Antifibrotic NEU3 inhibitor compounds and methods of use

Abstract

To provide methods of preventing or inhibiting fibrosis using small molecule sialidase inhibitors.SOLUTION: The present disclosure also relates to methods of treating obesity, liver inflammation, steatosis and cancer. These methods can involve administering the compounds to a patent at risk of developing fibrosis inflammation, obesity, steatosis or cancer so as to inhibit NEU3. The present disclosure relates to anti-fibrotic compounds and methods of preventing or inhibiting fibrosis using such compounds. The compounds and methods may also prevent or inhibit fibrocyte formation, including proliferation, or fibrocyte activity, including activation, that may give rise to fibrosis.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Statement of Government Interest This invention was made with federal support awarded under 1R01HL132919 and by the National Institutes of Health. The federal government has certain rights in this invention.

[0002] Field of Disclosure FIELD OF THE DISCLOSURE The present disclosure relates to anti-fibrotic, anti-cancer, anti-steatotic, anti-liver inflammatory and anti-obesity agents, more particularly to inhibitors of the sialidase NEU3. [Background technology]

[0003] background Fibrocytes are a specialized cell type that plays a key role in the body's response to injury and inflammation. Fibrocytes form upon differentiation from CD14+ peripheral blood monocytes. Fibrocytes express markers of both hematopoietic (blood-producing) cells (CD45, MHC class II, CD34) and interstitial (structural tissue) cells (types I and III collagen, and fibronectin). Mature fibrocytes secrete cytokines, extracellular matrix proteins, and pro-angiogenic molecules.

[0004] Fibrocytes and the molecules they express or release extracellularly often lead to fibrosis, which is the development of scar tissue. Rather than normal wound healing in response to injury, fibrosis, which may result from inappropriate fibrocyte formation or activity, can be harmful if it occurs to too great an extent, for too long, or in the wrong location.

[0005] Consequently, controlling the formation of fibrocytes and their activity in the body can help control harmful fibrosis, thereby avoiding or treating any resulting diseases or disorders.

[0006] Obesity is the accumulation of body fat as a result of excessive food intake and / or lack of exercise. Obesity shortens life expectancy and is associated with approximately 300,000 deaths per year in the United States. Obesity also increases the likelihood of conditions such as type 2 diabetes, atherosclerosis, and hypertension.

[0007] Transforming growth factor-β1 (TGF-β1) is a protein signal. Increased extracellular levels of active TGF-β1 are strongly associated with fibrosis. TGF-β1 is produced as an inactive protein complex with latency-associated peptide (LAP), and upon release from the LAP complex, TGF-β1 alone drives the fibrotic process.

[0008] Sialidases are enzymes that remove sialic acid from complex carbohydrates. Sialidases, such as NEU1 and NEU3, are upregulated in patients with pulmonary fibrosis. NEU3 is also upregulated in some cancers, such as colon, renal, ovarian, and prostate cancer. Overexpression of NEU3 in human colon cancer cells promotes cell proliferation and adhesion, suggesting that the high levels of NEU3 observed in some tumors may be tumor-stimulating. Supporting the role of NEU3 in cancer, Neu3- / - knockout mice exhibit a reduced incidence of colitis-associated colon cancer.

[0009] In some cancers, high levels of NEU3 increase the extracellular accumulation of the cytokine interleukin-6 (IL-6), which is also associated with fibrosis. IL-6 also upregulates NEU3 in cultured human cells and in some cancers.

[0010] Serum amyloid P (SAP) is a blood protein that inhibits fibrocyte differentiation. Supporting the hypothesis that sialidases stimulate fibrosis, recombinant human NEU2, NEU3, and NEU4 stimulate fibrocyte differentiation when added to human peripheral blood mononuclear cells (PBMCs), attenuating the ability of human SAP to inhibit fibrocyte differentiation.

[0011] Thus, sialidase can stimulate fibrosis and cancer through the combined effects of increased TGF-β1 and IL-6 levels.

[0012] In the liver, excess calories lead to Kupffer cell (liver macrophage) activation, which in turn leads to inflammation, increased fatty acid synthesis in hepatocytes, and hepatic steatosis (abnormal lipid retention within hepatocytes), which in turn can lead to fibrosis or cirrhosis. Summary of the Invention [Means for solving the problem]

[0013] overview The present disclosure provides a compound of formula (I)

[0014] [ka] or a salt thereof, wherein:

[0015] In Formula I, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, -CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0016] In Formula I, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, -COCF3, -COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0017] In Formula I, R5 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0018] In Formula I, R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0019] In formula I, X can be selected from carbon, oxygen, or nitrogen.

[0020] The present disclosure also provides a compound of formula (II)

[0021] [ka] or a salt thereof, wherein:

[0022] In formula II, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0023] In Formula II, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0024] In Formula II, R5 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0025] In Formula II, R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0026] In formula II, X can be selected from carbon, nitrogen, or oxygen.

[0027] The present disclosure also provides a compound of formula (III)

[0028] [ka] or a salt thereof, wherein:

[0029] In formula III, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0030] In formula III, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0031] In Formula III, R5 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0032] In formula III, R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0033] In formula III, X can be selected from carbon, oxygen, or nitrogen.

[0034] The present disclosure also provides a compound of formula (IV)

[0035] [ka] or a salt thereof, wherein:

[0036] In formula IV, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole or other heterocycles.

[0037] In Formula IV, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0038] In Formula IV, R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6alkyl), or may be absent.

[0039] In formula IV, X can be selected from carbon, oxygen, or nitrogen.

[0040] In formula IV, Y can be selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group.

[0041] The present disclosure provides a compound of formula (V)

[0042] [ka] or a salt thereof, wherein:

[0043] In formula V, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0044] In Formula V, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0045] In Formula V, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0046] In Formula V, R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0047] In formula V, X can be selected from carbon, oxygen, or nitrogen.

[0048] In formula V, Y can be selected from carbon or nitrogen.

[0049] In formula V, Z can be selected from carbon, nitrogen, oxygen, or sulfur.

[0050] The present disclosure provides a compound of formula (VI):

[0051] [ka] or a salt thereof, wherein:

[0052] In formula VI, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0053] In Formula VI, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0054] In Formula VI, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0055] In Formula VI, R5 is hydrogen, methyl, -CF3, C1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0056] In formula VI, X can be selected from carbon, oxygen, or nitrogen.

[0057] The present disclosure provides a compound of formula (VII):

[0058] [ka] or a salt thereof, wherein:

[0059] In Formula VII, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0060] In Formula VII, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0061] In Formula VII, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0062] In Formula VII, R5 is hydrogen, methyl, —CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0063] In formula VII, X can be selected from carbon, oxygen, or nitrogen.

[0064] In formula VII, Y can be selected from carbon or nitrogen.

[0065] In formula VII, Z can be selected from carbon, nitrogen, oxygen, or sulfur.

[0066] The present disclosure provides a compound of formula (VIII):

[0067] [ka] or a salt thereof, wherein:

[0068] In Formula VIII, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0069] In Formula VIII, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0070] In Formula VIII, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0071] In Formula VIII, R5 is hydrogen, methyl, —CF3, C1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0072] In formula VIII, X can be selected from carbon, oxygen, or nitrogen.

[0073] The present disclosure provides a compound of formula (IX):

[0074] [ka] or a salt thereof, wherein:

[0075] In formula IX, B1, B2, B3, B4, B5, B6 and / or B7 can be selected from a single bond or a double (olefinic) bond.

[0076] In Formula IX, R1 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0077] In formula IX, R2 to R6 are hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0078] In formula IX, R7 is hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0079] In formula IX, X can be selected from carbon, oxygen, or nitrogen.

[0080] In formula IX, Y can be selected from carbon, nitrogen, oxygen, or sulfur.

[0081] The above methods may be combined with each other and, unless expressly mutually exclusive, may further comprise one or more of the following additional features, alone or in combination: i. the method can inhibit desialylation of LAP; ii. the method is capable of inhibiting desialylation of SAP; iii. the method can inhibit the formation or activation of fibrocytes; iv. the method can reduce the level or activity of TGF-β1 in a human; v. The compound can reduce the level of interleukin-6 in humans; vi. The method can reduce the level or activity of sialidase in a human; vii. The method can inhibit more than one sialidase; viii. The compounds can be administered locally to humans in areas where human sialidase activity is abnormally high; ix. The formulation may be administered by intravenous or intraperitoneal injection, orally, topically, by inhalation, or by other means enterally, or by parenteral administration; x. the compound used in the method is DANA; xi. The compound used in the method is 4-hydroxypyridine-2-carboxylic acid; xii. The compound used in the method is 5-acetamidopyridine-2-carboxylic acid; xiii. The compound used in the method is picolinic acid; xiv. The compound used in the method is 2-acetylpyridine; xv. The compound used in the method is methyl picolinate; xvi. The compound used in the method is 4-aminopicolinic acid; xvii. The compound used in the method is 5-nitropicolinic acid; xviii. The compound used in the method is 4-methoxypicolinic acid; xix. The compound used in the method is picolinamide; xx. The compound used in the method is 5-acetylamino-4-aminopicolinic acid; xxi. The compound used in the method is 1,4,5,6-tetrahydropyridine-2-carboxylic acid salt; xxii. The compound used in the method is L-pipecolic acid; xxiii. The compound used in the method is nicotinic acid; xxiv. The compound used in the method is salicylic acid; xxv. The compound used in the method is O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine; xxvi. The compound used in the method is 6-(hydroxymethyl)picolinic acid; xxvii. The compound used in the method is 5-aminopyridine-2-carboxylic acid; xxviii. The compound used in the method is 2-nitropyridine; xxix. The compound used in the method is 1-methyl-2-piperidinecarboxylic acid; xxx. The compound used in this method is 4-(trifluoromethyl)picolinic acid; xxxi. The compound used in this method is 4-methylpicolinic acid; xxxii. The compound used in the method is 4-aminonicotinic acid; xxxiii. The compound used in this method is 4-oxo-1,4-dihydropyridine-2-carboxylic acid; xxxiv. The compound used in the method is 4-amino-2-piperidinecarboxylic acid; xxxv. The compound used in the method is 4-amino-1-methyl-2-piperidinecarboxylic acid; xxxvi. The compound used in this method is 6-methyl-2-pyridinecarboxylic acid; xxxvii. The compound used in the method is oseltamivir; xxxviii. The compound used in the method is D-proline; xxxix. The compound used in this method is pyrrole-2-carboxylic acid; xl. The compound used in the method is azepane-2-carboxylic acid; xli. The dose administered can be sufficient to establish a systemic concentration of at least 3 μM or a concentration in the area of ​​administration of at least 3 μM. Administration can be daily for at least 1 week, at least 2 weeks, at least 3 weeks, or indefinitely; xlii. The dose administered can be sufficient to reduce the amount of neutral lipids in the liver of a human; and xliii. The dose administered can be sufficient to reduce the activity level of sialidase in humans.

[0082] For purposes of this Summary, certain aspects, advantages, and novel features of the invention have been described herein. It should be understood that not necessarily all such advantages can be achieved in accordance with any particular embodiment of the invention. Thus, for example, one skilled in the art will recognize that the invention can be embodied or performed to achieve one advantage or a collection of advantages taught herein without necessarily achieving other advantages that may be taught or suggested herein.

[0083] The graphical portions of this specification are included to further demonstrate certain aspects of the invention. The figures are not intended to, and should not be construed to encompass the entirety of the invention. Furthermore, different aspects of the invention are often illustrated as separate figures for clarity. These aspects may be combined with one another unless clearly incompatible. [Brief explanation of the drawings]

[0084] [Figure 1] FIG. 1 is a schematic, not to scale, of the feedback pathway between sialidase and fibrosis.

[0085] [Figure 2A] FIG. 2A shows a Western blot of recombinant human LAP protein stained with Sambucus nigra lectin, which detects sialic acid on glycoconjugates.

[0086] [Figure 2B] Figure 2B is a graph of sialic acid staining of Sambucus nigra quantified for recombinant human LAP protein from Figure 2A. Values ​​are mean ± standard error (n = 3). ** = p < 0.01, *** = p < 0.001 compared to LAP (one-way ANOVA, Bonferroni's test).

[0087] [Figure 3]Figure 3 is a graph showing the quantification of an ELISA assay specific for activating TGF-β1 performed on recombinant human L-TGF-β1 synthesized from CHO cells treated with recombinant human NEU3. Values ​​are mean ± standard error (n = 6). ** = p < 0.01 compared to 0NEU3 (one-way ANOVA, Bonferroni's test).

[0088] [Figure 4-1] Figure 4A is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4B is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4C is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4D is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-2] Figure 4E is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4F is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4G is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4H is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-3]Figure 4I is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4J is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4K is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4L is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-4] Figure 4M is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4N is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4O is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4P is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-5]Figure 4Q is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4R is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4S is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4T is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-6] Figure 4U is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4V is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4W is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4X is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-7]Figure 4Y is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4Z is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AA is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AB is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-8] Figure 4AC is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AD is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AE is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AF is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-9]Figure 4AG is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AH is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AI is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AJ is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-10] Figure 4AK is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AL is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AM is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AN is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-11]Figure 4AO is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AP is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AQ is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AR is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-12] Figure 4AS is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AT is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AU is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AV is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-13]Figure 4AW is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AX is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AY is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4AZ is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-14] Figure 4BA is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4BB is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4BC is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4BD is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). [Figure 4-15]Figure 4BE is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4BF is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4BG is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3). Figure 4BH is a graph quantifying the inhibition of NEU3-catalyzed TGF-β1 activation as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n≧3).

