KR20220043919A - Compounds and methods for preventing or treating of respiratory disease - Google Patents

Abstract

The present invention relates to a medicinal use of compounds having inhibitory activity against pendrin, and provides a compound represented by formula 1 or 2 below, an E- or Z-isomer thereof, an optical isomer thereof, a precursor thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of two or more isomers thereof, and a composition for prevention, alleviation, or treatment of respiratory diseases, or a diuretic composition, each composition utilizing the inhibitory activity of the compound against pendrin.

Description

A composition for preventing or treating respiratory diseases and a method for preventing or treating them

The present invention relates to pharmaceutical compounds and compositions useful for the prevention or treatment of fendrine-associated respiratory diseases, and more particularly to compounds, compositions and methods for modulating downregulation of fendrine.

Pendrine is encoded by the SLC26A4 gene, which is an anion exchanger and a member of the SLC26 gene family, and exchanges Cl ⁻ for anions such as HCO ₃ ⁻ , I ⁻ , OH ⁻ and SCN ⁻ . Pendrine is a cell membrane protein expressed in the luminal membrane of airway epithelial cells. However, fendrine expression is associated with inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD), allergic rhinitis, asthma, pertussis infection, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and the common cold caused by rhinovirus. is strongly upregulated in , and upregulation of pendrins is observed when they are incubated with IL-4, IL-13 and IL-17A in primary airway epithelial cells. Interestingly, pendrine knockout (KO) ameliorated airway inflammation in all mouse models for COPD, allergic rhinitis, asthma, pertussis infection and rhinovirus infection. The pathophysiological role of pendrine in airway inflammation has not been clearly elucidated. However, new evidence indicates that pendrine is involved in airway surface fluid (ASL) volume conservation and regulation of mucus production in inflammatory airway disease.

ASL volume increase in primary mouse tracheal epithelial cell cultures by IL-13 was significantly higher in pendrine KO mice compared with WT mouse controls. IL-13-induced ASL volume increase in primary human nasal epithelial (HNE) cell cultures of deaf patients carrying the pendrine mutant (DFNB4) was significantly higher than that of normal controls. In addition, inhibition of fendrine by pendrine inhibitors significantly increased IL-13-induced ASL volume in primary cultures of human bronchial epithelial cells. These findings suggest that downregulation of pendrine may have a beneficial effect on the regulation of ASL volume homeostasis in inflammatory airway disease.

Excessive production of mucus is a common feature of inflammatory airway diseases such as asthma and COPD. Pendrine overexpression significantly increased MUC5AC gene expression in human lung cancer line NCI-H292 cells and mouse lung tissue. While IL-13 treatment significantly increased MUC5AC gene expression in HNE cells from normal subjects, IL-13 induced upregulation of MUC5AC was completely abolished in HNE cells from deaf patients carrying pendrine mutants. These findings suggest that downregulation of pendrine may be beneficial in the treatment of asthma and COPD.

As a prior art, US Patent Publication No. US 2019/0054071 discloses a small molecule inhibitor of phendrine ion exchange of a compound represented by the following formula (I) and its medicinal use as a therapeutic agent for respiratory diseases or a diuretic.

[Formula I]

The present invention is based on the discovery that certain compounds can act as pendrine inhibitors and thus can be used as diuretics or therapeutic agents for related diseases through inhibition of pendrine activity. The present invention provides that some compounds discovered through cell-based HTS screening for the identification of small molecule pendrine inhibitors or novel newly designed compounds can be used for asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic To provide a potential treatment or diuretic for respiratory diseases (inflammatory airway disease) such as fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD) based on the discovery that it can be done. The present invention is based on the finding that some small molecules can show that fendrine down-regulation reduced IL-13-induced up-regulation of MUC5AC gene expression in HNE cells differentiated from normal subjects. In addition, some molecules have been used as pendrine inhibitors to ameliorate airway inflammation in a mouse model of ovalbumin (OVA)-induced allergic asthma.

Accordingly, an object of the present invention is to provide a compound represented by the following Chemical Formula 1 or 2, a composition for preventing, improving or treating respiratory diseases through its pendrine inhibitory activity, and a composition for diuresis.

In order to solve the above problems, the present invention provides a compound represented by the following formula (1), its E- or Z- isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or two types thereof A mixture of isomers is provided:

[Formula 1]

In Formula 1,

V ¹ and V ² are each independently Aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ one of C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , With one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , NR ³ R ⁴ . optionally substituted, said aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C one of (O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl, hetero aryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl) , S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , with one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted,

i and j are each independently 0, 1 or 2,

R ¹ and R ² are hydrogen, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , independently selected from the group consisting of C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , said aryl, heteroaryl, heterocyclyl , C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O) one of OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ,

R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or

R ³ and R ⁴ may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,

로 이루어지는 군으로부터 선택되는 구조로 표시되고, A ¹ is

It is represented by a structure selected from the group consisting of,

X ¹ and X ² are each independently selected from the group consisting of O, S, CHR ⁴ and NR ⁴ ,

J is N or CH;

R ⁵ , R ⁶ and R ⁷ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C independently selected from the group consisting of ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, heterocyclyl, aryl, heteroaryl and trifluoromethyl, wherein one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C ₁ to C ₁₀ alkylaryl and heteroaryl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, tri Fluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl , S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and one or more groups independently selected from NR ³ R ⁴ , said aryl, arylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , one of OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethyl Toxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S (O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C optionally selected from one or more groups independently selected from (O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or

R ⁵ and A ¹ may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is Oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ optionally substituted with one or more groups independently selected from , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ .

In another aspect, the present invention provides a compound represented by the following formula (2), its E- or Z- isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or a mixture of two isomers thereof to provide:

[Formula 2]

In Formula 2,

V ³ and V ⁴ are each independently aryl, heteroaryl, C ₃ ~ C ₇ cycloalkyl, heterocycloalkyl, C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ heteroalkyl, C ₂ ~ C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C( O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ one of C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl , trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ optionally substituted with one or more groups independently selected from aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl) ), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR one of ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl , C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O ) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O) OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ;

i is each independently 0, 1 or 2,

R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or

R ³ and R ⁴ may be cyclized together to cyclize (form a ring) to a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, said carbocyclic, heterocyclic, One of the aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ optionally substituted with one or more groups independently selected from , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,

A ² is

It is represented by a structure selected from the group consisting of,

X ³ is hydrogen, OR ³ , aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O)OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ , wherein OR ³ , aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O) one of OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, Sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl , C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O) one independently selected from R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Optionally selected from the above group, the aryl, C ₁ ~ C ₁₀ alkylaryl, C ₃ ~ C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ ~ C ₁₀ alkyl, C ₂ ~ C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ one of hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl , heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R one or more independently selected from ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted with a group,

i is 0, 1 or 2,

X ⁴ is O, S, NR ⁵ , NSO ₂ R ⁵ , C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, aryl, arylalkyl, C ₁ to C ₁₀ alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR ⁵ , NSO ₂ R ⁵ , C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, aryl, arylalkyl, C ₁ ~ C ₁₀ alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ⁵ , C(O)R ⁵ , OR ⁵ , NR ⁵ C(O)OR ⁶ , C(O)NR ⁵ R ⁶ and NR ⁵ R ⁶ may be optionally substituted with one or more selected from the group consisting of,

R ⁵ to R ⁸ are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) independently selected from the group consisting of NR ³ R ⁴ and NR ³ R ⁴ , said aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) one of NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S (O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O) )OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , optionally selected from one or more groups independently selected from the group consisting of, said aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR one of ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, Halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl , C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), from S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . may be optionally substituted with one or more independently selected

R ⁵ and A ² may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,

I is 0, 1 or 2.

In a specific embodiment, the compound of Formula 2 is,

V ³ is C ₁ to C ₆ alkyl,

V ⁴ is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl includes 1 to 3 heteroatoms selected from the group consisting of N, O and S;

이고,A ² is

ego,

X ³ is OR ³ ,

R ³ is H;

R ₈ may be H.

In another specific embodiment, the compound of Formula 2 is,

V ³ is C ₁ to C ₄ alkyl,

V ⁴ is pyrrole,

이고,A ² is

ego,

X ³ is OH,

R ₈ may be H.

In another aspect, the invention relates to at least one of said compounds, at least one E- or Z-isomer thereof, at least one optical isomer thereof, at least one mixture of two isomers thereof, at least one precursor thereof, at least one thereof It provides a pharmaceutical composition for the prevention or treatment of respiratory diseases (inflammatory airway diseases) comprising a pharmaceutically acceptable salt or at least one solvate thereof as an active ingredient. In some embodiments, the composition can inhibit, prevent, ameliorate or treat a respiratory disease (inflammatory airway disease).

In a further aspect, the present invention provides a composition comprising a compound represented by Formula 1 or 2 or a mixture thereof, and a composition comprising the compound represented by Formula 1 or 2 or a mixture thereof together with a pharmaceutically acceptable carrier .

In a further aspect, the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof as a pendrine inhibitor.

In a further aspect, the present invention provides a compound represented by Formula 1 or 2, and a pharmaceutical composition thereof, which specifically modulates a chloride channel.

In a further aspect, the present invention provides a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which preserves the volume of airway surface liquid (ASL) and reduces the separation of mucin.

In a further aspect, the invention relates to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD).

In a further aspect, the present invention provides a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof for diuresis. In a further aspect, the present invention provides a compound represented by Formula 1 or 2, a mixture thereof, and the use of the pharmaceutical composition for prevention or improvement of diuresis as an active ingredient in a pharmaceutical composition.

In a further aspect, the present invention provides a compound and the use of the dietary supplement as a pendrine inhibitor for the prevention or improvement of respiratory diseases (inflammatory airway disease) as an active ingredient in a dietary supplement.

In a further aspect, the present invention provides a compound represented by Formula 1 or 2 and a health functional food, which specifically modulates chloride channels for the prevention or improvement of respiratory diseases (inflammatory airway disease) as an active ingredient in health functional foods to provide.

In a further aspect, the present invention relates to Formula 1, which preserves the volume of airway surface liquid (ASL) and reduces the separation of mucin for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in dietary supplements Or 2 provides a compound and its health functional food.

In a further aspect, the present invention provides a use for preventing or improving a respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food, wherein the respiratory disease (inflammatory airway disease) is asthma, acute or chronic bronchitis, allergic rhinitis , acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD). .

In a further aspect, the present invention provides a compound represented by Formula 1 or 2, a mixture thereof, and the use of the health functional food for diuresis as an active ingredient in a health functional food.

In a further aspect, the present invention provides a compound and its use as a fendrine inhibitor for diuresis as an active ingredient in nutraceuticals and nutraceuticals.

Other aspects and advantages of the present invention will become apparent to those skilled in the art upon consideration of the detailed description and drawings.

The compound represented by Formula 1 or 2 according to the present invention, its E- or Z-isomer, its optical isomer, its precursor, its pharmaceutically acceptable salt, its solvate, or a mixture of two isomers thereof is a pendrine inhibitor It is useful for the prevention, improvement or treatment of respiratory diseases, for example, inflammatory airway diseases, particularly asthma or acute lung injury, and can also be utilized as a diuretic.

1 is a diagram showing the principle of cell-based high-throughput screening and the results of finding a pendrine inhibitor.
2 is a graph confirming that the compounds F56, G23, G24 and G25 according to the present invention exhibit a dose-dependent Cl ^- /I ^- exchange inhibitory activity in WT-pendrin and CHO-K1 cells overexpressing iodide-sensitive YFP. am.
Figure 3 shows that the compounds F56, G23, G24 and G25 according to the present invention are high concentrations of Cl ⁻ Application of Cl − induces a decrease in intracellular pH through phendrine mediated Cl ⁻ /HCO ₃ ⁻ exchange and results in a decrease in YFP fluorescence, resulting in a dose It is a graph confirming that the inhibitory effect of pendrine-mediated Cl ^- /HCO ₃ ^- exchange activity is dependently.
4 is a graph showing that compounds F56 and G23 according to the present invention dose-dependently inhibit phendrine-mediated Cl ⁻ /I ⁻ and Cl ⁻ /HCO ₃ ⁻ exchange activity.
Figure 5 shows pendrine-mediated Cl ^- /I ^- , Cl ^- /SCN ^- , Cl-/HCO ₃ ^- and Cl ^- /OH ^- exchange activity by F56 measured in CHO-K1-YFP cells expressing pendrine. It is a graph confirming the inhibitory effect.
6 is a diagram showing the activity of inhibiting Cl-/HCO ₃ -exchange by F56 in SLC26 isoform ^- transformed cells.
7 shows that F56 dose-dependently inhibits mouse PDS (mPDS) mediated Cl ⁻ /I ⁻ exchange activity but does not alter CFTR and ANO1/TMEM16A Cl ⁻ channel activity. (A) Graph showing the inhibition of mPDS-mediated Cl ⁻ /I ⁻ exchange activity by F56 measured in CHO-K1-YFP cells expressing mouse pendrine. (mean ± SE, n=5). (B) As a result of measuring the effect of F56 on CFTR chloride channel activity in FRT cells expressing human wild-type CFTR, it is a graph showing that CFTR current was activated by 20 μM forskolin and inhibited by 10 μM CFTRinh-172. (C) The results of measuring apical membrane currents in FRT cells expressing ANO1/TMEM16A, and the right side summarizes the peak currents (mean ± SE, n=3).
Figure 8 shows the inhibition of endogenous phendrine-mediated Cl ⁻ /HCO ₃ ⁻ exchange activity by F56 in primary culture of human nasal epithelial (HNE) cells. (A) A representative immunoblot result of the pendrine protein is shown. HNE cells were incubated for 48 hours in the presence and absence of IL-4 (10 ng/ml), and CHO-K1 cells expressing human pendrine were used as positive controls. (B) Representative traces of intracellular pH of untreated (grey line) and IL-4 treated HNE cells. Pendrine was inhibited by F56 (50 μM). (C) Representative fendrine and ANO1 immunoblot results at the indicated time points after F56 (30 μM) treatment in IL-4 treated HNE cells. The graphs in the middle and right of C are bar graphs showing the results of summarizing the changes in band intensities (mean ± SE, n=5) of pendrin and ANO1, respectively. (D) PDS and ANO1 mRNA expression was determined at the indicated time points after F56 (30 μM) treatment by real-time quantitative PCR in IL-4 treated HNE cells (mean ± SE, n=5). *P < 0.05, **P < 0.01.
9 is a diagram showing the effect of F56-induced fendrine inhibition on airway hyper-responsiveness in an OVA-induced mouse model of allergic asthma.
10 is a diagram showing the improvement of allergic airway inflammation by F56 in a mouse model of asthma. (A) A graph showing the results of OVA-specific IgE levels in serum measured by ELISA (mean ± SE, n = 6). (B) Broncho-alveolar lavage fluid (BALF) is a graph showing the number of inflammatory cells quantified by light microscopy (mean ± SE, n = 6). (C) Photographs showing representative histological results of airways stained with hematoxylin and eosin. Scale bar: 100 μm. (D) A graph summarizing inflammation scores (mean ± SE, n = 6). *P < 0.05.
11 is a diagram showing the association of pendrine on mucin expression in airway epithelium. (A) Goblet cell proliferation of IL-4 (10ng/ml)-treated HNE cells in the absence or presence of F56 (30 μM) was confirmed by periodic acid-Schiff (PAS) staining. B) A diagram showing the results of PAS staining of airway sections of vehicle-treated, OVA-sensitized/challenged and F56 (10 mg/kg)-treated OVA-sensitized/challenged mice. (C) A graph showing MUC5AC mRNA expression determined at the indicated time points after F56 (30 μM) treatment by real-time quantitative PCR in IL-4 treated HNE cells (mean ± SE, n=4). *P < 0.05, ***P < 0.001.
12 is a dosing schedule designed to confirm the protective effect of G7 before and after treatment in an LPS-induced acute lung injury model.
13 is an LPS-induced acute lung injury model confirming the effect of suppressing the acute lung injury phenotype according to the treatment before and after G7, FIG. 13a is the average body weight of the mouse, FIG. 13b is the total number of BALF cells, and FIG. 13c is the BALF cytospin staining result. is shown.
14 is a view confirming the diuretic effect of G7 treatment in a mouse model.

1. Definition

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references provide those skilled in the art with general definitions of many of the terms used herein: The Cambridge dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et. al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins dictionary of Biology (1991). As used herein, the following terms have the meanings recited below, unless otherwise specified.

The term “or,” as used herein, is to be understood as inclusive, unless specifically stated or clear from the context.

As used herein, the term “about” is to be understood within the general tolerance of the art, eg, within two standard deviations of the mean, unless specifically stated or clear from context. A drug may be understood to be within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. there is. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.

The terms “active agent”, “drug” and “pharmaceutical agent” refer to a desired pharmacological effect (eg, reduction of inflammation) when administered to a subject by any means described herein (eg, any animal, including a human or non-human animal). used interchangeably herein to refer to a chemical substance or compound that induces a decrease (such as reduction).

As used herein, “additive” may refer to any additional ingredients that may be added to the compositions and formulas described herein. For example, an excipient may be an excipient (eg, one or more excipients), an antioxidant (eg, one or more antioxidants), a stabilizer (eg, one or more stabilizing agents), preservatives (eg, one or more preservatives), pH adjusting and/or buffering agents (eg, one or more pH adjusting and/or buffering agents), tonicity adjusting agents (eg, one or more isotonicity adjusting agents), thickening agents (eg, one or more thickening agents), suspending agents (eg, one or more suspending agents), binders (eg, one or more binders), viscosity increasing agents (eg, one or more viscosity increasing agents), and the like. In addition, additives include calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, treatment and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as low melting waxes, ion exchange resins, and the like. Other suitable pharmaceutically acceptable excipients may be appropriately selected from excipients well known in the art.

As used herein, the term “administration” refers to administration to a subject as oral administration, suppository, topical contact intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, intravitreal or subcutaneous administration, or sustained release device. , for example, the implantation of a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (eg, oral, nasal, pulmonary, rectal, buccal, vaginal, ocular, and transdermal routes).

“Analog” and “derivative” are used interchangeably herein and have the same core as the parent compound, but differ from the parent compound in the order of bonding in the absence or presence of one or more atoms and/or groups of atoms, and combinations thereof. refers to the compound. A derivative may differ from the parent compound in, for example, one or more substituents present on the core, which may include one or more atoms, functional groups or substructures. In addition, the derivative may differ from the parent compound in the order of bonding between atoms in the core. In general, derivatives can be predicted to be formed from the parent compound, at least theoretically, through chemical and/or physical processes.

As used herein, “antioxidant” may refer to an artificial or natural substance capable of preventing or delaying some types of cell damage and/or oxidation. Antioxidants are found in many foods, including fruits and vegetables. Also, they can be used as a dietary supplement. Exemplary antioxidants may include β-carotene, lutein, lycopene, selenium, vitamin A, vitamin C, and vitamin E. In addition, other antioxidants known to those skilled in the art may be used. The antioxidants described herein may be used in any suitable amount.

"Co-administration" means that a compound or composition described herein is administered simultaneously immediately before or immediately after administration of an additional treatment or active agent or excipient described herein. A compound or composition of the present disclosure may be administered alone or co-administered to a patient. Co-administration is construed to include the simultaneous or sequential administration of the compounds individually or in combination (one or more compounds or agents). If desired, the preparations may also be combined with other active substances.

In the present disclosure, "comprises", "comprising", "containing" and "having" and the like may have the meaning belonging to them, and may mean "comprise", "comprising" and the like; “Consisting essentially of” or “consisting essentially of” may likewise have the meanings pertaining to them and the terms are open-ended and recite unless the basic or novel characteristic of the recited is altered by the existence of more than one recited. While more than that described above is permitted, prior art embodiments are excluded.

As used herein, “simultaneous administration” includes, at least in part, overlapping durations. For example, when two agents (eg, any agent or class of agents described herein having bioactivity) are administered simultaneously, their administration occurs within a certain desired time period. Administration of the formulation may start and end on the same day. In addition, administration of one agent may precede administration of a second agent as long as the two agents are taken at least once on the same day. Similarly, administration of one agent may be extended beyond administration of a second agent as long as both agents are taken at least once on the same day. The bioactive agent/agent need not be taken at the same time each day to include simultaneous administration.

As used herein, an “effective amount” or “therapeutically effective amount” is an amount sufficient to effect a desired biological effect, such as beneficial outcome, including clinical outcome. Thus, an “effective amount” depends on the circumstances in which it is applied. An effective amount may vary depending on factors known in the art, such as the disease state, age, sex and weight of the individual being treated. Several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the urgency of the therapeutic situation. In addition, the compositions/agents of the present disclosure may be administered as often as necessary to achieve a therapeutic amount.

As used herein, the term “gel” may refer to a material that is not readily flowable liquid and is not a solid, ie, semi-solid. Gels can be formed from natural or synthetic materials. The gel is not aligned but slightly aligned, showing birefringence and liquid crystal properties. The gel may be administered topically.

As used herein, the term "respiratory disease" has its conventional medical meaning and includes asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infections, acute upper respiratory tract infections, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome ( ARDS), acute lung injury (ALI) or chronic obstructive pulmonary disease (COPD), and closely related diseases and disorders of the respiratory system.

As used herein, the term “inhibit” means to prevent, reduce, slow down or stop. In one embodiment, if the amount or rate of a process or reaction that occurs in the presence of the compound or composition is reduced by at least about 10%, compared to the amount or rate in the absence of the compound or composition, the composition or compound comprises at least one It is considered to inhibit the viability of proteins (eg, pendrins). In other embodiments, a composition or compound is a process or reaction if the amount or rate of a process or reaction that occurs in the presence of the compound or composition decreases by at least about 20%, as compared to the amount or rate in the absence of the compound or composition. is considered to inhibit In other embodiments, the amount or rate of inhibition that occurs in the presence of the compound or composition is at least about 25%, about 30%, about 40%, about 50%, about A compound or composition is considered to inhibit one or more proteins (eg, pendrine) when reduced by 60%, about 70%, about 75%, or about 80%. In other embodiments, the compound or composition is considered to inhibit the viability of one or more proteins, ie, arrest their development.

As used herein, "intermittent dosing" refers to a period of time during which an agent is administered (this may be considered a "first dosing period") followed by a period during which no agent is ingested or at a lower dose (this is referred to as an "off-period"). may be considered), followed by a period during which the agent is re-administered, which may be referred to as a “second dosing period.” Generally, during the second dosing period, the dosage level of the agent is adjusted for the first dosing period. It is consistent with that administered during the period, but may be increased or decreased as medically necessary.

A "jelly" according to the present disclosure is composed of a gel, which is a semi-solid system composed of a suspension consisting of either small inorganic particles or large organic molecules impregnated by a liquid containing a high fraction of a structurally cohesive matrix, usually water.

As used herein, "liquid" is a dosage form consisting of a composition in a liquid state. Liquids can be spilled; It flows and behaves in a container at room temperature. Liquids exhibit Newtonian or pseudoplastic flow behavior.

In embodiments, “semi-liquid,” as used herein, can have the properties of both liquids and other formulations (ie, suspensions, emulsions, solutions, creams, gels, jellies, etc.).

As used herein, the term “ointment” may refer to a highly viscous liquid or semi-liquid formulation that may be used in the therapeutic treatment of a disease, syndrome or condition.

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. The type of carrier can be selected based on the intended route of administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile topical solutions or dispersions. The use of such media and agents for pharmaceutically active substances is well known in the art. To the extent that any conventional medium or agent is incompatible with the composition (eg, a derivative or analog of Formula 1, a derivative or analog of Formula 1 described herein, or a pharmaceutically acceptable salt, solvent, hydrate or polymorph thereof), the present disclosure Its use in compositions for

As used herein, "pharmaceutical carrier" or "carrier" may further comprise a pharmaceutically acceptable carrier, excipient or stabilizer that is not toxic to cells or mammals at the dosages and concentrations employed. Physiologically acceptable carriers are often aqueous pH buffered solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween ^™ , polyethylene glycol (PEG) and Pluronics ^™ . Additionally, 'pharmaceutically acceptable' means a federal or state regulatory agency or may be approved or may be approved by such agency in a country other than the United States, or may be used in animals, and more particularly in humans, in the United States Pharmacopoeia or other generally means listed in a recognized pharmacopeia.

The term "pharmaceutically acceptable salt or complex" refers to a salt or complex of a compound represented by Formula 1 specified below. Examples of such salts are organic or inorganic such as hydroxides, carbonates or bicarbonates of metal cations such as those selected from the group consisting of alkali metals (eg sodium, potassium or lithium) and alkaline earth metals (eg calcium or magnesium). base addition salts formed by the reaction of a compound represented by Formula 1 with a base or with a primary, secondary, or tertiary alkyl amine. Methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, morpholine, N-methyl-D-glucamine, N,N'-bis(phenylmethyl)-1,2-ethanediamine, Amine salts derived from tromethamine, ethanolamine, diethanolamine, ethylene diamine, N-methylmorpholine, procaine, piperidine, piperazine, and the like are contemplated as being within the scope of the present invention.

Also, as used herein, “salt” or “salt form” or “pharmaceutically acceptable salt” refers to an inorganic base such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxide and, for example, base addition salts (formed with free carboxyl or other anionic groups) derived from organic bases such as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like. These salts are formed as acid addition salts with any free cationic group, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with, for example, acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid , is generally formed with organic acids such as organic acids such as mandelic acid and the like. Salts of the present disclosure may include amine salts formed by protonation of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the present disclosure also include amine salts formed by protonation of an amino group with a suitable organic acid such as p-toluenesulfonic acid, acetic acid, and the like.

As used herein, the term “pH agent” or “buffer” may refer to a compound or buffer useful as a pH adjusting agent. These may include, but are not limited to, glycerol buffers, citrate buffers, borate buffers, acetate buffers, gluconate buffers, phosphate buffers or citric acid-phosphate buffers. A pH agent or buffer may be used in any suitable amount.

As used herein, the term “preservative” may refer to a substance or chemical that prevents undesirable chemical changes in a compound or composition or formula as described herein. Suitable preservatives are, for example, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium sorbic acid, Onamer M polyquat, cetyl bromide, cetyl pyridinium chloride, benzyl Bromide, EDTA, phenylmercury nitrate, phenylmercuric acetate, thimerosal, merthiolate, acetate and phenylmercuric borate, polymyxin B sulfate, methyl and propyl parabens, quaternary ammonium chloride, sodium benzoate, sodium propionate and sodium perborate, and other agents known to those skilled in the art, or combinations thereof. Preservatives may be used in any suitable amount.

As used herein, the terms “prevent,” “preventing,” or “prevention,” and other grammatical equivalents, are intended to reduce the incidence of a syndrome, as well as prevent the development, occurrence, disturbance or avoidance of a disease or condition syndrome. include for Prevention can be complete (ie, no detectable symptoms) or partial, so that fewer symptoms can be observed than in the absence of treatment. The term further includes prophylactic benefit. To prevent a disease or condition, the composition may be administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological syndromes of the disease, although not being diagnosed with the disease.

