CN101360707A

CN101360707A - Thrombopoietin activity modulating compounds and methods

Info

Publication number: CN101360707A
Application number: CNA2006800509960A
Authority: CN
Inventors: 智林; 迪安·P·飞利浦; 杰克莱恩·E·达尔加德; 理查德·J·帕努利亚; 马修·H·麦克尼尔; 陈全兴; 卡塔利娜·奎尔沃; 罗伯特·伊谷奇; 李永恺; 奥利弗·龙; 科尼利斯·阿尔干·万厄费伦
Original assignee: Ligand Pharmaceuticals Inc
Current assignee: Ligand Pharmaceuticals Inc
Priority date: 2005-11-23
Filing date: 2006-11-21
Publication date: 2009-02-04

Abstract

Disclosed herein are amide containing heterocyclic compounds, pharmaceutical compositions comprising the compounds, methods of modulating the activity a thrombopoietin receptor using the compounds, methods of identifying compounds as thrombopoietin receptor modulators, and methods of treating disease by administering the compounds to a patient in need thereof.

Description

Thrombopoietin activity modulating compounds and method

Invention field

[0001] the present invention relates to the chemistry and the Compounds and methods for of pharmaceutical field.More specifically, the present invention relates to regulate one or more TPO activities and/or with thrombopoietin receptor bonded compound, and relate to preparation and use the method for this compound.

Background

[0002] thrombopoietin (TPO) is also referred to as c-Mp1 part, mp1 part, megapoietin and megakaryocyte growth and the growth factor, and it is to be proved to be to relate to thrombopoietic glycoprotein.Referring to for example, Wendling, people such as F., Biotherapy 10 (4): 269-77 (1998); People such as Kuter D.J., The Oncologist, 1:98-106 (1996); Metcalf, Nature 369:519-520 (1994) is incorporated herein by reference its full content at this.TPO has been cloned and the cDNA sequence of its aminoacid sequence and this aminoacid sequence of coding is described.Referring to for example, U.S.5,766,581; Kuter, people such as D.J., Proc.Natl.Acad.Sci., 91:11104-11108 (1994); People such as de Sauvage F.V., Nature, 369:533-538 (1994); Lok, people such as S., Nature 369:565-568 (1994); Wending, people such as F., Nature, 369:571-574 (1994) is incorporated herein by reference its full content at this.

[0003] in some cases, TPO activity combining from TPO and TPO acceptor (being also referred to as MPL).Described TPO acceptor has been cloned and its aminoacid sequence is described.Referring to for example, people such as Vigon, Proc.Natl.Acad.Sci., 89:5640-5644 (1992) is incorporated herein by reference its content at this.

[0004] in some cases, the TPO conditioning agent can be used for the treatment of many hematopoiesis diseases, includes but not limited to thrombocytopenia.Referring to for example, people such as Baser, Blood89:3118-3128 (1997); People such as Fanucchi, New Engl.J.Med.336:404-409 (1997) is incorporated herein by reference at this full content with these two pieces of articles.For example, experience includes but not limited to that the chemotherapy and/or the radiotherapy that are used for the treatment of cancer may have the platelet levels of reduction some interior chemotherapeutic patient.In some cases, use these patients of selectivity TPO modulators for treatment to improve platelet levels.In some cases, the excite nerve generation of spongiocyte of selectivity TPO conditioning agent, it can impel the reparation of impaired neurocyte.

Summary of the invention

[0005] in certain embodiments, the invention provides compound or the acceptable salt of its medicine, ester, acid amides or the prodrug of formula I, II, III, IV, V or VI:

Wherein:

R ¹Be selected from hydrogen, halogen, OR ¹⁴, NO ₂, CN, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or carboxylic acid bioisostere;

Each R ²Be independently selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl;

R ³And R ⁴Be independently selected from hydrogen, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl;

R ⁵Be selected from hydrogen, halogen, OR ¹⁴, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆The halo alkyl of mixing;

R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl or the optional C that replaces ₁-C ₁₀Assorted alkyl, each R ⁶Randomly heteroaryl-condensed with aryl that replaces or replacement, perhaps R ⁶Be selected from (CH ₂) _mR ¹⁸, C (O) NHR ¹⁸, C ≡ CR ¹⁸, CR ³=CR ⁴R ¹⁸Or CR ³=R ¹⁸

R ⁷Be selected from CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or carboxylic acid bioisostere;

Each R ⁸With each R ⁹Be independently selected from hydrogen, OR ¹⁶, NR ¹⁶R ¹⁷, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, (CH ₂) _mR ¹⁸Perhaps do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

R ¹⁰Be selected from hydrogen, halogen, oxo, OR ¹⁶, NR ¹⁶R ¹⁷, SR ¹⁶, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl;

R ¹¹Be selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵Or SR ¹⁴Perhaps R ¹¹And R ⁴Connection is to form the optional heterocycle that replaces;

R ¹²Be selected from hydrogen, halogen, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆The halo alkyl of mixing;

R ¹³Be selected from hydrogen, halogen, CN, NO ₂, CO ₂R ¹⁴, S (O) _mR ¹⁴, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄The halo alkyl of mixing;

R ¹⁴Be selected from hydrogen, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆Assorted halo alkyl;

R ¹⁵Be selected from hydrogen, SO ₂R ¹⁹, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆Assorted halo alkyl;

R ¹⁶And R ¹⁷Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or (CH ₂) _mR ¹⁸Perhaps R ¹⁶And R ¹⁷In one be the optional C that replaces ₂-C ₆Alkyl, and R ¹⁶And R ¹⁷In another do not exist; Perhaps R ¹⁶And R ¹⁷Connection is to form the C of the optional optional replacement that replaces ₃-C ₈Ring;

R ¹⁸Be selected from optional replace randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems, wherein work as R ¹⁸When containing non-aromatic heterocyclic or carbocyclic ring, link position can be on non-aromatic heterocyclic or the carbocyclic ring or on the aromatic ring system;

R ¹⁹Be selected from hydrogen, C ₁-C ₃Alkyl, C ₁-C ₃Halo alkyl or the optional aryl that replaces;

D be randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems;

E be randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems;

L is NH or does not exist;

Q be randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Y comprises one or more optional C that replace that are selected from ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆The spacer of 1 to 4 atom of assorted alkyl, the optional phenyl that replaces or the optional heteroaryl that replaces;

Z is selected from:

Do not exist,

Be selected from the optional C that replaces ₆-C ₁₀Aryl or the optional C that replaces ₁-C ₈The spacer of 2 to 5 atoms of heteroaryl, each substituted radical randomly with the optional non-aromatic heterocyclic that replaces or carbocyclic fused, perhaps

Be selected from the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or the optional C that replaces ₁-C ₆The spacer of 1 to 5 atom of halo alkyl, each substituted radical randomly with the optional C that replaces ₆-C ₁₀Aryl-condensed;

M is 0,1,2 or 3; And

N is 0 or 1;

Each optional group that replaces or unsubstituted, or replaced by one or more groups that are independently selected from following group: alkyl, assorted alkyl, the halo alkyl, assorted halo alkyl, cyclic hydrocarbon radical, aryl, the aryl alkyl, heteroaryl, non-aromatic heterocyclic, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, cyano group, halogen, carbonyl, thiocarbonyl, the O-carbamyl, the N-carbamyl, the O-thiocarbamyl, the N-thiocarbamyl, the C-amido, the N-amido, the S-sulfonamido, the N-sulfonamido, the C-carboxyl, the O-carboxyl, isocyanato-, thiocyanato, isothiocyanato, nitro, silyl, three methyl halide alkylsulfonyls,=O,=S, the derivative of amino or protected amino group;

Prerequisite is if Y is directed to form the inferior pyrazolyl of dihydro in the compound of formula I or II Then:

(i) if X is N, W is NH, then D is not a naphthyl,

If (ii) X is that CH, W are that NH, Z are phenyl and R ¹⁰Or R ¹¹Be-(CH ₂) _0-6OH, then D is not a phenyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

Another prerequisite is if in the compound of formula III or VI, and X is that N, W are NH, then R ⁶, R ¹⁰And R ¹¹Do not contain carboxyl, amido, ester or sulphur functional group or carboxylic acid bioisostere.

[0006] in certain embodiments, the invention provides compound or the acceptable salt of its medicine, ester, acid amides or the prodrug of aforesaid formula I, II or III:

Wherein:

R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl, the optional C that replaces ₁-C ₁₀Assorted alkyl, (CH ₂) _mR ¹⁸, C (O) NHR ¹⁸, C ≡ CR ¹⁸, CR ³=CR ⁴R ¹⁸Or CR ³=R ¹⁸

Each R ⁸With each R ⁹Be independently selected from hydrogen, OR ¹⁶, NR ¹⁶R ¹⁷, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Or R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

R ¹⁶And R ¹⁷Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or (CH ₂) _mR ¹⁸Perhaps R ¹⁶And R ¹⁷In one be the optional C that replaces ₂-C ₆Alkyl and R ¹⁶And R ¹⁷In another do not exist; Perhaps R ¹⁶And R ¹⁷Connection is to form the optional C that replaces ₃-C ₈Ring;

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

Be selected from the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or the optional C that replaces ₁-C ₆1 to 5 atomic separation base of halo alkyl, each substituted radical randomly with the optional C that replaces ₆-C ₁₀Aryl-condensed;

M is 0,1,2 or 3; And

N is 0 or 1;

(i) if X is N, W is NH, then D is not a naphthyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

Another prerequisite is if in the compound of formula III, and X is that N, W are NH, then R ⁶, R ¹⁰And R ¹¹Do not contain carboxyl, amido, ester or sulphur functional group or carboxylic acid bioisostere.

[0007] in certain embodiments, the invention provides the compound of aforesaid formula I, II or III; Or the acceptable salt of its medicine, ester, acid amides or prodrug, wherein: R ¹Be selected from halogen, OR ¹⁴, NO ₂, CN, NR ¹⁴R ¹⁵, C ₁-C ₄Alkyl, C ₁-C ₄The halo alkyl, the optional C that replaces ₁-C ₄Assorted alkyl, CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or be selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Or

The carboxylic acid bioisostere, wherein A, B and C are selected from O, S or NR independently of one another ²⁰

Each R ²Be independently selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄Assorted halo alkyl;

R ³And R ⁴Be independently selected from hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl or the optional C that replaces ₁-C ₄Assorted alkyl;

R ⁵Be selected from hydrogen, OR ¹⁴, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄The halo alkyl of mixing;

R ⁶Be selected from C ₁-C ₁₀Alkyl, C ₁-C ₁₀Halo alkyl, the optional C that replaces ₁-C ₁₀Assorted alkyl, (CH ₂) _mR ¹⁸, C (O) NHR ¹⁸, C ≡ CR ¹⁸, CR ³=CR ⁴R ¹⁸Or CR ³=R ¹⁸

R ⁷Be selected from CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or be selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Or

The carboxylic acid bioisostere, wherein A, B and C are selected from O, S or N independently of one another;

Each R ⁸With each R ⁹Be independently selected from hydrogen, OR ¹⁶, NR ¹⁶R ¹⁷, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, the optional C that replaces ₁-C ₄Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

R ¹⁰Be selected from hydrogen, halogen, oxo, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl or the optional C that replaces ₁-C ₄Assorted alkyl;

R ¹²Be selected from hydrogen, halogen, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄The halo alkyl of mixing;

R ¹⁴Be selected from hydrogen, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄Assorted halo alkyl;

R ¹⁵Be selected from hydrogen, SO ₂R ¹⁹, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl or C ₁-C ₄Assorted alkyl;

R ¹⁶And R ¹⁷Be selected from hydrogen, C independently of one another ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, the optional C that replaces ₁-C ₄Assorted alkyl or (CH ₂) _mR ¹⁸Perhaps R ¹⁶And R ¹⁷In one be C ₂-C ₆Alkyl and R ¹⁶And R ¹⁷In another do not exist; Perhaps R ¹⁶And R ¹⁷Connection is to form the optional C that replaces ₄-C ₇Ring;

R ¹⁹Be selected from hydrogen, C ₁-C ₃Alkyl, C ₁-C ₃Halo alkyl or aryl;

G is selected from O, S or NR ¹⁴

J is selected from O, S, NR ¹⁴Or CR ¹⁴R ¹⁵

K is O or S;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Y is selected from:

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

Prerequisite is if Y is directed to form the inferior pyrazolyl of dihydro in the compound of formula I or II

Then:

(i) if X is N, W is NH, then D is not a naphthyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

[0008] in certain embodiments, the invention provides compound or the acceptable salt of its medicine, ester, acid amides or the prodrug of aforesaid formula IV, V or VI:

Wherein:

Each R ⁸With each R ⁹Be independently selected from hydrogen, OR ¹⁶, NR ¹⁶R ¹⁷, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

Be selected from the optional C that replaces ₆-C ₁₀Aryl or the optional C that replaces ₁-C ₈The spacer of 2 to 5 atoms of heteroaryl, each aryl or heteroaryl randomly with the optional non-aromatic heterocyclic that replaces or carbocyclic fused, perhaps

M is 0,1,2 or 3; And

N is 0 or 1;

Prerequisite is that then D is not a phenyl if X is N, W is NH; And

Another prerequisite is if in the compound of formula VI, and X is that N, W are NH, then R ⁶, R ¹⁰And R ¹¹Do not contain carboxyl, amido, ester or sulphur functional group or carboxylic acid bioisostere.

[0009] in certain embodiments, the invention provides compound or the acceptable salt of its medicine, ester, acid amides or the prodrug of formula IV, V or VI, wherein:

R ¹Be selected from hydrogen, halogen, OR ¹⁴, NO ₂, CN, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Perhaps be selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Or

R ²Be selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl;

R ⁷Be selected from CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Perhaps be selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Or

The carboxylic acid bioisostere, wherein A, B and C are selected from O, S or N independently of one another.

[0010] in certain embodiments, the invention provides compound or the acceptable salt of its medicine, ester, acid amides or the prodrug of formula I, II, III, IV, V or VI:

Wherein:

R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl or the optional C that replaces ₁-C ₁₀Assorted alkyl, each substituted radical be heteroaryl-condensed with aryl that replaces or replacement randomly, perhaps R ⁶Be selected from (CH ₂) _mR ¹⁸, C (O) NHR ¹⁸, C ≡ CR ¹⁸, CR ³=CR ⁴R ¹⁸Or CR ³=R ¹⁸

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

Be selected from the optional C that replaces ₆-C ₁₀Aryl or the optional C that replaces ₁-C ₈2 to 5 atomic separation bases of heteroaryl, each aryl or heteroaryl randomly with the optional non-aromatic heterocyclic that replaces or carbocyclic fused, perhaps

M is 0,1,2 or 3; And

N is 0 or 1;

Prerequisite is, if X is N, W is that NH and Y are not-N=CR ¹²-directed forming pyrazoline, and Z or R ⁶Be not and the optional non-aromatic ring that replaces of the optional aromatic ring condensed that replaces; If perhaps X is N, W is NH, R ⁶Be alkoxyl group, the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces, Y is-N=CR ¹²-directed is not the optional non-aromatic ring of aromatic ring condensed that replaces that replace and optional to form pyrazoline and Z; Then D is not a phenyl;

Prerequisite is, if X is N, W is that NH and Y are-N=CR ¹²-directed to form pyrazoline, then D is not a naphthyl;

Prerequisite is, if U is NH; If perhaps D and R ¹⁰And R ¹¹In one form the 5-hydroxypyrazoles, X is that N and W are NH; If perhaps E and R ¹⁰And R ¹¹In one form the 5-hydroxypyrazoles, X is that N and W are NH; If perhaps E is a phenyl, R ¹⁰Or R ¹¹In one be-(CH ₂) _0-6OH, X are C, and W is NH, R ⁶Be optional aryl that replaces or the optional heteroaryl that replaces, and Z does not exist, be the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces; If perhaps E is a phenyl, R ¹⁰Or R ¹¹In one be-(CH ₂) _0-6OH, X are N, and W is NH, and Z does not exist, is the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces, and R ⁶Be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group ,-(CH ₂) _0-6OR ²⁰, the optional aryl that replaces, optional heteroaryl, the NR that replaces ²¹R ²²Or the represented heterocycle methylene radical substituting group of formula VII; If perhaps D is a phenyl, R ¹⁰Or R ¹¹In one be-(CH ₂) _0-6OH, X are C, and W is NH, and Z is an aromatics, and R ⁶Be alkoxyl group, the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces; Then Y is not-N=CR ¹²-directed to form pyrazoline;

R ²⁰Be selected from the alkyl of hydrogen, replacement, the aryl of replacement or the heteroaryl of replacement;

R ²¹And R ²²Be selected from hydrogen, alkyl or aryl independently of one another; Perhaps R ²¹And R ²²Represent with the nitrogen that they connected and to contain other heteroatomic 5 or 6 yuan of saturated rings that are selected from oxygen or nitrogen at the most;

Wherein A, B, C and V are selected from O, S or NR independently of one another ²⁰

[0011] in certain embodiments, the invention provides and be selected from following compound or the acceptable salt of medicine, ester or the prodrug of these compounds arbitrarily:

3 '-{ [1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-2 '-xenol-3-carboxylic acid (compound 101);

2,4-resorcylic acid N '-1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] and ethyl } hydrazides (compound 102);

3-{3-[(5-chloro-2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 103);

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 104);

3 '-{ [1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-4-fluoro-2 '-xenol-3-carboxylic acid (compound 105);

2-(3 '-{ [1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-2 '-xenol-3-yl)-2 Methylpropionic acid (compound 106);

3 '-{ [1-(3, the 4-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-2 '-xenol-3-carboxylic acid (compound 107);

4-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 108);

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 109);

3-{3-[(2-hydroxyl-3 ', 5-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } methyl benzoate (compound 110);

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } methyl benzoate (compound 111);

3-{3-[(5-fluoro-2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 112);

3-{3-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit amino]-2-oxo-2,3-Er hydrogen benzoxazole-7-yl } phenylformic acid (compound 113);

3-{3-[(2-hydroxyl-5,3 ', 4 '-trimethylammonium biphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 114);

3-hydroxy-benzoic acid N '-and 1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 115);

1-(3, the 5-3,5-dimethylphenyl)-3-{1-[2-(4-hydroxy phenyl)-2-oxo-ethylamino] ethylidene }-the 6-Trifluoromethyl-1,3-Indolin-2-one (compound 116);

3-{3-[(5-fluoro-2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 117);

3-{3-[(2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 118);

3-{3-[(2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 119);

3-{3-[(2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 120);

4-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-2,3-indoline-1-yl } butyric acid (compound 121);

2-chloro-3-(4-{[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-the 3-hydroxy phenyl) vinylformic acid (compound 122);

4-hydroxy-benzoic acid N '-and 1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 123);

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-5-nitro-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 124);

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 125);

3-{3-[(2-hydroxyl-5,3 ', 5 '-trimethylammonium biphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 126);

4-benzaminic acid N '-and 1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 127);

3-(7-{N '-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] diazanyl }-the 1H-indol-3-yl) propionic acid (compound 128);

4-{3-[N '-(4-methyl benzoyl) diazanyl methylene radical]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 129);

3-{2-oxo-6-trifluoromethyl-3-[4-(3-trifluoromethyl)-1H-pyrroles-2-methylene]-2,3-indoline-1-yl } phenylformic acid (compound 130);

3-(7-{N '-[1-(3, the 4-3,5-dimethylphenyl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit] diazanyl }-the 1H-indol-3-yl) propionic acid (compound 131);

3-(3-{[4-(3, the 4-3,5-dimethylphenyl) thiazol-2-yl amino] methylene radical }-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl) phenylformic acid (compound 132);

3-(3-{[4-(4-p-methoxy-phenyl) thiazol-2-yl amino] methylene radical }-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl) phenylformic acid (compound 133);

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 134);

3-{3-[(4-(4-aminomethyl phenyl)-2-thiazolyl amino) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 135);

3-{3-[(3,4-dimethylbenzoyl diazanyl) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 136);

3-{3-[(4-chlorobenzene formacyl diazanyl) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 137);

3-{3-[(4-anisoyl diazanyl) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 138);

3-{3-[(3,4-dimethylbenzoyl diazanyl) methylene radical]-2-oxo-6-chloro-2,3-indoline-1-yl } phenylformic acid (compound 139);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(2,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 140);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 141);

1-(3, the 4-3,5-dimethylphenyl)-3-[(2,4-dihydroxy-benzene formyl radical diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 142);

1-(3, the 5-3,5-dimethylphenyl)-3-[1-(2,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 143);

1-(3, the 5-3,5-dimethylphenyl)-3-[1-(4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 144);

1-(3, the 5-3,5-dimethylphenyl)-3-[(2,4-dihydroxy-benzene formyl radical diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 145);

1-(3, the 5-3,5-dimethylphenyl)-3-[(4-hydroxy benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 146);

3-(3-[1-(3,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-6-chloro-2,3-indoline-1-yl) phenylformic acid (compound 147);

1-(3, the 4-3,5-dimethylphenyl)-3-[(4-hydroxy benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 148);

1-(3, the 4-3,5-dimethylphenyl)-3-[(3,5-di-isopropyl-2-hydroxy benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 149);

1-(3, the 5-3,5-dimethylphenyl)-3-[1-(3,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 150);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 151);

3-(6-chloro-3-[(2-hydroxyl-3,5-di-isopropyl benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline-1-yl) phenylformic acid (compound 152);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(2,5-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 153);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3-nitro-4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 154);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3-amino-sulfonyl-4-chlorobenzene formacyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 155);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3-amino-4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 156);

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(4-methoxyl group-2-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 157);

3-{3-(1-(3, the 5-3,5-dimethylphenyl)-2-oxo-2, the inferior indyl of 3-dihydro-3-) methylamino-2-hydroxy phenyl } phenylformic acid (compound 158);

3-{3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene)-and 2-oxo-2,3-dihydro-1-indyl } phenylformic acid (compound 159);

3-{3-(1-(3, the 4-3,5-dimethylphenyl)-2-oxo-2, the inferior indyl of 3-dihydro-3-) methylamino-2-hydroxy phenyl } phenylformic acid (compound 160);

4-{1-(6-fluoro-2-oxo-2,3-dihydro-3-(2-(3, the 5-3,5-dimethylphenyl)-aminocarbonyl-phenyl) aminomethylene) indyl } butyric acid (compound 161);

4-{1-(6-chloro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) indyl } butyric acid (compound 162);

3-{1-(6-chloro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) indyl } phenylformic acid (compound 163);

4-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) indyl } butyric acid (compound 164);

3-{3-(1-(1-(3, the 5-3,5-dimethylphenyl)-6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-3-) ethylamino)-2-hydroxy phenyl } phenylformic acid (compound 165);

3-{3-(1-(1-(3, the 4-3,5-dimethylphenyl)-6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-3-) ethylamino)-2-hydroxy phenyl } phenylformic acid (compound 166);

3-{1-(6-trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl) hydrazono-) indyl } phenylformic acid (compound 167);

3-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(1-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl) amino) ethylidene) indyl } phenylformic acid (compound 168);

3-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl) aminomethylene) indyl } phenylformic acid (compound 169);

4-{2-hydroxyl-3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } butyric acid (compound 170);

4-{2-hydroxyl-3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino phenyl } butyric acid (compound 171);

3-{3-(7-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)-3-) methylamino) indyl } propionic acid (compound 172);

3-{3-(7-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)-3-) methylamino) indyl } propionic acid (compound 173);

4-{2-hydroxyl-3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } butyric acid (compound 174);

2-chloro-3-{3-hydroxyl-4-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 175);

2-chloro-3-{3-hydroxyl-4-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 176);

2-ethyl-3-{3-hydroxyl-4-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 177);

2-ethyl-3-{3-hydroxyl-4-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 178);

2-ethyl-3-{3-hydroxyl-4-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 179);

4-{2-hydroxyl-3-(the inferior pyrazolyl of 4-(2-(3, the 4-3,5-dimethylphenyl)-3-oxo-3,4-dihydro-5-methyl)) methylamino phenyl } butyric acid (compound 180);

(Z)-and 4-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } butyric acid (compound 181);

(E)-and 4-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } butyric acid (compound 182);

(Z)-and 3-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } phenylformic acid (compound 183);

(E)-and 3-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } phenylformic acid (compound 184);

4-{3-(4-oxo-2-sulfo--5-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) hydrazono-) thiazolidyl } butyric acid (compound 185);

3-{2-(3-(1-(3, the 5-3,5-dimethylphenyl)-6-chloro-2-oxo-2,3-indolylidene) methylamino) phenyl amino } phenylformic acid (compound 186);

3-{2-(3-(1-(3, the 5-3,5-dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-indolylidene) methylamino) phenyl amino } phenylformic acid (compound 187);

3-{2-(4-(2-(3, the 5-3,5-dimethylphenyl)-5-methyl-3-oxo-3, the inferior pyrazolyl of 4-dihydro) methylamino) phenyl amino } phenylformic acid (compound 188);

(±)-3-methyl-5-{2-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) phenyl } valeric acid (compound 189);

(±)-3-{1-(6-chloro-2-oxo-2,3-dihydro-3-(3-(1-(3, the 5-3,5-dimethylphenyl)-2-oxo-2,3-dihydro) indyl) aminomethylene) indyl } phenylformic acid (compound 190);

3-{4-(3-hydroxyl-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3, the 5-3,5-dimethylphenyl) indyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 191);

3-{4-(3-hydroxyl-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) pyridine alkyl } phenylformic acid (compound 192);

3-{4-(3-hydroxyl-2-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) pyridine alkyl } phenylformic acid (compound 193);

3-{4-(3-hydroxyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3, the 5-3,5-dimethylphenyl) indyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 194);

3-{5-(4-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) pyridine alkyl } phenylformic acid (compound 195);

3-{5-(4-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3, the 5-3,5-dimethylphenyl) indyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 196);

3-{5-(4-hydroxyl-3-(4-(3-oxo-3,4-dihydro-5-methyl-2-(3, the 4-3,5-dimethylphenyl) pyrazolyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 197);

4-{2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3, the 4-3,5-dimethylphenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 198);

3-{2-amino-5-methyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) phenyl } phenylformic acid (compound 199);

3-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(3-(3, the 4-3,5-dimethylphenyl) phenyl) aminomethylene) indyl } phenylformic acid (compound 200);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(3-(3, the 4-3,5-dimethylphenyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 201);

(3-(5-fluoro-2-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino)-1-pyrazolyl) acetate (compound 202);

(3-(5-fluoro-2-hydroxyl-3-(3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino)-1-pyrazolyl) acetate (compound 203);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 204);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 205);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(4-methyl) phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 206);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3-methyl) phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 207);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-methyl) phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 208);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(1-naphthyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 209);

3-{1-(5-nitro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl) aminomethylene) indyl } phenylformic acid (compound 210);

3-{1-(5-nitro-2-oxo-2,3-dihydro-3-(5-fluoro-2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl) aminomethylene) indyl } phenylformic acid (compound 211);

2-hydroxyl-3-{3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino } phenylformic acid (compound 212);

2-hydroxyl-3-{3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino } phenylformic acid (compound 213);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(3-methyl-1-butene base) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 214);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-heptyl phenyl) hydrazono-) pyrazolyl } butyric acid (compound 215);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(4-methyl) phenyl) ethenylphenyl) hydrazono-) pyrazolyl } butyric acid (compound 216);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(3-methyl) phenyl) ethenylphenyl) hydrazono-) pyrazolyl } butyric acid (compound 217);

4-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-methyl) phenyl) ethylphenyl) hydrazono-) indyl } butyric acid (compound 218);

2-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl) hydrazono-) indyl } acetate (compound 219);

2-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-methyl) phenyl) ethylphenyl) hydrazono-) indyl } acetate (compound 220);

4-{4-(2-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino) thiazolyl } phenylformic acid (compound 221);

3-{1-(5-nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl base-3-(1-diamantane) phenyl) aminomethylene) indyl } phenylformic acid (compound 222);

3-{1-(6-trifluoromethyl-2-oxo-2,3-dihydro-3-(4-hydroxyl-5-(3, the 4-3,5-dimethylphenyl) pyridine alkyl) hydrazono-) indyl } phenylformic acid (compound 223);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(2-methyl) phenyl)-ethylphenyl) aminomethylene) pyrazolyl } butyric acid (compound 224);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(2-fluorine) phenyl)-ethylphenyl) aminomethylene) pyrazolyl } butyric acid (compound 225);

[0012] in certain embodiments, the invention provides and be selected from following compound or the acceptable salt of medicine, ester or the prodrug of these compounds arbitrarily:

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(1-naphthyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 226);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(3, the 5-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 227);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-p-methoxy-phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 228);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluoro-3-methyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 229);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluoro-3-methyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 230);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(4-phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 231);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-cyano-phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 232);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-chloro-phenyl-)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 233);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 234);

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-trifluoromethyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 235);

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluorophenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 236);

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-methyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 237);

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2,5-dimethyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 238);

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2,6-dimethyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 239);

3-{2-(5-phenyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 240);

3-{2-(the 5-tertiary butyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 241);

3-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-aminomethyl phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 242);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 243);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3, the 4-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 244);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(4-phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 245);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-p-methoxy-phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 246);

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluoro-3-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 247);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-trifluoromethyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 248);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-cyano-phenyl) ethyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 249);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-chloro-phenyl-) ethyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 250);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 251);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-ethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 252);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-dichlorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 253);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 254);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluoro-6-three fluoro-aminomethyl phenyls) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 255);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indanyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 256);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 257);

(±)-4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1-indanyl methyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 258);

(±)-3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1-indanyl methyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 259);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethyl)-phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 260);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluoro-3-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 261);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 262);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 263);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-dichlorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 264);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-methyl-6-trifluoromethyl) ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 265);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indanyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 266);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indenyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 267);

(E)-and 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-vinyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 268);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 269);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-6-methyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) pyrazolyl } butyric acid (compound 270);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-2-(3, the 4-3,5-dimethylphenyl)-4-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 271);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-2-(3, the 5-3,5-dimethylphenyl)-4-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 272);

3-{1-(6-trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) indyl } phenylformic acid (compound 273);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-benzyl phenyl) hydrazono-)-pyrazolyl } butyric acid (compound 274);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(3-aminomethyl phenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 275);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-phenyl propyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 276);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(2-aminomethyl phenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 277);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 278);

(E)-and 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-pyridyl) ethyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 279);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-(Z)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 280);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-benzofuryl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 281);

(Z)-and 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-bromo vinyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 282);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(3-methyl-1-butene base) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 283);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(2-cyclopropyl vinyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 284);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-methyl butyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 285);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-5-fluoro-3-(3, the 5-3,5-dimethylphenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 286);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 287);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 288);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 289);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 290);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 291);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 292);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(2-aminomethyl phenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 293);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-benzofuryl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 294);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(2-fluorophenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 295);

3-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl)-phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 296);

3-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 297);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl)-phenyl) aminomethylene) pyrazolyl } butyric acid (compound 298);

3-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) hydrazono-) indyl } propionic acid (compound 299);

3-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-benzyl phenyl) hydrazono-)-indyl } phenylformic acid (compound 300);

3-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethyl) phenyl)-hydrazono-) indyl } propionic acid (compound 301);

3-{1-(6-chloro-2-oxo-2,3-dihydro-3 (Z)-(2-hydroxyl-3-(3-(3-aminomethyl phenyl) propyl group)-phenyl) aminomethylene) indyl } phenylformic acid (compound 302);

(±)-3-{1-(6-chloro-2-oxo-2,3-dihydro-3 (Z)-(2-hydroxyl-3-(1,2-dihydro-1-methyl-2-indyl phenyl) aminomethylene) indyl } phenylformic acid (compound 303);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-aminomethyl phenyl carbonyl-amino) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 304);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxyl-3-(2-aminomethyl phenyl-carbonylamino) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 305);

3-{2-hydroxyl-3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(2-(2-fluorophenyl) ethyl))-diazanyl phenyl } phenylformic acid (compound 306);

3-{2-hydroxyl-3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(2-(2-chloro-phenyl-) ethyl))-diazanyl phenyl } phenylformic acid (compound 307);

3-{3-hydroxyl-2-(5-methyl-3-oxo-2,3-dihydro-2-(3, the 4-3,5-dimethylphenyl)-Ya pyrazolyl) diazanyl-4-pyridyl } phenylformic acid (compound 308);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 309);

3-{3-hydroxyl-2-(2-oxo-2, the inferior indyl-diazanyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)-3-)-4-pyridyl } phenylformic acid (compound 310);

3-{1-(2-oxo-2,3-dihydro-3-(3-hydroxyl-6-methyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) indyl } phenylformic acid (compound 311);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-6-methyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 312);

3-{3-hydroxyl-4-(2-oxo-2, the inferior indyl diazanyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)-6-trifluoromethyl-3-)-2-pyridyl } phenylformic acid (compound 313);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-2-(3, the 5-3,5-dimethylphenyl)-4-pyridyl) hydrazono-) pyrazolyl } butyric acid (compound 314);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-5-phenyl-2-benzothienyl)-hydrazono-) pyrazolyl } butyric acid (compound 315);

3-{3-hydroxyl-2-(5-methyl-3-oxo-2, the inferior pyrazolyl of 3-dihydro-2-(3, the 4-3,5-dimethylphenyl)-4-) diazanyl-5-benzothienyl } phenylformic acid (compound 316);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-(2,3-dimethoxy carbonyl phenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 317);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3,5-diisopropyl phenyl)-carbonyl hydrazide methylene) pyrazolyl } butyric acid (compound 318);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl)-aminomethylene) pyrazolyl } butyric acid (compound 319);

(±)-4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2,3-dihydro-1-methyl-2-oxo-3-indyl) methyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 320);

3-{1-(2-oxo-2,3-dihydro-5-fluoro-3-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethyl) phenyl)-hydrazono-) indyl } propionic acid (compound 321);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 322);

(±)-3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2,3-dihydro-1-methyl-2-oxo-3-indyl) methyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 323);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1, the inferior indyl of 2-dihydro-1-methyl-2-oxo-3-) methyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 324);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(5-fluoro-2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 325);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (E)-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 326);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-methyl phenyl) hydrazono-)-pyrazolyl } phenylformic acid (compound 327);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1, the inferior indyl of 2-dihydro-1-methyl-2-oxo-3-) methyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 328);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(5-fluoro-2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 329);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-difluorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 330);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-3,5-dimethylphenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 331);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-aminomethyl phenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 332);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(5-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 333);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (Z)-(2-(5-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 334);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 335);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 336);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 337);

4-{2-(5-methyl-3-oxo-2.3-dihydro-4-(2-hydroxyl-3 (E)-(2-phenyl vinyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 338);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-phenylacetylene base)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 339);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethynyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 340);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethynyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 341);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluorophenyl) ethynyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 342);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-trifluoromethyl)-ethynyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 343);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-trifluoromethyl-phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 344);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1-methyl isophthalic acid-indenyl-2-) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 345);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3,3-dimethyl-2-indenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 346);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methyl oxygen base-3-(2-indenyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 347);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(4,7-dimethyl-2-indenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 348);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(4,7-two fluoro-2-indenyls) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 349);

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-6-Trifluoromethyl-1-(2-(2-aminomethyl phenyl)-ethyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 350);

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-6-Trifluoromethyl-1-(2-indenyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 351);

(±) 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(1,2,3, the 4-tetrahydrochysene)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 352);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3, the 4-dihydro)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 353);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(the inferior indanyl of 1-)-aminomethyl phenyl) hydrazono-) pyrazolyl } butyric acid (compound 354);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(5-fluoro-2-trifluoromethyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 355);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(6-fluoro-2-three fluoro-aminomethyl phenyls) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 356);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(6-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 357);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 358);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 359);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 360);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 5-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 361);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluoro-2-three fluoro-aminomethyl phenyls) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 362);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-ethynyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 363);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(1-(1,2,3, the 4-tetrahydrochysene)-naphthylidene) aminomethyl phenyl) hydrazono-) pyrazolyl } butyric acid (compound 364);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluoro-5-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 365);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3,5-dimethyl-4-isoxazolyl) vinyl) phenyl) hydrazono-) pyrazolyl) butyric acid (compound 366);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,5-dimethyl-4-isoxazolyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 367);

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-1-(2 (E)-(2-aminomethyl phenyl) vinyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 368);

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-1-(2 (E)-(2,4 difluorobenzene base) vinyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 369);

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-1-(2-indenyl)-3 (Z)-Ya indyls) methyl-aminophenyl } phenylformic acid (compound 370);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(5-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 371);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-methyl phenyl) hydrazono-)-pyrazolyl } butyric acid (compound 372);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(the inferior indanyl methyl of 2-) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 373);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indanyl methyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 374);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2,4 difluorobenzene base)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 375);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 376);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 377);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluoro-6-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 378);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 3-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 379);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 3-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 380);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluoro-4-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 381);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-chloro-phenyl-)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 382);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-dichlorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 383);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3-chloro-phenyl-)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 384);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 5-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 385);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-chloro-4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 386);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-trifluoromethyl-4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 387);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2,4 dichloro benzene base)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 388);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-chloromethyl-4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 389);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2,4-dichloromethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 390);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3, the 4-dihydro)-naphthyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 353);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-8-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 392);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-8-methyl)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 393);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-methyl)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 394);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 395);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-6-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 396);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-5-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 397);

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-8-chlorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 398);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 399).