[0089] [Figure 5-1] Figure 5A is a graph quantifying the extracellular accumulation of IL-6 in human PBMC cultures after treatment with NEU1, NEU2, NEU3, or NEU4. Values ​​are means ± standard errors (n = 3). * = p < 0.05 (t-test).

[0090] [Figure 5-2] Figures 5B and 5C are graphs quantifying extracellular accumulation of IL-6 in human PBMC cultures after treatment with NEU3 in serum-free medium. Figure 5B shows IL-6 accumulation after 48 hours, and Figure 5C shows IL-6 accumulation after 5 days. Values ​​are means ± standard error (n = 3). * = p < 0.05, ** = p < 0.01, compared to NEU3 (t-test).

[0091] [Figure 5-3] Figures 5D and 5E are graphs quantifying extracellular accumulation of IL-6 in human PBMC cultures after treatment with NEU3 in serum-containing medium. Figure 5D shows IL-6 accumulation after 48 hours, and Figure 5E shows IL-6 accumulation after 5 days. Values ​​are means ± standard error (n = 3). * = p < 0.05, compared with 0NEU3 (t-test).

[0092] [Figure 6-1] Figure 6A is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6B is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6C is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6D is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). [Figure 6-2] Figure 6E is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6F is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6G is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6H is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). [Figure 6-3]Figure 6I is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6J is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6K is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6L is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). [Figure 6-4] Figure 6M is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6N is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6O is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6P is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-5]Figure 6Q is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6R is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6S is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6T is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). [Figure 6-6] Figure 6U is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6V is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6W is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). Figure 6X is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and selected compounds. Values ​​are means ± standard error (n≧3). [Figure 6-7]Figure 6Y is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6Z is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AA is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AB is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-8] Figure 6AC is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AD is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AE is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AF is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-9]Figure 6AG is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AH is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AI is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AJ is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-10] Figure 6AK is a graph showing the quantification of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AL is a graph showing the quantification of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AM is a graph showing the quantification of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AN is a graph showing the quantification of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-11]Figure 6AO is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AP is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AQ is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AR is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-12] Figure 6AS is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AT is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AU is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AV is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). [Figure 6-13]Figure 6AW is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6X is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AY is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3). Figure 6AZ is a graph quantifying the amount of extracellular accumulation of IL-6 in human PBMC cultures after 48 hours of treatment with NEU3 and select compounds. Values ​​are means ± standard error (n≧3).

[0093] [Figure 7] Figures 7A-7B are graphs quantifying the inhibition of recombinant murine NEU3-catalyzed TGF-β1 activation by 2-acetylpyridine (Figure 7A) and methyl picolinate (Figure 7B) as measured by a TGF-β1 ELISA kit. Values ​​are means ± standard error (n = 3).

[0094] [Figure 8]Figures 8A-8F are graphs quantifying the number of cells found in mouse bronchoalveolar lavage fluid after treatment with bleomycin. Figure 8A shows the total cell counts in bronchoalveolar lavage fluid after various treatments: saline (S), bleomycin (B), saline + 2-acetylpyridine (2AP), bleomycin + 2-acetylpyridine, saline + methyl picolinate (MP), bleomycin + methyl picolinate, saline + 4-amino-1-methyl-2-piperidinecarboxylic acid (AMPCA), and bleomycin + 4-amino-1-methyl-2-piperidinecarboxylic acid. Figures 8B-8F categorize the total cell counts by cell type: CD11b-positive cells (Figure 8B), CD11c-positive cells (Figure 8C), CD45-positive cells (Figure 8D), Ly6G-positive cells (Figure 8E), and Ly6C-positive cells (Figure 8F). Values ​​are means ± standard error (n≥3). *=p≤0.05, **=p≤0.01, ***=p≤0.001, ****=p≤0.0001 (one-way ANOVA, Bonferroni's test), #=p≤0.05, ##=p≤0.01, ###=p≤0.001 (t-test).

[0095] [Figure 9]9A-9H are photomicrographs of a set of sections of mouse lungs from mice treated with saline, bleomycin, saline + 2-acetylpyridine, bleomycin + 2-acetylpyridine, saline + methyl picolinate, bleomycin + methyl picolinate, saline + 4-amino-1-methyl-2-piperidinecarboxylic acid, and bleomycin + 4-amino-1-methyl-2-piperidinecarboxylic acid stained with Sirius Red to reveal collagen. Figure 9A is a saline-treated control, Figure 9B is bleomycin-treated, Figure 9C is saline and 2-acetylpyridine-treated, Figure 9D is bleomycin and 2-acetylpyridine-treated, Figure 9E is saline and methyl picolinate-treated, Figure 9F is bleomycin and methyl picolinate-treated, Figure 9G is saline and 4-amino-1-methyl-2-piperidinecarboxylic acid-treated, and Figure 9H is bleomycin and 4-amino-1-methyl-2-piperidinecarboxylic acid-treated. The bar in Figure 9A is 200 μM.

[0096] [Figure 10] Figure 10 is a graph quantifying the amount of staining in the micrographs of Figures 9A-H. Values ​​are means ± standard errors (n = 3). **** = p < 0.0001 (one-way ANOVA, Bonferroni's test), # = p < 0.05 (t-test).

[0097] [Figure 11]Figures 11A-D are graphs measuring percent body weight change over 21 days in mice treated with saline, bleomycin (bleo), saline + 2-acetylpyridine (2AP), bleomycin + 2-acetylpyridine, saline + methyl picolinate (MP), bleomycin + methyl picolinate, saline + 4-amino-1-methyl-2-piperidinecarboxylic acid (AMPCA), and bleomycin + 4-amino-1-methyl-2-piperidinecarboxylic acid (AMPCA). Figure 11A shows saline and bleomycin without drugs, Figure 11B shows saline and bleomycin with 2AP, Figure 11C shows saline and bleomycin with MP, and Figure 11D shows saline and bleomycin with AMPCA. Values ​​are mean ± standard error (n = 3). * = p < 0.05, ** = p < 0.01, *** = p < 0.001 (t-test).

[0098] [Figure 12] Figure 12 shows a graph quantifying the number of Mac2-positive cells per square millimeter of liver tissue in C57BL / 6 and Neu3- / - mice fed a standard (control) or high-fat diet (HFD). Liver sections were stained with Mac2 antibody to detect macrophages. Values ​​are means ± standard error (n = 3). * indicates p < 0.05, ** p < 0.01 (one-way ANOVA, Dunnett's test).

[0099] [Figure 13] Figures 13A-C are graphs quantifying the number of cells per square millimeter of liver tissue in C57BL / 6 and Neu3- / - mice fed a standard (control) or high-fat diet (HFD) for A) F4 / 80, B) CD64, and C) CLEC4f. Values ​​are means ± standard error (n=3). * indicates p<0.05, **p<0.01 (one-way ANOVA, Dunnett's test).

[0100] [Figure 14]Figure 14 is a graph quantifying the amount of fat in the liver of C57BL / 6 mice fed a standard (control) diet or a high-fat diet (HFD) and given either DANA or saline. Liver sections were stained with oil red O to detect neutral lipid accumulation. The percentage of stained area was quantified as a percentage of the total liver area. Values ​​are means ± standard error (n = 3). ***p < 0.001 (one-way ANOVA, Dunnett's test).

[0101] [Figure 15] Figure 15 is a graph quantifying the number of F4 / 80-positive cells per square millimeter of liver tissue from C57BL / 6 mice fed a standard (control) diet or a high-fat diet (HFD) and given either DANA or saline. Liver sections were stained with anti-F4 / 80 antibody to detect macrophages. Values ​​are means ± standard error (n = 3). * indicates p < 0.05 (one-way ANOVA, Dunnett's test).

[0102] [Figure 16] Figure 16 is a graph quantifying body weight change in C57BL / 6 mice fed a standard (control) diet or a high-fat diet (HFD) and given either DANA or saline. Mice were injected with PBS or DANA every 48 hours for 35 days. Mice were weighed daily. Values ​​are means ± standard errors (n = 6 mice per group). * indicates p < 0.05 (t-test) comparing HFD with HFD + DANA at each time point.

[0103] [Figure 17] Figure 17 shows a graph quantifying glucose levels in C57BL / 6 mice fed a standard (control) diet or a high-fat diet (HFD) and given either DANA or saline. Values ​​are means ± standard error (n = 5-6). * indicates p < 0.05 comparing HFD with HFD + DANA (t-test).

[0104] [Figure 18]Figure 18 is a graph quantifying glucose tolerance in C57BL / 6 mice over a 120-minute period, as assessed by area under the curve (AUC) analysis of Figure 17. Values ​​are means ± standard error (n = 5-6). "ns" indicates not significant. * indicates p < 0.05, ** p < 0.01 (one-way ANOVA, Dunnett's test). [Figure 19] Figure 19 is a graph quantifying organ weights in C57BL / 6 mice fed a standard (control) diet or a high-fat diet (HFD) and given either DANA or saline. After euthanasia, organs were weighed, including testicular interscapular white and brown adipose tissue, liver, spleen, lungs, and kidneys. Values ​​are percentages of body weight for each mouse. Values ​​are mean ± standard error (n = 3). **p<0.01, ***p<0.001, comparing HFD with HFD + DANA (one-way ANOVA, Holm-Sidak test). DETAILED DESCRIPTION OF THE INVENTION

[0105] Detailed Description The present disclosure relates to anti-fibrotic compounds and methods of using such compounds to prevent or inhibit fibrosis. The compounds and methods can also prevent or inhibit fibrocyte formation, including proliferation, or fibrocyte activity, including activation, that can lead to fibrosis.

[0106] The compounds are capable of inhibiting sialidases, particularly human NEU3.

[0107] The method can include administering the compound to a patient having or at risk of developing fibrosis, or to a patient having or at risk of developing abnormal fibrocyte formation, including proliferation, or activity, including activation. The amount of compound administered, the mode of administration, its dose, and any repetition frequency can vary depending on the compound and the effect to be achieved.

[0108] The method can also include administering the compound to a patient having or at risk for steatosis or non-alcoholic steatohepatitis. The amount of compound administered, the mode of administration, the dose, and the frequency of any repetitions can vary depending on the compound and the effect to be achieved.

[0109] The method can also include administering the compound to a patient with or at risk of cancer, including cancers with upregulated NEU3. The amount of compound administered, the mode of administration, the dose, and the frequency of any repetitions can vary depending on the compound and the effect to be achieved.

[0110] The method can also include administering the compound to a patient with or at risk of obesity, including obesity caused by a high-fat diet. The amount of compound administered, the mode of administration, the dose, and the frequency of any repetition can vary depending on the compound and the effect to be achieved. Sialidase and Fibrosis

[0111] Proteins with polysaccharides attached are called glycosylated proteins. Many of the polysaccharides on glycosylated proteins contain sialic acid monosaccharides (called terminal sialic acid), especially at the distal end of the protein. Sialidase (also called neuraminidase) is an enzyme that removes sialic acid from the polysaccharides found on glycosylated proteins.

[0112] Sialidases are used by a wide range of organisms, including harmful viruses and bacteria. Mammals have four sialidases, designated NEU1, NEU2, NEU3, and NEU4.

[0113] NEU1 is generally expressed at higher levels than the other three sialidases, and is expressed in most tissues, with higher levels in lung and airway epithelial cells than in most other cells. NEU1 is located in lysosomes and at the plasma membrane surface, with its catalytic domain located on the outside of the cell. NEU1 preferentially desialylates terminal sialic acids with α(2,3)-linked groups, to a lesser extent with α(2,6)-linked groups, and with some activity with α(2,8)-linked groups.

[0114] NEU2 is a soluble cytosolic enzyme that preferentially desialylates terminal sialic acids with α(2,3)-, α(2,6)-, and α(2,8)-linked groups.

[0115] NEU3 is a plasma membrane-associated sialidase and the only sialidase found extracellularly. NEU3 preferentially desialylates terminal sialic acids with α(2,6)-linking groups.

[0116] NEU4 has two isoforms, one localized to mitochondria and the other bound to intracellular membranes, and preferentially desialylates terminal sialic acids with α(2,3)-, α(2,6)-, and α(2,8)-linked groups.

[0117] Variants of these four sialidases are known in humans and other mammals, particularly variants with single nucleotide polymorphisms (SNPs).

[0118] Sialidase is associated with inflammation in mammals, and inflammation increases the abundance of sialidase. Thus, a positive feedback loop exists between inflammation and sialidase in mammals.

[0119] The present disclosure exploits a newly discovered feedback pathway between sialidase and fibrosis in mammals, including humans, at least a portion of which is illustrated in FIG.

[0120] SAP20, in its normal glycosylated form, binds to DC-SIGN30 via binding pathway 120. This causes DC-SIGN30 to inhibit the activation of profibrotic innate immune cells 50 via inhibitory pathway 140.

[0121] SAP20, in its normal glycosylated form, can also bind to Fc gamma receptor 1 (FcγRl) 40 via binding pathway 130. This causes FcγRl to inhibit the activation of profibrotic innate immune cells 50 via inhibitory pathway 150.

[0122] In the absence of inhibition, profibrotic innate immune cells 50 can secrete cytokines, including TGF-β1, tumor necrosis factor α (TNFα), interleukin-4 (IL-4), IL-6, and IL-13. These cytokines act via pathway 160 to cause the formation or activation of fibroblasts 60. Fibroblasts 60 can then proceed to induce fibrosis.

