CN103933032B - The application method and purposes of pyrazole derivatives as anticancer drug - Google Patents

Abstract

The present invention relates to increase purposes, method and its pharmaceutical composition in relevant disease in treatment or prevention and treatment kidney type glutaminase active by leading to a series of pyrazole derivatives that formula (II) indicates.

Description

The application method and purposes of pyrazole derivatives as anticancer drug

Technical field

The present invention relates to pyrazole derivatives, combination and treatment comprising these compounds or prevention and treatment kidney type glutamine Enzymatic activity increases the purposes in relevant disease.

Background technique

The fast-growth amount of needing not only to of tumour cell, and it is new thin to be also required to nucleic acid, fatty acid and protein progress The generation of born of the same parents.Glutamine plays during the advolution of tumour cell as amino acid the most abundant in human body It is vital effect (referring to document DeBerardinis, R.J.et al. (2008) The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation.Cell Metabolism7: 11-20 and document Hsu, P.P.and Sabatini, D.M. (2008) Warburg and beyard.Cell134:703- 707).Therefore, many tumour cells are described as the cell of " glutamine of wallowing in " (addicted to glutamine) (referring to Wise D.R.and Thompson C.B. (2010) Glutamine addiction:a new therapeutic Target in cancer.Trends in Biochemical Sciences35:427-433).

During glutamine metabolism, one of them important enzyme is glutaminase, it is located in cell The inner membrance of mitochondria is (referring to Shapiro, R.A.et al. (1985) The orientation of phosphate- dependent glutaminase on the inner membrane of rat renal mitochondria.Arch Biochem Biophys243:1-7), it can be catalyzed the reaction that glutamic acid is generated by glutamine, glutamic acid is in glutamate dehydrogenase It is changed into α-ketoglutaric acid under the action of enzyme, tricarboxylic acid cycle is entered in the form of substrate, is that the macromolecular of tumour cell synthesizes The intermediate of metabolism is provided (referring to Lu W.Q.et al. (2010) Cancer metabolism:is glutamine Sweeter than glucose.Cancer Cell18:199-200).Glutaminase can be divided into two kinds of hypotypes (isoform), one kind being called kidney type glutaminase (GLS1), and another kind is liver type glutaminase (GLS2).GLS2 Only liver periphery cell expression after birth；And GLS1 body parts such as: the tissues such as kidney, brain, intestines are all There is abundant expression, it is often more important that be normally present in tumour cell extensively (referring to Shapiro et al., " Isolation, Characterisation, and In vitro Expression of a cDNA that Encodes the Kidney Isoenzyme of the Mitochondrial Glutaminase, " J.Biol.Chem.266:18792-18796 (1991) And Szeliga, M and Obara- Michlewska, M. (2009) Glutamine in neoplastic cells:focus On the expression and role of glutaminases.Neurochem Int55:71-75).Both hypotypes Although height is similar in the sequence of amino acid, they from different related gene (Curthoys et al., " Regulation of Glutaminase Activity and Glutamine Metabolism, " Annu.Rev.Nutr.16:133-159 (1995)), there is different protein structure and dynamic characteristic, to exercise different Function, and the adjustment mechanism being related to is also different.

The vicious transformation of cell is dramatically increased along with what nucleic acid and protein synthesized.The tumour cell of rapid growth is come The high speed synthesis for saying protein, needs constantly to provide required and nonessential amino acid, glutamine is as most abundant in human body Amino acid, provide guarantee (referring to Souba, W., " Gutamine and Cancer, " for this huge demand Ann.Surg.218:715-728 (1993)).It is carried out in the mitochondria of glutamine metabolism in the cell, therefore glutamine must Need to be by cell membrane from extracellularly encountering in cytoplasm, then transported in mitochondria from cytoplasm by mitochondrial membrane.Study table Bright, tumour cell is fast more than normal cell by cell membrane transport glutamine.At Emhorn ascites (Ehrlich asctites) Research on cancer cell, also demonstrating present on the cell mitochondrial film a kind of special glutamine transport system can be with Glutamine transport is entered mitochondria (referring to Molina, M.et al. (1995) Glutamine faster than normal cell transport by vesicles isolated from tumor cell mitochondrial inner Membrane.Biochem is J.308:629-633).Because the activity of glutaminase be to rely on Phos concentration (referring to Quesada et al., " Purification of Phosphate-Dependent Glutaminase from Isolated Mitochondria of Ehrlich Ascites Tumor Cells, " Biochem.J.255:1031-1035 (1988)), And inorganic phosphorus concentration is high in tumour cell mitochondria, so the activity of its glutaminase is also high.In fact scientific research proves The high activity of glutaminase and the fast-growth of tumour cell are closely related (referring to Souba, W.W., " Glutamine and Cancer, " Ann.Surg.218:715-728 (1993)).Studies have shown that being interfered in ehrlich ascites cell with antisense mRNA Method be substantially reduced the expression of GLSl gene after, not only the growth of tumour cell is suppressed but also form is also become Change.By in this cell inoculation to Mice Body, cell loses the blastomogenic ability of production, such mouse and healthy animal completely It is just the same (referring to Baskerville A, Hambleton P, Benbough JE, et al.Pathological Features of glutaminase toxicity [J] .Br J Exp Pathol, 1980,61 (2): 132-138 and Lobo, C.et al.(2000)Inhibition of glutaminase expression by antisense mRNA Decreases growth and tumourgenicity of tumor cells.Biochem.J.348:257-261).This A little scientific discoveries have absolutely proved that the activity of glutaminase is closely related with tumour occurrence and development, and glutaminase has become The target gene greatly paid close attention in antitumor therapy by people.

But there has been no effectively inhibit the drug or therapy of tumour by effectively inhibiting glutaminase so far Report.

Summary of the invention

The present invention relates in structure formula (II) compound or its pharmaceutical salt or solvate for make inhibit paddy The purposes of the active drug of transglutaminase:

Wherein:

Y expression-C (O)-N (R⁵)-or-O-；A and B is independent to be selected from-C (O)-NH-R¹Or

R¹Indicate H or independently selected from:

a)C_1-16Alkyl or the group can optionally be replaced by following group:

1) 1-5 halo groups are to highest perhaloalkyl groups；

2) 1 oxo group；

3) 1-2 hydroxyl group；

4) 1-2 C_1-10Alkoxy base or the group can optionally be replaced by following group: 5 halogenated or halogen of highest For alkoxy, 1 hydroxyl or CO₂R^aGroup；

5) 1 CO₂R^aOr S (O)_pR^d

6) l-2 aryl, Hetcy or HAR group or the group can optionally be replaced by following group:

A.1-5 a halo groups,

B.1 a hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

C.1-2 a C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 are halogenated, Highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；

D.1-2 a benzyl ring or the group can optionally be replaced by following group: 1-5 halo groups to highest perhalogeno Generation, 1-3 C_1-10Alkyl or alkoxy base, it is further optionally halogenated a to highest perhalogeno or 1-2 by 1-5 respectively Hydroxyl or CO₂R^aGroup；

B) aryl, HAR, Hetcy or the group is optional is replaced by following group:

1) 1-3 C_1-10Alkyl or alkoxy base or the group is optional is replaced by following group: 1-5 halogen For group, 1-2 hydroxyl group；CO₂R^aGroup；CN；S(O)_pR^d, phenyl or the group can optionally replace by following group:

I.1-5 a halo groups；

Ii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Iii.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 halogen Generation, highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；With

2) phenyl, the phenyl are optionally replaced by following group:

I.1-5 a halo groups；

Ii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Iii.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 halogen Generation, highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；

Aryl described above, HAR, Hetcy group can also be replaced on carbon by group selected from the following；

3) 1-5 halo groups；

4) 1-2 hydroxyl group；

5) 1 CN, S (O)_pR^dOr NO₂Group；

6) 1-2 CO₂R^aGroup；

7)C(O)NR^bR^cGroup；

R²It is independent selected from H or:

A) halogenated, hydroxyl, CO₂R^a, CN, S (O)_pR^dOr NO₂Group,

b)C_1-6Alkyl or OC_1-6Alkyl, the C_1-6Alkyl or OC_1-6Alkyl is optionally replaced by following group:

1) 1-5 halo groups are to highest perhaloalkyl groups；

2)CO₂R^a, CN, S (O)_pR^dOr hydroxyl group；

3) phenyl or the group can optionally be replaced by following group:

I.1-5 a halo groups；

Ii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Iii.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 is halogenated, Highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup

R³It is H or C_1-3Alkyl；

R⁵It is H or C_1-6Alkyl；

R⁶Selected from H, hydroxyl and C_1-3Alkyl；

R⁷It is H or F or R⁶And R⁷Oxo is indicated together；

R^aIt is H or C_1-10Alkyl, the C_1-10Alkyl is optionally by phenyl, hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6 Alkyl and 1-3 halogenated alkyl replace；

R^bIt is H or C_1-10Alkyl；

R^cIt is that H or independent is selected from:

a)C_1-10Alkyl, the C_1-10Alkyl is optionally by hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl and 1-3 are a Halogenated alkyl replaces；

B) aryl or Ar-C_1-6Alkyl, the aryl or Ar-C_1-6Alkyl is optionally selected by 1-5 halogen or 1-3 Replace from following component: CN, hydroxyl, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy optionally further by 1-5 halo groups are to highest perhalogeno；

C) Hetcy or Hetcy-C_1-6Alkyl, the Hetcy or Hetcy-C_1-6Alkyl is optionally by 1-5 halogen Replace with 1-3 selected from following group: oxo, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy optionally into One step is by 1-5 halo groups to highest perhalogeno；With

D) HAR or HAR-C_1-6Alkyl, the HAR or HAR-C_i-6Alkyl is optionally selected by 1-5 halogen and 1-3 Replace from following group: C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optionally further halogenated by 1-5 Group is to highest perhalogeno；

R^dIt is C_1-10Alkyl, Aryl or Ar-C_1-10Alkyl；

M is the integer selected from 0,1 and 2；

N is the integer selected from 0 to 6；

P is the integer selected from 0,1 and 2, and if at least one m and n are not that 0, Z is selected from CO₂R^a, 5- tetrazole and 5- (2- oxo -1,3,4- 4-oxadiazole base)；If m and n are that 0, Z is selected from 5- tetrazole and 5- (2- oxo -1,3,4- oxygen Miscellaneous di azoly),

X is selected from CH or N

In another embodiment of the invention, provides a kind of compound using in structure formula (III) or it can medicine Salt or solvate are used to make the purposes for the drug for inhibiting glutaminase active:

Wherein:

A indicates that wherein 0-4 hetero atom is N and 0-1 miscellaneous containing 1-4 heteroatomic 9-10 membered bicyclic hetero-aromatic rings Atom is O or S

The bicyclic heteroaryl is optional to be replaced by following group:

A) 1-5 halogen group；

B) 1 CO₂R^a, CN, S (O)_pR^d, NO₂, C (O) NR^bR^cAnd NR^bR^cGroup；

C) 1-2 C_1-10Alkyl or alkoxy base, the group is optional to be replaced by following group:

1) 1-5 halogen group is to whole haloalkyl；

2) 1 oxo group；

3) 1-2 hydroxyl group；

4) 1-2 C_1-10Alkoxy, the group are optional by 1 to 5 halogens or perhaloalkoxy groups, 1 hydroxyl Or CO₂R^aGroup replaces；

5) 1 CO₂R^aOr S (O)_pR^d

6) 1-2 aryl, Hetcy or HAR group, the group is optional to be replaced by following group:

A) 1-5 halogen group,

B) 1 hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

C) 1-2 C_1-10Alkyl or alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup replaces；With

D) aryl, HAR, Hetcy, the group is optional to be replaced by following group:

I.1-5 a halogen group；

Ii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Iii.1-2 C_1-10Alkyl and alkoxy, each optionally by 1-5 halogen, until whole haloalkyl and 1-2 Hydroxyl or CO₂R^aGroup；

The aryl, HAR, Hetcy base is also optional to be replaced by group selected from the following；

1) 1-5 halogen group；

2) 1-2 hydroxyl group；

3) 1 CN, S (O)_pR^dOr NO₂Group；

4) 1-2 CO₂R^aGroup；

5)C(O)NR^bR^cGroup；

R^aIt is H or C_1-10Alkyl, the group are optional by phenyl, hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl Replace with 1-3 halogen；

R^bIt is H or C_1-10Alkyl；

R^cIt is that H or independent is selected from:

a)C_1-10Alkyl, the group are optional by hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl and 1-3 are a halogenated Alkyl replaces；

B) aryl or Ar-C_1-6Alkyl, the group is optional to be taken by 1-5 halogen and 1-3 selected from following component Generation: CN, hydroxyl, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optional further by 1-5 halo groups to most High perhalogeno；

C) Hetcy or Hetcy-C_1-6Alkyl, the group is optional to be selected from following group by 1-5 halogen and 1-3 Replace: oxo, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy it is optional further by 1-5 halo groups extremely Highest perhalogeno；With

D) HAR or HAR-C_1-6Alkyl, the group is optional to be taken by 1-5 halogen and 1-3 selected from following group Generation: C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optional further by 1-5 halo groups to highest perhalogeno Generation；

R^dIt is C_1-10Alkyl, Aryl or Ar-C_1-10Alkyl；

P is the integer selected from 0,1 and 2；

Each R¹It is independent to be selected from H or group below:

A) halogen；CO₂R^a, CN, hydroxyl, S (O)_pR^d, NO₂, C (O) NR^bR^cAnd NR^bR^C；

b)C_1-10Alkyl or OC_1-10Alkyl, the group is optional to be replaced by following group:

1) 1-5 halogen is until whole haloalkyl；

2) 1 oxo group；

3) 1-2 hydroxyl；

4) 1-2 C_1-10Alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl Base or CO₂R^aGroup replaces；

5) 1 CO₂R^aOr S (O)_pR^d

6) 1-2 aryl, Hetcy or HAR group, the group is optional to be replaced by following group:

A) 1-5 halogen group,

B) 1 hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

C) 1-2 C_1-10Alkyl or alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup replaces；With

D) aryl, HAR, Hetcy, the group is optional to be replaced by following group:

I.1-5 a halogen group；

Ii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Iii.1-2 C_1-10Alkyl and alkoxy, each optionally by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl Base or CO₂R^aGroup；

The aryl, HAR, Hetcy base is optional further to be replaced by group selected from the following:

1) 1-5 halogen group；

2) 1-2 hydroxyl group；

3) 1 CN, S (O)_pR^dOr NO₂Group；

4) 1-2 CO₂R^aGroup；

5)C(O)NR^bR^cGroup；

Wherein R^a, R^b, R^c, R^dIt is as defined above with p；

R²Selected from hydrogen and C_1-6Alkyl

In another embodiment of the invention, provides a kind of compound using in structure formula (IV) or its is pharmaceutically acceptable Salt or solvate be used for make inhibition glutaminase active drug purposes:

Wherein:

Each R¹It is independent to be selected from hydrogen or following group:

A) halogen；CO₂R^a, CN, hydroxyl, S (O)_pR^d, NO₂；

B) C optionally replaced by following group_1-6Alkyl or OC_l-6Alkyl:

1) 1-5 halogen is until whole haloalkyl；

2)CO₂R^a；

3) phenyl optionally replaced by following group:

A.1-5 a halogen,

B.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

C.1-2 a C_1-10Alkyl or C_1-10Alkoxy；

R³It is hydrogen or C_1-3Alkyl；

R^aIt is H, C_1-6Alkane；

R⁵Selected from following group: C_l-10Alkyl, aryl or Ar-C_1-10Alkyl；

R⁶And R⁷Expression H or C independent_1-3Alkyl, and p is 0, l or 2.