Ranges provided herein are understood to be shorthand for all values within the range. For example, a range from 1 to 10 includes all intermediate decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 and 1.9, as well as 1, 2, 3 , 4, 5, 6, 7, 8, 9 or 10 is understood to include any number, combination of numbers, or subranges. With respect to subranges, “nested subranges” extending from one of the endpoints of the range are particularly contemplated. For example, overlapping subranges of an example range of 1 to 50 may include 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 50 in the other direction. 30, 50 to 20, and 50 to 10. Ranges may be expressed herein as “about” one particular value and/or “about” another particular value. When such ranges are expressed, other aspects include the one particular value and/or the other particular value. Similarly, when values are expressed as approximations using the antecedent "about," it is understood that the particular value forms another aspect. It is further understood that the endpoints of each range are important with respect to and independently of the other endpoints. Also, it is understood that there are a number of values disclosed herein, and that each value is also disclosed herein as “about” that particular value in addition to the value itself. Also, throughout applications, it is understood that data is presented in a number of different formats, and that such data represents endpoints and starting points and ranges for any combination of data points. For example, where specific data point “10” and specific data point “15” are disclosed, between 10 and 15, as well as more than, more than, less than, less than, and equal to, 10 and 15 are considered disclosed. It is also understood that each unit between two specific units is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13 and 14 are also disclosed.

Additional excipients contemplated for use in the practice of the present disclosure may include, without limitation, known excipients available to those skilled in the art.

A “semi-solid gel” according to the present disclosure is a semi-solid. The apparent viscosity of a semi-solid formulation may increase with concentration.

As used herein, "sequential administration" means that administration of two agents (eg, a compound or composition described herein) occurs separately on the same day or does not occur on the same day (eg, occurs on consecutive days) ) is included.

A “solution” according to the present disclosure may be a clear, homogeneous liquid dosage form containing one or more chemical substances dissolved in a solvent or mixture of solvents that are miscible with one another. Solutions are liquid formulations containing one or more dissolved chemicals in a suitable solvent or mixture of solvents that are miscible with one another. Because the molecules of the drug substance in solution are uniformly dispersed, the use of the solution as a dosage form generally provides assurance of a uniform dosage upon administration and good accuracy when the solution is diluted or otherwise mixed.

As used herein, the term “solvent” refers to a liquid solvent that is aqueous or non-aqueous. The choice of solvent depends, inter alia, on the solubility of the composition in said solvent and the mode of administration. Aqueous solvents may consist solely of water, or they may consist of water and one or more miscible solvents, and may contain dissolved solutes such as sugars, buffers, salts or other excipients. More commonly used non-aqueous solvents are short-chain organic alcohols such as methanol, ethanol, propanol, short-chain ketones such as acetone, and polyalcohols such as glycerol.

"Subject" or "patient" means a human or non-human animal, such as a mammal. A "subject" may include any animal, including horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish and birds. A human subject may refer to a patient.

As used herein, a “suspension” is a liquid dosage form containing solid particles dispersed in a liquid vehicle.

As used herein, “viscosity” refers to the flow resistance of a fluid. Viscous agents can be used herein, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, known to those skilled in the art. other agents, or combinations thereof.

The term "weight percentage" or "% (w/w)" refers to the percentage of a component in a solution calculated based on the weight of the component and solvent. For example, a 1% (w/w) solution of a component would have 1 g of component dissolved in 100 g of solvent. The term “volume percentage” or “% (v/v)” refers to the percentage of a component in a solution calculated based on the volume of the component and solvent. For example, a 1% (v/v) solution of a component will have 1 ml of the component dissolved in 100 ml of solvent. The term "weight/volume percentage" or "% (w/v)" refers to the percentage of a component in a solution calculated based on the weight of the component and the volume of solvent. For example, a 1.0% (w/v) solution of a component would have 1 g of component dissolved in 100 ml of solvent.

As used herein, the term “syndrome” refers to a condition characterized by a group or series of related symptoms that occur continuously together. A syndrome (eg, acute respiratory distress syndrome) can be a set of medical signs and symptoms that are interrelated and often associated with a particular disease. On the other hand, a disease may be a health condition with a clearly defined reason behind it. However, the syndrome (from the Greek meaning 'to run together') can cause a number of symptoms without an identifiable cause. They can imply the likelihood of an underlying disease or the likelihood that a disease will develop.

As used herein, the terms “treat,” “treating,” or “treatment,” and other grammatical equivalents refer to alleviation, alleviation, amelioration, or prevention of a disease, condition (eg, acute respiratory distress syndrome) or symptom, or treatment of an additional symptom. prevention, amelioration or prophylaxis of the underlying metabolic cause of a symptom, inhibition of a disease or condition, such as arresting the development of the disease or condition, alleviation of the disease or condition, regression of the disease or condition, alleviation of the condition caused by the disease or condition; or cessation of symptoms of a disease or condition, and is intended to include prevention. The term further includes achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Further, since a therapeutic benefit is achieved in eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disorder.

The term "nutraceuticals" refers to foods or food supplements manufactured or processed with raw materials, functional ingredients, active pharmaceutical ingredients or additives useful for improving and/or nutrition and/or preservation of physiological functions of the human body.

The term “acute respiratory distress syndrome (ARDS)” refers to a medical condition that occurs in severe patients with widespread inflammation in the lungs. ARDS is a clinical phenotype that can result from various pathologies such as pneumonia and sepsis. Extensive damage to cells that form the alveolar barrier, surfactant dysfunction, abnormal clotting and activation of the innate immune response are hallmarks of ARDS.

The term “acute lung injury (ALI) refers to an inflammatory syndrome and increased permeability associated with hypoxemia and a classic radiological appearance. At the most severe end of this spectrum is ARDS.

The term “airway surface liquid (ASL)” refers to a thin layer of fluid that coats the apical surface of the airway epithelium at the air interface. ASL plays a pivotal role in maintaining airway homeostasis. ASL volume, pH and ionic balance are directly involved in the regulation of antimicrobial activity, ciliary function and mucosal clearance.

The term “inflammatory airway disease” refers to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI). ), chronic obstructive pulmonary disease (COPD), and other inflammatory airway disorders.

The term "inhibitor" as used in the context of the present invention is defined as a molecule, two or more molecules or a pharmaceutical composition that completely or partially inhibits the activity of a target or two or more targets that induce a desired biological effect. Non-limiting examples of targets include enzymes, receptors, ion-channels or transporters (eg, pendrins), and the like. An “inhibitor” is capable of reversibly or irreversibly inhibiting a target, and reversible inhibition includes competitive inhibition, uncompetitive inhibition, non-competitive inhibition, and mixed inhibition. The term “alkyl,” when used alone or in combination with other terms, includes straight-chain or branched C ₁ -C ₂₀ alkyl, which refers to a monovalent alkyl group having from 1 to 20 carbon atoms. These terms include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethyl propyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, tetrahydrogeranyl (tetrahydrogeranyl), n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl , n-octadecyl, n-nonadecyl and n-eicosanyl. Preferably, they include C ₁ -C ₉ alkyl, more preferably C ₁ -C ₆ alkyl, particularly preferably C ₁ -C ₄ alkyl, which likewise include monovalent alkyl groups having 1 to 9 carbon atoms; a monovalent alkyl group having 1 to 6 carbon atoms and a monovalent alkyl group having 1 to 4 carbon atoms, respectively.

The term “alkenyl,” when used alone or in combination with other terms, includes straight-chain or branched C ₂ -C ₂₀ alkenyl. It can have any available number of double bonds at any available position, and the configuration of the double bond can be either the (E) or (Z) configuration. These terms include vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3 -Methyl-2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hex Cenyl, 4-hexenyl, 5- hexenyl, 1-heptenyl, 1-octenyl, geranyl, 1-decenyl, 1-tetradecenyl, 1-octadecenyl, 9-octadecenyl, 1- eicocenyl and 3,7,11,15-tetramethyl-1-hexadecenyl and the like. Preferably, they include C ₂ -C ₈ alkenyl, more preferably C ₂ -C ₆ alkenyl. Among them, vinyl or ethenyl (-CH = CH ₂ ), n-2-propenyl (allyl, -CH ₂ CH = CH ₂ ), isopropenyl, 1-propenyl, 2-methyl-1-propenyl , 1-butenyl, 2-butenyl, 3-methyl-2-butenyl and the like are particularly preferred.

The term “alkynyl,” when used alone or in combination with other terms, includes straight-chain or branched C ₂ -C ₂₀ alkynyl. It may have any available number of triple bonds in any available position. This term includes ₂ to 20 carbon atoms and any It is exemplified by the group such as alkynyl group which may have double bond or triple bond.In particular, they include C ₂ -C ₈ alkynyl, more preferably C ₂ -C ₆ alkynyl etc. Preferably 2 to 6 carbons C ₂ -C ₆ alkynyl, which has an atom and refers to a group having alkynyl unsaturation in at least one or two positions.

The term "heteroalkyl" refers to C ₁ -C ₁₂ -alkyl, preferably C ₁ -C ₆ -alkyl, wherein at least one carbon is a hetero selected from O, N or S, including 2-methoxyethyl and the like. replaced by atoms.

The term “aryl” refers to a single ring (eg, phenyl) or multiple condensed rings (eg, indenyl, naphthyl, 2,3-dihydro-1H-indenyl, 1,2,3,4 tetrahydronaphthyl). refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having Aryl includes phenyl, naphthyl, anthryl, phenanthrenyl and the like.

The term “C ₁ -C ₆ alkyl aryl” refers to aryl groups having C ₁ -C ₆ alkyl substituents including methyl phenyl, ethyl phenyl, t-butyl phenyl, and the like.

The term “aryl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an aryl substituent including 3-phenylpropanyl, benzyl, and the like.

The term “heteroaryl” refers to a monocyclic heteroaromatic, or bicyclic or tricyclic fused-ring heteroaromatic group. Specific examples of heteroaromatic groups are optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1H-pyrazolyl , 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro] benzofuryl, isobenzofuryl, benzothienyl, benzo Triazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-azolyl, quinolizinyl, Quinazolinyl, phthalazinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3 -b] pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, Carbazolyl, xanthenyl, benzoquinolyl, benzo[d][1,3]dioxol-5-yl, 3,4-dihydro-1H-pyrano[4,3-c]pyridyl, quinoline- 2(1H)-one, 4H-chromene, 1H-indole, and the like.

The term “C ₁ -C ₆ alkyl heteroaryl” refers to heteroaryl groups having C ₁ -C ₆ alkyl substituents including methyl furyl, t-butyl furyl, and the like.

The term “heteroaryl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having a heteroaryl substituent including furyl methyl and the like.

The term “C ₂ -C ₆ alkenyl aryl” refers to an aryl group having a C ₂ -C ₆ alkenyl substituent, including vinyl phenyl and the like.

The term “aryl C ₂ -C ₆ alkenyl” refers to a C ₂ -C ₆ alkenyl group having an aryl substituent including phenyl vinyl and the like.

The term “C ₂ -C ₆ alkenyl heteroaryl” refers to a heteroaryl group having a C ₂ -C ₆ alkenyl substituent, including vinyl pyridinyl and the like.

The term “heteroaryl C ₂ -C ₆ alkenyl” refers to a C ₁ -C ₆ alkenyl group having a heteroaryl substituent including pyridinyl vinyl and the like.

The term “C ₃ -C ₈ -cycloalkyl” refers to a saturated carbocyclic group of 3 to 8 carbon atoms having a single ring (eg cyclohexyl) or multiple condensed rings (eg norbornyl). C ₃ -C ₈ -cycloalkyl includes cyclopentyl, cyclohexyl, norbornyl, and the like.

The term "heterocycloalkyl" refers to C ₃ -C ₈ -cycloalkyl according to the definition above, wherein up to 3 carbon atoms are replaced with a heteroatom selected from the group consisting of O, S and NR (wherein R is defined as hydrogen or methyl) or Refers to multiple condensed rings. Heterocycloalkyl includes lactams or lactones. Non-limiting examples include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, decahydroisoquinolinyl, octahydro-1H-pyrano[3,4-c]pyridinyl, 4-methylene-5(4H)-one, pyrrolidin-2-one, and the like.

The term “C ₁ -C ₆ alkyl C ₃ -C ₈ cycloalkyl” refers to a C ₃ -C ₈ cycloalkyl group having a C ₁ -C ₆ alkyl substituent including methyl cyclopentyl and the like.

The term “C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having C ₃ -C ₈ -cycloalkyl substituents including 3-cyclopentyl propyl and the like.

The term “C ₁ -C ₆ alkyl heterocycloalkyl” refers to a heterocycloalkyl group having a C ₁ -C ₆ alkyl substituent including 4-methylpiperidinyl and the like.

The term “heterocycloalkyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having a heterocycloalkyl substituent including (1-methylpiperidin-4-yl)methyl and the like.

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

The term “carboxy C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having a carboxy substituent including 2-carboxyethyl and the like.

The term “acyl” refers to the group —C(O)R, including acetyl and the like, where R is H, “alkyl” preferably “C ₁ -C ₆ alkyl” “aryl” “heteroaryl” “C ₃ —C ₈ cycloalkyl” “heterocycloalkyl” “aryl C ₁ -C ₆ alkyl” “heteroaryl C ₁ -C ₆ alkyl” “C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl”.

The term “acyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an acyl substituent including 2-acetylethyl and the like.

The term “acyl aryl” refers to an aryl group having an acyl substituent including 2-acetylphenyl and the like.

The term "acyloxy" refers to the group -OC(O)R, including acetyloxy and the like, wherein R is H, "C ₁ -C ₆ alkyl", "C ₂ -C ₆ alkenyl""C ₂ - C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl C ₁ —C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl”.

The term “acyloxy C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an acyloxy substituent including 2-(ethylcarbonyloxy)ethyl and the like.

The term “alkoxy” refers to the group —OR, wherein R is “C ₁ -C ₆ alkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl” or “heteroaryl C ₁ -C ₆ alkyl". Preferred alkoxy groups include, for example, methoxy, ethoxy, phenoxy, and the like.

The term “alkoxy C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an alkoxy substituent, including methoxyethyl and the like.

The term “alkoxycarbonyl” refers to the group —C(O)OR, wherein R is “C ₁ -C ₆ alkyl”, “aryl”, “heteroaryl”, “aryl C ₁ -C ₆ alkyl”, “ heteroaryl C ₁ -C ₆ alkyl” or “heteroalkyl”.

The term “alkoxycarbonyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an alkoxycarbonyl substituent including 2-(benzyloxycarbonyl)ethyl and the like.

The term “aminocarbonyl” refers to the group —C(O)NRR′, including N-phenyl carbonyl and the like, wherein R and R′ are independently H, C ₁ -C ₆ alkyl, aryl, heteroaryl, “aryl C ₁ -C ₆ alkyl” or “heteroaryl C ₁ -C ₆ alkyl”.

The term "aminocarbonyl C ₁ -C ₆ alkyl" has aminocarbonyl substituents including 2-(dimethylaminocarbonyl)ethyl, N-ethyl acetamidyl, N,N-diethyl-acetamidyl, and the like. refers to an alkyl group.

The term “acylamino” refers to the group —NRC(O)R′, including acetylamino and the like, wherein R and R′ are independently H, “C ₁ -C ₆ alkyl” “C ₂ -C ₆ alkenyl. ” “C ₂ -C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “cycloalkyl C ₁ - C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl”.

The term “acylamino C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an acylamino substituent including 2-(propionylamino)ethyl and the like.

The term "ureido" refers to the group -NRC(O)NR'R'', wherein R, R' and R'' are independently H, "C ₁ -C ₆ alkyl""alkenyl" “alkynyl” “C ₃ -C ₈ cycloalkyl” “heterocycloalkyl” “C ₁ -C ₆ aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “Aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl” wherein R′ and R′′ together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring.

The term “ureido C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having a ureido substituent including 2-(N′-methylureido)ethyl and the like.

The term “carbamate” refers to the group —NRC(O)OR′, wherein R and R′ are independently “C ₁ -C ₆ alkyl” “C ₂ -C ₆ alkenyl” “C ₂ -C ₆ alkyl” nyl” “C ₃ -C ₈ -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “C ₁ -C ₆ alkyl aryl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “cycloalkyl C ₁ -C ₆ alkyl” or “heterocyclo alkyl C ₁ -C ₆ alkyl”, and R may be hydrogen.

The term "amino" refers to the group -NRR', wherein R and R' are independently H, "C ₁ -C ₆ alkyl", "aryl", "heteroaryl", "C ₁ -C ₆ alkyl aryl" , "C ₁ -C ₆ alkyl heteroaryl""cycloalkyl" or "heterocycloalkyl", wherein R and R' together with the nitrogen atom to which they are attached, optionally form a 3-8 membered heterocycloalkyl ring can be formed

The term “amino alkyl” refers to an alkyl group having an amino substituent including 2-(1-pyrrolidinyl)ethyl and the like.

The term "ammonium" refers to the positively charged group -N ⁺ RR'R'', wherein R, R' and R'' are independently "C ₁ -C ₆ alkyl", "C ₁ -C ₆ alkyl. aryl”, “C ₁ -C ₆ alkyl heteroaryl” “cycloalkyl” or “heterocycloalkyl”, wherein R and R′ together with the nitrogen atom to which they are attached, are a 3-8 membered heterocycloalkyl ring can be formed arbitrarily.

The term “ammonium alkyl” refers to an alkyl group having an ammonium substituent including 1-ethylpyrrolidinium and the like.

The term “halogen” refers to fluoro, chloro, bromo and iodine atoms.

The term “sulfonyloxy” refers to the group —OSO ₂ R, where R is a “C ₁ -C ₆ alkyl” substituted with a “C ₁ -C ₆ alkyl” halogen, such as the group —OSO ₂ CF ₃ , “ C ₂ -C ₆ alkenyl” “alkynyl” “C ₃ -C ₈ cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl alkyl”.

The term “sulfonyloxy C ₁ -C ₆ alkyl” refers to an alkyl group having a sulfonyloxy substituent including 2-(methylsulfonyloxy)ethyl and the like.

The term “sulfonyl” refers to the group “—SO ₂ R”, wherein R is “C ₁ -C ₆ alkyl” substituted with “aryl” “heteroaryl” “C ₁ -C ₆ alkyl” halogen, such as, —SO ₂ CF ₃ group, “C ₂ -C ₆ alkenyl” “C ₂ -C ₆ alkynyl” “C ₃ -C ₈ cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl", "heteroaryl C ₁ -C ₆ alkyl""aryl C ₂ -C ₆ alkenyl""heteroaryl C ₂ -C ₆ alkenyl""aryl C ₂ -C ₆ alkynyl""heteroaryl C ₂ -C ₆ alkynyl” “cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl”.

The term “sulfonyl C ₁ -C ₆ alkyl” refers to an alkyl group having a sulfonyl substituent including 2-(methylsulfonyl)ethyl and the like.

The term “sulfinyl” refers to the group “—S(O)R”, where R is “alkyl” substituted with an “alkyl” halogen, such as a —SOCF ₃ group, “C ₂ -C ₆ al kenyl” “C ₂ -C ₆ alkynyl” “C ₃ -C ₈ cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl”.

The term “sulfinyl alkyl” refers to an alkyl group having a sulfinyl substituent including 2-(methylsulfinyl)ethyl and the like.

The term "sulfanyl" refers to the group -SR, wherein R is H, "C ₁ -C ₆ alkyl", "C ₁ -C ₆ alkyl" substituted by halogen, eg, -SCF ₃ group, “C ₂ -C ₆ alkenyl” “C ₂ -C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “alkynylheteroaryl” “cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl.” Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl and the like.

The term “sulfanyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₅ -alkyl group having a sulfanyl substituent including 2-(ethylsulfanyl)ethyl and the like.

The term “sulfonylamino” refers to the group —NRSO ₂ R′, wherein R and R′ are independently “C ₁ -C ₆ alkyl” “C ₂ -C ₆ alkenyl” “C ₂ -C ₆ alkynyl. ” “C ₃ -C ₈ -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl C ₂ -C ₆ alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “C ₃ -C ₈ cycloalkyl C ₁ -C ₆ alkyl” or “heterocycloalkyl C ₁ -C ₆ alkyl.”

The term “sulfonylamino C ₁ -C ₆ alkyl” refers to an alkyl group having a sulfonylamino substituent including 2-(ethylsulfonylamino)ethyl and the like.

The term "aminosulfonyl" refers to the group -SO ₂ NRR', wherein R and R' are independently H, "C ₁ -C ₆ alkyl""C ₂ -C ₆ alkenyl""C ₂ -C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl” “heterocycloalkyl” “aryl” “heteroaryl” “aryl C ₁ -C ₆ alkyl”, “heteroaryl C ₁ -C ₆ alkyl” “aryl alkenyl” “heteroaryl C ₂ -C ₆ alkenyl” “aryl C ₂ -C ₆ alkynyl” “heteroaryl C ₂ -C ₆ alkynyl” “C ₃ -C ₈ -cycloalkyl C ₁ -C ₆ alkyl” or “ heterocycloalkyl C ₁ -C ₆ alkyl", wherein R and R' together with the nitrogen atom to which they are attached may optionally form a 3-8 membered heterocycloalkyl ring. The aminosulfonyl group is cyclohexyl aminosulfonyl, piperidinylsulfonyl, and the like.

The term “aminosulfonyl C ₁ -C ₆ alkyl” refers to a C ₁ -C ₆ alkyl group having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like.

Unless otherwise limited by the definition of individual substituents, all of the above substituents are to be understood as being all optionally substituted.

Unless otherwise limited by the definition of an individual substituent, the term “substituted” means “C ₁ -C ₆ alkyl”, “C ₂ -C ₆ alkenyl”, “C ₂ -C ₆ alkynyl”, “C ₃ -C ₈ cycloalkyl”, “heterocycloalkyl”, “C ₁ -C ₆ alkyl aryl”, “C ₁ -C ₆ alkyl heteroaryl”, “C ₁ -C ₆ alkyl cycloalkyl”, “C ₁ -C ₆ alkyl heterocycloalkyl”, “amino”, “aminosulfonyl”, “ammonium”, “acyl amino”, “amino carbonyl”, “aryl”, “heteroaryl”, “sulfinyl”, “sulfonyl” 1 to 5 selected from the group consisting of , "alkoxy", "alkoxy carbonyl", "carbamate", "sulfanyl", "halogen", trihalomethyl, cyano, hydroxy, mercapto, nitro, etc. It refers to a group substituted with a substituent.

2. Compounds

One aspect of the present invention provides a compound represented by the following formula (1) or (2), its E- or Z- isomer, its optical isomer, its two isomer mixture, its precursor, its pharmaceutically acceptable salt or its solvate do:

One aspect of the present invention provides a compound represented by the following formula (1), its E- or Z- isomer, its optical isomer, a mixture of two isomers, a precursor thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[Formula 1]

In Formula 1,

V ¹ and V ² are each independently Aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ one of C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , With one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , NR ³ R ⁴ . optionally substituted, said aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C one of (O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl, hetero aryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl) , S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , with one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted,

i and j are each independently 0, 1 or 2,

R ¹ and R ² are hydrogen, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , independently selected from the group consisting of C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , said aryl, heteroaryl, heterocyclyl , C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O) one of OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ,

R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or

R ³ and R ⁴ may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,

로 이루어지는 군으로부터 선택되는 구조로 표시되고, A ¹ is

It is represented by a structure selected from the group consisting of,

X ¹ and X ² are each independently selected from the group consisting of O, S, CHR ⁴ and NR ⁴ ,

J is N or CH;

R ⁵ , R ⁶ and R ⁷ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C independently selected from the group consisting of ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, heterocyclyl, aryl, heteroaryl and trifluoromethyl, wherein one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C ₁ to C ₁₀ alkylaryl and heteroaryl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, tri Fluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl , S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and one or more groups independently selected from NR ³ R ⁴ , said aryl, arylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , one of OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethyl Toxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S (O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C optionally selected from one or more groups independently selected from (O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or

R ⁵ and A ¹ may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is Oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ optionally substituted with one or more groups independently selected from , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ .

[Formula 2]

In Formula 2,

V ³ and V ⁴ are each independently aryl, heteroaryl, C ₃ ~ C ₇ cycloalkyl, heterocycloalkyl, C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ heteroalkyl, C ₂ ~ C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C( O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ one of C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl , trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ optionally substituted with one or more groups independently selected from aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl) ), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR one of ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl , C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O ) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O) OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ;

i is each independently 0, 1 or 2,

R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or

R ³ and R ⁴ taken together may form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo , halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , optionally substituted with one or more groups independently selected from NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,

A ² is

It is represented by a structure selected from the group consisting of,

X ³ is hydrogen, OR ³ , aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O)OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ , wherein OR ³ , aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O) one of OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, Sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl , C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O) one independently selected from R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Optionally selected from the above group, the aryl, C ₁ ~ C ₁₀ alkylaryl, C ₃ ~ C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ ~ C ₁₀ alkyl, C ₂ ~ C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ one of hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl , heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R at least one independently selected from ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted with a group,

i is 0, 1 or 2,

X ⁴ is O, S, NR ⁵ , NSO ₂ R ⁵ , C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, aryl, arylalkyl, C ₁ to C ₁₀ alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR ⁵ , NSO ₂ R ⁵ , C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, aryl, arylalkyl, C ₁ ~ C ₁₀ alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ⁵ , C(O)R ⁵ , OR ⁵ , NR ⁵ C(O)OR ⁶ , C(O)NR ⁵ R ⁶ and NR ⁵ R ⁶ may be optionally substituted with one or more selected from the group consisting of,

R ⁵ to R ⁸ are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) independently selected from the group consisting of NR ³ R ⁴ and NR ³ R ⁴ , said aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) one of NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S (O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O) )OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , optionally selected from one or more groups independently selected from the group consisting of, said aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR one of ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, Halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl , C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), from S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . may be optionally substituted with one or more independently selected

R ⁵ and A ² may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,

I is 0, 1 or 2.

Non-limiting examples of the compound according to Formula 1 or 2 include the following compounds shown in Tables 1 and 2.

In the present specification, the term 'compound of the present invention' and equivalent expressions include compounds represented by Formula 1 or 2 described above, and these expressions include its E- or Z-isomer, its optical isomer, and a mixture of two isomers thereof. , a precursor thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, and is newly synthesized.