[0123] Furthermore, TGF-β1, which is present in increased amounts inside innate immune cells 50 or is otherwise secreted by innate immune cells 50 present in the extracellular environment, can increase the expression of sialidase 10 via pathway 170.

[0124] Sialidase 10, in turn, can activate TGF-β1. TGF-β1 can be bound by LAP, which inactivates TGF-β1. Sialidase 10 can cleave sialic acid from LAP, releasing and activating TGF-β1.

[0125] When SAP20 binds to either DC-SIGN30, FcγRl40, or both, causing inhibition of profibrotic innate immune cells50, this in turn reduces the secretion of profibrotic cytokines and reduces the formation or activation of fibroblasts60.

[0126] Sialidase 10 can act through the common pathway 100 to promote cytokine secretion by the formation or activation of profibrotic innate immune cells 50 and fibroblasts 60 .

[0127] Pathway 100 may include various subpathways, but in at least one subpathway, sialidase 10 acts on glycosylated SAP20 to cleave terminal sialic acids from the SAP polysaccharide. Sialidase 10 may be NEU1, which is capable of cleaving the type of sialic acid linking group present in glycosylated SAP. Sialidase 10 may also be NEU2, NEU3, NEU4, or any combination of sialidases.

[0128] Cleavage of sialic acid from glycosylated SAP20 is an inhibitory process, as exemplified by pathway 110. SAP20 lacking sialic acid cannot effectively bind to DC-SIGN30 or FcγR140 via pathway 120 or pathway 130, and therefore SAP20 cannot inhibit profibrotic innate immune cells 50 via inhibitory pathways 140 and 150. This leaves profibrotic innate immune cells 50 free to promote the formation or activation of fibroblasts 60.

[0129] Profibrotic innate immune cells 50, or potentially fibroblasts 60, also act through pathway 170 to further activate sialidase 10 in addition to promoting the formation or activation of fibroblasts 60. Thus, fibrocyte formation or activation and sialidase activity form a positive feedback loop through pathways 100 and 170.

[0130] This positive feedback loop can be beneficial in some biological situations, but can also contribute to escaping fibrosis in fibrotic diseases and disorders. Thus, the present disclosure provides compounds that disrupt this positive feedback loop and methods of using such compounds to prevent or control the damaging effects of fibrocyte formation or activation.

[0131] As an example of this positive feedback loop, NEU3 induces IL-6 accumulation in human PBMCs, which in turn induces NEU3 accumulation in human PBMCs. For this reason, NEU3 is a preferential, though not exclusive, target for compounds 1-31.

[0132] Similarly, TGF-β1 can trigger a positive feedback loop. TGF-β1 is synthesized as an inactive complex, L-TGF-β1, which binds to two inactive latency-associated peptides (LAPs). These LAPs release TGF-β1 upon sialylation and desialylation. NEU3 can desialylate LAPs, thus releasing TGF-β1. Just as with IL-6 above, active TGF-β1 induces the accumulation of NEU3 in human PBMCs, forming a feedback loop. This provides another reason why NEU3 is a preferred, if not exclusive, target for compounds 1–31.

[0133] As a third example of this positive feedback loop, one sialidase, such as NEU2, can increase the expression of another sialidase, such as NEU3. All of these example feedback loops can exist in the same cell or biological system, and other feedback loops may exist as well. Sialidase and Steatosis

[0134] Steatosis (fatty liver, commonly caused by obesity, diabetes, or alcohol consumption) affects approximately 25-30% of the US population. A subset of the population with steatosis, including approximately 5% of the US population, has a more severe form of liver disease called nonalcoholic steatohepatitis ("NASH"). NASH involves liver damage and an excess of immune cells (inflammation) in the liver. Patients with NASH are at risk of developing liver fibrosis (cirrhosis) and liver cancer.

[0135] In the liver, excess calories lead to Kupffer cell (liver macrophage) activation, which in turn leads to inflammation, i.e., increased fatty acid synthesis in hepatocytes, leading to hepatic steatosis (abnormal lipid retention in hepatocytes), and ultimately to fibrosis or cirrhosis. Because sialidase inhibition reduces inflammation and fibrosis, and steatosis is associated with inflammation and fibrosis, the present specification also relates to the use of sialidase inhibitors to treat steatosis and NASH. Sialidase and Cancer

[0136] NEU3 is significantly upregulated in many types of cancer, including colon cancer, ovarian cancer, prostate cancer and renal cancer, and suppresses the apoptosis of cancer cells. In the human renal cell carcinoma cell line ACHN, IL-6 treatment increases NEU3 promoter activity and sialidase activity. Therefore, the present specification relates to the use of NEU3 inhibitors for treating cancer, including cancers with high NEU3 activity. Sialidase and Obesity

[0137] Obese rodents and humans have altered levels of NEU1 and NEU3 mRNA, NEU1 and NEU3 protein, and neuraminidase enzyme activity in white fat, intestine, and liver. Compared with non-obese control mice (db / +), obese (db / db) mice fed a standard diet have reduced NEU1 mRNA levels and NEU1 enzyme activity in liver tissue, but increased NEU1 enzyme activity in epididymal white fat. Compared with non-obese humans, obese patients have higher NEU3 mRNA in the small intestine, and NEU3 protein is also increased in the small intestine of HFD-treated mice compared with mice on a standard diet. Furthermore, oral administration of the sialidase inhibitor DANA inhibited NEU3 enzyme activity in the small intestine, but not in the liver or white adipose tissue, and oral administration of DANA attenuated hepatic steatosis and HFD-induced weight gain in mice. Overexpression of NEU3 in the liver using adenovirus-mediated expression improved glucose tolerance and insulin sensitivity but increased hepatic triglyceride and glycogen stores, inducing hyperlipidemia. Together, these disparate results suggest a link between obesity and sialidase.

[0138] Altered sialidase levels appear to result in altered insulin signaling. NEU1 can desialylate both insulin and insulin-like growth factor 1 receptors, resulting in improved insulin receptor signaling at lower insulin concentrations. In mice exposed to an HFD, long-term hepatic NEU1 overexpression by adenovirus-based gene transfer increases glucose intolerance and insulin resistance. In mice, decreased hepatic NEU3 protein levels also appear to be associated with decreased insulin signaling, while increased hepatic NEU3 protein improves insulin sensitivity and glucose tolerance.

[0139] The sialidase inhibitor DANA prevents weight gain in mice fed a high-fat diet, and has no effect on mice fed a normal diet, suggesting that DANA has a low risk of side effects. Sialidase inhibitors

[0140] The present disclosure includes sialidase inhibitors, particularly human NEU3 inhibitors, and their use in preventing or inhibiting fibrosis, obesity, liver inflammation, steatosis, and cancer.

[0141] A human NEU3 inhibitor can inhibit the enzymatic activity of all human sialidases, a subset of human sialidases, or NEU3 alone, all of which include the wild-type form alone or one or more active variants. Enzymatic activity can be defined as inhibited if the rate in an in vitro assay using a substrate with a terminal sialic acid is inhibited by at least 50%. More specifically, a NEU3 inhibitor can be a compound that inhibits the rate of NEU3 by at least 50% in an in vitro assay using the fluorometric substrate 4MU-NANA [2'-(4-methylumbelliferyl)-α-DN-acetylneuraminic acid].

[0142] Human NEU3 inhibitors can also inhibit TGF-β1 activity or levels, which can interrupt the positive feedback loop described in Figure 1, thus also preventing or inhibiting fibrosis.

[0143] Human NEU3 inhibitors can also inhibit extracellular IL-6 accumulation or concentration, which may reduce inflammation.

[0144] Human NEU3 inhibitors can also reduce the elevated NEU3 activity observed in many cancers, thereby treating cancer.

[0145] Human sialidase inhibitors can also reduce weight gain and improve glucose tolerance.

[0146] Human sialidase inhibitors can also inhibit liver inflammation.

[0147] Human sialidase inhibitors can also inhibit steatosis. Small molecule NEU3 inhibitors

[0148] Small molecule NEU3 inhibitors, particularly human NEU3 inhibitors, are compounds having the following structural formula: [ka] may include:

[0149] Compound 1, also known as DANA, exhibited an inhibitory concentration (IC) that reduced enzyme activity by 50% in the TGF-β1 release assay of 250 μM. 50 ) inhibits human NEU3.

[0150] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0151] Compound 2, also known as 4-hydroxypyridine-2-carboxylic acid, exhibited an IC of 2.1 μM in the TGF-β1 concentration assay. 50 Compound 2 inhibits human NEU3 at IL-6 concentrations with an IC of >300 μM in the IL-6 concentration assay. 50 It has.

[0152] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0153] Compound 3, also known as 5-acetamidopyridine-2-carboxylic acid, had an IC of 11 nM in the TGF-β1 concentration assay.50 Compound 3 inhibits human NEU3 at IL-6 concentration with an IC of 6.2 μM in the IL-6 concentration assay. 50 It has.

[0154] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0155] Compound 4, also known as picolinic acid, exhibited an IC of <10 pM in the TGF-β1 concentration assay. 50 Compound 4 inhibits human NEU3 at IL-6 concentrations with an IC of >100 μM in the IL-6 concentration assay. 50 It has.

[0156] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0157] Compound 5, also known as 2-acetylpyridine, had an IC value of 42 nM in the TGF-β1 concentration assay. 50 Compound 5 inhibits human NEU3 at IL-6 concentration with an IC of 32 μM in the IL-6 concentration assay. 50 It has.

[0158] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0159] Compound 6, also known as methyl picolinate, had an IC of 14 pM in the TGF-β1 concentration assay. 50 Compound 6 inhibits human NEU3 at IL-6 concentrations with an IC of >100 μM in the IL-6 concentration assay. 50 It has.

[0160] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0161] Compound 7, also known as 4-aminopicolinic acid, had an IC of 4.0 nM in the TGF-β1 concentration assay. 50 Compound 7 inhibits human NEU3 at IL-6 concentrations with an IC of >100 μM in the IL-6 concentration assay. 50 It has.

[0162] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0163] Compound 8, also known as 5-nitropicolinic acid, had an IC50 of 43 nM in the TGF-β1 concentration assay. 50 Compound 8 inhibits human NEU3 at IL-6 concentration with an IC of 79 nM in the IL-6 concentration assay. 50 It has.

[0164] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0165] Compound 9, also known as 4-methoxypicolinic acid, had an IC of 3.2 nM in the TGF-β1 concentration assay. 50 Compound 9 inhibits human NEU3 at IL-6 concentrations with an IC of >100 μM in the IL-6 concentration assay. 50 It has.

[0166] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0167] Compound 10, also known as picolinamide, had an IC of 22 nM in the TGF-β1 concentration assay. 50 Compound 10 inhibits human NEU3 at IL-6 concentrations of >100 μM. 50 It has.

[0168] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0169] Compound 11, also known as 5-acetylamino-4-aminopicolinic acid, had an IC of 0.11 μM in the TGF-β1 concentration assay. 50 inhibits human NEU3.

[0170] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0171] Compound 12, also known as sodium 1,4,5,6-tetrahydropyridine-2-carboxylate, had an IC value of 120 μM in the TGF-β1 concentration assay. 50 inhibits human NEU3.

[0172] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0173] Compound 13, also known as L-pipecolic acid, had an IC of 0.49 nM in the TGF-β1 concentration assay.50 Compound 13 inhibits human NEU3 at IL-6 concentration with an IC of 7.9 μM in the IL-6 concentration assay. 50 It has.

[0174] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0175] Compound 14, also known as nicotinic acid, had an IC of 11 pM in the TGF-β1 concentration assay. 50 Compound 14 inhibits human NEU3 at IL-6 concentration with an IC of 1.5 μM in the IL-6 concentration assay. 50 It has.

[0176] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0177] Compound 15, also known as salicylic acid, had an IC of 1.8 μM in the TGF-β1 concentration assay. 50 inhibits human NEU3.

