KR101319593B1 - Methylidene-heterocyclic compounds - Google Patents

Abstract

The present invention relates to a methylidene-heterocyclic compound, a pharmaceutically acceptable salt thereof, a method for preparing the compound, and a pharmaceutical composition containing the compound as an active ingredient.
Since the compound of the present invention has a strong inhibitory activity against IκB kinase-b (IKK-b), which is involved in the process of NF-κB activation, rheumatoid arthritis, juvenile arthritis, asthma, Spondyloarthopathies, gout, osteoarthritis, allergic rhinitis, atopic dermatitis, gallbladder, systemic lupuserythematosus, psoriasis, ulcerative colitis, systemic inflammatory syndrome, pneumonia, multiple It is useful as a medicament for the treatment of various inflammatory diseases including myositis and nodular polyarteritis.

Description

Methylidene-heterocyclic compounds

The present invention relates to a methylidene-heterocyclic compound, a pharmaceutically acceptable salt thereof, a method for preparing the compound, and a composition for preventing or treating inflammatory diseases containing the compound as an active ingredient.

Nuclear Factor kappa B (NF-κB) is a transcription factor that plays a key role in inflammatory reactions and autoimmune diseases. It is a homodimer or heterodimer consisting of five proteins: p50, p52, c-Rel, RelA, and RelB. Protein complex present. These five proteins have RHD (Rel homology domain) that forms dimers at the N terminus or is involved in DNA binding. In normal state, NF-κB binds to its inhibitor, IκB protein, forms an IKK complex, and is present in the cytoplasm in an inactive state by obscuring the nuclear localization signal of NF-κB. However, when stimulated by bacterial or viral infections, stress, oxidants, various cytokines, etc., the IKK complex is activated and NF-κB is degraded from IκB. That is, when the IKK complex is activated, it phosphorylates two serine groups (IκBα is Ser32 and Ser36 and IκBβ is Ser19 and Ser23) at the N- terminus of the IκB protein, and phosphorylated IκB is poly-ubiquitin The degradation of IκB is induced by proteosomes rapidly through poly ubiquitination. The active NF-κB released from IκB enters the nucleus and binds to the target gene to induce the expression of various genes encoding proteins involved in cell proliferation, cell death inhibition, immune and inflammatory responses.

Recently, IKK-β in the IKK complex has been shown to be the most attractive target for the development of inflammatory diseases in the NF-κB activation pathway through various animal experiments, and thus, strong anti-inflammatory and immunomodulation in vivo through IKK-β inhibition. By causing the effect can be expected to treat the various inflammatory diseases. Proteins regulated by the transcription factor NF-κB are important for normal physiological functions such as development and immune responses, but abnormal NF-κB activation is associated with arthritis and asthma (Yang L. et al., J. Exp. Med. 188). , 1739-1750, 1998; Barnes P., et al, Trends Pharmacol., Therapeut. 18, 46-50, 1997), allergic rhinitis, atopic dermatitis, gallbladder, systemic lupus erythematosus, psoriasis, ulcerative colitis, Various inflammatory diseases including systemic inflammatory syndrome, pneumonia, multiple myositis, nodular polyarteritis, Alzheimer's disease (Keith T. Akama et al, Proc. Natl. Acad. Sci. USA, 95, 5795-5800, 1998) It is known to be closely related to. Therefore, by regulating abnormal activation of NF-κB, it is possible to suppress the development or progression of degenerative and refractory diseases, and to treat refractory diseases caused by abnormal cell death and inflammatory responses. Rheumatoid arthritis is a representative example of a degenerative disease that can be treated by regulating abnormal activation of NF-κB.

Rheumatoid arthritis is a degenerative disease known to occur mainly in the elderly, but recently, the incidence of young women is increasing rapidly and attention is focused on its treatment. Rheumatoid arthritis causes deformity and long-term damage within two years, and if it is not treated early in the disease, it can cause mental illnesses such as depression due to the cost of treatment and severe pain. More than half of patients with rheumatoid arthritis (65%) have mental disorders, with 45% experiencing depression and 13% feeling anxious. Thus, rheumatoid arthritis is not only a problem of the disease itself, but also a mental disease such as depression, which is a big social problem. Rheumatoid arthritis, which is known to affect 0.5% to 1% of the world's population, is a chronic inflammatory disease that develops around the synovial membrane, cartilage, and bones when the synovial membrane, the thin film that surrounds the joint, becomes inflamed. Multiple arthritis involving the joints. In general, it appears 2 to 3 times higher in females than in males, and can occur at all ages, but shows a high incidence in mainly 40 to 60s. In addition, symptoms appear symmetrically, and involve other organs besides joints, and may be accompanied by diseases such as vasculitis, pulmonary fibrosis, and amyloidosis. The cause of the development of rheumatoid arthritis has not been clearly identified, but autoimmune phenomena attacking the human body due to the abnormality of the immune system defending the body against foreign substances is known as the main mechanism. In general, the cause of the autoimmune phenomenon can be seen as environmental factors and genetic factors, such as bacterial or viral infection, and is known to be easy to occur even after physical or mental stress.

Drugs currently used for the treatment of rheumatoid arthritis include nonsteroidal analgesic drugs (NSAIDs), which alleviate symptoms, and anti-rheumatic drugs (DMARDs), which alleviate the progression of arthritis by suppressing adverse immune reactions. There is a biological agent being used. Among biologics, TNF inhibitors Enbrel, Humira and Remicade currently occupy the majority of the rheumatoid arthritis market. However, nonsteroidal analgesic drugs (NSAIDs) and anti-rheumatic drugs (DMARDs) have significant side effects, and the number of patients who do not respond to TNF inhibitors is increasing.

Therefore, the present inventors have synthesized a novel compound using a high-efficiency screening system to develop a therapeutic agent that inhibits the activity of IKK-β, which plays an important role in the NF-κB activity pathway, which is closely related to various inflammatory diseases. The novel compounds synthesized in the present invention inhibit the activity of IKK-β to complete the present invention by confirming through experiments that it is useful for treating various inflammatory diseases such as rheumatoid arthritis.

It is an object of the present invention to provide a methylidene-heterocyclic compound of novel structure and a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the novel compound.

Further, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of inflammatory diseases containing the novel compound as an active ingredient.

In order to achieve the above object, the present invention is a methylidene-heterocyclic compound represented by the following formula (1), a pharmaceutically acceptable salt thereof, a method for preparing the compound, and preventing an inflammatory disease comprising the compound as an active ingredient And a therapeutic pharmaceutical composition.

[Formula 1]

In Formula 1,

X is O; Or S,

Y is S; NR ³ ; Or CH ₂ ,

R ¹ is a hydrogen atom; C ₁ -C ₁₅ alkyl unsubstituted or substituted with a substituent selected from the group consisting of hydroxy, acetoxy, NR ⁴ R ⁵ and C (O) NR ⁴ R ⁵ ; Or phenyl unsubstituted or substituted with a substituent selected from the group consisting of halo and carbamoyl,

R ² is carbamoyl; Phenyl substituted or unsubstituted C ₂ -C ₆ alkenyl; Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, ildolyl and pyridinyl; Naphthyl; Or a substituent or non-substituted substituent including a substituent selected from the group consisting of halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁴ R ⁵ , R ⁴ R ⁵ NC ₁ -C ₆ alkoxy and phenoxy Ring phenyl, the heteroaryl may be unsubstituted or substituted with a substituent selected from the group consisting of phenyl or carbamoylphenyl, and the phenoxy is halo, cyano, nitro, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ alkylsulfonyl, aminosulfonyl, acetamido omicron], carbamoyl, mono (C ₁ ~C ₆ alkyl) aminocarbonyl And it may be unsubstituted or substituted with a substituent selected from the group consisting of di (C ₁ -C ₆ alkyl) aminocarbonyl,

R ³ is a hydrogen atom; Or C ₁ -C ₆ alkyl,

R ⁴ and R ⁵ are each hydrogen atom; Or C ₁ -C ₆ alkyl, R ⁴ and R ⁵ may be bonded to each other to form a heterocycle selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl, wherein the heterocycle It may be substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, amino, acetamino, acetyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkylsulfonyl and benzyl.

The methylidene-heterocyclic compound represented by Formula 1 according to the present invention effectively inhibits the activity of IKK-β, which plays an important role in the NF-κB activity pathway. Therefore, the methylidene-heterocyclic compound represented by Chemical Formula 1 according to the present invention can be usefully used as an agent for preventing and treating various inflammatory diseases caused by abnormal activation of NF-κB.

Inflammatory diseases in the present invention, rheumatoid arthritis, juvenile arthritis, asthma, asthma, spondyloarthopathies, gout, osteoarthritis, allergic rhinitis, atopic dermatitis , Pneumonia, systemic lupuserythematosus, psoriasis, ulcerative colitis, systemic inflammatory syndrome, pneumonia, multiple myositis, nodular polyarteritis.

Preferably in the methylidene-heterocyclic compound represented by the formula (1) according to the present invention

X is O; Or S,

Y is S; NR ³ ; Or CH ₂ ,

R ¹ is a hydrogen atom; C ₁ -C ₆ alkyl; (C ₅ -C ₇ cycloalkyl) C ₁ -C ₆ alkyl; Substituted (C ₅ -C ₇ cycloalkyl) C ₁ -C ₆ alkyl comprising a substituent of hydroxy or acetoxy; Amino-C ₁ ~C ₆ alkyl, [mono (C ₁ ~C ₆ alkyl) amino] C ₁ ~C ₆ alkyl, [di (C ₁ ~C ₆ alkyl) amino] C ₁ ~C ₆ alkyl, (pyrrolidine 1-yl) C ₁ ~C ₆ alkyl, (morpholine-1-yl) C ₁ ~C ₆ alkyl, (piperidin-1-yl) C ₁ ~C ₆ alkyl, (4-amino-piperidine 1-yl) C ₁ ~C ₆ alkyl, [4- (4-acetamido-amino) piperidin-1-yl] C ₁ ~C _{6 alkyl, [4 - ((C 1} ~C 6 alkyl) sulfonyl) P 1-yl] C ₁ ~C ₆ alkyl, (piperazin-1-yl) C ₁ ~C ₆ alkyl, [4- (C ₁ ~C ₆ alkyl) piperazin-1-yl] C ₁ ~ C ₆ alkyl, [4- (C ₂ -C ₆ alkenyl) piperazin- ₁ -yl] C ₁ -C ₆ alkyl, (4-phenylpiperazin- ₁ -yl) C ₁ -C ₆ alkyl, (4 -benzyl-piperazin-1-yl) C ₁ ~C ₆ alkyl, [4-hydroxy-piperazin-1-yl] C ₁ ~C ₆ alkyl, (4-acetyl-piperazin-1-yl) C ₁ ~C _{6 alkyl, [4 - ((C 1} ~C 6 alkyl) sulfonyl) piperazin-1-yl] C ₁ ~C ₆ alkyl, [4- (C ₁ ~C ₆ alkyl) piperazin-1-ylcarbonyl Nil] C ₁ -C ₆ alkyl; Phenyl; Or phenyl substituted with halo or carbamoyl,

R ² is carbamoyl; C ₂ -C ₆ alkenyl; Phenyl substituted C ₂ -C ₆ alkenyl; Furanyl; Cyenyl; Pyrrolyl; Pyridinyl; Indole; Naphthyl; Phenyl; Halo, hydroxy, C ₁ -C ₆ alkyl, amino, mono (C ₁ -C ₆ alkyl) amino, di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkoxy, aminoC ₁ -C ₆ alkoxy , [Mono (C ₁ -C ₆ alkyl) amino] C ₁ -C ₆ alkoxy, [di (C ₁ -C ₆ alkyl) amino] C ₁ -C ₆ alkoxy, [piperazin- ₁ -yl] C 1- Substituted phenyl comprising a substituent selected from the group consisting of C ₆ alkoxy and [4- (C ₁ -C ₆ alkyl) piperazin- ₁ -yl] C ₁ -C ₆ alkoxy; Phenoxyphenyl; Halo, cyano, nitro, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, aminosulfonyl, acetamy Substituted phenoxyphenyl comprising a substituent selected from the group consisting of carbamoyl, mono (C ₁ -C ₆ alkyl) aminocarbonyl, and di (C ₁ -C ₆ alkyl) aminocarbonyl; Phenylfuranyl; Substituted phenylfuranyl including carbamoyl,

R ³ is a hydrogen atom; Or C ₁ -C ₆ alkyl.

More preferably in the methylidene-heterocyclic compound represented by Formula 1 according to the present invention

X is O, or S,

Y is S, NH, or CH ₂ ,

R ¹ is hydrogen atom, methyl, (diethylamino) ethyl, (diethylamino) propyl, (pyrrolidin-1-yl) propyl, (piperidin-1-yl) propyl, (4-aminopi Ferridin-1-yl) propyl, (4-methanesulfonylpiperidin-1-yl) propyl, (4-acetaminopiperidin-1-yl) propyl, (morpholin-1 -yl) propyl, ( Piperazin-1-yl) methyl, (piperazin-1-yl) ethyl, (piperazin-1-yl) propyl, (piperazin-1-yl) butyl, (piperazin-1-yl) pentyl, ( 4-methylpiperazin-1-yl) methyl, (4-methylpiperazin-1-yl) ethyl, (4-methylpiperazin-1-yl) propyl, (4-isopropylpiperazin-1-yl) Propyl, (4-prop-2-enylpiperazin-1-yl) propyl, (4-hydroxypiperazin-1-yl) propyl, (4-acetylpiperazin-1-yl) propyl, (4- Aminopiperazin-1-yl) propyl, (4-phenylpiperazin-1-yl) propyl, (4-benzylpiperazin-1-yl) propyl, (4-methylpiperazin-1-yl) butyl, ( 4-methylpiperazin-1-ylcarbonyl) butyl, (4-methylpipera Is 1-yl) pentyl, (4-hydroxy-1-yl) pentyl, (4-acetoxy-cyclo-hexyl) propyl, 4-chlorophenyl, 4-fluorophenyl, or 4-carbamoyl-phenyl,

R ² represents carbamoyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 4 - tert - butylphenyl, 3-methoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 4-di Methylaminophenyl, 4- (dimethylaminopropoxy) phenyl, 4- (diethylaminopropoxy) phenyl, (4-phenylpiperazin-1-yl) propoxyphenyl, (4-phenylpiperazin-1- 1) butoxyphenyl, (4-phenylpiperazin-1-yl) pentoxyphenyl, (4-chlorophenoxy) phenyl, (4-fluorophenoxy) phenyl, (4-bromophenoxy) phenyl, (4-cyanophenoxy) phenyl, (4-methylphenoxy) phenyl, (4- tert -butylphenoxy) phenyl, (4-trifluoromethylphenoxy) phenyl, (4-methoxyphenoxy) Phenyl, (4-nitrophenoxy) phenyl, (4-aminosulfonylphenoxy) phenyl, (4-methanesulfonylphenoxy) phenyl, (2-carbamoylphenoxy) phenyl, (3-carbamoylphenoxy C) or (4-carbamoylphenoxy) phenyl.

Specific examples of the methylidene-heterocyclic compound represented by Formula 1 are as follows:

(1) 5- (4-hydroxyphenyl) methylene-3- (4-hydroxyphenyl) -2-thioxo-4-thiazolidinone;

(2) 5- [4- (3-diethylaminopropoxy) phenyl] methylene-3- (4-hydroxyphenyl) -2-thioxo-4-thiazolidinone hydrochloride;

(3) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- (4-hydroxyphenyl) -2-thioxo-4-thiazolidinone;

(4) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- (3-methoxyphenyl) -2-thioxo-4-thiazolidinone;

(5) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- (3-methoxyphenyl) -2-thioxo-4-thiazolidinone;

(6) 5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-3- (3-methoxyphenyl) -2-thioxo-4-thiazolidinone;

(7) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- (3-methoxyphenyl) -2-thioxo-4-thiazolidinone;

(8) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (4-hydroxyphenyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(9) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (4-hydroxy-3-methoxy phenyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(10) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (3,4-dichlorophenyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(11) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (2,6-dichlorophenyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(12) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (4-dimethylaminophenyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(13) 3- [4- (3-diethylaminopropoxy) phenyl] -5- {3- [4-dimethylaminophenyl] -2-propene-1-ylidene} -2-thioxo- 4-thiazolidinone hydrochloride;

(14) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (3-furanyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(15) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (3-thienyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(16) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (3-pyrrolyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(17) 3- [4- (3-diethylaminopropoxy) phenyl] -5- ( 1H -indol-2-yl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(18) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (1-naphthyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(19) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (3,3-diphenyl-2-propene-1-ylidene) -2-thioxo-4-thia Zolidinone hydrochloride;

(20) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (2-pyridinyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(21) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (3-pyridinyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(22) 3- [4- (3-diethylaminopropoxy) phenyl] -5- (4-pyridinyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(23) 5- (4- tert -butylphenyl) methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride;

(24) 3- [4- (3-diethylaminopropoxy) phenyl] -5- [4- (3-diethylaminopropoxy) phenyl] methylene-2-thioxo-4-thiazolidinone di Hydrochloride;

(25) 5- (4-carbamoylphenyl) methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazolidinone;

(26) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazolidinone;

(27) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazolidinone;

(28) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(29) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(30) 5- [5- (3-carbamoylphenyl) -2-furanyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazoli Dinone hydrochloride;

(31) 5- [5- (4-carbamoylphenyl) -2-furanyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2-thioxo-4-thiazoli Dinone hydrochloride;

(32) 5- (3,4-dichlorophenyl) methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride;

(33) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thia Zolidinone hydrochloride;

(34) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(35) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(36) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(37) 5- (3,4-dichlorophenyl) methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thiazolidinone hydrochloride ;

(38) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone hydrochloride;

(39) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;

(40) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;

(41) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;

(42) 5- [5- (3-carbamoylphenyl) -2-furanyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone;

(43) 5- [5- (4-carbamoylphenyl) -2-furanyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone hydrochloride;

(44) 5- (3,4-dichlorophenyl) methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thiazolidinone hydrochloride ;

(45) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone hydrochloride;

(46) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;

(47) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;

(48) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;

(49) 3- {4- [3- (4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2-thioxo-4 Thiazolidinone bis-trifluoroacetic acid;

(50) 3- {4- [3- ( N- acetyl-4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2- Thioxo-4-thiazolidinone;

(51) 5- [4- (4-chlorophenoxy) phenyl] methylene3- {4- [3- ( N- methylsulfonyl-4-amino-1-piperidinyl) propoxy] phenyl} -2 -Thioxo-4-thiazolidinone;

(52) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-hydroxy-1-piperidinyl) propoxy] phenyl} -2-thioxo4 Thiazolidinone;

(53) 3- {4- [3- (4-acetyloxy-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2-thioxo- 4-thiazolidinone;

(54) 5- (3,4-dichlorophenyl) methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone dihydrochloride;

(55) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2 -Thioxo-4-thiazolidinone dihydrochloride;

(56) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(57) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(58) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(59) 5- [4- (4-carboxyphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;

(60) 5- {4- [4- (dimethylaminocarbonyl) phenoxy] phenyl} methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl}- 2-thioxo-4-thiazolidinone;

(61) 5- [4- (4-aminosulfonylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo -4-thiazolidinone dihydrochloride;

(62) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(63) 5- [4- (4-trifluoromethylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thio Oxo-4-thiazolidinone dihydrochloride;

(64) 5- [4- (4-methylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;

(65) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(66) 5- [4- (4- tert -butylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo -4-thiazolidinone dihydrochloride;

(67) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(68) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;

(69) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(70) 3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone dihydrochloride;

(71) 3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene-2-thioxo- 4-thiazolidinone dihydrochloride;

(72) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;

(73) 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(74) 5- {4- [4- (methylsulfonylamino) phenoxy] phenyl} methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2 -Thioxo-4-thiazolidinone;

(75) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4-thiazoli Dinone trifluoroacetic acid;

(76) 3- {4- [3- (4-acetyl-piperazin-1-yl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2-thioxo- 4-thiazolidinone hydrochloride;

(77) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylsulfonylpiperazin-1-yl) propoxy] phenyl} -2-thioxo -4-thiazolidinone;

(78) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-benzyl-piperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(79) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4- (2-propen-1-yl) piperazin-1-yl) propoxy] Phenyl} -2-thioxo-4-thiazolidinone;

(80) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-carbamoylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(81) 5- (3,4-dichlorophenyl) methylene-3- [4- (2-diethylaminoethoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride;

(82) 3- [4- (2-diethylaminoethoxy) phenyl] -5- (3,3-diphenyl-2-propene-1-ylidene) -2-thioxo-4-thia Zolidinone hydrochloride;

(83) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- [4- (2-diethylaminoethoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(84) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- [4- (2-diethylaminoethoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(85) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (2-diethylaminoethoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;

(86) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(87) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(88) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(89) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;

(90) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -2-thioxo-4-thio Azolidinone;

(91) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -2-thioxo-4-thia Zolidinone;

(92) 3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo-4- Thiazolidinone;

(93) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -2-thioxo-4-thio Azolidinone;

(94) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(95) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2-thioxo-4 Thiazolidinone;

(96) 3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;

(97) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(98) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(99) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone;

(100) 3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;

(101) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(102) 5- {4- [4- (dimethylaminocarbonyl) phenoxy] phenyl} methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl}- 2-thioxo-4-thiazolidinone;

(103) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(104) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo-4 Thiazolidinone;

(105) 3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;

(106) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(107) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(108) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo-4 Thiazolidinone;

(109) 3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;

(110) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone;

(111) 3- [4- (4-chlorophenoxy) phenyl] -5- (4-hydroxyphenyl) methylene-2-thioxo-4-thiazolidinone hydrochloride;

(112) 3- [4- (4-chlorophenoxy) phenyl] -5- [4- (3-diethylaminopropoxy) phenyl] methylene-2-thioxo-4-thiazolidinone hydrochloride;

(113) 3- [4- (4-carbamoylphenoxy) phenyl] -5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2-thioxo- 4-thiazolidinone;

(114) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2,4-imidazolidinedione hydrochloride;

(115) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2,4-imidazolidinedione hydrochloride;

(116) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2,4-imidazolidinedione hydrochloride;

(117) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2,4-imidazolidinedione hydrochloride;

(118) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imida Zolidinedione;

(119) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imi Dazolidinedione;

(120) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imi Dazolidinedione;

(121) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2,4-imi Dazolidinedione;

(122) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2,4-imi Dazolidinedione hydrochloride;