[0013] in certain embodiments, the compound of formula I, II, III, IV, V or VI is a selectivity TPO conditioning agent.In some such embodiment, the compound of formula I, II, III, IV, V5 or VI is the TPO stand-in.

[0014] in certain embodiments, the invention provides the active method of TPO of regulating.Some such method comprises contacts cell and one or more compound of the present invention.Such method includes but not limited to make TPO and/or TPO acceptor to contact with one or more compounds of the present invention.

[0015] in certain embodiments, the invention provides the method that discriminating can be regulated the active compound of TPO, this method comprises: a) allow to produce the active cell of TPO and contact with compound of the present invention; And b) monitoring is to the effect of this cell.In some such embodiment, this cell expressing TOP acceptor.

[0016] in certain embodiments, the invention provides treatment patient's method, this method comprises compound of the present invention described patient's administration.In certain embodiments, such patient suffers from thrombocytopenia.In certain embodiments, before chemotherapy, bone marrow transplantation and/or the radiotherapy, during or afterwards, with one or more compounds of the present invention to patient's administration.In certain embodiments, with one or more compounds of the present invention to suffering from patient's administration of aplastic anemia, marrow failure and/or essential thrombocytopenia.In certain embodiments, with one or more The compounds of this invention to suffering from patient's administration of nervous system disorders.In certain embodiments, with one or more The compounds of this invention to suffering from amyotrophic lateral sclerosis, multiple sclerosis or multiple dystrophic patient's administration.In certain embodiments, with one or more The compounds of this invention to having patient's administration of nerve injury (including but not limited to Spinal injury).

[0017] in certain embodiments, the invention provides pharmaceutical composition, this pharmaceutical composition comprises: i) physiology acceptable carrier, thinner or vehicle or its combination; And ii) one or more compounds of the present invention.

[0018] in certain embodiments, the invention provides selectivity TPO conditioning agent.In certain embodiments, the invention provides selectivity TPO receptor stimulant.In certain embodiments, the invention provides the TPO receptor antagonist.In certain embodiments, the invention provides selectivity TPO partial agonist.In certain embodiments, the invention provides selectivity TPO receptor binding compounds.In certain embodiments, the invention provides the TPO stand-in.

Describe in detail

[0019] is appreciated that above general introduction and following detailed description only are exemplary with indicative, rather than the present invention who asks for protection is limited.In this application, unless specify in addition, use odd number to comprise plural number.In this application, except as otherwise noted, use " or (or) " to mean " and/or (and/or) ".In addition, use term " to comprise (including) " and wait other form to be not restrictive such as " includes " and " included ".

[0020] in this article, the title of employed various piece is only used for organizational goal and it can not be interpreted as restriction to described theme.For any purpose, include but not limited to patent, patent application, article, books, handbook and bar that the application is quoted as proof are incorporated herein by reference clearly about the full content of the part of interior all files or file.

Definition

[0021] unless clear and definite definition is provided, analytical chemistry as herein described, synthetic organic chemistry and medical science and pharmaceutical chemical experimental implementation and technology and employed relevant nomenclature are well known in the art.The chemical symbol of standard can exchange with full name of these symbol representatives and use.Therefore, for example be appreciated that term " hydrogen " has identical meaning with " H ".Standard technique can be used for chemosynthesis, chemical analysis, medication preparation, preparation and conveying and patient treatment.Standard technique can be used for the synthetic and tissue culture of recombinant DNA, oligonucleotide and conversion (for example electroporation, fat transfection).For example can use test kit according to manufacturer's specification sheets or finish reaction and purification technique according to this area usual method or method as herein described.Usually can be according to ordinary method well known in the art and run through multiple general reference that this specification sheets quotes and discuss more specifically the method described in the reference usually carry out above-mentioned technology and operation.For example referring to people such as Sambrook, Molecular Cloning:A LaboratoryManual (molecular cloning: (2d ed. laboratory manual), Cold Spring Harbor LaboratoryPress, Cold Spring Harbor, N.Y. (1989)), be incorporated herein the document as a reference for any purpose.

[0022] except as otherwise noted, define following term used herein with following meaning.

[0023] term " selective binding compound " refers to optionally the arbitrary portion bonded compound with one or more targets.

[0024] term " selectivity TPO receptor binding compounds " refers to optionally the arbitrary portion bonded compound with the TPO acceptor.

[0025] term " selective binding " refers to and the combination of non-target acceptor is compared, and the selective binding compound is with the ability of high affinity and target receptors bind more.In certain embodiments, selective binding refers to compare with the avidity to non-target, at least 10,50,100,250,500 or 1000 times of the bonded avidity height of target.

[0026] refer to can be by the part of selectivity binding compounds bonded acceptor or acceptor for term " target acceptor ".In certain embodiments, the target acceptor is the TPO acceptor.

[0027] term " conditioning agent " refers to change active compound.For example, the active value when not having conditioning agent is compared, and conditioning agent can cause the increase or the minimizing of certain active value.In certain embodiments, conditioning agent is an inhibitor, and it reduces one or more active values.In certain embodiments, inhibitor suppresses one or more biological activitys fully.In certain embodiments, conditioning agent is a promoting agent, and it improves at least a active value.In certain embodiments, the existence of conditioning agent causes the activity that do not take place when not having conditioning agent.

[0028] term " selective modulator " refers to the active compound of selectivity adjusting target.

[0029] term " selectivity TPO conditioning agent " refers to that selectivity regulates the active compound of at least a TPO.Selection of terms TPO conditioning agent includes but not limited to " TPO stand-in ", and it refers to such compound, causes at least a TPO activity when it exists.Described the TPO stand-in among WO03/103686A1 and the WO 01/21180, its full content has been incorporated herein by reference at this.

[0030] term " selectivity adjusting " refer to non-target active adjusting compare, selective modulator is with the active ability of wider adjusting target.

[0031] term " target activity " refers to the biological activity that can be regulated by the selectivity conditioning agent.Some exemplary target activity includes but not limited to the propagation of binding affinity, signal transduction, enzymic activity, progenitor cell and/or alleviating of differentiation, hematoblastic generation and disease or morbid state symptom.

[0032] term " TPO activity " refers to by the direct or indirect biological activity that produces of the existence of TPO.Exemplary TPO activity includes but not limited to the propagation of progenitor cell and/or breaks up to produce thrombocyte; Hemopoietic; The growth of neurogliocyte and/or growth; The reparation of neurocyte; And the alleviating of thrombocytopenia.

[0033] term " thrombocytopenia " refers to that the PC in the blood samples of patients wherein is lower than the morbid state that healthy patients is considered to normal PC.In certain embodiments, thrombocytopenia is that platelet count is lower than 450,000,400,000,350,000,300,000,250,000,200,000,150,000,140,000,130,000,120,000,110,000,100,000, the every microliters of blood of 75,000 or 50,000 thrombocytes.

[0034] term " receptor-mediated activity " refers to by part and receptors bind and any biological activity that directly or indirectly produces.

[0035] term " agonist " refers to such compound, and the biological activity that its existence causes acceptor to produce is identical with the biological activity that naturally occurring part produces acceptor.

[0036] term " partial agonist " refers to such compound, its existence cause biological activity that acceptor produces and naturally occurring part make the biological activity of acceptor generation have just as type, but value is lower.

[0037] term " antagonist " refers to the compound that its existence causes the active value of receptor biological to reduce.In certain embodiments, the existence of antagonistic causes the active inhibition fully of receptor biological.

[0038] term " alkyl " refers to aliphatic hydrocarbon groups.Alkyl can be " a saturated alkyl ", this means that it does not contain any alkene or alkynes group.Hydrocarbyl group can be " a undersaturated alkyl ", and it comprises at least one alkene or alkynes group.Whether no matter saturated, alkyl can be side chain or straight chain.Alkyl can be a cyclic or acyclic.Cyclic hydrocarbon group can comprise the polycyclic system of condensed alkyl ring.Alkyl can be that replace or unsubstituted.Alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, vinyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc., and each in them can be optional the replacement.

[0039] in certain embodiments, alkyl comprises 1 to 20 carbon atom (no matter when it occurs, and all refers to each integer in this given range such as the digital scope of " 1 to 20 "; For example, " 1 to 20 carbon atom " means can comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until and comprise the hydrocarbyl group of 20 carbon atoms, although term " alkyl " also comprises the unappropriated situation of digital scope of carbon atom).

[0040] term " lower alkyl " refers to comprise the alkyl of 1 to 5 carbon atom.Term " intermediate alkyl " refers to comprise the alkyl of 5 to 10 carbon atoms.Alkyl can be designated as " C ₁-C ₄Alkyl " or similarly specify.As just example, " C ₁-C ₄Alkyl " expression contains the alkyl of, two, three or four carbon atom, for example is selected from the alkyl of methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, vinyl, propenyl, butenyl, ethynyl, proyl or butynyl.

[0041] term " thiazolinyl " refers to comprise the hydrocarbyl group of at least one carbon-to-carbon double bond.

[0042] term " alkynyl " refers to comprise the hydrocarbyl group of at least one carbon-to-carbon three key.

[0043] term " halo alkyl " refers to that at least one hydrogen atom wherein is by alkyl that halogen atom replaced.Some two or more hydrogen atom by the embodiment that halogen atom replaced in, halogen atom is identical from one another.In some such embodiment, halogen atom is incomplete same each other.

[0044] term " assorted alkyl " refers to comprise alkyl and one or more heteroatomic group.Some assorted alkyl is the acyl group alkyl, and wherein one or more heteroatomss are in hydrocarbyl chain.The example of assorted alkyl includes but not limited to CH ₃C (=O) CH ₂-, CH ₃C (=O) CH ₂CH ₂-, CH ₃CH ₂(C=O) CH ₂CH ₂-, CH ₃C (=O) CH ₂CH ₂CH ₂-, CH ₃OCH ₂CH ₂-, CH ₃NHCH ₂-etc.

[0045] term " straight chain alkoxyl group " refers to comprise formula-(CH ₂) _pThe group of O-, wherein p is arbitrary integer.The straight chain alkoxyl group does not comprise alkoxy base replacement or side chain.

[0046] term " non-straight chain alkoxyl group mix alkyl " refers to not be the arbitrary assorted alkyl of the assorted alkyl of straight chain alkoxyl group.Therefore, the assorted alkyl of for example non-straight chain alkoxyl group includes but not limited to: 2, and the 2-isopropoxy; 1, the 2-propoxy-; 1, the 1-oxyethyl group; Methylamino-; Ethylamino; Third amino; Methylpyrrolidin-1-base and methyl piperidine subbase.

[0047] term " alkene " refers to the C=C key.

[0048] term " assorted halo alkyl " refers to that at least one hydrogen atom wherein is by assorted alkyl that halogen atom replaced.

[0049] term " carbocyclic ring " refers to comprise the group of covalently closed circle, and each atom that wherein forms described ring is carbon atom.Can or form carbocyclic ring by 3,4,5,6,7,8,9 more than 9 carbon atom.Carbocyclic ring can be optional the replacement.

[0050] term " heterocycle " refers to comprise the group of covalently closed circle, and at least one atom that wherein forms described ring is a heteroatoms.Can form heterocycle by 3,4,5,6,7,8,9 carbon atoms more than 9.These atoms of any number can be heteroatoms (be heterocycle can comprise 1,2,3,4,5,6,7,8,9 or more than 9 heteroatoms).In comprising two or more heteroatomic heterocycles, these two or more heteroatomss can be same to each other or different to each other.Heterocycle can be optional the replacement.Can combine with heterocycle at the heteroatoms place or by carbon atom.For example, the combination of benzene condensed derivative can be via the carbon of benzene type ring.The heterocyclic example includes but not limited to following radicals:

Wherein D, E, F and G represent heteroatoms independently.Each D, E, F and G can be identical or different each other.

[0051] term " heteroatoms " refers to carbon or hydrogen atom in addition.Heteroatoms is independently selected from oxygen, sulphur, nitrogen or phosphorus usually, but is not limited to these atoms.In having two or more heteroatomic embodiments, described two or more heteroatomss can be all mutually the same, and some or all in perhaps described two or more heteroatomss have nothing in common with each other.

[0052] term " aromatic group " refers to comprise the group of the covalently closed circle with delocalization π-electron system.Can or form aromatic ring by 5,6,7,8,9 more than 9 atom.Aromatic group can be optional the replacement.The example of aromatic group includes but not limited to phenyl, naphthyl, phenanthryl, anthryl, tetralyl, fluorenyl, indenyl and indanyl.The term aromatic group comprises; for example pass through a benzene type group that becomes ring carbon atom to connect, and described benzene type group randomly has one or more following substituting groups that are selected from: aryl, heteroaryl, cyclic hydrocarbon radical, non-aromatic heterocyclic, halogen, hydroxyl, amino, cyano group, nitro, alkyl amido, acyl group, C _1-6Alkoxyl group, C _1-6Alkyl, C _1-6Hydroxy alkylene, C _1-6Hydrocarbyl amino, C _1-6Alkyl amino, alkyl sulfenyl, alkyl sulfinyl, alkyl alkylsulfonyl, sulfamyl or trifluoromethyl.In certain embodiments, the one or more positions of aromatic group in contraposition, a position and/or ortho position are substituted.The example that comprises substituent aromatic group includes but not limited to phenyl, the 3-halogenophenyl, the 4-halogenophenyl, the 3-hydroxy phenyl, the 4-hydroxy phenyl, the 3-aminophenyl, the 4-aminophenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 4-Trifluoromethoxyphen-l, the 3-cyano-phenyl, the 4-cyano-phenyl, xylyl, naphthyl, the hydroxyl naphthyl, hydroxymethyl phenyl, (trifluoromethyl) phenyl, alkoxyl phenyl, 4-morpholine-4-base phenyl, 4-tetramethyleneimine-1-base phenyl, 4-pyrazolyl phenyl, 4-triazolyl phenyl and 4-(2-oxo-pyrrolidine-1-yl) phenyl.

[0053] term " aryl " refers to that each atom of Cheng Huan wherein is the aromatic ring of carbon atom.Can or form aromatic ring by 5,6,7,8,9 more than 9 carbon atom.Aromatic yl group can be optional the replacement.

[0054] to refer to wherein to form at least one atom of aromatic ring be heteroatomic aromatic group to term " heteroaryl ".Can or form hetero-aromatic ring by 3,4,5,6,7,8,9 more than 9 carbon atom.Heteroaryl groups can be optional the replacement.The example of heteroaryl groups includes but not limited to comprise 1 oxygen or sulphur atom or nearly 4 nitrogen-atoms or 1 oxygen or sulphur atoms and nearly the aromatics C of the combination of 2 nitrogen-atoms _3-8Heterocyclic group, and for example become the derivative and the benzene of its replacement of ring carbon atom connection to condense and pyridine condensed derivative by one.In certain embodiments, use one or more optional substituted heteroaryl groups of substituting group that are independently selected from following group: halogen, hydroxyl, amino, cyano group, nitro, alkyl amido, acyl group, C _1-6Alkoxyl group, C _1-6Alkyl, C _1-6Hydroxy alkylene, C _1-6Hydrocarbyl amino, C _1-6Alkyl amino, alkyl sulfenyl, alkyl sulfinyl, alkyl alkylsulfonyl, sulfamyl or trifluoromethyl.The example of heteroaryl groups includes but not limited to unsubstituted and monobasic or dibasic derivative of following compound: furans, cumarone, thiophene, thionaphthene, the pyrroles, pyridine, indoles oxazole benzoxazole isoxazole, benzoisoxazole, thiazole, benzothiazole, isothiazole, imidazoles, benzoglyoxaline, pyrazoles, indazole, tetrazolium, quinoline, isoquinoline 99.9, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2, the 3-oxadiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, triazole, benzotriazole, pteridine Fen oxazole oxadiazole, benzopyrazoles, quinolizine, cinnolines, phthalazines, quinazoline and quinoxaline.In certain embodiments, described substituting group is halogen, hydroxyl, cyano group, O-C _1-6Alkyl, C _1-6Alkyl, hydroxyl-C _1-6Alkyl or amino-C _1-6Alkyl.

[0055] term " non-aromatic ring " refers to comprise the group of the covalently closed circle with delocalization π-electron system.

[0056] term " cyclic hydrocarbon radical " refers to comprise wherein each to become annular atoms is the group of the non-aromatic ring of carbon atom.Can or form the cyclic hydrocarbon basic ring by 3,4,5,6,7,8,9 more than 9 carbon atom.Cyclic hydrocarbon radical can comprise polycyclic system (for example condensed ring system).Cyclic hydrocarbon radical can be optional the replacement.In certain embodiments, cyclic hydrocarbon radical comprises one or more unsaturated link(age)s.The example of cyclic hydrocarbon radical includes but not limited to cyclopropane, tetramethylene, pentamethylene, cyclopentenes, cyclopentadiene, hexanaphthene, tetrahydrobenzene, 1, suberane and suberene.

[0057] term " non-aromatic heterocyclic " refers to comprise wherein one or more to become annular atomses is the group of heteroatomic non-aromatic ring.Can or form non-aromatic heterocyclic by 3,4,5,6,7,8,9 more than 9 carbon atom.Non-aromatic heterocyclic can be optional the replacement.In certain embodiments, non-aromatic heterocyclic comprises one or more carbonyls or thiocarbonyl group, for example contains the group of aerobic and sulphur.The example of non-aromatic heterocyclic includes but not limited to lactan, lactone, cyclic imide, the ring-type thioimines, cyclic carbamate, tetrahydric thiapyran, the 4H-pyrans, tetrahydropyrans, piperidines, 1, the 3-dioxin, 1, the 3-diox, 1, the 4-dioxin, 1, the 4-diox, piperazine, 1, the 3-oxathiane, 1, the 4-oxathiin, 1, the 4-oxathiane, tetrahydrochysene-1, the 4-thiazine, 2H-1, the 2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituricacid, dioxygen piperazidine, glycolylurea, dihydrouracil, morpholine trioxane, six hydrogen-1,3, the 5-triazine, tetramethylene sulfide, tetrahydrofuran (THF), pyrroline, tetramethyleneimine, pyrrolidone (pyrrolidone), pyrrolidone (pyrrolidione), pyrazoline, pyrazolidine, tetrahydroglyoxaline, imidazolidine, 1, the 3-dioxole, 1, the 3-dioxolane, 1, the 3-dithiole, 1,3-dithiolane isoxazoline isoxazole alkyl oxazoline oxazolidine oxazolidone, thiazoline, thiazolidine and 1,3-oxygen thia penta ring.

[0058] term " aryl alkyl " refers to comprise the group of the aromatic yl group that is connected with hydrocarbyl group.

[0059] term " carbocyclic ring alkyl " refers to comprise the group of carbocyclic ring shape cyclic hydrocarbon basic ring.Can or form carbocyclic ring alkyl ring by 3,4,5,6,7,8,9 more than 9 carbon atom.The carbocyclic ring hydrocarbyl group can be optional the replacement.

[0060] term " ring " refers to any covalence closed structure.Ring comprises, for example carbocyclic ring (as aryl and cyclic hydrocarbon radical), heterocycle (as heteroaryl and non-aromatic heterocyclic), aromatic group (as aryl and heteroaryl) and non-aromatic group (as cyclic hydrocarbon radical and non-aromatic heterocyclic).Ring can be optional the replacement.Ring can form the part of member ring systems.

[0061] term " member ring systems " refers to monocycle or two or more ring, and wherein, if there are two or more rings, then described two or more rings are condensed.Term " condenses " structure that refers to the shared one or more keys of wherein two or more rings.

[0062] term " carboxylic acid bioisostere " refer to biologically with the group of carboxylic acid equivalence.For example, the carboxylic acid bioisostere includes but not limited to tetrazolium, NHSO ₂R ¹⁵, OC (S) NR ¹⁰R ¹¹, SC (O) NR ¹⁰R ¹¹, thiazolidinedione, oxazolidinedione and 1-oxa--2,4-diazole alkane (diazolidine)-3,5-diketone.In certain embodiments, the carboxylic acid bioisostere comprises following structure:

Wherein A, B and C are selected from O, S or N independently of one another.

[0063] term " spacer " refers to make separate atom of two or more groups or atomic group with the atom of desired amt.For example, in certain embodiments, may expect with 1,2,3,4,5,6 or more than the two or more groups of 6 atom separates.In such embodiments, can use any atom or atomic group these groups to be separated with the atom of desired amt.Spacer is optional the replacement.In certain embodiments, spacer comprises saturated or unsaturated alkyl, assorted alkyl and/or halo alkyl.In certain embodiments, spacer comprises the atom as the part of ring.

[0064] only limits above-mentioned definition for purpose of explanation and not, the example of some spacers is provided.The example of 1-atomic separation Ji Bao includes but not limited to following group:

Wherein A and B represent the group of the atom separates of the quantity that is supposed to.The example of 2-atomic separation base includes but not limited to following group:

Wherein A and B represent the group of the atom separates of the quantity that is supposed to.

[0065] example of 3-atomic separation base includes but not limited to:

Wherein A and B represent the group of the atom separates of the quantity that is supposed to.Apparent from above-mentioned example, the atom itself that produces the separation of expectation can be the part of group.Described group can be the alkyl of alkyl, assorted alkyl, halo alkyl, assorted halo alkyl, cyclic hydrocarbon radical, aryl, aryl alkyl, heteroaryl, non-aromatic heterocyclic or replacement for example, and it is optional the replacement all.Therefore, term " 1 to 5 atomic separation base " refers to the total size with the group of the spacer of 1,2,3,4 or 5 atom separates two group and undeclared this spacer of formation.

[0066] term used in the present invention " to connect to form ring " refers to such situation, wherein be bonded to single atom or finally several atoms of self bonding two atoms all with the linking group bonding, make the structure formation of gained encircle.The ring of this gained comprises connection with two atoms that form ring, atom and the connector that before links to each other with these atoms.For example, if following A " is connected to form ring " with B

Then the ring of gained comprises A, B, C and linking group.Except as otherwise noted, linking group can be random length and can be optional the replacement.With reference to above-mentioned example, the structure that obtains includes but not limited to:

Deng.

[0067] in certain embodiments, two substituting groups that form ring together directly with identical atomic linkage.For example, if following A is connected with B to form ring:

The ring that then obtains comprises A, B, connected two atoms and the linking group of A and B.The example of resulting structures includes but not limited to:

Deng.

[0068] in certain embodiments, form two atoms of ring together by three or more atom separates.For example, if following A is connected with B to form ring:

The ring that then obtains comprises A, B, connected 3 atoms and the linking group of A and B.The example of resulting structures includes but not limited to:

Deng.

[0069] term used in the present invention " forms key " and refers to such situation together, and wherein two substituting groups of contiguous atom do not exist, and contiguous interatomic key becomes two keys.For example, if following A and B " form key " together

The structure that then obtains is:

[0070] term " does not exist " and refers to that group is not present in the structure.For example in structure

In, be in the example of N wherein,, R ' or R so if X is N at some X " in one do not exist, meaning only has three groups and N bonding.

[0071] substituting group of alkyl, cyclic hydrocarbon radical, aryl, heteroaryl (by the ring bond with carbon) or non-aromatic heterocyclic (by the ring bond with carbon) appears separately and does not refer to be selected from the substituting group " R " of numerical markings.

[0072] term " O-carboxyl " refers to the formula RC (=O) group of O-.

[0073] term " C-carboxyl " refers to the group of formula-C (O) OR.

[0074] term " ethanoyl " refers to formula-C (=O) CH ₃Group.

[0075] term " three methyl halide alkylsulfonyls " refers to formula X ₃CS (=O) ₂-group, wherein X is a halogen.

[0076] term " cyano group " refers to the group of formula-CN.

[0077] term " isocyanato-" refers to the group of formula-NCO.

[0078] term " thiocyanato " refers to the group of formula-CNS.

[0079] term " isothiocyanato " refers to the group of formula-NCS.

[0080] term " alkylsulfonyl " refer to formula-S (=O)-group of R.

[0081] term " S-sulfonamido " refer to formula-S (=O) ₂The group of NR.

[0082] term " N-sulfonamido " refer to formula RS (=O) ₂The group of NH-.

[0083] term " three methyl halide sulfonamidos " refers to formula X ₃CS (=O) ₂The group of NR-.

[0084] term " O-carbamyl " refer to formula-OC (=O)-group of NR.

[0085] term " N-carbamyl " refers to the formula ROC (=O) group of NH-.

[0086] term " O-thiocarbamyl " refer to formula-OC (=S)-group of NR.

[0087] term " N-thiocarbamyl " refers to the formula ROC (=S) group of NH-.

[0088] term " C-amido " refer to formula-C (=O)-NR ₂Group.

[0089] term " N-amido " refers to the formula RC (=O) group of NH-.

[0090] term " oxo " refers to the group of formula=O.

[0091] term " the inferior pyrazolyl of dihydro " refers to the diradical of the optional pyrazoline ring that replaces, and wherein pyrazoline has following structure:

And wherein said two free radicals can be in the optional position on the ring.

[0092] term " pyrazolyl " refers to the free radical of pyrazoles ring, and wherein said pyrazoles ring has following structure:

And wherein said free radical can be in the optional position on the ring.

[0093] term " ester " refer to have formula-(R) _nThe chemical part of-COOR ', wherein R and R ' are independently selected from alkyl, cyclic hydrocarbon radical, aryl, heteroaryl (by the ring bond with carbon) or non-aromatic heterocyclic (by the ring bond with carbon), and wherein n is 0 or 1.

[0094] term " acid amides " refer to have formula-(R) _n-C (O) NHR ' or-(R) _nThe chemical part of-NHC (O) R ', wherein R and R ' are independently selected from alkyl, cyclic hydrocarbon radical, aryl, heteroaryl (by the ring bond with carbon) or heterolipid cyclic group (by the ring bond with carbon), and wherein n is 0 or 1.In certain embodiments, acid amides can be amino acid or peptide.

[0095] term " amine ", " hydroxyl " and " carboxyl " comprise esterified or amidated these groups.Be used to realize esterification and amidated operation and concrete group be known in those skilled in the art and can be easily such as Greene and Wuts, ProtectiveGroups in Organic Synthesis (blocking group in the organic synthesis), 3rd Ed., JohnWiley﹠amp; Sons, New York, NY finds in 1999 the reference, at this its full content is incorporated herein by reference.

[0096] except as otherwise noted; term " the optional replacement " refers to such group, wherein do not have hydrogen atom or one or more than one hydrogen atom by individually one or more and be independently selected from following group and replace: alkyl; assorted alkyl; the halo alkyl; assorted halo alkyl; cyclic hydrocarbon radical; aryl; the aryl alkyl; heteroaryl; non-aromatic heterocyclic; hydroxyl; alkoxyl group; aryloxy; sulfydryl; alkylthio; arylthio; cyano group; halogen; carbonyl; thiocarbonyl; the O-carbamyl; the N-carbamyl; the O-thiocarbamyl; the N-thiocarbamyl; the C-amido; the N-amido; the S-sulfonamido; the N-sulfonamido; the C-carboxyl; the O-carboxyl; isocyanato-; thiocyanato; isothiocyanato; nitro; silyl; three methyl halide alkylsulfonyls or comprise single the replacement and the amino of the derivative of dibasic amino group and protected amino group.Those skilled in the art are known and can find such protection derivative (and the protecting group that can form such protection derivative) from the reference such as above-mentioned Greene andWuts.In two or more therein hydrogen atom substituted embodiments, the substituting group group can form ring together.

[0097] run through whole specification sheets, those skilled in the art can select group and substituting group thereof so that stable part and compound to be provided.

[0098] term " carrier " refers to help another kind of compound to incorporate the compound of cell or tissue into.For example, dimethyl sulfoxide (DMSO) (DMSO) is to improve the common carrier that some organic compound is incorporated cell or tissue into.

[0099] term " medicament " refers to induce the compound or the composition of the curative effect of expectation in the patient.In certain embodiments, medicament comprises the promoting agent of the curative effect of hoping inductive phase.In certain embodiments, medicament comprises prodrug.In certain embodiments, medicament comprises non-active ingredient, for example carrier, vehicle etc.

[0100] term " treatment significant quantity " refers to that medicament is enough to realize expecting the amount of curative effect.

[0101] term " prodrug " refers to be converted into from more weak activity form in vivo the medicament of corresponding stronger activity form.

[0102] term " medicine is acceptable " refers to that the preparation of this compound is not significantly eliminated biological activity, pharmacologically active and/or other character of this compound when compound that will preparation during to patient's administration.In certain embodiments, the acceptable preparation of medicine does not cause significant stimulation to the patient.

[0103] term " altogether administration " refer to more than a kind of medicament to patient's administration.In certain embodiments, be total to the medicament of administration with single dose unit's administration together.In certain embodiments, be total to the medicament separate administration of administration.In certain embodiments, the medicament of administration administration simultaneously altogether.In certain embodiments, be total to the medicament of administration in the different time administration.

[0104] term " patient " comprises the humans and animals individuality.