In another embodiment of the invention, provides a kind of compound using in structure formula (I) or its is pharmaceutically acceptable Salt or solvate be used for make inhibition glutaminase active drug purposes:

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The method of high related illness, the method includes to mammal apply a effective amount of logical formula (II) compound represented or Its pharmaceutical salt or solvate

Wherein:

Y expression-C (O)-N (R⁵)-or-O-；A and B is independent to be selected from-C (O)-NH-R¹Or

R¹Indicate H or independently selected from:

c)C_1-16Alkyl or the group can optionally be replaced by following group:

7) 1-5 halo groups are to highest perhaloalkyl groups；

8) 1 oxo group；

9) 1-2 hydroxyl group；

10) 1-2 C_1-10Alkoxy base or the group can optionally be replaced by following group: 5 halogenated or halogen of highest For alkoxy, 1 hydroxyl or CO₂R^aGroup；

11) 1 CO₂R^aOr S (O)_pR^a

12) 1-2 aryl, Hetcy or HAR group or the group can optionally be replaced by following group:

E.1-5 a halo groups,

F.1 a hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

G.1-2 a C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 are halogenated, Highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；

H.1-2 a benzyl ring or the group can optionally be replaced by following group: 1-5 halo groups to highest perhalogeno Generation, 1-3 C_1-10Alkyl or alkoxy base, it is further optionally halogenated a to highest perhalogeno or 1-2 by 1-5 respectively Hydroxyl or CO₂R^aGroup；

D) aryl, HAR, Hetcy or the group is optional is replaced by following group:

8) 1-3 C_1-10Alkyl or alkoxy base or the group is optional is replaced by following group: 1-5 halogen For group, 1-2 hydroxyl group；CO₂R^aGroup；CN；S(O)_pR^d, phenyl or the group can optionally replace by following group:

Iv.1-5 halo groups；

V.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Vi.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 halogen Generation, highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；With

9) phenyl, the phenyl are optionally replaced by following group:

Iv.1-5 halo groups；

V.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Vi.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 halogen Generation, highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；

Aryl described above, HAR, Hetcy group can also be replaced on carbon by group selected from the following；

10) 1-5 halo groups；

11) 1-2 hydroxyl group；

12) 1 CN, S (O)_pR^dOr NO₂Group；

13) 1-2 CO₂R^aGroup；

14)C(O)NR^bR^cGroup；

R²It is independent selected from H or:

C) halogenated, hydroxyl, CO₂R^a, CN, S (O)_pR^dOr NO₂Group,

d)C_1-6Alkyl or OC_1-6Alkyl, the C_1-6Alkyl or OC_1-6Alkyl is optionally replaced by following group:

4) 1-5 halo groups are to highest perhaloalkyl groups；

5)CO₂R^a, CN, S (O)_pR^dOr hydroxyl group；

6) phenyl or the group can optionally be replaced by following group:

Iv.1-5 halo groups；

V.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Vi.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 is halogenated, Highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup

R³It is H or C_1-3Alkyl；

R⁵It is H or C_1-6Alkyl；

R⁶Selected from H, hydroxyl and C_1-3Alkyl；

R⁷It is H or F or R⁶And R⁷Oxo is indicated together；

R^aIt is H or C_1-10Alkyl, the C_1-10Alkyl is optionally by phenyl, hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6 Alkyl and 1-3 halogenated alkyl replace；

R^bIt is H or C_1-10Alkyl；

R^cIt is that H or independent is selected from:

e)C_1-10Alkyl, the C_1-10Alkyl is optionally by hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl and 1-3 are a Halogenated alkyl replaces；

F) aryl or Ar-C_1-6Alkyl, the aryl or Ar-C_1-6Alkyl is optionally selected by 1-5 halogen or 1-3 Replace from following component: CN, hydroxyl, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy optionally further by 1-5 halo groups are to highest perhalogeno；

G) Hetcy or Hetcy-C_1-6Alkyl, the Hetcy or Hetcy-C_1-6Alkyl is optionally by 1-5 halogen Replace with 1-3 selected from following group: oxo, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy optionally into One step is by 1-5 halo groups to highest perhalogeno；With

H) HAR or HAR-C_1-6Alkyl, the HAR or HAR-C_1-6Alkyl is optionally selected by 1-5 halogen and 1-3 Replace from following group: C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optionally further halogenated by 1-5 Group is to highest perhalogeno；

R^dIt is C_1-10Alkyl, Aryl or Ar-C_1-10Alkyl；

M is the integer selected from 0,1 and 2；

N is the integer selected from 0 to 6；

P is the integer selected from 0,1 and 2, and if at least one m and n are not that 0, Z is selected from CO₂R^a, 5- tetrazole and 5- (2- oxo -1,3,4- 4-oxadiazole base)；If m and n are that 0, Z is selected from 5- tetrazole and 5- (2- oxo -1,3,4- oxygen Miscellaneous di azoly),

X is selected from CH or N

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The method of high related illness, the method includes applying a effective amount of logical formula (III) compound represented to mammal Or its pharmaceutical salt or solvate

A indicates that wherein 0-4 hetero atom is N and 0-1 miscellaneous containing 1-4 heteroatomic 9-10 membered bicyclic hetero-aromatic rings Atom is O or S

The bicyclic heteroaryl is optional to be replaced by following group:

D) 1-5 halogen group；

E) 1 CO₂R^a, CN, S (O)_pR^d, NO₂, C (O) NR^bR^cAnd NR^bR^cGroup；

F) 1-2 C_1-10Alkyl or alkoxy base, the group is optional to be replaced by following group:

7) 1-5 halogen group is to whole haloalkyl；

8) 1 oxo group；

9) 1-2 hydroxyl group；

10) 1-2 C_1-10Alkoxy, the group are optional by 1 to 5 halogens or perhaloalkoxy groups, 1 hydroxyl Or CO₂R^aGroup replaces；

11) 1 CO₂R^aOr S (O)_pR^d

12) 1-2 aryl, Hetcy or HAR group, the group is optional to be replaced by following group:

E) 1-5 halogen group,

F) 1 hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

G) 1-2 C_1-10Alkyl or alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup replaces；With

H) aryl, HAR, Hetcy, the group is optional to be replaced by following group:

Iv.1-5 halogen group；

V.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Vi.1-2 C_1-10Alkyl and alkoxy, each optionally by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl Base or CO₂R^aGroup；

The aryl, HAR, Hetcy base is also optional to be replaced by group selected from the following；

6) 1-5 halogen group；

7) 1-2 hydroxyl group；

8) 1 CN, S (O)_pR^dOr NO₂Group；

9) 1-2 CO₂R^aGroup；

10)C(O)NR^bR^cGroup；

R^aIt is H or C_1-10Alkyl, the group are optional by phenyl, hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl Replace with 1-3 halogen；

R^bIt is H or C_1-10Alkyl；

R^cIt is that H or independent is selected from:

e)C_1-10Alkyl, the group are optional by hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl and 1-3 are a halogenated Alkyl replaces；

F) aryl or Ar-C_1-6Alkyl, the group is optional to be taken by 1-5 halogen and 1-3 selected from following component Generation: CN, hydroxyl, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optional further by 1-5 halo groups to most High perhalogeno；

G) Hetcy or Hetcy-C_1-6Alkyl, the group is optional to be selected from following group by 1-5 halogen and 1-3 Replace: oxo, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy it is optional further by 1-5 halo groups extremely Highest perhalogeno；With

H) HAR or HAR-C_1-6Alkyl, the group is optional to be taken by 1-5 halogen and 1-3 selected from following group Generation: C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optional further by 1-5 halo groups to highest perhalogeno Generation；

R^dIt is C_1-10Alkyl, Aryl or Ar-C_1-10Alkyl；

P is the integer selected from 0,1 and 2；

Each R¹It is independent to be selected from H or group below:

C) halogen；CO₂R^a, CN, hydroxyl, S (O)_pR^d, NO₂, C (O) NR^bR^cAnd NR^bR^c；

d)C_1-10Alkyl or OC_1-10Alkyl, the group is optional to be replaced by following group:

7) 1-5 halogen is until whole haloalkyl；

8) 1 oxo group；

9) 1-2 hydroxyl；

10) 1-2 C_1-10Alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 Hydroxyl or CO₂R^aGroup replaces；

11) 1 CO₂R^aOr S (O)_pR^d

12) 1-2 aryl, Hetcy or HAR group, the group is optional to be replaced by following group:

E) 1-5 halogen group,

F) 1 hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

G) 1-2 C_1-10Alkyl or alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup replaces；With

H) aryl, HAR, Hetcy, the group is optional to be replaced by following group:

Iv.1-5 halogen group；

V.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Vi.1-2 C_1-10Alkyl and alkoxy, each optionally by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl Or CO₂R^aGroup；

The aryl, HAR, Hetcy base is optional further to be replaced by group selected from the following:

6) 1-5 halogen group；

7) 1-2 hydroxyl group；

8) 1 CN, S (O)_pR^dOr NO₂Group；

9) 1-2 CO₂R^aGroup；

10)C(O)NR^bR^cGroup；

Wherein R^a, R^b, R^c, R^dIt is as defined above with p；

R²Selected from hydrogen and C_1-6Alkyl

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The method of high related illness, the method includes to mammal apply a effective amount of logical formula (IV) compound represented or Its pharmaceutical salt or solvate

Each R¹It is independent to be selected from hydrogen or following group:

C) halogen；CO₂R^a, CN, hydroxyl, S (O)_pR^d, NO₂；

D) C optionally replaced by following group_1-6Alkyl or OC_1-6Alkyl:

4) 1-5 halogen is until whole haloalkyl；

5)CO₂R^a；

6) phenyl optionally replaced by following group:

D.1-5 a halogen,

E.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

F.1-2 a C_1-10Alkyl or C_1-10Alkoxy；

R³It is hydrogen or C_1-3Alkyl；

R^aIt is H, C_1-6Alkane；

R⁵Selected from following group: C_1-10Alkyl, aryl or Ar-C₁-₁₀Alkyl；

R⁶And R⁷Expression H or C independent_1-3Alkyl, and p is 0,1 or 2.

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The method of high related illness, the method includes to mammal apply a effective amount of logical formula (I) compound represented or Its pharmaceutical salt or solvate

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The high related method for increasing related tumour with kidney type glutaminase active, the method includes applying to mammal A effective amount of logical formula (I), (II), (III) or (IV) compound represented or its pharmaceutical salt or solvate.

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The high related side for increasing related breast cancer, lung cancer, the cancer of the brain, cancer of pancreas and colon cancer with kidney type glutaminase active Method, the method includes to mammal apply a effective amount of logical formula (I), (II), (III) or (IV) compound represented or Its pharmaceutical salt or solvate.

In another embodiment of the invention, provide it is a kind for the treatment of or prevention and treatment with kidney type glutaminase active increase The high related side for increasing related breast cancer, lung cancer, the cancer of the brain, cancer of pancreas and colon cancer with kidney type glutaminase active Method, the method includes to mammal apply a effective amount of logical formula (I), (II), (III) or (IV) compound represented or Its pharmaceutical salt or solvate, method of application include intestinal canal administration, oral administration, subcutaneous administration, intravenous injection, muscle note It penetrates or peritonaeum external administration.

In another embodiment of the invention, provide a kind of for treating or preventing and treating and kidney type glutamine enzyme activity Property increase the pharmaceutical compositions of related neoplastic conditions, the composition include logical formula (I), (II), shown in (III) or (IV) Compound and its pharmaceutically acceptable salt or solvate, one or more other active pharmaceutical ingredients and one or more Pharmaceutically acceptable excipient.

In another embodiment of the invention, provide a kind of for treating or preventing and treating and kidney type glutamine enzyme activity Property increase the pharmaceutical compositions of related neoplastic conditions, the composition include logical formula (I), (II), shown in (III) or (IV) Compound and its pharmaceutically acceptable salt or solvate, one or more other anticancer drugs and it is one or more can medicine Use excipient.

In another embodiment of the invention, provides one kind and reduce in cell or tissue by glutamine enzymatic The method for decomposing the glutamic acid generated, this method include inhibiting the activity of glutaminase in nucleus tissue and effectively dropping The generation of hypoglutamatergic.

In another embodiment of the invention, provides one kind and reduce in cell or tissue by glutamine enzymatic The method for decomposing the glutamic acid generated, this method include inhibiting the activity of glutaminase in nucleus tissue and effectively dropping The medicinal purposes of relevant illness is increased in the generation of hypoglutamatergic to treat or prevent and treat to glutaminase active.

Detailed description of the invention

Fig. 1: the inhibition to kidney type glutaminase active

Fig. 2: gross tumor volume is with administration time change curve

Fig. 3: mouse weight is with administration time change curve

Detailed description of the invention

The present invention relates to the glutamic acid generated by glutaminase catalytic decomposition is reduced in cell or tissue.This method packet The generation for including the activity for inhibiting glutaminase in nucleus tissue and being effectively reduced glutamic acid..

The present invention provides a kind of completely new methods to determine and develop the drug for inhibiting glutaminase active.By Betide that glutamine metabolism is closely related, and the present invention can have a major impact in anticancer drug development field in tumour.

The present invention relates to a kind of pharmaceutical composition, one of ingredient of the composition is the change of structural formula I, II, III or IV Close object and pharmaceutically acceptable salt or solvate.

