CN101611014B

CN101611014B - Acylaminopyrazoles as FGFR inhibitors

Info

Publication number: CN101611014B
Application number: CN2007800516051A
Authority: CN
Inventors: K·M·富特; M·-E·西奥克利托; A·P·汤玛斯; D·巴塔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2006-12-21
Filing date: 2007-12-20
Publication date: 2012-05-30
Anticipated expiration: 2027-12-20
Also published as: ES2364864T3; AR110227A2; CN101611014A; UA96969C2

Abstract

There is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof. There are also provided processes for the manufacture of a compound of Formula 1, and the use of a compound of Formula 1 as a medicament and in the treatment of cancer.

Description

Amido pyrazole compound as the FGFR suppressor factor

The present invention relates to pyrazole derivatives, prepare their method, comprise their pharmaceutical composition, be used for the method for pharmaceutical compositions, and their purposes in treatment.

Protein kinase is one type of protein (enzyme) of regulating various cell functions.This is that phosphorylation through specific amino acids on protein substrate makes the substrate protein conformational change accomplish.Active or itself and other the interactional ability of binding partners of substrate is regulated in the variation of conformation.The enzymic activity of protein kinase is meant that kinases adds the speed of phosphate groups on the substrate.This can measure through for example measuring the amount of the substrate that is converted into product and the function of time.The phosphorylation that occurs substrate in the active sites of protein kinase.

Tyrosylprotein kinase is converted into the Asia group of the protein kinase of tyrosine residues for the terminal phosphate of catalysis Triphosaden (ATP) on protein substrate.These kinases have vital role in the propagation of the growth factor signal conduction that causes cell proliferation, differentiation and migration.

Fibroblast growth factor (FGF) is considered to the important medium of many physiological processs (taking place like form in growth and the blood vessel generating process).Exist at present and surpass 25 kinds known FGF family member.Fibroblast growth factor acceptor (FGFR) family comprises four members, and it respectively is made up of the outer ligand binding domain of born of the same parents, single span film district and cell endoplasm protein tyrosine kinase district.Under FGF stimulated, dimerisation and transphosphorylation took place in FGFR, and this causes receptor activation.The activation of acceptor is enough to recover and activate specific downstream signal mating partner; Said downstream signal mating partner is participated in the adjusting of various processes such as cell growth, cellular metabolism and cell survival and (is summarized in Eswarakumar; V.P. etc.; Cytokine&Growth Factor Reviews 2005,16, the 139-149 page or leaf).As a result, FGF and FGFR might cause and/or promote tumour to form.

Present considerable evidence shows that the conduction of FGF signal is directly relevant with human cancer.There is the expression of various FGF in tumor type such as bladder, kidney cell and prostate gland (and the other) tumour of the different range of being reported in to increase.FGF also is described to strong angiogenesis factor.Report that in addition FGFR expresses in endotheliocyte.The activated mutant of various FGFR and bladder cancer and multiple myeloma (and other) are relevant, have document proof acceptor on prostate gland and bladder cancer and other, also to have expression (to summarize in Grose R. etc. simultaneously; Cytokine&Growth FactorReviews 2005,16,179-186 page or leaf and Kwabi-Addo; B. etc.; Endocrine-Related Cancer 2004,11, the 709-724 page or leaf).Owing to these reasons, particularly because the treatment of target FGFR and/or the conduction of FGF signal can directly influence tumour cell and tumor vessel takes place, the FGF signal transducting system is attractive treatment target spot.

The invention provides formula (I) compound or its pharmacy acceptable salt:

Wherein

Optional 5-or the 6-unit aromatic group that comprises at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur of ring A representative;

Optional 5-or the 6-unit aromatic group that comprises at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur of ring B representative;

R ¹Independent separately expression

Halogen,

Oh group,

Cyano group,

C ₁-C ₃Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁴R ⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

C _3-5Group of naphthene base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁶R ⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

C ₂-C ₃Kiki alkenyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁸R ⁹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

Phenyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ¹⁰R ¹¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

4 to 6-unit's heterocyclic radical groups, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ¹²R ¹³(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

C ₁-C ₃Alkoxy grp, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

-NR ¹⁶R ¹⁷Group,

-OCOR ¹⁸Group,

-CO ₂R ¹⁹Group,

-CONR ²⁰R ²¹Group,

-NR ²²COR ²³Group,

-NR ²⁴CO ₂R ²⁵Group,

-OSO ₂R ²⁶Group,

Perhaps two adjacent R ¹The atom that group connects with them forms 4 to 7-unit's carbocyclic ring or heterocycles, and said carbocyclic ring or heterocycle are optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ²⁷R ²⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

R ²Independent separately expression

Oh group,

Halogen,

Cyano group,

-CO ₂R ²⁹Group,

-CONR ³⁰R ³¹Group,

-NR ³²COR ³³Group,

-NR ³⁴CO ₂R ³⁵Group,

-NR ³⁶R ³⁷Group,

-SO ₂R ³⁸Group,

-SO ₂NR ³⁹R ⁴⁰Group,

-NR ⁴¹SO ₂R ⁴²Group,

C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴³R ⁴⁴(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by one or more substituted 4 to 7-unit's heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl), halogen, hydroxyl and 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), cyanic acid, halogen and hydroxyl,

C ₃-C ₆Group of naphthene base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁸R ⁴⁹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁰R ⁵¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

C ₂-C ₆Kiki alkenyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵²R ⁵³(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁴R ⁵⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, cyanic acid, C _1-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, oxo, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

C ₁-C ₆Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base ,-NR ⁶²R ⁶³(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁶⁴R ⁶⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

Perhaps two adjacent R ²The atom that group connects with them forms 4 to 7-unit's carbocyclic ring or heterocycles, and said carbocyclic ring or heterocycle are optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁶⁶R ⁶⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

R ³Represent hydrogen,

C ₁-C ₃Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁶⁸R ⁶⁹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

A is 0,1,2,3 or 4;

B is 0,1,2,3 or 4;

R ⁴And R ⁵Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁴And R ⁵The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁶And R ⁷Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁶And R ⁷The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁸And R ⁹Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁸And R ⁹The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ¹⁰And R ¹¹Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ¹⁰And R ¹¹The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ¹²And R ¹³Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ¹²And R ¹³The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ¹⁴And R ¹⁵Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ¹⁴And R ¹⁵The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ¹⁶And R ¹⁷Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ¹⁶And R ¹⁷The nitrogen-atoms that connects with their forms 4 to 6-unit's saturated heterocyclics, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ¹⁸Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ¹⁹Represent hydrogen, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²⁰And R ²¹Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ²⁰And R ²¹The nitrogen-atoms that connects with their forms 4 to 6-unit's saturated heterocyclics, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²²Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²³Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²⁴Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²⁵Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²⁶Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ²⁷And R ²⁸Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ²⁷And R ²⁸The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ²⁹Represent hydrogen, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³⁰And R ³¹Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ³⁰And R ³¹The nitrogen-atoms that connects with their forms 4 to 6-unit's saturated heterocyclics, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³²Represent hydrogen, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³³Represent hydrogen, C ₁-C ₄Alkyl, C ₃-C ₆Naphthenic base or optional comprises 5-or the 6-unit aromatic group of at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³⁴Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³⁵Represent hydrogen, C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³⁶And R ³⁷Independent separately hydrogen, the C of representing ₁-C ₄Alkyl, C ₂-C ₄Alkynyl, C ₃-C ₆Naphthenic base or optional 5-or the 6-unit aromatic group that comprises at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, or R ³⁶And R ³⁷The nitrogen-atoms that connects with their forms 4 to 6-unit's saturated heterocyclics, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl, trifluoromethyl and can choose wantonly: halogen, C by one or more substituted 4 to 7-unit carbocylic radical or heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl, trifluoromethyl);

R ³⁸Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ³⁹And R ⁴⁰Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ³⁹And R ⁴⁰The nitrogen-atoms that connects with their forms 4 to 6-unit's saturated heterocyclics, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ⁴¹Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ⁴²Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl);

R ⁴³And R ⁴⁴Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁴³And R ⁴⁴The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁴⁵And R ⁴⁶Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁴⁵And R ⁴⁶The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁴⁷Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁴⁸And R ⁴⁹Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁴⁸And R ⁴⁹The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁵⁰And R ⁵¹Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁵⁰And R ⁵¹The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁵²And R ⁵³Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁵²And R ⁵³The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁵⁴And R ⁵⁵Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁵⁴And R ⁵⁵The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁵⁶And R ⁵⁷Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁵⁶And R ⁵⁷The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁵⁸Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁵⁹And R ⁶⁰Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁵⁹And R ⁶⁰The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁶¹Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁶²And R ⁶³Independent separately hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁶²And R ⁶³The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁶⁴And R ⁶⁵Independent separately hydrogen, the C of representing ₁-C ₆Alkyl or C ₃-C ₆Naphthenic base, or R ⁶⁴And R ⁶⁵The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁶⁶And R ⁶⁷Independent separately hydrogen, the C of representing ₁-C ₆Alkyl or C ₃-C ₆Naphthenic base, or R ⁶⁶And R ⁶⁷The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁶⁸And R ⁶⁹Independent separately hydrogen, the C of representing ₁-C ₆Alkyl or C ₃-C ₆Naphthenic base, or R ⁶⁸And R ⁶⁹The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics; And wherein

When Y represents CH ₂The time, X represents CH ₂, O, NR ⁷⁰Or S (O) _X, R wherein ⁷⁰Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base and x are 0,1 or 2; Perhaps

When X represents CH ₂The time, Y represents CH ₂, O, NR ⁷¹Or S (O) _y, R wherein ⁷¹Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base and y are 0,1 or 2.

The invention provides formula (I) compound or its pharmacy acceptable salt:

Wherein

R ¹Independent separately expression

Halogen,

Oh group,

Cyano group,

C _3-5Group of naphthene base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C _{3 alkane}The base sulfenyl ,-NR ⁶R ⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

-NR ¹⁶R ¹⁷Group,

-OCOR ¹⁸Group,

-CO ₂R ¹⁹Group,

-CONR ²⁰R ²¹Group,

-NR ²²COR ²³Group,

-NR ²⁴CO ₂R ²⁵Group,

-OSO ₂R ²⁶Group,

R ²Independent separately expression

Oh group,

Halogen,

Cyano group,

-CO ₂R ²⁹Group,

-CONR ³⁰R ³¹Group,

-NR ³²COR ³³Group,

-NR ³⁴CO ₂R ³⁵Group,

-NR ³⁶R ³⁷Group,

-SO ₂R ³⁸Group,

-SO ₂NR ³⁹R ⁴⁰Group,

-NR ⁴¹SO ₂R ⁴²Group,

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, cyanic acid, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, oxo, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

R ³Represent hydrogen,

A is 0,1,2,3 or 4;

B is 0,1,2,3 or 4;

R ⁴⁷Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁵⁸Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁶¹Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁶⁸And R ⁶⁹Independent separately hydrogen, the C of representing ₁-C ₆Alkyl or C ₃-C ₆Naphthenic base, or R ⁶⁸And R ⁶⁹The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics; Wherein

When X represents CH ₂The time, Y represents CH ₂, O, NR ⁷¹Or S (O) _y, R wherein ⁷¹Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base and y are 0,1 or 2; And

Precondition is that said compound does not do

4-benzamido--N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM,

6-anilino-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide,

N-[5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-yl] carboxylamine third-2-alkenyl esters,

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-pyrazol-1-yl-pyridine-3-carboxamide, or

6-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] Nicotinicum Acidum methyl esters.

Another aspect of the present invention provides formula (I) compound or its pharmacy acceptable salt:

Wherein

R ¹Independent separately expression

Halogen,

Oh group,

Cyano group,

-NR ¹⁶R ¹⁷Group,

-OCOR ¹⁸Group,

-CO ₂R ¹⁹Group,

-CONR ²⁰R ²¹Group,

-NR ²²COR ²³Group,

-NR ²⁴CO ₂R ²⁵Group,

-OSO ₂R ²⁶Group,

R ²Independent separately expression

Oh group,

Halogen,

Cyano group,

-CO ₂R ²⁹Group,

-CONR ³⁰R ³¹Group,

-NR ³²COR ³³Group,

-NR ³⁴CO ₂R ³⁵Group,

-NR ³⁶R ³⁷Group,

-SO ₂R ³⁸Group,

-SO ₂NR ³⁹R ⁴⁰Group,

-NR ⁴¹SO ₂R ⁴²Group,

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

R ³Represent hydrogen,

A is 0,1,2,3 or 4;

B is 0,1,2,3 or 4;

R ⁶And R ^{7 respectively}From independent hydrogen, the C of representing ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base, or R ⁶And R ⁷The nitrogen-atoms that connects with them forms 4 to 6-unit's saturated heterocyclics;

R ⁴⁷Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁵⁸Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁶¹Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

Another aspect of the invention provides formula (I) compound or its pharmacy acceptable salt:

Wherein

R ¹Independent separately expression

Halogen,

Oh group,

Cyano group,

-NR ¹⁶R ¹⁷Group,

-OCOR ¹⁸Group,

-CO ₂R ¹⁹Group,

-CONR ²⁰R ²¹Group,

-NR ²²COR ²³Group,

-NR ²⁴CO ₂R ²⁵Group,

-OSO ₂R ²⁶Group,

R ²Independent separately expression

Oh group,

Halogen,

Cyano group,

-CO ₂R ²⁹Group,

-CONR ³⁰R ³¹Group,

-NR ³²COR ³³Group,

-NR ³⁴CO ₂R ³⁵Group,

-NR ³⁶R ³⁷Group,

-SO ₂R ³⁸Group,

-SO ₂NR ³⁹R ⁴⁰Group,

-NR ⁴¹SO ₂R ⁴²Group,

C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴³R ⁴⁴(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by one or more substituted 4 to 7-unit's heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl), halogen, hydroxyl and 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

R ³Represent hydrogen,

A is 0,1,2,3 or 4;

B is 0,1,2,3 or 4;

R ³⁶And R ³⁷Independent separately hydrogen, the C of representing ₁-C ₄Alkyl, C ₂-C ₄Alkynyl, C ₃-C ₆Naphthenic base or optional 5-or the 6-unit aromatic group that comprises at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur, or R ³⁶And R ³⁷The nitrogen-atoms that connects with their forms 4 to 6-unit's saturated heterocyclics, and (said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl, trifluoromethyl and optional 5-or the 6-unit aromatic yl group that comprises at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur);

R ⁴⁷Represent hydrogen, C ₁-C ₄Alkyl or C ₃-C ⁶Naphthenic base;

R ⁵⁸Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

R ⁶¹Represent C ₁-C ₄Alkyl or C ₃-C ₆Naphthenic base;

In the context of this specification sheets; Except as otherwise noted otherwise term " alkyl " comprises the alkyl group of straight chain and side chain, but with regard to concrete group, only refer in particular to linear form like " n-propyl "; And with regard to concrete side chain form, for example " sec.-propyl " only refers in particular to the side chain form.Similarly application of rules is in other groups.

For example, " C ₁-C ₆Alkyl " and " C ₁-C ₄Alkyl " instance comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl." C ₁-C ₆Alkoxyl group " and " C ₁-C ₃Alkoxyl group " instance comprise methoxyl group, oxyethyl group, positive propoxy and isopropoxy." C ₂-C ₆Alkenyl " instance comprise vinyl, allyl group and 1-propenyl." C ₃-C ₆Naphthenic base " instance comprise cyclopropyl, cyclopentyl and cyclohexyl." single-and two-C ₁-C ₆Alkylamino " instance comprise methylamino, dimethylamino, ethylamino, diethylamino and ethylmethylamino." C ₁-C ₆The alkyl sulfenyl " instance comprise methylthio group, ethylmercapto group and rosickyite base.

The instance of halogen comprises fluorine, chlorine, bromine and iodine.

Except as otherwise noted, otherwise " 4 to 7-unit carbon ring group " comprise and contain the saturated of 4,5,6 or 7 carbon atoms and unsaturated wholly or in part monocycle." 4 to 7-unit's carbocylic radical group " comprises group such as C ₄-C ₇Naphthenic base, C ₄-C ₇Cycloalkenyl and C ₆Aryl.

" optional 5-or the 6-unit aromatic group that comprises the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur " or " optional 5-or the 6-unit aromatic yl group that comprises the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur " is for containing the complete unsaturated aromatic monocyclic of 5 or 6 atoms; At least one is selected from the heteroatoms of nitrogen, oxygen and sulphur in the said atom, except as otherwise noted otherwise its can connect through carbon or nitrogen.Suitable " optional 5-or the 6-unit aromatic ring that comprises the ring hetero atom that at least one is selected from nitrogen, oxygen and sulphur " is furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazole base, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazinyl and triazole basic ring.

Except as otherwise noted; Otherwise " 4 to 7-unit heterocyclic radical group " comprise and contain the saturated of 4,5,6 or 7 atoms and undersaturated wholly or in part monocycle; At least one is selected from the heteroatoms of nitrogen, oxygen and sulphur in the said atom, and except as otherwise noted otherwise its can connect through carbon or nitrogen.Suitable " 4 to the 7-unit's heterocyclic radical group " that comprise at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur comprises azetidine, gamma-butyrolactone, Diazesuberane, dioxolane, dioxane, Er Qing oxazine, dihydro-thiophene, dithiolane, furans, six hydrogen azepines, imidazoles, tetrahydroglyoxaline, imidazolidine, isothiazole 、 isoxazole, morpholine 、 oxadiazole 、 oxazine 、 oxazole, trimethylene oxide, piperidines, piperazine, α-pyrans, γ-pyrans, pyrazine, pyrazolidine, pyrazoles, pyrazoline, pyridazine, pyridine, pyrimidine, pyrroles, tetramethyleneimine, pyrroline, THF, THF ketone, tetrahydropyrans, tetrazine, tetrazolium, thiadiazoles, thiazole, thiacyclopentane (thiolan), thiomorpholine, thiomorpholine S, S-dioxide, thiophene and triazine.

Work as R ⁴And R ⁵, or R ⁶And R ⁷, or R ⁸And R ⁹, or R ¹⁰And R ¹¹, or R ¹²And R ¹³, or R ¹⁴And R ¹⁵, or R ²⁷And R ²⁸, or R ⁴³And R ⁴⁴, or R ⁴⁵And R ⁴⁶, or R ⁴⁸And R ⁴⁹, or R ⁵⁰And R ⁵¹, or R ⁵²And R ⁵³, or R ⁵⁴And R ⁵⁵, or R ⁵⁶And R ⁵⁷, or R ⁵⁹And R ⁶⁰, or R ⁶²And R ⁶³, or R ⁶⁴And R ⁶⁵, or R ⁶⁶And R ⁶⁷, or R ⁶⁸And R ⁶⁹Represent 4 to 6-units during saturated heterocyclic, should be understood that it is and R when only having a heteroatoms ⁴And R ⁵, or R ⁶And R ⁷, or R ⁸And R ⁹, or R ¹⁰And R ¹¹, or R ¹²And R ¹³, or R ¹⁴And R ¹⁵, or R ²⁷And R ²⁸, or R ⁴³And R ⁴⁴, or R ⁴⁵And R ⁴⁶, or R ⁴⁸And R ⁴⁹, or R ⁵⁰And R ⁵¹, or R ⁵²And R ⁵³, or R ⁵⁴And R ⁵⁵, or R ⁵⁶And R ⁵⁷, or R ⁵⁹And R ⁶⁰, or R ⁶²And R ⁶³, or R ⁶⁴And R ⁶⁵, or R ⁶⁶And R ⁶⁷, or R ⁶⁸And R ⁶⁹The nitrogen-atoms that connects.Except as otherwise noted, otherwise " 4 to 6-unit saturated heterocyclic " comprise the saturated monocycle that contains 4,5 or 6 atoms, and wherein at least one atom is that nitrogen remains atom and is selected from carbon, nitrogen, oxygen and sulphur.Suitable " 4 to 6-unit's saturated heterocyclic " comprises tetramethyleneimine, pyrazolidine, imidazolidine, piperidines, piperazine, morpholine, thiomorpholine, thiomorpholine S, S-dioxide.

Except as otherwise noted; Otherwise " optional and 4 to 7-unit's carbocylic radicals or heterocyclic radical group condensed 4 to 7-unit's heterocyclic radical groups " comprise saturated and undersaturated wholly or in part monocycle or two rings; At least one annular atoms that each ring comprises 4,5,6 or 7 atoms and a ring is the heteroatoms that is selected from nitrogen, oxygen and sulphur, except as otherwise noted otherwise connect through carbon or nitrogen.Suitable " optional and 4 to 7-unit's carbocylic radicals or heterocyclic radical group condensed 4 to the 7-unit's heterocyclic radical groups " that comprise at least one ring hetero atom that is selected from nitrogen, oxygen and sulphur comprise azetidine, cumarone, benzoglyoxaline, thionaphthene, gamma-butyrolactone, diazacyclo heptene, dioxolane, dioxane, Er Qing oxazine, dihydro-thiophene, dithiolane, furans, six hydrogen azepines, imidazoles, tetrahydroglyoxaline, imidazolidine, indazole, indoles, isothiazole 、 isoxazole, morpholine 、 oxadiazole 、 oxazine 、 oxazole, trimethylene oxide, piperidines, piperazine, α-pyrans, γ-pyrans, pyrazine, pyrazolidine, pyrazoles, pyrazoline, pyridazine, pyridine, pyrimidine, pyrroles, tetramethyleneimine, pyrroline, quinazoline, quinoline, THF, THF ketone, tetrahydropyrans, tetrahydroquinoline, tetrazine, tetrazolium, thiadiazoles, thiazole, thiacyclopentane (thiolan), thiomorpholine, thiomorpholine S, S-dioxide, thiophene and triazine.

For fear of doubt, when indicating substituting group and can have the substituting group of multi-substituent more, for example at term as " optional by one or more substituted C of following substituting group that are selected from ₁-C ₃Alkyl group: C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁴R ⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl) " definition in, it is understood to be in group C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃Alkyl sulfenyl and-NR ⁴R ⁵In (do not consider at R ⁴Or R ⁵Definition in any other substituting group of defining) can have optional substituent atom such as carbon atom through the displacement hydrogen group and can be selected from following substituting group and replace by one or more: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl.For example, R ⁴Or R ⁵Also can be selected from following substituting group and replace: halogen, C by one or more ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl.

The suitable pharmacy acceptable salt of The compounds of this invention does; The acid salt that for example has the The compounds of this invention of enough alkalescence; For example with inorganic or organic acid additive salt, for example hydrochloride, hydrobromate, vitriol, phosphoric acid salt, trifluoroacetate, Citrate trianion or toxilic acid.In addition; Suitable pharmacy acceptable salt with enough tart The compounds of this invention is an alkali metal salt (for example sodium salt or a sylvite); Alkaline earth salt (for example calcium salt or magnesium salts); Ammonium salt or with the salt that acceptable cationic organic bases forms on the physiology is provided, the salt that for example forms with methylamine, dimethyl amine, Trimethylamine, piperidines, morpholine or three-(2-hydroxyethyl) amine.

The interior hydrolyzable ester of body that contains formula (I) compound of carboxyl or oh group is for example pharmaceutically acceptable ester, and its hydrolysis in human or animal body produces parent acid or alcohol.The suitable pharmaceutically acceptable ester of carboxylic acid comprises C _1-6The alkoxy methyl ester is methoxymethyl ester for example; C _1-6Alkyloyl oxygen ylmethyl ester is pivaloyl group oxygen ylmethyl ester, phthalidyl ester for example; C _3-8Cyclo alkoxy carbonyl oxygen base C _1-6Alkyl ester is 1-cyclohexyl-carbonyl oxygen base ethyl ester for example; 1,3-dioxole-2-ketone group methyl ester, 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl; And C _1-6The alkoxy-carbonyl oxy ethyl ester is 1-methoxycarbonyl oxygen base ethyl and any carboxylic group can form in The compounds of this invention ester for example.

Formula (I) compound of hydrolyzable ester comprises inorganic ester such as SULPHOSUCCINIC ACID ESTER and alpha-acyloxy alkyl oxide and related compound in the body of hydroxyl group, and said compound is as the ester oh group of hydrolytic deterioration generation parent in vivo.Alpha-acyloxy alkyl oxide instance comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.The selection that is used for hydrolyzable ester in the hydroxyl organizer comprises alkyloyl, benzoyl-, phenyl acetyl and substituted benzoyl-and phenyl acetyl, alkoxy carbonyl (obtaining alkyl carbonate), dialkyl amido formyl radical and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (obtaining carbamate), dialkyl amido ethanoyl and carboxyl ethanoyl.Substituent instance on benzoyl-comprises morpholino and the piperazine that is connected with the 3-or the 4-position of benzoyl ring through the methene base from theheterocyclic nitrogen atom-1-base (piperazino).

Some formula (I) compound can have chiral centre and/or rotamerism center (E-and Z-type isomer), and should be understood that the present invention includes all these has FGFR and suppress active optics, diastereomer and geometrical isomer.

The present invention relates to have any and all tautomeric forms that FGFR suppresses active formula (I) compound.For example, formula (IA) compound is the tautomer of formula (I) compound.

Should be understood that some formula (I) compound can solvation form and the existence of non-solvent form, for example hydrate forms.Should be understood that the present invention includes all these has FGFR and suppress active solvation form.

The occurrence of variable group is following.These values can be used in any suitable part in preamble or the civilian defined definition in back, claim or the embodiment.

In another embodiment of the present invention, A represents furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazole base, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazinyl (trazinyl) or triazole basic ring.

In another embodiment of the present invention, A represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thienyl or thiazole basic ring.

In another embodiment of the present invention, A represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl or thiophene basic ring.

In another embodiment of the present invention, A represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl or pyrimidine-ring.

In another aspect of this invention, A represents furyl, phenyl, pyridyl or pyrimidine-ring.

In another aspect of this invention, A represents furyl, phenyl or pyridyl ring.

In another aspect of this invention, A represents furyl or benzyl ring.

In another aspect of this invention, A represents benzyl ring.

In another embodiment of the present invention, B represents furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazole base, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazinyl (trazinyl) or triazole basic ring.

In another embodiment of the present invention, B represents furyl, isothiazolyl, isoxazolyl, oxadiazole base, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl or thiophene basic ring.

In another embodiment of the present invention, B represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thienyl or thiazole basic ring.

In another embodiment of the present invention, B represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl or thiophene basic ring.

In another embodiment of the present invention, B represents phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl or pyrimidine-ring.

In another embodiment of the present invention, B represents phenyl, pyrazinyl, pyridyl, thienyl or pyrimidine-ring.

In another aspect of this invention, B represents pyridyl, pyrimidyl or phenyl ring.

In another embodiment of the present invention, B represents phenyl, pyrazinyl, thienyl or pyrimidine-ring.

In another aspect of this invention, B represents phenyl ring.

In one embodiment of the invention, R ¹The independent separately halogen of representing; Oh group; C ₁-C ₃Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁴R ⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; C ₁-C ₃Alkoxy grp, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; Or-CONR ²⁰R ²¹Group.

In another embodiment of the present invention, R ¹The independent separately halogen of representing; Oh group; C ₁-C ₃Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁴R ⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; C ₁-C ₃Alkoxy grp, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;-CONR ²⁰R ²¹Group; Or two adjacent R ¹The atom that group connects with them forms 4 to 7-unit's carbocyclic ring or heterocycles, and said carbocyclic ring or heterocycle are optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ²⁷R ²⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another embodiment of the present invention, R ¹The independent separately halogen of representing; Oh group; C ₁-C ₃Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; Or-CONR ²⁰R ²¹Group.

In another embodiment of the present invention, R ¹The independent separately C that represents ₁-C ₃Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another embodiment of the present invention, R ¹The independent separately C that represents ₁-C ₃Alkoxy base, said group is optional to be selected from following substituting group and to replace by one or more: methoxyl group ,-N (Me) ₂And hydroxyl.

In another aspect of this invention, R ¹Independent separately representative-CONR ²⁰R ²¹Group.

In another aspect of this invention, R ¹Independent separately representation methoxy group;-OCH ₂CH ₂OMe;-CH ₂NMe ₂Or two adjacent R ¹Group forms-OCH together ₂The O-bridge.

In another aspect of this invention, R ¹Independent separately representation hydroxy group;-CONH ₂-CONHMe;-CONMe ₂Or methoxy group.

In another aspect of this invention, R ¹Independent separately representative-CONHMe or methoxy group.

In another aspect of this invention, R ¹Representative-CONHMe.

In another aspect of this invention, R ¹Representation methoxy.

In another embodiment of the present invention, R ²Independent separately representative-NR ³⁶R ³⁷Group; C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴³R ⁴⁴(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by one or more substituted 4 to 7-unit's heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl), halogen, hydroxyl and 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, cyanic acid, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, oxo, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; Or it is optional by one or more substituted C of following substituting group that are selected from ₁-C ₆Alkoxy grp: C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base ,-NR ⁶²R ⁶³(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁶⁴R ⁶⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another embodiment of the present invention, R ²Independent separately representative-NR ³⁶R ³⁷Group; Optional by one or more substituted C of following substituting group that are selected from ₁-C ₆Alkyl group: C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴³R ⁴⁴(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by one or more substituted 4 to 7-unit's heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl), halogen, hydroxyl and 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; Or it is optional by one or more substituted C of following substituting group that are selected from ₁-C ₆Alkoxy base: C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base ,-NR ⁶²R ⁶³(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁶⁴R ⁶⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another aspect of this invention, R ²Independent separately representative-NR ³⁶R ³⁷Group; C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement :-NR that are selected from ⁴³R ⁴⁴(it can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by the one or more substituted morpholine of following substituting group, piperidines or piperazines of being selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl) and optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; Or it is optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another aspect of this invention, R ²Independent separately representative is optional by the substituted methyl or methoxy group of morpholine, piperidines or piperazine group, and said morpholine, piperidines or piperazine group are optional separately by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another aspect of this invention, R ²Independent separately representative is optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, cyanic acid, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, oxo, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another aspect of this invention, R ²Independent separately representative is optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl.

In another aspect of this invention, R ²Independent separately representative-Cl;-F;-I;-OH;-CN;-CH ₃-CH ₂OH;-CH ₂N (CH ₃) ₂-CH ₂CH (CH ₃) NH ₂-OCH ₃-OCH ₂CH ₂OH;-OCH ₂CH ₂OCH ₂CH ₃-SO ₂CH ₃-N (CH ₃) ₂-NHPh;-NHCH ₂C ≡ CH;-NHCH ₂CH ₃-NHCH ₂CH ₂N (CH ₃) ₂-NHCO ₂CH ₂CH=CH ₂-NHCOCH ₃-NHCOH;-NHCOPh;-CONH ₂-NHSO ₂Me;-SO ₂N (CH ₃) ₂-CO ₂H;-CO ₂CH ₃-CO ₂CH ₂CH ₃

In another aspect of this invention, R ²Independent separately representative-Cl;-F;-I;-OH;-CN;-CH ₃-CH ₂OH;-CH ₂N (CH ₃) ₂-CH ₂CH (CH ₃) NH ₂-OCH ₃-OCH ₂CH ₂OH;-OCH ₂CH ₂OCH ₂CH ₃-SO ₂CH ₃-OCH ₂CH ₂OH;-N (CH ₃) ₂-NHPh;-NHCH ₂C ≡ CH;-NHCH ₂CH ₃-NHCH ₂CH ₂N (CH ₃) ₂-NHCO ₂CH ₂CH=CH ₂-NHCOCH ₃-NHCOH;-NHCOPh;-CONH ₂-NHSO ₂Me;-SO ₂N (CH ₃) ₂-CO ₂H;-CO ₂CH ₃-CO ₂CH ₂CH ₃

In another aspect of this invention, R ²Independent separately representative-OMe;-OCH ₂CH ₂OCH ₂CH ₃-OCH ₂CH ₂OH;-CH ₂N (CH ₃) ₂-NHCH ₂CH ₂N (CH ₃) ₂

In another aspect of this invention, R ²Independent separately representative-NHCH ₂CH ₂N (CH ₃) ₂

In another aspect of this invention, R ²Independent separately representative

In another aspect of this invention, R ²Independent separately representative

In another aspect of this invention, R ²Independent separately representative

In another aspect of this invention, R ²Representative

In another aspect of this invention, R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^C1, R ^C2, R ^C3And R ^C4Independently be selected from C separately ₁-C ₃Alkyl, C ₂-C ₃Alkenyl, C ₂-C ₃Alkynyl, C ₃-C ₅Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), hydrogen, halogen and hydroxyl, or

R ^C1And R ^C2And/or R ^C3And R ^C4The atom that connects with their forms 3 to 6-unit's carbocyclic ring or heterocycles, and said carbocyclic ring or heterocycle are optional to be selected from following substituting group and to replace by one or more: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl, perhaps

R ^C1And R ^C3Atom that is connected with them and R ^N1The nitrogen-atoms that group connects forms 5 to 7-unit's carbocyclic ring or heterocycles together, and said carbocyclic ring or heterocycle are optional to be selected from following substituting group and to replace by one or more: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl and

R ^N1Be selected from C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₂-C ₄Alkynyl, C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: cyanic acid, halogen, C by said each group ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), hydrogen and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-C ₅Naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, or

R ^N1And R ^C4The atom that connects with them forms 4 to 7-unit's heterocycles, and said heterocycle is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₂-C ₃Alkenyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₃-C ₅Naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl.

In another aspect of this invention, R ²Independent representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^C1, R ^C2, R ^C3And R ^C4Independently be selected from hydrogen, methyl, ethyl, methylol, hydroxyethyl, methoxymethyl, methoxy ethyl, 2,2 separately, the 2-trifluoroethyl, perhaps

R ^C3And R ^C4The atom that connects with their form 3 to 5-unit's carbocyclic rings and

R ^N1Be selected from C ₁-C ₂Alkyl, C ₂-C ₃Alkenyl, C ₂-C ₃Alkynyl, C ₃-C ₅Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl) and hydrogen, perhaps

R ^N1And R ^C4The atom that connects with them forms 4 to 7-unit's heterocycles.

In another aspect of this invention, R ²Independent representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^C3And R ^C4The atom that connects with their form cyclopropyl rings and

R ^N1Be selected from hydrogen, methyl, ethyl, methoxy ethyl, ethoxyethyl group, hydroxyethyl, propenyl, proyl, propyl group, sec.-propyl ,-CH (CH ₃) CH ₂OH, cyclopropyl, cyclobutyl, cyclopentyl, or

R ^N1And R ^C4The atom that connects with them forms 5-or 6-unit heterocycle.

In another aspect of this invention, R ²Independent representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^C1, R ^C2, R ^C3And R ^C4Independently be selected from hydrogen, methyl, ethyl, methylol, hydroxyethyl, methoxymethyl, methoxy ethyl, 2,2 separately, the 2-trifluoroethyl, or

R ^C3And R ^C4The atom that connects with their form cyclopropyl rings and

R ^N1Be selected from hydrogen, methyl, ethyl, methoxy ethyl, ethoxyethyl group, hydroxyethyl, propenyl, proyl, sec.-propyl ,-CH (CH ₃) CH ₂OH, cyclopropyl, cyclobutyl, cyclopentyl, or

R ^N1And R ^C4The atom that connects with them forms 5-or 6-unit heterocycle.

In another aspect of this invention, R ³Represent hydrogen.

In another embodiment of the present invention, X represents CH ₂Or O.

In another embodiment of the present invention, Y represents CH ₂

In another embodiment of the present invention, a is 0,1 or 2.

In another embodiment of the present invention, b is 0,1 or 2.

In another aspect of this invention, b is 1.

In another aspect of this invention ,-A-(R ¹) _aRepresentative

In another aspect of this invention ,-A-(R ¹) _aRepresentative

In another aspect of this invention ,-B-(R ²) _bRepresentative

In another aspect of this invention ,-B-(R ²) _bRepresentative

In another aspect of this invention ,-B-(R ²) _bRepresentative

In one embodiment of the invention, Asia group or its pharmacy acceptable salt of formula (I) compound is provided, wherein:

Ring A represents furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazole base, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazinyl (trazinyl) or triazole basic ring;

Ring B represents furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazole base, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazinyl (trazinyl) or triazole basic ring;

R ¹Independent separately representative

C ₁-C ₃Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, or

-CONR ²⁰R ²¹Group;

R ²Independent separately representative

-NR ³⁶R ³⁷Group;

C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴³R ⁴⁴(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by one or more substituted 4 to 7-unit's heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl), halogen, hydroxyl and 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, cyanic acid, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, oxo, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, or

C ₁-C ₆Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base ,-NR ⁶²R ⁶³(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁶⁴R ⁶⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 0,1 or 2.

R ¹Independent separately representative

-CONR ²⁰R ²¹Group;

R ²Independent separately representative

-NR ³⁶R ³⁷Group;

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, or

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 0,1 or 2.

One embodiment of the invention provide Asia group or its pharmacy acceptable salt of formula (I) compound, wherein:

R ¹Independent separately representative

Halogen,

Oh group,

C ₁-C ₃Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl,

-CONR ²⁰R ²¹Group; Or

Two adjacent R ¹The atom that group connects with them forms 4 to 7-unit's carbocyclic ring or heterocycles, and said carbocyclic ring or heterocycle are optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ²⁷R ²⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

R ²Independent separately representative

Oh group,

Halogen,

Cyano group,

-CO ₂R ²⁹Group,

-CONR ³⁰R ³¹Group,

-NR ³²COR ³³Group,

-NR ³⁴CO ₂R ³⁵Group,

-NR ³⁶R ³⁷Group,

-SO ₂R ³⁸Group,

-SO ₂NR ³⁹R ⁴⁰Group,

-NR ⁴¹SO ₂R ⁴²Group,

C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴³R ⁴⁴(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by one or more substituted 4 to 7-unit's heterocyclic radical groups of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl), halogen, hydroxyl and 4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), cyanic acid, halogen and hydroxyl;

4 to 7-unit's heterocyclic radical groups, said heterocyclic group is optional with 4 to 7-unit's carbocylic radicals or the heterocyclic radical group condenses and optionally be selected from following substituting group and replace by one or more: C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, perhaps

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 0,1 or 2.

Another embodiment of the present invention provides Asia group or its pharmacy acceptable salt of formula (I) compound, wherein:

Ring A represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl or thiophene basic ring;

Ring B represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl or thiophene basic ring;

R ¹Independent separately representative

C ₁-C ₃Alkoxy base, said group is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkoxyl group, C ₃-naphthenic base ,-NR ¹⁴R ¹⁵(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl; Perhaps

-CONR ²⁰R ²¹Group;

R ²Independent separately representative

-NR ³⁶R ³⁷Group,

C ₁-C ₆Alkyl group, said group is optional by one or more following substituting group replacement :-NR that are selected from ⁴³R ⁴⁴(it is optional to be selected from following substituting group and to replace by one or more: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl and optional: halogen, C by the one or more substituted morpholine of following substituting group, piperidines or piperazines of being selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, C ₃-C ₆Naphthenic base, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, cyanic acid, hydroxyl, trifluoromethyl) and optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁴⁵R ⁴⁶,-CO ₂R ⁴⁷(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, perhaps

Optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₂-C ₆Alkenyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl-carbonyl, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, cyanic acid, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, oxo, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 0,1 or 2.

R ¹Independent separately representative

-CONR ²⁰R ²¹Group;

R ²Independent separately representative

-NR ³⁶R ³⁷Group;

Optional by the one or more substituted morpholine of following substituting group, piperidines or piperazine: C of being selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₃-C ₆Naphthenic base, C ₁-C ₆The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₃Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 0,1 or 2.

Ring A represents furyl, phenyl or pyridyl ring;

Ring B represents phenyl, pyrazinyl, pyridyl, pyrimidyl or thiophene basic ring;

R ¹Independent separately representative

Methoxy group ,-OCH ₂CH ₂Ome ,-CH ₂NMe ₂Or two adjacent R ¹Group forms-OCH together ₂The O-bridge;

R ²Independent separately representative

-Cl、-F、-I、-OH、-CN、-CH ₃、-CH ₂OH、-CH ₂N(CH ₃) ₂、-CH ₂CH(CH ₃)NH ₂、-OCH ₃、-OCH ₂CH ₂OH、-OCH ₂CH ₂OCH ₂CH ₃、-SO ₂CH ₃、-N(CH ₃) ₂、-NHPh、-NHCH ₂C≡CH、-NHCH ₂CH ₃、-NHCH ₂CH ₂N(CH ₃) ₂、-NHCO ₂CH ₂CH＝CH ₂、-NHCOCH ₃、-NHCOH、-NHCOPh、-CONH ₂、-NHSO ₂Me、-SO ₂N(CH ₃) ₂、-CO ₂H、-CO ₂CH ₃、-CO ₂CH ₂CH ₃、

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 0,1 or 2.

Another aspect of the present invention provides formula (I) compound or its pharmacy acceptable salt, wherein:

Ring A represents furyl, phenyl, pyridyl or pyrimidine-ring;

Ring B represents phenyl, pyridyl, pyrimidyl or thiophene basic ring;

R ¹Independent separately representative-CONHMe or methoxy group;

R ²Representative

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 1.

Ring A represents furyl, phenyl, pyridyl or pyrimidine-ring;

Ring B represents phenyl, pyridyl or pyrimidine-ring;

R ¹Representation methoxy;

R ²Representative

X represents CH ₂Or O;

A is 0,1 or 2; With

B is 1,

Or its pharmacy acceptable salt.

-A-(R ¹) _aRepresentative

R ²Independent separately representative

-OMe、-OCH ₂CH ₂OCH ₂CH ₃、-OCH ₂CH ₂OH、-CH ₂N(CH ₃) ₂、-NHCH ₂CH ₂N(CH ₃) ₂、

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

B is 1.

-A-(R ¹) _aRepresentative

-B-(R ²) _bRepresentative

X represents CH ₂Or O,

Or its pharmacy acceptable salt.

-A-(R ¹) _aRepresentative

-B-(R ²) _bRepresentative

X represents CH ₂,

Or its pharmacy acceptable salt.

-A-(R ¹) _aRepresentative

-B-(R ²) _bRepresentative

X represents O,

Or its pharmacy acceptable salt.

-A-(R ¹) _aRepresentative

-B-(R ²) _bRepresentative

-A-(R ¹) _aRepresentative

-B-(R ²) _bRepresentative

Ring A represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thienyl or thiazole basic ring;

Ring B represents furyl, phenyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, thienyl or thiazole basic ring;

R ¹Independent separately representative

-CONR ²⁰R ²¹Group;

R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^C1And R ^C2And/or R ^C3And R ^C4The atom that connects with their forms 3 to 6-unit's carbocyclic ring or heterocycles, and said carbocyclic ring or heterocycle are optional to be selected from following substituting group and to replace by one or more: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl, or

R ^C1And R ^C3Connected atom and and R ^N1The nitrogen-atoms that group connects forms 5 to 7-unit's carbocyclic ring or heterocycles together, and said carbocyclic ring or heterocycle are optional to be selected from following substituting group and to replace by one or more: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl and

R ^N1And R ^C4The atom that connects with them forms 4 to 7-unit's heterocycles, and said heterocycle is optional by one or more following substituting group replacement: C that are selected from ₁-C ₃Alkyl, C ₂-C ₃Alkenyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₃-C ₅Naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁵⁶R ⁵⁷, SO ₂R ⁵⁸(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), halogen, hydroxyl;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 1.

R ¹Independent separately representative

-CONR ²⁰R ²¹Group;

R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^N1Be selected from C ₁-C ₄Alkyl, C ₂-C ₄Alkenyl, C ₂-C ₄Alkynyl, C ₃-C ₆Naphthenic base (can choose wantonly by one or more and be selected from following substituting group and replace: halogen, C by said each group ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), hydrogen and optional by one or more substituted 4 to 7-unit's heterocyclic radical group: C of following substituting group that are selected from ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₃-C ₅Naphthenic base, C ₁-C ₃The alkyl sulfenyl ,-NR ⁵⁹R ⁶⁰,-SO ₂R ⁶¹(said each group can be chosen wantonly by one or more and be selected from following substituting group and replace: halogen, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, C ₁-C ₂Alkyl sulfenyl, amino (NH ₂), single-and two-C ₁-C ₂Alkylamino, hydroxyl and trifluoromethyl), halogen and hydroxyl, or

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 1.

Ring A represents furyl, phenyl or pyridyl ring;

R ¹Independent separately representative

-CONR ²⁰R ²¹Group;

R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 1.

Ring A represents benzyl ring;

R ¹Independent separately representative

-CONR ²⁰R ²¹Group;

R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 1.

Ring A represents phenyl ring;

R ¹Independent separately representative

C ₁-C ₃Alkoxy base;

R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^N1And R ^C4The atom that connects with them forms 4 to 7-unit's heterocycles;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂

A is 0,1 or 2; With

B is 1.

A (R ¹) _aRepresent 3, the 5-Dimethoxyphenyl;

Ring B represents phenyl, pyrazinyl, pyrimidyl or thiophene basic ring;

R ²Representative

Wherein

G ¹Be C or N,

N is 1 or 2,

R ^C3And R ^C4The atom that connects with them forms cyclopropyl rings,

With

R ^N1And R ^C4The atom that connects with them forms 5-or 6-unit heterocycle;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂With

B is 1.

A (R ¹) _aRepresent 3, the 5-Dimethoxyphenyl;

Ring B represents phenyl, pyrazinyl, pyrimidyl or thiophene basic ring;

R ²Representative

Wherein

G ¹Be C or N,

N is 1,

R ^C3And R ^C4The atom that connects with them forms cyclopropyl rings,

With

R ^N1And R ^C4The atom that connects with them forms 5-or 6-unit heterocycle;

R ³Represent hydrogen;

X represents CH ₂Or O;

Y represents CH ₂With

B is 1.

In another embodiment of the present invention, R ^C1And R ^C2Or R ^C1And R ^C3Or R ^C3And R ^C4Or R ^N1And R ^C4In only an atom that connects with their form ring.

In another embodiment of the present invention, R ^C1And R ^C2The atom that connects with them forms ring, and R ^C3And R ^C4Or R ^N1And R ^C4In only one can form ring with the atom that their connect.

In another embodiment of the present invention, R ^C1, R ^C2, R ^C3And R ^C4Independently be selected from hydrogen and methyl separately.

Instance of the present invention comprises:

1.	4-(4-N-METHYL PIPERAZINE-1-yl)-N-(5-styroyl-2H-pyrazole-3-yl) BM
		2.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM
3.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-methoxyl group-BM
		4.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-morpholine-4-base-BM
5.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3-fluoro-piperidino) methyl] BM
		6.	N-[5-[2-[3-(2-methoxy ethoxy) phenyl] ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM
7.	4-(4-N-METHYL PIPERAZINE-1-yl)-N-[5-(2-pyridin-3-yl ethyl)-2H-pyrazole-3-yl] BM
		8.	N-[5-[2-(2-furyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM
9.	N-[5-[2-(3-furyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM
		10.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM
11.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM
		12.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM
13.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-methyl-pyridine-3-carboxamide
		14.	6-methoxyl group-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide
15.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-methyl sulphonyl-BM

16.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-5-methyl-pyrazine-2-methane amide
		17.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-5-(Propargyl is amino) pyridine-2-carboxamide
18.	6-ethylamino-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-methane amide
		19.	4-acetylaminohydroxyphenylarsonic acid N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM
20.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) pyrazine-2-methane amide
		21.	4-benzamido--N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM
22.	6-(2-methoxy ethoxy)-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-yl] pyridine-3-carboxamide
		23.	4-cyanic acid-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM
24.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] benzene-1, the 4-diformamide
		25.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-pyrazol-1-yl-BM
26.	6-anilino-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide
		27.	4-methanesulfonamido-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM
28.	4-(methylol)-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM
		29.	5-formamido group-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-2-methane amide
30.	4-(dimethylamino alkylsulfonyl)-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-yl] BM

31.	6-hydroxy-n-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide
		32.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-morpholine-4-base-pyridine-3-carboxamide
33.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(1,3-oxazole-5-yl) BM
		34.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(tetrazolium-1-yl) BM
35.	N-[5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-yl] carboxylamine third-2-alkene ester
		36.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(1,2, the 4-triazol-1-yl) BM
37.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-pyrazol-1-yl-pyridine-3-carboxamide
		38.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-fluoro-BM
39.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-3-methoxyl group-BM
		40.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-3-morpholine-4-base-BM
41.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-2-methoxyl group-BM
		42.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-ethoxy ethoxy) BM
43.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(piperidino) BM
		44.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-piperidyl methoxy base) BM
45.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-piperazine-1-base-benzene

?	Methane amide
		46.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-6-piperazine-1-base-pyridine-3-carboxamide
47.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(dimethylaminomethyl) BM
		48.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-hydroxyl-oxethyl) BM
49.	4-(2-aminopropyl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM
		50.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(3,3-dimethyl--piperidino) methyl] BM
51.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[4-(2-hydroxyethyl) piperazine-1-yl] BM
		52.	4-[(7-cyanic acid-3,4-dihydro-1H-isoquinoline 99.9-2-yl) methyl]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM
53.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(3-fluoro-piperidino) methyl] BM
		54.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-morpholine-4-base oxethyl) BM
55.	4-[2-(4,4-two fluoro-piperidino) oxyethyl group]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM
		56.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-morpholine-4-base ethyl) BM
57.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(methyl-(tetrahydrofuran-2-ylmethyl) amino) methyl] BM
		58.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-piperidyl) BM
59.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-dimethylamino-

?	BM
		60.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-5-piperazine-1-base-thiophene-2-carboxamide derivatives
61.	6-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-3-methyl-formiate
		62.	6-chloro-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide
63.	6-cyanic acid-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide
		64.	4-hydroxy-n-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-2-carboxamide
65.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-(2-tetramethyleneimine-1-base ethyl) pyridine-3-carboxamide
		66.	5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-formic acid
67.	5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-methyl-formiate
		68.	5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-ethyl formate
69.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) pyridine-2-carboxamide
		70.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(the 2-dimethyl aminoethyl is amino) BM
71.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-methoxyl group-BM
		72.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-6-piperazine-1-base-pyridine-3-carboxamide
73.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl]-2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide

88.	4-(4-cyclobutyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM
		89.	4-(4-ethanoyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM
90.	N-[5-[2-(3-p-methoxy-phenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-methyl sulphonyl piperazine-1-yl) BM
		91.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(1-methyl-4-piperidyl) BM
92.	4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM
		93.	4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM
94.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(4-N-METHYL PIPERAZINE-1-yl) methyl] BM
		95.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM
96.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4,5-tri methyl piperazine-1-yl) BM
		97.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) thiophene-2-carboxamide derivatives
98.	4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM
		99.	4-(1-cyclopropyl piperidine-4-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM
100.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,5-lupetazin-1-yl] BM
		101.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM

102.	4-[5-[[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] formamyl] thiophene-2-yl] piperazine-1-t-butyl formate
		103.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(1-methyl piperidine-4-yl) BM
104.	4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM
		105.	5-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide
106.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxamide derivatives
		107.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxamide derivatives
108.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3,3-lupetazin-1-yl) pyrazine-2-methane amide
		109.	5-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide
110.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-yl]-4-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] BM
		111.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,3-lupetazin-1-yl) BM
112.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,5-lupetazin-1-yl] pyrazine-2-methane amide
		113.	5-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide
114.	5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide
		115.	5-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide

116.	4-(4-cyclopropyl piperazine-1-yl) N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM
		117.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-methyl-4-oxidation (oxido) piperazine-4--1-yl) BM
118.	4-(4-cyclobutyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM
		119.	2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide
120.	5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] thiophene-2-carboxamide derivatives
		121.	5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] thiophene-2-carboxamide derivatives
122.	5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide
		123.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) pyrazine-2-methane amide
124.	N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) pyrazine-2-methane amide
		125.	N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-yl]-5-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] pyrazine-2-methane amide
126.	2-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide
		127.	2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide
128.	2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide
		129.	5-[(3R, 5S)-4-(cyano methyl)-3,5-lupetazin-1-yl]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

And any pharmacy acceptable salt.

In another aspect of this invention, particular compound of the present invention is any pharmacy acceptable salt of embodiment 1-20 or its.

In another aspect of this invention, particular compound of the present invention is any or its any pharmacy acceptable salt among the embodiment.

In another aspect of this invention, particular compound of the present invention is any or its any pharmacy acceptable salt in embodiment 1,2,3,4,5,10,11,12,20,42,43,44,45,46,47,48,50,51,53,54,55,56,57,58,59,60,69,70,71,72,73,74,75,80,81,85,87,88,89,92,93,94,95 or 96.

In another aspect of this invention, particular compound of the present invention is any or its any pharmacy acceptable salt in embodiment 2,3,4,5,10,11,12,20,42,43,44,45,46,47,48,50,51,53,54,55,56,57,58,59,60,69,70,71,72,73,74,75,80,81,85,87,88,89,92,93,94,95 or 96.

In another aspect of this invention, particular compound of the present invention is any or its any pharmacy acceptable salt in embodiment 10,11,12,20,43,44,45,46,50,51,53,54,55,56,57,58,59,60,69,70,72,73,74,75,80,81,85,87,88,89,92,93,94,95 or 96.

In another aspect of this invention, particular compound of the present invention is any or its any pharmacy acceptable salt in embodiment 2,3,4,10,11,12,20,42,43,45,47,50,56,57,59,60,69,70,71,73,75,80,81,85,87,88,89,92,93,94,96,97,98,99,100,101,103,104,105,106,107,108,109,110,111,112,113,114,115,116,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,144,145,146,147,148,151,152,153,154,155,156,157,158,159,161,165,166,167,168,169,170,171,172,174,175,176,177,179 or 180.

In another aspect of this invention, particular compound of the present invention is any or its any pharmacy acceptable salt in embodiment 12,45,73,75,81,92,98,99,100,103,104,110,121,137,144,148,152,154,155,159,167,179 or 180.

The present invention also provides formula (I) compound of definition in a kind of preparation as indicated or the method for its pharmacy acceptable salt, and said method comprises formula (II) compound and the reaction of formula (III) compound, obtains formula (I) compound,

Wherein Z represent leavings group (for example, halogen such as chlorine ,-CN ,-N ₃,-OH or-OR ,-OC (O) R ,-OCR (NR ^aR ^b) ₂Or-OC (=NR) NR ^aR ^bGroup, wherein R is optional substituted alkyl, aryl, heteroaryl or alkylaryl and R ^a, R ^bIndependently separately be hydrogen or choose substituted alkyl, aryl or alkylaryl wantonly), and B, R ²With the definition of b such as preamble to formula (I) compound,

Wherein Q be hydrogen or blocking group (for example t-Bu or BOC group or as at " blocking group in the organic synthesis (Protective groups in Organic Synthesis) "; Second edition; T.W.Greene and P.G.M.Wuts; And A, R group described in the Wiley-Interscience (1991)), ¹, R ³, X, Y and a such as preamble be for the definition of formula (I) compound.

And choose wantonly and carry out one or more following steps:

● resulting compound conversion is obtained other compounds of the present invention

● form the pharmacy acceptable salt of said compound.

Suitable formula (II) compound comprises the reactive derivative of carboxylic acid or carboxylic acid.The reactive derivative of carboxylic acid or carboxylic acid comprises carboxylic acid halides, like the acyl chlorides that forms through carboxylic acid and inorganic acyl chlorides (for example THIONYL CHLORIDE 97) reaction; Mixed acid anhydride, the acid anhydrides that for example forms through acid and carbonochloridic acid ester (like the carbonochloridic acid isobutylate) reaction; Active ester, the ester that for example forms through carboxylic acid and phenol (like Pentafluorophenol) reacts the ester of formation through carboxylic acid and ester (like the trifluoroacetic acid pentafluorophenyl esters) or with alcohol (like methyl alcohol, ethanol, Virahol, butanols or N-hydroxybenzotriazole); Acylazide, the trinitride that for example forms through said acid and trinitride (like xenyl phosphoryl trinitride) reaction; Acyl cyanide, the prussiate that for example forms through acid and prussiate (like diethylammonium phosphoryl prussiate); Or the product of acid and carbodiimide (like NSC 57182) or said acid and carbamide compound (like phosphofluoric acid 2-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea (V)) reaction.