[0105] term " pure basically " meaning is that target substance (as compound) is existing advantage material (promptly based on mole number, it is higher than other any individual substance in composition).In certain embodiments, pure basically part is a composition, wherein the total material that constitute to exist of target substance at least about 50% (based on mol ratio).In certain embodiments, pure basically composition constitute whole kinds of being present in the composition greater than about 80%, 85%, 90%, 95% or 99%.In certain embodiments, target substance is purified to basic homogeneity (can not detecting pollutent by the routine measurement method in composition), wherein said composition is made up of one matter basically.

[0106] term " tissue selectivity " refer to compound in a tissue than in another tissue with higher or regulate bioactive ability than low degree.Biological activity in different tissues can be identical or different.Can be by the biological activity in the target acceptor adjusting different tissues of same type.For example, in certain embodiments, the compound of tissue selectivity can be regulated receptor-mediated biological activity and can not regulate receptor-mediated biological activity in another types of organization in a tissue, or to regulate receptor-mediated biological activity than low degree.

[0107] term " monitoring " refers to observing effect or observes not existing of any effect.In certain embodiments, cell is being contacted the described cell of back monitoring with The compounds of this invention.The example of the effect that can monitor includes but not limited to the interaction between the compound of the variation of cell phenotype, cell proliferation, receptor active or acceptor and known and receptors bind.

[0108] term " cell phenotype " refers to physics or biological nature.The example that constitutes the characteristic of phenotype includes but not limited to the utilization (as glucose uptake) of cell size, cell proliferation, cytodifferentiation, cell survival, apoptosis (necrocytosis) or metabolic nutrition thing.Use technology known in the art to be easy to monitor some variation in the cell phenotype or do not have variation.

[0109] term " cell proliferation " phalangeal cell splitted speed.In certain embodiments, cell in-situ is in the organism.In certain embodiments, cell growth in vitro in container.Those skilled in the art can carry out quantitatively (for example use microscope or count determining the cell in the zone by lab setup that use to measure cell density in the suitable culture medium) to the cell quantity of growing in the container.Those skilled in the art can or determine that repeatedly cell number calculates cell proliferation by twice.

[0110] term " contact " instigates two or more materials fully near interacting to them.In certain embodiments, contact can realize in the container such as test tube, petri culture dish etc.In certain embodiments, contact can be carried out in the presence of other material.In certain embodiments, contact can be carried out in the presence of cell.In some such embodiment, one or more materials that are touched can be in cell.Cell can be survival or dead.Cell can be complete or incomplete.

Some compound

[0111] regulate one or more TPO active and/or with some compounds affect healthy state of TPO receptors bind.In certain embodiments, compound of the present invention is used for the treatment of the disease or the morbid state of any kind.

[0112] in certain embodiments, the invention provides selectivity TPO conditioning agent.In certain embodiments, the invention provides selectivity TPO receptor-binding agents.In certain embodiments, the invention provides the method for preparation and use selectivity TPO conditioning agent and/or selectivity TPO receptor-binding agents.In certain embodiments, selectivity TPO conditioning agent is agonist, partial agonist and/or the antagonist of TPO acceptor.

[0113] in certain embodiments, the present invention relates to compound or the acceptable salt of its medicine, ester, acid amides or the prodrug of formula I, II, III, IV, V or VI:

[0114] in certain embodiments, R ¹Be selected from hydrogen, halogen, OR ¹⁴, NO ₂, CN, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or carboxylic acid bioisostere.In some such embodiment, the carboxylic acid bioisostere is selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Perhaps

Wherein A, B and C are selected from O, S or N independently of one another.

[0115] in certain embodiments, each R ²Be independently selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl.

[0116] in certain embodiments, R ³And R ⁴Be independently selected from hydrogen, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl.

[0117] in certain embodiments, R ⁵Be selected from hydrogen, halogen, OR ¹⁴, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆The halo alkyl of mixing.

[0118] in certain embodiments, R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl or the optional C that replaces ₁-C ₁₀Assorted alkyl, each above-mentioned group be heteroaryl-condensed with aryl that replaces or replacement randomly, perhaps R ⁶Be (CH ₂) _mR ¹⁸Or C (O) NHR ¹⁸In certain embodiments, R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl or the optional C that replaces ₁-C ₁₀Assorted alkyl, each above-mentioned group be heteroaryl-condensed with aryl that replaces or replacement randomly, perhaps R ⁶Be selected from (CH ₂) _mR ¹⁸, C (O) NHR ¹⁸, C ≡ CR ¹⁸, CR ³=CR ⁴R ¹⁸Or CR ³=R ¹⁸

[0119] in certain embodiments, R ⁷Be selected from CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or carboxylic acid bioisostere.In some such embodiment, the carboxylic acid bioisostere is selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Perhaps

Wherein A, B and C are selected from O, S or N independently of one another.

[0120] in certain embodiments, each R ⁸With each R ⁹Be independently selected from hydrogen, OR ¹⁶, NR ¹⁶R ¹⁷, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring.

[0121] in certain embodiments, R ¹⁰Be selected from hydrogen, halogen, oxo, OR ¹⁶, NR ¹⁶R ¹⁷, SR ¹⁶, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl or the optional C that replaces ₁-C ₆Assorted alkyl.

[0122] in certain embodiments, R ¹¹Be selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵Or SR ¹⁴In certain embodiments, R ¹¹And R ⁴Connection is to form the optional heterocycle that replaces.

[0123] in certain embodiments, R ¹²Be selected from hydrogen, halogen, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆The halo alkyl of mixing.

[0124] in certain embodiments, R ¹³Be selected from hydrogen, halogen, CN, NO ₂, CO ₂R ¹⁴, S (O) _mR ¹⁴, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄The halo alkyl of mixing.

[0125] in certain embodiments, R ¹⁴Be selected from hydrogen, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆Assorted halo alkyl.

[0126] in certain embodiments, R ¹⁵Be selected from hydrogen, SO ₂R ¹⁹, C ₁-C ₆Alkyl, C ₁-C ₆Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆Assorted halo alkyl.

[0127] in certain embodiments, R ¹⁶And R ¹⁷Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or (CH ₂) _mR ¹⁸In certain embodiments, R ¹⁶And R ¹⁷In one be the optional C that replaces ₂-C ₆Alkyl, R ¹⁶And R ¹⁷In another be not exist.In certain embodiments, R ¹⁶And R ¹⁷Connection is to form the optional C that replaces ₃-C ₈Ring.

[0128] in certain embodiments, R ¹⁸Be selected from optional replace randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems, wherein work as R ¹⁸When containing non-aromatic heterocyclic or carbocyclic ring, link position can be on non-aromatic heterocyclic or the carbocyclic ring or on the aromatic ring system;

[0129] in certain embodiments, R ¹⁹Be selected from hydrogen, C ₁-C ₃Alkyl, C ₁-C ₃Halo alkyl or the optional aryl that replaces.

[0130] in certain embodiments, D be randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems.

[0131] in certain embodiments, E be randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems.

[0132] in certain embodiments, L is NH or does not exist.

[0133] in certain embodiments, Q be randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems.

[0134] in certain embodiments, U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist.

[0135] in certain embodiments, W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist.

[0136] in certain embodiments, X is N or CR ⁵

[0137] in certain embodiments, Y is the spacer of 1 to 4 atom, and it comprises one or more optional C that replace that are selected from ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆The group of assorted alkyl, the optional phenyl that replaces or the optional heteroaryl that replaces.In certain embodiments, if Y is directed to form the inferior pyrazolyl of dihydro in the compound of formula I or II

Then:

(i) if X is N, W is NH, then D is not a naphthyl, if (ii) X is that CH, W are that NH, Z are phenyl and R ¹⁰Or R ¹¹Be-(CH ₂) _0-6OH, then D is not a phenyl, (iii)

Be not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and (iv) U not NH.In certain embodiments, be NH if X is N and W, then D is not a phenyl.

[0138] in certain embodiments, Z is selected from and does not exist; Be selected from the optional C that replaces ₆-C ₁₀Aryl or the optional C that replaces ₁-C ₈The spacer of 2 to 5 atoms of heteroaryl, each substituted radical randomly with the optional non-aromatic heterocyclic that replaces or carbocyclic fused; Perhaps be selected from the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or the optional C that replaces ₁-C ₆The spacer of 1 to 5 atom of halo alkyl, each substituted radical randomly with the optional C that replaces ₆-C ₁₀Aryl-condensed.

[0139] in certain embodiments, m is 0,1 or 2.In certain embodiments, m is 0,1,2 or 3.

[0140] in certain embodiments, n is 0 or 1.

[0141] in certain embodiments, if in the compound of formula III or VI, X is that N and W are NH, then R ⁶, R ¹⁰And R ¹¹Do not contain carboxyl, amido, ester or sulphur functional group or carboxylic acid bioisostere.

[0142] in having the embodiment of two or more special groups, select the characteristic of these two or more special groups independently, therefore, they can be mutually the same or different.For example, some compound of the present invention comprises two or more R ¹⁴Group.These two or more R ¹⁴The characteristic of group is selected independently of one another.Therefore, in certain embodiments, these R ¹⁴Group is all identical each other; In certain embodiments, these R ¹⁴Group has nothing in common with each other each other; And in certain embodiments, these R ¹⁴In the group some is mutually the same, and some differs from one another.This independently selection is applicable to any group that once appears in the compound that surpasses.

[0143] in certain embodiments, the compound of formula I, II, III, IV, V or VI is a selectivity TPO conditioning agent.In certain embodiments, the compound of formula I, II, III, IV, V or VI is a selectivity TPO receptor stimulant.In certain embodiments, the compound of formula I, II, III, IV, V or VI is a selectivity TPO receptor antagonist.In certain embodiments, the compound of formula I, II, III, IV, V or VI is a selectivity TPO acceptor portion agonist.In certain embodiments, the compound of formula I, II, III, IV, V or VI is an organizing specific selectivity TPO conditioning agent.In certain embodiments, the compound of formula I, II, III, IV, V or VI is a selectivity TPO receptor binding compounds.In certain embodiments, the compound of formula I, II, III, IV, V or VI is the TPO stand-in.

[0144] in certain embodiments, the invention provides and be selected from following compound or the acceptable salt of medicine, ester, acid amides or the prodrug of these compounds arbitrarily:

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } methyl benzoate (compound 110);

4-hydroxy-benzoic acid N '-1-[1-(3, the 5-3,5-dimethylphenyl])-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 123);

3-(7-{N '-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] diazanyl }-the 1H-indol-3-yl) phenylpropionic acid compound 128);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluoro-3-methyl-phenyl]) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 229);

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 399).In certain embodiments, such compound is a selectivity TPO conditioning agent.

[0145] some compound of the present invention can be used as the steric isomer that comprises optically active isomer.The disclosure is intended to comprise the racemic mixture and the single enantiomorph of all steric isomers and these steric isomers, and this single enantiomorph can split according to method well known in the art maybe can be got rid of single enantiomorph by the synthetic schemes that mainly produces another kind of enantiomorph with respect to a kind of enantiomorph known in the art.

Some synthetic method

[0146] in certain embodiments, some compound of the present invention can use following scheme synthetic.

Scheme I

[0147] process of scheme I is the multistep synthesis step, its start from palladium catalytic such as structure 2 phenyl-boron dihydroxide and such as the cross-coupling of the aromatic bromide of structure 1 to form dibenzyl structure 3.Behind the methyl ether deprotection by nitrated and hydrogenation, to obtain xenyl amino acid such as structure 4.Under standard conditions,, and use suitable coupling mating partner (coupling partner) to handle then to obtain the end product of structure 6 with described amino group diazotization.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

Scheme II

[0148] process of scheme II is the multistep synthesis step, and it starts from catalytic oxindole and the oxindole that replaces with the N-that obtains structure 8 of the cross-coupling of aryl or alkyl bromide such as structure 7 of copper.Then the oxindole that replaces by N-with such as the amino acid whose diazonium salt coupling of the xenyl of structure 4 to obtain the end product of structure 9.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

Scheme III

[0149] process of scheme III is the multistep synthesis step, and it starts from catalytic oxindole and the oxindole that replaces with the N-that obtains structure 8 of the cross-coupling of aryl or alkyl bromide such as structure 7 of copper.The oxindole of N-replacement is by being converted into structure 10 with dimethylformamide dimethyl acetal (or equivalent) or triethyl orthoformate reaction then.Structure 10 obtains structure 11 with the amine reaction more then.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

Scheme IV

[0150] process of scheme IV is the single step synthesis step, in the presence of alkali, makes from the oxindole 8 of the arylation of scheme I and the pyrrole aldehyde 12 that suitably replaces in conjunction with to obtain 13.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

Plan V

[0151] process of plan V is the single step synthesis step, wherein 14 with the synthetic equivalent reaction of phosgene or some to produce 15.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

Plan V I

[0152] process of plan V I is the multistep synthesis step, and it starts from forming thionaphthene from aryl thioethers 16.Thionaphthene is by being converted into structure 19 with diazonium salt 18 reactions then.

Plan V II

[0153] process of plan V II is the multistep synthesis step, its start from such as the phenyl aldehyde of structure 20 and such as the Wittig alkylene of the phosphonium bromide of structure 21 to form alkene 22.The reduction of nitryl group (and/or alkene) obtains the aniline such as structure 23.Under standard conditions,, and use suitable coupling mating partner to handle to obtain the end product of structure 24 with described amino group diazotization.Group in " the optional replacement " definition that " R " is selected from above to be provided.

Plan V III

[0154] process of plan V III is the multistep synthesis step, and oxindole or its analogue that its N-that starts from structure 25 replaces form enamine or enol ether.Then it is converted into structure 27 by reacting with the amine mating partner.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

Scheme IX

[0155] general process of scheme IX starts from the diazotization of aminocompound 28 under standard conditions, and the compound with structure 25 carries out linked reaction to obtain the hydrazone product of structure 29 then.Group in " the optional replacement " definition that " R " can occur 0,1,2 or 3 time and each R is independently selected from above to be provided.

[0156] those skilled in the art can approve, similarly synthetic schemes can be used for synthetic similar compounds.Those skilled in the art can approve, can use other synthetic schemes to synthesize compound of the present invention.In certain embodiments, the invention provides the pairing salt of any compound provided herein.

[0157] in certain embodiments, the invention provides salt corresponding to selectivity TPO conditioning agent.In certain embodiments, the invention provides salt corresponding to selectivity TPO receptor-binding agents.In certain embodiments, obtain salt by the acid-respons that makes compound and all example hydrochloric acids, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Whitfield's ointment etc.In certain embodiments, by making compound and alkali reaction to generate salt, ammonium salt for example, an alkali metal salt such as sodium salt or sylvite, such as the alkaline earth salt of calcium salt or magnesium salts, such as the salt of the organic bases of choline, dicyclohexyl amine, N-methyl D-glucosamine, trihydroxymethylaminomethane, 4-(2-hydroxyethyl)-morpholine, 1-(2-hydroxyethyl)-tetramethyleneimine, thanomin and with amino acid whose salt such as arginine, Methionin etc.In certain embodiments, the free acid form by making selectivity TPO conditioning agent or selectivity TPO wedding agent and many molar equivalents such as alkali reactions such as two sodium, di-methylcarbinol amine to obtain salt.

[0158] in certain embodiments, the salt corresponding to The compounds of this invention is selected from: acetate, ammonium salt, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, Ca-EDTA salt, camsilate, carbonate, muriate, the choline hydrochlorate, clavulanate, Citrate trianion, dihydrochloride, diphosphate, edetate, ethanedisulphonate, bay sulfuric acid propyl ester (estolate), esilate, fumarate, gluceptate, gluconate, glutaminate, the glycolyl arsanilate, Sucrets salt, Hai Baming salt (hydrabanine), hydrobromate, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactic acid salt, lactobionate, lauroleate, magnesium salts, malate, maleate, mandelate, mucate, naphthalenesulfonate, nitrate, N-methyl glucoside amine salt, oxalate, pamoate (embonate), palmitate, pantothenate, phosphoric acid salt, Polygalacturonate, sylvite, salicylate, sodium salt, stearate, subacetate, succinate, vitriol, tannate, tartrate, teoclate, tosylate, the triethyl salt compounded of iodine, Apiroserum Tham, leptodactyline or valerate.

[0159] in certain embodiments, one or more carbon atoms of The compounds of this invention are replaced by silicon.Referring to, WO 03/037905A1 for example; Tacke and Zilch, Endeavour, NewSeries, 10,191-197 (1986); Bains and Tacke, Curr.Opin.Drug DiscovDevel.Jul:6 (4): 526-43 (2003) is incorporated herein by reference its full content at this.In certain embodiments, the The compounds of this invention that comprises one or more Siliciumatoms has the character of some expectation, include but not limited to that when not compared by the identical compound that Siliciumatom replaces with there being carbon atom, it has higher stability and/or longer transformation period in the patient.

Some mensuration

[0160] in certain embodiments, but use test is regulated active level with the TPO that measures The compounds of this invention.For example, luciferase assay can be tested the usefulness of The compounds of this invention as selectivity TPO conditioning agent, as people's such as Lamb Nucleic Acids Research, and people's such as 23:3283-3289 (1995) and/or Seidel Proc.Nat.Acad.Sci.USA; Described in the 92:3041-3045 (1995), at this its full content is incorporated herein by reference.

[0161] can also use in-vitro multiplication and/or differentiation assays, people's such as Bartley Cell for example, described in people's such as 77:1117-1124 (1994) and/or Cwirla the Science, 276:1696-1699 (1997), at this its full content is incorporated herein by reference.

The some drugs composition

[0162] in certain embodiments, at least a selectivity TPO conditioning agent or the acceptable salt of its medicine, ester, acid amides and/or prodrug form medicament separately or are combined to form medicament with one or more medicine acceptable carriers.The technology that is used for the preparation of The compounds of this invention and administration can be such as " Remington ' s Pharmaceutical Sciences " (" Lei Mingdun pharmacopedics "), Mack Publishing Co., Easton, PA, 18th edition, find in 1990, its full content is incorporated herein by reference at this.

[0163] in certain embodiments, use the known technology preparation to comprise the medicament of one or more The compounds of this invention, this technology includes but not limited to mixing, dissolving, granulation, manufacturing lozenge, grinding, emulsification, bag quilt, holds back or pressed disc method.

[0164] in certain embodiments, the medicament that comprises one or more The compounds of this invention is liquid (for example suspension, elixir and/or a solution).In some such embodiment, use composition preparation known in the art to comprise the liquid preparation of one or more The compounds of this invention, this composition includes but not limited to water, ethylene glycol, oil, alcohol, seasonings, sanitas and tinting material.

[0165] in certain embodiments, the medicament that comprises one or more The compounds of this invention is solid (for example powder, tablet and/or a capsule).In some such embodiment, use composition preparation known in the art to contain the solid chemicals of one or more The compounds of this invention, this composition includes but not limited to starch, sugar, thinner, granulating agent, lubricant, tackiness agent and disintegrating agent.

[0166] in certain embodiments, the medicament that will comprise one or more The compounds of this invention is mixed with depot (depot) preparation.Some such depot formulation has longer action time than non-depot formulation usually.In certain embodiments, by implanting (for example subcutaneous or intramuscular) or such preparation being carried out administration by intramuscularly.In certain embodiments, use suitable polymers raw material or hydrophobic raw material (for example at the emulsion that can accept in the oil) or ion exchange resin to prepare depot formulation, perhaps be prepared as sl. sol. derivative, as sl. sol. salt.

[0167] in certain embodiments, the medicament that comprises one or more The compounds of this invention comprises delivery system.The example of delivery system includes but not limited to liposome and emulsion.Some delivery system can be used for preparing some medicament, and it comprises that those comprise the medicament of hydrophobic compound.In certain embodiments, use some organic solvent, as methyl-sulphoxide.

[0168] in certain embodiments, the kit that comprises one or more The compounds of this invention contains one or more and is designed to the tissue specificity delivery of molecules of described drug delivery to particular organization or cell type.For example, in certain embodiments, medicament comprises the liposome with the tissue specificity antibody sandwich.

[0169] in certain embodiments, the medicament that comprises one or more The compounds of this invention comprises cosolvent system (co-solvent system).Some such cosolvent system comprise such as phenylcarbinol, non-polar surfactant, can be miscible with water organic polymer and water.In certain embodiments, such cosolvent system is used to hydrophobic compound.The limiting examples of such cosolvent system is a VPD cosolvent system, and it is for comprising 3%w/v phenylcarbinol, 8%w/v non-polar surfactant Polysorbate 80 ^TMEthanol solution with the 65%w/v Liquid Macrogol.Significantly do not changing under the condition of its solvability and toxic characteristic, the ratio of such cosolvent system can carried out sizable change.In addition, can change the characteristic of cosolvent component: for example, can use other tensio-active agent to replace Polysorbate 80 ^TMCan change the clip size of polyoxyethylene glycol; Other biocompatible polymer can replace polyoxyethylene glycol, as polyvinylpyrrolidone; And other sugar or polysaccharide can replace dextrose.

[0170] in certain embodiments, the medicament that comprises one or more The compounds of this invention comprises slow-released system.The limiting examples of such slow-released system is the semi-permeable matrix of solid hydrophobic polymkeric substance.In certain embodiments, according to its chemical property, slow-released system can discharge compound in a few hours, a couple of days, several weeks or several months.

[0171] can be provided for some compound of medicament of the present invention with the form of the acceptable salt of medicine with the compatible gegenion of medicine.Can form the compatible salt of medicine with multiple acid, this acid includes but not limited to hydrochloric acid, sulfuric acid, acetate, lactic acid, tartrate, oxysuccinic acid, succsinic acid etc.

[0172] in certain embodiments, the medicament that comprises one or more The compounds of this invention comprises the treatment effective amount of actives.In certain embodiments, the treatment significant quantity is enough to prevent, alleviate or improves the symptom of disease or prolong and treated the individual life-span.Determining fully in those skilled in the art's limit of power of treatment significant quantity.

[0173] in certain embodiments, the medicament that will comprise one or more The compounds of this invention is formulated as prodrug.In certain embodiments, prodrug is favourable, because they are easier to administration than corresponding activity form.For example, in some cases, but prodrug has more biology availability (for example passing through oral administration) than corresponding activity form.In some cases, the activity form corresponding with it compared, and prodrug can have the solubleness of improvement.In certain embodiments, prodrug is an ester.In certain embodiments, prodrug has littler water-soluble than corresponding activity form.In some cases, such prodrug has good cytolemma perviousness, and moves water-soluble being unfavorable at the cytolemma place.In certain embodiments, the ester in such prodrug is hydrolyzed to carboxylic acid by metabolism.In some cases, the compound that contains carboxylic acid is corresponding activity form.In certain embodiments, prodrug comprises and acid groups bonded small peptide (polyamino acid).In some such embodiment, described peptide by metabolism to form corresponding activity form.

[0174] in certain embodiments, the medicament that comprises one or more The compounds of this invention can be used for treating the disease or the illness of Mammals, especially human patients.That suitable route of administration includes but not limited to is oral, rectum, stride in mucous membrane, the intestines, in intestines, part, suppository, suction, sheath, in the ventricle, in the intraperitoneal, nose, intraocular and parenteral (for example in vein, intramuscular, the marrow and subcutaneous) approach.In certain embodiments, administration exposes but not systemic exposure to realize the part in the medicine sheath.For example, can realize the regional direct injection medicament (for example at kidney zone or heart area) of effect in expectation.

[0175] in certain embodiments, will comprise the form administration (for example tablet, capsule, bolus etc.) of the medicament of one or more The compounds of this invention with dose unit.In certain embodiments, such dose unit contains the selectivity TPO conditioning agent of 1 μ g/kg body weight to the 50mg/kg body weight of having an appointment.In certain embodiments, such dose unit contains the selectivity TPO conditioning agent of 2 μ g/kg body weight to the 25mg/kg body weight of having an appointment.In certain embodiments, such dose unit contains the selectivity TPO conditioning agent of 10 μ g/kg body weight to the 5mg/kg body weight of having an appointment.In certain embodiments, as required with medicament once a day, twice of every day, every day three times or every day four times or multiple dosing.Those skilled in the art recognize that, concrete dosage, frequency and the duration depend on many factors, its biological activity that includes but not limited to expect, disease of patient state and to the tolerance of medicament.

[0176] in certain embodiments, prepare the medicament that comprises The compounds of this invention and be used for oral administration.In some such embodiment, by with one or more The compounds of this invention and one or more medicine acceptable carrier co-formulated medicaments.Some such carrier can be formulated as The compounds of this invention tablet, pill, lozenge, capsule, liquid, gel, syrup, paste, suspension etc., is used for the oral absorption of patient.In certain embodiments, the medicament by one or more The compounds of this invention and one or more solid excipients mixing being obtained be used to orally use.Suitable vehicle includes but not limited to weighting agent, for example comprises the sugar of lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol; Cellulose preparation such as W-Gum, wheat starch, Starch rice, yam starch, gelatin, tragakanta, methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone (PVP).In certain embodiments, such mixture is randomly ground and is randomly added auxiliary material.In certain embodiments, form medicament to obtain tablet core or lozenge nuclear.In certain embodiments, add disintegrating agent (for example crosslinked kollidon, agar or alginic acid or its salt, for example sodium alginate).

[0177] in certain embodiments, provide lozenge nuclear with dressing.In some such embodiment, can use spissated sugar soln, it can randomly contain gum arabic, talcum, polyvinylpyrrolidone, carbopol gel, polyoxyethylene glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be joined in tablet coating or the lozenge dressing.

[0178] in certain embodiments, the medicament that is used for oral administration is sucking fit formula (push-fit) capsule that gelatin is made.Some such sucking fit formula capsule comprises one or more The compounds of this invention, and it is with one or more weighting agents such as lactose etc., mix such as the tackiness agent of starch etc. and/or such as the lubricant of talcum or Magnesium Stearate and optional stablizer.In certain embodiments, the medicament that is used for oral administration is by gelatin and the soft seal capsule made such as the softening agent of glycerine or sorbyl alcohol.In some soft capsule, one or more The compounds of this invention dissolve or are suspended in the suitable liquid, for example in fatty oil, whiteruss or the liquid macrogol.In addition, can add stablizer.

[0179] in certain embodiments, preparation is used for the medicament of orally administering.Some such medicament is tablet or the lozenge with the ordinary method preparation.

[0180] in certain embodiments, preparation is used for the medicament (for example, intravenous injection, subcutaneous injection, intramuscularly etc.) of drug administration by injection.In some such embodiment, medicament comprises carrier and is configured to the aqueous solution, and for example water or physiology compatible buffers are as Hank solution, Ringer solution or normal saline buffer solution.In certain embodiments, comprise other composition (for example promoting to dissolve or be used as the composition of sanitas).In certain embodiments, use preparation injectable suspensions such as suitable liquid vehicle, suspensoid.Some medicament that is used to inject exists with unit dosage, for example in ampoule or multi-dose container.Some medicament that is used for injecting is suspension, solution or the emulsion at oiliness or aqueous medium, and can contain the preparaton (formulatory agent) such as suspensoid, stablizer and/or dispersion agent.Some solvent that is applicable to the injection medicament includes but not limited to lipophilic solvent and such as the fatty oil of sesame oil, such as the Acrawax of ethyl oleate or triglyceride level, and liposome.The water-based injection suspension can contain the material that increases this suspension viscosity, for example Xylo-Mucine, sorbyl alcohol or dextrose.Randomly, such suspension can also contain suitable stabilizers or increase described compound dissolution degree to allow the reagent of the highly enriched solution of preparation.

[0181] in certain embodiments, preparation is used to stride the medicament of mucosa delivery.In some such embodiment, can in preparation, use the permeate agent that is applicable to barrier to be penetrated.Such permeate agent is normally known in the art

[0182] in certain embodiments, preparation is used for the medicament of inhalation.The medicament that is used for sucking that some is such is prepared into the aerosol spray form of supercharging bag or atomizer.Some such medicament comprises propellant, as Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other gas that is fit to.In some embodiment of using pressurized aerosol, can determine dose unit by the valve of conveying and metering amount.In certain embodiments, can be formulated in capsule and the cartridge case (cartridge) that uses in sucker or the insufflator.Some such preparation comprises The compounds of this invention and powdered mixture such as the suitable powder matrix of lactose or starch.

[0183] in certain embodiments, preparation is used for the medicament of rectal administration, for example suppository or enema,retention.Some such medicament comprises known composition, for example theobroma oil and/or other glyceryl ester.

[0184] in certain embodiments, preparation is used for the medicament of topical.Some such medicament comprises non-irritating humidification matrix, for example ointment or emulsifiable paste.Exemplary suitable ointment base includes but not limited to Vaseline, and Vaseline adds volatile silicone, and lanolin and water-in-oil emulsion are as can be from Beiersdorf (Cincinnati, the Eucerin that Ohio) obtains ^TMExemplary suitable emulsifiable paste matrix includes but not limited to can be from Beiersdorf (Cincinnati, the Nivea that Ohio) obtains ^TMCream, cold cream (USP), can be from Johnson﹠amp; The Purpose Cream that Johnson (New Brunswick, New Jersey) obtains ^TM, hydrophilic ointment (USP) and the Lubriderm that can obtain from Pfizer (Morris Plains, New Jersey) ^TM

[0185] in certain embodiments, can select preparation, route of administration and the dosage of medicament of the present invention according to concrete patient disease state.(referring to people such as for example Fingl, 1975, p.1 " The Pharmacological Basis of Therapeutics (pharmacological basis of treatment) ", Ch.1 all are incorporated herein by reference the document at this).In certain embodiments, with single dose with the medicament administration.In certain embodiments, in one day or a couple of days with twice or repeatedly serial dosage with the medicament administration.

[0186] in certain embodiments, to the patient with the human dosage established about 0.1% to 500%, 5% to 200%, 10% to 100%, 15% to 85%, 25% to 75% or 40% to 60% with medicament administration of the present invention.When not having the human dosage of establishing, suitable human dosage can be from ED ₅₀Or ID ₅₀Value or infer from other suitable value of studying in external or the body.

[0187] in certain embodiments, patient's dosage regimen every day comprises the oral dosage of the The compounds of this invention of 0.1mg to 2000mg, 5mg to 1500mg, 10mg to 1000mg, 20mg to 500mg, 30mg to 200mg or 40mg to 100mg.In certain embodiments, with dosage regimen administration every day of single dose every day.In certain embodiments, with twice, three times, four times or more than four times dosage regimen administration every day.

[0188] in certain embodiments, by the successive venoclysis with medicament administration of the present invention.In some such embodiment, every day is with the present composition administration of 0.1mg to 500mg.

[0189] in certain embodiments, with medicament of the present invention administration during treating continuously.For example, can be with medicament administration of the present invention in a couple of days, several weeks, several months or several years.

[0190] can regulate dosage, medication interval and treatment time length to reach desired effects.In certain embodiments, regulate dosage and medication interval in the patient, to keep the expectation concentration of compound.For example, in certain embodiments, regulate dosage and medication interval, provide the plasma concentration of The compounds of this invention, make it with the amount that is enough to reach desired effects.In some such embodiment, plasma concentration is maintained more than the minimal effective concentration (MEC).In certain embodiments, make plasma concentration in 10% to 90% time, in 30% to 90% time or in 50% to 90% time, maintain dosage regimen more than the MEC medicament administration of the present invention with design.

[0191] in some embodiment, can adjust the partial concn of dosage regimen with the The compounds of this invention that reaches expectation with the medicament topical.

[0192] in certain embodiments, medicament can be placed packing or distribution device, this packing or distribution device can comprise one or more unit dosage that contains activeconstituents.Described packing can for example comprise metal or plastic foil, as Blister Package (blister pack).Described packing or divider can have the administration specification sheets.Described packing or divider can also have the precaution relevant with described container, these precaution are the forms by government organs' regulation of management drug manufacture, use or sale, and these precaution have reflected that described medicament forms is used for the mankind or beasts administration by this mechanism's approval.Such precaution for example, can be the labels that is used for prescription drugs that indicates food and drug administration's approval, or the product description of approval.Can also prepare and contain the composition that is formulated in the The compounds of this invention in the compatible pharmaceutical carrier, be placed in the suitable containers, and indicate that it is used to specify treatment of diseases.

[0193] in certain embodiments, medicament is a powder type, is used for making up before use with such as suitable carriers such as sterilization pyrogen-free matter water.

Some combination therapy

[0194] in certain embodiments, with one or more pharmaceutical compositions of the present invention and the administration altogether of one or more other medicaments.In certain embodiments, one or more such other medicaments are designed to treat the identical disease or the morbid state for the treatment of with one or more pharmaceutical compositions of the present invention.In certain embodiments, one or more such other medicaments are designed to treat the different diseases or the morbid state for the treatment of with one or more pharmaceutical compositions of the present invention.In certain embodiments, one or more such other medicaments are designed to treat the effect of not expecting that one or more medicaments of the present invention cause.In certain embodiments, one or more medicaments of the present invention and another kind of medicament are total to administration to treat the effect of not expecting that other medicament causes.In certain embodiments, one or more medicaments of the present invention and one or more other medicaments administrations simultaneously.In certain embodiments, one or more medicaments of the present invention and one or more other medicaments are in the different time administration.In certain embodiments, the preparation together in unitary agent with one or more medicaments of the present invention and one or more other medicaments.In certain embodiments, prepare one or more medicaments of the present invention and one or more other medicaments respectively.