The present invention relates to the compounds for using structural formula I, II, III or IV and pharmaceutically acceptable salt or solvate The method for treating mammalian subject tumor disease.

The method for treating mammalian subject tumor disease by inhibiting glutaminase active the present invention relates to one, The effective dose of compound and pharmaceutically acceptable salt treatment tumour including structural formula I, II, III or IV.

In certain embodiments, cancer may be one or acute lymphoblastic leukemia (ALL), the white blood of acute myeloid Sick (AML), adrenocortical carcinoma, the relevant cancer of AIDS, cancer of anus, annex cancer, atypia monster sample/rhabdoid tumor One mutation, basal-cell carcinoma, bile duct cancer, bladder cancer, bone tumour, brain tumor, breast cancer, tumor of bronchus, Brukitt Lymthoma, chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), colon cancer, the carcinoma of the rectum, Gastrointestinal Stromal Tumor (GIST), gastric cancer, gastrointestinal associated cancers tumour, head and neck neoplasm, cardiac tumor, liver cancer (liver) cancer, non-small cell lung cancer, oral cavity Cancer, carcinoma of mouth, lip and oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma bone, oophoroma, cancer of pancreas, cutaneum carcinoma, carcinoma of small intestine, Small Cell Lung Cancer, t cell lymphoma.

At its widest aspect, the present invention relates to the compound of formula II or its drug acceptable salts or solvate Purposes, method and pharmaceutical composition:

Wherein: Y expression-C (O)-N (R⁵)-or-O-；A and B is independent to be selected from-C (O)-NH-R¹Or

R¹Indicate H or independently selected from:

e)C_1-16Alkyl or the group can optionally be replaced by following group:

13) 1-5 halo groups are to highest perhaloalkyl groups；

14) 1 oxo group；

15) 1-2 hydroxyl group；

16) 1-2 C_1-10Alkoxy base or the group can optionally be replaced by following group: 5 halogenated or halogen of highest For alkoxy, 1 hydroxyl or CO₂R^aGroup；

17) 1 CO₂R^aOr S (O)_pR^d

18) 1-2 aryl, Hetcy or HAR group or the group can optionally be replaced by following group:

I.1-5 a halo groups,

J.1 a hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

K.1-2 a C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 are halogenated, Highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；

1.1-2 benzyl ring or the group can optionally be replaced by following group: 1-5 halo groups to highest perhalogeno Generation, 1-3 C_1-10Alkyl or alkoxy base, it is further optionally halogenated a to highest perhalogeno or 1-2 by 1-5 respectively Hydroxyl or CO₂R^aGroup；

F) aryl, HAR, Hetcy or the group is optional is replaced by following group:

15) 1-3 C_1-10Alkyl or alkoxy base or the group is optional is replaced by following group: 1-5 halogen For group, 1-2 hydroxyl group；CO₂R^aGroup；CN；S(O)_pR^d, phenyl or the group can optionally replace by following group:

Vii.1-5 halo groups；

Viii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Ix.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 halogen Generation, highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；With

16) phenyl, the phenyl are optionally replaced by following group:

Vii.1-5 halo groups；

Viii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Ix.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 halogen Generation, highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup；

Aryl described above, HAR, Hetcy group can also be replaced on carbon by group selected from the following；

17) 1-5 halo groups；

18) 1-2 hydroxyl group；

19) 1 CN, S (O)_pR^dOr NO₂Group；

20) 1-2 CO₂R^aGroup；

21)C(O)NR^bR^cGroup；

R²It is independent selected from H or:

E) halogenated, hydroxyl, CO₂R^a, CN, S (O)_pR^dOr NO₂Group,

f)C_1-6Alkyl or OC_1-6Alkyl, the C_1-6Alkyl or OC_1-6Alkyl is optionally replaced by following group:

7) 1-5 halo groups are to highest perhaloalkyl groups；

8)CO₂R^a, CN, S (O)_pR^dOr hydroxyl group；

9) phenyl or the group can optionally be replaced by following group:

Vii.1-5 halo groups；

Viii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Ix.1-2 C_1-10Alkyl or alkoxy base or the group can optionally be replaced by following group: 1-5 is halogenated, Highest whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup

R³It is H or C_1-3Alkyl；

R⁵It is H or C_1-6Alkyl；

R⁶Selected from H, hydroxyl and C_1-3Alkyl；

R⁷It is H or F or R⁶And R⁷Oxo is indicated together；

R^aIt is H or C_1-10Alkyl, the C_1-10Alkyl is optionally by phenyl, hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6 Alkyl and 1-3 halogenated alkyl replace；

R^bIt is H or C_1-10Alkyl；

R^cIt is that H or independent is selected from:

i)C_1-10Alkyl, the C_1-10Alkyl is optionally by hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl and 1-3 are a Halogenated alkyl replaces；

J) aryl or Ar-C_1-6Alkyl, the aryl or Ar-C_1-6Alkyl is optionally selected by 1-5 halogen or 1-3 Replace from following component: CN, hydroxyl, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy optionally further by 1-5 halo groups are to highest perhalogeno；

K) Hetcy or Hetcy-C_1-6Alkyl, the Hetcy or Hetcy-C_1-6Alkyl is optionally by 1-5 halogen Replace with 1-3 selected from following group: oxo, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy optionally into One step is by 1-5 halo groups to highest perhalogeno；With

L) HAR or HAR-C_1-6Alkyl, the HAR or HAR-C_1-6Alkyl is optionally selected by 1-5 halogen and 1-3 Replace from following group: C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optionally further halogenated by 1-5 Group is to highest perhalogeno；

R^dIt is C_1-10Alkyl, Aryl or Ar-C_1-10Alkyl；

M is the integer selected from 0,1 and 2；

N is the integer selected from 0 to 6；

P is the integer selected from 0,1 and 2, and if at least one m and n are not that 0, Z is selected from CO₂R^a, 5- tetrazole and 5- (2- oxo -1,3,4- 4-oxadiazole base)；If m and n are that 0, Z is selected from 5- tetrazole and 5- (2- oxo -1,3,4- oxygen Miscellaneous di azoly),

X is selected from CH or N

The present invention relates to the compound of formula II I or the purposes, method and medicines of its drug acceptable salt or solvate Compositions

Wherein,

A indicates that wherein 0-4 hetero atom is N and 0-1 miscellaneous containing 1-4 heteroatomic 9-10 membered bicyclic hetero-aromatic rings Atom is O or S

The bicyclic heteroaryl is optional to be replaced by following group:

G) 1-5 halogen group；

H) 1 CO₂R^a, CN, S (O)_pR^d, NO₂, C (O) NR^bR^cAnd NR^bR^cGroup；

I) 1-2 C_1-10Alkyl or alkoxy base, the group is optional to be replaced by following group:

13) 1-5 halogen group is to whole haloalkyl；

14) 1 oxo group；

15) 1-2 hydroxyl group；

16) 1-2 C_1-1-Alkoxy, the group are optional by 1 to 5 halogens or perhaloalkoxy groups, 1 hydroxyl Or CO₂R^aGroup replaces；

17) 1 CO₂R^aOr S (O)_pR^d

18) 1-2 aryl, Hetcy or HAR group, the group is optional to be replaced by following group:

I) 1-5 halogen group,

J) 1 hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

K) 1-2 C_1-10Alkyl or alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup replaces；With

L) aryl, HAR, Hetcy, the group is optional to be replaced by following group:

Vii.1-5 halogen group；

Viii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Ix.1-2 C_1-10Alkyl and alkoxy, each optionally by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl Base or CO₂R^aGroup；

The aryl, HAR, Hetcy base is also optional to be replaced by group selected from the following；

11) 1-5 halogen group；

12) 1-2 hydroxyl group；

13) 1 CN, S (O)_pR^dOr NO₂Group；

14) 1-2 CO₂R^aGroup；

15)C(O)NR^bR^cGroup；

R^aIt is H or C_1-10Alkyl, the group are optional by phenyl, hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl Replace with 1-3 halogen；

R^bIt is H or C_1-10Alkyl；

R^cIt is that H or independent is selected from:

i)C_1-10Alkyl, the group are optional by hydroxyl, OC_1-6Alkyl, CO₂H, CO₂C_1-6Alkyl and 1-3 are a halogenated Alkyl replaces；

J) aryl or Ar-C_1-6Alkyl, the group is optional to be taken by 1-5 halogen and 1-3 selected from following component Generation: CN, hydroxyl, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optional further by 1-5 halo groups to most High perhalogeno；

K) Hetcy or Hetcy-C_1-6Alkyl, the group is optional to be selected from following group by 1-5 halogen and 1-3 Replace: oxo, C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy it is optional further by 1-5 halo groups extremely Highest perhalogeno；With

1) HAR or HAR-C_1-6Alkyl, the group is optional to be taken by 1-5 halogen and 1-3 selected from following group Generation: C_1-10Alkyl and OC_1-10Alkyl, the alkyl and alkoxy are optional further by 1-5 halo groups to highest perhalogeno Generation；

R^dIt is C_1-10Alkyl, Aryl or Ar-C_1-10Alkyl；

P is the integer selected from 0,1 and 2；

Each R¹It is independent to be selected from H or group below:

E) halogen；CO₂R^a, CN, hydroxyl, S (O)_pR^d, NO₂, C (O) NR^bR^cAnd NR^bR^c；

f)C_1-10Alkyl or OC_1-10Alkyl, the group is optional to be replaced by following group:

13) 1-5 halogen is until whole haloalkyl；

14) 1 oxo group；

15) 1-2 hydroxyl；

16) 1-2 C_1-10Alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 Hydroxyl or CO₂R^aGroup replaces；

17) 1 CO₂R^aOr S (O)_pR^d

18) 1-2 aryl, Hetcy or HAR group, the group is optional to be replaced by following group:

I) 1-5 halogen group,

J) 1 hydroxyl, CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

K) 1-2 C_1-10Alkyl or alkoxy, the group is optional by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl or CO₂R^aGroup replaces；With

1) aryl, HAR, Hetcy, the group is optional to be replaced by following group:

Vii.1-5 halogen group；

Viii.1 CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^cGroup；

Ix.1-2 C_1-10Alkyl and alkoxy, each optionally by 1-5 halogen, until whole haloalkyl and 1-2 hydroxyl Or CO₂R^aGroup；

The aryl, HAR, Hetcy base is optional further to be replaced by group selected from the following:

11) 1-5 halogen group；

12) 1-2 hydroxyl group；

13) 1 CN, S (O)_pR^dOr NO₂Group；

14) 1-2 CO₂R^aGroup；

15)C(O)NR^bR^cGroup；

Wherein R^a, R^b, R^c, R^dIt is as defined above with p；

R²Selected from hydrogen and C_1-6Alkyl

The present invention relates to the compound of structural formula IV or the purposes, method and medicines of its drug acceptable salt or solvate Compositions

Wherein,

A R¹It is independent to be selected from hydrogen or following group:

E) halogen；CO₂R^a, CN, hydroxyl, S (O)_pR^d, NO₂；

F) C optionally replaced by following group_1-6Alkyl or OC_1-6Alkyl:

7) 1-5 halogen is until whole haloalkyl；

8)CO₂R^a；

9) phenyl optionally replaced by following group:

G.1-5 a halogen,

H.1 a CO₂R^a, CN, S (O)_pR^d, NO₂Or C (O) NR^bR^c,

I.1-2 a C_1-10Alkyl or C_1-10Alkoxy；

R³It is hydrogen or C_1-3Alkyl；

R^aIt is H, C_1-6Alkane；

R⁵Selected from following group: C_1-10Alkyl, aryl or Ar-C_1-10Alkyl；

R⁶And R⁷Expression H or C independent_1-3Alkyl, and p is 0,1 or 2.

The present invention relates to the compound of structural formula I or the purposes, method and drugs of its drug acceptable salt or solvate Composition

Optical siomerism-diastereomer-geometric isomer-tautomer

Compound of many with structural formula I includes one or more center of asymmetries.Therefore, they may be used as racemization Body and raceme mixture, single enantiomter, non-enantiomer mixture and each diastereomer exist.The present invention includes All these isomeric forms of the compound, pure form and mixture.

Some compounds as described herein include olefinic double bonds, unless otherwise described, it is meant that including E and Z geometrical isomerism Both bodies.

Some compounds as described herein may exist different hydrogen tie points, referred to as tautomer.These examples can To be in the form of ketone and its enol form, referred to as ketone-enol tautomers.Each tautomer and its mixture are included in knot In structure Formula II

Salt and solvate

The salt and solvate of compound with structural formula I are included in the present invention.Term " drug acceptable salt " Refer to including that inorganic or organic or organic acid drug is subjected to salt made of significant non-toxic alkali or acid, and can be converted At the salt of drug acceptable salt.Salt derived from inorganic base include aluminium, ammonium, calcium, high-speed rail, ferrous iron, lithium, magnesium, manganese salt, sub- manganese, potassium, Sodium, zinc and analog.Especially preferably ammonium, calcium potassium, sodium salt.The salt for being subjected to organic non-toxic bases derived from drug includes Primary, secondary and tertiary amine, substituted amine (including cyclosubstituted amine naturally occur), cyclic amine and deacidite, such as essence Propylhomoserin, glycine betaine, caffeine, choline, N, N '-dibenzylethylenediamine, diethylamide, 2- diethylamino alcohol, 2- diformazan Base ethylaminoethanol, ethanol amine, ethylene diamine, N-ethylmorpholine, N-ethylpiperidine, gucosamine, Glucosamine, group ammonia Acid, kappa amine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidines, polynary polyimide resin, procaine, purine, Theobromine, triethylamine, Trimethylamine, tripropylamine, tromethamine and analog.

It is treated in combination

As previously mentioned, the compound in formula II can be used for treating, prevention, postpone and kidney type glutamine enzyme activity Property increase related illness, wherein preferably as anticancer drug use.Meanwhile the compound in formula II can with it is described herein Other diseases and the other medicines of symptom be used in combination.In a specific embodiment, pharmaceutical composition of the invention is also Include one or more other active medicine components.The compound of the present invention can be with the active medicine group in one or more fields Divide and is administered together.The composition can be single containing the compounds of this invention and one or more other active medicine components The form of composition.Alternatively, the composition can be two or more individual combination of compositions forms, wherein chemical combination of the invention Object is included in a kind of composition, and one or more other active medicine components are included in one or more individual compositions In.The other active medicine component described in the pharmaceutical composition for example can be another anti-tumor drug.It is described Anti-tumor drug can be selected from gemcitabine, Taxol, AZD-6244, RDEA119, ARRY-142886.

