills, tablets, capsules and the like of solid compositions. In such compositions, the thiazolidinedione-vinyl fused-benzene derivative is typically a minor component (about 0.1 to 50% by weight or preferably about 1 to 40% by weight), the remainder being various excipients or carriers and processing aids to aid in the formation of the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles containing buffers, suspending and dispersing agents, colors, flavors, and the like. The solid form may include, for example, any of the following ingredients or compounds of similar nature: a binder (such as microcrystalline cellulose, tragacanth or gelatin), an excipient (such as starch or lactose), a disintegrant (such as alginic acid, Primogel, or corn starch), a lubricant (such as magnesium stearate), a glidant (such as colloidal silicon dioxide), a sweetening agent (such as sucrose or saccharin), or a flavoring agent (such as peppermint, methyl salicylate, or orange flavoring).

Injectable compositions are typically based on sterile injectable saline or phosphate buffered saline or other injectable carriers known in the art. As noted above, the thiazolidinedione-vinyl fused-benzene derivatives of formula (I) are generally small amounts, often in the range of 0.05 to 10% by weight, the remainder being injectable carriers and the like in such compositions.

The above ingredients for oral or injectable compositions are representative only. Further materials and processing techniques, etc. can be found in Part 5 of Remington's Pharmaceutical Sciences, 20^thEdition, 2000, Marck publishing company, Easton, Pennsylvania, incorporated herein by reference.

The compounds of the present invention may be administered in sustained release form or from a sustained release drug delivery system. A description of representative sustained release materials is also provided above in Remington's Pharmaceutical Sciences.

The present invention will be illustrated below by means of some examples, which should not be construed as limiting the scope of the invention. The following abbreviations are used in the examples: min (min), hr (h), g (g), mmol (mmol), m.p. (melting point), eq (equivalent), mL (mL), μ L (μ L), ACN (acetonitrile), Boc (tert-butyloxycarbonyl), Cbz (carboxybenzyl), CDCl (carboxybenzyl), cbl (t-butyl-c-butyl₃(deuterated chloroform), cHex (cyclohexane), dba (dibenzylideneacetone), DCM (dichloromethane) DEAD (azo)Diethyl dicarboxylate), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMAP (4-dimethylaminopyridine), DME (dimethoxyethane), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d6 (deuterated dimethyl sulfoxide), EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), EtOAc (ethyl acetate), Et₂O (diethyl ether), Fmoc (9-fluorenylmethoxycarbonyl), HOBt (1-hydroxybenzotriazole), K₂CO₃(Potassium carbonate, MgSO)₄(magnesium sulfate), MsCl (methylsulfonyl chloride), MTBE (tert-butyl methyl ether), NaH (sodium hydride), NaHCO₃(sodium bicarbonate), nBuLi (N-butyllithium), PCC (pyridinium chlorochromate), PE (petroleum ether), QCl (tetrabutylammonium chloride), rt (room temperature), TBTU (O-benzotriazolyl-N, N, N 'N' -tetramethyluronium-tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TMOF (trimethyl orthoformate), TMAD (N, N, N 'N' -tetramethylazocarboxamide), TosCl (p-toluenesulfonyl chloride).

Examples

The following compounds were synthesized according to the following method:

name of the embodiment

15- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

25- (1, 3-benzodioxol-5-ylmethylene) -2-thioxo-1, 3-thiazolidin-4-one

35- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethylene) -1, 3-thiazolidine-2, 4-dione

45- (2, 3-dihydro-1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

55- [ (7-methoxy-1, 3-benzodioxol-5-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

65- [ (9, 10-dioxo-9, 10-dihydroanthracen-2-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

7 (5- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

8 (5Z) -5- (1, 3-dihydro-2-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

95- (1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

105- [ (4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

115- (1, 3-benzodioxol-5-ylmethylene-2-imino-1, 3-thiazolidin-4-one

125-quinolin-6-ylmethylene-thiazolidine-2, 4-dione

135-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

142-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

155- (3-methyl-benzo [ d ] isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione

165- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

175- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

185- [ (4-amino-quinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

195- [ (4-piperidin-1-ylquinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

205- [ (4-morpholin-4-ylquinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

215- { [4- (benzylamino) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

225- { [4- (diethylamino) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

235- ({4- [ (pyridin-2-ylmethyl) amino ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

245- ({4- [ (pyridin-3-ylmethyl) amino ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

251- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] quinazolin-4-yl } piperidine-3-carboxylic acid ethyl ester

261- {6- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] quinazolin-4-yl } piperidine-4-carboxylic acid ethyl ester

271- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] quinazolin-4-yl } -L-proline tert-butyl ester

285- { [4- (4-methylpiperazin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

295- { [4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

305- ({4- [4- (4-fluorophenyl) piperidin-1-yl ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

315- { [4- (4-benzylpiperidin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

325- ({4- [4- (2-phenylethyl) piperidin-1-yl ] quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

335- { [4- (4-methylpiperidin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

345- { [4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

351- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) quinazolin-4-yl ] -piperidine-4-carboxylic acid

361- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) quinazolin-4-yl ] -piperidine-3-carboxylic acid

371- [6- (2, 4-dioxo-thiazolidin-5-ylmethyl) quinazolin-4-yl ] -pyrrolidine-2-carboxylic acid

385- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

395- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

402-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

412-imino-5- (4-piperidinyl-quinazolin-6-ylmethylene) -thiazolidin-4-one

422-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

435- (2-methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

445- (3-methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

455- (3-ethyl-3H-benzimidazol-5-ylmethylene) -thiazolidine-2, 4-dione

465- { [1- (4-phenylbutyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

475- [ (1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

485- [ (1- {2- [4- (trifluoromethyl) phenyl ] ethyl } -1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

495- ({1- [2- (4-hydroxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

504- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1H-benzimidazol-1-yl } cyclohexanecarboxylic acid methyl ester

515- ({1- [2- (5-methoxy-1H-indol-3-yl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

525- ({1- [ (1-methyl-1H-pyrazol-4-yl) methyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

535- ({1- [2- (3, 4-dimethoxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

545- ({1- [2- (4-phenoxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

555- ({1- [4- (trifluoromethyl) benzyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

564- {6- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1H-benzimidazol-1-yl } cyclohexanecarboxylic acid

575- [ (1-isobutyl-1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

585- ({1- [2- (1, 3-benzodioxol-4-yl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

595- ({1- [2- (2-phenoxyphenyl) ethyl ] -1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione

605- { [1- (3, 3-Diphenylpropyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

615- { [1- (2-methoxybenzyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

625- { [1- (3-furylmethyl) -1H-benzimidazol-6-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

635- [1- (1-propyl-1H-benzimidazol-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

645-quinoxalin-6-ylmethylene-thiazolidine-2, 4-dione

655-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-ones

662-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-one

675-benzothiazol-6-ylmethylene-thiazolidine-2, 4-dione

685- (3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

695- (2-bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

705- (3-bromo-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

713- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -acrylic acid ethyl ester

723- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -acrylic acid

735- [3- (3-oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene ] -thiazolidine-2, 4-dione

741- ((3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -prop-2-enoyl) proline methyl ester

751- ((3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -prop-2-enoyl) -D-proline methyl ester

76 (5- ({3- [ (3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl) -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

775- ({3- [ 3-morpholin-4-yl-3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

781- (3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -prop-2-enoyl) -L-proline methyl ester

79N-cyclohexyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N-methylacrylamide

803- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N-ethyl-N- (2-hydroxyethyl) acrylamide

81N-cyclobutyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -acrylamide

825- ({3- [ 3-azetidin-1-yl-3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

835- ({3- [3- (1, 3-dihydro-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione

845- ({3- [ 3-azepan-1-yl-3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

853- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N-piperidin-1-ylacrylamide

863- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl ] -1-benzofuran-3-yl } -N- (pyridin-3-ylmethyl) acrylamide

87N-cyclohexyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1-benzofuran-3-yl } acrylamide

885- ({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl ] methylene } -1, 3-thiazolidine-2, 4-dione

89N-cycloheptyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1-benzofuran-3-yl } acrylamide

905- ({3- [3- (2, 5-dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl ] -1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione

91N-cyclopentyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl ] -1-benzofuran-3-yl } acrylamide

923- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -propionic acid ethyl ester

933- [5- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -benzofuran-3-yl ] -propionic acid

945- [3- (3-oxo-piperidin-1-yl-propyl) -benzofuran-5-yl ] methylene ] -thiazolidine-2, 4-dione

956- (2, 4-dioxo-thiazolidin-5-ylmethyl) -2, 3-dihydro-benzo [1, 4] oxazine-4-carboxylic acid tert-butyl ester

965- (3, 4-2H-dihydro-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

975- (4-benzoyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

985- (4-acetyl-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

996- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzo [1, 4] oxazine-4-carboxylic acid tert-butyl ester

100 [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] oxazin-4-yl ] acetic acid methyl ester

101N-benzyl-2- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] oxazin-4-yl ] -acetamide

1025- (4-butyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

1035- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

1045- (2-chloro-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

1055- (3-amino-benzo [ d ] isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione

1065- (3-Phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

1075-benzo [1, 2, 5] thiadiazol-5-ylmethylene-thiazolidine-2, 4-dione

1085-benzo [1, 2, 5] oxadiazol-5-ylmethylene-thiazolidine-2, 4-dione

1095- (2-methyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

1105- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

1115- (3-bromo-2-fluoro-2, 3-dihydro-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

1125- (2-fluoro-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

The following intermediate aldehydes are commercially available: 2, 2-difluoro-1, 3-benzodioxole-5-carbaldehyde, 1, 4-benzodioxan-6-carbaldehyde, 9, 10-dioxo-9, 10-dihydro-anthracene-2-carbaldehyde, 2, 3-dihydro-benzo [ b ] furan-5-carbaldehyde, 3-methoxy-4, 5-methylenedioxybenzaldehyde.

Thiazolidinediones and rhodanine are commercially available. The intermediate aldehyde can be synthesized according to the following method.

The HPLC, NMR and MS data in the following examples were obtained as follows: HPLC: column Waters Symmetry C850x4.6mm, conditions: MeCN/H2O, 5-100% (8min), max plot 230- "400 nm"; mass spectrum: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: waters ZMD (ES);¹H NMR：Bruker DPX-300MHz。

purification was performed as follows: preparative HPLC Waters Prep LC 4000 System, equipped with columnsHR C186μm40X30mm (maximum loading 100mg) or 40X300mm (maximum loading 1 g). All purifications were done with a gradient of MeCN/water 0.09% TFA.

Intermediate 1: preparation of 5-formyl-1-benzofuran

Step I: ethyl 2-formyl-4-bromophenoxyacetate:

adding 5-bromosalicylaldehyde (50g, 0.248mol), ethyl bromoacetate (42g, 0.248mol) and K₂CO₃A mixture of (68g, 0.49mol) in dry DMF (200mL) was stirred at RT for 12 h. The reaction mixture was filtered and the filtrate was diluted with water. The mixture was extracted with ether (4 × 200mL), washed with brine, and concentrated to give crude ethyl 2-formyl-4-bromophenoxyacetate (64g, 90%) as a solid.

Step II: 4-bromo-2-formylphenoxyacetic acid:

a mixture of ethyl 2-formyl-4-bromophenoxyacetate (60g, 0.192mol), LiOH (7.5g, 0.31mol), THF (250mL) and water (100mL) was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 1.5N HCl to pH 2. The resulting solid precipitate was filtered and dried to give 4-bromo-2-formylphenoxyacetic acid (50g, 94%).

Step III: 5-bromo-1-benzofuran:

to a mixture of 2-formyl 4-bromophenoxyacetic acid (50g, 0.192mol), sodium acetate (100g, 1.21mol) in acetic acid (250mL) was added acetic anhydride (100mL) in portions over 3h at 100 ℃. The reaction mixture was refluxed for 20h, the solvent was evaporated and the residue was diluted with 3N HCl (500mL) and refluxed for 2 h. The reaction mixture was then concentrated under reduced pressure and the product was extracted with petroleum ether (3x200 mL). The organic layer was washed with 10% NaHCO₃The solution was washed and evaporated to give 5-bromo-1-benzofuran (15g, 40%) as a pale yellow liquid.

Step IV: 5-formyl-1-benzofuran (example 9, P1a in scheme 2)

A mixture of 5-bromo-1-benzofuran (0.5g, 0.038mol), Mg (0.92g, 0.038mol), iodine (1 crystal) in dry THF (2.5mL) was dissolved in N₂Reflux for 30min under atmosphere. When the iodine color disappeared, a solution of 5-bromo-1-benzofuran (4.5g) in 25mL dry THF was added immediately and refluxed for 2 h. The reaction mixture was then cooled to-40 ℃, dried DMF (3.6g) was added dropwise and slowly warmed to RT for 12 h. The reaction mixture was then cooled to 0 ℃, acidified to pH 2 with 3N HCl, stirred for 30min, then diluted with water (500mL), extracted with ethyl acetate (2 × 200mL), washed with brine and dried. Evaporating the solvent under reduced pressure, and purifying by silica gel column chromatography (petroleum ether/CH)₂Cl₂) To give 5-formyl-1-benzofuran (2g, 54%) as a liquid. LC-MS: M/Z ESI: 1.47min, 147.34(M + 1).

Intermediate 2: 4-methyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Preparation of oxazine-6-formaldehyde

Step I: 2- (N-methylamino) -phenol

1g of benzoxazole was dissolved in 20mL of THF. 0.9g of NaBH was added under nitrogen with stirring₄. The suspension was cooled to 0 ℃ and a solution of 0.86mL acetic acid in 5mL THF was slowly added maintaining the reaction temperature below 5 ℃. The reaction was stirred at 0 ℃ for 30min and at RT for a further 12 h. The reaction mixture was cooled to 0 ℃ again, and 50mL of saturated NH were carefully added₄And (4) Cl solution. The phases were separated and the aqueous layer was extracted 2 times with EtOAc. The combined organic layers were washed with brine, over MgSO₄Drying and filtering. After evaporation of the solvent 0.97g of pure 2- (N-methylamino) -phenol are obtained.

Step II: 4-methyl-4H-benzo [1, 4]]Oxazin-3-ones

1g of 2- (N-methylamino) -phenol was dissolved in chloroform, then 10mL of saturated NaHCO was added₃An aqueous solution. To this suspension is slowly added a solution of 1g of 2-chloroacetyl chloride in acetone with vigorous stirring. The reaction mixture was stirred at RT for 2 h. The layers were separated. The organic layer was washed with water and Na₂SO₄And (5) drying. After evaporation of the solvent, the red oil was collected with 30mL of DMF and 1g K was added₂CO₃The resulting slurry was heated at 70 ℃ for a further 2 h. Cyclization was performed by TLC. 200mL EtOAc was added and the organic layer was washed 3 times with 0.1N HCl, 5 times with brine, and MgSO₄Drying and filtering. Evaporation of EtOAc under reduced pressure gave 1.45g of pure 4-methyl-4H-benzo [1, 4]]Oxazin-3-ones.

Step III: 4-methyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazine-6-carbaldehyde

1g of AlCl₃Suspended in 10mL DCM and 0.5mL nitromethane was added to dissolve the AlCl₃The solution was cooled to 0 ℃. Reacting 4-methyl-4H-benzo [1, 4]]Oxazin-3-one (0.5g, 3.06mmol) was dissolved in DCM and added to the above solution and stirred at 0 deg.C for 15 min. To this solution was added 0.36mL of di-chloroSolution of methyl-methyl ether in DCM. The reaction mixture was stirred at 0 ℃ for 15min and at RT for 3 h. The crude reaction mixture was poured onto ice, the layers separated and the organic phase was washed with NaHCO₃And a brine wash. With MgSO₄Drying, filtration and evaporation of the solvent gave 0.43g of crude product. Purify the dark oil by flash chromatography using EtOAC and cyclohexane as eluent to yield 0.2g (37%) of 4-methyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazine-6-carbaldehyde as a colorless solid.