[0195] can with medicament of the present invention altogether the example of the medicament of administration include but not limited to anticancer therapy, include but not limited to chemotherapy and radiotherapy; Cortin includes but not limited to prednisone; Immunoglobulins includes but not limited to vein immunoglobulin (Ig) (IVIg); Anodyne (for example Paracetamol); Anti-inflammatory agent includes but not limited to nonsteroidal anti-inflammatory drug (for example Ibuprofen BP/EP, COX-I inhibitor and cox 2 inhibitor); Salicylate; Microbiotic; Antiviral agent; Anti-mycotic agent; Antidiabetic (for example biguanides, glucosidase inhibitor, Regular Insulin, sulfonylurea and thiazolidinediones); Suprarenal gland properties-correcting agent; Diuretic(s); Hormone (for example anabolic steroids, male sex hormone, oestrogenic hormon, calcitonin, Progesterone, Somatostatin and Triiodothyronine); Immunomodulator; Muscle relaxant; Antihistaminic agent; Osteoporosis agent (for example Diphosphonate, calcitonin and oestrogenic hormon); Prostaglandin(PG), antineoplastic agent; Psychotherapeutic agent; Tranquilizer; Toxicodendron (poison oak) or poison lacquer (poison sumac) product; Antibody and vaccine.

Some indication

[0196] in certain embodiments, the invention provides treatment patient's method, it comprises one or more The compounds of this invention is carried out administration.In certain embodiments, such patient suffers from thrombocytopenia.In some such embodiment, thrombocytopenia is caused by chemotherapy and/or radiotherapy.In certain embodiments, thrombocytopenia causes the marrow failure that caused by bone marrow transplantation and/or aplastic anemia.In certain embodiments, thrombocytopenia is geneogenous.In certain embodiments, in conjunction with gathering the peripheral blood progenitor cell and/or in conjunction with the thrombocyte Apheresis, with one or more The compounds of this invention to patient's administration.Can before this collection, during and/or carry out such administration afterwards.

[0197] in certain embodiments, to suffering from patient's administration of the systemic disease state that affects the nerves, this morbid state includes but not limited to the disease of the system of affecting the nerves and to neural damage with one or more The compounds of this invention.Such disease includes but not limited to amyotrophic lateral sclerosis, multiple sclerosis and multiple malnutrition.Neural damage is included but not limited to the infringement of Spinal injury or peripheral nerve, its include but not limited to by wound or in wind-induced damage.In certain embodiments, one or more The compounds of this invention are used to promote the growth and/or the growth of neurogliocyte.Such neurogliocyte can be repaired neurocyte.In certain embodiments, The compounds of this invention is used for the treatment of psychological disorders, includes but not limited to cognitive disorder.

Embodiment

[0198] provide the following example of the result who comprises experiment and obtain only should be interpreted as limiting the present invention for purposes of illustration and not.Represented to have when chemical structure and do not filled valent atomic time, should be understood to valency and satisfy with one or more hydrogen atoms.

Embodiment 1

3 '-{ [1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-2 '-xenol-3-carboxylic acid (compound 101)

[0199] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.05(s，1H)，11.35(d，J＝13.3Hz，1H)，9.40(s，1H)，8.12(t，J＝1.6Hz，1H)，7.97(d，J＝7.9Hz，1H)，7.95(ddd，J＝7.7，1.6，1.3Hz，1H)，7.81-7.78(m，2H)，7.60(t，J＝7.7Hz，1H)，7.44(dq，J＝7.9，0.9Hz，1H)，7.14(t，J＝7.8Hz，1H)，7.12(s，1H)，7.11(m，2H)，7.07(dd，J＝7.8，1.5Hz，1H)，6.94(q，J＝0.9Hz，1H)，2.36(s，6H)。

Embodiment 2

2,4-resorcylic acid N '-1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] and ethyl } hydrazides (compound 102)

[0200] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，CD ₃OD)δ8.49(s，1H)，7.71(m，1H)，7.67(m，1H)，7.34(m，1H)，7.16(s，1H)，7.04(s，2H)，6.93(s，1H)，6.39(m，1H)，6.34(s，1H)，2.64(s，3H)，2.41(s，6H)。

Embodiment 3

3-{3-[(5-chloro-2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 103)

[0201] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.29(s，1H)，12.95(s，1H)，9.36(s，1H)，8.08(t，J＝1.7Hz，1H)，8.04(ddd，J＝7.7，1.7，1.2Hz，1H)，7.82(m，2H)，7.74(t，J＝7.7Hz，1H)，7.65(d，J＝2.6Hz，1H)，7.34(m，1H)，7.33(td，J＝7.6，1.3Hz，1H)，7.27(dd，J＝8.0，1.8Hz，1H)，7.23(d，J＝8.0Hz，1H)，7.22(td，J＝7.6，0.9Hz，1H)，6.94(dm，J＝7.6Hz，1H)，6.93(d，J＝2.6Hz，1H)，2.28(s，3H)，2.27(s，3H)。

Embodiment 4

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 104)

[0202] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)13.29(s，1H)，13.04(s，1H)，9.11(s，1H)，8.08(t，J＝1.8Hz，1H)，8.04(ddd，J＝7.7，1.8，1.2Hz，1H)，7.83(ddd，J＝7.7，1.8，1.2Hz，1H)，7.75(m，1H)，7.74(t，J＝7.7Hz，1H)，7.69(dd，J＝7.7，1.6Hz，1H)，7.31(td，J＝7.6，1.3Hz，1H)，7.22(td，J＝7.6，0.9Hz，1H)，7.15(m，2H)，7.06(t，J＝7.7Hz，1H)，7.00(m，1H)，6.95(m，1H)，6.94(dd，J＝7.7，1.6Hz，1H)，2.33(s，6H)。

Embodiment 5

3 '-{ [1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-4-fluoro-2 '-xenol-3-carboxylic acid (compound 105)

[0203] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)δ13.35(s，1H)，11.34(d，J＝13.3Hz，1H)，9.41(s，1H)，9.08(d，J＝13.3Hz，1H)，8.01(dd，J＝7.2，2.3Hz，1H)，7.96(d，J＝7.9Hz，1H)，7.79(dd，J＝7.9，1.5Hz，1H)，7.78(ddd，J＝8.4，4.4，2.3Hz，1H)，7.44(dq，J＝7.9，0.9Hz，1H)，7.42(dd，J＝10.6，8.4Hz，1H)，7.13(t，J＝7.9Hz，1H)，7.12(m，1H)，7.10(m，2H)，7.06(dd，J＝7.9，1.5Hz，1H)，6.94(m，1H)，2.36(s，6H)。

Embodiment 6

2-(3 '-{ [1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-2 '-xenol-3-yl)-2 Methylpropionic acid (compound 106)

[0204] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)δ12.39(s，1H)，11.36(d，J＝13.3Hz，1H)，9.32(s，1H)，9.08(d，J＝13.3Hz，1H)，7.97(d，J＝7.9Hz，1H)，7.76(dd，J＝7.9，1.5Hz，1H)，7.54(m，1H)，7.45-7.42(m，3H)，7.35(m，1H)，7.12(t，J＝7.9Hz，1H)，7.12(m，1H)，7.11(m，2H)，7.02(dd，J＝7.9，1.5Hz，1H)，6.95(q，J＝0.8Hz，1H)，2.37(s，6H)，1.52(s，6H)。

Embodiment 7

3 '-{ [1-(3, the 4-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-2 '-xenol-3-carboxylic acid (compound 107)

[0205] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)δ13.03(s，1H)，11.31(d，J＝13.7Hz，1H)，9.38(s，1H)，9.06(d，J＝13.7Hz，1H)，8.09(t，J＝1.5Hz，1H)，7.91-7.95(m，2H)，7.77(m，2H)，7.58(t，J＝7.3Hz)，7.41(dd，J＝7.8，1.0Hz，1H)，7.34(d，J＝7.8Hz，1H)，7.26(d，J＝2.0Hz，1H)，7.19(dd，J＝7.8，2.0Hz，1H)，7.11(t，J＝7.8Hz，1H)，7.04(dd，J＝7.8，1.5Hz，1H)，6.90(d，J＝1.5Hz，1H)，2.29(s，3H)，2.28(s，3H)。

Embodiment 8

4-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 108)

[0206] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.18(s，1H)，13.05(s，1H)，9.13(s，1H)，8.14(d，J＝8.5Hz，2H)，7.75(m，1H)，7.70(m，2H)，7.69(dd，J＝7.8，1.6Hz，1H)，7.32(td，J＝7.6，1.2Hz，1H)，7.23(td，J＝7.6，0.7Hz，1H)，7.15(s，2H)，7.06(t，J＝7.8Hz，1H)，7.03(m，1H)，7.00(s，1H)，6.94(dd，J＝7.8，1.6Hz，1H)，2.33(s，6H)。

Embodiment 9

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 109)

[0207] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.30(s，1H)，13.20(s，1H)，9.27(s，1H)，8.11(t，J＝1.8Hz，1H)，8.07(ddd，J＝7.8，1.8，1.2Hz，1H)，7.94(d，J＝7.9Hz，1H)，7.86(ddd，J＝7.8，1.8，1.2Hz，1H)，7.77(t，J＝7.8Hz，1H)，7.74(dd，J＝7.8，1.6Hz，1H)，7.56(dq，J＝7.9，0.7Hz，1H)，7.15(m，2H)，7.09(t，J＝7.8Hz，1H)，7.08(m，1H)，7.01(m，1H)，6.99(dd，J＝7.8，1.6Hz，1H)，2.33(s，6H)。

Embodiment 10

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } methyl benzoate (compound 110)

[0208] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.20(s，1H)，9.27(s，1H)，8.15(dd，J＝2.1，1.6Hz，1H)，8.10(ddd，J＝7.9，1.6，1.1Hz，1H)，7.94(d，J＝7.9Hz，1H)，7.90(ddd，J＝7.9，2.1，1.1Hz，1H)，7.80(t，J＝7.9Hz，1H)，7.74(dd，J＝7.9，1.6Hz，1H)，7.57(dq，J＝7.9，0.8Hz，1H)，7.15(m，2H)，7.09(t，J＝7.9Hz，1H)，7.08(m，1H)，7.01(m，1H)，7.00(dd，J＝7.9，1.6Hz，1H)，3.90(s，3H)，2.33(s，6H)。

Embodiment 11

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } methyl benzoate (compound 111)

[0209] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.04(s，1H)，9.11(s，1H)，8.12(m，1H)，8.06(ddd，J＝7.8，1.6，1.2Hz，1H)，7.87(ddd，J＝7.8，2.2，1.2Hz，1H)，7.77(t，J＝7.8Hz，1H)，7.75(m，1H)，7.69(dd，J＝7.8，1.6Hz，1H)，7.31(td，J＝7.6，1.2Hz，1H)，7.22(td，J＝7.6，0.9Hz，1H)，7.15(m，2H)，7.06(t，J＝7.8Hz，1H)，7.00(m，1H)，6.95(m，1H)，6.94(dd，J＝7.8，1.6Hz，1H)，3.90(s，3H)，2.33(s，6H)。

Embodiment 12

3-{3-[(5-fluoro-2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 112)

[0210] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.29(s，1H)，12.97(s，1H)，9.06(s，1H)，8.08(m，1H)，8.04(ddd，J＝7.8，2.2，1.1Hz，1H)，7.83(m，1H)，7.81(d，J＝7.6Hz，1H)，7.74(t，J＝7.8Hz，1H)，7.45(dd，J＝9.5，3.0Hz，1H)，7.33(t，J＝7.6Hz，1H)，7.22(t，J＝7.6Hz，1H)，7.19(s，2H)，7.02(s，1H)，6.94(d，J＝7.6Hz，1H)，6.75(dd，J＝9.5，3.0Hz，1H)，2.33(s，6H)。

Embodiment 13

3-{3-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit amino]-2-oxo-2,3-Er hydrogen benzoxazole-7-yl } phenylformic acid (compound 113)

[0211] as described in the plan V, with 3 '-N '-[1-(3,5-dimethyl-phenyl)-2-oxo-6-Trifluoromethyl-1,2-dihydro-indoles-3-subunit]-diazanyl }-2 '-hydroxyl-biphenyl-3-carboxylic acid (153mg, 0.28mmol, 1.0 the two-phase mixture of the saturated sodium bicarbonate aqueous solution/2.0M aqueous sodium hydroxide solution (6mL) of (6mL) solution of methylene dichloride equivalent) and 1: 1 at room temperature adds in the triphosgene (83mg, 0.28mmol, 3.0 equivalents).To this mixture is stirred 4h, use the 6MHCl acidifying then.Remove organic layer, use twice of dichloromethane extraction water layer then.Each washing of the organic layer that water and salt solution are combined is once used dried over sodium sulfate, filters and concentrating under reduced pressure.By silica gel chromatography (gradient: hexane/EtOAc to 3 of 9: 1: hexane/EtOAc to 59.9 of 2: 40: 0.1 hexane/EtOAc/HOAc) resistates is carried out purifying, grind to obtain compound 113 with methyl alcohol then. ¹H?NMR(500MHz，DMSO-d ₆)δ13.25(s，1H)，8.45(dd，J＝2.0，1.5Hz，1H)，8.09(ddd，J＝7.8，2.0，1.0Hz，1H)，8.05(ddd，J＝8.3，1.5，1.0Hz，1H)，7.86(d，J＝8.1Hz，1H)，7.73(dd，J＝7.8，7.8Hz，1H)，7.64(dd，J＝8.0，1.2Hz，1H)，7.46(m，2H)，7.36(dd，J＝7.8，1.2Hz，1H)，7.21(s，3H)，6.86(d，J＝1.6Hz，1H)，2.38(s，6H)。

Embodiment 14

3-{3-[(2-hydroxyl-5,3 ', 4 '-trimethylammonium biphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 114)

[0212] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.28(s，1H)，13.03(s，1H)，8.81(s，1H)，8.08(dd，J＝1.5，1.0Hz，1H)，8.04(ddd，J＝7.8，1.5，1.5Hz，1H)，7.83(ddd，J＝7.9，2.2，1.2Hz，1H)，7.75(m，2H)，7.51(d，J＝2.1Hz，1H)，7.30(m，2H)，7.23(m，3H)，6.94(d，J＝7.9Hz，1H)，6.76(dd，J＝2.1，0.7Hz，1H)，2.34(s，3H)，2.27(s，3H)，2.26(s，3H)。

Embodiment 15

3-hydroxy-benzoic acid N '-and 1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 115)

[0213] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)δ11.76(s，1H)，11.08(s，1H)，9.84(s，1H)，7.70(d，J＝8.3Hz，1H)，7.35(m，4H)，7.13(s，1H)，7.07(s，2H)，7.02(dt，J＝5.2，3.7Hz，1H)，6.92(d，J＝1.5Hz，1H)，2.58(s，3H)，2.36(s，6H)。

Embodiment 16

1-(3, the 5-3,5-dimethylphenyl)-3-{1-[2-(4-hydroxy phenyl)-2-oxo-ethylamino] ethylidene }-the 6-Trifluoromethyl-1,3-Indolin-2-one (compound 116)

[0214] prepares this compound according to the described method of plan V III. ¹H NMR (500MHz, methyl alcohol-d ₄) δ 8.54 (s, 1H), 7.98 (d, J=8.8Hz, 2H), 7.65 (d, J=8.3Hz, 1H), 7.32 (d, J=7.8Hz, 1H), 7.15 (s, 1H), 7.03 (s, 2H), 6.93 (s, 1H), 6.90 (d, J=8.3Hz, 2H), 5.14 (s, 2H), 2.67 (s, 3H), 2.41 (s, 6H).

Embodiment 17

3-{3-[(5-fluoro-2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 117)

[0215] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.28(s，1H)，13.09(s，1H)，9.18(s，1H)，8.09(d，J＝2Hz，1H)，8.07(m，1H)，8.0(d，J＝7.8Hz，1H)，7.87(m，1H)，7.77(t，J＝7.9Hz，1H)，7.58(d，J＝7.8Hz，1H)，7.52(dd，J＝9.4，3.1Hz，1H)，7.19(s，2H)，7.07(s，1H)，7.03(s，1H)，6.82(dd，J＝9.5Hz，1H)，2.33(s，6H)。

Embodiment 18

3-{3-[(2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 118)

[0216] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.28(s，1H)，13.18(s，1H)，9.23(s，1H)，8.11(t，J＝1.7Hz，1H)，8.07(dd，J＝7.6，1.2Hz，1H)，7.94(d，J＝7.8Hz，1H)，7.85(m，1H)，7.78(d，J＝8.1Hz，1H)，7.73(m，1H)，7.57(t，J＝8.8Hz，1H)，7.33(s，1H)，7.24(dd，J＝13.9，4.9Hz，2H)，7.09(m，1H)，6.99(dd，J＝7.7，1.6Hz，1H)，2.26(s，3H)，2.25(s，3H)。

Embodiment 19

3-{3-[(2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 119)

[0217] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.28(s，1H)，13.04(s，1H)，9.09(s，1H)，8.08(m，1H)，8.04(dt，J＝7.8，1.4Hz，1H)，7.83(ddd，J＝8.0，2.2，1.2Hz，1H)，7.74(t，J＝7.7Hz，2H)，7.68(dd，J＝7.8，1.5Hz，1H)，7.31(m，2H)，7.23(m，3H)，7.06(t，J＝7.9Hz，1H)，6.94(dt，J＝5.9，3.9Hz，2H)，2.26(s，3H)，2.25(s，3H)。

Embodiment 20

3-{3-[(2-hydroxyl-3 ', 4 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 120)

[0218] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)δ13.23(s，1H)，11.15(d，J＝13.2Hz，1H)，9.08(s，1H)，8.88(dd，J＝13.18Hz，1H)，8.04(m，1H)，7.99(m，1H)，7.81(m，2H)，7.70(m，2H)，7.33(s，1H)，7.24(m，2H)，7.09(m，3H)，6.93(m，2H)，2.27(s，3H)，2.26(s，3H)。

Embodiment 21

4-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-2,3-indoline-1-yl } butyric acid (compound 121)

[0219] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)δ13.02(s，1H)，12.14(s，1H)，9.06(s，1H)，7.63(dd，J＝7.8，1.5Hz，2H)，7.33(td，J＝7.7，1.1Hz，1H)，7.21(t，1H)，7.13(m，3H)，7.03(t，J＝7.8Hz，1H)，7.00(s，1H)，6.91(m，1H)，3.85(t，J＝6.8Hz，2H)，2.33(m，8H)，1.88(t，J＝6.8Hz，2H)。

Embodiment 22

2-chloro-3-(4-{[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-ylidenylmethyl] amino }-the 3-hydroxy phenyl) vinylformic acid (compound 122)

[0220] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)δ11.20(d，J＝14.2Hz，1H)，10.6(br?s，1H)，9.06(d，J＝12.7Hz，1H)，7.94(d，J＝8.3Hz，1H)，7.75(d，J＝8.8Hz，1H)，7.63(s，2H)，7.43(d，J＝8.8Hz，1H)，7.45-7.29(m，1H)，7.13(s，1H)，7.11(s，2H)，6.94(s，1H)，2.37(s，6H).

Embodiment 23

4-hydroxy-benzoic acid N '-1-[1-(3, the 5-3,5-dimethylphenyl])-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 123)

[0221] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)12.04(s，1H)，10.92(s，1H)，10.11(s，1H)，7.82(dt，J＝6.0，4.8Hz，2H)，7.66(d，J＝8.2Hz，1H)，7.33(d，J＝7.8Hz，1H)，7.12(s，1H)，7.06(s，2H)，6.91(s，1H)，6.85(d，J＝8.3Hz，2H)，2.60(s，3H)，2.36(s，6H)。

Embodiment 24

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-yl) hydrazono-]-5-nitro-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 124)

[0222] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.29(s，1H)，13.11(s，1H)，9.29(s，1H)，8.52(d，J＝2.4Hz，1H)，8.20(dd，J＝8.8，2.4Hz，1H)，8.10(m，2H)，7.84(m，2H)，7.78(dd，J＝7.8，7.8Hz，1H)，7.15(d，J＝0.9Hz，2H)，7.10(m，2H)，7.01(dd，J＝7.6，1.6Hz，2H)，2.33(s，6H)。

Embodiment 25

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 125)

[0223] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)δ13.2(s，1H)，11.17(d，J＝13.7Hz，1H)，9.11(s，1H)，8.89(d，J＝13.2Hz，1H)，8.04(t，J＝1.8Hz，1H)，7.99(m，1H)，7.80(m，2H)，7.71(m，2H)，7.14(m，2H)，7.10(m，2H)，7.06(m，1H)，7.00(s，1H)，6.94(m，2H)，2.32(s，6H)。

Embodiment 26

3-{3-[(2-hydroxyl-5,3 ', 5 '-trimethylammonium biphenyl-3-yl) hydrazono-]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 126)

[0224] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，CD ₃OD-d ₄)δ8.10(m，2H)，7.75(d，J＝6.8Hz，1H)，7.68(m，2H)，7.54(d，J＝2.0Hz，1H)，7.26(ddd，J＝7.8，7.3，1.0Hz，1H)，7.19(dd，J＝7.3，7.3Hz，1H)，7.10(s，2H)，6.99(s，1H)，6.93(d，J＝7.8Hz，1H)，6.74(d，J＝2.0Hz，1H)，2.36(s，3H)，2.35(s，6H)。

Embodiment 27

4-benzaminic acid N '-and 1-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] ethyl } hydrazides (compound 127)

[0225] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)δ11.83(s，1H)，10.71(s，1H)，7.67(m，3H)，7.35(d，J＝7.8Hz，1H)，7.12(s，1H)，7.06(s，2H)，6.91(s，2H)，6.60(d，J＝8.8Hz，2H)，5.84(s，2H)，2.57(s，3H)，2.36(s，6H)。

Embodiment 28

3-(7-{N '-[1-(3, the 5-3,5-dimethylphenyl)-2-oxo-6-Trifluoromethyl-1,2-indoline-3-subunit] diazanyl }-the 1H-indol-3-yl) phenylpropionic acid compound 128)

[0226] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ13.48(s，1H)，12.11(s，1H)，10.78(s，1H)，8.39(d，J＝8.3Hz，1H)，7.56(d，J＝8.1Hz，1H)，7.39(d，J＝7.8Hz，1H)，7.27(d，J＝2.7Hz，1H)，7.18(s，2H)，7.11(m，1H)，7.05(t，J＝7.7Hz，1H)，7.00(s，1H)，2.98(t，J＝7.32Hz，2H)，2.63(t，J＝7.8Hz，2H)，2.37(s，6H)。

Embodiment 29

4-{3-[N '-(4-methyl benzoyl) diazanyl methylene radical]-2-oxo-2,3-indoline-1-yl } phenylformic acid (compound 129)

[0227] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)δ13.8(s，1H)，8.17(d，J＝8.3Hz，2H)，7.82(d，J＝7.8Hz，2H)，7.78(d，J＝7.8Hz，1H)，7.70(J＝8.3Hz，2H)，7.46(dd，J＝7.8，7.8Hz，1H)，7.43(d，J＝8.3Hz，2H)，7.28(dd，J＝7.8，7.8Hz，1H)，7.00(d，J＝7.8Hz，1H)，2.40(s，3H)。

Embodiment 30

3-{2-oxo-6-trifluoromethyl-3-[4-(3-trifluoromethyl)-1H-pyrroles-2-methylene]-2,3-indoline-1-yl } phenylformic acid (compound 130)

[0228] prepares this compound according to the described method of scheme IV. ¹H NMR (500MHz, acetone-d ₆) δ 13.70 (s, 1H), 8.27 (s, 1H), 8.2 (d, J=7.8Hz, 1H), 7.91 (m, 5H), 7.82 (m, 5H), 7.59 (s, 1H), 7.47 (d, J=7.8Hz, 1H), 7.13 (s, 1H), 6.74 (m, 1H).

Embodiment 31

3-(7-{N '-[1-(3, the 4-3,5-dimethylphenyl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit] diazanyl }-the 1H-indol-3-yl) propionic acid (compound 131)

[0229] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)δ12.10(s，1H)，10.62(s，1H)，7.75(s，1H)，7.67(d，J＝8.1Hz，1H)，7.49(d，J＝7.8Hz，1H)，7.27(d，J＝6.8Hz，1H)，7.22(d，J＝8.3Hz，1H)，7.09(t，J＝7.8Hz，1H)，2.97(t，J＝7.4Hz，1H)，2.62(t，J＝7.8Hz，1H)，2.43(s，3H)，2.28(s，3H)，2.24(s，3H)。

Embodiment 32

3-(3-{[4-(3, the 4-3,5-dimethylphenyl) thiazol-2-yl amino] methylene radical }-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl) phenylformic acid (compound 132)

[0230] prepares this compound according to the described method of scheme III. ¹H NMR (500MHz, acetone-d ₆) δ 8.98 (s, 1H), 8.24 (s, 1H), 8.16 (d, J=7.8Hz, 1H), 7.99 (d, J=7.8Hz, 1H), 7.88 (d, J=8.5Hz, 1H), 7.79 (m, 2H), 7.74 (d, J=7.8Hz, 1H), 7.48 (s, 1H), 7.47 (d, J=9.0Hz, 1H), 7.21 (m, 2H), 2.33 (s, 3H), 2.29 (s, 3H).

Embodiment 33

3-(3-{[4-(4-p-methoxy-phenyl) thiazol-2-yl amino] methylene radical }-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl) phenylformic acid (compound 133)

[0231] prepares this compound according to the described method of scheme III. ¹H NMR (500MHz, acetone-d ₆) δ 8.98 (s, 1H), 8.24 (s, 1H), 8.16 (dt, J=7.8,1.2Hz, 1H), 8.00 (d, J=8.1Hz, 1H), 7.96 (d, J=9.3Hz, 2H), 7.88 (d, J=7.8Hz, 1H), 7.79 (t, J=7.8Hz, 1H), 7.46 (d, J=7.3Hz, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 7.01 (d, J=8.8Hz, 2H), 3.85 (s, 3H).

Embodiment 34

3-{3-[(2-hydroxyl-3 ', 5 '-dimethyl diphenyl-3-base is amino) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 134)

[0232] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)δ11.35(d，J＝13.4Hz，1H)，9.24(s，1H)，9.10(d，J＝13.2Hz，1H)，8.00(m，2H)，7.99(d，J＝8.3Hz，1H)，7.74(m，2H)，7.68(t，J＝7.6Hz，1H)，7.46(d，J＝7.3Hz，1H)，7.14(s，2H)，7.08(t，J＝7.9Hz，1H)，7.03(s，1H)，6.99(m，2H)，2.32(s，6H)。

Embodiment 35

3-{3-[(4-(4-aminomethyl phenyl)-2-thiazolyl amino) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 135)

[0233] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.25(s，2H)，11.81(d，J＝12.1，1H)，11.41(d，J＝13.0，1H)，8.96(d，J＝12.1，1H)，8.59(d，J＝13.0，1H)，8.35(m，1H)，8.11-8.00(m，5H)，7.93(d，J＝8.2，2H)，7.84(d，J＝8.2，2H)，7.84(m，1H)，7.81-7.72(m，3H)，7.67(m，1H)，7.65(s，1H)，7.55(m，1H)，7.47(dq，J＝7.9，0.7，1H)，7.27(d，J＝8.1，4H)，7.04(s，1H)，6.98(s，1H)，2.35(s，3H)，2.34(s，3H)。

Embodiment 36

3-{3-[(3,4-dimethylbenzoyl diazanyl) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 136)

[0234] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.24(br?s，1H)，11.30(d，J＝13.0，1H)，10.28(d，J＝13.0，1H)，8.42(br?s，1H)，8.10-7.96(m，2H)，7.82-7.64(m，4H)，7.38(d，J＝8.1，1H)，7.31(d，J＝7.6，1H)，7.01(s，1H)，6.95(br?s，1H)，2.31(s，6H)。

Embodiment 37

3-{3-[(4-chlorobenzene formacyl diazanyl) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 137)

[0235] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)15.42(s，1H)，13.24(s，1H)，11.47(s，1H)，8.43(s，1H)，8.10-7.89(m，4H)，7.84-7.70(m，3H)，7.65(d，J＝8.4，2H)，7.38(d，J＝7.7，1H)，7.01(s，1H)。

Embodiment 38

3-{3-[(4-anisoyl diazanyl) methylene radical]-2-oxo-6-trifluoromethyl-2,3-indoline-1-yl } phenylformic acid (compound 138)

[0236] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.32(s，1H)，11.30(d，J＝12.2，1H)，10.27(d，J＝12.2，1H)，8.43(s，1H)，8.11-7.65(m，7H)，7.38(d，J＝8.1，1H)，7.09(d，J＝8.5，2H)，7.01(s，1H)，3.85(s，3H)。

Embodiment 39

3-{3-[(3,4-dimethylbenzoyl diazanyl) methylene radical]-2-oxo-6-chloro-2,3-indoline-1-yl } phenylformic acid (compound 139)

[0237] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.22(s，1H)，11.20(br，2H)，8.25(s，1H)，8.05-7.93(m，4H)，7.88(m，1H)，7.78(m，1H)，7.74-7.69(m，5H)，7.68-7.64(m，3H)，7.60(m，2H)，7.54(s，1H)，7.32-7.29(m，2H)，7.14(m，1H)，7.07(dd，J＝8.2，1.9，1H)，6.83(d，J＝1.9，1H)，6.78(m，1H)，2.30(s，12H)。

Embodiment 40

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(2,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 140)

[0238] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)11.76(s，1H)，11.43(s，1H)，10.73(s，1H)，10.25(s，1H)，7.73(d，J＝8.6，1H)，7.51(m，1H)，7.32(d，J＝8.1，1H)，7.21(d，J＝2.0，1H)，7.14(dd，J＝8.1，2.0，1H)，7.07-6.99(m，2H)，6.79(m，1H)，6.38(dd，J＝8.6，2.4，1H)，6.34(d，J＝2.4，1H)，2.47(s，3H)，2.30(s，3H)，2.29(s，3H)。

Embodiment 41

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 141)

[0239] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)11.44(s，1H)，10.75(s，1H)，10.21(s，1H)，7.81(d，J＝8.8，2H)，7.51(m，1H)，7.32(d，J＝8.2，1H)，7.21(d，J＝2.0，1H)，7.14(dd，J＝8.2，2.0，1H)，7.07-6.99(m，2H)，6.88(d，J＝8.8，2H)，6.79(m，1H)，2.47(s，3H)，2.30(s，3H)，2.29(s，3H)。

Embodiment 42

1-(3, the 4-3,5-dimethylphenyl)-3-[(2,4-dihydroxy-benzene formyl radical diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 142)

[0240] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)12.04(s，1H)，11.94(s，1H)，11.02(s，1H)，10.28(s，1H)，10.25(s，1H)，9.64(d，J＝11.5，1H)，8.11(s，1H)，7.80(m，1H)，7.76-7.70(m，2H)，7.58(d，J＝10.4，1H)，7.55-7.50(m，2H)，7.42(d，J＝11.5，1H)，7.34-7.27(m，2H)，7.23(d，J＝1.6，1H)，7.18-6.96(m，7H)，6.79-6.71(m，2H)，6.40-6.31(m，4H)，2.29(s，6H)，2.28(s，3H)，2.27(s，3H)。

Embodiment 43

1-(3, the 5-3,5-dimethylphenyl)-3-[1-(2,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 143)

[0241] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)11.77(s，1H)，11.44(s，1H)，10.73(s，1H)，10.26(s，1H)，7.73(d，J＝8.8，1H)，7.51(m，1H)，7.09-7.01(m，5H)，6.82(m，1H)，6.38(dd，J＝8.8，2.3，1H)，6.34(d，J＝2.3，1H)，2.47(s，3H)，2.35(s，6H)。

Embodiment 44

1-(3, the 5-3,5-dimethylphenyl)-3-[1-(4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 144)

[0242] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)11.45(s，1H)，10.76(s，1H)，10.22(s，1H)，7.81(d，J＝8.8，2H)，7.51(m，1H)，7.09-6.97(m，5H)，6.88(d，J＝8.8，2H)，6.82(m，1H)，2.48(s，3H)，2.35(s，6H)。

Embodiment 45

1-(3, the 5-3,5-dimethylphenyl)-3-[(2,4-dihydroxy-benzene formyl radical diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 145)

[0243] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)11.98(m，2H)，11.02(s，2H)，10.28(s，1H)，10.26(s，1H)，9.65(d，J＝11.6，1H)，8.12(s，1H)，7.80(m，1H)，7.77-7.70(m，2H)，7.56-7.50(m，2H)，7.42(d，J＝11.6，1H)，7.08-6.96(m，10H)，6.83-6.72(m，2H)，6.40-6.31(m，4H)，2.35(s，6H)，2.33(s，6H)。

Embodiment 46

1-(3, the 5-3,5-dimethylphenyl)-3-[(4-hydroxy benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 146)

[0244] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)11.00(s，2H)，10.20(s，1H)，10.19(s，1H)，9.65(m，1H)，8.10(s，1H)，7.84-7.74(m，5H)，7.54(m，1H)，7.40(d，J＝10.3，1H)，7.10-6.95(m，10H)，6.91-6.84(m，4H)，6.78(m，1H)，3.18(s，1H)，3.16(s，1H)，2.35(s，6H)，2.33(s，6H)。