This reaction can be carried out in the presence of suitable inert solvent or thinner easily; For example halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin, alcohol or ester such as methyl alcohol, ethanol, propyl alcohol or ETHYLE ACETATE, ether such as THF or 1; 4-diox, aromatic solvent such as toluene.This reaction also can be at dipolar aprotic solvent such as N, and dinethylformamide, DMAC N,N, N-methylpyrrolidin-2-ketone or methyl-sulphoxide carry out under existing.This for example is reflected at-20 ℃ to 100 ℃, preferred 0 ℃ and to the TR of room temperature, carries out easily, and this depends on the reaction carried out and the character of leavings group Z.

This reaction can be carried out in the presence of alkali usually.Suitable alkali comprises organic amine alkali such as pyridine, 2,6-lutidine, N, N-diisopropyl ethyl amine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene; The carbonate of basic metal or earth alkali metal or oxyhydroxide are like yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or Pottasium Hydroxide; Alkali metal ammonia compound, like hexamethyl dimethyl silanyl sodium amide (NaHMDS) or alkalimetal hydride such as sodium hydride, this depends on the reaction carried out and the character of leavings group Z.

This reaction also can for example be carried out in the presence of the trimethylaluminium in Lewis acid, and this depends on the reaction carried out and the character of leavings group Z.

Perhaps, the present invention also provides formula (I) compound of definition in a kind of preparation as indicated or the method for its pharmacy acceptable salt, and said method comprises formula (IV) compound and the reaction of formula V compound, obtains formula (I) compound

Wherein Q be hydrogen or blocking group (for example t-Bu or BOC group or as " blocking group in organic synthesis (Protective Groups in Organic Synthesis) "; Second edition; T.W.Greene and P.G.M.Wuts are described in the Wiley-Interscience (1991)), and B, R ², R ³With the definition of b such as preamble for formula (I) compound,

L wherein ¹Represent OH or leavings group such as halogen or OTs; And A, R ¹With the definition of a such as preamble for formula (I) compound

And choose wantonly and carry out one or more following steps:

● resulting compound is changed into other compounds of the present invention

● form the pharmacy acceptable salt of said compound.

This reaction can be in suitable solvent such as methylene dichloride, 0 ℃ to the TR of room temperature, carry out easily.Work as L ¹During for OH, this reaction is carried out in the presence of diisopropyl azodiformate and triphenylphosphine usually.Work as L ¹During for halogen or OTs, this reaction can be at suitable solvent such as N, in dinethylformamide or the acetonitrile, carry out easily under the TR of room temperature to 100 ℃.This reaction can be carried out in the presence of mineral alkali such as salt of wormwood and sodium hydride usually.

Formula (II), (III), (IV) or (V) compound be commercially available, or be that document is known, maybe can use the known technology preparation.

Wherein Z be halogen or-formula (II) compound of OR can be through the document currently known methods by formula (II) compound for-OH of Z wherein.For example, can use the method that becomes known for preparing acyl chlorides or ester by carboxylic acid.

Wherein X represents CH ₂Formula (III) but compound through type (VI) compound

Prepare with the hydrazine reaction of formula (VII)

This reaction can be in solvent such as ethanol, carry out easily under the TR of 60-80 ℃.

Perhaps, wherein X represent O formula (III) but compound through type (VIII) compound

React with formula (IX) compound and to prepare

This reaction can be in solvent such as methylene dichloride, 0 ℃ to the TR of room temperature, carry out easily.This reaction can be carried out in the presence of diisopropyl azodiformate and triphenylphosphine usually.

Formula (IV) but compound through type (X) compound

React with formula (II) compound and to prepare

Wherein Z represent leavings group (for example, halogen such as chlorine ,-CN ,-N ₃,-OH or-OR ,-OC (O) R ,-OCR (NR ^aR ^b) ₂Or-OC (=NR) NR ^aR ^bGroup, wherein R is optional substituted alkyl, aryl, heteroaryl or alkylaryl and R ^a, R ^bIndependent separately is hydrogen or optional substituted alkyl, aryl or alkylaryl);

P represent H or blocking group (as " blocking group in organic synthesis (ProtectiveGroups in Organic Synthesis) ', second edition, T.W.Greene and P.G.M.Wuts are described in the Wiley-Interscience (1991));

Q be hydrogen or blocking group (for example t-Bu or BOC group or as " blocking group in organic synthesis (Protective Groups in Organic Synthesis) "; Second edition; T.W.Greene and P.G.M.Wuts are described in the Wiley-Interscience (1991)); With

B, R ², R ³With the definition of b such as preamble for formula (I) compound,

And, when P is blocking group; Slough blocking group P.

Formula (VI), (VII), (VIII) and (IX) compound be the commercial compound, or be that document is known, maybe can be through standard method preparation known in the art.

Adopt standard method can formula (I) compound be converted into other formulas (I) compound.The instance of spendable conversion reaction type comprises through aromatics substitution reaction, substituent reduction reaction, substituent alkylation reaction and substituent oxidizing reaction introduces substituting group.The reagent and the reaction conditions that are used for these methods are that chemical field is well-known.The instance of aromatics substitution reaction comprises use concentrated nitric acid introducing nitryl group; Under Friedel Crafts condition, use for example carboxylic acid halides and Lewis acid (like aluminum chloride), introduce carboxyl groups; For example under the Suzuki condition, use aryl halide, introduce aromatic yl group; Under the Buchwald condition, use for example aryl halide and amine, introduce amino group; Under Friedel Crafts condition, use alkyl halide and Lewis acid (like aluminum chloride), introduce alkyl group; With the introducing halogen group.The instance of reduction reaction comprise with nickel catalyzator through catalytic hydrogenation or hydrochloric acid exist and heating down through nitryl group being reduced into amino group with the iron processing; Comprise with the specific examples of oxidizing reaction the alkyl sulfenyl is oxidized to alkyl sulphinyl or alkyl sulphonyl.Above-mentioned these reagent and reaction conditions are well-known in the art.

Those skilled in the art should be understood that some functional group such as the hydroxyl of in preparation method of the present invention initial reagent or midbody compound or amino group possibly protected by blocking group.Therefore, the preparation of formula (I) compound can relate to the interpolation of one or more blocking groups or removes in different steps.

The protection of functional group and deprotection are at " blocking group in organic chemistry (Protective Groups in Organic Chemistry) "; Edit by J.W.F.McOmie; Plenum Press (1973) and " blocking group in organic synthesis (Protective Groups inOrganic Synthesis) "; Second edition, T.W.Greene and P.G.M.Wuts, Wiley-Interscience states in (1991).

Can be with being converted into pharmacy acceptable salt with following formula (I) compound, for example acid salt example hydrochloric acid salt, hydrobromate, phosphoric acid salt, acetate, fumarate, PHENRAMINE MALEATE, tartrate, Citrate trianion, oxalate, mesylate or tosilate or an alkali metal salt such as sodium salt or sylvite.

Some formula (I) compound can exist by stereoisomer form.Should be understood that all geometrical isomers and optical isomer (comprising epimer) that the present invention includes formula (I) compound and composition thereof comprises the application of racemic modification.

Some formula (I) compound, its pharmacy acceptable salt is separable is amorphous solid or crystalline solid.If said compound is a crystallized form, it can exist by multiple different polycrystalline form.The examples of compounds that is separated into amorphous solid or crystalline solid comprises: (2-Theta ° 3.521 (100%) with the isolating embodiment 10 of crystallized form; 7.025 (14.8%); 9.274 (16.9%); 9.654 (15.2%); 10.162 (14.8%); 10.508 (19.3%); 11.628 (49.8%); 12.047 (19.3%); 14.516 (21%); 16.242 (26.3%); 17.682 (18.5%); 18.099 (31.3%); 18.615 (92.6%); 19.315 (56.8%); 20.353 (16%); 20.581 (17.3%); 21.192 (10.3%); 22.467 (23%); 23.057 (88.1%); 23.28 (52.3%); 24.261 (34.2%); 25.363 (10.7%); 27.546 (15.6%); 28.285 (14%) and 29.862 (11.9%); With the isolating embodiment 75 of amorphous solid; With the isolating embodiment 81 of amorphous solid; (2-Theta ° 3.62 (100%), 7.247 (4.6%), 10.013 (5.1%), 10.889 (8.1%), 11.294 (7.7%), 12.185 (8.6%), 14.091 (19%), 18.2 (12.7%), 19.102 (8.9%), 19.789 (15.2%) and 20.608 (32.7%) with the isolating embodiment 144 of crystallized form; (2-Theta ° 4.293 (100%) with the isolating embodiment 99 of crystallized form; 8.498 (14%); 10.694 (8.1%); 13.078 (4.5%); 15.056 (49.4%); 16.14 (8.1%); 16.298 (11.1%); 17.425 (34.6%); 17.812 (23.1%); 18.157 (9.6%); 19.224 (15%); 20.931 (20.2%); 21.819 (27.9%); 22.248 (16.2%); 22.593 (23.7%); 23.416 (8.8%); 24.726 (26%); 25.295 (11.6%); 25.859 (5.6%); 27.001 (5.9%); 27.754 (5.3%); 28.442 (4.8%); 29.861 (4.3%); 30.89 (3.8%); 32.264 (5.9%) and 32.896 (5.4%); (2-Theta ° 4.492 (91.3%) with the isolating embodiment 147 of crystallized form; 12.465 (23.1%); 13.862 (26.3%); 14.56 (14.4%); 15.811 (16.3%); 17.226 (24.4%); 17.886 (20%); 18.3 (15%); 18.9 (100%); 21.328 (20%); 21.705 (28.1%); 23.263 (27.5%); 23.699 (19.4%); 24.005 (53.8%); 24.333 (37.5%); 25.184 (11.9%); 26.114 (11.3%); 26.573 (10.6%) and 27.803 (16.9%); (2-Theta ° 3.754 (29.6%) with the isolating embodiment 151 of crystallized form; 8.495 (13.9%); 10.235 (19.1%); 10.98 (29.6%); 12.014 (23.5%); 13.38 (18.3%); 14.591 (33%); 15.924 (41.7%); 17.057 (26.1%); 17.379 (30.4%); 18.219 (32.2%); 18.791 (36.5%); 19.201 (100%); 19.577 (47.8%); 20.788 (33%); 21.394 (27%); 22.07 (33%); 23.285 (25.2%); 23.922 (29.6%) and 25.533 (33%); (2-Theta ° 5.833 (89.6%) with the isolating embodiment 154 of crystallized form; 9.786 (21.9%); 10.784 (32.8%); 12.121 (30.7%); 13.394 (35.4%); 13.709 (45.3%); 14.939 (28.1%); 16.799 (35.4%); 17.664 (25%); 18.223 (21.9%); 18.646 (50%); 19.29 (25.5%); 20.563 (35.4%); 21.32 (100%); 22.747 (37.5%); 24.154 (38.5%); 25.197 (23.4%); 25.704 (15.1%); 26.752 (16.7%) and 31.134 (12%); With with the isolating embodiment 155 of amorphous solid.Except as otherwise noted, otherwise the X-ray powder diffraction pattern through crystalline substance being installed on Siemens silicon single crystal (SSC) the wafer mounts and under the help of slide glass, sample being sprawled lamellar and measure.Sample is changeed rotation (improving counting statistics) and uses Siemens Diffraktometer 5000 with PM 30, use the x-ray radiation of wavelength 1.5418 dusts that produce by the copper length-fine focusing X spool of under 40kV and 40mA, operating.Collimated x-ray source directly passes through 2mm anti-scatter slit and 0.2mm detector slit through the radioactive rays that automated variable divergent slit (automatic variable divergence slit) is set at V20 and reflection.Increment with 0.02 ° of 2-θ (continuous sweep mode) exposes sample 1 second to the open air with the theta-theta pattern 2 ° to 40 ° 2-theta scopes.This instrument is equipped with scintillometer as detector.Dell Optiplex 686 NT 4.0 Workstation through with the Diffrac+ software operation control and data gathering.

One skilled in the art should appreciate that to be that diffractogram data given in the literary composition are not interpreted as absolute (for further information referring to Jenkins; R & Snyder; R.L. ' Introduction to X-Ray powder Diffractometry ' John Wiley & Sons, 1996).Therefore, should be understood that crystallized form is not to be defined in the crystal with X-ray powder diffraction pattern identical with the ray powder diffraction pattern of X-described in the literary composition.The present invention comprises that also those have any crystal with essentially identical X-ray powder diffraction pattern described in the literary composition.The technician in X-ray powder diffraction pattern field can judge the basic similarity of X-ray powder diffraction pattern and can understand difference and possibly come from the error at measurment (like instrument, specimen preparation or used machine) that various factors is for example produced by condition determination; Come from the strength difference of condition determination and specimen preparation; The peak relative intensity that is produced by the variation of crystallographic dimension or non-single ratio changes; With the position of reflection, it can receive zero the calibrating and the planeness of sample surfaces influences of precise height and diffractometer in the sample diffractometer of living in.

Formula (I) compound has the activity as medicine, particularly as the activity of FGFR active regulator or suppressor factor, and can be used for treatment propagation and excess proliferative disease/illness, and the example comprises following cancer:

(1) cancer comprises the cancer of bladder, brain, mammary gland, colon, kidney, liver, lung, ovary, pancreas, prostate gland, stomach, uterine cervix, colon, Tiroidina and skin;

(2) hematopoietic system cancer of lymphatic system comprises acute lymphoblastic leukemia, B-cell lymphoma and Burketts lymphoma;

(3) hematopoietic system cancer of myeloid lineage comprises acute and chronic myelogenous leukemia and promyelocytic leukemia;

(4) tumour in mesenchyme source comprises fibrosarcoma and rhabdomyoma; With

(5) other tumours comprise melanoma, spermocytoma, tetratocarcinoma, neuroblastoma and neural gluey knurl.

In one embodiment, The compounds of this invention is used to treat bladder, mammary gland and tumor of prostate and multiple myeloma.

Therefore, the invention provides formula (I) compound or its pharmacy acceptable salt of definition as indicated that is used for treating.

Formula (I) compound of definition or the purposes of its pharmacy acceptable salt in the method for treatment human body or animal body during another aspect of the present invention provides as indicated.

Aspect another, the purposes of the medicine that formula (I) compound of definition or its pharmacy acceptable salt are used for treating in preparation in the invention provides as indicated.

In the content of this specification sheets, only if stress different implications, otherwise term " treatment " also comprises " prevention ".Term " treatment " should be explained with " remedially " accordingly.

The present invention also provides a kind of treatment method for cancer, and said method comprises formula (I) compound or its pharmacy acceptable salt of middle definition as indicated that the patient treatment of needs significant quantity is arranged.

We have found that the compound or its pharmacy acceptable salt that define among the present invention are effective anticarcinogen, and its character is considered to by the active adjusting of FGFR or suppresses to produce.Therefore The compounds of this invention be supposed to only to be used to treat or part by the disease or the medical conditions of FGFR mediation, promptly said compound is used in and produces the FGFR restraining effect in the warm-blooded animal that needs these treatments.

Therefore compound of the present invention provides a kind of treatment method for cancer that suppresses FGFR that is characterized as, promptly said compound can through suppress FGFR separately or the part mediation produce antitumous effect.

This The compounds of this invention is supposed to have the broad spectrum anticancer characteristic, because in numerous human cancers, observed among the FGFR, includes but not limited to mammary gland, bladder, prostate gland and multiple myeloma.Therefore expect that The compounds of this invention will have the antitumour activity of these cancers of antagonism.In addition, the expectation The compounds of this invention will have leukemia, lymph malignant tumour and solid tumor as at tissue like the activity of cancer in liver, kidney, bladder, prostate gland, mammary gland and the pancreas and sarcoma.In one embodiment, The compounds of this invention is supposed to advantageously delay the for example primary of skin, colon, Tiroidina, lung and ovary and the growth of recidivity solid tumor.More specifically; The compounds of this invention or its pharmacy acceptable salt are supposed to suppress the growth of tumor relevant with FGFR; Particularly grow and spread those tumours that significantly depend on FGFR, comprise the for example tumour and the multiple myeloma of some bladder, prostate gland, mammary gland.

Therefore this aspect of the present invention provides formula (I) compound or its pharmacy acceptable salt of middle definition as indicated as medicine.

Formula (I) compound of definition or its pharmacy acceptable salt were used for producing the purposes in the inhibiting medicine of FGFR warm-blooded animal such as people in preparation during the present invention provided as indicated on the other hand.

Formula (I) compound of definition or its pharmacy acceptable salt were used for the purposes in the medicine of warm-blooded animal such as people's generation antitumous effect in preparation during this aspect of the present invention provided as indicated.

Formula (I) compound of definition or its pharmacy acceptable salt were used for treating the purposes of the medicine of following disease during the present invention provided as indicated on the other hand in preparation: melanoma; Papillary thyroid carcinoma; Cholangiocarcinoma; Colorectal carcinoma; Ovarian cancer; Lung cancer; White blood disease; The lymph malignant tumour; Multiple myeloma; Cancer in liver, kidney, bladder, prostate gland, mammary gland and the pancreas and sarcoma; Solid tumor with the primary and the recidivity of skin, colon, Tiroidina, lung and ovary

Formula (I) compound or its pharmacy acceptable salt of definition produced the inhibiting purposes of FGFR during the present invention provided as indicated on the other hand in warm-blooded animal such as people.

Middle as indicated formula (I) compound that defines in this aspect of the present invention or its pharmacy acceptable salt produce antitumous effect in warm-blooded animal such as people purposes.

Formula (I) compound of definition or its pharmacy acceptable salt purposes in the following disease of treatment during the present invention provides as indicated on the other hand: melanoma; Papillary thyroid carcinoma; Cholangiocarcinoma; Colorectal carcinoma; Ovarian cancer; Lung cancer; White blood disease; The lymph malignant tumour; Multiple myeloma; Cancer in liver, kidney, bladder, prostate gland, mammary gland and the pancreas and sarcoma; Solid tumor with the primary and the recidivity of skin, colon, Tiroidina, lung and ovary.

Another feature of this aspect of the present invention provides among a kind of warm-blooded animal such as people in these treatments of needs and has produced the inhibiting method of FGFR, said method comprise give said animal effective dose as indicated in formula (I) compound or its pharmacy acceptable salt of definition.

The another characteristic of this aspect of the present invention provides the method that produces antitumous effect among a kind of warm-blooded animal such as people in these treatments of needs, said method comprise give said animal effective dose as indicated in formula (I) compound or its pharmacy acceptable salt of definition.

A characteristic again of this aspect of the present invention provide a kind of treat the warm-blooded animal that needs these treatments such as the people the method for the following disease of trouble: melanoma; Papillary thyroid carcinoma; Cholangiocarcinoma; Colorectal carcinoma; Ovarian cancer; Lung cancer; White blood disease; The lymph malignant tumour; Multiple myeloma; Cancer in liver, kidney, bladder, prostate gland, mammary gland and the pancreas and sarcoma; With the solid tumor of the primary and the recidivity of skin, colon, Tiroidina, lung and ovary, said method comprise give said animal effective dose as indicated in formula (I) compound or its pharmacy acceptable salt of definition.

Another aspect of the present invention provides a kind of being used for to produce the inhibiting pharmaceutical composition of FGFR warm-blooded animal such as people, formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of definition during said compsn comprises as indicated.

Another aspect of the present invention provides a kind of pharmaceutical composition that is used at warm-blooded animal such as people's generation antitumous effect, formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of definition during said compsn comprises as indicated.

Another aspect of the present invention provide a kind of be used to treat warm-blooded animal such as philtrum the pharmaceutical composition of the following disease of trouble: melanoma; Papillary thyroid carcinoma; Cholangiocarcinoma; Colorectal carcinoma; Ovarian cancer; Lung cancer; White blood disease; The lymph malignant tumour; Multiple myeloma; Cancer in liver, kidney, bladder, prostate gland, mammary gland and the pancreas and sarcoma; Comprise middle as indicated formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier that defines with the primary of skin, colon, Tiroidina, lung and the said compsn of solid tumor of recidivity.

Can only use formula (I) compound and pharmacy acceptable salt itself thereof, but usually give with the form of pharmaceutical composition, its Chinese style (I) compound or salt (activeconstituents) combine acceptable accessories, diluent or carrier.Pharmaceutical composition can comprise total composition weight 0.01-99%w (weight percent), 0.05-80%w, 0.10-70%w and or even the activeconstituents of 0.10-50%w, this depends on the mode of giving.

The present invention also provides pharmaceutical composition, formula (I) compound or its pharmacy acceptable salt of definition during said pharmaceutical composition comprises as indicated, and acceptable accessories, diluent or carrier.

The present invention further provides a kind of method for preparing pharmaceutical composition of the present invention, and said pharmaceutical composition comprises that formula (I) compound or its pharmacy acceptable salt with middle definition as indicated mixes with acceptable accessories, diluent or carrier.

Pharmaceutical composition can local (for example, skin or lung and/or air flue) give, for example with the form of ointment, solution, suspensoid, hexafluoro alkane aerosol and dry powder formulations; Or whole body gives, for example with the oral administration of tablet, capsule, syrup, pulvis or granule form; Or with the parenteral administration of solution or suspensoid form; Or subcutaneous giving; Or with the rectal administration of suppository form; Or transdermal administration.

Use conventional medicine vehicle well known in the art can obtain the present composition through ordinary method.Therefore, the compsn that is intended to be used to orally use can comprise for example one or more tinting materials, sweeting agent, correctives and/or sanitas.

The suitable pharmaceutically acceptable vehicle that is used for tablet prepn comprises for example inert diluent such as lactose, yellow soda ash, calcium phosphate or lime carbonate; Granulating agent and disintegrating agent such as W-Gum or algenic acid; Tackiness agent such as starch; Lubricant such as Magnesium Stearate, Triple Pressed Stearic Acid or talcum powder; Sanitas such as ethylparaben or propyl ester and oxidation inhibitor such as xitix.Tablet not dressing or use conventional dressing material well known in the art and method dressing improve its disintegration and subsequently activeconstituents or improve its stability and/or outward appearance in GI absorption.

Be used for oral compsn and can be the hard gelatin capsule form, wherein for example lime carbonate, calcium phosphate or kaolin mix activeconstituents with inert solid diluent; Or can be the soft gelatin capsule form, wherein activeconstituents and water or oil are like peanut oil, whiteruss or mixed with olive oil.

The suspendible aqueous solution comprises the activeconstituents and one or more suspending agents such as Xylo-Mucine, methylcellulose gum, HPMC, sodium-alginate, Vinylpyrrolidone polymer, tragakanta and gum arabic of fine powder form usually; Disperse or wetting agent such as Yelkin TTS or 1; The condensation product of 2-epoxy alkane and lipid acid (for example polyoxyethylene stearic acid ester); Or the condensation product of oxyethane and long chain aliphatic alcohol (for example 17 carbon vinyloxy group Tego Alkanol 16s); Or the condensation product (like octadecanoic acid ester of polyethylene glycol) of oxyethane and lipid acid and hexitol deutero-partial ester; Or the condensation product of oxyethane and long chain aliphatic alcohol (for example 17 carbon vinyloxy group Tego Alkanol 16s); Or the condensation product (like octadecanoic acid ester of polyethylene glycol) of oxyethane and lipid acid and hexitol deutero-partial ester, or the condensation product of oxyethane and lipid acid and hexitol acid anhydrides deutero-partial ester (polyoxyethylene sorbitan monooleate for example? Polyethylenesorbitan monooleate).The suspendible aqueous solution also can comprise one or more sanitass (like ethylparaben or propyl ester), oxidation inhibitor (like xitix), tinting material, correctives and/or sweeting agent (like sucrose, asccharin or aspartame).

The oiliness suspensoid can prepare through activeconstituents being suspended in vegetables oil (like peanut oil, sweet oil, til or Oleum Cocois) or the MO (like whiteruss).The oiliness suspensoid also can comprise thickening material such as beeswax, paraffinum durum or hexadecyl alcohol.Can add as before listed those sweeting agents and correctives obtain good to eat oral prepns.These compsns can be preserved through adding oxidation inhibitor such as xitix.

Be adapted to pass through and add dispersible pulvis and granule that water prepares aqueous suspension usually through comprising activeconstituents and dispersion or wetting agent, suspending agent and one or more sanitass.Suitable dispersion agent or wetting agent and suspending agent mentioned through above those illustrate.Also can there be other vehicle such as sweeting agent, correctives and tinting material.

Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetables oil such as sweet oil or peanut oil, or MO such as whiteruss, or the mixture of any of these.Suitable emulsifying agent can be for example naturally occurring natural gum such as gum arabic or tragakanta; Naturally occurring phosphatide such as soybean phospholipid, Yelkin TTS are derived from the ester of lipid acid and hexitol acid anhydrides or the condensation product such as the T 46155 sorbitan monooleate of partial ester (sorbitol monooleate for example anhydrates) and said partial ester and oxyethane.Emulsion also can comprise sweeting agent, correctives and sanitas.

Syrup and elixir can be prepared with sweeting agent such as USP Kosher, Ucar 35, sorbyl alcohol, aspartame or sucrose, also can comprise analgesic agent, sanitas, correctives and/or tinting material simultaneously.

Pharmaceutical composition also can be the form of aseptic injection water-based or oiliness suspensoid, and it can use suitable dispersion agent or wetting agent and the suspending agent of having mentioned more than one or more according to currently known methods.Aseptic injection preparation also can be aseptic injectable solution or the suspensoid in nontoxic, parenteral-acceptable diluent or solvent (the for example solution in 1,3 butylene glycol).

Suppository can be through preparing activeconstituents and suitable non-irritating mixed with excipients, and this vehicle is solid at normal temperatures but under rectal temperature, discharges medicine for therefore liquid also melt in rectum.Suitable vehicle comprises for example theobroma oil and polyoxyethylene glycol.

Topical preparation such as ointment, ointment, gelifying agent and water-based or butyrous solution or suspensoid can use ordinary method well known in the art through obtaining with activeconstituents and conventional, local acceptable vehicle or thinner preparation usually.

The compsn that is blown into administration for example can contain median size 30 μ or littler tiny dispersive powder gives, and this powder only contains activeconstituents itself or dilutes with one or more physiology acceptable carriers such as lactose.The powder that will be used for being blown into easily subsequently places and contains the for example capsule of 1-50mg activeconstituents, uses with turbine suction apparatus (turbo-inhaler device), for example is used to be blown into the known drug FPL-670.

Warp sucks the form that the compsn that gives can be conventional pressurised aerosol, and this pressurised aerosol is mixed with activeconstituents the aerosol that contains tiny dispersible solid or drop.Can use conventional aerosol propellant such as volatility to fluoridize hydro carbons or hydro carbons and the aerosol device measured easily the amount of activeconstituents.

For the information of other preparations, the reader can be with reference to Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board) the 25.2nd chapter in the 5th volume in, Pergamon Press 1990.

According to well-known medical science principle, be used for therapeutic purpose The compounds of this invention the big young pathbreaker of dosage naturally according to age of the character of illness and severity, animal or patient and surname not and route of administration change.

Generally speaking, the The compounds of this invention that gives also can give with the divided dose form so that obtain the for example per daily dose of the activeconstituents of 0.1mg to 1000mg scope/kg body weight if desired.But per daily dose will be necessarily with changing according to the host who is treated, concrete route of administration, the severity of the disease of controlling.Therefore, optimal dose can be by doctor's decision of any concrete patient of treatment.Generally speaking, when using the parenteral route approach, give lower dosage.Therefore, for example for intravenous administration, will use usually at the for example dosage of 0.1mg to 30mg activeconstituents/kg body weight.Similarly, give, will use usually at the for example dosage of 0.1mg to 25mg activeconstituents/kg body weight for suction.But preferred oral administration.The preparation that for example is intended to the human oral administration will comprise 0.1mg to 2g activeconstituents usually.

For the information of other administration route and dosage, the reader can be with reference to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman ofEditorial Board) the 25.3rd chapter in the 5th volume in, Pergamon Press 1990.

The anticancer therapy of preamble definition can be used as monotherapy or can except The compounds of this invention, also comprise routine operation or radiotherapy or chemotherapy.This based chemotherapy can comprise the antineoplastic agent of one or more following kinds:

(i) be used for other the antiproliferative/antitumour drugs and the combination thereof of Internal Medicine-Oncology, like alkylating agent (like cis-platinum, oxaliplatin, carboplatin, endoxan, mustargen, melphalan, TV, busulfan, TM and nitrourea); Antimetabolite (like gemcitabine and antifol such as fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur, ZD-1694, methotrexate, cytosine arabinoside and hydroxyurea); Antitumor antibiotics (like anthracene nucleus class such as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu and Plicamycin); Antimitotic agent (like vinca alkaloids such as vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine, Taxan such as taxol and Docetaxel and polokinase suppressor factor); And topoisomerase enzyme inhibitor (like podophyllin such as VP and teniposide, amsacrine, hycamtin and NSC 94600);

(ii) cytostatic agent such as antiestrogen (like tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogen (like bicalutamide, flutamide, RU-23908 and acetate SH-881), lhrh antagonist or LHRH agonist (like goserelin, leuprorelin and buserelin), progestogens (like the acetate megestrol), aromatase inhibitor (like Anastrozole, letrozole, vorozole and FCE-24304) and 5 ^*-reductase inhibitor such as finasteride;

The (iii) medicine of anticancer invasion (for example c-Src kinases man's group inhibitor such as 4-(6-chloro-2,3-methylene dioxo group aniline base)-7-[2-(4-N-METHYL PIPERAZINE-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-aminomethyl phenyl)-2-{6-[4-(2-hydroxyethyl) piperazine-1-yl]-2-methylpyrimidine-4-base is amino } thiazole-5-methane amide (dasatinib, BMS-354825; J.Med.Chem., 2004,47,6658-6661) and inhibitors of metalloproteinase such as Marimastat and the suppressor factor of urokinase plasminogen activator receptor function or the antibody of Heparanase;

(iv) growth factor depressant of functions: for example this type of suppressor factor comprises that growth factor antibodies and growth factor receptor antibody are (like anti-erbB 2 antibody trastuzumab [Herceptin ^TM], anti-EGFR-antibodies handkerchief Buddhist nun monoclonal antibody, anti-erbB1 antibody Cetuximab [Erbitux; C225]) and by Stern etc. at Critical reviews in oncology/haematology; 2005, the 54 volumes, disclosed any growth factor or growth factor receptor antibody in the 11-29 page or leaf); These suppressor factor also comprise tyrosine kinase inhibitor for example the epidermal growth factor family suppressor factor (like EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (ZD1939 (gefitinib; AZD1839), N-(3-ethynyl phenyl)-6; Two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib; OSI-774) and 6-acyl group amido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), erbB2 tyrosine kinase inhibitor such as lapatinibditosylate, pHGF man group inhibitor, Thr6 PDGF BB man group inhibitor such as imatinib, serine/threonine kinase suppressor factor (for example Ras/Raf signal conduction depressant drug such as farnesyl transferase inhibitor, for example Xarelto (BAY43-9006)); Through MEK and/or the kinase whose cell signaling suppressor factor of AKT, pHGF man group inhibitor, c-kit suppressor factor, abl SU11752, IGF acceptor (rhIGF-1) SU11752; Aurora SU11752 (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin kinase suppressor factor such as CDK2 and/or CDK4 suppressor factor;

(v) anti-angiogenic agent is as suppressing the anti-angiogenic agent of VEGF effect, (like anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF [Avastin ^TM] and vegf receptor tyrosine kinase suppressor factor such as 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline (ZD6474; Embodiment 2 among the WO 01/32651), 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline (AZD2171; Embodiment 240 among the WO 00/47212), cut down Ta Lani (PTK787; WO98/35985) and SU11248 (Sutent; WO 01/60814), as be disclosed in the compound of International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and the compound (like linomide, integrin alpha v b3 depressant of functions and angiostatin) through other machining function;

(vi) blood vessel injury agent such as combretastatin A4 be disclosed in the compound of International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapy is like the therapy to above-mentioned target, like ISIS 2503 (anti-ras antisense);

(viii) gene therapy, comprise as substitute the distortion gene like the method for distortion p53 or distortion BRCA1 or BRCA2, GDEPT (gene targeting property enzyme prodrug therapy) method as with the method for Isocytosine deaminase, thymidine kinase or bacterium TNT nitroreductase and raising patient method such as MDRG therapy to chemotherapy or radiotherapy tolerance; With

(ix) immunotherapy; Comprise like therapy in therapy and the body in the elder generation that the increases the patient tumors cell immunogenicity external back body; As with cytokine such as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor transfection; Reduce the method for T-cell anergy, with the method for the BMDC of transfection immunocyte such as cytokine transfection, with the method for cytokine transfection tumor cell line with the method for antiidiotypic antibody;

Embodiment

Further explain the present invention referring now to following illustrative embodiment, wherein except as otherwise noted, otherwise:

(i) temperature that provides be degree centigrade (℃); Operate in room temperature or envrionment temperature, be to carry out under the temperature of 18-25 ℃ of scope;

(ii) use anhydrous magnesium sulfate drying organic solution; Under paramount 60 ℃ bath temperature with rotatory evaporator decompression (600-4000Pascals; 4.5-30mmHg) carry out the evaporation of solvent;

(iii) chromatography is meant flash chromatography on silica gel; Thin-layer chromatography (TLC) carries out on silica-gel plate;

(iv) common, reaction process is monitored with TLC, and the reaction times that provides only is used to illustrate;

(v) end product has good proton nuclear magnetic resonance (NMR) spectrum and/or mass-spectrometric data;

(yield that vi) provides only is used to illustrate, and is not necessarily perfect through continuous method improvement and yield that obtain; More if desired raw materials then can repeat preparation;

Only if (vii) indicate in addition, otherwise the δ value form of the NMR The data main mark proton that provides, (ppm) counts very much with respect to hundred of internal standard substance tetramethyl-silicomethane (TMS) in unit, at DMSO-d ₆In measure at 300MHz;

(vii) chemical symbol has its implication commonly used; Use SI units and symbol;

(ix) solvent ratio that provides is a volume: volume (v/v) ratio; With

(x) mass spectrum (MS) data produce in the LC/MS system; Wherein the HPLC assembly generally includes Agilent 1100 or Waters Alliance HT (2790&2795) instrument and at Phemonenex Gemini C185 μ m; 50x 2mm post (or similar post) is gone up operation; With acid elutriant (for example, use 0-95% water/acetonitrile (contain 5% at 50: 50 water: gradient elution 1% formic acid in acetonitrile (v/v) mixture); Or use the equivalent solvent system wash-out that replaces acetonitrile with methyl alcohol), or alkaline eluant (for example, uses 0-95% water/acetonitrile (mixture in acetonitrile that contains 5% 0.1%880 ammonia) gradient elution; Generally include Waters ZQ spectrograph with the MS assembly.The color atlas of generation electrospray (ESI) positive and negative base peak intensity and the UV at 220-300nm place always absorb color atlas (Total Absorption Chromatogram) and provide the value of m/z; Usually, only report is represented the ion of parent quality, and except as otherwise noted, otherwise the value of quoting is positive ion mode (M+H) ⁺(M-H) with negative ion mode ^-

(xi) preparation HPLC carries out on the C18 reverse phase silica gel; For example at Waters ' Xterra ' preparation reversed-phase column (5 microns silica gel; Diameter is 19mm; Length is 100mm), use polarity as elutriant, for example uses polarity to pursue the mixture of the water that increases (containing 1% acetate or 1% ammonium hydroxide aqueous solution (d=0.88) and acetonitrile) by the mixture that increases;

(xii) use following abbreviation:

The THF THF;

DMF N, dinethylformamide;

EtOAc ETHYLE ACETATE;

The DCM methylene dichloride; With

The DMSO methyl-sulphoxide

DIPEA N, N-diisopropyl ethyl amine (being also referred to as N-ethyl-N-third-2-base-third-2-amine)

The PBS phosphate buffered saline buffer

HEPES N-[2-hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid]

The DTT WR 34678

The ATP Triphosaden

The BSA bovine serum albumin

The Eagle nutrient solution of DMEM Dulbecco improvement (Dulbecco ' s modifiedEagle ' s Medium)

MOPS 3-(N-morpholino) propanesulfonic acid

(xiii) use suitable name software: Openeye Lexichem version 1.4 uses the IUPAC naming rule to the compound name;

(xiv) except as otherwise noted, otherwise starting raw material is commodity.

Table 1

Embodiment 1

4-(4-N-METHYL PIPERAZINE-1-yl)-N-(5-styroyl-2H-pyrazole-3-yl) BM

Under 0 ℃ with oxalyl chloride (the DCM solution of 2M, 250 μ l, 0.50mmol; 1.1 equivalent) drop to 4-(4-N-METHYL PIPERAZINE-1-yl) phenylformic acid (100mg, 0.45mmol, 1 equivalent) at DCM (5ml; Contain several DMF) and DIPEA (171 μ l, 0.95mmol, 2.1 equivalents) in mixture in.After stirring 1 hour under 0 ℃, the solution of Dropwise 5-styroyl-2H-pyrazoles-3-amine (128mg, 0.68mmol, 1.5 equivalents) in DCM (2ml).This mixture was kept 2 hours down at 0 ℃, progressively let it be warming up to room temperature subsequently and spend the night.Dilute this mixture, use NaHCO with DCM (50ml) ₃The aqueous solution (50ml) washing and with DCM (50ml) aqueous layer extracted.The organic layer that merges is concentrated.Prepare HPLC purifying crude product through alkaline anti-phase, use acetonitrile/water (the containing 1% volatile caustic) gradient elution of 30-50%, obtain title compound (8mg, 3% yield).

¹H?NMR(300.132MHz，DMSO)δ2.23(3H，s)，2.44(4H，t)，2.84-2.95(4H，m)，3.26-3.30(4H，m)，6.41(1H，s)，6.96(2H，d)，7.15-7.33(5H，m)，7.89(2H，d)，10.30(1H，s)，12.08(1H，s).MS?m/z?390(MH+)

FGFR kinases analysis-Elisa, IC ₅₀0.22 μ M

Embodiment 2

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM

At ambient temperature with Benzoyl chloride 99min. (56 μ l; 0.47mmol, 1.1 equivalents) and drop to 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (150mg; 0.43mmol; 1 equivalent) and in the mixture of pyridine (104 μ l, 1.29mmol, 3 equivalents) in DCM (1.5ml).After stirring 2 hours at ambient temperature, drip the solution of TFA (321 μ l, 4.32mmol, 10 equivalents) in DCM (2.7ml) and continue again and stirred 1 hour.Reaction mixture is concentrated and prepares HPLC purifying crude product through alkaline anti-phase, use the 33-53% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Get each clarifying level and divide and evaporation, obtain the title compound (100mg, 66% yield) of colourless foam shape solid form.

¹H?NMR(399.902MHz，DMSO)δ2.81(4H，s)，3.65(6H，s)，6.26-6.25(1H，m)，6.35(2H，d)，6.41(1H，s)，7.50-7.39(3H，m)，7.91(2H，d)，10.56(1H，s)，12.07(1H，s).MS：m/z?352(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.140 μ M

Be prepared as follows 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate as raw material:

The drips of solution of tert-Butyl dicarbonate (464mg, 2.12mmol, 1.05 equivalents) in DCM (2ml) added to 5-, and [2-(3; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (500mg; 2.02mmol, 1 equivalent) and containing the KOH aqueous solution (4.5N, 3.6ml; About 16mmol, 8 equivalents) in the mixture among the DCM (18ml).Reaction mixture is transferred to separating funnel and layering.Water (10ml), salt solution (10ml) washing organic layer are also used dried over sodium sulfate.After the filtration, solvent evaporated under reduced pressure obtains light yellow oil, and this light yellow oil hold over night after fixing obtains Off-white solid (704mg, 100% yield).

¹H?NMR(399.902MHz，DMSO)δ1.56(9H，s)，2.68-2.63(2H，m)，2.80-2.75(2H，m)，3.73(6H，s)，5.22(1H，s)，6.23(2H，br.s)，6.32-6.31(1H，m)，6.44(2H，d).MS：m/z?370([M+Na]+).

Be prepared as follows 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine as raw material:

Add in the slurry of sodium hydride (dispersion-s of 1.75g in MO, 43.61mmol, 1.2 equivalents) in dry toluene (70ml) acetonitrile (2.29ml, 43.61mmol, 1.2 equivalents) and this mixture at room temperature stirred 30 minutes.Be added in the toluene (60ml) 3-(3, the 5-Dimethoxyphenyl) ethyl propionate (8.66g, 36.34mmol, 1 equivalent) and with reaction mixture refluxed 18 hours.After the cooling, this reaction mixture of water quencher and solvent evaporated under reduced pressure.Resistates is dissolved in 2M HCl (50ml).With this acidic solution of ethyl acetate extraction.Merge organic extract liquid and water, brine wash and through dried over mgso.After the filtration, solvent evaporated under reduced pressure obtains the crude product of yellow oily.This oily matter merges required branch at different levels and evaporation through purification by silica gel column chromatography (using the DCM wash-out), obtains Off-white solid (3.76g, 44% yield).

In the Off-white solid in ethanol (55ml) (3.72g, 15.96mmol, 1 equivalent), add Hydrazine Hydrate 80 (852 μ l, 17.56mmol, 1.1 equivalents).With reaction mixture refluxed 24 hours, with its cooling of relief.Behind the reduction vaporization, resistates extracts with DCM.Organic layer water, brine wash through dried over mgso, are filtered and reduction vaporization, obtain 5-[2-(3, the 5-Dimethoxyphenyl) the ethyl]-2H-pyrazoles-3-amine (3.76g, 42% liang of step) of light yellow solid shape. ¹H?NMR(300.132MHz，DMSO)δ2.64-2.82(4H，m)，3.71(6H，s)，4.07-4.72(2H，m)，5.20(1H，s)，6.31(1H，t)，6.38(2H，d).MS：m/z?248(MH+)

Embodiment 3

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-methoxyl group-BM

With 1-chloro-N, N, 2-trimethylammonium third-1-alkene-1-amine (89 μ l, 0.63mmol, 1.05 equivalents) drop in the 4-methoxybenzoic acid (97mg, 0.63mmol, 1 equivalent) in DCM (1.5ml) at ambient temperature.After stirring 1.5 hours at ambient temperature; With 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (199mg, 0.57mmol; 0.9 equivalent) and pyridine (142 μ l; 1.74mmol, 2.75 equivalents) and solution in DCM (2ml) adds to this reaction mixture, continues at ambient temperature to stir other 3 hours.Add the mixture of TFA (386 μ l, 5.2mmol, 8.25 equivalents) in DCM (3.5ml) subsequently and continue at ambient temperature and stirred 18 hours.Reaction mixture is concentrated and prepares HPLC purifying crude product through alkaline anti-phase, use the 33-53% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Get each clarifying level and divide and evaporation, obtain the title compound (113mg, 52% yield) of colourless foam shape solid form.

¹H?NMR(399.902?MHz，DMSO)δ2.88(4H，s)，3.73(6H，s)，3.84(3H，s)，6.34-6.32(1H，m)，6.42(2H，d)，6.47(1H，s)，7.01(2H，d)，7.99(2H，d)，10.48(1H，br.s)，12.12(1H，br.s).MS：m/z?382(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.132 μ M

Adopt the method among the embodiment 2 to prepare 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate as raw material.

Embodiment 4

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-morpholine-4-base-BM

The preparation method is similar to embodiment 3, obtains the title compound (125mg, 50% yield) of solid form.

¹H?NMR(399.902MHz，DMSO)δ2.88(4H，s)，3.26-3.24(4H，m)，3.76-3.72(10H，m)，6.34-6.32(1H，m)，6.46-6.42(3H，m)，6.98(2H，d)，7.92(2H，d)，10.35(1H，br.s)，12.10(1H，br.s).MS：m/z?437(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.068 μ M

Embodiment 5

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(4-fluorine piperidines-1-yl) methyl] BM

At ambient temperature with solution (1M, 0.65ml, the 0.65mmol of NaHMDS in THF; 1.5 [2-(3 equivalent) to be added drop-wise to 5-amino-3-; The 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (150mg, 0.43mmol, 1 equivalent) and 4-[(4-fluorine piperidines-1-yl) methyl] oil of Niobe (131mg; 0.52mmol, 1.2 equivalents) and in the mixture in THF (0.5ml).Reaction mixture stirred 1 hour at ambient temperature.Subsequently it is concentrated and prepare HPLC purifying crude product, use the 39-49% acetonitrile/water solution gradient wash-out that contains 1% volatile caustic through alkaline anti-phase.Get each clarifying level and divide and evaporation, obtain the title compound (33mg, 16% yield) of colorless solid shape.

¹H?NMR(399.902MHz，DMSO)δ1.78-1.67(2H，m)，1.94-1.80(2H，m)，2.35-2.29(2H，m)，2.57-2.55(2H，m)，2.89(4H，s)，3.55(2H，s)，3.73(6H，s)，4.79-4.61(1H，m)，6.34-6.33(1H，m)，6.43(2H，d)，6.48(1H，s)，7.40(2H，d)，7.95(2H，d)，10.59(1H，br.s)，12.15(1H，br.s).MS：m/z?467(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.063 μ M

5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate as raw material adopts the method preparation among the embodiment 2.

Be prepared as follows 4-[(4-fluorine piperidines-1-yl) methyl] oil of Niobe as raw material:

With disposable 4-(brooethyl) oil of Niobe (500mg that adds to of 4-fluorine piperidine hydrochlorate (366mg, 2.62mmol, 1.2 equivalents); 2.18mmol, 1 equivalent) and MP-carbonic ether (2.74mmol/g, 1.912g; 5.24mmol, 2.4 equivalents) and in the mixture in MeCN (10ml).Reaction mixture stirred 18 hours at ambient temperature.Disposable adding loads on the isocyanic ester (1mmol/g, 500mg, 0.5mmol, 0.5 equivalent) on the polymkeric substance and continues to stir 4 hours.Filter reaction mixture, this resin washs with MeCN, concentrates the filtrating that merges, and obtains clarifying oily matter (478mg, 87% yield, purity 80%).

¹H?NMR(399.902MHz，CDCl3)δ1.98-1.83(4H，m)，2.40-2.34(2H，m)，2.61-2.54(2H，m)，3.55(2H，s)，3.91(3H，s)，4.77-4.60(1H，m)，7.40(2H，d)，8.00-7.98(2H，m).MS：m/z?252(MH+).

Embodiment 6

N-[5-[2-[3-(2-methoxy ethoxy) phenyl] ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

0 ℃ down toward several N of the middle adding of the 4-in methylene dichloride (10ml) (4-N-METHYL PIPERAZINE-1-yl) phenylformic acid (440mg, 2mmol, 1 equivalent), dinethylformamide drips the dichloromethane solution (1.1ml, 2.2mmol, 1.1 equivalents) of 2M oxalyl chloride subsequently.Being reflected at 0 ℃ kept 1 hour down.Drip 5-[2-[3-(2-methoxy ethoxy) phenyl] the ethyl]-2H-pyrazoles-3-amine (628mg, 2.4mmol, 1.2 equivalents) in methylene dichloride (10ml) subsequently, add DIPEA (750 μ l, 4.20mmol, 2.1 equivalents) subsequently.Be reflected at and kept under 0 ℃ 1 hour again, it is warming up to ambient temperature overnight with relief.Dilute this mixture with DCM (50ml), use NaHCO ₃The aqueous solution (50ml) washing.With DCM (50ml) aqueous layer extracted.Merge organic extract liquid, use brine wash, through dried over mgso and reduction vaporization.Crude product prepares the HPLC purifying through acid anti-phase.The branches at different levels that contain product are captured on the SCX-2 post.After methanol wash, discharge this crude product with 10% ammonia hydroxide/methanol.Behind the reduction vaporization, crude product prepares HPLC purifying again through alkaline anti-phase, uses the 20-45% acetonitrile/water gradient elution that contains 1% volatile caustic, obtains white solid (22.9mg, 2.5%) after the evaporation.

¹H?NMR(300.132MHz，DMSO)δ2.22(3H，s)，2.44(4H，t)，2.88(4H，s)，3.27(4H，t)，3.30(3H，s)，3.64(2H，dd)，4.06(2H，dd)，6.41(1H，s)，6.72-6.84(3H，m)，6.95(2H，d)，7.18(1H，t)，7.88(2H，d)，10.30(1H，s)，12.06(1H，s)MS：m/z?464(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.058 μ M

Be prepared as follows 5-[2-[3-(2-methoxy ethoxy) phenyl] ethyl]-2H-pyrazoles-3-amine as raw material:

Add in the sodium hydride (1.065g, 26.57mmol, 1.1 equivalents) anhydrously 1,4-diox (40ml) adds anhydrous acetonitrile (1.52ml, 29mmol, 1.2 equivalents) subsequently.Be added in subsequently anhydrous 1, the 3-in the 4-diox (35ml) [3-(2-methoxy ethoxy) phenyl] propionic acid 2-methoxyl group ethyl ester (6.82g, 24.16mmol, 1 equivalent).With reaction mixture refluxed 18 hours.After the cooling, this brown solution of water quencher.Solvent evaporated under reduced pressure and with this aqueous residue of 2M HCl acidifying and use ethyl acetate extraction.Merge organic layer, with 2M HCl, water and brine wash.After dried over mgso, solution is filtered and reduction vaporization.Crude product is through purified, with 0-50% ethyl acetate/hexane wash-out.After the evaporation, obtain the required midbody (3.24g, 54%) of yellow oily.In this midbody in ethanol (65ml) (3.24g, 13.10mmol, 1 equivalent), add a Hydrazine Hydrate 80 (700 μ l, 14.41mmol, 1.1 equivalents).With reaction mixture 85 ℃ of refluxed 18 hours.Solvent evaporated under reduced pressure.Resistates is used ethyl acetate extraction, and water and brine wash through dried over mgso, are filtered and reduction vaporization, obtain yellow oil (2.78g, 81%).

¹H?NMR(300.132MHz，DMSO)δ2.68-2.84(4H，m)，3.31(3H，s)，3.65(2H，dd)，4.06(2H，dd)，4.40(2H，s)，5.19(1H，s)，6.71-6.81(3H，m)，7.17(1H，t)，11.08(1H，s)；MS：m/z?262(MH+).

Be prepared as follows 3-[3-(2-methoxy ethoxy) phenyl] propionic acid 2-methoxyl group ethyl ester as raw material:

Toward at N, add salt of wormwood (17.28g, 125mmol, 3 equivalents) in the 3-in the dinethylformamide (150ml) (3-hydroxy phenyl) propionic acid (8.31g, 50mmol, 1 equivalent), add 2-bromo-ethyl-methyl ether (10.34ml, 110mmol, 2.20 equivalents) subsequently.With reaction mixture stirred overnight at room temperature.Reaction mixture is evaporated to dried.Use the ethyl acetate extraction resistates, water and brine wash through dried over mgso, are filtered and evaporation, obtain about 11.38g yellow oil.Reaction mixture uses 0-30% ethyl acetate/hexane gradient elution through column chromatography purification.In this midbody (9.82g, 43.76mmol, 1 equivalent), add N, dinethylformamide (50ml) adds salt of wormwood (9.1g, 65.64mmol, 2.5 equivalents) and 2-bromo-ethyl-methyl ether (4.94ml, 52.5mmol, 1.2 equivalents) subsequently.Reaction mixture heated 18 hours down at 60 ℃.Reaction mixture is used N, and dinethylformamide (50ml) dilution adds other 4.55g salt of wormwood, adds 2-bromo-ethyl-methyl ether (2.45ml) subsequently.With reaction mixture at 60 ℃ of following heated overnight (reheat 20 hours).After being cooled to room temperature, filter mutually and solvent evaporated under reduced pressure inorganic.Use the ethyl acetate extraction resistates, organic layer water, saturated sodium bicarbonate and brine wash.After dried over mgso, also filter, the reduction vaporization organic layer obtains yellow oil.Crude product is through column chromatography purification, with 0-50% ethyl acetate/hexane gradient elution.Obtain the required product (8.755g, 71%) of clarified yellow oil shape.

¹H?NMR(300.132MHz，DMSO)δ2.63(2H，t)，2.82(2H，t)，3.25(3H，s)，3.31(3H，s)，3.50(2H，m)，3.65(2H，m)，4.06(2H，m)，4.13(2H，dd)，6.73-6.82(3H，m)，7.18(1H，t)；MS：m/z?283(MH+).

Embodiment 7

4-(4-N-METHYL PIPERAZINE-1-yl)-N-[5-(2-pyridin-3-yl ethyl)-2H-pyrazole-3-yl] BM

The preparation method is similar to embodiment 1, but raw materials used be 5-(2-pyridin-3-yl ethyl)-2H-pyrazoles-3-amine (189mg, 1mmol, 1.5 equivalents), obtain the above title compound (15mg, 6% yield) of white solid.

¹H?NMR(300.132MHz，DMSO)δ2.23(3H，s)，2.44(4H，t)，2.89-2.98(4H，m)，3.28(4H，t)，6.40(1H，s)，6.96(2H，d)，7.28-7.33(1H，m)，7.65(1H，dt)，7.89(2H，d)，8.40(1H，dd)，8.45(1H，d)，10.31(1H，s)，12.09(1H，s).MS?m/z?391(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.047 μ M

Be prepared as follows 5-(2-pyridin-3-yl ethyl)-2H-pyrazoles-3-amine as raw material:

Acetonitrile (2.9ml, 54.8mmol, 1.3 equivalents) is added to sodium hydride (2.2g, 54.8mmol, 1.3 equivalents) anhydrous 1, in the soup compound in the 4-diox (50ml).Subsequently toward wherein adding 3-pyridin-3-yl methyl propionate (6.96g, 42mmol, 1 equivalent) anhydrous 1, the solution in the 4-diox (50ml).With reaction mixture reflux 18 hours.After the cooling, add ethanol (5ml), add hydrazine hydrogen chloride (3181mg, 46.43mmol, 1.1 equivalents) subsequently.Reaction mixture heated 20 hours down at 100 ℃, let it be cooled to room temperature, subsequently reduction vaporization.Orange residue is dissolved in water (50ml) and adds ETHYLE ACETATE (2x75ml) with in two alternate distribution, merge organic layer and also wash with 2M HCl.Merge acid water layer and wash with ETHYLE ACETATE.Separate water layer, add the alkalization of 8N ammonia soln and use ethyl acetate extraction.Use the brine wash organic layer,, obtain orange buttery title compound through dried over mgso, filtration and reduction vaporization.With this oily matter be dissolved in acetonitrile (10ml) and on alkaline reversed-phase HPLC purifying, use acetonitrile/water (the containing 1% volatile caustic) gradient elution of 2-20%.Merge required branch at different levels and evaporation, obtain title compound (348mg, 5% yield).

¹H?NMR(400.132MHz，DMSO)δ2.74(2H，t)，2.87(2H，t)，4.43(2H，s)，5.17(1H，s)，7.29(1H，ddd)，7.61(1H，dddd)，8.39(1H，dd)，8.42(1H，d)，11.08(1H，s).MS；m/z?189(MH+).

Obtain more product through adopting alkaline anti-phase to prepare the HPLC purifying by the water layer that alkalizes.Reduction vaporization uses this solution of 2M HCl acidifying after required level branch is concentrated into small volume.Product is captured on the SCX-2 post.Use 10% ammonia/methanol solution wash-out post, obtain product.Obtain yellow oil (657mg, 9% yield) behind the reduction vaporization.