Unless otherwise prescribed, the present invention is described in detail using term defined below herein.

" alkyl ", and it is other with prefix " alkyl ", and such as alkoxy, alkanoyl and similar group are to comprising meaning The carbochain of number of carbon atoms can be straight chain, branch or ring-type, or combinations thereof.If be not specified by, linear or branched alkyl group base Group is expected to have 1-10 carbon atom.The example of alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, secondary and tertiary fourth Base, amyl, hexyl, heptyl, octyl, nonyl and analog.Naphthenic base is the subset of alkyl；If being not specified by atomicity, 3- 10 carbon atoms are desired, 1-3 carbocyclic ring rings condensed of formation.The example of naphthenic base includes naphthenic base, cyclobutyl, ring Amyl, cyclohexyl, suberyl, decahydro naphthalene and analog.

" alkenyl " refers to the carbochain comprising at least one carbon-to-carbon double bond, and can be linear chain or branched chain or combinations thereof.Chain The example of alkenyl includes vinyl, allyl, isoolefine propyl, pentenyl, hexenyl, heptenyl, 1- acrylic, 2- cyclobutenyl, 2- methyl-2-butene base and analog.

" alkynyl " refers to the carbochain comprising at least one carbon-carbon triple bond, and can be linear chain or branched chain or combinations thereof.Alkynyl Example include acetenyl, propargyl, 3- methyl-1-pentene alkynyl, 2- heptynyl and similar combination.

" aryl " (Ar) refers to the mono- and bicyclic aromatic ring comprising 6-12 carbon atom.The example of aryl includes phenyl, naphthalene Base, indenyl and analog." aryl " further includes the single ring being fused on aryl group.Example includes tetralyl, indenes Full base and analog.

" heteroaryl " (HAR) refers to the heteroatomic mono- or bicyclic aromatic ring or ring that O, S and N are selected from comprising at least one System, wherein each ring includes 5-6 atom.Example includes pyrrole radicals, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl group, evil Oxazolyl, thiadiazolyl group, thiazolyl, imidazole radicals, tetrazole radical, furyl, triazine radical, thienyl, pyrimidine radicals, is rattled away at 4-oxadiazole base Ying base, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzo thio-phenyl, furan (2,3-b) pyridine Base, quinolyl, indyl, isoquinolyl and analog.Heteroaryl further includes for heterocycle (being non-aromatic or partially aromatic) On aromatic heterocyclic group and aromatic heterocyclic group be used for cycloalkyl ring.Heteroaryl further includes these groups of charged species, such as Pyridinium.

" heterocycle " (Hetcy) refer to comprising at least one be selected from N, S and O heteroatomic mono- and bicyclic saturated rings with Ring system, each described ring have 3-10 atom, and wherein tie point can be carbon or nitrogen.The example of " heterocycle " includes pyrroles Alkyl, piperidyl, piperazinyl, imidazolidinyl, 2,3- dihydro furan (2,3-b) pyridyl group, benzoxazinyl-, tetrahydric quinoline group, four Hydrogen isoquinoline base, indolinyl and analog.The term further includes the part unsaturation monocycle for not being aromatics, such as passes through nitrogen 2- or 4- pyridone or the N- substitution of connection-(1H, 3H)-pyrimidine -2,4- diketone (uracil that N- replaces).Heterocycle is in addition These parts including charged species, as piperidines drone.

" halogen " (halogenated) includes fluorine, chlorine, bromine and iodine.

The compound of the present invention can be made according to the method summarized in following general synthetic schemes

In one embodiment of the invention, compound I can be made of intermediate II (videing infra)

Wherein R¹It is as defined above with A

Compound II is known in the literature and can facilitate preparation by a variety of methods well-known to those skilled in the art, Such as be disclosed in Katritsky et al., Advances in Heterocyclic Chemistry, Vol.6, pg347-429's Content, a route is as shown in scheme 1.Market goods is purchased to be esterified by using the methanol or ethyl alcohol of the acid containing such as sulfuric acid The ester 1 and 2 anionic condensation of methyl ketone prepared by corresponding carboxylic acid obtains diketone 3.Reaction is using the alkali of such as sodium hydride for example It is reacted 16 to 24 hours in the polar non-solute of tetrahydrofuran at 0to25 DEG C, referring to March, Advanced or ganic Chemistry, 3^rdEd., pg439 is incorporated in this compound 2 is purchased from market goods and can pass through art technology as a reference A variety of method preparations known to personnel.Then at 0to25 DEG C, diketone 3 is condensed instead in the polar solvent of such as toluene with hydrazine 4 It answers 16 to 24 hours, the acid of such as acetic acid or hydrochloric acid is contained in polar solvent.By using in such as tetrahydrofuran, dioxy six Ring, methanol, the sodium hydroxide of ethyl alcohol or similar in the mixed solvent or lithium hydroxide saponification ester II, the third ammonia of beta- can be carried out The processing herein of acid esters 8.Use 1- ethyl -3- (3- dimethylamino-propyl)-carbodiimides (EDCI) or 1- hydroxy phenyl three Azoles (HOBt) and the usually alkali of diisopropylethylamine are in such as n,N-Dimethylformamide (DMF) or the solvent of methylene chloride It reacts 3 to 48 hours at room temperature and obtains compound 5.By using in such as tetrahydrofuran, dioxane, methanol, ethyl alcohol or phase Intermediate compound I is obtained like the sodium hydroxide of in the mixed solvent or the saponification ester of lithium hydroxide.

According to scheme 2, benzyl hydrazine 4 passes through at an elevated temperature in the nonpolar solvent of such as toluene, in the presence of acetic acid phase The carbonyl analog answered is condensed 16 to 24 hours with tert-butyl carbazate and heads direct for.Then intermediate 6 uses such as cyano hydroboration The hydro-reduction agent of sodium and the reduction of 1 eq. of p-toluene sulfonic acid, should be added in a manner of being added dropwise.It reacts at room temperature, for example It is carried out 16-48 hours in the polar non-solute of tetrahydrofuran.Or if acetic acid is used as solvent, reaction can also not have It is carried out in the presence of p-methyl benzenesulfonic acid.After carrying out water phase processing, by being slowly added to sodium hydrate aqueous solution or other highly basic, boron Alkane complex compound can be decomposed to obtain carbamate 7.By at room temperature in methylene chloride at the acid of such as trifluoroacetic acid Reason 0.25-2 hours carries out BOC protecting group and sloughs.Reaction can be added or be added without tri isopropyl silane.Hydrazine 4 can deprotect again It is used directly in the form of trifluoroacetate afterwards, or free alkali can be prepared and passed through, aqueous hydrochloric acid solution is added and evaporates molten Agent is used in the form of hydrochloride.

Another method of synthetic compound of formula i includes the alkylation of pyrazoles III

Wherein R¹Is as defined above with A

Compound III is known in the literature and can prepare with a variety of methods well-known to those skilled in the art.Such as It is disclosed in the interior of Katritsky et al., Advances in Heterocyclic Chemistry, Vol.6, pg347-429 Hold.One route is as shown in Scheme 3.Be purchased from market goods by using containing such as sulfuric acid acid methanol or ethyl alcohol esterification by The ester 1 and 2 anionic condensation of methyl ketone of corresponding carboxylic acid preparation obtain diketone 3.Reaction is using the alkali of such as sodium hydride such as four It is reacted 16 to 24 hours in the polar non-solute of hydrogen furans at 0to25 DEG C, referring to March, Advanced or ganic Chemistry, 3^rdEd., pg439 is incorporated in this compound 2 is purchased from market goods and can pass through art technology as a reference A variety of method preparations known to personnel.Then at 0to25 DEG C, diketone 3 in the polar solvent of such as toluene with hydrazine

4 condensation reactions 16 to 24 hours contain the acid of such as acetic acid or hydrochloric acid in polar solvent.

As shown in Scheme 4, intermediate III can be converted into Formulas I via 9.The alkane of pyrazoles III and 4- carboalkoxy benzylbromide Baseization can be molten in the polarity of usually dimethylformamide using the alkali of such as sodium hydride or cesium carbonate after pyrazoles deprotonation In agent 0-25 DEG C reaction 3-24 hours.Sometimes the mixture of isomers will be formed.Then such as to the conversion gram of final compound Previously carried out to shown in ester 9.Sometimes, it will further be reacted from the product reacted described in scheme 4.These operation include but It is not limited to substitution, reduction, oxidation, alkylation, acylation and hydrolysis.

In another embodiment of the present invention, compound can be prepared by intermediate compound IV and (be seen below)

Wherein R¹Surely have as above and R indicates alkyl

Compound IV is known in the literature and can be prepared by a variety of methods well-known to those skilled in the art, these sides Method is for example disclosed in Katritsky, et al., Advances in Heterocyclic Chemistry, Vol.6, pg347- In 429.A kind of route is as shown in scheme 5.Be purchased from market or by using containing sulfuric acid acid methanol or ethyl alcohol esterification by Corresponding carboxylic acid obtains two ketone esters 11 with 2 anionic condensation of methyl ketone come the diester 10 of the oxalic acid prepared.In such as tetrahydrofuran In polar non-solute using such as hexamethyl silicon substrate azane lithium -78 DEG C -0 DEG C of reaction 2-24 hours, referring to March, Advanced Organic Chemistry, 3^rdEd., pg439 and be incorporated in this as reference.Compound 2 is purchased from market goods It can be prepared by a variety of methods well-known to those skilled in the art.Then at 0to25 DEG C, polarity of the diketone 3 in such as toluene With 4 condensation reaction of hydrazine 16 to 24 hours in solvent, the acid of such as acetic acid or hydrochloric acid is contained in polar solvent.

As shown in scheme 6, intermediate compound IV can be converted to Formulas I c.Pyrazoles IV and 4- methoxycarbonyl base benzyl bromide sodium hydride Or cesium carbonate does alkali, in dimethylformamide, is alkylated within 3-24 hours being alkylated 0-25 DEG C of reaction.In general, Alkylated primary product obtains compound 12, obtains the mixture of isomers sometimes.As W.C.Still it is equal J.Org.Chem., 43,2923, (1978) are described.

If the protecting group of compound 12 is tert-butyl, pyrazole carboxylic acid 13 at room temperature, with the dichloro of trifluoroacetic acid Dichloromethane processing 0.5-3 is obtained.Realize acid and the coupling of aromatic amine, can by dimethylformamide or methylene chloride, It is coupling reagent, diisopropyl second with 1- ethyl -3- (3- dimethylamino-propyl)-carbodiimides or 1- this triazole of hydroxyl -7- Amine does alkali, and reaction obtains amide 14 in 3-48 hours.If amine 15 is diamines, by being returned in the polar aprotic solvent of such as acetic acid Stream 30 minutes to 6 hours, intermediate 14 can be cyclized to form benzimidazole.By in such as tetrahydrofuran, methanol, ethyl alcohol or phase The saponification of methyl esters 14, and the condition being coupled using foregoing amides are carried out using sodium hydroxide or lithium hydroxide like in the mixed solvent, The coupling for realizing acid with beta- alanine 8, obtains compound Ic.

The route of preparation 17 is well known to those skilled in the art and easy can synthesize.Scheme 7, which is shown, works as heteroaryl Synthetic method when base is the quinoline of 3- substitution.At high temperature, such as with toluene make solvent, with ethoxy methylene malonic acid dimethyl Ester and the aniline reaction properly replaced obtain 4- oxyquinoline 16 (Reigel, B.；Lappin, B.H.；Adelson, B.H.； Jackson, R.I.；Albisetti, C.J.；Dodson, R.M.；Baker, R.H >, JACS vol68p12641946).With all Such as phosphorus oxychloride chlorinating agent handles 16 at high temperature and obtains chloro -16, then with such as palladium/carbon catalyst in atmosphere of hydrogen Reduction obtains compound 17.If desired, saponification 17 obtains acid.

As shown in scheme 8, the route of other synthetic intermediate III includes being condensed alkynyl ketone 19 with hydrazine.The route is disclosed in In the Thetrahedron Asymmetry, Vol.11, pg2483-2493,2000 that Cabarrocas et al. is delivered.Usually in example As DMF polar solvent in 0-25 DEG C reaction 16-24 hours.It is different that the preparation of intermediate 19 is included in -78 DEG C of uses such as two Propyl amido lithium is coupled alkynes with the amide of functionalized carboxylic acid appropriate in the polar non-solute of such as tetrahydrofuran 18. this reaction is disclosed in Tetrahedron Lett., Vol.22, pg3815,1981. alkynes 18 or purchased from market, Huo Zheyou Corresponding halide and alkynyl magnesium iodide preparation.With reference to the of Negishi et al., J.Org.Chem., Vol62, pg, 8957- 8960,1997 and Org.Lett.Vol.3, pg3111-3113,2001.