Embodiment 47

3-(3-[1-(3,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-6-chloro-2,3-indoline-1-yl) phenylformic acid (compound 147)

[0245] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.55(s，1H)，8.02(dt，J＝7.6，1.5，1H)，7.98(t，J＝1.5，1H)，7.78-7.65(m，4H)，7.53(d，J＝8.2，1H)，7.30(d，J＝8.2，1H)，7.10(dd，J＝8.2，2.0，1H)，6.84(d，J＝2.0，1H)，2.52(s，3H)，2.30(s，6H)。

Embodiment 48

1-(3, the 4-3,5-dimethylphenyl)-3-[(4-hydroxy benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 148)

[0246] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)10.99(s，2H)，10.19(s，1H)，10.18(s，1H)，9.64(d，J＝12.0，1H)，8.09(s，1H)，7.83-7.74(m，5H)，7.54(m，1H)，7.40(m，1H)，7.31(d，J＝8.0，1H)，7.29(d，J＝8.0，1H)，7.23(m，1H)，7.18-7.14(m，2H)，7.10(dd，J＝8.0，2.0，1H)，7.07-7.02(m，2H)，7.00-6.97(m，3H)，6.89-6.84(m，4H)，6.77(m，1H)，6.73(m，1H)，2.30(s，3H)，2.29(s，3H)，2.28(s，3H)，2.27(s，3H)。

Embodiment 49

1-(3, the 4-3,5-dimethylphenyl)-3-[(3,5-di-isopropyl-2-hydroxy benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline (compound 149)

[0247] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)12.29(s，1H)，12.22(s，1H)，11.52(s，2H)，9.71(d，J＝10.6，1H)，8.14(s，1H)，7.82(m，1H)，7.68-7.58(m，2H)，7.54-7.48(m，2H)，7.34-7.23(m，5H)，7.19-7.16(m，2H)，7.13-6.96(m，5H)，6.78(m，1H)，6.74(m，1H)，3.27(m，2H)，2.86(m，2H)，2.31(s，3H)，2.30(s，3H)，2.29(s，3H)，2.28(s，3H)，1.23(d，J＝6.8，6H)，1.23(d，J＝6.8，6H)，1.20(d，J＝6.8，6H)，1.20(d，J＝6.8，6H)。

Embodiment 50

1-(3, the 5-3,5-dimethylphenyl)-3-[1-(3,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 150)

[0248] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.47(s，1H)，7.51(m，1H)，7.35(d，J＝1.5，1H)，7.30(dd，J＝8.3，1.5，1H)，7.10-7.01(m，5H)，6.86-6.80(m，2H)，2.47(s，3H)，2.35(s，6H)。

Embodiment 51

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3,4-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 151)

[0249] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.47(br?s，1H)，10.68(br?s，1H)，9.70(br?s，1H)，9.31(br?s，1H)，7.50(m，1H)，7.36-7.27(m，3H)，7.21(s，1H)，7.14(m，1H)，7.06-6.99(m，2H)，6.83(m，1H)，6.79(m，1H)，2.47(s，3H)，2.30(s，3H)，2.29(s，3H)。

Embodiment 52

3-(6-chloro-3-[(2-hydroxyl-3,5-di-isopropyl benzoyl diazanyl) methylene radical]-2-oxo-2,3-indoline-1-yl) phenylformic acid (compound 152)

[0250] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.22(s，2H)，12.25(s，1H)，12.16(s，1H)，11.58(s，2H)，8.32-8.25(m，2H)，8.06-7.94(m，5H)，7.81-7.55(m，9H)，7.33-7.24(m，2H)，7.20-7.04(m，2H)，6.83(d，J＝1.6，1H)，6.79(d，J＝1.6，1H)，3.26(m，2H)，2.86(m，2H)，1.23(d，J＝6.3，6H)，1.22(d，J＝6.3，6H)，1.20(d，J＝6.8，6H)，1.19(d，J＝6.8，6H)。

Embodiment 53

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(2,5-dihydroxy-benzene formyl radical diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 153)

[0251] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.49(s，1H)，10.77(s，1H)，10.72(s，1H)，9.14(s，1H)，7.51(m，1H)，7.32(d，J＝8.0，1H)，7.23(d，J＝3.0，1H)，7.21(d，J＝2.0，1H)，7.14(dd，J＝8.0，2.0，1H)，7.06-7.00(m，2H)，6.89(dd，J＝8.8，3.0，1H)，6.83(d，J＝8.8，1H)，6.79(m，1H)，2.48(s，3H)，2.30(s，3H)，2.29(s，3H)。

Embodiment 54

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3-nitro-4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 154)

[0252] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.30(s，1H)，9.84(s，1H)，8.36(d，J＝2.3，1H)，7.98(dd，J＝8.7，2.3，1H)，7.42(ddd，J＝7.7，1.2，0.5，1H)，7.29(d，J＝7.9，1H)，7.16(d，J＝8.7，1H)，7.16(d，J＝2.1，1H)，7.10(dd，J＝7.9，2.1，1H)，6.96(td，J＝7.7，1.2，1H)，6.90(td，J＝7.7，1.2，1H)，6.76(ddd，J＝7.7，1.2，0.5，1H)，5.05(br?s，1H)，2.60(s，3H)，2.29(s，3H)，2.28(s，3H)。

Embodiment 55

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3-amino-sulfonyl-4-chlorobenzene formacyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 155)

[0253] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.48(s，1H)，11.29(s，1H)，8.52(d，J＝2.2，1H)，8.13(dd，J＝8.3，2.2，1H)，7.86(d，J＝8.3，1H)，7.79(s，2H)，7.52(m，1H)，7.32(d，J＝8.0，1H)，7.22(d，J＝2.2，1H)，7.15(dd，J＝8.0，2.2，1H)，7.07-7.01(m，2H)，6.79(m，1H)，2.50(m，3H)，2.30(s，3H)，2.29(s，3H)。

Embodiment 56

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(3-amino-4-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 156)

[0254] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)7.54-7.42(m，3H)，7.31(m，1H)，7.17(s，1H)，7.11(m，1H)，7.08-7.00(m，2H)，6.88(br?s，1H)，6.78(m，1H)，4.61(br?s，1H)，3.91(s，2H)，2.53(s，3H)，2.34(s，3H)，2.33(s，3H)。

Embodiment 57

1-(3, the 4-3,5-dimethylphenyl)-3-[1-(4-methoxyl group-2-hydroxy benzoyl diazanyl) ethylidene]-2-oxo-2,3-indoline (compound 157)

[0255] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.91(s，1H)，11.44(s，1H)，10.83(s，1H)，7.83(d，J＝8.8，1H)，7.51(m，1H)，7.32(d，J＝8.0，1H)，7.21(d，J＝1.9，1H)，7.14(dd，J＝8.0，1.9，1H)，7.06-7.00(m，2H)，6.79(m，1H)，6.57(dd，J＝8.8，2.4，1H)，6.51(d，J＝2.4，1H)，3.80(s，3H)，2.48(s，3H)，2.30(s，3H)，2.29(s，3H)。

Embodiment 58

3-{3-(1-(3, the 5-3,5-dimethylphenyl)-2-oxo-2, the inferior indyl of 3-dihydro-3-) methylamino-2-hydroxy phenyl } phenylformic acid (compound 158)

[0256] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.16(d，J＝13.0，1H)，9.26(s，1H)，8.84(d，J＝13.0，1H)，8.12(t，J＝1.7，1H)，7.94(ddd，J＝7.7，1.7，1.2，1H)，7.81-7.72(m，3H)，7.60(t，J＝7.7，1H)，7.13-7.05(m，6H)，7.01(dd，J＝7.7，1.5，1H)，6.85(m，1H)，2.35(s，6H)。

Embodiment 59

3-{3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene)-and 2-oxo-2,3-dihydro-1-indyl } phenylformic acid (compound 159)

[0257] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.20(d，J＝13.1，1H)，9.17(br?s，1H)，8.95(d，J＝13.1，1H)，8.02(s，1H)，7.97(d，J＝7.7，1H)，7.76-1.66(m，4H)，7.14(s，2H)，7.07(t，J＝7.7，1H)，7.00(s，1H)，6.97(d，J＝7.7，1H)，6.90-6.86(m，2H)，2.32(s，6H)。

Embodiment 60

3-{3-(1-(3, the 4-3,5-dimethylphenyl)-2-oxo-2, the inferior indyl of 3-dihydro-3-) methylamino-2-hydroxy phenyl } phenylformic acid (compound 160)

[0258] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.03(s，1H)，11.14(d，J＝13.0，1H)，9.25(s，1H)，8.83(d，J＝13.0，1H)，8.11(t，J＝1.7，1H)，7.94(ddd，J＝7.7，1.7，1.1，1H)，7.80-7.75(m，2H)，7.73(dd，J＝7.8，1.5，1H)，7.59(t，J＝7.7，1H)，7.32(d，J＝8.0，1H)，7.25(d，J＝2.1，1H)，7.18(dd，J＝8.0，2.1，1H)，7.10(t，J＝7.8，1H)，7.07-7.03(m，2H)，7.00(dd，J＝7.8，1.5，1H)，6.81(m，1H)，2.30(s，3H)，2.30(s，3H)。

Embodiment 61

4-{1-(6-fluoro-2-oxo-2,3-dihydro-3-(2-(3, the 5-3,5-dimethylphenyl)-aminocarbonyl-phenyl) aminomethylene) indyl } butyric acid (compound 161)

[0259] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)12.11(s，1H)，12.00(d，J＝12.8，1H)，10.32(s，1H)，8.67(d，J＝12.8，1H)，7.84(d，J＝8.2，1H)，7.80(dd，J＝7.9，1.5，1H)，7.63(m，1H)，7.60(dd，J＝9.3，2.6，1H)，7.35(s，2H)，7.23(m，1H)，7.01(dd，J＝8.5，4.3，1H)，6.91(ddd，J＝9.5，8.5，2.6，1H)，6.79(s，1H)，3.77(t，J＝7.3，2H)，2.29(s，6H)，2.26(t，J＝7.3，2H)，1.80(qn，J＝7.3，3H)。

Embodiment 62

4-{1-(6-chloro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) indyl } butyric acid (compound 162)

[0260] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.25(d，J＝12.9，1H)，10.68(s，1H)，8.65(d，J＝12.9，1H)，8.05(s，1H)，7.60(d，J＝8.0，1H)，7.57(dd，J＝7.9，1.3，1H)，7.16(d，J＝1.8，1H)，7.11(m，2H)，7.02(dd，J＝7.9，7.7，1H)，7.02(m，1H)，7.00(dd，J＝8.0，1.8，1H)，6.94(dd，J＝7.7，1.3，1H)，3.94(t，J＝7.2，2H)，2.43(t，J＝7.2，2H)，2.35(m，6H)，2.01(qn，J＝7.2，2H)。

Embodiment 63

3-{1-(6-chloro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) indyl } phenylformic acid (compound 163)

[0261] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.25(s，1H)，11.17(d，J＝13.3，1H)，9.15(s，1H)，8.94(d，J＝13.3，1H)，8.03-7.99(m，2H)，7.80(m，1H)，7.80(d，J＝8.1，1H)，7.72(t，J＝7.8，1H)，7.70(d，J＝7.8，1H)，7.16(dd，J＝8.131.9，1H)，7.14(s，2H)，7.06(t，J＝7.8，1H)，7.00(s，1H)，6.97(dd，J＝7.8，1.2，1H)，6.88(d，J＝1.9，1H)，2.32(s，6H)。

Embodiment 64

4-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) indyl } butyric acid (compound 164)

[0262] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.30(d，J＝12.8，1H)，10.69(s，1H)，8.69(d，J＝12.8，1H)，8.06(s，1H)，7.58(dd，J＝8.2，1.4，1H)，7.45(dd，J＝9.3，2.6，1H)，7.11(m，2H)，7.07-7.01(m，3H)，6.94(dd，J＝7.7，1.5，1H)，6.86(ddd，J＝9.7，8.2，2.6，1H)，3.92(t，J＝7.2，2H)，2.41(t，J＝7.2，2H)，2.35(m，6H)，2.00(qn，J＝7.2，2H)。

Embodiment 65

3-{3-(1-(1-(3, the 5-3,5-dimethylphenyl)-6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-3-) ethylamino)-2-hydroxy phenyl } phenylformic acid (compound 165)

[0263] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.86(s，1H)，8.31(t，J＝1.5，1H)，8.06(d，J＝7.8，1H)，7.77(d，J＝7.8，1H)，7.53(t，J＝7.8，1H)，7.46(d，J＝8.1，1H)，7.33(dq，J＝8.1，0.9，1H)，7.30(dd，J＝7.7，1.3，1H)，7.13(dd，J＝7.7，1.3，1H)，7.06(s，2H)，7.02(t，J＝7.7，1H)，6.99-6.97(m，2H)，2.42(s，3H)，2.37(s，6H)。

Embodiment 66

3-{3-(1-(1-(3, the 4-3,5-dimethylphenyl)-6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-3-) ethylamino)-2-hydroxy phenyl } phenylformic acid (compound 166)

[0264] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.91(s，1H)，8.32(br?s，1H)，8.06(d，J＝7.8，1H)，7.76(d，J＝7.8，1H)，7.54(t，J＝7.8，1H)，7.48(d，J＝8.1，1H)，7.35-7.28(m，3H)，7.18(s，1H)，7.16-7.10(m，2H)，7.08(s，1H)，7.04(t，J＝7.6，1H)，2.49(s，3H)，2.33(s，3H)，2.32(s，3H)。

Embodiment 67

3-{1-(6-trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl) hydrazono-) indyl } phenylformic acid (compound 167)

[0265] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，DMSO-d ₆)13.30(s，1H)，13.03(s，1H)，9.44(s，1H)，8.11(dd，J＝2.1，1.7，1H)，8.08(ddd，J＝7.8，1.7，1.2，1H)，7.99(d，J＝8.0，1H)，7.85(ddd，J＝7.8，2.1，1.2，1H)，7.77(t，J＝7.8，1H)，7.56(d，J＝2.5，1H)，7.54(dq，J＝8.0，0.8，1H)，7.04(m，1H)，6.92(d，J＝2.5，1H)，2.97(m，1H)，1.81-1.67(m，5H)，1.44-1.31(m，4H)，1.25(m，1H)。

Embodiment 68

3-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(1-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl) amino) ethylidene) indyl } phenylformic acid (compound 168)

[0266] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.93(s，1H)，8.00-7.97(m，2H)，7.72-7.66(m，2H)，7.34(dd，J＝10.1，1.8，1H)，7.23(d，J＝2.5，1H)，7.12(d，J＝2.5，1H)，6.91-6.84(m，2H)，2.95(m，1H)，2.49(s，3H)，1.82-1.67(m，5H)，1.43-1.32(m，4H)，1.29-1.20(m，1H)。

Embodiment 69

3-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl) aminomethylene) indyl } phenylformic acid (compound 169)

[0267] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)11.09(d，J＝13.2，1H)，9.38(br?s，1H)，8.91(d，J＝13.2，1H)，8.02(t，J＝1.8，1H)，7.99(ddd，J＝7.8，1.8，1.2，1H)，7.77(ddd，J＝7.8，1.8，1.2，1H)，7.70(t，J＝7.8，1H)，7.67(m，1H)，7.66(d，J＝2.3，1H)，6.90(d，J＝2.3，1H)，6.90-6.87(m，2H)，2.95(m，1H)，1.81-1.66(m，5H)，1.44-1.22(m，5H)。

Embodiment 70

4-{2-hydroxyl-3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } butyric acid (compound 170)

[0268] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.27(d，J＝13.6，1H)，9.01(d，J＝13.6，1H)，7.94(d，J＝8.1，1H)，7.60(d，J＝7.6，1H)，7.41(d，J＝8.1，1H)，7.12(s，1H)，7.10(s，2H)，6.94(t，J＝7.6，1H)，6.93(s，1H)，6.88(d，J＝7.6，1H)，2.65(t，J＝7.4，2H)，2.37(s，6H)，2.23(t，J＝7.4，2H)，1.77(qn，J＝7.4，2H)。

Embodiment 71

4-{2-hydroxyl-3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino phenyl } butyric acid (compound 171)

[0269] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO-d ₆)8.72(s，1H)，7.76(d，J＝7.6，1H)，7.44(m，1H)，7.38-7.30(m，2H)，7.22(d，J＝1.7，1H)，7.15(dd，J＝8.0，1.7，1H)，6.97-6.89(m，3H)，2.70(t，J＝7.2，2H)，2.36(s，6H)，2.33(t，J＝7.2，2H)，1.87(qn，J＝7.2，2H)。

Embodiment 72

3-{3-(7-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)-3-) methylamino) indyl } propionic acid (compound 172)

[0270] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)12.10(s，1H)，11.32(m，1H)，10.94(d，J＝12.8，1H)，8.92(d，J＝12.8，1H)，7.95(d，J＝7.8，1H)，7.43(d，J＝7.8，1H)，7.40(m，1H)，7.30(d，J＝7.8，1H)，7.19(d，J＝2.4，1H)，7.14(m，1H)，7.12(m，2H)，7.09(t，J＝7.8，1H)，6.94(m，1H)，2.94(t，J＝7.6，2H)，2.61(t，J＝7.6，2H)，2.37(s，6H)。

Embodiment 73

3-{3-(7-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)-3-) methylamino) indyl } propionic acid (compound 173)

[0271] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)12.09(s，1H)，11.33(d，J＝2.2，1H)，10.92(d，J＝12.8，1H)，8.91(d，J＝12.8，1H)，7.94(d，J＝8.0，1H)，7.43(d，J＝8.0，1H)，7.40(m，1H)，7.37(d，J＝8.0，1H)，7.30-7.28(m，2H)，7.22(dd，J＝8.0，2.0，1H)，7.19(d，J＝2.2，1H)，7.09(t，J＝8.0，1H)，6.92(d，J＝1.6，1H)，2.94(t，J＝7.7，2H)，2.60(t，J＝7.7，2H)，2.32(s，3H)，2.31(s，3H)。

Embodiment 74

4-{2-hydroxyl-3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } butyric acid (compound 174)

[0272] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)12.07(s，1H)，11.08(d，J＝13.0，1H)，8.77(d，J＝13.0，1H)，7.74(m，1H)，7.54(d，J＝7.8，1H)，7.10-7.02(m，5H)，6.91(m，1H)，6.85-6.81(m，2H)，2.64(m，2H)，2.36(s，6H)，2.23(m，2H)，1.77(m，2H)。

Embodiment 75

2-chloro-3-{3-hydroxyl-4-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 175)

[0273] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.48(br?s，1H)，11.06(d，J＝12.6，1H)，10.61(s，1H)，8.84(d，J＝12.6，1H)，7.85(s，1H)，7.78-7.73(m，3H)，7.41(d，J＝7.4，1H)，7.10-7.05(m，5H)，6.84(m，1H)，2.36(s，6H)。

Embodiment 76

2-chloro-3-{3-hydroxyl-4-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 176)

[0274] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.53(s，1H)，11.22(d，J＝13.2，1H)，10.72(s，1H)，9.08(d，J＝13.2，1H)，7.95(d，J＝7.8，1H)，7.87(s，1H)，7.81(d，J＝8.5，1H)，7.75(d，J＝1.8，1H)，7.44(m，1H)，7.43(dd，J＝8.5，1.8，1H)，7.36(d，J＝8.0，1H)，7.28(d，J＝2.1，1H)，7.21(dd，J＝8.0，2.1，1H)，6.92(m，1H)，2.32(s，3H)，2.31(s，3H)。

Embodiment 77

2-ethyl-3-{3-hydroxyl-4-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 177)

[0275] prepares this compound according to the described method of plan V III. ¹H NMR (500MHz, acetone-d ₆) 11.42 (d, J=12.9,1H), 9.53 (s, 1H), 8.93 (d, J=12.9,1H), 7.87 (d, J=8.1,1H), 7.73 (d, J=8.1,1H), 7.59 (s, 1H), 7.38 (m, 1H), 7.36 (d, J=8.1,1H), 7.32 (d, J=2.1,1H), 7.25 (dd, J=8.1,2.1,1H), 7.22 (d, J=1.7,1H), 7.11 (dd, J=8.1,1.7,1H), 7.06 (m, 1H), 2.59 (q, J=7.4,2H), 2.36 (s, 6H), 1.19 (t, J=7.4,3H).

Embodiment 78

2-ethyl-3-{3-hydroxyl-4-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 178)

[0276] prepares this compound according to the described method of plan V III. ¹H NMR (500MHz, acetone-d ₆) 11.42 (d, J=12.8,1H), 9.54 (s, 1H), 8.94 (d, J=12.8,1H), 7.87 (d, J=8.0,1H), 7.74 (d, J=8.5,1H), 7.59 (s, 1H), 7.38 (dq, J=8.0,0.9,1H), 7.22 (d, J=1.7,1H), 7.16 (m, 2H), 7.13 (m, 1H), 7.11 (dd, J=8.5,1.7,1H), 7.08 (s, 1H), 2.59 (q, J=7.4,2H), 2.40 (m, 6H), 1.19 (t, J=7.4,3H).

Embodiment 79

2-ethyl-3-{3-hydroxyl-4-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino phenyl } vinylformic acid (compound 179)

[0277] prepares this compound according to the described method of plan V III. ¹H NMR (500MHz, acetone-d ₆) 11.24 (d, J=12.3,1H), 9.40 (br s, 1H), 8.71 (d, J=12.3,1H), 7.70 (m, 1H), 7.67 (d, J=8.4,1H), 7.59 (s, 1H), 7.21 (d, J=1.8,1H), 7.14 (m, 2H), 7.11-7.02 (m, 4H), 6.90 (m, 1H), 2.60 (q, J=7.4,2H), 2.39 (s, 6H), 1.19 (t, J=7.4,3H).

Embodiment 80

4-{2-hydroxyl-3-(the inferior pyrazolyl of 4-(2-(3, the 4-3,5-dimethylphenyl)-3-oxo-3,4-dihydro-5-methyl)) methylamino phenyl } butyric acid (compound 180)

[0278] prepares this compound according to the described method of plan V III. ¹H NMR (500MHz, methyl alcohol-d ₄) 8.46 (s, 1H), 7.58 (s, 1H), 7.49 (d, J=8.3,1H), 7.43 (m, 1H), 7.14 (d, J=8.3,1H), 7.01-6.88 (m, 2H), 6.92 (t, J=7.3,1H), 2.70 (t, J=7.3,2H), 2.35 (t, J=7.3,2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.87 (qn, J=7.3,2H).

Embodiment 81

(Z)-and 4-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } butyric acid (compound 181)

[0279] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CDCl ₃)10.08(d，J＝12.8，1H)，7.30(dt，J＝12.8，0.8，1H)，7.06(s，3H)，7.03(dd，J＝7.8，1.8，1H)，6.95(t，J＝7.8，1H)，6.89(dd，J＝7.8，1.8，1H)，3.64(t，J＝6.8，2H)，3.35(d，J＝0.8，2H)，2.40(t，J＝7.4，2H)，2.37(s，6H)，1.97(m，2H)。

Embodiment 82

(E)-and 4-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } butyric acid (compound 182)

[0280] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，CDCl ₃)7.91(dt，J＝13.8，1.5，1H)，7.13(dd，J＝7.8，1.6，1H)，7.06(s，1H)，7.04(s，2H)，6.99(t，J＝7.8，1H)，6.90(dd，J＝7.8，1.6，1H)，6.81(d，J＝13.8，1H)，3.64(t，J＝6.7，2H)，3.23(d，J＝1.5，2H)，2.39(t，J＝7.3，2H)，2.38(s，6H)，1.96(m，2H)。

Embodiment 83

(Z)-and 3-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } phenylformic acid (compound 183)

[0281] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, acetone-d ₆) 10.28 (d, J=12.8,1H), 8.15 (m, 1H), 8.04 (ddd, J=7.9,1.7,1.2,1H), 7.90 (s, 1H), 7.82 (dt, J=12.8,1.1,1H), 7.72 (ddd, J=7.9,2.1,1.2,1H), 7.63 (t, J=7.9,1H), 7.34 (dd, J=7.8,1.5,1H), 7.08 (m, 2H), 7.00 (m, 1H), 6.98 (t, J=7.8,1H), 6.86 (dd, J=7.8,1.5,1H), 3.54 (d, J=1.1,2H), 2.33 (s, 3H), 2.33 (s, 3H).

Embodiment 84

(E)-and 3-{1-(2,5-dioxy-3-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) aminomethylene) pyrrolidyl } phenylformic acid (compound 184)

[0282] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, acetone-d ₆) 8.12 (m, 1H), 8.04 (dt, J=7.8,1.5,1H), 7.98 (dt, J=13.6,1.8,1H), 7.84 (d, J=13.6,1H), 7.69 (ddd, J=7.8,2.0,1.5,1H), 7.63 (t, J=7.8,1H), 7.33 (dd, J=7.8,1.6,1H), 7.09 (m, 2H), 7.01 (t, J=7.8,1H), 7.01 (m, 1H), 6.92 (dd, J=7.8,1.6,1H), 3.57 (d, J=1.8,2H), 2.34 (m, 6H).

Embodiment 85

4-{3-(4-oxo-2-sulfo--5-(3-(3, the 5-3,5-dimethylphenyl)-2-hydroxy phenyl) hydrazono-) thiazolidyl } butyric acid (compound 185)

[0283] prepares this compound according to the described method of scheme I. ¹H NMR (500MHz, methyl alcohol-d ₄) 8.51 (s, 1H), 7.13-7.09 (m, 2H), 7.02-6.89 (m, 3H), 4.21 (m, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 2.33 (m, 2H), 2.03 (m, 2H).

Embodiment 86

3-{2-(3-(1-(3, the 5-3,5-dimethylphenyl)-6-chloro-2-oxo-2,3-indolylidene) methylamino) phenyl amino } phenylformic acid (compound 186)

[0284] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)10.96(d，J＝13.0，1H)，8.90(d，J＝13.0，1H)，7.94(m，1H)，7.82(m，1H)，7.75(d，J＝8.2，1H)，7.34-7.28(m，2H)，7.27-7.24(m，2H)，7.24(t，J＝7.8，1H)，7.13(td，J＝7.6，1.2，1H)，7.10(dd，J＝8.2，2.0，1H)，7.07(m，1H)，6.97(m，2H)，6.93(m，1H)，6.68(d，J＝2.0，1H)，2.32(s，6H)。

Embodiment 87

3-{2-(3-(1-(3, the 5-3,5-dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-indolylidene) methylamino) phenyl amino } phenylformic acid (compound 187)

[0285] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.13(d，J＝13.2，1H)，9.07(d，J＝13.2，1H)，7.99(s，1H)，7.95(d，J＝8.0，1H)，7.88(m，1H)，7.42(dd，J＝8.0，1.0，1H)，7.34(td，J＝7.5，1.1，1H)，7.32-7.26(m，3H)，7.25(t，J＝7.6，1H)，7.17(td，J＝7.5，1.1，1H)，7.10(m，1H)，7.00(m，2H)，6.95(m，1H)，6.86(d，J＝1.0，1H)，2.33(s，6H)。

Embodiment 88

3-{2-(4-(2-(3, the 5-3,5-dimethylphenyl)-5-methyl-3-oxo-3, the inferior pyrazolyl of 4-dihydro) methylamino) phenyl amino } phenylformic acid (compound 188)

[0286] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.50(d，J＝12.0，1H)，8.66(d，J＝12.0，1H)，8.08(s，1H)，7.86(m，1H)，7.67(d，J＝2.0，1H)，7.62(dd，J＝8.3，2.0，1H)，7.38-7.33(m，2H)，7.32-7.29(m，2H)，7.30(t，J＝7.7，1H)，7.23(td，J＝7.6，1.3，1H)，7.10(d，J＝8.3，1H)，7.02(m，1H)，2.28(s，3H)，2.21(s，3H)，2.18(s，3H)。

Embodiment 89

(±)-3-methyl-5-{2-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) phenyl } valeric acid (compound 189)

[0287] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.29(d，J＝13.4，1H)，9.01(d，J＝13.4，1H)，7.94(d，J＝8.0，1H)，7.58(dd，J＝8.0，1.5，1H)，7.41(dq，J＝8.0，0.7，1H)，7.13(m，1H)，7.10(m，2H)，6.95-6.91(m，2H)，6.89(dd，J＝7.7，1.5，1H)，2.71-2.58(m，2H)，2.37(s，6H)，2.31(dd，J＝15.0，5.5，1H)，2.04(dd，J＝15.0，8.5，1H)，1.87(m，1H)，1.56(m，1H)，1.42(m，1H)，0.95(d，J＝6.6，3H)。

Embodiment 90

(±)-3-{1-(6-chloro-2-oxo-2,3-dihydro-3-(3-(1-(3, the 5-3,5-dimethylphenyl)-2-oxo-2,3-dihydro) indyl) aminomethylene) indyl } phenylformic acid (compound 190)

[0288] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.20(s，1H)，7.93(ddd，J＝7.8，1.6，1.1，1H)，7.73(m，1H)，7.58(t，J＝7.8，1H)，7.35(m，1H)，7.30(dd，J＝7.8，1.8，1H)，7.23(td，J＝7.7，1.2，1H)，7.14-7.08(m，4H)，7.00(s，2H)，6.89(t，J＝7.7，1H)，6.67(d，J＝7.8，1H)，6.63(d，J＝2.0，1H)，6.31(m，1H)，2.33(s，6H)。

Embodiment 91

3-{4-(3-hydroxyl-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3, the 5-3,5-dimethylphenyl) indyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 191)

[0289] prepares this compound according to the described method of scheme IX. ¹H?NMR(300MHz，DMSO-d ₆)8.52(s，1H)，8.16(m，1H)，7.98(m，1H)，7.96(m，1H)，7.60-7.52(m，2H)，7.59(t，J＝7.8，1H)，7.20-7.16(m，3H)，6.98(s，1H)，2.50(s，3H)，2.37(s，6H)。

Embodiment 92

3-{4-(3-hydroxyl-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) pyridine alkyl } phenylformic acid (compound 192)

[0290] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)9.06(s，1H)，8.55(s，1H)，8.20(m，1H)，7.99(d，J＝7.8，1H)，7.93(d，J＝7.8，1H)，7.61(s，1H)，7.56(t，J＝7.8，1H)，7.48(d，J＝7.8，1H)，7.13(m，1H)，7.11(m，2H)，6.94(m，1H)，2.50(s，3H)，2.37(s，6H)。

Embodiment 93

3-{4-(3-hydroxyl-2-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) pyridine alkyl } phenylformic acid (compound 193)

[0291] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)9.13(d，J＝12.9，1H)，8.52(s，1H)，8.24(m，1H)，8.17(m，1H)，8.03-7.99(m，2H)，7.84(m，1H)，7.65(t，J＝7.7，1H)，7.50(dq，J＝7.9，0.6，1H)，7.14(m，1H)，7.12(m，2H)，6.95(q，J＝0.851H)，2.37(s，6H)。

Embodiment 94

3-{4-(3-hydroxyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3, the 5-3,5-dimethylphenyl) indyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 194)

[0292] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO-d ₆)13.22(s，1H)，8.50(s，1H)，8.21(m，1H)，8.16(d，J＝7.7，1H)，8.04(d，J＝7.8，1H)，8.01(d，J＝7.7，1H)，7.80(d，J＝5.4，1H)，7.68(t，J＝7.7，1H)，7.60(dq，J＝7.8，0.7，1H)，7.19(m，1H)，7.17(m，2H)，6.98(m，1H)，2.37(s，3H)，2.37(s，3H)。

Embodiment 95

3-{5-(4-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) pyridine alkyl } phenylformic acid (compound 195)

[0293] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.10(d，J＝13.8，1H)，8.95(d，J＝13.8，1H)，8.39(t，J＝1.7，1H)，8.35(d，J＝1.3，1H)，8.10(d，J＝1.3，1H)，7.98(ddd，J＝7.7，1.7，1.2，1H)，7.88(ddd，J＝7.7，1.7，1.2，1H)，7.86(d，J＝7.9，1H)，7.53(t，J＝7.7，1H)，7.43(dq，J＝7.9，0.9，1H)，7.12(m，1H)，7.10(m，2H)，6.94(m，1H)，2.37(s，6H)。

Embodiment 96

3-{5-(4-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3, the 5-3,5-dimethylphenyl) indyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 196)

[0294] prepares this compound according to the described method of scheme IX. ¹H?NMR(300MHz，DMSO-d ₆)12.91(s，1H)，8.39(t，J＝1.7，1H)，8.17(d，J＝1.4，1H)，8.06(d，J＝1.4，1H)，7.99(m，1H)，7.94-7.86(m，2H)，7.53(m，1H)，7.53(t，J＝7.7，1H)，7.18-7.15(m，3H)，6.97(m，1H)，2.37(s，6H)。

Embodiment 97

3-{5-(4-hydroxyl-3-(4-(3-oxo-3,4-dihydro-5-methyl-2-(3, the 4-3,5-dimethylphenyl) pyrazolyl) hydrazono-) pyridine alkyl } phenylformic acid (compound 197)

[0295] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO-d ₆)13.43(s，1H)，12.99(s，1H)，12.33(s，1H)，8.40(t，J＝1.6，1H)，8.16(s，1H)，8.10(s，1H)，7.99(m，1H)，7.91(m，1H)，7.71(m，1H)，7.63(dd，J＝8.1，1.9，1H)，7.55(t，J＝7.7，1H)，7.21(d，J＝8.1，1H)，2.31(s，3H)，2.27(s，3H)，2.23(s，3H)。

Embodiment 98

4-{2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3, the 4-3,5-dimethylphenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 198)

[0296] prepares this compound according to the described method of scheme I. ¹H?NMR(300MHz，CDCl ₃)13.45(s，1H)，7.58(s，1H)，7.47-7.31(m，4H)，7.26(s，1H)，7.22(d，J＝7.7，1H)，3.84(t，J＝6.8，2H)，2.42(t，J＝6.8，2H)，2.34(s，3H)，2.07(qn，J＝6.8，2H)，2.31(s，3H)，2.27(s，3H)。

Embodiment 99

3-{2-amino-5-methyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino) phenyl } phenylformic acid (compound 199)

[0297] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)10.91(d，J＝13.1，1H)，8.94(d，J＝13.1，1H)，7.98-7.93(m，3H)，7.65(m，1H)，7.62(t，J＝7.6，1H)，7.43-7.40(m，2H)，7.12(m，1H)，7.09(m，2H)，6.93(d，J＝1.4，1H)，6.81(m，1H)，4.38(br?s，2H)，2.36(s，6H)，2.33(s，3H)。

Embodiment 100

3-{1-(5-fluoro-2-oxo-2,3-dihydro-3-(3-(3, the 4-3,5-dimethylphenyl) phenyl) aminomethylene) indyl } phenylformic acid (compound 200)

[0298] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.23(s，1H)，10.85(d，J＝12.8，1H)，8.96(d，J＝12.8，1H)，8.06(m，1H)，7.99(m，1H)，7.82-7.78(m，2H)，7.74-7.69(m，2H)，7.56(s，1H)，7.51-7.39(m，4H)，7.26(d，J＝7.8，1H)，6.94-6.86(m，2H)，2.32(s，3H)，2.28(s，3H)。

Embodiment 101

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(3-(3, the 4-3,5-dimethylphenyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 201)

[0299] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, methyl alcohol-d ₄) 8.52 (s, 1H), 7.63 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.30 (m, 2H), 7.23-7.09 (m, 2H), 3.80 (t, J=6.8,2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.28 (m, 2H), 2.26 (s, 3H), 2.01 (qn, J=6.8,2H).