Specifically, the compounds represented by Formula 1 or 2 are any one selected from the group consisting of the following compounds:

4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F1 ),

2-(4-(tert-butyl)phenyl)-4-(thiazol-5-ylmethylene)oxazol-5(4H)-one ( F2 ),

2-(4-(tert-butyl)phenyl)-4-((2-methyl-1H-indol-3-yl)methylene)oxazol-5(4H)-one ( F3 ),

tert-Butyl 3-((2-(4-(tert-butyl)phenyl)-5-oxoxazol-4(5H)-ylidene)methyl)-1H-indole-1-carboxylate ( F4 ),

4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-di-hydrooxazol-2-yl) benzonitrile ( F5 ),

2-(4-(tert-butyl)phenyl)-4-((1-methyl-1H-pyrrol-2-yl)methylene)oxazol-5(4H)-one ( F6 ),

methyl 4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzoate ( F7 ),

2-(4-(tert-butyl)phenyl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F8 ),

2-(4-(tert-butyl)phenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F9 ),

4-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F10 ),

4- (benzo [b] thiophen-2-ylmethylene) -2- (4- (tert-butyl) phenyl) oxazol-5 (4H) -one ( F11 ),

4-((1H-pyrrol-2-yl)methylene)-2-(4-isopropylphenyl)oxazol-5(4H)-one ( F12 ),

2-(4-(tert-butyl)phenyl)-4-(quinolin-4-ylmethylene)oxazol-5(4H)-one ( F13 ), 2-(4-isobutylphenyl)-4-(thi ofen-2-ylmethylene)oxazol-5(4H)-one ( F14 ),

2-(4-isobutyl phenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F15 ),

4- (benzo [b] thiophen-3-ylmethylene) -2- (4-isopropylphenyl) oxazol-5 (4H) -one ( F16 ),

4-((1H-pyrrol-2-yl)methylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F17 ),

4-(thiophen-3-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F18 ),

4-(furan-2-ylmethylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F19 ),

4-((1H-pyrrol-2-yl)methylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F20 ),

4- (benzo [b] thiophen-3-ylmethylene) -2- (4-isobutylphenyl) oxazol-5 (4H) -one ( F21 ),

2-(4-bromophenyl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F22 ),

2-cyclo-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F23 ),

2-([1,1'-biphenyl]-4-yl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F24 ),

4-((1H-pyrrol-2-yl)methylene)-2-([1,1'-biphenyl]-4-ylmethyl)oxazol-5(4H)-one ( F25 ),

4-((1H-pyrrol-2-yl)methylene)-2-(4-butylphenyl)oxazol-5(4H)-one ( F26 ),

2-(4-(tert-butyl)phenyl)-4-((1-phenyl-1H-pyrrol-2-yl)methylene)oxazol-5(4H)-one ( F27 ),

2-([1,1'-biphenyl]-4-ylmethyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F28 ),

2-(2,3-dihydro-1H-inden-5-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F29 ),

4-((1H-pyrrol-2-yl)methylene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F30 ),

methyl 4-(4-(furan-2-ylmethylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzoate ( F31 ),

methyl 4- (5-oxo-4- (thiophen-3-ylmethylene) -4,5-dihydrooxazol-2-yl) benzoate ( F32 ),

N- (4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl) acetamide ( F33 ),

2- (2-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F34 ),

N-(tert-butyl)-4-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-di-hydrooxazol-2-yl)benzene sulfonamide ( F35 ),

N-isopropyl-4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzene sulfonamide ( F36 ),

2-([1,1'-biphenyl]-4-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F37 ),

2-(4-(tert-butyl)phenyl)-4-(furan-2-ylmethylene)oxazol-5(4H)-one ( F38 ),

2-(4-(tert-butyl)phenyl)-4-((1-methyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F39 ),

2-(4-(tert-butyl)phenyl)-4-(pyridin-3-ylmethylene)oxazol-5(4H)-one ( F40 ),

2-(4-(tert-butyl)phenyl)-4-(pyridin-4-ylmethylene)oxazol-5(4H)-one ( F41 ),

2-([1,1'-biphenyl]-4-yl)-4-(pyridin-3-ylmethylene)oxazol-5(4H)-one ( F42 ), 2-(4-(tert-butyl) )phenyl)-4-(4-(methylthio)benzylidene)oxazol-5(4H)-one ( F43 ),

4-benzylidene-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F44 ),

2- (4-bromophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F45 ),

2- (4-isopropylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F46 ),

2-(4-isopropylphenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F47 ),

4-(furan-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F48 ),

4- (furan-2-ylmethylene) -2- (4-isopropylphenyl) oxazol-5 (4H) -one ( F49 ),

2- (4-bromophenyl) -4- (furan-2-ylmethylene) oxazol-5 (4H) -one ( F50 ),

2- (4-bromophenyl) -4- (thiophen-3-ylmethylene) oxazol-5 (4H) -one ( F51 ),

2-(naphthalen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F52 ),

2- (4-butylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F53 ),

2-(4-butylphenyl)-4-(furan-2-ylmethylene)oxazol-5(4H)-one ( F54 ),

2- (4- (difluoromethoxy) phenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F55 ),

2-(4-(tert-butyl)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F56 ), 4-(2-nitrobenzylidene)-2- phenyloxazol-5(4H)-one ( F57 ),

4-((2-(4-(tert-butyl)phenyl)-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate ( F58 ),

2- (3-chlorobenzo [b] thiophen-2-yl) -4- (4- (dimethylamino) benzylidene) oxazol-5 (4H) -one ( F59 ),

4-((2-(4-methoxyphenyl)-5-oxooxazol-4(5H)-ylidene)methyl)benzoic acid ( F60 ),

2-phenyl-4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F61 ),

4-(4-isopropylbenzylidene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F62 ),

2-(3-iodo-4-methylphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F63 ),

4-(4-(benzyloxy)benzylidene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F64 ),

4-((1-(2-chlorobenzyl)-1H-pyrrol-2-yl)methylene)-2-phenyloxazol-5(4H)-one ( F65 ),

N-(4-(4-(2-(allyloxy)-4-(diethylamino)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)-5-bro monicotinamide ( F66 ),

4-((2-(2-chlorophenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl 4-(tert-butyl)benzoate ( F67 ),

4-((Z)-1-(3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-ylidene)butan-2-ylidene)-2-phenyloxazole-5(4H )-on ( F68 ),

4-((2-(4-acetamidophenyl)-5-oxoxazol-4(5H)-ylidene)methyl)-2-ethoxyphenyl thiophene-2-carboxylate ( F69 ),

4-((6-ethoxy-2-(phenylthio)quinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F70 ),

2-(3-bromophenyl)-4-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F71 ),

4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-bromophenyl)oxazol-5(4H)-one ( F72 ),

2-(4-(tert-butyl)phenyl)-4-((5-(3-(trifluoro-methyl)phenyl)furan-2-yl)methylene)oxazol-5(4H)-one ( F73 ),

4-((7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F74 ),

2-(4-methoxyphenyl)-4-(2-(thiophen-2-yl)-4H-chromen-4-ylidene)oxazol-5(4H)-one ( F75 ),

N,N-dimethyl-3-((5-oxo-2-(p-tolyl)oxazol-4(5H)-ylidene)methyl)-1H-indole-1-sulfonamide ( F76 ),

2-((2-(4-chlorophenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl 4-acetamidobenzenesulfonate ( F77 ),

4-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)phenyl furan-2-carboxylate ( F78 ),

2,2'-(1,4-phenylene)bis(4-((5-methylfuran-2-yl)methylene)oxazol-5(4H)-one) ( F79 ),

2-((2-(4-(tert-butyl)phenyl)-5-oxooxazol-4(5H)-ylidene)methyl)phenyl benzenesulfonate ( F80 ),

4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F81 ),

4-((1-acetyl-3-phenyl-1H-pyrazol-4-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F82 ),

4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-2-(p-tolyl)oxazol-5(4H)-one ( F83 ),

4-((6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F84 ),

4-(2,6-diphenyl-4H-thiopyran-4-ylidene)-2-phenyloxazol-5(4H)-one ( F85 ),

N-(4-(4-(4-((2-chloroethyl)(methyl)amino)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F86 ),

2- (4-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F87 ),

2- (4-chlorophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F88 ),

2-(thiophen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F89 ),

4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl acetate ( F90 ),

2- (4-chloro-3-nitrophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F91 ),

2- (2-chlorophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F92 ),

2- (2-chloro-4-nitrophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F93 ),

4- (thiophen-2-ylmethylene) -2- (3,4,5-trimethoxy phenyl) oxazol-5 (4H) -one ( F94 ),

2- (4-phenoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F95 ),

2-(4-(tert-butyl)phenyl)-4-((5-methylthiophen-2-yl)methylene)oxazol-5(4H)-one ( F96 ),

2- (benzo [d] [1,3] dioxol-5-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F97 ),

2-(4-(2-oxo-pyrrolidin-1-yl)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F98 ),

4-((5-chlorothiophen-2-yl)methylene)-2-(4-methoxyphenyl)oxazol-5(4H)-one ( F99 ),

2-(benzo[d][1,3]dioxol-5-yl)-4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)oxazole-5( 4H)-on ( F100 ),

2- (3,4-diethoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F101 ),

2-(4-(difluoromethoxy)-3-methoxyphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F102 ),

2-(5-ethyl-4-methylthiophen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F103 ),

2- (3-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F104 ),

4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F105 ),

N-(4-(4-((4-bromothiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F106 ),

N-(4-(4-((5-bromothiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F107 ),

N-(4-(4-((5-(dimethylamino)thiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F108 ) ,

2-(4-(benzyloxy)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F109 ),

2-((E)-styryl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F110 ),

2-(5-methylthiophen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F111 ),

N,N-diethyl-3-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F112 ),

2-(2-methoxyphenyl)-4-((2,4,5-trimethylthieno[2,3-d]pyrimidin-6-yl)methylene)oxazol-5(4H)-one ( F113 ),

4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F114 ),

4-((5-methylthiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F115 ),

N,N-dimethyl-3-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F116 ),

4-((5-bromothiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F117 ),

4-((5-bromothiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F118 ),

2-(5-methylthiophen-2-yl)-4-((5-methylthiophen-2-yl)methylene)oxazol-5(4H)-one ( F119 ),

4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F120 ),

4-((5-bromothiophen-2-yl)methylene)-2-(2-(difluoro-methoxy)phenyl)oxazol-5(4H)-one ( F121 ),

2-(4-(tert-butyl)phenyl)-4-(2-(difluoromethoxy)benzylidene)oxazol-5(4H)-one ( F122 ),

4-((1-(2-chlorobenzyl)-1H-pyrazol-4-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F123 ),

2-(4-(tert-butyl)phenyl)-4-((1-phenyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F124 ),

2-(2-methoxyphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F125 ),

N-(tert-butyl)-4-(4-((5-methylfuran-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F126 ) ,

N,N-diethyl-4-(4-(1-methylpyridin-2(1H)-ylidene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F127 ) ,

2-(4-((2-(2-methoxyphenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenoxy)acetamide ( F128 ),

N-(4-((2-(4-isopropoxyphenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl)acetamide ( F129 ),

4-((1-benzyl-1H-pyrazol-4-yl)methylene)-2-(4-isopropoxyphenyl)oxazol-5(4H)-one ( F130 ),

N,N-diethyl-3-(4-((1-methyl-1H-pyrazol-4-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F131 ),

4-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(2-iodophenyl)oxazol-5(4H)-one ( F132 ),

4-(4-((3,5-Dimethylisoxazol-4-yl)methoxy)-3-methoxybenzylidene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F133 ),

N-(4-(4-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl) acetamide ( F134 ),

2-(2-(difluoromethoxy)phenyl)-4-((E)-3-(furan-2-yl)allylidene)oxazol-5(4H)-one ( F135 ),

4-((1-(tert-butyl)-1H-pyrazol-4-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F136 ),

methyl 2- (5-oxo-1-phenyl-4- (thiophen-2-ylmethylene) -4,5-dihydro-1H-pyrazol-3-yl) acetate ( F137 ),

3- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoic acid ( F138 ),

3-(4-chlorophenyl)-5-((5-methylthiophen-2-yl)methylene)thiazolidine-2,4-dione ( F139 ),

2-(2,4-dioxo-5-(thiophen-2-ylmethylene)thiazolidin-3-yl)-N-(p-tolyl)acetamide ( F140 ),

3-(4-ethoxyphenyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F141 ),

3-((diethylamino)methyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F142 ),

3-(3-nitrobenzyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F143 ), 3-phenyl-5-(thiophen-2-ylmethylene)thia Zolidine-2,4-dione ( F144 ),

methyl 2- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoate ( F145 ),

2-(4-((3-(3-chlorophenyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)phenoxy)acetic acid ( F146 ),

2-(3-((Z)-((Z)-2-((4-ethoxyphenyl)imino)-3-methyl-4-oxothiazolidin-5-ylidene)methyl)-1H- indol-1-yl)acetic acid ( F147 ),

5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-3-phenyl-2-thioxothiazolidin-4-one ( F148 ),

3-benzyl-5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F149 ),

3-methyl-1- (4-nitrophenyl) -4- (thiophen-2-ylmethylene) -1H-pyrazol-5 (4H) -one ( F150 ),

4-(3-methyl-4-((5-methylthiophen-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzene sulfonamide ( F151 ) ,

3-methyl-4-((5-methylthiophen-2-yl)methylene)-1-(naphthalen-2-yl)-1H-pyrazol-5(4H)-one ( F152 ),

3-(3-methyl-4-((5-(4-methyl-2-nitrophenyl)furan-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazole-1 -yl) benzoic acid ( F153 ),

Ethyl 4-methyl-2-(3-methyl-5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydro-1H-pyrazol-1-yl)thiazole-5-carr carboxylate ( F154 ),

3-methyl-1-phenyl-4-(thiophen-2-ylmethylene)-1H-pyrazol-5(4H)-one ( F155 ),

2,6-bis((5-bromothiophen-2-yl)methylene)cyclohexanone ( F156 ),

2-(4-(dimethylamino)benzylidene)-6-(thiophen-2-ylmethylene)cyclo-hexanone ( F157 ),

2,6-bis(thiophen-2-ylmethylene)cyclohexanone ( F158 ),

4-((5-(2-methoxy-4-nitrophenyl)furan-2-yl)methylene)-3-phenylisoxazol-5(4H)-one ( F159 ),

2-chloro-5- (5- ((2- (3-chloro-4-methylphenyl) hydrazinylidene) methyl) furan-2-yl) benzoic acid ( F160 ),

5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F161 ),

5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F162 ),

6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-5-imino-2-propyl-5H-[1,3,4]thia diazolo[3,2-a]pyrimidin-7(6H)-one ( F163 ),

4-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-1-(cyclohexa-1,3-dien-1-yl)pyrazolidine -3,5-dione ( F164 ),

6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-2-ethyl-5-imino-5H-[1,3,4]thia diazolo[3,2-a]pyrimidin-7(6H)-one ( F165 ),

5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione ( F166 ),

5-((5-ethyl-3-(4-methoxybenzoyl)thiophen-2-yl)amino)-3,3-dimethyl-5-oxopentanoic acid ( F167 ),

2-((1,7-dibenzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)acetic acid ( F168 ),

4-((E)-3-phenylallylidene)-3-(p-tolyl)isoxazol-5(4H)-one ( F169 ),

4-(2-(allyloxy)benzylidene)-3-(4-nitrophenyl)isoxazol-5(4H)-one ( F170 ),

4-((4-methylthiazol-5-yl)methylene)-2-(4-propylphenyl)oxazol-5(4H)-one ( F171 ),

4-((1H-pyrrol-2-yl)methylene)-2-(4-butoxyphenyl)oxazol-5(4H)-one ( F172 ),

2-(4-hexylphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F173 ),

4-((1H-indol-2-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F174 ),

4-(furan-2-ylmethylene)-2-(4-pentylphenyl)oxazol-5(4H)-one ( F175 ),

2- (4-butoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F176 ),

5-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)-3,5-dihydro-4H-imidazol-4-one ( F177 ),

methyl 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G1 ),

methyl 2-(4-(tert-butyl)benzamido)-3-(thiophen-2-yl)acrylate ( G2 ),

2-(4-(tert-butyl)benzamido)-3-(thiophen-2-yl)acrylic acid ( G3 ),

Methyl 2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylate ( G4 ),

2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylic acid ( G5 ),

tert-butyl 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G6 ),

2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G7 ),

2-(4-(tert-butyl)benzamido)-3-(thiophen-3-yl)acrylic acid ( G8 ),

2-(4-(tert-butyl)benzamido)-3-(4-methylthiazol-5-yl)acrylic acid ( G9 ),

2-(4-(tert-butyl)benzamido)-3-(1-methyl-1H-pyrazol-4-yl)acrylic acid ( G10 ),

methyl 2-(4-butylbenzamido)-3-(1H-pyrrol-2-yl)acrylate ( G11 ),

2-(4-butylbenzamido)-3-(thiophen-2-yl)acrylic acid ( G12 ),

2-(4-(tert-butyl)benzamido)-3-(1-phenyl-1H-pyrrol-2-yl)acrylic acid ( G13 ),

methyl 2-(4-(tert-butyl)benzamido)-3-(1-phenyl-1H-pyrrol-2-yl)acrylate ( G14 ),

methyl 3-(1H-pyrrol-2-yl)-2-(4-(trifluoro-methyl)benzamino)acrylate ( G15 ),

2-(4-bromobenzamido)-3-(furan-2-yl)acrylic acid ( G16 ),

methyl 3-(furan-2-yl)-2-(4-(trifluoromethyl)benzamino)acrylate ( G17 ),

3-(furan-2-yl)-2-(4-(trifluoromethyl)benzamido)acrylic acid ( G18 ),

2-(4-bromobenzamido)-3-(thiophen-2-yl)acrylic acid ( G19 ),

methyl 2-(4-bromobenzamido)-3-(furan-2-yl)acrylate ( G20 ),

2-(4-bromobenzamido)-3-(furan-2-yl)acrylic acid ( G21 ),

2-(4-butylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G22 ),

(E)-N'-(1-(naphthalen-2-yl)ethylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carbohydrazide ( G23 ),

(E)-2-((1H-benzo[d]imidazol-2-yl)thio)-N'-(3-methylbenzylidene)acetohydrazide ( G24 ),

N′-(2-(thiophen-2-yl)acetyl)-4-(trifluoro-methyl)benzohydrazide ( G25 ),

4-chloro-N'-(2-(thiophen-2-yl)acetyl)benzohydrazide ( G26 ),

2-(2-(2-(benzo[d]thiazol-2-ylthio)acetamido)thiazol-4-yl)acetic acid ( G27 ),

N-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-hydroxypropyl)-N-(4-methoxyphenyl)benzenesulfonamide ( G28 ) ,

4-Amino-N5-(furan-2-ylmethyl)-N5-(2-oxo-2-(tert-pentylamino)-1-(quinolin-6-yl)ethyl)isothiazol-3,5- dicarboxamide ( G29 ),

4-(tert-butyl)-N-(3-((4-chlorophenyl) amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl)benzamide ( G30 ),

4-(tert-butyl)-N-(3-((furan-3-ylmethyl)amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl) benzamide ( G31 ),

3-(furan-2-yl)-2-(4-isobutoxybenzamido)acrylic acid ( G32 ),

N-(1-(furan-2-yl)-3-(methylamino)-3-oxoprop-1-en-2-yl)-4-isobutoxybenzamide ( G33 ),

N-(3-amino-1-(furan-2-yl)-3-oxoprop-1-en-2-yl)-4-(tert-butyl)benzamide ( G34 ),

methyl-2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G35 ),

2-(2-naphtamido)-3-(thiophen-3-yl)acrylic acid ( G36 ),

3-(benzo[b]thiophen-3-yl)-2-(4-(tert-butyl)benzamido)acrylic acid ( G37 ),

2-(4-isobutyl-benzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G38 ),

2-(1-naphtamido)-3-(4-methylthiazol-5-yl)acrylic acid ( G39 ) and

2-(4-Propylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G40 ).

In a more specific aspect, the compound of Formula 1 or 2 according to the present invention may be each of the following specific compounds.

methyl 2- (5-oxo-1-phenyl-4- (thiophen-2-ylmethylene) -4,5-dihydro-1H-pyrazol-3-yl) acetate ( F137 ),

3- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoic acid ( F138 ),

3-(4-chlorophenyl)-5-((5-methylthiophen-2-yl)methylene)thiazolidine-2,4-dione ( F139 ),

2-(2,4-dioxo-5-(thiophen-2-ylmethylene)thiazolidin-3-yl)-N-(p-tolyl)acetamide ( F140 ),

3-(4-ethoxyphenyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F141 ),

3-((diethylamino)methyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F142 ),

3-(3-nitrobenzyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F143 ), 3-phenyl-5-(thiophen-2-ylmethylene)thia Zolidine-2,4-dione ( F144 ),

methyl 2- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoate ( F145 ),

2-(4-((3-(3-chlorophenyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)phenoxy)acetic acid ( F146 ),

2-(3-((Z)-((Z)-2-((4-ethoxyphenyl)imino)-3-methyl-4-oxothiazolidin-5-ylidene)methyl)-1H- indol-1-yl)acetic acid ( F147 ),

5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-3-phenyl-2-thioxothiazolidin-4-one ( F148 ),

3-benzyl-5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F149 ),

3-methyl-1- (4-nitrophenyl) -4- (thiophen-2-ylmethylene) -1H-pyrazol-5 (4H) -one ( F150 ),

4-(3-methyl-4-((5-methylthiophen-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzene sulfonamide ( F151 ) ,

3-methyl-4-((5-methylthiophen-2-yl)methylene)-1-(naphthalen-2-yl)-1H-pyrazol-5(4H)-one ( F152 ),

3-(3-methyl-4-((5-(4-methyl-2-nitrophenyl)furan-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazole-1 -yl) benzoic acid ( F153 ),

Ethyl 4-methyl-2-(3-methyl-5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydro-1H-pyrazol-1-yl)thiazole-5-carr carboxylate ( F154 ),

3-methyl-1-phenyl-4-(thiophen-2-ylmethylene)-1H-pyrazol-5(4H)-one ( F155 ),

2,6-bis((5-bromothiophen-2-yl)methylene)cyclohexanone ( F156 ),

2-(4-(dimethylamino)benzylidene)-6-(thiophen-2-ylmethylene)cyclo-hexanone ( F157 ),

2,6-bis(thiophen-2-ylmethylene)cyclohexanone ( F158 ),

4-((5-(2-methoxy-4-nitrophenyl)furan-2-yl)methylene)-3-phenylisoxazol-5(4H)-one ( F159 ),

2-chloro-5- (5- ((2- (3-chloro-4-methylphenyl) hydrazinylidene) methyl) furan-2-yl) benzoic acid ( F160 ),

5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F161 ),

5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F162 ),

6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-5-imino-2-propyl-5H-[1,3,4]thia diazolo[3,2-a]pyrimidin-7(6H)-one ( F163 ),

4-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-1-(cyclohexa-1,3-dien-1-yl)pyrazolidine -3,5-dione ( F164 ),

6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-2-ethyl-5-imino-5H-[1,3,4]thia diazolo[3,2-a]pyrimidin-7(6H)-one ( F165 ),

5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione ( F166 ),

5-((5-ethyl-3-(4-methoxybenzoyl)thiophen-2-yl)amino)-3,3-dimethyl-5-oxopentanoic acid ( F167 ),

2-((1,7-dibenzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)acetic acid ( F168 ),

4-((E)-3-phenylallylidene)-3-(p-tolyl)isoxazol-5(4H)-one ( F169 ),

4-(2-(allyloxy)benzylidene)-3-(4-nitrophenyl)isoxazol-5(4H)-one ( F170 ),

(E)-N'-(1-(naphthalen-2-yl)ethylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carbohydrazide ( G23 ),

(E)-2-((1H-benzo[d]imidazol-2-yl)thio)-N'-(3-methylbenzylidene)acetohydrazide ( G24 ),

N′-(2-(thiophen-2-yl)acetyl)-4-(trifluoro-methyl)benzohydrazide ( G25 ),

4-chloro-N'-(2-(thiophen-2-yl)acetyl)benzohydrazide ( G26 ),

2-(2-(2-(benzo[d]thiazol-2-ylthio)acetamido)thiazol-4-yl)acetic acid ( G27 ),

N-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-hydroxypropyl)-N-(4-methoxyphenyl)benzenesulfonamide ( G28 ) ,

4-Amino-N5-(furan-2-ylmethyl)-N5-(2-oxo-2-(tert-pentylamino)-1-(quinolin-6-yl)ethyl)isothiazol-3,5- dicarboxamide ( G29 ),

4-(tert-butyl)-N-(3-((4-chlorophenyl) amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl)benzamide ( G30 ),

4-(tert-butyl)-N-(3-((furan-3-ylmethyl)amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl) benzamide ( G31 ),

3-(furan-2-yl)-2-(4-isobutoxybenzamido)acrylic acid ( G32 ),

N-(1-(furan-2-yl)-3-(methylamino)-3-oxoprop-1-en-2-yl)-4-isobutoxybenzamide ( G33 ), and

N-(3-Amino-1-(furan-2-yl)-3-oxoprop-1-en-2-yl)-4-(tert-butyl)benzamide ( G34 ).

3. Manufacturing method

Another aspect of the present invention provides a method for preparing a compound represented by Formula 1 or 2. The synthesis method is well described in the detailed examples set out herein.

In some embodiments, during organic synthesis, the use of a base may be an organic or inorganic base. Non-limiting examples of such organic bases include pyridine, trimethylamine, N,N-diisopropylethylamine (DIPEA) and 1,8-diazabicyclo[5.4.0]unde-7-ene (DBU). . Non-limiting examples of such inorganic bases include sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. They may be used alone or in combination in stoichiometric or excess. Non-limiting examples of solvents that can be used include ethers (such as tetrahydrofuran (THF), diethyl ether and 1,2-dimethoxyethane), alcohols (such as methanol, ethanol, propanol and butanol), dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), dichloromethane (DCM), dichloroethane, water, and acetone. These solvents may be used alone or in combination.

4. Compositions and Formulations

The present invention includes pharmaceutical compositions comprising a compound as described herein and a formulation suitable for administration of a compound as described herein. Formulations of pharmaceutical compositions suitable for administration by any medically acceptable means are encompassed by the present invention. The pharmaceutical formulation may contain a pharmaceutically acceptable excipient or carrier suitable for the means of administration and a pharmaceutically acceptable compound (composition).

The compounds described herein may be used as excipients (eg, one or more excipients), antioxidants (eg, one or more antioxidants), stabilizers (eg, one or more stabilizers), preservatives (eg, one or more preservatives), pH control and/or Buffers (eg, one or more pH adjusting and/or buffering agents), tonicity adjusting agents (eg, one or more tonicity adjusting agents), thickening agents (eg, one or more thickening agents), suspending agents (eg, one or more suspending agents), binders (such as , one or more binders), viscosity increasing agents (eg, one or more viscosity increasing agents), and the like, provided as additional ingredients that are pharmaceutically acceptable for the particular condition being treated. In some embodiments, the formulation may include a combination of additional ingredients as described herein (eg, 2, 3, 4, 5, 6, 7, 8 or more additional ingredients). In some embodiments, the additive is, for example, calcium phosphate, magnesium stearate, talc, monosaccharide, disaccharide, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-beta-cyclo treatment and drug delivery modifiers, enhancers, and combinations of any two or more thereof, such as dextrins, polyvinylpyrrolidone, low melting waxes, ion exchange resins, and the like.

Other suitable pharmaceutically acceptable excipients may include, without limitation, excipients commonly known in the art. Formulations of the compositions described herein may include inhalation, nasal spray, intravenous, intramuscular injection, intravitreal injection, as an ointment or solution; It may be suitable for oral administration which may consist of suspensions, semi-liquids, semi-solids, gels, semi-solid gels, jellies, emulsions, ointments, tablets, liquids and creams. Tablet forms include lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid and other excipients, colorants, fillers, binders, diluents , buffers, humectants, preservatives, flavoring agents, dyes, disintegrants and pharmaceutically suitable carriers. The capsule may contain suitable excipients with the compound or the compound may be used alone in the shell. All of these formulated compounds may be administered alone, co-administered, intermittently administered, sequentially or concurrently.

5. Administration

Compositions of the present invention include those that can be administered in any manner of oral, parenteral, sublingual, transdermal, rectal, transmucosal, topical, via inhalation, buccal or intranasal administration, or combinations thereof, not limited Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal and intraarterial. In addition, the compositions of the present invention may be administered as an implant, which allows for slow, controlled intravenous administration as well as slow release of the composition.

The dosage administered to an individual in single or multiple doses will depend on a variety of factors including pharmacokinetic characteristics, patient condition and characteristics (sex, age, weight, health, size), severity of symptoms, concurrent treatment, frequency of treatment and desired effect. so it will vary.

According to one embodiment of the present invention, the compound according to the present invention and a pharmaceutical formulation thereof may be administered alone or together with an adjuvant useful for the treatment of respiratory disorders or diseases. According to another embodiment of the present invention, the compound according to the present invention and a pharmaceutical formulation thereof may be administered together with radiation therapy.