HPLC：2.07min。LC-MS：M/Z ESI：1.31min，192，28(M+1)。

Intermediate 3: 4-methyl-3, 4-dihydro-2H-benzo [1, 4]]Preparation of oxazine-7-formaldehyde

Step 1: 4-methyl-3, 4-dihydro-2H-benzo [1, 4]]Oxazines

0.97g of 2- (N-methylamino) -phenol was dissolved in 50mL of acetone, followed by the addition of 2g K₂CO₃Solution in water. To this suspension was slowly added a solution of 2.66g of dibromoethane in acetone. The reaction mixture was stirred at reflux for 22 h. The acetone was evaporated, 200mL EtOAc was added, and the organic phase was washed with 3X 0.1N HCl and 3X brine. The organic phase is MgSO₄Drying, filtering and evaporation of the EtOAc under reduced pressure gave 1g of pure 4-methyl-3, 4-dihydro-2H-benzo [1, 4] -e]Oxazines.

Step II: 4-methyl-3, 4-dihydro-2H-benzo [1 ]，4]Oxazine-7-carbaldehyde

4-methyl-3, 4-dihydro-2H-benzo [1, 4] is reacted under argon]Oxazines were dissolved in 200 μ L DMF. Under argon, POCl was added₃. The reaction mixture was heated in a sealed vial at 90 ℃ for 75 min. A1 mL solution of NaAc in water was added and stirred, whereupon a brown oil formed. The oil was extracted with DCM. For organic phaseWashed with brine, dried and evaporated to dryness to give 0.18g (76%) of 4-methyl-3, 4-dihydro-2H-benzo [1, 4]]Oxazine-7-carbaldehyde as a colorless solid.

LC-MS：M/Z ESI：1.37min，178.35(M+1)。

Intermediate 4: 1，Preparation of 3-dihydroisobenzofuran-5-carbaldehyde

Step I: (1，3-dihydro-isobenzofuran-5-yl) -methanol

A round-bottomed flask equipped with a reflux condenser was charged at room temperature with a solution of 1.0g of 3-prop-2-ynyloxy-propyne and 2.08g of propargyl alcohol in 10mL of ethanol, followed by 9.8g of tris (triphenylphosphine) rhodium chloride (Wilkinson's catalyst). The reaction solution was heated to 70 ℃ and the color of the reaction solution quickly changed to yellow. After stirring for 1 day, TLC analysis indicated complete conversion of the starting material. The solvent was evaporated, diluted with DCM, extracted with water and MgSO₄And (5) drying. The brown mixture was purified by flash chromatography using 8/2 cHex/AcOEt as the mobile phase to give (1, 3-dihydro-isobenzofuran-5-yl) -methanol as a pure colorless solid (0.92g, 60%).

Step II: 1，3-dihydroisobenzofuran-5-carbaldehyde

(1, 3-dihydro-isobenzofuran-5-yl) -methanol (440mg, 2.9mmol) was dissolved in 20mL DCM, 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-phenyliodoxy (benzidoxol) -3(1H) -one (Dess-Martin reagent) (1.3g, 3.2mmol) was added, and the reaction was stirred at r.t. for 4H. Diluting the reaction mixture with diethyl ether, extracting 2 times with 1N NaOH, 2 times with water, MgSO 2₄And (5) drying. The crude product was sufficiently pure to be used without further purification.

HPLC：2.00min。LC-MS：M/Z ESI：1.50min，149.18(M+1)。

Intermediate 5: preparation of quinoline-6-carbaldehyde

Step I: quinoline-6-Base ofMethanol

5g of methyl quinoline-6-carboxylate were dissolved in dry THF. 1M LiAlH was added at-20 ℃ under argon₄Solution in THF (2 eq.). The reaction was stirred at the same temperature for 1 h. Isopropanol was added slowly and the crude product was filtered through celite, washed with DCM and concentrated to give 3.6g (85%) of pure alcohol.

HPLC：1.10min。LC-MS M/Z ESI：0.91min，160.43(M+1)。

Step II: quinoline-6-carbaldehyde

2g of quinolin-6-ylmethanol are dissolved in DCM. 15g of MnO were added₂The reaction mixture was stirred for 5 h. The crude product was filtered through celite and washed thoroughly with DCM and concentrated to give 1.85g (93%) of pure aldehyde.

HPLC：0.8min。LC-MS ESI：1.07min，158.37(M+1)。¹H NMR(DMSO-d6)δ10.19(s，1H)，9.06(t，J＝3Hz，1H)，8.6-8.66(m，2H)，8.15(s，2H)，7.68(dd，J＝3Hz，9Hz，1H)。

The following intermediates were synthesized in the same manner using the appropriate starting materials:

intermediate 6: 3-methyl-benzo [ d ]]Preparation of isoxazole-5-carbaldehyde

HPLC：2.06min。LC-MS：M/Z ESI：1.26min，162.31(M+1)。¹H NMR(DMSO-d6)δ10.10(s，1H)，8.52(s，1H)，8.16(d，J＝12Hz，1H)，8.15(s，2H)，7.90(d，J＝9Hz，1H)，2.63(s，3H)。

Intermediate 7: preparation of 4-chloro-quinazoline-6-carboxylic acid methyl ester

Step I: 4-Nitro-isophthalic acid

A mixture of 3-methyl-4-nitrobenzoic acid (150g, 0.825mol), pyridine (1.5L) and water (1.5L) was heated to reflux. The hot reaction mixture was added KMnO in portions₄(10mol) and refluxing for 72 h. The hot reaction mixture was filtered through celite, washing with hot water. The filtrate was concentrated in vacuo and the residue was diluted with water (750mL) and acidified with concentrated HCl at 0 ℃. The resulting solid was filtered, washed with water and dried in vacuo to give 4-nitro-isophthalic acid (98g, 56%).

TLC, chloroform/methanol, 7: 3, R_f＝0.2。

Step II: 4-amino-isophthalic acid

To a solution of 4-nitro-isophthalic acid (98g, 0.457mol) in methanol (5L) was added Pd/C (20%) and hydrogenated at RT for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford 4-amino-isophthalic acid as a solid (72g, 87%). TLC, chloroform/methanol, 7: 3, R_f＝0.4。

Step III: 4-oxo-3, 4-dihydro-quinazoline-6-carboxylic acid

A mixture of 4-amino-isophthalic acid (17g, 0.093mol) and formamide (85mL) was heated at 180 ℃ for 5 h. The reaction mixture was cooled to RT and acetone was added. The resulting solid precipitate was stirred for 2h, filtered and dried to give 4-oxo-3, 4-dihydroquinazoline-6-carboxylic acid (11g, 61%).

TLC, chloroform/methanol, 8: 2, R_f＝0.25

Step IV: 4-oxo-3，4-dihydro-quinazoline-6-carboxylic acid methyl ester

To a solution of 4-oxo-3, 4-dihydroquinazoline-6-carboxylic acid (24g, 0.125mol) in dry methanol (800mL) at 5 deg.C was added thionyl chloride (37g) and refluxed at 80 deg.C for 5 h. The reaction mixture was concentrated in vacuo and the crude product was collected with ethyl acetate (250 mL). The organic phase was treated with 10% NaHCO₃Washing with water and brine, and drying. The solvent was evaporated in vacuo to give 4-oxo-3, 4-dihydro-quinazoline-6-carboxylic acid methyl ester (24g, 92%) as a solid.

TLC, chloroform/methanol, 8: 2, Rf 0.6

Step V: 4-Chloroquinazoline-6-carboxylic acid methyl ester

A mixture of methyl 4-oxo-3, 4-dihydroquinoline-6-carboxylate (12g, 0.058mol) and phosphorus oxychloride (180mL) was heated at reflux for 7 h. Excess phosphorus oxychloride was evaporated off and the crude product was dissolved in ethyl acetate (250 mL). The organic phase was treated with 10% NaHCO₃Washing with water solution, water, and brine, and drying. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to give 4-chloroquinazoline-6-carboxylic acid methyl ester as a solid (4.5g, 34%).

TLC, petroleum ether/ethyl acetate, 1: 1, R_f＝0.65

LC-MS：M/Z ESI：1.50min，223.19(M+1)。¹H NMR(DMSO-d6)δ8.66(d，J＝1.9Hz，1H)，8.39(s，1H)，8.30(dd，J＝0.6Hz，8.5Hz，1H)，7.79(d，J＝8.5Hz，1H)，3.90(s，3H)

Intermediate 8: preparation of 4-methoxy-quinazoline-6-carboxylic acid methyl ester

200mg of 4-chloroquinoline-6-carboxylic acid methyl ester in 5mL of MeOH in the presence of 1eq.DIEA, stirred at 60 ℃ for 24 h. MeOH was evaporated off, the crude product was dissolved in EtOAc and taken up with NH₄Cl washes to give a white solid, pure enough to be used in the next step.

HPLC：2.3min，LC-MS M/Z ESI：1.19min，219.17(M+1)。

The following intermediates were prepared following the synthesis of intermediate 8.

Intermediate 9: preparation of 4-methylamino-quinazoline-6-carboxylic acid methyl ester

HPLC：1.12min，LC-MS M/Z ESI：1.06min，218.31(M+1)。

Intermediate 10: preparation of 4-methoxy-quinazoline-6-carbaldehyde

This intermediate was prepared starting from methyl 4-methoxy-quinazoline-6-carboxylate following the synthesis of intermediate 5.

HPLC：1.41min，LC-MS M/Z ESI：1.24min，189.31(M+1)。

Intermediate 11: preparation of 4-methylamino-quinazoline-6-carbaldehyde

This intermediate was prepared starting from methyl 4-methylamino-quinazoline-6-carboxylate following the synthesis of intermediate 5.

HPLC：1.3min，LC-MS M/Z ESI：0.90min，188.34(M+1)。

Intermediate 12: preparation of 4-chloro-quinazoline-6-carbaldehyde

Step I: 4-chloro-quinazolin-6-ylmethanol

DIBAL-H (4.4g, 0.031mol) was added to a solution of methyl 4-chloroquinazoline-6-carboxylate (3.5g, 0.015mol) in dry THF (35mL) at-25 ℃ and stirred at-25 ℃ to RT for 2H. The reaction mixture was cooled to-10 ℃ with 10% NaHCO₃The reaction was quenched with aqueous solution (9 mL). The reaction mixture was extracted with ethyl acetate (100mL), washed with water, brine and dried. Evaporation of the solvent in vacuo gave 4-chloro-quinazolin-6-ylmethanol (2g, 66%).

TLC, chloroform/methanol, 8: 2, R_f＝0.35

Step II: 4-chloro-quinazoline-6-carbaldehyde

To a solution of 4-chloro-quinazolin-6-ylmethanol (3.5g, 0.018mol) in dry DCM (100mL) was added Dess-Martin periodinane reagent (8.4g, 0.019mol) and stirred at RT for 30 min. With 10% NaHCO₃The reaction mixture was washed with aqueous solution (75mL), water and brine and dried. The solvent was evaporated in vacuo to give 4-chloro-quinazoline-6-carbaldehyde (3g, 88%) as a pale yellow solid.

TLC, chloroform/methanol, 9: 1, R_f＝0.6

Intermediate 13: preparation of 4-phenyl-quinazoline-6-carbaldehyde

4-chloro-quinazoline-6-carbaldehyde (50mg, 0.26mmol), Pd (PPh)₃)₄(13mg, 0.01mmol), phenylboronic acid (63mg, 0.52mmol) and sodium carbonate (saturated solution, 50. mu.l) were heated in toluene at 100 ℃ for 12 h. After evaporation of the solvent, the residue was dissolved in ethyl acetate and washed 2 times with brine. The organic phase was concentrated and the crude product was purified on silica gel eluting with DCM/EtOH 95: 5 to give 50mg (82%) of the desired product in 85% purity.

HPLC：2.68min。LC-MS：M/Z ESI：1.25min，235.30(M+1)。

Intermediate 14: preparation of 4-dimethylamino-quinazoline-6-carbaldehyde

4-chloro-quinazoline-6-carbaldehyde (200mg, 1mmol) was dissolved in 10mL dioxane. To this solution was added an aqueous solution of dimethylamine (5 eq.). The mixture was stirred at r.t. for 2 h. The solvent and excess amine were evaporated under high vacuum to give 4-dimethylamino-quinazoline-6-carbaldehyde as a yellow solid which was used in the next step without further purification (190mg, 91%).

HPLC：0.91min.LC-MS：M/Z ESI：1.23min，202.33(M+1)。¹H NMR (DMSO-d6) δ 10.19(s, 1H), 8.70(s, 1H), 8.50(d, J ═ 3Hz, 1H), 8.15(dd, J ═ 3Hz, 9Hz, 1H), 7.88(d, J ═ 9Hz, 1H). The following intermediates were synthesized in a similar manner using the appropriate amine as the nucleophile.

No.	Intermediates	M/ZESI：(M+1)
No.	Intermediates	M/ZESI：(M+1)	15	4-piperidin-1-yl-quinazoline-6-carbaldehyde	242.27
16	4-amino-quinazoline-6-carbaldehyde	174.18	15	4-piperidin-1-yl-quinazoline-6-carbaldehyde	242.27
16	4-amino-quinazoline-6-carbaldehyde	174.18	17	4-benzylamino-quinazoline-6-carbaldehyde	264.30
18	4- [ (pyridin-2-ylmethyl) -amino]-quinazoline-6-carbaldehyde	265.33	17	4-benzylamino-quinazoline-6-carbaldehyde	264.30
18		265.33	19	4- [ (pyridin-3-ylmethyl) -amino group]-quinazoline-6-carbaldehyde	265.33
20	4- (4-methyl-piperazin-1-yl) -quinazoline-6-carbaldehyde	257.31	19		265.33
20	4- (4-methyl-piperazin-1-yl) -quinazoline-6-carbaldehyde	257.31	21	4-diethylamino-quinazoline-6-carbaldehyde	230.28
22	4-morpholin-4-yl-quinazoline-6-carbaldehyde	244.26	21	4-diethylamino-quinazoline-6-carbaldehyde	230.28
22	4-morpholin-4-yl-quinazoline-6-carbaldehyde	244.26	23	1- (6-formyl-quinazolin-4-yl) -piperidine-3-carboxylic acid ethyl ester	314.36
24	1- (6-formyl-quinazolin-4-yl) -pyrrolidine-2-carboxylic acid tert-butyl ester	328.39	23		314.36
24		328.39	25	1- (6-formyl-quinazolin-4-yl) -piperidine-4-carboxylic acid ethyl ester	314.36
26	4- (4-hydroxy-piperidin-1-yl) -quinazoline-6-carbaldehyde	258.30	25		314.36
26	4- (4-hydroxy-piperidin-1-yl) -quinazoline-6-carbaldehyde	258.30	27	4- (4-methyl-piperidin-1-yl) -quinazoline-6-carbaldehyde	256.32
28	4- (4-phenethyl-piperidin-1-yl) -quinazoline-6-carbaldehyde	346.42	27	4- (4-methyl-piperidin-1-yl) -quinazoline-6-carbaldehyde	256.32
28	4- (4-phenethyl-piperidin-1-yl) -quinazoline-6-carbaldehyde	346.42	29	4- (4-benzyl-piperidin-1-yl) -quinazoline-6-carbaldehyde	332.40
30	4- [4- (4-fluoro-phenyl) -piperidin-1-yl]-quinazoline-6-carbaldehyde	336.38	29	4- (4-benzyl-piperidin-1-yl) -quinazoline-6-carbaldehyde	332.40
30		336.38	31	4- (4-pyrimidin-2-yl-piperazin-1-yl) -quinazoline-6-carbaldehyde	321.36

Intermediate 32: preparation of methyl-benzotriazole-5-carboxylate

1g of methyl benzotriazole-5-carboxylate (5.64mmol) was dissolved in 20mL of DMF at 0 ℃. To this solution was added 1eq. nah (60%) at 0 ℃. The mixture was stirred at 0 ℃ for 30min, 801mg (1eq.) of methyl iodide were slowly added and the resulting mixture was stirred at rt for 2 h. EtOAc was added and the organic layer was washed well with brine and water, MgSO₄Drying and filtration afforded 1g of crude methyl-benzotriazole-5-carboxylic acid methyl ester as three different regioisomers, which was separated on silica gel with EtOAc/CH 3: 7 as eluent.

Intermediate 32 a: preparation of methyl 2-methyl-2H-benzotriazole-5-carboxylate

The first eluting component was methyl 2-methyl-2H-benzotriazole-5-carboxylate (250mg, 22%).