Embodiment 8

N-[5-[2-(2-furyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

The preparation method is similar to embodiment 1, but raw materials used be 5-[2-(2-furyl) ethyl]-2H-pyrazoles-3-amine (178mg, 1mmol, 1.5 equivalents), obtain the above title compound (24.8mg, 10% yield) of brown solid-like.

¹H?NMR(300.132MHz，DMSO)δ2.23(3H，s)，2.44(4H，t)，2.89-2.98(4H，m)，3.28(4H，t)，6.40(1H，s)，6.96(2H，d)，7.28-7.33(1H，m)，7.65(1H，dt)，7.89(2H，d)，8.40(1H，dd)，8.45(1H，d)，10.31(1H，s)，12.09(1H，s).MS；m/z?380(MH+).

Average n=1, FGFR kinases analysis-Elisa, IC ₅₀0.0795 μ M

Be prepared as follows 5-[2-(2-furyl) ethyl]-2H-pyrazoles-3-amine as raw material:

A) 2-triphenylphosphine subunit (phosphoranylidene) ETHYLE ACETATE (34.84g, 100mmol, 1 equivalent) and the mixture of furans-2-formaldehyde (9609mg, 100mmol, 1 equivalent) in anhydrous THF (200ml) were at room temperature stirred 24 hours.Solvent evaporated under reduced pressure, resistates and ether grind, and obtain brown solution and deposition.Leach solid, wash and remove.The evaporation of will filtrating subsequently.Through the purification by silica gel column chromatography product, eluent is the 0-20% ethyl acetate/hexane.Evaporate required level and divide, obtain the suitable/back mixing compound (NMR show be mainly trans product) (15.5g, 93%) of (E)-3-(2-furyl) third-2-olefin(e) acid ethyl ester of light yellow oily.

B) (E)-3-(2-furyl) third-2-olefin(e) acid ethyl ester (15.5g, 93.27mmol, 1 equivalent) is stirred in the ethanol (120ml) that contains 10% palladium on carbon (775mg, 5% weight).Under hydrogen atmosphere, reaction mixture was stirred 4 hours.Add 10% Pd/C (775mg, 5% weight) of amount in addition.Under hydrogen atmosphere with reaction mixture restir 95 minutes.Filter reaction mixture and reduction vaporization.Through purification by silica gel column chromatography, eluent is 20% ethyl acetate/hexane with crude product.Required level lease making reduction vaporization obtains clarifying buttery ethyl 3-(2-furyl)-propanoate (3.69g, 24% yield).

¹H?NMR(300.132MHz，CDCl3)δ1.25(3H，t)，2.64(2H，t)，2.97(2H，t)，4.15(2H，q)，6.02(1H，td)，6.27(1H，dd)，7.30(1H，dd)

Subsequently according to the preparation method who is similar to raw material among the embodiment 2 (5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-amine); Use ethyl 3-(2-furyl)-propanoate (6.33g; 37.64mmol; 1 equivalent) as feedstock production 5-[2-(2-furyl) ethyl]-2H-pyrazoles-3-amine (2.09g, 54% liang of step).

¹H?NMR(300.132MHz，CDCl3)δ2.98(4H，t)，3.45(2H，s)，6.04(1H，d)，6.28(1H，dd)，7.30(1H，dd).MS?m/z?178(MH+).

Embodiment 9

N-[5-[2-(3-furyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

The preparation method is similar to embodiment 1, but raw materials used be 5-[2-(3-furyl) ethyl]-2H-pyrazoles-3-amine (178mg, 1mmol, 1.5 equivalents), obtain the title compound (17.3mg, 7% yield) of brown solid-like.

¹H?NMR(300.132MHz，DMSO)δ2.23(3H，s)，2.45(4H，t)，2.67-2.89(4H，m)，3.28(4H，t)，6.39(1H，d)，6.43(1H，s)，6.96(2H，d)，7.45(1H，s)，7.56(1H，t)，7.89(2H，d)，10.29(1H，s)，12.07(1H，s).MS?m/z?380(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.137 μ M

The preparation method who is used as 5-[2-(3-furyl) the ethyl]-2H-pyrazoles-3-amine (3.94g, 59% last two steps) of raw material is similar to the synthetic of the 5-shown in the embodiment 8 [2-(2-furyl) ethyl]-2H-pyrazoles-3-amine.

Embodiment 10

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

The preparation method is similar to embodiment 1, and difference is that raw material is 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (566mg, 2.30mmol, 1.5 equivalents), obtains the title compound (183.5mg, 27% yield) of beige solid shape.

¹H?NMR(300.132MHz，DMSO)δ2.23(3H，s)，2.44(4H，t)，2.86(4H，s)，3.27(4H，t)，3.72(6H，s)，6.32(2H，t)，6.35-6.42(3H，m)，6.96(2H，d)，7.89(2H，d)，10.31(1H，s)，12.08(1H，s).MS：m/z?450(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00085 μ M

5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine as raw material prepares according to embodiment 2 described methods.

Embodiment 11

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

The preparation method is similar to embodiment 1, and difference is that raw material is 5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-amine (148mg, 0.68mmol, 1.5 equivalents), obtains the title compound (8.2mg, 4% yield) of solid form.

¹H?NMR(300.132?MHz，DMSO)δ2.23(3H，s)，2.44(4H，t)，2.89(4H，s)，3.26-3.31(4H，m)，3.73(3H，s)，6.16(1H，s)，6.69-6.86(3H，m)，6.96(2H，d)，7.20(1H，t)，7.89(2H，d)，10.31(1H，s)，12.08(1H，s).MS?m/z?420(MH+)

Average n=1, FGFR kinases analysis-Elisa, IC ₅₀0.0828 μ M

Be prepared as follows 5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-amine as raw material:

Acetonitrile (3.36ml, 64.25mmol, 1 equivalent) is added to sodium hydride (dispersion-s of 2.57g in MO, 64.25mmol, 1 equivalent) anhydrous 1, in the soup compound in the 4-diox (50ml), mixture was at room temperature stirred 20 minutes.Be added in 1, (1 equivalent was with reaction mixture refluxed 2 hours for 10.4g, 53.54mmol for the 3-in the 4-diox (25ml) (3-p-methoxy-phenyl) methyl propionate.Reaction mixture and water quencher.Resistates is dissolved in 2M HCl and uses ethyl acetate extraction.Separate organic layer, with 2M HCl, water and brine wash, through dried over mgso.Reduction vaporization obtains yellow oil, and with this yellow oil of silica gel chromatography, eluent is a 0-50% ethyl acetate/hexane mixture.Merge the level that contains product and divide and evaporation remaining 5-(3-p-methoxy-phenyl)-3-oxo-valeronitrile (5.37g, 49% yield).

¹H?NMR(300.132MHz，CDCl3)δ2.86(4H，s)，3.32(2H，s)，3.73(3H，s)，6.64-6.72(3H，m)，7.14(1H，t)

In the 5-in ethanol (80ml) (3-p-methoxy-phenyl)-3-oxo-valeronitrile (5.37g, 26.42mmol, 1 equivalent), add Hydrazine Hydrate 80 (1.41ml, 29.06mmol, 1.1 equivalents).With reaction mixture refluxed 3.5 hours, with its cooling of relief.With this mixture reduction vaporization.Resistates is dissolved in ETHYLE ACETATE, and water, brine wash organic layer through dried over mgso, filter and evaporation, obtain yellow oil (leaving standstill after fixing).With this yellow oil acidifying and through the SCX-3 column chromatography purification.With 10% ammonia/this compound of methanol solution wash-out.Obtain 5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-amine (5.48g, 96% yield) after the evaporation.

¹H?NMR(300.132MHz，DMSO)：δ2.64-2.87(4H，m)，3.73(3H，s)，4.40(1H，s)，5.19(1H，s)，6.71-6.82(3H，m)，7.18(1H，t)，11.07(1H，s).MS；m/z?218(MH+)

Embodiment 12

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

The preparation method is similar to embodiment 1, but raw materials used be 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate, obtain beige solid shape title compound (34mg, 13% yield).

¹H?NMR(300.132MHz，DMSO)δ2.23(3H，s)，2.44(4H，t)，3.27-3.32(4H，m)，3.75(6H，s)，5.07(2H，s)，5.57(1H，s)，6.44-6.45(1H，m)，6.59(2H，d)，7.01(2H，d)，7.85(2H，d)，10.64(1H，s)，11.54(1H，s).MS?m/z?452(MH+)

Average n=1, FGFR kinases analysis-Elisa, IC ₅₀0.06 μ M

Be prepared as follows 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate as raw material:

Under nitrogen atmosphere with 3-amino-5-hydroxypyrazoles (8g, 80.74mmol) and triphenylphosphine (25.45g 96.88mmol) stirs in DCM (110ml), this mixture of cooling in ice bath.(19.08ml, stirred reaction mixture 1 hour 96.88mmol) (temperature＜10 ℃) in ice bath to drip diisopropyl azodiformate.Dropping in DCM (35ml) 3, (16.30g 96.88mol), lets reaction mixture be warming up to room temperature and under nitrogen atmosphere, stirred 4 days the 5-dimethoxy-benzyl alcohol.Mixture is filtered, and with the DCM washing, filtrating is with 1M HCl (aqueous solution) extraction (3x50ml).The water extract that merges causes the product deposition with DCM (50ml) washing.Filter to collect product, water, DCM washing, vacuum-drying obtains the title compound (358mg, 1.8% yield) of white solid.After letting initial DCM layer at room temperature staticly settle, further obtain another batch product.The solid collected by filtration product with DCM washing and dry under vacuum, obtains pale solid (1.127g, 5.6% yield).

¹H?NMR(300.132?MHz，DMSO)δ3.75(s，6H)，5.18(s，2H)，5.26(s，1H)，6.50(t，1H)，6.60(d，2H).MS：m/z?250(MH+)

Embodiment 13

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-methyl-pyridine-3-carboxamide

With 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine (0.2g, 0.73mmol) be dissolved in toluene (10ml) and toward wherein add 6-picoline-3-methyl-formiate (122mg, 0.73mmol) and AlMe ₃(0.93ml, 1.8mmol).With the reaction mixture stirred overnight.Reaction mixture stirs reaction mixture 20 minutes with DCM (15ml) dilution and with the moist careful quencher of sodium sulphite, and subsequent filtration and solvent removed in vacuo obtain yellow jelly.This yellow jelly is dissolved in formic acid (12ml) and 82 ℃ of following heated overnight.Reaction mixture is evaporated to dried, the product that obtains through the SCX post, is used methanol-eluted fractions at first, use 2N ammonia/methanol-eluted fractions subsequently.Except that after desolvating, obtain yellow solid, this yellow solid and hot acetonitrile are ground, obtain white solid.Filter this solid and dry (117mg, 48%). ¹H?NMR(400.132?MHz，DMSO)δ2.54(s，3H)，2.91(s，4H)，3.74(s，3H)，6.45(s，1H)，6.76(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，7.36(d，1H)，8.21(dd，1H)，9.01(s，1H)，10.81(s，1H)，12.21(s，1H)；MS：m/z?409(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.95 μ M

Be prepared as follows 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine as raw material:

With rough 5-(3-methoxyl group-phenyl)-3-oxo-valeronitrile (10g, 0.049mol), tertiary butyl hydrazonium salt hydrochlorate (7.29g, 0.059mol) and TEA (8.20ml 0.059mol) is dissolved in ethanol (300ml), reflux 3 hours.With reaction mixture cooling and solvent removed in vacuo, obtain the heavy-gravity brown oil; Water (100ml) quencher, with extracted with diethyl ether (3x200ml), dry (sal epsom), solvent removed in vacuo obtains darkorange oily matter.This darkorange oily matter through rectifying purifying under 165 ℃, 0.40mbar, is obtained clarifying heavy-gravity oily matter, and this oily matter leaves standstill after fixing.

¹H?NMR(400.132MHz，CDCl3)δ1.55(s，9H)，2.76-2.71(m，2H)，2.85-2.80(m，2H)，3.40(brs，2H)，3.72(s，3H)，5.31(s，1H)，6.66(dd，1H)，6.71(s，1H)，6.76(d，1H)，7.11(t，1H)；MS：m/z?274(MH+).

Be prepared as follows 5-(3-methoxyl group-phenyl)-3-oxo-valeronitrile as raw material:

Under nitrogen atmosphere, with LDA (34ml 0.068mol) adds to THF (300ml) and be cooled to-78 ℃, toward wherein slowly be added in acetonitrile among the THF (20ml) (2.8g, 0.068mol).Under-78 ℃, reaction mixture was stirred 10 minutes, add fast subsequently 3-(3-p-methoxy-phenyl) methyl propionate (10g, 0.052mol).Reaction mixture was stirred 30 minutes, and it is warming up to room temperature with relief.With this reaction mixture of 1.0N HCl (100ml) quencher, with extracted with diethyl ether (2x200ml), dry (sal epsom), solvent removed in vacuo obtains yellow jelly.As if this yellow jelly can slowly decompose, and it is used for next step immediately.

Embodiment 14

6-methoxyl group-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide

The preparation method is similar to embodiment 13, and difference is to use 6-methoxypyridine-3-methyl-formiate as raw material (168mg, 65%).

¹H?NMR(400.132MHz，DMSO)δ2.90(s，4H)，3.74(s，3H)，3.93(s，3H)，6.45(s，1H)，6.77-6.75(m，1H)，6.83-6.81(m，2H)，6.90(d，1H)，7.20(t，1H)，8.25(dd，1H)，8.81(d，1H)，10.70(s，1H)，12.17(s，1H)；MS：m/z?353(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.61 μ M

Embodiment 15

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-sulfonyloxy methyl-BM

The preparation method is similar to embodiment 13, and difference is to use 4-sulfonyloxy methyl ethyl benzoate as raw material (82mg, 28%).

¹H?NMR(400.132MHz，DMSO)δ2.91(s，4H)，3.28(s，3H)，3.74(s，3H)，6.49(s，1H)，6.78-6.75(m，1H)，6.84-6.81(m，2H)，7.20(t，1H)，8.03(d，2H)，8.20(d，2H)，10.96(s，1H)，12.23(s，1H)；MS：m/z?400(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.11 μ M

Embodiment 16

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-5-methyl-pyrazine-2-methane amide

The preparation method is similar to embodiment 13, and difference is to use 5-methylpyrazine-2-methyl-formiate as raw material (63mg, 26%).

¹H?NMR(400.132MHz，DMSO)δ2.62(s，3H)，2.91(s，4H)，3.73(s，3H)，6.48(s，1H)，6.77-6.75(m，1H)，6.85-6.80(m，2H)，7.20(t，1H)，8.67(s，1H)，9.13(s，1H)，10.26(s，1H)，12.28(s，1H)；MS：m/z?338(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.75 μ M

Embodiment 17

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-5-(Propargyl is amino) pyridine-2-carboxamide

The preparation method is similar to embodiment 13, and difference is to use 5-(Propargyl is amino) pyridine-2-methyl-formiate as raw material (39mg, 14%).

¹H NMR (400.132MHz, CDCl3) δ 2.28 (t, 1H), 2.96 (s, 4H), 3.77 (s, 3H); 4.00 (s, 2H), 4.56 (s, 1H), 6.47 (s, 1H), 6.76-6.73 (m; 2H), 6.78 (d, 1H), 7.04 (dd, 1H), 7.21-7.17 (m, 1H); 7.96 (d, 1H), 8.09 (d, 1H), 10.14 (s, 1H), NH disappears; MS:m/z 376 (MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.66 μ M

Embodiment 18

6-ethylamino-N-{5-[2-(3-methoxyl group-phenyl)-ethyl]-2H-pyrazole-3-yl }-vitamin PP

The preparation method is similar to embodiment 13, and difference is to use 6-ethylamino-nicotinic acid methyl ester as raw material (44mg, 16%).

¹H?NMR(400.132?MHz，DMSO)δ1.15(t，3H)，2.89(s，4H)，3.35-3.30(m，2H)，3.74(s，3H)，6.46-6.42(m，2H)，6.77-6.75(m，1H)，6.82-6.81(m，2H)，7.06(s，1H)，7.20(t，1H)，7.93(d，1H)，8.65(s，1H)，10.28(s，1H)，12.06(s，1H)；MS：m/z?366(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.54 μ M

Embodiment 19

4-acetylaminohydroxyphenylarsonic acid N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM

With 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine (0.2g 0.73mmol) is dissolved in THF/ pyridine (5ml/1ml), toward wherein add 4-kharophen Benzoyl chloride 99min. (190mg, 0.95mmol), with the reaction mixture stirred overnight.Reaction mixture is evaporated to dried, through purified, eluent is 0-5% MeOH/DCM, and evaporation obtains white foam.Resistates is dissolved in formic acid (12ml), 82 ℃ of following heated overnight.Reaction mixture is evaporated to dried, product is through the SCX column purification.Remove and desolvate, obtain yellow solid, this yellow solid and acetonitrile are ground, obtain white solid.Leach this solid and vacuum-drying (16mg, 6%); MS:m/z378 (MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.40 μ M

According to 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine of the preparation of the method described in the embodiment 13 as raw material.

Embodiment 20

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) pyrazine-2-methane amide

Under nitrogen atmosphere with NaHMDS (the THF solution of 1M, 0.645ml, 0.644mmol; 1.5 equivalent) drop to the 5-amino-3-[(3 that is stirring; The 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (150mg, 0.429mmol, 1 equivalent) and 5-(4-N-METHYL PIPERAZINE-1-yl) pyrazine-2-methyl-formiate (122mg; 0.515mmol, 1.2 equivalents) and in the solution in anhydrous THF (2.5ml).Reaction mixture at room temperature stirred 50 minutes, used saturated NH subsequently ₄The neutralization of the Cl aqueous solution, water (5ml) dilution.Organic phase is with ETHYLE ACETATE (3x8ml) extraction, and the organic extract liquid of merging filters and evaporation through dried over mgso.Residual solid prepares the HPLC purifying through anti-phase, uses the 31-51% acetonitrile/water gradient elution that contains 1% volatile caustic, obtains the product (88mg, 45%) of white solid.

¹H?NMR(399.902MHz，DMSO)δ2.24(s，3H)，2.41-2.46(m，4H)，3.72-3.78(m，4H)，3.75(s，6H)，5.08(s，2H)，5.84(s，1H)，6.44(t，1H)，6.59(d，2H)，8.33(s，1H)，8.72(s，1H)，10.81(s，1H)，11.35(s，1H).MS：m/z?454(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.046 μ M

Be prepared as follows 5-(4-N-METHYL PIPERAZINE-1-yl) pyrazine-2-methyl-formiate as raw material:

In 120 ℃ microwave reactor, 5-chloropyrazine-2-methyl-formiate (100mg, 0.579mmol, 1 equivalent), 1-N-METHYL PIPERAZINE (65 μ l, 0579mmol, 1 equivalent) and salt of wormwood (161mg, 1.159mmol, 2 equivalents) were heated 5 minutes in DMSO.Reaction mixture is poured on the SCX post (10g), uses methanol wash, use 2M ammonia/methanol-eluted fractions subsequently.In DMSO (3ml), repeat this reaction with 5-chloropyrazine-2-methyl-formiate (150mg), 1-N-METHYL PIPERAZINE (98 μ l) and salt of wormwood (241mg) as stated.To divide from the product level of two reactions to merge, vacuum-evaporation obtains the product (283mg, 83%) of yellow solid shape.

¹H?NMR(399.902MHz，DMSO)δ2.23(s，3H)，2.42(t，4H)，3.73(t，4H)，3.82(s，3H)，8.38(d，1H)，8.66(d，1H).MS：m/z?237(MH+).

Embodiment 21

4-benzamido--N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM

With 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine (0.2g, 0.73mmol) be dissolved in toluene (10ml) and toward wherein add 4-benzamido-oil of Niobe (200mg, 0.80mmol) and AlMe ₃(0.93ml, 1.8mmol).With the reaction mixture stirred overnight.Reaction mixture is with DCM (15ml) dilution, with moist sodium sulphite quencher reaction.Reaction mixture was stirred 20 minutes, subsequent filtration, solvent removed in vacuo obtains yellow jelly.This jelly is dissolved in formic acid (12ml), 82 ℃ of following heated overnight.Reaction mixture is evaporated to dried, originally the product that obtains uses methanol-eluted fractions through the SCX post, uses 2N ammonia/methanol-eluted fractions subsequently.Except that after desolvating, obtain yellow solid, yellow solid and hot acetonitrile are ground, obtain white solid.Leach this solid and dry (66mg, 21%);

1H?NMR(400.132MHz，DMSO)δ2.91(s，4H)，3.74(s，3H)，6.46(brs，1H)，6.77(d，1H)，6.83(s，2H)，7.20(t，1H)，7.64-7.54(m，3H)，7.90(d，2H)，8.02-7.97(m，4H)，10.46(s，1H)，10.55(s，1H)，12.15(s，1H)；MS：m/z441(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀231 μ M

Embodiment 22

6-(2-methoxy ethoxy)-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide

(0.15g 0.36mmol) adds in the pipe and is dissolved in 2-methyl cellosolve (15ml) with 6-chloro-N-[5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazole-3-yl] pyridine-3-carboxamide.(51mg, 1.0mmol), reaction mixture is 80 ℃ of following heated overnight to add NaH.Reaction mixture is evaporated to dried,, originally uses methanol-eluted fractions, use 2N ammonia/methanol-eluted fractions subsequently through the SCX post.Elutriant is evaporated to dried.Subsequently the jelly that obtains is dissolved in formic acid and 80 ℃ of following heated overnight.Reaction mixture is evaporated to dried,, originally uses methanol-eluted fractions, use 2N ammonia/methanol-eluted fractions subsequently through the SCX post.Elutriant is evaporated to dried, the jelly that obtains prepares the HPLC purifying through alkaline anti-phase, uses the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Obtain the product (19mg, 13%) of solid-like;

¹H?NMR(400.132MHz，DMSO)δ2.90(s，4H)，3.31(s，3H)，3.69-3.67(m，2H)，3.74(s，3H)，4.47-4.44(m，2H)，6.45(s，1H)，6.76(d，1H)，6.82(s，2H)，6.90(d，1H)，7.20(t，1H)，8.25(d，1H)，8.78(s，1H)，10.69(s，1H)，12.17(s，1H)；MH+397.

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.72 μ M

Use 6-chloro-N-[5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazole-3-yl] pyridine-3-carboxamide (1.02g, 33%) of 6-chloropyridine-3-methyl-formiate preparation according to the method for embodiment 21 as raw material;

¹H?NMR(400.132MHz，CDCl3)δ1.65(s，9H)，2.98-2.88(m，4H)，3.79(s，3H)，6.20(brs，1H)，6.73(dd，1H)，6.79(s，1H)，6.83(d，1H)，7.19(t，1H)，7.52-7.47(m，2H)，8.12(brs，1H)，8.83(brs，1H)；MS：m/z?413(MH+).

Embodiment 23

4-cyanic acid-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM

5-[(4-cyanic acid benzoyl-) amino]-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate is added in acetonitrile (5ml) and the 6.0N HCl/ propane-2-alcohol (10ml).With the reaction mixture stirred overnight, obtain white solid, leach this white solid and be dissolved in methanol.Make this solution through the SCX post subsequently.After the solvent removed in vacuo, obtain white solid (0.29g, 67%);

¹H?NMR(400.132MHz，DMSO)δ2.91(s，4H)，3.74(s，3H)，6.48(s，1H)，6.76(d，1H)，6.83(s，2H)，7.20(t，1H)，7.97(d，2H)，8.12(d，2H)，10.95(s，1H)，12.24(s，1H)；MH+347.

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀28.6 μ M

Be prepared as follows 5-[(4-cyanic acid benzoyl-) amino]-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate as raw material:

With 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate (0.4g 1.26mmol) is dissolved in DCM/ pyridine (6ml, 5: 1), toward wherein add the 4-cyano-benzoyl chloride (0.27g, 0.95mmol).With the reaction mixture stirred overnight.Reaction mixture is evaporated to dried, obtains the black jelly, this black jelly need not to be further purified and promptly can be used for next step.

Be prepared as follows 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate as raw material:

With 5-[2-(3-methoxyl group-phenyl)-ethyl]-2H-pyrazole-3-yl amine (5g, 23mmol) and Boc ₂(6.5g 30mmol) is dissolved in DCM (200ml) and stirred overnight at room temperature to O.Reaction mixture is evaporated to dried, is dissolved in ether.Toward wherein adding isohexane, under vacuum, slowly remove and desolvate, up to visible solid.With this solution scratched and supersound process, obtain 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate (6.3g, 86%) of white solid;

¹H?NMR(400.132MHz，CDCl3)δ7.20(t，1H)，6.82(d，1H)，6.79(s，1H)，6.74(d，1H)，5.22(s，1H)，3.79(s，3H)，2.93-2.88(m，2H)，2.86-2.81(m，2H)，1.65(s，9H)；MH+318.

Embodiment 24

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] benzene-1, the 4-diformamide

With 4-cyanic acid-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM (embodiment 23) (0.2g; 0.58mmol) and NaOH (69mg; 1.73mmol) add in the ethanol/water solution (20ml, 3: 1), heating is consumed up to observing raw material fully under 80 ℃.Need careful operation, reason is that acid amides further is hydrolyzed to formic acid.With DCM (3x50ml) extractive reaction mixture, dry and solvent removed in vacuo obtains white solid.This white solid and DCM are ground, obtain white solid (20mg, 10%);

¹H?NMR(400.132MHz，DMSO)δ2.90(s，4H)，3.75(s，3H)，6.42(s，1H)，6.82-6.75(m，3H)，7.20(t，1H)，7.46(s，1H)，7.95(d，2H)，8.16-8.03(m，3H)，10.82(s，1H)，12.18(s，1H)；MH+366.

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.43 μ M

Embodiment 25

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-pyrazol-1-yl-BM

With 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine (0.2g, 0.73mmol) be dissolved in toluene (10ml) and toward wherein add 4-pyrazol-1-yl oil of Niobe (177mg, 0.88mmol) and AlMe ₃(0.93ml, 1.8mmol).With the reaction mixture stirred overnight.Reaction mixture with moist sodium sulphite quencher, further stirred subsequent filtration with DCM (15ml) dilution 20 minutes.Solvent removed in vacuo obtains yellow jelly.This yellow jelly is dissolved in formic acid (12ml) and 82 ℃ of following stirred overnight.Reaction mixture is evaporated to dried, originally the product that obtains uses methanol-eluted fractions through the SCX post, uses 2N ammonia/methanol-eluted fractions subsequently.Except that after desolvating, obtain yellow solid, this yellow solid and hot acetonitrile grind, and obtain white solid.Leach this solid and dry (155mg, 55%);

¹H?NMR(400.132MHz，DMSO)δ2.92(s，4H)，3.74(s，3H)，6.48(s，1H)，6.60(s，1H)，6.77(d，1H)，6.84-6.82(m，2H)，7.20(t，1H)，7.81(s，1H)，7.96(d，2H)，8.14(d，2H)，8.63(s，1H)，10.69(s，1H)，12.18(s，1H)；MS：m/z?388(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.94 μ M

Embodiment 26

6-anilino-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (200mg 0.88mmol), obtains title compound (106mg, 35%) to 6-anilino Nicotinicum Acidum methyl esters.

¹H?NMR(400.132MHz，DMSO)δ2.90(s，4H)，3.74(s，3H)，6.44(s，1H)，6.76(d，1H)，6.87-6.82(m，3H)，6.97(t，1H)，7.20(t，1H)，7.31(t，2H)，7.70(d，2H)，8.11(d，1H)，8.79(s，1H)，9.41(s，1H)，10.51(s，1H)，12.13(s，1H)；MH+414

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀64 μ M

Embodiment 27

4-methanesulfonamido-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (200mg 0.88mmol), obtains title compound (125mg, 41%) to 4-methanesulfonamido oil of Niobe;

¹H?NMR(400.132?MHz，DMSO)δ2.90(s，4H)，3.06(s，3H)，3.74(s，3H)，6.42(s，1H)，6.76(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，7.24(d，2H)，7.97(d，2H)，10.54(s，1H)，12.09(vbrs，1H)；MH+416

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.26 μ M

Embodiment 28

4-(methylol)-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (146mg 0.88mmol), obtains title compound (136mg, 53%) to 4-(methylol) oil of Niobe;

¹HNMR(400.132MHz，DMSO)δ2.90(s，4H)，3.74(s，3H)，4.57(d，2H)，5.28(t，1H)，6.45(s，1H)，6.76(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，7.41(d，2H)，7.95(d，2H)，10.58(s，1H)，12.14(s，1H)；MH+352.

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.074 μ M

Embodiment 29

5-formamido group-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-2-carboxamide

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (222mg 0.88mmol), obtains title compound (72mg, 27%) to 5-[(2-methylpropane-2-yl) oxygen base carbonylamino] pyridine-2-methyl-formiate;

¹H?NMR(400.132MHz，DMSO)δ2.91(s，4H)，3.73(s，3H)，6.47(s，1H)，6.76(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，8.12(d，1H)，8.26(dd，1H)，8.44(s，1H)，8.87(s，1H)，10.13(vbrs，1H)，10.74(s，1H)，12.23(s，1H)；MH+366

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.87 μ M

Embodiment 30

4-(dimethylamino alkylsulfonyl)-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] BM

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (214mg 0.88mmol), obtains title compound (126mg, 40%) to 4-(dimethylamino alkylsulfonyl) oil of Niobe;

¹H?NMR(400.132MHz，DMSO)δ2.66(s，6H)，2.91(s，4H)，3.74(s，3H)，6.49(s，1H)，6.77(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，7.85(d，2H)，8.20(d，2H)，10.93(s，1H)，12.23(s，1H)；MH+429.

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.80 μ M

Embodiment 31

6-hydroxy-n-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (147mg 0.88mmol), obtains title compound (28mg, 11%) to 6-pyridone-3-methyl-formiate; ¹H NMR (400.132 MHz, DMSO) δ 2.89 (s, 4H), 3.73 (s, 3H), 6.37-6.34 (m, 2H), 6.76 (d, 1H), 6.82-6.80 (m, 2H), 7.19 (t, 1H), 7.97 (dd, 1H), 8.18 (d, 1H), 10.44 (s, 1H), 12.03 (vbrs, 1H); MH+339

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀1.05 μ M

Embodiment 32

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-morpholine-4-base-pyridine-3-carboxamide

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (195mg 0.88mmol), obtains title compound (140mg, 47%) to 6-morpholine-4-yl pyridines-3-methyl-formiate;

¹HNMR(400.132MHz，DMSO)δ2.90(s，4H)，3.59-3.57(m，4H)，3.71-3.69(m，4H)，3.74(s，3H)，6.44(s，1H)，6.76(d，1H)，6.82-6.81(m，2H)，6.86(d，1H)，7.20(t，1H)，8.13(d，1H)，8.76(s，1H)，10.45(s，1H)，12.11(s，1H)；MH+408

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.027 μ M

Be prepared as follows 6-morpholine-4-yl pyridines-3-methyl-formiate as raw material:

With 6-morpholine-4-yl pyridines-3-formic acid (2.56g, 13.6mmol) and salt of wormwood (2.8g, 20.4mmol) add among the DMF (40ml) and toward wherein add MeI (0.97ml, 15mmol).Reaction mixture heated 3 hours down at 50 ℃.Solvent removed in vacuo obtains dark solid, and this dark solid is washed with DCM (3X100ml) with 2.0N NaOH (100ml) quencher, and dry (sal epsom), solvent removed in vacuo obtains brown solid.This solid is dissolved in hot acetonitrile and lets its cooling, obtain white solid, leach this white solid, repeat this process, obtain title compound (1.8g, 60%) with mother liquor;

1H?NMR(400.132MHz，CDCl3)3.65(t，4H)，3.81(t，4H)，3.87(s，3H)，6.53(d，1H)，8.04(dd，1H)，8.80(d，1H)；MH+223.

Embodiment 33

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(1,3-oxazole-5-yl) BM

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (177mg 0.88mmol), obtains title compound (28mg, 10%) to 4-(1,3-oxazole-5-yl) oil of Niobe;

¹H?NMR(400.132MHz，DMSO)δ2.91(s，4H)，3.74(s，3H)，6.48(s，1H)，6.77(d，1H)，6.82(m，2H)，7.20(t，1H)，7.87-7.83(m，3H)，8.10(d，2H)，8.51(s，1H)，10.73(s，1H)，12.18(s，1H)；MH+389.

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀1.2 μ M

Embodiment 34

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(tetrazolium-1-yl) BM

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (179mg 0.88mmol), obtains title compound (16mg, 6%) to 4-(tetrazolium-1-yl) oil of Niobe;

¹H?NMR(400.132MHz，DMSO)δ2.92(s，4H)，3.74(s，3H)，6.50(s，1H)，6.77(d，1H)，6.84-6.82(m，2H)，7.21(t，1H)，8.06(d，2H)，8.25(d，2H)，10.19(s，1H)，10.89(s，1H)，12.22(s，1H)；MH+390.

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀1 μ M

Embodiment 35

N-[5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-yl] carboxylamine third-2-alkenyl esters

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (208mg 0.88mmol), obtains title compound (38mg, 12%) to the Nicotinicum Acidum methyl esters to 6-(third-2-allyloxycarbonyl is amino);

¹H?NMR(400.132MHz，DMSO)δ2.90(s，4H)，3.74(s，3H)，4.66(d，2H)，5.25(d，1H)，5.40(d，1H)，6.02-5.95(m，1H)，6.46(s，1H)，6.76(d，1H)，6.84-6.80(m，2H)，7.20(t，1H)，7.91(d，1H)，8.32(d，1H)，8.87(s，1H)，10.56(s，1H)，10.74(s，1H)，12.17(s，1H)；MH+422.

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀76 μ M

The preparation method who is used as 6-(third-2-allyloxycarbonyl is amino) the Nicotinicum Acidum methyl esters of raw material is similar to the synthetic of 6-morpholine among the embodiment 32-4-yl pyridines-3-methyl-formiate; Difference is that raw material is 6-(third-2-allyloxycarbonyl is amino) Nicotinicum Acidum (880mg; 3.96mmol); Obtain title compound (0.35g, 37%);

1HNMR(400.132MHz，CDCl3)3.93(s，3H)，4.75(dt，2H)，5.32(dq，1H)，5.41(dq，1H)，6.09-5.99(m，1H)，8.07(d，1H)，8.30(dd，1H)，8.97(d，1H)，9.45(brs，1H)；MH+237.

Embodiment 36

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(1,2, the 4-triazol-1-yl) BM

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (177mg 0.88mmol), obtains title compound (83mg, 29%) to 4-(1,2, the 4-triazol-1-yl) oil of Niobe;

¹H?NMR(400.132MHz，DMSO)δ2.92(s，4H)，3.74(s，3H)，6.48(s，1H)，6.77(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，8.00(d，2H)，8.19(d，2H)，8.29(s，1H)，9.42(s，1H)，10.79(s，1H)，12.20(s，1H)；MH+389.

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.66 μ M

Embodiment 37

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-pyrazol-1-yl-pyridine-3-carboxamide

Use is similar to the method preparation of embodiment 25, and difference is that raw material is that (177mg 0.88mmol), obtains title compound (151mg, 54%) to 6-pyrazol-1-yl Nicotinicum Acidum methyl esters;

¹HNMR(400.132MHz，DMSO)δ2.92(s，4H)，3.74(s，3H)，6.49(s，1H)，6.63(dd，1H)，6.77(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，7.90(s，1H)，8.01(d，1H)，8.52(d，1H)，8.70(s，1H)，9.03(s，1H)，10.95(s，1H)，12.23(s，1H)；MH+389.

Average n=3, FGFR kinases analysis-Caliper, IC ₅₀69 μ M

Be prepared as follows 6-pyrazol-1-yl Nicotinicum Acidum methyl esters as raw material:

With pyrazoles (2.4g 35.4mmol) adds to DMA (100ml), toward wherein slowly add NaH (1.85g, 38.6mmol).Under nitrogen atmosphere, reaction mixture was stirred 10 minutes.Chloropyridine-(5.5g, 32.2mmol), reaction mixture is 95 ℃ of following stirred overnight for the 3-methyl-formiate to add 6-in the negatively charged ion that obtains.Reaction mixture is evaporated to dried, with 2.0NNaOH (100ml) quencher, with DCM (3x100ml) extraction, dry (sal epsom), solvent removed in vacuo obtains brown solid.This solid is through purification by silica gel column chromatography, and eluent is 0-40% ether/isohexane.Obtain white solid, this white solid is dissolved in hot isohexane.After the cooling, obtain white solid, white solid is leached and dry (2.6g, 40%);

¹H?NMR(400.132MHz，CDCl3)δ3.96(s，3H)，6.50(s，1H)，7.77(s，1H)，8.05(d，1H)，8.40(dd，1H)，8.62(d，1H)，9.02(d，1H)；MH+203.

Embodiment 38

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-fluoro-BM

Under 0 ℃ with oxalyl chloride (the DCM solution of 2M, 1.40ml, 2.75mmol; 1.1 equivalent) drop to and contain several DMF (10 μ l, 0.12mmol, 0.05 equivalent) and DIPEA (937 μ l; 5.25mmol; 2.1 in the mixture of 4-fluorobenzoic acid equivalent) (350mg, 2.50mmol, 1 equivalent) in methylene dichloride (15ml).Stirred 60 minutes down at 0 ℃, through the solution of 15 minutes Dropwise 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (742mg, 3mmol, 1.2 equivalents) in DCM (10ml).This mixture was kept 2 hours at 0 ℃ again, progressively let it be warming up to ambient temperature overnight subsequently.Dilute this mixture with DCM (50ml), use NaHCO ₃The aqueous solution (50ml) washing.With DCM (50ml) aqueous layer extracted.Collecting the organic layer that merges also concentrates.Crude product prepares the HPLC purifying through anti-phase, uses the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Evaporate required level and divide, obtain the title compound (31.5mg, 3% yield) of beige solid shape

¹H?NMR(300.132MHz，DMSO)δ2.87(4H，s)，3.72(6H，s)，6.32(1H，t)，6.42(2H，d)，6.46(1H，s)，7.31(2H，t)，8.06(2H，m)，10.69(1H，s)，12.16(1H，s).MS：m/z?370(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.165 μ M

According to 5-[2-(3,5-Dimethoxyphenyl) the ethyl]-2H-pyrazoles-3-amine of the preparation of the method shown in the feedstock production among the embodiment 2 as raw material.

Embodiment 39

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-3-methoxyl group-BM

With 1-chloro-N, N, 2-trimethylammonium third-1-alkene-1-amine (89 μ l, 0.67mmol, 1.05 equivalents) drop in the 3-methoxybenzoic acid (97mg, 0.63mmol, 1 equivalent) in DCM (1.5ml) at ambient temperature.After stirring 1.5 hours at ambient temperature; With 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (199mg, 0.57mmol; 0.9 equivalent) and pyridine (142 μ l; 1.74mmol, 2.75 equivalents) and solution in DCM (2ml) adds in this reaction mixture, continues at ambient temperature to stir 3 hours.Add the solution of TFA (386 μ l, 5.2mmol, 8.25 equivalents) in DCM (3.5ml) subsequently, continue at ambient temperature to stir 18 hours.Reaction mixture is concentrated and prepares HPLC purifying crude product through alkaline anti-phase, use the acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Get each clarifying level and divide and evaporation, obtain the title compound (129mg, 59% yield) of colorless solid shape.

¹H?NMR(399.902MHz，DMSO)δ2.89(4H，s)，3.73(6H，s)，3.84(3H，s)，6.34-6.33(1H，m)，6.43(2H，d)，6.48(1H，s)，7.12-7.10(1H，m)，7.42-7.37(1H，m)，7.59-7.56(2H，m)，10.65(1H，br.s)，12.16(1H，br.s).MS：m/z?382(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.37 μ M

5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate as raw material adopts the method preparation among the embodiment 2.

Embodiment 40

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-3-morpholine-4-base-BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (130mg 0.63mmol), obtains the title compound (105mg, 42% yield) of solid form to 3-morpholine-4-yl benzoic acid;

¹H?NMR(399.902MHz，DMSO)δ2.89(4H，s)，3.21-3.19(4H，m)，3.73(6H，s)，3.79-3.76(4H，m)，6.34-6.33(1H，m)，6.43(2H，d)，6.48(1H，s)，7.12(1H，d)，7.35-7.31(1H，m)，7.43(1H，d)，7.57(1H，s)，10.62(1H，br.s)，12.15(1H，br.s).MS：m/z?437(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.71 μ M

Embodiment 41

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-2-methoxyl group-BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (95.8mg 0.63mmol), obtains the title compound (100mg, 46% yield) of solid form to O-Anisic Acid;

¹H?NMR(399.902MHz，DMSO)δ2.89(4H，s)，3.73(6H，s)，3.97(3H，s)，6.34-6.33(1H，m)，6.43(2H，d)，6.49(1H，s)，7.12-7.07(1H，m)，7.21(1H，d)，7.56-7.51(1H，m)，7.85-7.82(1H，m)，10.16(1H，br.s)，12.14(1H，br.s).MS：m/z?382(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀2.61 μ M

Embodiment 42

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-ethoxy ethoxy) BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (132mg 0.63mmol), obtains the title compound (126mg, 50% yield) of solid form to 4-(2-ethoxy ethoxy) phenylformic acid;

¹H?NMR(399.902MHz，DMSO)δ1.15(3H，t)，2.88(4H，s)，3.52(2H，q)，3.73(8H，s)，4.19-4.16(1H，m)，6.34-6.32(1H，m)，6.43(2H，d)，6.46(1H，s)，7.02(2H，d)，7.98(2H，d)，10.47(1H，br.s)，12.11(1H，br.s).MS：m/z?440(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.075 μ M

Embodiment 43

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(piperidino) BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (129mg 0.63mmol), obtains the title compound (97.5mg, 39% yield) of solid form to 4-(piperidino) phenylformic acid;

¹H?NMR(399.902MHz，DMSO)δ1.60(6H，s)，2.88(4H，s)，3.33-3.31(6H，m)，3.73(1H，s)，6.33-6.32(2H，m)，6.42(1H，d)，6.45(2H，s)，6.94(2H，d)，10.26(1H，br.s)，12.07(1H，br.s).MS：m/z435(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.438 μ M

Embodiment 44

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-piperidyl methoxy base) BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (211mg 0.63mmol), obtains the title compound (40mg, 15% yield) of solid form to phenylformic acid to 4-[[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-4-piperidyl] methoxyl group];

¹H?NMR(399.902MHz，DMSO)?

1.72-1.67(2H，m)，1.87-1.79(2H，m)，2.48-2.45(1H，m)，2.88(4H，s)，2.98-2.94(2H，m)，3.73(6H，s)，3.88(2H，d)，6.34(1H，s)，6.46-6.42(3H，m)，7.00(2H，d)，7.97(2H，d)，10.48(1H，br.s)，12.14(1H，br.s).MS：m/z?465(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.025 μ M

Embodiment 45

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-piperazine-1-base-BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (193mg 0.63mmol), obtains the title compound (100mg, 40% yield) of solid form to 4-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] phenylformic acid;

¹H?NMR(399.902MHz，DMSO)δ2.84-2.82(4H，m)，2.88(4H，s)，3.21-3.15(4H，m)，3.73(6H，s)，6.33(1H，s)，6.46-6.42(3H，m)，6.94(2H，d)，7.89(2H，d)，10.30(1H，br.s)，12.09(1H，br.s).MS：m/z?436(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.026 μ M

Embodiment 46

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-6-piperazine-1-base-pyridine-3-carboxamide

The preparation method is similar to embodiment 39, and the raw material of employing is that (193mg 0.63mmol), obtains the title compound (96mg, 39% yield) of solid form to 6-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] Nicotinicum Acidum;

¹H?NMR(399.902MHz，DMSO)δ2.79-2.76(4H，m)，2.88(4H，s)，3.56-3.53(4H，m)，3.73(6H，s)，6.34-6.32(1H，m)，6.45-6.42(3H，m)，6.82(1H，d)，8.10-8.07(1H，m)，8.73(1H，d)，10.43(1H，br.s)，12.12(1H，br.s).MS：m/z?437(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.040 μ M

Embodiment 47

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(dimethylaminomethyl) BM

Oxalyl chloride (61 μ l, 0.69mmol, 1.1 equivalents) is dropped in 4-(dimethylaminomethyl) phenylformic acid (113mg, 0.63mmol, 1 equivalent) in DCM (2.5ml) that contains 1 DMF.After stirring 1.5 hours at ambient temperature; With 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (196mg, 0.56mmol; 0.9 equivalent) and pyridine (137 μ l; 1.69mmol, 2.70 equivalents) and solution in DCM (2ml) adds to this reaction mixture, continues at ambient temperature to stir 2 hours.Add the solution of TFA (384 μ l, 5.16mmol, 8.25 equivalents) in DCM (3.5ml) subsequently, continue at ambient temperature to stir 18 hours.Reaction mixture is concentrated and prepares HPLC purifying crude product through alkaline anti-phase, use the acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Get each clarifying level and divide and evaporation, obtain the title compound (65mg, 25% yield) of colorless solid shape.

¹H?NMR(399.902MHz，DMSO)δ2.09(6H，s)，2.81(4H，s)，3.38(2H，s)，3.65(6H，s)，6.26-6.25(1H，m)，6.35(2H，d)，6.40(1H，s)，7.31(2H，d)，7.87(2H，d)，10.51(1H，br.s)，12.07(1H，br.s).MS：m/z409(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.019 μ M

1H?NMR(399.902MHz，DMSO)δ1.56(9H，s)，2.68-2.63(2H，m)，2.80-2.75(2H，m)，3.73(6H，s)，5.22(1H，s)，6.23(2H，br.s)，6.32-6.31(1H，m)，6.44(2H，d).MS：m/z?370([M+Na]+).

Embodiment 48

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-hydroxyl-oxethyl) BM

At ambient temperature with THF solution (1M, 1.15ml, the 1.15mmol of NaHMDS; 2 equivalents) [2-(3 to drop to 5-amino-3-; The 5-Dimethoxyphenyl) ethyl] pyrazoles-1-formic acid tertiary butyl ester (200mg, 0.58mmol, 1 equivalent) and 4-(2-hydroxyl-oxethyl) oil of Niobe (136mg; 0.69mmol, 1.2 equivalents) and in the mixture in THF (1ml).Reaction mixture stirred 1 hour at ambient temperature.Subsequently it is concentrated and prepare HPLC purifying crude product, use the acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide through alkaline anti-phase.Get each clarifying level and divide and evaporation, obtain the title compound (29mg, 12% yield) of colorless solid shape;

¹H?NMR?(399.902MHz，DMSO)δ2.89(4H，s)，3.77-3.72(8H，m)，4.07(2H，t)，4.88(1H，t)，6.34-6.33(1H，m)，6.43(2H，d)，6.46(1H，s)，7.01(2H，d)，7.98(2H，d)，10.46(1H，br.s)，12.12(1H，br.s).MS：m/z412(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.039 μ M

Embodiment 49

4-(2-aminopropyl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM

At ambient temperature with THF solution (1M, 0.86ml, the 0.86mmol of NaHMDS; 1.5 [2-(3 equivalent) to drop to 5-amino-3-; The 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (200mg, 0.58mmol, 1 equivalent) and 4-(2-aminopropyl) oil of Niobe (133mg; 0.69mmol, 1.2 equivalents) and in the mixture in THF (1ml).Reaction mixture stirred 2 hours at ambient temperature.Subsequently it is concentrated and prepare HPLC purifying crude product, use the acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide through alkaline anti-phase.Get each clarifying level and divide and evaporation, obtain the title compound (10mg, 4% yield) of light yellow glue.

¹H?NMR(399.902MHz，DMSO)δ0.89(3H，d)，2.53-2.47(2H，m)，2.80(4H，s)，3.01-2.93(1H，m)，3.65(6H，s)，6.25-6.24(1H，m)，6.34(2H，d)，6.40(1H，s)，7.21(2H，d)，7.84(2H，d)，10.47(1H，br.s)，12.06(1H，br.s).MS：m/z?409(MH+)

Cell?FGFR，IC ₅₀?1.47μM。

Embodiment 50

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(3,3-dimethyl--piperidino) methyl] BM

The preparation method is similar to embodiment 49, and the raw material of employing is that (180mg 0.69mmol), obtains the title compound (44mg, 16% yield) of colorless solid shape to 4-[(3,3-dimethyl--piperidino) methyl] oil of Niobe;

¹H?NMR(399.902MHz，DMSO)δ0.92(3H，s)，1.23-1.20(2H，m)，1.59-1.52(2H，m)，2.01-1.99(2H，m)，2.35-2.29(2H，m)，2.89(4H，s)，3.48(2H，s)，3.73(6H，s)，6.34-6.32(1H，m)，6.43(2H，d)，6.48(1H，s)，7.40(2H，d)，7.94(2H，d)，10.57(1H，br.s)，12.14(1H，br.s).MS：m/z?477(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.001 μ M

Be prepared as follows 4-[(3,3-dimethyl--piperidino) methyl] oil of Niobe as raw material:

With 3,3-lupetidine (170mg, 1.5mmol, 1.5 equivalents) is disposable to be added in 4-(brooethyl) oil of Niobe (230mg, 1mmol, 1 equivalent) and the mixture of MP-carbonic ether (2.74mmol/g, 1.46g, 4mmol, 4 equivalents) in MeCN (5ml).Reaction mixture stirred 18 hours at ambient temperature.Disposable adding loads on the isocyanic ester (1mmol/g, 1g, 1mmol, 1 equivalent) on the polymkeric substance and continues to stir 4 hours.Filter reaction mixture is used the MeCN washing resin, concentrates the filtrating that merges, and obtains clarified liq (216mg, 83% yield);

¹H?NMR(399.902MHz，DMSO)δ0.91(6H，s)，1.22-1.19(2H，m)，1.58-1.52(2H，m)，1.99(2H，s)，2.33-2.28(2H，m)，3.49(2H，s)，3.85(3H，s)，7.46(2H，d)，7.92(2H，d).MS：m/z?262(MH+)

Embodiment 51

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[4-(2-hydroxyethyl) piperazine-1-yl] BM

The preparation method is similar to embodiment 49, and the raw material of employing is that (182mg 0.69mmol), obtains the title compound (11mg, 4% yield) of colorless solid shape to 4-[4-(2-hydroxyethyl) piperazine-1-yl] oil of Niobe;

¹H?NMR(399.902MHz，DMSO)δ2.45(2H，t)，2.58-2.55(4H，m)，2.88(4H，s)，3.29-3.26(4H，m)，3.58-3.53(2H，m)，3.73(6H，s)，4.42(1H，t)，6.34-6.32(1H，m)，6.42(2H，d)，6.45(1H，s)，6.96(2H，d)，7.90(2H，d)，10.30(1H，br.s)，12.08(1H，br.s).MS：m/z?480(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.081 μ M

Be prepared as follows 4-[4-(2-hydroxyethyl) piperazine-1-yl] oil of Niobe as raw material:

At ambient temperature with the trimethyl silyl diazomethane solution (hexane solution of 2M; 1.2ml, 2.4mmol, 1.2 equivalents) and drop to 4-(4-[2-hydroxyethyl] piperazine-1-yl) phenylformic acid (501mg in toluene (14ml) and methyl alcohol (4ml); 2mmol, 1 equivalent) in.Reaction mixture was stirred 5 hours, removal of solvent under reduced pressure, resistates is dry under high vacuum, obtains 4-(2-bromine oxethyl) oil of Niobe (342mg, 65% yield) of Off-white solid form.MS：m/z?265(MH+)。

Embodiment 52

4-[(7-cyanic acid-3,4-dihydro-1H-isoquinoline 99.9-2-yl) methyl]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM

The preparation method is similar to embodiment 53, and the raw material of employing is that (211mg 0.69mmol), obtains the title compound (45mg, 15% yield) of light yellow glue to 4-[(7-cyanic acid-3,4-dihydro-1H-isoquinoline 99.9-2-yl) methyl] oil of Niobe;

¹H?NMR(399.902MHz，DMSO)? 2.67-2.64(2H，m)，2.81(4H，s)，2.86-2.83(2H，m)，3.54(2H，s)，3.67-3.64(8H，m)，6.26-6.24(1H，m)，6.35(2H，d)，6.41(1H，s)，7.26(1H，d)，7.39(2H，d)，7.51-7.47(2H，m)，7.91(2H，d)，10.53(1H，br.s)，12.07(1H，br.s).MS：m/z?522(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.486 μ M

Be prepared as follows 4-[(7-cyanic acid-3,4-dihydro-1H-isoquinoline 99.9-2-yl) methyl] oil of Niobe as raw material:

With 1,2,3,4-tetrahydroisoquinoline-7-formonitrile HCN hydrochloride (292mg; 1.5mmol, 1.5 equivalents) and disposable 4-(brooethyl) oil of Niobe (230mg, 1mmol, 1 equivalent) and the MP-carbonic ether (2.74mmol/g of adding to; 1.46g, 4mmol, 4 equivalents) and in the mixture in MeCN (5ml).This mixture stirred 18 hours at ambient temperature.Disposable adding loads on the isocyanic ester (1mmol/g, 1g, 1mmol, 1 equivalent) on the polymkeric substance, continues to stir 4 hours.Filter reaction mixture is used the MeCN washing resin, concentrates the filtrating that merges, and obtains light yellow oil, this light yellow oil hold over night after fixing (292mg, 95% yield);

¹H?NMR(399.902MHz，DMSO)?

2.70-2.63(2H，m)，2.89-2.82(2H，m)，3.53(2H，s)，3.68(2H，s)，3.78(3H，s)，7.25(1H，d)，7.51-7.38(4H，m)，7.89-7.86(2H，m).MS：m/z?307(MH+)

Embodiment 53

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(3-fluoro-piperidino) methyl] BM

At ambient temperature with THF solution (1M, 0.86ml, the 0.86mmol of NaHMDS; 1.5 [2-(3 equivalent) to drop to 5-amino-3-; The 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (200mg, 0.58mmol, 1 equivalent) and 4-[(3-fluoro-piperidino) methyl] oil of Niobe (174mg; 0.69mmol, 1.2 equivalents) and in the mixture in THF (1ml).At ambient temperature reaction mixture was stirred 2 hours.Concentrated reaction mixture subsequently, crude product prepares the HPLC purifying through acid anti-phase, uses the acetonitrile/water gradient elution that contains 0.1%TFA.Collection clarification level is divided and evaporation, resistates is dissolved in 3: 1 DCM: in the MeCN mixture (4ml), adding MP-carbonic ether (2.74mmol/g, 1g, 2.74mmol).Mixture was stirred 4 hours, filter and evaporated filtrate, obtain the title compound (43mg, 16% yield) of light yellow glue;

¹HNMR(399.902MHz，DMSO)? 1.46-1.34(2H，m)，1.82-1.61(2H，m)，2.36-2.28(2H，m)，2.66-2.56(2H，m)，2.81(4H，s)，3.50(2H，s)，3.65(6H，s)，4.66-4.47(1H，m)，6.26-6.24(1H，m)，6.35(2H，d)，6.40(1H，s)，7.32(2H，d)，7.88(2H，d)，10.51(1H，br.s)，12.07(1H，br.s).MS：m/z?467(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.090 μ M

Be prepared as follows 4-[(3-fluoro-piperidino) methyl] oil of Niobe as raw material:

Add in 4-(brooethyl) oil of Niobe (230mg, 1mmol, 1 equivalent) and the mixture of MP-carbonic ether (2.74mmol/g, 1.46g, 4mmol, 4 equivalents) in MeCN (5ml) 3-fluorine piperidine hydrochlorate (210mg, 1.5mmol, 1.5 equivalents) is disposable.At ambient temperature reaction mixture was stirred 18 hours.Disposable adding loads on the isocyanic ester (1mmol/g, 1g, 1mmol, 1 equivalent) on the polymkeric substance, continues to stir 4 hours.Filter reaction mixture is used the MeCN washing resin, concentrates the filtrating that merges, and obtains clarifying oily matter (217mg, 86% yield).