The present invention includes the administration of a compound according to the present invention or a pharmaceutical formulation thereof, wherein the compound according to the present invention or a pharmaceutical formulation thereof is administered in a therapeutically effective amount to another therapeutic regimen or adjuvant useful for the treatment of cancer (e.g., multiple drug therapy), either simultaneously or sequentially, to the subject. The compound according to the present invention or a pharmaceutical formulation thereof administered simultaneously with the adjuvant may be administered in the same or different composition(s) and by the same or different route(s) of administration.

In one embodiment, the patient according to the present invention has bronchial asthma, bronchitis, allergic rhinitis, adult respiratory syndrome, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary viral infection (influenza), pulmonary hypertension, idiopathic pulmonary fibrosis and chronic Patients suffering from a respiratory disorder or disease such as obstructive pulmonary disease (COPD) and the like.

In another embodiment, the compound according to the present invention and a pharmaceutical formulation thereof may be administered alone or in combination with one or more other diuretics. The diuretic is furosemide, torasemide (torasemide), bumetanide (bumetanide), etacrynic acid (etacrynic acid), azosemide (azosemide), muzolimine (muzolimine), pyretanide (piretanide), Tripamide, bendroflumethazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methychlothiazide , polythiazide, trichlormethiazide, chlorthialidone, indapamide, metolazone, quinethazone, etozolin , triamteren (triamteren), amiloride (amiloride) and may be selected from the group consisting of pharmaceutically acceptable derivatives thereof, but is not limited thereto.

Preferably, the compound according to the present invention or a pharmaceutical formulation thereof is administered together with furosemide, and may be administered at an appropriate ratio in consideration of the toxicity of each drug. For example, the compound or a pharmaceutical formulation thereof and furosemide may be administered in a weight ratio of about 1:10, but is not limited thereto.

6. Use according to the invention

In another embodiment, the present invention provides the use of a compound represented by Formula 1 or 2, a mixture of compounds, or a pharmaceutical composition thereof for the prevention, improvement or treatment of a respiratory disease (inflammatory airway disease).

In another embodiment, the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof as a pendrine inhibitor.

In another embodiment, there is provided the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which preserves the volume of airway surface liquid (ASL) and reduces secretion of mucin.

In another embodiment, the present invention relates to asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury ( ALI) or chronic obstructive pulmonary disease (COPD) and the like.

In another embodiment, the present invention provides the use of a compound, a mixture of compounds, or a pharmaceutical composition thereof for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in a health functional food.

In another embodiment, the present invention provides the use of a compound represented by Formula 1 and a pharmaceutical composition thereof as a pendrine inhibitor for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in health functional foods.

In another embodiment, the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which as an active ingredient in a health functional food, a chloride channel for the prevention or improvement of respiratory diseases (inflammatory airway diseases) specifically regulated.

In another embodiment, the present invention provides the use of a compound represented by Formula 1 or 2 and a pharmaceutical composition thereof, which is an airway surface liquid for the prevention or improvement of respiratory diseases (inflammatory airway diseases) as an active ingredient in a health functional food (ASL) preserves the volume and reduces the secretion of mucin.

In another embodiment, the present invention provides a use for preventing or improving a respiratory disease (inflammatory airway disease) as an active ingredient in a health functional food, wherein the respiratory disease (inflammatory airway disease) is asthma, acute or chronic bronchitis, allergy one or more from the group consisting of rhinitis, acute respiratory infection, acute upper respiratory tract infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or chronic obstructive pulmonary disease (COPD). is chosen

Another aspect of the present invention provides the use of a compound represented by Formula 1 or Formula 2, a mixture of compounds, or a pharmaceutical composition thereof, which exhibits a diuretic effect.

In another embodiment, the present invention provides the use of a compound represented by Formula 1 or Formula 2, a mixture of compounds, or a health functional food composition thereof, which exhibits a diuretic effect as an active ingredient in a health functional food.

[Example]

Non-limiting examples of detailed experiments that are not exhaustive are described herein. The description of the present invention described herein serves as an example, and a person having general knowledge of the technology related to the present invention can easily change it to other specific areas or forms without changing the technical spirit or essential characteristics of the present invention. should understand The invention described is by way of illustration, but not limitation, of the following examples.

Names of compounds were generated by ChemDraw Professional V.15.1. The compound according to the present invention includes a compound represented by Formula 1, a tautomer thereof, a geometric isomer (eg, e, z isomer) thereof, an optically active form as an optical isomer, a diisomer and a racemic form thereof, as well as , and a pharmaceutically acceptable salt thereof. Derivatives exemplified herein can be prepared from readily available starting materials using the following general methods and procedures. Given typical or preferred experimental conditions (ie, reaction temperature, time, moles of reagent, solvent, etc.), it will be understood that other experimental conditions may be used unless otherwise stated. Optimal reaction conditions may vary with the particular reactants or solvents employed, but such conditions can be determined by one of ordinary skill in the art using routine optimization procedures.

The references cited herein are incorporated herein by reference in their entirety. The invention is not limited in scope to the specific embodiments described herein, which are intended as single examples of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Example 1: Preparation of compounds

Some synthesized compounds may exist as isomers or mixtures of isomers due to the nature of synthetic chemistry or their intrinsic physical/chemical properties. In some cases, they may be interconverted into other isomers. For example, compound 'F1' is (E)-4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5 (4H)-one, (Z )-4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one or a mixture of two isomers. This phenomenon is well documented by the study of Graziano et al (Tetrahedron 62 ( 2006 ) 1165-1170).

Example 1.1: 4- (thiophen-2-ylmethylene) -2- (4- (trifluoromethyl) phenyl) oxazol-5 (4H) -one ( F1 )

Glycine (180 mg, 2.40 mmol) and 4-(trifluoromethyl)benzoyl chloride (0.411 ml, 2.758 mmol) were sequentially added to 10% NaOH solution (24 ml) at room temperature under stirring and stirred at this temperature for 2 hours. . HCl aq. After acidification with solution to pH 2, the resulting solid was filtered through a filter funnel and the solid was washed with methylene chloride to give 2-(4-(trifluoromethyl)benzamido)acetic acid. This 2-(4-(trifluoromethyl)benzamido)acetic acid (529 mg, 2.14 mmol) and 1-ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (410 mg, 2.14 mmol) was sequentially added to methylene chloride (21 ml) at room temperature under stirring. ml). Then 1H-pyrrole-2-carbaldehyde (200 mg, 1.783 mmol) and triethylamine (0.497 ml, 3.567 mmol) were added under stirring at room temperature and stirred at this temperature for 12 hours. The solvent was evaporated under reduced pressure. The resulting solid was filtered through a filter funnel and washed with methanol to obtain the desired product (4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazole-5 (4H)- On, F1).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.22 (d, 2H, J = 8.4 Hz), 8.08 (d, 1H, J = 5.2 Hz), 7.96 (d, 2H, J = 8.4 Hz), 7.86 (d, 1H, J = 3.6 Hz), 7.79 (s, 1H), 7.24 (t, 1H, J = 4.2 Hz).

ESI (m/z) 324 (MH ⁺ ).

Example 1.2: 2-(4-(tert-butyl)phenyl)-4-(thiazol-5-yl methylene)oxazol-5(4H)-one ( F2 )

Thionyl chloride (2.038 ml, 28.05 mmol) and dimethyl formamide (10 drops) were added sequentially to 4-tert-butylbenzoic acid (500 mg, 2.81 mmol) in methylene chloride under stirring and the mixture was heated for 12 h. The solvent was evaporated to give the intermediate (0.542 ml, 2.758 mmol). Glycine (180 mg, 2.398 mmol) and this intermediate were mixed with 10% NaOH aq. It was added sequentially to the solution (24 ml) and stirred at this temperature for 2 hours. up to pH 2 aq. After acidification with HCl solution, the resulting solid was filtered through a filter funnel and washed with methylene chloride to obtain 2-(4-(tert-butyl)benzamido)acetic acid. Stir 2-(4-(tert-butyl)benzamido)acetic acid (500 mg, 2.125 mmol) and 1-ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (448 mg, 2.338 mmol) were sequentially added to methylene chloride (21 ml) in Silhorn under Thiazole-5-carbaldehyde (216 mg, 1.913 mmol) and triethylamine (0.519 ml, 3.70 mmol) were added sequentially to this mixture at room temperature under stirring, and the whole mixture was stirred for 12 hours. The solvent was removed under reduced pressure. The resulting solid was obtained through a filtration funnel and the solid was washed with methanol to obtain the desired product (2-(4-(tert-butyl)phenyl)-4-(thiazol-5-yl methylene)oxazol-5(4H) -on, F2) was provided.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.15 (d, 1H, J = 2.8 Hz), 8.10 (d, 1H, J = 2.8 Hz), 8.03 (d, 2H, J = 8.4 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.40 (s, 1H), 1.30 (s, 9H).

ESI (m/z) 313 (MH ⁺ ).

Example 1.3: 2-(4-(tert-butyl)phenyl)-4-((2-methyl-1H-indol-3-yll)methylene)oxazol-5(4H)-one ( F3 )

Thionyl chloride (2.04 ml, 28.05 mmol) and dimethyl formamide (10 drops) were sequentially added to a methylene chloride solution of 4-tert-butylbenzoic acid (500 mg, 2.81 mmol) at room temperature under stirring and the mixture was stirred for 12 h. heated. The solvent was removed under reduced pressure to give the intermediate (0.542 ml, 2.758 mmol). Glycine (180 mg, 2.398 mmol) and this intermediate were mixed with 10% NaOH aq. The solution (24 ml) was added sequentially. The whole mixture was stirred at room temperature for 2 hours. After acidification with HCl until pH 2 was reached, the resulting solid was filtered through a filter funnel and washed with methylene chloride to give 2-(4-(tert-butyl)benzamido)acetic acid. Stir 2-(4-(tert-butyl)benzamido)acetic acid (400 mg, 2.073 mmol) and 1-ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (433.54 mg, 2.262 mmol) was sequentially added to methylene chloride (20 ml) at room temperature under 2-Methyl-1H-indole-3-carboaldehyde (300 mg, 1.885 mmol) and triethylamine (0.315 ml, 2.262 mmol) were added sequentially to this mixture at room temperature under stirring and the whole mixture was stirred for 12 hours. . The solvent was removed under reduced pressure and the resulting solid was obtained by filtration through a filter funnel. The solid was washed with methanol and the desired product (2-(4-(tert-butyl)phenyl)-4-((2-methyl-1H-indol-3-yl)methylene)oxazol-5(4H)-one , F3 ) were provided.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.25 (s, 1H), 9.16 (d, 1H, J = 7.9 Hz), 7.96 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H) , J = 8.0 Hz), 7.37 (s, 2H), 7.25 - 7.18 (m, 2H), 2.62 (s, 3H), 1.30 (s, 9H).

ESI (m/z) 359 (MH ⁺ ) , 357 (MH ⁻ ).

Example 1.4: tert-Butyl 3-((2-(4-(tert-butyl)phenyl)-5-oxoxazol-4(5H)-ylden)methyl)-1H-indole-1-carboxylate (F4)

To a stirred solution of indole-5-carbaldehyde (200 mg, 1.38 mmol) in 4 mL of acetonitrile was added di-tert-butyl dicarbonate (361 mg, 1.65 mmol) followed by 4-dimethylaminopyridine (DMAP; 17 mg, 0.14 mmol) was added. The mixture was stirred for 2 h at room temperature. Water was added (20 mL) and the product was extracted with dichloromethane (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate:hexane = 1:5) to give tert-butyl 3-formyl-1H-indole-1-carboxylate (step 1).

Thionyl chloride (2.0 ml, 28.05 mmol) and dimethyl formamide (10 drops) were added sequentially to a 0.1 M methylene chloride solution of 4-tert-butyl benzoic acid (500 mg, 2.81 mmol) under stirring. The mixture was heated for 12 h and the solvent was removed under reduced pressure to give the intermediate chloride (step 2). Glycine (180 mg, 2.398 mmol) and intermediate chloride (0.542 ml, 2.758 mmol) were sequentially added to 10% NaOH solution (23.98 ml) at room temperature under reduced pressure and the mixture was stirred for 2 h. The mixture was acidified with HCl until pH 2 was reached and passed through a filter funnel to give the resulting solid. The solid was washed with methylene chloride to give 2-(4-(tert-butyl)benzamido)acetic acid (step 3). 2-(4-(tert-butyl)benzamido)acetic acid (200mg, 0.85mmol) and 1-ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (179.25mg, 0.935mmol) were stirred under stirring. It was added sequentially to methylene chloride (8.5 ml) at room temperature. tert-Butyl 3-formyl-1H-indole-1-carboxylate (208 mg, 0.085 mmol) and triethylamine (0.208 ml, 2.550 mmol) were added sequentially to this mixture at room temperature under stirring and the whole mixture was stirred at 12 stirred for hours at room temperature. The solvent was removed under reduced pressure and the resulting solid was obtained by passing it through a filter funnel. The obtained solid was washed with methanol to obtain the desired product (tert-butyl 3-((2-(4-(tert-butyl)phenyl)-5-oxoxazol-4(5H)-ylden)methyl)-1H -indole-1-carboxylate, F4 ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.84 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.99 (d, J ) = 8.4 Hz, 2H), 7.67 - 7.60 (m, 3H), 7.45 - 7.33 (m, 2H), 1.67 (s, 9H), 1.31 (s, 9H).

Example 1.5: 4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzonitrile ( F5 )

Glycine (180 mg, 2.40 mmol) and 4-cyanobenzoyl chloride (460 mg, 2.76 mmol) were sequentially added to 10% NaOH solution (24 ml) at room temperature under stirring and the mixture was stirred at this temperature for 2 h. After the mixture was acidified with HCl until pH 2 was reached, the resulting solid (2-(4-cyanobenzamido)acetic acid) was filtered through a filter funnel and washed with methylene chloride. 2- (4-cyanobenzamido)acetic acid (400 mg, 1.96 mmol) and 1-ethyl-3- (3-dimethylamino)propyl carbodiimide hydrochloride (410 mg, 2.14 mmol) were stirred at room temperature under stirring. Methylene chloride (20 ml) was added sequentially and the mixture was stirred for 12 h. Thiophene-2-carboaldehyde (200 mg, 1.783 mmol) and triethylamine (0.5 ml, 3.57 mmol) were added sequentially to this solution at room temperature under stirring and the whole mixture was stirred for 12 h. The solvent was removed under reduced pressure and the resulting solid was obtained by filtration through a filter funnel. The solid was washed with methanol to give the desired product (4-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzonitrile, F5 ) .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.18 (d, 2H, J = 8.4 Hz), 8.07 (t, 3H, J = 7.6 Hz), 7.87 (d, 1H, J = 3.6 Hz), 7.81 (s, 1H), 7.25 (t, 1H, J = 4.4 Hz).

Example 1.6: 2-(4-(tert-butyl)phenyl)-4-((1-methyl-1H-pyrrol-2-yl)methylene)oxazol-5(4H)-one ( F6 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.95 (d, 2H, J = 8.4 Hz), 7.58 (d, 3H, J = 8.0 Hz), 7.24 (s, 1H), 7.17 (s, 1H) ), 6.33 (t, 1H, J = 3.0 Hz), 3.78 (s, 3H), 1.29 (s, 9H).

ESI (m/z) 309 (MH ⁺ )

Example 1.7: Methyl 4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzoate ( F7 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.16 (q, 4H, J = 8.8 Hz), 8.08 (d, 1H, J = 5.2 Hz), 8.02 (s, 1H), 7.86 (d, 1H) , J = 3.6 Hz), 7.79 (s, 1H), 3.88 (s, 3H).

ESI (m/z) 314 (MH ⁺ )

Example 1.8 : 2-(4-(tert-butyl)phenyl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F8 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.28 (s, 1H), 7.95 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.53 (s, 1H) ), 2.59 (s, 3H), 1.29 (s, 9H).

ESI (m/z) 327 (MH ⁺ ).

Example 1.9: 2-(4-(tert-butyl)phenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F9 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.44 (d, 1H, J = 2.4 Hz), 8.01 - 7.99 (m, 3H), 7.71 - 7.69 (m, 1H), 7.59 (d, 2H, J = 8.8 Hz), 7.37 (s, 1H), 1.29 (s, 9H).

ESI (m/z) 312 (MH ⁺ ).

Example 1.10 : 4-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F10 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.53 (s, 1H), 8.08 (d, 2H, J = 8.2 Hz), 7.58 (d, 2H, J = 8.3 Hz), 7.32 (s, 1H) ), 7.19 (s, 1H), 7.06 (s, 1H), 6.34 (s, 1H), 1.29 (s, 9H).

ESI (m/z) 295 (MH ⁺ ).

Example 1.11: 4- (benzo [b] thiophen-2-ylmethylene) -2- (4- (tert-butyl) phenyl) oxazol-5 (4H) -one ( F11 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.23 (s, 1H), 8.31 (d, 1H, J = 8.0 Hz), 8.09 (d, 3H, J = 8.4 Hz), 7.64 - 7.62 (m) , 3H), 7.53 - 7.44 (m, 2H), 1.31 (s, 9H).

ESI (m/z) 362 (MH ⁺ ).

Example 1.12: 4-((1H-pyrrol-2-yl)methylene)-2-(4-isopropylphenyl)oxazol-5(4H)-one ( F12 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.52 (s, 1H), 8.08 (d, 2H, J = 8.0 Hz), 7.43 (d, 2H, J = 8.0 Hz), 7.32 (s, 1H) ), 7.19 (s, 1H), 7.05 (s, 1H), 6.34 (s, 1H), 3.01 - 2.91 (m, 1H), 1.21 (d, 6H, J = 6.8 Hz).

ESI (m/z) 281 (MH ⁺ ).

Example 1.13: 2- (4- (tert-butyl) phenyl) -4- (quinolin-4-ylmethylene) oxazol-5 (4H) -one ( F13 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.08 (d, 1H, J = 4.4 Hz), 8.64 (d, 1H, J = 4.8 Hz), 8.44 (d, 1H, J = 8.4 Hz), 8.10 - 8.07 (m, 3H), 7.95 (s, 1H), 7.83 (t, 1H, J = 7.6 Hz), 7.71 (d, 1H, J = 8.0 Hz),7.66 (d, 2H, J = 8.0 Hz) ), 1.31 (s, 9H).

ESI (m/z) 357 (MH ⁺ ).

Example 1.14: 2- (4-isobutylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F14 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.01 (d, 1H, J = 5.2 Hz), 7.96 (d, 2H, J = 7.2 Hz), 7.81 (d, 1H, J = 3.2 Hz), 7.67 (s, 1H), 7.39 (d, 2H, J = 7.2 Hz), 7.22 (t, 1H, J = 4.4 Hz), 2.53 (d, 2H, J = 6.8 Hz), 1.91 - 1.81 (m, 1H) ), 0.84 (d, 6H, J = 6.4 Hz).

ESI (m/z) 312 (MH ⁺ ).

Example 1.15: 2- (4-isobutylphenyl) -4- (thiophen-3-ylmethylene) oxazol-5 (4H) -one ( F15 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.45 (d, 1H, J = 2.4 Hz), 8.01 - 7.99 (m, 3H), 7.69 (q, 1H, J = 2.8 Hz), 7.39 (s) , 1H), 7.37 (s, 2H), 2.53 (d, 2H, J = 7.2 Hz), 1.92 - 1.81 (m, 1H), 0.85 (d, 6H, J = 6.8 Hz).

ESI (m/z) 312 (MH ⁺ ).

Example 1.16 : 4- (benzo [b] thiophen-3-ylmethylene) -2- (4-isopropylphenyl) oxazol-5 (4H) -one ( F16 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.24 (s, 1H), 8.30 (d, 1H, J = 7.6 Hz), 8.09 (m, 3H), 7.61 (s, 1H), 7.52 - 7.44 (m, 4H), 3.03 - 2.96 (m, 1H), 1.22 (d, 6H, J = 6.8 Hz).

Example 1.17: 4-((1H-pyrrol-2-yl)methylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F17 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.67 (s, 1H), 8.39 (d, 2H, J = 7.6 Hz), 7.95 (d, 2H, J = 8.0 Hz), 7.42 (s, 1H) ), 7.33 (s, 1H), 7.15 (s, 1H), 6.41 (s, 1H).

ESI (m/z) 305 (MH ^- ), 307 (MH ⁺ )

Example 1.18: 4- (thiophen-3-ylmethylene) -2- (4- (trifluoromethyl) phenyl) oxazol-5 (4H) -one ( F18 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.55 (d, 1H, J = 1.9 Hz), 8.32 (d, 2H, J = 8.1 Hz), 8.07 (d, 1H, J = 5.0 Hz), 7.98 (d, 2H, J = 8.2 Hz), 7.78 - 7.74 (m, 1H), 7.53 (s, 1H).

Example 1.19: 4-(furan-2-ylmethylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F19 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.97 (d, 2H, J = 8.0 Hz), 7.55 (d, 1H, J = 3.6 Hz), 7.36 (d, 2H) , J = 8.0 Hz), 7.14 (s, 1H), 6.79 (d, 1H, J = 2.0 Hz), 2.52 (d, 2H, J = 6.4 Hz), 1.90 - 1.80 (m, 1H), 0.84 (d) , 6H, J = 6.4 Hz)

Example 1.20: 4-((1H-pyrrol-2-yl)methylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F20 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.51 (s, 1H), 8.06 (d, 2H, J = 8.0 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.31 (s, 1H) ), 7.18 (s, 1H), 7.04 (s, 1H), 6.33 (s, 1H), 2.51 (d, 2H, J = 6.8 Hz), 1.90 - 1.80 (m, 1H), 0.84 (d, 6H, J = 6.4 Hz).

Example 1.21: 4- (benzo [b] thiophen-3-ylmethylene) -2- (4-isobutylphenyl) oxazol-5 (4H) -one ( F21 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.24 (s, 1H), 8.29 (d, 1H, J = 8.0 Hz), 8.08 (d, 3H, J = 8.0 Hz), 7.60 (s, 1H) ), 7.52 - 7.43 (m, 2H), 7.39 (d, 2H, J = 7.6 Hz), 2.54 (d, 2H, J = 6.8 Hz), 1.89 - 1.84 (m, 1H), 0.85 (d, 6H, J = 6.4 Hz).

Example 1.22: 2- (4-bromophenyl) -4- ((4-methylthiazol-5-yl) methylene) oxazol-5 (4H) -one ( F22 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 7.96 (d, 2H, J = 8.4 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.63 (s, 1H) ), 2.62 (s, 3H).

ESI (m/z) 350 (MH ⁺ ).

Example 1.23: 2-cyclohexyl-4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F23 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.96 (d, 1H, J = 5.2 Hz), 7.74 (d, 1H, J = 3.6 Hz), 7.57 (s, 1H), 7.18 (t, 1H) , J = 4.2 Hz), 2.71 - 2.66 (m, 1H), 1.96 - 1.93 (m, 2H), 1.74 - 1.71 (m, 2H), 1.61 - 1.58 (m, 1H), 1.53 - 1.44 (m, 2H) ), 1.38 - 1.18 (m, 3H).

ESI (m/z) 262 (MH ⁺ ).

Example 1.24: 2-([1,1'-biphenyl]-4-yl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F24 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 8.12 (d, 2H, J = 8.4 Hz), 7.93 (d, 2H, J = 8.0 Hz), 7.77 (d, 2H) , J = 7.6 Hz), 7.61 (s, 1H), 7.50 (t, 2H, J = 7.4 Hz), 7.43 (t, 1H, J = 7.4 Hz), 2.63 (s, 3H).

Example 1.25: 4-((1H-pyrrol-2-yl)methylene)-2-([1,1'-biphenyl]-4-ylmethyl)oxazol-5(4H)-one ( F25 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.44 (s, 1H), 7.63 (d, 4H, J = 8.0 Hz), 7.44 - 7.41 (m, 4H), 7.34 - 7.31 (m, 1H) , 7.25 (s, 1H), 7.13 (s, 1H), 7.02 (s, 1H), 6.30 (s, 1H), 4.05 (s, 2H).

ESI (m/z) 329 (MH ⁺ ), 327 (MH ⁻ ).

Example 1.26: 4-((1H-pyrrol-2-yl)methylene)-2-(4-butylphenyl)oxazol-5(4H)-one ( F26 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.56 (s, 1H), 8.11 (d, 2H, J = 7.9 Hz), 7.43 (d, 2H, J = 8.0 Hz), 7.35 (s, 1H) ), 7.22 (s, 1H), 7.08 (s, 1H), 6.37 (s, 1H), 2.69 (t, 2H, J = 7.6 Hz), 1.65 - 1.55 (m, 2H), 1.38 - 1.27 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz).

Example 1.27: 2-(4-(tert-butyl)phenyl)-4-((1-phenyl-1H-pyrrol-2-yl)methylene)oxazol-5(4H)-one ( F27 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.98 (d, 2H, J = 8.4 Hz), 7.77 (d, 1H, J = 3.9 Hz), 7.62 - 7.57 (m, 4H), 7.55 - 7.51 (m, 1H), 7.50 - 7.48 (m, 1H), 7.45 (d, 2H, J = 7.5 Hz), 6.74 (s, 1H), 6.58 (t, 1H, J = 3.4 Hz), 1.30 (s, 9H).

Example 1.28: 2-([1,1'-biphenyl]-4-ylmethyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F28 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.98 (d, 1H, J = 4.8 Hz), 7.76 (d, 1H, J = 3.6 Hz), 7.65 (s, 2H), 7.63 (s, 3H) ), 7.46 - 7.41 (m, 4H), 7.33 (t, 1H, J = 7.2 Hz), 7.19 (t, 1H, J = 4.4 Hz), 4.10 (s, 2H).

Example 1.29: 2- (2,3-dihydro-1H-inden-5-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F29 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.01 (d, 1H, J = 5.2 Hz), 7.89 (s, 1H), 7.83 (d, 1H, J = 7.6 Hz), 7.80 (d, 1H) , J = 3.6 Hz), 7.65 (s, 1H), 7.43 (d, 1H, J = 8.0 Hz), 7.23 - 7.21 (m, 1H), 2.93 (t, 4H, J = 7.3 Hz), 2.08 - 2.00 (m, 2H).

ESI (m/z) 296 (MH ⁺ ).

Example 1.30: 4-((1H-pyrrol-2-yl)methylene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F30 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.62 (s, 1H), 9.31 (d, 1H, J = 8.0 Hz), 8.29 (d, 1H, J = 7.2 Hz), 8.20 (d, 1H) , J = 8.4 Hz), 8.06 (d, 1H, J = 8.0 Hz), 7.76 (t, 1H, J = 7.6 Hz), 7.65 (q, 2H, J = 8.4 Hz), 7.36 (s, 1H), 7.28 (s, 2H), 6.43 (t, 1H, J = 2.8 Hz).

ESI (m/z) 289 (MH ⁺ ).

Example 1.31: Methyl 4-(4-(furan-2-ylmethylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzoate ( F31 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.21 (s, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 8.11 - 8.10 (m, 2H), 7.60 (d, 1H, J = 3.2 Hz), 7.27 (s, 1H), 6.84 - 6.82 (m, 1H), 3.87 (s, 3H).

Example 1.32: Methyl 4- (5-oxo-4- (thiophen-3-ylmethylene) -4,5-dihydrooxazol-2-yl) benzoate ( F32 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.47 (s, 1H), 8.16 - 8.00 (m, 5H), 7.70 (s, 1H), 7.44 (s, 1H), 3.85 (s, 3H) .