HPLC：2.32min。¹H NMR(DMSO-d6)δ8.56(s，1H)，8.02(d，J＝9Hz，1H)，7.93(d，J＝9Hz，1H)，4.55(s，3H)，3.90(s，1H)。

Intermediate 32 b: preparation of methyl 3-methyl-3H-benzotriazole-5-carboxylate

The second eluted fraction was methyl 3-methyl-3H-benzotriazole-5-carboxylate (130mg, 12%).

HPLC：2.03min。¹H NMR(DMSO-d6)δ8.56(s，1H)，8.13(d，J＝6Hz，1H)，7.93(d，J＝9Hz，1H)，4.39(s，3H)，3.92(s，3H)。

Intermediate 32 c: preparation of methyl 1-methyl-1H-benzotriazole-5-carboxylate

The third eluted fraction was methyl 1-methyl-3H-benzotriazole-5-carboxylate (135mg, 12%).

HPLC：2.03min。¹H NMR(DMSO-d6)δ8.62(s，1H)，8.11(d，J＝9Hz，1H)，7.97(d，J＝9Hz，1H)，4.35(s，3H)，3.90(s，3H)。

Intermediate 33: 2-methyl-2H-benzotriazole-5-carbaldehyde

This intermediate was synthesized following the procedure for intermediate 5 starting from methyl 2-methyl-2H-benzotriazole-5-carboxylate (intermediate 32 a).

HPLC：1.88min。¹H NMR(DMSO-d6)δ10.12(s，1H)，8.65(s，1H)，8.06(d，J＝9Hz，1H)，7.85(d，J＝9Hz，1H)，4.57(s，3H)。

Intermediate 34: 3-methyl-3H-benzotriazole-5-carbaldehyde

This intermediate was synthesized following the procedure for intermediate 5, starting from methyl 3-methyl-3H-benzotriazole-5-carboxylate (intermediate 32 b).

HPLC：1.49min。¹H NMR(DMSO-d6)δ10.18(s，1H)，8.54(s，1H)，8.20(d，J＝9Hz，1H)，7.88(d，J＝9Hz，1H)，4.41(s，3H)。

Intermediate 35: 1-methyl-1H-benzotriazole-5-carbaldehyde

This intermediate was synthesized following the procedure for intermediate 5 starting from methyl 1-methyl-1H-benzotriazole-5-carboxylate (intermediate 32 c).

HPLC：1.49min。LC-MS：M/Z ESI：1.07min，162.32(M+1)。¹H NMR(DMSO-d6)δ10.13(s，1H)，8.70(s，1H)，8.05(s，2H)，4.36(s，3H)。

Intermediate 36: 5- (4-amino-3-ethylamino-benzylidene) -thiazolidine-2, 4-dione

Step I: 3-fluoro-4-nitrobenzyl alcohol (bioorg. Med. chem.7, 1999, 2647)

Ice-cooled NaBH is added within 30min₄(204mg, 5.4mmol) in THF (10mL) was added dropwise a solution of 3-fluoro-4-nitrobenzoic acid (500mg, 2.7mmol, 1eq.) in THF (10 mL). Then BF is added dropwise within 30min₃-Et₂O (7.3mmol, 2.7 eq.). The solution was stirred at rt overnight. Dropwise addition of 1N HCl to decompose excess NaBH₄. The solvent was evaporated in vacuo and the residue was dissolved in DCM, washed with water, brine and the organic layer was MgSO₄Drying and evaporation of the solvent in vacuo gave 425mg of 3-fluoro-4-nitrobenzyl alcohol (92% yield). Used in the next step without further purification.

¹H NMRδ＝(400MHz，CDCl₃)：7.97(m，1H)，7.28(m，1H)，7.18(m，1H)，4.75(m，2H)。

Step II: 3-fluoro-4-nitrobenzylaldehyde

3-fluoro-4-nitrobenzyl alcohol (116mg, 0.68mmol, 1eq.) was dissolved in DCM (10mL) with MnO₂(580mg, 6.73mmol, 10eq.) and the suspension stirred at rt overnight. Filtering out MnO with diatomaceous earth₂The solvent was evaporated to give the corresponding aldehyde as a white solid (66% yield).

¹H NMRδ＝(400MHz，CDCl₃)：9.98(s，1H，CHO)，8.08(m，1H，ArH)，7.78(m，2H，ArH)。

Step III: 5- (3-fluoro-4-nitro-benzylidene) -thiazolidine-2, 4-dione (J.Med.chem.37, 2, 1994, 322)

A mixture of 3-fluoro-4-nitrobenzaldehyde (280mg, 1.65mmol, 1eq.) thiazolidinedione (193mg, 1.65mmol, 1eq.) and beta-alanine (95mg, 1.1mmol, 0.65eq.) in acetic acid (5mL) was stirred at 100 ℃ overnight. The cooled reaction mixture was added to water and stirred for 1 h. The precipitated product was filtered, washed with water and dried to give the final product as a yellow/orange solid (77% yield).

¹H NMRδ＝(400MHz，(CD₃)₂CO)：8.0(m，1H，ArH)，7.68(m，2H，ArH)，7.53(s，1H，CH＝C)。

Step IV: 5- (3-ethylamino-4-nitro-benzylidene) -thiazolidine-2, 4-dione.

5- (3-fluoro-4-nitro-benzylidene) -thiazolidine-2, 4-dione (200mg, 0.75mmol, 1eq.) was dissolved in DME (6mL) and TEA (208. mu.L, 1.5mmol, 2eq.) and a solution of ethylamine (2eq.) was added. The reaction mixture was shaken overnight at 60 ℃. The solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate, washed with 10% aqueous ammonium chloride and the organic layer was washed with Na₂SO₄Drying and evaporation of the solvent gave the corresponding aniline derivative as a red oil. It was used in the next step without further purification.

Step V: 5- (3-ethylamino-4-amino-benzylidene) -thiazolidine-2, 4-dione

To a stirring solution of 5- (3-ethylamino-4-nitro-benzylidene) -thiazolidine-2, 4-dione in THF was slowly added an aqueous solution of sodium bisulfite (3eq.) followed by K₂CO₃An aqueous solution. The reaction mixture was refluxed overnight. THF was evaporated in vacuo and the residue was extracted with ethyl acetate. Na for organic layer₂SO₄Drying and evaporating the solvent to obtain the corresponding aniline derivative, which can be used without further purification.

The following intermediates were synthesized as shown in intermediate 36, step IV, using the appropriate amine as the nucleophile. The resulting 3-alkylamino-4-nitro-benzylidene) -thiazolidine-2, 4-dione is reduced as shown in intermediate 36, step V, to give 3-alkylamino-4-amino-benzylidene) -thiazolidine-2, 4-dione.

No.	Intermediates	M/Z ESI：(M+1)
No.	Intermediates	M/Z ESI：(M+1)	37	5- [ 4-amino-3- (4-phenyl-butylamino) -benzylidene]Thiazolidine-2, 4-diones	368.2
38	5- { 4-amino-3- [2- (4-trifluoromethyl-phenyl) -ethylamino]-benzylidene } -thiazolidine-2, 4-diones	408.12	37		368.2
38		408.12	39	5- { 4-amino-3- [2- (4-hydroxy-phenyl) -ethylamino]-benzylidene } -	356.13
	Thiazolidine-2, 4-dione		39		356.13

No.	Intermediates	M/Z ESI：(M+1)
No.	Intermediates	M/Z ESI：(M+1)	40	4- [ 2-amino-5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -phenylamino]Cyclohexanecarboxylic acid methyl ester	376.35
41	5- { 4-amino-3- [2- (1H-indol-3-yl) -ethylamino]Benzylidene thiazolidine-2, 4-diones	409.21	40		376.35
41		409.21	42	5- { 4-amino-3- [ (1-methyl-1H-pyrazol-4-ylmethyl) -amino]Benzylidene thiazolidine-2, 4-diones	331.1
43	5- { 4-amino-3- [2- (3, 4-dimethoxy-phenyl) -ethylamino ] -ethyl]Benzylidene thiazolidine-2, 4-diones	400.21	42		331.1
43		400.21	44	5- [ 4-amino-3- (4-trifluoromethyl-benzylamino) benzylidene]Thiazolidine-2, 4-dione	394.15
45	4- [ 2-amino-5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -phenylamino]Cyclohexanecarboxylic acids	362.17	44		394.15
45		362.17	46	5- (4-amino-3-isobutylamino-benzylidene) -thiazolidine-2, 4-dione	292.22
47	5- [ 4-amino-3- (2-benzo [1, 3]]Dioxol-4-yl-ethylamino) benzylidene]Thiazolidine-2, 4-dione	384.26	46		292.22
47		384.26	48	5- { 4-amino-3- [2- (2-phenoxy-phenyl) -ethylamino]Benzylidene thiazolidine-2, 4-diones	432.28
49	5- [ 4-amino-3- (3, 3-diphenyl-propylamino) benzylidene]Thiazolidine-2, 4-dione	430.27	48		432.28
49		430.27	50	5- (4-amino-3-prop-2-ynylamino) benzylidene]Thiazolidine-2, 4-dione	274.21
51	5- [ 4-amino-3- (2-methoxy-benzylamino) benzylidene]Thiazolidine-2, 4-dione	356.23	50		274.21
51		356.23	52	5- { 4-amino-3- [ (furan-3-ylmethyl) -amino group]Benzylidene thiazolidine-2, 4-diones	316.21

No.	Intermediates	M/Z ESI：(M+1)
No.	Intermediates	M/Z ESI：(M+1)	53	5- (4-amino-3-propylamino-benzylidene) -thiazolidine-2, 4-dione	278.16
54	5- { 4-amino-3- [2- (4-phenoxy-phenyl) -ethylamino]Benzylidene thiazolidine-2, 4-diones	432.23	53		278.16

Intermediate 55: quinoxaline-6-carbaldehyde

Step I: quinoxaline-6-carbonylChlorine

In a 1L three-necked flask, a solution of quinoxaline-6-carboxylic acid (20.2g) in 500mL of THF was placed. To this solution was slowly added thionyl chloride (42mL, 5 eq.). The reaction mixture was mechanically stirred and heated to reflux, then quenched by HPLC with NH₄The OH stops the reaction. After refluxing for 3h, starting material had not been present, the solvent was removed under reduced pressure and SOCl was driven off with toluene₂3 times. The solid was suspended in 100mL EtOAc and filtered to give 23.47g of a beige solid.

HPLC：1.114min。¹H NMR(DMSO-d6)δ9.01-7.40(m，5H)。

Step I: quinoxaline-6-carbaldehyde

A solution of quinoxaline-6-carbonyl chloride in 600mL DME was placed in a 1L three-necked flask under argon. Lithium tri-tert-butoxyaluminum hydride (1eq.) was added to the solution over 1.5h at-78 ℃. The reaction was maintained at this temperature for 5 h. Ice was added and the reaction was diluted with AcOEt and filtered through celite. The two layers were separated and the organic layer was saturated NaHCO₃Washing and evaporation of the solvent gave quinoxaline-6-carbaldehyde (73% yield) as a yellow solid.

HPLC：1.49min。LC-MS M/Z ESI：0.81min.159.37(M+1)。¹H NMR(CDCl3)δ10.28(s，1H)，8.97(s，2H)，8.61(s，1H)，8.27(q，6Hz，9Hz，2H)。

Intermediate 56: benzothiazole-6-carbaldehyde

This intermediate was synthesized starting from benzothiazole-6-carboxylic acid using the synthesis procedure for intermediate 55.

HPLC：1.92min。LC-MS M/Z ESI：0.97min.164.27(M+1)。¹H NMR(CDCl3)δ10.1(s，1H)，9.60(s，1H)，8.60(s，1H)，8.20(m，1H)，8.10(d，1H)。

Intermediate 57: 3-methyl-benzofuran-5-carbaldehyde

This intermediate was obtained by the same route as intermediate 1 using ethyl 2-acetyl-4-bromophenoxyacetate as starting material.

LC-MS M/Z ESI：1.55min.161.34(M+1)。¹H NMR(DMSO-d6)δ10.1(s，1H)，8.21(d，J＝1.5Hz，1H)，7.92(d，J＝1.3Hz，1H)，7.88-7.84(dd，J＝1.6Hz，1H)，7.73-7.71(d，J＝8.5，1H)，2.25(s，3H)。

Intermediate 58: 3-bromo-benzofuran-5-carbaldehyde

Step I: 2, 3-dibromo-2, 3-dihydrobenzofuran-5-carbaldehyde

Intermediate 1(2g, 13.7mmol) was dissolved in 10mL CHCl₃In (1), cooling to-10 ℃. To this solution was added bromine in CHCl₃Solution (1.55eq., c: 4.162 mol/L). The reaction mixture turned dark and reached rt within 1 h. HPLC showed complete addition of bromine. The solvent and remaining bromine were removed under reduced pressure to give a reddish oil (4.1g, 90%) which was used in the next step without further purification.

HPLC：3.43min。

Step II: 3-bromo-1-benzofuran-5-carbaldehyde

To a solution of 2, 3-dibromo-2, 3-dihydro-1-benzofuran-5-carbaldehyde (4.1g) in dry ethanol (15mL) was added a solution of KOH (2.2eq.) in dry ethanol (14mL), and the mixture was refluxed at 70 ℃ for 1 hour. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3 × 50 mL). The organic layer was washed with water, brine, dried, the solvent removed in vacuo, and the residue purified by flash chromatography (petroleum ether/EtOAc 99.5: 0.5) to give the title compound as a light yellow solid (2.91g, (80% purity), 78% yield).

HPLC：3.35min。¹H NMR(DMSO-d6)δ10.12(s，1H)，8.47(s，1H)，8.14(d，J＝1.5Hz，1H)，7.97(dd，J＝8.6，1.5Hz，1H)，7.87(d，J＝8.6，1H)。

Intermediate 59: 3-Phenylethynyl-benzofuran-5-carbaldehyde

In a dry flask 3-bromo-1-benzofuran-5-carbaldehyde (16, 4.4mmol) was dissolved in anhydrous THF (50 mL). To the solution was added bis (triphenylphosphine) palladium (II) chloride (160mg, 0.2mmol), TEA (2.81mL, 5eq.) CuI (40mg, 0.2mmol) and phenylacetylene (897mg, 8.8mmol) under argon. The reaction solution was heated at 55 ℃ for 2 days. The crude product was filtered through celite and purified on silica gel eluting with cyclohexane-ethyl acetate (7-3) to give 680mg (56% yield).

HPLC：4.71min。¹H NMR(DMSO-d6)δ10.14(s，1H)，8.64(s，1H)，8.38(s，1H)，7.97(dd，J＝1.5Hz，8.3Hz，，1H)，7.90(d，J＝8.6，1H)，7.65(m，2H)，7.46(m，3H)。

Intermediate 60: 3- (5-formyl-benzofuran-3-yl) -acrylic acid ethyl ester

In a sealed tube, 3-bromo-1-benzofuran-5-carbaldehyde (500mg, 2.22mmol) was dissolved in 7mL of ACN. To this solution PPh was added₃(1.16g, 4.44mmol), palladium (II) acetate (500mg, 2.2mmol), Et₃N (0.73mL, 5.55mmol) and finally ethyl acrylate (2.41mL, 22mmol) were added. The reaction tube was sealed and heated at 120 ℃ for 1 h. The crude product was filtered over celite to remove inorganic impurities, the solvent evaporated and the crude product chromatographed on silica gel eluting with cyclohexane-AcOEt 95-5 to 50-50 to give a pale yellow solid (400mg, 42% yield).

HPLC：3.69min。¹H NMR(DMSO-d6)δ10.15(s，1H)，8.70(s，2H)，7.97(d，J＝9Hz，1H)，7.88(s，1H)，7.82(s，1H)，6.76(d，J＝15Hz，1H)，4.23(q，J＝6Hz，12Hz，2H)，1.28(t，J＝9Hz，3H)。

Intermediate 61: 2, 3-dihydro-benzo [1, 4]]Oxazine-4, 6-dicarboxylic acid 4-tert-butyl 6-methyl ester

Step I: 3-amino-4-hydroxy-benzoic acid methyl ester

To a 2000mL three-necked flask containing methyl 3-nitro-4-hydroxybenzoate (43g, 218mmol) and MeOH (860mL, 20 vol) was added a palladium/carbohydrate suspension (2g in 10mL water). Ammonium formate (68.76g, 5eq.) was added once with stirring. After 2-3min a precipitate was observed and the temperature was increased from 20 ℃ to 30 ℃. The reaction mixture was cooled to 20 ℃ with an ice bath and stirred at this temperature for 40min until the reaction was complete (no longer yellow). The reaction mixture was filtered on a silica gel plug, washed with MeOH, and the filtrate was concentrated in vacuo to give a green oil, which was dissolved in ethyl acetate (400 mL). The organic phase was washed 2 times with water and MgSO₄Drying, filtration and concentration gave 31.35g (86%) of a creamy solid.