Step A:2- { 1- [4- (carbethoxyl group) phenyl] ethylidene } hydrazine carboxylic acid's tert-butyl ester

Tert-butyl carbazate (13.90g, 105mmol) and 4- acetylbenzoic acid ethyl ester (20.00g, 0.104mol) exist The appearance of toluene (120mL) is stirred overnight (15 hours) at 80 DEG C.2- { 1- [4- (carbethoxyl group) benzene is separated by crystalline solid Base] ethylidene } hydrazine carboxylic acid's tert-butyl ester.HPLC/MS:m/z=307.3 (M+1)⁺, R₁=3.47min.¹H NMR (500 MHz, CDCl₃): δ 8.05 (2H, d, J=8.5Hz), 7.88 (2H, d, J=8.5Hz), 7.79 (1H, brs), 4.41 (2H, q, J= 7.0Hz), 2.24 (3H, s), 1.58 (9H, s), 1.43 (3H, t, J=7.0Hz)

Step B:2- { 1- [4- (carbethoxyl group) phenyl] ethyl } hydrazine carboxylic acid's tert-butyl ester:

Under nitrogen atmosphere, NaBH₃CN (6.0g, 0.095mol) and 2- { 1- [4- (carbethoxyl group) phenyl] ethylidene } hydrazine Carboxylic acid tert-butyl ester (25.6g, 0.084mol) is dissolved in tetrahydrofuran (200mL).By p-methyl benzenesulfonic acid monohydrate (17.3g, Tetrahydrofuran (50mL) solution 0.091mol) is slowly dropped in above-mentioned system.After being added dropwise, by mixture acetic acid second Ester (200mL) dilution and with saturated common salt water washing (150mL).By organic phase drying, it is concentrated to get white solid.The white is solid Body is molten in methylene chloride and to be added 1N sodium hydroxide strong stirring after 1 hour, is washed with brine, dry, to be concentrated into volume big About 50 milliliters.White solid precipitated product is collected by filtration, is washed to obtain title compound with n-hexane.HPLC/MS:m/z= 331.3(M+Na)⁺, R_t=3.24min.¹H NMR (500MHz, CDCl₃): δ 8.03 (2H, d, J=8.0Hz), 7.44 (2H, d, J =8.0Hz), 5.99 (1H, br s), 4.40 (2H, q, J=7.0Hz), 4.29 (IH, m), 1.45 (9H, s), 1.41 (3H, U J =7.0Hz), 1.35 (3H, d, J=6.5Hz)

Step C:2- { 1- [4- (carbethoxyl group) phenyl] ethyl } hydrazine hydrochloride

2- { 1- [4- (carbethoxyl group) phenyl] ethyl } hydrazine carboxylic acid's tert-butyl ester (29g, 94mmol) is dissolved in 100 milliliters of TFA- In the mixed solution of DCM- tri isopropyl silane (20:20:1), handle 1 hour under room temperature.It, will be remaining after mixture concentration Object is dissolved in water, is washed with methylene chloride.Hydrochloric acid (5N, 20 milliliters) is added into aqueous solution and is concentrated into about 50 milliliters.Second is added Nitrile (50 milliliters) and be lyophilized obtain title compound.NMR (500MHz, acetone-d₆) δ: 1.34 (3H, t, J=7.1Hz)； 1.67 (3H, d, J=6.8Hz)；4.33 (2H, q, J=7.1Hz), 4.97 (1H, q, J=6.8Hz), 7.76 (2H, d, J= 8.5Hz), 7.97 (2H, d, J=8.5Hz) .MSC₁₁H_i6N₂O₂CaId:208.12；Obsd (M+1): 209.19.

Step A:2- [4- (carbometoxyl) benzyl] hydrazine carboxylic acid's tert-butyl ester

Title compound is prepared using the method for above-mentioned intermediate step A A and B.1H NMR (300MHz, DMSO-d₆) δ: 1.38 (9H, s)；3,84 (3H, s)；3.92 (2H, d, J=4.2Hz)；4.95 (1H, d, J=4.2Hz)；7.47 (2H, d, J= 8.4Hz)；7.90 (2H, d, J=8.1Hz)；8.29 (1H, s)

Step B. [4- (carbometoxyl) benzyl] hydrazine hydrochloride

Title compound is prepared using the method in above-mentioned intermediate step A C.NMR (500MHz, CD₃OD) δ: 3.91 (3H, s)；4.19 (2H, s)；7.54 (2H, d, J=8.3Hz)；8.05 (2H, d, J=8.3Hz) .MSC₉H₁₂N₂O₂CaId: 180.09；Obsd (M+1): 181.12.

Intermediate C

3- (3,5- dichlorophenyl) -1- [4- (methoxycarbonyl) phenyl] -1H- pyrazoles -5- carboxylic acid

Step A:3,5- Dichloro-N-methoxy-N-methyl-benzamide

At 0 DEG C, N, O- bis- is added into 50 milliliters of dichloromethane solutions of 3,5- dichlorobenzoyl chloride (5g, 23.9mmol) (under room temperature, above-mentioned system stirs methylhydroxylamine hydrochlorid by 2.56g, 26.3mmol and pyridine (4.3mL, 52.6mmo1) 16 hours.Water quenching reaction is added, is extracted with dichloromethane.Combined organic phase is dry, concentration, and by residue silica gel Post separation purifies to obtain title compound (SiO₂, 20% ethyl acetate/petroleum ether).¹H NMR (500MHz, CDCl₃) δ: 7.61 (2H, d, J=1.9Hz)；7.50 (1H, d, J=1.9Hz)；3.60 (3H, s)；3.40 (3H, s)

Step B:1- (3,5- dichlorophenyl) ethyl ketone

Methyl-magnesium-bromide is added dropwise into the 100mL tetrahydrofuran solution of step A product (5.42g, 23.2mmol) (11.6mL, 34.8mmol).After stirring 25 minutes at room temperature, 1N hydrochloric acid is added and is extracted with ethyl acetate.Combined organic phase Drying is concentrated to get title compound.¹H NMR (500MHz, CDCl₃) δ: 7.84 (2H, d, J=1.9Hz)；7.58 (1H, d, J =1.8Hz)；2.63 (3H, s)

Step C:4- (3,5- dichlorophenyl) -2,4- dioxobutyric acids tert-butyl ester

Two (trimethyl first silicon are added into the 100mL diethyl ether solution of step B product (4.1g, 21.7mmol) at -78 DEG C Alkane) amide lithium (23.9mL, 23.9mmol).After stirring 50 minutes, in -78 DEG C of addition solid di-t-butyl ethanedioic acid esters (4.18g, 20.66mmol).After stirring 2 hours under room temperature, be added another solid di-t-butyl ethanedioic acid ester (530mg, 2.6mmol), and continue stirring 16 hours.150mL1N hydrochloric acid is added and stirs 1 hour.Mixture is extracted with ethyl acetate It takes.Organic phase saturated common salt water washing, is dried and concentrated to obtain title compound.¹H NMR (500MHz, CDCl₃) δ: 7.84 (2H, d, J=1.9Hz)；7.59 (H, d, J=1.9Hz)；6.93 (1H, s)；1.56 (9H, s)

Step D:3- (3,5- dichlorophenyl) -1H- pyrazoles -5- carboxylic acid tert-butyl ester

Into the 125mL ethanol solution of step C product (6.8g, 21.7mmol) be added hydrazine (0.75mL, 23.9mmol) and 10mL glacial acetic acid.Reaction mixture is stirred at room temperature 16 hours, is suspended in ethyl acetate after concentration and by residue with full With sodium bicarbonate aqueous solution and brine It.Organic phase drying is concentrated to get title compound.

Step E:3- (3,5- dichlorophenyl) -1- [4- (methoxycarbonyl group) benzyl]-lH- pyrazoles -5- carboxylic acid tert-butyl ester

To the 50mLN of step D product (6.8g, 21.7mmol), cesium carbonate is added in the solution of dinethylformamide (10.6g, 32.6mmol) and gained mixture is stirred at room temperature 15 minutes.4- (bromomethyl) methyl benzoate is added It (5.46g, 23.9mmol) and continuously stirs 3 hours.Reactant dilutes with ethyl acetate and uses water and saturated common salt water washing.Have Machine uses silicagel column (SiO2,5% ethyl acetate/petroleum ether) separating-purifying to obtain title compound after being mutually dried and concentrated.¹H NMR (500MHz, CDCl₃) δ: 8.03 (2H, d, J=8.4Hz)；7.75 (2H, d, J=1.8Hz)；7.35 (3H, m)；7.12 (1H, s)；5.88 (2H, s)；3.94 (3H, s)；1.57 (9H, s)

Step F:3- (3,5- dichlorophenyl) -1- [4- (methoxycarbonyl group) benzyl] -1H- pyrazoles -5- carboxylic acid

13mL trifluoroacetic acid is added into the 30mL dichloromethane solution of step E product (5.54g, 12mmol) and in room temperature Lower stirring is concentrated after 16 hours.Residue dissolution is removed into excessive trifluoroacetic acid in concentration in methylene chloride and obtains white solid Title compound.¹H NMR (500MHz, CDCl₃) δ: 8.00 (2H, d, J=8.2Hz)；7.83 (2H, d, J=1.8Hz)； 7.41 (1H, d, J=1.9Hz)；7.36 (2H, d, J=8.3Hz)；7.32 (1H, s)；5.94 (2H, s)；4.87 (3H, s)

Embodiment 1

3- (6- ((3- (3 ' 5- dichlorophenyl) -5- (6- methoxyl group -2- naphthalene) -1H- pyrazol-1-yl) methyl) niacinamide Base) alanine

Step A:1- (3,5- dichlorophenyl) -3- (6- methoxyl group -2- naphthalene) propane -1,3- diketone

3,5- methyl p-dichlorobenzene is added into the tetrahydrofuran (1.5L) containing sodium hydride (38.9g, 974mmol) (160g, 730mmol).The reaction mixture be heated to 70C and be added 1- (6- methoxyl group -2- naphthalene) ethyl ketone (97g, 487mmol).By reaction mixture heated overnight at reflux.It is cooled to 0C water (1L) is added and the solid of generation is collected by filtration and obtain Title compound (160g, 88%).¹H NMR (DMSO): δ 7.77-7.89 (4H, m), 7.52 (1H, s), 7.30-7.36 (3H, M), 6.24 (1H, s)

Step B:3- (3,5- dichlorophenyl) -5- (6- methoxyl group -2- naphthalene) -1H- pyrazoles

Hydrazine hydrate (1.5mL) is added into ethyl alcohol (200mL) solution of step A product (10g, 26.8mmol) and heats back Flow through night.After being cooled to room temperature, generation solid is collected by filtration and obtains title compound (3.2g, 35%).¹H NMR (400MHz, Dmso) δ, 8.25 (1H, s), 7.96-7.87 (4H, m), 7.83 (1H, d, J=9.0Hz), 7.55 (1H, d, J=1.8Hz), 7.46 (1H, s), 7.34 (1H, d, J=2.5Hz), 7.20 (1H, dd, J=8.9,2.5Hz), 3.88 (3H, s)

Step C:6- (bromomethyl) methyl nicotinate

N- bromo is added into the solution of the carbon tetrachloride (20mL) containing 6- methyinicotinate (1.51g, 10mmol) Succinimide (1.78g, 10mmol) and AIBN (164mg, 0.1mmol).Heating after 2 hours, is cooled to room temperature filtering back Solid is removed, obtains title compound with silicagel column separating-purifying (15% ethyl acetate/petroleum ether) after filtrate concentration.¹H NMR (CDCl₃, 500MHz): 9.2 (d, J=2.0Hz, IH), 8.34 (dd, J=2.1,8.0Hz, IH), 7.58 (d, J=8.2Hz, IH), 4.6 (s, 2H), 4.0 (s, 3H) .LC-MS=1.71min；(M+H)=230.0.

Step D:6- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazoles -1- methyl) niacin first Ester

Into DMF (10mL) solution of step B product (522mg, 1.66mmol) be added step C product (460mg, 2.0mmol), cesium carbonate (815mg, 2.5mmol) then is added.It stirs 3 hours at room temperature, water quenching reaction is added and uses acetic acid Ethyl ester extraction.Organic phase saturated common salt water washing, after dry, concentration, with silicagel column separating-purifying (30% ethyl acetate/stone Oily ether) obtain title compound..¹H NMR(CDCl₃): δ 9.17 (1H, d, J=1.6Hz), 8.25 (1H, dd, J=8.0Hz, 2.0Hz), 7.75-7.79 (4H, m), 7.68 (1H, d, J=9.2Hz), 7.43 (1H, dd, J=8.8Hz, 2.0Hz), 7.32 (1H, t, J=2.0Hz), 7.19 (1H, dd, J=9.2Hz, 2.4Hz), 7.14 (1H, d, J=2.4Hz), 7.10 (1H, d, J= 8.0Hz), 6.77 (1H, s), 5.63 (2H, s), 3.95 (3H, s), 3.94 (3H, s)

Step E:6- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazoles -1- methyl) niacin

5N hydrogen-oxygen is added to of tetrahydrofuran containing step D product (0.14g, 0.24mmol)/methanol (1:1,10ml) Change sodium water solution (1mL).It stirs 2 hours at room temperature, concentration.Residue is acidified with 1N aqueous hydrochloric acid solution (10ml) and with acetic acid second Ester extraction obtains title compound after drying and concentrating.

Step F:3- (6- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazol-1-yl) methyl) Niacin hydroxyacyl amine) alanine ethyl ester

To containing step E product (65mg, 0.122mmol) DM (2mL) solution in be added HOAt (25mg, 0.184mmol), Beta-alanine carbethoxy hydrochloride (34mg, 0.184mmol), DIEA (64 μ L, 0.37mmo1) and EDCI (36mg, 0.l84mmol).Mixture is stirred overnight at room temperature, and water quenching reaction is added, is urged with ethyl acetate.Organic phase saturated common salt Water washing, gained residue obtains title compound with silicagel column separating-purifying (30% ethyl acetate/petroleum ether) after dry concentration Object.¹H NMR(CDCl₃): δ 8.93 (1H, d, 1.6Hz), 8.03 (1H, dd, J=8.4Hz, 2.4Hz), 7.75-7.81 (4H, m), 7.69 (1H, d, J=8.4Hz), 7.44 (1H, dd, J=8.4Hz, 1.6Hz), 7.30 (1H, t, J=2.0Hz), 7.19 (1H, Dd, J=8.8Hz, 2.4Hz), 7.14 (1H, d, J=1.6Hz), 7.10 (1H, d, J=8.4Hz), 6.90 (1H, t, J= 6.0Hz), 6.76 (1H, s), 5.60 (2H, s), 4.17 (2H, q, J=7.2Hz), 3.94 (3H, s), 3.73 (2H, q, J= 6.0Hz), 2.84 (2H, t, J=6.0Hz), 1.27 (3H, t, J=7.2Hz)

Step G:3- (6- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazol-1-yl) methyl) Nicotinoyl amido) alanine

Step F product (0.14g, 0.24mmol) is handled to obtain title compound with the method for step E.¹H NMR (CDCl₃): δ 9.11 (1H, d, J=1.2Hz), 8.32 (1H, dd, J=8.0Hz, 1.6Hz), 7.74-7.76 (3H, m), 7.72 (1H, s), 7.66-7.69 (2H, m), 7.35 (1H, dd, J=8.4Hz, 1.6Hz), 7.31 (1H, t, J=1.2Hz), 7.13- 7.19 (3H, m), 6.74 (1H, s), 5.60 (2H, s), 3.92 (3H, s), 3.67-3.73 (2H, m), 2.57 (2H, t, J= 5.2Hz).