¹H?NMR(399.902MHz，DMSO)?

1.59-1.42(2H，m)，1.90-1.67(2H，m)，2.42-2.36(2H，m)，2.73-2.63(2H，m)，3.59(2H，s)，3.86(3H，s)，4.73-4.56(1H，m)，7.46(2H，d)，7.93(2H，d).MS：m/z?252(MH+)

Embodiment 54

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-morpholine-4-base oxethyl) BM

The preparation method is similar to embodiment 53, and the raw material of employing is that (183mg 0.69mmol), obtains the title compound (21mg, 7.5% yield) of light yellow glue to 4-(2-morpholine-4-base oxethyl) oil of Niobe;

¹H?NMR(399.902MHz，CDCl3)?

2.59-2.57(4H，m)，2.81(2H，t)，2.99-2.90(4H，m)，3.75-3.72(4H，m)，3.77(6H，s)，4.14(2H，t)，6.36-6.32(4H，m)，6.67(1H，br.s)，6.96(2H，d)，7.83(2H，d)，8.53(1H，br.s).MS：m/z?481(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.096 μ M

Be prepared as follows 4-(2-morpholine-4-base oxethyl) oil of Niobe as raw material:

With MP-carbonic ether (2.74mmol/g, 529mg, 1.45mmol; 1.5 equivalent) add to 4-(2-bromine oxethyl) oil of Niobe (250mg, 0.96mmol, 1 equivalent), morpholine (93 μ l; 1.06mmol, 1.1 equivalents), Soiodin (150mg, 1mmol; 1.05 equivalent), in the microwave reaction container, add MeCN (5ml), in microwave reactor, reaction mixture be heated to 120 ℃ and kept 10 minutes.Reaction mixture is transferred to the SCX-2 post, uses the MeOH wash-out, use 3.5N ammonia/methanol solution wash-out subsequently.The level that merges the back wash-out is divided and evaporation, obtains clarifying oily matter, leaves standstill after fixing and obtains Off-white solid (146mg, 57% yield).

¹H?NMR(400.132MHz，CDCl3)δ2.59-2.57(4H，m)，2.82(2H，t)，3.74-3.72(4H，m)，3.88(3H，s)，4.16(2H，t)，6.93-6.91(2H，m)，7.99-7.97(2H，m).MS：m/z?266(MH+)

Embodiment 55

4-[2-(4,4-two fluoro-piperidino) oxyethyl group]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM

The preparation method is similar to embodiment 53, and the raw material of employing is that (104mg 0.35mmol), obtains clarifying the title compound (5mg, 1.7% yield) of jelly form to 4-[2-(4,4-two fluoro-piperidino) oxyethyl group] oil of Niobe;

¹H?NMR(399.902MHz，CDCl3)δ2.06-1.96(4H，m)，2.70-2.67(4H，m)，2.88-2.85(2H，m)，2.97-2.92(4H，m)，3.77-3.76(8H，m)，4.12(2H，t)，6.33-6.32(2H，m)，6.35-6.35(2H，m)，6.65(1H，br.s)，6.95(2H，d)，7.83(2H，d)，8.59(1H，s).MS：m/z?515(MH+)

Cell?FGFR1，IC ₅₀?0.46μM。

Be prepared as follows 4-[2-(4,4-two fluoro-piperidino) oxyethyl group] oil of Niobe as raw material:

MP-carbonic ether (2.74mmol/g, 1.234g, 3.38mmol, 2.5 equivalents) is added to 4-(2-bromine oxethyl) oil of Niobe (350mg; 1.35mmol, 1 equivalent), 4,4-difluoro piperidine hydrochlorate (235mg; 1.49mmol, 1.1 equivalents), Soiodin (212mg, 1.42mmol; 1.05 equivalent), in the microwave reaction container, add MeCN (6ml), in microwave reactor, reaction mixture be heated to 120 ℃ and kept 10 minutes.Reaction mixture is transferred to the SCX-2 post, uses the MeOH wash-out, use 3.5N ammonia/methanol solution wash-out subsequently.The level that merges the back wash-out is divided and evaporation, obtains colorless solid (104mg, 35% yield).

¹H?NMR(400.132MHz，CDCl3)?

2.08-1.98(4H，m)，2.74-2.71(4H，m)，2.90(2H，t)，3.89(3H，s)，4.16(2H，t)，6.93-6.91(2H，m)，8.00-7.98(2H，m).MS：m/z?300(MH+)

Embodiment 56

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-morpholine-4-base ethyl) BM

The preparation method is similar to embodiment 53, and the raw material of employing is that (172mg 0.69mmol), obtains clarifying the title compound (42mg, 15.6% yield) of jelly form to oil of Niobe to 4-(2-morpholine-4-base ethyl);

¹H?NMR(399.902MHz，DMSO)?

2.37-2.35(4H，m)，2.49-2.45(2H，m)，2.73(2H，t)，2.80(4H，s)，3.50(4H，t)，3.65(6H，s)，6.26-6.24(1H，m)，6.34(2H，d)，6.40(1H，s)，7.26(2H，d)，7.83(2H，d)，10.47(1H，br.s)，12.06(1H，br.s).MS：m/z?465(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.120 μ M

Be prepared as follows 4-(2-morpholine-4-base ethyl) phenylformic acid as raw material:

At ambient temperature trimethyl silyl diazomethane solution (2M hexane solution, 1.2ml, 2.4mmol, 1.2 equivalents) is dropped in 4-(2-bromotrifluoromethane) phenylformic acid (459mg, 2mmol, 1 equivalent) in toluene (14ml) and methyl alcohol (4ml).Reaction mixture was stirred 5 hours, removal of solvent under reduced pressure, resistates is dry under high vacuum, obtains 4-(2-bromine oxethyl) oil of Niobe (487mg, 100% yield) of light yellow liquid form.

¹H?NMR(399.902MHz，DMSO)δ3.20(2H，t)，3.76(2H，t)，3.83(3H，s)，7.42(2H，d)，7.89(2H，d).

With MP-carbonic ether (2.74mmol/g, 270mg, 0.74mmol; 0.6 equivalent) add to 4-(2-bromine oxethyl) oil of Niobe (300mg, 1.23mmol, 1 equivalent), morpholine (0.12ml; 1.36mmol, 1.1 equivalents), Soiodin (193mg, 1.29mmol; 1.05 equivalent), in the microwave reaction container, add MeCN (6ml), in microwave reactor, reaction mixture is heated to 120 ℃ and kept 10 minutes.Reaction mixture is transferred to the SCX-2 post, uses the MeOH wash-out, use 3.5N ammonia/methanol solution wash-out subsequently.The level that merges the back wash-out is divided and evaporation, obtains light yellow solid (130mg, 52% yield).

¹H?NMR(399.902MHz，CDCl3)δ2.53-2.51(4H，m)，2.64-2.60(2H，m)，2.88-2.84(2H，m)，3.75-3.72(4H，m)，3.90(3H，s)，7.28-7.26(2H，m)，7.97-7.94(2H，m).MS：m/z?250(MH+)

Embodiment 57

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(methyl-(tetrahydrofuran-2-ylmethyl) amino) methyl] BM

The preparation method is similar to embodiment 53, and the raw material of employing is that (181mg 0.69mmol), obtains clarifying the title compound (56mg, 20% yield) of jelly form to 4-[(methyl-(tetrahydrofuran-2-ylmethyl) amino) methyl] oil of Niobe;

¹H?NMR(399.902MHz，DMSO)δ1.56-1.42(1H，m)，1.81-1.74(2H，m)，1.98-1.90(1H，m)，2.20(3H，s)，2.44(2H，d)，3.31(4H，s)，3.66-3.59(3H，m)，3.73(6H，s)，4.01-3.94(2H，m)，6.34-6.33(1H，m)，6.43(2H，d)，6.48(1H，s)，7.40(2H，d)，7.95(2H，d)，10.58(1H，br.s)，12.15(1H，br.s).MS：m/z?479(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0053 μ M

Be prepared as follows 4-[(methyl-(tetrahydrofuran-2-ylmethyl) amino) methyl] oil of Niobe as raw material:

MP-carbonic ether (2.74mmol/g, 1.44g, 4mmol, 2 equivalents) is added among 4-(brooethyl) oil of Niobe (500mg, 2mmol, 1 equivalent), N-methyl isophthalic acid-(tetrahydrofuran-2-yl) methylamine (231mg, 2mmol, 1 equivalent) and the MeCN (10ml).Let reaction mixture stir at ambient temperature 18 hours, be transferred to the SCX-2 post subsequently, use the MeOH wash-out, use 3.5N ammonia/methanol solution wash-out subsequently.The level that merges the back wash-out is divided and evaporation, obtains light yellow solid (355mg, 64% yield).

1H?NMR(399.902MHz，CDCl3)δ1.54-1.47(1H，m)，1.87-1.80(2H，m)，2.01-1.93(1H，m)，2.28(3H，s)，2.46-2.42(1H，m)，2.55-2.50(1H，m)，3.68-3.57(2H，m)，3.76-3.71(1H，m)，3.87-3.81(1H，m)，3.91(3H，s)，4.08-4.01(1H，m)，7.41(2H，d)，7.98(2H，d).MS：m/z?264(MH+)

Embodiment 58

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-piperidyl) BM

The preparation method is similar to embodiment 53, and the raw material of employing is that (176mg 0.69mmol), obtains the title compound (20mg, 8% yield) of light yellow glue to 4-(4-piperidyl) oil of Niobe hydrochloride;

¹H?NMR(399.902MHz，DMSO)δ1.69-1.57(2H，m)，1.84-1.76(2H，m)，2.76-2.68(2H，m)，2.93(4H，s)，3.17-3.12(2H，m)，3.77-3.76(7H，m)，6.38-6.37(1H，m)，6.47(2H，d)，6.53(1H，s)，7.38(2H，d)，7.98(2H，d)，10.61(1H，s)，12.20(1H，s).MS：m/z?435(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.001 μ M

Embodiment 59

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-dimethylamino-BM

The preparation method is similar to embodiment 39, and the raw material of employing is that (102mg 0.63mmol), obtains the title compound (139mg, 63% yield) of solid form to the 4-dimethylaminobenzoic acid;

¹H?NMR(399.902MHz，DMSO)δ2.87(4H，s)，3.00(6H，s)，3.73(6H，s)，6.33-6.32(1H，m)，6.42(2H，d)，6.45(1H，s)，6.72(2H，d)，7.89(2H，d)，10.21(1H，brs)，12.06(1H，br.s).MS：m/z395(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.134 μ M

Embodiment 60

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-5-piperazine-1-base-thiophene-2-carboxamide derivatives (2,2, the 2-trifluoroacetate)

(150mg mmol) is dissolved in anhydrous THF (10ml), adds 1-chloro-N with 5-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] thiophene-2-carboxylic acid under nitrogen atmosphere; N; (177 μ l, mmol), this mixture at room temperature stirred 3.5 hours 2-trimethylammonium-third-1-alkene-1-amine.(167mg, mmol) (47 μ l mmol), heat reaction mixture 18 hours down at 65 ℃ with pyridine to add 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate.Subsequently reaction mixture is cooled to room temperature, and adding 4M HCl/ diox (2.0ml, 2.0mmol).Mixture is stirred overnight at room temperature, evaporation, and resistates prepares the HPLC purifying through acidity, with the 24-32% MeCN/ water gradient elution that contains 0.1%TFA.Collect clarifying level and divide and evaporation, obtain the title compound (28.7mg, 11%) of light green solid-like;

¹H?NMR(399.902MHz，DMSO)δ2.79(s，4H)，3.21(s，4H)，3.34(s，4H)，3.64(s，6H)，6.29(m，5H)，7.77(m，1H)，8.71(s，1H)，10.37(s，1H)MS：m/z＝442(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.022 μ M

Be prepared as follows 5-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] thiophene-2-carboxylic acid as raw material:

With 4-(5-formyl radical thiophene-2-yl) piperazine-1-t-butyl formate (2.51g; 8.50mmol) disposable Silver Nitrate (the I) (10.0g that adds to of solution in ethanol (85ml); 58.8mmol) and sodium hydroxide (4.83g is 120.6mmol) in the solution in water (85ml).Stir this mixture and descend heating 22 hours at 65 ℃.Add ice with this mixture cooling, subsequent filtration is removed silver salt.Careful evaporated filtrate filters the aqueous solution that obtains to remove tarry matters through glass fiber mats to remove ethanol once more.Filtrate volume is diluted to TV is 400ml to water subsequently, and using the acetate acidifying subsequently is 5 as pH.Leach deposition, use water washing, dried overnight in 45 ℃ vacuum drying oven obtains 5-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] thiophene-2-carboxylic acid (1.88g, 71%) subsequently.

1H?NMR(399.9MHz，DMSO-d ₆)δ1.41(9H，s)，3.18(4H，m)，3.45(4H，m)，6.20(1H，d)，7.43(1H，d)

MS：m/z?313(MH+)

Be prepared as follows 4-(5-formyl radical thiophene-2-yl) piperazine-1-t-butyl formate as raw material:

Under 130 ℃, nitrogen atmosphere with 5-bromothiophene-2-formaldehyde (3.82g; 20.0mmol), piperazine-1-t-butyl formate (4.1g; 22.0mmol), N-ethyl-N, the N-diisopropylamine (7.0ml, 40.0mmol) and the mixture of methyl-sulphoxide (5.0ml) stirred 18 hours.Distribute between ETHYLE ACETATE and water through the refrigerative mixture.Water, brine wash organic phase are through dried over mgso and evaporation.The dark red solid that obtains is used the methylene dichloride wash-out earlier through purification by silica gel column chromatography, uses ethyl acetate/dichloromethane (15%) wash-out subsequently, obtains 4-(5-formyl radical thiophene-2-yl) piperazine-1-t-butyl formate (4.3g, 73%).

1H?NMR(399.9MHz，DMSO-d ₆)δ1.41(9H，s)，3.34(4H，m)，3.47(4H，m)，6.36(1H，d)，7.70(1H，d)，9.49(1H，s)

MS：m/z?297(MH+)

Embodiment 61

6-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] Nicotinicum Acidum methyl esters

(0.285g 1.58mmol) adds to DCM (40ml), and (0.165ml is 1.90mmol) with several dry DMF toward wherein adding oxalyl chloride with 5-methoxycarbonyl pyridine-2-formic acid.Reaction mixture was stirred 30 minutes, add subsequently 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate (0.50g, 1.58mmol) and pyridine (2.0ml).With the reaction mixture stirred overnight.Reaction mixture is evaporated to dried, obtains jelly.In this jelly, add formic acid.Reaction mixture was stirred 1 hour, be evaporated to dried subsequently.The jelly that obtains with DCM extraction (3x50ml), through dried over mgso and solvent removed in vacuo, obtains the heavy-gravity jelly with saturated potassium carbonate (30ml) quencher.Grind with acetonitrile, obtain the required product (24mg, 4%) of little yellow solid shape;

¹H?NMR(400.132MHz，DMSO)δ2.92(s，4H)，3.74(s，3H)，3.95(s，3H)，6.50(s，1H)，6.76(d，1H)，6.83-6.82(m，2H)，7.20(t，1H)，8.26(d，1H)，8.53(d，1H)，9.17(s，1H)，10.38(s，1H)，12.31(s，1H)；MH+381.

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀68 μ M

Adopt the method among the embodiment 23 to prepare 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate as raw material.

Be prepared as follows 4-(4-N-METHYL PIPERAZINE-1-yl) Benzoyl chloride 99min. as raw material:

In the suspension-s of 4-(4-N-METHYL PIPERAZINE-1-yl) phenylformic acid (500mg, 2.27mmol, 1 equivalent) in DCM (20ml), add DMF (1), drip oxalyl chloride (219 μ l, 2.50mmol, 1.1 equivalents) subsequently.Mixture was stirred 18 hours, after this this mixture is concentrated into driedly, need not to be single step purification or to characterize and promptly can be used for next step.

Embodiment 62

6-chloro-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide

6-bromopyridine-3-formic acid (122mg, 0.82mmol, 1.3 equivalents) is dissolved in DCM (5mL), drips oxalyl chloride (72 μ l, 0.82mmol, 1.3 equivalents), drip 1 DMF subsequently.Reaction mixture was stirred 1 hour at ambient temperature, add N subsequently, N-diethylammonium ethamine (1mL, 1.89mmol, 3 equivalents) adds 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate (200mg, 0.63mmol, 1 equivalent) subsequently.Reaction mixture was stirred 2 hours, subsequently with the DCM dilution, water, brine wash, dry (sal epsom) filters and evaporation, obtains the compound of yellow gelationus rough Boc-protection.This jelly is dissolved in 2-propyl alcohol (5mL), adds the 2-propanol solution (4mL) of 6M HCl.With this solution stirred overnight at ambient temperature, be evaporated to driedly subsequently, load on the SCX-2 post.This post is used methanol wash, with 2N ammonia/methanol-eluted fractions product, obtains orange solids.Grind with the methyl alcohol of less volume, obtain 6-chloro-N-[5-[2-(3-p-methoxy-phenyl) the ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide (39mg, 17%) of white solid;

¹H?NMR(400.13MHz，DMSO)δ2.89(4H，s)，3.74(3H，s)，6.46(1H，s)，6.75(1H，m)，6.81(2H，m)，7.20(1H，t)，7.65(1H，d)，8.35(1H，m)，8.95(1H，d)，10.99(1H，s)，12.23(1H，s)MS?m/z?357(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀4.54 μ M

According to 5-amino-3-[2-(3-p-methoxy-phenyl) ethyl] pyrazoles-1-t-butyl formate of embodiment 23 described method preparations as raw material.

Embodiment 63

6-cyanic acid-N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-3-carboxamide

According to being similar to embodiment 62 described method preparations, difference is to use 6-cyanopyridine-3-formic acid (122mg, 0.82mmol, 1.3 equivalents) as raw material.Behind the SCX column purification, this material prepares HPLC through alkaline anti-phase and is further purified, and uses the 30-50% acetonitrile/water gradient elution that contains 1% volatile caustic.Get each clarifying level and divide and evaporation, obtain the title compound (58mg, 27% yield) of Off-white solid form;

¹H?NMR(400.13MHz，DMSO)δ2.9(4H，s)，3.74(3H，s)，6.48(1H，s)，6.75(1H，m)，6.8(2H，m)，7.2(1H，t)，8.15(1H，d)，8.52(1H，m)，9.22(1H，d)，11.19(1H，s)，12.26(1H，s)MS?m/z?348(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀3.77 μ M

Embodiment 64

4-hydroxy-n-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] pyridine-2-carboxamide

According to being similar to embodiment 62 described method preparations, difference is to use 4-pyridone-2-formic acid (114mg, 0.82mmol, 1.3 equivalents) as raw material.Behind the SCX column purification, this material prepares HPLC through alkaline anti-phase and is further purified, and uses the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Get each clarifying level and divide and evaporation, obtain the title compound (10mg, 5% yield) of white solid;

¹H?NMR(400.13MHz，DMSO)?

2.9(4H，s)，3.73(3H，s)，6.47(1H，s)，6.75(1H，m)，6.8(2H，m)，6.92(1H，s)，7.19(1H，t)，7.47(1H，s)，8.32(1H，s)，10.2(1H，s)，12.21(1H，s)MS?m/z?339(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀5 μ M

Embodiment 65

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl]-6-(2-tetramethyleneimine-1-base ethyl) pyridine-3-carboxamide

According to being similar to embodiment 62 described method preparations, difference is to use 6-(2-tetramethyleneimine-1-base ethyl) Nicotinicum Acidum (180mg, 0.82mmol, 1.3 equivalents) as raw material.Behind the SCX column purification, this material prepares HPLC through alkaline anti-phase and is further purified, and uses the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Get each clarifying level and divide and evaporation, obtain the title compound (5mg, 2% yield) of white solid;

¹H?NMR(400.13MHz，DMSO)?

1.66(4H，m)，2.77(2H，t)，2.89(4H，s)，2.94(2H，t)，3.27(4H，m)，3.73(3H，s)，6.46(1H，s)，6.75(1H，m)，6.82(1H，m)，7.19(1H，t)，7.40(1H，d)，8.21(1H，m)，9.01(1H，d)，10.79(1H，s)，12.17(1H，s)MS?m/z420(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.24 μ M

Embodiment 66

5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-formic acid

According to being similar to embodiment 62 described method preparations, difference is to use 6-methoxycarbonyl Nicotinicum Acidum (149mg, 0.82mmol, 1.3 equivalents) as raw material.Behind the SCX column purification, this material prepares HPLC through alkaline anti-phase and is further purified, with the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.In this purge process, the ester hydrolysis obtains acid product.Get each clarifying level and divide and evaporation, obtain the title compound (66mg, 40% yield) of white solid;

¹H?NMR(400.13MHz，DMSO)?

2.90(4H，s)，3.74(3H，s)，6.46(1H，s)，6.75(1H，m)，6.83(2H，m)，7.19(1H，t)，8.01(1H，d)，9.12(1H，d)，11.01(1H，s)，12.2(1H，s)MS?m/z?367(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀1.02 μ M

Embodiment 67

5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-methyl-formiate

In 5-[[5-[2-(3-p-methoxy-phenyl) the ethyl]-2H-pyrazole-3-yl] formamyl] suspension-s of pyridine-2-formic acid (55mg, 0.15mmol, 1 equivalent) in methyl alcohol (0.5mL) that is stirring, drip sulfuryl chloride (23 μ l, 0.32mmol, 2.1 equivalents).The solution that obtains heated 3 hours down at 50 ℃.This mixture of vacuum concentration obtains orange solids.This solid is dissolved in DCM, with saturated sodium bicarbonate aqueous solution and brine wash.Organic layer filters and concentrates through dried over mgso, obtains the crude product of yellow solid shape.Grind with ether, obtain the title compound (27mg, 47%) of white solid;

¹H?NMR(400.13MHz，DMSO)?

2.92(4H，s)，3.74(3H，s)，3.92(3H，s)，6.49(1H，s)，6.25(1H，m)，6.82(2H，m)，7.19(1H，t)，8.14(1H，d)，8.46(1H，m)，9.20(1H，d)，11.11(1H，s)，12.25(1H，s)MS?m/z?381(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀2.86 μ M

According to 5-[[5-[2-(3-p-methoxy-phenyl) the ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-formic acid of the method preparation of describing among the embodiment 66 as raw material.

Embodiment 68

5-[[5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-ethyl formate

According to being similar to embodiment 67 described method preparations; Difference is to use 5-[[5-[2-(3-p-methoxy-phenyl) the ethyl]-2H-pyrazole-3-yl] formamyl] pyridine-2-formic acid (55mg in ethanol (0.5mL); 0.15mmol; 1 equivalent), obtain (title compound 9mg, 15% yield) of white solid;

¹H?NMR(400.13MHz，DMSO)?

1.40(3H，t)，2.97(4H，s)，3.79(3H，s)，4.44(2H，q)，6.54(1H，s)，6.8(1H，m)，6.87(2H，m)，7.25(1H，t)，8.19(1H，d)，8.52(1H，m)，9.25(1H，s)，11.17(1H，s)，12.3(1H，s)MS?m/z?395(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.724 μ M

Embodiment 69

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) pyridine-2-carboxamide

Under nitrogen atmosphere with NaHMDS (the THF solution of 1M, 0.45ml, 0.451mmol; 1.5 equivalent) drop to the 5-amino-3-[(3 that is stirring; The 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (105mg, 0.301mmol, 1 equivalent) and 5-(4-N-METHYL PIPERAZINE-1-yl) pyridine-2-methyl-formiate (85mg; 0.361mmol, 1.2 equivalents) and in the suspension-s in anhydrous THF (2.5ml).This solution at room temperature stirred 1 hour.Use saturated NH ₄The Cl aqueous solution this solution of neutralization and water (5ml) dilution.Organic phase is with ETHYLE ACETATE (3x8ml) extraction, and the organic extract liquid of merging filters and evaporation through dried over mgso.Scale with 0.338mmol repeats this reaction.Thick extraction liquid and above-mentioned extraction liquid are merged,, use the 0-6%MeOH/DCM wash-out, obtain the title compound (92mg, 35% yield) of light brown solid form through purification by silica gel column chromatography;

¹H?NMR(399.902MHz，DMSO)δ2.25(s，3H)，2.45-2.50(m，4H)，3.37-3.43(m，4H)，3.75(s，6H)，5.08(s，2H)，5.88(bs，1H)，6.45(t，1H)，6.60(d，2H)，7.45-7.49(m，1H)，7.94(d，1H)，8.35(d，1H)，10.89(bs，1H)，11.36(bs，1H)MS：m/z?453(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.122 μ M

Be prepared as follows pyridine-2-formic acid 5-(4-N-METHYL PIPERAZINE-1-yl) ester as raw material:

Under nitrogen atmosphere with 5-bromine 2-methyl-formiate (250mg, 1.16mmol, 1 equivalent), potassiumphosphate (334mg, 1.62mmol, 1.4 equivalents), S-Phos (96mg, 0.231mmol, 0.2 equivalent) and Pd ₂Dba ₃(13mg, 0.058mmol, 0.05 equivalent) stirs in toluene (5ml).Add N methyl piperazine (155 μ l, 1.39mmol, 1.2 equivalents) and this compound was stirred 48 hours down at 100 ℃, it was cooled to room temperature and restir 48 hours with relief.Reaction mixture is poured on the SCX post and with MeOH, use 2M NH subsequently ₃This product of/MeOH wash-out.Evaporate level branch obtains orange buttery pyridine-2-formic acid 5-(4-N-METHYL PIPERAZINE-1-yl) ester, and this oily matter leaves standstill post crystallization (194mg, 72% yield).

¹H?NMR(399.902MHz，DMSO)δ2.24(s，3H)，2.43-2.48(m，4H)，3.35-3.40(m，4H)，3.81(s，3H)，7.32-7.37(m，1H)，7.88(d，1H)，8.38(d，1H).MS：m/z?236(MH+)

According to 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate of the method preparation of describing among the embodiment 70 as raw material.

Embodiment 70

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(the 2-dimethyl aminoethyl is amino) benzamide hydrochloride salt

With 5-amino-3-[(3; The 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (150mg; 0.429mmol) and 4-[2-dimethyl aminoethyl-[tert-butoxycarbonyl] amino] oil of Niobe (166mg 0.515mmol) is dissolved among the anhydrous THF (2.5ml).(the THF solution of 1M, 0.645ml), this mixture at room temperature stirred 1 hour under nitrogen atmosphere, to drip NaHMDS.

Use NH ₄This mixture of Cl aqueous solution neutralization, dilute with water is also used ethyl acetate extraction.Extraction liquid is merged dry and evaporation.Crude product is used the 0-8%MeOH/DCM gradient elution through purification by silica gel column chromatography.Merge pure level and divide and evaporation, obtain brown oil (74mg).Oily matter is dissolved in THF (10ml), adds 4M HCl/ diox (2ml).Reaction mixture was at room temperature stirred 18 hours.Solid collected by filtration with hexane wash and dry, obtains N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(the 2-dimethyl aminoethyl is amino) benzamide hydrochloride salt (38.6mg, 20% total recovery) of white solid;

¹H?NMR(399.902MHz，DMSO)δ2.84(d，J＝4.0Hz，6H)，3.25(m，2H)，3.75(s，6H)，5.08(s，2H)，5.67(s，1H)，6.45(t，J＝2.2Hz，1H)，6.60(d，J＝2.2Hz，2H)，6.72(d，J＝8.8Hz，2H)，7.83(d，J＝8.8Hz，2H)，9.85(s，1H)，10.53(s，1H).MS：m/z＝440(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.031 μ M

Be prepared as follows 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate as raw material:

(11.19g 199.4mmol) adds to 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (7.121g) and is dissolved in the solution in the methylene dichloride (40ml) will to be dissolved in the Pottasium Hydroxide of water (44.8ml).Add carbonic acid (2-methylpropane-2-yl) the oxygen base carbonyl ester tert-butyl ester be dissolved among the DCM (35ml) (6.8g, 31.2mmol), with reaction mixture vigorous stirring 4 hours at room temperature.Separate reacted mixture and water (2x15ml), salt solution (2x15ml) washing organic layer through dried over sodium sulfate, filter; Evaporation and vacuum-drying; Obtain 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (8.70g, 99%) of Off-white solid form.

¹H?NMR(399.902MHz，DMSO)δ1.55(s，9H)，3.75(s，6H)，4.93(s，1H)，5.06(s，2H)，6.38(s，2H)，6.45(t，J＝2.2Hz，1H)，6.60(d，J＝2.3Hz，2H).MS：m/z＝350(MH+)

Be prepared as follows 4-[2-dimethyl aminoethyl-[tert-butoxycarbonyl] amino] oil of Niobe as raw material:

(1.00g 4.50mmol) is dissolved in THF (30ml) with 4-(2-[dimethylamino] ethylamino) oil of Niobe.(1.035g 4.72mmol), refluxes this solution 3 hours to add carbonic acid (2-methylpropane-2-yl) the oxygen base carbonyl ester tert-butyl ester.Evaporating solvent is dissolved in DCM with resistates subsequently, with the saturated aqueous ammonium chloride washing, through dried over sodium sulfate, filters and evaporation, obtains brown buttery 4-[2-dimethyl aminoethyl-[tert-butoxycarbonyl] amino] oil of Niobe (1.07g, 74%).

¹H?NMR(399.902MHz，DMSO)δ1.41(s，9H)，2.13(s，6H)，2.34(t，J＝6.9Hz，2H)，3.73(t，J＝6.8Hz，2H)，3.86(s，3H)，7.43(d，J＝8.5Hz，2H)，7.94(d，J＝8.5Hz，2H).MS：m/z＝323(MH+)

Be prepared as follows 4-(2-[dimethylamino] ethylamino) oil of Niobe as raw material:

4-iodo-benzoic acid methyl esters (1.19g, 4.54mmol, 1.0 equivalents) is dissolved in the anhydrous dimethyl formamide (10ml).Add N, N-dimethyl-ethane-1,2-diamines (400mg; 4.54mmol, 1.0 equivalents), cesium carbonate (2.69g, 9.08mmol; 2.0 equivalent), 2-acetyl cyclohexanone (120 μ l, 0.908mmol, 0.20 equivalent [20mol%]) and cupric iodide (I) (44mg; 0.227mmol, 0.05 equivalent [5mol%]), under 90 ℃, nitrogen atmosphere, this mixture was stirred 18 hours.Concentrate this reaction mixture, be dissolved in methyl alcohol and be adsorbed on the SCX-2 cation exchange resin column, with this post of methanol wash, product is with 2M ammonia/methanol-eluted fractions.Evaporate branches at different levels, obtain brown gelationus 4-(2-[dimethylamino] ethylamino) oil of Niobe (1.00g, 99%).

¹H?NMR(399.902MHz，DMSO)δ2.19(s，6H)，2.44(t，J＝6.3Hz，5H)，3.17(m，2H)，3.75(s，3H)，6.33(t，J＝5.3Hz，1H)，6.62(d，J＝8.9Hz，2H)，7.69(d，J＝8.7Hz，2H).MS：m/z＝223(MH+)

Embodiment 71

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-methoxyl group-BM

Will be under nitrogen atmosphere at the 4-methoxy benzoyl chloride (54mg among the THF (2ml); 0.315mmol, 1.1 equivalents) and drop to 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (100mg; 0.286mmol; 1 equivalent) in the solution in THF (3ml), this solution was heated under refluxing 14 hours totally, at room temperature stirred subsequently 16 hours.Evaporating solvent, resistates uses 55-75%MeCN/H through preparation HPLC purifying ₂O (containing 1% volatile caustic) gradient elution.Each product level branch is evaporated to dried, and is dissolved among the DCM (4ml).Add 4M HCl/ diox (1ml), this mixture at room temperature stirred 1 hour, was evaporated to dried subsequently.Resistates is at ETHYLE ACETATE (6ml) and NaHCO ₃Distribute between the aqueous solution (6ml), separate each layer, with ETHYLE ACETATE (3x6ml) aqueous layer extracted once more.The organic extract liquid that merges is through Na ₂SO ₄Drying is filtered and evaporation, obtains the title compound (22mg, 20% yield) of pale solid form;

¹H?NMR(400.132MHz，DMSO)δ3.74(s，6H)，3.82(s，3H)，5.06(s，2H)，5.59(s，1H)，6.43(t，1H)，6.59(d，2H)，7.00(d，2H)，7.96(d，2H)MS：m/z?384(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.157 μ M

Be used as 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate of raw material according to the method preparation of describing among the embodiment 70.

Embodiment 72

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-6-piperazine-1-base-pyridine-3-carboxamide

(150mg 0.412mmol) is dissolved in anhydrous THF (10ml), adds 1-chloro-N with 6-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] Nicotinicum Acidum under nitrogen atmosphere; N; (65 μ l 0.412mmol), at room temperature stir mixture 2-trimethylammonium-third-1-alkene-1-amine.(40 μ L, 0.412mmol) (142mg 0.343mmol), stirs this mixture 18 hours down at 65 ℃ with 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate to add pyridine.Subsequently mixture is cooled to room temperature, with 4M HCl/ diox (1.8ml, 7.20mmol) stirred overnight.Subsequently mixture is filtered, use the hexane wash solid.Through acid preparation HPLC purified product, with 16-26%MeCN/ water (containing 0.1%TFA) gradient elution.Use NaHCO ₃Aqueous solution neutralization contains the level of product and divides, and under vacuum, removes acetonitrile.Product is precipitated out and is collected through filtering.Further, obtain the title compound (39mg, 26%) of white solid with this product of water washing and vacuum-drying;

¹H?NMR(399.902MHz，DMSO)δ2.82(t，J＝5.1Hz，4H)，3.61(t，J＝4.8Hz，4H)，3.80(s，6H)，5.13(s，2H)，5.62(bs，1H)，6.50(s，1H)，6.65(d，J＝2.2Hz，2H)，6.92(d，J＝8.9Hz，1H)，8.09(d，J＝9.3Hz，1H)，8.76(d，J＝2.3Hz，1H)，10.74(bs，1H)，11.64(bs，1H).MS：m/z＝439(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.025 μ M

(11.19g 199.4mmol) adds to 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (7.121g) and is dissolved in the solution in the methylene dichloride (40ml) will to be dissolved in the Pottasium Hydroxide of water (44.8ml).(6.8g, the 31.2mmol) solution in DCM (35ml) is at room temperature with this reaction mixture vigorous stirring 4 hours to add carbonic acid (2-methylpropane-2-yl) the oxygen base carbonyl ester tert-butyl ester.Separate reacted mixture and water (2x15ml) and salt solution (2x15ml) washing organic layer, through dried over sodium sulfate; Filter, evaporate and vacuum-drying, obtain the 5-amino-3-[(3 of Off-white solid form; The 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (8.70g, 99%).

Embodiment 73

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl]-2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide

Under nitrogen atmosphere with NaHMDS (the THF solution of 1M, 0.39ml, 0.386mmol; 1.5 equivalent) drop to the 5-amino-3-[(3 that is stirring; The 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (90mg, 0.258mmol, 1 equivalent) and 2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate (74mg; 0.309mmol, 1.2 equivalents) and in the solution in anhydrous THF (5ml).This solution at room temperature stirred 1 hour, used saturated NH subsequently ₄The neutralization of the Cl aqueous solution, water (15ml) dilutes, and extracts with ETHYLE ACETATE (3x15ml).The organic extract liquid that merges filters and evaporation through dried over mgso, obtains orange jelly.This jelly is through purification by silica gel column chromatography, with 0-2.5% MeOH/DCM gradient elution.Under nitrogen atmosphere, this thick material that comprises raw material 2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate is dissolved in THF (5ml) again.Add 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (50mg, 0.143mmol), drip subsequently NaHMDS (the THF solution of 1M, 0.32ml, 0.32mmol).This solution was at room temperature stirred 45 minutes, use NH ₄The neutralization of Cl saturated aqueous solution, water (10ml) are diluted and are extracted with ETHYLE ACETATE (3x10ml).The organic extract liquid that merges filters and evaporation through dried over mgso.Gummy residue with 0-8% MeOH/DCM gradient elution, obtains the title compound (16mg, 14% yield) of light brown solid-like through purification by silica gel column chromatography;

¹H?NMR(399.9MHz，DMSO-d ₆+d4-AcOD)δ2.42(3H，s)，2.67-2.70(4H，m)，3.75(6H，s)，3.91-3.94(4H，m)，5.08(2H，s)，5.75(1H，s)，6.45(1H，t)，6.59(2H，d)，8.90(2H，s).MS：m/z?454(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.044 μ M

Be prepared as follows 2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under nitrogen atmosphere, be suspended in 2-chloropyrimide 5-formic acid (100mg, 0.631mmol, 1 equivalent) in the mixture of toluene (3ml) and methyl alcohol (0.8ml) and in ice bath, cool off.Drip trimethyl silyl diazomethane (hexane solution of 2M, 0.347ml, 0.694mmol, 1.1 equivalents).Solution was stirred 10 minutes down at 0 ℃, and it was warming up to room temperature and restir 1 hour with relief.Drip 1-N-METHYL PIPERAZINE (70 μ l, 0.631mmol, 1 equivalent) and triethylamine (88 μ l, 0.631mmol, 1 equivalent) and at room temperature continue and stirred 2 hours.Evaporating solvent is dissolved in resistates in ETHYLE ACETATE (20ml) and the water (15ml).Layering, water layer is through further add ethyl acetate extraction (2x10ml) in batches.The extraction liquid that merges filters and evaporation through dried over mgso.As above repeat this reaction, extraction liquid and above-mentioned extraction liquid are merged, obtain 2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate (76mg, 25% yield) of yellow colloidal solid form.

¹H?NMR(399.902MHz，DMSO)δ2.12(s，3H)，2.27(t，4H)，3.70(s，3H)，3.75(t，4H)，8.68(s，2H).MS：m/z?237(MH+)

Embodiment 74

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl]-3-piperazine-1-base-BM

Under nitrogen atmosphere with 1-chloro-N; N-2-trimethylammonium-1-propenyl amine (78 μ l, 0.588mmol, 1.2 equivalents) drops to 3-[4-(tert-butoxycarbonyl) piperazine-1-yl] phenylformic acid (150mg that is stirring; 0.588mmol, 1.2 equivalents) and solution in THF (10ml).With mixture stirred overnight at room temperature.Add 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (172mg, 0.490mmol, 1 equivalent) and pyridine (48 μ l, 0.588mol, 1.2 equivalents), with mixture 65 ℃ of following heated overnight.Let mixture be cooled to room temperature, add 4M HCl/ diox (2ml).Continue stirred overnight at room temperature.Filter the yellow solid of collecting precipitation, wash with THF.Solid NaHCO ₃(4ml) aqueous solution and DCM (2ml) grind.There is a small amount of brown jelly in the solution.Filter and collect this jelly, water and ether washing.Contain filter liquor with ETHYLE ACETATE (3x10ml) extraction, the extraction liquid of merging filters and evaporation through dried over mgso.Merge through the product of extraction and from filtering jelly, through purification by silica gel column chromatography, with 10-12% MeOH/DCM gradient elution.Evaporate level branch obtains the title compound (27mg, 10% yield) of white solid;

¹H?NMR(399.902MHz，DMSO+d4-AcOD)δ3.13-3.21(m，4H)，3.33-3.40(m，4H)，3.68(s，6H)，5.02(s，2H)，5.71(s，1H)，6.38(t，1H)，6.52(d，2H)，7.12-7.17(m，1H)，7.33(t，1H)，7.37-7.41(m，1H)，7.46-7.49(m，1H).MS：m/z?438(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.130 μ M

Embodiment 75

4-(1,4-Diazesuberane-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl] benzamide hydrochloride salt

With 5-amino-3-[(3; The 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (176mg; 0.50mmol) and 4-(4-methoxycarbonyl phenyl)-1, (168mg 0.60mmol) is dissolved among the anhydrous THF (5ml) 4-Diazesuberane-1-t-butyl formate.(the THF solution of 1M 0.754ml), at room temperature stirs mixture 1 hour under nitrogen atmosphere, to drip NaHMDS.(the THF solution of 1M, 0.754ml), reaction mixture stirred 30 minutes under nitrogen atmosphere to add the NaHMDS that measures in addition.Use saturated NH ₄Cl aqueous solution neutralization reaction mixture, water (20ml) dilute and extract with ETHYLE ACETATE (3x30ml).Extraction liquid is merged,, filter and evaporation through dried over mgso.Resistates is used the 0-3%MeOH/DCM wash-out through purification by silica gel column chromatography.Evaporate branches at different levels, obtain brown oil (51mg), this brown oil is through silica gel column chromatography purifying again, with 0-1% MeOH/DCM wash-out.Each pure level divided merge, evaporation also is dissolved in THF (10ml) with resistates.(1.5ml is 1.5mmol) and with solution stirred overnight at room temperature to add 4M HCl/ diox.Filter collecting precipitation, use hexane wash, vacuum-drying obtains the title compound (18.7mg, 6.5%) of white solid;

¹H?NMR(399.902MHz，DMSO)δ2.01(m，2H)，3.08(m，2H)，3.20(m，2H)，3.53(m，2H)，3.68(s，6H)，3.72(t，J＝5.2Hz，2H)，5.01(s，2H)，5.60(s，1H)，6.38(t，J＝2.4Hz，1H)，6.52(d，J＝2.3Hz，2H)，6.81(d，J＝9.2Hz，2H)，7.82(d，J＝8.9Hz，2H)，8.69(s，1H)，10.49(s，1H).MS：m/z＝452(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.0085 μ M

Be prepared as follows 4-(4-methoxycarbonyl phenyl)-1,4-Diazesuberane-1-t-butyl formate as raw material:

4-iodo-benzoic acid methyl esters (1.00g, 3.82mmol, 1.0 equivalents) is dissolved in DMF, adds 1; 4-Diazesuberane-1-t-butyl formate (765mg, 3.82mmol, 1.0 equivalents), cesium carbonate (2.49g; 7.63mmol, 2.0 equivalents), 2-acetyl cyclohexanone (101 μ l, 0.76mmol; 0.20 equivalent [20mol%]) and cupric iodide (37mg, 0.19mmol, 0.05 equivalent [5mol%]).Under nitrogen atmosphere, reaction mixture was stirred 7 hours down at 90 ℃.Evaporation reaction mixture is dissolved in DCM (50ml), and water (20ml), saturated ammonium chloride solution (20ml) washing through dried over mgso, are filtered and evaporation.Crude product is used the 0-1%MeOH/DCM wash-out through purification by silica gel column chromatography.Merge the branches at different levels that contain product, evaporate and vacuum-drying, obtain the 4-(4-methoxycarbonyl phenyl)-1 of yellow oil form, 4-Diazesuberane-1-t-butyl formate (168mg, 13%).

¹H?NMR(399.902MHz，DMSO)δ1.12(s，5H)，1.24(s，4H)，1.72(m，2H)，3.12(m，1H)，3.42(m，1H)，3.49(m，3H)，3.59(m，2H)，3.69(s，3H)，6.72(d，J＝9.1Hz，2H)，7.67(d，J＝9.0Hz，2H)MS：m/z＝335(MH+)

Be prepared as follows 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate:

(11.19g 199.4mmol) adds to 5-[(3, the 5-Dimethoxyphenyl) the methoxyl group]-2H-pyrazoles-3-amine (7.121g) that is dissolved in the methylene dichloride (40ml) will to be dissolved in Pottasium Hydroxide in the water (44.8ml).Add carbonic acid (2-methylpropane-2-yl) the oxygen base carbonyl ester tert-butyl ester be dissolved among the DCM (35ml) (6.8g, 31.2mmol), with reaction mixture vigorous stirring 4 hours at room temperature.Separate reacted mixture and water (2x15ml) and salt solution (2x15ml) washing organic layer through dried over sodium sulfate, filter; Evaporation and vacuum-drying; Obtain 5-amino-3-[(3, the 5-Dimethoxyphenyl) methoxyl group] pyrazoles-1-t-butyl formate (8.70g, 99%) of Off-white solid form.

Embodiment 76

N-[5-[2-[5-(dimethylaminomethyl)-2-furyl] ethyl]-1H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

At room temperature with the potassium hydroxide solution (aqueous solution of 4.5M; 1.8ml, 8.10mmol, 8.10 equivalents) and add to the 5-that stirring (2-{5-[(dimethylamino) methyl]-2-furyl } ethyl)-1H-pyrazoles-3-amine (235mg; 1.0mmol, 1.0 equivalents) and in the solution in methylene dichloride.Add the solution of tert-Butyl dicarbonate (230mg, 1.05mmol, 1.05 equivalents) in methylene dichloride (2.0ml) subsequently, with reaction mixture vigorous stirring 18 hours.With reaction mixture impouring separating funnel and layering.Dichloromethane layer water (10ml) and saturated brine (10ml) washing; Through anhydrous sodium sulfate drying; Filter and solvent removed in vacuo, obtain 5-amino-3-(2-{5-[(dimethylamino) methyl]-2-furyl } the ethyl)-1H-pyrazoles-1-t-butyl formate (320mg) of golden oily matter form.Need not can this material of a part be used as follows through single step purification:

Under nitrogen atmosphere, room temperature, incite somebody to action two (trimethyl silyl) sodium amide solution (tetrahydrofuran solution of 1.0M, 0.7ml, 0.69mmol; 1.50 equivalent) drop to that 5-amino-3-of stirring (2-{5-[(dimethylamino) methyl]-2-furyl } ethyl)-1H-pyrazoles-1-t-butyl formate is (rough; 154mg, 0.46mmol, 1.0 equivalents) and 4-(4-N-METHYL PIPERAZINE-1-yl) oil of Niobe (130mg; 0.55mmol, 1.20 equivalents) and in the solution in anhydrous tetrahydro furan (1.0ml).Let this mixture hold over night at room temperature, solvent evaporated under reduced pressure obtains brown gluey crude product subsequently.This jelly is dissolved in methyl alcohol (5ml), this solution is loaded to the SCX-2 post.With this post of methanol wash that contains 10% water.Use this post of 2.0M anhydrous ammonia/methanol-eluted fractions subsequently.The branches at different levels that will contain product merge and evaporation, obtain the brown jelly of 235mg.This material is further purified through silica gel column chromatography, with 3-10% methyl alcohol (containing 2M ammonia)/methylene dichloride wash-out.Merge each pure products level branch and evaporation, obtain 32.9mg light brown jelly.This material prepares HPLC through alkaline anti-phase and is further purified, and with the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide, gets each clarifying level and divides and evaporation, obtains the title compound (8mg, 4% yield) of solid-like;

¹H NMR (500.13MHz, DMSO-d6) δ 2.17 (6H, d), 2.26 (3H, s), 2.48 (4H, t); 2.88-2.96 (4H, m), 3.30 (4H, t), 3.39 (2H, s); 6.03 (1H, d), 6.12 (1H, d), 6.95 (2H, d); 7.88 (2H, d), 9.95 (1H, wide cutting edge of a knife or a sword s), 11.80 (1H, wide cutting edge of a knife or a sword s) .MS:m/z 437 (MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.34 μ M

Be prepared as follows as the 5-of raw material (2-{5-[(dimethylamino) methyl]-2-furyl } ethyl)-1H-pyrazoles-3-amine:

(0.258ml, (dispersion-s of 196mg in MO 4.88mmol) in the soup compound in no Shui diox (15ml), at room temperature stirred mixture 5 minutes under nitrogen atmosphere 4.88mmol) to add to sodium hydride with acetonitrile.Add 3-{5-[(dimethylamino) methyl]-2-furyl subsequently } and ethyl propionate (917mg, 4.07mmol), with reaction mixture refluxed 18 hours.Mixture is cooled to room temperature, adds ethanol (1.9ml), add subsequently hydrazine hydrogen chloride (558mg, 8.14mmol).Mixture was refluxed 1 hour.After the cooling, solvent evaporated under reduced pressure.Resistates is dissolved in the methylene dichloride (50mL) that contains 10% methyl alcohol the filtering insoluble impurities.Evaporated filtrate obtains the golden buttery crude product of 1.07g.This material is through purification by silica gel column chromatography, with 0-10% methyl alcohol (containing 2M ammonia)/dichloromethane gradient wash-out.Merge each pure products level branch and evaporation, obtain clarifying oily matter (520mg, 55% yield);

¹H?NMR(399.9MHz，DMSO-d6)δ2.16(6H，s)，2.70-2.74(2H，m)，2.81-2.85(2H，m)，3.40(2H，s)，5.20(1H，s)，6.03(1H，d)，6.15(1H，d).MS：m/z?235(MH+)

Be prepared as follows 3-{5-[(dimethylamino) methyl]-2-furyl as raw material } ethyl propionate:

At room temperature stir ethyl 3-(2-furyl)-propanoate (12.11g, 72.0mmol), alkyl dimethyl ammonium chloride (6.76g, 82.8mmol), (6.43g, the 79.2mmol) mixture in acetate (75ml) is up to forming solution for 37% formalin.Let this solution left standstill 44 hours.Evaporate this mixture, obtain oily matter.This oily matter is suspended in water and with ethyl acetate extraction (2x250ml).Is that pH is 11 with the 4M sodium hydroxide solution with water layer (containing product) acidifying, uses ethyl acetate extraction (2x250ml) subsequently.With the extraction liquid of these merging of brine wash, through dried over mgso, and evaporation, obtain the dark-brown crude product of 6.5g.This material is through purification by silica gel column chromatography, with 0-10% methyl alcohol (containing 2M ammonia)/dichloromethane gradient wash-out.The branches at different levels that will contain product merge and evaporation, obtain light brown oily thing (3.44g).This material is through purification by silica gel column chromatography, with 0-5% methyl alcohol (containing 2M ammonia)/dichloromethane gradient wash-out.The branches at different levels that will contain product merge and evaporation, obtain light brown oily thing (1.36g, 8% yield).

1H?NMR(399.9MHz，CDCl3)δ1.24(3H，t)，2.29(6H，s)，2.62-2.65(2H，m)，2.95(2H，t)，3.47(2H，s)，4.11-4.15(2H，m)，5.95(1H，d)，6.11(1H，d).MS：m/z?226(MH+)

Embodiment 77

N-[5-(2-benzo [1,3] dioxole-5-base ethyl)-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

At 5 ℃ of past down 5-amino-3-(2-benzos [1 that stirring; 3] pyrazoles-1-t-butyl formate (229mg dioxole-5-base ethyl); 0.69mmol; 1.0 equivalent) add in the solution in pyridine (5ml) in 4-(4-N-METHYL PIPERAZINE-1-yl) Benzoyl chloride 99min. (181mg, 0.76mmol, 1.1 equivalents).This reaction mixture was stirred 24 hours down at 60 ℃.After the completion, enriched mixture also is dissolved in DCM (10ml) once more.Add trifluoroacetic acid (464 μ l, 6.25mmol, 8.25 equivalents), reaction mixture was stirred 2 hours down at 25 ℃.Concentrated reaction mixture subsequently.Prepare HPLC purifying crude product through alkaline anti-phase, with the 30-50% acetonitrile/water gradient elution that contains 1% solution of ammonium hydroxide.Merge each clarifying level and divide and evaporation, obtain the title compound (12mg, 4%) of white solid;

¹H?NMR(300.132MHz，DMSO)δ2.28(s，3H)，2.49(t，2H)，2.89(s，2H)，3.31-3.37(m，8H)，6.01(s，2H)，6.43(s，1H)，6.74(d，1H)，6.86(d，2H)，7.01(d，2H)，7.94(d，2H)，10.36(s，1H)，12.11(s，1H)；MS：m/z?434(MH+).

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.14 μ M

Be prepared as follows 5-amino-3-(2-benzo [1,3] dioxole-5-base ethyl) pyrazoles-1-t-butyl formate as raw material:

In the 5-that is stirring (2-benzo [1,3] dioxole-5-base the ethyl)-solution of 2H-pyrazoles-3-amine in DCM (10ml), add the 4.5M KOH aqueous solution (1.9ml, 8.66mmol, 8 equivalents).Add BOC subsequently ₂The solution of O (464mg, 2.12mmol, 1.05 equivalents) in DCM (2ml) was with reaction mixture vigorous stirring 3 hours.With reaction mixture impouring separating funnel and layering.Water (10ml), salt solution (10ml) washing organic layer, dry (Na ₂SO ₄), filter and evaporating solvent, obtain the title compound (325mg, 91%) of white solid;

¹H?NMR(300.132?MHz，DMSO)δ1.55(s，9H)，2.58-2.64(m，2H)，2.73-2.78(m，2H)，5.19(s，1H)，5.95(s，2H)，6.21(s，2H)，6.68-6.71(m，1H)，6.80(d，1H)，6.85(d，1H)

Be prepared as follows 5-(2-benzo [1,3] dioxole-5-base ethyl)-2H-pyrazoles-3-amine as raw material:

According to being similar to 5-(2-benzo [1,3] dioxole-5-base ethyl)-2H-pyrazoles-3-amine that the method preparation for preparing 5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-amine among the embodiment 11 is used as raw material.Obtain the product (3.04g, 44% yield) of yellow oily.

1H?NMR(300.132MHz，DMSO)：δ2.63-2.79(m，4H)，4.40(s，2H)，5.18(s，1H)，5.95(s，2H)，6.66(dd，1H)，6.77-6.81(m，2H).MS：m/z?232(MH+).

Embodiment 78

N-[5-[2-(2, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

According to the preparing method's preparation that is similar to compound described in the embodiment 77, use 5-amino-3-[2-(2, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate (240mg; 0.69mmol; 1 equivalent), obtains the title compound (27mg, 9%) of white solid as raw material;

¹H?NMR(300.132MHz，DMSO)δ2.23(s，3H)，2.43-2.46(m，4H)，2.80-2.88(m，4H)，3.26-3.29(m，4H)，3.68(s，3H)，3.76(s，3H)，6.43(s，1H)，6.72-6.77(m，2H)，6.88(d，1H)，6.96(d，2H)，7.89(d，2H)，10.29(s，1H)，12.06(s，1H)

MS：m/z?450(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.47 μ M

5-amino-3-[2-(2, the 5-Dimethoxyphenyl) ethyl] pyrazoles-1-t-butyl formate as raw material prepares according to the method that is similar to preparation 5-amino-3-among the embodiment 77 (2-benzo [1,3] dioxole-5-base ethyl) pyrazoles-1-t-butyl formate; [2-(2 to use 5-; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (200mg, 0.87mmol, 1 equivalent) is as raw material; Obtain the title compound (283mg, 94%) of white solid.