LC-MS：M/Z ESI：0.81min，168.37(M+1)。

Step II: 3，4-dihydro-2H-benzo [1 ]，4]Oxazine-6-carboxylic acid methyl ester hydrochloride

In N₂Next, to a 2000mL three-necked flask containing methyl 3-amino-4-hydroxy-benzoate (31.35g, 187mmol) and anhydrous DMF (630mL, 20 volumes) was added K at RT in one portion₂CO₃(103g, 4eq.) followed by the addition of 1, 2-dibromoethane (65mL, 4eq.) in one portion. The reaction mixture was stirred at 70 ℃ for 12 h. The temperature was cooled to RT, 1N HCl was added to pH 8 and extracted with ether (3 × 200 mL). The organic phase was washed with water (2x200mL), MgSO₄Drying and concentration gave a solid as a brown-red oil, which was dissolved in ether (450mL) and THF (50mL) and filtered to remove the white solid. To the filtrate was added 1N HCl, diethyl ether (130mL) was added, the suspension was stirred at RT for 5min and filtered to give 27.6g of crude product. The aqueous phase was extracted with additional ethyl acetate to give an additional 6.23g of product. The combined fractions (32g) were recrystallized from EtOH (420mL, 13 vol), filtered and dried to give a white powder (19.47g (16.37g free base)) in 40% yield.

HPLC：1.954min。LC-MS ESI：1.27min，194.45(M+1)。

Step III: 2, 3-dihydro-benzo [1, 4]]Oxazine-4, 6-dicarboxylic acid 4-tert-butyl 6-methyl ester

In N₂To one side of a catalyst containing 3, 4-dihydro-2H-benzo [1, 4]]Oxazine-6-carboxylic acid methyl ester hydrochloride THF (145mL, 10 volumes) suspension in a 500mL three-necked flask DIEA (27mL, 2.5eq.) was added at RT in one portion and partial dissolution was observed. Boc anhydride (16.4g, 1.2eq.) was added in one portion and the reaction was stirred for 5 days at 65 ℃. During this period 0.2eq.Boc was added in small portions₂O and DIEA. THF was removed in vacuo and the residue was dissolved in 150mL of DCM. The organic phase was saturated NaHCO₃And then washed with brine solution. MgSO (MgSO)₄After drying, filtration, volatiles were removed in vacuo and the residue was recrystallized from EtOH (80mL) to give cream crystals (14.8g, 76%).

HPLC：4.038min。¹H NMR(CDCl3)δ8.49(s，1H)，7.68(dd，J＝3Hz，9Hz，1H)，6.89(d，J＝9Hz，1H)，4.30(q，J＝3Hz，9Hz，2H)，3.89(m，5H)，1.62(s，9H)。

Intermediate 62: 6-formyl-2, 3-dihydrobenzo [1, 4]]Oxazine-4-carboxylic acid tert-butyl ester

This intermediate was obtained by oxidation-reduction according to the procedure described for intermediate 5.

HPLC：3.727min。LC-MS ESI：1.81min，264.34(M+1)。¹H NMR(DMSO-d6)δ9.83(s，1H)，8.35(s，1H)，7.53(d，J＝6Hz，1H)，7.05(d，J＝9Hz，1H)，4.31(t，J＝3Hz，，2H)，3.83(t，J＝6Hz，2H)，1.50(s，9H)。

Intermediate 63: 6-formyl-benzo [1, 4]]Oxazole (oxazole) (I)Oxazine-4-carboxylic acid tert-butyl ester

Step I: 2, 3-dibromo-2, 3-dihydro-benzo [1, 4]]Oxazine-4, 6-dicarboxylic acid 4-tert-butyl 6-methyl ester

To a solution of 4-tert-butyl 6-methyl 2, 3-dihydro-benzo [1, 4] oxazine-4, 6-dicarboxylate (500mg, 1.7mmol) in dry carbon tetrachloride (20mL) was added N-bromosuccinimide (667mg, 3.75mmol) and a catalytic amount of benzoyl peroxide. The resulting mixture was stirred and heated to reflux with a bulb (100W) for 45 min. The mixture was cooled and the succinimide filtered off. The filtrate was evaporated to give an oil (767mg, 99%) which was sufficiently pure for the next step.

HPLC：3.978min。

Step II: benzo [1, 4] s]Oxazine-4, 6-dicarboxylic acid 4-tert-butyl 6-methyl ester

The 4-tert-butyl 6-methyl 2, 3-dibromo-2, 3-dihydro-benzo [1, 4] oxazine-4, 6-dicarboxylate (767mg, 1.7mmol) obtained in the previous step was stirred in acetone (14mL) with NaI (1.27g, 8.5mmol) at RT for 2 h. The solvent was removed and EtOAc, water and 1M sodium thiosulfate were added. After separation of the two phases, the organic phase was washed with brine. The solvent was evaporated and the crude product was purified on silica gel, eluting with CH/EtOAc 7: 3 to give a colorless oil (456mg, 92%).

HPLC：4.386min。

Step III: 6-hydroxymethyl-benzo [1, 4]]Oxazine-4-carboxylic acid tert-butyl ester

Step IV: 6-formyl-benzo [1, 4]]Oxazine-4-carboxylic acid tert-butyl ester

Steps III and IV were carried out according to the intermediate 5 synthesis method.

HPLC：3.388min。

Intermediate 64: (6-formyl-3-oxo-2, 3-dihydro-benzo [1, 4]]Oxazin-4-yl) acetic acid methyl ester

Step I: 3-amino-4-hydroxybenzoic acid methyl ester

To a solution of 3-amino-4-hydroxybenzoic acid (100g, 0.65mmol) in methanol (1.5L) was added dropwise thionyl chloride (233g, 1.96mmol) with stirring at 5-10 ℃ and then refluxed at 65 ℃ for 16 h. The excess thionyl chloride and methanol were distilled and the crude product was dissolved in ethyl acetate (500 mL). The organic phase was washed with 5% NaHCO₃Washing with water solution, water and saline water,and (5) drying. The solvent was removed in vacuo to give methyl 3-amino-4-hydroxybenzoate (105g, 95%).

Step II: methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxylic acid methyl ester

To a mixture of methyl 3-amino-4-hydroxybenzoate (105g, 0.62mol) and benzyltriethylammonium chloride (142g, 0.62mol) in dry CHCl was added with stirring₃(1.5L) to the mixture NaHCO was added₃(211g, 2.5 mol). The reaction mixture was cooled to-5 ℃ and chloroacetyl chloride (85g, 0.75mol) was added to dry CHCl at the same temperature over 1.5h₃(350 mL). The reaction mixture was then heated to 55 ℃ for 16 h. The solvent was evaporated in vacuo, water (3L) was added and the solid filtered. The solid product was dried and recrystallized from ethanol to give methyl 3-oxo-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxylate (108g, 83%).

Step III: 6- (hydroxymethyl) -2H-1, 4-benzoxazin-3 (4H) -one

Methyl 3-oxo-3, 4-dihydro-2H-1, 4-benzoxazine-6-carboxylate (30g, 0.145mol) in dry CH₂Cl₂(500mL) the solution was cooled to-78 deg.C and DIBAL-H (51g, 0.36mol) was added over 45min and then stirred at the same temperature for 14H. The reaction was quenched with 1.5N HCl and the solid product was filtered and dried in vacuo to give 6- (hydroxymethyl) -2H-1, 4-benzoxazin-3 (4H) -one (18g, 69%).

Step IV: TBDMS-6- (hydroxymethyl) -2H-1, 4-benzoxazine-3 (4H) -one

To a solution of 6- (hydroxymethyl) -2H-1, 4-benzoxazin-3 (4H) -one (18g, 0.10mol) in dry DMF (250mL) was added imidazole (13.7g, 0.2mol) and stirred at 0 ℃ for 30 min. TBDMSiCl (23g, 0.15mol) was added portionwise to the above mixture and stirred at RT for 4 h. The reaction mixture was diluted with water and the resulting solid was filtered and dried in vacuo to give TBDMS-6- (hydroxymethyl) -2H-1, 4-benzoxazin-3 (4H) -one (24.5g, 83%).

Step V: [6- (hydroxymethyl) -3-oxo-2, 3-dihydro-4H-1, 4-benzoxazin-4-yl]Acetic acid methyl ester

To a suspension of NaH (0.3g, 0.01mol) in dry DMF (15mL) was added TBDMS-6- (hydroxymethyl) -2H-1, 4-benzoxazin-3 (4H) -one (2g, 0.0068mol) with stirring at 0 deg.C and the RT was stirred for 2H. The reaction mixture was cooled to 0 ℃ and methyl chloroacetate (1g, 0.0088mol) was added and stirred at RT for 12 h. The reaction mixture was cooled again to 0 ℃ and 50mL of 1.5N HCl solution were added and stirred at RT for 12 h. The reaction mixture was diluted with water (200mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with 10% NaHCO₃Washing with aqueous solution, brine, drying, evaporating the solvent in vacuo, and purifying the crude product by silica gel column chromatography (CHCl)₃Methanol, 99.5: 0.5) to give [6- (hydroxymethyl) -3-oxo-2, 3-dihydro-4H-1, 4-benzoxazin-4-yl]Methyl acetate (1.2g, 70%).

Step VI: [6- (formyl) -3-oxo-2, 3-dihydro-4H-1, 4-benzoxazin-4-yl]Acetic acid methyl ester

PCC (4.2g, 0.019mol) and diatomaceous earth (4g) in dry CH₂Cl₂(100mL) the mixture was cooled to 0 ℃ under N₂Slowly adding [6- (hydroxymethyl) -3-oxo-2, 3-dihydro-4H-1, 4-benzoxazine-4-yl in the air]Methyl acetate (1.2g, 0.0048mol) in CH₂Cl₂(30 mL). The reaction mixture was stirred at RT for 2h, passed through celite, with CH₂Cl₂Washing (50mL) and concentration gave the crude product, which was purified on silica gel to give 1.05g (87%).

LC-MS ESI：1.15min.250.41(M+1)。¹H NMR(DMSO-d6)δ9.88(s，1H)，7.65-7.60(m，2H)，7.24(d，J＝8.1Hz，1H)，4.85(d，J＝9.9Hz，，4H)，3.71(s，3H)。

Intermediate 65: 4-butyl-3-oxo-3，4-dihydro-2H-benzo [1 ]，4]Oxazine-6-carbaldehyde

The intermediate was synthesized according to the synthesis method of intermediate 2. The total yield is 33%.

LC-MS ESI：1.60min，234.35(M+1)。¹H NMR(DMSO-d6)δ7.66(d，J＝0.7Hz，1H)，7.58(dd，J＝1.7Hz，8.1Hz，1H)，7.18(d，J＝8.2Hz，，1H)，4.77(s，2H)，3.96(t，J＝7.3Hz，1H)，1.671-1.512(m，3H)，1.97-1.27(m，3H)，0.91(t，J＝7.3Hz，3H)。

Intermediate 66: 4-benzyl-3-oxo-3，4-dihydro-2H-benzo [1 ]，4]Oxazine-6-carbaldehyde

The intermediate was synthesized according to the synthesis method of intermediate 2. The total yield is 29%.

¹H NMR(DMSO-d6)δ9.78(s，1H)，7.58(dd，J＝1.5Hz，7.9Hz，1H)，7.47(d，J＝1.9Hz，1H)，7.40-7.18(m，6H)，5.22(s，2H)，4.95(s，2H)，3.3(d，J＝7.2Hz，1H)。

Intermediate 67: 2-chloro-5- [1, 3] dioxan-2-yl-benzofurans

Step I: 5- [1,3]Dioxane-2-yl-benzofurans

A mixture of benzofuran-5-carbaldehyde (150mg, 1.03mmol), ethylene glycol (230 μ l, 4eq.), trimethyl orthoformate (123 μ l, 1.1eq.), and tetrabutylammonium tribromide (49mg, 0.1eq.) was stirred at RT overnight. By TSome starting material could be detected by LC. However, the reaction mixture was poured into saturated NaHCO₃In solution, the product was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. Purification by flash chromatography eluting with cyclohexane/ethyl acetate 20: 0.75 gave the title compound in 36% yield (70 mg).

(pp79-99)

LC-MS：M/Z ESI：1.51min，191.30(M+1)。

Step II: 2-chloro-5- [1, 3]Dioxane-2-yl-benzofurans

Mixing 5- [1, 3%]Dioxane-2-yl-benzofuran (50mg, 0.26mmol) was dissolved in THF (2mL) and the solution was cooled to-78 ℃. Butyllithium (180. mu.L, 1.1mmol) was added dropwise. The mixture was stirred at 25 ℃ for 30 min. The reaction mixture was then cooled to-78 ℃ and a solution of NCS (39mg, 1.1eq.) in 1mL THF was added dropwise. After 1.5h at-78 ℃ only small amounts of starting material were detected. The temperature was slowly raised to room temperature overnight. To the mixture were added water and ethyl acetate, and the aqueous phase was extracted 3 times. The combined organic phases were separated by MgSO₄Drying, filtering and concentrating to obtain 2-chloro-5- [1, 3]Dioxane-2-yl-benzofuran (48.1mg, 81%) was sufficiently pure for the next step.

LC-MS：M/Z ESI：1.77min，225.23(M+1)。

Intermediate 68: 3-amino-benzo [ d ]]Isoxazole-5-carbaldehyde

Kaiser oxime resin (Novabiochem 01-64-0188) (250mg) was washed with DCM and THF (3 times 5min), 2mL of THF was added followed by 300. mu.L of potassium tert-butoxide (1M in THF, 1.2eq.) at r.t.. The resin turns orange, in Quest210^TMShaking for 15 min. Adding 2-fluoro-5-formyl-benzylA solution of nitrile (75mg, 2eq.) in 1mL THF. The reaction solution was heated at 55 ℃ for 12 h. The resin was washed with DCM, MeOH, water (2X5min) and MeOH (4X5min), dried with a stream of argon at 40 ℃ for 30min, and then cleaved.

The resin thus dried was treated with TFA/5N HCl 4: 1(2.5mL) at 55 ℃ for 2 h. The solution was collected in a 20mL vial and the resin was washed 2 times with 4mL DCM. The collected fractions were evaporated to dryness using Genevac HT4 to yield 37mg (92%) of pure 3-amino-benzo [ d ] isoxazole-5-carbaldehyde.

HPLC：1.47min。LC-MS：M/Z ESI：0.82min，163.26(M+1)。

Intermediate 69: 4-piperidin-1-yl-quinazoline-6-carboxylic acid methyl ester

This intermediate was prepared following the synthesis of intermediate 8, starting from methyl 4-chloro-quinazoline-6-carboxylate (intermediate 7).

HPLC：1.81min。LC-MS：M/Z ESI：1.78min，272.32(M+1)。

Intermediate 70: 4-piperidin-1-yl-quinazoline-6-carbaldehyde

This intermediate was prepared following the synthesis of intermediate 5, starting from methyl 4-piperidine-quinazoline-6-carboxylate (intermediate 71).

HPLC：1.36min。LC-MS：M/Z ESI：1.40min，242.32(M+1)。

Intermediate 71: 3- (5-formyl-benzofuran-3-yl) -propionic acid ethyl ester

100mg of ethyl 3- (5-formyl-benzofuran-3-yl) acrylate (intermediate 62) were dissolved in ethyl acetate in the presence of palladium on carbon and argon. Hydrogen balloon was attached to it and hydrogenation was carried out for 12 h. The palladium was removed by filtration and the solvent was evaporated to give the pure title compound (80mg, 80%).