[0178] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0179] Compound 16, also known as O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine, had an IC of 2.6 μM in the TGF-β1 concentration assay. 50 inhibits human NEU3. [ka]

[0180] Compound 17, also known as 6-(hydroxymethyl)picolinic acid, had an IC of 50 pM in the TGF-β1 concentration assay. 50 Compound 17 inhibits human NEU3 at IL-6 concentration with an IC of 0.038 μM in the IL-6 concentration assay. 50 It has. [ka]

[0181] Compound 18, also known as 5-aminopyridine-2-carboxylic acid, had an IC value of 40 nM in the TGF-β1 concentration assay. 50 Compound 18 inhibits human NEU3 at IL-6 concentration with an IC of 0.14 μM in the IL-6 concentration assay. 50 It has. [ka]

[0182] Compound 19, also known as 2-nitropyridine, had an IC of 40 nM in the TGF-β1 concentration assay. 50 Compound 19 inhibits human NEU3 at IL-6 concentration with an IC of 0.02 μM in the IL-6 concentration assay. 50 It has. [ka]

[0183] Compound 20, also known as 1-methyl-2-piperidinecarboxylic acid, had an IC value of 0.50 μM in the TGF-β1 concentration assay. 50 Compound 20 inhibits human NEU3 at IL-6 concentration with an IC of 0.03 μM in the IL-6 concentration assay. 50 It has. [ka]

[0184] Compound 21, also known as 4-(trifluoromethyl)picolinic acid, had an IC of 0.08 nM in the IL-6 concentration assay. 50 It has. [ka]

[0185] Compound 22, also known as 4-methylpicolinic acid, had an IC of 0.13 μM in the TGF-β1 concentration assay. 50 Compound 22 inhibits human NEU3 at IL-6 concentration with an IC of 4.7 μM in the IL-6 concentration assay. 50 It has. [ka]

[0186] Compound 23, also known as 4-aminonicotinic acid, had an IC of 5.0 nM in the TGF-β1 concentration assay. 50 Compound 23 inhibits human NEU3 at IL-6 concentration with an IC of 10 μM in the IL-6 concentration assay. 50 It has. [ka]

[0187] Compound 24, also known as 4-oxo-1,4-dihydropyridine-2-carboxylic acid, had an IC value of 0.13 μM in the TGF-β1 concentration assay. 50 Compound 24 inhibits human NEU3 at IL-6 concentration with an IC of 8.5 μM in the IL-6 concentration assay. 50 It has. [ka]

[0188] Compound 25, also known as 4-amino-2-piperidinecarboxylic acid, had an IC50 of 2.0 nM in the TGF-β1 concentration assay. 50Compound 25 inhibits human NEU3 at IL-6 concentration with an IC of 0.13 nM in the IL-6 concentration assay. 50 It has. [ka]

[0189] Compound 26, also known as 4-amino-1-methyl-2-piperidinecarboxylic acid, had an IC of <10 pM in the TGF-β1 concentration assay. 50 Compound 26 inhibits human NEU3 at 10 pM in the IL-6 concentration assay. 50 It has. [ka]

[0190] Compound 27, also known as 6-methyl-2-pyridinecarboxylic acid, had an IC of <10 pM in the TGF-β1 concentration assay. 50 Compound 27 inhibits human NEU3 at IL-6 concentration with an IC of 4.1 nM in the IL-6 concentration assay. 50 It has.

[0191] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0192] Compound 28, also known as oseltamivir, had an IC of 570 nM in the TGF-β1 concentration assay. 50 Compound 28 inhibits human NEU3 at IL-6 concentration with an IC of 47 μM in the IL-6 concentration assay. 50 It has.

[0193] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0194] Compound 29, also known as D-proline, had an IC of 63 nM in the TGF-β1 concentration assay. 50 Compound 29 inhibits human NEU3 at IL-6 concentration with an IC of 4.2 μM in the IL-6 concentration assay. 50 It has.

[0195] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0196] Compound 30, also known as pyrrole-2-carboxylic acid, had an IC value of 164 μM in the TGF-β1 concentration assay. 50 Compound 30 inhibits human NEU3 at IL-6 concentration with an IC of 9.5 μM in the IL-6 concentration assay. 50 It has.

[0197] Small molecule NEU3 inhibitors also include compounds having the following structural formula: [ka] may include:

[0198] Compound 31, also known as azepane-2-carboxylic acid, had an IC of 2.4 nM in the TGF-β1 concentration assay. 50 Compound 31 inhibits human NEU3 at IL-6 concentration with an IC of 35 nM in the IL-6 concentration assay. 50 It has.

[0199] The present disclosure also provides a compound of formula (I)

[0200] [ka] or a salt thereof.

[0201] In Formula I, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0202] In Formula I, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0203] In Formula I, R5 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0204] In Formula I, R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0205] In formula I, X can be selected from carbon, oxygen, or nitrogen.

[0206] The present disclosure also provides a compound of formula (II)

[0207] [ka] or a salt thereof, wherein:

[0208] In formula II, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0209] In Formula II, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0210] In Formula II, R5 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0211] In Formula II, R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0212] In formula II, X can be selected from carbon, nitrogen, or oxygen.

[0213] The present disclosure also provides a compound of formula (III) [ka] or a salt thereof, wherein:

[0214] In formula III, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0215] In formula III, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0216] In Formula III, R5 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0217] In formula III, R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0218] In formula III, X can be selected from carbon, oxygen, or nitrogen.

[0219] The present disclosure also provides a compound of formula (IV)

[0220] [ka] or a salt thereof, wherein:

[0221] In formula IV, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0222] In Formula IV, R2, R3 and R4 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0223] In Formula IV, R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0224] In formula IV, X can be selected from carbon, oxygen, or nitrogen.

[0225] In formula IV, Y can be selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group.

[0226] The present disclosure provides a compound of formula (V): [ka] or a salt thereof, wherein:

[0227] In formula V, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0228] In Formula V, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0229] In Formula V, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2)1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0230] In Formula V, R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0231] In formula V, X can be selected from carbon, oxygen, or nitrogen.

[0232] In formula V, Y can be selected from carbon or nitrogen.

[0233] In formula V, Z can be selected from carbon, nitrogen, oxygen, or sulfur.

[0234] The present disclosure provides a compound of formula (VI): [ka] or a salt thereof, wherein:

[0235] In formula VI, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0236] In Formula VI, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0237] In Formula VI, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0238] In Formula VI, R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0239] In formula VI, X can be selected from carbon, oxygen, or nitrogen.

[0240] The present disclosure provides a compound of formula (VII): [ka] or a salt thereof, wherein:

[0241] In Formula VII, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0242] In Formula VII, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0243] In Formula VII, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0244] In Formula VIII, R5 is hydrogen, methyl, —CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0245] In formula VIII, X can be selected from carbon, oxygen, or nitrogen.

[0246] In formula VII, Y can be selected from carbon or nitrogen.

[0247] In formula VII, Z can be selected from carbon, nitrogen, oxygen, or sulfur.

[0248] The present disclosure also provides a compound of formula (VIII) [ka] or a salt thereof, wherein:

[0249] In Formula VIII, R1 is hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0250] In Formula VIII, R2 and R3 are hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6(alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0251] In Formula VIII, R4 is hydrogen, halogen, an alkyl group, an aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0252] In Formula VIII, R5 is hydrogen, methyl, —CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0253] In formula VIII, X can be selected from carbon, oxygen, or nitrogen.

[0254] The present disclosure also provides a compound of formula (IX) [ka] or a salt thereof.

[0255] In formula IX, B1, B2, B3, B4, B5, B6 and / or B7 can be selected from a single bond or a double (olefinic) bond.

[0256] In Formula IX, R1 is hydrogen, methyl, -CF3, C 1~6Alkyl, aryl, -CO(C 1~6 alkyl), or may be absent.

[0257] In formula IX, R2 to R6 are hydrogen, halogen, an alkyl group, an aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles.

[0258] In formula IX, R7 is hydrogen, halogen, an alkyl group, an aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles.

[0259] In formula IX, X can be selected from carbon, oxygen, or nitrogen.

[0260] In formula IX, Y can be selected from carbon, nitrogen, oxygen, or sulfur.

[0261] The above methods may be combined with each other and may further comprise, alone or in combination, one or more of the following additional features, unless expressly mutually exclusive: i. the method can inhibit desialylation of LAP; ii. the method can inhibit extracellular accumulation of IL-6; iii. the method is capable of inhibiting desialylation of SAP; iv. the method can inhibit the formation or activation of fibrocytes; v. the method can reduce the level or activity of TGF-β1; vi. The method can reduce the level or activity of a sialidase in a human. vii. The method can inhibit more than one sialidase; viii. The compounds can be administered locally to humans in areas where human sialidase activity is abnormally high; ix. The formulation may be administered by intravenous or intraperitoneal injection, orally, topically, by inhalation, or by other means enterally, or by parenteral administration; x. the compound used in the method is DANA; xi. The compound used in the method is 4-hydroxypyridine-2-carboxylic acid; xii. The compound used in the method is 5-acetamidopyridine-2-carboxylic acid; xiii. The compound used in the method is picolinic acid; xiv. The compound used in the method is 2-acetylpyridine; xv. The compound used in the method is methyl picolinate; xvi. The compound used in the method is 4-aminopicolinic acid; xvii. The compound used in the method is 5-nitropicolinic acid; xviii. The compound used in the method is 4-methoxypicolinic acid; xix. The compound used in the method is picolinamide; xx. The compound used in the method is 5-acetylamino-4-aminopicolinic acid; xxi. The compound used in the method is 1,4,5,6-tetrahydropyridine-2-carboxylic acid salt; xxii. The compound used in the method is L-pipecolic acid; xxiii. The compound used in the method is nicotinic acid; xxiv. The compound used in the method is salicylic acid; xxv. The compound used in the method is O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine; xxvi. The compound used in the method is 6-(hydroxymethyl)picolinic acid; xxvii. The compound used in the method is 5-aminopyridine-2-carboxylic acid; xxviii. The compound used in the method is 2-nitropyridine; xxix. The compound used in the method is 1-methyl-2-piperidinecarboxylic acid; xxx. The compound used in this method is 4-(trifluromethyl)picolinic acid; xxxi. The compound used in this method is 4-methylpicolinic acid; xxxii. The compound used in the method is 4-aminonicotinic acid; xxxiii. The compound used in this method is 4-oxo-1,4-dihydropyridine-2-carboxylic acid; xxxiv. The compound used in the method is 4-amino-2-piperidinecarboxylic acid; xxxv. The compound used in the method is 4-amino-1-methyl-2-piperidinecarboxylic acid; xxxvi. The compound used in this method is 6-methyl-2-pyridinecarboxylic acid; xxxvii. The compound used in the method is oseltamivir; xxxviii. The compound used in the method is D-proline; xxxix. The compound used in this method is pyrrole-2-carboxylic acid; xl. The compound used in the method is azepane-2-carboxylic acid; xli. The dose administered can be sufficient to establish a systemic concentration of at least 3 μM or a concentration in the area of ​​administration of at least 3 μM. Administration can be daily for at least 1 week, at least 2 weeks, at least 3 weeks, or indefinitely; xlii. The dose administered can be sufficient to establish a systemic concentration of at least 0.6 μM or a concentration in the area of ​​administration of at least 0.6 μM. Administration can be daily for at least 1 week, at least 2 weeks, at least 3 weeks, or indefinitely; xliii. the dose administered can be sufficient to reduce fibrosis in a human; xliv. the dose administered can be sufficient to reduce fibrosis in an animal; xlv. the dose administered can be sufficient to reduce tumor growth in humans; xlvi. the dose administered can be sufficient to reduce tumor growth in an animal; xlvii. the dose administered can be sufficient to inhibit cancer in a human; xlviii. the dose administered can be sufficient to inhibit cancer in an animal; xlix. the administered dose can be sufficient to inhibit liver inflammation in humans; l. the dose administered can be sufficient to inhibit liver inflammation in an animal; 1. The dose administered can be sufficient to inhibit weight gain in humans; lii. the dose administered can be sufficient to reduce the amount of neutral lipids in the liver of the animal; liii. the dose administered can be sufficient to reduce the activity level of sialidase in the animal; liv. The administered dose can be sufficient to reduce the amount of neutral lipids in the liver of a human; and lv. The dose administered can be sufficient to reduce the activity level of sialidase in humans; Fibrotic disorders

[0262] NEU3 inhibitors can be used to prevent or inhibit fibrosis in any of several fibrogenic diseases in mammals, particularly humans.

[0263] For example, NEU3 inhibitors may prevent or inhibit fibrosis, tumors, including cancerous tumors, occurring in the liver, gallbladder, kidneys, lungs, upper respiratory tract (including but not limited to the nose, esophagus, and larynx), heart and pericardium, blood or lymphatic vessels, lymph nodes, eyes, skin, mouth, pancreas, gastrointestinal tract, brain, spinal cord, breast, bone marrow, bones and joints, genitourinary system, thyroid, parathyroid, or adrenal glands, musculoskeletal system, or wounds.

[0264] In general, NEU3 inhibitors can prevent or inhibit fibrosis due to conditions including, but not limited to, rheumatoid arthritis, lupus, psoriatic arthritis, ankylosing spondylitis, pathogenic fibrosis, fibrogenic diseases, fibrotic lesions such as those formed after Schistosoma japonicum infection, radiation injury, autoimmune diseases, Lyme disease, chemotherapy-induced fibrosis, HIV- or infection-induced focal sclerosis, failed spinal surgery syndrome due to scarring from spinal surgery, abdominal adhesions after surgical scarring, fibrocyst formation, fibrosis after spinal cord injury, surgery-induced fibrosis, mucosal fibrosis, peritoneal fibrosis caused by dialysis, tumor-associated fibrosis, and anti-TNF-associated pulmonary fibrosis.

[0265] Specifically, in the liver, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, alcohol-, drug-, and / or chemical-induced cirrhosis, ischemia-reperfusion injury after liver transplantation, necrotizing hepatitis, hepatitis B, C, D, E, hepatitis induced by other viruses, hepatitis caused by bacterial or parasitic infections, primary biliary cirrhosis, primary sclerosing cholangitis, steatosis, autoimmune hepatitis (including, but not limited to, autoantibody-driven hepatitis), or hepatitis caused by genetic conditions such as alpha-1-antitrypsin deficiency, and Wilson's disease.

[0266] With respect to the gallbladder, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, fibrosis associated with chronic cholecystitis.

[0267] With respect to the kidney, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, proliferative and sclerosing glomerulonephritis, nephrogenic fibrosing dermopathy, diabetic nephropathy, lupus nephritis, renal tubular fibrosis, focal segmental glomerulosclerosis, and fibrosis caused by infection of the kidney or urinary tract.