1H?NMR(300.132MHz，DMSO)δ1.60(s，9H)，2.61-2.67(m，2H)，2.79-2.84(m，2H)，3.73(s，3H)，3.79(s，3H)，5.25(s，1H)，6.26(s，2H)，6.75-6.79(m，1H)，6.84(d，1H)，6.92(d，1H)

Be prepared as follows 5-[2-(2, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine as raw material:

Under nitrogen atmosphere with sodium hydride (60%, 0.240g, (1.125g, 5mmol) 1, (0.314ml is in the solution in 6mmol) for 4-oxane (25ml)/anhydrous acetonitrile 6mmol) to add to 3-(2, the 5-Dimethoxyphenyl) methyl propionate that stirring.Under nitrogen atmosphere, mixture was at room temperature stirred 10 minutes, postheating refluxed 18 hours.After the completion, mixture is cooled to room temperature, forms deposition.Add ethanol (2ml), add subsequently a hydrochloric acid close hydrazine (0.686g, 10mmol).Mixture heating up was refluxed 4 hours.During this period, deposition gets into solution and solid occurs.After the filtration, the vacuum concentration reaction mixture distributes between 2N HCl and ETHYLE ACETATE (each 25ml).Using solution of ammonium hydroxide is 8 with the pH acidifying of water layer, with ethyl acetate extraction and through dried over mgso.Filter, vacuum evaporating solvent obtains orange (0.690g, 56%).

Be used as 4-(4-N-METHYL PIPERAZINE-1-yl) benzoyl of raw material according to the method preparation of embodiment 61.

Embodiment 79

N-[5-[2-(4-methoxyl group-2-methyl-phenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

According to the preparation method who is similar to compound described in the embodiment 77; Use 5-amino-3-[2-(4-methoxyl group-2-methyl-phenyl) ethyl] pyrazoles-1-t-butyl formate (229mg, 0.69mmol, 1 equivalent) as raw material; Obtain the title compound (15mg, 5%) of white solid;

¹H?NMR(300.132MHz，DMSO)δ2.26(s，3H)，2.72-2.83(m，5H)，2.88(t，4H)，3.41(t，4H)，3.69(s，3H)，5.70(s，1H)，6.41(s，1H)，6.65-6.73(m，2H)，6.99(d，2H)，7.06(d，1H)，7.91(d，2H)

[NB: add D4-acetate]

MS：m/z434(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.2 μ M

5-amino-3-[2-(4-methoxyl group-2-methyl-phenyl) ethyl] pyrazoles-1-t-butyl formate that is used as raw material is according to being similar to 5-amino-3-(2-benzo [1 among the embodiment 77; 3] preparation method of pyrazoles-1-t-butyl formate dioxole-5-base ethyl); Use 5-[2-(4-methoxyl group-2-methyl-phenyl) ethyl]-2H-pyrazoles-3-amine (214mg, 0.87mmol, 1 equivalent) as raw material; Obtain the title compound (256mg, 89%) of white solid.

1H?NMR(300.132MHz，DMSO)δ1.60(s，9H)，2.30(s，3H)，2.58-2.64(m，2H)，2.76-2.81(m，2H)，3.75(s，3H)，5.26(s，1H)，6.26(s，2H)，6.70-6.74(m，1H)，6.77(d，1H)，7.13(d，1H)

Be prepared as follows 5-[2-(4-methoxyl group-2-methyl-phenyl) ethyl]-2H-pyrazoles-3-amine as raw material:

5-[2-(4-methoxyl group-2-methyl-phenyl) the ethyl]-2H-pyrazoles-3-amine that is used as raw material is according to being similar to the method that is used for synthetic 5-[2-(3-p-methoxy-phenyl) ethyl]-2H-pyrazoles-3-amine among the embodiment 11; Use 3-(4-methoxyl group-2-methyl-phenyl) methyl propionate as raw material, obtain 5-[2-(4-methoxyl group-2-methyl-phenyl) the ethyl]-2H-pyrazoles-3-amine of red solid shape.MS：m/z232(MH+)。

Be used as 4-(4-N-METHYL PIPERAZINE-1-yl) Benzoyl chloride 99min. of raw material according to the method preparation of embodiment 61.

Embodiment 80

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(3,5-lupetazin-1-yl) BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(3,5-lupetazin-1-yl) BM is according to the method preparation of embodiment 94; But raw materials used is 4-(3 in THF (5ml); 5-lupetazin-1-yl) oil of Niobe (221mg, 0.84mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (244mg; 0.7mmol) and 1M NaHMDS (1.13ml, 1.13mmol).Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 34-54% acetonitrile/water gradient elution that contains 1% 0.880 ammonia.Get each clarifying level and divide and evaporation, obtain the title compound (34mg, 10%) of white solid;

¹H?NMR(399.9MHz，DMSO-d ₆)δ1.04(6H，d)，2.22(2H，t)，2.53(2H，d)，2.82(2H，t)，2.87(4H，s)，3.71(1H，s)，3.73(7H，s)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，6.94(2H，d)，7.89(2H，d)，10.27(1H，s)，12.07(1H，s).

MS：m/z?464(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.011 μ M

Under nitrogen atmosphere with 2, the 6-lupetazin (3.43g, 30.00mmol) add to 4-ethyl fluoro benzoate in the DMSO that is warmed to 120 ℃ (10ml) (1.101ml, 7.5mmol) in.The solution that obtains stirred 20 hours down at 120 ℃.With reaction mixture cooling and evaporating solvent.Crude product is through purification by silica gel column chromatography, with the 10% ethanol/methylene wash-out that contains 1%0.880 ammoniacal liquor.Each pure level divided be evaporated to driedly, obtain 4-(3, the 5-lupetazin-1-yl) ethyl benzoate (1.490g, 76%) of colorless solid shape.

1H NMR (399.9MHz, CDCl ₃) δ 1.15 (6H, d), 1.37 (3H, t), 2.39 (1H, d), 2.42 (1H, d), 2.97-3.05 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q), 6.84-6.87 (2H, m), 7.90-7.93 (2H, m)-NH do not observe.MS：m/z＝264(MH+)。

Adopt the method among the embodiment 2 to prepare 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate as raw material.

Embodiment 81

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM is according to the method preparation of embodiment 94; But raw materials used is 4-(3 in THF (5ml); 4-lupetazin-1-yl) oil of Niobe (221mg, 0.84mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (244mg; 0.7mmol) and 1M NaHMDS (1.13ml, 1.13mmol).Crude product prepares the HPLC purifying through acid anti-phase, uses the 38-58% acetonitrile/water gradient elution that contains 1% 0.880 volatile caustic.Get each clarifying level and divide and evaporation, obtain the title compound (63mg, 19%) of white solid;

¹H?NMR(500.13MHz，DMSO-d ₆)δ1.12(3H，d)，1.89-1.90(3H，m)，2.32(3H，s)，2.35-2.40(1H，m)，2.64-2.68(1H，m)，2.86-2.91(1H，m)，2.89(4H，t)，3.00(1H，s)，3.64-3.68(2H，m)，3.74(6H，s)，6.32(1H，s)，6.33(1H，t)，6.42(2H，d)，6.94-6.96(2H，m)，7.86-7.88(2H，m).MS：m/z?464(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.04 μ M

With 1, (0.914g, 8.00mmol) (0.587ml 4mmol) is dissolved in DMA (6ml) and being sealed in the microwave tube to 2-dimethyl--piperazine with the 4-ethyl fluoro benzoate.Reaction mixture is heated to 150 ℃ kept 90 minutes in microwave reactor, be cooled to room temperature.Evaporation reaction mixture, crude product are through purification by silica gel column chromatography, with 5% MeOH/DCM (containing 0.1% 0.880 ammonia) wash-out.Each pure level divided be evaporated to driedly, obtain 4-(3, the 4-lupetazin-1-yl) ethyl benzoate (0.380g, 36.2%) of colourless wax shape solid form.

1H?NMR(399.9MHz，CDCl ₃)δ1.15(3H，d)，1.37(3H，t)，2.20-2.25(1H，m)，2.34(3H，s)，2.37-2.41(1H，m)，2.61-2.67(1H，m)，2.87-2.92(1H，m)，2.99-3.06(1H，m)，3.58-3.62(1H，m)，3.65-3.70(1H，m)，4.33(2H，q)，6.83-6.87(2H，m)，7.90-7.94(2H，m).MS：m/z＝263(MH+).

Embodiment 82

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-iodo-BM

At room temperature with trifluoroacetic acid (3.85ml, 50.02mmol) disposable add to 3-(3,5-dimethoxy styroyl)-5-(4-iodobenzene formamido group)-1H-pyrazoles-1-t-butyl formate in DCM (10ml) (288mg, 0.5mmol) in.With the solution stirring that obtains 24 hours.Reaction mixture is evaporated to dry doubling is dissolved in MeOH (5ml) again.Crude product carries out the ion exchange chromatography purifying through the SCX post.Required product uses 3.5M NH ₃/ methyl alcohol wash-out from the post divides each pure level to be evaporated to driedly, obtains the brown solid.This solid and DCM grind, and obtain the title compound (58.0mg, 24.3%) of white solid form;

¹H?NMR(399.9MHz，DMSO-d6)δ2.88(4H，s)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.47(1H，s)，7.77(2H，d)，7.87(2H，d)，10.73(1H，s)，12.17(1H，s).

MS?m/z：478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.021 μ M

Be prepared as follows 3-(3,5-dimethoxy styroyl)-5-(4-iodobenzene formamido group)-1H-pyrazoles-1-t-butyl formate as raw material:

With 4-iodobenzene formyl chloride (1.332g, 5.00mmol) add to 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate in DCM (15ml) (1.737g, 5mmol) and pyridine (0.445ml, 5.50mmol) in.The suspension-s that obtains was stirred 24 hours down at 25 ℃.Reaction mixture is evaporated to dry doubling is dissolved in EtOAc (25ml) again, water (10ml) and saturated brine (10ml) washing successively.Organic layer filters and evaporation through dried over mgso, obtains crude product.Crude product is through purification by silica gel column chromatography, with 5-20%EtOAc/ isohexane gradient elution.Each pure level divided be evaporated to driedly, obtain 3-(3,5-dimethoxy styroyl)-5-(4-iodobenzene the formamido group)-1H-pyrazoles-1-t-butyl formate (1.187g, 41.1%) of white solid.

1H?NMR(399.9MHz，CDCl3)δ1.70(9H，s)，2.95(4H，s)，3.78(6H，s)，6.32(1H，t)，6.42(2H，d)，6.91(1H，s)，7.64-7.67(2H，m)，7.88-7.90(2H，m)，11.13(1H，s).MS?m/z：478(MH+).

Embodiment 83

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-2-[(3-methyl isophthalic acid, 2-oxazole-5-yl) methylamino] BM

Under nitrogen atmosphere with NaHMDS (the THF solution of 1M, 0.83ml, 0.828mmol; 2.5 [2-(3 equivalent) to drop to the 5-amino-3-that is stirring; The 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (90mg, 0.364mmol, 1.1 equivalents) and 2-{ [(3-methyl-isoxazole-5-yl) methyl] amino }-oil of Niobe (115mg; 0.331mmol, 1 equivalent) and in the solution in THF (4ml).This solution at room temperature stirred 50 minutes.Use saturated NH ₄This solution of Cl aqueous solution quencher, water (5ml) dilution is with ethyl acetate extraction (3x8ml).Crude product is used the 0-1.5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Evaporation contains the branches at different levels of product and prepares HPLC through anti-phase and is further purified, with the MeCN/H that contains 0.1%TFA ₂The O gradient elution obtains the title compound (16mg, 10% yield) of pale solid form;

¹H?NMR(399.902MHz，DMSO)δ2.20(s，3H)，2.88(s，4H)，3.73(s，6H)，4.57(s，2H)，6.21(s，1H)，6.33(t，1H)，6.41(bs，1H)，6.43(d，3H)，6.65(t，1H)，6.77(d，1H)，7.28-7.34(m，1H)，7.75-7.79(m，1H)，8.10(bs，1H)，10.50(s，1H).MS：m/z?462(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀1.0 μ M

Be prepared as follows 2-{ [(3-methyl-isoxazole-5-yl) methyl] amino as raw material }-oil of Niobe:

Under nitrogen atmosphere with 1-(3-methyl-isoxazole-5-yl) methylamine (155mg, 1.37mmol, 1.2 equivalents), potassiumphosphate (341mg, 1.60mmol, 1.4 equivalents), S-Phos (95mg, 0.230mmol, 0.2 equivalent) and Pd ₂Dba ₃(13mg, 0.06mmol, 0.05 equivalent) stirs in toluene (5ml).Add 2-iodo-benzoic acid methyl esters (300mg, 1.14mmol, 1 equivalent), mixture was at room temperature stirred 3 days, stirred 6 hours down at 90 ℃ subsequently.Let reaction mixture cool off, also extract in the impouring water (100ml) with ETHYLE ACETATE (3x60ml).The extraction liquid that merges is used brine wash, through dried over mgso, filters and evaporation.Remaining gelled fuel and ether grind, and are settled out a small amount of yellow solid and filtering.Evaporated filtrate also grinds filtering second throw out with methyl alcohol once more.Evaporated filtrate is with after purification by silica gel column chromatography is used the DCM wash-out.Evaporate each product level branch, obtain 2-{ [(3-methyl-isoxazole-5-yl) methyl] amino of yellow oily jelly form-oil of Niobe (128mg, 45% yield);

¹H?NMR(399.902MHz，CDCl ₃)δ2.25(s，3H)，3.88(s，3H)，4.53(d，2H)，5.99(s，1H)，6.62-6.70(m，2H)，7.32-7.38(m，1H)，7.92-7.96(m，1H)，8.19(t，1H).MS：m/z?247(MH+)

Embodiment 84

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methane amide

Under nitrogen atmosphere with NaHMDS (1.500ml; 1.50mmol) THF (1.0M) solution add to the 5-amino-3-that is stirring that is cooled to 0 ℃ [2-(3; The 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (0.347g; 1.0mmol) and 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methyl-formiate (0.284g is 1.20mmol) in the solution in THF (5.00ml).The solution that obtains stirred 70 minutes at ambient temperature.Subsequently mixture is distributed between the saturated aqueous ammonium chloride of ETHYLE ACETATE and water (1: 2) dilution.The filtering solid obtains the crude product of white solid.This crude product is through preparation LCMC purifying, and the mixture that uses polarity water (containing 0.1%TFA) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.127g, 28.1%) of white solid.

¹H?NMR(500.13MHz，DMSO-d ₆，CD ₃CO ₂D)δ2.69(3H，s)，2.89-2.95(4H，m)，3.07-3.08(4H，m)，3.75(6H，s)，3.92-3.97(4H，m)，6.34(1H，s)，6.42(3H，s)，7.41(1H，d)，8.00(1H，d)

MS：m/z?452(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.39 μ M

Be prepared as follows 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methyl-formiate as raw material:

With 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methane amide (221mg, 1.00mmol) sodium hydroxide (the 2.0M aqueous solution) (10.000ml, the suspension returning in 20.00mmol) stirred 3 hours, it is cooled to room temperature with relief.Through adding 2M HCl (10mL) and saturated NaHCO ₃With the pH regulator of reaction mixture is 7.Crude product is through using SCX2 post ion exchange chromatography purifying.Use methyl alcohol with required product from the post wash-out, branches at different levels are evaporated to dried, obtain 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-formic acid of white solid.Also (0.729ml 10.00mmol) handled 5 minutes with sulfuryl chloride under 0 ℃, this material to be suspended in methyl alcohol (10.00ml).The suspension-s that obtains is in stirring at ambient temperature 18 hours.Add sodium hydrogen carbonate solution up to being alkalescence, use ETHYLE ACETATE (2x75mL) extraction mixture subsequently.(100mL) further extracts this solution with the 1-butanols.Merge organic extract liquid and be evaporated to driedly, obtain 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methyl-formiate of 212mg white solid.

1H?NMR(399.9MHz，DMSO-d ₆)δ2.24(3H，s)，2.43(4H，t)，3.74(4H，t)，3.88(3H，s)，7.30(1H，d)，7.84(1H，d)

MS：m/z?237(MH+)

Be prepared as follows 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methane amide as raw material:

(0.315g, 2mmol) (0.555ml 5.00mmol) is suspended in 2-propyl alcohol (2.000ml) and being sealed in the microwave tube with the 1-N-METHYL PIPERAZINE with 6-chlorine pyridazine-3-methane amide.Reaction mixture is heated to 130 ℃ and kept 30 minutes in microwave reactor, is cooled to envrionment temperature.Filter and collect the deposition that obtains, with 2-propyl alcohol (10ml) washing and vacuum-drying, obtain 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methane amide (0.333g, 75%) of white solid, it need not to be further purified and can use.Crude product sample (100mg) uses the water that reduces (to contain 1%NH through preparation LCMS purifying ₃) and the polar compound of MeCN as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain 6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methane amide (54mg) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ2.24(3H，s)，2.44(4H，t)，3.71(4H，t)，7.34(1H，d)，7.50(1H，s)，7.84(1H，d)，8.11(1H，s)

MS：m/z?222(MH+)

Embodiment 85

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide

Under nitrogen atmosphere through 5 minutes with NaHMDS (2.100ml; 2.10mmol) THF (1.0M) solution add to the 5-amino-3-that is stirring [2-(3; The 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (0.486g; 1.4mmol) and 2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate (0.397g is 1.68mmol) in the solution among the THF (7.00ml is cooled to-20 ℃).The solution that obtains was at room temperature stirred 18 hours.Mixture heating up was refluxed 90 minutes, be cooled to room temperature subsequently.(2.100ml 2.10mmol) and with mixture stirred 70 minutes to add more NaHMDS.Let mixture leave standstill 96 hours, between ETHYLE ACETATE and 2.0M aqueous hydrochloric acid, distribute subsequently.Separate water layer and, use ETHYLE ACETATE (75ml) extraction subsequently with the alkalization of 50% aqueous sodium hydroxide solution.With saturated brine (50ml) washing organic layer,, obtain crude product with after dried over mgso is filtered and evaporation.Crude product is through preparation LCMS purifying, and the mixture that uses polarity water (containing 1% ammonia) decrescence and MeCN is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (4.00mg, 0.633%) of white solid;

¹H?NMR(500.13MHz，DMSO-d ₆，CD ₃CO ₂D)δ2.34(3H，s)，2.53(4H，t)，2.90(4H，t)，3.74(6H，s)，3.89(4H，t)，6.33(1H，t)，6.35(1H，s)，6.42(2H，d)，8.89(2H，s)

MS：m/z?452(MH+)

FGFR kinases analysis-Caliper, IC ₅₀0.118 μ M

FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0149 μ M

(0.863g, 5.0mmol), N, (0.697ml, 5.00mmol) (0.565ml 5.09mmol) is suspended in 2-propyl alcohol (10.00ml) and being sealed in the microwave tube to N-diethylammonium ethamine with the 1-N-METHYL PIPERAZINE with 2-chloropyrimide-5-methyl-formiate.In microwave reactor, reaction mixture is heated to 100 ℃ and kept 10 minutes, is cooled to room temperature.Filter collecting precipitation, with EtOH (5ml) washing and vacuum-drying, obtain 2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate (0.405g, 34.3%) of white solid, it need not to be further purified and can use.MS：m/z237(MH+)

Embodiment 86

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-carbonyl) BM

Under nitrogen atmosphere through 10 minutes with NaHMDS solution (the THF solution of 1M) (2.86ml; 2.86mmol) drop to 4-(4-N-METHYL PIPERAZINE-1-carbonyl) oil of Niobe (0.250g that is stirring; 0.95mmol) and 5-amino-3-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.397g is 1.14mmol) in the solution in THF (2ml) for 1H-pyrazoles-1-t-butyl formate.The solution that obtains was at room temperature stirred 18 hours.With the saturated NH of reaction mixture impouring ₄Cl (25ml) with EtOAc (2x25ml) extraction, with the saturated brine washing, through dried over mgso, filters and evaporation, obtains the crude product (0.501g) of yellow jelly form.The mixture that crude product uses polarity water (containing 1% volatile caustic) and MeCN decrescence through preparation HPLC purifying is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.257g, 56.5%) of yellow solid shape.

¹H?NMR(399.9MHz，DMSO-d6)δ2.21(3H，s)，2.25-2.40(4H，m)，2.89(4H，s)，3.16-3.20(1H，d)，3.32(4H，s)，3.72(6H，d)，6.33(1H，m)，6.42-6.44(2H，d)，7.46-7.50(2H，d)，8.02-8.06(2H，d)

MS：m/z?478(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.096 μ M

Be prepared as follows 4-(4-N-METHYL PIPERAZINE-1-carbonyl) oil of Niobe as raw material:

(0.533ml, (1g is 5.55mmol) in the suspension-s in DCM (20ml) 6.11mmol) to drop to 4-(methoxycarbonyl) phenylformic acid that is stirring with oxalyl chloride under nitrogen atmosphere.The suspension-s that obtains was at room temperature stirred 30 minutes.Under nitrogen atmosphere, drip DMF (0.05ml).The suspension-s that obtains was stirred 90 minutes.Nitrogen atmosphere, 0 ℃ dripped through 60 minutes down the 1-N-METHYL PIPERAZINE (0.554ml, 5.00mmol) and pyridine (1.211ml, 14.99mmol) solution in DCM (15ml).The solution that obtains was at room temperature stirred 3 hours.Reaction mixture is evaporated to dried, obtains the crude product (1.791g) of darkorange solid-like.This solid is dissolved in DCM again and uses NaHCO ₃Washing.Organic layer is evaporated to dried, obtains 4-(4-N-METHYL PIPERAZINE-1-carbonyl) oil of Niobe (0.890g, 61.1%) of orange jelly form, this jelly leaves standstill after fixing, and it need not to be further purified and can use.

1H?NMR(399.9MHz，CDCl3)δ2.78(4H，s)，3.43(4H，s)，7.42-7.45(2H，m)，8.04-8.06(2H，m)

MS：m/z?263(MH+)

Embodiment 87

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-propane-2-base piperazine-1-yl) BM

[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl]-4-(4-propane-2-base piperazine-1-yl) BM prepares according to the method for embodiment 94; But raw materials used is 4-(4-propane-2-base-piperazine-1-yl) oil of Niobe (263mg, 0.84 mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (244mg in THF (5ml); 0.7mmol) and 1M NaHMDS (1.13ml, 1.13mmol).Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 38-58% acetonitrile/water gradient elution that contains 1%0.880 ammonia.Get each clarifying level and divide and evaporation, obtain the title compound (18mg, 5%) of white solid;

¹H?NMR(399.9MHz，DMSO-d ₆)δ1.02(6H，d)，2.55-2.61(4H，m)，2.65-2.76(1H，m)，2.89(2H，s)，3.21-3.28(4H，s)，3.31(2H，s)，3.72(6H，s)，6.33(1H，t)，6.42(2H，d)，6.45(1H，s)，6.95(2H，d)，7.90(2H，d)，10.29(1H，s)，12.07(1H，s)

MS：m/z?478(MH+).

Average n=5, FGFR kinases analysis-Caliper, IC ₅₀0.0004 μ M

Be prepared as follows 4-(4-propane-2-base-piperazine-1-yl) oil of Niobe as raw material:

Three (two benzal benzylacetone roots) are closed two palladiums (0) (0.014g; 0.02mmol) add to the 1-sec.-propyl piperazine (0.151g of deoxidation; 1.18mmol), the 4-methyl-bromobenzoate (0.215g, 1mmol), salt of wormwood (0.193g, 1.4mmol) with 2-dicyclohexyl phosphino--2 '-(N; The N-dimethylamino) (0.012g is 0.03mmol) in the suspension-s in DME (4ml) and be sealed in the microwave tube for biphenyl.Reaction mixture is heated to 130 ℃ and kept 10 minutes in microwave reactor, is cooled to room temperature.Reaction mixture is evaporated to dried, is dissolved in EtOAc (25ml) again and water (15ml) and saturated brine (15ml) wash successively.Organic layer filters and evaporation through dried over mgso, obtains crude product.Crude product is through purification by silica gel column chromatography, with 5% MeOH/DCM wash-out.Each pure level divided be evaporated to driedly, obtain 4-(4-propane-2-base-piperazine-1-yl) oil of Niobe (0.170g, 64.8%) of brown solid-like.

1H?NMR(399.9MHz，CDCl3)δ1.09(6H，d)，2.66(4H，t)，2.73(1H，q)，3.34(4H，t)，3.86(3H，s)，6.84-6.88(2H，m)，7.89-7.93(2H，m).MS：m/z?264(MH+).

Embodiment 88

4-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM

4-(4-cyclopropyl piperazine-1-yl)-[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] BM is according to the preparation of the method for embodiment 94; But raw materials used be in THF (5ml) 4-(4-cyclopropyl piperazine-1-yl) ethyl benzoate (193mg, 0.7mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (292mg; 0.84mmol) and 1M NaHMDS (1.23ml, 1.23mmol).Crude product prepares the HPLC purifying through acid anti-phase, uses the 16-36% acetonitrile/water gradient elution that contains 0.1%TFA.The clarifying branch at different levels that neutralizes, evaporation obtains the title compound (40mg, 12%) of white solid;

¹H?NMR(500.13MHz，DMSO-d ₆+d ₄?Acetic?Acid)δ0.46(2H，d)，0.50(2H，d)，1.79-1.84(1H，m)，2.78(4H，t)，2.90(4H，s)，3.24-3.31(4H，m)，3.75(6H，s)，6.32(1H，s)，6.33(1H，t)，6.42(2H，d)，6.94-6.96(2H，m)，7.86-7.88(2H，m).

FGFR kinases analysis-Caliper, IC ₅₀0.156 μ M

FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00077 μ M

Be prepared as follows 4-(4-cyclopropyl piperazine-1-yl) ethyl benzoate as raw material:

(0.153ml, 1.04mmol) (0.2637g 2.09mmol) is dissolved among the DMA (2ml) and is sealed in the microwave tube with 1-cyclopropyl piperazine with the 4-ethyl fluoro benzoate.Reaction mixture is heated to 150 ℃ and kept 90 minutes in microwave reactor, is cooled to room temperature.Evaporation reaction mixture obtains brown jelly, and this jelly leaves standstill after fixing.Crude product is through purification by silica gel column chromatography, with 10%MeOH (containing 0.1% ammoniacal liquor)/DCM wash-out.Each pure level divided be evaporated to driedly, obtain the not pure products of yellow solid shape.Through silica gel column chromatography this pure products not of purifying once more, with 0-2.5% MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 4-(the 4-cyclopropyl piperazine-1-yl) ethyl benzoate (0.096g, 33.6%) of beige solid shape.

1H?NMR(399.9MHz，CDCl3)δ0.45-0.52(5H，m)，1.36(3H，t)，2.75(4H，t)，3.29(4H，t)，4.32(2H，q)，6.84-6.88(2H，m)，7.90-7.93(2H，m)

m/z(ES+)(M+H)+＝275

Be prepared as follows 1-cyclopropyl piperazine as raw material:

Under nitrogen atmosphere, room temperature, with 4-cyclopropyl piperazine-1-t-butyl formate (0.792g, 3.50mmol) at 4M HCl/1,4-diox (4.37ml, the solution stirring in 17.50mmol) 3 hours.Filter reaction mixture and with ether washing obtains the 1-cyclopropyl piperazine (0.659g) of rough white solid.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 3.5M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the 1-cyclopropyl piperazine (0.264g, 59.7%) of yellow oil form.

1H?NMR(399.9MHz，DMSO-d6)δ0.25-0.30(2H，m)，0.35-0.40(2H，m)，1.54-1.60(1H，m)，2.43(4H，t)，2.60-2.65(4H，t)，3.30(1H，s)

Be prepared as follows 4-cyclopropyl piperazine-1-t-butyl formate as raw material:

Under nitrogen atmosphere with MeOH (0.3ml), ((1-oxyethyl group cyclopropyl) oxygen base) trimethyl silane (2g; 11.47mmol) and acetate (1.051ml; 18.35mmol) (1.068g is 5.735mmol) in the solution in THF (40ml) to add to the piperazine-1-t-butyl formate that is stirring.Through added in 10 minutes in batches sodium cyanoborohydride (0.541g, 8.60mmol).The mixture that obtains stirred 24 hours down at 60 ℃.Reaction mixture is evaporated to dry doubling to be mixed with water (80ml) and 1MHCl (25ml).This solution is used K with EtOAc (2x50ml) washing ₂CO ₃The alkalization water layer extracts with EtOAc (2x30ml).Merge organic layer, with saturated brine (30ml) washing, through dried over mgso, filter and evaporation, obtain the 4-cyclopropyl piperazine-1-t-butyl formate (0.792g, 61.1%) of colorless oil, this colorless oil leaves standstill post crystallization.

1H?NMR(399.9MHz，DMSO-d6)δ0.30-0.34(2H，m)，0.40-0.44(2H，m)，1.41(9H，s)，1.60-1.65(1H，m)，2.47(4H，t)，3.26(4H，t)

Embodiment 89

4-(4-cyclobutyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM

4-(4-cyclobutyl piperazine-1-yl)-[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] BM is according to the preparation of the method for embodiment 94; But raw materials used be in THF (5ml) 4-(4-cyclobutyl 1 piperazine-1-yl) ethyl benzoate (202mg, 0.7mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (292mg; 0.84mmol) and 1M NaHMDS (1.23ml, 1.23mmol).Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 39-59% acetonitrile/water gradient elution that contains 1%0.880 ammonia.Merge clarifying branch at different levels and evaporation, obtain title compound (21mg, 6%);

¹H?NMR(399.9MHz，DMSO-d ₆)δ1.61-1.71(2H，m)，1.81-1.86(2H，m)，1.99-2.02(2H，m)，2.38(4H，t)，2.75(1H，s)，2.85-2.87(4H，m)，3.26-3.27(4H，m)，3.72(6H，d)，6.33(1H，t)，6.42-6.43(2H，m)，6.45(1H，s)，6.95(2H，d)，7.90(2H，d)，10.29(1H，s)，12.07(1H，s).MS＝m/z?490(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.009 μ M

4-(4-cyclobutyl piperazine-1-yl) ethyl benzoate as raw material is prepared as follows:

(0.225ml, 1.53mmol) (0.430g 3.07mmol) places DMA (3ml) and being sealed in the microwave tube with 1-cyclobutyl piperazine with the 4-ethyl fluoro benzoate.Reaction mixture is heated to 150 ℃ and kept 90 minutes in microwave reactor, is cooled to room temperature.Therefore react incomplete, with reaction mixture reheat 1 hour again under 150 ℃.Reaction mixture is evaporated to dried, crude product is used the 0-2.5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(the 4-cyclobutyl piperazine-1-yl) ethyl benzoate (0.050g, 11.31%) of yellow solid shape.

1H?NMR(399.9MHz，CDCl3)δ1.29(3H，t)，1.65-1.70(2H，m)，1.86(2H，t)，2.00(2H，q)，2.41(4H，d)，2.68-2.75(1H，m)，3.27(4H，t)，4.25(2H，q)，6.79(2H，d)，7.85(2H，d).MS＝m/z＝289(MH+).

Be prepared as follows 1-cyclobutyl piperazine as raw material:

(7.84ml, (2.445g 10.17mmol) in the solution in DCM (25ml), stirred 24 hours down at 20 ℃ 101.73mmol) to add to the 4-cyclobutyl piperazine-1-t-butyl formate that is stirring that is cooled to 0 ℃ with trifluoroacetic acid under nitrogen atmosphere.Reaction mixture is evaporated to dried, dilutes with DCM (30ml).Use saturated NaHCO subsequently ₃(2x10ml) washing is evaporated to organic layer dried.Product still is present in water layer, therefore with 2M NaOH water layer is alkalized, with DCM (3x10ml) and EtOAc (1x10ml) extraction.Merge each organic grade of branch and be evaporated to driedly, obtain 1-cyclobutyl piperazine (0.430g, 30.1%).

1H?NMR(399.9MHz，DMSO-d6)δ1.60-1.67(2H，m)，1.72-1.80(2H，m)，1.93-1.97(2H，m)，2.25(4H，s)，2.57-2.60(1H，d)，2.82(4H，t)

4-cyclobutyl piperazine-1-t-butyl formate as raw material is prepared as follows:

Under nitrogen atmosphere with water (0.3ml), cyclobutanone (2.000g, 28.53mmol) and acetate (3.48ml, (3.54g is 19.02mmol) in the solution in THF (40ml) 60.86mmol) to add to the piperazine-1-t-butyl formate that is stirring.Through added in 10 minutes in batches sodium cyanoborohydride (1.793g, 28.53mmol).The mixture that obtains was stirred 19 hours down at 60 ℃.Reaction mixture is evaporated to dry doubling to be mixed with water (80ml) and 1M HCl (25ml).Solution is used K with EtOAc (2x50ml) washing ₂CO ₃Alkalization also extracts with EtOAc (2x30ml).Wash organic layer with saturated brine,, filter and evaporation, obtain the 4-cyclobutyl piperazine-1-t-butyl formate (2.445g, 53.5%) of pure colorless oil through dried over mgso.

1H?NMR(399.9MHz，DMSO-d6)δ1.40(9H，s)，1.60-1.65(2H，m)，1.75-1.80(1H，m)，1.90-2.00(2H，m)，2.17(1H，t)，2.65-2.75(1H，m)，3.30(4H，d).MS＝m/z?241(MH+).

Embodiment 90

4-(4-ethanoyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM

4-(4-ethanoyl piperazine-1-yl)-[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] BM is according to the preparation of the method for embodiment 94; But raw materials used is 4-(4-ethanoyl piperazine-1-yl) oil of Niobe (221mg, 0.84 mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (244mg in THF (5ml); 0.7mmol) and 1M NaHMDS (1.13ml, 1.13mmol).Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 31-51% acetonitrile/water gradient elution that contains 1%0.880 ammonia.Get each clarifying level and divide and evaporation, obtain the title compound (3mg, 1.0%) of white solid;

¹H?NMR(399.9MHz，DMSO-d ₆)δ2.06(3H，s)，2.78(4H，s)，3.28(2H，s)3.25(2H，t)，3.49-3.56(4H，m)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.45(1H，s)，6.99(2H，d)，7.92(2H，d)，10.32(1H，s)，12.08(1H，s).

MS：m/z?478(MH+).

Average n=5, FGFR kinases analysis-Caliper, IC ₅₀0.056 μ M

Under nitrogen atmosphere, 100 ℃ with 1-ethanoyl piperazine (0.308g; 2.40mmol), the 4-methyl-bromobenzoate (0.430g, 2mmol), the ortho-phosphoric acid tripotassium (0.594g, 2.80mmol), 2-dicyclohexyl phosphino--2 '; 6 '-dimethoxy-1; 1 '-(0.164g, (0.092g, 0.10mmol) suspension-s through deoxidation in toluene (10ml) stirred 24 hours biphenyl 0.40mmol) to close two palladiums (O) with three (two benzal benzylacetone roots).Filtration obtains crude product through refrigerative reaction mixture and evaporation.Crude product is used the 0-5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(the 4-ethanoyl piperazine-1-yl) oil of Niobe (0.295g, 56.2%) of yellow solid shape.

1H?NMR(399.9MHz，CDCl3)δ2.07(3H，s)，3.24-3.30(4H，m)，3.56(2H，t)，3.70-3.72(2H，m)，3.80(3H，s)，6.78-6.81(2H，m)，7.85-7.89(2H，m).MS：m/z?263(MH+).

Embodiment 91

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-sulfonyloxy methyl piperazine-1-yl) BM

Under 85 ℃ with formic acid (5ml, 130.36mmol) and N-(the 1-tertiary butyl-3-(3-anisole ethyl)-1H-pyrazoles-5-yl)-4-(4-(sulfonyloxy methyl) piperazine-1-yl) BM (255mg, solution stirring 0.47mmol) 2 hours.With reaction mixture cooling and be evaporated to dried.Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 36-46% acetonitrile/water gradient elution that contains 1%0.880 ammonia.Merge clarifying branch at different levels and evaporation, obtain the title compound (43.0mg, 18.82%) of white solid;

¹H?NMR(499.9MHz，DMSOd ₆+CD ₃CO ₂D)δ2.87(3H，s)，2.88-2.92(4H，m)，3.28-3.32(4H，m)，3.39-3.42(4H，m)，3.73(3H，s)，6.30(1H，s)，6.71-6.74(1H，m)，6.77(1H，s0，6.80(2H，d)，6.94-6.98(2H，m)，7.16(1H，t)，7.85-7.89(2H，m).

MS：m/z＝484(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.25 μ M

Be prepared as follows N-(the 1-tertiary butyl-3-(3-anisole ethyl)-1H-pyrazoles-5-yl)-4-(4-(sulfonyloxy methyl) piperazine-1-yl) BM as raw material:

Under 0 ℃ with methylsulfonyl chloride (0.042ml; 0.55mmol) add to N-(the 1-tertiary butyl-3-(3-anisole ethyl)-1H-pyrazoles-5-yl)-4-(piperazine-1-yl) BM (0.231g; 0.5mmol) and N, (0.077ml is 0.55mmol) in the solution in DCM (4ml) for N-diethylammonium ethamine.The solution that obtains was stirred 1 hour down at 20 ℃.Reaction mixture filters with saturated sodium bicarbonate (10ml) dilution, and solid washs with DCM (2x10ml).Merge the washing of organic layer and water (20ml) and saturated brine (20ml).Organic phase is filtered and evaporation through dried over mgso, obtains crude product.Crude product is through purification by silica gel column chromatography, with 0-5% MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain N-(the 1-tertiary butyl-3-(3-anisole ethyl)-1H-pyrazoles-5-yl)-4-(4-(sulfonyloxy methyl) piperazine-1-yl) BM (0.255g, 94%) of white solid.MS：m/z＝540(MH+)。

N-(the 1-tertiary butyl-3-(3-anisole ethyl)-1H-pyrazoles-5-yl)-4-(piperazine-1-yl) BM is prepared as follows:

At nitrogen atmosphere, 5 minutes (6.25ml of the toluene with the 2M trimethylaluminium of 4 ℃ of following warps; 12.50mmol) drips of solution adds to the 1-tertiary butyl-3-(3-anisole the ethyl)-1H-pyrazoles-5-amine (1.367g that is stirring; 5.00mmol) and 4-(piperazine-1-yl) ethyl benzoate (1.171g is 5mmol) in the solution in toluene (20ml).The solution that obtains was stirred 18 hours down at 20 ℃.Reaction mixture filters and evaporation with methyl alcohol (20ml) quencher, obtains the brown solid.Crude product is through purification by silica gel column chromatography, with the 0-10%MeOH/DCM gradient elution that contains 0.1% ammonia.Each pure level divided be evaporated to driedly, obtain N-(the 1-tertiary butyl-3-(3-anisole ethyl)-1H-pyrazoles-5-yl)-4-(piperazine-1-yl) BM (0.520g, 22.53%) of white solid.

1H?NMR(399.9MHz，CDCl ₃)δ1.59(9H，s)，2.81-2.91(4H，m)，2.96-2.99(4H，m)，3.23(3H，t)，3.25-3.42(1H，m)，3.72(3H，s)，6.17(1H，s)，6.64-6.68(1H，m)，6.73(1H，t)，6.78(1H，d)，6.84-6.88(2H，m)，7.12(1H，t)，7.38(1H，s)，7.67-7.71(2H，m).

Under nitrogen atmosphere with piperazine (17.23g, 200.00mmol) add to 4-ethyl fluoro benzoate in the DMSO that is warmed to 120 ℃ (50ml) (7.34ml, 50mmol) in.The solution that obtains was stirred 20 hours down at 120 ℃.With reaction mixture cooling, evaporating solvent.Product is distributed between saturated sodium bicarbonate aqueous solution (100ml) and ETHYLE ACETATE (100ml).With ETHYLE ACETATE (2x75ml) extraction,,, filter and evaporation through dried over mgso with the salt brine solution washing.Crude product is through purification by silica gel column chromatography, with the 10% ethanol/methylene wash-out that contains 0.1%0.880 ammonia.Each pure level divided be evaporated to driedly, obtain the product of solid-like.Make this insoluble solid pulping and stirring 1 hour in DCM (500ml).Filter this solution, organic solution is filtered and evaporation through dried over mgso, obtains the product of blocks of solid form.This solid is merged, obtain 4-(piperazine-1-yl) ethyl benzoate (9.53g, 81%).

1H?NMR(399.9MHz，CDCl ₃)δ1.28-1.32(3H，m)，2.94-2.96(4H，m)，3.20-3.22(4H，m)，4.26(2H，q)，6.77-6.81(2H，m)，7.84-7.87(2H，m).MS：m/z＝236(MH+)

Method according to describing among the embodiment 13 prepares 5-[2-(3-p-methoxy-phenyl) the ethyl]-2-tertiary butyl-pyrazoles-3-amine.

Embodiment 92

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(1-methyl-4-piperidyl) BM

Under nitrogen atmosphere through 10 minutes with NaHMDS solution (the THF solution of 1M) (5.91ml; 5.91mmol) drop to 4-(1-methyl piperidine-4-yl) oil of Niobe (0.4594g that is stirring; 1.97mmol) and 5-amino-3-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.821g is 2.36mmol) in the solution in THF (4ml) for 1H-pyrazoles-1-t-butyl formate.The solution that obtains was at room temperature stirred 18 hours.With the saturated NH of reaction mixture impouring ₄Among the Cl (25ml),,, filter and evaporation, obtain the crude product (1.0719g) of orange jelly form with the saturated brine washing and through dried over mgso with EtOAc (2x25ml) extraction.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.142g, 16.08%) of white solid;

¹H?NMR(399.9MHz，DMSO-d6)δ1.64-1.78(4H，m)，1.97-2.01(2H，m)，2.22(3H，s)，2.53-2.58(1H，m)，2.88-2.91(6H，m)，3.73(6H，s)，6.33(1H，t)，6.42-6.44(3H，m)，7.35(2H，d)，7.93(2H，d)，10.57(1H，s)，12.08(1H，s)

MS：m/z?449(MH+)

Average n=1, FGFR kinases analysis-Caliper, IC ₅₀0.0079 μ M

Be prepared as follows 4-(1-methyl piperidine-4-yl) oil of Niobe as raw material:

Under nitrogen atmosphere with water (0.2ml), Paraformaldehyde 96 (0.470g, 15.64mmol) and acetate (0.895ml, (1g is 3.91mmol) in the suspension-s in THF (20ml) 15.64mmol) to add to 4-(4-(methoxycarbonyl) phenyl) the piperidines muriate that is stirring.Through added in 10 minutes in batches sodium cyanoborohydride (0.369g, 5.87mmol).The mixture that obtains was stirred 19 hours down at 60 ℃.Reaction mixture is evaporated to dry doubling to be mixed with water (20ml) and 1M HCl (5ml).With EtOAc (2x15ml) washing soln, use K ₂CO ₃Alkalization also extracts with EtOAc (2x15ml).Wash organic layer with saturated brine, through dried over mgso, filter and evaporation, obtain pure 4-(1-methyl piperidine-4-yl) oil of Niobe (0.459g, 50.4%) of colorless oil, this oily matter leaves standstill post crystallization.

1H?NMR(399.9MHz，DMSO-d6)δ1.63-1.72(2H，m)，1.73-1.77(2H，m)，1.96-2.03(2H，m)，2.21(3H，s)，2.87-2.90(2H，m)，3.85(3H，s)，4.30-4.31(1H，m)，7.40(2H，d)，7.88-7.91(2H，m)

Embodiment 93

4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM

Method according to embodiment 94 prepares 4-(3,4,6,7; 8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM; But raw materials used is 4-(3,4,6,7 in THF (5ml); 8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) oil of Niobe (193mg, 0.7mmol), [2-(3 for 5-amino-3-; The 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (292mg, 0.84mmol) and 1MNaHMDS (1.23ml, 1.23mmol).Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 33-53% acetonitrile/water gradient elution that contains 1%0.880 ammonia.Merge clarifying branch at different levels and evaporation, obtain title compound (34mg, 10%);

¹H?NMR(399.9MHz，DMSO-d ₆)δ1.37-1.41(1H，m)，1.67-1.77(2H，m)，1.84-1.88(1H，m)，1.99-2.06(1H，m)，2.09(1H，t)，2.18-2.25(1H，m)，2.80-2.84(1H，m)，2.87(4H，s)，3.01-3.06(2H，m)，3.73(6H，s)，3.80-3.83(1H，m)，3.96-3.98(1H，m)，6.33(1H，t)，6.42-6.45(3H，m)，6.97(2H，d)，7.90(2H，d)，10.28(1H，s)，12.07(1H，s)

MS＝m/z476(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.037 μ M

Be prepared as follows 4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) oil of Niobe as raw material:

Under nitrogen atmosphere with 4-iodo-benzoic acid methyl esters (2.076g, 7.92mmol), cesium carbonate (5.16g, 15.85mmol), the 2-acetyl cyclohexanone (0.209ml, 1.58mmol) and cupric iodide (I) (0.075g; 0.40mmol) add to stirring 1,2,3,4; 6,7,8; (1g is 7.92mmol) in the solution in DMF (20ml) for 8a-octahydro pyrrolo-[1,2-a] pyrazine.The suspension-s that obtains was stirred 20 hours down at 90 ℃.Reaction mixture is evaporated in the mixture that dry doubling is dissolved in the first alcohol and water again.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 3.5MNH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains brown gelationus title compound (1.243g, 60.2%).

1H?NMR(399.9MHz，DMSO-d6)δ1.33-1.43(1H，m)，1.57-1.79(3H，m)，1.81-1.89(1H，m)，1.99-2.03(1H，m)，2.07(1H，q)，2.16-2.23(1H，m)，2.56(1H，t)，2.83-2.95(2H，m)，3.00-3.05(2H，m)，3.06-3.09(1H，m)，3.75-3.78(3H，m)，3.86(1H，t)，3.98-4.01(1H，m)，6.98-7.02(2H，m)，7.77-7.80(2H，m).

MS＝m/z261(MH+).

Embodiment 94

4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM

Nitrogen atmosphere, 0 ℃ down through 5 minutes THF solution with 1M NaHMDS (1.13ml, 1.05mmol) add to 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate of stirring (244mg, 0.7mmol) and 4-(1; 3,4,6; 7,8,9; 9a-octahydro pyrido [2,1-c] pyrazine-2-yl) (231mg is 0.84mmol) in the solution in THF (5ml) for oil of Niobe.Under 0 ℃,, stirred 18 hours down at 20 ℃ subsequently reaction mixture restir 15 minutes.Add additional quantity 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (80mg, 0.23mmol) with the THF solution of 1M NaHMDS (1.13ml, 1.13mmol).With reaction mixture restir 3 hours.Reaction mixture extracts with ETHYLE ACETATE (3x20ml) with saturated ammonium chloride (20ml) quencher.Extraction liquid through dried over mgso and evaporation, obtains crude product with saturated brine solution (15ml) washing.Crude product prepares the HPLC purifying through acid anti-phase, uses the 38-58% acetonitrile/water gradient elution that contains 1%0.880 volatile caustic.Get each clarifying level and divide and evaporation, obtain the title compound (32mg, 9%) of white solid;

¹H?NMR(500.13MHz，DMSO-d ₆)δ1.25(1H，s)，1.62(2H，t)，1.72(1H，d)，1.93-1.95(2H，m)，2.19-2.20(1H，m)，2.44(1H，s)，2.81(3H，q)，2.87(4H，s)，3.28(1H，s)，3.69(1H，s)，3.72(6H，s)，3.77(1H，d)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，6.96(2H，d)，7.89(2H，d)，10.29(1H，s)，12.07(1H，s).MS：m/z?490(MH+).

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.081 μ M

Be prepared as follows 4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl) oil of Niobe as raw material:

Through using SCX post ion exchange chromatography with 2,3,4,6,7,8,9, the solution of 9a-octahydro-1H-pyrido [1,2-a] pyrazine (5g) in the mixture of methyl alcohol and water (1: 1) is converted into free alkali.Use 7M NH ₃/ MeOH is required product wash-out from post, with each pure level divide be evaporated to dried, obtain the yellow solid shape required compound (1.5224g, 10.86mmol).

Under nitrogen atmosphere with 4-iodo-benzoic acid methyl esters (2.84g, 10.86mmol), cesium carbonate (7.07g, 21.71mmol), the 2-acetyl cyclohexanone (0.286ml, 2.17mmol) and cupric iodide (I) (0.103g; 0.54mmol) add to stirring 2,3,4,6; 7,8,9; (1.5224g is 10.86mmol) in the solution in DMF (30ml) for 9a-octahydro-1H-pyrido [1,2-a] pyrazine.The suspension-s that obtains was stirred 20 hours down at 90 ℃.Reaction mixture is evaporated to dry doubling is dissolved in methyl alcohol.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 3.5M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains brown jelly.This jelly is passed through silica gel column chromatography purifying once more, with 5%MeOH (containing 0.1% volatile caustic)/DCM wash-out.Each pure level divided be evaporated to driedly, obtain the required compound (0.503g, 16.8%) of orange solids shape.

¹H?NMR(399.9MHz，CDCl ₃)δ1.29-1.33(1H，m)，1.26-1.40(1H，m)，1.62(1H，d)，1.64(1H，d)，1.65-1.68(1H，m)，1.69(1H，s)，1.80-1.82(1H，m)，2.04-2.10(2H，m)，2.32-2.39(1H，m)，2.61(1H，d)，2.89(2H，d)，3.01-3.08(1H，m)，3.58-3.63(1H，m)，3.70-3.75(1H，m)，3.86(3H，s)，6.83-6.87(2H，m)，7.89-7.93(2H，m).MS?m/z＝275(MH+).

Embodiment 95

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(4-N-METHYL PIPERAZINE-1-yl) methyl] BM

Under nitrogen atmosphere through 10 minutes with NaHMDS solution (the THF solution of 1M) (2.83ml; 2.83mmol) drop to 4-((4-N-METHYL PIPERAZINE-1-yl) methyl) oil of Niobe (0.351g that is stirring; 1.41mmol) and 5-amino-3-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.589g is 1.70mmol) in the solution in THF (3ml) for 1H-pyrazoles-1-t-butyl formate.Add DMA (3ml).The solution that obtains was at room temperature stirred 60 hours.Drip other a NaHMDS (1.415ml, 1.415mmol), with this solution restir 90 minutes at room temperature.With the saturated NH of reaction mixture impouring ₄Cl (25ml) with EtOAc (2x25ml) extraction, with the saturated brine washing and through dried over mgso, filters and evaporation, obtains orange gelationus crude product (0.8776g).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.034g, 5.19%) of white solid;

¹HNMR(500.0MHz，DMSO-d6)δ2.18(3H，s)，2.34-2.37(2H，m)，3.54(2H，s)，3.73(3H，s)，6.32-6.33(1H，t)，6.41-6.42(2H，d)，7.38-7.39(1H，d)，7.90-7.92(1H，d)，10.02(1H，s)，11.79(1H，s)

MS：m/z?464(MH+)

Average n=2, FGFR kinases analysis-Caliper, IC ₅₀0.14 μ M

Be prepared as follows 4-((4-N-METHYL PIPERAZINE-1-yl) methyl) oil of Niobe as raw material:

Under nitrogen atmosphere through 10 minutes with (trimethyl silyl) diazomethane ((0.611ml; 3.84mmol); 2.0M diethyl ether solution) (0.75g is 3.20mmol) in the suspension-s in toluene (21ml) and methyl alcohol (7ml) to drop to 4-((4-N-METHYL PIPERAZINE-1-yl) methyl) phenylformic acid that is stirring.The suspension-s that obtains was at room temperature stirred 3 hours.(1.222ml, 7.68mmol), this solution is restir 18 hours at room temperature to drip other portion (trimethyl silyl) diazomethane.Reaction mixture is evaporated to dried, obtains the crude product (0.723 g) of white solid.Be dissolved among the DCM this crude product and the filtering insolubles.Filtrating is evaporated to dried, obtains crude product.Be dissolved among the DCM once more crude product and the more insolubles of filtering, obtain 4-((4-N-METHYL PIPERAZINE-1-yl) methyl) oil of Niobe (0.351g, 44.2%), it need not purifying and can use.

1H?NMR(399.9MHz，CDCl3)δ2.60-2.61(3H，m)，2.77(4H，t)，2.99(4H，s)，3.58(1H，s)，3.62(1H，s)，3.85(2H，d)，7.29-7.38(2H，m)，7.92-7.80(2H，m)

MS：m/z249(MH+)

Embodiment 96

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4,5-tri methyl piperazine-1-yl) BM

Prepare N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4 according to the method described in the embodiment 94; 5-tri methyl piperazine-1-yl) BM, but raw materials used be 4-(3,4 in THF (5ml); 5-tri methyl piperazine-1-yl) ethyl benzoate (310mg, 0.86mmol), 5-amino-3-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazoles-1-t-butyl formate (225mg; 0.65mmol) and 1M NaHMDS (2.59ml, 2.59mmol).Crude product prepares the HPLC purifying through alkaline anti-phase, uses the 38-58% acetonitrile/water gradient elution that contains 1%0.880 ammonia.Get each clarifying level and divide and evaporation, obtain the title compound (23mg, 5.6%) of white solid;

¹H?NMR(399.99MHz，CDCl ₃)δ1.09(6H，d)，2.17-2.28(2H，m)，2.22(3H，s)，2.56(2H，t)，2.81-2.90(4H，m)，3.48(2H，d)，3.68(6H，s)，6.22(1H，t)，6.28(2H，s)，6.56(1H，s)，6.78(2H，d)，7.68(2H，d0，8.86(1H，s)，9.65(1H，s).MS：m/z?464(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00054 μ M

Be prepared as follows 4-(3,4,5-tri methyl piperazine-1-yl) ethyl benzoate as raw material:

With titanium isopropylate (IV) (0.598ml, 2.00mmol) add to 4-(3,5-lupetazin-1-yl) ethyl benzoate in ethanol (5ml) (0.262g, 1mmol) and Paraformaldehyde 96 (0.120g, 4.00mmol) in.Under nitrogen atmosphere, the solution that obtains was stirred 30 minutes down at 60 ℃.It is cooled to 20 ℃, and disposable adding Peng Qinghuana (0.095g, 2.5mmol).Solution heated 24 hours down at 60 ℃.Reaction mixture filters with 0.880 ammonia (0.5ml) quencher, with ether (2x5ml) washing, and the evaporation organic extract liquid.Crude product is through purification by silica gel column chromatography, with the 0-5%MeOH/DCM gradient elution that contains 0.1% ammonia.Branches at different levels are evaporated to dried, obtain oily matter.This oily matter is dissolved in acetonitrile (20ml), add the isocyanic ester load on the polymkeric substance (1mmol/g, 2g), with the suspension-s stirred overnight.The filtering resin to doing, obtains 4-(3,4, the 5-tri methyl piperazine-1-yl) ethyl benzoate (0.310g, 112%) of white solid with solution evaporation.MS：m/z?278(MH+)。

Embodiment 97

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) thiophene-2-carboxamide derivatives

Under 80 ℃, nitrogen atmosphere through 4 hours toluene solution (1.250ml with the 2M trimethylaluminium; 2.50mmol) drop to the 5-(3 that is stirring; 4-lupetazin-1-yl) the thiophene-2-carboxylic acid ethyl ester (0.268g, 1mmol) and 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (0.286g; 1.00mmol) in the solution in toluene (7.14ml), kept 18 hours down at 70 ℃ subsequently.(5mL) adds to this reaction mixture with ETHYLE ACETATE, adds sodium-potassium tartrate (5mL, 20% aqueous solution) subsequently.Add more polyacetic acid ethyl ester (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel, removes water layer.Wash ethyl acetate layer with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains the crude product of yellow jelly form.Crude product is through preparation LCMS purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.036g, 7.63%) of white solid.1H?NMR(500.13MHz，DMSO-d6)δ1.07(3H，d)，2.26-3.12(4H，m)，3.38-3.47(3H，m)，3.78(6H，s)，5.09(2H，s)，5.55(1H，s)，6.17(1H，d)，6.45(1H，s)，6.61(2H，d)，7.64(1H，s).MS：m/z472(MH+)

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00046 μ M

Adopt the method among the embodiment 12 to prepare 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate as raw material.