HPLC：3.53min。LC-MS M/Z ESI：1.68min，247.25(M+1)。

Intermediate 72: 2-methyl-5- [1, 3]Dioxane-2-yl-benzofurans

Mixing 5- [1, 3%]Dioxane-2-yl-benzofuran (50mg, 0.26mmol) was dissolved in THF (2mL) and the solution was cooled to-78 ℃. Butyl lithium (180. mu.L, 1.1eq.) was added dropwise. The mixture was stirred at 25 ℃ for 30min, then cooled to-78 ℃ and a solution of methyl iodide (18.1 μ L, 1.1eq.) in 1mL THF was added dropwise. The temperature was slowly raised to room temperature overnight. Although some starting material was also detected, water and ethyl acetate were added to the mixture and the aqueous phase was extracted 3 times. The combined organic phases were separated by MgSO₄Drying, filtering and concentrating to obtain 2-methyl-5- [1, 3]Dioxane-2-yl-benzofuran (41.2mg, 70%) was sufficiently pure for the next step.

LC-MS：M/Z ESI：1.71min，205.34(M+1)。

Intermediate 73: 5- [1,3]Dioxapentan-2-ylbenzofuran-2-carboxylic acid methyl ester

Mixing 5- [1, 3%]Dioxane-2-yl benzofuran (50mg, 0.26mmol) was dissolved in THF (2mL) and the solution was cooled to-78 ℃. Butyl lithium (180. mu.L, 1.1eq.) was added dropwise. The mixture was stirred at 25 ℃ for 30 min. The reaction mixture was then cooled to-78 ℃ and a solution of methyl cyanoformate (23 μ L, 1.1eq.) in 1mL THF was added dropwise. After 1.5h, only a small amount of starting material could be detected, forming 2 main compounds (expected product/dimer 73: 27). The temperature was slowly raised to room temperature overnight. Water and ethyl acetate were added to the mixture, and the aqueous phase was extracted 3 times. The combined organic phases were separated by MgSO₄Drying, filtering and evaporating to obtain 5- [1, 3] mixed with dimer]Dioxane-2-yl benzofuran-2-carboxylic acid methyl ester (31.9mg, 44%) (expected product/dimer 46: 54). The mixture was used directly in the next step.

LC-MS: M/Z ESI: 1.54min, 249.26(M + 1); 1.88min, 407.20(M +1, dimer).

Intermediate 74: 3-bromo-2-fluoro-benzofuran-5-carbaldehyde

In a polypropylene tube, benzofuran-5-carbaldehyde (100mg, 0.68mmol) was placed in ether (1mL), and a cold (-78 ℃ C.) solution of NBS (158mg, 1.3eq.) and pyridinium polyhydrofluoride 70% (0.850mL) in ether (4mL) was added. The reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into ice water and extracted with ether. The ether phase was washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated to give 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (141.6 mg). Purification on reverse phase HPLC (solvent gradient water/CH)₃CN 0.1% TFA) to give the title compound (62mg, 37%) which was used in the next step. LC-MS: M/Z ESI: 1.56 min. HPLC 3.11min (99.34).¹H NMR：(DMSO-d6)δ9.94(s，1H)，8.09(d，1H，³J＝1.8Hz)，7.99(dd，1H，³J＝8.4，1.8Hz)，7.38(d，1H，³J＝8.4Hz)，6.87(d，1H，²J_H-F＝59Hz)，6.01(d，1H，³J_H-F＝15.1Hz)。¹⁹F NMR：(DMSO-d6)δ-114.80，-114.88。

Intermediate 75: 2-fluoro-5- [1, 3]Dioxane-2-yl-benzofurans

Mixing 5- [1, 3%]Dioxane-2-yl-benzofuran (50mg, 0.26mmol) was dissolved in THF (2mL) and the solution was cooled to-78 ℃. Butyl lithium (180. mu.L, 1.1eq) was added dropwise. The mixture was stirred at 25 ℃ for 30 min. The mixture was cooled to-78 ℃ and a solution of N-fluorobenzenesulfonamide (91mg, 1.1eq) dissolved in 1mL of THF was added dropwise. The mixture was stirred overnight between-78 ℃ and room temperature. Water and ethyl acetate were added and the aqueous phase was extracted 3 times. The combined organic phases were separated by MgSO₄Drying, filtering and evaporating to obtain the mixed by-product 2-fluoro-5- [1, 3%]Dioxan-2-yl-benzofuran (75 mg). It is pure enough to be used in the next step.

The following examples were synthesized:

example 1: preparation of 5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

In a 100mL round bottom flask were placed 20g thiazolidine, 15.6g piperonal, 7.7g beta-alanine and 80mL acetic acid. The reaction mixture is stirred for 3h at 100 ℃ and then slowly cooled to room temperature, whereupon the desired condensation product crystallizes out. The crystals were filtered, washed with acetic acid (rt) and water, and recrystallized from DME (25mL) to give 28g (84%) of pure 5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione. The corresponding sodium salt was obtained by the following route: 5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione was suspended in THF and 1N KOH solution (1.0eq) was added. A clear solution was obtained which was freeze-dried to give the pure potassium salt of 5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione.

HPLC: 3.48 min. LC-MS: M/Z ESI: 1.31min, 248.12 (M-1). NMR (parent compound):¹H NMR(DMSO-d6)δ12.5(br.s，1H)，7.71(s，1H)，7.06-7.16(m，3H)，6.12(s，2H)。

if the final product cannot be crystallized out of the reaction solution, a small amount of water is added to precipitate the desired condensation product.

The crude product precipitated from the reaction mixture is either sufficiently pure or recrystallized from a suitable solvent (e.g. DME, methanol, EtOAc) or purified by flash chromatography using a mixture of EtOAc, cyclohexane as eluent.

Alternatively, the final product can be synthesized in parallel according to the following scheme:

in parallel synthesizer Quest210^TMThe corresponding aldehyde was placed in, and a mixture of piperidine (17.9 mg/tube) and 2, 4-thiazolidinedione (49.2 mg/tube) in DME (2 mL/tube) was added. The reaction was stirred at 120 ℃ for 3h, then cooled to room temperature with shaking, and 2mL of water was added. The precipitated compound was filtered off through the lower leg. The clear solution left was reduced in volume and then water was added. The solid thus formed was filtered off and washed with a small amount of DME to give the pure condensation product.

Example 2: preparation of 5- (1, 3-benzodioxol-5-ylmethylene) -2-thioxo-1, 3-thiazolidin-4-one

A24 mL vial was charged with a solution of 1g of commercially available rhodanine, 1.3g of piperonal, and 0.5mL of TEA in 10mL of DME. The reaction was stirred at 120 ℃ for 5h and then cooled to room temperature, whereupon the final product precipitated out. The solid was filtered and washed with DME to give 1.6g (80%) of an orange powder.

LC-MS: M/Z ESI: 1.46min, 266.00(M + 1). NMR (parent compound):¹H NMR(DMSO-d6)δ13.75(br.s，1H)，7.58(s，1H)，7.08-7.18(m，3H)，6.14(s，2H)。

example 3: preparation of 5- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethylene) -1, 3-thiazolidine-4-dione

The title compound was obtained by following the procedure of example 1, starting from 2, 3-dihydro-1, 4-benzodioxin-6-carbaldehyde and 1, 3-thiazolidine-2, 4-dione.

HPLC：2.58min。LC-MS：M/Z ESI：1.32min，262.16(M-1)。¹H NMR(DMSO-d6)δ12.52(br.s，1H)，7.68(s，1H)，7.09(dd，2H，J＝1.9，7.1)，7.00(d，1H，J＝9.0Hz)，4.36-4.22(m，4H)。

Example 4: preparation of 5- (2, 3-dihydro-1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-4-dione

The title compound was obtained by following the general procedure outlined in example 1, starting from 2, 3-dihydro-1-benzofuran-5-carbaldehyde and 1, 3-thiazolidine-2, 4-dione.

HPLC：3.27min。LC-MS：M/Z ESI：1.37min，246.18(M-1)。¹H NMR(DMSO-d6)δ9.80(br.s，1H)，7.37(s，1H)，7.25(d，1H，J＝8.3)，7.21(s，1H)，6.80(d，1H，J＝8.3Hz)，4.54(t，2H，J＝8.85)，3.19(t，2H，J＝8.85)。

Example 5: 5- [ (7-methoxy-1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazole Process for preparing alkane-2, 4-diones Preparation of

Following the general procedure outlined in example 1, starting from 7-methoxy-1, 3-benzodioxol-5-yl) carbaldehyde and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.57min。LC-MS：M/Z ESI：1.30min，278.07(M-1)。¹H NMR(DMSO-d6)δ12.63(br.s，1H)，7.78(s，1H)，7.65(s，1H)，7.57(d，1H，J＝8.5Hz)，7.45(dd，2H，J＝0.8，7.6)。

Example 6: 5- [ (9, 10-dioxo-9, 10-dihydroanthracen-2-yl) methylene]Preparation of (E) -1, 3-thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from (9, 10-dioxo-9, 10 dihydroanthracen-2-yl) carboxaldehyde and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：4.12min。LC-MS：M/Z ESI：1.50min，334.09(M-1)。

Example 7: process for preparing 5- [ (2, 2 difluoro-1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione Preparation of

Following the general procedure outlined in example 1, starting from (2, 2-difluoro-1, 3-benzodioxol-5-yl) carbaldehyde and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.85min。LC-MS：M/Z ESI：3.15min，284.11(M-1)。¹H NMR(DMSO-d6)δ12.63(br.s，1H)，7.78(s，1H)，7.65(s，1H)，7.57(d，1H，J＝8.5Hz)，7.45(dd，2H，J＝0.8，7.6)。

Example 8: preparation of 5- (1, 3-dihydro-2-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 1, 3-dihydro-2-benzofuran-5-carbaldehyde (intermediate 4) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.89min。LC-MS：M/Z ESI：1.20min，246.20(M-1)。¹H NMR(DMSO-d6)δ12.60(br.s，1H)，7.80(s，1H)，7.56-7.42(m，2H)，5.03(s，4H)。

Example 9: preparation of 5- (1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 1-benzofuran-5-carbaldehyde (intermediate 1) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.54min。LC-MS：M/Z ESI：1.47min，244.20(M-1)。¹H NMR(DMSO-d6)δ12.58(br.s，1H)，8.10(d，1H，J＝2.2Hz)，7.92(s，2H)，7.74(d，1H，J＝8.6Hz)，7.57(d，1H，J＝8.6Hz)，7.07(s，1H)。

Example 10: 5- [ (4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-ylmethylene) -1, 3-thiazolidine-2, 4- Preparation of diketones

Following the general procedure outlined in example 1, starting from [ (4-methyl-3-oxo-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) -carbaldehyde (intermediate 2) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.79min。LC-MS：M/Z ESI：1.19min，289.22(M-1)。¹H NMR(DMSO-d6)δ12.58(br.s，1H)，7.81(s，1H)，7.41(s，1H)，7.13-7.26(d，2H)，2.99(s，3H)。

Example 11: preparation of 5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidin-4-one

The title compound is obtained by following the general procedure outlined in example 1, starting from 1, 3-benzodioxole-5-carbaldehyde and 2-imino-1, 3-thiazolidin-4-one.

HPLC：2.29min。LC-MS：M/Z ESI：1.21min，247.25(M-1)。

Example 12: preparation of 5-quinolin-6-ylmethylene-thiazolidine-2, 4-dione

The title compound was obtained following the general procedure outlined in example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and 1, 3-thiazolidine-2, 4-dione.

HPLC：1.445min。LC-MS：M/Z ESI：1.17min，257.21(M+1)。¹H NMR(DMSO-d6)δ8.88(d，J＝6Hz，1H)，8.40(d，J＝9Hz，1H)，8.07-7.90(m，3H)，7.55(q，J＝6Hz，9Hz，，1H)，7.45(s，1H)。

Example 13: preparation of 5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

Following the general procedure outlined in example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and rhodanine, the title compound was obtained.

HPLC：2.05min。LC-MS：M/Z ESI：1.25min，273.14(M-1)。¹H NMR(DMSO-d6)δ14.00(br.s，1H)，8.97(d，J＝2.3，1H)，8.23(d，J-9Hz，1H)，8.10(d，J＝9Hz，1H)，7.95(d，J＝9Hz，1H)，7.79(s，1H)，7.61(q，J＝3Hz，9Hz，1H)。

Example 14: preparation of 2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

The title compound was obtained by following the general procedure outlined in example 1, starting from quinoline-6-carbaldehyde (intermediate 5) and 2-imino-1, 3-thiazolidin-4-one.

HPLC：1.16min。LC-MS：M/Z ESI：1.10min，256.18(M+1)。¹H NMR(DMSO-d6)δ12.58(br.s，1H)，8.84(s，1H)，8.37(d，J＝6Hz，1H)，8.02-7.86(m，3H)，7.52(q，J＝6Hz，9Hz，1H)，7.26(s，1H)，7.02(b.s，1H)。

Example 15: 5- (3-methyl-benzo [ d ]]Preparation of isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione Prepare for

Following the general procedure outlined in example 1, starting from 3-methyl-benzoxazole-5-carbaldehyde (intermediate 6) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.99min。LC-MS：M/Z ESI：1.30min，259.17(M-1)。¹H NMR(DMSO-d6)δ12.58(br.s，1H)，8.08(s，1H)，7.95(s，1H)，7.85(s，2H)，2.59(s，3H)。

Example 16: preparation of 5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 4-phenyl-quinazoline-6-carbaldehyde (intermediate 13) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.45min。LC-MS：M/Z ESI：1.25min，334.15(M+1)。¹H NMR(DMSO-d6)δ12.74(br.s，1H)，9.43(s，1H)，8.24(m，2H)，8.00-7.86(m，2H)，7.72-7.66(m，5H)。

Example 17: preparation of 5- (4-dimethylamino-quinoxalin-6-ylmethylene) -quinazoline-2, 4-dione

Following the general method outlined in example 1, starting from 4-dimethylamino-quinazoline-6-carbaldehyde (intermediate 14) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：1.47min。LC-MS：M/Z ESI：1.26min，301.26(M-1)。¹H NMR(DMSO-d6)δ8.81(s，1H)，8.54(s，1H)，8.16-7.95(m，3H)，7.13-7.26(d，2H)，3.63(s，6H)。

The following examples were synthesized as described in examples 1 and 17, starting from intermediates 15 to 31 and 1, 3-thiazolidine-2, 4-dione.

Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)
Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)	18	16	5- [ (4-aminoquinazolin-6-yl) methylene]-1, 3-thiazolidine-2, 4-dione	273.29
19	15	5- [ (4-piperidin-1-ylquinazolin-6-yl) methylene]-1, 3-thiazolidine-2, 4-dione	341.40	18	16		273.29
19	15		341.40	20	22	5- [ (4-morpholin-4-ylquinazolin-6-yl) methylene]-1, 3-thiazoles	343.2
		Alkane-2, 4-diones	0	20	22		343.2
		Alkane-2, 4-diones	0	21	17	5- { [4- (benzylamino) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	363.10
22	21	5- { [4- (diethylamino) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	329.30	21	17		363.10
22	21		329.30	23	18	5- ({4- [ (pyridin-2-ylmethyl) amino group]Quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	364.40
24	19	5- ({4- [ (pyridin-3-ylmethyl) amino group]Quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	364.40	23	18		364.40
24	19		364.40	25	23	1- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]Quinazolin-4-yl piperidine-3-carboxylic acid ethyl ester	413.20
26	25	1- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]Quinazolin-4-yl } piperidine-4-carboxylic acid ethyl ester	413.30	25	23		413.20
26	25		413.30	27	24	1- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]Quinazolin-4-yl } -L-proline tert-butyl ester	427.20
28	20	5- { [4- (4-methylpiperazin-1-yl) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	356.13	27	24		427.20
28	20		356.13	29	31	5- { [4- (4-pyrimidin-2-ylpiperazin-1-yl) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	420.20

Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)
Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)	30	30	5- ({4- [4- (4-fluorophenyl) piperidin-1-yl)]Quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	435.30
31	29	5- { [4- (4-Benzylpiperidin-1-yl) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	431.30	30	30		435.30
31	29		431.30	32	28	5- ({4- [4- (2-phenylethyl) piperidin-1-yl)]Quinazolin-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	445.40
33	27	5- { [4- (4-methylpiperidin-1-yl) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	355.20	32	28		445.40
33	27		355.20	34	26	5- { [4- (4-hydroxypiperidin-1-yl) quinazolin-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	357.40

Example 35: 1- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -quinazolin-4-yl]-piperidine-4-carboxylic acid

50mg of 1- {6- [ (2, 4-dioxo-1, 3-thiazolidin-5-yl) methyl ] quinazolin-4-yl } piperidine-4-carboxylic acid ethyl ester (example 26) were dissolved in a solution of 2mL THF/water (1/1). A few drops of 5N NaOH were added and the reaction was stirred at rt for 12 h. After completion of the reaction, the solvent was evaporated and the title product precipitated from ether as a yellow solid (40mg, 82%).