(123) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -1-methyl-2,4-imidazolidinedione Hydrochloride;

(124) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -1-ethyl-2,4-imidazolidinedione Hydrochloride;

(125) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -1-propyl-2,4-imidazolidinedione Hydrochloride;

(126) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -1-butyl-2,4-imidazolidinedione Hydrochloride;

(127) 3- [4- (4-chlorophenoxy) phenyl] -5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2,4-imida Zolidinedione;

(128) 3- [4- (4-carbamoylphenoxy) phenyl] -5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2,4-imi Dazolidinedione;

(129) 3- [4- (4-fluorophenoxy) phenyl] -5- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2,4-imi Dazolidinedione;

(130) 3- [4- (4-fluorophenoxy) phenyl] -5- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} methylene-2,4-imi Dazolidinedione;

(131) 3- [4- (4-fluorophenoxy) phenyl] -5- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} methylene-2,4-imi Dazolidinedione;

(132) 3- [4- (4-chlorophenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-pyrroli Dindione;

(133) 3- [4- (4-carbamoylphenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-py Rollidinedione;

(134) 3- [4- (4-fluorophenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-pipe Rollidinedione;

(135) 3- [4- (4-fluorophenoxy) phenyl] methylene-1- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2,5-pipe Rollidinedione;

(136) 3- [4- (4-fluorophenoxy) phenyl] methylene-1- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2,5-pipe Rollidinedione;

(137) 1- [4- (4-chlorophenoxy) phenyl] -3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2,5-pyrroli Dindione;

(138) 1- [4- (4-carbamoylphenoxy) phenyl] -3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2,5-py Rollidinedione;

(139) 1- [4- (4-fluorophenoxy) phenyl] -3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} methylene-2,5-py Rollidinedione;

(140) 1- [4- (4-fluorophenoxy) phenyl] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} methylene-2,5-py Rollidinedione;

(141) 1- [4- (4-fluorophenoxy) phenyl] -3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} methylene-2,5-py Rollidinedione;

(142) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(143) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(144) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-isopropylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(145) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-phenylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(146) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(147) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione dihydrochloride;

(148) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(149) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(150) 5- [4- (4-methylphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;

(151) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;

(152) 3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene thiazolidine-2 , 4-dione;

(153) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;

(154) 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2,4- Diones;

(155) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;

(156) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;

(157) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;

(158) 3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-methylphenoxy) phenyl] methylene thiazolidine-2, 4-dione;

(159) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;

(160) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;

(161) 3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene thiazolidine-2 , 4-dione;

(162) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;

(163) 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine- 2,4-dione;

 (164) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;

(165) 3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} -5- [4- (4-methylphenoxy) phenyl] methylene thiazoli Din-2,4-dione;

(166) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;

(167) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;

(168) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;

(169) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thiazoli Din-2,4-dione;

(170) 3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene cya Zolidine-2,4-dione;

(171) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thiazoli Din-2,4-dione;

(172) 5- [4- (4-fluorophenoxy) benzylidine-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2, 4-dione;

(173) 4- {4-[(3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2,4-dioxazolidine-5-yridine) methyl ] Phenoxy} benzonitrile;

(174) 3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -5- [4- (4-nitrophenoxy) benzylidene] thiazolidine-2 , 4-dione;

(175) 5- [4- (4-chlorophenoxy) benzylidene] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2, 4-dione;

(176) 5- [4- (4-bromophenoxy) benzylidene] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2 , 4-dione; And

(177) 5- [4- (4-methylphenoxy) benzylidene] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2, 4-dione.

The methylidene-heterocyclic compound represented by Chemical Formula 1 according to the present invention may be used in the form of a pharmaceutically acceptable salt by a conventional method in the art. As salts, acid addition salts formed by pharmaceutically acceptable free acids are useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanthios. Obtained from non-toxic organic acids such as acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suverate Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dynatro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, claw Benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention is dissolved in a conventional method, for example, the compound represented by Chemical Formula 1 in an excess of aqueous acid solution, and the salt is water-miscible organic solvent such as methanol, ethanol, acetone or aceto. It can be prepared by precipitation using nitrile. In addition, the same amount of the compound represented by the formula (1) and the acid or alcohol in the aqueous solution may be heated and then the mixture is evaporated to dryness, or the precipitated salt may be produced by suction filtration.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Metal salts include salts of alkali metals or alkaline earth metals, and in particular, it is pharmaceutically suitable to prepare sodium salts, potassium salts or calcium salts. In order to prepare a metal salt, the compound represented by Chemical Formula 1 is dissolved in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtered to remove the undissolved compound, and the filtrate is obtained by evaporation and drying. In addition, corresponding silver salts can be prepared, and the alkali metal salts or alkaline earth metal salts prepared above are reacted with a suitable silver salt compound (eg, silver nitrate).

In addition, the methylidene-heterocyclic compound represented by Formula 1 according to the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates, and solvates that can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

The present invention also provides a method for preparing a methylidene-heterocyclic compound represented by Chemical Formula 1 according to the present invention.

The preparation method of the present invention can be divided into several methods depending on the structure of the heterocycle.

Recipe 1

The first production method is a method for preparing a compound (X = Y = S) represented by Formula 1a, wherein the heterocycle portion is rhodanine. The preparation method is as shown in Scheme 1 below,

A cyclization reaction of the aniline compound represented by the following Chemical Formula 2 to prepare a 3-phenylrhodanine compound represented by the following Chemical Formula 3 (step 1); And condensation reaction of a compound represented by the following Chemical Formula 3 with an aldehyde compound represented by R ² -C (O) H under acidic conditions to prepare a 5-methylidene-3-phenylrodanine compound represented by the following Chemical Formula 1a Step (step 2); It may be prepared by a manufacturing method comprising a.

[Reaction Scheme 1]

(In Reaction Scheme 1, R ¹ and R ² are as defined in Formula 1, respectively.)

Hereinafter, the preparation method according to Scheme 1 will be described in more detail.

First, in Step 1, the aniline compound represented by Formula 2 may be heated to reflux at a temperature of 100 ° C. to 110 ° C. in a mixed solvent of bis (carboxymethyl) trithiocarbonate, water, and alcohol to perform a cyclization reaction. At this time, the alcohol may be selected from among lower alcohols having 1 to 4 carbon atoms, the alcohol may be used in the range of 0.5 to 2 volume ratio based on water, and preferably the alcohol is mixed in the range of 1 to 1.5 volume ratio. In addition, in Step 1, a cyclization reaction may be performed by stirring the aniline compound represented by Chemical Formula 2, 1,1′-thiocarbonyldiimidazole, and mercaptoacetate in a methylene chloride solvent.

Next, in step 2, the condensation reaction may be performed by heating to reflux at a temperature of 110 ℃ to 130 ℃ in an acetic acid solvent in the presence of sodium acetate (NaOAc) base. At this time, it is preferable that the aldehyde compound represented by R <^2> -C (O) H is used from the group which consists of the following compounds.

(In the aldehyde compound structure, R ⁷ is F, Cl, Br, CN, CF ₃ , tert- Bu, NO ₂ , CH ₃ , OCH ₃ , SO ₂ CH _3, SO ₂ NH _2, CONH ₂ , and CON ( CH ₃ ) ₂ ).

Recipe 2

The second production method is a method for preparing a compound (X = O, Y = N) represented by the following Chemical Formula 1b, wherein the heterocycle portion is hydantoin. The preparation method is as shown in Scheme 2 below,

Reacting an aniline compound represented by Formula 2 with ethyl 2-isocyanatoacetate to prepare a urea compound represented by Formula 4 below (step 1); Preparing a 3-phenylhydantoin compound represented by the following Chemical Formula 5 by cyclizing the compound represented by the following Chemical Formula 4 under acidic conditions (Step 2); And condensation reaction of a compound represented by the following Chemical Formula 5 with an aldehyde compound represented by R ² -C (O) H under acidic conditions to prepare a 5-methylidene-3-phenylhydantoin compound represented by the following Chemical Formula 1b. Step (step 3); It may be prepared by a manufacturing method comprising a.

[Reaction Scheme 2]

(R ¹ , R ² , and R ³ in Scheme 2 are the same as defined in Chemical Formula 1, respectively.)

Hereinafter, the preparation method according to Scheme 2 will be described in more detail.

First, in step 1, the aniline compound represented by Chemical Formula 2 and ethyl 2-isocyanatoacetate are stirred in a conventional organic solvent such as methylene chloride to prepare a urea compound represented by Chemical Formula 4.

Next, in step 2, the compound represented by Chemical Formula 4 is heated to reflux at a temperature of 100 ° C. to 110 ° C. using 6 N HCl / ethanol (1: 1) solvent to perform a cyclization reaction.

Next, in step 3, the condensation reaction is performed by heating and refluxing the compound represented by Chemical Formula 5 at 110 ° C to 130 ° C in the presence of an aldehyde compound, pyrrolidine, and MgSO ₄ . At this time, the aldehyde compound may be used typically benzaldehyde compound, the benzaldehyde compound is preferably used a phenoxy benzaldehyde compound substituted with halo or carbamoyl.

Recipe 3

The third manufacturing method is a method for preparing a compound (X = O, Y = CH ₂ ) represented by the following Chemical Formula 1c, wherein the heterocycle portion is succinimide. The preparation method is as shown in Scheme 3 below,

Reacting an aniline compound represented by Formula 2 with maleic anhydride to prepare an amide compound represented by Formula 6 (step 1); Preparing a N- phenyl-1 H -pyrrole-2,5-dione compound represented by the following Chemical Formula 7 by cyclizing the compound represented by the following Chemical Formula 6 under acidic conditions (step 2); And witig reacting the compound represented by Formula 7 with an aldehyde compound represented by R ² -C (O) H to prepare 3-methylidene-1-phenylsuccinimide compound represented by Formula 1c. (Step 3); It may be prepared by a manufacturing method comprising a.

Scheme 3

(In Reaction Scheme 3, R ¹ and R ² are each as defined in Formula 1 above.)

Hereinafter, the preparation method according to Scheme 3 will be described in more detail.

First, in step 1, the aniline compound represented by Chemical Formula 2 and maleic anhydride are reacted using a conventional organic solvent such as tetrahydrofuran.

Next, in step 2, the compound represented by Chemical Formula 6 is heated and refluxed at a temperature of 110 ° C. to 130 ° C. in an acetic anhydride solvent in the presence of sodium acetate (NaOAc) base to perform a cyclization reaction.

Next, in step 3, the condensation reaction is performed by heating and refluxing the compound represented by Chemical Formula 7 at a temperature of 70 ° C. to 80 ° C. using an aldehyde compound, triphenylphosphine (PPh ₃ ), and tetrahydrofuran solvent. to be. At this time, the aldehyde compound may be used typically benzaldehyde compound, the benzaldehyde compound is preferably used a phenoxy benzaldehyde compound substituted with halo or carbamoyl.

Recipe 4

The fourth manufacturing method is a method for preparing a compound (X = O, Y = S) represented by the following Chemical Formula 1d, wherein the heterocycle portion is a glitazone. The preparation method is as shown in Scheme 4 below,

Reacting an aniline compound represented by Chemical Formula 2 with chloroacetyl chloride to prepare 2-chloro- N- phenylacetylamide compound represented by Chemical Formula 8 (step 1); Reacting a compound represented by Formula 8 with potassium thiocyanate to prepare a 2-imino- N- phenylthiazolidin-4-one compound represented by Formula 9 (step 2); Reacting the compound represented by Formula 9 under acidic conditions to prepare an N- phenyl-glitazone compound represented by Formula 10 (step 3); And condensation-reacting the compound represented by Chemical Formula 10 with an aldehyde compound represented by R ² -C (O) H to prepare 3-methylidene-1-phenylglitazone compound represented by Chemical Formula 1d ( Step 4); It may be prepared by a manufacturing method comprising a.

[Reaction Scheme 4]

(In Reaction Scheme 4, R ¹ , and R ² are as defined in Formula 1).

Hereinafter, the preparation method according to Scheme 4 will be described in more detail.

First, in step 1, the aniline compound represented by Chemical Formula 2 and chloroacetyl chloride are reacted using a conventional organic solvent such as anhydrous methylene chloride.

Next, in step 2, the compound represented by Formula 8 and potassium thiocyanate are reacted by heating to reflux at 90 ° C. to 100 ° C. in an acetonitrile solvent.

Next, in step 3, the compound represented by Chemical Formula 9 is reacted by heating to reflux at a temperature of 100 ° C. to 110 ° C. in a 2% HCl aqueous solution.

Next, in step 4, the compound represented by Chemical Formula 10 and the aldehyde compound are condensation reaction by heating to reflux at a temperature of 110 ° C. to 130 ° C. in an acetic acid solvent in the presence of sodium acetate (NaOAc) base. At this time, the aldehyde compound may be used typically benzaldehyde compound, the benzaldehyde compound is preferably used a phenoxybenzaldehyde compound substituted with halo, cyano, nitro, methyl, or methoxy.

Recipe 5

In the preparation method 5, the typical manufacturing method of manufacturing the glitazone compound which has R < ¹ > -aminoalkoxy substituent among the 3-methylidene- 1-phenylglitazone compound represented by said General formula (1d) is illustrated. The preparation method is as shown in Scheme 5 below,

Reacting an aminophenol compound with chloroacetyl chloride to prepare 2-chloro- N- phenylacetylamide compound represented by Chemical Formula 11 (step 1); Reacting a compound represented by Formula 11 with potassium thiocyanate to prepare a 2-imino- N- (hydroxyphenyl) thiazolidin-4-one compound represented by Formula 12: Step 2); Reacting the compound represented by Chemical Formula 12 under acidic conditions to prepare an N- (hydroxyphenyl) glitazone compound represented by Chemical Formula 13 (step 3); Alkylating the compound represented by Formula 13 with a dihaloalkane compound to prepare an N- (haloalkoxyphenyl) glitazone compound represented by Formula 14 (step 4); Reacting a compound represented by Formula 14 with an amine compound to prepare an N- (aminoalkoxyphenyl) glitazone compound represented by Formula 15 (step 5); And a compound represented by the following formula (15) is condensed with an aldehyde compound represented by R ² -C (O) H to form a 3-methylidene-1- (aminoalkoxyphenyl) glitazone compound represented by the following formula (1e). Manufacturing step (step 6); It may be prepared by a manufacturing method comprising a.

[Reaction Scheme 5]

(In Scheme 5, R ² , R ⁴ , and R ⁵ are each as defined in Formula 1, X is a halogen atom, n is an integer of 1 to 6.)

Hereinafter, the preparation method according to Scheme 5 will be described in more detail.

The manufacturing process of Step 1, Step 2, and Step 3 can be carried out with reference to Scheme 4.

Next, in step 4, the compound represented by Chemical Formula 13 is heated to reflux with dihaloalkane at 80 ° C. to 90 ° C. under an alkali metal salt base such as potassium carbonate and an acetonitrile solvent. .

Next, in step 5, the compound represented by Chemical Formula 14 is reacted with a specific amine compound under an acetonitrile solvent with an alkali metal salt base such as potassium carbonate. In this case, the amine compound is typically ammonia, mono (C ₁ -C ₆ alkyl) amine, di (C ₁ -C ₆ alkyl) amine, pyrrolidine, morpholine, piperidine, piperazine, 4- (C _1- C ₆ alkyl) piperazine and the like can be used.

Next, in step 6, the compound represented by Chemical Formula 15 is heated to reflux at a temperature of 110 ° C. to 130 ° C. in an acetic acid solvent in the presence of sodium acetate (NaOAc) base to perform a condensation reaction with the aldehyde compound. At this time, the aldehyde compound may be used typically benzaldehyde compound, the benzaldehyde compound is preferably used a phenoxybenzaldehyde compound substituted with halo, cyano, nitro, methyl, or methoxy.

Preparation method 6

In the preparation method 6, the typical manufacturing method which manufactures the glitazone compound which has R < ¹ > -amidoalkoxy substituent among the 3-methylidene- 1-phenylglitazone compound represented by said General formula (1d) is illustrated. The preparation method is as shown in Scheme 6 below,

Reacting the nitrophenol and the amaidoalkyl chloride compound to prepare a nitro compound represented by Chemical Formula 16 (step 1); Preparing a amine compound represented by Chemical Formula 17 by reducing a compound represented by Chemical Formula 16 (step 2); Reacting a compound represented by Formula 17 with chloroacetyl chloride to prepare a chloroacetylamide compound represented by Formula 18 (step 3); Reacting a compound represented by Formula 18 with potassium thiocyanate to prepare a 2-imino-thiazolidin-4-one compound represented by Formula 19 (step 4); To react the compound represented by the formula (19) under acidic conditions, to prepare a glitazone compound represented by the formula (20) (step 5); And a compound represented by the following Formula 20, condensation reaction with an aldehyde compound represented by R ² -C (O) H, and a 3-methylidene-1- (amidoalkoxyphenyl) glitazone compound represented by the following Formula 1f: Preparing (step 6); It may be prepared by a manufacturing method comprising a.

[Reaction Scheme 6]

(In Reaction Scheme 6, R ² , R ⁴ , and R ⁵ are each as defined in Chemical Formula 1, and n is an integer of 1 to 6.)

Hereinafter, the preparation method according to Scheme 6 will be described in more detail.

First, in step 1, the nitrophenol and the amaidoalkyl chloride compound are reacted in a conventional organic solvent such as acetonitrile.

Next, in step 2, the compound represented by Chemical Formula 16 is reduced to reduce the nitro group to an amine group. The reduction reaction is carried out under hydrogen gas flow conditions in the presence of conventional reducing conditions, for example Pd / C (10%) catalyst.

Next, in step 3, the compound represented by Chemical Formula 17 is reacted with chloroacetyl chloride and anhydrous methylene chloride solvent.

Next, in step 4, the compound represented by Chemical Formula 18 is heated to reflux at a temperature of 90 ° C. to 110 ° C. in a potassium thiocyanate and acetonitrile solvent.

Next, in step 5, the compound represented by Formula 19 is performed by heating to reflux at a temperature of 100 ℃ to 110 ℃ in a 2% HCl aqueous solution.

Next, in step 6, the compound represented by Chemical Formula 20 is heated to reflux at a temperature of 110 ° C. to 130 ° C. in an acetic acid solvent in the presence of sodium acetate (NaOAc) base to perform a condensation reaction with an aldehyde compound. At this time, the aldehyde compound may be used typically benzaldehyde compound, the benzaldehyde compound is preferably used a phenoxybenzaldehyde compound substituted with halo, cyano, nitro, methyl, or methoxy.

Compounds prepared through the preparation methods of Schemes 1 to 6 may be diluted and washed with a general separation and purification process, for example, an organic solvent, and the organic layer may be concentrated under reduced pressure, and, if necessary, purified by column chromatography.

The present invention also provides a pharmaceutical composition or a disease treatment agent comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the purpose of preventing and treating a disease caused by NF-κB activity. .

Diseases caused by the activity of NF-κB are inflammatory diseases, for example, rheumatoid arthritis, juvenile arthritis, asthma, spondyloarthopathies, gout, Osteoarthritis, allergic rhinitis, atopic dermatitis, gallbladder, systemic lupuserythematosus, psoriasis, ulcerative colitis, systemic inflammatory syndrome, pneumonia, multiple myositis, nodular polyarthritis, and the like.

The pharmaceutical composition of the present invention is suitable for oral or parenteral administration by formulating in a conventional formulation method including other conventional carriers, adjuvants or diluents together with the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof. It may be prepared in the form. In the case of oral administration, it can be prepared in the form of tablets, capsules, solutions, syrups, suspensions, etc. In the case of parenteral administration, it can be prepared in the form of injections for peritoneal, subcutaneous, muscular and transdermal administration.

The effective daily dosage of the pharmaceutical composition of the present invention as a therapeutic agent for inflammatory diseases is 0.01 to 1000 mg / day in adults, but the dosage varies depending on the patient's age, weight, sex, dosage form, health condition and degree of disease. In some cases, the doctor or pharmacist may decide to divide and administer once or several times a day at regular intervals.

Hereinafter, the present invention will be described in detail by the following examples and experimental examples, the following examples are merely to illustrate the present invention, the content of the present invention is not limited by the following examples.