Be prepared as follows 5-(3,4-lupetazin-1-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

Under 20 ℃, nitrogen atmosphere with acid chloride (II) (0.112g, 0.50mmol) add to 5-bromothiophene-2-ethyl formate (0.571g, 5mmol), 1; 2-dimethyl--piperazine (1.175g; 5mmol), racemize-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (0.311g; 0.50mmol) and cesium carbonate (2.281g is 7.00mmol) in the mixture in toluene (50.0ml).The suspension-s that obtains was stirred 23 hours down at 110 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post.Thick substance dissolves in methyl alcohol, is carried on the post subsequently.Use 2M NH ₃The required product of/methyl alcohol wash-out from post divides each pure level to be evaporated to driedly, obtains brown buttery crude product.With this material further through purification by silica gel column chromatography, with 1-5% MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 5-(3,4-lupetazin-1-yl) the thiophene-2-carboxylic acid ethyl ester (0.640g, 47.7%) of light brown solid-like.

1H?NMR(399.9MHz，CDCl3)δ1.11-1.13(3H，m)，1.33(3H，t)，2.24-2.29(1H，m)，2.33(3H，s)，2.37-2.44(1H，m)，2.73(1H，d)，2.82-2.87(1H，m)，3.08-3.14(1H，m)，3.36-3.40(1H，m)，3.43-3.48(1H，m)，4.28(2H，q)，6.01(1H，d)，7.54(1H，d)

MS：m/z?269(MH+)

Embodiment 98

4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM

Under nitrogen atmosphere through 5 minutes toluene solutions with the 2M trimethylaluminium (0.853ml, 1.71mmol) drop to 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine of stirring (0.170g, 0.68mmol) and 4-(1; 3,4,6; 7,8,9; 9a-octahydro pyrido [2,1-c] pyrazine-2-yl) (0.187g is 0.68mmol) in the solution in toluene (10ml) for oil of Niobe.The solution that obtains was at room temperature stirred 18 hours.React incomplete, therefore dripped trimethylaluminium again (0.853ml 1.71mmol), stirred solution 4 hours down at 60 ℃ through 5 minutes.In reaction mixture cooling and impouring acetone (50ml),, filter and be evaporated to dried with moist sodium sulphite quencher.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.105g, 31.3%) of white solid.

1H?NMR(500.13MHz，DMSO-d6)δ1.21-1.26(1H，m)，1.30-1.33(1H，m)，1.53-1.57(1H，m)，1.63(1H，d)，1.65(1H，d)，1.76(1H，d)，1.98(1H，d)，1.98-2.03(1H，m)，2.22-2.27(1H，m)，2.55(1H，d)，2.79(1H，t)，2.83(2H，d)，3.68-3.70(1H，m)，3.78(7H，s)，5.10(2H，s)，5.67(1H，s)，6.46(1H，t)，6.61-6.62(2H，m)，6.97(2H，d)，7.84(2H，d)，10.20(1H，s)，11.15(1H，s).MS：m/z?492(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.003 μ M

2,3,4,6,7,8,9, the solution of 9a-octahydro-1H-pyrido [1,2-a] pyrazine dihydrochloride (5g) in methyl alcohol (20ml) and water (10ml) carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃The required product of/MeOH wash-out from post divides each pure level to be evaporated to driedly, obtains 2,3,4,6,7,8,9 of yellow solid shape, and 9a-octahydro-1H-pyrido [1,2-a] pyrazine (1.5224g, 10.86mmol).

Under nitrogen atmosphere with 4-iodo-benzoic acid methyl esters (2.84g, 10.86mmol), cesium carbonate (7.07g, 21.71mmol), the 2-acetyl cyclohexanone (0.286ml, 2.17mmol) and cupric iodide (I) (0.103g; 0.54mmol) add to stirring 2,3,4,6; 7,8,9; (1.5224g is 10.86mmol) in the solution in DMF (30ml) for 9a-octahydro-1H-pyrido [1,2-a] pyrazine.The suspension-s that obtains was stirred 20 hours down at 90 ℃.Reaction mixture is evaporated to dried.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 3.5M NH ₃The required product of/MeOH wash-out from post is evaporated to branches at different levels dried, obtains the crude product of impure brown jelly form.Crude product is through purification by silica gel column chromatography, with 5%MeOH (0.1% ammoniacal liquor)/DCM wash-out.Each pure level divided be evaporated to driedly, obtain the required compound (0.681g, 22.87%) of orange solids shape.

1H?NMR(399.9MHz，CDCl3)δ1.29-1.33(1H，m)，1.26-1.40(1H，m)，1.62(1H，d)，1.64(1H，d)，1.65-1.68(1H，m)，1.69(1H，s)，1.80-1.82(1H，m)，2.04-2.10(2H，m)，2.32-2.39(1H，m)，2.61(1H，d)，2.89(2H，d)，3.01-3.08(1H，m)，3.58-3.63(1H，m)，3.70-3.75(1H，m)，3.86(3H，s)，6.83-6.87(2H，m)，7.89-7.93(2H，m).MS：m/z?275(MH+).

Embodiment 99

4-(1-cyclopropyl piperidine-4-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM

Under nitrogen atmosphere with the toluene solution (1.250ml of 2M trimethylaluminium; 2.50mmol) 4-(1-cyclopropyl piperidine-4-yl) oil of Niobe (0.259g of processing in toluene (10ml); 1mmol), 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.247g, 1.00mmol).Reaction mixture heated 18 hours down at 60 ℃.With the reaction mixture cooling, with methyl alcohol (40ml) quencher reaction, with 2N HCl (1ml) acidifying.Crude product mixture is carried out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃The required product of/MeOH wash-out from post is evaporated to branches at different levels dried.Crude product is through purification by silica gel column chromatography, with 0-5% methyl alcohol (containing 2.5M ammonia)/DCM gradient elution.Each pure level divided be evaporated to driedly, product crystallization in the DCM/ ether obtains the title compound (0.170g, 35.8%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ0.31-0.33(2H，m)，0.43-0.45(2H，m)，1.58-1.66(3H，m)，1.74(1H，d)，1.77(1H，s)，2.25-2.30(2H，m)，2.55(1H，d)，2.88(4H，s)，3.05(2H，d)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.47(1H，s)，7.34(2H，d)，7.92(2H，d)，10.54(1H，s)，12.13(1H，s).MS：m/z?475(MH+).

Average n=3, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00091 μ M

Be prepared as follows 4-(1-cyclopropyl piperidine-4-yl) oil of Niobe as raw material:

(1.279g 5mmol) is dissolved in the mixture of THF (15ml) and methyl alcohol (1ml) with 4-piperidin-4-yl oil of Niobe.Add [(1-oxyethyl group cyclopropyl) oxygen base] trimethyl silane (2.001ml, 10.00mmol), add subsequently acetate (0.916ml, 16.00mmol).Add DCM (15.00ml) to help dissolving.Through added in 5 minutes in batches the solid sodium cyanoborohydride (0.471g, 7.50mmol).Reaction mixture was stirred 18 hours down at 60 ℃.With the reaction mixture cooling, with saturated ammonium chloride solution (5ml) quencher, with methyl alcohol (20ml) dilution, through carrying out the ion exchange chromatography partial purification with the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains oily matter.Crude product is used the 5%MeOH/DCM wash-out through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain the required compound (0.548g, 42.3%) of white solid.

1H?NMR(399.9MHz，CDCl3)δ0.42-0.50(4H，m)，1.60-1.65(2H，m)，1.70-1.75(1H，m)，1.80-1.85(2H，m)，2.25-2.32(2H，m)，2.55-2.61(1H，m)，3.15-3.18(2H，m)，3.89(3H，s)，7.27-7.30(2H，m)，7.94-7.97(2H，m).MS：m/z?260(MH+).

Be prepared as follows 4-piperidin-4-yl oil of Niobe:

Through (5.0g 17mmol) is converted into free alkali, uses 7M NH with 4-(piperidin-4-yl) oil of Niobe hydrochloride with SCX post ion exchange chromatography ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains 4-(piperidin-4-yl) oil of Niobe (4.20g, 95%) of white solid.MS：m/z?260(MH+)。

According to 5-[2-(3,5-Dimethoxyphenyl) the ethyl]-2H-pyrazoles-3-amine of the preparation of the method described in the embodiment 2 as raw material.

Embodiment 100

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,5-lupetazin-1-yl] BM

At nitrogen atmosphere, 5 minutes (1.875ml of the toluene solution with the 2M trimethylaluminium of 20 ℃ of following warps; 3.75mmol) drop to the 4-((3R that is stirring; 5S)-3,5-lupetazin-1-yl) ethyl benzoate (0.394g, 1.50mmol) and 5-[(3; The 5-Dimethoxyphenyl) methoxyl group]-(0.374g is 1.5mmol) in the solution in toluene (10ml) for 2H-pyrazoles-3-amine.The solution that obtains was stirred 5 hours down at 60 ℃.With the reaction mixture cooling, through also add the sodium sulphite quencher of excessive humidity with acetone (100ml) dilution in batches.Reaction mixture was stirred 60 minutes.The solid that filtering obtains is with 10% methyl alcohol/DCM washing.Evaporated filtrate obtains crude product.Crude product is through purification by silica gel column chromatography, with 0-5% MeOH (containing 2M ammonia)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (0.287g, 41.1%) of white solid.

1H?NMR(500.13MHz，DMSO-d6)δ1.08(6H，d)，2.31(2H，t)，3.70-3.73(2H，m)，3.78(6H，s)，5.10(2H，s)，5.64(1H，s)，6.46(1H，t)，6.62(2H，d)，6.95-6.97(2H，m)，7.83-7.85(2H，m)，10.21(1H，s)，11.09(1H，s).MS：m/z?466(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0014 μ M

Be prepared as follows as the 4-of raw material ((3R, 5S)-3,5-lupetazin-1-yl) ethyl benzoate:

Under nitrogen atmosphere will (2S, 6R)-2, the 6-lupetazin (6.85g, 60.00mmol) add to 4-ethyl fluoro benzoate in the DMSO that is warmed to 120 ℃ (40ml) (2.201ml, 15mmol) in.The solution that obtains was stirred 20 hours down at 120 ℃.With reaction mixture cooling and evaporating solvent.Crude product is through purification by silica gel column chromatography, with the 0-10% ethanol/methylene gradient elution that contains 1%880 ammonia.Each pure level divided be evaporated to driedly, obtain brown buttery required compound (2.83g, 71.9%).

1H?NMR(399.9MHz，CDCl3)δ1.15(6H，d)，1.37(3H，t)，2.38(1H，d)，2.41(1H，d)，2.96-3.04(2H，m)，3.65-3.69(2H，m)，4.33(2H，q)，6.84-6.87(2H，m)，7.89-7.93(2H，m).MS：m/z?263(MH+).

Be prepared as follows 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine:

With MP-carbonic ether (2.74mmol/g) (12.00g, 32.88mmol) add to 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate in methyl alcohol (200ml) and water (20ml) (5g, 17.50mmol) in.The suspension-s that obtains was at room temperature stirred 18 hours.Filter reaction mixture is with 10%MeOH/DCM washing MP-carbonic ether.Be evaporated to driedly, obtain 5-[(3, the 5-Dimethoxyphenyl) the methoxyl group]-2H-pyrazoles-3-amine (2.94g, 67.5%) of orange waxy solid form

1H?NMR(399.9MHz，DMSO-d6)δ3.74(6H，s)，4.76(1H，s)，4.97(2H，s)，6.42(1H，t)，6.55(2H，d).

Embodiment 101

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM is according to the method preparation of embodiment 100; But raw materials used is 4-(3; 4-lupetazin-1-yl) ethyl benzoate (0.394g, 1.50mmol), 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (0.374g; 1.5mmol) and the toluene solution of 2M trimethylaluminium (1.875ml, 3.75mmol).Crude product is through purification by silica gel column chromatography, with 0-5%MeOH (containing 2M ammonia)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (0.301g, 43.1%) of white solid.

1H?NMR(500.13MHz，DMSO-d6)δ1.06-1.10(3H，m)，2.22-2.30(1H，m)，2.20-2.63(4H，m)，2.61-2.65(1H，m)，2.83-2.86(1H，m)，2.96-3.02(1H，m)，3.63-3.70(2H，m)，3.78(6H，s)，5.11(2H，s)，5.66(1H，s)，6.46(1H，t)，6.62(2H，d)，6.96-6.98(2H，m)，7.83-7.86(2H，m)，10.15(1H，s)，11.07(1H，s).MS：m/z?466(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.021 μ M

Be prepared as follows 4-(3,4-lupetazin-1-yl) ethyl benzoate as raw material:

With 1, (2.284g, 20.00mmol) (1.467ml 10mmol) is dissolved in DMA (12ml) and being sealed in the microwave tube to the 2-lupetazin with the 4-ethyl fluoro benzoate.Reaction mixture is heated to 150 ℃ and kept 90 minutes in microwave reactor, is cooled to room temperature.Reaction mixture 150 ℃ of following reheat 30 minutes, is cooled to room temperature.Evaporation reaction mixture, crude product are through purification by silica gel column chromatography, with the 5%MeOH/DCM wash-out that contains 0.1%0.880 ammonia.Each pure level divided be evaporated to driedly, obtain 4-(3, the 4-lupetazin-1-yl) ethyl benzoate (0.853g, 32.5%) of colourless wax shape solid form.

1H?NMR(399.9MHz，CDCl3)δ1.14(3H，d)，1.37(3H，t)，2.20-2.25(1H，m)，2.33(3H，s)，2.34-2.41(1H，m)，2.62(1H，t)，2.87-2.91(1H，m)，2.99-3.05(1H，m)，3.57-3.62(1H，m)，3.65-3.70(1H，m)，4.33(2H，q)，6.83-6.87(2H，m)，7.90-7.94(2H，m).MS：m/z?263.

Adopt the method among the embodiment 100 to prepare 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine as raw material.

Embodiment 102

4-[5-[[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] formamyl] thiophene-2-yl] piperazine-1-t-butyl formate

Under 20 ℃, nitrogen atmosphere with the toluene solution (1.250ml of 2M trimethylaluminium; 2.50mmol) drop to 4-(5-(methoxycarbonyl) thiophene-2-yl) piperazine-1-t-butyl formate (0.326g that is stirring; 1mmol) and 5-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.247g is 1.00mmol) in the solution in toluene (7.14ml) for 2H-pyrazoles-3-amine.Reaction mixture stirred 20 hours down at 20 ℃.Temperature is increased to 60 ℃, reaction mixture was stirred 20 hours, with its cooling of relief.Reaction mixture is with acetone (10ml) dilution, with moist sodium sulphite quencher.Mixture was stirred 30 minutes, add 10% methyl alcohol/DCM (10mL) subsequently, with this mixture restir 30 minutes.Filtering suspension liquid, solid washs with 10% methyl alcohol/DCM (20mL); The filtrating that evaporation merges obtains yellow foam.Crude product is through purification by silica gel column chromatography, with 1-10% methyl alcohol (containing 2M ammonia)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain crude product.Crude product is further purified through preparation HPLC, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain 4-[5-[[5-[2-(3, the 5-Dimethoxyphenyl) the ethyl]-2H-pyrazole-3-yl] formamyl] thiophene-2-yl] piperazine-1-t-butyl formate (0.272g, 50.2%) of white dry film form.

1H?NMR(500.13MHz，DMSO-d6)δ1.46(9H，s)，2.89-2.90(6H，m)，3.22(4H，t)，3.52(4H，t)，3.75(6H，s)，6.18(1H，d)，6.27(1H，s)，6.34(1H，t)，6.42-6.42(2H，m)，7.72(1H，d)，9.81(1H，s)，11.71(1H，s)；MS：m/z?542(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.028 μ M

Be prepared as follows 4-(5-(methoxycarbonyl) thiophene-2-yl) piperazine-1-t-butyl formate as raw material:

Diethyl ether solution (0.525ml with 2.0M (trimethyl silyl) diazomethane; 1.05mmol) drop to 5-[4-[(2-methylpropane-2-yl) the oxygen base carbonyl] piperazine-1-yl] thiophene-2-carboxylic acid (0.312g that is stirring; 1mmol) in the solution in methyl alcohol (2.000ml), mixture was stirred 20 hours at ambient temperature.(0.500ml 1.00mmol), stirs mixture 2 hours to add the diethyl ether solution of more 2.0M (trimethyl silyl) diazomethane.Evaporating mixture, crude product are used the 1-3%EtOAc/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain the required compound (0.141g, 43.2%) of Off-white solid form.

1H?NMR(399.9MHz，CDCl3)δ1.48(9H，s)，3.22(4H，t)，3.58(4H，t)，3.82(3H，s)，6.06(1H，d)，7.55(1H，d).MS：m/z?327(MH+)

Thiophene-2-carboxylic acid can be according to document (Stokes, Elaine Sophie Elizabeth as the 5-[4-[(2-methylpropane-2-yl) oxygen base carbonyl] piperazine-1-yl] of raw material; Waring, MichaelJames; Gibson, Keith Hopkinson, Preparation of amides as inhibitors ofhistone deacetylase (as the preparation of the acid amides of histone deacetylase inhibitors), the method preparation of describing in WO2003/092686).

Embodiment 103

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(1-methyl piperidine-4-yl) BM

[5-[(3 for N-; The 5-Dimethoxyphenyl) methoxyl group]-the 2H-pyrazole-3-yl]-4-(1-methyl piperidine-4-yl) BM prepares according to the method described in the embodiment 159; But raw materials used be 4-(1-methyl piperidine-4-yl) oil of Niobe (0.25g, 1.07mmol), 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (0.267g; 1.07mmol) and the toluene solution of 2M trimethylaluminium (2.14ml, 4.29mmol).Crude product (contains 2.5M NH through purification by silica gel column chromatography with 0-8%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, be dissolved in DCM again, grind and be evaporated to dried with ether, obtain the title compound (0.225g, 46.5%) of white solid.

1HNMR(399.9MHz，DMSO-d6)δ1.69(1H，d)，1.73(2H，d)，1.77(1H，s)，1.95-2.02(2H，m)，2.21(3H，s)，2.88(2H，d)，3.76(6H，s)，5.09(2H，s)，5.62(1H，s)，6.45(1H，s)，6.60(2H，s)，7.41-7.42(2H，m)，7.89-7.91(2H，m)，10.85(1H，s)，11.58(1H，s).MS：m/z?451(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00094 μ M

Under nitrogen atmosphere with water (0.4ml), Paraformaldehyde 96 (0.742g; 24.71mmol) and acetate (1.415ml; 24.71mmol) (1.58g is 6.18mmol) in the suspension-s in THF (40ml) to add to the 4-piperidines-1-base-4-yl benzoic acid methyl esters muriate that is stirring.Through added in 10 minutes in batches sodium cyanoborohydride (0.582g, 9.27mmol).The mixture that obtains was stirred 18 hours down at 60 ℃.Reaction mixture is evaporated to dry doubling to be mixed with water (30ml) and 1M HCl (10ml).Solution is with ETHYLE ACETATE (2x 25ml) washing, with solid carbonic acid potashization, and extracts with ETHYLE ACETATE (2x 25ml).With the washing of organic layer saturated brine, through dried over mgso, filter and evaporation, obtain pure 4-(1-methyl piperidine-4-yl) oil of Niobe (0.784g, 54.4%) of colorless oil, this oily matter leaves standstill after fixing.

1H?NMR(399.9MHz，DMSO-d6)δ1.62-1.71(2H，m)，1.72-1.74(2H，m)，1.95-2.02(2H，m)，2.21(3H，s)，2.54-2.59(1H，m)，2.88(2H，d)，3.85(3H，s)，7.39-7.42(2H，m)，7.88-7.91(2H，m).MS：m/z?234(MH+).

Embodiment 104

4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM

4-(3,4,6,7; 8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM prepares according to the method described in the embodiment 159; But raw materials used is 4-(3,4,6,7; 8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) oil of Niobe (0.25g, 0.96mmol), 5-[(3; The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (0.239g, 0.96mmol) with the toluene solution of 2M trimethylaluminium (1.2ml, 2.4mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.124g, 27%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.37-1.44(1H，m)，1.67-1.74(2H，m)，1.83-1.89(1H，m)，1.99-2.04(1H，m)，2.08(1H，q)，2.18-2.25(1H，m)，2.82-2.89(1H，m)，3.01-3.06(2H，m)，3.75(6H，s)，3.85(1H，d)，3.99-4.02(1H，m)，5.08(2H，s)，5.57(1H，s)，6.44(1H，s)，6.59-6.60(2H，m)，7.04(2H，d)，7.85(2H，d)，10.61(1H，s)，11.49(1H，s).MS：m/z478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0013 μ M

Under nitrogen atmosphere with 4-iodo-benzoic acid methyl esters (2.076g, 7.92mmol), cesium carbonate (5.16g, 15.85mmol), the 2-acetyl cyclohexanone (0.209ml, 1.58mmol) and cupric iodide (I) (0.075g; 0.40mmol) add to stirring 1,2,3,4; 6,7,8; (1g is 7.92mmol) in the solution in DMF (20ml) for 8a-octahydro pyrrolo-[1,2-a] pyrazine.The suspension-s that obtains was stirred 20 hours down at 90 ℃.Reaction mixture is evaporated to the mixture that dry doubling is dissolved in methyl alcohol and water again.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 3.5M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains brown gelationus 4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) oil of Niobe (1.243g, 60.2%).

1H?NMR(399.9MHz，DMSO-d6)δ1.33-1.43(1H，m)，1.57-1.79(3H，m)，1.81-1.89(1H，m)，1.99-2.03(1H，m)，2.07(1H，q)，2.16-2.23(1H，m)，2.56(1H，t)，2.83-2.95(2H，m)，3.00-3.05(2H，m)，3.06-3.09(1H，m)，3.75-3.78(3H，m)，3.86(1H，t)，3.98-4.01(1H，m)，6.98-7.02(2H，m)，7.77-7.80(2H，m).MS：m/z?261(MH+).

Embodiment 105

5-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with 2,3,4; 6,7,8; 9,9a-octahydro-1H-pyrido [1,2-a] pyrazine (477mg; 3.40mmol) disposable add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in anhydrous dimethyl sulphoxide (1.70ml) (659mg, 1.70mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the polar compound that uses decrescence water (containing 1% formic acid) and MeCN is as eluent.Make subsequently sample through alkaline HPLC system to obtain free alkali.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (395mg, 47%) of Off-white solid form.

1H?NMR(500.133MHz，DMSO)δ1.19-1.35(3H，m)，1.51-1.60(1H，m)，1.64(1H，t)，1.73-1.79(1H，m)，1.93-2.08(2H，m)，2.17-2.25(1H，m)，2.73(1H，dd)，2.81-2.93(6H，m)，3.13(1H，td)，3.73(6H，s)，4.28-4.33(1H，m)，4.37-4.42(1H，m)，6.32(1H，t)，6.38-6.41(3H，m)，8.26(1H，d)，8.70(1H，d)，9.59(1H，br?s)，11.82(1H，br?s).MS：m/z?492(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.13 μ M

Be prepared as follows 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide as raw material:

At ambient temperature with trimethylaluminium (2M toluene solution; 9.64ml; 19.28mmol) [2-(3 to drop to the 5-that is stirring; The 5-Dimethoxyphenyl) ethyl]-(1.91g, 7.71mmol) (1.33g is 7.71mmol) in the suspension-s in dry toluene (38.6ml) with 5-chloropyrazine-2-methyl-formiate for 2H-pyrazoles-3-amine.Subsequently under nitrogen atmosphere, envrionment temperature with gained solution stirring 18 hours.Therefore react incomplete, temperature is increased to 60 ℃, reaction mixture restir 3 hours.Reaction mixture is with methyl alcohol (10ml) and HCl (the 2M aqueous solution) quencher.Dilute this mixture with EtOAc (100ml) and water (250ml), with HCl (the 2N aqueous solution) acidifying.Remove organic layer, water layer is further used EtOAc (2x100ml) extraction.The organic layer water (200ml) that merges, salt solution (200ml) washing, through dried over mgso, concentrating under reduced pressure.Form deposition in case concentrate the back.Filter collecting precipitation, with MeOH (10ml) washing and air-dry, obtain the required compound (1.88g, 63%) of yellow solid shape, it need not to be further purified and can use.

1H?NMR(399.9MHz，DMSO-d ₆)δ2.88-2.89(4H，m)，3.73(6H，s)，6.33(1H，t)，6.43(2H，d)，6.49(1H，s)，8.93(1H，s)，9.09(1H，s)，10.44(1H，s)，12.31(1H，s).MS：m/z?388(MH+).

Embodiment 106

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxamide derivatives

Under 20 ℃, nitrogen atmosphere with the toluene solution (1.250ml of 2M trimethylaluminium; 2.50mmol) drop to 5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxylic acid ethyl ester (0.254g that is stirring; 1mmol) and 5-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.247g is 1.00mmol) in the solution in toluene (7.14ml) for 2H-pyrazoles-3-amine.Reaction mixture was stirred 16 hours at ambient temperature, heated 24 hours down at 65 ℃ subsequently.(5mL) adds to reaction mixture with ETHYLE ACETATE, adds sodium tartrate potassium solution (5mL, 20% aqueous solution) subsequently.Add more ETHYLE ACETATE (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel and removes water layer.Ethyl acetate layer washs with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains the crude product of yellow solid form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.154g, 33.8%) of white solid.

1H?NMR(500.13MHz，DMSO-d6，CD3CO2D)δ2.32(3H，d)，2.58(4H，t)，2.88(4H，s)，3.26(4H，t)，3.73(3H，s)，3.74(3H，s)，6.13(1H，d)，6.25(1H，s)，6.32(1H，d)，6.40(2H，d)，7.68-7.69(1H，m)；MS：m/z?456(MH+)

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.001 μ M

Be prepared as follows 5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

Under 20 ℃, nitrogen atmosphere with acid chloride (II) (0.225g; 1.00mmol) add to 5-bromothiophene-2-ethyl formate in toluene (100ml) (2.351g, 10mmol), the 1-N-METHYL PIPERAZINE (1.331ml, 12.00mmol), racemize-2; 2 '-two (diphenylphosphino)-1; 1 '-dinaphthalene (0.623g, 1.00mmol) and cesium carbonate (4.56g, 14.00mmol).The suspension-s that obtains was stirred 23 hours down at 110 ℃.Mixture is through the Celite diatomite filtration and filtrating is evaporated to dried, obtains brown oil.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the crude product of brown jelly form.This material is further through purification by silica gel column chromatography, with 0-3% methyl alcohol/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain orange buttery required compound (1.380g, 54.3%).

1H?NMR(399.9MHz，CDCl3)δ1.33(3H，t)，2.34(3H，s)，2.54(4H，t)，3.28(4H，t)，4.28(2H，q)，6.02(1H，d)，7.55(1H，d)；MS：m/z?255(MH+)

Embodiment 107

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxamide derivatives

Under 20 ℃, nitrogen atmosphere with the toluene solution (1.250ml of 2M trimethylaluminium; 2.50mmol) drop to 5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxylic acid ethyl ester (0.254g that is stirring; 1mmol) and 5-[(3; The 5-Dimethoxyphenyl) methoxyl group]-(0.286g is 1.00mmol) in the solution in toluene (7.14ml) for 2H-pyrazoles-3-amine hydrochlorate.Reaction mixture at room temperature stirred 18 hours, heated 6 hours down at 65 ℃ subsequently.(5mL) adds to reaction mixture with ETHYLE ACETATE, adds sodium tartrate potassium solution (5mL, 20% aqueous solution) subsequently.Add more ETHYLE ACETATE (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel and removes water layer.Ethyl acetate layer washs with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains the crude product of yellow solid form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.147g, 32.1%) of white solid.

1H?NMR(500.13MHz，DMSO-d6，CD3CO2D)δ2.29(3H，s)，2.53-2.55(4H，m)，3.25-3.28(4H，m)，3.77(6H，s)，5.09(2H，s)，5.63(1H，s)，6.16(1H，d)，6.45(1H，t)，6.60(2H，d)，7.64(1H，d)；MS：m/z?458(MH+)

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0011 μ M

According to 5-(4-N-METHYL PIPERAZINE-1-yl) the thiophene-2-carboxylic acid ethyl ester of the preparation of the method described in the embodiment 106 as raw material.

Embodiment 108

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3,3-lupetazin-1-yl) pyrazine-2-methane amide

Under 25 ℃ with 2, the 2-lupetazin (343mg, 3.00mmol) disposable add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in anhydrous dimethyl sulphoxide (1.00ml) (388mg, 1mmol).The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post, uses 7MNH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (217mg, 47%) of yellow solid shape.

1H?NMR(399.9MHz，DMSO-d6)δ1.06(6H，s)，2.04(1H，s)，2.82-2.88(6H，m)，3.51(2H，s)，3.65(2H，t)，3.72(6H，s)，6.33(1H，t)，6.42(2H，d)，6.46(1H，s)，8.32(1H，s)，8.66(1H，s)，9.71(1H，s)，12.17(1H，s).MS：m/z?466(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.002 μ M

Prepare 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide according to the method shown in the embodiment 105.

Embodiment 109

5-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide

[5-[(3 with 5-chloro-N-under 25 ℃; The 5-Dimethoxyphenyl) methoxyl group]-the 2H-pyrazole-3-yl] pyrazine-2-methane amide (390mg; 1.00mmol) disposable 1-cyclopropyl piperazine, the 2HCl (398mg that adds in anhydrous dimethyl sulphoxide (1.00ml); 2.00mmol) and N-ethyl-N-propane-2-base propane-2-amine (and 0.52ml, 3.00mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-10%MeOH ₃)/DCM gradient elution.The branches at different levels that will contain required product are evaporated to dried, obtain yellow solid.This solid is placed DCM and and Et ₂O grinds, and obtains solid, filters and collects this solid, and vacuum-drying obtains the title compound (130mg, 27%) of yellow solid shape.

1H?NMR(399.9MHz，DMSO-d6)δ0.38-0.40(2H，m)，0.45-0.49(2H，m)，1.66-1.70(1H，m)，2.66(4H，t)，3.71(4H，t)，3.75(6H，s)，5.08(2H，s)，5.84(1H，s)，6.45(1H，s)，6.59(2H，s)，8.33(1H，s)，8.72(1H，s)，10.80(1H，s)，11.35(1H，s).MS：m/z?480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.003 μ M

Be prepared as follows 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide as raw material:

At ambient temperature with the trimethylaluminium (toluene solution of 2M; 7.44ml; 14.88mmol) drop to the 5-[(3 that is stirring; The 5-Dimethoxyphenyl) methoxyl group]-(1.70g, 5.95mmol) (1.03g is 5.95mmol) in the suspension-s in dry toluene (29.8ml) with 5-chloropyrazine-2-methyl-formiate for 2H-pyrazoles-3-amine hydrochlorate.Subsequently under nitrogen atmosphere, envrionment temperature with the solution stirring that obtains 18 hours.Reaction mixture is with methyl alcohol (5ml) and HCl (the 2M aqueous solution) quencher, and water (200ml) dilutes and extracts with EtOAc (3x150ml).Organic phase, is filtered and is concentrated through dried over mgso through water (200ml), salt solution (200ml) washing.After the evaporation, form deposition, filter to collect and be somebody's turn to do deposition, with MeOH (20ml) washing and air-dry, obtain the required compound (1.65g, 71%) of orange solids shape, it need not to be further purified and can use.

1H?NMR(500.13MHz，DMSO-d6，373K)δ3.78(6H，s)，5.12(2H，s)，5.94(1H，s)，6.46(1H，s)，6.62(2H，s)，8.87(1H，s)，9.09(1H，s)，10.99(1H，s)，11.24(1H，s).MS：m/z?390(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.060 μ M

Embodiment 110

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] BM

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,4; 5-tri methyl piperazine-1-yl] BM is according to the preparation of the method for embodiment 100, but raw materials used be 4-((3R, 5S)-3; 4,5-tri methyl piperazine-1-yl) ethyl benzoate (0.276g, 1.00mmol) and 5-[(3; The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (0.249g, 1mmol) with the toluene solution of 2M trimethylaluminium (1.25ml, 2.5mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1% NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.027g, 5.63%) of white solid.

1HNMR(500.133MHz，DMSO-d6+CD3COOD)δ：1.13(6H，d)，2.31(3H，s)，2.60-2.68(2H，m)，3.19(2H，s)，3.70(1H，s)，3.65(6H，s)，5.08(2H，s)，5.68(1H，s)，6.40-6.44(1H，m)，6.58(2H，s)，6.97(2H，d)，7.82(2H，d).MS：m/z?480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00068 μ M

Be prepared as follows as the 4-of raw material ((3R, 5S)-3,4,5-tri methyl piperazine-1-yl) ethyl benzoate:

Under nitrogen atmosphere through 45 minutes with titanium isopropylate (IV) (2.99ml; 10.00mmol) add to 4-in the ethanol that is warmed to 60 ℃ (25ml) ((3R, 5S)-3,5-lupetazin-1-yl) ethyl benzoate (1.312g; 5.00mmol) and formaldehyde (0.601g, 20.00mmol) in.The solution that obtains is cooled to 20 ℃, and (0.473g 12.50mmol), stirs suspension-s 18 hours down at 60 ℃ disposable adding Peng Qinghuana.React with ammonia (2ml) quencher.The filtering solid also washs with 10%MeOH/DCM (2x50ml).Organic layer is evaporated to dried, crude product is through purification by silica gel column chromatography, with the 0-5%MeOH/DCM gradient elution that contains 0.1% ammonia.Branches at different levels are evaporated to dried, obtain oily matter.This oily matter is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the required compound (0.320g, 23.16%) of white crystalline solid shape.

1H?NMR(399.9MHz，CDCl3)δ1.11(6H，d)，1.29(3H，t)，2.24(3H，s)，2.25-2.30(2H，m)，2.59(1H，d)，2.62(1H，d)，3.53-3.57(2H，m)，4.26(2H，q)，6.75-6.79(2H，m)，7.82-7.86(2H，m).MS：m/z?277(MH+).

Embodiment 111

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,3-lupetazin-1-yl) BM

Under 20 ℃, nitrogen atmosphere through 5 minutes toluene solution (0.691ml with the 2M trimethylaluminium; 1.38mmol) drop to the 4-(3 that is stirring; 3-lupetazin-1-yl) ethyl benzoate (145mg; 0.55mmol) and 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (138mg is 0.55mmol) in the solution in toluene (5ml).The solution that obtains was stirred 24 hours down at 20 ℃.(25ml) dilutes and adds the sodium sulphite of excessive humidity with acetone.Mixture was stirred 1 hour and the filtering solid.Solid washs with 10%MeOH/DCM, will merge organic layer and be evaporated to dried.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (27.0mg, 10.49%) of colourless jelly form.

1HNMR(500.13MHz，DMSO-d6373K)δ：1.11(6H，s)，2.85-2.91(2H，m)，3.03(2H，s)，3.18-3.22(2H，m)，3.78(6H，s)，5.09(2H，s)，5.62(1H，s)，6.44(1H，t)，6.60(2H，s)，6.92(2H，d)，7.82(2H，d)，10.19(1H，s)，11.12(1H，s).MS：m/z?466(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00076 μ M

Be prepared as follows 4-(3,3-lupetazin-1-yl) ethyl benzoate as raw material:

(0.151ml, 1mmol), 2, (0.137g, 1.20mmol) (0.349ml 2.00mmol) is dissolved in DMA (2ml) and being sealed in the microwave tube to the 2-lupetazin with N-ethyl-N-propane-2-base propane-2-amine with the 4-ethyl fluoro benzoate.Reaction mixture is heated to 200 ℃ and kept 4 hours in microwave reactor, is cooled to room temperature.Crude mixture carries out the ion exchange chromatography purifying through the SCX post.Use 3.5M ammonia/methyl alcohol with required product wash-out from post, branches at different levels are evaporated to dried, obtain oily matter.Crude product is through purification by silica gel column chromatography, with 0-10% MeOH (containing 2M ammonia)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 4-(3, the 3-lupetazin-1-yl) ethyl benzoate (0.145g, 55.3%) of white solid.

1HNMR(399.9MHz，CDCl3)δ1.15(6H，d)，1.37(3H，t)，2.38(1H，d)，2.41(1H，d)，2.96-3.04(2H，m)，3.65-3.69(2H，m)，4.33(2H，q)，6.84-6.87(2H，m)，7.89-7.93(2H，m).MS：m/z266(MH+).

Embodiment 112

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,5-lupetazin-1-yl] pyrazine-2-methane amide

Following at 25 ℃ with (2S; 6R)-2, (228mg 2.00mmol) disposablely adds to 5-chloro-N-in anhydrous dimethyl sulphoxide (1.00ml) [[2-(3 for 5-the 6-lupetazin; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] pyrazine-2-methane amide (388mg, 1.00mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (164mg, 35%) of Off-white solid form.

1H NMR (399.9MHz, DMSO-d6) δ 1.05-1.06 (6H, d), 2.43-2.50 (2H, m), 2.72-2.78 (2H, m); 2.88 (4H, s), 3.72 (6H, s), 4.39 (2H, d), 6.33 (1H; T), 6.42 (2H, d), 6.46 (1H, s), 8.34 (1H, d); 8.69 (1H, d), 9.73 (1H, s), 12.18 (1H s), does not observe NH.MS:m/z 466 (MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0017 μ M

Prepare 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide according to the method described in the embodiment 105.

Embodiment 113

5-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

[[2-(3 for 5-with 5-chloro-N-under 25 ℃; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] pyrazine-2-methane amide (388mg; 1.00mmol) the disposable 1-cyclopropyl piperazine dihydrochloride (398mg that adds in anhydrous dimethyl sulphoxide (1.00ml); 2.00mmol) and N-ethyl-N-propane-2-base propane-2-amine (and 0.52ml, 3.00mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1% NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (45mg, 9%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d6)δ0.39(2H，t)，0.46-0.48(2H，m)，1.67-1.70(1H，m)，2.66(4H，q)，2.88(4H，s)，3.69-3.72(4H，m)，3.72(6H，s)，6.33(1H，t)，6.42(2H，d)，6.46(1H，s)，8.35(1H，d)，8.71(1H，d)，9.76(1H，s)，12.18(1H，s).MS：m/z?478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0023 μ M

Embodiment 114

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with 1,2,3; 4,6,7; 8,8a-octahydro pyrrolo-[1,2-a] pyrazine (429mg; 3.40mmol) disposable add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in anhydrous dimethyl sulphoxide (1.70ml) (659mg, 1.70mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post, uses 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%TFA) and MeCN decrescence is as eluent.Make this material through alkaline HPLC subsequently, obtain free alkali.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (438mg, 54%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d6)δ1.35-1.45(1H，m)，1.63-1.80(2H，m)，1.82-1.91(1H，m)，1.93-2.01(1H，m)，2.09(1H，q)，2.16-2.20(1H，m)，2.70-2.76(1H，m)，2.88(4H，s)，3.04-3.11(3H，m)，3.72(6H，s)，4.47(1H，d)，4.63(1H，d)，6.33(1H，t)，6.42(2H，d)，6.47(1H，s)，8.36(1H，d)，8.71(1H，d)，9.76(1H，s)，12.18(1H，s).MS：m/z?478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0016 μ M

Embodiment 115

5-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide (585mg, 1.50mmol) disposable add in anhydrous dimethyl sulphoxide (1.50ml) 2,3; 4,6,7; 8,9,9a-octahydro-1H-pyrido [1; 2-a] the pyrazine hydrochloride (530mg, 3.00mmol) with N-ethyl-N-propane-2-base propane-2-amine (1.04ml, 6.00mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (302mg, 41%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d6)δ1.21-1.29(2H，m)，1.49-1.67(1H，m)，1.60-1.64(2H，m)，1.74(1H，d)，1.90(1H，t)，1.93-2.00(1H，m)，2.10-2.17(1H，m)，2.67-2.73(1H，m)，2.82(2H，d)，3.06-3.13(1H，m)，3.75(6H，s)，4.38(1H，d)，4.46(1H，d)，5.08(2H，s)，5.84(1H，s)，6.44(1H，s)，6.59(2H，d)，8.34(1H，s)，8.71(1H，s)，10.79(1H，s)，11.35(1H，s).MS：m/z?494(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0023 μ M

Method according to describing among the embodiment 109 prepares 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide.

Embodiment 116

4-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM

(4-cyclopropyl piperazine-1-yl)-[5-[(3 for N-to prepare 4-according to the method described in the embodiment 100; The 5-Dimethoxyphenyl) methoxyl group]-the 2H-pyrazole-3-yl] BM; Raw material be 4-(4-cyclopropyl piperazine-1-yl) ethyl benzoate (0.329g, 1.2mmol), 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (0.343g; 1.20mmol) and the toluene solution of 2M trimethylaluminium (1.500ml, 3.00mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.022g, 3.84%) of white solid.

1H?NMR(500.13MHz，DMSOd6)δ0.34-0.40(2H，m)，0.45-0.50(2H，m)，1.67-1.75(1H，m)，2.67-2.73(4H，m)，3.24-3.32(4H，m)，3.78(6H，s)，5.08(2H，s)，5.68(1H，s)，6.42-6.46(1H，m)，6.58-6.61(2H，m)，6.95(2H，d)，7.83(2H，d)，10.30(1H，s)，11.01(1H，s).MS：m/z?478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00093 μ M

4-(the 4-cyclopropyl piperazine-1-yl) ethyl benzoate that is used as raw material is according to being used to prepare 4-((3R; 5S)-3; 5-lupetazin-1-yl) method of ethyl benzoate (embodiment 100) preparation; Raw material be in DMSO (15ml) the 4-ethyl fluoro benzoate (0.880ml, 6mmol) with 1-cyclopropyl piperazine (1.666g, 13.20mmol).Crude product is through purification by silica gel column chromatography, with 0-8% MeOH (containing 2.5M ammonia)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the required compound (1.405g, 85%) of beige solid form.

1H?NMR(399.9MHz，CDCl3)δ0.43-0.52(4H，m)，1.34-1.39(3H，m)，1.63-1.68(1H，m)，2.75(4H，t)，3.29(4H，t)，4.32(2H，q)，6.84-6.88(2H，m)，7.90-7.97(2H，m).MS：m/z275(MH+).

Be prepared as follows 1-cyclopropyl piperazine as raw material:

(1.493g 7.5mmol) is dissolved in water (5.00ml) and methyl alcohol (5.00ml), is converted into its free alkali through carrying out ion exchange chromatography with the SCX post with 1-cyclopropyl piperazine dihydrochloride.Use 3.5M ammonia/methyl alcohol with required product wash-out from post, each pure level is divided be evaporated to driedly, obtain buttery 1-cyclopropyl piperazine (0.796g, 84%).

1H?NMR(399.9MHz，CDCl3)δ0.31-0.39(4H，m)，1.51-1.56(1H，m)，1.63-1.67(1H，m)，2.51(4H，s)，2.77(4H，t).

1-cyclopropyl piperazine dihydrochloride is prepared as follows:

(42.7ml, (7.73g is 34.16mmol) in the solution in the mixture of methyl alcohol (50.0ml) and ETHYLE ACETATE (200ml) 170.78mmol) to add to the 4-cyclopropyl piperazine-1-t-butyl formate that is stirring with 4.0M HCl/ diox.Under nitrogen atmosphere, the suspension-s that obtains was at room temperature stirred 24 hours.The filtering white solid obtains 1-cyclopropyl piperazine dihydrochloride (6.30g, 93%).

1H?NMR(399.9MHz，DMSO-d6)δ0.73-0.86(2H，m)，1.07-1.18(2H，m)，2.85-2.99(1H，m)，3.30-3.40(4H，m)，3.52-3.65(4H，m)，9.89(2H，s)，11.99(1H，s).

4-cyclopropyl piperazine-1-t-butyl formate is prepared as follows:

Following at 20 ℃ with sodium cyanoborohydride (4.71g; 75.00mmol) processing piperazine-1-t-butyl formate (9.31g; 50mmol), [(1-oxyethyl group cyclopropyl) oxygen base] trimethyl silane (20.11ml; 100.00mmol) and acetate (14.31ml, 250.00mmol) solution in THF (100ml) and methyl alcohol (10ml).The solution that obtains was stirred 18 hours down at 60 ℃.With the reaction mixture cooling, filter and be evaporated to dried.Add 1N HCl (40ml) and water (60ml), (3x50ml) extracts this solution with ETHYLE ACETATE.Use solid carbonic acid potassium that the water layer acidifying is pH10, extract with ETHYLE ACETATE (4x50ml).Handle organic extract liquid with saturated nacl aqueous solution (50ml),, filter and be evaporated to dried, obtain the 4-cyclopropyl piperazine-1-t-butyl formate (7.73g, 68.3%) of white waxy solid form through dried over mgso.

¹H?NMR(399.9MHz，CDCl3)δ0.33-0.40(4H，m)，1.39(9H，s)，1.52-1.55(1H，m)，2.48(4H，t)，3.31(4H，t).

Embodiment 117

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-methyl-4-oxidation (oxido) piperazine-4--1-yl) BM

At ambient temperature with 3-chloroperoxybenzoic acid (129mg; 0.53mmol) disposablely add to N-in acetone (15ml) [[2-(3 for 5-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM (225mg, 0.50mmol) in.The solution that obtains was stirred 2 hours at ambient temperature.On silica gel, concentrate this reaction mixture, crude product (contains 7M NH through purification by silica gel column chromatography with 0-10%MeOH ₃)/DCM to 100% methyl alcohol gradient elution.Resistates is further purified through carrying out ion exchange chromatography with the SCX post.Use 7MNH ₃/ MeOH is required product wash-out from post, is evaporated to driedly, obtains the title compound (183mg, 79%) of Off-white solid form.

1H?NMR(700.034MHz，DMSO)δ2.85(4H，s)，2.94(2H，d)，3.09(3H，s)，3.44(2H，td)，3.53(2H，td)，3.65(2H，d)，3.70(6H，s)，6.31(1H，t)，6.37(1H，s)，6.40(2H，d)，7.00(2H，d)，7.90(2H，d)，10.37(1H，s)，12.00(1H，s).MS：m/z?466(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0013 μ M

Method according to describing among the embodiment 10 prepares N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM.

Embodiment 118

4-(4-cyclobutyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM

(4-cyclobutyl piperazine-1-yl)-[5-[(3 for N-for 4-; The 5-Dimethoxyphenyl) methoxyl group]-the 2H-pyrazole-3-yl] BM is according to the preparation of the method described in the embodiment 100, and raw material is 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine (0.173g; 0.69mmol), 4-(4-cyclobutyl piperazine-1-yl) ethyl benzoate (0.2g; 0.69mmol) and the toluene solution of 2M trimethylaluminium (1.387ml, 2.77mmol), reaction 20 hours in toluene (10ml) at room temperature.With reaction mixture impouring acetone (20ml), with the sodium-chlor quencher of excessive humidity, filter and evaporation, obtain yellow solid.Add acetonitrile (10ml) and filtration, obtain the title compound (0.079g, 23.17%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.63-1.66(1H，m)，1.67-1.70(1H，m)，1.78-1.89(2H，m)，1.97-2.03(2H，m)，2.38(4H，t)，2.75(1H，t)，3.75(6H，s)，5.08(2H，s)，5.58(1H，s)，6.45(1H，s)，6.60-6.60(2H，m)，7.01(2H，d)，7.86(2H，d)，10.61(1H，s)，11.49(1H，s).MS：m/z?492(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0011 μ M

Be prepared as follows 4-(4-cyclobutyl piperazine-1-yl) ethyl benzoate as raw material:

Under nitrogen atmosphere with the 4-ethyl fluoro benzoate (0.753g, 4.48mmol) add to 1-cyclobutyl piperazine (0.571g, 4.07mmol) and salt of wormwood (0.563g is 4.07mmol) in the solution in DMSO (8ml).The solution that obtains was stirred 18 hours down at 100 ℃, be evaporated to dried.Resistates and ether grind, filter, and evaporation, crude product is through purification by silica gel column chromatography, with 0-2.5%2.5N MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 4-(the 4-cyclobutyl piperazine-1-yl) ethyl benzoate (0.387g, 32.9%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.28-1.32(3H，t)，1.62-1.70(2H，m)，1.77-1.88(2H，m)，1.95-2.04(2H，m)，2.35-2.39(4H，t)，2.70-2.78(1H，m)，3.28-3.32(4H，t)，4.22-4.27(2H，m)，6.96-6.98(2H，d)，7.66-7.80(2H，d).MS：m/z?289(MH+).

Be prepared as follows 1-cyclobutyl piperazine as raw material:

Under nitrogen atmosphere with water (0.15ml), cyclobutanone (1g, 14.27mmol) and acetate (1.742ml, (1.772g is 9.51mmol) in the solution in THF (20ml) 30.44mmol) to add to the piperazine-1-t-butyl formate that is stirring.Through added in 10 minutes in batches sodium cyanoborohydride (0.897g, 14.27mmol).The mixture that obtains was stirred 20 hours down at 60 ℃.Reaction mixture is evaporated to dry doubling to be mixed with water (40ml) and 1M HCl (15ml).This solution is used solid K with EtOAc (2x25ml) washing ₂CO ₃Alkalization also extracts with EtOAc (2x15ml).Wash organic layer with saturated brine,, filter and evaporation, obtain the pure 4-cyclobutyl piperazine-1-t-butyl formate (1.155g, 50.5%) of colorless oil through dried over mgso.

1H?NMR(399.9MHz，DMSO-d6)δ1.40(9H，s)，1.62-1.65(2H，m)，1.75-1.80(2H，m)，1.92-1.98(2H，m)，2.17(4H，t)，2.68(1H，t)，3.28-3.30(4H，s).

(1.669ml 48.07mmol) handles 4-cyclobutyl piperazine-1-t-butyl formate (1.1553g, 4.81mmol) solution in ETHYLE ACETATE (10ml) and methyl alcohol (10.00ml) and stirring 40 hours under room temperature, nitrogen atmosphere with 4M HCl/ dioxane solution.Therefore react incomplete, add 4M HCl/ dioxane solution (10mL), this solution is restir 2 hours at room temperature.Reaction mixture is evaporated to dried, obtains solid.Crude product carries out the ion exchange chromatography purifying through the SCX post, uses 3.5M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the 1-cyclobutyl piperazine (0.571g, 85%) of yellow oily.

1H?NMR(399.9MHz，DMSO-d6)δ1.64(2H，s)，1.74-1.75(2H，m)，1.92(2H，s)，2.14(4H，s)，2.63-2.66(4H，m)，3.18(1H，s).

Embodiment 119

2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

(toluene solution of 2M, 2.15ml 4.30mmol) drop to 5-[(3, the 5-Dimethoxyphenyl) the methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (491mg that is stirring with trimethylaluminium under 25 ℃; 1.72mmol) and 2-(1,3,4,6; 7,8,9; 9a-octahydro pyrido [2,1-c] pyrazine-2-yl) (475mg is 1.72mmol) in the suspension-s in toluene (8.6ml) for pyrimidine-5-methyl-formiate.The solution that obtains stirred 18 hours at ambient temperature, stirred 2 hours down at 60 ℃ subsequently.Also handle with careful this reaction mixture of quencher of methyl alcohol (20ml) with HCl (the 2N aqueous solution is up to the solution that obtains freely stirring).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains crude product with required product wash-out and be evaporated to driedly from post.This impurity is through preparation HPLC purifying, and the mixture that uses polarity water (containing 0.1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (361mg, 43%) of solid-like.

1H?NMR(500.13MHz，DMSO-d6，373K)δ1.21-1.27(1H，m)，1.28-1.35(1H，m)，1.52-1.59(1H，m)，1.59-1.64(2H，m)，1.76(1H，d)，1.85-1.91(1H，m)，1.98-2.03(1H，m)，2.10-2.15(1H，m)，2.68-2.73(1H，m)，2.80-2.84(2H，m)，3.08-3.13(1H，m)，3.78(6H，s)，4.57-4.61(1H，m)，4.67-4.71(1H，m)，5.11(2H，s)，5.70(1H，s)，6.46(1H，t)，6.62(2H，d)，8.86(2H，s)，10.30(1H，s)，11.30(1H，s).MS：m/z?494(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0033 μ M

Method according to describing among the embodiment 127 prepares 2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl) pyrimidine-5-methyl-formiate.

Method according to describing among the embodiment 12 prepares 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate.

Embodiment 120

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] thiophene-2-carboxamide derivatives

(1.525ml 3.05mmol) drops to the 5-(3,4 that is stirring with the toluene solution of 2M trimethylaluminium under 20 ℃, nitrogen atmosphere; 6,7,8; 8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) the thiophene-2-carboxylic acid ethyl ester (0.342g, 1.22mmol) and 5-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.302g is 1.22mmol) in the solution in toluene (8.71ml) for 2H-pyrazoles-3-amine.Reaction mixture stirred 18 hours at ambient temperature, subsequently 65 ℃ of following stirring heating 20 hours.In this reaction mixture, carefully add ETHYLE ACETATE (5mL), add sodium tartrate potassium solution (5mL, 20% aqueous solution) subsequently.Add more ETHYLE ACETATE (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel and removes water layer.Wash ethyl acetate layer with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains the crude product of 640mg yellow jelly form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%TFA) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the tfa salt of said product.It is dissolved in methyl alcohol and through carrying out the ion exchange chromatography purifying with the SCX2 post.Use 2M NH ₃/ methyl alcohol is required product wash-out from post, each pure level divided be evaporated to driedly, grinds with acetonitrile subsequently, obtains the title compound (0.174g, 29.6%) of solid-like.

1H?NMR(500.13MHz，DMSO-d6，CD3CO2D)δ1.41-1.43(1H，m)，1.73-1.78(2H，m)，1.87-1.91(2H，m)，2.16-2.23(2H，m)，2.34-2.38(1H，m)，2.68-2.72(1H，m)，2.89(4H，s)，3.00-3.08(3H，m)，3.50-3.53(1H，m)，3.66-3.69(1H，m)，3.74(6H，d)，6.12(1H，d)，6.25(1H，s)，6.33(1H，t)，6.41(2H，d)，7.70(1H，t)；MS：m/z?482(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00098 μ M

Be prepared as follows 5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

Under 20 ℃, nitrogen atmosphere with acid chloride (II) (0.112g, 0.50mmol) add to 5-bromothiophene-2-ethyl formate in toluene (50.0ml) (1.175g, 5mmol), 1,2; 3,4,6,7; 8, and 8a-octahydro pyrrolo-[1,2-a] pyrazine (0.631g, 5.00mmol), racemize-2; 2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (0.311g, 0.50mmol) and cesium carbonate (2.281g, 7.00mmol).The suspension-s that obtains was stirred 23 hours down at 110 ℃.Mixture is through the Celite diatomite filtration, with the ETHYLE ACETATE washing and filtrating is evaporated to dried, obtains brown oil.Crude product is through carrying out the ion exchange chromatography purifying with the SCX2 post.Thick substance dissolves in methyl alcohol, is loaded on the post subsequently.Use 2M NH ₃/ methyl alcohol is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the crude product of brown solid shape.This material is used the 0-4%MeOH/DCM gradient elution further through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain the required compound (0.727g, 51.9%) of white solid.