HPLC：1.43min。LC-MS：M/Z ESI：1.15min，385，20(M+1)。

Example 36: 1- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -quinazolin-4-yl]-piperidine-3-carboxylic acid

The title compound was obtained by following the general procedure outlined in example 35.

HPLC：1.50min。LC-MS：M/Z ESI：1.10min，385.40(M+1)。

Example 37: 1- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -quinazolin-4-yl]-pyrrolidine-2-carboxylic acid

10mg of 1- {6- [ (2, 4-dioxo-1, 3-thiazolidin-5-yl) methyl ] quinazolin-4-yl } -L-prolinetert-butyl ester (example 27) in 25% (TFA/DCM) solution was stirred for 12h at rt. The solvent was evaporated in vacuo and pure 1- [6- (2, 4-dioxo-thiazolidin-5-ylmethyl) quinazolin-4-yl ] -pyrrolidine-2-carboxylic acid (7mg, 81%) was precipitated from ether.

HPLC：1.43min。LC-MS：M/Z ESI：1.10min，371.30(M+1)。

Example 38: 5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：1.43min。LC-MS：M/Z ESI：1.03min，287.19(M+1)。¹H NMR(DMSO-d6)δ11.97(b.s，1H)，8.53(b.s，2H)，8.37(s，1H)，7.92(d，J＝8Hz，1H)，7.76(s，2H)，3.03(s，3H)。

Example 39: 5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

Following the general method outlined in example 1, starting from 4-methoxy-quinazoline-6-carbaldehyde (intermediate 10) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.57min。LC-MS：M/Z ESI：1.12min，288.20(M+1)。¹H NMR(DMSO-d6)δ12.74(br.s，1H)，8.86(s，1H)，8.32(s，1H)，8.11(m，1H)，8.03-7.98(m，2H)，4.18(s，3H)。

Example 40: preparation of 2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

Following the general procedure outlined in example 1, starting from 4-methylamino-quinazoline-6-carbaldehyde (intermediate 11) and 2-imino-1, 3-thiazolidin-4-one, the title compound was obtained.

HPLC：2.43min。LC-MS：M/Z ESI：1.07min，286.14(M+1)。

Practice ofExample 41: 2-imino-5- (4-piperidin-quinazolin-6-ylmethylene) -thiazolidin-4-one

Following the general procedure outlined in example 1, starting from 4-piperidine-quinazoline-6-carbaldehyde (intermediate 72) and 2-imino-1, 3-thiazolidin-4-one, the title compound was obtained.

HPLC：1.78min。LC-MS：M/Z ESI：1.40min，340.26(M-1)。¹H NMR(DMSO-d6)δ8.76(s，1H)，8.18(s，1H)，8.16(d，J＝6Hz，1H)，7.88(d，J＝9Hz，1H)，7.80(s，1H)，4.09(s，4H)，1.80(s，6H)。

Example 42: 2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

Following the general procedure outlined in example 1, starting from 4-piperidine-quinazoline-6-carbaldehyde (intermediate 14) and 2-imino-1, 3-thiazolidin-4-one, the title compound was obtained.

HPLC：1.32min。LC-MS：M/Z ESI：1.54min，300.23(M-1)。¹H NMR(DMSO-d6)δ8.82(s，1H)，8.543s，1H)，8.16(d，J＝9Hz，1H)，7.87(t，J＝9Hz，2H)，3.65(s，6H)。

Example 43: 5- (2-methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 2-methyl-2H-benzotriazole-5-carbaldehyde (intermediate 33) and thiazolidinedione, the title compound was obtained.

HPLC：2.68 min.1H NMR(DMSO-d6)δ12.58(br.s，1H)，7.98(s，1H)，7.92(d，J＝9Hz，1H)，7.62(d，J＝6Hz，1H)，7.43(s，1H)，4.48(s，3H)。

Example 44: 5- (3-methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 3-methyl-3H-benzotriazole-5-carbaldehyde (intermediate 34) and thiazolidinedione, the title compound was obtained.

HPLC：2.35 min。LC-MS：M/Z ESI：1.22min，259.23(M-1)。¹H NMR(DMSO-d6)δ12.58(br.s，1H)，8.17(d，J＝9Hz，1H)，8.07(s，1H)，7.62(d，J＝6Hz，1H)，7.73(s，1H)，4.33(s，3H)。

Example 45: 5- (3-ethyl-3H-benzimidazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (4-amino-3-ethylamino-benzylidene) -thiazolidine-2, 4-dione (50mg, 0.19mmol) (intermediate 36) was dissolved in formic acid (5mL) and the solution was stirred at 100 ℃ overnight. Formic acid was evaporated in vacuo. The crude product was purified by silica gel column to give the title compound (35mg, 63%).

HPLC：1.71min。LC-MS：M/Z ESI：0.82min，274.21(M+1)。

The following examples were synthesized as described in example 45, starting from intermediates 37 to 54 and 1, 3-thiazolidine-2, 4-dione.

Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)
Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)	46	37	5- { [1- (4-phenylbutyl) -1H-benzimidazol-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	378.30
47	50	5- [ (1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) ylidene	284.24	46	37		378.30
47	50	5- [ (1-prop-2-yn-1-yl-1H-benzimidazol-6-yl) ylidene	284.24			Methyl radical]-1, 3-thiazolidine-2, 4-dione
48	38	5- [ (1- {2- [4- (trifluoromethyl) phenyl)]Ethyl } -1H-benzimidazol-6-yl) methylene]-1, 3-thiazolidine-2, 4-dione	418.17			Methyl radical]-1, 3-thiazolidine-2, 4-dione
48	38		418.17	49	39	5- ({1- [2- (4-hydroxyphenyl) ethyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	366.26
50	40	4- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1H-benzimidazol-1-yl } cyclohexanecarboxylic acid methyl ester	386.35	49	39		366.26
50	40		386.35	51	41	5- ({1- [2- (5-methoxy-1H-indol-3-yl) ethyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	419.21
52	42	5- ({1- [ (1-methyl-1H-pyrazol-4-yl) methyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	340.99	51	41		419.21
52	42		340.99	53	43	5- ({1- [2- (3, 4-Dimethoxyphenyl) ethyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	410.37
54	54	5- ({1- [2- (4-Phenoxyphenyl) ethyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	442.51	53	43		410.37
54	54		442.51	55	44	5- ({1- [4- (trifluoromethyl) benzyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	404.16

Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)
Examples	Intermediate # as starting material	Name of Compound	Quality (M +1)	56	45	4- {6- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1H-benzimidazol-1-yl } cyclohexanecarboxylic acid	372.18
57	46	5- [ (1-isobutyl-1H-benzimidazol-6-yl) methylene]-1, 3-thiazolidine-2, 4-dione	302.25	56	45		372.18
57	46		302.25	58	47	5- ({1- [2- (1, 3-benzodioxol-4-yl) ethyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	349.27
59	48	5- ({1- [2- (2-phenoxyphenyl) ethyl]-1H-benzimidazol-6-yl } methylene) -1, 3-thiazolidine-2, 4-dione	442.29	58	47		349.27
59	48		442.29	60	49	5- { [1- (3, 3-Diphenylpropyl) -1H-benzimidazol-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	440.27
61	51	5- { [1- (2-methoxybenzyl) -1H-benzimidazol-6-yl]Methylene } -1, 3-thiazolidine-2, 4-diones	366.33	60	49		440.27
61	51		366.33	62	52	5- { [1- (3-furylmethyl) -1H-benzimidazole-6-Base of]Methylene } -1, 3-thiazolidine-2, 4-diones	326.24
63	53	5- [1- (1-propyl-1H-benzimidazol-6-yl) methylene]-1, 3-thiazolidine-2, 4-dione	288.18	62	52		326.24

Example 64: 5-quinoxalin-6-ylmethylene-thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and a thiazolidinedione, the title compound was obtained.

HPLC：2.48 min。LC-MS：M/Z ESI：1.01min，256.20(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，8.93(d，J＝9Hz，2H)，8.18(s，1H)，8.10(d，J＝9Hz，1H)，8.03(d，J＝9Hz，1H)，7.51(s，1H)。

Example 65: 5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-ones

Following the general procedure outlined in example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and rhodanine, the title compound was obtained.

HPLC：3.10 min。LC-MS：M/Z ESI：1.17min，272.13(M-1)。¹H NMR：(DMSO-d6)δ12.00(br.s.1H)，9.02(s，2H)，8.31(s，1H)，8.21(d，J＝9Hz，1H)，8.04(d，J＝9Hz，1H)，7.90(s，1H)。

Example 66: 2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-ones

The title compound is obtained by following the general procedure outlined in example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and 2-imino-1, 3-thiazolidin-4-one.

HPLC：1.97min。LC-MS：M/Z ESI：1.02min，255.19(M-1)。¹H NMR：(DMSO-d6)δ9.57-9.30(b.d.J＝81Hz，2H)，9.00(s，2H)，8.26-8.07(m，3H)，7.84(s，1H)。

Example 67: 5-benzothiazol-6-ylmethylene-thiazolidine-2, 4-diones

Following the general procedure outlined in example 1, starting from quinoxaline-6-carbaldehyde (intermediate 56) and a thiazolidinedione, the title compound was obtained.

HPLC：2.85 min。LC-MS：M/Z ESI：1.06min，261.11(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，9.39(s，2H)，8.27(s，1H)，8.11(d，J＝9Hz，1H)，7.70(d，J＝9Hz，1H)，7.42(s，1H)。

Example 68: 5- (3-methylbenzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 3-methylbenzofuran-5-carbaldehyde (intermediate 57) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：1.47 min。LC-MS：M/Z ESI：1.15min，257.21(M-1)。¹H NMR：(DMSO-d6)δ12.50(br.s.1H)，8.87(d，J＝6Hz，1H)，8.38(d，J＝9，1H)，8.07(t，J＝12Hz，2H)，7.92(d，J＝9Hz，1H)，7.53(q，J＝6Hz，12Hz，1H)，7.45(s，1H)。

Example 69: 5- (2-bromo-3-methylbenzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

In a 25mL three-necked flask at 0 deg.C were placed 5- (3-methylbenzofuran-5-ylmethylene) thiazolidine-2, 4-dione (100mg, 0.39mmol) (example 68) and bromine (20. mu.L, 1eq) in 2mL AcOH to warm the reaction mixture to room temperature. An additional equivalent of bromine was added after RT 2 h. After 3h the reaction was filtered to give the yellow product as the title compound (87mg, 66%). LC-MS: M/ZESI: 1.69min, 339.8(M + 1).¹H NMR：(DMSO-d6)δ12.50(br.s.1H)，7.93(s，1H)，7.82(s，1H)，7.72(d，J＝6Hz，1H)，7.54(d，J＝6Hz，1H)，2.20(s，3H)。

Example 70: 5- (3-bromo-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 3-bromo-benzofuran-5-carbaldehyde (intermediate 58) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.92 min。LC-MS：M/Z ESI：1.57min，325.17(M+1)。¹H NMR：(DMSO-d6)δ12.60(br.s.1H)，8.42(s，1H)，8.00(s，1H)，7.85(d，J＝23Hz，1H)，7.76(d，J＝23Hz，1H)。

Example 71: 3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl]-acrylic acid ethyl ester

Following the general procedure outlined in example 1, starting from 3- (formyl-benzofuran-3-yl) -acrylic acid ethyl ester (intermediate 60) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：4.00 min。LC-MS：M/Z ESI：1.60min，342.20(M-1)。¹H NMR：(DMSO-d6)δ12.50(br.s.1H)，8.63(s，1H)，8.42(s，1H)，8.08(s，1H)，7.83(m，2H)，7.62(s，1H)，4.22(q，J＝6Hz，9Hz，2H)。

Example 72: 3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl]-acrylic acid

Reacting 3- [5- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -benzofuran-3-yl]Ethyl acrylate (205mg, 0.6mmol) (example 71) was dissolved in THF/water 4: 2. To this solution was added 81mg (4eq) of LiOH.H with stirring₂And O. The reaction solution is stirred for 15 hours, the solvent is evaporated,the residue was precipitated with diethyl ether. The solid was washed with 1N HCl and dried to yield 170mg (90%) of pure 3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl]-acrylic acid.

HPLC：3.25 min。LC-MS：M/Z ESI：1.01min，314.11(M-1)。¹H NMR：(DMSO-d6)δ8.22(s，1H)，8.03(s，1H)，7.58(dd，J＝9Hz，33Hz，2H)，7.43(s，1H)，7.25(d，J＝18Hz，1H)，7.07(s，1H)。

Example 73: 5- [3- (3-oxo-3-piperidin-1-yl-propenyl) -benzofuran-5-ylmethylene]Thiazolidine-2, 4-diones

180mg (0.57mmol) of 3- [5- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -benzofuran-3-yl ] -acrylic acid (example 72) are suspended in THF (25 mL). To the suspension were added DIEA (2eq) and piperidine (3 eq). PyBOP (1.5eq) was added with stirring. After 30min the reaction mixture became clear. After a further 1h a precipitate formed. The reaction was stirred overnight. The precipitate was filtered off and washed with THF and 1N HC1 to give the title product in high purity.

HPLC：3.91min。LC-MS：M/Z ESI：1.58min，383.22(M+1)。¹H NMR：(DMSO-d6)δ8.46(s，1H)，8.19(s，1H)，7.71-

7.51(m，4H)，7.23(d，J＝15，1H)，3.73(d，J＝48Hz，2H)，1.51(d，J＝36Hz，3H)。

The following amides were synthesized according to the synthesis method of example 73.