Embodiment 102

(3-(5-fluoro-2-hydroxyl-3-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino)-1-pyrazolyl) acetate (compound 202)

[0300] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.26(s，1H)，11.35(s，1H)，11.26(d，J＝13.0，1H)，9.06(d，J＝13.0，1H)，7.97(d，J＝2.4，1H)，7.93(d，J＝7.9，1H)，7.71(dd，J＝10.3，2.8，1H)，7.46(dq，J＝7.9，0.9，1H)，7.42(dd，J＝9.5，2.8，1H)，7.36(d，J＝8.0，1H)，7.29(d，J＝2.1，1H)，7.22(dd，J＝8.0，2.1，1H)，7.03(d，J＝2.4，1H)，6.94(m，1H)，5.15(s，2H)，2.32(s，3H)，2.31(s，3H)。

Embodiment 103

(3-(5-fluoro-2-hydroxyl-3-(3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino)-1-pyrazolyl) acetate (compound 203)

[0301] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)13.26(s，1H)，11.30(s，1H)，11.13(d，J＝12.7，1H)，8.83(d，J＝12.7，1H)，7.96(d，J＝2.4，1H)，7.75(m，1H)，7.66(dd，J＝10.4，2.8，1H)，7.35(dd，J＝9.6，2.8，1H)，7.11-7.07(m，5H)，7.01(d，J＝2.4，1H)，6.87(m，1H)，5.14(s，2H)，2.36(s，6H)。

Embodiment 104

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 204)

[0302] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, methyl alcohol-d ₄) 8.47 (s, 1H), 7.42 (m, 1H), 7.28-7.14 (m, 5H), 6.94-6.85 (m, 2H), 3.81 (t, J=6.7,2H), 3.02-2.84 (m, 4H), 2.32 (t, J=7.6,2H), 2.26 (s, 3H), 2.00 (m, 2H).

Embodiment 105

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 205)

[0303] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.54 (m, 1H), 7.28-7.12 (m, 5H), 6.92-6.84 (m, 2H), 3.79 (t, J=6.8,2H), 3.00-2.84 (m, 4H), 2.34 (t, J=7.4,2H), 2.26 (s, 3H), 2.01 (m, 2H).

Embodiment 106

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(4-methyl) phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 206)

[0304] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.53 (m, 1H), 7.11-7.03 (m, 4H), 6.91-6.86 (m, 2H), 3.79 (t, J=6.6,2H), 2.93 (m, 2H), 2.85 (m, 2H), 2.34 (t, J=7.3,2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H).

Embodiment 107

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3-methyl) phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 207)

[0305] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.53 (m, 1H), 7.12 (m, 1H), 7.04-6.87 (m, 5H), 3.79 (t, J=6.6,2H), 2.98-2.82 (m, 4H), 2.34 (t, J=7.3,2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H).

Embodiment 108

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-methyl) phenyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 208)

[0306] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.54 (m, 1H), 7.16-7.04 (m, 4H), 6.93-6.84 (m, 2H), 3.80 (t, J=6.7,2H), 2.90 (m, 4H), 2.34 (t, J=7.3,2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H).

Embodiment 109

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(1-naphthyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 209)

[0307] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 8.17 (d, J=7.9,1H), 7.86 (d, J=7.9,1H), 7.71 (d, J=7.9,1H), 7.57-7.43 (m, 3H), 7.36 (m, 1H), 7.31 (m, 1H), 6.91-6.86 (m, 2H), 3.80 (t, J=6.6,2H), 3.37 (dd, J=9.2,6.5,2H), 3.09 (dd, J=9.2,6.5,2H), 2.35 (t, J=7.3,2H), 2.27 (s, 3H), 2.02 (m, 2H).

Embodiment 110

3-{1-(5-nitro-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl) aminomethylene) indyl } phenylformic acid (compound 210)

[0308] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.28(s，1H)，11.26(d，J＝13.4，1H)，9.29(d，J＝13.4，1H)，9.26(s，1H)，8.82(d，J＝2.4，1H)，8.06-8.03(m，2H)，8.02(dd，J＝8.8，2.4，1H)，7.82(ddd，J＝8.1，2.1，1.3，1H)，7.79(m，1H)，7.75(t，J＝8.1，1H)，7.14(m，2H)，7.09(t，J＝7.7，1H)，7.06(d，J＝8.8，1H)，7.01(dd，J＝7.7，1.5，1H)，7.01(m，1H)，2.33(s，6H)。

Embodiment 111

3-{1-(5-nitro-2-oxo-2,3-dihydro-3-(5-fluoro-2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl) aminomethylene) indyl } phenylformic acid (compound 211)

[0309] prepares this compound according to the described method of scheme III. ¹H NMR (300MHz, acetone-d ₆) 11.43 (d, J=13.3,1H), 9.15 (d, J=13.3,1H), 8.67 (d, J=2.3,1H), 8.24 (t, J=1.7,1H), 8.15 (m, 1H), 8.08 (dd, J=8.8,2.3,1H), 7.88 (m, 1H), 7.78 (t, J=7.8,1H), 7.66 (dd, J=10.0,2.9,1H), 7.14 (m, 2H), 7.14 (d, J=8.8,1H), 7.04 (m, 1H), 6.78 (dd, J=9.2,2.9,1H), 2.34 (s, 6H).

Embodiment 112

2-hydroxyl-3-{3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino } phenylformic acid (compound 212)

[0310] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.02(d，J＝12.8，1H)，8.84(d，J＝12.8，1H)，7.96(dd，J＝8.1，1.5，1H)，7.74(m，1H)，7.52(dd，J＝8.1，1.5，1H)，7.10-7.06(m，5H)，7.04(t，J＝8.1，1H)，6.85(m，1H)，2.36(s，3H)，2.36(s，3H)。

Embodiment 113

2-hydroxyl-3-{3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)) methylamino } phenylformic acid (compound 213)

[0311] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)11.18(d，J＝12.9，1H)，9.07(d，J＝12.9，1H)，8.00(dd，J＝8.0，1.4，1H)，7.93(d，J＝7.8，1H)，7.57(dd，J＝8.0，1.4，1H)，7.44(dq，J＝7.8，0.9，1H)，7.36(d，J＝8.1，1H)，7.28(d，J＝2.1，1H)，7.21(dd，J＝8.1，2.1，1H)，7.06(t，J＝8.0，1H)，6.92(m，1H)，2.32(s，3H)，2.31(s，3H)。

Embodiment 114

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(3-methyl-1-butene base) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 214)

[0312] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, methyl alcohol-d ₄) 8.49 (s, 1H), 7.49 (d, J=7.6,1H), 7.02-6.90 (m, 2H), 6.30 (d, J=11.1,1H), 5.65 (dd, J=11.1,10.3,1H), 3.80 (t, J=6.7,2H), 2.66 (m, 1H), 2.31 (t, J=7.5,2H), 2.27 (s, 3H), 2.00 (m, 2H), 1.01 (d, J=6.7,6H).

Embodiment 115

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-heptyl phenyl) hydrazono-) pyrazolyl } butyric acid (compound 215)

[0313] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.53 (dd, J=7.6,1.5,1H), 6.97 (dd, J=7.6,1.5,1H), 6.91 (t, J=7.6,1H), 3.79 (t, J=6.7,2H), 2.65 (t, J=7.7,2H), 2.34 (t, J=7.3,2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.60 (m, 2H), 1.42-1.27 (m, 8H), 0.90 (t, J=6.8,3H).

Embodiment 116

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(4-methyl) phenyl) ethenylphenyl) hydrazono-) pyrazolyl } butyric acid (compound 216)

[0314] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.60 (d, J=7.9,1H), 7.50-7.41 (m, 4H), 7.21-7.08 (m, 3H), 7.01 (t, J=7.9,1H), 3.79 (t, J=6.6,2H), 2.34 (s, 3H), 2.34 (t, J=7.3,2H), 2.27 (s, 3H), 2.01 (m, 2H).

Embodiment 117

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(3-methyl) phenyl) ethenylphenyl) hydrazono-) pyrazolyl } butyric acid (compound 217)

[0315] prepares this compound according to the described method of plan V II. ¹H NMR (300MHz, methyl alcohol-d ₄) 7.59 (d, J=7.8,1H), 7.09-6.95 (m, 4H), 6.88 (d, J=7.8,1H), 6.79 (t, J=7.8,1H), 6.73 (d, J=12.2,1H), 6.59 (d, J=12.2,1H), 3.79 (t, J=6.7,2H), 2.34 (t, J=7.3,2H), 2.27 (s, 3H), 2.20 (s, 3H), 2.01 (m, 2H).

Embodiment 118

4-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-methyl) phenyl) ethylphenyl) hydrazono-) indyl } butyric acid (compound 218)

[0316] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO-d ₆)13.04(s，1H)，9.13(br?s，1H)，7.61(dd，J＝7.7，0.7，1H)，7.51(dd，J＝7.7，1.6，1H)，7.33(td，J＝7.7，1.2，1H)，7.23(m，1H)，7.20(d，J＝7.7，1H)，7.16-7.07(m，4H)，6.91(t，J＝7.7，1H)，6.83(dd，J＝7.7，1.5，1H)，3.84(t，J＝7.1，2H)，2.89-2.79(m，4H)，2.32(t，J＝7.1，2H)，2.29(s，3H)，1.88(qn，J＝7.1，2H)。

Embodiment 119

2-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl) hydrazono-) indyl } acetate (compound 219)

[0317] prepares this compound according to the described method of scheme II. ¹H NMR (500MHz, methyl alcohol-d ₄) 7.66 (dd, J=7.7,1.6,1H), 7.65 (m, 1H), 7.27 (td, J=7.7,1.1,1H), 7.14-7.10 (m, 3H), 7.01 (m, 1H), 6.99 (t, J=7.7,1H), 6.95 (d, J=7.7,1H), 6.89 (dd, J=7.7,1.6,1H), 4.55 (s, 2H), 2.36 (s, 6H).

Embodiment 120

2-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-methyl) phenyl) ethylphenyl) hydrazono-) indyl } acetate (compound 220)

[0318] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO-d ₆)12.95(s，1H)，9.16(s，1H)，7.62(dd，J＝7.6，1.0，1H)，7.53(dd，J＝7.7，1.6，1H)，7.30(td，J＝7.6，1.2，1H)，7.23(m，1H)，7.16-7.07(m，5H)，6.91(t，J＝7.7，1H)，6.84(dd，J＝7.7，1.6，1H)，4.59(s，2H)，2.89-2.79(m，4H)，2.29(s，3H)。

Embodiment 121

4-{4-(2-(3-(6-trifluoromethyl-2-oxo-2, the inferior indyl of 3-dihydro-1-(3, the 4-3,5-dimethylphenyl)) methylamino) thiazolyl } phenylformic acid (compound 221)

[0319] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO-d ₆)12.99(s，2H)，11.83(d，J＝12.2，1H)，11.39(d，J＝12.2，1H)，8.95(d，J＝12.2，1H)，8.56(d，J＝12.2，1H)，8.32(d，J＝7.8，1H)，8.16(d，J＝8.5，2H)，8.08(d，J＝8.5，2H)，8.08(m，1H)，8.03(d，J＝8.5，2H)，8.02(d，J＝8.5，2H)，7.93(s，1H)，7.91(s，1H)，7.51(d，J＝7.8，1H)，7.44(dq，J＝7.8，0.9，1H)，7.37(d，J＝7.9，1H)，7.36(d，J＝7.9，1H)，7.30(d，J＝2.1，1H)，7.24(d，J＝2.1，1H)，7.23(dd，J＝7.9，2.1，1H)，7.18(dd，J＝7.9，2.1，1H)，6.91(m，1H)，6.85(m，1H)，2.32(s，3H)，2.31(s，3H)，2.31(s，3H)，2.30(s，3H)。

Embodiment 122

3-{1-(5-nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl base-3-(1-diamantane) phenyl) aminomethylene) indyl } phenylformic acid (compound 222)

[0320] prepares this compound according to the described method of scheme III. ¹H?NMR(500MHz，DMSO-d ₆)13.28(s，1H)，11.22(d，J＝13.7，1H)，9.19(d，J＝13.7，1H)，8.81(d，J＝2.4，1H)，8.40(s，1H)，8.09-8.04(m，2H)，8.01(dd，J＝8.8，2.4，1H)，7.83-7.73(m，2H)，7.50(d，J＝1.5，1H)，7.07(d，J＝8.8，1H)，6.79(d，J＝1.5，1H)，2.33(s，3H)，2.09-2.06(m，6H)，2.05-2.02(m，3H)，1.75-1.72(m，6H)。

Embodiment 123

3-{1-(6-trifluoromethyl-2-oxo-2,3-dihydro-3-(4-hydroxyl-5-(3, the 4-3,5-dimethylphenyl) pyridine alkyl) hydrazono-) indyl } phenylformic acid (compound 223)

[0321] prepares this compound according to the described method of scheme I. ¹H NMR (500MHz, methyl alcohol-d ₄) 8.25 (s, 1H), 8.11 (dt, J=7.7,1.6,1H), 8.07 (t, J=1.6,1H), 7.90 (d, J=7.8,1H), 7.82 (m, 1H), 7.66 (t, J=7.7,1H), 7.62 (m, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.34 (m, 1H), 7.17 (d, J=7.8,1H), 7.08 (br s, 1H), 2.30 (s, 3H), 2.28 (s, 3H).

Embodiment 124

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(2-methyl) phenyl)-ethylphenyl) aminomethylene) pyrazolyl } butyric acid (compound 224)

[0322] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, methyl alcohol-d ₄) 8.47 (s, 1H), 7.43 (m, 1H), 7.15-7.03 (m, 4H), 6.93-6.86 (m, 2H), 3.81 (t, J=6.8,2H), 2.90 (m, 4H), 2.32 (t, J=7.4,2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.00 (m, 2H).

Embodiment 125

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(2-fluorine) phenyl)-ethylphenyl) aminomethylene) pyrazolyl } butyric acid (compound 225)

[0323] prepares this compound according to the described method of plan V III. ¹H NMR (300MHz, methyl alcohol-d ₄) 8.47 (s, 1H), 7.43 (m, 1H), 7.23-7.14 (m, 2H), 7.07-6.97 (m, 2H), 6.90-6.85 (m, 2H), 3.81 (t, J=6.8,2H), 2.96 (m, 4H), 2.32 (t, J=7.3,2H), 2.26 (s, 3H), 2.00 (m, 2H).

Embodiment 126

[0324] 4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(1-naphthyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 226)

[0325] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)8.48(s，1H)，8.17(d，J＝8.6Hz，1H)，7.85(d，J＝7.4Hz，1H)，7.71(d，J＝7.4Hz，1H)，7.55-7.28(m，5H)，6.91-6.88(m，2H)，3.82(t，J＝6.7Hz，2H)，3.37(dd，J＝9.3，6.4Hz，2H)，3.10(dd，J＝9.3，6.4Hz，2H)，2.33(t，J＝7.5Hz，2H)，2.27(s，3H)，2.01(m，2H)。

Embodiment 127

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(3, the 5-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 227)

[0326] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.47(br?s，1H)，7.42(m，1H)，6.94-6.88(m，2H)，6.82-6.79(m，3H)，3.80(t，J＝6.7Hz，2H)，2.92(m，2H)，2.79(m，2H)，2.32(t，J＝7.5Hz，2H)，2.26(s，3H)，2.24(s，6H)，2.00(m，2H)。

Embodiment 128

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-p-methoxy-phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 228)

[0327] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.47(s，1H)，7.41(m，1H)，7.24-7.04(m，3H)，6.94-6.78(m，4H)，3.82(s，3H)，3.81(m，2H)，2.89(s，4H)，2.36-2.24(m，5H)，2.01(m，2H)。

Embodiment 129

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluoro-3-methyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 229)

[0328] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)7.47-7.30(m，1H)，7.07-6.85(m，6H)，3.82(m，2H)，2.98-2.88(m，4H)，2.30-2.20(m，8H)，2.00(m，2H)。

Embodiment 130

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluoro-3-methyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 230)

[0329] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.45(s，1H)，7.64(d，J＝7.6Hz，1H)，7.56-7.32(m，4H)，7.16(m，1H)，6.91(s，2H)，3.81(t，J＝6.5Hz，2H)，3.12-2.93(m，4H)，2.29(t，J＝7.4Hz，2H)，2.25(m，3H)，2.00(m，2H)。

Embodiment 131

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(4-phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 231)

[0330] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)7.59-7.56(m，3H)，7.51(d，J＝7.8Hz，2H)，7.46-7.37(m，4H)，7.33-7.26(m，4H)，6.95-6.91(m，2H)，3.81(t，J＝6.5Hz，2H)，3.04-2.92(m，4H)，2.32(t，J＝7.7Hz，2H)，2.27(s，3H)，2.02(m，2H)。

Embodiment 132

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-cyano-phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 232)

[0331] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.45(s，1H)，7.65(d，J＝7.5Hz，1H)，7.55(t，J＝7.5Hz，1H)，7.48-7.32(m，3H)，6.92-6.81(m，2H)，3.80(t，J＝6.7Hz，2H)，3.13(m，2H)，3.05(m，2H)，2.30(m，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 133

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-chloro-phenyl-)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 233)

[0332] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.47(s，1H)，7.43(m，1H)，7.35(m，1H)，7.24-7.14(m，3H)，6.93-6.85(m，2H)，3.81(t，J＝6.7Hz，2H)，3.08-2.94(m，4H)，2.32(t，J＝7.5Hz，2H)，2.26(s，3H)，2.00(m，2H)。

Embodiment 134

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 234)

[0333] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.48(s，1H)，7.45(m，1H)，6.98-6.87(m，5H)，3.81(t，J＝6.9Hz，2H)，2.93(m，2H)，2.83(m，2H)，2.32(t，J＝7.1Hz，2H)，2.29(s，6H)，2.27(s，3H)，2.00(m，2H)。

Embodiment 135

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-trifluoromethyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 235)

[0334] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO)8.81(s，1H)，8.66(dd，J＝2.2，1.5Hz，1H)，8.24(ddd，J＝8.2，2.2，1.1Hz，1H)，7.84(ddd，J＝7.7，1.5，1.1Hz，1H)，7.78(dd，J＝8.0，1.6Hz，1H)，7.70(m，1H)，7.66-7.59(m，3H)，7.44(m，1H)，7.03(dd，J＝7.7，1.6Hz，1H)，6.97(dd，J＝8.0，7.7Hz，1H)，3.05-2.93(m，4H)。

Embodiment 136

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluorophenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 236)

[0335] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO)9.84(s，1H)，8.79(s，1H)，8.65(dd，J＝2.2，1.6Hz，1H)，8.23(ddd，J＝8.2，2.2，1.1Hz，1H)，7.84(ddd，J＝7.8，1.6，1.1Hz，1H)，7.75(m，1H)，7.62(dd，J＝8.2，7.8Hz，1H)，7.33(m，1H)，7.25(m，1H)，7.18-7.09(m，2H)，7.01(dd，J＝7.8，1.5Hz，1H)，6.93(t，J＝7.8Hz，1H)，3.00-2.85(m，4H)。

Embodiment 137

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-methyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 237)

[0336] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO)9.80(s，1H)，8.80(m，1H)，8.65(dd，J＝2.2，1.5Hz，1H)，8.23(ddd，J＝8.2，2.2，1.1Hz，1H)，7.84(ddd，J＝7.8，1.5，1.1Hz，1H)，7.77(m，1H)，7.63(dd，J＝8.2，7.8Hz，1H)，7.22(m，1H)，7.17-7.05(m，4H)，6.96(t，J＝7.8Hz，1H)，2.90(m，2H)，2.82(m，2H)，2.29(s，3H)。

Embodiment 138

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2,5-dimethyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 238)

[0337] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.65(dd，J＝2.2，1.6Hz，1H)，8.60(s，1H)，8.23(ddd，J＝8.1，2.2，1.0Hz，1H)，7.92(ddd，J＝7.8，1.6，1.0Hz，1H)，7.56(dd，J＝8.1，7.8Hz，1H)，7.47(m，1H)，7.00-6.86(m，5H)，2.93(m，2H)，2.85(m，2H)，2.25(s，3H)，2.24(s，3H)。

Embodiment 139

3-{2-(5-trifluoromethyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2,6-dimethyl-phenyl) ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 239)

[0338] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.66(dd，J＝2.1，1.6Hz，1H)，8.60(s，1H)，8.25(ddd，J＝8.1，2.1，1.0Hz，1H)，7.92(ddd，J＝7.7，1.6，1.0Hz，1H)，7.57(dd，J＝8.1，7.7Hz，1H)，7.48(m，1H)，6.99-6.94(m，5H)，2.95(m，2H)，2.85(m，2H)，2.31(s，6H)。

Embodiment 140

3-{2-(5-phenyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 240)

[0339] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，DMSO)8.79(dd，J＝2.1，1.6Hz，1H)，8.69(br?s，1H)，8.36(ddd，J＝8.2，2.1，1.1Hz，1H)，7.94-7.89(m，2H)，7.78(ddd，J＝7.8，1.6，1.1Hz，1H)，7.67-7.51(m，5H)，7.08-7.00(m，3H)，6.96-6.88(m，2H)，2.87(m，2H)，2.77(m，2H)，2.25(s，6H)。

Embodiment 141

3-{2-(the 5-tertiary butyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 241)

[0340] prepares this compound according to the described method of plan V III. ¹H?NMR(300MHz，CD ₃OD)8.65(dd，J＝2.1，1.7Hz，1H)，8.58(s，1H)，8.25(m，1H)，7.83(m，1H)，7.50(t，J＝7.9Hz，1H)，7.36(m，1H)，6.99-6.84(m，5H)，2.95-2.80(m，4H)，2.24(s，3H)，2.23(s，3H)，1.47(s，9H)。

Embodiment 142

3-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-aminomethyl phenyl)-ethyl) phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 242)

[0341] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)11.86(d，J＝13.6Hz，1H)，9.50(br?s，1H)，8.71(d，J＝13.6Hz，1H)，8.66(dd，J＝2.1，1.6Hz，1H)，8.26(ddd，J＝8.1，2.1，1.1Hz，1H)，7.71(ddd，J＝7.7，1.6，1.1Hz，1H)，7.64(dd，J＝8.0，1.5Hz，1H)，7.53(dd，J＝8.2，7.7Hz，1H)，7.22(m，1H)，7.16-7.07(m，3H)，6.98(dd，J＝7.6，1.5Hz，1H)，6.94(m，1H)，2.88(m，2H)，2.82(m，2H)，2.32(s，3H)，2.29(s，3H)。

Embodiment 143

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2-fluorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 243)

[0342] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.53(m，1H)，7.23-7.15(m，2H)，7.07-6.97(m，2H)，6.91-6.83(m，2H)，3.79(t，J＝6.6Hz，2H)，2.95(s，4H)，2.34(t，J＝7.3Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 144

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3, the 4-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 244)

[0343] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.54(m，1H)，6.93-6.88(m，2H)，6.83-6.79(m，3H)，3.79(t，J＝6.6Hz，2H)，2.92(m，2H)，2.80(m，2H)，2.34(t，J＝7.4Hz，2H)，2.26(s，3H)，2.25(s，6H)，2.01(m，2H)。

Embodiment 145

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(4-phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 245)

[0344] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.61-7.49(m，5H)，7.41(t，J＝7.4Hz，2H)，7.33-7.26(m，3H)，6.96-6.87(m，2H)，3.80(t，J＝6.7Hz，2H)，3.02-2.94(m，4H)，2.33(t，J＝7.4Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 146

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-p-methoxy-phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 246)

[0345] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.51(m，1H)，7.19-7.04(m，2H)，6.93-6.78(m，4H)，3.82(s，3H)，3.79(t，J＝6.8Hz，2H)，2.88(s，4H)，2.34(t，J＝7.5Hz，2H)，2.25(s，3H)，2.01(m，2H)。

Embodiment 147

4-{2-(5-methyl-2-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluoro-3-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 247)

[0346] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.52(m，1H)，7.22-6.83(m，5H)，3.79(t，J＝6.7Hz，2H)，2.92(s，4H)，2.34(t，J＝7.5Hz，2H)，2.26-2.22(m，6H)，2.01(qn，J＝7.0Hz，2H)。

Embodiment 148

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-trifluoromethyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 248)

[0347] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.65(d，J＝7.6Hz，1H)，7.58-7.47(m，2H)，7.44-7.32(m，2H)，6.96-6.86(m，2H)，3.79(t，J＝6.6Hz，2H)，3.07(m，2H)，2.97(m，2H)，2.35(t，J＝7.5Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 149

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-cyano-phenyl) ethyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 249)

[0348] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)9.60(s，1H)，7.78(d，J＝7.5Hz，1H)，7.64(t，J＝7.5Hz，1H)，7.53-7.47(m，2H)，7.41(t，J＝7.5Hz，1H)，6.95-6.84(m，2H)，3.69(t，J＝6.6Hz，2H)，3.05(m，2H)，2.99(m，2H)，2.26(t，J＝7.0Hz，2H)，2.20(s，3H)，1.86(m，2H)。

Embodiment 150

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-chloro-phenyl-) ethyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 250)

[0349] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.53(m，1H)，7.35(m，1H)，7.24-7.14(m，3H)，6.92-6.83(m，2H)，3.79(t，J＝6.7Hz，2H)，3.08-2.92(m，4H)，2.34(t，J＝7.3Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 151

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 251)

[0350] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.54(d，J＝7.6Hz，1H)，6.97-6.85(m，5H)，3.79(t，J＝6.7Hz，2H)，2.93(m，2H)，2.82(m，2H)，2.34(t，J＝7.4Hz，2H)，2.30(s，6H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 152

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-ethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 252)

[0351] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.54(m，1H)，7.19-7.06(m，4H)，6.93-6.86(m，2H)，3.79(t，J＝6.7Hz，2H)，2.92(s，4H)，2.66(q，J＝7.5Hz，2H)，2.34(t，J＝7.3Hz，2H)，2.26(s，3H)，2.01(m，2H)，1.19(t，J＝7.5Hz，3H)。

Embodiment 153

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-dichlorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 253)

[0352] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)13.60(s，1H)，12.07(s，1H)，9.43(s，1H)，7.50-7.43(m，3H)，7.27(m，1H)，6.91(m，1H)，6.83(m，1H)，3.69(t，J＝6.7Hz，2H)，3.15(m，2H)，2.89(m，2H)，2.25(t，J＝7.6Hz，2H)，2.20(s，3H)，1.85(m，2H)。

Embodiment 154

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 254)

[0353] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.54(m，1H)，7.00-6.95(m，2H)，6.92-6.85(m，3H)，3.79(t，J＝6.7Hz，2H)，2.93-2.80(m，4H)，2.34(t，J＝7.4Hz，2H)，2.26(s，3H)，2.24(s，3H)，2.22(s，3H)，2.01(m，2H)。

Embodiment 155

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluoro-6-three fluoro-aminomethyl phenyls) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 255)

[0354] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.56(m，1H)，7.52(m，1H)，7.47-7.31(m，2H)，6.96-6.87(m，2H)，3.80(t，J＝6.7Hz，2H)，3.11(m，2H)，2.95(m，2H)，2.34(t，J＝7.4Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 156

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indanyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 256)

[0355] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.55(dd，J＝7.9，1.5Hz，1H)，7.24-7.20(m，2H)，7.16-7.12(m，2H)，7.06(dd，J＝7.9，1.5Hz，1H)，6.92(t，J＝7.9Hz，1H)，4.01(m，1H)，3.80(t，J＝6.7Hz，2H)，3.35(dd，J＝15.3，8.2Hz，2H)，3.02(dd，J＝15.3，7.6Hz，2H)，2.34(t，J＝7.4Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 157

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 257)

[0356] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)12.11(br?s，1H)，9.53(br?s，1H)，7.59(m，1H)，7.52-7.45(m，3H)，7.36(m，1H)，7.28(m，1H)，7.19(m，1H)，7.10(m，1H)，3.89(s，2H)，3.70(t，J＝6.7Hz，2H)，2.26(t，J＝7.2Hz，2H)，2.21(s，3H)，1.87(m，2H)。

Embodiment 158

(±)-4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1-indanyl methyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 258)

[0357] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.58(dd，J＝7.7，1.1Hz，1H)，7.19(m，1H)，7.13-7.06(m，3H)，6.98-6.91(m，2H)，3.79(t，J＝6.7Hz，2H)，3.51(m，1H)，3.19(dd，J＝13.8，6.1Hz，1H)，2.93(m，1H)，2.78(m，1H)，2.72(dd，J＝13.8，9.4Hz，1H)，2.34(t，J＝7.3Hz，2H)，2.27(s，3H)，2.10(m，1H)，2.01(m，2H)，1.78(m，1H)。

Embodiment 159

(±)-3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1-indanyl methyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 259)

[0358] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)8.58(dd，J＝1.9，1.5Hz，1H)，8.49(s，1H)，8.12(m，1H)，7.83(ddd，J＝7.8，1.5，1.0Hz，1H)，7.62(dd，J＝7.6，1.7Hz，1H)，7.48(t，J＝7.8Hz，1H)，7.19(m，1H)，7.15-7.07(m，3H)，7.00-6.93(m，2H)，3.53(m，1H)，3.21(dd，J＝14.0，5.8Hz，1H)，2.94(m，1H)，2.80(m，1H)，2.74(dd，J＝14.0，9.4Hz，1H)，2.38(s，3H)，2.12(m，1H)，1.80(m，1H)。

Embodiment 160

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethyl)-phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 260)

[0359] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.78(s，1H)，9.64(s，1H)，8.56(t，J＝1.6Hz，1H)，8.20(m，1H)，7.79(m，1H)，7.60(t，J＝7.9Hz，1H)，7.56(m，1H)，7.22(m，1H)，7.16-7.08(m，3H)，7.02(d，J＝7.5Hz，1H)，6.97(t，J＝7.5Hz，1H)，3.60(m，2H)，2.90(m，2H)，2.83(m，2H)，2.35(s，3H)，2.29(s，3H)，1.76(m，2H)。

Embodiment 161

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluoro-3-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 261)

[0360] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.75(br?s，1H)，13.15(br?s，1H)，9.66(br?s，1H)，8.55(dd，J＝2.2，1.6Hz，1H)，8.20(ddd，J＝8.2，2.2，1.0Hz，1H)，7.79(ddd，J＝7.8，1.6，1.0Hz，1H)，7.60(dd，J＝8.2，7.8Hz，1H)，7.55(dd，J＝7.4，2.2Hz，1H)，7.16-7.10(m，2H)，7.01(t，J＝7.4Hz，1H)，6.99-6.93(m，2H)，2.94(m，2H)，2.88(m，2H)，2.34(s，3H)，2.23(d，J＝1.7Hz，3H)。