Example Synthesis of Compound

Example 1. 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

Step 1: Preparation of 1- (3-bromopropoxy) -4-nitrobenzene

4-nitrophenol (10.0 g, 71.8 mmol) was dissolved in acetonitrile and then K ₂ CO ₃ (14.9 g, 107.7 mmol) and 1,3-dibromopropane (36.5 mL, 359 mmol) were added. The reaction was heated to reflux at 80 ° C. for 4 hours. After the reaction was completed, the precipitate was filtered, distilled under reduced pressure to remove the solvent, and then purified by column chromatography (ethyl acetate: n-hexane = 1:10) to obtain 13.0 g of the target compound in a yield of 70.0%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.34-2.40 (m, 2H), 3.61 (t, J = 6.3 Hz, 2H), 4.22 (t, J = 5.8 Hz, 2H), 6.97 (d, J = 9.3 Hz, 2H), 8.21 (d, J = 9.3 Hz, 2H)

Step 2: Preparation of 1- [3- (4-methylpiperazin-1-yl) propoxy] -4-nitrobenzene

1- (3-bromopropoxy) -4-nitrobenzene (5.9 g, 22.6 mmol) prepared in step 1 was dissolved in acetonitrile, followed by K ₂ CO ₃ (4.7 g, 33.9 mmol) and 1 Methylpiperazine (5 mL, 45.2 mmol) was added and then heated to reflux for 1 h. After the reaction was completed, the precipitate was filtered off, and the filtrate was extracted with ethyl acetate and water. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure to remove the solvent to obtain 5.7 g of the target compound in a yield of 79.4%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.97-2.04 (m, 2H), 2.30 (s, 3H), 2.46 (bs, 8H), 2.53 (t, J = 7.2 Hz, 2H), 4.11 (t, J = 6.3 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H), 8.19 (d, J = 9.2 Hz, 2H)

Step 3: Preparation of 4- [3- (4-methylpiperazin-1-yl) propoxy] aniline

1- [3- (4-methylpiperazin-1-yl) propoxy] -4-nitrobenzene (3.8 g, 15.2 mmol) prepared in step 2 was dissolved in methanol and 10% Pd / C 380 mg After addition, the reaction reacted under a hydrogen stream. After completion of the reaction, the reaction solution was filtered using Celite, the filtrate was distilled under reduced pressure to remove the solvent to give 4.4 g of the target compound in a yield of 98.8%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.89-1.96 (m, 2H), 2.45-2.53 (m, 10H), 3.41 (bs, 2H), 3.93 (t, J = 6.3 Hz, 2H), 6.63 ( d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz, 2H)

Step 4: Preparation of 3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4-thiozolidinone

4- [3- (4-methylpiperazin-1-yl) propoxy] aniline (3.8 g, 15.2 mmol) prepared in step 3 above was dissolved in a solvent of ethanol / water (4: 3). Bis (carboxymethyl) trithiocarbonate (3.8 g, 16.7 mmol) was added at 90 ° C. and then heated to reflux for 1 hour. After completion of the reaction, sodium hydrogen carbonate (1.27 g, 15.2 mmol) was slowly added, extracted with methylene chloride, and the organic layer was dried over anhydrous MgSO ₄ . The solvent was removed by distillation under reduced pressure and recrystallized from ethyl acetate to obtain 2.1 g of the title compound in a yield of 37.9%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.84-1.89 (m, 2H), 2.14 (s, 3H), 2.31 (bs, 8H), 2.40 (t, J = 7.1 Hz, 2H), 4.02 ( t, J = 6.3 Hz, 2H), 4.34 (s, 2H), 7.02 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H)

Step 5: Preparation of 4- (4-fluorophenoxy) benzaldehyde

4-fluorobenzaldehyde (1.5 g, 12.1 mmol) was dissolved in 15 mL of dimethylformamide. K ₂ CO ₃ (1.5 g, 14.5 mmol) and 4-fluorophenol (1.5 g, 13.3 mmol) were added and then heated to reflux for 8 hours. After the reaction was completed, the mixture was extracted using ethyl acetate and aqueous sodium hydroxide solution (1 N), the organic layer was dried over anhydrous MgSO _4, and distilled under reduced pressure to obtain 2.23 g of the target compound in a yield of 85.4%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.8 Hz, 2H), 7.05-7.14 (m, 4H), 7.85 (d, J = 8.8 Hz, 2H), 9.93 (s, 1H)

Step 6: 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- Preparation of 4-thiazolidinone

3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4-thiozolidinone (50 mg, 0.14 mmol) prepared in step 4, 4- (4-fluorophenoxy) benzaldehyde (35 mg, 0.16 mmol) and NaOAc (34 mg, 0.42 mmol) were dissolved in 1 mL of acetic acid and heated to reflux for 2 hours. After the reaction was completed, the mixture was diluted with water and neutralized with 28.0% ammonia water. After extraction with methylene chloride, the organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure to remove the solvent. After dissolving again in tetrahydrofuran, HCl (2N) dissolved in ethyl acetate was added dropwise to obtain 68 mg of the target compound in the form of HCl in a yield of 76.2%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.20-2.21 (m, 2H), 2.81 (bs, 3H), 3.34-3.78 (m, 10H), 4.13 (t, J = 6.0 Hz, 2H), 7.08-7.12 (m, 4H), 7.18-7.23 (m, 2H), 7.27-7.33 (m, 4H), 7.70 (d, J = 9.0 Hz, 2H), 7.80 (s, 1H), 11.76 (bs, 2H)

Example 2. 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

Step 1: Preparation of 3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4-thiazolidinone

3- [3- (4-methylpiperazine) prepared by dissolving 1,1'-thiocarbonyldiimidazole (427 mg, 2.40 mmol) in anhydrous methylene chloride solution and then in the method of step 3 of Example 1. Methylchloride dissolved in -1-yl) propoxy] aniline (500 mg, 2.00 mmol) was slowly dropped. Ethyl 2-mercaptoacetate (0.26 mL, 2.40 mmol) was added dropwise and stirred at room temperature for 2 hours. After the reaction was completed, 0.5 mL of acetic acid was added thereto, followed by distillation under reduced pressure to remove the solvent, and the reaction was carried out in the next step without purification.

Step 2: 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-carbamoylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

After dissolving 3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4-thiazolidinone prepared in Step 1 in 0.5 mL of acetic acid, , NaOAc (98 mg, 1.20 mmol) and 4- (4-fluorophenoxy) benzaldehyde (104 mg, 0.48 mmol) were added and heated to reflux for 3 hours. After the reaction was completed, the mixture was diluted with water, neutralized with 28.0% ammonia water, and extracted with methylene chloride. The organic layer was dried over anhydrous MgSO ₄ , distilled under reduced pressure to remove the solvent, and recrystallized with diethyl ether and ethyl acetate to obtain 105 mg of the target compound in a yield of 46.6%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.93-2.00 (m, 2H), 2.28 (s, 3H), 2.49 (bs, 8H), 2.51 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 6.3 Hz, 2H), 6.80 (dd, J = 2.0, 2.2 Hz, 1H), 6.84 (dd, J = 2.0, 7.8 Hz, 1H), 7.02-7.13 (m, 7H), 7.43 (dd, J = 7.8, 8.3 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H)

Hereinafter, rhodanine compounds were synthesized in the same manner as in Example 1 and Example 2, and the structure and ¹ H NMR data are shown in Table 1 below.

Example Chemical structure ¹ H NMR (ppm) δ
3

6.88 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.73 ( s, 1H), 9.87 (bs, 1H), 10.48 (bs, 1H)
4

1.23 (t, J = 7.0 Hz, 6H), 2.18-2.14 (m, 2H), 3.10-3.20 (m, 6H), 4.17 (t, J = 5.8 Hz, 2H), 7.12 (d, J = 8.1 Hz , 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.66 (s, 1H), 10.47 (bs, 1H), 13.77 (bs, 1H)
5

6.89 (d, J = 8.8 Hz, 2H), 7.15-7.19 (m, 6H), 7.51 (d, J = 9.0 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H ), 9.89 (s, 1 H)
6

3.83 (s, 3H), 6.80 (dd, J = 2.1, 2.2 Hz, 1H), 6.86 (ddd, J = 0.9, 2.0, 8.0 Hz, 1H), 7.03-7.13 (m, 7H), 7.45 (dd, J = 8.0, 8.2 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.75 (s, 1H)
7

3.83 (s, 3H), 6.80 (dd, J = 2.1, 2.2 Hz, 1H), 6.86 (ddd, J = 0.8, 2.0, 8.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 3H), 7.07 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.46 (dd, J = 8.0, 8.2 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H)
8

3.08 (s, 3H), 3.84 (s, 3H), 6.81 (dd, J = 2.0, 2.2 Hz, 1H), 6.87 (dd, J = 2.0, 7.9 Hz, 1H), 7.06 (dd, J = 2.2, 8.3 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.46 (dd, J = 7.9, 8.3 Hz, 1H), 7.77 (s, 1H) , 7.96 (d, J = 8.8 Hz, 2H)
9

3.77 (s, 3H), 6.98 (dd, J = 1.8, 7.8 Hz, 1H), 7.05 (dd, J = 1.8, 2.4 Hz, 1H), 7.09 (dd, J = 2.4, 8.2 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.37 (bs, 1H), 7.46 (dd, J = 7.8, 8.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.84 (s, 1H), 7.98 (d, J = 8.8 Hz, 3H)
10

0.95 (t, J = 7.0 Hz, 6H), 1.80-1.87 (m, 2H), 2.45-2.53 (m, 6H), 4.06 (t, J = 6.0 Hz, 2H), 6.95 (d, J = 8.7 Hz , 2H), 7.05 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.74 (s, 1H), 10.50 (bs , 1H)

11

1.23 (t, J = 7.1 Hz, 6H), 2.14-2.17 (m, 2H), 3.14-3.21 (m, 6H), 3.85 (s, 3H), 4.14 (t, J = 5.8 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 7.25 (s, 1H), 7.32 (d, J = 8.5 Hz , 2H), 7.75 (s, 1H), 10.02 (bs, 1H), 10.20 (bs, 1H)
12

1.23 (t, J = 7.1 Hz, 6H), 2.13-2.15 (m, 2H), 3.14-3.17 (m, 6H), 4.14 (t, J = 5.8 Hz, 2H), 7.11 (d, J = 8.8 Hz , 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 2.0, 8.5 Hz, 1H), 7.83 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 8.01 (s, 1H), 9.98 (bs, 1H)
13

1.21 (t, J = 7.1 Hz, 6H), 2.12-2.15 (m, 2H), 3.13-3.24 (m, 6H), 4.13 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.8 Hz , 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.51-7.55 (m, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.77 (s, 1H), 9.78 (bs, 1H)
14

1.22 (t, J = 7.2 Hz, 6H), 2.12-2.16 (m, 2H), 3.03 (s, 6H), 3.13-3.22 (m, 6H), 4.13 (t, J = 5.8 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 9.0 Hz, 2H), 7.69 (s , 1H), 10.0 (bs, 1H)

15

1.21 (t, J = 7.2 Hz, 6H), 2.12-2.15 (m, 2H), 3.05 (s, 6H), 3.11-3.21 (m, 6H), 4.12 (t, J = 5.9 Hz, 2H), 6.73 (d, J = 8.9 Hz, 2H), 6.84 (dd, J = 11.8, 15.3 Hz, 1H), 7.07 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 7.30 (t, J = 15.3 Hz, 1H), 7.50 (d, J = 11.8 Hz, 1H), 7.56 (d, J = 8.9 Hz, 2H), 9.91 (bs, 1H)
16

1.21 (t, J = 7.14 Hz, 6H), 2.12-2.15 (m, 2H), 3.13-3.16 (m, 6H), 4.13 (t, J = 5.8 Hz, 2H), 6.86 (s, 1H), 7.08 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.75 (s, 1H), 7.93 (s, 1H), 8.37 (s, 1H), 9.84 (bs, 1H)
17

1.21 (t, J = 7.3 Hz, 6H), 2.08-2.15 (m, 2H), 3.14-3.17 (m, 6H), 4.13 (t, J = 5.9 Hz, 2H), 7.08 (d, J = 8.6 Hz , 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 5.0 Hz, 1H), 7.79 (dd, J = 2.8, 5.0 Hz, 1H), 7.86 (s, 1H), 8.18 -8.19 (m, 1H), 9.67 (bs, 1H)
18

1.21 (t, J = 7.2 Hz, 6H), 2.10-2.17 (m, 2H), 3.13-3.21 (m, 6H), 4.13 (t, J = 5.8 Hz, 2H), 6.42-6.44 (m, 1H) , 6.64 (s, 1H), 7.07 (d, J = 9.0 Hz, 2H), 7.29 (d, J = 9.0 Hz, 2H), 7.31-7.33 (m, 1H), 7.68 (s, 1H), 9.84 ( bs, 1 H), 11.91 (bs, 1 H)
19

1.23 (t, J = 7.2 Hz, 6H), 2.17-2.21 (m, 2H), 3.12-3.21 (m, 6H), 4.15 (t, J = 5.8 Hz, 2H), 7.10 (d, J = 8.7 Hz , 2H), 7.17-7.30 (m, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 7.8 Hz, 1H), 7.95-7.97 (m, 2H), 8.10 (s, 1H), 10.64 (bs, 1H), 12.54 (bs, 1H)
20

1.22 (t, J = 7.1 Hz, 6H), 2.13-2.17 (m, 2H), 3.14-3.20 (m, 6H), 4.16 (t, J = 5.8 Hz, 2H), 7.11 (d, J = 8.8 Hz , 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.63-7.77 (m, 4H), 8.06 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 8.46 (s, 1H), 9.90 (bs, 1H)
21

1.20 (t, J = 7.0 Hz, 6H), 2.11-2.13 (m, 2H), 3.12-3.20 (m, 6H), 4.11 (t, J = 5.8 Hz, 2H), 6.98-7.10 (m, 4H) , 7.24-7.26 (m, 4H), 7.42 (s, 5H), 7.51-7.52 (m, 3H), 9.89 (bs, 1H)
22

1.22 (t, J = 7.2 Hz, 6H), 2.13-2.17 (m, 2H)), 3.10-3.21 (m, 6H), 4.13 (t, J = 5.9 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.45-7.48 (m, 1H), 7.85 (s, 1H), 7.91-8.00 (m, 2H), 8.83 (d, J = 4.8 Hz , 1H), 10.17 (bs, 1H)

23

1.22 (t, J = 7.1 Hz, 6H), 2.14-2.15 (m, 2H), 3.13-3.21 (m, 6H), 4.14 (t, J = 6.1 Hz, 2H), 7.10 (d, J = 9.0 Hz , 2H), 7.34 (d, J = 9.0 Hz, 2H), 7.63 (dd, J = 4.8, 7.9 Hz, 1H), 7.88 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 8.70 (d, J = 4.8 Hz, 1H), 8.95 (s, 1H), 10.01 (bs, 1H)

24

1.24 (t, J = 7.2 Hz, 6H), 2.15-2,19 (m, 2H), 3.12-3.20 (m, 6H), 4.15 (t, J = 5.9 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 5.5 Hz, 3H), 8.88 (d, J = 5.5 Hz, 2H), 10.32 (bs, 1H)

25

1.22 (t, J = 7.2 Hz, 6H), 1.30 (s, 9H), 2.12-2.16 (m, 2H), 3.11-3.20 (m, 6H), 4.13 (t, J = 5.8 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 HZ, 2H), 7.58-7.63 (m, 4H), 7.79 (s, 1H), 9.96 (bs, 1H)

26

1.23 (t, J = 7.3 Hz, 12H), 2.11-2.18 (m, 4H), 3.14-3.17 (m, 12H), 4.14 (t, J = 6.0 Hz, 2H), 4.19 (t, J = 6.0 Hz , 2H), 7.10 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.5 Hz, 2H ), 7.81 (s, 1H), 9.71 (bs, 1H), 9.83 (bs, 1H)
27

0.97 (t, J = 6.6 Hz, 6H), 1.84-1.87 (m, 2H), 2.50-2.66 (m, 6H), 4.07 (t, J = 6.0 Hz, 2H), 7.08 (d, J = 8.6 Hz , 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.55 (bs, 1H), 7.76 (d, J = 8.2 Hz, 2H), 7.86 (s, 1H), 8.02 (d, J = 8.2 Hz , 2H), 8.13 (bs, 1H)
28

1.04 (t, J = 7.1 Hz, 6H), 1.92-1.99 (m, 2H), 2.55 (q, J = 7.1 Hz, 4H), 2.62 (t, J = 7.2 Hz, 2H), 4.06 (t, J = 6.3 Hz, 2H), 7.02-7.06 (m, 6H), 7.18 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H ), 7.75 (s, 1 H)


29

1.04 (t, J = 7.1 Hz, 6H), 1.94-1.97 (m, 2H), 2.56 (q, J = 7.1 Hz, 4H), 2.62 (t, J = 7.2 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 5.75 (bs, 1H), 6.97 (dd, J = 0.9, 8.2 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H ), 7.18 (d, J = 9.0 Hz, 2H), 7.26 (bs, 1H), 7.34 (dd, J = 7.8, 8.0 Hz, 1H), 7.50 (ddd, J = 1.7, 8.0, 8.2 Hz, 1H) , 7.57 (d, J = 8.7 Hz, 2H), 7.76 (s, 1H), 8.27 (dd, J = 1.7, 7.8 Hz, 1H)


30

1.21 (t, J = 7.0 Hz, 6H), 2.13-2.15 (m, 2H), 3.12-3.22 (m, 6H), 4.13 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.8 Hz , 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 8.8 Hz, 2H), 7.47 (bs, 1H), 7.54 (dd , J = 7.9, 7.9 Hz, 1H), 7.60 (s, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 8.05 (bs, 1H), 9.85 (bs, 1H)

31

1.24 (t, J = 7.2 Hz, 6H), 2.15-2.19 (m, 2H), 3.12-3.22 (m, 6H), 4.15 (t, J = 5.9 Hz, 2H), 7.11 (d, J = 9.0 Hz , 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 9.0 Hz, 2H), 7.37 (bs, 1H), 7.75 (d , J = 8.9 Hz, 2H), 7.84 (s, 1H), 7.97 (d, J = 9.0 Hz, 2H), 8.00 (bs, 1H), 10.23 (bs, 1H)

32

1.21 (t, J = 7.1 Hz, 6H), 2.11-2.14 (m, 2H), 3.14-3.29 (m, 6H), 4.13 (t, J = 6.0 Hz, 2H), 7.09 (d, J = 8.8 Hz , 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.41 (t, J = 4.4 Hz, 2H), 7.53 (bs, 1H), 7.67 (dd, J = 7.7, 7.8 Hz, 1H), 7.72 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 8.13 (bs, 1H), 8.37 (s, 1H), 9.67 (bs, 1H)

33

1.25 (t, J = 7.2 Hz, 6H), 2.15-2.20 (m, 2H), 3.13-3.20 (m, 6H), 4.15 (t, J = 5.2 Hz, 2H), 7.11 (d, J = 8.8 Hz , 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 3.7 Hz, 1H), 7.47 (d, J = 3.7 Hz, 1H), 7.50 48 (bs, 1H), 7.72 ( s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 8.09 (bs, 1H), 10.50 (bs, 1H)

34

1.86-1.88 (m, 2H), 1.99-2.00 (m, 2H), 2.15-2.19 (m, 2H), 2.99-3.01 (m, 2H), 3.27-3.29 (m, 2H), 3.53-3.55 (m , 2H), 4.13 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.62 (dd, J = 2.0, 8.4 Hz , 1H), 7.82 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 10.60 (bs, 1H)
35

1.89-1.90 (m, 2H), 1.97-1.98 (m, 2H), 2.12-2.16 (m, 2H), 2.98-3.00 (m, 2H), 3.25-3.27 (m, 2H), 3.49-3.52 (m , 2H), 4.10 (t, J = 6.0 Hz, 2H), 6.98-7.08 (m, 4H), 7.24-7.26 (m, 4H), 7.42 (s, 5H), 7.51-7.55 (m, 3H), 10.07 (bs, 1 H)

36

1.87-1.88 (m, 2H), 2.00-2.01 (m, 2H), 2.13-2.17 (m, 2H), 3.00-3.02 (m, 2H), 3.15-3.16 (m, 2H), 3.54-3.56 (m , 2H), 4.12 (t, J = 5.9 Hz, 2H), 7.07-7.11 (m, 5H), 7.30-7.35 (m, 3H), 7.48 (bs, 1H), 7.52 (dd, J = 7.7, 7.7 Hz, 1H), 7.69 (d, J = 8.9 Hz, 4H), 7.80 (s, 1H), 10.10 (bs, 1H)


37

1.87-1.89 (m, 2H), 1.99-2.00 (m, 2H), 2.12-2.16 (m, 2H), 2.99-3.01 (m, 2H), 3.26-3.28 (m, 2H), 3.54-3.55 (m , 2H), 4.12 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H ), 7.33 (d, J = 8.9 Hz, 2H), 7.47 (bs, 1H), 7.54 (dd, J = 7.9, 7.9 Hz, 1H), 7.59 (s, 1H), 7.73 (d, J = 8.8 Hz , 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 8.04 (bs, 1H), 10.08 (bs, 1H)

38

1.86-1.89 (m, 2H), 2.00-2.01 (m, 2H), 2.13-2.18 (m, 2H), 3.00-3.01 (m, 2H), 3.28-3.30 (m, 2H), 3.54-3.55 (m , 2H), 4.13 (t, J = 6.0 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H ), 7.32 (d, J = 8.7 Hz, 2H), 7.36 (bs, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.83 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H ), 7.98 (bs, 1H), 10.53 (bs, 1H)

39

2.19-2.22 (m, 2H), 3.07-3.09 (m, 2H), 3.25-3.26 (m, 2H), 3.44-3.47 (m, 2H), 3.75-3.81 (m, 2H), 3.94-3.98 (m , 2H), 4.13 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 2.0, 8.5 Hz , 1H), 7.82 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 10.81 (bs, 1H)

40

2.19-2.23 (m, 2H), 3.08-3.10 (m, 2H), 3.25-3.26 (m, 2H), 3.44-3.47 (m, 2H), 3.76-3.79 (m, 2H), 3.94-3.97 (m , 2H), 4.10 (t, J = 5.8 Hz, 2H), 6.98-7.07 (m, 4H), 7.21-7.29 (m, 4H), 7.42 (s, 5H), 7.51-7.54 (m, 3H), 10.69 (bs, 1 H)

41

2.17-2.18 (m, 2H), 3.07-3.10 (m, 2H), 3.31-3.32 (m, 2H), 3.46-3.49 (m, 2H), 3.69-3.75 (m, 2H), 3.96-3.99 (m , 2H), 4.13 (t, J = 5.8 Hz, 2H), 7.07-7.11 (m, 5H), 7.30-7.34 (m, 3H), 7.48 (bs, 1H), 7.50-7.54 (m, 1H), 7.79 (d, J = 8.8 Hz, 4H), 7.80 (s, 1H), 10.33 (bs, 1H)

42

2.20-2.21 (m, 2H), 3.07-3.10 (m, 2H), 3.26-3.28 (m, 2H), 3.45-3.48 (m, 2H), 3.74-3.79 (m, 2H), 3.95-3.98 (m , 2H), 4.13 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.29-7.34 (m, 3H), 7.47 (bs, 1H), 7.54 (dd, J = 7.8, 7.9 Hz, 1H), 7.60 (s, 1H), 7.71-7.76 (m, 3H), 7.82 (s, 1H), 8.05 (bs, 1H), 10.69 (bs, 1 H)

43

2.22-2.23 (m, 2H), 3.05-3.10 (m, 2H), 3.28-3.32 (m, 2H), 3.46 (d, J = 11.6 Hz, 2H), 3.75 (t, J = 11.9 Hz, 2H) , 3.97 (d, J = 11.6 Hz, 2H), 4.13 (t, J = 5.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.36 (bs, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 8.4 Hz , 2H), 7.98 (bs, 1H), 10.60 (bs, 1H)

44

1.85-1.87 (m, 2H), 2.36-2.41 (m, 4H), 2.43 (t, J = 7.0 Hz, 2H), 3.55-3.58 (m, 4H), 4.06 (t, J = 6.2 Hz, 2H) , 7.07 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.40 (s, 2H), 7.53 (bs, 1H), 7.67 (dd, J = 7.7, 7.8 Hz, 1H), 7.72 (bs, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 8.11 (bs, 1H), 8.36 (s, 1H)