Example 1.33: N- (4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl) acetamide ( F33 )

Example 1.34: 2- (2-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F34 )

Example 1.35: N- (tert-butyl) -4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzene sulfonamide ( F35 )

Example 1.36: N-isopropyl-4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzene sulfonamide ( F36 )

Example 1.37: 2-([1,1'-biphenyl]-4-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F37 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.23 (d, 2H, J = 8.3 Hz), 7.79 - 7.71 (m, 3H), 7.69 - 7.61 (m, 3H), 7.53 - 7.46 (m, 3H), 7.45 - 7.38 (m, 1H), 7.17 (t, 1H).

ESI (m/z) 332 (MH ⁺ ).

Example 1.38: 2- (4- (tert-butyl) phenyl) -4- (furan-2-ylmethylene) oxazol-5 (4H) -one ( F38 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.05 (s, 1H), 7.99 (d, 2H, J = 8.4 Hz), 7.60 (d, 2H, J = 8.4 Hz), 7.55 (d, 1H) , J = 3.2 Hz), 7.15 (s, 1H), 6.81 (br s, 1H), 1.29 (s, 9H).

ESI (m/z) 296 (MH ⁺ ).

Example 1.39: 2-(4-(tert-butyl)phenyl)-4-((1-methyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F39 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.52 (s, 1H), 8.18 (s, 1H), 8.05 (d, 2H, J = 8.5 Hz), 7.63 (d, 2H, J = 8.5 Hz) ), 7.35 (s, 1H), 3.96 (s, 3H), 1.34 (s, 9H).

ESI (m/z) 310 (MH ⁺ ).

Example 1.40: 2- (4- (tert-butyl) phenyl) -4- (pyridin-3-ylmethylene) oxazol-5 (4H) -one ( F40 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.28 (d, 1H, J = 1.9 Hz), 8.78 (dt, 1H, J = 8.1, 1.7 Hz), 8.65 (dd, 1H, J = 4.8, 1.6 Hz), 8.09 (d, 2H), 7.68 (d, 2H, J = 8.6 Hz), 7.61 - 7.56 (m, 1H), 7.40 (s, 1H), 1.34 (s, 9H).

ESI (m/z) 307 (MH ⁺ ).

Example 1.41: 2- (4- (tert-butyl) phenyl) -4- (pyridin-4-ylmethylene) oxazol-5 (4H) -one ( F41 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.71 (d, 2H, J = 5.2 Hz), 8.13 (d, 2H, J = 5.5 Hz), 8.07 (d, 2H), 7.66 (d, 2H) , J = 8.3 Hz), 7.27 (s, 1H), 1.31 (s, 9H).

ESI (m/z) 307 (MH ⁺ ).

Example 1.42: 2-([1,1'-biphenyl]-4-yl)-4-(pyridin-3-ylmethylene)oxazol-5(4H)-one ( F42 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.25 (s, 1H), 8.78 (d, 1H, J = 7.8 Hz), 8.63 (s, 1H), 8.19 (d, 2H, J = 7.8 Hz) ), 7.92 (d, 2H, J = 7.9 Hz), 7.77 (d, 2H, J = 7.1 Hz), 7.61 - 7.54 (m, 1H), 7.50 (t, 2H, J = 6.9 Hz), 7.47 - 7.36 (m, 2H).

ESI (m/z) 327 (MH ⁺ ).

Example 1.43: 2- (4- (tert-butyl) phenyl) -4- (4- (methylthio) benzylidene) oxazol-5 (4H) -one ( F43 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.20 (br s, 2H), 8.00 (br s, 2H), 7.63 (br s, 2H), 7.37 (s, 2H), 7.27 (s, 1H) ), 2.53 (s, 3H), 1.31 (s, 9H).

ESI (m/z) 352 (MH ⁺ ).

Example 1.44: 4-benzylidene-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F44 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.26 (d, 2H, J = 6.8 Hz), 8.00 (d, 2H, J = 8.4 Hz), 7.61 (d, 2H, J = 8.0 Hz), 7.52 - 7.45 (m, 3H), 7.28 (s, 1H), 1.29 (s, 9H).

ESI (m/z) 306 (MH ⁺ ).

Example 1.45: 2- (4-bromophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F45 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.05 (s, 1H), 7.95 (d, 2H, J = 7.6 Hz), 7.83 (s, 2H), 7.81 (s, 1H), 7.73 (s) , 1H), 7.23 (s, 1H).

Example 1.46: 2- (4-isopropylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F46 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.02 (d, 1H, J = 5.2 Hz), 7.97 (d, 2H, J = 8.0 Hz), 7.81 (d, 1H, J = 3.6 Hz), 7.67 (s, 1H), 7.48 (d, 2H, J = 8.4 Hz), 7.22 (t, 1H, J = 4.4 Hz), 3.02 - 2.92 (m, 1H), 1.21 (d, 6H, J = 6.8 Hz) ).

ESI (m/z) 298 (MH ⁺ ).

Example 1.47: 2- (4-isopropylphenyl) -4- (thiophen-3-ylmethylene) oxazol-5 (4H) -one ( F47 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (d, 1H, J = 2.8 Hz), 8.02 - 8.00 (m, 3H), 7.70 (q, 1H, J = 2.8 Hz), 7.47 (d, 2H, J = 7.2 Hz), 7.38 (s, 1H), 3.03 - 2.93 (m, 1H), 1.21 (d, 6H, J = 6.8 Hz).

ESI (m/z) 298 (MH ⁺ ).

Example 1.48: 4- (furan-2-ylmethylene) -2- (4- (triple furomethyl) phenyl) oxazol-5 (4H) -one ( F48 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.25 (d, 2H, J = 8.2 Hz), 8.10 (s, 1H), 7.94 (d, 2H, J = 8.3 Hz), 7.60 (d, 1H) , J = 3.5 Hz), 7.28 (s, 1H), 6.83 - 6.81 (m, 1H).

Example 1.49: 4- (furan-2-ylmethylene) -2- (4-isopropylphenyl) oxazol-5 (4H) -one ( F49 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.04 (s, 1H), 7.97 (d, 2H, J = 8.1 Hz), 7.54 (d, 1H, J = 3.3 Hz), 7.44 (d, 2H) , J = 8.1 Hz), 7.13 (s, 1H), 6.83 - 6.76 (m, 1H), 3.01 - 2.88 (m, 1H), 1.19 (d, 6H, J = 6.9 Hz).

Example 1.50 : 2- (4-bromophenyl) -4- (furan-2-ylmethylene) oxazol-5 (4H) -one ( F50 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.11 (s, 1H), 8.07 - 7.98 (m, 2H), 7.88 - 7.77 (m, 2H), 7.62 (s, 1H), 7.25 (s, 1H), 6.85 (s, 1H).

Example 1.51: 2- (4-bromophenyl) -4- (thiophen-3-ylmethylene) oxazol-5 (4H) -one ( F51 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.47 (d, 1H, J = 1.6 Hz), 8.01 - 7.99 (m, 3H), 7.80 (s, 1H), 7.78 (s, 1H), 7.70 - 7.68 (m, 1H), 7.43 (s, 1H).

Example 1.52 : 2- (naphthalen-2-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F52 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.70 (s, 1H), 8.52 (d, 1H, J = 2.4 Hz), 8.21 - 8.17 (m, 2H), 8.12 (s, 1H), 8.09 (t, 1H, J = 4.8 Hz), 8.02 (d, 1H, J = 8.0 Hz), 7.74 - 7.72 (m, 1H), 7.69 - 7.61 (m, 2H), 7.44 (s, 1H).

ESI (m/z) 306 (MH ⁺ ).

Example 1.53: 2- (4-butylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F53 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.02 (d, 1H, J = 5.0 Hz), 7.96 (d, 2H, J = 8.2 Hz), 7.81 (d, 1H, J = 3.6 Hz), 7.67 (s, 1H), 7.42 (d, 2H, J = 8.2 Hz), 7.25 - 7.20 (m, 1H), 2.66 (t, 2H, J = 7.7 Hz), 1.61 - 1.51 (m, 2H), 1.37 - 1.22 (m, 2H), 0.87 (t, 3H, J = 7.3 Hz).

Example 1.54 : 2- (4-butylphenyl) -4- (furan-2-ylmethylene) oxazol-5 (4H) -one ( F54 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.09 (d, 1H, J = 1.5 Hz), 8.02 (d, 2H, J = 8.2 Hz), 7.60 (d, 1H, J = 3.5 Hz), 7.45 (d, 2H, J = 8.2 Hz), 7.19 (s, 1H), 6.86 - 6.83 (m, 1H), 2.69 (t, 2H, J = 7.7 Hz), 1.66 - 1.54 (m, 2H), 1.39 - 1.27 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz).

Example 1.55 : 2- (4- (difluoromethoxy) phenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F55 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.10 (d, 2H, J = 8.8 Hz), 8.03 (d, 1H, J = 5.2 Hz), 7.82 (d, 1H, J = 3.6 Hz), 7.69 (s, 1H), 7.41 (s, 1H), 7.38 (d, 2H, J = 8.8 Hz), 7.24 - 7.22 (m, 1H).

Example 1.56 : 2-(4-(tert-butyl)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F56 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.02 (d, 1H, J = 5.2 Hz), 7.96 (d, 2H, J = 7.6 Hz), 7.80 (d, 1H, J = 3.6 Hz), 7.66 (s, 1H), 7.61 (d, 2H, J = 7.6 Hz), 7.22 (t, 1H, J = 4.0 Hz), 1.30 (s, 9H).

¹³ C NMR (400 MHz, DMSO-d6) δ 166.7, 162.1, 157.2, 137.6, 136.9, 136.6, 130.7, 129.6, 129.1, 129.1, 126.4, 126.4, 124.9, 122.8, 35.46, 31.2, 31.2, 31.2.

Example 1.57: 4- (2-nitrobenzylidene) -2-phenyloxazol-5 (4H) -one ( F57 )

Example 1.58: 4-((2-(4-(tert-butyl)phenyl)-5-oxooxazol-4(5H)-ylden)methyl)phenylacetate ( F58 )

Example 1.59: 2- (3-chlorobenzo [b] thiophen-2-yl) -4- (4- (dimethylamino) benzylidene) oxazol-5 (4H) -one ( F59 )

Example 1.60: 4-((2-(4-methoxyphenyl)-5-oxooxazol-4(5H)-ylden)methyl)benzoic acid ( F60 )

Example 1.61: 2-phenyl-4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F61 )

Example 1.62: 4- (4-isopropylbenzylidene) -2- (naphthalen-1-yl) oxazol-5 (4H) -one ( F62 )

Example 1.63: 2- (3-iodo-4-methylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F63 )

Example 1.64: 4-(4-(benzyloxy)benzylidene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F64 )

Example 1.65: 4-((1-(2-chlorobenzyl)-1H-pyrrol-2-yl)methylene)-2-phenyloxazol-5(4H)-one ( F65 )

Example 1.66: N-(4-(4-(2-(allyloxy)-4-(diethylamino)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl )-5-bromonicothiamide ( F66 )

Example 1.67: 4-((2-(2-chlorophenyl)-5-oxooxazol-4(5H)-ylden)methyl)phenyl4-(tert-butyl)benzoate ( F67 )

Example 1.68: 4-((Z)-1-(3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-ylden)butan-2-ylden)-2-phenyl Oxazol-5(4H)-one ( F68 )

Example 1.69: 4-((2-(4-acetamidophenyl)-5-oxoxazol-4(5H)-ylden)methyl)-2-ethoxyphenylthiophene-2-carboxylate ( F69 )

Example 1.70: 4-((6-ethoxy-2-(phenylthio)quinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F70 )

Example 1.71: 2- (3-bromophenyl) -4- ((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl) methylene) oxazol-5 (4H) -one ( F71 )

Example 1.72: 4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-bromophenyl)oxazol-5(4H)-one ( F72 )

Example 1.73: 2-(4-(tert-butyl)phenyl)-4-((5-(3-(trifluoromethyl)phenyl)furan-2-yl)methylene)oxazole-5(4H)- On ( F73 )

Example 1.74 : 4-((7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F74 )

Example 1.75: 2- (4-methoxyphenyl) -4- (2- (thiophen-2-yl) -4H-chromen-4-ylden) oxazol-5 (4H) -one ( F75 )

Example 1.76: N,N-dimethyl-3-((5-oxo-2-(p-tolyl)oxazol-4(5H)-ylden)methyl)-1H-indole-1-sulfonamide ( F76 )

Example 1.77: 2-((2-(4-chlorophenyl)-5-oxooxazol-4(5H)-ylden)methyl)phenyl4-acetamidobenzenesulfonate ( F77 )

Example 1.78: 4-((5-oxo-2-phenyloxazol-4(5H)-ylden)methyl)phenylfuran-2-carboxylate ( F78 )

Example 1.79: 2,2'-(1,4-phenylene)bis(4-((5-methylfuran-2-yl)methylene)oxazol-5(4H)-one) ( F79 )

Example 1.80: 2-((2-(4-(tert-butyl)phenyl)-5-oxoxazol-4(5H)-ylden)methyl)phenylbenzenesulfonate ( F80 )

Example 1.81: 4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F81 )

Example 1.82: 4-((1-acetyl-3-phenyl-1H-pyrazol-4-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F82 )

Example 1.83: 4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-2-(p-tolyl)oxazol-5(4H)-one ( F83 )

Example 1.84: 4-((6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F84 )

Example 1.85: 4- (2,6-diphenyl-4H-thiopyran-4-ylden) -2-phenyloxazol-5 (4H) -one ( F85 )

Example 1.86: N-(4-(4-(4-((2-chloroethyl)(methyl)amino)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl ) acetamide ( F86 )

Example 1.87: 2- (4-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F87 )

Example 1.88: 2- (4-chlorophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F88 )

Example 1.89: 2- (thiophen-2-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F89 )

Example 1.90: 4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl acetate ( F90 )

Example 1.91: 2- (4-chloro-3-nitrophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F91 )

Example 1.92: 2- (2-chlorophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F92 )

Example 1.93: 2- (2-chloro-4-nitrophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F93 )

Example 1.94: 4- (thiophen-2-ylmethylene) -2- (3,4,5-trimethoxyphenyl) oxazol-5 (4H) -one ( F94 )

Example 1.95: 2- (4-phenoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F95 )

Example 1.96: 2-(4-(tert-butyl)phenyl)-4-((5-methylthiophen-2-yl)methylene)oxazol-5(4H)-one ( F96 )

Example 1.97: 2- (benzo [d] [1,3] dioxoyl-5-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F97 )

Example 1.98: 2-(4-(2-oxopyrrolidin-1-yl)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F98 )

Example 1.99: 4-((5-chlorothiophen-2-yl)methylene)-2-(4-methoxyphenyl)oxazol-5(4H)-one ( F99 )

Example 1.100: 2-(benzo[d][1,3]dioxoyl-5-yl)-4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)oxa Zol-5(4H)-one ( F100 )

Example 1.101: 2- (3,4-diethoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F101 )

Example 1.102: 2-(4-(difluoromethoxy)-3-methoxyphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F102 )

Example 1.103: 2- (5-ethyl-4-methylthiophen-2-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F103 )

Example 1.104: 2- (3-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F104 )

Example 1.105: 4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F105 )

Example 1.106: N-(4-(4-((4-bromothiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F106 )

Example 1.107: N-(4-(4-((5-bromothiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F107 )

Example 1.108: N-(4-(4-((5-(dimethylamino)thiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acet Amide ( F108 )

Example 1.109: 2-(4-(benzyloxy)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F109 )

Example 1.110: 2-((E)-styryl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F110 )

Example 1.111: 2- (5-methylthiophen-2-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F111 )

Example 1.112: N,N-diethyl-3-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzene sulfonamide ( F112 )

Example 1.113: 2- (2-methoxyphenyl) -4- ((2,4,5-trimethylthieno [2,3-d] pyrimidin-6-yl) methylene) oxazole-5 (4H) -On ( F113 )

Example 1.114: 4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F114 )

Example 1.115: 4-((5-methylthiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F115 )

Example 1.116: N,N-dimethyl-3-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F116 )

Example 1.117: 4-((5-bromothiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F117 )

Example 1.118: 4-((5-bromothiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F118 )

Example 1.119: 2- (5-methylthiophen-2-yl) -4- ((5-methylthiophen-2-yl) methylene) oxazol-5 (4H) -one ( F119 )

Example 1.120: 4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F120 )

Example 1.121: 4-((5-bromothiophen-2-yl)methylene)-2-(2-(difluoromethoxy)phenyl)oxazol-5(4H)-one ( F121 )

Example 1.122: 2- (4- (tert-butyl) phenyl) -4- (2- (difluoromethoxy) benzylidene) oxazol-5 (4H) -one ( F122 )

Example 1.123: 4-((1-(2-chlorobenzyl)-1H-pyrazol-4-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F123 )

Example 1.124: 2-(4-(tert-butyl)phenyl)-4-((1-phenyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F124 )

Example 1.125: 2-(2-methoxyphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F125 )

Example 1.126: N-(tert-butyl)-4-(4-((5-methylfuran-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfone Amide ( F126 )

Example 1.127: N,N-diethyl-4-(4-(1-methylpyridin-2(1H)-ylden)-5-oxo-4,5-dihydrooxazol-2-yl)benzene sulfonamide ( F127 ),

Example 1.128: 2-(4-((2-(2-methoxyphenyl)-5-oxoxazol-4(5H)-ylden)methyl)phenoxy)acetamide ( F128 )

Example 1.129: N-(4-((2-(4-isopropoxyphenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl)acetamide ( F129 )

Example 1.130: 4-((1-benzyl-1H-pyrazol-4-yl)methylene)-2-(4-isopropoxyphenyl)oxazol-5(4H)-one ( F130 )

Example 1.131: N,N-diethyl-3-(4-((1-methyl-1H-pyrazol-4-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl ) Benzenesulfonamide ( F131 )

Example 1.132: 4-(4-(1H-1,2,4-thiazol-1-yl)benzylidene)-2-(2-iodophenyl)oxazol-5(4H)-one ( F132 )

Example 1.133: 4-(4-((3,5-dimethylisoxazol-4-yl)methoxy)-3-methoxybenzylidene)-2-(2-methoxyphenyl)oxazole-5 (4H)-on ( F133 )

Example 1.134: N-(4-(4-(4-(1H-1,2,4-thiazol-1-yl)benzylidene)-5-oxo-4,5-dihydrooxazole-2 -yl)phenyl)acetamide ( F134 )

Example 1.135: 2-(2-(difluoromethoxy)phenyl)-4-((E)-3-(furan-2-yl)allylidene)oxazol-5(4H)-one ( F135 )

Example 1.136: 4-((1-(tert-butyl)-1H-pyrazol-4-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F136 )

Example 1.137 : Methyl 2- (5-oxo-1-phenyl-4- (thiophen-2-ylmethylene) -4,5-dihydro-1H-pyrazol-3-yl) acetate ( F137 )

.

Example 1.138 : 3- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoic acid ( F138 )

.

.

Example 1.139 : 3- (4-chlorophenyl) -5- ((5-methylthiophen-2-yl) methylene) thiazolidine-2,4-dione ( F139 )

.

.

Example 1.140 : 2- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) -N- (p-tolyl) acetamide ( F140 )

.

.

Example 1.141 : 3-(4-ethoxyphenyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F141 )

.

.

Example 1.142 : 3-((diethylamino)methyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F142 )

.

.

Example 1.143 : 3-(3-nitrobenzyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F143 )

.

.

Example 1.144 : 3-phenyl-5- (thiophen-2-ylmethylene) thiazolidine-2,4-dione ( F144 )

.

.

Example 1.145 : Methyl 2- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoate ( F145 )

.

.

Example 1.146 : 2- (4- ((3- (3-chlorophenyl) -4-oxo-2-thioxothiazolidin-5-ylidene) methyl) phenoxy) acetic acid ( F146 )

.

.

Example 1.147 : 2-(3-((Z)-((Z)-2-((4-ethoxyphenyl)imino)-3-methyl-4-oxothiazolidin-5-ylidene)methyl )-1H-indol-1-yl)acetic acid ( F147 )

.

.

Example 1.148 : 5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-3-phenyl-2-thioxothiazolidin-4-one ( F148 )

.

.

Example 1.149 : 3-benzyl-5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F149 )

.

.

Example 1.150 : 3-methyl-1- (4-nitrophenyl) -4- (thiophen-2-ylmethylene) -1H-pyrazol-5 (4H) -one ( F150 )

.

.

Example 1.151 : 4-(3-methyl-4-((5-methylthiophen-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfone Amide ( F151 )

.

.

Example 1.152 : 3-methyl-4-((5-methylthiophen-2-yl)methylene)-1-(naphthalen-2-yl)-1H-pyrazol-5(4H)-one ( F152 )

.

.

Example 1.153 : 3-(3-methyl-4-((5-(4-methyl-2-nitrophenyl)furan-2-yl)methylene)-5-oxo-4,5-dihydro-1H- Pyrazol-1-yl)benzoic acid ( F153 )

.

.

Example 1.154 : ethyl 4-methyl-2- (3-methyl-5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydro-1H-pyrazol-1-yl) thiazole -5-carboxylate ( F154 )

.

.

Example 1.155 : 3-methyl-1-phenyl-4-(thiophen-2-ylmethylene)-1H-pyrazol-5(4H)-one ( F155 )

.

Example 1.156 : 2,6-bis ((5-bromothiophen-2-yl) methylene) cyclohexanone ( F156 )

.

Example 1.157 : 2- (4- (dimethylamino) benzylidene) -6- (thiophen-2-ylmethylene) cyclohexanone ( F157 )

.

Example 1.158 : 2,6-bis (thiophen-2-ylmethylene) cyclohexanone ( F158 )

.

.

Example 1.159 : 4-((5-(2-methoxy-4-nitrophenyl)furan-2-yl)methylene)-3-phenylisoxazol-5(4H)-one ( F159 )

.

.

Example 1.160 : 2-chloro-5- (5- ((2- (3-chloro-4-methylphenyl) hydrazinylidene) methyl) furan-2-yl) benzoic acid ( F160 )

.

.

Example 1.161 : 5- (2- (2- (4- (tert-butyl) phenoxy) ethoxy) benzylidene) -2-thioxothiazolidin-4-one ( F161 )

.

.

Example 1.162 : 5- (4- (2- (4- (tert-butyl) phenoxy) ethoxy) benzylidene) -2-thioxothiazolidin-4-one ( F162 )

.

.

Example 1.163 : 6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-5-imino-2-propyl-5H-[1,3 ,4]thiadiazolo[3,2-a]pyrimidin-7(6H)-one ( F163 )

.

.

Example 1.164 4-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-1-(cyclohexane-1,3-dien-1-yl ) pyrazolidine-3,5-dione ( F164 )

.

.

Example 1.165 : 6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-2-ethyl-5-imino-5H-[1,3 ,4]thiadiazolo[3,2-a]pyrimidin-7(6H)-one ( F165 )

.

.

Example 1.166 : 5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)pyrimidine-2,4,6(1H, 3H, 5H)-trione ( F166 )

.

.

Example 1.167 : 5-((5-ethyl-3-(4-methoxybenzoyl)thiophen-2-yl)amino)-3,3-dimethyl-5-oxopentanoic acid ( F167 )

.

.

Example 1.168 : 2-((1,7-dibenzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)acetic acid ( F168 )

.

Example 1.169 : 4-((E)-3-phenylallylidene)-3-(p-tolyl)isoxazol-5(4H)-one ( F169 )

.

Example 1.170 : 4- (2- (allyloxy) benzylidene) -3- (4-nitrophenyl) isoxazol-5 (4H) -one ( F170 )

.

Example 1.171 : 4-((4-methylthiazol-5-yl)methylene)-2-(4-propylphenyl)oxazol-5(4H)-one ( F171 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 9.94 (d, 2H, J = 8.0 Hz), 7.53 (s, 1H), 7.41 (d, 2H, J = 8.0 Hz) , 2.63 (t, 2H, J = 7.6 Hz), 2.59 (s, 3H), 1.64 - 1.55 (m, 2H), 0.87 (t, 3H, J = 7.2 Hz).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.1, 12.6, 160.62, 159. 76, 149.2, 132.0, 129.9, 129.3, 126.5, 123.0, 121.3, 37.7, 24.1, 16.2, 14.0

Example 1.172 : 4-((1H-pyrrol-2-yl)methylene)-2-(4-butoxyphenyl)oxazol-5(4H)-one ( F172 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.50 (s, 1H), 8.08 (d, 2H, J = 8.4 Hz), 7.29 (s, 1H), 7.13 (s, 1H), 7.07 (d, 2H, J = 8.4 Hz), 7.00 (s, 1H), 6.31 (s, 1H), 4.03 (t, 2H, J = 6.0 Hz), 1.70 - 1.67 (m, 2H), 1.45 - 1.36 (m, 2H) ), 0.91 (t, 3H, J = 5.2 Hz).

Example 1.173 : 2- (4-hexylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F173 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (d, 1H, J = 3.6 Hz), 7.95 (d, 2H, J = 8.0 Hz), 7.80 (br s, 1H), 7.66 (s, 1H) ), 7.41 (d, 2H, J = 8.0 Hz), 7.22 (br s, 1H), 2.64 (t, 2H, J = 7.2 Hz), 1.56 (br s 2H), 1.24 (s, 6H), 0.81 ( br s, 3H).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.7, 162.2, 149.2, 137.6, 136.9, 136.6, 130.7, 129.7, 128.6, 128.2, 124.8, 123.0, 35.7, 31.5, 30.9, 28.7, 22.5, 14.4

Example 1.174 : 4-((1H-indol-2-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F174 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.27 (s, 1H), 8.18 (d, 2H, J = 8.0 Hz), 7.63 (t, 4H, J = 7.4 Hz), 7.35 (d, 2H, J = 8.8 Hz), 7.25 (t, 1H, J = 7.4 Hz), 7.05 (t, 1H, J = 7.6 Hz), 1.30 (s, 9H).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.9, 161.9, 157.1, 139.7, 133.2, 130.8, 128.5, 128.2, 126.5, 125.6, 122.9, 122.1, 121.0, 120.8, 113.4, 113.0, 35.3, 31.2

Example 1.175 : 4- (furan-2-ylmethylene) -2- (4-pentylphenyl) oxazol-5 (4H) -one ( F175 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (s, 1H), 7.97 (d, 2H, J = 7.6 Hz), 7.56 - 7.55 (m, 1H), 7.40 (d, 2H, J = 7.6) Hz), 7.15 (s, 1H), 6.80 (br s, 1H), 2.64 (t, 2H, J = 7.4 Hz), 1.59 - 1.57 (m, 2H), 1.26 (br s, 4H), 0.82 (t) , 3H, J = 6.2 Hz).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 167.0, 162.8, 150.4, 149.3, 148.3, 130.5, 129.7, 128.4, 123.0, 120.8, 117.4, 114.6, 35.6, 31.3, 30.7, 22.3, 14.3

Example 1.176 : 2- (4-butoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F176 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 - 7.96 (m, 3H), 7.78 (d, 1H, J = 3.2 Hz), 7.60 (s, 1H), 7.21 (t, 1H, J = 4.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 4.05 (t, 2H, J = 6.4 Hz), 1.73 - 1.66 (m, 2H), 1.46 - 1.37 (m, 2H), 0.91 (t, 3H) , J = 7.2 Hz).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.8, 163.4, 162.0, 137.7, 136.5, 136.1, 130.9, 130.3, 129.5, 123.8, 117.4, 115.8, 69.2, 31.0, 19.1, 14.1.