Embodiment 2

4- (4- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazol-1-yl) methyl) phenoxy group) Butyric acid

Step A:4- (4- formvlphenoxv) ethyl butyrate

Sodium hydride is added in drying DMF (150mL) solution of 0 DEG C of 4- hydroxy benzenes first (5.0g, 41mmol) to cooling (1.96g, 49.1mmol).After stirring 15 minutes, it is added 4- bromobutyrate (7.02g, 49.1mmol).At room temperature, reactant It is stirred overnight.Water quenching reaction is added, and is extracted with ethyl acetate, with saturated common salt water washing.After organic phase is dried and concentrated, Residue is obtained into title compound with silicagel column separating-purifying (10% ethyl acetate/petroleum ether).¹H NMR(CDCl₃, 500MHz): 9.89 (1H, s), 7.84 (2H, d, J=8.7Hz), 7.01 (2H, d, J=8.7Hz), 4.18 (2H, q, J= 5.9Hz), 4.1 (2H, t, J=5.9Hz), 2.55 (2H, t, J=7.3Hz), 2.17 (2H, m), 1.28 (2H, t, J=7.4Hz) .LC-MS=I.89min, (M+H)=237.1.

Step B:4- [4- (methylol) phenoxy group] ethyl butyrate

Sodium borohydride is added into methanol (200mL) solution of the product (8.3g, 35.17mmol) from step A (1.96g, 52.7mmol).After being stirred at room temperature 2 hours, concentration.Residue is suspended in ethyl acetate, and with unsaturated carbonate hydrogen Sodium water solution and brine It.Title compound is obtained after the dry concentration of organic phase.¹H NMR(CDCl₃, 500MHz): 7.27 (2H, d, J=8.7Hz), 6.87 (2H, d, J=8.4Hz), 4.51 (2H, s), 4.16 (2H, q, J=7.1Hz), 4.0 (2H, t, J =6.0Hz), 2.52 (2H, t, J=7.3Hz), 2.1 (2H, m), 1.26 (3H, t, J=I.1Hz) .LC-MS=2.6min；(M+ 23)=261.1.

Step C:4- [4- (iodomethyl) phenoxy group] methyl butyrate

Triphenylphosphine (1.45g, 5.5mmol) is added into the acetonitrile solution of the product (1g, 4.24mmol) from step B With imidazoles (0.4g, 5.93mmol) and iodine (1.51g, 5.94mmol).It is stirred at room temperature after twenty minutes, with saturation Na₂S₂O₃It is water-soluble Liquid is quenched.It is extracted with ethyl acetate, organic phase saturated common salt water washing, after dry concentration, residue is mentioned with silica gel post separation Pure (15% ethyl acetate/petroleum ether) obtains title compound.¹H NMR(CDCl₃, 500MHz): 7.32 (2H, d, J=8.7Hz), 6.82 (2H, d, J=8.7Hz), 4.48 (2H, s), 4.18 (2H, q, J=6.1Hz), 4.01 (2H, t, J=6.1Hz), 2.53 (2H, t, J=7.4Hz), 2.14 (2H, m), 1.29 (3H, t, J=7.1Hz) .LC-MS=2.36min；(M+23)=371.0.

Step D:4- (4- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazol-1-yl) methyl) Phenoxy group) ethyl butyrate

It is added into DMF (5mL) solution of the product (85mg, 0.21mmol) from 1 step B of embodiment and comes from step C Intermediate (111mg, 0.31mmol), then be added cesium carbonate (103mg, 0.31mmol).It is stirred at room temperature 3 hours, water is added It is quenched, and is extracted with ethyl acetate.Organic phase saturated common salt water washing uses silicagel column separating-purifying (25% after dry concentration Ethyl acetate/petroleum ether) obtain title compound.¹H NMR(CDCl₃): δ 7.76-7.79 (3H, m), 7.72 (1H, s), 7.69 (1H, d, J=8.8Hz), 7.40 (1H, dd, J=8.4Hz, 1.6Hz), 7.29 (1H, t, J=2.0Hz), 7.20 (1H, dd, J= 8.8Hz, 2.8Hz), 7.17 (1H, d, J=2.4Hz), 7.06 (2H, d, J=8.8Hz), 6.81 (2H, d, J=8.8Hz), 6.67 (1H, s), 5.34 (2H, s), 4.14 (2H, q, J=6.8Hz), 3.98 (2H, t, J=6.0Hz), 3.95 (3H, s), 2.50 (2H, T, J=7.2Hz), 2.06-2.13 (2H, m), 1.25 (3H, t, J=7.2Hz)

Step E:4- (4- ((3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazol-1-yl) methyl) Phenoxy group) butyric acid

The intermediate (0.14g) from step D is handled using the operating method of step E in embodiment 1 and is marked Inscribe compound.¹H NMR(CDCl₃): δ 7.76-7.79 (3H, m), 7.73 (1H, s), 7.69 (1H, d, J=8.8Hz), 7.40 (1H, dd, J=8.4Hz, 1.6Hz), 7.29 (1H, t, J=1.6Hz), 7.20 (1H, dd, J=8.8Hz, 2.4Hz), 7.17 (1H, d, J=2.0Hz), 7.06 (2H, d, J=8.4Hz), 6.81 (2H, d, J=8.4Hz), 6.67 (1H, s), 5.35 (2H, S), 3.98 (2H, t, J=6.0Hz), 3.95 (3H, s), 2.56 (2H, t, J=7.2Hz), 2.05-2.12 (2H, m)

Embodiment 3

3- (4- ((3- (3,5- dichlorophenyl) -5- (6- methoxyl group -2- naphthalene) -1H- pyrazol-1-yl) methyl) benzoyl Base)-beta- alanine

Step A:4 ((3- (3,5- dichlorophenyl) -5- (6- methoxyl group naphthalene -2- base) -1H- pyrazol-1-yl) methyl) benzene Ethyl formate

To be mixed with 1- (3,5- dichlorophenyl) -3- (6- methoxynaphthalene -2- base) propane -1,3- diketone (100mg, 0.27mmol) heated back with toluene (20mL) solution of [4- (carbometoxyl) benzyl] hydrazine hydrochloride (40mg, 0.27mmol) Flow through night.After reaction system is concentrated, residue is obtained into title with silicagel column separating-purifying (petroleum ether: ethyl acetate=4:1) Compound (mg, 43%).¹H NMR (400MHz, cdcl₃) δ 7.96 (2H, d, J=8.1Hz), 7.75 (3H, t, J=5.5Hz), 7.69-7.60 (2H, m), 7.37-7.22 (6H, m), 7.21-7.11 (4H, m), 6.70 (1H, s), 5.45 (2H, s), 3.91 (6H, d, J=16.4Hz)

Step B:4- ((3- (3,5- dichlorophenyl) -5- (6- methoxyl group naphthalene -2- base) -1H- pyrazol-1-yl) methyl) benzene Formic acid

The intermediate (0.14g) from step A is operated using the operating method of step E in embodiment 1 and is marked Inscribe compound.

Step C:3- (4- ((3- (3,5- dichlorophenyl) -5- (6- methoxyl group naphthalene -2- base) -1H- pyrazol-1-yl) first Base) benzoyl)-beta- alanine ethyl ester

The intermediate (65mg, 0.122mmol) of step B handle using the operating method of step F in embodiment 1 To title compound.

Step D:3- (4- ((3- (3,5- dichlorophenyl) -5- (6- methoxyl group -2- naphthalene) -1H- pyrazol-1-yl) methyl) Benzoyl)-beta- alanine

Using the operating method of step E in embodiment 1 to the intermediate (0.14g, 0.24mmol) from step F at Reason obtains title compound.¹H NMR (DMSO-d6) δ: 8.44 (1H, t, NH, J=5.6Hz), 7.93 (2H, d, J=1.9Hz), 7.91 (1H, d, J=8.4Hz), 7.86 (1H, d, J=1.7Hz), 7.83 (1H, d, J=9.0Hz), 7.72 (2H, d, J= 8.4Hz), 7.56 (1H, t, J=1.9Hz), 7.43 (1H, dd, J=1.7,8.4Hz), 7.39 (1H, d, J=2.6Hz), 7.23 (1H, dd, J=2.6,9.0Hz), 7.20 (2H, d, J=8.4Hz), 7.16 (1H, s), 5.76 (2H, q, J=7.0Hz), 3.41 (2H, q, J=7Hz), 2.47 (2H, t, J=7Hz), 1.90 (3H, d, J=7.0Hz)

Embodiment 4

4- ((3- (3,5- dichlorophenyl) -5- (6- methoxyl group naphthalene -2- base) -1H- pyrazol-1-yl) methyl)-N- (1H- Tetrazolium -5- base) benzamide

Using the operating method of step F in embodiment 1 to the intermediate (65mg, 0.122mmol) of step B in embodiment 3 It is handled to obtain title compound.¹H NMR (400MHz, dmso) δ 8.07-7.87 (5H, m), 7.82 (1H, d, J= 9.2Hz), 7.54 (2H, dd, J=8.2,6.3Hz), 7.37 (1H, d, J=2.4Hz), 7.28-7.11 (3H, m), 5.60 (2H, S), 3.88 (3H, s)

Embodiment 5

3- (4- ((3- (3,5- dichlorophenyl) -5- (2,3- dihydro -1H- indenes -2- base carbonyl) -1H- pyrazol-1-yl) first Base) benzoyl)-beta- alanine

Step A:3- (3,5- dichlorophenyl)-N- (2,3- dihydro -1H- indenes -2- base) -1H- pyrazoles -5- formamide

Using the operating method of 1 step F of embodiment to (0.39g, 1.0mmo1) and 2- amino indenes (34mg, 0.184mmol It is handled to obtain title compound.

Step B:4- ((3- (3,5- dichlorophenyl) -5- (2,3- dihydro -1H- indenes -2- base carbonyl) -1H- pyrazol-1-yl) Methyl) methyl benzoate

Using the operating method of 1 step G of embodiment to intermediate (85mg, 0.21mmol) and 4- (bromine first from step A Base) methyl benzoate (111mg, 0.31mmol) handled to obtain title compound.¹H NMR(CDCl₃): δ 7.98 (2H, d, J =8.0Hz), 7.66 (2H, d, J=1.6Hz), 7.35 (2H, d, J=8.0Hz), 7.29 (1H, t, J=1.6Hz), 7.19- 7.25 (4H, m), 6.74 (1H, s), 6.19 (1H, d, J=7.6Hz), 5.85 (2H, s), 4.81-4.86 (1H, m), 3.90 (3H, S), 3.97 (2H, dd, J=16.4Hz, 7.2Hz), 2.84 (2H, dd, J=16.0Hz, 3.6Hz)

Step C:3- (4- ((3- (3,5- dichlorophenyl) -5- (2,3- dihydro -1H- indenes -2- base carbonyl) -1H- pyrazoles -1- Base) methyl) benzoic acid

It is handled to obtain title to from step B (0.14g) intermediate using the operating method of step E in embodiment 1 Compound.¹H NMR (DMSO): δ 8.16 (1H, d, J=7.2Hz), 7.81-7.83 (2H, m), 7.75 (2H, d, J=1.6Hz), 7.55 (1H, t, J=2.0Hz), 7.49 (1H, s), 7.12-7.23 (6H, m), 5.77 (2H, s), 4.80-4.85 (1H, m), 3.23 (2H, dd, J=16.4Hz, 7.6Hz), 2.89 (2H, dd, J=16.0Hz, 6.0Hz)

Step D:3- (4- ((3- (3,5- dichlorophenyl) -5- (2,3- dihydro -1H- indenes -2- base carbonyl) -1H- pyrazoles -1- Base) methyl) benzoyl)-beta- alanine ethyl ester

Using the operating method of step F in embodiment 1 to the intermediate (65mg, 0.122mmol) and Beta-alanine of step C Carbethoxy hydrochloride (34mg, 0.184mmol) is handled to obtain title compound.¹H NMR(CDCl₃): δ 7.67-7.71 (3H, M), 7.64 (2H, d, J=2.0Hz), 7.35 (2H, d, J=8.0Hz), 7.28 (1H, t, J=2.0Hz), 7.19-7.25 (3H, M), 6.83 (1H, t, J=6.0Hz), 6.76 (1H, s), 6.35 (1H, d, J=7.6Hz), 5.83 (2H, s), 4.81-4.87 (1H, M), 4.16 (2H, q, J=7.2Hz), 3.70 (2H, q, J=5.6Hz), 3.37 (2H, dd, J=16.0Hz, 6.8Hz), 2.85 (2H, dd, J=16.4Hz, 4.0Hz), 2.62 (2H, t, J=5.6Hz), 1.26 (3H, t, J=7.2Hz)

Step E:3- (4- ((3- (3,5- dichlorophenyl) -5- (2,3- dihydro -1H- indenes -2- base carbonyl) -1H- pyrazoles -1- Base) methyl) benzoyl)-beta- alanine

Using the operating method of step E in embodiment 1 to the intermediate (0.14g, 0.24mmol) from step F at Reason obtains title compound.¹H NMR (DMSO): δ 8.78 (1H, d, J=7.2Hz), 8.48 (1H, t, J=5.6Hz), 7.74- 7.79 (4H, m), 7.56 (1H, t, J=2.0Hz), 7.48 (1H, s), 7.27 (2H, d, J=8.0Hz), 7.21-7.23 (2H, M), 7.13-7.15 (2H, m), 5.80 (2H, s), 4.59-4.65 (1H, m), 3.42 (2H, q, J=6.0Hz), 3.23 (2H, dd, J=16.0Hz, 7.6Hz), 2.88 (2H, dd, J=16.0Hz, 6.0Hz), 2.47 (2H, t, J=6.8Hz)

Embodiment 6

(R) -3- (4- ((3- (3,5- dichlorophenyl) -5- (1- PhenethyIamino carbonyl) -1H- pyrazol-1-yl) methyl) benzene Formoxyl)-beta- alanine

Use the operation synthesising title compound of step A to E in embodiment 5.¹H NMR (DMSO): δ 8.91 (1H, d, J= 8.4Hz), 8.47 (1H, t, J=4.2Hz), 7.80 (2H, d, J=2.0Hz), 7.73 (2H, d, J=8.0Hz), 7.58-7.60 (2H, m), 7.30-7.35 (4H, m), 7.21-7.25 (3H, m), 5.75 (2H, s), 5.04-5.15 (1H, m), 3.43 (2H, q, J =6.0Hz), 2.48 (2H, t, J=7.2Hz), 1.45 (3H, d, J=6.8Hz)

Embodiment 7

3- (4- ((3- (3,5- dichlorophenyl) -5- (phenyl amino carbonyl) -1H- pyrazol-1-yl) methyl) benzoyl) - Beta- alanine

Use the operation synthesising title compound of step A to E in embodiment 5.¹H NMR (DMSO): δ 12.29-12.46 (1H, brs), 10.37 (1H, s), 8.48 (1H, t, J=4.2Hz), 7.84 (2H, d, J=1.6Hz), 7.76 (2H, d, J= 8.4Hz), 7.69-7.71 (3H, m), 7.62 (1H, t, J=2.0Hz), 7.37 (2H, t, J=8.4Hz), 7.30 (2H, d, J= 8.4Hz), 7.14 (1H, t, J=7.6Hz), 5.83 (2H, s), 3.42 (2H, q, J=5.6Hz), 2.46 (2H, t, J= 6.8Hz).