45

2.18-2.19 (m, 2H), 3.08-3.11 (m, 2H), 3.30-3.31 (m, 2H), 3.47-3.49 (m, 2H), 3.68-3.74 (m, 2H), 3.97-4.00 (m , 2H), 4.12-4.13 (m, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 3.6 Hz, 1H), 7.47 (d, J = 3.6 Hz, 1H), 7.48 (bs, 1H), 7.72 (s, 1H), 7.94 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.3 Hz, 3H), 10.18 (bs, 1 H)

46

1.36-1.40 (m, 1H), 1.76-1.82 (m, 5H), 2.15-2.18 (m, 2H), 2.87-2.90 (m, 2H), 3.18-3.20 (m, 2H), 3.45-3.48 (m , 2H), 4.12 (t, J = 5.7 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H ), 7.82 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 9.54 (bs, 1H)

47

1.35-1.38 (m, 1H), 1.67-1.77 (m, 5H), 2.15-2.19 (m, 2H), 2.85-2.87 (m, 2H), 3.15-3.16 (m, 2H), 3.43-3.45 (m , 2H), 4.09 (t, J = 5.9 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.98-7.07 (m, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.24 -7.26 (m, 2H), 7.41 (s, 5H), 7.51-7.53 (m, 3H), 9.94 (bs, 1H)

48

1.09-1.10 (m, 1H), 1.70-1.78 (m, 5H), 2.17-2.19 (m, 2H), 2.87-2.89 (m, 2H), 3.17-3.18 (m, 2H), 3.45-3.48 (m , 2H), 4.12 (t, J = 5.9 Hz, 2H), 7.07-7.11 (m, 5H), 7.32-7.33 (m, 3H), 7.48 (bs, 1H), 7.52 (dd, J = 7.5, 7.9 Hz, 1H), 7.68-7.70 (m, 4H), 7.80 (s, 1H), 9.77 (bs, 1H)

49

1.33-1.41 (m, 1H), 1.68-1.77 (m, 5H), 2.18-2.22 (m, 2H), 2.85-2.89 (m, 2H), 3.15-3.19 (m, 2H), 3.43-3.46 (m , 2H), 4.12 (t, J = 5.8 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 7.9 Hz, 1H ), 7.32 (d, J = 9.0 Hz, 2H), 7.47 (bs, 1H), 7.53 (dd, J = 7.9, 7.9 Hz, 1H), 7.60 (s, 1H), 7.72 (d, J = 8.8 Hz , 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 8.05 (bs, 1H), 10.15 (bs, 1H)

50

1.36-1.40 (m, 1H), 1.68-1.78 (m, 5H), 2.17-2.21 (m, 2H), 2.84-2.91 (m, 2H), 3.16-3.21 (m, 2H), 3.44-3.47 (m , 2H), 4.12 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H ), 7.33 (d, J = 8.9 Hz, 2H), 7.36 (bs, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.82 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H ), 7.98 (bs, 1H), 9.93 (bs, 1H)
51

2.19-2.20 (m, 2H), 2.81 (bs, 3H), 3.47-3.76 (m, 10H), 4.13 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.62 (dd, J = 2.0, 8.4 Hz, 1H), 7.82-7.84 (m, 2H), 7.99 (d, J = 2.0 Hz, 1H), 11.83 (bs, 2H)

52

2.18-2.19 (m, 2H), 2.80 (bs, 3H), 3.25-3.76 (m, 10H), 4.11 (t, J = 5.8 Hz, 2H), 6.98-7.07 (m, 4H), 7.24 (m, 4H), 7.42 (s, 5H), 7.51-7.52 (m, 3H), 11.70 (bs, 2H)
53

2.19-2.20 (m, 2H), 2.81 (bs, 3H), 3.34-3.49 (m, 10H), 4.12 (t, J = 5.9 Hz, 2H), 7.07-7.11 (m, 5H), 7.30-7.33 ( m, 3H), 7.49-7.52 (m, 2H), 7.68-7.70 (m, 4H), 7.80 (s, 1H), 11.66 (bs, 2H)

54

2.21-2.22 (m, 2H), 2.81 (bs, 3H), 3.42-3.73 (m, 10H), 4.13 (t, J = 5.8 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.29-7.33 (m, 3H), 7.47 (bs, 1H), 7.53 (dd, J = 7.8, 7.9 Hz, 1H), 7.60 (s, 1H), 7.72 ( d, J = 8.8 Hz, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 8.05 (bs, 1H), 11.77 (bs, 2H)

55

1.36-1.40 (m, 1H), 1.68-1.78 (m, 5H), 2.17-2.21 (m, 2H), 2.84-2.91 (m, 2H), 3.16-3.21 (m, 2H), 3.44-3.47 (m , 2H), 4.12 (t, J = 5.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H ), 7.33 (d, J = 8.9 Hz, 2H), 7.36 (bs, 1H), 7.74 (d, J = 8.9 Hz, 2H), 7.82 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H ), 7.98 (bs, 1H), 9.93 (bs, 1H)

56

1.97-2.01 (m, 2H), 2.29 (s, 3H), 2.48 (bs, 8H), 2.53 (t, J = 7.3 Hz, 2H), 3.05 (bs, 3H), 3.12 (bs, 3H), 4.06 (t, J = 6.3 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.18 (d , J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H)

57

2.20-2.21 (m, 2H), 2.81 (bs, 3H), 3.41-3.65 (m, 10H), 4.14 (t, J = 5.6 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.39 (bs, 2H), 7.76 (d, J = 8.6 Hz , 2H), 7.87 (d, J = 8.6 Hz, 2H), 11.75 (bs, 2H)

58

2.19-2.20 (m, 2H), 2.80 (bs, 3H), 3.32-3.81 (m, 10H), 4.13 (m, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.85 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 11.69 (bs, 2H)
59

2.19-2.21 (m, 2H), 2.80 (bs, 3H), 3.33-3.71 (m, 10H), 3.77 (s, 3H), 4.13 (t, J = 5.6 Hz, 2H), 7.00-7.12 (m, 8H), 7.32 (d, J = 8.9 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.79 (s, 1H), 11.58 (bs, 2H)
60

2.20-2.21 (m, 2H), 2.32 (s, 3H), 2.81 (bs, 3H), 3.35-3.77 (m, 10H), 4.13 (t, J = 5.7 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 7.08-7.10 (m, 4H), 7.27 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H) , 7.79 (s, 1 H), 11.74 (bs, 2 H)
61

2.17-2.19 (m, 2H), 2.81 (bs, 3H), 3.26-3.83 (m, 10H), 4.13 (t, J = 5.8 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 7.26 -7.34 (m, 6H), 7.76 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 7.84 (s, 1H), 11.61 (bs, 2H)
62

1.30 (s, 9H), 2.18-2.19 (m, 2H), 2.80 (bs, 3H), 3.26-3.89 (m, 10H), 4.12 (m, 2H), 7.00-7.11 (m, 6H), 7.32 ( d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.85 (s, 1H), 11.42 (bs, 2H)
63

2.19-2.20 (m, 2H), 2.80 (bs, 3H), 3.26-3.60 (m, 10H), 4.13 (m, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.16-7.19 (m, 4H), 7.32 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H), 7.72 (d, J = 8.9 Hz, 2H), 7.82 (s, 1H), 11.58 (bs, 2H)
64

2.20-2.21 (m, 2H), 2.81 (bs, 3H), 3.36-3.80 (m, 10H), 4.13 (t, J = 5.8 Hz, 2H), 7.08-7.13 (m, 4H), 7.17 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.81 (s, 1H) , 11.69 (bs, 2H)

65

2.16-2.23 (m, 2H), 2.81 (bs, 3H), 3.22 (s, 3H), 3.26-3.39 (m, 4H), 3.47-3.79 (m, 6H), 4.13 (t, J = 5.6 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.29-7.34 (m, 6H), 7.78 (d, J = 9.0 Hz, 2H), 7.85 (s, 1H), 7.97 (d, J = 8.9 Hz, 2H), 11.64 (bs, 2H)
66

2.20-2.21 (m, 2H), 2.81 (bs, 3H), 3.53-3.79 (m, 10H), 4.13-4.14 (m, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 7.32-7.36 (m, 4H), 7.80 (d, J = 9.0 Hz, 2H), 7.86 (s, 1H), 8.30 (d, J = 9.0 Hz, 2H), 11.72 ( bs, 2H)

67

1.98-2.02 (m, 2H), 2.10 (s, 3H), 2.44-2.48 (m, 4H), 2.56 (t, J = 7.1 Hz, 2H), 3.48 (t, J = 4.7 Hz, 2H), 3.64 (t, J = 4.9 Hz, 2H), 4.08 (t, J = 6.1 Hz, 2H), 7.02-7.06 (m, 4H), 7.07 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H)

68

1.25 (bs, 1H), 1.58-1.61 (m, 2H), 1.91-1.94 (m, 2H), 1.97-2.01 (m, 2H), 2.16-2.17 (m, 2H), 2.52 (t, J = 7.3 Hz, 2H), 2.79-2.81 (m, 2H), 3.72 (m, 1H), 4.06 (t, J = 6.2 Hz, 2H), 7.02-7.08 (m, 6H), 7.18 (d, J = 9.0 Hz , 2H), 7.37 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.75 (s, 1H)
69

1.26 (t, J = 7.2 Hz, 6H), 3.19-3.25 (m, 4H), 3.51-3.52 (m, 2H), 4.43 (t, J = 5.0 Hz, 2H), 7.15 (d, J = 8.9 Hz , 2H), 7.36 (d, J = 8.9 Hz, 2H), 7.62 (dd, J = 2.0, 8.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 2.0 Hz , 1H), 10.41 (bs, 1H)

70

1.24 (t, J = 7.1 Hz, 6H), 3.18-3.25 (m, 4H), 3.50-3.51 (m, 2H), 4.38-4.39 (m, 2H), 6.98-7.07 (m, 2H), 7.10 ( d, J = 8.9 Hz, 2H), 7.24-7.26 (m, 2H), 7.29 (d, J = 8.9 Hz, 2H), 7.51 (s, 5H), 7.51-7.53 (m, 3H), 10.09 (bs , 1H)

71

1.25 (t, J = 7.2 Hz, 6H), 3.16-3.24 (m, 4H), 3,52-3.53 (m, 2H), 4.42 (t, J = 4.7 Hz, 2H), 7.08-7.11 (m, 3H), 7.14 (d, J = 9.0 Hz, 2H), 7.32 (dd, J = 7.7, 7.7 Hz, 1H), 7.36 (d, J = 9.0 Hz, 2H), 7.49 (bs, 1H), 7.52 ( dd, J = 7.7, 7.7 Hz, 1H), 7.68-7.70 (m, 4H), 7.80 (s, 1H), 10.25 (bs, 1H)


72

1.25 (t, J = 7.2 Hz, 6H), 3.19-3.25 (m, 4H), 3.31-3.54 (m, 2H), 4.40 (t, J = 4.9 Hz, 2H), 7.15 (d, J = 9.0 Hz , 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.31 (dd, J = 1.9, 7.9 Hz, 1H), 7.37 (d, J = 9.0 Hz, 2H), 7.47 (bs, 1H), 7.54 (dd, J = 7.9, 7.9 Hz, 1H), 7.60 (t, J = 1.9 Hz, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.82 (s, 1H), 8.04 (bs, 1H), 9.80 (bs, 1H)

73

1.25 (t, J = 7.2 Hz, 6H), 3.20-3.25 (m, 4H), 3.53-3.54 (m, 2H), 4.40 (t, J = 5.0 Hz, 2H), 7.15 (d, J = 8.9 Hz , 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.36 (s, 1H), 7.37 (d, J = 8.8 Hz, 2H), 7.74 (d , J = 8.9 Hz, 2H), 7.83 (s, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.98 (bs, 1H), 9.85 (bs, 1H)

74

1.79-1.89 (m, 4H), 2.79 (bs, 3H), 3.13-3.75 (m, 10H), 4.06 (t, J = 5.0 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.35 (bs, 1H), 7.73 (d, J = 8.4 Hz , 2H), 7.82 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.98 (bs, 1H), 11.57 (bs, 2H)

75

1.82-1.90 (m, 4H), 2.81 (bs, 3H), 3.24-3.60 (m, 10H), 4.07 (t, J = 5.5 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H), 7.20-7.24 (m, 2H), 7.28-7.33 (m, 4H), 7.71 (d, J = 8.9 Hz, 2H), 7.81 (s, 1H), 11.28 ( bs, 2H)


76

1.45-1.49 (m, 2H), 1.76-1.77 (m, 4H), 2.49 (bs, 3H), 3.15-3.71 (m, 10H), 4.04 (t, J = 6.1 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H), 7.36 (bs, 1H) , 7.74 (d, J = 8.8 Hz, 2H), 7.83 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.98 (bs, 1H), 11.63 (bs, 2H)

77

1.48-1.50 (m, 2H), 1.77-1.80 (m, 4H), 2.80 (bs, 3H), 3.24-3.62 (m, 10H), 4.05 (t, J = 6.1 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 7.20-7.23 (m, 2H), 7.29-7.33 (m, 4H), 7.71 (d, J = 8.7 Hz, 2H), 7.81 (s, 1 H), 11.43 (bs, 2 H)
78

2.31 (s, 3H), 2.50-2.51 (m, 8H), 3.58 (s, 2H), 7.03-7.13 (m, 6H), 7.16 (d, J = 7.7 Hz, 1H), 7.28 (s, 1H) , 7.43-7.47 (m, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H)
79

2.31 (s, 3H), 2.50-2.52 (m, 8H), 3.58 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.16 (d , J = 7.7 Hz, 1H), 7.28 (s, 1H), 7.37 (d, J = 8.9 Hz, 2H), 7.43-7.50 (m, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.74 (s, 1H)
80

2.32 (s, 3H), 2.43-2.54 (m, 8H), 3.08 (s, 3H), 3.58 (s, 2H), 7.16-7.21 (m, 5H), 7.29 (s, 1H), 7.44-7.52 ( m, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.77 (s, 1H), 7.97 (d, J = 8.9 Hz, 2H)

81

2.14 (s, 3H), 2.32-2.36 (m, 8H), 3.52 (s, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.29 (d , J = 7.8 Hz, 1H), 7.33 (bs, 1H), 7.37 (s. 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.50 (dd, J = 7.4, 7.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.84 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.97 (bs, 1H)

82

2.29 (s, 3H), 2.46-2.61 (m, 8H), 2.81 (t, J = 5.8 HZ, 2H), 4.12 (t, J = 5.8 Hz, 2H), 6.81 (dd, J = 2.1, 2.2 Hz , 1H), 6.85 (dd, J = 2.1, 8.1 Hz, 1H), 7.01-7.13 (m, 7H), 7.44 (dd, J = 8.1, 8.1 Hz, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.74 (s, 1 H)

83

2.29 (s, 3H), 2.47 (bs, 4H), 2.61 (bs, 4H), 2.81 (t, J = 5.8 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 6.81 (dd, J = 2.1, 2.2 Hz, 1H), 6.86 (dd, J = 2.1, 7.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 3H), 7.07 (d, J = 8.8 Hz, 2H), 7.37 (d , J = 8.8 Hz, 2H), 7.44 (dd, J = 7.8, 8.1 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H)


84

2.29 (s, 3H), 2.46 (bs, 4H), 2.61 (bs, 4H), 2.82 (t, J = 5.8 Hz, 2H), 3.08 (s, 3H), 4.12 (t, J = 5.8 Hz, 2H ), 6.82 (dd, J = 2.0, 2.4 Hz, 1H), 6.88 (ddd, J = 0.7, 2.0, 2.4, 7.9 Hz, 1H), 7.05 (ddd, J = 0.7, 2.4, 8.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.45 (dd, J = 7.9, 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.77 (s, 1 H), 7.96 (d, J = 8.7 Hz, 2 H)


85

2.29 (s, 3H), 2.48 (bs, 4H), 2.61 (bs, 4H), 2.82 (t, J = 5.8 Hz, 2H), 4.12 (t, J = 5.8 Hz, 2H), 5.67 (bs, 1H ), 7.04 (bs, 1H), 6.82 (dd, J = 2.0, 2.4 Hz, 1H), 6.86 (ddd, J = 0.8, 2.0, 7.9 Hz, 1H), 7.05 (ddd, J = 0.8, 2.4, 8.4 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.44 (dd, J = 7.9, 8.3 Hz, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.76 (s, 1H), 7.86 (d, J = 8.8 Hz, 2H)


86

1.95-1.99 (m, 2H), 2.29 (s, 3H), 2.45 (bs, 8H), 2.52 (t, J = 7.2 Hz, 2H), 4.03 (t, J = 6.3 Hz, 2H), 6.80 (dd , J = 2.1, 2.2 Hz, 1H), 6.84 (dd, J = 2.1, 7.8 Hz, 1H), 7.04 (d, J = 8.9 Hz, 3H), 7.01 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 7.44 (dd, J = 7.8, 8.1 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H)


87

1.94-2.01 (m, 2H), 2.28 (s, 3H), 2.46 (bs, 8H), 2.52 (t, J = 7.3 Hz, 2H), 3.08 (s, 3H), 4.03 (t, J = 6.3 Hz , 2H), 6.81 (dd, J = 2.1, 2.4 Hz, 2H), 6.86 (dd, J = 2.4, 8.4 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.44 (dd, J = 7.8, 8.4 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.77 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H)

88

1.94-2.01 (m, 2H), 2.29 (s, 3H), 2.36-2.54 (m, 10H), 4.03 (t, J = 6.2 Hz, 2H), 5.68 (bs, 1H), 6.04 (bs, 1H) , 6.81 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = 2.0, 8.3 Hz, 1H), 7.11-7.15 (m, 4H), 7.44 (dd, J = 8.0 , 8.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H)


89

1.95-1.99 (m, 2H), 2.28 (s, 3H), 2.44 (bs, 8H), 2.51 (t, J = 7.3 Hz, 2H), 3.05 (bs, 3H), 3.12 (bs, 3H), 4.03 (t, J = 6.3 Hz, 2H), 6.81 (dd, J = 2.0, 2.3 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = 2.3, 8.5 Hz, 1H) , 7.10 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.9 Hz, 2H), 7.44 (dd, J = 8.1, 8.5 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H) , 7.53 (d, J = 8.9 Hz, 2H), 7.75 (s, 1H)

90

1.65-1.71 (m, 2H), 1.78-1.83 (m, 2H), 2.31 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.44-2.50 (m, 8H), 3.99 (t, J = 6.3 Hz, 2H), 6.78 (dd, J = 2.0, 2.1 Hz, 1H), 6.85 (dd, J = 2.1, 8.0 Hz, 1H), 7.05-7.11 (m, 7H), 7.43 (dd, J = 8.0, 8.1 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.74 (s, 1H)

91

1.65-1.71 (m, 2H), 1.78-1.85 (m, 2H), 2.31 (s, 3H), 2.42 (t, J = 7.5 Hz, 2H), 2.51 (bs, 8H), 3.99 (t, J = 6.3 Hz, 2H), 6.78 (dd, J = 2.1, 2.3 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 7.01-7.08 (m, 5H), 7.37 (d, J = 8.5 Hz, 2H), 7.43 (dd, J = 7.9, 8.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 2H), 7.74 (s, 1H)


92

1.65-1.68 (m, 2H), 1.79-1.83 (m, 2H), 2.29 (s, 3H), 2.41 (t, J = 7.5 Hz, 2H), 2.46 (bs, 8H), 3.99 (t, J = 6.2 Hz, 2H), 6.79 (dd, J = 2.1, 2.2 Hz, 1H), 6.85 (d, J = 8.1 Hz, 2H), 7.03 (dd, J = 2.1, 8.4 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.7 Hz, 2H), 7.44 (dd, J = 8.1, 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.77 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H)


93

1.64-1.70 (m, 2H), 1.78-1.84 (m, 2H), 2.28 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.45 (bs, 8H), 3.99 (t, J = 6.3 Hz, 2H), 5.69 (bs, 1H), 6.02 (bs, 1H), 6.79 (dd, J = 2.0, 2.1 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 7.02 (dd, J = 2.0, 8.4 Hz, 1H), 7.11-7.15 (m, 4H), 7.44 (dd, J = 7.9, 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H ), 7.86 (d, J = 8.6 Hz, 2H)

94

1.44-1.48 (m, 2H), 1.52-1.57 (m, 2H), 1.78-1.82 (m, 2H), 2.28 (s, 3H), 2.35 (t, J = 7.6 Hz, 2H), 2.45 (bs, 8H), 3.96 (t, J = 6.4 Hz, 2H), 6.78 (dd, J = 1.9, 2.2 Hz, 1H), 6.84 (ddd, J = 0.9, 1.9, 7.9 Hz, 1H), 7.02-7.11 (m , 7H), 7.43 (dd, J = 7.9, 8.1 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.74 (s, 1H)


95

1.44-1.56 (m, 4H), 1.78-1.82 (m, 2H), 2.28 (s, 3H), 2.35 (t, J = 7.6 Hz, 2H), 2.45 (bs, 8H), 3.96 (t, J = 6.4 Hz, 2H), 6.78 (dd, J = 2.0, 2.1 Hz, 1H), 6.84 (dd, J = 2.0, 7.8 Hz, 1H), 7.03 (d, J = 8.7 Hz, 3H), 7.07 (d, J = 8.9 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.43 (dd, J = 7.8, 8.1 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.74 (s, 1H)


96

1.47-1.63 (m, 4H), 1.77-1.84 (m, 2H), 2.29 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H), 2.47 (bs, 8H), 3.08 (s, 3H) , 3.97 (t, J = 6.3 Hz, 2H), 6.78 (s, 1H), 6.83 (d, J = 7.7 Hz, 1H), 7.03 (dd, J = 1.9, 8.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.44 (dd, J = 7.9, 8.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H)


97

1.46-1.49 (m, 2H), 1.53-1.58 (m, 2H), 1.77-1.84 (m, 2H), 2.28 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H), 2.46 (bs, 8H), 3.97 (t, J = 6.5 Hz, 2H), 5.59 (bs, 1H), 5.98 (bs, 1H), 6.78 (dd, J = 2.0, 2.2 Hz, 1H), 6.84 (dd, J = 2.0 , 7.9 Hz, 1H), 7.02 (dd, J = 2.2, 8.3 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H), 7.44 (dd, J = 7.9, 8.3 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H)
98

6.95 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.9 Hz, 2H), 7.49 ( d, J = 8.9 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 10.49 (bs, 1H)
99

1.21 (t, J = 7.2 Hz, 6H), 1.96-2.16 (m, 2H), 3.10-3.20 (m, 6H), 4.18 (t, J = 5.9 Hz, 2H), 7.14-7.16 (m, 6H) , 7.41 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 7.80 (s, 1H), 9.99 (bs, 1H)