Example 1.177 : 5-((1H-pyrrol-2-yl)methylene)-2-(4-(tert-butyl)phenyl)-3,5-dihydro-4H-imidazol-4-one ( F177 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (s, 1H). 11.38 (s, 1H), 8.14 (d, 2H, J = 7.6 Hz), 7.52 (d, 2H, J = 8.0 Hz), 7.20 (s, 1H), 6.90 (s, 1H), 6.85 (br s, 1H), 6.24 (s, 1H), 1.28 (s, 9H).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 171.5, 157.0, 155.1, 135.3, 129.0, 127.5, 126.5, 126.0, 125.9, 118.9, 116.2, 111.2, 35.2, 31.3

Example 2.1 : Methyl 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G1 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.56 (s, 1H), 9.73 (s, 1H), 7.94 (d, 2H, J = 8.1 Hz), 7.50 (d, 2H, J = 8.1 Hz) ), 7.45 (s, 1H), 6.97 (s, 1H), 6.54 - 6.47 (m, 1H), 6.12 (s, 1H), 3.64 (s, 3H), 1.29 (s, 9H).

Example 2.2 : Methyl 2-(4-(tert-butyl)benzamido)-3-(thiophen-2-yl)acrylate ( G2 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.77 (s, 1H), 7.95 (d, 2H, J = 8.3 Hz), 7.88 (s, 1H), 7.70 (d, 1H, J = 5.0 Hz) ), 7.57 - 7.50 (m, 3H), 7.12 - 7.09 (m, 1H), 3.69 (s, 3H), 1.29 (s, 9H).

Example 2.3: 2-(4-(tert-butyl)benzamido)-3-(thiophen-2-yl)acrylate ( G3 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.62 (s, 1H), 9.64 (s, 1H), 7.93 (d, 2H, J = 8.3 Hz), 7.83 (s, 1H), 7.66 (d) , 1H, J = 5.0 Hz), 7.54 - 7.49 (m, 3H), 7.09 (t, 1H, J = 4.0 Hz), 1.29 (s, 9H).

ESI (m/z) 352 (MNa ⁺ ), 328 (MH ⁻ ).

Example 2.4: Methyl 2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylate ( G4 ).

2-(4-(tert-butyl)phenyl)-4-(furan-2-ylmethylene)oxazol-5(4H)-one ( F38 ) (300 mg, 1.02 mmol) was stirred with MeOH (10 ml) was added to When the suspension became a clear solution, triethylamine (0.425 ml, 3.05 mmol) was added to the mixture and stirred for 1 h. After the reaction was complete (TLC), the solvent was removed under reduced pressure. Passed through a filter funnel and recrystallized from methanol to give the resulting solid (2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylate ( G4 ).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.87 (s, 1H), 7.92 (d, 2H, J = 8.3 Hz), 7.81 (s, 1H), 7.51 (d, 2H, J = 8.3 Hz) ), 7.24 (s, 1H), 6.84 (d, 1H, J = 3.4 Hz), 6.60 - 6.57 (m, 1H), 3.68 (s, 3H), 1.29 (s, 9H).

ESI (m/z) 328 (MH ⁺ ), 350 (MNa ⁺ ), 326 (MH ⁻ ).

Example 2.5: 2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylic acid ( G5 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.67 (s, 1H), 9.72 (s, 1H), 7.90 (d, 2H, J = 8.2 Hz), 7.78 (s, 1H), 7.50 (d , 2H, J = 8.3 Hz), 7.23 (s, 1H), 6.78 (d, 1H, J = 3.3 Hz), 6.58 - 6.55 (m, 1H), 1.28 (s, 9H).

ESI (m/z) 336 (MNa ⁺ ), 312 (MH ⁻ ).

Example 2.6: tert-butyl 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G6 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.24 (s, 1H), 9.49 (s, 1H), 7.90 (d, 2H, J = 8.3 Hz), 7.50 (d, 2H, J = 8.3 Hz) ), 7.33 (s, 1H), 6.94 (s, 1H), 6.48 (s, 1H), 6.10 (s, 1H), 1.39 (s, 9H), 1.29 (s, 9H).

Example 2.7: 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G7 )

4-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F10 ) (1.02 mmol) was stirred with acetone (5 ml ) was added. When the suspension became a clear solution, 1% NaOH (3.05 mmol) was added to the mixture and stirred for 1 h. After completion of the reaction (TLC), after acidification with 10% HCl, the solid (2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylic acid was passed through a filter funnel. ( G7 ) was provided.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.23 (s, 1H), 11.24 (s, 1H), 9.48 (s, 1H), 7.92 (d, 2H, J = 8.4 Hz), 7.50 (d , 2H, J = 8.0 Hz), 7.43 (s, 1H), 6.95 (s, 1H), 6.47 (s, 1H), 6.11 (s, 1H), 1.29 (s, 9H).

Example 2.8: 2-(4-(tert-butyl)benzamido)-3-(thiophen-3-yl)acrylic acid ( G8 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.59 (S, 1H), 9.76 (s, 1H), 7.91 (d, 3H, J = 9.6 Hz), 7.51 (d, 4H, J = 7.2 Hz) ), 7.37 (d, 1H, J = 4.8 Hz), 1.29 (s, 9H).

Example 2.9: 2-(4-(tert-butyl)benzamido)-3-(4-methylthiazol-5-yl)acrylic acid ( G9 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.83 (s, 1H), 9.73 (s, 1H), 9.00 (s, 1H), 7.92 (d, 2H, J = 8.4 Hz), 7.74 (s) , 1H), 7.53 (d, 2H, J = 8.4 Hz), 2.47 (s, 3H), 1.29 (s, 9H).

Example 2.10: 2-(4-(tert-butyl)benzamido)-3-(1-methyl-1H-pyrazol-4-yl)acrylic acid ( G10 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.39 (s, 1H), 9.57 (s, 1H), 7.95 - 7.88 (m, 3H), 7.61 (s, 1H), 7.51 (d, 2H, J = 8.0 Hz), 7.39 (s, 1H), 3.79 (s, 3H), 1.29 (s, 9H).

ESI (m/z) 328 (MH ⁺ ), 350 (MNa ⁺ ), 327 (MH ⁻ ).

Example 2.11: Methyl 2-(4-butylbenzamido)-3-(1H-pyrrol-2-yl)acrylate ( G11 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.35 (s, 1H), 9.64 (s, 1H), 7.95 (d, 2H, J = 6.7 Hz), 7.49 (s, 1H), 7.34 (d) , 2H, J = 6.8 Hz), 7.02 (s, 1H), 6.55 (s, 1H), 6.16 (s, 1H), 3.68 (s, 3H), 2.72 - 2.60 (m, 2H), 1.65 - 1.52 ( m, 2H), 1.40 - 1.25 (m, 2H), 0.98 - 0.84 (m, 3H).

ESI (m/z) 327 (MH ⁺ ), 349 (MNa ⁺ ), 325 (MH ⁻ ).

Example 2.12: 2-(4-butylbenzamido)-3-(thiophen-2-yl)acrylic acid ( G12 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.67 (s, 1H), 9.67 (s, 1H), 7.95 (d, 2H, J = 7.9 Hz), 7.87 (s, 1H), 7.70 (d) , 1H, J = 4.9 Hz), 7.59 - 7.49 (m, 1H), 7.36 (d, 2H, J = 7.9 Hz), 7.13 (d, 1H, J = 4.4 Hz), 2.67 (t, 2H, J = ) 7.6 Hz), 1.66 - 1.55 (m, 2H), 1.40 - 1.26 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz).

ESI (m/z) 330 (MH ⁺ ), 328 (MH ⁻ ).

Example 2.13: 2-(4-(tert-butyl)benzamido)-3-(1-phenyl-1H-pyrrol-2-yl)acrylic acid ( G13 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.39 (s, 1H), 9.70 (s, 1H), 7.98 (d, 2H, J = 7.8 Hz), 7.65 - 7.49 (m, 5H), 7.38 (d, 2H, J = 7.4 Hz), 7.23 (s, 1H), 7.16 (s, 1H), 6.78 (s, 1H), 6.34 (s, 1H), 1.33 (s, 9H).

ESI (m/z) 389 (MH ⁺ ), 387 (MH ⁻ ).

Example 2.14: Methyl 2-(4-(tert-butyl)benzamido)-3-(1-phenyl-1H-pyrrol-2-yl)acrylate ( G14 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.81 (s, 1H), 7.96 (d, 2H, J = 7.7 Hz), 7.62 - 7.45 (m, 5H), 7.35 (d, 2H, J = 7.3 Hz), 7.22 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 6.33 (s, 1H), 3.58 (s, 3H), 1.30 (s, 9H).

ESI (m/z) 403 (MH ⁺ ), 425 (MNa ⁺ ), 401 (MH ⁻ ).

Example 2.15: Methyl 3-(1H-pyrrol-2-yl)-2-(4-(trifluoromethyl)benzamido)acrylate ( G15 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.37 (s, 1H), 9.98 (s, 1H), 8.22 (d, 2H, J = 8.1 Hz), 7.93 (d, 2H, J = 8.2 Hz) ), 7.53 (s, 1H), 7.04 (s, 1H), 6.56 (s, 1H), 6.18 (s, 1H), 3.70 (s, 3H).

ESI (m/z) 339 (MH ⁺ ), 361 (MNa ⁺ ), 337 (MH ⁻ ).

Example 2.16: 2- (4-bromobenzamido) -3- (furan-2-yl) acrylic acid ( G16 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.78 (s, 1H), 9.93 (s, 1H), 7.94 (d, 2H, J = 8.2 Hz), 7.82 (s, 1H), 7.75 (d , 2H, J = 8.4 Hz), 7.30 (s, 1H), 6.84 (d, 1H, J = 3.3 Hz), 6.64 - 6.58 (m, 1H).

ESI (m/z) 336 (MH ⁺ ), 338 (MH ⁺ ), 334 (MH ⁻ ), 335 (MH ⁻ ).

Example 2.17: Methyl 3-(furan-2-yl)-2-(4-(trifluoromethyl)benzamido)acrylate ( G17 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.23 (s, 1H), 8.19 (d, 2H, J = 8.0 Hz), 7.93 (d, 2H, J = 8.2 Hz), 7.88 - 7.86 (m) , 1H), 7.35 (s, 1H), 6.93 (d, 1H, J = 3.4 Hz), 6.66 - 6.62 (m, 1H), 3.73 (s, 3H).

ESI (m/z) 340 (MH ⁺ ), 362 (MNa ⁺ ), 338 (MH ⁻ ).

Example 2.18: 3-(furan-2-yl)-2-(4-(trifluoromethyl)benzamido)acrylic acid ( G18 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.83 (s, 1H), 10.10 (s, 1H), 8.19 (d, 2H, J = 7.9 Hz), 7.93 (d, 2H, J = 8.2 Hz) ), 7.83 (s, 1H), 7.34 (s, 1H), 6.87 (d, 1H, J = 3.3 Hz), 6.63 - 6.59 (m, 1H).

ESI (m/z) 326 (MH ⁺ ), 324 (MH ⁻ ).

Example 2.19: 2- (4-bromobenzamido) -3- (thiophen-2-yl) acrylic acid ( G19 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.74 (s, 1H), 9.87 (s, 1H), 7.98 (d, 2H, J = 8.5 Hz), 7.90 (s, 1H), 7.78 (d , 2H, J = 8.5 Hz), 7.72 (d, 1H, J = 5.1 Hz), 7.56 (d, 1H, J = 3.3 Hz), 7.16 - 7.12 (m, 1H).

ESI (m/z) 354 (MH ⁺ ), 352 (MH ⁺ ), 352 (MH ⁻ ), 350 (MH ⁻ ).

Example 2.20: methyl 2- (4-bromobenzamido) -3- (furan-2-yl) acrylate ( G20 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.03 (s, 1H), 7.91 (d, 2H, J = 8.5 Hz), 7.82 (d, 1H, J = 1.5 Hz), 7.72 (d, 2H) , J = 8.5 Hz), 7.27 (s, 1H), 6.86 (d, 1H, J = 3.5 Hz), 6.61 - 6.58 (m, 1H), 3.69 (s, 3H).

ESI (m/z) 350 (MH ⁺ ), 352 (MH ⁺ ), 348 (MH ⁻ ), 350 (MH ⁻ ).

Example 2.21: 2- (4-bromobenzamido) -3- (furan-2-yl) acrylic acid ( G21 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.78 (s, 1H), 9.93 (s, 1H), 7.94 (d, 2H, J = 8.5 Hz), 7.82 (d, 1H, J = 1.5 Hz) ), 7.75 (d, 2H, J = 8.5 Hz), 7.31 (s, 1H), 6.84 (d, 1H, J = 3.4 Hz), 6.63 - 6.59 (m, 1H).

ESI (m/z) 336 (MH ⁺ ), 338 (MH ⁺ ), 334 (MH ⁻ ), 336 (MH ⁻ ).

Example 2.22: 2-(4-butylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid (G22)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ12.28 (s, 1H), 11.28 (s, 1H), 9.51 (s, 1H), 7.94 (d, 2H, J = 8.0 Hz), 7.47 (s) , 1H), 7.33 (d, 2H, J = 8.0 Hz), 6.99 (s, 1H), 6.51 (s, 1H), 6.14 (d, 1H, J = 2.7 Hz), 2.66 (t, 2H, J = 2.7 Hz) 7.6 Hz), 1.64 - 1.54 (m, 2H), 1.38 - 1.27 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz).

Example 2.23: (E)-N'-(1-(naphthalen-2-yl)ethylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carbohydrazide ( G23 )

Example 2.24: (E)-2-((1H-benzo [d]imidazol-2-yl)thio)-N'-(3-methylbenzylidene)acetohydrazide ( G24 )

Example 2.25: (E)-2-chloro-5-(5-((2-(3-chloro-4-methylphenyl)hydrazinylidene)methyl)furan-2-yl)benzoic acid ( G25 )

Example 2.26: 4-Chloro-N'-(2-(thiophen-2-yl)acetyl)benzohydrazide ( G26 )

Example 2.27: 2- (2- (2- (benzo [d] thiazol-2-ylthio) acetamido) thiazol-4-yl) acetic acid ( G27 )

Example 2.28: N- (3- (4,4-dimethyl-2,5-dioxoimidazolidin-1-yl) -2-hydroxypropyl) -N- (4-methoxyphenyl) benzenesulfonamide ( G28 )

Example 2.29: 4-amino-N5-(furan-2-ylmethyl)-N5-(2-oxo-2-(tert-pentylamino)-1-(quinolin-6-yl)ethyl)isothiazole- 3,5-dicarboxamide ( G29 )

Example 2.30: 4-(tert-butyl)-N-(3-((4-chlorophenyl)amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2- Japanese) Benzamide ( G30 )

Example 2.31: 4-(tert-butyl)-N-(3-((furan-3-ylmethyl)amino)-3-oxo-1-(thiophen-2-yl)prop-1-ene- 2-day) Benzamide ( G31 )

Example 2.32: 3-(furan-2-yl)-2-(4-isobutoxybenzamido)acrylic acid ( G32 )

Example 2.33: N-(1-(furan-2-yl)-3-(methylamino)-3-oxoprop-1-en-2-yl)-4-isobutoxybenzamide ( G33 )

Example 2.34: N-(3-amino-1-(furan-2-yl)-3-oxoprop-1-en-2-yl)-4-(tert-butyl)benzamide ( G34 )

Example 2.35: methyl-2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G35 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.31 (s, 1H), 9.61 (s, 1H), 7.94 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 8.0 Hz) , 7.46 (s, 1H), 6.98 (s, 1H), 6.52 (s, 1H), 6.13 (s, 1H), 3.65 (s, 3H), 1.29 (s, 9H)

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.1, 165.9, 154.9, 131.4, 128.0, 126.6, 126.5, 125.6, 122.6, 119.7, 113.9, 111.0, 52.2, 35.1, 31.4

Example 2.36: 2- (2-naphtamido) -3- (thiophen-3-yl) acrylic acid ( G36 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 10.03 (s, 1H), 8.63 (s, 1H), 8.05 - 8.03 (m, 3H), 7.98 (d, 1H, J) = 7.6 Hz), 7.94 (br s, 1H), 7.64 - 7.59 (m, 2H), 7.56 (s, 1H), 7.53 - 7.52 (m, 1H), 7.41 (d, 1H, J = 4.4 Hz)

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.9, 166.4, 135.8, 134.8, 132.6, 131.3, 130.3, 129.4, 128.7, 128.5, 128.3, 128.2, 128.1, 127.3, 127.2, 125.9, 124.7

Example 2.37: 3- (benzo [b] thiophen-3-yl) -2- (4- (tert-butyl) benzamido) acrylic acid ( G37 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.78 (s, 1H), 9.90 (s, 1H), 8.10 (s, 1H), 8.01 (d, 1H, J = 7.6 Hz), 7.96 (d, 1H, J = 7.6 Hz), 7.91 (d, 2H, J = 8.0 Hz), 7.67 (s, 1H), 7.50 (d, 2H, J = 8.0 Hz), 7.46 - 7.38 (m, 2H), 1.28 ( s, 9H)

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 166.6, 166.3, 139.2, 138.5, 131.2, 129.5, 129.0, 128.9, 128.1, 125.6, 125.4, 125.2, 123.9, 123.4, 131.9, 35.1, 31.4

Example 2.38: 2-(4-isobutylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G38 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.26 (2, 1H), 11.25 (s, 1H), 9.48 (s, 1H), 7.91 (d, 2H, J = 7.2 Hz), 7.44 (s, 1H), 7.27 (d, 2H, J = 7.6 Hz), 6.95 (s, 1H), 6.50 (s, 1H), 6.11 (s, 1H), 2.50 (d, 2H, J = 2.8 Hz), 1.90 - 1.91 (m, 1H), 0.85 (d, 6H, J = 6.8 Hz)

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 167.0, 165.9, 145.4, 132.0, 129.3, 129.0, 126.7, 126.1, 122.2, 120.7, 113.4, 110.8, 44.8, 30.0, 22.57

Example 2.39: 2-(1-naphtamido)-3-(4-methylthiazol-5-yl)acrylic acid ( G39 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.98 (br s, 1H), 9.97 (s, 1H), 9.09 (s, 1H), 8.40 - 8.39 (m, 1H), 8.6 (d, 1H, J = 8.0 Hz), 7.99 - 7.98 (m, 1H), 7.89 (d, 1H, J = 7.2 Hz), 7.80 (s, 1H), 7.62 (t, 1H, J = 7.6 Hz), 7.57 - 7.55 ( m, 2H), 2.54 (s, 3H).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.3, 166.1, 156.8, 156.6, 134.1, 133.6, 130.8, 130.3, 128.6, 127.3, 126.8, 126.2, 126.1, 126.0, 125.9, 125.4, 124.9, 16.1

Example 2.40: 2-(4-propylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G40 )

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.30 (br s, 1H), 11.25 (s, 1H), 9.48 (s, 1H), 7.91 (d, 2H, J = 7.6 Hz), 7.44 (s) , 1H), 7.30 (d, 2H, J = 4.0 Hz), 6.95 (s, 1H), 6.48 (s, 1H), 6.11 (s, 1H), 2.60 (t, 2H, J = 7.2 Hz), 1.64 - 1.55 (m, 2H), 0.87 (t, 3H, J = 7.0 Hz).

¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 167.0, 165.9, 146.4, 131.9, 129.7, 128.1, 126.7, 126.1, 122.1, 120.7, 113.4, 110.8, 37.5, 24.3, 14.0

Example 3: Confirmation of the function of the compound according to the present invention as a pendrine inhibitor

Example 3.1: Cell Culture

Chinese Hamster Ovary (CHO)-K1 cells were maintained in DMEM medium containing 10% fetal bovine serum (FBS), 100 units/ml penicillin and 100 μg/ml streptomycin. CHO-K1 cells were stably transfected with pcDNA3.1 encoding halide sensors YFP-H148Q/I152L/F46L and human wild-type (WT)-pendrine. For differentiation of primary cultures of human nasal epithelial (HNE) cells, passage-2 cells were transwell-trans-well cultured at a density of 2 x 10 ⁵ cells/cm ² with a 0.45 μm pore size (Costar Co., Cambridge, MA). The insert was seeded. Cells were maintained in a 1:1 mixture of Dulbecco's modified Eagle's medium (Lonza, Walkersville, MD) and bronchial epithelial growth medium (Lonza) supplemented with the following growth factors according to the manufacturer's instructions. Cells were soaked for the first 7 days and then exposed to the apical air interface for the remainder of the culture period. Cells were used between 14 and 21 days after establishment of the air-liquid interface. At all stages of culture, cells were maintained at 37° C. under 5% CO ₂ in an air incubator.

Example 3.2: Cell-based high-throughput screening

CHO-K1 cells expressing human WT pendrin and YFP-F46L/H148Q/I152L were plated in 96-well microplates at a density of 2×10 ⁴ cells per well and incubated for 48 hours. Each well of the cell culture 96-well plate was washed twice with 200 μL of PBS and filled with 50 μL of each HEPES buffer solution. Test compound (1 μL) was added to a final concentration of 50 μM. After incubation at 37° C. for 10 minutes, the 96-well plates were placed in a FLUOstar Omega microplate reader (BMG Labtech, Ortenberg, Germany) for fluorescence analysis. Each well was individually analyzed for pendrin-mediated I ^- influx by recording fluorescence continuously (400 ms per point) for 1 s (baseline), followed by 50 µL of NaI-displacement using a liquid injector at 1 s. HEPES buffer solution (NaI replacing NaCl) was added and YFP fluorescence was recorded for 5 s. The initial iodide influx rate was determined from the initial slope of fluorescence by nonlinear regression after iodide injection (see Fig. 1).

Example 3.3: Measurement of short circuit current

Snapwell inserts containing ANO1- and CFTR-expressing FRT and primary cultures of human nasal epithelial (HNE) cells were mounted on a Ussing chamber (Physiologic Instruments, San Diego, CA, USA). To measure the short-circuit current in HNE cells, the apical and basal baths were filled with symmetric HCO ₃ ⁻ buffer solution. For ANO1- and CFTR-expressing FRTs, the apical bath was filled with half-Cl ⁻ solution and the lateral bath with HCO ₃ ⁻ buffer solution. The apical membrane currents of ANO1 and CFTR were measured by permeating the basal membrane with 250 μg/mL amphotericin B. Short-circuit current and apical membrane current were measured with an EVC4000 multi-channel V/I clamp (World Precision Instruments, Sarasota, FL, USA) and a PowerLab 4/35 (AD Instruments, Castle Hill, Australia). Data were recorded and analyzed using Labchart Pro 7 (AD Instruments). The sampling rate was 4 Hz.

Example 3.4: Cl ^- /I ^- Exchange activity measurement

For the determination of Cl ⁻ /I ⁻ exchange activity, YFP fluorescence was measured in CHO-K1 cells expressing pendrine and halide sensor YFP. Each well of the cell cultured 96-well plate was washed twice with 200 μL of PBS, and 50 μL of HEPES buffer (140 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 1 mM CaCl ₂ , 10 mM glucose). and 10 mM HEPES (pH 7.4)), respectively. Test compound (1 μL) was added to a final concentration of 50 μM. After incubation at 37° C. for 10 min, 96-well plates were placed on a FLUOstar Omega micro plate reader (BMG Labtech, Ortenberg, Germany) for fluorescence analysis.

Each well was individually analyzed for pendrin-mediated I ^- influx by recording fluorescence continuously (400 ms per point) for 1 s (baseline), followed by 50 µL of NaI-displacement using a liquid injector at 1 s. HEPES buffer solution (140 mM NaI, 5 mM KCl, 1 mM MgCl ₂ , 1 mM CaCl ₂ , 10 mM glucose and 10 mM HEPES (pH 7.4)) was added and YFP fluorescence was recorded for 5 seconds. The initial iodide influx rate was determined from the initial slope of fluorescence by non-linear regression after iodide injection.

Example 3.5: Cl ^- /HCO ₃ ^- Exchange activity measurement

For the measurement of Cl ⁻ /HCO ₃ ⁻ exchange activity, intracellular pH (pH _i ) was measured in WT-pendrine expressing CHO-K1 and HNE cells using a pH sensor SNARF5-AM (Molecular Probes). Cells were treated with 5 µM SNARF5-AM for 30 min, then inverted fluorescence microscopy (Nikon, Tokyo, Japan) equipped with a cooled charge-coupled device camera (Zyla sCMOS), image acquisition and analysis software (Meta Imaging Series 7.7) ) in the perfusion chamber. Cells were perfused with HCO ₃ ^-buffer solution containing (in mM) 120 NaCl, 5 KCl, 1 MgCl ₂ , 1 CaCl ₂ , 10 D-glucose, 5 HEPES, and 25 NaHCO ₃ (pH 7.4). To measure the Cl ⁻ /HCO ₃ ⁻ exchange activity, the HCO ₃ ⁻ buffer solution was changed to a Cl ⁻ -free HCO ₃ ⁻ buffer solution. Applying an external Cl ⁻ -free HCO ₃ ⁻ buffer solution increases the efflux of Cl ⁻ and the influx of HCO ₃ ⁻ through pendrine. To maintain the pH of the HCO ₃ ^-buffered solution, the solution was successively gassed with 95%O ₂ and 5%CO ₂ . SNARF5 fluorescence was recorded at 515 ± 10 nm of excitation wavelength and 640 ± 10 nm of emission wavelength, intracellularly with a solution containing 145 mM KCl, 10 mM HEPES and 5 mM nigerisin with a pH corrected to 6.2-7.6. A pH correction was performed.

Example 3.6: Cl ^- / SCN ^- Exchange activity measurement

For the determination of Cl ⁻ /SCN ⁻ exchange activity, YFP fluorescence was measured in CHO-K1 cells expressing pendrine and halide sensor YFP. To measure Cl ⁻ /SCN ⁻ exchange activity, HEPES buffer was mixed ^with NaSCN ^- substituted HEPES buffer (140 mM NaSCN, 5 mM KCl, 1 mM MgCl ₂ , 1 mM CaCl ₂ , 10 mM glucose and 10 mM HEPES (pH 7.4)). Changes in YFP fluorescence due to SCN ^- influx were monitored using a FLUOstar Omega microplate reader (BMG Labtech) and MARS data analysis software (BMG Labtech).

Example 3.7: Cl ^- /OH ^- Exchange activity measurement

For the measurement of Cl ⁻ /OH ⁻ exchange activity, intracellular pH (pH _i ) was measured in WT-pendrin expressing CHO-K1 and HNE cells using a pH sensor SNARF5-AM (Molecular Probes). Cells were treated with 5 μM SNARF5-AM for 30 min, then inverted fluorescence microscopy (Nikon, Tokyo, Japan) equipped with a cooled charge-coupled device camera (Zyla sCMOS), image acquisition and analysis software (Meta Imaging Series 7.7) ) in the perfusion chamber. To measure the Cl ⁻ /OH ⁻ exchange activity, HEPES buffer was mixed with Cl ⁻ efflux of cytosol through pendrine and Changed to Cl ⁻ -free HEPES buffer solution for generation of Cl ⁻ gradient driving OH ⁻ influx.