[0268] With respect to the lungs and airways, including but not limited to the nose, esophagus, and pharynx, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, pulmonary interstitial fibrosis, sarcoidosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, diffuse alveolar damage disease, pulmonary hypertension, neonatal bronchopulmonary dysplasia, chronic asthma, eosinophilic esophagitis, pharyngeal fibrosis, and emphysema. There are several subnames or synonyms for pulmonary fibrosis, including, but not limited to, idiopathic fibrosing alveolitis, diffuse interstitial fibrosis, idiopathic interstitial pneumonia, Hamman-Rich syndrome, silicosis, asbestosis, beryllium pneumoconiosis, melanoconiosis, anthraxosis, miner's asthma, anthraxosis, and anthrax silicosis.

[0269] With respect to the heart and / or pericardium, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, myocardial fibrosis, atherosclerosis, coronary restenosis, congestive cardiomyopathy, dilated cardiomyopathy, heart failure, and other post-ischemic conditions.

[0270] With respect to the lymphatic system, NEU3 inhibitors can prevent or inhibit fibrosis due to conditions including, but not limited to, fibrosis associated with chronic lymphedema, lymphocytic fibrosis, fibrosis linked to autoimmune disease, cancer, or infection.

[0271] With respect to the eye, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, Graves' exophthalmos, proliferative vitreoretinopathy, anterior capsular cataract, corneal fibrosis, surgical corneal scarring, trabeculectomy-induced fibrosis, progressive subretinal fibrosis, multifocal granulomatous chorioretinitis, and other ocular fibroses.

[0272] With respect to the skin, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, Dupuytren's contracture, scleroderma, keloid scarring, psoriasis, hypertrophic scarring from burns, atherosclerosis, restenosis, and pseudoscleroderma caused by spinal cord injury.

[0273] With respect to the mouth and / or esophagus, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, periodontal scarring, gingival hypertrophy secondary to drugs, and congenital esophageal strictures.

[0274] With respect to the pancreas, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, pancreatic fibrosis, interstitial remodeling pancreatitis, and interstitial fibrosis.

[0275] With respect to the gastrointestinal tract, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, collagenous colitis, villous atrophy, crypt hyperplasia, polyp formation, fibrosis in Crohn's disease, and healing gastric ulcers.

[0276] With respect to the brain, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, glial scar tissue. With respect to the breast, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, fibrocystic disease and the stromal desmoplastic response to breast cancer.

[0277] With respect to bone marrow, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, myelofibrosis, myelodysplasia, and fibrosis in neoplastic diseases.

[0278] With respect to bone, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriatic arthritis, ankylosing spondylitis, and rheumatoid pannus formation.

[0279] With respect to the genitourinary system, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, endometriosis, uterine fibroids, ovarian fibroids, and Peyronie's disease.

[0280] With respect to the thyroid and parathyroid glands, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, fibrosis associated with hyperparathyroidism, hypoparathyroidism, chronic thyroiditis, Riedel's thyroiditis, chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), and acute suppurative goiter.

[0281] With respect to the musculoskeletal system, NEU3 inhibitors can prevent or inhibit fibrosis resulting from conditions including, but not limited to, musculoskeletal disorders such as carpal tunnel syndrome, muscle or ligament or other connective tissue damage following injury, autoimmune, or infectious, or muscle fibrosis associated with muscular dystrophies such as Duchenne muscular dystrophy, and age-related fibrosis.

[0282] With respect to radiation-induced damage, NEU3 inhibitors can prevent or inhibit fibrosis associated with the treatment of, but not limited to, head and neck, ovarian, prostate, lung, gastrointestinal, colon, and breast cancers. [Example]

[0283] The following examples illustrate aspects of the present invention. The examples are not intended to be comprehensive. Furthermore, while some examples may represent separate embodiments of the present invention, aspects of such examples may be combined in this manner with other variations of the invention described above or in different examples, unless the combination would be clearly inoperable to one of ordinary skill in the art.

[0284] Unless otherwise specified, for example, when discussing data derived from mouse samples, the sialidase tested in these examples was a human sialidase. Example 1: Effect of sialidase on the LAP assay

[0285] To determine the effect of sialidase on latency-associated peptide (LAP), 400 ng / ml human recombinant LAP (246-LP / CF, R&D Systems, Minneapolis, MN) was diluted in a total volume of 20 μl of phosphate-buffered saline (PBS; #SH30256.01, GE Lifesciences, Marlborough, MA) (pH 6.9) with 200 ng / ml of human recombinant sialidase NEU1 (TP300386, Origene, Rockville, MD), NEU2 (TP319858, Origene), NEU3 (TP316537, Origene), or NEU4 (TP303948, Origene) or C. perfringens neuraminidase (N2876-2.5UN, Sigma-Aldrich, St. Louis, MO), or 1 μl of 0.1N. The mixture was incubated with and without HCl (H613-05, Avantor Performance Materials LLC., Center Valley, PA). PBS was adjusted to pH 6.9, which roughly corresponds to the extracellular pH of normal tissue, using 12 N HCl (H613-05, Avantor Performance Materials LLC). The reaction mixture was incubated in a clean 1.7 ml microfuge tube (22-281, Genesee Scientific, San Diego, CA) for 2 hours at 37°C. After incubation, 5 μl of 4× Laemmli buffer containing 20 mM dithiothreitol (GTX16355, GeneTex, Nottingham Business Park, Nottingham, UK) was added to the reaction mixture, which was then heated at 100°C for 5 minutes. After heating, 15 μl of the reaction mixture was electrophoresed in Tris / glycine / SDS running buffer (13.5 g Tris base, 7.2 g glycine, 5 g SDS / liter) on a 4–20% Tris / glycine polyacrylamide precast gel (12001-058, VWR, Radnor, PA) for 90–120 min at room temperature.

[0286] Proteins were transferred to polyvinylidene difluoride (Immobilon P; Millipore, Bedford, MA) membranes in Tris / glycine / SDS buffer containing 20% ​​methanol according to the manufacturer's protocol. The membranes were blocked with 1× carbo-block solution (SP-5040, Vector, Burlingame, CA) diluted in water for 1 h at room temperature and then incubated with 2 μg / ml biotinylated Sambucus nigra lectin (SNA) (B-1305, Vector) in PBS (pH 6.9) for 30 min at room temperature. The membranes were then washed with PBS containing 0.1% Tween®-20 for 30 minutes and then incubated with horseradish peroxidase-streptavidin (405103, Biolegend, San Diego, CA) diluted 1:5,000 in PBS-bovine serum albumin (BSA) for 1 hour at room temperature. Peroxidase was visualized using SuperSignal West Pico chemiluminescent substrate (34087, Thermo Scientific, Rockford, IL) according to the manufacturer's protocol using a ChemiDoc XRS+ system (Bio-Rad, Hercules, CA). Statistical analysis was performed using Prism software (Graphpad, La Jolla, CA).

[0287] The results are shown in Figure 2A-B. The data show that exposure to NEU3 and NEU4 significantly reduced SNA lectin binding to LAP, indicating a decrease in the number of polysaccharides containing sialic acid with α(2,6)-linked groups. Values ​​are means ± standard error (n = 3). ** = p ≤ 0.01, *** = p ≤ 0.001 (one-way ANOVA, Bonferroni's test). Example 2: NEU3-induced L-TGF-β1 activation assay

[0288] To determine whether NEU3 can induce latent transforming growth factor-β1 (L-TGF-β1) to release active TGF-β1, 200 ng / ml recombinant human L-TGF-β1 (299-LT / CF, R&D Systems) was incubated with various concentrations of recombinant human NEU3 (TP316537, Origene) in a total volume of 100 μl of PBS (pH 6.9) in a 96-well microplate (651261, Greiner Bio-one, Monroe, NC). The microplate was covered with aluminum foil and incubated at 37°C for 2 hours. After incubation, the reaction mixture was assayed using a TGF-β1 ELISA kit (DY240, R&D Systems) according to the manufacturer's protocol, except that the reaction mixture was not treated with acid to measure only active TGF-β1, not total TGF-β1. Absorbance was read using a SynergyMX plate reader (BioTek, Winooski, VT).

[0289] The results are shown in Figure 3. The data indicate that exposure to NEU3 activated L-TGF-β1 by removing sialic acid from the LAP protein. The LAP protein then released active TGF-β1. Values ​​are means ± standard error (n = 6). ** = p ≤ 0.01 (one-way ANOVA, Bonferroni's test). Example 3: NEU3 inhibitors prevent activation of L-TGF-β1 by NEU3

[0290] To determine the ability of compounds 1–31 to inhibit human recombinant NEU3 in vitro, the compounds were dissolved in 5 ml of water to 20 mM in 15 ml tubes (89039-664, VWR, Radnor, PA), except that 4-hydroxypyridine-2-carboxylic acid, nicotinic acid, and 4-aminopicolinic acid were dissolved in 50 μl of DMSO to 2 M, which was then added to 4.95 ml of water to create a 20 mM stock solution; O-(tetrahydro-2H-pyran-2yl)hydroxylamine and salicylic acid were dissolved in 50 μl of methanol to 2 M, which was then added to 4.95 ml of water to create a 20 mM stock solution. All stock solutions were stored at 4°C and used within 2 weeks of preparation. Ten-fold dilution series of compounds starting at 2 mM were made in PBS (pH 6.9) in 1.7 ml clean microfuge tubes (22-281, Genesee Scientific). 100 μL of diluted compound was added to wells of a 96-well plate, and then 50 μL of 400 ng / mL recombinant human sialidase NEU3 (TP316537, Origene) in PBS (pH 6.9) was added to each well (50 μL of PBS (pH 6.9) for the control), and the plate was incubated at 37° C. for 30 minutes. Next, 50 μL of 800 ng / mL L-TGF-β1 (299-LT / CF, R&D Systems) in PBS (pH 6.9) was added to each well. The plate was covered with aluminum foil and incubated at 37° C. for 2 hours, and the released active TGF-β1 was assayed as described above.

[0291] The results are shown in Figure 4A-BH. NEU3 inhibition ranged from >100 μM to <1 nM. Values ​​are means ± standard error (n≧3). Example 4: Effect of NEU3 on IL-6 production by PBMC assay

[0292] Human peripheral blood was collected from healthy volunteers who provided written informed consent and had specific approval from the Texas A&M University Human Subjects Review Board. Peripheral blood mononuclear cells (PBMCs) were isolated from the blood using Ficoll-Paque density gradient centrifugation (95021-205, GE Healthcare, Cincinnati, OH) according to the manufacturer's protocol. 5 × 10 cells were cultured in a 96-well flat-bottom tissue culture plate (type 62406-081; VWR, Radnor, PA) containing RPMI-1640 (12001-560, VWR) supplemented with 10% bovine calf serum (BCS) (10158-358, VWR), 100 U / ml penicillin, 100 μg / ml streptomycin (12001-692, VWR), and 2 mM glutamine (12001-698, VWR) in a final volume of 200 μl per well. 4 PBMCs were cultured at 5 × 10 cells / ml in serum-free medium (RPMI-1640 supplemented with 10 mM HEPES (12001-708, VWR), 1× non-essential amino acids (12001-634, VWR), 1 mM sodium pyruvate (12001-636, VWR), 2 mM glutamine (12001-698, VWR), 100 U / ml penicillin, 100 μg / ml streptomycin (12001-692, VWR), and 1× ITS-3 (12771, Sigma-Aldrich, St. Louis, MO)) in a final volume of 200 μl per well. 4 Cells were also plated at 1 × 10 cells / ml. When cells were plated, human recombinant sialidases NEU1 (TP300386, Origene, Rockville, MD), NEU2 (TP319858, Origene), NEU3 (TP316537, Origene), or NEU4 (TP303948, Origene) were added to a final concentration of 0 or 100 ng / ml. In other experiments, recombinant human NEU3 was added to a final concentration of 0–500 ng / ml. Sialidases were diluted into 100 μl of the same medium as the cells, and then diluted to 1 × 10 cells / ml. 5 In a well, add 1 x 10 cells / ml to 100 μl of cells. 4A total volume of 200 μl containing 100 cells / well was prepared. The cells were then incubated at 37°C in a humidified incubator containing 5% CO2. After 2 or 5 days, culture supernatants were harvested and assayed using an IL-6 ELISA kit (430501, Biolegend, San Diego, CA) according to the manufacturer's protocol. Absorbance was read using a SynergyMX plate reader (BioTek, Winooski, VT). Statistics were analyzed using Prism software (Graphpad, La Jolla, CA). At least three different donors were used for each assay.

[0293] The results are shown in Figures 5A-C. Figure 5A shows that NEU3 alone significantly increased extracellular IL-6 accumulation compared to serum-free medium (SFM) controls. Figures 5B-C show IL-6 accumulation as a function of NEU3 concentration in serum-free medium after 48 hours (Figure 5B) and 5 days (Figure 5C). Values ​​are means ± standard error (n = 3). * = p ≤ 0.05, ** = p ≤ 0.01 (t-test). Figures 5D-E show IL-6 accumulation as a function of NEU3 concentration in serum-containing medium after 48 hours (Figure 5D) and 5 days (Figure 5E). Values ​​are means ± standard error (n = 3). * = p ≤ 0.05 (t-test). Example 5: Effect of compounds on the ability of NEU3 to induce extracellular accumulation of IL-6 by human immune cells

[0294] To determine the ability of compounds to inhibit NEU3-induced IL-6 production by human PBMCs, a 10-fold dilution series of compounds was made in serum-free medium (prepared as described above) starting at 4 mM in a clean 1.7 ml microfuge tube (22-281, Genesee Scientific). 50 μl of diluted compound was added to wells of a 96-well plate. Next, 50 μl of 400 ng / ml recombinant human sialidase NEU3 (TP316537, Origene) in serum-free medium was added to each well (50 μl of serum-free medium for the control), and the plate was incubated at 37°C in a humidified incubator containing 5% CO for 30 minutes. 1 × 10 5 Add 100 μl of PBMC at 1 x 10 cells / ml in the well. 4 A total volume of 200 μl containing cells / well was prepared and incubated for 48 hours at 37°C in a humidified incubator with 5% CO2. IL-6 in the culture supernatants was then assayed as described above. At least three different donors were used for each assay.