100

1.86-1.91 (m, 2H), 2.13 (s, 3H), 2.31-2.33 (m, 8H), 2.40 (t, J = 7.2 Hz, 2H), 4.09 (t, J = 6.3 Hz, 2H), 7.12 -7.14 (m, 4H), 7.20 (d, J = 8.9 Hz, 2H), 7.34 (bs, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H) , 7.80 (s, 1 H), 7.95 (d, J = 8.8 Hz, 3 H)

Example 101. 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone dihydrochloride

5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} prepared by the method of Example 1 2-thioxo-4-thiazolidinone dihydrochloride (50 mg, 0.14 mmol) was dissolved in 1 mL of ethanol and then con. 1 to 2 drops of HCl were dropped and heated to reflux for 24 hours. After the reaction is completed, lower the temperature to room temperature, filter, and wash the target compound several times with tetrahydrofuran to remove the target compound. 4 mg was obtained with a yield of 7.9%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.17-2.31 (m, 2H), 2.81 (bs, 3H), 3.37-3.76 (m, 10H), 4.13 (t, J = 5.5 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.76 ( d, J = 8.7 Hz, 2H), 7.84 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 11.47 (bs, 2H), 12.93 (bs, 1H)

Example 102. 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- Preparation of 4-thiazolidinone dihydrochloride

3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene prepared by the method of Example 1 above Dissolve 2-thioxo-4-thiazolidinone dihydrochloride (140 mg, 0.21 mmol) in 2 mL of tetrahydrofuran and add 140 mg of Raney-Ni, followed by 2 hours under hydrogen gas. Was stirred. After the reaction was completed, the resultant was filtered using Celite, and then distilled under reduced pressure to remove the solvent, thereby obtaining 116 mg of the target compound in a yield of 77.2%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.10-2.11 (m, 2H), 2.75 (s, 3H), 3.04-3.18 (m, 10H), 4.11 (t, J = 6.0 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.08 (d, J = 9.0 Hz, 2H), 7.31 ( d, J = 8.9 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.79 (s, 1H), 9.21 (bs, 2H)

Example 103. 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2- as prepared in Example 103 above Thioxo-4-thiazolidinone (50 mg, 0.09 mmol) was dissolved in 0.5 mL of tetrahydrofuran. And acetic anhydride (0.017 mL, 0.18 mmol) was added and stirred at room temperature for 15 minutes. After the reaction was completed, the resulting precipitate was filtered using a minimum amount of tetrahydrofuran to obtain 21 mg of the target compound in a yield of 39.5%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.85-1.87 (m, 2H), 2.04 (s, 3H), 2.13 (s, 3H), 2.31-2.43 (m, 10H), 4.04 (t, J = 6.2 Hz, 2H), 7.04-7.10 (m, 6H), 7.28 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H ), 7.80 (s, 1 H), 10.02 (bs, 1 H)

Example 104. 5- {4- [4- (methylsulfonylamino) phenoxy] phenyl} methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl}- Preparation of 2-thioxo-4-thiazolidinone

5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl}-prepared by the method of Example 103 above. 2-thioxo-4-thiazolidinone dihydrochloride (35 mg, 0.053 mmol) was dissolved in 1 mL of tetrahydrofuran and then N, N -diisopropylethylamine (0.012 mL, 0.063 mmol) was added. . Methanesulfonylchloride (5.0 mL, 0.055 mmol) was added at 0 ° C and then stirred. After completion of the reaction, the mixture was extracted with water and ethyl acetate, dried over anhydrous MgSO ₄ , and distilled under reduced pressure to remove the solvent, obtaining 13.3 mg of the target compound in a yield of 33.3%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.96-2.03 (m, 2H), 2.30 (s, 3H), 2.52-2.56 (m, 10H), 3.05 (s, 3H), 4.06 (t, J = 6.3 Hz, 2H), 7.03-7.11 (m, 6H), 7.18 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 8.8 Hz, 3H), 7.52 (d, J = 8.9 Hz, 2H), 7.76 (s, 1 H)

Example 105. 5- [4- (4-Chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4-thia Preparation of zolidinone trifluoroacetic acid

4- [3- (4- {5- [4- (4-chlorophenoxy) benzylidene] -4-oxo-2-thioxo-thiazolidine-3- prepared by the method of Example 1 above Phenoxy) propyl] piperazine-1-carboxylic acid- tert -butyl ester (50 mg, 0.075 mmol) was dissolved in 1 mL of a methylene chloride solution containing 10% trifluoroacetic acid and stirred at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain 48 mg of the compound in a yield of 96.5%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.20-2.21 (m, 2H), 3.31-3.72 (m, 10H), 4.14 (t, J = 5.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.16-7.18 (m, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.81 (s, 1 H), 9.63 (bs, 2 H), 11.81 (bs, 1 H)

Hereinafter, rhodanine compounds were synthesized in the same manner as in Example 105, and the structure and ¹ H NMR data thereof are shown in Table 2 below.

Example Chemical structure ¹ H NMR (ppm) δ

106

1.83-1.86 (m, 2H), 2.11-2.17 (m, 4H), 3.04-3.05 (m, 2H), 3.21-3.39 (m, 3H), 3.60-3.62 (m, 2H), 4.12-4.14 (m , 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.18 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H ), 7.51 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8.9 Hz, 2H), 7.82 (s, 1H), 8.28 (bs, 3H), 10.12 (bs, 1H)

Example 107. 5- [4- (4-Chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylsulfonyl-piperazin-1-yl) propoxy] phenyl} -2- Preparation of Thioxo-4-thiazolidinone

5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4 prepared in Example 105 above. -Thiazolidinone (50 mg, 0.088 mmol) was dissolved in 1 mL of anhydrous methylene chloride and then triethylamine (0.025 mL, 0.18 mmol) was added. Methanesulfonyl chloride (0.01 mL, 0.13 mmol) was added dropwise at 0 ° C. and stirred at 0 ° C. for 10 minutes. After completion of the reaction, the mixture was filtered using a minimum amount of methylene chloride, and extracted with methylene chloride and water to obtain more compound in the filtrate, and then recrystallized with methylene chloride / diethyl ether to give the target compound 38.9 mg in a yield of 68.3%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.98-2.01 (m, 2H), 2.58-2.61 (m, 6H), 2.79 (s, 3H), 3.26 (m, 4H), 4.07 (t, J = 6.1 Hz, 2H), 7.02-7.05 (m, 4H), 7.08 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.75 (s, 1H)

Example 108. 5- [4- (4-Chlorophenoxy) phenyl] methylene-3- {4- [3- ( N- methylsulfonyl-4-amino-1-piperidinyl) propoxy] phenyl} Preparation of 2-thioxo-4-thiazolidinone

3- {4- [3- (4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2- prepared in Example 106 above. Thioxo-4-thiazolidinone (50 mg, 0.086 mmol) was dissolved in 1 mL of methylene chloride, and triethylamine (0.02 mL, 0.017 mmol) was added thereto. Methanesulfonyl chloride (0.01 mL, 0.13 mmol) was added dropwise at 0 ° C., followed by stirring at 2 ° C. for 2 hours. After the reaction was completed, the mixture was extracted with methylene chloride and water, the organic layer was dried using anhydrous MgSO ₄ and then distilled under reduced pressure to remove the solvent. Purification by column chromatography (methylene chloride / methanol = 30: 1, 0.5% NH ₄ OH) gave 25.2 mg of the title compound in a yield of 44.4%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.55-1.60 (m, 2H), 1.97-2.02 (m, 4H), 2.12 (t, J = 10.9 Hz, 2H), 2.52 (t, J = 7.0 Hz, 2H), 2.86 (d, J = 11.4 Hz, 2H), 2.99 (s, 3H), 3.34-3.37 (m, 1H), 4.06 (t, J = 6.2 Hz, 2H), 4.18 (d, J = 7.7 Hz, 1H), 7.03 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.75 (s, 1H)

Example 109. 5- [4- (4-Chlorophenoxy) phenyl] methylene-3- {4- [3- (4-benzyl-piperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4 prepared in Example 105 above. -Thiazolidinone trifluoroacetic acid (50 mg, 0.088 mmol) was dissolved in 1 mL of dimethylformamide. K ₂ CO ₃ (14 mg, 0.11 mmol) and benzyl bromide (0.01 mL, 0.088 mmol) were added and stirred at room temperature for 3.5 hours. After the reaction was completed, the mixture was extracted with ethyl acetate and water, and the organic layer was dried over anhydrous MgSO ₄ . After distillation under reduced pressure to remove the solvent, the residue was purified using column chromatography (methylene chloride: methanol = 40: 1, 0.8% ammonia water) to obtain 30 mg of the target compound in a yield of 51.7%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.96-2.00 (m, 2H), 2.51-2.54 (m, 10H), 3.52 (s, 2H), 4.05 (t, J = 6.3 Hz, 2H), 7.03 ( d, J = 9.0 Hz, 2H), 7.04 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.25-7.26 (m, 1H), 7.18 (d, J = 8.8 Hz, 2H), 7.31-7.32 (m, 4H), 7.37 (d, J = 9.0 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.74 (s, 1H)

Example 110. 5- [4- (4-Chlorophenoxy) phenyl] methylene-3- {4- [3- (4- (2-propen-1-yl) piperazin-1-yl) propoxy ] Phenyl} -2-thioxo-4-thiazolidinone

5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4 prepared in Example 105 above. Thiazolidinone (50 mg, 0.088 mmol) was dissolved in 1 mL of dimethylformamide. K ₂ CO ₃ (15 mg, 0.088 mmol), allyl iodide (8 mL, 0.088 mmol) was added and stirred at room temperature for 1.5 hours. After the reaction was completed, water was added to form crystals, followed by filtration and purification by column chromatography (methylene chloride: methanol = 30: 1, 0.5% ammonia water) to obtain 17 mg of the target compound in a yield of 28.3%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.97-2.04 (m, 2H), 2.54-2.58 (m, 10H), 3.03 (d, J = 6.6 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 5.15-5.23 (m, 2H), 5.85-5.91 (m, 1H), 7.02 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H), 7.74 (s, 1H)

Example 111. 5- [4- (4-Chlorophenoxy) phenyl] methylene-3- {4- [3- (4-carbamoylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4 prepared in Example 105 above. Thiazolidinone (100 mg, 0.18 mmol) was dissolved in 1.5 mL of 60% acetic acid aqueous solution. Potassium cyanate (71 mg, 0.88 mmol) was dissolved in 1 mL of water and then slowly dropped and stirred at room temperature for 2 hours. After the reaction was completed, the resulting solution was filtered after adjusting the pH 7 to 8 by treating with sodium hydroxide aqueous solution (1 N). The filtered compound was dissolved in a tetrahydrofuran solvent, dried over anhydrous MgSO ₄ , distilled under reduced pressure to remove the solvent, and 90.3 mg of the target compound was obtained in a yield of 83.9%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.88-1.92 (m, 2H), 2.31 (t, J = 4.7 Hz, 4H), 2.45 (t, J = 7.0 Hz, 2H), 3.26 (t, J = 4.7 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 5.92 (bs, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.15-7.18 (m, 4H), 7.29 ( d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.82 (s, 1H)

Example 112. 3- {4- [3- ( N- acetyl-4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-thi Preparation of oxo-4-thiazolidinone

3- {4- [3- (4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2- prepared in Example 106 above. Thioxo-4-thiazolidinone was dissolved in 0.5 mL of acetic anhydride and stirred at room temperature for 4 hours. After completion of the reaction, the mixture was filtered using a minimum amount of acetic anhydride and washed with water to obtain 6.8 mg of the target compound in a yield of 22.9%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.33-1.35 (m, 2H), 1.68 (d, J = 10.8 Hz, 2H), 1.76 (s, 3H), 1.85-1.94 (m, 4H), 2.40 (t, J = 6.7 Hz, 2H), 2.79 (d, J = 10.8 Hz, 2H), 3.46-3.49 (m, 1H), 4.04 (t, J = 6.4 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.9 Hz, 2H), 7.28 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.7 Hz, 3H), 7.81 (s, 1H)

Hereinafter, rhodanine compounds were synthesized in the same manner as in Example 112, and the structure and ¹ H NMR data thereof are shown in Table 3 below.

Example Chemical structure ¹ H NMR (ppm) δ

113

1.69-1.72 (m, 2H), 1.91-2.02 (m, 4H), 2.06 (s, 3H), 2.26-2.28 (m, 2H), 2.52 (t, J = 7.2 Hz, 2H), 2.73-2.74 ( m, 2H), 4.06 (t, J = 6.2 Hz, 2H), 4.77-4.80 (m, 1H), 7.02-7.08 (m, 6H), 7.18 (d, J = 8.8 Hz, 2H), 7.37 (d , J = 8.8 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.75 (s, 1H)

Example 114. 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imi Preparation of Dazolidinediones

Step 1: Preparation of ethyl 2- { N- 4- [3- (4-methylpiperazin-1-yl) propoxy] phenylcarbamoyl} aminoacetate

4- [3- (4-methylpiperazin-1-yl) propoxy] aniline (1.0 g) prepared in step 3 of Example 1 in a methylene chloride solvent in which ethyl isocyanatoacetate (4.01 mmol) was dissolved. , 4.01 mmol) in which methylene chloride solution is slowly added dropwise and stirred at room temperature for 1 hour. When the reaction was terminated, the solvent was distilled off under reduced pressure, and the solvent was removed, followed by recrystallization with diethyl ether to obtain 1.47 g of the title compound in a yield of 96.8%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.27 (t, J = 7.1 Hz, 3H), 1.92-1.99 (m, 2H), 2.29 (s, 3H), 2.45-2.53 (m, 10H), 3.98 ( t, J = 6.3 Hz, 2H), 4.02 (d, J = 5.4 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 5.27 (t, J = 5.4 Hz, 1H), 6.50 (bs, 1H), 6.86 (d, J = 8.9 Hz, 2H), 7.20 (d, J = 8.9 Hz, 2H)

Step 2: Preparation of 3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imidazolidinedione

Ethyl 2- { N- 4 [3- (4-methylpiperazin-1-yl) propoxy] phenylcarbamoyl} aminoacetate (500 mg, 1.32 mmol) prepared in step 1 was dissolved in ethanol solvent. Then HCl (6N) aqueous solution was added and heated to reflux for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, ethanol was added thereto, and the solvent was removed by distillation under reduced pressure. This process was repeated several times to remove water completely and recrystallized from ethyl acetate to obtain 508 mg of the target compound in 94.8% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.20-2.22 (m, 2H), 2.80 (bs, 3H), 3.41-3.65 (m, 10H), 4.04 (s, 2H), 4.10 (t, J = 6.1 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 8.29 (s, 1H), 12.24 (bs, 2H)

Step 3: 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imida Preparation of zolidinedione

3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imidazolidinedione (50 mg, 0.12 mmol) prepared in step 2 was added to ethanol. After dissolution, anhydrous MgSO ₄ (1.2 eq, 0.14 mmol), pyrrolidine (0.6 eq, 0.072 mmol), 4- (4-chlorophenoxy) benzaldehyde (1.2 eq, 0.14 mmol) were added and heated for 2 hours. Reflux. After the reaction was completed, the mixture was filtered under reduced pressure, and the crystals were dissolved in water again, and the precipitate was filtered to give 42 mg of the target compound in a yield of 62.2%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.84-1.90 (m, 2H), 2.14 (s, 3H), 2.20-2.43 (m, 10H), 4.03 (t, J = 6.4 Hz, 2H), 6.59 (s, 1H), 7.02 (d, J = 9.0 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.9 Hz, 2H), 10.89 (bs, 1H)

Hydantoin compounds were synthesized in the same manner as in Example 114, and their structures and ¹ H NMR data are shown in Table 4 below.

Example Chemical structure ¹ H NMR (ppm) δ

115

1.21 (t, J = 6.8 Hz, 6H), 2.00-2.12 (m, 2H), 3.10-3.14 (m, 6H), 4.11 (t, J = 5.6 Hz, 2H), 6.61 (s, 1H), 7.05 (d, J = 8.6 Hz, 4H), 7.10 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.72 (d , J = 8.6 Hz, 2H), 9.77 (bs, 1H), 10.96 (bs, 1H)

116

0.94 (t, J = 6.9 Hz, 6H), 1.78-1.85 (m, 2H), 2.43-2.54 (m, 6H), 4.03 (t, J = 6.1 Hz, 2H), 6.59 (s, 1H), 6.98 -7.03 (m, 5H), 7.26 (dd, J = 7.4, 7.6 Hz, 1H), 7.31 (d, J = 8.9 Hz, 2H), 7.48 (dd, J = 7.4, 7.8 Hz, 1H), 7.52 ( bs, 1H), 7.64 (bs, 1H), 7.70 (d, J = 8.5 Hz, 3H), 10.68 (bs, 1H)

117

1.21 (t, J = 7.2 Hz, 6H), 2.12-2.14 (m, 2H), 3.13-3.16 (m, 6H), 4.11 (t, J = 6.1 Hz, 2H), 6.62 (s, 1H), 7.07 (d, J = 8.8 Hz, 4H), 7.23-7.25 (m, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.48 (bs, 1H), 7.50 (dd, J = 7.8, 7.8 Hz, 1H), 7.53 (s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 8.03 (bs, 1H), 9.89 (bs, 1H), 10.96 (bs, 1H)

118

1.21 (t, J = 6.9 Hz, 6H), 2.30-2.31 (m, 2H), 3.14-3.16 (m, 6H), 4.11 (t, J = 5.8 Hz, 2H), 6.62 (s, 1H), 7.02 -7.11 (m, 6H), 7.32 (bs, 1H), 7.35 (d, J = 9.0 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H) , 7.93 (bs, 1H), 9.74 (bs, 1H), 10.97 (bs, 1H)

119

1.86-1.89 (m, 2H), 2.14 (s, 3H), 2.32-2.43 (m, 10H), 4.04 (t, J = 6.5 Hz, 2H), 6.63 (s, 1H), 7.03 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.9 Hz, 3H), 7.76 (d, J = 8.7 Hz , 2H). 7.93 (d, J = 8.8 Hz, 2H), 7.95 (bs, 1H), 10.96 (bs, 1H)

120

1.96-2.00 (m, 2H), 2.29 (s, 3H), 2.45 (bs, 8H), 2.52 (t, J = 7.3 Hz, 2H), 4.03 (t, J = 6.3 Hz, 2H), 6.81 (s , 1H), 6.97-7.11 (m, 8H), 7.34 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.81 (bs, 1H)

121

1.54-1.58 (m, 2H), 1.71-1.75 (m, 2H), 2.13 (s, 3H), 2.29-2.32 (m, 10H), 4.02 (t, J = 6.4 Hz, 2H), 6.60 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 7.13-7.16 (m, 2H), 7.24-7.30 (m, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 10.93 (bs, 1H)

122

1.43-1.51 (m, 2H), 1.54-1.59 (m, 2H), 1.78-1.83 (m, 2H), 2.28 (s, 3H), 2.36 (t, J = 7.5 Hz, 2H), 2.46 (bs, 8H), 3.97 (t, J = 6.4 Hz, 2H), 6.81 (s, 1H), 6.96 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 7.01-7.11 ( m, 4H), 7.34 (d, J = 8.9 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H)

123

1.85-1.89 (m, 2H), 2.32 (s, 3H), 2.37-2.44 (m, 10H), 4.05 (t, J = 6.2 Hz, 2H), 6.61 (s, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.46-7.48 (m, 4H), 7.66 (d, J = 8.9 Hz, 2H) , 10.89 (bs, 1H)

124

1.85-1.88 (m, 2H), 2.14 (s, 3H), 2.32-2.43 (m, 10H), 4.05 (t, J = 6.0 Hz, 2H), 6.61 (s, 1H), 6.98 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.31 (bs, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.7 Hz, 3H), 10.96 (bs, 1H)

125

1.85-1.88 (m, 2H), 2.14 (s, 3H), 2.32 (bs, 8H), 2.41 (t, J = 7.2 Hz, 2H), 4.05 (t, J = 6.4 Hz, 2H), 6.60 (s , 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 7.13-7.16 (m, 2H), 7.25-7.29 (m, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 10.98 (bs, 1H)

126

1.48-1.53 (m, 2H), 1.82-1.85 (m, 2H), 2.29 (s, 3H), 2.37 (t, J = 7.3 Hz, 2H), 2.48 (bs, 8H), 3.72 (d, J = 2.3 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.99-7.06 (m, 6H), 7.32 (d, J = 8.9 Hz, 2H) , 7.48 (d, J = 8.8 Hz, 2H), 7.68 (t, J = 2.3 Hz, 1H)

127

1.40-1.47 (m, 4H), 1.71-1.74 (m, 2H), 2.13 (s, 3H), 2.25 (t, J = 7.0 Hz, 2H), 2.29 (bs, 8H), 4.01 (t, J = 6.4 Hz, 2H), 6.60 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 7.13-7.16 (m, 2H), 7.24-7.29 ( m, 2H), 7.44 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 10.90 (bs, 1H)

Example 128. 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -1-methyl-2,4-imidazolidine Preparation of Ion Hydrochloride

5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- [4- (3-diethylaminopropoxy) phenyl] -2,4-imidazoli prepared by the method of Example 112 above Deandione hydrochloride (100 mg, 0.19 mmol) was dissolved in 2 mL of dimethylformamide followed by the addition of NaH (60%, 8 mg, 0.21 mmol). After stirring for 30 minutes, methyl iodide (0.012 mL, 0.19 mmol) was added dropwise at -20 ° C, and the mixture was stirred for 1 hour while gradually raising to room temperature. After the reaction was completed, water was added and extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , distilled under reduced pressure to remove the solvent, and purified by column chromatography (methylene chloride: methanol = 15: 1, 1% aqueous ammonia). The purified compound was dissolved in ethyl acetate, and ethyl acetate containing HCl (2N) was added dropwise to obtain 14 mg of the target compound in the form of HCl in a yield of 12.8%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.21 (t, J = 7.2 Hz, 6H), 1.96-1.97 (m, 2H), 2.96 (s, 3H), 3.13-3.18 (m, 6H), 4.11 (t, J = 5.9 Hz, 2H), 6.83 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 9.0 Hz, 3H), 7.50 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.8 Hz, 3H), 9.80 (bs, 1H)

Hydantoin compounds were synthesized in the same manner as in Example 127, and their structures and ¹ H NMR data are shown in Table 5 below.