1H?NMR(399.9MHz，CDCl3)δ1.33(3H，t)，1.43-1.53(1H，m)，1.63(1H，s)，1.73-1.93(3H，m)，2.10-2.22(2H，m)，2.33-2.40(1H，m)，2.74(1H，t)，3.07-3.16(3H，m)，3.51-3.55(1H，m)，3.67-3.71(1H，m)，4.28(2H，q)，6.01(1H，d)，7.55(1H，d)

Embodiment 121

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] thiophene-2-carboxamide derivatives

(1.525ml 3.05mmol) drops to the 5-(3,4 that is stirring with the toluene solution of 2M trimethylaluminium under 20 ℃, nitrogen atmosphere; 6,7,8; 8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) the thiophene-2-carboxylic acid ethyl ester (0.342g, 1.22mmol) and 5-[(3; The 5-Dimethoxyphenyl) methoxyl group]-(0.304g is 1.22mmol) in the solution in toluene (8.71ml) for 2H-pyrazoles-3-amine.Reaction mixture was at room temperature stirred 18 hours, heated 6 hours down at 65 ℃ subsequently.(5mL) adds to this reaction mixture with ETHYLE ACETATE, adds sodium tartrate potassium solution (5mL, 20% aqueous solution) subsequently.Add more ETHYLE ACETATE (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel and removes water layer.Ethyl acetate layer washs with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains the crude product of yellow jelly form.Crude product is through preparation LCMS purifying, and the mixture that uses polarity water (containing 1%TFA) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the tfa salt of product.It is dissolved in methyl alcohol and through carrying out the ion exchange chromatography purifying with the SCX2 post.Use 2M NH ₃/ methyl alcohol is required product wash-out from post, each pure level divided be evaporated to driedly, grinds with ether subsequently, obtains the title compound (0.266g, 45.1%) of white solid.

1H?NMR(500.13MHz，DMSO-d6，CD3CO2D)δ1.40-1.44(1H，m)，1.72-1.80(2H，m)，1.85-1.90(2H，m)，2.17-2.22(2H，m)，2.34-2.39(1H，m)，2.73(1H，t)，3.03-3.09(3H，m)，3.52-3.54(1H，m)，3.67-3.70(1H，m)，3.77(6H，s)，5.09(2H，s)，5.62(1H，s)，6.16(1H，d)，6.45(1H，t)，6.60(2H，d)，7.64(1H，d)；MS：m/z?484(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00079 μ M

Prepare 5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) thiophene-2-carboxylic acid ethyl ester according to the method described in the embodiment 120.

Embodiment 122

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide (585mg, 1.50mmol) disposable add in anhydrous dimethyl sulphoxide (1.50ml) 1; 2,3,4; 6,7,8; 8a-octahydro pyrrolo-[1,2-a] pyrazine (379mg, 3.00mmol) in.The solution that obtains was stirred 18 hours down at 100 ℃.Resistates carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the not pure products of yellow solid shape.Subsequently with this impurity through silica gel column chromatography repurity, (contain 7M NH with 0-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (269mg, 37%) of yellow solid shape.

1H?NMR(500.133MHz，DMSO，373K)δ1.38-1.46(1H，m)，1.67-1.82(2H，m)，1.85-1.91(1H，m)，2.04-2.10(1H，m)，2.17(1H，q)，2.22-2.29(1H，m)，2.78(1H，dd)，3.02-3.16(3H，m)，3.76(6H，s)，4.41(1H，d)，4.57(1H，d)，5.09(2H，s)，5.85(1H，s)，6.44(1H，s)，6.59(2H，d)，8.26(1H，d)，8.71(1H，s)，10.42(1H，s)，11.13(1H，s).MS：m/z?480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0013 μ M

Prepare 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide according to the method shown in the embodiment 109.

Embodiment 123

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) pyrazine-2-methane amide

[[2-(3 for 5-with 5-chloro-N-under 25 ℃; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] pyrazine-2-methane amide (388mg; 1.00mmol) disposable add in anhydrous dimethyl sulphoxide (2.00ml) 1,2-dimethyl--piperazine (228mg, 2.00mmol) in.The solution that obtains was stirred 2 hours at ambient temperature.Resistates carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-10%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (375mg, 81%) of yellow solid shape.

1H?NMR(399.9MHz，DMSO-d6)δ1.07-1.09(3H，d)，2.06-2.20(2H，m)，2.23(3H，s)，2.76-2.86(2H，m)，2.87(4H，s)，3.13-3.19(1H，m)，3.72(6H，s)，4.27-4.30(2H，m)，6.33(1H，t)，6.42(2H，d)，6.46(1H，s)，8.35(1H，d)，8.70(1H，d)，9.75(1H，s)，12.18(1H，s).MS：m/z?466(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0022 μ M

According to the 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] of preparation shown in the embodiment 105 pyrazine-2-methane amide.

Embodiment 124

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) pyrazine-2-methane amide

[5-[(3 with 5-chloro-N-under 25 ℃; The 5-Dimethoxyphenyl) methoxyl group]-the 2H-pyrazole-3-yl] pyrazine-2-methane amide (390mg; 1.00mmol) disposable add in anhydrous dimethyl sulphoxide (2.00ml) 1,2-dimethyl--piperazine (228mg, 2.00mmol) in.The solution that obtains stirred 2 hours at ambient temperature.Resistates carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-10%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (392mg, 84%) of yellow solid shape.

1H?NMR(399.902MHz，DMSO)δ1.08(3H，d)，2.06-2.12(1H，m)，2.18(1H，td)，2.23(3H，s)，2.77-2.88(2H，m)，3.14-3.21(1H，m)，3.75(6H，s)，4.32(2H，t)，5.08(2H，s)，5.84(1H，s)，6.44(1H，t)，6.59(2H，d)，8.34(1H，s)，8.71(1H，s)，10.79(1H，s)，11.35(1H，s).MS：m/z468(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0015 μ M

Embodiment 125

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] pyrazine-2-methane amide

Under 25 ℃ with 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide (271mg, 0.70mmol) disposable 3: the 1 (2R that adds in anhydrous dimethyl sulphoxide (1.40ml); 6S)-1; 2,6-tri methyl piperazine and 2-[(2S, 6R)-2; 6-lupetazin-1-yl] (180mg is in mixture 1.40mmol) for acetonitrile.The solution that obtains stirred 2 hours at ambient temperature.React incomplete, (0.24ml, 1.40mmol), solution was 60 ℃ of following restir 2 hours to add N-ethyl-N-propane-2-base propane-2-amine.Reaction mixture carries out the ion exchange chromatography purifying with methyl alcohol (20ml) dilution and through the SCX post.Use 7MNH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (246mg, 73%) of yellow solid shape.

1H?NMR(399.9MHz，DMSO-d6)δ1.10-1.12(6H，d)，2.15-2.21(2H，m)，2.20(3H，s)，2.75(2H，t)，2.88(4H，s)，3.72(6H，s)，4.37(2H，d)，6.33(1H，s)，6.42-6.43(2H，m)，6.46(1H，s)，8.37(1H，s)，8.70(1H，s)，9.75(1H，s)，12.18(1H，s).MS：m/z?480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0017 μ M

As raw material (2R, 6S)-1,2,3: 1 mixture of 6-tri methyl piperazine and 2-[(2S, 6R)-2,6-lupetazin-1-yl] acetonitrile is prepared as follows:

Under 25 ℃ with macropore triethyl ammonium methylated polystyrene cyanic acid hydroborate (2.31mmol/g; 5.05g; 11.67mmol) add to suitable-3 in methyl alcohol (9.33ml), and 5-dimethyl--piperazine-1-t-butyl formate (1.00g, 4.67mmol), 37% formalin (6.99ml; 93.33mmol) and acetate (0.53ml, 9.33mmol) in.Under nitrogen atmosphere, the suspension-s that obtains was stirred 24 hours at ambient temperature.Remove by filter macropore triethyl ammonium methylated polystyrene cyanic acid hydroborate, wash with methyl alcohol (50ml).Filtrating is carried out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is with required product wash-out and be evaporated to dried from post.

Resistates is dissolved in ETHYLE ACETATE (21.00ml) and the methyl alcohol (10.00ml), and (4.21ml 16.84mmol) handles for 1 of 4M, 4-dioxane solution with hydrogenchloride under 25 ℃, nitrogen atmosphere.The solution that obtains stirred 3 days at ambient temperature.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, be evaporated to dried, obtain 3: 1 (2R, 6S)-1,2,6-tri methyl piperazine and 2-[(2S, 6R)-2,6-N-METHYL PIPERAZINE-1-yl] acetonitrile (645mg, the mixture of colorless oil quantitatively).It need not to be further purified and can directly use.

Embodiment 126

2-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

Under 25 ℃ with the trimethylaluminium (toluene solution of 2M; 1.92ml; 3.85mmol) [2-(3 to drop to the 5-that is stirring; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (381mg, 1.54mmol) and 2-(4-cyclopropyl piperazine-1-yl) pyrimidine-5-methyl-formiate (404mg is 1.54mmol) in the suspension-s in toluene (7.7ml).The solution that obtains was stirred 18 hours at ambient temperature, heated 2 hours down at 60 ℃ subsequently.Reaction mixture is handled with HCl (the 2N aqueous solution) with methyl alcohol (20ml) quencher.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 0.1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (100mg, 14%) of solid-like.

1H?NMR(399.9MHz，DMSO-d6)δ0.36-0.41(2H，m)，0.45-0.47(2H，m)，1.65-1.68(1H，m)，2.61(4H，t)，2.88(4H，s)，3.72(6H，s)，3.80(4H，t)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，8.90(2H，s)，10.60(1H，s)，12.14(1H，s).MS：m/z?478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0036 μ M

2-(4-cyclopropyl piperazine-1-yl) pyrimidine-5-methyl-formiate as raw material is prepared as follows:

Under room temperature, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (900mg; 5.22mmol) solution in methylene dichloride (7.50ml) adds to the 1-cyclopropyl piperazine dihydrochloride (1038mg that is stirring; 5.22mmol) and N-ethyl-N-propane-propane-(4.10ml is 23.47mmol) in the solution in methylene dichloride (13ml) for 2-amine for the 2-base.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is poured on the ice (100ml), and with methylene dichloride (3x75ml) extraction, organic layer filters and evaporation through dried over mgso, obtains white solid.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the required compound (880mg, 64%) of white solid.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ0.36-0.39(2H，m)，0.45-0.47(2H，m)，1.65-1.68(1H，m)，2.61(4H，t)，3.81(3H，s)，3.81-3.84(4H，t)，8.79(2H，s).MS：m/z?263(MH+).

Embodiment 127

2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

(toluene solution of 2M, 1.45ml 2.90mmol) drop to 5-[2-(3, the 5-Dimethoxyphenyl) the ethyl]-2H-pyrazoles-3-amine (286mg that is stirring with trimethylaluminium under 25 ℃; 1.16mmol) and 2-(1,3,4,6; 7,8,9; 9a-octahydro pyrido [2,1-c] pyrazine-2-yl) (320mg is 1.16mmol) in the suspension-s in toluene (5.8ml) for pyrimidine-5-methyl-formiate.The solution that obtains stirred 18 hours at ambient temperature, stirred 2 hours down at 60 ℃ subsequently.Reaction mixture is also handled with HCl (the 2N aqueous solution is up to the solution that obtains freely stirring) with methyl alcohol (20ml) quencher.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 0.1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (238mg, 42%) of solid-like.

1H?NMR(399.9MHz，DMSO-d6)δ1.14-1.32(2H，m)，1.46-1.55(1H，m)，1.61(2H，d)，1.73(1H，d)，1.80-1.83(1H，m)，1.92-1.99(1H，m)，2.03-2.10(1H，m)，2.64-2.70(1H，m)，2.79(2H，d)，2.88(4H，s)，3.02-3.09(1H，m)，3.72(6H，s)，4.55-4.59(1H，m)，4.65-4.68(1H，m)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，8.89(2H，s)，10.59(1H，s)，12.15(1H，s).MS：m/z?492(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0029 μ M

2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl) pyrimidine-5-methyl-formiate as raw material is prepared as follows:

Under room temperature, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (900mg, 5.22mmol) solution in methylene dichloride (7.50ml) add to stirring 2,3; 4,6,7; 8,9,9a-octahydro-1H-pyrido [1; 2-a] (1106mg is 6.26mmol) with N-ethyl-N-propane-propane-(3.19ml is 18.25mmol) in the suspension-s in methylene dichloride (13.00ml) for 2-amine for the 2-base for the pyrazine hydrochloride.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is poured on the ice (50ml), and with DCM (3x50ml) extraction, organic layer filters and evaporation through dried over mgso, obtains yellow solid.Crude product is recrystallization purifying from IPA, obtains the title compound (591mg, 41%) of white solid.Filtrating is still contained some products, through purification by silica gel column chromatography, (contains 7M NH with 0-10%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain another sample (402mg, 28%) of the title compound of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.14-1.30(2H，m)，1.46-1.55(1H，m)，1.61(2H，d)，1.72(1H，d)，1.81(1H，t)，1.95(1H，m)，2.06(1H，m)，2.67-2.70(1H，m)，2.80(2H，d)，3.05-3.12(1H，m)，3.81(3H，s)，4.59(1H，m)，4.68(1H，d)，8.79(2H，s).MS：m/z?277(MH+).

Embodiment 128

2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

([2-(3 5.10mmol) to drop to the 5-that is stirring for the toluene solution of 2M, 2.55ml with trimethylaluminium under 25 ℃; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (504mg, 2.04mmol) and 2-(3,4; 6,7,8; 8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) (535mg is 2.04mmol) in the suspension-s in toluene (10.20ml) for pyrimidine-5-methyl-formiate.The solution that obtains stirred 18 hours at ambient temperature, stirred 2 hours down at 60 ℃ subsequently.Reaction mixture is also handled with HCl (the 2N aqueous solution is up to the solution that obtains freely stirring) with methyl alcohol (20ml) quencher.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 0.1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (288mg, 30%) of solid-like.

1H?NMR(399.9MHz，DMSO-d6)δ1.36-1.40(1H，m)，1.68-1.75(2H，m)，1.83-1.90(2H，m)，2.07(2H，q)，2.67-2.72(1H，m)，2.88(4H，s)，3.01-3.08(3H，m)，3.72(6H，s)，4.71-4.75(1H，m)，4.87(1H，d)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，8.90(2H，s)，10.59(1H，s)，12.15(1H，s).MS：m/z?478(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.003 μ M

2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) pyrimidine-5-methyl-formiate as raw material is prepared as follows:

Under room temperature, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (1.56g, 9.04mmol) solution in methylene dichloride (7.50ml) add to stirring 1,2; 3,4,6; 7,8,8a-octahydro pyrrolo-[1; 2-a] (1.37g is 10.85mmol) with N-ethyl-N-propane-propane-(3.95ml is 22.60mmol) in the solution in methylene dichloride (22.60ml) for 2-amine for the 2-base for pyrazine.The solution that obtains was stirred 18 hours at ambient temperature.Reaction mixture is poured on the ice (100ml), and with methylene dichloride (3x100ml) extraction, organic layer filters and evaporation through dried over mgso, obtains yellow solid.Water layer carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains crude product with required product wash-out and be evaporated to driedly from post.The crude product that merges (contains 7M NH through purification by silica gel column chromatography with 0-10%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain the required compound (1.36g, 57%) of yellow solid shape.

1H?NMR(399.902MHz，DMSO)δ1.33-1.44(1H，m)，1.63-1.78(2H，m)，1.80-1.93(2H，m)，2.04-2.11(2H，m)，2.72(1H，dd)，3.00-3.09(3H，m)，3.81(3H，s)，4.74(1H，d)，4.88(1H，d)，8.79(2H，s).MS：m/z?263(MH+).

Embodiment 129

5-[(3R, 5S)-4-(cyano methyl)-3,5-lupetazin-1-yl]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide (271mg, 0.70mmol) disposable 3: the 1 (2R that adds in anhydrous dimethyl sulphoxide (1.40ml); 6S)-1; 2,6-tri methyl piperazine and 2-[(2S, 6R)-2; 6-lupetazin-1-yl] (180mg is in mixture 1.40mmol) for acetonitrile.The solution that obtains stirred 2 hours at ambient temperature.React incomplete, add N-ethyl-N-propane-2-base propane-2-amine (0.24ml, 1.40mmol), with solution 60 ℃ of following restir 2 hours.Reaction mixture carries out the ion exchange chromatography purifying with methyl alcohol (20ml) dilution through the SCX post.Use 7MNH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (77mg, 22%) of yellow solid shape.

1H NMR (399.9MHz, CDCl3) δ 1.22 (6H, d), 2.71-2.79 (2H, m), 2.84 (1H, d), 2.87 (1H; D), 2.90-3.00 (4H, m), 3.77 (6H, s), 3.83 (2H, s), 4.32-4.35 (2H; M), 6.33 (1H, t), 6.36 (2H, d), 6.55 (1H, s); 8.01 (1H, d), 8.92 (1H, d), 9.73 (1H, s), 1 NH does not observe .MS:m/z 505 (MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0035 μ M

Embodiment 130

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] pyrazine-2-methane amide

Under 25 ℃ with 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide (273mg, 0.70mmol) disposable 3: the 1 (2R that adds in anhydrous dimethyl sulphoxide (1.40ml); 6S)-1; 2,6-tri methyl piperazine and 2-[(2S, 6R)-2; 6-lupetazin-1-yl] (180mg is in mixture 1.40mmol) for acetonitrile.The solution that obtains was stirred 2 hours at ambient temperature.React incomplete, add N-ethyl-N-propane-2-base propane-2-amine (0.24ml, 1.40mmol), with solution 60 ℃ of following restir 2 hours.Reaction mixture methyl alcohol (20ml) carries out the ion exchange chromatography purifying with dilution through the SCX post.Use 7MNH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (248mg, 74%) of yellow solid shape.

1H?NMR(500.13MHz，DMSO-d6，373K)δ1.13-1.14(6H，m)，2.24(3H，s)，2.25-2.31(2H，m)，2.81(1H，d)，2.83(1H，d)，3.78(6H，s)，4.30-4.33(2H，m)，5.11(2H，s)，5.90(1H，s)，6.46(1H，t)，6.62(2H，d)，8.27(1H，d)，8.72(1H，d)，10.3(1H，s)，11.1(1H，s).MS：m/z482(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00059 μ M

Embodiment 131

5-[(3R, 5S)-4-(cyano methyl)-3,5-lupetazin-1-yl]-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with 5-chloro-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide (273mg, 0.70mmol) disposable 3: the 1 (2R that adds in anhydrous dimethyl sulphoxide (1.40ml); 6S)-1; 2,6-tri methyl piperazine and 2-[(2S, 6R)-2; 6-lupetazin-1-yl] (180mg is in mixture 1.40mmol) for acetonitrile.The solution that obtains was stirred 2 hours at ambient temperature.React incomplete, add the N-ethyl diisopropyl amine (0.24ml, 1.40mmol), with solution 60 ℃ of following restir 2 hours.Reaction mixture carries out the ion exchange chromatography purifying with methyl alcohol (20ml) dilution through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out from post.Spissated elutriant (contains 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (65mg, 18%) of yellow solid shape.

1H?NMR(399.9MHz，CDCl3)δ1.22(6H，t)，2.72-2.77(2H，m)，2.86(1H，d)，2.89(1H，d)，3.80(6H，s)，3.83(2H，s)，4.33-4.37(2H，m)，5.18(2H，s)，5.50(1H，s)，6.41(1H，t)，6.61(2H，d)，7.99(1H，d)，8.88(1H，d)，9.62(1H，s)，10.7(1H，s).MS：m/z?507(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0035 μ M

Embodiment 132

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-2-(3,4-lupetazin-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.29ml; 2.58mmol) drop to 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (295mg, 1.03mmol) and 2-(3; 4-lupetazin-1-yl) (258mg is 1.03mmol) in the suspension-s in toluene (5.16ml) for pyrimidine-5-methyl-formiate.The solution that obtains was stirred 5 hours down at 60 ℃.With reaction mixture impouring methyl alcohol (50ml), with HCl (the 2M aqueous solution) acidifying.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.This not pure products (contain 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain the title compound (298mg, 62%) of white crystalline solid shape.

1H?NMR(500.133MHz，DMSO，373K)δ1.05(3H，d)，2.10-2.20(2H，m)，2.24(3H，s)，2.81(1H，dt)，2.91(1H，dd)，3.24-3.29(1H，m)，3.76(6H，s)，4.39-4.47(2H，m)，5.09(2H，s)，5.71(1H，s)，6.44(1H，t)，6.60(2H，d)，8.84(2H，s)，10.30(1H，s)，11.28(1H，s).MS：m/z468(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0036 μ M

Be prepared as follows 2-(3,4-lupetazin-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under room temperature, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (500mg; 2.90mmol) solution in methylene dichloride (7.50ml) add to stirring 1; 2-lupetazin (331mg; 2.90mmol) and N-ethyl-N-propane-propane-(1.26ml is 7.24mmol) in the solution in methylene dichloride (7.25ml) for 2-amine for the 2-base.The solution that obtains was stirred 5 hours at ambient temperature.The concentrating under reduced pressure reaction mixture, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.This not pure products (contain 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain the required compound (713mg, 98%) of yellow solid shape.

1H?NMR(399.9MHz，DMSO-d6)δ1.04-1.06(3H，m)，1.98-2.05(1H，m)，2.06-2.13(1H，m)，2.21(3H，s)，2.78-2.84(2H，m)，3.14-3.21(1H，m)，3.81(3H，s)，4.46-4.55(2H，m)，8.78(2H，s).MS：m/z?251(MH+).

Embodiment 133

2-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (2M toluene solution; 2.00ml; 4.00mmol) drop to the 5-[(3 that is stirring; The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (459mg, 1.60mmol) and 2-(4-cyclopropyl piperazine-1-yl) pyrimidine-5-methyl-formiate (421mg is 1.60mmol) in the suspension-s in toluene (8.0ml).The solution that obtains was stirred 18 hours at ambient temperature, stirred 2 hours down at 60 ℃ subsequently.Reaction mixture is also handled with HCl (the 2N aqueous solution is up to the solution that obtains freely stirring) with methyl alcohol (20ml) quencher.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 0.1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (94mg, 12%) of solid-like.1H?NMR(500.13MHz，DMSO-d6，373K)δ0.40-0.43(2H，m)，0.44-0.49(2H，m)，1.71-1.75(1H，m)，2.65(4H，t)，3.78(6H，s)，3.84(4H，t)，5.11(2H，s)，5.71(1H，s)，6.46(1H，t)，6.62(2H，d)，8.86(2H，s)，10.3(1H，s)，11.3(1H，s).MS：m/z?480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0039 μ M

Method according to describing among the embodiment 126 prepares 2-(4-cyclopropyl piperazine-1-yl) pyrimidine-5-methyl-formiate.

Embodiment 134

2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

(2M toluene solution, 2.50ml 5.00mmol) drop to the 5-[(3 that is stirring with trimethylaluminium under 25 ℃; The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (572 mg, 2.00mmol) and 2-(3,4; 6,7,8; 8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl) (525mg is 2.00mmol) in the suspension-s in toluene (10.00ml) for pyrimidine-5-methyl-formiate.The solution that obtains was stirred 18 hours at ambient temperature, stirred 2 hours down at 60 ℃ subsequently.Careful with methyl alcohol (20ml) quencher reaction mixture, handle with HCl (the 2N aqueous solution is up to the solution that obtains freely stirring).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 0.1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (269mg, 28%) of solid form.

1H?NMR(500.13MHz，DMSO-d6，373K)δ1.39-1.47(1H，m)，1.69-1.75(1H，m)，1.76-1.82(1H，m)，1.84-1.90(1H，m)，1.99-2.03(1H，m)，2.13-2.21(2H，m)，2.72-2.78(1H，m)，3.04-3.13(3H，m)，3.78(6H，s)，4.70-4.75(1H，m)，4.85-4.88(1H，m)，5.11(2H，s)，5.72(1H，s)，6.46(1H，t)，6.62(2H，d)，8.87(2H，s)，10.30(1H，s)，11.30(1H，s).MS：m/z480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0024 μ M

5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate is according to the method preparation of describing among the embodiment 12.

According to 2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2, the 1-c] pyrazine-2-yl) pyrimidine-5-methyl-formiate of the method preparation of describing among the embodiment 128 as raw material.

Embodiment 135

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(3,4-lupetazin-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.31ml; 2.62mmol) drop to 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (260mg, 1.05mmol) and 2-(3; 4-lupetazin-1-yl) (263mg is 1.05mmol) in the suspension-s in toluene (5.26ml) for pyrimidine-5-methyl-formiate.Gained solution stirred 18 hours down at 60 ℃.With reaction mixture impouring methyl alcohol (50ml) and with HCl (the 2M aqueous solution is to obtain the clarifying solution that freely stirs) acidifying.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.This not pure products (contain 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/dichloromethane gradient wash-out.The branches at different levels that will contain product are evaporated to dried, obtain still impure material.Resistates is through preparation HPLC purifying again, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (175mg, 36%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.05-1.07(3H，m)，1.99-2.05(1H，m)，2.07-2.13(1H，m)，2.22(3H，s)，2.76-2.84(2H，m)，2.88(4H，s)，3.12-3.19(1H，m)，3.72(6H，s)，4.46-4.55(2H，m)，6.33(1H，t)，6.42(3H，m)，8.89(2H，s)，10.60(1H，s)，12.12(1H，s).MS：m/z466(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0026 μ M

According to 2-(3, the 4-lupetazin-1-yl) pyrimidine-5-methyl-formiate of the method preparation of describing among the embodiment 132 as raw material.

Embodiment 136

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] pyrimidine-5-methane amide

([2-(3 2.08mmol) to drop to 5-for 2M toluene solution, 1.04ml with trimethylaluminium under 25 ℃; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (205mg; 0.83mmol) and 2-((3R, 5S)-3,4; 5-tri methyl piperazine-1-yl) (220mg is 0.83mmol) in the suspension-s in toluene (5.257ml) for pyrimidine-5-methyl-formiate.The solution that obtains was stirred 18 hours down at 60 ℃.With reaction mixture impouring methyl alcohol (50ml) and with HCl (the 2M aqueous solution is to obtain clarifying the solution that freely stirs) acidifying.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (157mg, 39%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.09-1.10(6H，m)，2.08-2.14(2H，m)，2.20(3H，s)，2.71(1H，d)，2.74(1H，d)，2.87(4H，s)，3.72(6H，s)，4.55-4.59(2H，m)，6.33(1H，t)，6.42(3H，m)，8.89(2H，s)，10.61(1H，s)，12.15(1H，s).MS：m/z?480(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0019 μ M

Be prepared as follows as the 2-of raw material ((3R, 5S)-3,4,5-tri methyl piperazine-1-yl) pyrimidine-5-methyl-formiate:

(2.31mmol/g, 3.15g 7.29mmol) add to 2-((3R in methyl alcohol (5.83ml) with macropore triethyl ammonium methylated polystyrene cyanic acid hydroborate under 25 ℃; 5S)-3; 5-lupetazin-1-yl) pyrimidine-5-methyl-formiate (730mg, 2.92mmol), formaldehyde (37% aqueous solution, 4.43ml; 59.13mmol) and acetate (0.334ml, 5.83mmol) in.Gained suspension-s stirred 5 hours at ambient temperature.Remove by filter macropore triethyl ammonium methylated polystyrene cyanic acid hydroborate, wash with methyl alcohol (50ml).Filtrating is carried out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.This not pure products (contain 7MNH through purification by silica gel column chromatography with 0-6%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain white buttery required compound (474mg, 62%), this oily matter leaves standstill after fixing.

1H?NMR(399.9MHz，DMSO-d6)δ1.09(6H，d)，2.07-2.15(2H，m)，2.19(3H，s)，2.73-2.76(2H，m)，3.81(3H，s)，4.56-4.60(2H，m)，8.79(2H，s).MS：m/z?265(MH+).

Be prepared as follows as the 2-of raw material ((3R, 5S)-3,5-lupetazin-1-yl) pyrimidine-5-methyl-formiate:

Under room temperature, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (535mg; 3.10mmol) solution in methylene dichloride (7.50ml) adds to (2S that is stirring; 6R)-2; (354mg is 3.10mmol) with N-ethyl-N-propane-propane-(1.35ml is 7.75mmol) in the solution in methylene dichloride (7.24ml) for 2-amine for the 2-base for the 6-lupetazin.The solution that obtains stirred 3 hours at ambient temperature.The concentrating under reduced pressure reaction mixture, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.This not pure products (contain 7MNH through purification by silica gel column chromatography with 0-5%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain the required compound (740mg, 95%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.02-1.04(6H，m)，2.33(1H，s)，2.43-2.46(2H，m)，2.64-2.69(2H，m)，3.81(3H，s)，4.62-4.66(2H，m)，8.77(2H，s).MS：m/z?251(MH+).

Embodiment 137

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[4-(1-hydroxy propane-2-yl) piperazine-1-yl] BM

With 2-(piperazine-1-yl) propane-1-alcohol dihydrochloride (0.274g, 1.26mmol) add to N-ethyl-N-propane-2-base propane-2-amine in DMSO (5ml) (0.330ml, 1.89mmol) in.Reaction mixture was at room temperature stirred 10 minutes.(0.233g 0.63mmol), heats mixture 18 hours down at 110 ℃ under nitrogen atmosphere to add N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-fluorobenzamide.Continue heating 12 days.Cooling reaction, crude mixture carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains crude product.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1% NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.048g, 15.44%) of Off-white solid form.

1H?NMR(500.13MHz-DMSO-d6+CD3COOD373K)：1.02(3H，d)，2.70-2.81(5H，m)，2.89(4H，s)，3.28-3.34(4H，m)，3.37-3.44(1H，m)，3.50-3.55(1H，m)，3.73(6H，s)，6.27-6.32(2H，m)，6.40(2H，s0，6.92(2H，d)，7.82-7.88(2H，m).MS：m/z(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00057 μ M

Be prepared as follows 2-(piperazine-1-yl) propane-1-alcohol dihydrochloride as raw material:

Under 0 ℃, nitrogen atmosphere through 10 minutes with the solution (12.00ml of 1M borine THF mixture in THF; 12.00mmol) (2.58g is 10mmol) in the suspension-s in THF (50ml) to drop to 2-(the 1-tert-butoxycarbonyl piperazine-4-yl) propionic acid that is stirring.The solution that obtains was stirred 8 hours down at 60 ℃.With acetic acid/water (10ml, 1: 2 mixture) quencher, be evaporated to dried.Resistates is dissolved in ETHYLE ACETATE (50ml),,, filters and be evaporated to dried, obtain 4-(1-hydroxy propane-2-yl) piperazine-1-t-butyl formate (0.810g, 33.2%) through dried over mgso with saturated sodium bicarbonate (25ml) and water washing.

1H?NMR(399.9MHz，CDCl3)δ0.83(3H，d)，1.39(9H，s)，2.30(2H，t)，2.51-2.57(3H，m)，2.71-2.82(1H，m)，3.34-3.40(2H，m)，3.35-3.39(4H，m).

(12.00ml 48.00mmol) handles 4-(1-hydroxy propane-2-yl) piperazine-1-t-butyl formate (0.782g, 3.2mmol) suspension-s in the mixture of ETHYLE ACETATE (10ml) and methyl alcohol (10.00ml) at room temperature to drip 4.0M HCl/ diox.Reaction mixture was stirred 18 hours.Reaction mixture dilutes with ether, and the filtering white solid with ether washing and air-dry, obtains 2-(piperazine-1-yl) propane-1-alcohol (0.525g, 76%) of its dihydrochloride form.

Be prepared as follows N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-fluorobenzamide as raw material:

At room temperature with the toluene solution (3.00ml of 2M trimethylaluminium; 3.00mmol) drop to and stirring 4-ethyl fluoro benzoate (0.440ml; 3.00mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(0.742g is 3mmol) in the solution in toluene (10ml) for 2H-pyrazoles-3-amine.Reaction mixture was at room temperature stirred 18 hours.With reaction mixture impouring acetone (50ml), handle with the sodium sulphite of excessive humidity.Reaction mixture carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains yellow jelly.Crude product is through purification by silica gel column chromatography, with 0-5%2.5M ammonia/MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the required compound (0.245g, 22.11%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ2.88(4H，s)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.47(1H，s)，7.32(2H，t)，8.05-8.09(2H，m)，10.69(1H，s)，12.16(1H，s).MS：m/z?370(MH+).

Embodiment 138

N-(3-(3,5-dimethoxy benzyloxy)-1H-pyrazoles-5-yl)-2-((3R, 5S)-3,4,5-tri methyl piperazine-1-yl) pyrimidine-5-methane amide

(2M toluene solution, 1.04ml 2.07mmol) drop to 5-[(3 with trimethylaluminium under 25 ℃; The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (237mg; 0.83mmol) and 2-((3R, 5S)-3,4; 5-tri methyl piperazine-1-yl) (219mg is 0.83mmol) in the suspension-s in toluene (4.2ml) for pyrimidine-5-methyl-formiate.The solution that obtains was stirred 2 hours down at 60 ℃.With reaction mixture impouring methyl alcohol (50ml) and with HCl (the 2M aqueous solution) acidifying.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Pure products is not through preparation HPLC purifying for this, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (158mg, 40%) of white solid.

1H?NMR(500.133MHz，DMSO，373K)δ1.10(6H，d)，2.14-2.20(2H，m)，2.22(3H，s)，2.74-2.79(2H，m)，3.76(6H，s)，4.53-4.57(2H，m)，5.08(2H，s)，5.71(1H，s)，6.44(1H，t)，6.59(2H，d)，8.84(2H，s)，10.32(1H，s)，11.31(1H，s).MS：m/z?482(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0026 μ M

Prepare 2-((3R, 5S)-3,4,5-tri methyl piperazine-1-yl) pyrimidine-5-methyl-formiate according to the method for describing among the embodiment 136.

Embodiment 139

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(3,3-lupetazin-1-yl) BM

(0.1g, 0.27mmol) with 2, (0.124g 1.04mmol) stirred 20 minutes down at 60 ℃ the 2-lupetazin with N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-fluorobenzamide.(0.033ml, 0.54mmol) and DMSO (1ml), reaction mixture stirred 16 days in 120 ℃ ST to add salt of wormwood.With reaction mixture cooling and evaporation.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1% NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (6.00mg, 2.000%) of colourless jelly form.

1H?NMR(399.9MHz，CDCl3)δ1.19(6H，s)，2.92-2.95(4H，m)，3.02(4H，d)，3.04(1H，s)，3.17(2H，t)，3.75(6H，s)，6.32-6.35(3H，m)，6.84(2H，d)，7.77(2H，d)，8.73(1H，s).MS：m/z?465(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00047 μ M

With the toluene solution of 2M trimethylaluminium (3.54ml, 7.08mmol) drop to 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine in toluene (35ml) (0.7g, 2.83mmol) in.(0.366ml 2.83mmol), at room temperature stirred the solution that obtains 18 hours to add the 4-fluorophenyl carbamate subsequently.Add additional quantity the 4-fluorophenyl carbamate (0.183ml, 1.42mmol), with this solution restir 20 hours at room temperature.With reaction mixture impouring acetone (40ml), handle with excessive moist sodium sulfide solution.Suspension-s was stirred 2 hours, filter, filtrating (contains 2.5N NH through purification by silica gel column chromatography with 2.5-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the required compound of beige solid shape, it is white solid (0.147g, 14.06%) that this beige solid leaves standstill after fixing.

1H?NMR(399.9MHz，DMSO-d6)δ2.88(4H，s)，3.73(6H，s)，6.33(1H，t)，6.43(2H，d)，6.47(1H，s)，7.31(2H，t)，8.05-8.09(2H，m)，10.69(1H，s)，12.16(1H，s).MS：m/z?370(MH+).

Embodiment 140

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,3-lupetazin-1-yl) thiophene-2-carboxamide derivatives

Under 65 ℃, nitrogen atmosphere with the toluene solution (1.250ml of 2M trimethylaluminium; 2.50mmol drop to the 5-(3 that is stirring; 3-lupetazin-1-yl) thiophene-2-carboxylic acid ethyl ester (0.268g; 1mmol) and 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (0.286g is 1.00mmol) in the solution in toluene (7.14ml).With reaction mixture 65 ℃ of following stirring heating 4 hours, subsequently 50 ℃ of following stirring heating 18 hours, subsequently 80 ℃ of following stirring heating 5 hours.(5mL) adds to this reaction mixture with ETHYLE ACETATE, adds sodium tartrate potassium solution (5mL, 20% aqueous solution) subsequently.Add more ETHYLE ACETATE (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel, removes water layer.Ethyl acetate layer washs with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains the crude product of yellow jelly form.Crude product is through preparation LCMS purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.073g, 15.48%) of white solid.

1H?NMR(500.13MHz，DMSO-d6，CD3CO2D)δ1.36(6H，s)，3.24(4H，s)，3.40(2H，t)，3.74(6H，s)，5.06(2H，s)，5.64(1H，s)，6.24(1H，d)，6.41(1H，s)，6.57(2H，s)，7.62-7.63(1H，m)；MS：m/z?472(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00098 μ M

Be prepared as follows 5-(3,3-lupetazin-1-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

Under 20 ℃, nitrogen atmosphere with acid chloride (II) (0.112g, 0.50mmol) add to 5-bromothiophene-2-ethyl formate in toluene (50.0ml) (1.175g, 5mmol), 2; 2-dimethyl--piperazine (0.571g; 5.00mmol), racemize-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (0.311g; 0.50mmol) and cesium carbonate (2.281g, 7.00mmol) in.The suspension-s that obtains was stirred 23 hours down at 110 ℃.Crude product is through carrying out the ion exchange chromatography purifying with the SCX2 post.Thick substance dissolves in methyl alcohol, is carried on the post subsequently.Use 2M NH ₃/ methyl alcohol is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the crude product of brown solid form.This material is used the 0-4%MeOH/DCM gradient elution further through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 5-(3,3-lupetazin-1-yl) the thiophene-2-carboxylic acid ethyl ester (0.484g, 36.1%) of brown jelly form.

1H?NMR(399.9MHz，CDCl3)δ1.20(6H，s)，1.33(3H，t)，2.98(2H，s)，3.05(2H，d)，3.16-3.19(2H，m)，4.28(2H，q)，6.00(1H，d)，7.54(1H，d)

MS：m/z?269(MH+)

Embodiment 141

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-ethyl piperazidine-1-yl) thiophene-2-carboxamide derivatives

Under 25 ℃ with the trimethylaluminium (toluene solution of 2M; 1.40ml; 2.79mmol) drop to the 5-[(3 that is stirring; The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (319mg, 1.12mmol) and 5-(4-ethyl piperazidine-1-yl) thiophene-2-carboxylic acid ethyl ester (300mg is 1.12mmol) in the suspension-s in toluene (5.60ml).Subsequently with the solution that obtains under nitrogen atmosphere, 60 ℃ stirred 5 hours down.With the carefully quencher in methyl alcohol (100ml) of this reaction mixture, with HCl (the 2M aqueous solution) acidifying, mixture carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains impurity with required product wash-out and be evaporated to driedly from post.Crude product (contains 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/DCM gradient elution.Branches at different levels are evaporated to dried, obtain impure N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-ethyl piperazidine-1-yl) thiophene-2-carboxamide derivatives of Off-white solid form.Resistates is through preparation HPLC purifying again, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (72mg, 14%) of white solid.

1H?NMR(500.133MHz，DMSO，373K)δ1.04(3H，t)，2.43(2H，q)，2.53-2.54(4H，m)，3.23-3.25(4H，m)，3.76(6H，s)，5.07(2H，s)，5.60(1H，s)，6.14(1H，d)，6.44(1H，t)，6.59(2H，d)，7.63(1H，d)，10.05(1H，s)，11.09(1H，s).MS：m/z?472(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00086 μ M

Be prepared as follows 5-(4-ethyl piperazidine-1-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

Under 25 ℃, nitrogen atmosphere, successively three (two benzal benzylacetone roots) are closed two palladiums (O) (183mg; 0.20mmol) and sodium tert-butoxide (538mg, 5.60mmol) add to 5-bromothiophene-2-ethyl formate in toluene (20.00ml) (1.034g, 4.40mmol), 1-ethyl piperazidine (0.51ml; 4.00mmol) and (racemize)-(-)-2; 2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (249mg, 0.40mmol) in.The suspension-s that obtains was stirred 18 hours down at 110 ℃.Through the refrigerative reaction mixture, carry out the ion exchange chromatography purifying with the methyl alcohol dilution through the SCX post.Use 7MNH ₃/ MeOH obtains crude product with required product wash-out and be evaporated to driedly from post.Resistates (contains 7M NH through purification by silica gel column chromatography with 0-3%MeOH ₃)/DCM gradient elution.The branches at different levels that will contain required product are evaporated to dried, obtain impure orange.This impurity is further through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain 5-(4-ethyl piperazidine-1-yl) the thiophene-2-carboxylic acid ethyl ester (339mg, 32%) of yellow oily.

1H?NMR(399.902MHz，DMSO)δ1.03(3H，t)，1.25(3H，t)，2.38(2H，q)，2.49(4H，m)，3.24(4H，m)，4.19(2H，q)，6.21(1H，d)，7.51(1H，d).MS：m/z?269(MH+)

Embodiment 142

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) thiophene-2-carboxamide derivatives

Under 20 ℃ with 5-(4-methyl isophthalic acid; 4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester (0.201g; 0.75mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.185g, 0.75mmol) stirring in toluene (10ml); The toluene solution of dropping 2M trimethylaluminium (0.938ml, 1.88mmol).Reaction mixture is nitrogen atmosphere, 60 ℃ of following stirrings 18 hours.With the reaction mixture cooling, quencher in the impouring methyl alcohol (50ml) is with several 2N hcl acidifyings.Crude product carries out the ion exchange chromatography purifying through the SCX post, uses 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains crude product.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1% NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.162g, 46.0%) of brown solid-like.

1H?NMR(399.9MHz，DMSO-d6)δ1.89-1.93(2H，m)，2.28(3H，s)，2.50-2.54(2H，m)，2.63(1H，d)，2.64-2.65(1H，m)，2.85(4H，s)，3.43(2H，t)，3.50(2H，t)，3.72(6H，s)，5.86(1H，d)，6.32-6.34(2H，m)，6.41(2H，d)，7.79(1H，d)，10.15(1H，s)，12.00(1H，s).MS：m/z470(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0021 μ M

Under nitrogen atmosphere, 5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester is prepared as follows: (0.135g 0.60mmol) adds to 5-bromothiophene-2-ethyl formate (1.411g in being warmed to 80 ℃ of De dioxs (40ml) with acid chloride (II); 6mmol), 1-methyl isophthalic acid; The 4-Diazesuberane (0.822g, 7.20mmol), BINAP (0.374g, 0.60mmol) and cesium carbonate (2.74g; 8.40mmol) in, be warmed to 80 ℃ following 18 hours.Crude mixture is carried out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is with required product wash-out from post.Branches at different levels are evaporated to dried, obtain crude product.Crude product is through purification by silica gel column chromatography, with 0-5%3M ammonia/MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain yellow gelationus 5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester (0.204g, 12.67%).

1H?NMR(399.9MHz，CDCl3)δ：1.34(3H，t)，1.97-2.04(2H，m)，2.38(3H，s)，2.55-2.61(2H，m)，2.67(2H，m)，3.48(2H，t)，3.54-3.57(2H，m)，4.28(4H，q)，5.79(1H，d)，7.55(1H，d).MS：m/z?269(MH+).

Embodiment 143

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-ethyl-3-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide

At room temperature with trimethylaluminium (2M toluene solution; 1.65ml; 3.31mmol) drop to 2-(4-ethyl-3-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate (303mg that is stirring; 1.15mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) the ethyl]-suspension-s of 2H-pyrazoles-3-amine (283mg, 1.15 mmol) in toluene (5.73ml) in.With the solution that obtains 60 ℃ of following stirred overnight.Reaction mixture quencher in methyl alcohol (100ml) is handled with HCl (the 2N aqueous solution is 7 or lower up to pH).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the not pure products of yellow dry film shape.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (269mg, 49%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d ₆)δ0.99(3H，d)，1.03(3H，d)，2.20-2.26(1H，m)，2.35-2.43(2H，m)，2.74-2.79(1H，m)，2.83(1H，m)，2.88(4H，s)，3.02-3.07(1H，m)，3.30-3.38(1H，m)，3.72(6H，s)，4.27-4.31(2H，m)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，8.89(2H，s)，10.58(1H，s)，12.15(1H，s).MS：m/z?480(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0027 μ M

2-(4-ethyl-3-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methyl-formiate as raw material is prepared as follows:

Under 25 ℃, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (300mg; 1.74mmol) solution in methylene dichloride (4.30ml) adds to the 1-ethyl-2-N-METHYL PIPERAZINE (223mg that is stirring; 1.74mmol) and N-ethyl-N-propane-propane-(0.75ml is 4.35mmol) in the solution in methylene dichloride (4.40ml) for 2-amine for the 2-base.The solution that obtains was at room temperature stirred 4 hours.The concentrating under reduced pressure reaction mixture also dilutes with MeOH (10ml).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product (contains 7M NH through purification by silica gel column chromatography with 0-3%MeOH ₃)/dichloromethane gradient wash-out.Each pure level divided be evaporated to driedly, obtain the required compound (382mg, 83%) of colorless oil.

1H?NMR(399.9MHz，DMSO-d ₆)δ0.98(3H，t)，1.02(3H，d)，2.20-2.27(1H，m)，2.33-2.38(1H，m)，2.40-2.45(1H，m)，2.71-2.79(1H，m)，2.81-2.85(1H，m)，3.06-3.11(1H，m)，3.35-3.42(1H，m)，3.81(3H，s)，4.28-4.35(2H，m)，8.78(2H，s).MS：m/z?265(MH+)

Embodiment 144

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(1-third-2-thiazolinyl piperidin-4-yl) BM

[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl]-4-(1-third-2-thiazolinyl piperidin-4-yl) BM is prepared as follows according to the method described in the embodiment 99; Raw materials used be in toluene (10ml) 4-(1-third-2-thiazolinyl piperidin-4-yl) oil of Niobe (0.259g, 1.00mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.247g; 1mmol) with the 2M trimethylaluminium (1.250ml, 2.50mmol).Crude product is through purification by silica gel column chromatography, with 0-5%2.5M ammonia/methyl alcohol/DCM gradient elution.Each pure level divided be evaporated to driedly, product crystallization in the DCM/ ether obtains the title compound (0.182g, 38.3%) of white solid after the filtration.

1H?NMR(399.9MHz，DMSO-d ₆)δ1.66-1.70(2H，m)，1.73-1.79(2H，m)，1.99-2.05(2H，m)，2.55(1H，d)，2.88(4H，s)，2.95(1H，s)，2.99(3H，d)，3.73(6H，s)，5.12-5.18(1H，m)，5.22(1H，t)，5.83-5.89(1H，m)，6.33(1H，t)，6.43(2H，d)，6.47(1H，s)，7.35(2H，d)，7.93(2H，d)，10.55(1H，s)，12.13(1H，s).MS：m/z?475(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.000041 μ M

Be prepared as follows 4-(1-third-2-thiazolinyl piperidin-4-yl) oil of Niobe as raw material:

Under room temperature, nitrogen atmosphere through 5 minutes with 3-bromine third-1-alkene (0.433ml; 5.00mmol) drip the 4-piperidin-4-yl oil of Niobe (1.096g stirring; 5mmol) (2.066ml is 12.50mmol) in the solution in DCM (10ml) with N-ethyl-N-sec.-propyl propane-2-amine.Reaction mixture was at room temperature stirred 1 hour.Reaction mixture is evaporated to dried, the purifying on SCX post top is with 3.5N ammonia/methanol-eluted fractions.Merge the branches at different levels that contain product, be evaporated to dried.Crude product is used the 5%MeOH/DCM wash-out through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain the required compound (1.004g, 77%) of white solid.

1H?NMR(399.9MHz，CDCl3)δ1.78-1.86(4H，m)，2.02-2.08(2H，m)，2.53-2.57(1H，m)，3.03-3.05(3H，m)，3.07(1H，t)，3.90(3H，s)，5.14-5.23(2H，m)，5.85-5.97(1H，m)，7.28-7.31(2H，m)，7.95-7.98(2H，m).MS：m/z?260(MH+).

Method according to describing among the embodiment 99 prepares 4-piperidin-4-yl oil of Niobe.

The method of describing according to embodiment 2 prepares 5-[2-(3, the 5-Dimethoxyphenyl) the ethyl]-2H-pyrazoles-3-amine as raw material.

Embodiment 145

4-(1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM

4-(1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM is prepared as follows according to the method described in the embodiment 99; Raw materials used is 4-(1 in toluene (10ml); 4-Diazesuberane-1-yl) ethyl benzoate (0.497g, 2mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.495g; 2.00mmol) and the 2M trimethylaluminium (2.50ml, 5.0mmol).Crude product is through purification by silica gel column chromatography, with 0-10%2.5M ammonia MeOH/DCM gradient elution.The branches at different levels that will contain product are evaporated to dry doubling and are further purified through preparation HPLC, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.024g, 2.67%) of white solid.

1H?NMR(500.13MHz，DMSO-d6+d4HOAc)δ2.07(2H，t)，2.90(4H，s)，3.10(2H，t)，3.24(2H，t)，3.62(2H，t)，3.74-3.76(8H，m)，6.33(2H，t)，6.42(2H，d)，6.81-6.83(2H，m)，7.88-7.89(2H，m).MS：m/z?450(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0007 μ M

Be prepared as follows 4-(1,4-Diazesuberane-1-yl) ethyl benzoate as raw material:

(11.01ml, 75mmol) with 1, (30.0g 300.00mmol) is warmed to 100 ℃ to the 4-Diazesuberane in DMSO (150ml) with the 4-ethyl fluoro benzoate under nitrogen atmosphere.The solution that obtains was stirred 24 hours down at 100 ℃.With reaction mixture cooling and be evaporated to dried.Reaction mixture is with 2M NaOH (150ml) quencher, with EtOAc (3x75ml) extraction, with saturated brine (100ml) washing organic layer; Through dried over mgso, filter and evaporation, obtain the 4-(1 of colorless oil; 4-Diazesuberane-1-yl) ethyl benzoate (17.43g, 94%).

1H?NMR(399.9MHz，CDCl3)δ1.27-1.31(3H，m)，1.71(1H，s)，1.79-1.85(2H，m)，2.74(1H，d)，2.74(1H，d)，2.95(1H，d)，2.96(1H，d)，3.51(2H，t)，3.56(2H，t)，4.21-4.27(2H，m)，6.56-6.60(2H，m)，7.80-7.83(2H，m).MS：m/z?249(MH+).

Embodiment 146

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(1-Propargyl piperidin-4-yl) BM

[[2-(3 for 5-to prepare N-according to the method described in the embodiment 99; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl]-4-(1-Propargyl piperidin-4-yl) BM; Raw materials used be in dry toluene (10ml) 4-(1-Propargyl piperidin-4-yl) oil of Niobe (0.257g, 1.00mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.247g; 1mmol) with the 2M trimethylaluminium (1.250ml, 2.50mmol).Crude product is through purification by silica gel column chromatography, with 0-5%2.5M ammonia/methyl alcohol/DCM gradient elution.Each pure level divided be evaporated to driedly, product obtains the title compound (0.245g, 51.8%) of white solid with the crystallization of DCM/ ether.

1H?NMR(399.9MHz，DMSO-d6+d4HOAc)δ1.64-1.73(2H，m)，1.79(2H，d)，2.24-2.29(2H，m)，2.49-2.54(1H，m)，2.88(4H，s)，2.90(1H，s)，2.93(1H，s)，3.15(1H，t)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.44(1H，s)，7.36(2H，d)，7.93(2H，d)，10.57(1H，s)，11.95(4H，s).MS：m/z?473(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0011 μ M

4-(the 1-Propargyl piperidin-4-yl) oil of Niobe that is used as raw material is according to the method preparation that is used to prepare 4-(1-third-2-thiazolinyl piperidin-4-yl) oil of Niobe (embodiment 144); But raw materials used is 3-bromine third-1-alkynes (0.356ml in DCM (5ml); 4.00mmol) (80% toluene solution), 4-piperidin-4-yl oil of Niobe (0.877g; 4mmol) with N-ethyl-N-sec.-propyl propane-2-amine (1.653ml, 10.00mmol).Crude product is used the 5%MeOH/DCM wash-out through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain the required compound (0.748g, 72.7%) of white solid.

1H?NMR(399.9MHz，CDCl3)δ1.81-1.90(4H，m)，2.27(1H，t)，2.32-2.38(2H，m)，2.54-2.59(1H，m)，3.00-3.04(2H，m)，3.36(2H，d)，3.90(3H，s)，7.27-7.30(2H，m)，7.95-7.98(2H，m).MS：m/z258(MH+).

Method according to describing among the embodiment 144 prepares 4-piperidin-4-yl oil of Niobe.

Embodiment 147

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-[(3S, 5R)-3,5-lupetazin-1-yl] thiophene-2-carboxamide derivatives

At room temperature with the toluene solution (1.250ml of 2M trimethylaluminium; 2.50mmol) drop to the 5-((3R that is stirring; 5S)-3,5-lupetazin-1-yl) the thiophene-2-carboxylic acid ethyl ester (0.268g, 1mmol) and 5-[(3; The 5-Dimethoxyphenyl) methoxyl group]-(0.286g is 1.00mmol) in the solution in toluene (7.14ml) for 2H-pyrazoles-3-amine hydrochlorate.Subsequently under 80 ℃, nitrogen atmosphere with mixture heating up 4 hours, subsequently 70 ℃ of heating 18 hours down.(5mL) adds to this reaction mixture with ETHYLE ACETATE, adds sodium tartrate potassium solution (5mL, 20% aqueous solution) subsequently.Add more ETHYLE ACETATE (50mL) and water (25mL), mixture is through the Celite diatomite filtration.Filtrating is transferred to separating funnel, removes water layer.Ethyl acetate layer washs with saturated brine, with after dried over mgso.After the filtration, evaporating solvent obtains yellow gelationus crude product.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.154g, 32.7%) of white solid.

1H?NMR(500.13MHz，DMSO-d6，CD3CO2D)δ1.23(6H，d)，2.79(2H，t)，3.26-3.34(2H，m)，3.63-3.66(2H，m)，3.76(6H，s)，5.08(2H，s)，5.63(1H，s)，6.25(1H，d)，6.43(1H，t)，6.59(2H，d)，7.66(1H，d)，11.08(1H，s)

MS：m/z472(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0018 μ M

Be prepared as follows as the 5-of raw material ((3R, 5S)-3,5-lupetazin-1-yl) thiophene-2-carboxylic acid ethyl ester:

Under 20 ℃, nitrogen atmosphere with acid chloride (II) (0.225g, 1.00mmol) add to 5-bromothiophene-2-ethyl formate in the Zai diox (100ml) (2.351g, 10mmol), (2S; 6R)-2, and the 6-lupetazin (1.142g, 10.00mmol), racemize-2; 2 '-two (diphenylphosphino)-1; 1 '-dinaphthalene (0.623g, 1.00mmol) and cesium carbonate (4.56g, 14.00mmol) in.The suspension-s that obtains was stirred 23 hours down at 105 ℃.Mixture is evaporated to dried, obtains brown oil.This crude product is through carrying out the ion exchange chromatography purifying with the SCX2 post.Should thick substance dissolves in methyl alcohol, load on this post subsequently.Use 2M NH ₃/ methyl alcohol is required product wash-out from post, each pure level divided be evaporated to driedly, obtains the crude product of brown solid shape.

This material is further through purification by silica gel column chromatography, with 0-5% MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 5-((3S, 5R)-3,5-lupetazin-1-yl) thiophene-2-carboxylic acid ethyl ester (1.600g, 59.6%) of white solid.