Example 3.8: Measurement of protein expression level (immunoblot)

CHO-K1 and HNE cells were cultured in cell lysis buffer (50 mM Tris-HCl, pH 7.4, 1% Nonidet P-40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM Na ₃ VO ₄ , and protease inhibitory mixture). The whole cell lysate was centrifuged at 15,000 × g for 10 min at 4°C to remove cell debris, and the same amount (50 μg protein or 5 μg protein/lane) of the supernatant protein was added to 4-12% It was separated on a tris-glycine precast gel (KOMA BIOTECH, Seoul, Korea) and transferred to a PVDF membrane (Millipore, Billerica, MA, USA). Membranes were blocked with 5% nonfat skim milk in TBS with 0.1% Tween 20 (TBST) or 5% bovine serum albumin in TBS for 1 hour at room temperature. The membrane was then incubated at 4°C with pendrine (sc-50346; Santa Cruz Biotechnology, Santa Cruz, CA, USA), NF-κB p65 (4764S; Cell Signaling Technology, Danvers, MA, USA), p-NF-κB p65 (3033S; Cell Signaling Technology), IkBα (9242S; Cell Signaling Technology), p-IkBα (9141S; Cell Signaling Technology), β-actin (sc-47778; Santa Cruz Biotechnology), or ANO1 (ab64085; Abcam) for The primary antibody was incubated overnight. After washing with 0.05% Tween 20 (TBST) in PBS, the blot was further incubated for 60 minutes at room temperature with a secondary antibody (Cell Signaling Technology, Danvers, MA). The membranes were then washed three times with TBST for 5 min and then visualized using an ECL Plus Western Blotting Detection System (GE Healthcare Amersham; Piscataway, NJ, USA).

Example 3.9: Real-time RT-PCR analysis

Total messenger RNA (mRNA) was extracted using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) and reverse transcribed using random hexamer primers, oligo(dT) primers and SuperScript® III reverse transcriptase (Invitrogen). Quantitative real-time PCR was performed using the StepOnePlus Real-Time PCR system (Applied Biosystems, Foster City, CA, USA) and Thunderbird SYBR qPCR mix (Tokyobo, Osaka, Japan). Thermal cycling conditions included an initial phase in 96-well reaction plates at 95°C for 5 minutes, followed by 40 cycles at 95°C for 10 seconds, 55°C for 20 seconds, and 72°C for 10 seconds. Primer sequences are listed in Table 3 below.

Example 3.10: Characterization of phendrine inhibitors

The pendrin inhibitory effect of F56, G23, G24 and G25 was measured in CHO-K1 cells overexpressing WT-pendrin and iodide-sensitive YFP. All four inhibitors significantly inhibited the Cl ⁻ /I ⁻ exchange activity of pendrine in a dose-dependent manner ( FIGS. 2A-2D ).

We analyzed whether F56, G23, G24 and G25 could inhibit the Cl ⁻ /HCO ₃ ⁻ exchange activity of pendrine. When CHO-K1 cells overexpressing YFP sensitive to WT-pendrin and iodide are treated with a high concentration of Cl ^- solution, Cl ^- moves into the cell and HCO ₃ ^- moves out of the cell, and this change together with YFP causes acidification of the intracellular pH. induce As a result, all of the four phendrine inhibitors significantly inhibited Cl ⁻ /HCO ₃ ⁻ exchange activity in a dose-dependent manner ( FIGS. 3A to 3D ). Similar to the results of Cl ⁻ /I ⁻ exchange experiments, F56 and G23 strongly inhibited Cl ⁻ /HCO ₃ ⁻ exchange activity, but G24 and G25 weakly blocked Cl ⁻ /HCO ₃ ⁻ exchange activity. F56 was shown to inhibit Cl ⁻ /I ⁻ and Cl ⁻ /HCO ₃ ⁻ exchange activity by 50% at ˜3 μM and ˜10 μM, respectively. In addition, another inhibitor, G23, was shown to inhibit Cl ⁻ /I ⁻ and Cl ⁻ /HCO ₃ ⁻ exchange activity by 50% at ˜7 μM and ˜10 μM, respectively ( FIGS. 4A-4B ).

Example 3.11: Inhibitory effect of anion exchange by F56

The effect of F56 on various physiological functions such as Cl ^- /I ^- , Cl ^- /SCN ^- , Cl ^- /HCO ₃ ^- and Cl ^- /OH ^- exchange was measured, and the results are shown in FIG. 5 . As can be seen in FIG. 5 , it was shown that F56 significantly inhibited the pendrine-mediated Cl ^- /I ^- , Cl ^- /SCN ^- , Cl ^- /HCO ₃ ^- and Cl ^- /OH ^- exchange activity in a dose-dependent manner. gave.

Example 3.12: Inhibitory effect of F56 on SLC26 isoform

Cells were incubated for 10 min in conventional HCO ₃ ^-solution with F56 at final concentrations of 0, 1, 3, 10, 30, 100 μM. Then the solution was changed to 0 Cl ⁻ solution. The influx of HCO ₃ ⁻ through the Cl ⁻ /HCO ₃ ⁻ exchange activity of pendrine increases the intracellular pH. 6 shows the effect of F56 on the Cl ⁻ /HCO ₃ ⁻ exchange activity of the SLC26 isoform in cells transfected with the SLC26 isoform. F56 weakly inhibited SLC26A3 and SLC26A6 but did not affect the Cl ⁻ /HCO ₃ ⁻ exchange activity of SLC26A7 and SLC26A9.

Example 3.13: Effect of F56 on mPDS, CFTR and ANO1

Effects of F56 were observed on mouse PDS (mPDS) and other Cl ⁻ channels, cystic fibrosis transmembrane conductance modulators (CFTRs), and anoctamine-1/transmembrane protein 16A (ANO1/TMEM16A). 7 showed that F56 inhibited mPDS mediated Cl ⁻ /I ⁻ exchange activity in a dose dependent manner but did not alter CFTR and ANO1/TMEM16A Cl channel activity.

Example 3.14: Endogenous Pendrine Mediated Cl by F56 in Human Airway Epithelium ^- /HCO ₃ ^- Confirmation of the inhibitory effect of exchange activity

To investigate whether F56 inhibits endogenous phendrine in primary cultures of human airway epithelium, we phendrine-mediated Cl-/HCO ₃ ⁻ exchange in primary cultures of human nasal epithelial (HNE) cells. Activity was measured. As shown in Figure 8A, IL-4 (10 ng/ml, 48 h) treatment strongly increased the mRNA and protein expression of pendrine in HNE cells. In Figure 8B, application of OCl ^- solution significantly increased the alkalinization of intracellular pH in IL-4 treated HNE cells, and treatment with F56 significantly inhibited alkalinization of intracellular pH when OCl ^- solution was applied. . To investigate whether F56 affects pendrine protein expression levels, we observed the protein expression levels of pendrine and ANO1 in HNE cells incubated with F56 for 24 h and 48 h. As shown in Figure 8C, IL-4 treatment resulted in a strong elevation of protein expression levels of both fendrine and ANO1. However, F56 significantly reduced elevated fendrine protein levels without altering ANO1 protein levels. To elucidate whether F56 affects the mRNA expression levels of pendrin and ANO1, we performed real-time PCR analysis in HNE cells. As shown in Figure 8D, after 24 and 48 hours of F56 treatment, the mRNA expression levels of pendrine and other ion channels did not change significantly. These results suggest that F56 may have a direct effect on fendrine and reduce the protein stability of fendrine in human airway epithelial cells.

Example 3.15: Confirmation of reduction of airway hypersensitivity by pendrine inhibitor in asthma mouse model

Airway responses to methacholine (MCh) were measured 24 h after the last OVA exposure using a Flexivent system (Scireq, Montreal, QC, Canada). Mice were anesthetized by intraperitoneal injection of a mixture of Zoletil (30 mg/kg, Virbac Laboratories, Carros, France) and Rompun (10 mg/kg, Bayer, Leverkusen, Germany), followed by a tracheostomy and connection to a flexiVent. Baseline airway resistance was measured after saline spray for 10 seconds using an Aeroneb ultrasonic nebulizer (SCIREQ). After baseline measurements, mice were exposed to increasing concentrations of nebulized methacholine (0, 1.56, 3.13, 6.25, 12.5 and 25 mg/ml).

Example 3.16: Confirmation of reduction of inflammation by phendrine inhibitor in asthma mouse model

To determine whether the decrease in airway inflammation caused by the pendrine inhibitor F56 was due to dysfunction of the allergic reaction, OVA-specific IgE was measured in mouse serum. As shown in FIG. 10A , similar amounts of OVA-specific IgE were found between OVA-challenged mice and OVA-challenged mice treated with F56. Cells were counted in bronchoalveolar lavage fluid to identify differences in inflammatory cell recruitment (FIG. 10B). Examination of BALF cells from OVA-sensitized mice showed that eosinophils, neutrophils and lymphocytes were significantly influxed into the airways, and F56 treatment significantly reduced the number of eosinophils and neutrophils in BALF of OVA-sensitized mice. In histological analysis (Fig. C), a large amount of inflammatory cells and epithelial cell changes were detected in OVA-challenged mice, but it was confirmed that epithelial cell changes and inflammatory infiltration were reduced in OVA-challenged mice treated with phendrine inhibitors. became . Histological analysis revealed a significant increase in inflammatory cell infiltration and epithelial thickness, particularly in the peribronchial and perivascular regions, in OVA-challenged mice compared to the PBS-challenged group ( FIG. 10C ). Remarkably, the increased inflammatory infiltration and epithelial thickness were attenuated by treatment with F56. The mean inflammation score of OVA-challenged mice was significantly lower in the F56 treated group (1.7±0.8) than in the untreated group (3.6±0.7) ( FIG. 10D ).

Example 3.17: Inhibition of mucin expression and goblet cell proliferation by F56

Pendrine is associated with mucin expression in the airway epithelium. Therefore, the effect of F56 on mucin expression in primary cultured airway epithelial cells and airway sections in a mouse model of asthma was investigated. 11A , pretreatment with F56 (30 μM) attenuated IL-4-induced goblet cell proliferation in HNE cells. A similar phenomenon occurred in the asthma mouse model. It was confirmed that OVA-challenged mice had an increased number of goblet cells in the central airway compared to PBS-challenged mice, which were attenuated by treatment with F56 (10 mg/kg) ( FIG. 11B ). Real-time PCR was performed on IL-4 treated HNE cells to investigate the effect of F56 on the mRNA expression level of MUC5AC. IL-4 treatment induced a large (~10-fold) increase in the mRNA expression level of MUC5AC, and F56 significantly inhibited increased MUC5AC expression by IL-4 by up to 62.3 ± 9.2% in a time-dependent manner (Fig. 11C).

Example 3. 18: LPS-induced acute lung injury (Acute lung injury) model according to the compound effect confirmation

7 to 8 weeks of age, weighing 20 to 24 g Wild-type male BL6 mice were purchased from Orient Bio (Seongnam, Korea). As shown in Table 4, mice were divided into 8 groups and samples were treated according to the dosing schedule of FIG.

group number of objects
(number of animals) administration Vehicle control (Vehicle) 7 DMSO intraperitoneal injection before and after PBS intranasal inhalation administration LPS treatment group 5 LPS inhalation administration LPS+G7 treatment group
(G7 0.01 mg/kg) 8 G7 intraperitoneal injection by concentration before and after LPS inhalation administration LPS+G7 treatment group
(G7 0.03 mg/kg) 3 LPS+G7 treatment group (G7 0.1 mg/kg) 7 LPS+G7 treatment group (G7 0.3 mg/kg) 3 LPS+G7 treatment group (G7 1.0 mg/kg) 6 LPS+G7 treatment group (G7 10.0 mg/kg) 8

Specifically, LPS ( Escherichia coli , O111: B4, Sigma) (10 μg/g) dissolved in 50 μL PBS was administered by nasal (in) inhalation. Control group received 50 μL of sterile PBS intranasally. For pretreatment, 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, 1.0 mg/kg, and 10 mg/kg of G7 dissolved in 50 μL DMSO, respectively, were administered intraperitoneally (ip) 1 hour before LPS inhalation. For post-treatment, 0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg, 1.0 mg/kg, and 10 mg/kg of G7 were administered at 12 hours after LPS inhalation, respectively. The vehicle control group was intraperitoneally administered with 50 μL DMSO, respectively, at the same time points as the pre-treatment and post-treatment. Mice were euthanized 48 hours after LPS inhalation and the lungs were excised.

As a result, as confirmed in FIG. ///, the mice in the group treated with G7 before and after LPS inhalation significantly reduced the total number of BALF cells and protein concentration levels compared to the mice in the group treated with the vehicle before and after LPS inhalation. .

In addition, the degree of lung damage was observed by performing BALF cytospin staining and H&E lung tissue staining. As shown in FIG. 8 , the mice in the group treated with G7 before and after LPS inhalation significantly reduced lung damage compared to the mice in the group treated with the vehicle before and after LPS inhalation.

Example 3-19. Confirmation of diuretic effect in mouse model of compound according to the present invention

Recently, it has been reported that fendrine is related to the diuretic effect. Accordingly, it was attempted to confirm whether the compounds useful as fendrine inhibitors according to the present invention have a diuretic effect.

In order to confirm the diuretic effect of the compound according to the present invention, the compound of Example 2.7 of the present invention (2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G7 )), the experiment was conducted in the following way.

Wild-type male C57BL/6J mice weighing 20 to 24 g at 8 weeks of age were purchased from Orient Bio (Seongnam, Korea). Before the experiment, water and diet were restricted and the bladder was stimulated to induce urine.

G7 at a 100 mg/ml stock concentration dissolved in DMSO was prepared so that the final concentrations were 0.1 mg/kg/100ul, 0.5 mg/kg/100ul, and 1 mg/kg/100ul (1% DMSO + DW), respectively. Two intraperitoneal injections were performed at 3 hour intervals. After 6 hours, the urine volume of each group of mice was measured.

As a result, as confirmed in FIG. //, when G7 was administered alone for each concentration, the diuretic effect was shown in a dose-dependent response when the concentration was 0.5 mpk or less.

Through this, the potential of the compounds according to the present invention as a diuretic of the pendrine inhibitor was confirmed.

<110> YONSEI UNIVERSITY, UNIVERSITY - INDUSTRY FOUNDATION (UIF) <120> COMPOUNDS AND METHODS FOR PREVENTING OR TREATING OF RESPIRATORY DISEASE <130> DPP20213837KR <150> KR 10-2020-0127560 <151> 2020-09-29 <160> 14 <170> KoPatentIn 3.0 <210> 1 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Pendrin primer sequence 1 <400> 1 ttcccaaagt gccaatccat ag 22 <210> 2 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Pendrin primer sequence 2 <400> 2 ccgcagtgat ctcactccaa c 21 <210> 3 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ANO1 primer sequence 1 <400> 3 ggagaagcag catctatttg 20 <210> 4 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ANO1 primer sequence 2 <400> 4 gatctcatag acaatcgtgc 20 <210> 5 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CFTR primer sequence 1 <400> 5 aggaggcagt ctgtcctgaa 20 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> CFTR primer sequence 2 <400> 6 cactgctggt atgctctcca 20 <210> 7 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ENaC alpha primer sequence 1 <400> 7 cagcccatac caggtctcat 20 <210> 8 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ENaC alpha primer sequence 2 <400> 8 atggtggtgt tgttgcagaa 20 <210> 9 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ENaC beta primer sequence 1 <400> 9 tcctaccctc gtccctacct 20 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ENaC beta primer sequence 2 <400> 10 ccaggaagga gaaaaccaca 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ENaC gamma primer sequence 1 <400> 11 accaccagcc atggtctaag 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> ENaC gamma primer sequence 2 <400> 12 gttcaggtcc cgggatttat 20 <210> 13 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> beta-actin primer sequence 1 <400> 13 gcaaagacct gtacgccaac ac 22 <210> 14 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> beta-actin primer sequence 2 <400> 14 atctccttct gcatcctgtc 20

Claims (17)

A compound represented by the following formula (2), its E- or Z- isomer, its optical isomer, a mixture of two isomers, a precursor thereof, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient. A pharmaceutical composition for prophylaxis or treatment:
[Formula 2]

In Formula 2,
V ³ and V ⁴ are each independently aryl, heteroaryl, C ₃ ~ C ₇ cycloalkyl, heterocycloalkyl, C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ heteroalkyl, C ₂ ~ C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C( O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ one of C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl , trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ optionally substituted with one or more groups independently selected from aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl) ), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR one of ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl , C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O ) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O) OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ;
i is each independently 0, 1 or 2,
R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ³ and R ⁴ may be cycled together to a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring (which may form a ring), said carbocyclic, heterocyclic , one of the aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR optionally substituted with one or more groups independently selected from ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ;
A ² is

It is represented by a structure selected from the group consisting of,
X ³ is hydrogen, OR ³ , aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O)OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ , wherein OR ³ , aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O) one of OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, Sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl , C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O) one independently selected from R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Optionally selected from the above group, the aryl, C ₁ ~ C ₁₀ alkylaryl, C ₃ ~ C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ ~ C ₁₀ alkyl, C ₂ ~ C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ one of hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl , heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R one or more independently selected from ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted with a group,
i is 0, 1 or 2,
X ⁴ is O, S, NR ⁵ , NSO ₂ R ⁵ , C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, aryl, arylalkyl, C ₁ to C ₁₀ alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR ⁵ , NSO ₂ R ⁵ , C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, aryl, arylalkyl, C ₁ ~ C ₁₀ alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ⁵ , C(O)R ⁵ , OR ⁵ , NR ⁵ C(O)OR ⁶ , C(O)NR ⁵ R ⁶ and NR ⁵ R ⁶ may be optionally substituted with one or more selected from the group consisting of,

R ⁵ to R ⁸ are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) independently selected from the group consisting of NR ³ R ⁴ and NR ³ R ⁴ , said aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) one of NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S (O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O) )OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , optionally selected from one or more groups independently selected from the group consisting of, said aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR one of ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, Halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl , C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), from S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . may be optionally substituted with one or more independently selected
R ⁵ and A ² may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
I is 0, 1 or 2. The pharmaceutical composition according to claim 1, wherein the respiratory disease is an inflammatory airway disease. 3. The method of claim 2,
The inflammatory airway disease is asthma, acute or chronic bronchitis, allergic rhinitis, acute respiratory infection, acute upper respiratory infection, cystic fibrosis, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), acute lung injury (ALI) and chronic At least one selected from the group consisting of obstructive pulmonary disease (COPD), a pharmaceutical composition. The method of claim 1,
The active ingredient acts as a pendrine inhibitor, a pharmaceutical composition. The method of claim 1,
The active ingredient specifically controls a channel associated with respiratory disease, a pharmaceutical composition. The method of claim 1,
The active ingredient preserves the volume of airway surface liquid (ASL) and reduces the separation of mucin, a pharmaceutical composition. The method of claim 1,
A pharmaceutical composition, further comprising a pharmaceutically acceptable carrier. A compound represented by the following formula (2), its E- or Z- isomer, its optical isomer, a mixture of two isomers, a precursor thereof, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient. Health functional food for prevention or improvement:
[Formula 2]

In Formula 2,
V ³ and V ⁴ are each independently aryl, heteroaryl, C ₃ ~ C ₇ cycloalkyl, heterocycloalkyl, C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ heteroalkyl, C ₂ ~ C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C( O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ one of C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl , trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ optionally substituted with one or more groups independently selected from aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl) ), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR one of ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl , C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O ) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O) OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ;
i is each independently 0, 1 or 2,
R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ³ and R ⁴ may be cycled together to a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring (which may form a ring), said carbocyclic, heterocyclic , one of the aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR optionally substituted with one or more groups independently selected from ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ;
A ² is

It is represented by a structure selected from the group consisting of
X ³ is hydrogen, OR ³ , aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O)OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ , wherein OR ³ , aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O) one of OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, Sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl , C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O) one independently selected from R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Optionally selected from the above group, the aryl, C ₁ ~ C ₁₀ alkylaryl, C ₃ ~ C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ ~ C ₁₀ alkyl, C ₂ ~ C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ one of hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl , heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R at least one independently selected from ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted with a group,
i is 0, 1 or 2,
X ⁴ is O, S, NR ⁵ , NSO ₂ R ⁵ , C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, aryl, arylalkyl, C ₁ to C ₁₀ alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR ⁵ , NSO ₂ R ⁵ , C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, aryl, arylalkyl, C ₁ ~ C ₁₀ alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ⁵ , C(O)R ⁵ , OR ⁵ , NR ⁵ C(O)OR ⁶ , C(O)NR ⁵ R ⁶ and NR ⁵ R ⁶ may be optionally substituted with one or more selected from the group consisting of,

R ⁵ to R ⁸ are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) independently selected from the group consisting of NR ³ R ⁴ and NR ³ R ⁴ , said aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) one of NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S (O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O) )OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , optionally selected from one or more groups independently selected from the group consisting of, said aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR one of ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, Halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl , C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), from S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . may be optionally substituted with one or more independently selected
R ⁵ and A ² may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
I is 0, 1 or 2. A pharmaceutical composition for diuresis, comprising a compound represented by the following formula (1), its E- or Z- isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of two isomers thereof:
[Formula 1]

In Formula 1,
V ¹ and V ² are each independently Aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ one of C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , With one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , NR ³ R ⁴ . optionally substituted, said aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C one of (O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl, hetero aryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl) , S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , with one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted,
i and j are each independently 0, 1 or 2,
R ¹ and R ² are hydrogen, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , independently selected from the group consisting of C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , said aryl, heteroaryl, heterocyclyl , C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O) one of OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ,
R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ³ and R ⁴ may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
A ¹ is

It is represented by a structure selected from the group consisting of,
X ¹ and X ² are each independently selected from the group consisting of O, S, CHR ⁴ and (or?) NR ⁴ ,
J is N or CH;
R ⁵ , R ⁶ and R ⁷ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C independently selected from the group consisting of ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, heterocyclyl, aryl, heteroaryl and trifluoromethyl, wherein one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C ₁ to C ₁₀ alkylaryl and heteroaryl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, tri Fluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl , S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and one or more groups independently selected from NR ³ R ⁴ , said aryl, arylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , one of OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethyl Toxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S (O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C optionally selected from one or more groups independently selected from (O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ⁵ and A ¹ may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is Oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ optionally substituted with one or more groups independently selected from , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . A diuretic pharmaceutical comprising a compound represented by the following formula (2), its E- or Z- isomer, its optical isomer, a mixture of two isomers, a precursor thereof, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient Composition:
[Formula 2]

In Formula 2,
V ³ and V ⁴ are each independently aryl, heteroaryl, C ₃ ~ C ₇ cycloalkyl, heterocycloalkyl, C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ heteroalkyl, C ₂ ~ C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C( O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ one of C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl , trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ optionally substituted with one or more groups independently selected from aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl) ), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR one of ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl , C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O ) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O) OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ;
i is each independently 0, 1 or 2,
R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ³ and R ⁴ may be cycled together to a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring (which may form a ring), said carbocyclic, heterocyclic , one of the aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR optionally substituted with one or more groups independently selected from ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ;
A ² is

It is represented by a structure selected from the group consisting of
X ³ is hydrogen, OR ³ , aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O)OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ , wherein OR ³ , aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O) one of OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, Sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl , C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O) one independently selected from R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Optionally selected from the above group, the aryl, C ₁ ~ C ₁₀ alkylaryl, C ₃ ~ C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ ~ C ₁₀ alkyl, C ₂ ~ C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ one of hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl , heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R at least one independently selected from ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted with a group,
i is 0, 1 or 2,
X ⁴ is O, S, NR ⁵ , NSO ₂ R ⁵ , C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, aryl, arylalkyl, C ₁ to C ₁₀ alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR ⁵ , NSO ₂ R ⁵ , C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, aryl, arylalkyl, C ₁ ~ C ₁₀ alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ⁵ , C(O)R ⁵ , OR ⁵ , NR ⁵ C(O)OR ⁶ , C(O)NR ⁵ R ⁶ and NR ⁵ R ⁶ may be optionally substituted with one or more selected from the group consisting of,
R ⁵ to R ⁸ are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) independently selected from the group consisting of NR ³ R ⁴ and NR ³ R ⁴ , said aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) one of NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S (O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O) )OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , optionally selected from one or more groups independently selected from the group consisting of, said aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR one of ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, Halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl , C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), from S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . may be optionally substituted with one or more independently selected
R ⁵ and A ² may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
I is 0, 1 or 2. 11. The method of claim 10,
of the compound of Formula 2
V ³ is C ₁ to C ₆ alkyl,
V ⁴ is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl includes 1 to 3 heteroatoms selected from the group consisting of N, O and S,
A ² is

ego,
X ³ is OR ³ ,
R ³ is H;
R ₈ is H, the pharmaceutical composition. 11. The method of claim 10,
of the compound of Formula 2,
V ³ is C ₁ to C ₄ alkyl,
V ⁴ is pyrrole,
A ² is