Example rescue ¹ H NMR δ


129

0.77 (t, J = 7.0 Hz, 3H), 1.21 (t, J = 7.1 Hz, 6H), 2.11-2.14 (m, 2H), 3.15-3.20 (m, 6H), 3.59 (q, J = 7.0 Hz , 2H), 4.11 (t, J = 6.0 Hz, 2H), 6.87 (s, 1H), 7.06 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.13 (d , J = 8.7 Hz, 2H), 7.32 (bs, 1H), 7.34 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.8 Hz, 3H ), 9.77 (bs, 1 H)

130

0.53 (t, J = 7.3 Hz, 3H), 1.11-1.18 (m, 2H), 1.21 (t, J = 7.2 Hz, 6H), 2.11-2.16 (m, 2H), 3.11-3.22 (m, 6H) , 3.52 (t, J = 7.4 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 6.88 (s, 1H), 7.04 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.32 (bs, 1H), 7.35 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 7.93 (bs, 1H), 9.87 (bs, 1H)


131

0.65 (t, J = 7.3 Hz, 3H), 0.91-0.97 (m, 2H), 1.08-1.12 (m, 2H), 1.22 (t, J = 7.2 Hz, 6H), 2.11-2.15 (m, 2H) , 3.14-3.21 (m, 6H), 3.57 (t, J = 7.5 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 6.89 (s, 1H), 7.04 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.33 (bs, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 8.8 Hz, 2H), 7.95 (bs, 1H), 9.73 (bs, 1H)

Example 132. 3- [4- (4-chlorophenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-pipe Preparation of Lolidine Dione

Step 1: Preparation of (2Z) -4- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} amino-4-oxo-2-butanoic acid

Maleic anhydride (1.2 eq) was dissolved in a minimum amount of tetrahydrofuran. 4- [3- (4-methylpiperazin-1-yl) propoxy] aniline (500 mg, 2.0 mmol) prepared in Step 3 of Example 1 was dissolved in a minimum amount of tetrahydrofuran, and then slowly dropped, Stir at room temperature for 30 minutes. After the reaction was completed, 690 mg of the target compound was obtained by filtration under reduced pressure.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.86-1.93 (m, 2H), 2.63 (bs, 3H), 2.71-3.33 (m, 10H), 3.98 (t, J = 6.3 Hz, 2H), 6.28 (d, J = 12.2 Hz, 1H), 6.39 (d, J = 12.2 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.53 (d, J = 9.0 Hz, 2H), 10.72 ( bs, 1 H)

Step 2: Preparation of 1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -1 H- pyrrole-2,5-dione

(2Z) -4- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} amino-4-oxo-2-butanoic acid prepared in step 1 (690 mg, 1.98 mmol) ) Was dissolved in acetic anhydride and NaOAc (1.0 eq, 1.98 mmol) was added. Stir at 100 ° C. for 30-40 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure to purify the solvent, and the residue was purified using column chromatography (methylene chloride: methanol = 15: 1, 1% ammonia water) to obtain 142 mg of the target compound in a yield of 22.4%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.95-1.99 (m, 2H), 2.30 (s, 3H), 2.51-2.53 (m, 8H), 2.54 (t, J = 7.4 Hz, 2H), 4.03 ( t, J = 6.4 Hz, 2H), 6.83 (s, 2H), 6.97 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 9.0 Hz, 2H)

Succinimide compounds were synthesized in the same manner as in Example 132, and the structure and the ¹ H NMR data are shown in Table 6 below.

Example rescue ¹ H NMR (ppm) δ

133

1.86-1.90 (m, 2H), 2.15 (s, 3H), 2.32-2.43 (m, 10H), 3.81 (s, 2H), 4.04 (t, J = 6.2 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.34 (bs, 1H), 7.55 (s, 1H), 7.76 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.9 Hz, 3H)

134

1.96-2.00 (m, 2H), 2.29 (s, 3H), 2.49 (bs, 8H), 2.52 (t, J = 7.3 Hz, 2H), 3.70 (d, J = 2.3 Hz, 2H), 4.04 (t , J = 6.3 Hz, 2H), 7.00 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 7.04-7.12 (m, 4H), 7.26 (d, J = 9.0 Hz , 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.68 (t, J = 2.3 Hz, 1H)

135

1.63-1.71 (m, 2H), 1.78-1.85 (m, 2H), 2.28 (s, 3H), 2.40 (t, J = 7.5 Hz, 2H), 2.45 (bs, 8H), 3.69 (d, J = 2.1 Hz, 2H), 4.00 (t, J = 6.3 Hz, 2H), 6.97-7.11 (m, 8H), 7.26 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H) , 7.68 (t, J = 2.1 Hz, 1H)

136

1.45-1.49 (m, 2H), 1.55-1.57 (m, 2H), 1.79-1.83 (m, 2H), 2.28 (s, 3H), 2.37 (t, J = 7.6 Hz, 2H), 2.45 (bs, 8H), 3.70 (d, J = 2.3 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H) , 7.04-7.12 (m, 4H), 7.26 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.68 (t, J = 2.3 Hz, 1H)

37

1.86-1.89 (m, 2H), 2.14 (s, 3H), 2.30-2.33 (m, 8H), 2.41 (t, J = 7.1 Hz, 2H), 3.79 (d, J = 2.2 Hz, 2H), 4.07 (t, J = 6.3 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.0 Hz, 2H), 7.37 (d , J = 9.0 Hz, 2H), 7.47 (d, J = 9.0 Hz, 2H), 7.52 (t, J = 2.2 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H)

138

1.86-1.89 (m, 2H), 2.14 (s, 3H), 2.32-2.43 (m, 10H), 3.80 (d, J = 2.2 Hz, 2H), 4.07 (t, J = 6.2 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.32 (bs, 1H), 7.40 (d, J = 8.6 Hz , 2H), 7.53 (t, J = 2.2 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 8.6 Hz, 3H)

139

1.98-2.02 (m, 2H), 2.29 (s, 3H), 2.48 (bs, 8H), 2.54 (t, J = 7.2 Hz, 2H), 3.72 (d, J = 2.3 Hz, 2H), 4.90 (t , J = 6.3 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 7.02-7.07 (m, 6H), 7.32 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 8.8 Hz , 2H), 7.68 (t, J = 2.3 Hz, 1H)

140

1.64-1.72 (m, 2H), 1.80-1.85 (m, 2H), 2.29 (s, 3H), 2.41 (t, J = 7.3 Hz, 2H), 2.45 (bs, 8H), 3.72 (d, J = 2.3 Hz, 2H), 4.04 (t, J = 6.4 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 7.03-7.06 (m, 6H), 7.32 (d, J = 8.9 Hz, 2H) , 7.48 (d, J = 8.8 Hz, 2H), 7.68 (t, J = 2.3 Hz, 1H)

141

1.47-1.54 (m, 2H), 1.56-1.60 (m, 2H), 2.29 (s, 3H), 2.37 (t, J = 7.4 Hz, 2H), 2.45 (bs, 8H), 3.70 (d, J = 2.1 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.99-7.08 (m, 6H), 7.32 (d, J = 8.9 Hz, 2H) , 7.47 (d, J = 8.8 Hz, 2H), 7.67 (t, J = 2.1 Hz, 1H)

Example 142 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine- Preparation of 2,4-dione

Step 1: Preparation of 2-chloro- N- (hydroxyphenyl) acetamide

4-aminophenol (6 g, 54.9 mmol) was dissolved in anhydrous methylene chloride and chloroacetyl chloride was slowly added dropwise at 0 ° C. After stirring at 0 ° C. for 1 hour, the reaction was performed by stirring at room temperature for 3 hours. At the end of the reaction, ammonium chloride was added and extracted with methylene chloride. The organic layer was dried over anhydrous MgSO ₄ , and distilled under reduced pressure to obtain the target compound in a yield of 64%.

¹ H NMR (400 MHz, DMSO-d ₆ ) 4.18 (s, 2H), 6.71 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 9.43 (bs, 1H), 10.04 (s, 1 H)

Step 2: Preparation of 3- (4-hydroxyphenyl) -2-iminothiazolidin-4-one

2-chloro- N- (hydroxyphenyl) acetamide prepared in step 1 (4.7 g, 25.3 mmol) was dissolved in acetonitrile, then potassium thiocyanate (2.95 g, 30.4 mmol) was added and the mixture was heated to reflux at 90 ° C. for 7 hours. When the reaction was completed, the resulting precipitate was filtered under reduced pressure to obtain the target compound in a yield of 68%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.09 (s, 2H), 6.80 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 9.18 (s, 1H) , 9.67 (s, 1 H)

Step 3: Preparation of 3- (4-hydroxyphenyl) thiazolidine-2,4-dione

3- (4-hydroxyphenyl) -2-iminothiazolidin-4-one (3.6 g, 17.3 mmol) prepared in step 2 was dissolved in 37 mL of a 2% aqueous HCl solution and then 100 ° C. for 7 hours. Heated to reflux. After the reaction was completed, the temperature was lowered to room temperature and neutralized to pH 7 with sodium bicarbonate. The precipitate formed is filtered under reduced pressure with water to obtain the target compound. Obtained in a yield of 54.4%.

¹ H NMR (400 MHz, DMSO-d ₆ ) 4.27 (s, 2H), 6.83 (d, J = 8.7 Hz, 2H,), 7.06 (d, J = 8.7 Hz, 2H), 9.81 (s, 1H)

Step 4: Preparation of 3- [4- (3-bromopropoxy) phenyl] thiazolidine-2,4-dione

3- (4-hydroxyphenyl) thiazolidine-2,4-dione (1.5 g, 7.2 mmol) prepared in step 3 was added thereto, dissolved in acetonitrile, and then K ₂ CO ₃ (1.49 g, 10.8 mmol), 1,3-dibromopropane (4.38 mL, 43.2 mmol) were added sequentially and heated to reflux at 90 ° C. for 8 hours. After the reaction was completed, the reaction was confirmed and the temperature was lowered to room temperature. Then, water was added and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous MgSO ₄ , and distilled under reduced pressure. Separation and purification by column chromatography (ethyl acetate: n-hexane = 1: 2) gave the target compound in a yield of 81.2%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.24-2.27 (m, 2H), 3.68 (t, J = 6.5 Hz, 2H), 4.12 (t, J = 5.9 Hz, 2H), 4.27 (s, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H)

Step 5: 3- {4- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2,4-dione

3- [4- (3-bromopropoxy) phenyl] thiazolidine-2,4-dione (50 mg, 0.15 mmol) prepared in step 4, K ₂ CO ₃ (42 mg, 0.3 mmol ) Was dissolved in acetonitrile and then 1-methylpiperazine (0.03 mL, 0.3 mmol) was added dropwise. After stirring for 10 hours at room temperature, the reaction was terminated, water was added and extracted with methylene chloride. The extracted organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure. Separation and purification by column chromatography (methylene chloride: methanol = 15: 1, 1% ammonia water) afforded the target compound in a yield of 51%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.84-1.88 (m, 2H), 2.13 (s, 3H), 2.32 (bs, 8H), 2.40 (t, J = 7.1 Hz, 2H), 4.03 ( t, J = 6.3 Hz, 2H), 4.27 (s, 2H), 7.02 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H)

Step 6: 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione

3- (4- (3- (4-methylpiperazin-1-yl) propoxy) phenyl) thiazolidine-2,4-dione (25 mg, 0.07 mmol) prepared in step 5, 4 -(4-Floridephenoxy) benzaldehyde (31 mg, 0.14 mmol), and NaOAc (17.6 mg, 0.21 mmol) are dissolved in acetic acid and heated to reflux at 110 ° C. for 24 hours. After the reaction was completed, the pH was adjusted to 8 with ammonia water and extracted with methylene chloride. The extracted organic layer was dried over anhydrous MgSO ₄ , and evaporated under reduced pressure. Separation and purification by column chromatography (methylene chloride: methanol = 15: 1, 1% ammonia water) afforded the desired compound in 38% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.22 (bs, 2H), 2.81 (s, 3H), 3.60-3.79 (m, 10H), 4.13 (t, J = 5.3 Hz, 2H), 7.08 ( d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.9 Hz, 2H), 7.69 (d, J = 8.9 Hz, 2H), 7.95 (s, 1H)

Glitazone compounds were synthesized in the same manner as in Example 142. The structures and the ¹ H NMR data are shown in Table 7 below.

Example rescue ¹ H NMR (ppm) δ

143

2.28 (bs, 2H), 2.84 (s, 3H,), 3.60-3.79 (m, 10H), 4.15 (t, J = 5.8 Hz, 2H), 7.09 (d, J = 8.7 Hz, 2H), 7.24 ( d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 8.00 (s, 1H)

144

1.26 (d, J = 4.9 Hz, 6H,), 2.03 (q, J = 6.8 Hz, 2H), 2.73 (t, J = 7.1 Hz, 2H), 3.34-3.51 (m, 9H), 4.11 (t, J = 6.1 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 7.17 (d, J = 8.8 Hz, 4H), 7.35 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.97 (s, 1H)

145

2.25-2.26 (m, 2H), 3.10-3.20 (m, 6H), 3.33 (t, J = 4.8 Hz, 2H), 3.84 (d, J = 12.1 Hz, 2H), 4.16 (t, J = 5.8 Hz , 2H), 6.87 (t, J = 7.3 Hz, 1H), 7.01 ( J = 8.1 Hz, 2H), 7.11 ( J = 8.6 Hz, 4H), 7.20-7.22 (m, 2H), 7.25-7.33 (m , 4H), 7.37 (d, J = 8.8 Hz, 2H), 7.70 ( J = 8.8 Hz, 2H), 7.95 (s, 1H)

146

1.47 (m, 2H), 1.76-1.77 (m, 4H), 2.81 (s, 3H), 3.37 (bs, 8H), 3.60 (t, J = 6.56 Hz, 2H), 4.05 (t, J = 6.09, 2H), 7.07 (d, J = 8.85 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 7.19-7.22 (m, 2H), 7.29 (d, J = 8.66 Hz, 2H), 7.33- 7.35 (2H, d, J = 8.86 Hz, 2Ph), 7.69 (d, J = 8.76 Hz, 2H), 7.95 (s, 1H)

147

1.47 (m, 2H), 1.74-1.77 (m, 4H), 2.81 (s, 3H), 3.37 (bs, 8H), 3.59 (t, J = 6.5 Hz, 2H,), 4.04 (t, J = 6.1 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 4H), 7.34 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H)

148

1.47-1.49 (m, 2H), 1.75-1.76 (m, 4H), 2.80 (s, 3H), 3.36 (bs, 8H), 3.60 (t, J = 5.8 Hz, 2H), 4.05 (t, J = 6.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz , 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.96 (s, 1H)


149

1.41-1.47 (m, 4H), 1.74 (q, J = 6.5 Hz, 2H), 2.13 (s, 3H), 2.26 (t, J = 6.7 Hz, 2H), 2.32 (s, 3H), 2.36 (bs , 8H), 4.02 (t, J = 6.4 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 7.09 (t, J = 8.8 Hz, 2H ), 7.26 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H)

150

1.49 (m, 2H), 1.74-1.77 (m, 4H), 2.85 (s, 3H), 3.38 (bs, 10H), 3.77 (s, 3H), 4.04 (t, J = 6.09 Hz, 2H), 7.01 -7.12 (m, 8H), 7.34 (d, J = 8.92 Hz, 2H), 7.66 (d, J = 8.93 Hz, 2H), 7.93 (s, 1H)


151

1.41-1.47 (m, 4H), 1.74 (q, J = 6.5 Hz, 2H), 2.14 (s, 3H), 2.27 (t, J = 6.4 Hz, 2H), 2.35 (bs, 8H), 4.03 (t , J = 6.55 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 8.00 (s, 1H)

152

1.41-1.47 (m, 4H), 1.74 (q, J = 6.5 Hz, 2H), 2.13 (s, 3H), 2.26 (t, J = 6.6 Hz, 2H), 2.35 (bs, 8H), 4.02 (t , J = 6.36 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 9.0 Hz, 2H), 7.35 (t, J = 8.8 Hz, 4H), 7.79 (d, J = 8.6 Hz, 2H), 8.02 (s, 1H), 8.30 (d, J = 9.0 Hz, 2H)


153

1.39-1.46 (m, 4H), 1.73 (q, J = 6.9 Hz, 2H), 2.12 (s, 3H), 2.25 (t, J = 6.7 Hz, 2H), 2.33 (bs, 8H), 3.97 (t , J = 6.4 Hz, 2H), 6.98 (d, J = 7.9 Hz, 1H), 7.04 (s, 1H), 7.05 (s, 1H), 7.12 (d, J = 8.7 Hz, 2H), 7.19 (d , J = 6.7 Hz, 1H), 7.21 (d, J = 4.5 Hz, 1H), 7.30 (t, J = 8.8 Hz, 2H), 7.41 (t, J = 9.1 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H)


154

1.39-1.46 (m, 4H), 1.73 (q, J = 6.6 Hz, 2H), 2.12 (s, 3H), 2.25 (t, J = 7.1 Hz, 2H), 2.38 (bs, 8H), 3.97 (t , J = 6.5 Hz, 2H), 6.99 (dt, J = 0.8, 7.8 Hz, 1H), 7.04-7.06 (m, 1H), 7.17 (d, J = 8.8 Hz, 4H), 7.43 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.97 (s, 1H)


155

1.39-1.46 (m, 4H), 1.73 (q, J = 6.8 Hz, 2H), 2.12 (s, 3H), 2.25 (t, J = 6.7 Hz, 2H), 2.38 (bs, 8H), 3.97 (t , J = 6.4 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 7.05 ( J = 6.7 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 7.41 (t, J = 8.6 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.7 Hz, 2H), 7.97 (s, 1H)

156

1.39-1.46 (m, 4H), 1.75 (q, J = 6.5 Hz, 2H), 2.12 (s, 3H), 2.25 (t, J = 6.6 Hz, 2H), 2.38 (bs, 8H), 2.39 (s , 3H), 3.97 (t, J = 6.5 Hz, 2H), 6.98 (d, J = 7.9 Hz, 1H), 7.03-7.05 (m, 4H), 7.10 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.95 (s, 1H)

157

1.39-1.46 (m, 4H), 1.73 (q, J = 7.1 Hz, 2H), 2.12 (s, 3H), 2.25 (t, J = 6.7 Hz, 2H), 2.38 (bs, 8H), 3.77 (s , 3H), 3.97 (t, J = 6.4 Hz, 2H), 6.98 (d, J = 7.1 Hz, 1H), 7.01-7.07 (m, 6H), 7.11 (d, J = 8.9 Hz, 2H), 7.40 (t, J = 8.9 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H)

158

1.44-1.48 (m, 2H), 1.74-1.79 (m, 4H), 2.12 (s, 3H), 2.38 (bs, 10H), 4.01 (t, J = 6.1 Hz, 2H), 7.01 (d, J = 9.4 Hz, 1H), 7.06-7.08 (m, 2H), 7.24 ( J = 6.8 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.77 (d, J = 6.9 Hz, 2H), 7.91 (d, J = 8.8 Hz, 2H), 8.01 (s, 1H)


159

1.40-1.46 (m, 4H), 1.73 (q, J = 6.6 Hz, 2H), 2.12 (s, 3H), 2.25 (t, J = 6.7 Hz, 2H), 2.38 (bs, 8H), 3.97 (t , J = 6.5 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 7.06 (m, 2H), 7.28 (d, J = 10.4 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H ), 7.43 (t, J = 7.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 8.03 (s, 1H), 8.30 (d, J = 7.0 Hz, 2H)

Example 160. 5- [4- (4-Aminophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 Of 4-, dione

3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene prepared by the method of Example 142 above Thiazolidine-2,4-dione (80 mg, 0.13 mmol) was dissolved in methanol. Raney nickel (Raney-Ni) was added dropwise and stirred for 2.5 hours under hydrogen gas at room temperature. After the reaction was completed, the precipitate was filtered under reduced pressure using celite, The filtrate was distilled under reduced pressure to remove the solvent to give the target compound in a yield of 79%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41-1.46 (m, 4H), 1.74 (q, J = 6.5 Hz, 2H), 2.13 (s, 3H), 2.26 (t, J = 6.9 Hz, 2H), 2.35 (bs, 8H), 4.01 (t, J = 6.4 Hz, 2H), 5.09 (s, 2H), 6.62 (d, J = 6.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 6.9 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H) , 7.92 (s, 1 H)

Glitazone compounds were synthesized in the same manner as in Example 160. The structures and the ¹ H NMR data are shown in Table 8 below.

Example rescue ¹ H NMR (ppm) δ

161

1.39-1.46 (m, 4H), 1.73 (q, J = 6.8 Hz, 2H), 2.12 (s, 3H), 2.24 (t, J = 6.8 Hz, 2H), 2.38 (bs, 8H), 3.97 (t , J = 6.5 Hz, 2H), 6.62 (d, J = 6.6 Hz, 2H), 6.83 ( J = 6.3 Hz, 2H), 6.98 (dd, J ₁ = 0.9, 7.8 Hz, 1H), 6.99-7.05 ( m, 4H), 7.40 (t, J = 8.9 Hz, 1H), 7.64 (d, J = 8.9 Hz, 2H), 7.92 (s, 1H)


162

1.64 (q, J = 6.9 Hz, 2H), 1.75 (q, J = 6.2 Hz, 2H), 2.18 (s, 3H), 2.22 (t, J = 4.6 Hz, 2H), 2.28 (t, J = 4.7 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 3.42 (bs, 4H), 4.04 (t, J = 6.0 Hz, 2H), 5.10 (s, 2H), 6.63 (d, J = 6.6 Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 6.7 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 7.93 (s, 1H)

Example 163. 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo Preparation of 4-thiazolidinone

5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) propoxy] phenyl} cyc prepared by the method of Example 160 above Azolidine-2,4-dione (30 mg, 0.05 mmol) was dissolved in anhydrous methylenechloride. Dimethylaminopyridine (0.6 mg, 0.005 mmol) and acetic anhydride (0.005 mL, 0.05 mmol) were added dropwise. When the reaction is over, add water Extracted with methylene chloride. The organic layer was dried over anhydrous MgSO ₄ , and distilled under reduced pressure to obtain the target compound in a yield of 62.5%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.39-1.46 (m, 4H), 1.73 (q, J = 5.5 Hz, 2H), 2.05 (s, 3H), 2.13 (s, 3H), 2.26 ( t, J = 6.5 Hz, 2H), 2.35 (bs, 8H), 4.01 (t, J = 6.2 Hz, 2H), 7.05 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 8.9 Hz, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H), 10.02 (s, 1H)

Glitazone compounds were synthesized in the same manner as in Example 163. The structures and the ¹ H NMR data are shown in Table 9 below.