Embodiment 8

3- (4- ((5- (cyclohexylaminocarbonyl) -3- (3,5- dichlorophenyl) -1H- pyrazol-1-yl) methyl) benzoyl Base)-beta- alanine

Use the operation synthesising title compound of step A to E in embodiment 5.¹H NMR (DMSO): δ 12.13-12.31 (1H, brs), 8.47 (1H, t, J=4.2Hz), 8.32 (1H, d, J=8.0Hz), 7.75-7.78 (4H, m), 7.58 (1H, t, J =2.0Hz), 7.49 (1H, s), 7.27 (2H, d, J=8.4Hz), 5.79 (2H, s), 3.67-3.73 (1H, m), 3.43 (2H, q, J=5.6Hz), 2.48 (2H, t, J=7.2Hz), 1.71-1.81 (4H, m), 1.56-1.62 (1H, m), 1.21-1.31 (4H, M), 1.09-1.14 (1H, m)

Embodiment 9

3- (4- (1- (5- (6- methoxyl group naphthalene -2- base) -3- phenyl -1H- pyrazol-1-yl) ethyl) benzoyl) - Beta- alanine

Step A:1- (6- methoxyl group naphthalene -2- base) -3- phenylpropyl alcohol alkane -1,3- diketone

Title compound is prepared using the experimental method of step A in embodiment 1.¹H NMR(CDCl₃): δ 8.50 (1H, S), 8.02-8.06 (3H, m), 7.90 (1H, d, J=8.4Hz), 7.84 (1H, d, J=8.4Hz), 7.51-7.59 (3H, m), 7.24 (1H, dd, J=8.8Hz, 2.4Hz), 7.21 (1H, d, J=2.4Hz), 7.01 (1H, s), 3.97 (3H, s)

Step B:4- (1- (5- (6- methoxyl group naphthalene -2- base) -3- phenyl -1H- pyrazol-1-yl) ethyl) benzoic acid second Ester is using the experimental method of step A in embodiment 3 to intermediate and 2- { 1- [4- (carbethoxyl group) phenyl] second from step A Base } hydrazine hydrochloride reacted to obtain title compound.¹H NMR(CDCl₃): δ 7.97 (2H, d, J=8.0Hz), 7.93 (2H, D, J=8.4Hz), 7.75 (1H, d, J=8.4Hz), 7.67 (1H, d, J=8.8Hz), 7.64 (1H, d, J=2.0Hz), 7.43 (2H, t, J=7.6Hz), 7.30-7.34 (4H, m), 7.19 (1H, dd, J=8.8Hz, 2.8Hz), 7.16 (1H, d, J= 2.4Hz), 6.66 (1H, s), 5.59 (1H, q, J=7.2Hz), 4.36 (2H, q, J=7.2Hz), 3.95 (3H, s), 1.97 (3H, D, J=7.2Hz), 1.38 (3H, t, J=7.2Hz)

Step C:3- (4- (1- (5- (6- methoxyl group naphthalene -2- base) -3- phenyl -1H- pyrazol-1-yl) ethyl) benzoyl Base)-beta- alanine

It synthesizes to obtain title compound using the experimental method of step E to G in example 1.¹H NMR (DMSO): δ 12.19 (1H, s), 8.45 (1H, t, J=4.2Hz), 7.88-7.92 (4H, m), 7.84 (1H, d, J=8.8Hz), 7.73 (2H, d, J= 8.4Hz), 7.44-7.48 (3H, m), 7.40 (1H, d, J=2.4Hz), 7.34 (1H, t, J=7.2Hz), 7.21-7.25 (3H, M), 6.97 (1H, s), 5.74 (1H, q, J=6.0Hz), 3.91 (3H, s), 3.42 (2H, q, J=6.4Hz), 2.48 (2H, t, J =6.8Hz), 1.92 (3H, d, J=6.8Hz)

Embodiment 10

3- (4- (1- (3- (3,5- dichlorophenyl) -5- phenyl -1H- pyrazol-1-yl) ethyl) benzoyl)-beta- third Propylhomoserin

Step A:1- (3,5- dichlorophenyl) -3- phenylpropyl alcohol alkane -1,3- diketone

Title compound is obtained using the experimental method of step A in embodiment 1.¹H NMR (DMSO): δ 7.77-7.89 (4H, m), 7.52 (1H, s), 7.30-7.36 (3H, m), 6.24 (1H, s)

Step B:3- (4- (1- (3- (3,5- dichlorophenyl) -5- phenyl -1H- pyrazol-1-yl) ethyl) benzoyl) - Beta- alanine

Title compound is obtained using the experimental method of step E to G in step B in embodiment 9 and embodiment 1.¹HNMR (DMSO): δ 12.14-12.22 (1H, brs), 8.45 (1H, t, J=6.0Hz), 7.90 (2H, d, J=2.0Hz), 7.72 (2H, D, J=8.4Hz), 7.55 (1H, t, J=2.0Hz), 7.46-7.49 (3H, m), 7.35-7.37 (2H, m), 7.17 (2H, d, J= 8.4Hz), 7.08 (1H, s), 5.66 (1H, q, J=7.2Hz), 3.41 (2H, q, J=6.0Hz), 2.46 (2H, t, J= 6.0Hz), 1.87 (3H, d, J=7.2Hz)

Embodiment 11

N- (4- { 1- [3- (3,5- dichlorophenyl) -5- (7- methoxy quinoline -3- base) -1H- pyrazol-1-yl] ethyl } benzene Formoxyl)-beta- alanine

Step A:4- hydroxyl -7- methoxy quinoline -3- carboxylic acid, ethyl ester

Diethyl ethoxy methylene third is added into toluene (5mL) solution of m-toluidine (1.1Ig, 8.94mmo1) Two acid esters (1.93g, 8.94mmol).Reaction reflux is concentrated after 45 minutes.Residue is dissolved in phenylate (5mL) and is added to back In the phenylate of stream (10mL).Reflux was cooled to room temperature after 1 hour, and output solid is collected by filtration and obtains title compound.LC-MS: 2.08min；(M+H)=248.2.

The chloro- 7- methoxy quinoline -3- carboxylic acid, ethyl ester of step B:4-

Intermediate (890mg, mmol) from step A is suspended in POCl in phosphorus oxychloride₃(5mL) is simultaneously heated to reflux 1 Hour.It is poured into after cooling in the solution containing ice and 5N sodium hydroxide (30mL).It is extracted with ethyl acetate.Organic phase saturated carbon Sour hydrogen sodium solution and saturated common salt water washing.After dry concentration, gained residue obtains title compound with silicagel column separating-purifying Object.¹H NMR (500MHz, CDCl₃): 9.19 (1H, s), 8.33 (1H, s, 7=9.2Hz), 7.46 (1H, d, 7=2.5Hz), 7.36 (1H, dd, 7=2.5,9.1Hz), 4.53 (2H, q, 7=7.1Hz), 4.01 (3H, s), 1.5 (3H, t, 7=7.4Hz) .LC-MS:3.22min；(M+H)=266.1.

Step C:7- methoxy quinoline -3- carboxylic acid, ethyl ester

To from step B intermediate (400mg be added in the EtOH-EtOAc solution of 1:1 Pd/C (20mg) and It is stirred 3 hours under atmosphere of hydrogen.Excessive Pd/C is filtered to remove, gained filtrate is concentrated to get title compound.¹HNMR (500MHz, CDCl₃): 9.37 (1H, s), 9.26 (1H, s), 8.1 (1H, s), 8.09 (1H, d, 7=10.3Hz), 7.51 (1H, D, 7=9.3Hz), 4.49 (2H, q, 7=7.1Hz), 4.06 (3H, s), 1.42 (3H, t, 7=7.1Hz) .LC-MS:2.31min； (M+H)=232.1.

Step D:7- methoxy quinoline -3- carboxylic acid

The intermediate (399mg, mmol) of step C is handled using the experimental method of step E in embodiment 1 and is marked Inscribe compound.

Step E:N, 7- Dimethoxy-N-methyl -3- carboxylic acid amides

To the intermediate (1.5mmol) and N, O- dimethyl hydroxyl amine hydrochlorate (219mg, 2.25mmol) for deriving from step D Dichloromethane solution (20mL) in be added triethylamine (1.04mL, 7.5mmol) and bromination (tripyrrole alkane -1- base) phosphino- hexafluoro Phosphate (840mg, 1.8mmol).After reaction mixture is stirred at room temperature 3 hours, 1N hydrochloric acid (10mL) is added and is quenched.With two Chloromethanes extraction, organic phase are washed with saturated sodium bicarbonate aqueous solution, and after dry concentration, gained residue is mentioned with silica gel post separation Pure (70% ethyl acetate/petroleum ether) obtains title compound.¹H NMR (500MHz, CDCl₃): 9.15 (1H, d, 7= 1.8Hz), 8.5 (1H, d, 7=1.8Hz), 8.0 (1H, s), 7.7 (1H, d, 7=9.0Hz), 7.43 (1H, d, 7=2.2Hz), 7.24 (1H, dd, 7=2.5,9.0Hz), 3.96 (3H, s), 3.57 (3H, s), 3.43 (3H, s) .LC-MS:1.6min；(M+H) =247.1.

Step F:3- (3.5- dichlorophenyl) -1- (7- methoxy quinoline -3- base) propyl- 2- alkynes -1- ketone

To the chloro- 5- acetylenylbenzene (185mg, 1.08mmo1) of 1,3- bis- (in nitrogen atmosphere in anhydrous tetrahydrofuran solution Under be cooled to -78 DEG C), be added nButLi (750 μ L, 1.18mmol).The intermediate for deriving from step E is added in stirring after five minutes The tetrahydrofuran solution of (320mg, 1.3mmol).After reaction 30 minutes, it is quenched at room temperature with saturated aqueous ammonium chloride.Use second Acetoacetic ester extraction, and with saturated common salt water washing.Gained residue uses silicagel column separating-purifying (20% acetic acid after dry concentration Ethyl ester/petroleum ether) obtain title compound.¹H NMR (500MHz, CDCl₃): 9.54 (1H, d, 7=2.3Hz), 8.85 (1H, d, 7=2.1Hz), 7.92 (1H, d, 7=9.2Hz), 7.62 (2H, d, 7=2.0Hz), 7.5 (2H, m), 7.34 (1H, dd, 7= 2.5,8.9Hz), 4.04 (3H, s) .LC-MS:3.92min；(M+H)=356.0.

Step G:4- { 1- [3- (3,5- dichlorophenyl) -5- (7- methoxy quinoline -3- base) -1H- pyrazol-1-yl] ethyl } Benzene methyl ethyl ester

4- (diazanyl ethyl) benzene is added in tetrahydrofuran solution to the intermediate (118mg, 0.33mmo1) derived from step F Carboxvlate hvdrochloride (89mg, 0.36mmo1) and triethylamine (55 μ L, 0.39mmol).It is stirred overnight at room temperature.It is residual after concentration Excess water and ethyl acetate dilution.Organic phase saturated common salt water washing, the residue silica gel post separation after dry concentration Purification (25% ethyl acetate/petroleum ether) obtains title compound.¹H NMR (500MHz, CDCl₃): 8.76 (1H, d, 7= 2.0Hz), 8.04 (2H, d, 7=8.2Hz), 7.92 (1H, 1.8Hz), 7.85 (2H, d, 7=1.8Hz), 7.68 (1H, d, 7= 8.9Hz), 7.5 (1H, d, 7=2.1Hz), 7.36 (1H, t, 7=1.8Hz), 7.31 (2H, d, 7=8.0Hz), 6.76 (1H, s), 4.42 (1H, q, 7=7.0Hz), 4.03 (3H, s), 2.04 (3H, s), 2.01 (2H, t, 7=7.1Hz), 1.43 (3H, t, 7= 7.1Hz) .LC-MS:4.28min；(M+H)=546.0.

Step H:4- { 1- [3- (3,5- dichlorophenyl) -5- (7- methoxy quinoline -3- base) -1H- pyrazol-1-yl] ethyl } Benzoic acid

Using step E in embodiment 1 experimental method to derived from step G intermediate (67mg, 0.12mmol) at Reason obtains title compound.

Step I:N- (4- { 1- [3- (3,5- dichlorophenyl) -5- (7- methoxy quinoline -3- base) -1H- pyrazol-1-yl] second Base } benzoyl)-beta- alanine

Using the experimental method of step G in embodiment 1 to the intermediate (59mg, 0.11mmol) and β-the third for deriving from step H Propylhomoserin carbethoxy hydrochloride (33mg, 0.18mmol) is reacted to obtain title compound.¹H NMR (500MHz, CDCl₃): 8.75 (1H, bs), 7.9 (1H, s), 7.83 (2H, d, 7=1.8Hz), 7.75 (2H, d, 7=8.2Hz), 7.67 (1H, d, 7= 9.0Hz), 7.48 (1H, s), 7.34 (1H, t, 7=1.9Hz), 7.3 (2H, d, 7=8.3Hz), 6.92 (1H, t, 7=5.7Hz), 6.73 (1H, s), 5.56 (2H, q, 7=6.8Hz), 4.01 (3H, s), 3.71 (2H, q, 7=6.0Hz), 2.58 (2H, t, 7= 5.7Hz), 2.0 (3H, d, 7=6.9Hz), 1.48 (9H, s) .LC-MS:4.07min；(M+H)=645.0.

Step J:N- (4- { 1- [3- (3,5- dichlorophenyl) -5- (7- methoxy quinoline -3- base) -1H- pyrazol-1-yl] second Base } benzoyl)-beta- alanine

The intermediate (64mg) derived from step I is handled to obtain title using the experimental method of step E in embodiment 1 Compound.¹H NMR (DMSO, 500MHz) 8.8 (1H, d, 7=1.6Hz), 8.45 (1H, t, 7=5.5Hz), 8.38 (1H, s), 7.94 (2H, s), 7.92 (2H, d, 7=8.4Hz), 7.72 (2H, d, 7=8.0Hz), 7.58 (1H, s), 7.45 (1H, d, 7= 2.1Hz), 7.37 (1H, dd, 7=2.3,8.7Hz), 7.28 (1H, s), 7.2 (2H, d, 7=8.0Hz), 5.8 (1H, q, 7= 6.9Hz), 3.95 (3H, s), 3.41 (2H, q, 7=6.9Hz), 2.45 (2H, t, 7=7.1Hz), 1.93 (3H, d, 7= 6.9Hz) .LC-MS:3.53min；(M+H)=588.9.