Examples	Starting material amine	Name of Compound	Quality (M +1)
Examples	Starting material amine	Name of Compound	Quality (M +1)	74	Proline methyl ester	1- ((3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl group]-1-benzofuran-3-yl } -prop-2-enoyl) proline methyl ester	427.15
75	D-proline methyl ester	1- ((3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl group]-1-benzofuran-3-yl } -prop-2-enoyl) -D-proline methyl ester	413.15	74	Proline methyl ester		427.15
75	D-proline methyl ester		413.15	76	Pyrrolidine as a therapeutic agent	(5- ({3- [ (3-oxo-3-pyrrolidin-1-ylprop-1-en-1-yl) -1-benzofuran-5-yl)]Methylene } -1, 3-thiazolidine-2, 4-diones	369.52
77	Morpholine	5- ({3- [ 3-morpholin-4-yl-3-oxoprop-1-en-1-yl)]-1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione	385.07	76	Pyrrolidine as a therapeutic agent		369.52
77	Morpholine		385.07	78	L-proline methyl ester	1- (3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl group]-1-benzofuran-3-yl } -prop-2-enoyl	427.13
		Yl) -L-proline methyl ester		78	L-proline methyl ester		427.13
		Yl) -L-proline methyl ester		79	N-methylcyclohexylamine	N-cyclohexyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1-benzofuran-3-yl } -N-methylacrylamide	411.12
80	N-ethylhydroxyethylamine	3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1-benzofuran-3-yl } -N-ethyl-N- (2-hydroxyethyl) acrylamide	387.10	79	N-methylcyclohexylamine		411.12
80	N-ethylhydroxyethylamine		387.10	81	Cyclobutylamine	N-cyclobutyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl]-1-benzofuran-3-yl } -acrylamide	369.13

Examples	Starting material amine	Name of Compound	Quality (M +1)
Examples	Starting material amine	Name of Compound	Quality (M +1)	82	Azetidines	5- ({3- [ 3-azetidin-1-yl-3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl } methylene } -1, 3-thiazolidine-2, 4-dione	355.64
83	1, 3-dihydro-2H-isoindoles	5- ({3- [3- (1, 3-dihydro-2H-isoindol-2-yl) -3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione	415.00(M-1)	82	Azetidines		355.64
83	1, 3-dihydro-2H-isoindoles		415.00(M-1)	84	Azepanes as pharmaceutical agents	5- ({3- [ 3-azepan-1-yl-3-oxoprop-1-en-1-yl)]-1-benzofuran-5-yl } methylene } -1, 3-thiazolidine-2, 4-dione	387.46
85	Piperidin-1-ylamines	3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1-benzofuran-3-yl } -N-piperidin-1-yl ester-radical acrylamide	398.00	84	Azepanes as pharmaceutical agents		387.46
85	Piperidin-1-ylamines		398.00	86	Pyridin-3-ylmethylamines	3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1-benzofuran-3-yl } -N- (pyridin-3-ylmethyl) acrylamide	406.10
87	Cyclohexylamine	N-cyclohexyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1-benzofuran-3-yl } acrylamide	397.08	86	Pyridin-3-ylmethylamines		406.10
87	Cyclohexylamine		397.08	88	4-N-methylpiperazines	5- ({3- [3- (4-methylpiperazin-1-yl) -3-oxoprop-1-en-1-yl)]-1-benzofuran-5-yl } methylene } -1, 3-thiazolidine-2, 4-dione	398.02
89	Cycloheptylamine	N-cycloheptyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidin-5-ylidene) methyl]-1-benzofuran-3-yl } acrylamide	411.44	88	4-N-methylpiperazines		398.02
89	Cycloheptylamine		411.44	90	Pyrrolines	5- ({3- [3- (2, 5-dihydro-1H-pyrrol-1-yl) -3-oxoprop-1-en-1-yl]-1-benzofuran-5-yl } methylene) -1, 3-thiazolidine-2, 4-dione	367.11
91	Cyclopentylamine	N-cyclopentyl-3- {5- [ (2, 4-dioxo-1, 3-thiazolidine-5-ylidene) methyl]-1-benzofuran-3-yl } acrylamide	383.11	90	Pyrrolines		367.11

Example 92: 3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl]-propionic acid ethyl ester

Following the general method outlined in example 1, starting from 3- (5-formyl-benzofuran-3-yl) -propionic acid ethyl ester (intermediate 71) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.97 min。LC-MS：M/Z ESI：2.87min，346.15(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，7.92(d，J＝6Hz，3H)，7.72(d，J＝9Hz，1H)，7.53(d，J＝9Hz，1H)，4.03(q，J＝9Hz，15Hz，2H)，2.94(t，J＝9Hz，2H)，2.73(t，J＝6Hz，2H)，1.14(t，J＝6Hz)。

Example 93: 3- [5-2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl]-propionic acid

The title compound was obtained by standard saponification procedures as described for example 72, starting from example 92.

HPLC：3.09 min。LC-MS：M/Z ESI：1.19min，316.14(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，12.22(s，1H)，7，93(d，J＝12Hz，3H)，7.70(d，J＝9Hz，1H)，7.54(d，J＝9Hz，1H)，2.91(t，J＝9Hz，2H)，2.65(t，J＝6Hz，2H)。

Example 94: 5- [3- (3-oxo-3-piperidin-1-yl-propyl) -benzofuran-5-ylmethylene]Thiazolidine-2, 4-diones

The title compound was obtained according to the synthesis described for example 73, starting from example 93.

HPLC：3.783 min。LC-MS：M/Z ESI：1.46min，383.22(M+1)。¹H NMR：(DMSO-d6)δ12.66(br.s，1H)，8.06(s，3H)，8.10(s，1H)，7.79(s，1H)，3.50-1.60(m，14H)。

Example 95: 6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -2, 3-dihydro-benzo [1, 4]]Oxazine-4-carboxylic acid tert-butyl ester

Following the general procedure outlined in example 1, starting from tert-butyl 6-formyl-2, 3-dihydrobenzoxazine-4-carboxylate (intermediate 62) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.52 min。LC-MS：M/Z ESI：min，261.21(M-Boc-1)。

Example 96: 5- (3, 4-dihydro-2H-benzo [1, 4]]Oxazin-6-ylmethylene) -thiazolidine-2, 4-diones

100mg of 6-formyl-2, 3-dihydro-benzo [1, 4] oxazine-4-carboxylic acid tert-butyl ester (intermediate 62) was treated with TFA/DCM 25% for 2 h. The solvent was evaporated to dryness and the crude product left without further purification was used to carry out the Knoevenagel reaction described in example 1 to give the title compound as a yellow solid.

HPLC：2.56 min。LC-MS：M/Z ESI：1.14min，261.24(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，7，57(s，1H)，6.78(s，3H)，4.17(t，J＝3Hz，2H)，3.28(t，J＝6Hz，2H)。

Example 97: 5- (3, 4-dihydro-2H-benzo [1, 4]]Oxazin-6-ylmethylene) -thiazolidine-2, 4-diones

5- (3, 4-dihydro-2H-benzo [1, 4] with benzoyl chloride (156. mu.L, 10eq.) in the presence of DIEA (2eq.) in 4mL of THF]Oxazin-6-ylmethylene) -thiazolidine-2, 4-dione (example 96) (35mg, 0.13mmol) was treated for 3 h. Hydrolysis of excess benzoyl chloride, addition of EtOAc and organic layer with NaHCO₃And a brine wash. The crude product was purified on silica gel, eluting with EtOAc/cHex 3: 7, to give 14mg (35%) of the title product.

HPLC：4.57min。LC-MS：M/Z ESI：2.11min，364.91(M-1)。

The following examples were synthesized using the same procedures described in example 97.

Example 98: 5- (4-acetyl-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-6-ylmethylene) -thiazolidine-2, 4-diones

Yield 43mg (95%).

HPLC：2.65 min。LC-MS：M/Z ESI：1.12min，305.24(M+1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，8.30(bs，1H)，7.71(s，1H)，7.35(d，J＝9Hz，1H)，7.05(d，J＝9Hz，1H)，4.33(t，J＝6Hz，2H)，4.00(t，J＝6Hz，2H)。

Example 99: 6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -benzo [1, 4]]Oxazine-4-carboxylic acid tert-butyl ester

Following the general procedure outlined in example 1, starting from 6-formyl-benzo [1, 4] -oxazine-4-carboxylic acid tert-butyl ester (intermediate 63) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：4.23 min。LC-MS：M/Z ESI：1.82min，359.16(M-1)。¹H NMR：(DMSO-d6)δ12.50(br.s.1H)，7.63(d，J＝3，2H)，7.31(d，J＝3Hz，1H)，6.95(d，J＝9Hz，1H)，6.30(s，2H)。

Example 100: [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4]]Oxazine-4- Base of]Acetic acid methyl ester

Following the general method outlined in example 1, starting from methyl (6-formyl-3-oxo-2, 3-dihydro-benzo [1, 4] -oxazin-4-yl) acetate (intermediate 64) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.83 min。LC-MS：M/Z ESI：1.20min，347.25(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，7.76(s，1H)，7.36(s，1H)，7.20(m，2H)，4.82(d，J＝15Hz，4H)，3.71(s，3H)。

Example 101: n-benzyl-2- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4]] Oxazin-4-yl]-acetamide

[6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] is reacted with 2eq.LiOH]Oxazin-4-yl]Methyl acetate (195mg, 0.56mmol) (example 100) was saponified to give [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4]]Oxazin-4-yl]Acetic acid. The acid thus obtained (50mg, 0.15mmol) was dissolved in THF. HOBt (32mg, 1.5eq.), EDC (43mg, 1.5eq.), and benzylamine (25mg, 1.5eq.) were added with stirring. The reaction mixture was stirred at rt for 15 h. EtOAc was added and the organic phase was washed with 1N HCl, NaHCO₃And washed 3 times each with brine. After evaporation of the solvent, the crude residue was purified on silica gel using DCM/EtOAc as eluent to give the title compound as a colorless powder (35mg, 54%).

HPLC：3.06min。LC-MS：M/Z ESI：1.27min，424.21(M+1)。

Example 102: 5- (4-butyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-6-ylmethylene) -thiazolidine-2, 4- Diketones

Following the general method outlined in example 1, starting from 4-butyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4] -oxazine-6-carbaldehyde (intermediate 65) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.76 min。LC-MS：M/Z ESI：1.49min，331.23(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，7.85(s，1H)，7.43(s，1H)，7.24(d，J＝6Hz，1H)，7.15(d，J＝9Hz，1H)，4.73(s，2H)，3.91(t，J＝3Hz，2H)，1.57(m，2H)，1.36(m，2H)，0.91(t，J＝9Hz，3H)。

Example 103: 5- (4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4]]Oxazin-6-ylmethylene) -thiazolidine-2, 4- Diketones

Following the general procedure outlined in example 1, starting from 4-benzyl-3-oxo-3, 4-dihydro-2H-benzo [1, 4] -oxazine-6-carbaldehyde (intermediate 66) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.67 min。LC-MS：M/Z ESI：1.46min，365.17(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，7.68(s，1H)，7.38-7.22(m，8H)，5.24(m，2H)，4.97(s，2H)。

Example 104: 5- (2-chloro-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general method outlined in example 1, starting from 2-chloro-5- [1, 3] -dioxan-2-yl-benzofuran (intermediate 67) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：3.84 min。LC-MS：M/Z ESI：1.62min，278.12(M-1)。¹H NMR：(DMSO-d6)δ7.79-7.75(m，2H)，7.68(d，J＝9Hz，1H)，7.52(d，J＝9Hz，1H)，7.09(s，1H)。

Example 105: 5- (3-amino-benzo [ d ]]Isoxazol-5-ylmethylene) -thiazolidine-2, 4-diones

Following the general procedure outlined in example 1, starting from 3-amino-benzisoxazole-5-carbaldehyde (intermediate 68) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：2.45min。LC-MS：M/Z ESI：0.97min，260.17(M-1)。¹H NMR：(DMSO-d6)δ12.60(br.s，1H)，8.01(s，1H)，7.85(s，1H)，7.60(d，J＝9Hz，1H)，6.67(s，1H)。

Example 106: 5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 3-phenylethynyl-benzofuran-5-carbaldehyde (intermediate 59) and 1, 3-thiazolidine-2, 4-dione, the title compound was obtained.

HPLC：4.82 min。LC-MS：M/Z ESI：2.02min，344.18(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，8.49(s，1H)，7.92(s，1H)，7.7.2(d，J＝9Hz，1H)，7.62(m，3H)，7.45(m，4H)。

Example 107: 5-benzo [1, 2, 5]]Thiadiazol-5-ylmethylene-thiazolidine-2, 4-dione

The title compound was obtained following the general procedure outlined in example 1, starting from 2, 1, 3-benzothiadiazole-5-carbaldehyde and 1, 3-thiazolidine-2, 4-dione.

HPLC：3.03 min。LC-MS：M/Z ESI：1.14min，262.11(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，8.11(m，2H)，7.90(d，J＝9Hz，1H)，7.47(s，1H)。

Example 108: 5-benzo [1, 2, 5]]Oxadiazol-5-ylmethylene-thiazolidine-2, 4-diones

The title compound was obtained by following the general procedure outlined in example 1, starting from 2, 1, 3-benzoxadiazole-5-carbaldehyde and 1, 3-thiazolidine-2, 4-dione.

HPLC：3.02min。LC-MS：M/Z ESI：1.17min，246.17(M-1)。¹H NMR：(DMSO-d6)δ12.58(br.s.1H)，8.07(m，2H)，7.82(d，J＝9Hz，1H)，7.40(s，1H)。

Example 109: 5- (2-methyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 2-methyl-5- [1, 3]Starting with-dioxan-2-yl-benzofuran (intermediate 72) and 1, 3-thiazolidine-2, 4-dione, reverse phase HPLC (solvent gradient H)₂O/CH₃CN 0.1% TFA) to yield the title compound.

HPLC：3.65min，90.75％。LC-MS：M/Z ESI：1.65min，258.21(M-1)。¹H NMR：(DMSO-d6)δ12.45(s1，1H)，7.88(s，1H)，7.77(d，J＝1.5Hz，1H)，7.64(d，J＝8.6Hz，1H)，7.47(dd，1H，J＝8.6Hz，1.5Hz)，6.69(s，1H)，2.37(s，3H)。

Example 110: 5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 5- [1, 3]Starting with-dioxane-2-yl-benzofuran-2-carboxylic acid methyl ester (intermediate 73) and 1, 3-thiazolidine-2, 4-dione, reverse phase HPLC (solvent gradient H)₂O/CH₃CN 0.1% TFA) to yield the title compound.

HPLC：3.32 min。LC-MS：M/Z ESI：1.51min，302.19(M-1)。¹H NMR：(DMSO-d6)δ12.52(s1，1H)，7.97(d，J＝1.5Hz，1H)，7.82(m，3H)，7.69(dd，1H，J＝8.6，1.5Hz)，3.90(s，3H)。

Example 111: 5- (3-bromo-2-fluoro-2, 3-dihydro-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 3-bromo-2-fluoro-benzofuran-5-carbaldehyde (intermediate 74) and 1, 3-thiazolidine-2, 4-dione, reverse phase HPLC (solvent gradient H)₂O/CH₃CN 0.1% TFA) to yield the title compound. HPLC: 3.66 min. LC-MS: M/Z ESI: 1.56min, 343.09 (M-1).¹H NMR：(DMSO-d6)δ12.82(s1，1H)，8.00(d，J＝1.8Hz，1H)，7.88(dd，1H，J＝8.5，1.8Hz)，7.55(d，1H，J＝8.5Hz)，7.03(d，1H，²J_F＝59.5Hz)，6.20(d，1H，³J_F＝15.3Hz)。¹⁹F NMR：(DMSO-d6)δ-114.66。

Example 112: 5- (2-fluoro-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

Following the general procedure outlined in example 1, starting from 2-fluoro-5- [1, 3]Starting with dioxane-2-yl-benzofuran (intermediate 75) and 1, 3-thiazolidine-2, 4-dione, reverse phase HPLC (solvent gradient H)₂O/CH₃CN 0.1% TFA) to yield the title compound.

HPLC：3.67min.，99.47％。LC-MS：M/Z ESI：1.51min，262.14(M-1)。¹H NMR：(DMSO-d6)δ12.04(s1，1H)，7.89(d，J＝1.5Hz，1H)，7.83(d，1H，J＝1.5Hz)，7.73(d，1H，J＝8.6Hz)，7.55(dd，1H，J＝8.6，1.5Hz)，6.47(d，1H，³J_F＝6.4Hz)。¹⁹F NMR：(DMSO-d6)δ-111.28，-112.18.

Example 113: preparation of pharmaceutical formulations

The following formulation examples illustrate representative pharmaceutical compositions of the invention, but the invention is not so limited.

Preparation 1: tablet formulation

The compound of formula (I) is mixed in a dry powder with a dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was formulated into 240-270mg tablets (80-90 mg of active ingredient per tablet) in a tablet press.

Preparation 2: capsule

The compound of formula (I) is mixed as a dry powder with a starch diluent in a weight ratio of about 1: 1. The mixture was filled into 250mg capsules (125 mg of active oxazolidinone compound per capsule).

Preparation 3: liquid, method for producing the same and use thereof

The compound of formula (I) (1250mg), sucrose (1.75g) and xanthan gum (4mg) were mixed, passed through a No.10 U.S. sieve and then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11: 89, 50 mg). Sodium benzoate (10mg), flavoring agent and coloring agent were diluted with water and added under stirring. Sufficient water was then added to bring the total volume to 5 mL.

Preparation 4: tablet formulation

The compound of formula (I) is mixed in a dry powder with a dry gelatin binder in a weight ratio of about 1: 2. A small amount of magnesium stearate was added as a lubricant. The mixture was formulated into 450-900mg tablets (150-300 mg active oxazolidinone compound per tablet) in a tablet press.

Preparation 5: injection preparation

The compound of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.

Example 114: biological assay

The following tests were carried out with the compounds of the invention:

a) high throughput PI3K lipid kinase assay (binding assay):

this assay combines scintillation proximity assay technology (SPA, Amersham) with neomycin, a polycationic antibiotic, for its ability to bind to phospholipids with high affinity and specificity. Scintillation proximity assays are based on weakly emitting isotopes (e.g.³H、¹²⁵I、³³P) of the substrate. After incubation of SPA beads coated with neomycin with recombinant PI3K and radioactive ATP in the same well, phosphorylated lipid substrates were detected by specific binding to radioactive phospholipids on neomycin capture SPA beads.