Example rescue ¹ H NMR (ppm) δ

164

1.39-1.46 (m, 4H), 1.72 (q, J = 6.7 Hz, 2H), 2.05 (s, 3H), 2.12 (s, 3H), 2.25 (t, J = 6.8 Hz, 2H), 2.38 (bs , 8H), 3.97 (t, J = 6.5 Hz, 2H), 6.98 (d, J = 8.3 Hz, 1H), 7.04-7.07 (m, 2H), 7.09 (d, J = 8.9 Hz, 4H), 7.42 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 9.6 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.95 (s, 1H), 10.02 (s, 1H)

Example 165. 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thio Preparation of Azolidine-2,4-Dione

Step 1: Preparation of 5-chloro-1- (4-methylpiperazin-1-yl) pentan-1-one

1-methylpiperazine (0.6 mL, 5.4 mmol) and triethylamine (1.5 mL, 10.8 mmol) were dissolved in anhydrous methylene chloride and stirred at room temperature for 10 minutes. After 10 minutes 5-chlorovaleryl chloride (0.7 mL, 5.4 mmol) was slowly added dropwise at 0 ° C. The reaction was further stirred for 2 hours at room temperature. After the reaction was completed, water was added and extracted with methylene chloride. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure to obtain the target compound in 91.5% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.59 (q, J = 7.4 Hz, 2H), 1.73 (q, J = 7.9 Hz, 2H), 2.16 (s, 3H), 2.21 (t, J = 5.0 Hz, 2H), 2.27 (t, J = 4.9 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 3.41 (q, J = 4.8 Hz, 4H), 3.65 (t, J = 6.5 Hz , 2H)

Step 2: Preparation of 1- (4-methylpiperazin-1-yl) -5- (4-nitrophenoxy) pentan-1-one

4-nitrophenol (1.0 g, 7.2 mmol) was dissolved in acetonitrile and then 5-chloro-1- (4-methylpiperazin-1-yl) pentan-1-one (1.9) prepared in Step 1 above. g, 8.6 mmol), K ₂ CO ₃ (3.0 g, 21.6 mmol), 18-Crown-6 (1.9 g, 7.2 mmol) were added. The mixture was heated to reflux at 100 ° C. for 24 hours. After the reaction was completed, sodium hydrogen carbonate was added and extracted with diethyl ether. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure to obtain the target compound in a yield of 54%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.63 (q, J = 7.4 Hz, 2H), 1.76 (q, J = 6.4 Hz, 2H), 2.16 (s, 3H), 2.21 (t, J = 5.0 Hz, 2H), 2.27 (t, J = 4.9 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 3.42 (t, J = 4.7 Hz, 4H), 4.14 (t, J = 6.3 Hz , 2H), 7.14 (d, J = 7.1 Hz, 2H), 8.20 (d, J = 7.1 Hz, 2H)

Step 3: Preparation of 5- (4-aminophenoxy) -1- (4-methylpiperazin-1-yl) pentan-1-one

1- (4-methylpiperazin-1-yl) -5- (4-nitrophenoxy) pentan-1-one (500 mg, 1.56 mmol) prepared in step 2 was dissolved in methanol. Pd / C (5% Pd, one portion) was added dropwise and stirred at room temperature under hydrogen gas for 4 hours. After the reaction was completed, the mixture was filtered under reduced pressure using celite, and the filtrate was distilled under reduced pressure to obtain a target compound in a yield of 75%.

¹ H NMR (400 MHz, DMSO-d ₆ ) 1.61-1.68 (m, 4H), 2.16 (s, 3H), 2.21 (t, J = 5.0 Hz, 2H), 2.27 (t, J = 4.9 Hz, 2H ), 2.33 (t, J = 7.4 Hz, 2H), 3.41 (t, J = 4.8 Hz, 4H), 3.81 (t, J = 5.9 Hz, 2H), 4.56 (bs, 2H), 6.49 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H)

Step 4: Preparation of 2-chloro- N- (4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy) phenyl) acetamide

5- (4-aminophenoxy) -1- (4-methylpiperazin-1-yl) pentan-1-one (940 mg, 3.2 mmol) prepared in step 3 was dissolved in anhydrous methylene chloride, followed by chloro Acetyl chloride (0.3 mL, 3.9 mmol) was slowly added dropwise at 0 ° C. After stirring at 0 ° C. for 1 hour, the temperature was raised to room temperature, followed by stirring for 3 hours. At the end of the reaction, ammonium chloride was added and extracted with methylene chloride. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure to obtain the target compound in 95% yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.62 (q, J = 4.0 Hz, 2H), 1.69 (q, J = 7.5 Hz, 2H), 2.16 (s, 3H), 2.22 (t, J = 5.0 Hz, 2H), 2.27 (t, J = 4.9 Hz, 2H), 2.36 (t, J = 7.4 Hz, 2H), 3.43 (bs, 4H), 3.94 (t, J = 6.1 Hz, 2H), 4.21 (s, 2H), 6.89 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H), 10.16 (s, 1H)

Step 5: Preparation of 2-Imino-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy) phenyl) thiazolidin-4-one

2-chloro- N- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} acetamide (500 mg, 1.4 mmol) prepared in step 4 was dissolved in anhydrous acetone. After dissolving in potassium thiocyanate (198 mg, 2.0 mmol) was added. This mixture was heated to reflux at 75 ° C. for 24 h. After the reaction was completed, acetone was distilled under reduced pressure, water was added to the filtrate, and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure. Separation and purification by column chromatography (methylene chloride: methanol = 15: 1, 1% aqueous ammonia) gave the target compound in a yield of 23%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.64 (q, J = 7.1 Hz, 2H), 1.75 (q, J = 6.3 Hz, 2H), 2.17 (s, 3H), 2.22 (t, J = 4.9 Hz, 2H), 2.28 (t, J = 4.8 Hz, 2H), 2.37 (t, J = 7.4 Hz, 2H), 3.42 (bs, 4H), 4.01 (t, J = 6.1 Hz, 2H), 4.11 (s, 2H), 6.99 (d, J = 8.9 Hz, 2H), 7.13 (d, J = 8.9 Hz, 2H), 9.21 (s, 1H)

Step 6: Preparation of 3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thiazolidine-2,4-dione

2-imino-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy) phenyl) thiazolidin-4-one (280 mg) prepared in step 5 above , 0.72 mmol) was dissolved in 2% aqueous HCl solution (1.5 mL) and then heated at 50 ° C. for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, neutralized to pH 7 with sodium bicarbonate, extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO ₄ , and distilled under reduced pressure. Separation and purification by column chromatography (methylene chloride: methanol = 15: 1, 1% aqueous ammonia) gave the target compound in a yield of 54%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.65 (q, J = 7.3 Hz, 2H), 1.75 (q, J = 6.6 Hz), 2.17 (s, 3H), 2.22 (t, J = 4.9 Hz ), 2.28 (t, J = 4.8 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H), 3.42 (bs, 4H), 4.02 (t, J = 6.1 Hz, 2H), 4.28 (s, 2H ), 7.03 (d, J = 8.9 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H)

Step 7: 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Preparation of zolidine-2,4-dione

3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thiazolidine-2,4-dione prepared in step 6 (20 mg, 0.05 mmol), 4- (4-fluorophenoxy) benzaldehyde (22 mg, 0.1 mmol), and NaOAc (12.5 mg, 0.15 mmol) were dissolved in acetic acid and then heated to reflux at 110 ° C. for 24 hours. After the reaction was completed, the pH was adjusted to 8 with ammonia water and extracted with methylene chloride. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure. Separation and purification by column chromatography (methylene chloride: methanol = 15: 1, 1% aqueous ammonia) gave the target compound in a yield of 45%.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.65 (q, J = 7.2 Hz, 2H), 1.75 (q, J = 6.7 Hz, 2H), 2.17 (s, 3H), 2.22 (t, J = 4.8 Hz, 2H), 2.28 (t, J = 4.7 Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H), 3.42 (bs, 4H), 4.04 (t, J = 6.2 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.9 Hz, 2H), 7.61 (d , J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H)

Glitazone compounds were synthesized in the same manner as in Example 165, and their structures and ¹ H NMR data are shown in Table 10 below.

Example rescue ¹ H NMR (ppm) δ

166

1.64 (q, J = 7.6 Hz, 2H), 1.75 (q, J = 6.2 Hz, 2H), 2.16 (s, 3H), 2.22 (t, J = 4.7 Hz, 2H), 2.28 (t, J = 4.7 Hz, 2H), 2.38 (t, J = 7.6 Hz, 2H), 3.42 (bs, 4H), 4.04 (t, J = 6.1 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 7.17 ( d, J = 8.7 Hz, 4H), 7.33 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 7.96 (s, 1H)

167

1.64 (q, J = 7.2 Hz, 2H,), 1.75 (q, J = 6.5 Hz, 2H), 2.17 (s, 3H), 2.22 (t, J = 4.7 Hz, 2H), 2.28 (t, J = 4.7 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 3.42 (bs, 4H), 4.04 (t, J = 6.2 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.71 (d , J = 8.8 Hz, 2H), 7.97 (s, 1H)

168

1.65 (q, J = 6.9 Hz, 2H,), 1.75 (q, J = 6.6 Hz, 2H), 2.17 (s, 3H), 2.22 (t, J = 4.9 Hz, 2H), 2.28 (t, J = 4.1 Hz, 2H), 2.32 (s, 3H), 2.38 (t, J = 7.4 Hz, 2H), 3.43 (bs, 4H), 4.02 (t, J = 5.9 Hz, 2H), 7.02-7.10 (m, 6H), 7.26 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H)

169

1.65 (q, J = 6.9 Hz, 2H), 1.75 (q, J = 6.6 Hz, 2H), 2.16 (s, 3H), 2.22 (t, J = 4.9 Hz, 2H), 2.28 (t, J = 4.1 Hz, 2H), 2.38 (t, J = 7.5 Hz, 2H), 3.46 (bs, 4H), 3.77 (s, 3H), 4.03 (t, J = 6.1 Hz, 2H), 7.01-7.07 (m, 6H ), 7.11 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H)


170

1.62 (q, J = 7.2 Hz, 2H), 1.73 (q, J = 6.8 Hz, 2H), 2.17 (s, 3H), 2.21 (t, J = 4.7 Hz, 2H), 2.31 (t, J = 4.7 Hz, 2H), 2.38 (t, J = 7.4 Hz, 2H), 3.42 (bs, 4H), 4.04 (t, J = 6.2 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.24 ( d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H)


171

1.65 (q, J = 7.6 Hz, 2H), 1.74 (q, J = 6.2 Hz, 2H), 2.17 (s, 3H), 2.22 (t, J = 4.3 Hz, 2H), 2.28 (t, J = 4.7 Hz, 2H), 2.39 (t, J = 7.6 Hz, 2H), 3.42 (bs, 4H), 4.03 (t, J = 6.1 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 7.28 ( d, J = 9.1 Hz, 2H), 7.35 (t, J = 8.8 Hz, 4H), 7.70 (d, J = 8.8 Hz, 2H), 8.03 (s, 1H), 8.31 (d, J = 9.0 Hz, 2H)

172

1.71 (m, 2H), 1.86 (m, 2H), 2.33 (s, 3H), 2.44-2.70 (m, 10H), 4.03-4.07 (t, J = 6.3 Hz, 2H), 7.02-7.17 (m, 8H), 7.24-7.28 (d, J = 9.3 Hz, 2H), 7.53-7.56 (m, J = 9.0 Hz, 2H), 7.97 (s, 1H)
173

1.66-1.72 (m, 2H), 1.79-1.84 (m, 2H), 4.00-4.03 (t, J = 6.28 Hz, 2H), 6.99-7.13 (m, 8H), 7.21-7.24 (d, J = 8.84 , 2H), 7.50-7.52 (d, J = 8.6 Hz, 2H), 7.94 (s, 1H)

174

1.68-1.73 (m, 2H), 1.79-1.86 (m, 2H), 2.30 (s, 3H), 2.40-2.70 (m, 10H), 4.00-4.04 (t, J = 6.6 Hz, 2H), 7.00- 7.02 (d, J = 7.8 Hz, 2H), 7.12-7.14 (d, J = 8.1 Hz, 2H), 7.19-7.25 (m, 2H), 7.60-7.63 (d, J = 8.4 Hz, 2H), 7.97 (s, 1 H), 8.26-8.28 (d, J = 8.4 Hz, 2H)

175

1.68 (m, 2H), 1.82 (m, 2H), 2.30 (s, 3H), 2.40-2.70 (m, 10H), 4.03-3.99 (t, J = 12 Hz, 2H), 6.99-7.08 (m, 6H), 7.21-7.24 (d, J = 9.0 Hz, 2H), 7.35-7.38 (d, J = 8.7 Hz, 2H), 7.51-7.54 (d, J = 8.4 Hz, 2H), 7.94 (s, 1H )

176

1.68-1.76 (m, 2H), 1.81-1.88 (m, 2H), 2.33 (s, 3H), 2.40-2.70 (m, 10H), 4.02-4.07 (t, J = 6.6 Hz, 2H), 6.99- 7.05 (m, 4H), 7.09-7.12 (d, J = 8.7 Hz, 2H), 7.24-7.27 (d, J = 9.0 Hz, 2H), 7.52-7.57 (m, 4H), 7.97 (s, 1H)

177

1.68-1.69 (m, 2H), 1.81-1.83 (m, 2H), 2.29 (s, 3H), 2.39-2.70 (m, 10H), 3.83 (s, 3H), 4.00-4.03 (t, J = 6.28 Hz, 2H), 6.92-6.95 (d, J = 9.04 Hz, 2H), 6.99-7.05 (m, 6H), 7.21-7.24 (d, J = 8.91 Hz, 2H), 7.48-7.50 (d, J = 8.7 Hz, 2H), 7.93 (s, 1H)

[Experimental Example] Activity Search of Compound

Experimental Example 1. IKK-β phosphorylation inhibitory activity test

In order to confirm IKK-β phosphorylation inhibitory activity for the compound according to the present invention, the following experiment was performed using the TR-FRET method.

Specifically, phosphorylation was performed using a buffer to which DTT and 0.01% Tween-20 were added using a fluorescently labeled FAM-IκBα-derived peptide (5FAM-GRHDSGLDSMK-NH ₂ ) substrate. 10 μM of the test compound and the IKK-β enzyme were preincubated for 10 minutes, and then the experiment was performed by treating the substrate and ATP (Sigma). TR-FRET results were shown by measuring the fluorescence intensity at Tb donor emission (495 nm) and FAM-TR-FRET acceptor emission (520 nm). The weaker fluorescence intensity indicated a inhibition of phosphorylation of the substrate. IC ₅₀ values were measured for compounds that showed at least 50% inhibition in IKK-β inhibitors. Bayer 5a, known as an IKK-β inhibitor, was used as a control. The results are shown in Table 11 below.

Experimental compound % inhibition of IKK-β (10) IKK-β IC ₅₀ () Example 1 58.3 0.79 Example 2 62.2 5.09 Example 3 6.2 - Example 4 4.6 - Example 5 - - Example 6 - - Example 7 - - Example 8 - - Example 9 - - Example 10 25.3 - Example 11 - - Example 12 61.8 9.3 Example 13 3.4 - Example 14 - - Example 15 28.1 - Example 16 - - Example 17 - - Example 18 - - Example 19 - - Example 20 23.4 - Example 21 52.6 14.1 Example 22 1.0 - Example 23 2.7 - Example 24 3.2 - Example 25 16.0 - Example 26 - - Example 27 15.5 - Example 28 36.5 15.6 Example 29 4.8 - Example 30 84.9 7.3 Example 31 95.7 2.6 Example 32 87.1 5.7 Example 33 77.2 3.3 Example 34 11.3 - Example 35 19.5 - Example 36 21.3 - Example 37 57.3 6.3 Example 38 85.3 1.5 Example 39 3.6 - Example 40 47.8 - Example 41 18.6 - Example 42 83.0 6.3 Example 43 81.2 4.2 Example 44 1.4 - Example 45 - - Example 46 - - Example 47 48.8 - Example 48 - - Example 49 2.1 - Example 50 - - Example 51 43.2 - Example 52 14.8 - Example 53 72.7 3.5 Example 54 86.8 1.5 Example 55 90.1 0.35 Example 56 85.7 2.1 Example 57 83.7 0.6 Example 58 82.3 0.64 Example 59 75.3 0.84 Example 60 67.0 1.13 Example 61 17.0 - Example 62 27.2 - Example 63 58.7 0.82 Example 64 68.9 0.96 Example 65 70.8 0.9 Example 66 69.4 0.79 Example 67 6.3 - Example 68 26.4 - Example 69 3.2 - Example 70 2.0 - Example 71 1.6 - Example 72 17.1 - Example 73 62.6 8.7 Example 74 90.4 0.23 Example 75 84.0 0.88 Example 76 89.3 0.16 Example 77 87.0 0.44 Example 78 - - Example 79 3.9 - Example 80 3.6 - Example 81 44.9 - Example 82 65.9 7.62 Example 83 39.1 - Example 84 59.3 6.7 Example 85 68.6 7.73 Example 86 46.6 - Example 87 69.2 2.72 Example 88 63.1 2.77 Example 89 80.5 3.05 Example 90 62.3 3.04 Example 91 75.0 2.84 Example 92 73.4 2.19 Example 93 75.7 0.97 Example 94 71.7 2.45 Example 95 72.1 2.83 Example 96 67.9 0.93 Example 97 74.6 0.73 Example 98 6.7 - Example 99 73.3 2.7 Example 100 88.4 0.37 Example 101 50.2 9.88 Example 102 73.8 0.85 Example 103 66.6 0.84 Example 104 71.6 0.84 Example 105 93.8 2.51 Example 106 88.6 2.57 Example 107 5.6 - Example 108 18.8 - Example 109 3.6 - Example 110 8.4 - Example 111 63.3 3.95 Example 112 3.5 - Example 113 Synthesis of 2.0 - Example 114 77.1 0.81 Example 115 81.9 4.78 Example 116 0.8 - Example 117 8.2 - Example 118 84.1 5 Example 119 71.7 4.31 Example 120 0.8 - Example 121 19.3 - Example 122 59.5 0.65 Example 123 76.7 3.16 Example 124 68.0 8.61 Example 125 61.1 4.58 Example 126 84.5 2.37 Example 127 71.0 0.59 Example 128 0.7 - Example 129 1.7 - Example 130 4.2 - Example 131 7.2 - Example 132 75.9 0.69 Example 133 79.5 5.5 Example 134 60.3 2.77 Example 135 58.2 3.31 Example 136 63.8 0.82 Example 137 58.7 3.63 Example 138 45.3 - Example 139 35.4 - Example 140 51.4 9.73 Example 141 67.3 3.42 Example 142 [ 66.4 0.67 Example 143 66.5 0.61 Example 144 20.4 - Example 145 0.0 - Example 146 71.4 0.6 Example 147 65.6 0.7 Example 148 65.2 0.43 Example 149 60.8 0.87 Example 150 70.7 0.7 Example 151 79.3 0.17 Example 152 70.6 0.53 Example 153 79.5 6.06 Example 154 84.3 2.61 Example 155 85.8 2.67 Example 156 78.1 2.73 Example 157 82.9 2.43 Example 158 73.2 0.84 Example 159 76.9 0.84 Example 160 57.5 2.61 Example 161 81.2 8.07 Example 162 3.8 - Example 163 72.7 1.71 Example 164 -0.16 - Example 165 0.3 - Example 166 -1.15 - Example 167 0.02 - Example 168 1.5 - Example 169 -0.6 - Example 170 0.36 - Example 171 -1.1 - Example 172 70.7 0.38 Example 173 67.7 0.63 Example 174 71.3 0.39 Example 175 63.8 0.26 Example 176 67.9 0.27 Example 177 67.3 1.00

As shown in Table 11 above, in vitro IKK enzyme inhibition experiments, it was confirmed that the example compounds according to the present invention mostly have IKK-β enzyme inhibitory activity.

Experimental Example 2 NF-κB and TNF-α Inhibitory Activity Experiment

In order to confirm the inhibitory activity of NF-κB and TNF-α according to IKK-β phosphorylation inhibitory activity against the compound according to the present invention, an activity experiment was performed. In Table 11, a reperter gene activity test was performed to confirm NF-κB inhibitory activity of the compounds showing high inhibitory activity, and ELISA using a secondary antibody to measure the degree of inhibition of formation of a representative inflammatory cytokine, TNF-α. The experiment was performed. The results are shown in Table 12 below.