Embodiment 162

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 262)

[0361] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.75(s，1H)，9.68(s，1H)，8.55(t，J＝1.7Hz，1H)，8.20(m，1H)，7.78(m，1H)，7.59(t，J＝7.9Hz，1H)，7.55(m，1H)，7.33(m，1H)，7.25(m，1H)，7.17-7.11(m，2H)，6.97-6.92(m，2H)，2.95(m，2H)，2.90(m，2H)，2.34(s，3H)。

Embodiment 163

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 263)

[0362] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.79(s，1H)，9.55(s，1H)，8.56(t，J＝1.7Hz，1H)，8.20(ddd，J＝7.9，1.7，1.1Hz，1H)，7.79(ddd，J＝7.9，1.7，1.1Hz，1H)，7.60(t，J＝7.9Hz，1H)，7.57(dd，J＝7.8，1.6Hz，1H)，7.05-6.98(m，5H)，2.83(m，2H)，2.78(m，2H)，2.35(s，3H)，2.32(s，6H)。

Embodiment 164

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-dichlorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 264)

[0363] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)9.59(br?s，1H)，8.55(s，1H)，8.20(d，J＝7.6Hz，1H)，7.78(d，J＝7.6Hz，1H)，7.64-7.54(m，2H)，7.48-7.43(m，2H)，7.28(dd，J＝8.4，7.5Hz，1H)，7.00-6.86(m，2H)，3.17(m，2H)，2.93(m，2H)，2.35(s，3H)。

Embodiment 165

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-methyl-6-trifluoromethyl) ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 265)

[0364] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)9.58(br?s，1H)，8.55(s，1H)，8.21(d，J＝7.6Hz，1H)，7.79(m，1H)，7.64-7.50(m，5H)，7.02-6.88(m，2H)，3.04(m，2H)，2.92(m，2H)，2.35(s，3H)。

Embodiment 166

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indanyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 266)

[0365] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.78(br?s，1H)，9.67(br?s，1H)，8.56(s，1H)，8.20(d，J＝7.9Hz，1H)，7.78(m，1H)，7.60(t，J＝7.9Hz，1H)，7.56(d，J＝7.7Hz，1H)，7.28-7.12(m，5H)，6.98(t，J＝7.6Hz，1H)，4.03(m，1H)，3.29(dd，J＝15.6，7.9Hz，2H)，2.98(dd，J＝15.6，8.1Hz，2H)，2.35(s，3H)。

Embodiment 167

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indenyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 267)

[0366] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)8.57(s，1H)，8.21(d，J＝8.0Hz，1H)，7.79(m，1H)，7.65(d，J＝8.0Hz，1H)，7.60(t，J＝8.0Hz，1H)，7.53-7.50(m，2H)，7.47(m，1H)，7.41(m，1H)，7.29(t，J＝7.4Hz，1H)，7.20(t，J＝7.4Hz，1H)，7.13(t，J＝7.6Hz，1H)，3.91(s，2H)，2.36(s，3H)。

Embodiment 168

(E)-and 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-vinyl) phenyl) aminomethylene) pyrazolyl } butyric acid (compound 268)

[0367] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，CD ₃OD)8.48(br?s，1H)，7.78(m，1H)，7.57-7.43(m，3H)，7.25(d，J＝15.8Hz，1H)，7.03-6.95(m，3H)，3.81(t，J＝6.5Hz，2H)，2.27(t，J＝7.7Hz，2H)，2.26(s，3H)，2.00(m，2H)。

Embodiment 169

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 269)

[0368] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)8.62(m，1H)，8.21(m，1H)，8.03(m，1H)，7.93-7.87(m，2H)，7.61(m，1H)，7.58-7.53(m，2H)，7.37(m，1H)，2.42(s，3H)，2.38(s，3H)，2.37(s，3H)。

Embodiment 170

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-6-methyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) pyrazolyl } butyric acid (compound 270)

[0369] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)7.66(s，1H)，7.55(s，1H)，7.49(d，J＝7.1Hz，1H)，7.33(d，J＝7.1Hz，1H)，3.79(t，J＝6.6Hz，2H)，2.62(s，3H)，2.37(s，3H)，2.35(s，3H)，2.35(m，2H)，2.28(s，3H)，2.01(m，2H)。

Embodiment 171

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-2-(3, the 4-3,5-dimethylphenyl)-4-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 271)

[0370] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)8.62(s，1H)，8.23-8.12(m，2H)，7.97(m，1H)，7.89(m，1H)，7.60-7.51(m，3H)，7.41(m，1H)，2.42(s，3H)，2.39(s，3H)，2.39(s，3H)。

Embodiment 172

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-2-(3, the 5-3,5-dimethylphenyl)-4-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 272)

[0371] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)8.52(t，J＝1.6Hz，1H)，8.17(d，J＝6.3Hz，1H)，8.14(m，1H)，7.87(d，J＝6.3Hz，1H)，7.81(d，J＝7.8Hz，1H)，7.49(t，J＝7.8Hz，1H)，7.37(s，2H)，7.31(s，1H)，2.44(s，6H)，2.38(s，3H)。

Embodiment 173

3-{1-(6-trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) indyl } phenylformic acid (compound 273)

[0372] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.20(s，1H)，9.34(s，1H)，8.11(dd，J＝2.0，1.6Hz，1H)，8.08(ddd，J＝7.8，1.6，1.2Hz，1H)，7.92(d，J＝8.0Hz，1H)，7.86(ddd，J＝7.8，2.0，1.2Hz，1H)，7.77(t，J＝7.8Hz，1H)，7.62(dd，J＝7.8，1.7Hz，1H)，7.55(dq，J＝8.0，0.6Hz，1H)，7.22(m，1H)，7.15-7.07(m，3H)，7.06(m，1H)，6.95(t，J＝7.8Hz，1H)，6.91(dd，J＝7.8，1.7Hz，1H)，2.88(m，2H)，2.82(m，2H)，2.28(s，3H)。

Embodiment 174

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-benzyl phenyl) hydrazono-)-pyrazolyl } butyric acid (compound 274)

[0373] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)7.49(d，J＝7.7Hz，1H)，7.30-7.26(m，2H)，7.23-7.16(m，3H)，6.92(t，J＝7.7Hz，1H)，6.86(dd，J＝7.7，1.4Hz，1H)，4.02(s，2H)，3.69(t，J＝6.7Hz，2H)，2.24(t，J＝7.2Hz，2H)，2.19(s，3H)，1.85(m，2H)。

Embodiment 175

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(3-aminomethyl phenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 275)

[0374] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)9.43(s，1H)，7.47(d，J＝7.4Hz，1H)，7.16(t，J＝7.4Hz，1H)，7.03-6.90(m，5H)，3.69(t，J＝6.8Hz，2H)，2.67(t，J＝7.7Hz，2H)，2.58(m，2H)，2.27(s，3H)，2.25(t，J＝7.3Hz，2H)，2.19(s，3H)，1.85(m，4H)。

Embodiment 176

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-phenyl propyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 276)

[0375] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)9.44(s，1H)，7.47(d，J＝7.4Hz，1H)，7.28(t，J＝7.4Hz，2H)，7.21(m，2H)，7.17(tt，J＝7.4，1.4Hz，1H)，6.96(dd，J＝7.4，1.6Hz，1H)，6.92(t，J＝7.4Hz，1H)，3.69(t，J＝6.8Hz，2H)，2.68(t，J＝7.7Hz，2H)，2.62(m，2H)，2.25(t，J＝7.2Hz，2H)，2.19(s，3H)，1.86(t，J＝7.4Hz，4H)。

Embodiment 177

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(2-aminomethyl phenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 277)

[0376] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.59(s，1H)，12.09(s，1H)，9.45(s，1H)，7.48(dd，J＝7.8，1.2Hz，1H)，7.15-7.04(m，4H)，6.98(dd，J＝7.8，1.2Hz，1H)，6.93(t，J＝7.8Hz，1H)，3.69(t，J＝6.7Hz，2H)，2.72(t，J＝7.7Hz，2H)，2.60(t，J＝8.1Hz，2H)，2.25(t，J＝7.3Hz，2H)，2.23(s，3H)，2.19(s，3H)，1.86(m，2H)，1.78(m，2H)。

Embodiment 178

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 278)

[0377] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)7.48(m，1H)，7.34(td，J＝8.5，6.9Hz，1H)，7.16(ddd，J＝10.2，9.5，2.4Hz，1H)，7.01(tdd，J＝8.5，2.4，0.8Hz，1H)，6.94-6.84(m，2H)，3.69(t，J＝6.7Hz，2H)，2.95-2.80(m，4H)，2.25(t，J＝7.2Hz，2H)，2.19(s，3H)，1.86(m，2H)。

Embodiment 179

(E)-and 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-pyridyl) ethyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 279)

[0378] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)8.56(br?s，1H)，8.19(br?s，1H)，7.77(m，1H)，7.55(dd，J＝7.8，1.5Hz，1H)，7.38-7.28(m，2H)，6.98(dd，J＝7.8，1.5Hz，1H)，6.89(t，J＝7.8Hz，1H)，3.80(t，J＝6.7Hz，2H)，3.17(m，2H)，3.08(m，2H)，2.35(m，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 180

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-(Z)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 280)

[0379] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.48(d，J＝7.0Hz，1H)，7.09-6.95(m，3H)，6.88(d，J＝12.1Hz，1H)，6.70(d，J＝12.1Hz，1H)，6.55(t，J＝7.8Hz，1H)，6.44(d，J＝7.8Hz，1H)，3.79(t，J＝6.7Hz，2H)，2.34(t，J＝7.5Hz，2H)，2.24(s，3H)，2.13(s，6H)，2.01(m，2H)。

Embodiment 181

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-benzofuryl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 281)

[0380] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)7.71(d，J＝7.4Hz，1H)，7.69-7.62(m，3H)，7.48(s，1H)，7.34(t，J＝7.4Hz，1H)，7.27(t，J＝7.4Hz，1H)，7.17(m，1H)，3.71(t，J＝6.6Hz，2H)，2.26(t，J＝7.1Hz，2H)，2.22(s，3H)，1.87(m，2H)。

Embodiment 182

(Z)-and 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-bromo vinyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 282)

[0381] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.71-7.59(m，2H)，7.48(d，J＝7.9Hz，1H)，7.41(d，J＝13.8Hz，1H)，7.25-7.19(m，2H)，7.09-6.95(m，3H)，6.71(d，J＝7.9Hz，1H)，3.79(t，J＝6.6Hz，4H)，2.34(t，J＝7.3Hz，4H)，2.26(s，6H)，2.01(m，4H)。

Embodiment 183

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(3-methyl-1-butene base) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 283)

[0382] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.60(dd，J＝7.3，1.6Hz，1H)，7.00-6.90(m，2H)，6.30(d，J＝11.3Hz，1H)，5.65(dd，J＝11.3，10.4Hz，1H)，3.79(t，J＝6.6Hz，2H)，2.68(m，1H)，2.34(t，J＝7.3Hz，2H)，2.26(s，3H)，2.01(m，2H)，1.01(d，J＝6.6Hz，6H)。

Embodiment 184

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(2-cyclopropyl vinyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 284)

[0383] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.59(d，J＝7.8Hz，1H)，7.22(d，J＝7.8Hz，1H)，6.95(t，J＝7.8Hz，1H)，6.33(d，J＝11.0Hz，1H)，5.21(t，J＝11.0Hz，1H)，3.79(t，J＝6.6Hz，2H)，2.33(t，J＝7.4Hz，2H)，2.26(s，3H)，2.01(m，2H)，1.71(m，1H)，0.81(m，2H)，0.48(m，2H)。

Embodiment 185

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-methyl butyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 285)

[0384] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.51(d，J＝7.6Hz，1H)，6.96(d，J＝7.6Hz，1H)，6.91(t，J＝7.6Hz，1H)，3.78(t，J＝6.6Hz，2H)，2.66(t，J＝7.9Hz，2H)，2.32(t，J＝7.4Hz，2H)，2.25(s，3H)，2.01(m，2H)，1.62(m，1H)，1.49(m，2H)，0.97(d，J＝6.6Hz，6H)。

Embodiment 186

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-5-fluoro-3-(3, the 5-3,5-dimethylphenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 286)

[0385] prepares this compound according to the described method of scheme I. ¹H?NMR(300MHz，CD ₃OD)7.38(dd，J＝9.4，3.1Hz，1H)，7.13(s，2H)，7.04(s，1H)，6.78(dd，J＝9.2，3.1Hz，1H)，3.78(t，J＝6.1Hz，2H)，2.36(s，6H)，2.33(t，J＝7.3Hz，2H)，2.27(s，3H)，2.00(m，2H)。

Embodiment 187

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 287)

[0386] prepares this compound according to the described method of scheme I. ¹H?NMR(300MHz，CD ₃OD)7.66(m，1H)，7.28(s，1H)，7.23-7.20(m，2H)，7.08-6.99(m，2H)，3.78(t，J＝6.7Hz，2H)，2.33(m，2H)，2.32(s，3H)，2.31(s，3H)，2.27(s，3H)，2.00(m，2H)。

Embodiment 188

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 288)

[0387] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.47(d，J＝2.0Hz，1H)，6.96(d，J＝2.0Hz，1H)，3.78(t，J＝6.8Hz，2H)，2.93(m，1H)，2.34(t，J＝7.1Hz，2H)，2.26(s，3H)，2.00(m，2H)，1.91-1.72(m，5H)，1.58-1.27(m，5H)。

Embodiment 189

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 289)

[0388] prepares this compound according to the described method of scheme I. ¹H NMR (500MHz, acetone-d ₆) 10.58 (br s, 1H), 8.28 (br s, 1H), 7.70 (dd, J=7.6,1.9Hz, 1H), 7.11 (m, 2H), 7.08 (t, J=7.6Hz, 1H), 7.04 (dd, J=7.6,1.9Hz, 1H), 7.03 (m, 1H), 3.78 (t, J=7.0Hz, 2H), 2.38 (t, J=7.4Hz, 2H), 2.34 (m, 6H), 2.23 (s, 3H), 2.00 (m, 2H).

Embodiment 190

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 290)

[0389] prepares this compound according to the described method of scheme I. ¹H?NMR(500MHz，DMSO)13.75(s，1H)，9.56(s，1H)，8.56(t，J＝1.8Hz，1H)，8.19(ddd，J＝8.0，1.8，1.0Hz，1H)，7.78(ddd，J＝8.0，1.8，1.0Hz，1H)，7.68(dd，J＝5.5，4.1Hz，1H)，7.59(t，J＝8.0Hz，1H)，7.17(m，2H)，7.11(d，J＝4.1Hz，1H)，7.11(d，J＝5.5Hz，1H)，7.03(s，1H)，2.36(s，3H)，2.34(s，6H)。

Embodiment 191

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxyl-3-cyclohexyl phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 291)

[0390] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)8.53(m，1H)，8.19(d，J＝7.7Hz，1H)，7.79(d，J＝7.7Hz，1H)，7.59(t，J＝7.7Hz，1H)，7.48(d，J＝2.2Hz，1H)，7.04(d，J＝2.2Hz，1H)，2.97(m，1H)，2.35(s，3H)，1.84-1.67(m，6H)，1.46-1.20(m，4H)。

Embodiment 192

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 292)

[0391] prepares this compound according to the described method of scheme I. ¹H?NMR(300MHz，CD ₃OD)8.60(s，1H)，8.17(d，J＝7.8Hz，1H)，7.84(d，J＝7.8Hz，1H)，7.71(m，1H)，7.50(t，J＝7.8Hz，1H)，7.30(m，1H)，7.25-7.22(m，2H)，7.10-7.02(m，2H)，2.39(s，3H)，2.33(s，3H)，2.32(s，3H)。

Embodiment 193

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(2-aminomethyl phenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 293)

[0392] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)13.75(s，1H)，9.61(s，1H)，8.55(t，J＝1.6Hz，1H)，8.20(dd，J＝7.9，1.2Hz，1H)，7.78(d，J＝7.9Hz，1H)，7.59(t，J＝7.9Hz，1H)，7.55(dd，J＝7.9，1.2Hz，1H)，7.16-7.03(m，5H)，6.97(t，J＝7.9Hz，1H)，2.75(t，J＝7.8Hz，2H)，2.62(t，J＝7.8Hz，2H)，2.34(s，3H)，2.23(s，3H)，1.80(m，2H)。

Embodiment 194

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-benzofuryl) phenyl)-hydrazono-) pyrazolyl } phenylformic acid (compound 294)

[0393] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)8.57(t，J＝1.7Hz，1H)，8.20(m，1H)，7.80(m，1H)，7.75(m，1H)，7.73(m，1H)，7.70(dd，J＝7.9，1.3Hz，1H)，7.65(d，J＝1.9Hz，1H)，7.61(t，J＝7.9Hz，1H)，7.49(m，1H)，7.36(td，J＝7.5，1.2Hz，1H)，7.29(td，J＝7.5，0.8Hz，1H)，7.24(t，J＝7.9Hz，1H)，2.36(s，3H)。

Embodiment 195

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3-(2-fluorophenyl) propyl group)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 295)

[0394] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)13.74(s，1H)，9.61(s，1H)，8.55(t，J＝1.6Hz，1H)，8.20(m，1H)，7.78(m，1H)，7.59(t，J＝7.9Hz，1H)，7.54(m，1H)，7.31(m，1H)，7.24(m，1H)，7.16-7.11(m，2H)，7.02(m，1H)，6.97(t，J＝7.7Hz，1H)，2.72(t，J＝7.7Hz，2H)，2.67(t，J＝7.7Hz，2H)，2.34(s，3H)，1.85(m，2H)。

Embodiment 196

3-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl)-phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 296)

[0395] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)11.77(m，1H)，9.37(s，1H)，8.73(m，1H)，8.64(m，1H)，8.25(ddd，J＝8.1，2.2，1.0Hz，1H)，7.76(m，1H)，7.70(ddd，J＝7.7，1.6，1.0Hz，1H)，7.52(dd，J＝8.1，7.7Hz，1H)，7.34(m，1H)，7.26(dd，J＝7.8，1.7Hz，1H)，7.23(d，J＝7.8Hz，1H)，7.10-7.05(m，2H)，2.33(s，3H)，2.29(s，3H)，2.27(s，3H)。

Embodiment 197

3-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) aminomethylene) pyrazolyl } phenylformic acid (compound 297)

[0396] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)11.78(s，1H)，8.74(br?s，1H)，8.65(m，1H)，8.24(m，1H)，7.76(m，1H)，7.70(m，1H)，7.52(t，J＝7.9Hz，1H)，7.16(s，2H)，7.10-7.05(m，2H)，7.01(s，1H)，2.33(s，9H)。

Embodiment 198

4-{2-(5-methyl-3-oxo-3,4-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 4-3,5-dimethylphenyl)-phenyl) aminomethylene) pyrazolyl } butyric acid (compound 298)

[0397] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)8.53(s，1H)，7.64(m，1H)，7.33(d，J＝1.6Hz，1H)，7.25(dd，J＝7.7，1.6Hz，1H)，7.21(d，J＝7.7Hz，1H)，7.02-6.97(m，2H)，3.64(t，J＝6.7Hz，2H)，2.27(s，3H)，2.26(s，3H)，2.19(t，J＝7.4Hz，2H)，2.18(s，3H)，1.82(m，2H)。

Embodiment 199

3-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl)-phenyl) hydrazono-) indyl } propionic acid (compound 299)

[0398] prepares this compound according to the described method of scheme II. ¹H?NMR(500MHz，CD ₃OD)7.63(dd，J＝7.7，1.6Hz，1H)，7.61(m，1H)，7.27(td，J＝7.7，1.2Hz，1H)，7.12-7.08(m，4H)，7.00(m，1H)，6.98(t，J＝7.7Hz，1H)，6.88(dd，J＝7.7，1.6Hz，1H)，4.10(t，J＝7.2Hz，2H)，2.71(t，J＝7.2Hz，2H)，2.36(s，6H)。

Embodiment 200

3-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-benzyl phenyl) hydrazono-)-indyl } phenylformic acid (compound 300)

[0399] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.01(s，1H)，9.37(br?s，1H)，8.07(dd，J＝2.0，1.7Hz，1H)，8.05(ddd，J＝7.8，1.7，1.2Hz，1H)，7.82(ddd，J＝7.8，2.0，1.2Hz，1H)，7.74(t，J＝7.8Hz，1H)，7.72(dd，J＝7.5，1.0Hz，1H)，7.57(dd，J＝8.1，1.5Hz，1H)，7.29(td，J＝7.5，1.0Hz，1H)，7.28(t，J＝7.1Hz，2H)，7.23(m，2H)，7.20(td，J＝7.5，1.0Hz，1H)，7.18(tt，J＝7.1，1.5Hz，1H)，6.94-6.90(m，2H)，6.75(dd，J＝7.7，1.5Hz，1H)，4.02(s，2H)。

Embodiment 201

3-{1-(2-oxo-2,3-dihydro-3-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethyl) phenyl)-hydrazono-) indyl } propionic acid (compound 301)

[0400] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)7.61(d，J＝7.6Hz，1H)，7.49(dd，J＝8.0，1.4Hz，1H)，7.29(td，J＝7.6，0.9Hz，1H)，7.17-7.03(m，6H)，6.86(dd，J＝8.0，7.5Hz，1H)，6.73(dd，J＝7.5，1.4Hz，1H)，4.13(t，J＝7.3Hz，2H)，2.90(s，4H)，2.71(t，J＝7.3Hz，2H)，2.30(s，3H)。

Embodiment 202

3-{1-(6-chloro-2-oxo-2,3-dihydro-3 (Z)-(2-hydroxyl-3-(3-(3-aminomethyl phenyl) propyl group)-phenyl) aminomethylene) indyl } phenylformic acid (compound 302)

[0401] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)11.13(d，J＝13.4Hz，1H)，9.17(br?s，1H)，8.89(d，J＝13.4Hz，1H)，8.03-8.00(m，2H)，7.79(m，1H)，7.78(d，J＝8.1Hz，1H)，7.72(t，J＝7.9Hz，1H)，7.55(dd，J＝7.9，1.5Hz，1H)，7.15(t，J＝7.5Hz，1H)，7.14(dd，J＝8.1，2.0Hz，1H)，7.02-6.96(m，3H)，6.93(t，J＝7.9Hz，1H)，6.88(dd，J＝7.9，1.5Hz，1H)，6.86(d，J＝2.0Hz，1H)，2.67(t，J＝7.7Hz，2H)，2.58(m，2H)，2.27(s，3H)，1.83(m，2H)。

Embodiment 203

(±)-3-{1-(6-chloro-2-oxo-2,3-dihydro-3 (Z)-(2-hydroxyl-3-(1,2-dihydro-1-methyl-2-indyl phenyl) aminomethylene) indyl } phenylformic acid (compound 303)

[0402] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)11.14(d，J＝13.2Hz，1H)，9.78(br?s，1H)，8.94(d，J＝13.2Hz，1H)，8.03-7.99(m，2H)，7.79(m，1H)，7.79(d，J＝8.1Hz，1H)，7.72(t，J＝7.7Hz，1H)，7.67(dd，J＝8.1，1.2Hz，1H)，7.16(dd，J＝8.1，2.0Hz，1H)，7.14-7.08(m，3H)，7.03(t，J＝7.8Hz，1H)，6.87(d，J＝2.0Hz，1H)，6.76-6.70(m，2H)，4.65(dd，J＝11.2，8.7Hz，1H)，3.41(dd，J＝15.6，8.7Hz，1H)，2.72(dd，J＝15.6，11.2Hz，1H)，2.62(s，3H)。

Embodiment 204

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-aminomethyl phenyl carbonyl-amino) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 304)

[0403] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.57(br?s，1H)，12.12(br?s，1H)，10.50(s，1H)，10.27(br?s，1H)，7.63(m，1H)，7.54(m，1H)，7.45(m，1H)，7.37-7.32(m，2H)，7.24(m，1H)，7.02(m，1H)，3.70(t，J＝6.7Hz，2H)，2.44(s，3H)，2.26(t，J＝7.3Hz，2H)，2.21(s，3H)，1.87(m，2H)。

Embodiment 205

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxyl-3-(2-aminomethyl phenyl-carbonylamino) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 305)

[0404] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)10.30(br?s，1H)，7.65(d，J＝7.3Hz，1H)，7.48-7.40(m，3H)，7.36-7.32(m，2H)，3.69(t，J＝6.7Hz，2H)，2.43(s，3H)，2.26(t，J＝7.3Hz，2H)，2.21(s，3H)，1.86(m，2H)。

Embodiment 206

3-{2-hydroxyl-3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(2-(2-fluorophenyl) ethyl))-diazanyl phenyl } phenylformic acid (compound 306)

[0405] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO)13.03(s，1H)，12.97(s，1H)，9.23(s，1H)，8.12(t，J＝1.7Hz，1H)，7.95(ddd，J＝7.7，1.7，1.2Hz，1H)，7.79(ddd，J＝7.7，1.7，1.2Hz，1H)，7.67(dd，J＝8.1，1.6Hz，1H)，7.62(m，1H)，7.60(t，J＝7.7Hz，1H)，7.34-7.23(m，3H)，7.15-7.07(m，5H)，6.98(dd，J＝7.7，1.6Hz，1H)，4.04(dd，J＝7.2，6.8Hz，2H)，3.02(t，J＝7.2Hz，2H)。

Embodiment 207

3-{2-hydroxyl-3-(2-oxo-2, the inferior indyl of 3-dihydro-1-(2-(2-chloro-phenyl-) ethyl))-diazanyl phenyl } phenylformic acid (compound 307)

[0406] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO)13.03(s，1H)，12.97(s，1H)，9.23(s，1H)，8.12(t，J＝1.6Hz，1H)，7.94(ddd，J＝7.7，1.6，1.2Hz，1H)，7.79(ddd，J＝7.7，1.6，1.2Hz，1H)，7.68(dd，J＝7.8，1.6Hz，1H)，7.62(m，1H)，7.60(t，J＝7.7Hz，1H)，7.41(m，1H)，7.34(m，1H)，7.29(td，J＝7.7，1.2Hz，1H)，7.27-7.22(m，2H)，7.13-7.06(m，3H)，6.98(dd，J＝7.8，1.6Hz，1H)，4.05(t，J＝7.3Hz，2H)，3.10(t，J＝7.3Hz，2H)。

Embodiment 208

3-{3-hydroxyl-2-(5-methyl-3-oxo-2,3-dihydro-2-(3, the 4-3,5-dimethylphenyl)-Ya pyrazolyl) diazanyl-4-pyridyl } phenylformic acid (compound 308)

[0407] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO)8.53(t，J＝1.6Hz，1H)，8.20-8.15(m，2H)，8.04(ddd，J＝7.7，1.6，1.1Hz，1H)，7.71-7.64(m，3H)，7.61(dd，J＝8.4，2.3Hz，1H)，7.22(d，J＝8.4Hz，1H)，2.34(s，3H)，2.27(s，3H)，2.23(s，3H)。

Embodiment 209

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 309)

[0408] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.75(s，1H)，9.66(s，1H)，8.10(d，J＝8.8Hz，2H)，8.04(d，J＝8.8Hz，2H)，7.56(d，J＝7.6Hz，1H)，7.22(dd，J＝7.3，1.6Hz，1H)，7.16-7.08(m，3H)，7.02(d，J＝7.6Hz，1H)，6.97(t，J＝7.6Hz，1H)，2.93-2.87(m，2H)，2.86-2.80(m，2H)，2.35(s，3H)，2.29(s，3H)。

Embodiment 210

3-{3-hydroxyl-2-(2-oxo-2, the inferior indyl-diazanyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)-3-)-4-pyridyl } phenylformic acid (compound 310)

[0409] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO)13.02(br?s，1H)，9.68(br?s，1H)，8.52(br?s，1H)，8.25(br?s，1H)，8.16(br?s，1H)，7.96(d，J＝7.1Hz，1H)，7.76(d，J＝7.1Hz，1H)，7.61(t，J＝7.7Hz，1H)，7.60(m，1H)，7.35(td，J＝7.6，1.2Hz，1H)，7.21(td，J＝7.6，0.7Hz，1H)，7.16-7.13(m，3H)，6.89(d，J＝7.6Hz，1H)，2.37(s，6H)。

Embodiment 211

3-{1-(2-oxo-2,3-dihydro-3-(3-hydroxyl-6-methyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) indyl } phenylformic acid (compound 311)

[0410] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)12.93(s，1H)，8.07(t，J＝1.7Hz，1H)，8.04(m，1H)，7.81-7.74(m，2H)，7.74-7.60(m，3H)，7.42(s，1H)，7.35(t，J＝7.6Hz，1H)，7.23(t，J＝7.6Hz，1H)，7.20(d，J＝7.9Hz，1H)，6.92(d，J＝7.6Hz，1H)，2.47(s，3H)，2.28(s，3H)，2.27(s，3H)。

Embodiment 212

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-6-methyl-4-(3, the 4-3,5-dimethylphenyl)-2-pyridyl) hydrazono-) pyrazolyl } phenylformic acid (compound 312)

[0411] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)8.50(dd，J＝2.1，1.6Hz，1H)，8.15(ddd，J＝8.1，2.1，1.0Hz，1H)，7.82(ddd，J＝7.7，1.6，1.0Hz，1H)，7.71(s，1H)，7.62-7.54(m，2H)，7.62(dd，J＝8.1，7.7Hz，1H)，7.34(d，J＝7.8Hz，1H)，2.63(s，3H)，2.38(s，3H)，2.32(s，6H)。

Embodiment 213

3-{3-hydroxyl-4-(2-oxo-2, the inferior indyl diazanyl of 3-dihydro-1-(3, the 5-3,5-dimethylphenyl)-6-trifluoromethyl-3-)-2-pyridyl } phenylformic acid (compound 313)

[0412] prepares this compound according to the described method of scheme IX. ¹H?NMR(500MHz，DMSO)13.25(s，1H)，8.42(t，J＝1.5Hz，1H)，8.32(d，J＝6.1Hz，1H)，8.10(dd，J＝7.8，1.5Hz，1H)，8.10(m，1H)，8.03(d，J＝7.9Hz，1H)，7.93(d，J＝6.1Hz，1H)，7.72(t，J＝7.8Hz，1H)，7.61(dq，J＝7.9，0.8Hz，1H)，7.19(m，1H)，7.17(m，2H)，6.99(m，1H)，2.37(s，6H)。

Embodiment 214

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-2-(3, the 5-3,5-dimethylphenyl)-4-pyridyl) hydrazono-) pyrazolyl } butyric acid (compound 314)

[0413] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)7.89(m，1H)，7.80(m，1H)，7.45(s，2H)，7.19(s，1H)，3.79(t，J＝6.6Hz，2H)，2.41(s，6H)，2.36(t，J＝7.3Hz，2H)，2.28(s，3H)，2.01(m，2H)。

Embodiment 215

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-hydroxyl-5-phenyl-2-benzothienyl)-hydrazono-) pyrazolyl } butyric acid (compound 315)

[0414] prepares this compound according to the described method of plan V I. ¹H?NMR(500MHz，DMSO)12.13(s，1H)，11.25(s，1H)，8.04(d，J＝1.8Hz，1H)，7.89(d，J＝8.4Hz，1H)，7.74(m，2H)，7.70(dd，J＝8.4，1.8Hz，1H)，7.51(t，J＝7.6Hz，2H)，7.40(tt，J＝7.6，1.0Hz，1H)，3.85(t，J＝6.7Hz，2H)，2.31-2.23(m，5H)，1.92(m，2H)。

Embodiment 216

3-{3-hydroxyl-2-(5-methyl-3-oxo-2, the inferior pyrazolyl of 3-dihydro-2-(3, the 4-3,5-dimethylphenyl)-4-) diazanyl-5-benzothienyl } phenylformic acid (compound 316)

[0415] prepares this compound according to the described method of plan V I. ¹H?NMR(500MHz，DMSO)8.29(t，J＝1.6Hz，1H)，8.18(d，J＝1.7Hz，1H)，8.01(ddd，J＝7.8，1.6，0.9Hz，1H)，7.97(ddd，J＝7.8，1.6，0.9Hz，1H)，7.96(d，J＝8.3Hz，1H)，7.73(dd，J＝8.3，1.7Hz，1H)，7.69(d，J＝1.7Hz，1H)，7.64(t，J＝7.8Hz，1H)，7.62(dd，J＝8.3，1.7Hz，1H)，7.22(d，J＝8.3Hz，1H)，2.31(s，3H)，2.28(s，3H)，2.24(s，3H)。

Embodiment 217

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(3-(2,3-dimethoxy carbonyl phenyl) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 317)

[0416] prepares this compound according to the described method of scheme I. ¹H?NMR(500MHz，DMSO)12.13(s，1H)，7.99(dd，J＝7.6，1.2Hz，1H)，7.75(dd，J＝7.6，1.2Hz，1H)，7.71(t，J＝7.6Hz，1H)，7.58-7.55(m，2H)，7.50(m，1H)，7.15(m，1H)，3.86(s，3H)，3.69(t，J＝7.0Hz，2H)，3.63(s，3H)，2.26(t，J＝7.0Hz，2H)，2.18(s，3H)，1.86(qn，J＝7.0Hz，2H)。