[0295] The results are shown in Figures 6A-6A-6B. The data show that NEU3 inhibitors reduced NEU3-induced extracellular IL-6 accumulation. Values ​​are means ± standard error (n ≥ 3). Example 6: NEU3 inhibitors inhibit mouse NEU3

[0296] To determine whether the selected NEU3 inhibitors could be used in mice to inhibit mouse NEU3, we generated recombinant mouse NEU3 in HEK293 Freestyle human embryonic kidney cells. HEK293 Freestyle cells (Life Technologies, Grand Island, NY) were cultured in FreeStyle293 medium (12338-018, Life Technologies, Grand Island, NY). 1 × 10 cells were cultured in 100 μl of PBS (GE Lifesciences). 5The cells were mixed with 2 μg of a mouse Neu3-expressing clone (MR223297, Origene) at 100 μg / ml and transfected by electroporation using the 4D-Nucelofactor System (Lonza) according to the manufacturer's protocol. To harvest, the transfected cells were maintained at room temperature for 15 minutes. After this, the cells were cultured in 25 ml of Freestyle 293 medium containing 250 μg / ml of G418 antibiotic (345812, Calbiochem EMD Chemicals Inc., San Diego, CA) at 37°C in a humidified 200 ml cell culture flask (431464U, Corning) with 5% CO2. Transfected cells were then selected. After 10 days, the cells were isolated and lysed, and c-Myc-tagged recombinant mouse NEU3 protein was purified using the Myc-Trap_A kit (ytak-20, Chromotek, Hauppauge, NY) according to the manufacturer's protocol. The eluted protein was stored in 50 μl of 10% glycerol, 100 mM glycine, 25 mM Tris-HCl (pH 7.3).

[0297] To determine whether NEU3 inhibitors are effective in mice, they were tested against recombinant mouse NEU3. The inhibitors were dissolved in 5 ml of water in a 15 ml tube (89039-664, VWR, Radnor, PA) to 20 mM. All stock solutions were stored at 4°C and used within two weeks of preparation. Ten-fold dilution series of compounds, starting at 2 mM, were made in PBS (pH 6.9) in 1.7 ml clean microfuge tubes (22-281, Genesee Scientific). 100 μl of diluted compound was added to wells of a 96-well plate. Then, 50 μl of 400 ng / ml recombinant mouse NEU3 in PBS (pH 6.9) was added to each well (50 μl of PBS (pH 6.9) for the control), and the plate was incubated at 37°C for 30 minutes. Next, 50 μl of 800 ng / ml L-TGF-β1 (299-LT / CF, R&D Systems) in PBS (pH 6.9) was added to the wells, the plates were covered with aluminum foil, incubated at 37°C for 2 hours, and the released active TGF-β1 was assayed as described above.

[0298] The results are shown in Figures 7A-B. Both 2-acetylpyridine (Figure 7A) and methyl picolinate (Figure 7B) inhibited TGF-β1 activation of NEU3. Example 7: NEU3 inhibitors attenuate bleomycin-induced pulmonary fibrosis in mice

[0299] To determine whether selected compounds affect pulmonary fibrosis in mice, 8-10 week old, 26-30 g male C57BL / 6 mice (Jackson, Bar Harbor, ME) were given oropharyngeal aspiration of 3 units / kg bleomycin (2246-10, 50, BioVision Incorporated, Milpitas, CA) in 50 μl of 0.9% saline to induce pulmonary fibrosis, or oropharyngeal saline as a control, according to Current protocols in mouse biology 2, 167-175, (2012). Starting on day 10 of bleomycin administration, some of the bleomycin-treated mice received daily intraperitoneal injections of 100 μl of PBS, or 1 mg / kg 2-acetylpyridine (sc-254121, Santa Cruz Biotechnology, Inc., Dallas, TX), 1 mg / kg methyl picolinate (sc-228575, Santa Cruz Biotechnology, Inc.), or 0.1 mg / kg 4-amino-1-methyl-2-piperidinecarboxylic acid (A00285-13785-026, Sundia, Shanghai, China) in 100 μl of PBS. On day 21, mice were sacrificed by CO2 inhalation and subsequently resected. Current protocols in mouse biology 2, 167-175 (2012); Proceedings of the National Academy of Sciences Sciences of the United States of America 112, 11929-11934 (2015); Proceedings of the National Academy of Sciences of the United States of Proceedings of the National Academy of Sciences of the United States of America 111, 18291-18296 (2014); Proceedings of the National Academy of Sciences of the United States of America 112, 8385-8390 (2015); and Public Library of Science ONE 9, e93730 (2014) (all incorporated by reference) Bronchoalveolar lavage (BAL) fluid and cytospins of BAL cells were obtained as previously described in [the original text]. Whole cells from the cytospins were collected and submitted to [the original text]. Current protocols in mouse biology 2, 167-175, (2012); and Public Library of Science Quantification was performed as previously described in ONE 9, e93730 (2014). The lungs were inflated with Surgipath cryosection compound (3801480, Leica, Buffalo Grove, IL) and stored at -80°C. Six- to 10-μm cryosections of the lungs were placed on glass slides (48311-703, VWR). This experiment was performed in accordance with the recommendations in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The Texas A&M University Animal Care and Use Committee approved this protocol.

[0300] Cryosections were stained for collagen with 0.1% Sirius Red (09400, Polysciences, Warrington, PA) in saturated picric acid (26853-07, Electron Microscopy Sciences, Hatfield, PA) for 15 minutes at room temperature. Sections were washed in 0.5% acetic acid in water (v / v) for 10 minutes at room temperature with two washes. After dehydrating the sections in ethanol, the sections were mounted in Permount mounting medium (17986-01, Electron Microscopy Sciences). Sections were imaged on a Nikon Microphot-FX (Nikon, Tokyo, Japan), and staining was quantified using ImageJ.

[0301] Immunohistochemistry on BAL cytospins was performed using anti-CD11b (101202, clone M1 / 70 BioLegend, San Diego, CA) to detect blood and inflammatory macrophages, anti-CD11c (M100-3, clone 223H7, MBL International, Woburn, MA) to detect alveolar macrophages and dendritic cells, anti-CD45 (103102, clone 30-F11, BioLegend) for total leukocytes, anti-Ly-6G (127602, clone 1A8, BioLegend) to detect neutrophils, anti-Ly-6C (128001, clone HK1.4, BioLegend) to detect various inflammatory immune system cells, and an isotype-matched irrelevant antibody (BioLegend) as a control, Public Library of Science ONE 9, e93730 (2014); This was performed as previously described in Proceedings of the National Academy of Sciences of the United States of America 111, 18291-18296 (2014); and Proceedings of the National Academy of Sciences of the United States of America 112, 8385-8390 (2015).

[0302] Figures 8A–F show that daily intraperitoneal injections of a NEU3 inhibitor starting on day 10 reduced fibrosis at day 21 in a mouse bleomycin model. Figure 8A shows the total number of cells collected in bronchoalveolar lavage (BAL) samples from mice with bleomycin-induced fibrosis compared with mice without fibrosis. The NEU3 inhibitor reduced the number of cells collected from bleomycin-treated mice. Figures 8B–F show the total number of CD11b+, CD11c+, CD45, Ly6G, and Ly6C cells collected from BAL samples. CD11b+ is a marker for inflammatory neutrophils and macrophages. CD11c+ is a marker for resident lung macrophages and dendritic cells. Collectively, these results demonstrate that 2-acetylpyridine, methyl picolinate, and 2-piperidinecarboxylate-4-amino-1-methyl can reduce fibrosis-associated inflammation in a mouse model. Values ​​are means ± standard error (n=3). * = p ≤ 0.05, ** = p ≤ 0.01, *** = p ≤ 0.001 (one-way ANOVA, Bonferroni's test), # = p ≤ 0.05, ## = p ≤ 0.01, ### = p ≤ 0.001 (t-test).

[0303] Figures 9A-H show eight sets of cryosections stained for collagen with Sirius Red. Figure 10 shows quantification of Sirius Red staining. Compared to saline controls, bleomycin induced collagen accumulation in the lung (fibrosis), and this collagen deposition was reduced by treatment with 2-acetylpyridine (2AP), methyl picolinate (MP), or 2-piperidinecarboxylic acid-4-amino-1-methyl (AMPCA), indicating that inhibiting NEU3 inhibits fibrosis.

[0304] 11A-D show the percent weight change in mice. Compared to saline controls, bleomycin induced weight loss in mice, which was attenuated by treatment with 2-acetylpyridine, methyl picolinate, or 2-piperidinecarboxylate-4-amino-1-methyl. Example 8: Effects of high-fat diet-induced weight changes in Neu3 knockout mice

[0305] We demonstrated that NEU3 inhibitors inhibit bleomycin-induced pulmonary fibrosis, and that bleomycin-induced lung inflammation and fibrosis were significantly reduced in Neu3 knockout mice (Neu3 - / - ), we wished to determine whether Neu3 is involved in high-fat diet (HFD)-induced liver inflammation in mice and whether inhibiting one or more sialidases could inhibit high-fat diet-induced liver inflammation.

[0306] Twelve- to 16-week-old male C57BL / 6 mice (#000664; Jackson Laboratory, Farmington, CT) were fed a standard rodent diet (15% kcal from fat, Teklad 8604, Envigo, Madison WI), and obese C57BL / 6 mice (#380050; Jackson) were fed a high-fat diet (60% kcal from fat, D12492 formulation; Research Diets New Brunswick, NJ). 12-week-old male C57BL / 6 background Neu3 knockout mice (Neu3 - / - ) strain B6.129-Neu3 tm1Yamk (Yamaguchi, K., et al., Reduced Susceptibility to Colitis-Associated Colon Carcinogenesis in Mice Lacking Plasma Membrane-Associated Sialidase. PLoS ONE, 2012. 7(7): p. e41132) were also fed standard and HFD diets. Mice were fed a designated diet for 4 weeks before being placed on the designated diet. Mice were maintained on the designated diet for 5 weeks (35 days). Mice were weighed between 9:00 AM and noon. Animals were housed on a 12-hour / 12-hour light / dark cycle (lights on at 7:00 AM) with food and water ad libitum. All procedures were performed between 9:00 AM and 11:00 AM. This protocol was approved by the Texas A&M University Institutional Animal Care and Use Committee.

[0307] To determine whether Neu3 is involved in the accumulation of liver macrophages induced by a high-fat diet, liver tissue was removed after euthanasia on day 35 of the experiment and fixed in Zn-buffered formalin solution (0.1% ZnSO4; 4% formaldehyde) for 2 days, then placed in 10% and then 30% sucrose solutions in PBS for 2 days each (all compounds from VWR). Fixed tissue was then maintained in 70% ethanol until paraffinization and 5 μm sectioning. Prior to antibody staining, the paraffin was removed from fixed tissue sections using xylene and then rewetted through a graded series of alcohols and distilled water. The sections were then exposed to antigens by incubation in 10 mM sodium citrate (pH 6.0) at 98°C for 20 minutes. (Pilling D, et al., Serum Amyloid.) P and a Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin Ligand Inhibit High-Fat Diet-Induced Adipose Tissue and As described in Liver Inflammation and Steatosis in Mice Am J Pathol. 2019 Dec;189(12):2400-2413, sections were stained with 5 μg / ml of antibodies against Mac2 (rat mAb, clone M3 / 38, BioLegend, San Diego, CA) to detect inflammation and tissue macrophages, F4 / 80 (rabbit mAb, D2S9R, Cell Signaling Technology, Danvers, MA) to detect tissue-resident macrophages, CD64 (rabbit mAb 50086-R001, SinoBiological, Wayne, PA) to detect FcγRI expression, and CLEC4F (goat Ab, AF2784, Novus Biologicals, Littleton, CO) to specifically detect Kupffer cells.

[0308] Depending on the signals present in the liver environment, different types of liver macrophages can promote tissue regeneration and can drive inflammation and fibrosis. Elevated levels of Mac2 (galectin-3) present in macrophages are associated with liver inflammation and fibrosis. Figure 12 shows that HFD C57BL / 6 mice had significantly higher numbers of Mac2-positive cells in the liver compared to C57BL / 6 mice fed a standard rodent diet. Compared to C57BL / 6 mice fed a standard diet, Neu3 - / - HFD Neu3 mice had significantly fewer Mac2-positive cells in the liver. - / - The number of Mac2-positive cells in the livers of these mice was also significantly lower than in the livers of HFD C57BL / 6 mice.

[0309] Figures 13A-C show that HFD Neu3 mice have significantly higher IFN-γ levels than HFD C57BL / 6 mice. - / - Mice had significantly fewer F4 / 80-positive liver macrophages, but no difference in the number of Clec4f-positive Kupffer cells. These data suggest that loss of Neu3 attenuates HFD-induced liver inflammation. Example 9: DANA reduces HFD-induced lipid accumulation in the liver.