Experimental compound % inhibition of NF-κB (10 μM) TNFα IC ₅₀ (μM) Example 1 74.8 0.5 Example 28 71.4 3 Example 30 39.3 10 Example 31 46.6 8 Example 32 59.1 4 Example 33 57.4 25 Example 37 57.0 7 Example 38 58.5 5 Example 42 42.1 30 Example 43 48.2 30 Example 53 42.4 2 Example 54 64.7 5 Example 55 65.4 6 Example 57 8.5 - Example 58 35.0 4 Example 59 41.6 4 Example 60 30.1 5 Example 63 76.6 6 Example 64 76.6 3 Example 65 0.9 4 Example 66 51.1 2 Example 73 59.6 40 Example 99 52.6 5 Example 100 4.7 20 Example 102 28.8 6 Example 103 18.0 20 Example 104 14.0 8 Example 118 47.8 35

Claims (26)

A compound selected from a methylidene-heterocyclic compound represented by Formula 1 and a pharmaceutically acceptable salt:
[Formula 1]

In Chemical Formula 1,
X is O; Or S,
Y is S; NR ³ ; Or CH ₂ ,
R ¹ is C ₁ -C ₁₅ alkyl substituted with a substituent selected from the group consisting of NR ⁴ R ⁵ and C (O) NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are bonded to each other to form pyrrolidinyl, morpholinyl , Piperidinyl and piperazinyl may form a heterocycle selected from the group consisting of hydroxy, amino, acetamino, acetyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, May be substituted or unsubstituted with a substituent selected from the group consisting of C ₁ -C ₆ alkylsulfonyl and benzyl,
R ² is phenyl substituted or unsubstituted C ₂ -C ₆ alkenyl; Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, ildolyl and pyridinyl; Naphthyl; Or a substituent or non-substituted substituent including a substituent selected from the group consisting of halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁴ R ⁵ , R ⁴ R ⁵ NC ₁ -C ₆ alkoxy and phenoxy Ring phenyl, the heteroaryl may be unsubstituted or substituted with a substituent selected from the group consisting of phenyl or carbamoylphenyl, and the phenoxy is halo, cyano, nitro, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ alkylsulfonyl, aminosulfonyl, acetamido omicron], carbamoyl, mono (C ₁ ~C ₆ alkyl) aminocarbonyl And it may be unsubstituted or substituted with a substituent selected from the group consisting of di (C ₁ -C ₆ alkyl) aminocarbonyl,
R ³ is a hydrogen atom; Or C ₁ -C ₆ alkyl.
The method according to claim 1,
X is O; Or S,
Y is S; NR ³ ; Or CH ₂ ,
R ¹ represents (pyrrolidin-1-yl) C ₁ -C ₆ alkyl, (morpholin- ₁ -yl) C ₁ -C ₆ alkyl, (piperidin-1-yl) C ₁ -C ₆ alkyl , (4-aminopiperidin-1-yl) C ₁ -C ₆ alkyl, [4- (acetamino) piperidin-1-yl] C ₁ -C ₆ alkyl, [4-((C _1- C ₆ alkyl) sulfonyl) piperidin-1-yl] C ₁ -C ₆ alkyl, (piperazin- ₁ -yl) C ₁ -C ₆ alkyl, [4- (C ₁ -C ₆ alkyl) piperazine -1-yl] C ₁ -C ₆ alkyl, [4- (C ₂ -C ₆ alkenyl) piperazin- ₁ -yl] C ₁ -C ₆ alkyl, (4-phenylpiperazin-1-yl) C ₁ -C ₆ alkyl, (4-benzylpiperazin- ₁ -yl) C ₁ -C ₆ alkyl, [4-hydroxypiperazin- ₁ -yl] C ₁ -C ₆ alkyl, (4-acetylpiperazin- 1-yl) C ₁ -C ₆ alkyl, [4-((C ₁ -C ₆ alkyl) sulfonyl) piperazin- ₁ -yl] C ₁ -C ₆ alkyl, or [4- (C ₁ -C ₆ Alkyl) piperazin- _1- ylcarbonyl] C ₁ -C ₆ alkyl,
R ² is C ₂ -C ₆ alkenyl; Phenyl substituted C ₂ -C ₆ alkenyl; Furanyl; Cyenyl; Pyrrolyl; Pyridinyl; Indole; Naphthyl; Phenyl; Halo, hydroxy, C ₁ -C ₆ alkyl, amino, mono (C ₁ -C ₆ alkyl) amino, di (C ₁ -C ₆ alkyl) amino, C ₁ -C ₆ alkoxy, aminoC ₁ -C ₆ alkoxy , [Mono (C ₁ -C ₆ alkyl) amino] C ₁ -C ₆ alkoxy, [di (C ₁ -C ₆ alkyl) amino] C ₁ -C ₆ alkoxy, [piperazin- ₁ -yl] C 1- Substituted phenyl comprising a substituent selected from the group consisting of C ₆ alkoxy and [4- (C ₁ -C ₆ alkyl) piperazin- ₁ -yl] C ₁ -C ₆ alkoxy; Phenoxyphenyl; Halo, cyano, nitro, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, aminosulfonyl, acetamy Substituted phenoxyphenyl comprising a substituent selected from the group consisting of carbamoyl, mono (C ₁ -C ₆ alkyl) aminocarbonyl, and di (C ₁ -C ₆ alkyl) aminocarbonyl; Phenylfuranyl; Substituted phenylfuranyl including carbamoyl,
R ³ is a hydrogen atom; Or C ₁ -C ₆ alkyl.
The method according to claim 1,
X is O, or S,
Y is S, NH, or CH ₂ ,
R ¹ is (pyrrolidin-1-yl) propyl, (piperidin-1-yl) propyl, (4-aminopiperidin-1-yl) propyl, (4-methanesulfonylpiperidin-1 -Yl) propyl, (4-acetaminopiperidin-1-yl) propyl, (morpholin-1-yl) propyl, (piperazin-1-yl) methyl, (piperazin-1-yl) ethyl, (Piperazin-1-yl) propyl, (piperazin-1-yl) butyl, (piperazin-1-yl) pentyl, (4-methylpiperazin-1-yl) methyl, (4-methylpiperazin- 1-yl) ethyl, (4-methylpiperazin-1-yl) propyl, (4-isopropylpiperazin-1-yl) propyl, (4-prop-2-enylpiperazin-1-yl) propyl , (4-hydroxypiperazin-1-yl) propyl, (4-acetylpiperazin-1-yl) propyl, (4-aminopiperazin-1-yl) propyl, (4-phenylpiperazin-1- Yl) propyl, (4-benzylpiperazin-1-yl) propyl, (4-methylpiperazin-1-yl) butyl, (4-methylpiperazin-1-ylcarbonyl) butyl, (4-methylpipepe Razin-1-yl) pentyl, or (4-hydroxypiperazin-1-yl) pentyl,
R ² is 2,6-dichlorophenyl, 3,4-dichlorophenyl, 4 - tert - butylphenyl, 3-methoxy-4-hydroxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl , 4- (dimethylaminopropoxy) phenyl, 4- (diethylaminopropoxy) phenyl, (4-phenylpiperazin-1-yl) propoxyphenyl, (4-phenylpiperazin-1-yl) moiety Methoxyphenyl, (4-phenylpiperazin-1-yl) pentoxyphenyl, (4-chlorophenoxy) phenyl, (4-fluorophenoxy) phenyl, (4-bromophenoxy) phenyl, (4- Cyanophenoxy) phenyl, (4-methylphenoxy) phenyl, (4- tert -butylphenoxy) phenyl, (4-trifluoromethylphenoxy) phenyl, (4-methoxyphenoxy) phenyl, ( 4-nitrophenoxy) phenyl, (4-aminosulfonylphenoxy) phenyl, (4-methanesulfonylphenoxy) phenyl, (2-carbamoylphenoxy) phenyl, (3-carbamoylphenoxy) phenyl Or (4-carbamoylphenoxy) phenyl.
The method according to claim 1,
(32) 5- (3,4-dichlorophenyl) methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride;
(33) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thia Zolidinone hydrochloride;
(34) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;
(35) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;
(36) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- [4- (3-pyrrolidinylpropoxy) phenyl] -2-thioxo-4-thiazolidinone hydrochloride ;
(37) 5- (3,4-dichlorophenyl) methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thiazolidinone hydrochloride ;
(38) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone hydrochloride;
(39) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;
(40) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;
(41) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;
(42) 5- [5- (3-carbamoylphenyl) -2-furanyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone;
(43) 5- [5- (4-carbamoylphenyl) -2-furanyl] methylene-3- {4- [3- (4-morpholinyl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone hydrochloride;
(44) 5- (3,4-dichlorophenyl) methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thiazolidinone hydrochloride ;
(45) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone hydrochloride;
(46) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;
(47) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;
(48) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (1-piperidinyl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone hydrochloride;
(49) 3- {4- [3- (4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2-thioxo-4 Thiazolidinone bis-trifluoroacetic acid;
(50) 3- {4- [3- ( N- acetyl-4-amino-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2- Thioxo-4-thiazolidinone;
(51) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- ( N- methylsulfonyl-4-amino-1-piperidinyl) propoxy] phenyl}- 2-thioxo-4-thiazolidinone;
(52) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-hydroxy-1-piperidinyl) propoxy] phenyl} -2-thioxo4 Thiazolidinone;
(53) 3- {4- [3- (4-acetyloxy-1-piperidinyl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2-thioxo- 4-thiazolidinone;
(54) 5- (3,4-dichlorophenyl) methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4-thia Zolidinone dihydrochloride;
(55) 5- (3,3-diphenyl-2-propene-1-ylidene) -3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2 -Thioxo-4-thiazolidinone dihydrochloride;
(56) 5- [4- (2-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(57) 5- [4- (3-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(58) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(59) 5- [4- (4-carboxyphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;
(60) 5- {4- [4- (dimethylaminocarbonyl) phenoxy] phenyl} methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl}- 2-thioxo-4-thiazolidinone;
(61) 5- [4- (4-aminosulfonylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo -4-thiazolidinone dihydrochloride;
(62) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(63) 5- [4- (4-trifluoromethylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thio Oxo-4-thiazolidinone dihydrochloride;
(64) 5- [4- (4-methylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;
(65) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(66) 5- [4- (4- tert -butylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo -4-thiazolidinone dihydrochloride;
(67) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(68) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;
(69) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(70) 3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone dihydrochloride;
(71) 3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene-2-thioxo- 4-thiazolidinone dihydrochloride;
(72) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone dihydrochloride;
(73) 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(74) 5- {4- [4- (methylsulfonylamino) phenoxy] phenyl} methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2 -Thioxo-4-thiazolidinone;
(75) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (1-piperazinyl) propoxy] phenyl} -2-thioxo-4-thiazoli Dinone trifluoroacetic acid;
(76) 3- {4- [3- (4-acetyl-piperazin-1-yl) propoxy] phenyl} -5- [4- (4-chlorophenoxy) phenyl] methylene-2-thioxo- 4-thiazolidinone hydrochloride;
(77) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylsulfonylpiperazin-1-yl) propoxy] phenyl} -2-thioxo -4-thiazolidinone;
(78) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-benzyl-piperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(79) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4- (2-propen-1-yl) piperazin-1-yl) propoxy] Phenyl} -2-thioxo-4-thiazolidinone;
(80) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-carbamoylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(86) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(87) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(88) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(89) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone dihydrochloride;
(90) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -2-thioxo-4-thio Azolidinone;
(91) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -2-thioxo-4-thia Zolidinone;
(92) 3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo-4- Thiazolidinone;
(93) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3-[(4-methylpiperazin-1-yl) methyl] phenyl} -2-thioxo-4-thio Azolidinone;
(94) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(95) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2-thioxo-4 Thiazolidinone;
(96) 3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;
(97) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(98) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(99) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo-4 Thiazolidinone;
(100) 3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;
(101) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(102) 5- {4- [4- (dimethylaminocarbonyl) phenoxy] phenyl} methylene-3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl}- 2-thioxo-4-thiazolidinone;
(103) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(104) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo-4 Thiazolidinone;
(105) 3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;
(106) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(107) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(108) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo-4 Thiazolidinone;
(109) 3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-methylsulfonylphenoxy) phenyl] methylene-2-thioxo -4-thiazolidinone;
(110) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2-thioxo- 4-thiazolidinone;
(118) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imida Zolidinedione;
(119) 5- [4- (4-carbamoylphenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imi Dazolidinedione;
(120) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,4-imi Dazolidinedione;
(121) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2,4-imi Dazolidinedione;
(122) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2,4-imi Dazolidinedione hydrochloride;
(132) 3- [4- (4-chlorophenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-pyrroli Dindione;
(133) 3- [4- (4-carbamoylphenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-py Rollidinedione;
(134) 3- [4- (4-fluorophenoxy) phenyl] methylene-1- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -2,5-pipe Rollidinedione;
(135) 3- [4- (4-fluorophenoxy) phenyl] methylene-1- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2,5-pipe Rollidinedione;
(136) 3- [4- (4-fluorophenoxy) phenyl] methylene-1- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -2,5-pipe Rollidinedione;
(142) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(143) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(144) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [3- (4-isopropylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(145) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [3- (4-phenylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(146) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(147) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione dihydrochloride;
(148) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(149) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(150) 5- [4- (4-methylphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;
(151) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;
(152) 3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene thiazolidine-2 , 4-dione;
(153) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;
(154) 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {4- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} thiazolidine-2,4- Diones;
(155) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;
(156) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;
(157) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;
(158) 3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-methylphenoxy) phenyl] methylene thiazolidine-2, 4-dione;
(159) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;
(160) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione dihydrochloride;
(161) 3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene thiazolidine-2 , 4-dione;
(162) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2, 4-dione;
(163) 5- [4- (4-acetylaminophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) pentoxy] phenyl} thiazolidine-2 , 4-dione;
(164) 5- [4- (4-fluorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;
(165) 3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} -5- [4- (4-methylphenoxy) phenyl] methylene thiazoli Din-2,4-dione;
(166) 5- [4- (4-methoxyphenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;
(167) 5- [4- (4-bromophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;
(168) 5- [4- (4-cyanophenoxy) phenyl] methylene-3- {3- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thia Zolidine-2,4-dione;
(169) 5- [4- (4-chlorophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thiazoli Din-2,4-dione;
(170) 3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} -5- [4- (4-nitrophenoxy) phenyl] methylene cya Zolidine-2,4-dione;
(171) 5- [4- (4-aminophenoxy) phenyl] methylene-3- {4- [5- (4-methylpiperazin-1-yl) -5-oxopentyloxy] phenyl} thiazoli Din-2,4-dione;
(172) 5- [4- (4-fluorophenoxy) benzylidine-3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2, 4-dione;
(173) 4- {4-[(3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -2,4-dioxazolidine-5-yridine) methyl ] Phenoxy} benzonitrile;
(174) 3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} -5- [4- (4-nitrophenoxy) benzylidene] thiazolidine-2 , 4-dione;
(175) 5- [4- (4-chlorophenoxy) benzylidene] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2, 4-dione;
(176) 5- [4- (4-bromophenoxy) benzylidene] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2 , 4-dione; And
(177) 5- [4- (4-methylphenoxy) benzylidene] -3- {4- [4- (4-methylpiperazin-1-yl) butoxy] phenyl} thiazolidine-2, 4-dione;
Compound selected from the group consisting of.
The pharmaceutical composition for preventing and treating inflammatory diseases, characterized in that the compound of any one selected from claims 1 to 4 as an active ingredient.
The method according to claim 5,
The inflammatory disease is rheumatoid arthritis, juvenile arthritis, asthma, asthma, spondyloarthopathies, gout, osteoarthritis, allergic rhinitis, atopic dermatitis, choking, Systemic lupusery thematosus, psoriasis, ulcerative colitis, systemic inflammatory response syndrome, pneumonia, multiple myositis, and nodular polyarteritis, pharmaceutical composition for the prevention and treatment of inflammatory diseases, characterized in that selected from the group consisting of.
delete delete delete delete Step 1 step of preparing a urea compound represented by the formula (4) by reacting the aniline compound represented by the formula (2) and ethyl 2-isocyanatoacetate;
Step 2 step of preparing a 3-phenyl hydantoin compound represented by the formula (5) by cyclizing the compound represented by the formula (4) under acid conditions; And
A step of preparing a 5-methylidene-3-phenylhydantoin compound represented by the following Chemical Formula 1b by condensation reaction of the compound represented by the following Chemical Formula 5 with an aldehyde compound represented by R ² -C (O) H under acidic conditions (Step 3);
Method of producing a methylidene-heterocyclic compound comprising a.

(Wherein R ¹ is a hydrogen atom; C ₁ -C ₁₅ alkyl unsubstituted or substituted with a substituent selected from the group consisting of hydroxy, acetoxy, NR ⁴ R ⁵ and C (O) NR ⁴ R ⁵ ; or Phenyl unsubstituted or substituted with a substituent selected from the group consisting of halo and carbamoyl,
R ² is carbamoyl; Phenyl substituted or unsubstituted C ₂ -C ₆ alkenyl; Heteroaryl selected from the group consisting of furanyl, thienyl, pyrrolyl, ildolyl and pyridinyl; Naphthyl; Or a substituent or non-substituted substituent including a substituent selected from the group consisting of halo, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, NR ⁴ R ⁵ , R ⁴ R ⁵ NC ₁ -C ₆ alkoxy and phenoxy Ring phenyl, the heteroaryl may be unsubstituted or substituted with a substituent selected from the group consisting of phenyl or carbamoylphenyl, and the phenoxy is halo, cyano, nitro, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ ~C ₆ haloalkyl, C ₁ ~C ₆ alkoxy, C ₁ ~C ₆ alkylsulfonyl, aminosulfonyl, acetamido omicron], carbamoyl, mono (C ₁ ~C ₆ alkyl) aminocarbonyl And it may be unsubstituted or substituted with a substituent selected from the group consisting of di (C ₁ -C ₆ alkyl) aminocarbonyl,
R ³ is a hydrogen atom; Or C ₁ -C ₆ alkyl,
R ⁴ and R ⁵ are each hydrogen atom; Or C ₁ -C ₆ alkyl, R ⁴ and R ⁵ may be bonded to each other to form a heterocycle selected from the group consisting of pyrrolidinyl, morpholinyl, piperidinyl and piperazinyl, wherein the heterocycle Can be substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, amino, acetamino, acetyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₁ -C ₆ alkylsulfonyl and benzyl)
The method of claim 11,
Method for preparing a methylidene-heterocyclic compound, characterized in that the cyclization reaction of step 2 is carried out using 6 N HCl-ethanol.
The method of claim 11,
The condensation reaction of step 3 is carried out in the presence of pyrrolidine and MgSO ₄ Method for producing a methylidene-heterocyclic compound.
Step 1 process of preparing an amide compound represented by the formula (6) by reacting the aniline compound represented by the formula (2) and maleic anhydride;
A step 2 process of preparing a N- phenyl-1 H -pyrrole-2,5-dione compound represented by Chemical Formula 7 by cyclizing the compound represented by Chemical Formula 6 under acidic conditions; And
Step 3 to prepare a 3-methylidene-1-phenylsuccinimide compound represented by the formula (1c) by the Wittig reaction of the compound represented by the formula (7) with an aldehyde compound represented by R ² -C (O) H process;
Method for producing a methylidene-heterocyclic compound comprising a.

(Wherein R ¹ and R ² are each as defined in claim 11 above)
The method according to claim 14,
Method for preparing a methylidene-heterocyclic compound, characterized in that the cyclization reaction of step 2 is carried out using a sodium acetate (NaOAc) base and an acetic acid solvent.
The method according to claim 14,
The condensation reaction of step 3 is carried out in the presence of triphenylphosphine (PPh ₃ ) method of producing a methylidene-heterocyclic compound.
Step 1 step of preparing a 2-chloro- N- phenylacetylamide compound represented by the formula (8) by reacting the aniline compound represented by the formula (2) and chloroacetyl chloride;
Reacting the compound represented by Formula 8 with potassium thiocyanate to prepare a 2-imino- N- phenylthiazolidin-4-one compound represented by Formula 9;
Reacting the compound represented by Chemical Formula 9 under acidic conditions to prepare an N- phenyl-glitazone compound represented by Chemical Formula 10; And
Condensation reaction of a compound represented by Formula 10 with an aldehyde compound represented by R ² -C (O) H to prepare 3-methylidene-1-phenylglitazone compound represented by Formula 1d. ;
Method for producing a methylidene-heterocyclic compound comprising a.

(Wherein R ¹ and R ² are as defined in claim 11 above)
18. The method of claim 17,
Method of preparing a methylidene-heterocyclic compound, characterized in that in the step 3 reaction using HCl aqueous solution to maintain the acid conditions.
18. The method of claim 17,
The condensation reaction of step 4 is carried out using a sodium acetate (NaOAc) base and an acetic acid solvent, the method of producing a methylidene-heterocyclic compound.
Reacting the aminophenol compound with chloroacetyl chloride to prepare a 2-chloro- N- phenylacetylamide compound represented by the following Formula 11;
Step 2 to prepare a 2-imino- N- (hydroxyphenyl) thiazolidin-4-one compound represented by the formula (12) by reacting a compound represented by the formula (11) with potassium thiocyanate process;
Reacting the compound represented by Chemical Formula 12 under acidic conditions to prepare an N- (hydroxyphenyl) glitazone compound represented by Chemical Formula 13;
A step 4 process of preparing an N- (haloalkoxyphenyl) glitazone compound represented by Formula 14 by alkylating the compound represented by Formula 13 with a dihaloalkane compound;
Reacting a compound represented by Formula 14 with an amine compound to prepare an N- (aminoalkoxyphenyl) glitazone compound represented by Formula 15; And
Condensation reaction of a compound represented by the following formula (15) with an aldehyde compound represented by R ² -C (O) H to prepare 3-methylidene-1- (aminoalkoxyphenyl) glitazone compound represented by the following formula (1e) (Step 6);
Method for producing a methylidene-heterocyclic compound comprising a.

(Wherein R ² , R ⁴ , and R ⁵ are each as defined in claim 11 above, X is a halogen atom, n is an integer from 1 to 6)
The method of claim 20,
The reaction of the alkylation reaction of step 4 and the amine compound of step 5 is carried out in the presence of potassium carbonate base, characterized in that the methylidene-heterocyclic compound production method.
The method of claim 20,
The condensation reaction of step 4 is carried out using a sodium acetate (NaOAc) base and an acetic acid solvent, the method of producing a methylidene-heterocyclic compound.
Step 1 process of preparing a nitro compound represented by the following formula (16) by reacting the nitrophenol and amadoalkyl chloride compound;
A step 2 process of preparing an amine compound represented by Chemical Formula 17 by reducing a compound represented by Chemical Formula 16;
Step 3 process of preparing a chloroacetyl amide compound represented by the formula (18) by reacting the compound represented by the formula (17) with chloroacetyl chloride;
Reacting the compound represented by Formula 18 with potassium thiocyanate to prepare a 2-imino-thiazolidin-4-one compound represented by Formula 19;
Step 5 to prepare a glitazone compound represented by the formula (20) by reacting the compound represented by the formula (19) under acid conditions; And
Condensation reaction of a compound represented by the following formula (20) with an aldehyde compound represented by R ² -C (O) H to obtain a 3-methylidene-1- (amidoalkoxyphenyl) glitazone compound represented by the following formula (1f) Manufacturing step 6 process;
Method for producing a methylidene-heterocyclic compound comprising a.

(In the above scheme, R ² , R ⁴ , and R ⁵ are each as defined in claim 11, wherein n is an integer of 1 to 6)
24. The method of claim 23,
The reduction reaction of step 2 is a method for producing a methylidene-heterocyclic compound, characterized in that carried out under hydrogen stream conditions under a Pd / C catalyst.
24. The method of claim 23,
Method of preparing a methylidene-heterocyclic compound, characterized in that in the reaction of step 5 to use an aqueous HCl solution to maintain the acid conditions.
24. The method of claim 23,
The condensation reaction of step 6 is carried out using a sodium acetate (NaOAc) base and an acetic acid solvent, the method of producing a methylidene-heterocyclic compound.