Embodiment 218

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3,5-diisopropyl phenyl)-carbonyl hydrazide methylene) pyrazolyl } butyric acid (compound 318)

[0417] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，CD ₃OD)7.77(br?s，1H)，7.30-7.23(m，2H)，3.84(t，J＝6.7Hz，2H)，2.96-2.82(m，2H)，2.34(t，J＝7.5Hz，2H)，2.20(s，3H)，2.03(m，2H)，1.28(d，J＝7.0Hz，6H)，1.23(d，J＝6.7Hz，6H)。

Embodiment 219

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (Z)-(2-hydroxyl-3-(3, the 5-3,5-dimethylphenyl) phenyl)-aminomethylene) pyrazolyl } butyric acid (compound 319)

[0418] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，CD ₃OD)8.52(br?s，1H)，7.55(m，1H)，7.11-7.09(m，2H)，7.06-7.01(m，3H)，3.79(t，J＝6.8Hz，2H)，2.36(s，6H)，2.29(t，J＝7.5Hz，2H)，2.27(s，3H)，1.99(m，2H)。

Embodiment 220

(±)-4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2,3-dihydro-1-methyl-2-oxo-3-indyl) methyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 320)

[0419] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.64(dd，J＝8.0，1.3Hz，1H)，7.32(td，J＝7.7，0.9Hz，1H)，7.01-6.91(m，2H)，6.84(dd，J＝8.0，7.6Hz，1H)，6.78(m，1H)，6.62(dd，J＝7.6，1.3Hz，1H)，3.79(t，J＝6.7Hz，2H)，3.51(d，J＝14.4Hz，1H)，3.20(s，3H)，2.81(d，J＝14.4Hz，1H)，2.33(t，J＝7.5Hz，3H)，2.27(s，3H)，2.01(m，2H)。

Embodiment 221

3-{1-(2-oxo-2,3-dihydro-5-fluoro-3-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethyl) phenyl)-hydrazono-) indyl } propionic acid (compound 321)

[0420] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.10(s，1H)，9.24(s，1H)，8.08(t，J＝1.8Hz，1H)，8.04(m，1H)，7.82(m，1H)，7.74(t，J＝7.7Hz，1H)，7.61(dd，J＝7.9，1.6Hz，1H)，7.55(dd，J＝8.2，2.6Hz，1H)，7.22(m，1H)，7.16-7.07(m，4H)，6.96-6.92(m，2H)，6.88(dd，J＝7.6，1.6Hz，1H)，2.87(m，2H)，2.81(m，2H)，2.28(s，3H)。

Embodiment 222

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 5-3,5-dimethylphenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 322)

[0421] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.77(s，1H)，9.62(s，1H)，8.56(m，1H)，8.21(m，1H)，7.78(d，J＝7.8Hz，1H)，7.63-7.53(m，2H)，7.08-6.88(m，5H)，2.87(m，2H)，2.77(m，2H)，2.35(s，3H)，2.25(s，3H)，2.24(s，3H)。

Embodiment 223

(±)-3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2,3-dihydro-1-methyl-2-oxo-3-indyl) methyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 323)

[0422] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)8.59(dd，J＝2.1，1.6Hz，1H)，8.19(ddd，J＝8.2，2.1，1.0Hz，1H)，7.82(ddd，J＝7.7，1.6，1.0Hz，1H)，7.60(dd，J＝8.1，1.4Hz，1H)，7.49(dd，J＝8.2，7.7Hz，1H)，7.32(td，J＝7.6，1.2Hz，1H)，7.00-6.93(m，2H)，6.83-6.79(m，2H)，6.60(dd，J＝7.6，1.4Hz，1H)，3.51(d，J＝14.4Hz，1H)，3.20(s，3H)，2.80(d，J＝14.4Hz，1H)，2.34(s，3H)。

Embodiment 224

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1, the inferior indyl of 2-dihydro-1-methyl-2-oxo-3-) methyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 324)

[0423] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.65(br?s，1H)，13.16(br?s，1H)，10.54(s，1H)，8.53(dd，J＝2.1，1.6Hz，1H)，8.20(ddd，J＝8.2，2.1，1.0Hz，1H)，7.84-7.76(m，3H)，7.59(dd，J＝8.2，7.9Hz，1H)，7.46(m，1H)，7.40(d，J＝7.6Hz，1H)，7.34(td，J＝7.6，1.0Hz，1H)，7.16(m，1H)，7.07(d，J＝7.6Hz，1H)，6.93(td，J＝7.6，1.0Hz，1H)，3.24(s，3H)，2.37(s，3H)。

Embodiment 225

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(5-fluoro-2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 325)

[0424] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.77(s，1H)，13.15(s，1H)，9.66(s，1H)，8.55(dd，J＝2.1，1.6Hz，1H)，8.20(ddd，J＝8.2，2.1，1.0Hz，1H)，7.79(ddd，J＝7.8，1.6，1.1Hz，1H)，7.60(dd，J＝8.2，7.8Hz，1H)，7.57(dd，J＝7.9，1.6Hz，1H)，7.17(dd，J＝8.2，6.1Hz，1H)，7.07(dd，J＝10.3，2.8Hz，1H)，7.02(dd，J＝7.6，1.6Hz，1H)，6.97(m，1H)，6.92(ddd，J＝8.6，8.2，2.8Hz，1H)，2.90(m，2H)，2.83(m，2H)，2.35(s，3H)，2.25(s，3H)。

Embodiment 226

4-{2-(5-methyl-3-oxo-2,3-dihydro-4 (E)-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 326)

[0425] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，DMSO)7.85(m，1H)，7.62-7.45(m，3H)，7.36-7.14(m，3H)，7.01(m，1H)，3.69(t，J＝6.5Hz，2H)，2.25(t，J＝7.2Hz，2H)，2.20(s，3H)，1.86(m，2H)。

Embodiment 227

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-methyl phenyl) hydrazono-)-pyrazolyl } phenylformic acid (compound 327)

[0426] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)8.61(dd，J＝2.1，1.5Hz，1H)，8.20(ddd，J＝8.1，2.1，1.0Hz，1H)，7.84(ddd，J＝7.7，1.5，1.0Hz，1H)，7.54(m，1H)，7.52(dd，J＝8.1，7.7Hz，1H)，6.97(m，1H)，6.88(t，J＝7.8Hz，1H)，2.36(s，3H)，2.28(s，3H)。

Embodiment 228

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1, the inferior indyl of 2-dihydro-1-methyl-2-oxo-3-) methyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 328)

[0427] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.54(s，1H)，10.41(br?s，1H)，8.42(br，1H)，7.76(s，1H)，7.74(m，1H)，7.43-7.37(m，2H)，7.33(t，J＝7.8Hz，1H)，7.12(t，J＝7.8Hz，1H)，7.06(d，J＝7.8Hz，1H)，6.92(t，J＝7.8Hz，1H)，3.69(t，J＝6.6Hz，2H)，3.23(s，3H)，2.26(t，J＝7.1Hz，2H)，2.21(s，3H)，1.87(m，2H)。

Embodiment 229

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(5-fluoro-2-aminomethyl phenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 329)

[0428] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.53(m，1H)，7.09(dd，J＝8.4，6.1Hz，1H)，6.93-6.84(m，3H)，6.78(td，J＝8.4，2.8Hz，1H)，3.79(t，J＝6.7Hz，2H)，2.96-2.82(m，4H)，2.35(t，J＝7.4Hz，2H)，2.25(s，3H)，2.23(s，3H)，2.01(m，2H)。

Embodiment 230

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-difluorophenyl)-ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 330)

[0429] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.53(m，1H)，7.21(m，1H)，6.91-6.76(m，4H)，3.79(t，J＝6.6Hz，2H)，3.03-2.92(m，4H)，2.34(t，J＝7.3Hz，2H)，2.26(s，3H)，2.01(m，2H)。

Embodiment 231

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-3,5-dimethylphenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 331)

[0430] prepares this compound according to the described method of plan V II.

Embodiment 232

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-aminomethyl phenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 332)

[0431] prepares this compound according to the described method of plan V II.

Embodiment 233

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(5-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 333)

[0432] prepares this compound according to the described method of plan V II. ¹H?NMR(300MHz，CD ₃OD)7.63(d，J＝8.0Hz，1H)，7.49-7.29(m，4H)，7.18(dd，J＝8.3，6.2Hz，1H)，7.03(m，1H)，6.89(td，J＝8.3，2.3Hz，1H)，3.79(t，J＝6.6Hz，2H)，2.40(s，3H)，2.34(t，J＝7.4Hz，2H)，2.26(s，3H)，2.01(m，2H)。

[0433] prepares this compound according to the described method of plan V II.

Embodiment 234

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (Z)-(2-(5-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 334)

[0434] prepares this compound according to the described method of plan V II.

Embodiment 235

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 335)

[0435] prepares this compound according to the described method of plan V II.

Embodiment 236

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 336)

[0436] prepares this compound according to the described method of plan V II.

Embodiment 237

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 337)

[0437] prepares this compound according to the described method of plan V II.

Embodiment 238

4-{2-(5-methyl-3-oxo-2.3-dihydro-4-(2-hydroxyl-3 (E)-(2-phenyl vinyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 338)

[0438] prepares this compound according to the described method of plan V II.

Embodiment 239

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-phenylacetylene base)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 339)

[0439] prepares this compound according to the described method of plan V II.

Embodiment 240

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-aminomethyl phenyl) ethynyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 340)

[0440] prepares this compound according to the described method of plan V II.

Embodiment 241

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2, the 6-3,5-dimethylphenyl)-ethynyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 341)

[0441] prepares this compound according to the described method of plan V II.

Embodiment 242

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-fluorophenyl) ethynyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 342)

[0442] prepares this compound according to the described method of plan V II.

Embodiment 243

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2-trifluoromethyl)-ethynyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 343)

[0443] prepares this compound according to the described method of plan V II.

Embodiment 244

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-trifluoromethyl-phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 344)

[0444] prepares this compound according to the described method of plan V II.

Embodiment 245

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(1-methyl isophthalic acid-indenyl-2-) phenyl)-hydrazono-) pyrazolyl } butyric acid (compound 345)

Prepare this compound according to the described method of plan V II.

Embodiment 246

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(3,3-dimethyl-2-indenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 346)

[0445] prepares this compound according to the described method of plan V II.

Embodiment 247

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methyl oxygen base-3-(2-indenyl)-phenyl) hydrazono-) pyrazolyl } butyric acid (compound 347)

[0446] prepares this compound according to the described method of plan V II.

Embodiment 248

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(4,7-dimethyl-2-indenyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 348)

[0447] prepares this compound according to the described method of plan V II.

Embodiment 249

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(4,7-two fluoro-2-indenyls) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 349)

[0448] prepares this compound according to the described method of plan V II.

Embodiment 250

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-6-Trifluoromethyl-1-(2-(2-aminomethyl phenyl)-ethyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 350)

[0449] prepares this compound according to the described method of plan V III. ¹H?NMR(500MHz，DMSO)13.05(s，1H)，11.29(d，J＝13.4Hz，1H)，9.39(s，1H)，8.95(d，J＝13.4Hz，1H)，8.13(m，1H)，7.95(dd，J＝7.8，1.0Hz，1H)，7.83(d，J＝8.1Hz，1H)，7.80(m，1H)，7.75(d，J＝8.1Hz，1H)，7.61(t，J＝7.8Hz，1H)，7.31(d，J＝7.8Hz，1H)，7.20(m，1H)，7.16-7.07(m，5H)，7.05(d，J＝7.8Hz，1H)，4.06(t，J＝7.4Hz，2H)，2.93(t，J＝7.4Hz，2H)，2.32(s，3H)。

Embodiment 251

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-6-Trifluoromethyl-1-(2-indenyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 351)

[0450] prepares this compound according to the described method of plan V III.

Embodiment 252

(±) 4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(1,2,3, the 4-tetrahydrochysene)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 352)

[0451] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，CD ₃OD)7.57(dd，J＝8.0，1.6Hz，1H)，7.11-7.04(m，5H)，7.00(t，J＝8.0Hz，1H)，3.79(t，J＝6.7Hz，2H)，3.39(m，1H)，3.05-2.80(m，4H)，2.34(t，J＝7.3Hz，2H)，2.26(s，3H)，2.01(m，2H)，2.10-1.91(m，2H)。

Embodiment 253

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3, the 4-dihydro)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 353)

[0452] prepares this compound according to the described method of plan V II.

Embodiment 254

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(the inferior indanyl of 1-)-aminomethyl phenyl) hydrazono-) pyrazolyl } butyric acid (compound 354)

[0453] prepares this compound according to the described method of plan V II.

Embodiment 255

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(5-fluoro-2-trifluoromethyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 355)

[0454] prepares this compound according to the described method of plan V II.

Embodiment 256

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(6-fluoro-2-three fluoro-aminomethyl phenyls) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 356)

[0455] prepares this compound according to the described method of plan V II.

Embodiment 257

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(6-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 357)

[0456] prepares this compound according to the described method of plan V II.

Embodiment 258

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 358)

[0457] prepares this compound according to the described method of plan V II.

Embodiment 259

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 359)

[0458] prepares this compound according to the described method of plan V II.

Embodiment 260

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 360)

[0459] prepares this compound according to the described method of plan V II.

Embodiment 261

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 5-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 361)

[0460] prepares this compound according to the described method of plan V II.

Embodiment 262

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluoro-2-three fluoro-aminomethyl phenyls) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 362)

[0461] prepares this compound according to the described method of plan V II.

Embodiment 263

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(2,4 difluorobenzene base)-ethynyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 363)

[0462] prepares this compound according to the described method of plan V II.

Embodiment 264

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(1-(1,2,3, the 4-tetrahydrochysene)-naphthylidene) aminomethyl phenyl) hydrazono-) pyrazolyl } butyric acid (compound 364)

[0463] prepares this compound according to the described method of plan V II.

Embodiment 265

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluoro-5-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 365)

[0464] prepares this compound according to the described method of plan V II.

Embodiment 266

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3,5-dimethyl-4-isoxazolyl) vinyl) phenyl) hydrazono-) pyrazolyl) butyric acid (compound 366)

[0465] prepares this compound according to the described method of plan V II.

Embodiment 267

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,5-dimethyl-4-isoxazolyl) ethyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 367)

[0466] prepares this compound according to the described method of plan V II.

Embodiment 268

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-1-(2 (E)-(2-aminomethyl phenyl) vinyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 368)

[0467] prepares this compound according to the described method of plan V III.

Embodiment 269

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-1-(2 (E)-(2,4 difluorobenzene base) vinyl)-3 (Z)-Ya indyls) methylamino phenyl } phenylformic acid (compound 369)

[0468] prepares this compound according to the described method of plan V III.

Embodiment 270

3-{2-hydroxyl-3-(2-oxo-2,3-dihydro-1-(2-indenyl)-3 (Z)-Ya indyls) methyl-aminophenyl } phenylformic acid (compound 370)

[0469] prepares this compound according to the described method of plan V III.

Embodiment 271

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(5-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 371)

[0470] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.72(s，1H)，13.13(br?s，1H)，10.23(s，1H)，8.54(dd，J＝2.1，1.6Hz，1H)，8.21(ddd，J＝8.0，2.1，1.0Hz，1H)，7.79(ddd，J＝7.8，1.6，1.0Hz，1H)，7.65(dd，J＝7.9，1.3Hz，1H)，7.60(dd，J＝8.0，7.8Hz，1H)，7.60(dd，J＝7.9，1.3Hz，1H)，7.55(dd，J＝10.6，2.8Hz，1H)，7.50(d，J＝15.9Hz，1H)，7.35(dd，J＝15.9，1.5Hz，1H)，7.26(dd，J＝8.4，6.2Hz，1H)，7.07(t，J＝7.9Hz，1H)，7.04(td，J＝8.4，2.8Hz，1H)，2.39(s，3H)，2.35(s，3H)。

Embodiment 272

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-methyl phenyl) hydrazono-)-pyrazolyl } butyric acid (compound 372)

[0471] prepares this compound according to the described method of plan V II. ¹H?NMR(500MHz，DMSO)13.57(br?s，1H)，12.11(br?s，1H)，9.45(br?s，1H)，7.46(d，J＝7.8Hz，1H)，6.95(m，1H)，6.89(t，J＝7.8Hz，1H)，3.69(t，J＝6.8Hz，2H)，2.25(t，J＝7.2Hz，2H)，2.24(s，3H)，2.19(s，3H)，1.86(m，2H)。

Embodiment 273

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(the inferior indanyl methyl of 2-) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 373)

[0472] prepares this compound according to the described method of plan V II.

Embodiment 274

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-indanyl methyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 374)

[0473] prepares this compound according to the described method of plan V II.

Embodiment 275

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2,4 difluorobenzene base)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 375)

[0474] prepares this compound according to the described method of plan V II.

Embodiment 276

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 376)

[0475] prepares this compound according to the described method of plan V II.

Embodiment 277

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(4-fluoro-2-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 377)

[0476] prepares this compound according to the described method of plan V II.

Embodiment 278

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluoro-6-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 378)

[0477] prepares this compound according to the described method of plan V II.

Embodiment 279

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 3-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 379)

[0478] prepares this compound according to the described method of plan V II.

Embodiment 280

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 3-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 380)

[0479] prepares this compound according to the described method of plan V II.

Embodiment 281

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-fluoro-4-aminomethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 381)

[0480] prepares this compound according to the described method of plan V II.

Embodiment 282

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-chloro-phenyl-)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 382)

[0481] prepares this compound according to the described method of plan V II.

Embodiment 283

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 6-dichlorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 383)

[0482] prepares this compound according to the described method of plan V II.

Embodiment 284

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(3-chloro-phenyl-)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 384)

[0483] prepares this compound according to the described method of plan V II.

Embodiment 285

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2, the 5-difluorophenyl)-vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 385)

[0484] prepares this compound according to the described method of plan V II.

Embodiment 286

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-chloro-4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 386)

[0485] prepares this compound according to the described method of plan V II.

Embodiment 287

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-trifluoromethyl-4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 387)

[0486] prepares this compound according to the described method of plan V II.

Embodiment 288

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2,4 dichloro benzene base)-vinyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 388)

[0487] prepares this compound according to the described method of plan V II.

Embodiment 289

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2-chloromethyl-4-fluorophenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 389)

[0488] prepares this compound according to the described method of plan V II.

Embodiment 290

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3 (E)-(2-(2,4-dichloromethyl phenyl) vinyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 390)

[0489] prepares this compound according to the described method of plan V II.

Embodiment 291

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3, the 4-dihydro)-naphthyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 353)

[0490] prepares this compound according to the described method of plan V II.

Embodiment 292

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-8-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 392)

[0491] prepares this compound according to the described method of plan V II.

Embodiment 293

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-8-methyl)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 393)

[0492] prepares this compound according to the described method of plan V II.

Embodiment 294

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-methyl)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 394)

[0493] prepares this compound according to the described method of plan V II.

Embodiment 295

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 395)

[0494] prepares this compound according to the described method of plan V II.

Embodiment 296

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-6-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 396)

[0495] prepares this compound according to the described method of plan V II.

Embodiment 297

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-5-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 397)

[0496] prepares this compound according to the described method of plan V II.

Embodiment 298

4-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-8-chlorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } butyric acid (compound 398)

[0497] prepares this compound according to the described method of plan V II.

Embodiment 299

3-{2-(5-methyl-3-oxo-2,3-dihydro-4-(2-hydroxyl-3-(2-(3,4-dihydro-7-fluorine)-naphthyl) phenyl) hydrazono-) pyrazolyl } phenylformic acid (compound 399)

[0498] prepares this compound according to the described method of plan V II.

Claims

1. the compound of formula I, II, III, IV, V or VI or the acceptable salt of its medicine, ester, acid amides or prodrug:

Wherein:

R ⁷Be selected from CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR14R ¹⁵Or carboxylic acid bioisostere;

R ¹⁵Be selected from hydrogen, SO ₂R ¹⁹, C ₁-C ₆Alkyl, C ₁-C ₅Halo alkyl, C ₁-C ₆Assorted alkyl or C ₁-C ₆Assorted halo alkyl;

R ¹⁶And R ¹⁷Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or (CH ₂) _mR ¹⁸Perhaps R ¹⁶And R ¹⁷In one be the optional C that replaces ₂-C ₆Alkyl and R ¹⁶And R ¹⁷In another do not exist; Perhaps R ¹⁶And R ¹⁷Connection is to form the C of the optional optional replacement that replaces ₃-C ₈Ring;

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

Each optional group that replaces is unsubstituted, or is replaced by one or more groups that are independently selected from following group: alkyl, assorted alkyl, the halo alkyl, assorted halo alkyl, cyclic hydrocarbon radical, aryl, the aryl alkyl, heteroaryl, non-aromatic heterocyclic, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, cyano group, halogen, carbonyl, thiocarbonyl, the O-carbamyl, the N-carbamyl, the O-thiocarbamyl, the N-thiocarbamyl, the C-amido, the N-amido, the S-sulfonamido, the N-sulfonamido, the C-carboxyl, the O-carboxyl, isocyanato-, thiocyanato, isothiocyanato, nitro, silyl, three methyl halide alkylsulfonyls,=O,=S, the derivative of amino or protected amino group;

Prerequisite is if Y is directed to form the dihydro pyridylidene in the compound of formula I or II

Then:

(i) if X is N, W is NH, then D is not a naphthyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

2. the compound of formula I, II or III or the acceptable salt of its medicine, ester, acid amides or prodrug:

Wherein:

L is NH or does not exist;

Q optional contains one or more heteroatomic monocycles or bicyclic aromatic member ring systems, and Q randomly with non-aromatic heterocyclic or carbocyclic fused;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

Be selected from the optional C that replaces ₆-C ₁₀Aryl or the optional C that replaces ₁-C ₈The spacer of 2 to 5 atoms of heteroaryl, each substituted radical randomly with the optional non-aromatic heterocyclic that replaces or carbocyclic fused, or

M is 0,1,2 or 3; And

N is 0 or 1;

Then:

(i) if X is N, W is NH, then D is not a naphthyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

3. composition as claimed in claim 2, wherein:

R ¹Be selected from halogen, OR ¹⁴, NO ₂, CN, NR ¹⁴R ¹⁵, C ₁-C ₄Alkyl, C ₁-C ₄The halo alkyl, the optional C that replaces ₁-C ₄Assorted alkyl, CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or be selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Or

Each R ⁸With each R ⁹Be independently selected from hydrogen, OR, NR ¹⁶R ¹⁷, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, the optional C that replaces ₁-C ₄Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

G is selected from O, S or NR ¹⁴

J is selected from O, S, NR ¹⁴Or CR ¹⁴R ¹⁵

K is O or S;

Y is selected from:

4. the acceptable salt of the compound of formula IV, V or VI or medicine, ester, acid amides or prodrug:

Wherein:

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

Be selected from the optional C that replaces ₆-C ₁₀Aryl or the optional C that replaces ₁-C ₈The spacer of 2 to 5 atoms of heteroaryl, each aryl or heteroaryl randomly with the optional non-aromatic heterocyclic that replaces or carbocyclic fused, or

M is 0,1,2 or 3; And

N is 0 or 1;

Prerequisite is that then D is not a phenyl if X is N, W is NH; And

5. compound as claimed in claim 4, wherein:

The carboxylic acid bioisostere, wherein A, B and C are selected from O, S or N independently of one another; And

6. the compound of formula I, II, III, IV, V or VI or the acceptable salt of its medicine, ester, acid amides or prodrug:

Wherein:

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

Prerequisite is, if X is N, W is that NH and Y are not directed to form pyrazoline-N=CR ¹²-, and Z or R ⁶Be not and the optional non-aromatic ring that replaces of the optional aromatic ring condensed that replaces; If perhaps X is N, W is NH, R ⁶Be alkoxyl group, the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces, Y is directed to form pyrazoline-N=CR ¹²-and Z be not the optional non-aromatic ring of aromatic ring condensed that replaces that replace and optional; Then D is not a phenyl;

Prerequisite is, if X is N, W is that NH and Y are directed to form pyrazoline-N=CR ¹²-, then D is not a naphthyl;

Prerequisite is, if U is NH; If perhaps D and R ¹⁰And R ¹¹In one form the 5-hydroxypyrazoles, X is that N and W are NH; If perhaps E and R ¹⁰And R ¹¹In one form the 5-hydroxypyrazoles, X is that N and W are NH; If perhaps E is a phenyl, R ¹⁰Or R ¹¹In one be (CH ₂) _0-6OH, X are C, and W is NH, R ⁶Be optional aryl that replaces or the optional heteroaryl that replaces, and Z does not exist, be the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces; If perhaps E is a phenyl, R ¹⁰Or R ¹¹In one be-(CH ₂) _0-6OH, X are N, and W is NH, and Z does not exist, is the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces, and R ⁶Be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group ,-(CH ₂) _0-6OR ²⁰, the optional aryl that replaces, optional heteroaryl, the NR that replaces ²¹R ²²Or the heterocycle methylene radical substituting group shown in the formula VII; If perhaps D is a phenyl, R ¹⁰Or R ¹¹In one be-(CH ₂) _0-6OH, X are C, and W is NH, and Z is an aromatics, and R ⁶Be alkoxyl group, the optional alkyl that replaces, the optional aryl that replaces or the optional heteroaryl that replaces; Then Y is not directed to form pyrazoline-N=CR ¹²-;

R ²¹And R ²²Be selected from hydrogen, alkyl or aryl independently of one another; Perhaps R ²¹And R ²²Represent to contain other heteroatomic 5 or 6 yuan of saturated rings that are selected from oxygen or nitrogen at the most with the nitrogen that they connected;

7. the compound of formula I, II, III, IV, V or VI:

Wherein:

R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl or the optional C that replaces ₁-C ₁₀Assorted alkyl, each R ⁶Randomly heteroaryl-condensed with aryl that replaces or replacement, perhaps R ⁶Be (CH ₂) _mR ¹⁸Or C (O) NHR ¹⁸

R ⁸And R ⁹Be selected from hydrogen, OR independently of one another ¹⁶, NR ¹⁶R ¹⁷, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

R ¹⁸Be selected from optional replace randomly and randomly with non-aromatic heterocyclic or carbocyclic fused one or more heteroatomic monocycles or the bicyclic aromatic member ring systems of containing;

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

Then:

(i) if X is N, W is NH, then D is not a naphthyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

8. the compound of formula I, II or III:

Wherein:

R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl, the optional C that replaces ₁-C ₁₀Assorted alkyl, (CH ₂) _mR ¹⁸Or C (O) NHR ¹⁸

R ⁸And R ⁹Be selected from hydrogen, OR independently of one another ¹⁶, NR ¹⁶R ¹⁷, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Or R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

R ¹⁶And R ¹⁷Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl or (CH ₂) _mR ¹⁸Perhaps R ¹⁶And R ¹⁷In one be the optional C that replaces ₂-C ₆Alkyl, R ¹⁶And R ¹⁷In another do not exist; Perhaps R ¹⁶And R ¹⁷Connection is to form the optional C that replaces ₃-C ₈Ring;

R ¹⁸Be selected from optional replace randomly contain one or more heteroatomss and randomly with non-aromatic heterocyclic or carbocyclic fused monocycle or bicyclic aromatic member ring systems;

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

(i) if X is N, W is NH, then D is not a naphthyl,

(iii)

Not pyrazolyl or the optional 5-hydroxypyrazoles base that replaces, and

(iv) U is not NH;

Another prerequisite is that then D is not a phenyl if X is N, W is NH; And

9. compound as claimed in claim 2, wherein:

R ²Be selected from hydrogen, halogen, OR ¹⁴, NR ¹⁴R ¹⁵, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, C ₁-C ₄Assorted alkyl or C ₁-C ₄Assorted halo alkyl;

R ⁶Be selected from C ₁-C ₁₀Alkyl, C ₁-C ₁₀Halo alkyl, the optional C that replaces ₁-C ₁₀Assorted alkyl, (CH ₂) _mR ¹⁸Or C (O) NHR ¹⁸

R ⁸And R ⁹Be selected from hydrogen, OR, NR independently of one another ¹⁶R ¹⁷, C ₁-C ₄Alkyl, C ₁-C ₄Halo alkyl, the optional C that replaces ₁-C ₄Assorted alkyl, (CH ₂) _mR ¹⁸Or do not exist; Perhaps R ⁸And R ⁹Form the optional alkene that replaces together; Perhaps R ⁸And R ⁹Connection is to form the optional C that replaces ₃-C ₈Ring;

G is selected from O, S or NR ¹⁴

J is selected from O, S, NR ¹⁴Or CR ¹⁴R ¹⁵

K is O or S;

L is NH or does not exist; And

Y is selected from:

10. the acceptable salt of the compound of formula IV, V or VI or medicine, ester, acid amides or prodrug:

Wherein:

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

Prerequisite is that then D is not a phenyl if X is N, W is NH; And

11. compound as claimed in claim 4, wherein:

R ¹Be selected from hydrogen, halogen, OR ¹⁴, NO ₂, CN, NR ¹⁴R ¹⁵, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Halo alkyl, the optional C that replaces ₁-C ₆Assorted alkyl, CO ₂R ¹⁴, CONR ¹⁴R ¹⁵, SO ₃R ¹⁴, SO ₂NR ¹⁴R ¹⁵Or be selected from tetrazolium, NHSO ₂R ¹⁹, OC (S) NR ¹⁴R ¹⁵, SC (O) NR ¹⁴R ¹⁵Or

12. the compound of formula I, II, III, IV, V or VI:

Wherein:

R ⁶Be selected from the optional C that replaces ₁-C ₁₀Alkyl, the optional C that replaces ₁-C ₁₀Halo alkyl or the optional C that replaces ₁-C ₁₀Assorted alkyl, each substituted radical be heteroaryl-condensed with aryl that replaces or replacement randomly, perhaps R ⁶Be (CH ₂) _mR ¹⁸Or C (O) NHR ¹⁸

L is NH or does not exist;

U is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

W is selected from O, NR ⁴, CR ³R ⁴, CO or do not exist;

X is N or CR ⁵

Z is selected from:

Do not exist,

M is 0,1,2 or 3; And

N is 0 or 1;

13. compound as claimed in claim 3, wherein said compound are formula I.

14. compound as claimed in claim 3, wherein said compound are formula II.

15. compound as claimed in claim 3, wherein said compound is a formula III.

16. compound as claimed in claim 5, wherein said compound are formula IV.

17. compound as claimed in claim 5, wherein said compound are formula V.

18. compound as claimed in claim 5, wherein said compound are formula VI.

19. compound as claimed in claim 1, it is selected from following compound or the acceptable salt of medicine, ester or the prodrug of these compounds arbitrarily:

4-{2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3, the 4-3,5-dimethylphenyl) phenyl) hydrazono-hydrazono-) pyrazolyl } butyric acid (compound 198);

4-{2-(5-methyl-3-oxo-3,4-dihydro-4-(2-hydroxyl-3-(2-(2-fluorine) phenyl)-ethylphenyl) aminomethylene) pyrazolyl } butyric acid (compound 225).

20. compound as claimed in claim 1, it is selected from following compound or the acceptable salt of medicine, ester or the prodrug of these compounds arbitrarily:

21. the described compound of arbitrary as described above claim, it is a selectivity TPO conditioning agent.

22. as claim 21 described compound, it is the TPO stand-in.

23. compound as claimed in claim 21, it is a selectivity TPO receptor stimulant.

24. compound as claimed in claim 21, it is a selectivity TPO acceptor portion agonist.

25. compound as claimed in claim 21, it is a selectivity TPO receptor antagonist.

26. the described compound of arbitrary as described above claim, it is a selectivity TPO receptor binding compounds.

27. compound as claimed in claim 26, wherein said compound are the tissue specificity conditioning agents.

28. the active method of TPO in the adjusting cell, it comprises makes cell contact with the described compound of arbitrary aforementioned claim.

29. differentiate the method for regulating the active compound of TPO, it comprises makes the cell of expressing the TPO acceptor contact with the described compound of arbitrary claim in the claim 1 to 27; And monitor of the effect of described compound to described cell.

30. treatment patient's method, it comprises the described compound of arbitrary claim in the claim 1 to 27 is carried out administration to the patient.

31. method as claimed in claim 30, wherein said patient suffers from thrombocytopenia.

32. method as claimed in claim 31, wherein said thrombocytopenia is caused by radiation or chemotherapy.

33. method as claimed in claim 30, it also comprises from described patient gathers cell.

34. method as claimed in claim 30, wherein said treatment is preventative.

35. method as claimed in claim 30, wherein said patient suffers from the morbid state of the system of affecting the nerves.

36. method as claimed in claim 35, wherein said patient suffers from the amyotrophic lateral sclerosis of being selected from, multiple sclerosis or multiple dystrophic disease.

37. method as claimed in claim 35, wherein said patient suffers from nervous system injury.

38. method as claimed in claim 35, wherein said patient suffers from Spinal injury.

39. pharmaceutical composition, it comprises physiology acceptable carrier, thinner or vehicle; And the described compound of arbitrary claim in the claim 1 to 27.

40. the described pharmaceutical composition of claim 39 is used for the treatment of the morbid state of the morbid state that is selected from thrombocytopenia or affects the nerves system.