ego,
X ³ is OH,
R ₈ is H, the pharmaceutical composition. 11. The method of claim 9 or 10,
A pharmaceutical composition, wherein the compound of Formula 1 or 2 is selected from the group consisting of the following compounds:
4-(thiophen-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F1 ),
2-(4-(tert-butyl)phenyl)-4-(thiazol-5-ylmethylene)oxazol-5(4H)-one ( F2 ),
2-(4-(tert-butyl)phenyl)-4-((2-methyl-1H-indol-3-yl)methylene)oxazol-5(4H)-one ( F3 ),
tert-Butyl 3-((2-(4-(tert-butyl)phenyl)-5-oxoxazol-4(5H)-ylidene)methyl)-1H-indole-1-carboxylate ( F4 ),
4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-di-hydrooxazol-2-yl) benzonitrile ( F5 ),
2-(4-(tert-butyl)phenyl)-4-((1-methyl-1H-pyrrol-2-yl)methylene)oxazol-5(4H)-one ( F6 ),
methyl 4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzoate ( F7 ),
2-(4-(tert-butyl)phenyl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F8 ),
2-(4-(tert-butyl)phenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F9 ),
4-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F10 ),
4- (benzo [b] thiophen-2-ylmethylene) -2- (4- (tert-butyl) phenyl) oxazol-5 (4H) -one ( F11 ),
4-((1H-pyrrol-2-yl)methylene)-2-(4-isopropylphenyl)oxazol-5(4H)-one ( F12 ),
2-(4-(tert-butyl)phenyl)-4-(quinolin-4-ylmethylene)oxazol-5(4H)-one ( F13 ), 2-(4-isobutylphenyl)-4-(thi ofen-2-ylmethylene)oxazol-5(4H)-one ( F14 ),
2-(4-isobutyl phenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F15 ),
4- (benzo [b] thiophen-3-ylmethylene) -2- (4-isopropylphenyl) oxazol-5 (4H) -one ( F16 ),
4-((1H-pyrrol-2-yl)methylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F17 ),
4-(thiophen-3-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F18 ),
4-(furan-2-ylmethylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F19 ),
4-((1H-pyrrol-2-yl)methylene)-2-(4-isobutylphenyl)oxazol-5(4H)-one ( F20 ),
4- (benzo [b] thiophen-3-ylmethylene) -2- (4-isobutylphenyl) oxazol-5 (4H) -one ( F21 ),
2-(4-bromophenyl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F22 ),
2-cyclo-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F23 ),
2-([1,1'-biphenyl]-4-yl)-4-((4-methylthiazol-5-yl)methylene)oxazol-5(4H)-one ( F24 ),
4-((1H-pyrrol-2-yl)methylene)-2-([1,1'-biphenyl]-4-ylmethyl)oxazol-5(4H)-one ( F25 ),
4-((1H-pyrrol-2-yl)methylene)-2-(4-butylphenyl)oxazol-5(4H)-one ( F26 ),
2-(4-(tert-butyl)phenyl)-4-((1-phenyl-1H-pyrrol-2-yl)methylene)oxazol-5(4H)-one ( F27 ),
2-([1,1'-biphenyl]-4-ylmethyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F28 ),
2-(2,3-dihydro-1H-inden-5-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F29 ),
4-((1H-pyrrol-2-yl)methylene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F30 ),
methyl 4-(4-(furan-2-ylmethylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzoate ( F31 ),
methyl 4- (5-oxo-4- (thiophen-3-ylmethylene) -4,5-dihydrooxazol-2-yl) benzoate ( F32 ),
N- (4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl) acetamide ( F33 ),
2- (2-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F34 ),
N-(tert-butyl)-4-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-di-hydrooxazol-2-yl)benzene sulfonamide ( F35 ),
N-isopropyl-4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) benzene sulfonamide ( F36 ),
2-([1,1'-biphenyl]-4-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F37 ),
2-(4-(tert-butyl)phenyl)-4-(furan-2-ylmethylene)oxazol-5(4H)-one ( F38 ),
2-(4-(tert-butyl)phenyl)-4-((1-methyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F39 ),
2-(4-(tert-butyl)phenyl)-4-(pyridin-3-ylmethylene)oxazol-5(4H)-one ( F40 ),
2-(4-(tert-butyl)phenyl)-4-(pyridin-4-ylmethylene)oxazol-5(4H)-one ( F41 ),
2-([1,1'-biphenyl]-4-yl)-4-(pyridin-3-ylmethylene)oxazol-5(4H)-one ( F42 ), 2-(4-(tert-butyl) )phenyl)-4-(4-(methylthio)benzylidene)oxazol-5(4H)-one ( F43 ),
4-benzylidene-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F44 ),
2- (4-bromophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F45 ),
2- (4-isopropylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F46 ),
2-(4-isopropylphenyl)-4-(thiophen-3-ylmethylene)oxazol-5(4H)-one ( F47 ),
4-(furan-2-ylmethylene)-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-one ( F48 ),
4- (furan-2-ylmethylene) -2- (4-isopropylphenyl) oxazol-5 (4H) -one ( F49 ),
2- (4-bromophenyl) -4- (furan-2-ylmethylene) oxazol-5 (4H) -one ( F50 ),
2- (4-bromophenyl) -4- (thiophen-3-ylmethylene) oxazol-5 (4H) -one ( F51 ),
2-(naphthalen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F52 ),
2- (4-butylphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F53 ),
2-(4-butylphenyl)-4-(furan-2-ylmethylene)oxazol-5(4H)-one ( F54 ),
2- (4- (difluoromethoxy) phenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F55 ),
2-(4-(tert-butyl)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F56 ), 4-(2-nitrobenzylidene)-2- phenyloxazol-5(4H)-one ( F57 ),
4-((2-(4-(tert-butyl)phenyl)-5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate ( F58 ),
2- (3-chlorobenzo [b] thiophen-2-yl) -4- (4- (dimethylamino) benzylidene) oxazol-5 (4H) -one ( F59 ),
4-((2-(4-methoxyphenyl)-5-oxooxazol-4(5H)-ylidene)methyl)benzoic acid ( F60 ),
2-phenyl-4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F61 ),
4-(4-isopropylbenzylidene)-2-(naphthalen-1-yl)oxazol-5(4H)-one ( F62 ),
2-(3-iodo-4-methylphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F63 ),
4-(4-(benzyloxy)benzylidene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F64 ),
4-((1-(2-chlorobenzyl)-1H-pyrrol-2-yl)methylene)-2-phenyloxazol-5(4H)-one ( F65 ),
N-(4-(4-(2-(allyloxy)-4-(diethylamino)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)-5-bro monicotinamide ( F66 ),
4-((2-(2-chlorophenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl 4-(tert-butyl)benzoate ( F67 ),
4-((Z)-1-(3-ethyl-5-methoxybenzo[d]thiazol-2(3H)-ylidene)butan-2-ylidene)-2-phenyloxazole-5(4H )-on ( F68 ),
4-((2-(4-acetamidophenyl)-5-oxoxazol-4(5H)-ylidene)methyl)-2-ethoxyphenyl thiophene-2-carboxylate ( F69 ),
4-((6-ethoxy-2-(phenylthio)quinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F70 ),
2-(3-bromophenyl)-4-((5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F71 ),
4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-bromophenyl)oxazol-5(4H)-one ( F72 ),
2-(4-(tert-butyl)phenyl)-4-((5-(3-(trifluoro-methyl)phenyl)furan-2-yl)methylene)oxazol-5(4H)-one ( F73 ),
4-((7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F74 ),
2-(4-methoxyphenyl)-4-(2-(thiophen-2-yl)-4H-chromen-4-ylidene)oxazol-5(4H)-one ( F75 ),
N,N-dimethyl-3-((5-oxo-2-(p-tolyl)oxazol-4(5H)-ylidene)methyl)-1H-indole-1-sulfonamide ( F76 ),
2-((2-(4-chlorophenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl 4-acetamidobenzenesulfonate ( F77 ),
4-((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)phenyl furan-2-carboxylate ( F78 ),
2,2'-(1,4-phenylene)bis(4-((5-methylfuran-2-yl)methylene)oxazol-5(4H)-one) ( F79 ),
2-((2-(4-(tert-butyl)phenyl)-5-oxooxazol-4(5H)-ylidene)methyl)phenyl benzenesulfonate ( F80 ),
4-((1-acetyl-1H-indol-3-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F81 ),
4-((1-acetyl-3-phenyl-1H-pyrazol-4-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F82 ),
4-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-2-(p-tolyl)oxazol-5(4H)-one ( F83 ),
4-((6-Methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methylene)-2-phenyloxazol-5(4H)-one ( F84 ),
4-(2,6-diphenyl-4H-thiopyran-4-ylidene)-2-phenyloxazol-5(4H)-one ( F85 ),
N-(4-(4-(4-((2-chloroethyl)(methyl)amino)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F86 ),
2- (4-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F87 ),
2- (4-chlorophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F88 ),
2-(thiophen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F89 ),
4- (5-oxo-4- (thiophen-2-ylmethylene) -4,5-dihydrooxazol-2-yl) phenyl acetate ( F90 ),
2- (4-chloro-3-nitrophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F91 ),
2- (2-chlorophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F92 ),
2- (2-chloro-4-nitrophenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F93 ),
4- (thiophen-2-ylmethylene) -2- (3,4,5-trimethoxy phenyl) oxazol-5 (4H) -one ( F94 ),
2- (4-phenoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F95 ),
2-(4-(tert-butyl)phenyl)-4-((5-methylthiophen-2-yl)methylene)oxazol-5(4H)-one ( F96 ),
2- (benzo [d] [1,3] dioxol-5-yl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F97 ),
2-(4-(2-oxo-pyrrolidin-1-yl)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F98 ),
4-((5-chlorothiophen-2-yl)methylene)-2-(4-methoxyphenyl)oxazol-5(4H)-one ( F99 ),
2-(benzo[d][1,3]dioxol-5-yl)-4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)oxazole-5( 4H)-on ( F100 ),
2- (3,4-diethoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F101 ),
2-(4-(difluoromethoxy)-3-methoxyphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F102 ),
2-(5-ethyl-4-methylthiophen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F103 ),
2- (3-methoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F104 ),
4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F105 ),
N-(4-(4-((4-bromothiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F106 ),
N-(4-(4-((5-bromothiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F107 ),
N-(4-(4-((5-(dimethylamino)thiophen-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl)acetamide ( F108 ) ,
2-(4-(benzyloxy)phenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F109 ),
2-((E)-styryl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F110 ),
2-(5-methylthiophen-2-yl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F111 ),
N,N-diethyl-3-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F112 ),
2-(2-methoxyphenyl)-4-((2,4,5-trimethylthieno[2,3-d]pyrimidin-6-yl)methylene)oxazol-5(4H)-one ( F113 ),
4-((5-(dimethylamino)thiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F114 ),
4-((5-methylthiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F115 ),
N,N-dimethyl-3-(5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F116 ),
4-((5-bromothiophen-2-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F117 ),
4-((5-bromothiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F118 ),
2-(5-methylthiophen-2-yl)-4-((5-methylthiophen-2-yl)methylene)oxazol-5(4H)-one ( F119 ),
4-((5-(piperidin-1-yl)thiophen-2-yl)methylene)-2-(thiophen-2-yl)oxazol-5(4H)-one ( F120 ),
4-((5-bromothiophen-2-yl)methylene)-2-(2-(difluoro-methoxy)phenyl)oxazol-5(4H)-one ( F121 ),
2-(4-(tert-butyl)phenyl)-4-(2-(difluoromethoxy)benzylidene)oxazol-5(4H)-one ( F122 ),
4-((1-(2-chlorobenzyl)-1H-pyrazol-4-yl)methylene)-2-(naphthalen-2-yl)oxazol-5(4H)-one ( F123 ),
2-(4-(tert-butyl)phenyl)-4-((1-phenyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F124 ),
2-(2-methoxyphenyl)-4-((1-methyl-1H-pyrazol-4-yl)methylene)oxazol-5(4H)-one ( F125 ),
N-(tert-butyl)-4-(4-((5-methylfuran-2-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F126 ) ,
N,N-diethyl-4-(4-(1-methylpyridin-2(1H)-ylidene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F127 ) ,
2-(4-((2-(2-methoxyphenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenoxy)acetamide ( F128 ),
N-(4-((2-(4-isopropoxyphenyl)-5-oxoxazol-4(5H)-ylidene)methyl)phenyl)acetamide ( F129 ),
4-((1-benzyl-1H-pyrazol-4-yl)methylene)-2-(4-isopropoxyphenyl)oxazol-5(4H)-one ( F130 ),
N,N-diethyl-3-(4-((1-methyl-1H-pyrazol-4-yl)methylene)-5-oxo-4,5-dihydrooxazol-2-yl)benzenesulfonamide ( F131 ),
4-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-2-(2-iodophenyl)oxazol-5(4H)-one ( F132 ),
4-(4-((3,5-Dimethylisoxazol-4-yl)methoxy)-3-methoxybenzylidene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F133 ),
N-(4-(4-(4-(1H-1,2,4-triazol-1-yl)benzylidene)-5-oxo-4,5-dihydrooxazol-2-yl)phenyl) acetamide ( F134 ),
2-(2-(difluoromethoxy)phenyl)-4-((E)-3-(furan-2-yl)allylidene)oxazol-5(4H)-one ( F135 ),
4-((1-(tert-butyl)-1H-pyrazol-4-yl)methylene)-2-(2-methoxyphenyl)oxazol-5(4H)-one ( F136 ),
methyl 2- (5-oxo-1-phenyl-4- (thiophen-2-ylmethylene) -4,5-dihydro-1H-pyrazol-3-yl) acetate ( F137 ),
3- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoic acid ( F138 ),
3-(4-chlorophenyl)-5-((5-methylthiophen-2-yl)methylene)thiazolidine-2,4-dione ( F139 ),
2-(2,4-dioxo-5-(thiophen-2-ylmethylene)thiazolidin-3-yl)-N-(p-tolyl)acetamide ( F140 ),
3-(4-ethoxyphenyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F141 ),
3-((diethylamino)methyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F142 ),
3-(3-nitrobenzyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione ( F143 ), 3-phenyl-5-(thiophen-2-ylmethylene)thia Zolidine-2,4-dione ( F144 ),
methyl 2- (2,4-dioxo-5- (thiophen-2-ylmethylene) thiazolidin-3-yl) propanoate ( F145 ),
2-(4-((3-(3-chlorophenyl)-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)phenoxy)acetic acid ( F146 ),
2-(3-((Z)-((Z)-2-((4-ethoxyphenyl)imino)-3-methyl-4-oxothiazolidin-5-ylidene)methyl)-1H- indol-1-yl)acetic acid ( F147 ),
5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-3-phenyl-2-thioxothiazolidin-4-one ( F148 ),
3-benzyl-5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F149 ),
3-methyl-1- (4-nitrophenyl) -4- (thiophen-2-ylmethylene) -1H-pyrazol-5 (4H) -one ( F150 ),
4-(3-methyl-4-((5-methylthiophen-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)benzene sulfonamide ( F151 ) ,
3-methyl-4-((5-methylthiophen-2-yl)methylene)-1-(naphthalen-2-yl)-1H-pyrazol-5(4H)-one ( F152 ),
3-(3-methyl-4-((5-(4-methyl-2-nitrophenyl)furan-2-yl)methylene)-5-oxo-4,5-dihydro-1H-pyrazole-1 -yl) benzoic acid ( F153 ),
Ethyl 4-methyl-2-(3-methyl-5-oxo-4-(thiophen-2-ylmethylene)-4,5-dihydro-1H-pyrazol-1-yl)thiazole-5-carr carboxylate ( F154 ),
3-methyl-1-phenyl-4-(thiophen-2-ylmethylene)-1H-pyrazol-5(4H)-one ( F155 ),
2,6-bis((5-bromothiophen-2-yl)methylene)cyclohexanone ( F156 ),
2-(4-(dimethylamino)benzylidene)-6-(thiophen-2-ylmethylene)cyclo-hexanone ( F157 ),
2,6-bis(thiophen-2-ylmethylene)cyclohexanone ( F158 ),
4-((5-(2-methoxy-4-nitrophenyl)furan-2-yl)methylene)-3-phenylisoxazol-5(4H)-one ( F159 ),
2-chloro-5- (5- ((2- (3-chloro-4-methylphenyl) hydrazinylidene) methyl) furan-2-yl) benzoic acid ( F160 ),
5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F161 ),
5-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)-2-thioxothiazolidin-4-one ( F162 ),
6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-5-imino-2-propyl-5H-[1,3,4]thia diazolo[3,2-a]pyrimidin-7(6H)-one ( F163 ),
4-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-1-(cyclohexa-1,3-dien-1-yl)pyrazolidine -3,5-dione ( F164 ),
6-(4-(2-(4-(tert-butyl)phenoxy)ethoxy)-3-methoxybenzylidene)-2-ethyl-5-imino-5H-[1,3,4]thia diazolo[3,2-a]pyrimidin-7(6H)-one ( F165 ),
5-(2-(2-(4-(tert-butyl)phenoxy)ethoxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione ( F166 ),
5-((5-ethyl-3-(4-methoxybenzoyl)thiophen-2-yl)amino)-3,3-dimethyl-5-oxopentanoic acid ( F167 ),
2-((1,7-dibenzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio)acetic acid ( F168 ),
4-((E)-3-phenylallylidene)-3-(p-tolyl)isoxazol-5(4H)-one ( F169 ),
4-(2-(allyloxy)benzylidene)-3-(4-nitrophenyl)isoxazol-5(4H)-one ( F170 ),
4-((4-methylthiazol-5-yl)methylene)-2-(4-propylphenyl)oxazol-5(4H)-one ( F171 ),
4-((1H-pyrrol-2-yl)methylene)-2-(4-butoxyphenyl)oxazol-5(4H)-one ( F172 ),
2-(4-hexylphenyl)-4-(thiophen-2-ylmethylene)oxazol-5(4H)-one ( F173 ),
4-((1H-indol-2-yl)methylene)-2-(4-(tert-butyl)phenyl)oxazol-5(4H)-one ( F174 ),
4-(furan-2-ylmethylene)-2-(4-pentylphenyl)oxazol-5(4H)-one ( F175 ),
2- (4-butoxyphenyl) -4- (thiophen-2-ylmethylene) oxazol-5 (4H) -one ( F176 ),
5-((1H-pyrrol-2-yl) methylene)-2-(4-(tert-butyl)phenyl)-3,5-dihydro-4H-imidazol-4-one ( F177 ),
methyl 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G1 ),
methyl 2-(4-(tert-butyl)benzamido)-3-(thiophen-2-yl)acrylate ( G2 ),
2-(4-(tert-butyl)benzamido)-3-(thiophen-2-yl)acrylic acid ( G3 ),
Methyl 2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylate ( G4 ),
2-(4-(tert-butyl)benzamido)-3-(furan-2-yl)acrylic acid ( G5 ),
tert-butyl 2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G6 ),
2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G7 ),
2-(4-(tert-butyl)benzamido)-3-(thiophen-3-yl)acrylic acid ( G8 ),
2-(4-(tert-butyl)benzamido)-3-(4-methylthiazol-5-yl)acrylic acid ( G9 ),
2-(4-(tert-butyl)benzamido)-3-(1-methyl-1H-pyrazol-4-yl)acrylic acid ( G10 ),
methyl 2-(4-butylbenzamido)-3-(1H-pyrrol-2-yl)acrylate ( G11 ),
2-(4-butylbenzamido)-3-(thiophen-2-yl)acrylic acid ( G12 ),
2-(4-(tert-butyl)benzamido)-3-(1-phenyl-1H-pyrrol-2-yl)acrylic acid ( G13 ),
methyl 2-(4-(tert-butyl)benzamido)-3-(1-phenyl-1H-pyrrol-2-yl)acrylate ( G14 ),
methyl 3-(1H-pyrrol-2-yl)-2-(4-(trifluoro-methyl)benzamino)acrylate ( G15 ),
2-(4-bromobenzamido)-3-(furan-2-yl)acrylic acid ( G16 ),
methyl 3-(furan-2-yl)-2-(4-(trifluoromethyl)benzamino)acrylate ( G17 ),
3-(furan-2-yl)-2-(4-(trifluoromethyl)benzamido)acrylic acid ( G18 ),
2-(4-bromobenzamido)-3-(thiophen-2-yl)acrylic acid ( G19 ),
methyl 2-(4-bromobenzamido)-3-(furan-2-yl)acrylate ( G20 ),
2-(4-bromobenzamido)-3-(furan-2-yl)acrylic acid ( G21 ),
2-(4-butylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G22 ),
(E)-N'-(1-(naphthalen-2-yl)ethylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carbohydrazide ( G23 ),
(E)-2-((1H-benzo[d]imidazol-2-yl)thio)-N'-(3-methylbenzylidene)acetohydrazide ( G24 ),
N′-(2-(thiophen-2-yl)acetyl)-4-(trifluoro-methyl)benzohydrazide ( G25 ),
4-chloro-N'-(2-(thiophen-2-yl)acetyl)benzohydrazide ( G26 ),
2-(2-(2-(benzo[d]thiazol-2-ylthio)acetamido)thiazol-4-yl)acetic acid ( G27 ),
N-(3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-2-hydroxypropyl)-N-(4-methoxyphenyl)benzenesulfonamide ( G28 ) ,
4-Amino-N5-(furan-2-ylmethyl)-N5-(2-oxo-2-(tert-pentylamino)-1-(quinolin-6-yl)ethyl)isothiazol-3,5- dicarboxamide ( G29 ),
4-(tert-butyl)-N-(3-((4-chlorophenyl) amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl)benzamide ( G30 ),
4-(tert-butyl)-N-(3-((furan-3-ylmethyl)amino)-3-oxo-1-(thiophen-2-yl)prop-1-en-2-yl) benzamide ( G31 ),
3-(furan-2-yl)-2-(4-isobutoxybenzamido)acrylic acid ( G32 ),
N-(1-(furan-2-yl)-3-(methylamino)-3-oxoprop-1-en-2-yl)-4-isobutoxybenzamide ( G33 ),
N-(3-amino-1-(furan-2-yl)-3-oxoprop-1-en-2-yl)-4-(tert-butyl)benzamide ( G34 ),
methyl-2-(4-(tert-butyl)benzamido)-3-(1H-pyrrol-2-yl)acrylate ( G35 ),
2-(2-naphtamido)-3-(thiophen-3-yl)acrylic acid ( G36 ),
3-(benzo[b]thiophen-3-yl)-2-(4-(tert-butyl)benzamido)acrylic acid ( G37 ),
2-(4-isobutyl-benzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G38 ),
2-(1-naphtamido)-3-(4-methylthiazol-5-yl)acrylic acid ( G39 ) and
2-(4-Propylbenzamido)-3-(1H-pyrrol-2-yl)acrylic acid ( G40 ). The pharmaceutical composition according to claim 9 or 10, co-administered with another diuretic. The pharmaceutical composition according to claim 14, wherein the other diuretic is furosemide, and the pharmaceutical composition and the furosemide are administered in a weight ratio of 1:10. A health functional food for diuresis, comprising a compound represented by the following formula (1), its E- or Z- isomer, its optical isomer, its precursor, a pharmaceutically acceptable salt thereof, a solvate thereof, or a mixture of two isomers thereof :
[Formula 1]

In Formula 1,
V ¹ and V ² are each independently Aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ one of C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , With one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , NR ³ R ⁴ . optionally substituted, said aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C one of (O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl, hetero aryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl) , S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , with one or more groups independently selected from OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted,
i and j are each independently 0, 1 or 2,
R ¹ and R ² are hydrogen, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , independently selected from the group consisting of C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , said aryl, heteroaryl, heterocyclyl , C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O) one of OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ,
R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ³ and R ⁴ may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
A ¹ is

It is represented by a structure selected from the group consisting of,
X ¹ and X ² are each independently selected from the group consisting of O, S, CHR ⁴ and NR ⁴ ,
J is N or CH;
R ⁵ , R ⁶ and R ⁷ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C independently selected from the group consisting of ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, heterocyclyl, aryl, heteroaryl and trifluoromethyl, wherein one of alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, C ₁ to C ₁₀ alkylaryl and heteroaryl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, tri Fluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl , S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and one or more groups independently selected from NR ³ R ⁴ , said aryl, arylalkyl , heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , one of OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethyl Toxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S (O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C optionally selected from one or more groups independently selected from (O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ⁵ and A ¹ may be cycled together to form a 4-10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is Oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ optionally substituted with one or more groups independently selected from , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Diuretic health comprising a compound represented by the following formula (2), its E- or Z- isomer, its optical isomer, a mixture of two isomers, a precursor thereof, a pharmaceutically acceptable salt or a solvate thereof as an active ingredient Nutraceuticals:
[Formula 2]

In Formula 2,
V ³ and V ⁴ are each independently aryl, heteroaryl, C ₃ ~ C ₇ cycloalkyl, heterocycloalkyl, C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ heteroalkyl, C ₂ ~ C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C( O)R ³ , OR ³ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ , or NR ³ R ⁴ , said aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), OS(O) _i (aryl), S(O) _i NR ³ R ⁴ , C(O)R ³ , OR ³ , OCOR ³ , NR ³ one of C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl , trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ optionally substituted with one or more groups independently selected from aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl) ), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR one of ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl , C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O ) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O) OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ optionally substituted with one or more groups independently selected from R ⁴ ;
i is each independently 0, 1 or 2,
R ³ and R ⁴ are hydrogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, hetero Aryl, Heteroaryl(C ₁ ~ C ₁₀ Alkyl), C ₁ ~ C ₁₀ Alkylheteroaryl, C ₁ ~ C ₁₀ Alkyl, C ₂ ~ C ₆ Alkenyl, C ₂ ~ C ₆ Alkynyl, C ₃ ~ C ₆ independently selected from the group consisting of cycloalkyl, heterocyclyl and trifluoromethyl, said aryl, aryl (C ₁ to C ₁₀ alkyl), C ₁ to C ₁₀ alkylaryl, heteroaryl, heteroaryl (C ₁ to one of C ₁₀ alkyl), C ₁ to C ₁₀ alkylheteroaryl, C ₁ to C ₁₀ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl and heterocyclyl is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C( optionally substituted with one or more groups independently selected from O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , or
R ³ and R ⁴ may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
A ² is

It is represented by a structure selected from the group consisting of,
X ³ is hydrogen, OR ³ , aryl, heteroaryl, C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alkynyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O)OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ , wherein OR ³ , aryl, heteroaryl , C ₃ to C ₇ cycloalkyl, heterocycloalkyl, C ₁ to C ₆ alkyl, C ₁ to C ₆ heteroalkyl, C ₂ to C ₁₀ alkenyl, C ₀ to C ₃ methylenehydrazine, C ₂ to C ₁₀ alky nyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ , C(O)R ³ , OC(O)R ³ , (O)COR ³ , NR ³ C(O) one of OR ³ , NR ³ C(O)R ³ , C(O)NR ³ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, Sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, C ₃ to C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl , C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O) one independently selected from R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . Optionally selected from the above group, the aryl, C ₁ ~ C ₁₀ alkylaryl, C ₃ ~ C ₇ cycloalkyl, heteroaryl, heterocycloalkyl, C ₁ ~ C ₁₀ alkyl, C ₂ ~ C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ one of hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, C ₃ to C ₇ cycloalkyl , heteroaryl, heterocycloalkyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R at least one independently selected from ³ , OR ³ , OCR ³ F ₂ , OCOR ³ , NR ³ C(O)OR ⁴ , NR ³ C(O)R ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . optionally substituted with a group,
i is 0, 1 or 2,
X ⁴ is O, S, NR ⁵ , NSO ₂ R ⁵ , C ₁ to C ₆ alkyl, C ₁ to C ₆ alkoxy, aryl, arylalkyl, C ₁ to C ₁₀ alkylaryl, heteroaryl, cycloalkyl and heterocycle selected from the group consisting of ril, wherein the NR ⁵ , NSO ₂ R ⁵ , C ₁ ~ C ₆ alkyl, C ₁ ~ C ₆ alkoxy, aryl, arylalkyl, C ₁ ~ C ₁₀ alkylaryl, heteroaryl, cycloalkyl or hetero Cyclyl is optionally hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, sulfanyl, aryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ⁵ , C(O)R ⁵ , OR ⁵ , NR ⁵ C(O)OR ⁶ , C(O)NR ⁵ R ⁶ and NR ⁵ R ⁶ may be optionally substituted with one or more selected from the group consisting of,
R ⁵ to R ⁸ are hydrogen, cyano, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) independently selected from the group consisting of NR ³ R ⁴ and NR ³ R ⁴ , said aryl, C ₁ to C ₁₀ alkylaryl, arylalkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₆ alkyl, C ₂ to C ₆ alkenyl, C ₂ to C ₆ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl ), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C( O) one of NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S (O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O) )OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ , optionally selected from one or more groups independently selected from the group consisting of, said aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), S(O) _i NR one of ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ is hydrogen, oxo, Halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl , C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), S(O) _i (aryl), S(O) _i (heteroaryl), from S(O) _i NR ³ R ⁴ , C(O)OR ³ , C(O)R ³ , OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ . may be optionally substituted with one or more independently selected
R ⁵ and A ² may be cycled together to form a 4 to 10 membered carbocyclic, heterocyclic, aromatic or heteroaromatic ring, wherein one of the carbocyclic, heterocyclic, aromatic or heteroaromatic rings is hydrogen, oxo, halogen, cyano, azaido, nitro, trifluoromethyl, trifluoromethoxy, aryl, C ₁ to C ₁₀ alkylaryl, heteroaryl, heterocyclyl, C ₁ to C ₁₀ alkyl, C ₂ to C ₁₀ alkenyl, C ₂ to C ₁₀ alkynyl, C ₃ to C ₆ cycloalkyl, S(O) _i (C ₁ to C ₆ alkyl), C(O)OR ³ , C(O)R ³ , optionally substituted with one or more groups independently selected from OR ³ , NR ³ C(O)OR ⁴ , C(O)NR ³ R ⁴ and NR ³ R ⁴ ,
I is 0, 1 or 2.

Images