[0310] Twelve-week-old male C57BL / 6 mice (#000664; Jackson Laboratory, Farmington, CT) were fed a standard rodent chow (15% kcal from fat, Teklad 8604, Envigo, Madison, WI), and 12- to 16-week-old male C57BL / 6 mice (#380050; Jackson) were fed a high-fat diet (60% kcal from fat, D12492 formulation; Research Diets, New Brunswick, NJ). Mice were maintained on the designated diet for 6 weeks before treatment began. To determine whether the sialidase inhibitor DANA (#252926-10MG, Millipore-Sigma, Burlington, MA) reduces weight gain induced by a high-fat diet, mice were treated every 48 hours with intraperitoneal injections of 10 mg / kg DANA in phosphate-buffered saline (PBS) or PBS formulated at 4 mg / ml. Mice were maintained on their designated diet and injected every 48 hours for 5 weeks (35 days). Animals were housed on a 12-hour / 12-hour light / dark cycle (lights on at 7:00 AM) with food and water ad libitum. All injections were performed between 9:00 AM and 11:00 AM. This protocol was approved by the Texas A&M University Institutional Animal Care and Use Committee.

[0311] To determine the amount of steatosis (the amount of fat accumulated in liver cells), frozen sections were prepared by placing freshly isolated pieces of liver in Surgipath cryosection compound, freezing them on dry ice, and storing them at -80°C. (Mehlem, A., et al., Imaging of neutral lipids by oil red O for analyzing the metabolic status in As described in

[2013] , 10-12 μm cryosections of liver were placed on glass slides and stained with oil red O to detect lipid accumulation.

[0312] Figure 14 shows that saline-treated HFD C57BL / 6 mice had significantly more oil red O staining in the liver compared to saline-treated C57BL / 6 mice fed standard rodent chow. Compared to saline-treated HFD C57BL / 6 mice, DANA-treated HFD C57BL / 6 mice had significantly less oil red O staining. There was no significant difference in oil red O staining between saline- or DANA-treated standard diet-fed C57BL / 6 mice. These results indicate that DANA reduces HFD-induced neutral lipid accumulation in the liver. Example 10: DANA reduces HFD-induced tissue-resident F4 / 80-positive macrophages in the liver.

[0313] As in Example 9, mice were maintained on their designated diet and received injections of buffer or DANA every 48 hours for 5 weeks (35 days). After euthanasia, liver tissue was removed, fixed, and then sectioned as described above. Figure 15 shows that saline-treated HFD C57BL / 6 mice had significantly higher numbers of F4 / 80-positive liver-resident macrophages than saline-treated C57BL / 6 mice fed standard rodent chow. DANA-treated HFD mice had significantly fewer F4 / 80-positive cells than saline-treated HFD mice. There was no significant difference in F4 / 80 staining between saline- or DANA-treated C57BL / 6 mice fed a standard diet. These results indicate that DANA reduced the HFD-induced increase in F4 / 80-positive macrophages in the liver. Example 11: Effect of injection of DANA on mouse body weight.

[0314] Figure 16 shows that intraperitoneal injection of DANA, as described in Example 9, reduces weight gain induced by a high-fat diet. Control mice fed a standard diet and treated with either PBS or DANA injections did not have significant differences in body weight. In mice fed a high-fat diet (HFD), there was a significant reduction in weight gain observed in mice treated with DANA injections after 21 days of treatment compared to mice injected with PBS. The results shown in Figure 16 indicate that sialidase inhibitors such as DANA can improve the ability to regulate body weight in diet-induced obesity. Example 12: Effect of injection of DANA on glucose levels in mice.

[0315] Obesity is associated with type 2 diabetes, a condition in which the body's cells do not respond effectively to insulin, a process known as insulin resistance. This condition leads to elevated blood glucose levels, and after blood sugar rises (such as after a meal or glucose injection), the body takes longer than normal to lower blood glucose levels. To determine whether DANA can lower blood glucose levels, mice were fasted for 16 hours starting at 5 p.m. on the 33rd day of the experiment described in Example 15. On the 34th day, mice were IP injected with 1.5 g / kg glucose (Amresco, Solon, OH) formulated as 525 mg / ml in PBS. Using commercially available blood glucose test strips (CVS Pharmacy, Woonsocket, RI), blood glucose levels were measured before glucose administration (time 0), and 20, 40, 60, 90, and 120 minutes after injection.

[0316] Figure 17 shows that control mice fed standard rodent chow and treated with either DANA or PBS injections had no significant differences in fasting glucose levels (t = 0 min) or glucose levels after glucose injection, but HFD-fed mice injected with DANA had significantly lower blood glucose levels at 60 min compared to control HFD mice.

[0317] Figure 18 shows that HFD mice treated with DANA had significantly lower total glucose levels compared to the HFD control group. The results shown in Figures 17 and 18 indicate that in obese individuals, injection of DANA can improve the ability to regulate glucose levels. Example 13: Effect of DANA injection on mouse organ weights.

[0318] Obesity is associated with an increase in the size (weight) of many organs, including white fat and the liver. To determine whether the sialidase inhibitor DANA prevents the increase in organ weight induced by a high-fat diet, the epididymal white fat and interscapular brown adipose tissue, liver, spleen, lungs, and kidneys were weighed after euthanasia on day 35 of the experiment described in Example 9.

[0319] Figure 19 shows that control mice fed standard rodent chow and treated with either DANA or PBS injections did not have significant differences in the weight of any organ. As a percentage of body weight, control HFD mice had significantly higher white and brown adipose tissue weights than mice fed standard chow. HFD mice treated with DANA injections had significantly lower white and brown adipose tissue weights than control HFD mice.