Embodiment 12

3- (4- (1- (5- (6- bromo naphthalene -2- base) -3- (3,5- dichlorophenyl) -1H- pyrazol-1-yl) ethyl) benzoyl Base)-beta- alanine

Step A:1- (6- bromo naphthalene -2- base) ethyl ketone

Title compound is prepared using the experimental method of step A and B in intermediate C.¹H NMR (400MHz, cdcl₃) δ= 8.43 (1H, s), 8.09-8.03 (2H, m), 7.83 (2H, dd, J=10.8,8.8), 7.64 (1H, dd, J=8.7,1.9), 2.72 (3H, d, J=0.5)

Step B:1- (6- bromo naphthalene -2- base) -3- (3,5- dichlorophenyl) propane -1,3- diketone

It synthesizes to obtain title compound using step A in embodiment 9.¹H NMR (400MHz, dmso) δ 8.46 (1H, s), 8.18 (1H, d, J=1.6Hz), 8.08 (1H, d, J=8.4Hz), 7.99 (1H, d, J=8.8Hz), 7.86 (3H, d, J= 8.6Hz), 7.64-7.52 (2H, m), 6.43 (1H, s), 4.06 (1H, s), 3.15 (2H, s)

Step C:3- (4- (1- (5- (6- bromo naphthalene -2- base) -3- (3,5- dichlorophenyl) -1H- pyrazol-1-yl) ethyl) Benzoyl)-beta- alanine

Title compound is prepared using the synthetic method of step E to G in step B in embodiment 9 and embodiment 1.¹H NMR (400MHz, cdcl₃) δ 8.04 (1H, s), 7.86-7.75 (3H, m), 7.73-7.56 (5H, m), 7.41-7.32 (1H, M), 7.31-7.21 (3H, m), 6.84 (1H, t, J=6.0Hz), 6.71-6.63 (1H, m), 5.55 (1H, q, J=6.9Hz), 3.70 (2H, dd, J=11.6,5.9Hz), 2.67 (2H, t, J=5.7Hz), 1.97 (3H, dd, J=31.0,17.9Hz)

Embodiment 13

3- (4- (1- (3- (3,5- dichlorophenyl) -5- (quinoline -6- base) -1H- pyrazol-1-yl) ethyl) benzoyl) - Beta- alanine

Step A:1- (5- quinoline -6- base) ethyl ketone

Title compound is prepared using the experimental method of step A and B in intermediate C.¹H NMR (400MHz, cdcl₃)δ 9.00 (1H, dd, J=4.2,1.7Hz), 8.44 (1H, d, J=1.9Hz), 8.30-8.23 (2H, m), 8.15 (1H, d, J= 8.9Hz), 7.47 (1H, dd, J=8.3,4.2Hz), 2.75-2.71 (3H, m)

Step B:1- (3,5- dichlorophenyl) -3- (quinoline -6- base) propane -1,3- diketone

It synthesizes to obtain title compound using step A in embodiment 9.¹H NMR (400MHz, dmso) δ 9.04 (1H, d, J =2.6Hz), 8.94 (1H, s), 8.62-8.46 (2H, m), 8.24 (2H, d, J=1.8Hz), 8.16 (1H, d, J=8.9Hz), 7.94 (1H, s), 7.72-7.60 (2H, m)

Step C:3- (4- (1- (3- (3,5- dichlorophenyl) -5- (quinoline -6- base) -1H- pyrazol-1-yl) ethyl) benzene first Acyl group)-beta- alanine

Title compound is prepared using the synthetic method of step E to G in step B in embodiment 9 and embodiment 1.¹H NMR (400MHz, dmso) δ 8.96 (1H, d, J=2.6Hz), 8.79 (1H, s), 8.37 (1H, d, J=7.1Hz), 8.10 (1H, D, J=8.6Hz), 8.03 (1H, s), 7.94 (2H, d, J=1.9Hz), 7.73 (1H, d, J=8.7Hz), 7.67 (2H, d, J= 8.2Hz), 7.62-7.54 (2H, m), 7.23 (1H, s), 7.19 (2H, d, J=8.3Hz), 5.79 (1H, d, J=6.7Hz), 2.09 (3H, s), 1.91 (3H, d, J=6.9Hz)

Embodiment 14

3- (4- (1- (5- (6- methoxynaphthalene -2- base) -3- (4- (trifluoromethyl) phenyl) -1H- pyrazol-1-yl) ethyl) Benzoyl)-beta- alanine

Step A:1- (6- methoxynaphthalene -2- base) -3- (4- (trifluoromethyl) phenyl) propane -1,3- diketone

It synthesizes to obtain title compound using step A in embodiment 9.¹H NMR (400MHz, cdcl₃) δ 8.50 (1H, s), 8.14 (2H, d, J=8.7Hz), 8.03 (1H, dd, J=8.6,1.8Hz), 7.90 (1H, d, J=8.9Hz), 7.84 (1H, d, J =8.6Hz), 7.78 (2H, d, J=8.7Hz), 7.25 (1H, dd, J=8.9,2.5Hz), 7.20 (1H, d, J=2.4Hz), 7.01 (1H, s), 3.98 (3H, s)

Step B:3- (4- (1- (5- (6- methoxynaphthalene -2- base) -3- (4- (trifluoromethyl) phenyl) -1H- pyrazol-1-yl) Ethyl) benzoyl)-beta- alanine

Title compound is prepared using the synthetic method of step E to G in step B in embodiment 9 and embodiment 1.¹H NMR (400MHz, dmso) δ 8.44 (1H, t, J=5.5Hz), 8.12 (2H, d, J=8.2Hz), 7.94-7.87 (2H, m), 7.81 (3H, dd, J=16.8,8.7Hz), 7.72 (2H, d, J=8.3Hz), 7.44 (1H, d, J=8.5Hz), 7.39 (1H, d, J= 2.4Hz), 7.27-7.16 (3H, m), 7.10 (1H, s), 5.76 (1H, d, J=6.9Hz), 3.89 (3H, s), 3.41 (3H, dd, J =12.6,7.1Hz), 2.45 (2H, d, J=7.1Hz), 1.91 (3H, d, J=6.9Hz)

Embodiment 15

N- [4- ({ 3- (3,5- dichlorophenyl) -5- [5- (trifluoromethyl) -1H- benzimidazolyl-2 radicals-yl] -1H- pyrazoles -1- Base } methyl) benzoyl]-beta- alanine

Step A:4- ({ 3- (3,5- dichlorophenyl) -5- [5- (trifluoromethyl) -1H- benzimidazolyl-2 radicals-yl] -1H- pyrazoles - 1- yl } methyl) benzoic acid

3- (3,5- dichlorophenyl) -1- [4- (methoxycarbonyl group) benzyl] -1H- pyrazoles -5- carboxylic acid (36.7mg, 91umol), 4- (trifluoromethyl) benzene -1,2- diamines (52mg, 3eq.), DIEA (25ul, 1.5eq.) are dissolved in DMF (0.7ml) and are added DMF (0.2ml) solution of PyBOP (66mg, 1.4eq.).It stirs the mixture for 30 minutes, is quenched with acetonitrile: water (5%TFA). And purified to obtain title compound with reversed-phase HPLC.¹H NMR(CDC]₃): δ 9.42-9.48 (1H, brs), 8.13 (1H, s), 7.96 (2H, d, J=8.4Hz), 7.76 (2H, d, J=2.0Hz), 7.59 (1H, d, J=2.0Hz), 7.43 (2H, d, J= 8.4Hz), 7.36 (1H, t, J=2.0Hz), 7.05 (1H, s), 6.23 (2H, s), 3.88 (3H, s)

Step B:4- ({ 3- (3,5- dichlorophenyl) -5- [5- (trifluoromethyl) -1H- benzimidazolyl-2 radicals-yl] -1H- pyrazoles - 1- yl } methyl) benzoic acid

The intermediate (45mg, 82umol) of step A is handled to obtain using the experimental method of step E in embodiment 1 Title compound.¹H NMR (DMSO): δ 13.52 (1H, s), 12.80-12.96 (1H, brs), 7.99 (1H, s), 7.89 (1H, S), 7.81-7.83 (3H, m), 7.78 (2H, d, J=2.0Hz), 7.55-7.58 (2H, m), 7.32 (2H, d, J=8.0Hz), 6.24 (2H, s)

Step C:N- [4- ({ 3- (3,5- dichlorophenyl) -5- [5- (trifluoromethyl) -1H- benzimidazolyl-2 radicals-yl] -1H- pyrrole Azoles -1- base } methyl) benzoyl]-beta- alanine

The intermediate of above-mentioned steps B is handled to obtain title compound using step F and E in embodiment 1.¹HNMR (DMSO): δ 13.45-13.55 (1H, brs), 12.13-12.22 (1H, brs), 8.43 (1H, t, J=6.0Hz), 8.01-8.15 (1H, brs), 7.77-7.95 (3H, m), 7.73 (2H, d, J=8.0Hz), 7.63-7.65 (2H, m), 7.59 (1H, d, J= 8.0Hz), 7.35 (2H, d, J=8.0Hz), 6.20 (2H, s), 3.39 (2H, q, J=7.2Hz), 2.46 (2H, t, J= 7.2Hz).

Embodiment 16

N- (4- { (1S) -1- [3- (3,5- dichlorophenyl) -5- (6- methoxynaphthalene -2- base) -1H- pyrazol-1-yl] ethyl } Benzoyl)-beta- alanine

It synthesizes to obtain title compound using the synthetic method of step A to D in intermediate B and embodiment 3¹H NMR (DMSO-d6) δ: 8.44 (1H, t, NH, J=5.6Hz), 7.93 (2H, d, J=1.9Hz), 7.91 (1H, d, J=8.4Hz), 7.86 (1H, d, J=1.7Hz), 7.83 (1H, d, J=9.0Hz), 7.72 (2H, d, J=8.4Hz), 7.56 (1H, t, J= 1.9Hz), 7.43 (1H, dd, J=1.7,8.4Hz), 7.39 (1H, d, J=2.6Hz), 7.23 (1H, dd, J=2.6,9.0Hz), 7.20 (2H, d, J=8.4Hz), 7.16 (1H, s), 5.76 (1H, q, J=7.0Hz), 3.89 (3H, s), 3.41 (2H, q, J= 7Hz), 2.47 (2H, t, J=7Hz), 1.90 (3H, d, J=7.0Hz)

Bioassay

The section Example designed in the present invention is to pharmacodynamic study in glutaminase external activity test and animal body It is completed by following experiment.

Recombinate the active detection of glutaminase

Glutamic acid Enzyme assay system uses recombinase.The GAC (128~603 residue) of one section of encoding human is cloned into In pET128a carrier (Novagen production), it is transformed into Escherichia coli by BL21 competent cell.Albumen n end is marked with His Label, with ni-sepharose purification, dialysis is concentrated to 40uM, and -80 degree refrigerators save.Recombinate GAC (80nM) and untested compound (20uM) 37 Degree Celsius being incubated for 60 minutes reaction volumes is 22.5ul (PH8.0), and reaction buffer is 50mMTris- acetic acid (pH8.6), 0.2mM EDTA, 150mM KH₂PO₄.Compound is dissolved with DMSO, and the compound volume that all samples are added is constant, and protects The DMSO concentration that card reaction is incubated for is (0.2%v/v), and the L-Glutamine solution of final concentration 20mM is added in reaction, whole body Product 25ul, 37 degree of reaction 20min are added the 3M hydrochloric acid that 5ul is pre-chilled on ice and terminate reaction, 200ul second step reaction mixture packet Include 200mM hydrazine hydrate, 80mM Tris- acetic acid (pH9.4), 0.35mM adenosine diphosphate (ADP) (ADP), two core of 2mM nicotinamide adenine Thuja acid (NAD), 0.6U/mL glutamte dehydrogenase GDH), it is added in each reaction, final volume is 230ul (PH8.0), room temperature React 60min, the detection of wavelength 340nm light absorption.The light that sample absorbance value subtracts the reaction mixture of nothing-glutamine is inhaled Receipts value calculates the activity of enzyme.According to the above test method, different compounds are determined to kidney type glutaminase active (figure 1)

Internal pharmacodynamic study

Method:

The BALB/c Female nude mice (Beijing Vital River Experimental Animals Technology Co., Ltd.) of 6 week old is used for intracorporal medicine Effect learns research.5×10⁶The Colo-205 tumour cell (ATCC production) of volume is suspended in the RPMI-1640 of the serum-free of 100ul It cultivates in (Invitrogen production) base, is injected into mouse bilateral and tucks in down, detect gross tumor volume, the formula used with vernier caliper For gross tumor volume (cubic millimeter)=(w²× L)/2, the wherein length of the width L=tumour of w=tumour, unit is millimeter.When Gross tumor volume reaches 150~200 cubic millimeters, and mouse is randomly divided into four groups (every group of 4~5 mouse) and pyrazoles is administered orally respectively Class compound (300mg/kg), CT-034 (1mg/kg), pyrazole compound and CT-034 composite reagent, solvent are (20% SBE), it is administered once a day, is administered continuously 14 days, is analyzed in the 7th, 10,14 day measurement gross tumor volume and weight for data, meter Tumor growth inhibition (TGI) and changes of weight are calculated, compared with the control group.

As a result:

Pyrazole compound and mek inhibitor CT-034 drug combination are in nude mice Colo-205 heteroplastic transplantation tumor model Tumour growth shows apparent inhibitory effect (table 1).In Colo-205 tumor suppression model, in oral 300mg/kg pyrrole After 14 days, tumor control rate (TGI) is increased to 98% or more (pyrazoles for azole compounds and 1mg/kg CT-034 co-administered The tumor control rate that compound and CT-034 are administered alone is 60% and 73%) respectively.Meanwhile nude mice changes of weight is normal, does not have Show apparent toxic side effect (Fig. 2 and 3).

Table 1: tumor control rate and changes of weight after administration 14 days

。

Claims (1)

1. formula (I) compound represented or its pharmaceutical salt be used to treat increase with kidney type glutaminase active it is related Illness drug preparation in purposes,

Illness therein is breast cancer, lung cancer, the cancer of the brain, cancer of pancreas and colon cancer.