To a 384-well MTP containing 5 μ L of a test compound of formula (I) (test compound dissolved in 6% DMSO; test compound concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.001 μ M) the following test components were added: (1)5 μ L (58ng) of recombinant human GST-PI3K γ (in Hepes 40mM (pH7.4), DTT 1mM and ethylene glycol 5%) (2)10 μ L of lipid vesicles and (3)10 μ L of kinase buffer (, [2 ], [ 10 ], [2 ]³³P]γ-ATP 45μM/60nCi，MgCl₂30mM, DTT 1mM, beta-glycerophosphate 1mM, Na₃VO₄100 μ M, 0.3% sodium cholate in Hepes 40mM (pH 7.4)). After rt incubation for 180min with gentle agitation, 60 μ L of a solution containing 100 μ g of neomycin-coated PVT SPA beads in PBS containing ATP 10mM and MEDTA 5mM was added to stop the reaction. Incubation at rt for a further 60min with gentle agitation allowed the phospholipids to bind to neomycin-SPA beads. 1500x g precipitation of neomycin-coated PVT SPA beads for 5min, after centrifugation in Wallac Microbeta^TMScintillation counting in a plate counter and quantification of the radioactivity PtdIns (3) P.

Indicating that PI3K gamma value is IC₅₀I.e. the amount required to achieve 50% inhibition of the target. The values indicated that the oxazolidinone-vinyl fused-benzene derivatives of the invention have comparable efficacy against PI3K gamma.

The compounds of formula (I) tested showed an Inhibition (IC) of less than 2. mu.M, more preferably.1. mu.M, for PI 3K. gamma₅₀)。

Table 1 lists examples of inhibitory activity of test compounds 41, 61, 66, 73, 103, 107 and 110.

Table 1: IC of oxazolidinone-vinyl fused-benzene derivatives to PI3K gamma₅₀Value of

Example No.	PI3Kγ，IC(μM)
Example No.	PI3Kγ，IC(μM)	41	＜1
61	＜1	41	＜1
61	＜1	66	＜1
73	＜1	66	＜1
73	＜1	103	＜1
107	＜1	103	＜1
107	＜1	110	＜1

b) Cell-based ELISA for monitoring PI3K inhibition

Measurement of Akt/PKB phosphorylation in macrophages following C5a stimulation:

raw 264: raw 264-7 macrophages (cultured in DMEM-F12 medium containing 10% fetal bovine serum and antibiotics) were placed in 96MTP at 20000 cells/well 24h before cell stimulation. Cells were starved for 2h and pretreated with inhibitor for 20min before stimulating the cells with 50nM complement 5a (C5 a; which is a well known chemokine that stimulates cells used). After stimulation, cells were fixed with 4% formaldehyde for 20min and washed 3 times with PBS containing 1% Triton X-100 (PBS/Triton). At 0.6% H₂O₂And 0.1% sodium azide for 20min in PBS/Triton, and the endogenous peroxidase was blocked by 3 washes with PBS/Triton. Cells were then blocked by incubation with 10% fetal bovine serum (PBS/Triton) for 60 min. Phosphorylated Akt/PKB was then detected by incubation overnight at 4 ℃ with a 800-fold dilution of primary antibody (anti-phosphoserine 473 Akt IHC, Cell Signaling) in PBS/Triton containing 5% Bovine Serum Albumin (BSA). After 3 washes with PBS/Triton, cells were incubated with peroxidase-conjugated goat-anti-rabbit antibody (diluted with 5% BSAPBS/Triton 1/400) for 60min, washed 3 times with PBS/Triton, 2 times with PBS, and then 100. mu.L of substrate reagent solution (R)&D) Incubating for 20min, adding 50 μ M1M H₂SO₄The reaction was terminated and the absorbance was measured at 450 nm.

The values shown reflect the percent inhibition of AKT phosphorylation compared to basal levels. The values indicate a clear effect of the oxazolidinone-vinyl fused-benzene compounds on activation of AKT phosphorylation in macrophages.

The compounds of examples 1, 19, 66 and 107 completely (about 100%) inhibited C5 a-mediated AKT phosphorylation at 10 μ M use. Examples 17, 19 or 73 inhibited 95% of C5 a-mediated AKT-phosphorylation at 1. mu.M.

Claims

1. A compound of formula (Ia)

And the use of a pharmaceutically acceptable salt of the compound in the manufacture of a medicament for the prevention and/or treatment of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplant rejection or lung injury,

in formula (Ia):

v and W are each independently O, S or-NR³Wherein R is³Is H or C₁-C₆-an alkyl group;

g is C₁-C₅Alkylene or C₁-C₅An alkenylene group;

o and m are each independently 0 or 1;

q is an integer of 0 to 4;

Y¹is S, O or-NH;

z is S or O;

R¹is H;

R²selected from H, amino, C₂-C₆-alkenyl, C₁-C₆-alkanoyloxy, C₃-C₈-heterocycloalkyl, or C₁-C₆-an alkylaryl group;

n is 0, 1 or 2.

2. Use of a compound according to claim 1, wherein the disease is selected from multiple sclerosis, psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation.

3. Use of a compound according to claim 2, characterized in that the brain infection/inflammation is meningitis or encephalitis.

4. The compound for use according to claim 1, wherein the disease is selected from alzheimer's disease, huntington's disease, CNS trauma, stroke or ischemic disease.

5. Use of a compound according to claim 1, wherein the disease is selected from arteriosclerosis, cardiac hypertrophy, cardiac myocyte insufficiency, hypertension or vasoconstriction.

6. The compound for use according to claim 1, wherein the disease is selected from chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, platelet aggregation/activation, skeletal muscle atrophy/hypertrophy, self cell aggregation in cancer tissue, pancreatitis, multi-organ failure, angiogenesis, invasive metastasis, acute and chronic bacterial and viral infections, sepsis, graft rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial injury in lung or general lung airway inflammation.

7. Use of a compound according to claim 6, characterized in that said invasive metastasis is melanoma or Kaposi's sarcoma.

8. Use according to any one of claims 1 to 7, wherein Y is¹Oxygen.

9. The use according to any one of claims 1 to 7, wherein n is 1 or 2, R¹And R²Are all H.

10. Use of a compound according to any one of claims 1 to 7, wherein n is 0.

11. The use according to claim 1, wherein the thiazolidinone-vinyl fused benzene derivative has the structure of formula (Ib):

wherein Y is¹、R¹、R²V, Z, W, m, n, o, q are as defined in claim 1, p is an integer from 1 to 4.

12. The use according to claim 1 or 11, wherein the thiazolidinone-vinyl fused benzene derivative has the structure of formula (Ic):

wherein W and R¹And Y¹As defined in claim 1.

13. The use according to claim 1 or 11, wherein the thiazolidinone-vinyl fused benzene derivative has the structure of formula (Id):

wherein R is¹、R²Z and n are as defined in claim 1, o is 0 or 1, p is an integer from 1 to 4 and q is an integer from 0 to 4.

14. Use of a compound according to claim 1, wherein Z is 0, m is 0, n is 1, q is 1, R¹And R²Each as defined in claim 1.

15. Use of a compound according to claim 1, wherein m is 1, n is 0, q is 0, R is¹And R²Each as defined in claim 1.

16. The use according to claim 1, wherein m is 0, n is 1, q is 0, R is¹And R²Each as defined in claim 1.

17.Use of a compound according to claim 11, wherein Z is 0, m is 0, n is 1, p is 1 or 2, q is 1, R is¹And R²Each as defined in claim 1.

18. Use of a compound according to claim 11, wherein m is 1, n is 0, p is 1 or 2, q is 0, R is¹And R²Each as defined in claim 1.

19. The use according to claim 11, wherein m is 0, n is 1, p is 1 or 2, q is 0, R¹And R²Each as defined in claim 1.

20. The use according to claim 1 or 11 for modulating PI3 kinase activity.

21. The use of claim 20, for the modulation of PI3 kinase activity is inhibition of PI3 kinase activity.

22. The use of claim 20, wherein the PI3 kinase is PI3 kinase γ.

23. Thiazolidinone-vinyl fused benzene derivatives of the formula (II-a)

Wherein A is selected from dioxole, dioxin, dihydrofuran, furyl or dihydrofuryl, oxazinyl or dihydrooxazinyl, pyridyl, isoxazolyl, oxazolyl, naphthyl or dihydronaphthyl, pyrimidinyl, triazolyl, imidazolyl, piperazinyl, thiazolidinyl, thiadiazolyl, oxadiazolyl;

R²selected from H, halogen, acyl, amino, C₁-C₆Alkyl radical, C₂-C₆-alkenesBase, C₂-C₆-alkynyl, C₁-C₆-alkylcarboxy radical, C₁-C₆-alkyl acyl radical, C₁-C₆Alkyl alkoxycarbonyl, C₁-C₆-alkylaminocarbonyl radical, C₁-C₆-alkanoyloxy, C₁-C₆-alkyl acylamino, C₁-C₆Alkyl ureido, C₁-C₆Alkyl carbamates, C₁-C₆-alkylamino radical, C₁-C₆Alkyl alkoxy, C₁-C₆Alkyl sulfanyl, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, C₁-C₆-alkylsulfonylaminoaryl, aryl, C₃-C₈-cycloalkyl or heterocycloalkyl, C₁-C₆Alkyl aryl radical, C₂-C₆-alkenylaryl radical, C₂-C₆Alkynylaryl, carboxyl, cyano, hydroxyl, C₁-C₆-alkoxy, nitro, acylamino, ureido, sulfonylamino, sulfanyl, or sulfonyl.

24. Thiazolidinone-vinyl fused benzene derivatives of formula (II)

And pharmaceutically acceptable salts of the benzene derivatives, wherein:

Z、Y¹、R¹、R²as defined in claim 1, n is 0 or 1.

25. Thiazolidone-vinyl fused benzene derivatives according to claim 24 wherein Y is¹Is 0.

26. Thiazolidone-vinyl fused benzene derivatives according to claim 24 or 25 wherein R¹Is selected from C₁-C₆Alkyl radical, C₁-C₆Alkyl aryl, C₃-C₈-cycloalkyl or heterocycloalkyl, C₁-C₆Alkyl aryl radical, C₂-C₆-alkenylaryl or C₂-C₆-alkynylaryl.

27. Thiazolidinone-vinyl fused benzene derivatives of formula (III)

And pharmaceutically acceptable salts of the benzene derivatives,

wherein R is¹And R²As defined in claim 1.

28. Thiazolidinone-vinyl fused benzene derivatives of the formulae (IV), (V) and (VI)

Wherein R is¹Selected from hydrogen, halogen, cyano, C₁-C₆Alkyl radical, C₁-C₆-alkoxy, acyl, alkoxycarbonyl, R2 being as defined in claim 1.

29. Thiazolidinone-vinyl fused-benzene derivatives according to any of claims 23 to 28 selected from:

5- (1, 3-benzodioxol-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (1, 3-benzodioxol-5-ylmethylene) -2-thioxo-1, 3-thiazolidin-4-one

5- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (2, 3-dihydro-1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (1-benzofuran-5-ylmethylene) -1, 3-thiazolidine-2, 4-dione

5- (1, 3-benzodioxol-5-ylmethylene-2-imino-1, 3-thiazolidin-4-one

5-quinolin-6-ylmethylene-thiazolidine-2, 4-diones

5-quinolin-6-ylmethylene-2-thioxo-thiazolidin-4-one

2-imino-5-quinolin-6-ylmethylene-thiazolidin-4-one

5- (3-methyl-benzo [ d ] isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (4-phenyl-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

5- [ (4-amino-quinazolin-6-yl) methylene ] -1, 3-thiazolidine-2, 4-dione

5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

5- (4-methoxy-quinazolin-6-ylmethylene) -thiazolidine-2, 4-dione

2-imino-5- (4-methylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

2-imino-5- (4-piperidinyl-quinazolin-6-ylmethylene) -thiazolidin-4-one

2-imino-5- (4-dimethylamino-quinazolin-6-ylmethylene) -thiazolidin-4-one

5- (2-methyl-2H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-methyl-3H-benzotriazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-ethyl-3H-benzimidazol-5-ylmethylene) -thiazolidine-2, 4-dione

5-quinoxalin-6-ylmethylene-thiazolidine-2, 4-dione

5-quinoxalin-6-ylmethylene-2-thioxo-thiazolidin-4-ones

2-imino-5-quinoxalin-6-ylmethylene-thiazolidin-4-ones

5-benzothiazol-6-ylmethylene-thiazolidine-2, 4-diones

5- (3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5- (2-bromo-3-methyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-bromo-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

3- [5- (2, 4-dioxo-thiazolidin-5-ylmethyl) -benzofuran-3-yl ] -acrylic acid

5- (3, 4-2H-dihydro-benzo [1, 4] oxazin-6-ylmethylene) -thiazolidine-2, 4-dione

[6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] oxazin-4-yl ] acetic acid methyl ester

N-benzyl-2- [6- (2, 4-dioxo-thiazolidin-5-ylidenemethyl) -3-oxo-2, 3-dihydro-benzo [1, 4] oxazin-4-yl ] -acetamide

5- (2-chloro-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-amino-benzo [ d ] isoxazol-5-ylmethylene) -thiazolidine-2, 4-dione

5- (3-phenylethynyl-benzofuran-5-ylmethylene) -thiazolidine-2, 4-dione

5-benzo [1, 2, 5] thiadiazol-5-ylmethylene-thiazolidine-2, 4-diones

5-benzo [1, 2, 5] oxadiazol-5-ylmethylene-thiazolidine-2, 4-dione

5- (2-methyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

5- (2-carboxymethyl-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

5- (2-fluoro-benzofuran-6-ylmethylene) -thiazolidine-2, 4-dione

30. A thiazolidinone-vinyl fused benzene derivative according to any one of claims 23 to 28 for use as a medicament.

31. A pharmaceutical composition comprising at least one thiazolidinone-vinyl fused benzene derivative according to any of claims 23 to 28 and a pharmaceutically acceptable carrier, diluent or excipient therefor.

32. Use of a thiazolidinone-vinyl fused benzene derivative according to any one of claims 23 to 28 for the manufacture of a medicament for the prevention and/or treatment of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, graft rejection or lung injuries.

33. A thiazolidinone-vinyl fused benzene derivative according to claim 32 wherein the disease is selected from multiple sclerosis, psoriasis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel disease, lung inflammation, thrombosis or brain infection/inflammation.

34. A thiazolidinone-vinyl fused benzene derivative for use according to claim 33 wherein the brain infection/inflammation is meningitis or encephalitis.

35. A thiazolidinone-vinyl fused benzene derivative for use according to claim 32 wherein the disease is selected from alzheimer's disease, huntington's disease, CNS trauma, stroke or ischemic conditions.

36. A thiazolidinone-vinyl fused benzene derivative according to claim 32 wherein the disease is selected from arteriosclerosis, cardiac hypertrophy, cardiac myocyte insufficiency, hypertension or vasoconstriction.

37. A thiazolidinone-vinyl fused benzene derivative for use according to claim 32 wherein the disease is selected from chronic obstructive pulmonary disease, anaphylactic shock fibrosis, psoriasis, allergic diseases, asthma, stroke or ischemic conditions, ischemia-reperfusion, platelet aggregation/activation, skeletal muscle atrophy/hypertrophy, autopellular aggregation in cancer tissue, pancreatitis, multi-organ failure, angiogenesis, invasive metastasis, acute and chronic bacterial and viral infections, sepsis, graft rejection, glomerulosclerosis, glomerulonephritis, progressive renal fibrosis, endothelial and epithelial injury in lung or general lung airway inflammation.

38. A thiazolidinone-vinyl fused benzene derivative for use according to claim 37 wherein the invasive metastasis is melanoma or kaposi's sarcoma.

39. The use of any one of claims 32-38, for modulating PI3 kinase activity.

40. The use of claim 39, wherein said modulating PI3 kinase activity is inhibiting PI3 kinase activity.

41. The use of claim 39, wherein the PI3 kinase is PI3 kinase- γ.

42. A process for preparing thiazolidinone-vinyl fused benzene derivatives of formula (II) according to claim 24 comprising the steps of:

wherein R is¹、R²、Y¹And Z is as defined in claim 1, n is 0 or 1.

43. A process for preparing thiazolidinone-vinyl fused benzene derivatives according to claim 27 of formula (III) comprising the steps of:

wherein R is¹、R²As defined in claim 1, Y¹Is oxygen.