[0320] The above disclosed subject matter should be considered as illustrative, not limiting, and the appended claims are intended to encompass all such modifications, enhancements, and other embodiments that fall within the true spirit and scope of the present disclosure. For example, although the present disclosure focuses on inhibiting human sialidase, the disclosed sialidase inhibitors may be effective against other mammalian sialidases, particularly those with similar protein sequences or structures to human sialidase. The effectiveness of sialidase inhibitors against other mammalian sialidases can be easily determined using the methods described in the present disclosure. Furthermore, methods using such sialidase inhibitors to affect fibrocytes, fibrosis, inflammation, adiposity, obesity, and cancer can be adapted from the present disclosure. The present invention provides, for example, the following items. (Item 1) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (I): [ka] (R1 is hydrogen, -NO2, -CN, -COOH, -CONH2, -COCH3, C 2~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; X is selected from carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 2) 2. The method of item 1, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 3) 2. The method of item 1, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 4) 3. The method of item 2, wherein fibrocyte formation or activation is inhibited. (Item 5) 4. The method of item 3, wherein fibrocyte formation or activation is inhibited. (Item 6) Item 10. The method of claim 1, wherein the compound is methyl picolinate. (Item 7) Item 10. The method of claim 1, wherein the compound is 2-acetylpyridine. (Item 8) 2. The method of claim 1, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of TGF-β1 in a human. (Item 9) 2. The method of claim 1, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 10) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (II): [ka] or a salt thereof (wherein R1 is hydrogen, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6Alkyl ester, aryl ester, -ONH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen and oxygen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 11) 11. The method of item 10, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 12) 11. The method of item 10, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 13) 12. The method of claim 11, wherein fibrocyte formation or activation is inhibited. (Item 14) 13. The method of claim 12, wherein fibrocyte formation or activation is inhibited. (Item 15) 11. The method of claim 10, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of TGF-β1 in a human. (Item 16) 11. The method of claim 10, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 17) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (III): [ka] or a salt thereof (wherein R1 is hydrogen, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl Ether, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6alkyl), X is selected from oxygen, carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 18) 18. The method of item 17, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 19) 18. The method of item 17, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 20) 19. The method of item 18, wherein fibrocyte formation or activation is inhibited. (Item 21) 20. The method of item 19, wherein fibrocyte formation or activation is inhibited. (Item 22) 18. The method of claim 17, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 23) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (IV): [ka] or a salt thereof (wherein R1 is hydrogen, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl Ether, Halo, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from oxygen, carbon and nitrogen; Y is selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 24) 24. The method of item 23, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 25) 24. The method of item 23, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 26) 25. The method of item 24, wherein fibrocyte formation or activation is inhibited. (Item 27) 26. The method of item 25, wherein fibrocyte formation or activation is inhibited. (Item 28) 24. The method of claim 23, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 29) 24. The method of claim 23, further comprising administering the formulation in an amount and for a time sufficient to reduce the level of IL-6 in a human. (Item 30) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (I): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; X is selected from carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 31) 31. The method of item 30, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 32) 31. The method of item 30, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 33) 31. The method of claim 30, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 34) 31. The method of claim 30, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 35) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (II): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, halogens and COOH, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -ONH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, halogens, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen and oxygen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 36) 36. The method of item 35, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 37) 36. The method of item 35, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 38) 36. The method of claim 35, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 39) 36. The method of claim 35, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 40) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (III): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl ether, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2)1~3 NH2, -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, halogen and COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from oxygen, carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 41) 41. The method of item 40, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 42) 41. The method of item 40, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 43) 41. The method of claim 40, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 44) 41. The method of claim 40, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 45) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (IV): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, F, Cl, Br, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl ether, halogen, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from oxygen, carbon and nitrogen; Y is selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 46) 46. ​​The method of item 45, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 47) 46. ​​The method of item 45, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 48) 46. ​​The method of claim 45, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 49) 46. ​​The method of claim 45, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 50) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (V): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, alkyl group, aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles; R2 and R3 are hydrogen, halogen, alkyl group, aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole, 2-oxazolyl or other heterocycles; R4 is hydrogen, halogen, alkyl group, aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, oxygen and nitrogen; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 51) 51. The method of item 50, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 52) 51. The method of item 50, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 53) 52. The method of item 51, wherein fibrocyte formation or activation is inhibited. (Item 54) 53. The method of item 52, wherein fibrocyte formation or activation is inhibited. (Item 55) 51. The method of claim 50, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 56) 51. The method of claim 50, further comprising administering the formulation in an amount and for a time sufficient to reduce the level of IL-6 in a human. (Item 57) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (VI): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, alkyl group, aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles; R2 and R3 are hydrogen, halogen, alkyl group, aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R4 is hydrogen, halogen, alkyl group, aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, oxygen and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 58) 58. The method of item 57, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 59) 58. The method of item 57, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 60) 59. The method of item 58, wherein fibrocyte formation or activation is inhibited. (Item 61) 60. The method of item 59, wherein fibrocyte formation or activation is inhibited. (Item 62) 58. The method of claim 57, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 63) 58. The method of claim 57, further comprising administering the formulation in an amount and for a time sufficient to reduce the level of IL-6 in a human. (Item 64) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (VII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, alkyl group, aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles; R2 and R3 are hydrogen, halogen, alkyl group, aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R4 is hydrogen, halogen, alkyl group, aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, oxygen and nitrogen; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 65) 65. The method of item 64, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 66) 65. The method of item 64, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 67) 66. The method of item 65, wherein fibrocyte formation or activation is inhibited. (Item 68) 67. The method of item 66, wherein fibrocyte formation or activation is inhibited. (Item 69) 65. The method of claim 64, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 70) 65. The method of claim 64, further comprising administering the formulation in an amount and for a time sufficient to reduce the level of IL-6 in a human. (Item 71) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (VIII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, alkyl group, aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycles; R2 and R3 are hydrogen, halogen, alkyl group, aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R4 is hydrogen, halogen, alkyl group, aryl group, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --CONHOH, -OH, -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, C1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl or other heterocycles; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, oxygen and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 72) 72. The method of item 71, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 73) 72. The method of item 71, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 74) 73. The method of item 72, wherein fibrocyte formation or activation is inhibited. (Item 75) 74. The method of item 73, wherein fibrocyte formation or activation is inhibited. (Item 76) 72. The method of claim 71, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 77) 72. The method of claim 71, further comprising administering the formulation in an amount and for a time sufficient to reduce the level of IL-6 in a human. (Item 78) 1. A method of treating a fibrotic disorder, said method comprising administering to a subject a compound of formula (IX): [ka] or a salt thereof (wherein B1, B2, B3, B4, B5, B6 and B7 are selected from single or double (olefinic) bonds; R1 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; R2 to R6 are hydrogen, halogen, alkyl group, aryl group, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), --C(O)-NHOH, --NO2, --OH, --O-alkyl, --O-aryl, --CN, --COOH, --CONH2, --CHO, --COCH3, --CO(alkyl), --CO(aryl), --COCF3, --COCHF2, --CO2-alkyl, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 aryl), -SO2N(C 1~6 aryl)2, -SO3(C 1~6 alkyl), -SO3(C 1~6aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or other heterocycle; R7 is hydrogen, halogen, alkyl group, aryl group, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, --C(O)-NHOH, -OH, C 1~6 Alkyl, aryl, -COOH, -CONH2, -COCH3, --COCF3, --COCHF2, --CO2-aryl, -CONH(C 1~6 alkyl or aryl), -CON((C 1~6 (alkyl)2 or (aryl)2), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, aryl ether, -(CH2) 1~3 NH2, -SO2N(C 1~6 aryl)2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole, 2-oxazolyl or other heterocycles; X is selected from carbon, oxygen and nitrogen; Y1, Y2, Y3, Y4, Y5 and Y6 are independently selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 79) 79. The method of item 78, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 80) 79. The method of item 78, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 81) 80. The method of item 79, wherein fibrocyte formation or activation is inhibited. (Item 82) 81. The method of item 80, wherein fibrocyte formation or activation is inhibited. (Item 83) 79. The method of claim 78, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 84) 79. The method of claim 78, further comprising administering the formulation in an amount and for a time sufficient to reduce the level of IL-6 in a human. (Item 85) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (I): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; X is selected from carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 86) 86. The method of item 85, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 87) 86. The method of item 85, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 88) 86. The method of claim 85, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 89) 86. The method of claim 85, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 90) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (II): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, halogens and COOH, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -ONH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, halogens, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent, and X is selected from carbon, nitrogen, and oxygen 20. A method comprising administering a pharmaceutical formulation comprising: (Item 91) 91. The method of paragraph 90, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 92) 91. The method of item 90, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 93) 91. The method of claim 90, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 94) 91. The method of claim 90, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 95) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (III): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl ether, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, halogen and COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from oxygen, carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 96) 96. The method of item 95, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 97) 96. The method of item 95, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 98) 96. The method of claim 95, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 99) 96. The method of claim 95, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 100) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (IV): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, F, Cl, Br, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl ether, halogen, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from oxygen, carbon and nitrogen; Y is selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 101) 101. The method of paragraph 100, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 102) 101. The method of claim 100, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 103) 101. The method of claim 100, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of TGF-β1 in a human. (Item 104) 101. The method of claim 100, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 105) 1. A method of treating liver inflammation, said method comprising administering to a subject a compound of formula (V): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 106) 106. The method of item 105, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 107) 106. The method of item 105, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 108) 106. The method of claim 105, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 109) 106. The method of claim 105, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 110) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (VI): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole, and R2, R3 and R4 are selected from hydrogen, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 111) 111. The method of paragraph 110, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 112) 111. The method of item 110, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 113) 111. The method of claim 110, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 114) 111. The method of claim 110, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 115) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (VII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 116) 116. The method of item 115, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 117) 116. The method of item 115, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 118) 116. The method of claim 115, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 119) 116. The method of claim 115, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 120) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (VIII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole, and R2, R3 and R4 are selected from hydrogen, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 121) 121. The method of paragraph 120, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 122) 121. The method of item 120, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 123) 121. The method of claim 120, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 124) 121. The method of claim 120, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 125) 1. A method for the treatment of liver inflammation, said method comprising administering to a subject a compound of formula (IX): [ka] or a salt thereof (wherein B1, B2, B3, B4, B5, B6 and B7 are selected from single or double (olefinic) bonds; R1 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; R2 is one or more of hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, or absent; R3, R4, R5, R6, and R7 independently represent one or more of hydrogen, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl, or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y1, Y2, Y3, Y4, Y5 and Y6 are selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 126) 126. The method of item 125, wherein the activity of human NEU3 in desialylating LAP is inhibited. (Item 127) 126. The method of item 125, wherein the activity of human NEU3 in desialylating SAP is inhibited. (Item 128) 126. The method of claim 125, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 129) 126. The method of claim 125, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 130) 1. A method for treating obesity, said method comprising administering to a subject a compound of formula (I): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; X is selected from carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 131) 131. The method of claim 130, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 132) 131. The method of claim 130, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 133) 1. A method for treating obesity, said method comprising administering to a subject a compound of formula (II): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, halogens and COOH, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -ONH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen and oxygen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 134) 134. The method of claim 133, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 135) 134. The method of claim 133, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 136) 1. A method for treating obesity, said method comprising administering to a subject a compound of formula (III): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl ether, C 1~6 Alkyl, aryl, -COOH, -NHCO(C1~6 alkyl), -CO(C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, halogen and COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent, and X is selected from oxygen, carbon and nitrogen 20. A method comprising administering a pharmaceutical formulation comprising: (Item 137) Item 137. The method of item 136, wherein the compound comprises DANA. (Item 138) 137. The method of claim 136, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 139) 137. The method of claim 136, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 140) 1. A method of treating obesity, said method comprising administering to a subject a compound of formula (IV): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, F, Cl, Br, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl ether, halogen, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from oxygen, carbon and nitrogen; Y is selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 141) 141. The method of claim 140, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 142) 141. The method of claim 140, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 143) 1. A method of treating obesity, said method comprising administering to a subject a compound of formula (V): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 144) 144. The method of claim 143, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 145) 144. The method of claim 143, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 146) 1. A method of treating obesity, said method comprising administering to a subject a compound of formula (VI): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 147) 147. The method of claim 146, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 148) 147. The method of claim 146, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 149) A method of treating obesity, said method comprising administering to a subject a compound of formula (VII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 150) 150. The method of claim 149, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 151) 150. The method of claim 149, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 152) 1. A method for treating obesity, said method comprising administering to a subject a compound of formula (VIII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 153) 153. The method of claim 152, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 154) 153. The method of claim 152, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 155) 1. A method for treating obesity, said method comprising administering to a subject a compound of formula (IX): [ka] or a salt thereof (wherein B1, B2, B3, B4, B5, B6 and B7 are selected from single or double (olefinic) bonds; R1 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; R2 is one or more of hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, or absent; R3, R4, R5, R6, and R7 independently represent one or more of hydrogen, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl, or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y1, Y2, Y3, Y4, Y5 and Y6 are selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 156) 156. The method of claim 155, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 157) 156. The method of claim 155, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 158) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (I): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; X is selected from carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 159) 159. The method of claim 158, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 160) 159. The method of claim 158, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 161) 159. The method of claim 158, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 162) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (II): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, halogens and COOH, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -ONH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), and absent; X is selected from carbon, nitrogen and oxygen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 163) 163. The method of claim 162, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 164) 163. The method of claim 162, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 165) 163. The method of claim 162, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 166) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (III): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl ether, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, halogen and COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), and absent; X is selected from oxygen, carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 167) 167. The method of claim 166, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 168) 167. The method of claim 166, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 169) 167. The method of claim 166, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 170) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (IV): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, F, Cl, Br, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl ether, halogen, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), and absent; X is selected from oxygen, carbon and nitrogen; Y is selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 171) 171. The method of claim 170, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 172) 171. The method of claim 170, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 173) 171. The method of claim 170, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 174) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (V): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 175) 175. The method of claim 174, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 176) 175. The method of claim 174, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 177) 175. The method of claim 174, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 178) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (VI): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent, and X is selected from carbon, nitrogen, oxygen, and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 179) 179. The method of claim 178, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 180) 179. The method of claim 178, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 181) 179. The method of claim 178, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 182) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (VII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 183) 183. The method of claim 182, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 184) 183. The method of claim 182, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 185) 183. The method of claim 182, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 186) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (VIII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 187) 187. The method of claim 186, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of TGF-β1 in a human. (Item 188) 187. The method of claim 186, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 189) 187. The method of claim 186, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 190) 1. A method for the treatment of steatosis, said method comprising administering to a subject a compound of formula (IX): [ka] or a salt thereof (wherein B1, B2, B3, B4, B5, B6 and B7 are selected from single or double (olefinic) bonds; R1 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; R2 is one or more of hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, or absent; R3, R4, R5, R6, and R7 independently represent one or more of hydrogen, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl, or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y1, Y2, Y3, Y4, Y5 and Y6 are selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 191) 191. The method of claim 190, further comprising administering the formulation in an amount and for a time sufficient to reduce TGF-β1 levels or activity in a human. (Item 192) 191. The method of claim 190, further comprising administering the formulation in an amount and for a time sufficient to reduce the amount of neutral lipids in the liver of a human. (Item 193) 191. The method of claim 190, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human. (Item 194) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering a compound of formula (I): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -COOH, -NHCO(C 1~6 alkyl), -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; X is selected from carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 195) Item 195. The method of item 194, wherein the compound is methyl picolinate. (Item 196) Item 195. The method of item 194, wherein the compound is 2-acetylpyridine. (Item 197) 195. The method of claim 194, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 198) 195. The method of claim 194, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 199) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (II): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, halogens and COOH, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3NH2, -ONH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole or 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), and absent; X is selected from carbon, nitrogen and oxygen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 200) 200. The method of claim 199, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 201) 200. The method of claim 199, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 202) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering a compound of formula (III): [ka] or a salt thereof (wherein R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, halogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl ether, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, halogen, -CH2OH, hydroxypropyl, dihydroxypropyl, trihydroxypropyl, -NO2, -CN, -CF3, -NH2, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CONH2, -OH, C 1~6 Alkyl, aryl, -COOH, halogen and COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole and 2-oxazolyl; R6 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), and absent; X is selected from oxygen, carbon and nitrogen. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 203) 203. The method of claim 202, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 204) 203. The method of claim 202, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 205) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (IV): [ka] (R1 is hydrogen, F, Cl, Br, -NO2, -CN, -COOH, -CONH2, -COCH3, C 1~5 Achill, C 1~6 Alkyl ester, aryl ester, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6alkyl), -PO3H(C 1~6 aryl) and tetrazole, and R2, R3 and R4 are selected from hydrogen, F, Cl, Br, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 alkyl), -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -(CH2) 1~3 NH2, -CONH2, -OH, C 1~6 Alkyl ether, halogen, C 1~6 Alkyl, aryl, -COOH, -NHCO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(C 1~6 alkyl), -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl), and absent; X is selected from oxygen, carbon and nitrogen; Y is selected from oxygen, a hydroxyl group, a dimethyl nitrogen, or a methylene group. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 206) 206. The method of claim 205, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 207) 206. The method of claim 205, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 208) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (V): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 209) 209. The method of claim 208, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 210) 209. The method of claim 208, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 211) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (VI): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 212) 212. The method of claim 211, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 213) 212. The method of claim 211, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 214) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (VII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y is selected from carbon and nitrogen; Z is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 215) 215. The method of claim 214, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 216) 215. The method of claim 214, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 217) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (VIII): [ka] or a salt thereof (wherein R1 is hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl) and tetrazole; R2, R3 and R4 are hydrogen, -NO2, -CN, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6 alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, and 2-oxazolyl; R5 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; X is selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 218) 218. The method of claim 217, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 219) 218. The method of claim 217, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer. (Item 220) 1. A method of treating a cancer that overexpresses sialidase, said method comprising administering to a subject a compound of formula (IX): [ka] or a salt thereof (wherein B1, B2, B3, B4, B5, B6 and B7 are selected from single or double (olefinic) bonds; R1 is hydrogen, methyl, -CF3, C 1~6 Alkyl, aryl, -CO(C 1~6 alkyl) or absent; R2 is one or more of hydrogen, halogen, -NH2, NO2, -CN, -COOH, -CONH2, -COCH3, COCF3, COCHF2, C 2~5 Achill, C 1~6 Alkyl esters, aryl esters, -(CH2) 1~3 NH2, -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, or absent; R3, R4, R5, R6, and R7 independently represent one or more of hydrogen, —NO2, —CN, —CF3, —NH2, —NH(C 1~6 alkyl), -N(C 1~6 Alkyl, C 1~6 Alkyl), -CONH2, -OH, halogen, C 1~6 Alkyl, aryl, -COOH, -CH(OH)CH3, -CH(OH)(CH2OH), -CH(OH)(CH(OH)CH2OH), -NHCO(C 1~6alkyl), C 1~6 Alkyl ether, -(CH2) 1~3 NH2, -COCH3, C 2~5 Acyl, -CO(aryl), -SO3H, -SO2NH2, -SO2NH(C 1~6 alkyl), -SO2NH(C 1~6 aryl), -SO3(C 1~6 alkyl), -SO3(C 1~6 aryl), -PO3H2, -PO2H2, -PO2NH(C 1~6 alkyl), -PO2NH(C 1~6 aryl), -POH(C 1~6 alkyl), -POH(C 1~6 aryl), -PO3H(C 1~6 alkyl), -PO3H(C 1~6 aryl), tetrazole, 2-oxazolyl, or absent; X is selected from carbon, nitrogen, oxygen and sulfur; Y1, Y2, Y3, Y4, Y5 and Y6 are selected from carbon, nitrogen, oxygen and sulfur. 20. A method comprising administering a pharmaceutical formulation comprising: (Item 221) 221. The method of claim 220, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of NEU3 in a human cancer. (Item 222) 221. The method of claim 220, further comprising administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human cancer.

Claims

Claim 1: A pharmaceutical formulation for use in a method for the treatment of a fibrotic disorder, comprising compound 26: 【Chemical 1】 or a salt thereof.

2. A pharmaceutical formulation for use in a method for the treatment of a fibrotic disorder, comprising compounds 13, 20 and 25: 【Chemistry 2】 or a salt thereof.

3. The pharmaceutical formulation of claim 2, wherein the compound is 4-amino-2-piperidinecarboxylic acid.

4. The pharmaceutical formulation of claim 2, wherein the compound is 1-methyl-2-piperidinecarboxylic acid.

5. A pharmaceutical preparation according to claim 1 or 2, in which the activity of human NEU3 in desialylation of LAP is inhibited.

6. A pharmaceutical preparation according to claim 1 or 2, in which the activity of human NEU3 in desialylation of SAP is inhibited.

7. The pharmaceutical preparation described in claim 5, wherein the formation or activation of fibrocytes is inhibited.

8. The pharmaceutical preparation of claim 6, wherein the formation or activation of fibrocytes is inhibited.

9. The pharmaceutical formulation of claim 1, wherein the method further comprises administering the formulation in an amount and for a time sufficient to reduce the level or activity of TGF-β1 in a human.

10. The pharmaceutical formulation of claim 1 or 2, wherein the method further comprises administering the formulation in an amount and for a time sufficient to reduce the level or activity of sialidase in a human.

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