1H?NMR(399.9MHz，CDCl3)δ1.12-1.14(6H，m)，1.33(3H，t)，2.46-2.56(2H，m)，2.98-3.07(2H，m)，3.42-3.46(2H，m)，4.28(2H，q)，6.00(1H，d)，7.55(1H，d)

MS：m/z?269(MH+)

Embodiment 148

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[1-(2-methoxy ethyl) piperidin-4-yl] BM

[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl]-4-[1-(2-methoxy ethyl) piperidin-4-yl] BM is according to the described methods preparation of embodiment 99; Raw materials used be in toluene (10ml) 4-(1-(2-methoxy ethyl) piperidin-4-yl) oil of Niobe (0.428g, 1.25mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.309g; 1.25mmol) and the 2M trimethylaluminium (1.56ml, 3.13mmol).Crude product is through purification by silica gel column chromatography, with 0-5%2.5M ammonia/methyl alcohol/DCM gradient elution.Each pure level divided be evaporated to driedly, the crystallization from the DCM/ ether of this product obtains the title compound (0.215g, 34.9%) of pale solid shape.

1H?NMR(399.9MHz，CDCl3)δ1.76-1.91(4H，m)，2.10-2.17(2H，m)，2.54-2.58(1H，m)，2.63(2H，t)，2.92-2.96(4H，m)，3.10(2H，d)，3.37(3H，s)，3.56(2H，t)，3.76(6H，s)，6.33-6.35(3H，m)，6.68(1H，s)，7.32(2H，d)，7.80(2H，d)，8.65(1H，s)，9.28(1H，s).MS：m/z?493(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00087 μ M

Be prepared as follows 4-(1-(2-methoxy ethyl) piperidin-4-yl) oil of Niobe as raw material:

With 4-(piperidin-4-yl) oil of Niobe. hydrochloride (1.279g; 5mmol), N-ethyl-N-propane-2-base propane-2-amine (3.49ml; 20.00mmol) and 1-bromo-2-methyl ethyl ether 0.470ml, 5.00mmol) solution in methylene dichloride (10ml) heated 18 hours down at 40 ℃.Add several DMF to help dissolving.With the reaction mixture cooling, with DCM (30ml) dilution and water (2x30ml) and saturated nacl aqueous solution (30ml) washing.Through dried over mgso, filter and be evaporated to dried it.Crude product is used the 0-5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(1-(2-methoxy ethyl) piperidin-4-yl) oil of Niobe (0.723g, 52.1%) of colorless oil.

1H?NMR(399.9MHz，CDCl3)δ1.75(1H，t)，1.81-1.90(3H，m)，2.09-2.15(2H，m)，2.55(1H，q)，2.60-2.63(2H，m)，3.08-3.11(2H，m)，3.37(3H，s)，3.53-3.56(2H，m)，3.89-3.90(3H，m)，7.27-7.31(2H，m)，7.95-7.98(2H，m).MS：m/z?278(MH+).

Embodiment 149

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-[(3S)-and 3-propane-2-base piperazine-1-yl] pyrimidine-5-methane amide

At room temperature with trimethylaluminium (2M toluene solution; 1.23ml; 2.46mmol) drop to (S)-2-of stirring (3-propane-2-base piperazine-1-yl) pyrimidine-5-methyl-formiate (260mg; 0.98 mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(243mg is 0.98mmol) in the suspension-s in toluene (8.38ml) for 2H-pyrazoles-3-amine.Under nitrogen atmosphere, reaction mixture was stirred 18 hours down at 60 ℃ subsequently.The quencher in methyl alcohol (100ml) of this reaction mixture is also handled with HCl (the 2N aqueous solution is 7 or lower up to pH).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains not pure products.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (292mg, 62%) of white solid.

1H?NMR(399.9MHz，DMSO-d ₆)δ0.95-0.97(6H，d)，1.63(1H，m)，2.26-2.31(1H，m)，2.57-2.64(1H，m)，2.68(1H，d)，2.88(4H，s)，2.89-2.97(1H，m)2.98-3.02(1H，m)，3.72(6H，s)，4.57(1H，d)，4.66(1H，d)，6.33(1H，t)，6.41-6.44(3H，m)，8.88(2H，s)，10.56(1H，s)，12.14(1H，s).MS：m/z?480(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0044 μ M

Be prepared as follows (S)-2-(3-propane-2-base piperazine-1-yl) pyrimidine-5-methyl-formiate as raw material:

Down will be in that the solution (2S) in the methylene dichloride (4.40ml)-2-propane-(223mg, (300mg be 1.74mmol) in the solution in methylene dichloride (4.30ml) 1.74mmol) to add to the 2-chloropyrimide-5-methyl-formiate that is stirring for 2-base piperazine at 25 ℃.Adding N-ethyl-N-propane-2-base propane-2-amine (0.752ml, 4.35mmol).The solution that obtains was stirred 18 hours under room temperature, nitrogen atmosphere.Reaction mixture is concentrated and dilutes with methyl alcohol.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the required compound (456.1mg, 99%) of yellow oil.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d ₆)δ0.94-0.96(6H，m)，1.58-1.66(1H，m)，2.25-2.30(1H，m)，2.56-2.63(1H，m)，2.68-2.74(1H，m)，2.95-3.02(2H，m)，3.81(3H，s)，4.56-4.60(1H，m)，4.64-4.68(1H，m)，8.78(2H，s).MS：m/z?265(MH+)

Be prepared as follows (2S)-2-propane-2-base piperazine as raw material:

(2g, 8.76mmol) solution in the mixture of ETHYLE ACETATE (20ml) and methyl alcohol (20.00ml) at room temperature stirred 40 hours with 4M HCl/ diox (30ml) with (2S)-2-propane-2-base piperazine-1-t-butyl formate under nitrogen atmosphere.Reaction mixture is evaporated to dried.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 3.5M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains (2S)-2-propane-2-base piperazine (1.052g, 94%) of white solid.

(399.9MHz, DMSO-d6) (6H, m), (1H, m), (2H, m), (1H, m), (1H, m), 2.67 (1H, d), (2H, m)-2 proton does not observe 2.75-2.80 2.53-2.59 2.41-2.47 2.15-2.22 1.39-1.47 δ 0.83-0.87 1H NMR.

Embodiment 150

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-methyl-3-oxo piperazine-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.23ml; 2.46mmol) [2-(3 to drop to the 5-that is stirring; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (243mg, 0.98mmol) and 2-(4-methyl-3-oxo piperazine-1-yl) pyrimidine-5-methyl-formiate (246mg is 0.98mmol) in the suspension-s in toluene (5.00ml).The solution that obtains was stirred 24 hours down at 60 ℃.Reaction mixture is added in the methyl alcohol (100ml), use HCl (the 2N aqueous solution is 7 or lower up to pH) to handle subsequently.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains not pure products.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 0.1%TFA) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (204mg, 45%) of white solid.

1H?NMR(399.9MHz，DMSO-d ₆)δ2.88-2.91(7H，m)，3.44(2H，t)，3.72(6H，s)，4.08(2H，t)，4.33(2H，s)，6.33(1H，t)，6.40-6.47(3H，m)，8.95(2H，s)，10.66(1H，s)，12.16(1H，s).MS：m/z?466(MH+)

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.012 μ M

Be prepared as follows 2-(4-methyl-3-oxo piperazine-1-yl) pyrimidine-5-methyl-formiate as raw material:

(198mg, 1.74mmol) solution in methylene dichloride (4.00ml) adds to the 2-chloropyrimide-5-methyl-formiate that is stirring (300mg is 1.74mmol) in the solution in methylene dichloride (4.70ml) with 1-N-METHYL PIPERAZINE-2-ketone under 25 ℃.Under nitrogen atmosphere, the solution that obtains was at room temperature stirred 4 hours.Reaction mixture is concentrated and is dissolved in ETHYLE ACETATE (25ml) and NaOH (50ml, the 1M aqueous solution).With ETHYLE ACETATE (25ml) washing organic layer.Merge organic layer and with salt solution (50ml) washing, the use dried over mgso filters and is evaporated to dried, obtains 2-(4-methyl-3-oxo piperazine-1-yl) pyrimidine-5-methyl-formiate (246mg, 57%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d ₆)δ2.91(3H，s)，3.44(2H，t)，3.83(3H，s)，4.09(2H，t)，4.35(2H，s)，8.86(2H，s).MS：m/z?501(2MH+)

Embodiment 151

4-(1,2,3,4,4a, 5,7,7a-octahydro pyrrolo-[3,4-b] pyridine-6-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM

4-(1,2,3,4,4a; 5,7,7a-octahydro pyrrolo-[3,4-b] pyridine-6-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM prepares according to the method described in the embodiment 115; But raw materials used be 4-(1,2,3,4,4a; 5,7,7a-octahydro pyrrolo-[3,4-b] pyridine-6-yl) oil of Niobe (0.221g; 0.85mmol) and 5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (0.243g, 0.85mmol) with the toluene solution of 2M trimethylaluminium (1.06ml, 2.13mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.124g, 30.5%) of white solid.

1H NMR (399.9MHz, DMSO-d ₆) δ 1.36-1.45 (1H, m), 1.50-1.60 (1H, m), 1.63-1.75 (2H, m), 2.12 (1H, s), 2.27-2.38 (1H; M), 2.83 (1H, d), 3.16 (1H, d), 3.26-3.36 (2H, m), 3.37-3.45 (2H, m); 3.85 (6H, s), 5.08 (2H, s), 5.54 (1H, s), 6.44 (1H, s), 6.52 (2H; D), 6.57 (2H, s), 7.82 (2H, d), 10.46 (11.45 (1H, s) the .1 proton does not observe for 1H, s0.MS：m/z?478(MH+).

Average n=3, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0013 μ M

Be prepared as follows 4-(1,2,3,4,4a, 5,7,7a-octahydro pyrrolo-[3,4-b] pyridine-6-yl) oil of Niobe as raw material:

With 2,3,4,4a, 5,6,7, (0.813g 5mmol) is dissolved in water (10ml) and load on SCX2 post (50g) to 7a-octahydro-1H-pyrrolo-[3,4-b] pyridine dihydrochloride.Wash post with methyl alcohol, discharge free alkali from post with 7N ammonia/methyl alcohol.(0.291ml 2.25mmol) is dissolved in DMSO (10ml) and 120 ℃ of heating 12 hours down with free alkali and 4-fluorophenyl carbamate.Crude product mixture is through carrying out the ion exchange chromatography partial purification with the SCX post.Use 7M NH ₃/ MeOH is evaporated to branches at different levels dried required product wash-out from post.Crude product is through purification by silica gel column chromatography, with 0-10%3M ammonia/MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the required compound (0.230g, 17.67%) of white solid.

1HNMR(700.03MHz，CDCl3)δ：1.48-1.53(1H，m)，1.57-1.68(2H，m)，1.74-1.83(1H，m)，2.34-2.40(1H，m)，2.66-2.70(1H，m)，2.97-3.02(1H，m)，3.23-3.27(1H，m)，3.83-3.87(1H，m)，3.46-3.50(3H，m)，3.85(3H，s)，6.49(2H，d)，7.89(2H，d).MS：m/z?261(MH+).

Embodiment 152

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(1-methyl piperidine-4-yl) pyrazine-2-methane amide

At room temperature with trimethylaluminium (2M toluene solution; 1.73ml; 3.46mmol) [2-(3 to drop to the 5-that is stirring; The 5-Dimethoxyphenyl) ethyl]-(235mg is 1.00mmol) in the suspension-s in dry toluene (5.00ml) for 2H-pyrazoles-3-amine (247mg, 1.00 mmol) and 5-(1-methyl piperidine-4-yl) pyrazine-2-methyl-formiate.The solution that obtains was stirred 18 hours down at 60 ℃.With reaction mixture quencher and with HCl (the 2M aqueous solution, to pH be 7 or lower) processing in methyl alcohol (100ml), crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH is with required product wash-out from post.At this moment, white solid is precipitated out from elutriant.Through suction filtration collecting precipitation and vacuum-drying, obtain the product (90mg, 20%) of Off-white solid form.Concentrated filtrate, crystallization obtains second sample in methyl alcohol, obtains the title compound (93mg, 21%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d6)δ1.80-1.89(4H，m)，1.98-2.04(2H，m)，2.22(3H，s)，2.83-2.90(7H，m)，3.73(6H，s)，6.33(1H，t)，6.43(2H，d)，6.50(1H，d)，8.73(1H，d)，9.18(1H，d)，10.27(1H，s)，12.27(1H，s).MS：m/z?451(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0013 μ M

Be prepared as follows 5-(1-methyl piperidine-4-yl) pyrazine-2-methyl-formiate as raw material:

Under 25 ℃ with triacetyl oxygen base Peng Qinghuana (530mg; 2.50mmol) add to 5-(piperidin-4-yl) pyrazine-2-methyl-formiate in methyl alcohol (5.00ml) (221mg, 1.00mmol), formaldehyde (37% aqueous solution, 1.50ml; 20.00mmol) and acetate (0.11ml, 2.00mmol).The solution that obtains stirred 18 hours at ambient temperature.This reaction mixture of water (5ml) quencher, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 5-(1-methyl piperidine-4-yl) pyrazine-2-methyl-formiate (239mg, 100%) of yellow wax shape solid form with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl3)δ1.92-1.99(4H，m)，2.07-2.13(2H，m)，2.34(3H，s)，2.79-2.87(1H，m)，2.99-3.03(2H，m)，4.03(3H，s)，8.61(1H，d)，9.21(1H，d).MS：m/z?236(MH+).

Be prepared as follows 5-(piperidin-4-yl) pyrazine-2-methyl-formiate as raw material:

With hydrogenchloride (1 of 4M, the 4-dioxane solution, 0.37ml, 1.48mmol) add to 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl] piperidin-4-yl] pyrazine-2-methyl-formiate in MeOH (3.70ml) (120mg, 0.37mmol) in.The solution that obtains stirred 24 hours at ambient temperature.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 5-(piperidin-4-yl) pyrazine-2-methyl-formiate (83mg, 100%) of light yellow solid form with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H NMR (399.9MHz, CDCl3) δ 1.76-1.86 (2H, m), 1.92-1.97 (2H, m), 2.80 (2H; D), and 2.97-3.05 (1H, m), 3.23-3.27 (2H, m), 4.04 (3H; S), 8.61 (1H, d), 9.22 (1H, d), NH does not observe .MS:m/z 222 (MH+).

Be prepared as follows 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl] piperidin-4-yl] pyrazine-2-methyl-formiate as raw material:

Under hydrogen atmosphere, envrionment temperature and barometric point with 10% palladium on carbon (21mg; 0.20mmol) and 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3; 6-dihydro-2H-pyridin-4-yl] (183mg 0.57mmol) stirred 6 hours in ethanol (5.73ml) pyrazine-2-methyl-formiate.Through Celite diatomite filtration reaction mixture, concentrating under reduced pressure obtains yellow oil.Crude product is through purification by silica gel column chromatography, with 0-50%EtOAc/ isohexane gradient elution.Each pure level divided be evaporated to driedly, obtain 5-[1-[(2-methylpropane-2-yl) the oxygen base carbonyl] piperidin-4-yl] pyrazine-2-methyl-formiate (126mg, 68%) of yellow oily.

1H?NMR(DMSO，399.99MHz)δ1.43(9H，s)，1.58-1.68(2H，m)，1.89(2H，d)，2.88(2H，s)，3.07-3.14(1H，m)，3.92(3H，s)，4.07-4.11(2H，m)，8.78(1H，d)，9.13(1H，d).MS：m/z?322(MH+).

Be prepared as follows 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3,6-dihydro-2H-pyridin-4-yl] pyrazine-2-methyl-formiate as raw material:

Under 25 ℃, nitrogen atmosphere, saturated sodium bicarbonate aqueous solution (5.00ml) is added to 1, and the 5-chloropyrazine-2-methyl-formiate in the 2-glycol dimethyl ether (5.00ml) (173mg, 1.00mmol), 4-(4; 4,5,5-tetramethyl--1; 3,2-oxa-boron heterocycle pentane-2-yl)-3,6-dihydro-2H-pyridine-1-t-butyl formate (371mg; 1.20mmol), acid chloride (II) (11mg, 0.05mmol) and triphenylphosphine (52mg, 0.20mmol) in.The mixture that obtains was stirred 4 hours down at 80 ℃.Reaction mixture water (50mL) dilutes and washs with EtOAc (50ml).Using HCl (the 2M aqueous solution) is 1 with the pH regulator of water layer, extracts with EtOAc (2x50ml).The organic phase that merges is through dried over mgso, and concentrating under reduced pressure obtains 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3, the 6-dihydro-2H-pyridin-4-yl] pyrazine-2-formic acid (305mg, 100%) of yellow solid shape.It need not to be further purified and can directly be used for next reaction.

1H?NMR(DMSO，399.9MHz)δ1.45(9H，s)，2.64(2H，d)，3.58(2H，t)，4.13(2H，d)，7.02(1H，s)，9.01(1H，d)，9.12(1H，d)，13.40(1H，br?s).MS：m/z?306(MH+).

Embodiment 153

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl) pyrazine-2-methane amide

At ambient temperature with trimethylaluminium (2M toluene solution; 1.74ml; 3.48mmol) drop to 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine of stirring (343mg, 1.39mmol) and 5-(1-methyl-3; 6-dihydro-2H-pyridin-4-yl) (324mg is 1.39mmol) in the suspension-s in dry toluene (6.94ml) for pyrazine-2-methyl-formiate.Subsequently the solution that obtains was stirred 18 hours down at 60 ℃.With reaction mixture quencher in methyl alcohol (100ml), handle with HCl (the 2M aqueous solution is 7 or lower up to pH), carry out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (152mg, 24%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ2.33(3H，s)，2.63-2.64(4H，m)，2.86-2.89(4H，m)，3.16(2H，s)，3.73(6H，s)，6.33(1H，s)，6.43-6.43(2H，m)，6.50(1H，s)，7.04(1H，s)，8.96(1H，s)，9.17(1H，s)，10.26(1H，s)，12.28(1H，s).MS：m/z?449(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00082 μ M

Be prepared as follows 5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl) pyrazine-2-methyl-formiate as raw material:

(749mg 3.53mmol) adds to 5-(1,2 in methyl alcohol (7.00ml) with triacetyl oxygen base Peng Qinghuana under 25 ℃; 3; 6-tetrahydropyridine-4-yl) pyrazine-2-methyl-formiate (310mg, 1.41mmol), formaldehyde (37% aqueous solution, 2.10ml; 28.30mmol) and acetate (0.16ml, 2.83mmol) in.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is used saturated NaHCO ₃The aqueous solution (5ml) quencher, with methyl alcohol (10ml) dilution, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains the required compound (324mg, 98%) of brown waxy solid form with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl3)δ2.44(3H，s)，2.69-2.75(4H，m)，3.23-3.25(2H，m)，4.03(3H，s)，6.89-6.91(1H，m)，8.79(1H，d)，9.20(1H，d).MS：m/z?234(MH+).

Be prepared as follows 5-(1,2,3,6-tetrahydropyridine-4-yl) pyrazine-2-methyl-formiate as raw material:

At room temperature with hydrogenchloride (1 of 4M; The 4-dioxane solution, 1.57ml 6.29mmol) adds to 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3 in methyl alcohol (15.70ml); 6-dihydro-2H-pyridin-4-yl] pyrazine-2-methyl-formiate (502mg, 1.57mmol) in.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture water (20ml) dilution, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains the required compound (316mg, 92%) of yellow solid shape with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H NMR (399.9MHz, DMSO-d6) δ 2.47-2.54 (2H, m are partly covered by solvent peak), 2.94 (2H, t); 3.49 (2H, q), 3.92 (3H, s), 7.09-7.11 (1H, m); 9.00 (1H, d), 9.12 (1H, d), NH does not observe .MS:m/z 261 (M+MeCN+H+).

According to 5-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3, the 6-dihydro-2H-pyridin-4-yl] pyrazine-2-methyl-formiate of the method preparation of describing among the embodiment 152 as raw material.

Embodiment 154

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,5-lupetazin-1-yl] BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3; 5-lupetazin-1-yl] BM is according to the method described in the embodiment 155 preparation, difference be raw material be 4-((3R, 5S)-; 5-lupetazin-1-yl) ethyl benzoate (0.525g, 2mmol), 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.495g; 2.00mmol) and 2M trimethylaluminium (2.5ml, the toluene solution of 5.0mmol).Crude mixture is chromatography on the SCX post, with 7N ammonia/methanol-eluted fractions.Merge the branches at different levels and the evaporation that comprise product, obtain oily matter.This oily matter is suspended in methylene dichloride (20ml), and slowly crystallization goes out product.Filter, obtain title compound (0.465g, 50.2%).

1H?NMR(399.9MHz，DMSO-d6)δ1.04-1.05(6H，m)，1.92(2H，s)，2.20-2.25(2H，m)，2.80-2.82(1H，m)，2.81-2.84(1H，m)，2.87(4H，s)，3.71-3.74(2H，m)，3.73(6H，s)，6.33(1H，t)，6.40(1H，s)，6.42(2H，d)，6.95(2H，d)，7.89(2H，d)，10.30(1H，s).MS：m/z?464(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00075 μ M

Embodiment 155

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] BM

At room temperature with the toluene solution (2.500ml of 2M trimethylaluminium; 5.00mmol) drop to the 4-that stirring ((3R, 5S)-3,4; 5-tri methyl piperazine-1-yl) ethyl benzoate (0.643g; 2mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(0.495g is 2.00mmol) in the suspension-s in toluene (10ml) for 2H-pyrazoles-3-amine.Subsequently solution was heated 18 hours down at 60 ℃.With the reaction mixture cooling and with methyl alcohol (15ml) and 2N hydrochloric acid (5ml) quencher.Crude product mixture is the ion exchange chromatography purifying on the SCX post, with 7N ammonia/methanol-eluted fractions.Evaporate appropriate branches at different levels, obtain oily matter.Crude product is through purification by silica gel column chromatography, with 0-10%2.5N ammonia/MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, crystallization in the DCM/ ether obtains the title compound (0.322g, 33.7%) of Off-white solid form.

1HNMR(500.13MHz，DMSOd+CD3COOD373K)δ：1.16(6H，d)，2.34(3H，s)，2.48-2.55(2H，m)，2.66(2H，t)，2.88(4H，s)，3.69-3.75(2H，m)，3.73(3H，s)，6.28-6.92(2H，m)，6.47-6.49(2H，m)，6.92(2H，d)，7.85(2H，d).MS：m/z?478(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00045 μ M

Under 25 ℃ with triacetyl oxygen base Peng Qinghuana (5.30g, 25.00mmol) add to 4-in methyl alcohol (15ml) ((3R, 5S)-3,5-lupetazin-1-yl) ethyl benzoate (and 2.62g, 10mmol) and acetate (1.145ml, 20.00mmol) in.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is used saturated NaHCO ₃(15ml) quencher is 7 to pH, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains oily matter with required product wash-out and be evaporated to driedly from post.Crude product is used the 0-5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-((3R, 5S)-3,4,5-tri methyl piperazine-1-yl) ethyl benzoate (1.960g, 70.9%) of yellow oily.MS：m/z?277(MH+)。

Under nitrogen atmosphere will (2S, 6R)-2, the 6-lupetazin (6.85g, 60.00mmol) add to 4-ethyl fluoro benzoate in DMSO (40ml) (2.20ml, 15mmol) in, and be warmed to 120 ℃.The solution that obtains was stirred 20 hours down at 120 ℃.With reaction mixture cooling and evaporating solvent.Crude product is through purification by silica gel column chromatography, with the 0-10% ethanol/methylene gradient elution that contains 1%0.880 ammonia.Each pure level divided be evaporated to driedly, ((3R, 5S)-3,5-lupetazin-1-yl) ethyl benzoate (2.83g, 71.9%), this oily matter leaves standstill after fixing to obtain brown buttery 4-.

Embodiment 156

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) BM prepares according to the method described in the embodiment 115; But raw materials used is 4-(4-methyl isophthalic acid; 4-Diazesuberane-1-yl) oil of Niobe (0.372g, 1.5mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.371g; 1.5mmol) and the toluene solution of 2M trimethylaluminium (1.875ml, 3.75mmol).Crude product is through purification by silica gel column chromatography, with 0-10% 2.5M ammonia/MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly,, obtain the title compound (0.142g, 20.42%) of white solid the crystallization from the DCM/ ether of remaining oily matter.

1HNMR(500.13MHz，DMSOd6+CD3COOD373K)δ：2.08-2.15(2H，m)，2.69(3H，s)，2.88(4H，s)，3.11(2H，t)，3.19-3.24(2H，m)，3.56(2H，t)，3.72(3H，s)，3.74(2H，t)，6.30(1H，d)，3.32(1H，s)，6.49(2H，s)，6.79(2H，d)，7.86(2H，d).MS：m/z?464(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00081 μ M

Be prepared as follows 4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) oil of Niobe as raw material:

With the 1-methyl isophthalic acid, the 4-Diazesuberane (15.07g, 132.00mmol) add to 4-fluorophenyl carbamate in DMA (150ml) (7.76ml, 60mmol) in.The solution that obtains was stirred 40 hours down at 100 ℃.Evaporation reaction mixture is with 2M sodium hydroxide solution (50ml) quencher.Extract with DCM (3x50ml).The organic extract liquid that merges through dried over mgso, filters and is evaporated to dried with saturated brine (50ml) washing.Crude product is used the 0-10%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(4-methyl isophthalic acid, the 4-Diazesuberane-1-yl) oil of Niobe (3.59 g, 24.10%) of brown waxy solid form.

1H?NMR(399.9MHz，CDCl3)δ1.95(2H，q)，2.31(3H，s)，2.48(2H，d)，2.63-2.65(2H，m)，3.47(2H，t)，3.54-3.56(2H，m)，3.78(3H，s)，6.56-6.59(2H，m)，7.79-7.83(2H，m).

Embodiment 157

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3-dimethylamino tetramethyleneimine-1-yl) pyrazine-2-methane amide

Under 25 ℃ with N; N-dimethyl pyrrolidine-3-amine (114mg; 1.00mmol) add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in anhydrous dimethyl sulphoxide (1.75ml) (136mg, 0.35mmol) in.The solution that obtains was at room temperature stirred 20 minutes.Reaction mixture is with methyl alcohol (5.00ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains not pure products of brown buttery.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (130mg, 80%) of white solid.

1H?NMR(399.9MHz，DMSO-d ₆)δ1.86(1H，t)，2.16-2.21(1H，m)2.23(6H，s)，2.83-2.85(1H，m)，2.88(4H，s)，3.25-3.29(1H，m)，3.45-3.54(1H，m)，3.72(6H，s)，3.73-3.79(1H，m)，3.81-3.86(1H，m)，6.33(1H，t)，6.42(2H，d)，6.46(1H，s)，8.01(1H，d)，8.71(1H，d)，9.73(1H，s)，12.17(1H，s).MS：m/z?466(MH+)

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0024 μ M

Embodiment 158

5-(3-diethylamino tetramethyleneimine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

Under 25 ℃ with N; N-diethylammonium tetramethyleneimine-3-amine (142mg; 1.00mmol) add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in anhydrous dimethyl sulphoxide (1.75ml) (136mg, 0.35mmol) in.The solution that obtains was at room temperature stirred 50 minutes.Reaction mixture is with methyl alcohol (5.00ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the not pure products of brown dry film form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (141mg, 82%) of white solid.

1H?NMR(399.9MHz，DMSO-d ₆)δ0.99(6H，t)，1.80-1.90(1H，m)，2.17-2.23(1H，m)，2.56-2.68(4H，m)，2.88(4H，s)，3.20-3.26(1H，m)，3.34-3.41(1H，m)，3.43-3.50(1H，m)，3.72(6H，s)，3.73-3.78(1H，m)3.82-3.87(1H，m)，6.33(1H，t)，6.42(2H，d)，6.46(1H，s)，8.01(1H，d)，8.71(1H，d)，9.73(1H，s)，12.17(1H，s).MS：m/z?494(MH+)

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0029 μ M

Embodiment 159

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(1-ethyl piperidine-4-yl) BM

At room temperature with the toluene solution (0.413ml of 2M trimethylaluminium; 0.83mmol) be added drop-wise to 4-(1-ethyl piperidine-4-yl) oil of Niobe (0.082g; 0.33mmol) and 5-[2-(3; The 5-Dimethoxyphenyl) ethyl]-(0.082g is 0.33mmol) in the suspension-s in toluene (2ml) for 2H-pyrazoles-3-amine.Subsequently this solution was heated 18 hours down at 60 ℃.With the reaction mixture cooling, with methyl alcohol (2ml) and 2N hydrochloric acid (1ml) quencher.Reaction mixture carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is evaporated to branches at different levels dried required product wash-out from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.058g, 38.0%) of white solid.

1H?NMR(500.13MHz，DH4OAcDMSO-d6)δ1.21(3H，t)，1.26(2H，s)，1.84-1.93(1H，m)，1.95-2.04(2H，m)，2.77(2H，t)，2.89(4H，s)，2.94(2H，q)，3.34-3.40(2H，m)，3.72(6H，s)，6.30(1H，d)，6.35(1H，d)，6.41(2H，d)，7.34(2H，d)，7.89(2H，d).MS：m/z?463(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00097 μ M

Be prepared as follows 4-(1-ethyl piperidine-4-yl) oil of Niobe as raw material:

With triacetyl oxygen base Peng Qinghuana (0.397g; 1.88mmol) join the acetaldehyde (0.168ml in methyl alcohol (5ml) in batches; 3.00mmol), 4-(piperidin-4-yl) oil of Niobe hydrochloride (0.192g, 0.75mmol) and sodium acetate (0.062g, 0.75mmol) in.The solution that obtains was at room temperature stirred 18 hours.Reaction mixture is used saturated NaHCO ₃(3ml) quencher is 7 to pH, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains oily matter with required product wash-out and be evaporated to driedly from post.Crude product is used the 0-5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(1-ethyl piperidine-4-yl) oil of Niobe (0.082g, 44.2%) of colorless oil.MS：m/z?248(MH+)。

Embodiment 160

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-[3-(methoxymethyl) piperazine-1-yl] pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.596ml; 3.19mmol) [2-(3 to drop to 5-; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (314mg, 1.27mmol) and 2-(3-(methoxymethyl) piperazine-1-yl) pyrimidine-5-methyl-formiate (338mg is 1.27mmol) in the solution in toluene (6.35ml).Under nitrogen atmosphere, the mixture that obtains was stirred 18 hours down at 60 ℃.Reaction mixture is added to methyl alcohol (100ml), handle with HCl (the 2N aqueous solution is 7 or littler up to pH).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the crude product of yellow dry film form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (348mg, 57%) of white solid.

1H?NMR(399.9MHz，CDCl ₃)δ2.72-2.77(2H，m)，2.82-2.92(5H，m)，2.97-3.04(2H，m)，3.24-3.28(1H，m)，3.30(3H，s)，3.35-3.38(1H，m)，3.69(6H，s)，4.61(2H，d)，6.25-6.28(3H，m)，6.61(1H，s)，8.73(1H，s)，8.76(2H，s)，9.6(1H，s).MS：m/z?482(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0043 μ M

Be prepared as follows 2-(3-(methoxymethyl) piperazine-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃, nitrogen atmosphere with 2-chloropyrimide-5-methyl-formiate (300mg; 1.74mmol) solution in DCM (4.70ml) adds to 2-(methoxymethyl) piperazine (226mg that is stirring; 1.74mmol) and N-ethyl-N-propane-propane-(0.752ml is 4.35mmol) in the solution in DCM (4.00ml) for 2-amine for the 2-base.The solution that obtains was at room temperature stirred 6 hours.Concentrated reaction mixture also dilutes with MeOH.The mixture that filtration obtains.Filtrating is carried out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains 2-(3-(methoxymethyl) piperazine-1-yl) pyrimidine-5-methyl-formiate (346mg, 75%) of yellow solid shape.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl ₃)δ2.72-2.79(2H，m)，2.84-2.90(1H，m)，2.99-3.07(2H，m)，3.25-3.30(1H，m)，3.31(3H，s)，3.38-3.42(1H，m)，3.80(3H，s)，4.61-4.68(2H，m)，8.76(2H，s).MS：m/z?267(MH+)

Be prepared as follows 2-(methoxymethyl) piperazine as raw material:

Under hydrogen atmosphere, room temperature with 1,4-dibenzyl-2-(methoxymethyl) piperazine (1.578g, 5.08mmol) and palladium (10% palladium on carbon, 0.163g 1.53mmol) stirred 3 days at ethanol (50.8ml).Through Celite diatomite filtration reaction mixture, use washing with alcohol.The reaction mixture that obtains is evaporated to dried, obtains crude product.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains 2-(methoxymethyl) piperazine (0.559g, 84%) of yellow oily.This product need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl ₃)δ2.37-2.43(1H，m)，2.65-2.76(2H，m)，2.78-2.86(3H，m)，2.89-2.92(1H，m)，3.14-3.18(1H，m)，3.24-3.27(1H，m)，3.27(3H，s).

Be prepared as follows as 1 of raw material 4-dibenzyl-2-(methoxymethyl) piperazine:

(0.857g 21.42mmol) adds the Et that is stirring in batches with sodium hydride under 25 ℃, nitrogen atmosphere ₂Among the O (23.0ml).Under nitrogen atmosphere, add (1,4-dibenzyl piperazine-2-yl) methyl alcohol (1.411g, 4.76mmol) solution in DMF (8.0ml) in batches.The suspension-s that obtains was at room temperature stirred 1 hour.(0.454ml is 7.28mmol) at Et with methyl-iodide under 10 ℃, nitrogen atmosphere ₂Drips of solution among the O (7.0ml) adds in this reaction mixture.The mixture that obtains was at room temperature stirred 21 hours.Water (35ml) this reaction mixture of quencher is also used Et ₂O (3x50ml) extraction.Merge the washing of organic layer and water (50ml),, filter and evaporation, obtain 1 of yellow oily, 4-dibenzyl-2-(methoxymethyl) piperazine (1.580g, 107%) through dried over mgso.This product need not to be further purified and can directly use.

1H NMR (399.9MHz, DMSO-d ₆) δ 2.10-2.23 (3H, m), 2.44-2.48 (1H, m), 2.57-2.63 (3H, m); 3.21 (3H, s), 3.35-3.39 (1H, m), 3.44 (2H, d); 3.60-3.63 (1H, m), (1H, m), (10H, m) .1H is covered .MS:m/z 311 (MH+) by the water peak to 7.20-7.34 to 3.95-3.99

Embodiment 161

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3-methylamino tetramethyleneimine-1-yl) pyrazine-2-methane amide

Under 25 ℃ with hydrogenchloride (4M De dioxane solution; 0.57ml; 2.26mmol) [[[[[2-(3 for 5-for 5-for 1-to add to N-in methyl alcohol (2.80ml); The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] formamyl] pyrazine-2-yl] tetramethyleneimine-3-yl]-the N-methyl carbamic acid tert-butyl ester (312mg, 0.57mmol) in.The solution that obtains was at room temperature stirred 48 hours.React incomplete, (1.12mmol), this solution is restir 16 hours at room temperature for 4M De dioxane solution, 0.28ml to add more hydrogenchloride.Reaction mixture is with MeOH (5ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains not pure products.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (101mg, 39%) of white solid.

1H?NMR(399.9MHz，CDCl ₃)δ1.85-1.93(1H，m)，2.14-2.22(1H，m)，2.43(3H，s)，2.84-2.92(4H，m)，3.39-3.42(2H，m)，3.51-3.57(1H，m)，3.63-3.68(2H，m)，3.70(6H，s)，6.25-6.26(1H，m)，6.30(2H，d)，6.43(1H，s)，7.69(1H，d)，8.85(1H，d)，9.65(1H，s).MS：m/z452(MH+)

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.003 μ M

Be prepared as follows N-[1-[5-[[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] formamyl] pyrazine-2-yl] tetramethyleneimine-3-yl]-N-methyl carbamic acid tert-butyl ester as raw material:

Under 25 ℃ with the N-methyl-N-tetramethyleneimine-3-aminocarbamic acid tert-butyl ester (200mg; [[2-(3 for 5-1.00mmol the solution in the) Zai diox (0.75ml) adds to the 5-chloro-N-that is stirring; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] (136mg is 0.35mmol) in the solution among Zai diox (0.75ml) and the NMP (0.25ml) for pyrazine-2-methane amide.The solution that obtains was at room temperature stirred 24 hours.Therefore react incomplete, (0.06ml, 0.35mmol), this solution is restir 17 hours at room temperature to add N-ethyl-N-propane-2-base propane-2-amine.Reaction mixture is with MeOH (5ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the not pure products (312mg, 162%) of yellow oily.It need not to be further purified and can directly use.MS：m/z?552(MH+)

Embodiment 162

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(1-methyl piperidine-4-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.168ml; 2.34mmol) [2-(3 to drop to 5-; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (231mg, 0.93mmol) and 2-(1-methyl piperidine-4-yl) pyrimidine-5-methyl-formiate (220mg is 0.93mmol) in the suspension-s in dry toluene (4.671ml).The solution that obtains was stirred 2 hours down at 60 ℃.With reaction mixture impouring methyl alcohol (100ml), with 2M HCl acidifying, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is with required product wash-out from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (166mg, 39%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.80-1.88(2H，m)，1.94(2H，d)，1.98-2.03(2H，m)，2.21(3H，s)，2.80-2.85(3H，m)，2.89(4H，s)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.49(1H，s)，9.20(2H，s)，11.04(1H，s)，12.24(1H，s).MS：m/z?451(MH+).

Average n=4, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.036 μ M

Be prepared as follows 2-(1-methyl piperidine-4-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with triacetyl oxygen base Peng Qinghuana (532mg; 2.51mmol) add to 2-(piperidin-4-yl) pyrimidine-5-methyl-formiate in methyl alcohol (4.994ml) (222mg, 1.00mmol), formaldehyde (37% aqueous solution, 1.50ml; 20.07mmol) and acetate (0.115ml, 2.01mmol) in.The solution that obtains stirred 3 days at ambient temperature.Reaction mixture is with methyl alcohol (20ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 2-(1-methyl piperidine-4-yl) pyrimidine-5-methyl-formiate (223mg, 94%) of oyster white waxy solid form with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ1.77-1.88(2H，m)，1.95(2H，d)，2.00-2.07(2H，m)，2.22(3H，s)，2.83-2.90(3H，m)，3.91(3H，s)，9.19(2H，s).MS：m/z?236(MH+).

Be prepared as follows 2-piperidin-4-yl pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with hydrogenchloride (1 of 4M, the 4-dioxane solution, 3.04ml, (976mg is 3.04mmol) in the suspension-s in methyl alcohol (15.20ml) 12.15mmol) to add to 2-(1-(tert-butoxycarbonyl) piperidin-4-yl) pyrimidine-5-methyl-formiate that is stirring.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture carries out the ion exchange chromatography purifying through the SCX post.Required product uses 7M NH ₃/ MeOH wash-out and be evaporated to driedly from post obtains 2-(piperidin-4-yl) pyrimidine-5-methyl-formiate (600mg, 89%) of yellow solid shape.It need not to be further purified and can directly use.

1H NMR (399.9MHz, DMSO-d6) δ 1.63-1.73 (2H, m), 1.86-1.89 (2H, m), 2.58-2.65 (2H, m), 2.96-3.07 (3H, m), 3.91 (3H, s), 9.19 (2H, s), NH does not observe .MS:m/z 222 (MH+).

Be prepared as follows 2-[1-[(2-methylpropane-2-yl) oxygen base carbonyl] piperidin-4-yl] pyrimidine-5-methyl-formiate as raw material:

Will be under hydrogen atmosphere, normal atmosphere, the envrionment temperature at the 2-(1-(tert-butoxycarbonyl)-1 in ethanol (10ml) and the ETHYLE ACETATE (40.0ml); 2,3,6-tetrahydropyridine-4-yl) pyrimidine-5-methyl-formiate (960mg; 3.01mmol) and 10% palladium on carbon (96mg 0.09mmol) stirs 18 hours.Through Celite diatomite filtration reaction mixture; With methyl alcohol, ETHYLE ACETATE and washed with dichloromethane, concentrating under reduced pressure obtains 2-(1-(tert-butoxycarbonyl) piperidin-4-yl) pyrimidine-5-methyl-formiate (966mg of yellow oily; 100%), this oily matter leaves standstill post crystallization.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ1.42(9H，s)，1.61-1.70(2H，m)，1.97(2H，d)，2.91(2H，s)，3.10-3.16(1H，m)，3.91(3H，s)，4.03(2H，d)，9.20(2H，s).MS：322m/z(MH+).

Be prepared as follows 2-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3,6-dihydro-2H-pyridin-4-yl] pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃, nitrogen atmosphere through 2 minutes hexane solution (4.19ml with 2M (trimethyl silyl) diazomethane; 8.38mmol) drop to the 2-(1-(tert-butoxycarbonyl)-1 in toluene (12ml) and methyl alcohol (3.00ml); 2; 3,6-tetrahydropyridine-4-yl) pyrimidine-5-formic acid (1.28g, 4.19mmol) in.The solution that obtains stirred 2 hours at ambient temperature.Reaction mixture up to stopping foaming, is used EtOAc (100ml) and water (100ml) diluted reaction mixture through dripping the acetate quencher subsequently.Remove organic layer, to further extraction of water layer EtOAc (2x50ml).The organic phase that merges, is filtered and evaporation through dried over mgso with sodium hydrogencarbonate (100ml), water (100ml), salt solution (100ml) washing; Obtain 2-(1-(tert-butoxycarbonyl)-1,2,3 of yellow solid shape; 6-tetrahydropyridine-4-yl) pyrimidine-5-methyl-formiate (1.182g, 88%).It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ1.44(9H，s)，2.63-2.66(2H，m)，3.56(2H，t)，3.92(3H，s)，4.16(2H，d)，7.38(1H，s)，9.21(2H，s).MS：m/z?320(MH+).

Be prepared as follows 2-[1-[(2-methylpropane-2-yl) oxygen base carbonyl]-3,6-dihydro-2H-pyridin-4-yl] pyrimidine-5-formic acid as raw material:

Under 25 ℃, nitrogen atmosphere, saturated sodium bicarbonate aqueous solution (25.00ml) is added to 1, and the 2-chloropyrimide-5-methyl-formiate in the 2-glycol dimethyl ether (25.00ml) (0.863g, 5mmol), 4-(4; 4,5,5-tetramethyl--1; 3,2-oxa-boron heterocycle pentane-2-yl)-5,6-dihydropyridine-1 (2H)-t-butyl formate (1.855g; 6.00mmol), acid chloride (II) (0.056g, 0.25mmol) and triphenylphosphine (0.262g, 1.00mmol) in.The mixture that obtains was stirred 4 hours down at 80 ℃.Cooled reaction mixture is placed water (50ml), and with EtOAc (50ml) washing, using 2N HCl subsequently is 1 with the water layer acidifying as pH.With EtOAc (3x25ml) aqueous layer extracted, the organic layer that merges with brine wash, through dried over mgso, concentrating under reduced pressure obtains 2-(1-(tert-butoxycarbonyl)-1,2,3, the 6-tetrahydropyridine-4-yl) pyrimidine-5-formic acid (1.280g, 84%) of yellow solid shape.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ1.44(9H，s)，2.65(2H，q)，3.56(2H，t)，4.15(2H，m)，7.36(1H，s)，9.18(2H，s)，13.6(1H，s).MS：m/z?304(M-H).

Embodiment 163

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrazine-2-methane amide

Under 25 ℃ with the 1-methyl isophthalic acid, the 4-Diazesuberane (0.20ml, 1.60mmol) add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in DMSO (4.00ml) (310mg, 0.80mmol) in.The solution that obtains was at room temperature stirred 1 hour.Reaction mixture is with MeOH (5ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the crude product of orange dry film form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (296mg, 79%) of white solid.

1H NMR (399.9MHz, CDCl ₃) δ 1.95-2.01 (2H, m), 2.32 (3H, s), 2.53 (2H, t), 2.66 (2H; T), 2.84-2.92 (4H, m), 3.65-3.75 (2H, m), 3.70 (6H, s); 3.81-3.86 (2H, m), 6.26 (1H, t), 6.29 (2H, d), 6.45 (1H; S), 7.82 (1H, d), 8.83 (1H, d), 9.65 (1H, s) .MS:m/z 466 (MH+) is not observed at .1 NH peak.

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0018 μ M

Embodiment 164

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) BM prepares according to the same procedure described in the embodiment 159; But raw materials used be 4-(4-allyl group-1,4-Diazesuberane-1-yl) ethyl benzoate (0.288g, 1mmol); [2-(3 for 5-; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.247g, 1mmol) with the toluene solution of 2M trimethylaluminium (1.250ml, 2.50mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain jelly, and this jelly and DCM/ ether grind after fixing, obtain title compound (0.071g, 14.50%).

1H?NMR(399.9MHz，CDCl ₃)δ1.87-1.93(2H，m)，2.53(2H，t)，2.68(2H，t)，2.86-2.91(4H，m)，3.07(2H，d)，3.43(2H，t)，3.48(1H，t)，3.50(1H，d)，3.71(6H，s)，5.11-5.13(1H，m)，5.12-5.17(1H，m)，5.79-5.86(1H，m)，6.28(1H，t)，6.33(2H，d)，6.59(2H，d)，7.75(2H，d)，9.26(1H，s).MS：m/z?490(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00078 μ M

Be prepared as follows 4-(4-allyl group-1,4-Diazesuberane-1-yl) ethyl benzoate as raw material:

With 3-bromine third-1-alkene (0.433ml, 5.00mmol) add to 4-(1, the 4-Diazesuberane-1-yl) ethyl benzoate that stirring (1.242g, 5mmol) and DIPEA (2.183ml is 12.50mmol) in the suspension-s in methylene dichloride (20ml).Reaction mixture was stirred 24 hours under nitrogen atmosphere, room temperature.With methylene dichloride (20ml) dilution, water (2x25ml) and saturated nacl aqueous solution (20ml) washing through dried over mgso, filter and are evaporated to dried.Crude product is through purification by silica gel column chromatography, with 0-5%2.5M ammonia/MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 4-(4-allyl group-1, the 4-Diazesuberane-1-yl) ethyl benzoate (0.700g, 48.5%) of yellow oily.

1H?NMR(399.9MHz，CDCl ₃)δ1.36(3H，t)，1.94-2.00(2H，m)，2.57-2.60(2H，m)，2.75(1H，d)，2.77-2.77(1H，m)，3.10-3.12(2H，m)，3.54-3.64(4H，m)，4.31(2H，q)，5.11-5.15(1H，m)，5.11-5.19(1H，m)，5.78-5.91(1H，m)，6.62-6.66(2H，m)，7.87-7.90(2H，m).MS：m/z?289(MH+).

Will (11.01ml, 75mmol) with 1, (30.0g 300.00mmol) be warmed to 100 ℃ to the 4-Diazesuberane under nitrogen atmosphere at the 4-ethyl fluoro benzoate among the DMSO (150ml).The solution that obtains was stirred 24 hours down at 100 ℃.With reaction mixture cooling and be evaporated to dried.Reaction mixture is with 2M NaOH (150ml) quencher, with EtOAc (3x75ml) extraction, with saturated brine (100ml) washing organic layer; Through dried over mgso, filter and evaporation, obtain the 4-(1 of colorless oil; 4-Diazesuberane-1-yl) ethyl benzoate (17.43g, 94%).

Embodiment 165

4-(4-cyclopropyl-1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM

4-(4-cyclopropyl-1; 4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM according to embodiment 159 in the preparation of identical method: but raw materials used be 4-(4-cyclopropyl-1,4-Diazesuberane-1-yl) ethyl benzoate (0.288g; 1mmol), [2-(3 for 5-; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.247g, 1mmol) with the toluene solution of 2M trimethylaluminium (1.250ml, 2.50mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain jelly, and this jelly and DCM/ ether grind after fixing, obtain title compound (0.165g, 33.7%).

1H?NMR(500.13MHz，DMSOd6+CD3COOD373K)δ0.32-0.36(2H，m)，0.41-0.47(2H，m)，1.84-1.90(2H，m)，2.93-2.98(1H，m)，2.76(2H，t)，2.87(4H，s)，2.93(2H，t)，3.50-3.58(4H，m)，3.72(6H，s)，6.29(1H，s)，6.30-6.32(1H，m)，6.39(2H，d)，6.72(2H，d)，7.81(2H，d).MS：m/z?490(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.000064 μ M

Be prepared as follows 4-(4-cyclopropyl-1,4-Diazesuberane-1-yl) ethyl benzoate as raw material:

Following at 20 ℃ with sodium cyanoborohydride (0.393g; 6.25mmol) 4-(1 of processing in THF (50ml) and methyl alcohol (5ml); 4-Diazesuberane-1-yl) ethyl benzoate (0.621g; 2.5mmol), (1-ethoxy basic ring propoxy-) trimethyl silane (2.51ml, 12.50mmol) and acetate (0.286ml, 5.00mmol).The solution that obtains was stirred 18 hours down at 60 ℃.With the reaction mixture cooling, filter and be evaporated to dried.Add 1N HCl (40ml) and water (60ml), this solution extracts with ETHYLE ACETATE (3x50ml).Using solid carbonic acid potassium is 10 with the water layer alkalization as pH, and extracts with ETHYLE ACETATE (4x50ml).The organic extraction layer filters and is evaporated to dried with saturated NaCl (50ml) washing and through dried over mgso.Crude product is used the 0-5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(4-cyclopropyl-1, the 4-Diazesuberane-1-yl) ethyl benzoate (0.849g, 118%) of colorless oil.

1H?NMR(399.9MHz，CDCl ₃)δ0.33(1H，t)，0.34-0.35(1H，m)，0.36-0.41(1H，m)，0.37-0.40(1H，m)，1.29(3H，t)，1.74-1.79(1H，m)，1.84-1.90(2H，m)，2.69(2H，t)，2.86(2H，t)，3.47(2H，t)，3.49(2H，t)，4.24(2H，q)，6.58(1H，d)，6.60(1H，s)，7.81-7.84(2H，m).MS：m/z?289(MH+)(ESI+).

Embodiment 166

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-propane-2-base-1,4-Diazesuberane-1-yl) BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-propane-2-base-1,4-Diazesuberane-1-yl) BM use with embodiment 159 in identical method prepare; But raw materials used is 4-(4-sec.-propyl-1; 4-Diazesuberane-1-yl) ethyl benzoate (0.212g, 0.73mmol), 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.181g; 0.73mmol) and the toluene solution of 2M trimethylaluminium (0.913ml, 1.83mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain jelly, and this jelly and DCM/ ether grind after fixing, obtain the title compound (0.154g, 42.9%) of Off-white solid form.

1H?NMR(500.13MHz，DMSOd6+CD3COOD373K)δ1.00(6H，s)，1.85-1.90(2H，m)，2.64(2H，t)?2.80-2.85(2H，m)，2.88(4H，s)，2.94-3.01(1H，m)，3.53-3.59(4H，m)，3.72(6H，s)，6.29(1H，s)，6.30-6.32(1H，m)，6.40(2H，d)，6.73(2H，d)，7.81(2H，d).MS：m/z?492(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0007 μ M

Be prepared as follows 4-(4-sec.-propyl-1,4-Diazesuberane-1-yl) ethyl benzoate as raw material:

(0.293ml, 2mmol) with 1-sec.-propyl-1, (0.539ml, 4.00mmol) solution in DMSO 99.8MIN. (10ml) heated 18 hours down at 120 ℃ the 4-Diazesuberane with the 4-ethyl fluoro benzoate.Reaction mixture water (75ml) dilutes and extracts with ETHYLE ACETATE (3x25ml).Extraction liquid through dried over mgso, filters and is evaporated to dried with saturated nacl aqueous solution (50ml) washing.Crude product is used the 0-5%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 4-(4-sec.-propyl-1, the 4-Diazesuberane-1-yl) ethyl benzoate (0.212g, 36.5%) of yellow oily.

1H?NMR(399.9MHz，CDCl3)δ0.92(6H，d)，1.28(3H，t)，1.80-1.86(2H，m)，2.46(2H，t)，2.69(2H，t)，2.81-2.89(1H，m)，3.51(4H，t)，4.24(2H，q)，6.58(2H，d)，7.81(2H，d).MS：m/z?291(MH+)(ESI+).

Embodiment 167

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-propane-2-base-1,4-Diazesuberane-1-yl) pyrazine-2-methane amide

Under 25 ℃ with 1-sec.-propyl-1, the 4-Diazesuberane (228mg, 1.60mmol) add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in DMSO (4.00ml) (310mg, 0.80mmol) in.The solution that obtains was at room temperature stirred 2 hours.Therefore react incomplete, temperature is elevated to 60 ℃, reaction mixture restir 2 hours.Therefore react still incomplete, with reaction mixture restir 18 hours at room temperature.Reaction mixture is with MeOH (5ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the crude product of orange dry film form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (167mg, 42%) of light yellow solid form.

1H NMR (399.9MHz, CDCl ₃) δ 0.93 (6H, d), 1.83-1.89 (2H, m), 2.54 (2H, t), 2.72 (2H; T), 2.82-2.92 (5H, m), 3.70 (6H, s), 3.73-3.76 (4H, m); 6.26 (1H, d), 6.29 (2H, d), 6.43 (1H, s); 7.81 (1H, d), 8.82 (1H, d), 9.64 (1H, s) .1 NH signal do not observed .MS:m/z 494 (MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00063 μ M

Embodiment 168

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-propane-2-base-1,4-Diazesuberane-1-yl) thiophene-2-carboxamide derivatives

Under 25 ℃ with trimethylaluminium (0.751ml; 1.50mmol) [2-(3 to drop to the 5-that is stirring; The 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (148mg; 0.60mmol) and 5-(4-propane-2-base-1,4-Diazesuberane-1-yl) (178mg is 0.60mmol) in the suspension-s in toluene (3.002ml) for the thiophene-2-carboxylic acid ethyl ester.The solution that obtains was stirred 18 hours down at 60 ℃.Should add in the methyl alcohol (50ml) by cooled reaction mixture, and handle, carry out the ion exchange chromatography purifying through the SCX post with HCL (the 2M aqueous solution is to pH 7 or lower).Use 7M NH ₃/ MeOH obtains impurity with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (123mg, 41%) of yellow solid shape.

1H?NMR(399.9MHz，DMSO-d6)δ0.95-0.96(6H，m)，1.79-1.85(2H，m)，2.54-2.56(2H，m)，2.72(2H，m)，2.85(4H，s)，2.88(1H，m)，3.42-3.48(4H，m)，3.72(6H，s)，5.86(1H，d)，6.33(1H，s)，6.34(1H，s)，6.41(2H，d)，7.78(1H，d)，10.14(1H，s)，12.00(1H，s).MS：m/z498(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0015 μ M

Be prepared as follows 5-(4-propane-2-base-1,4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

At room temperature with triacetyl oxygen base Peng Qinghuana (396mg, 1.87mmol) join in batches 5-(1,4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester in acetone (1.917ml) (190mg, 0.75mmol) and acetate (0.086ml, 1.49mmol) in.The solution that obtains stirred 18 hours under envrionment temperature, nitrogen atmosphere.Reaction mixture is concentrated and water (200ml) dilution, alkalize with 2M NaOH.Water is with ether (3x100ml) extraction, and water (200ml) and saturated brine (200ml) washing successively.Organic layer filters and evaporation through dried over mgso, obtains required product 5-(4-sec.-propyl-1,4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester (181mg, 82%).It need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl ₃)δ0.99-1.01(6H，m)，1.33(3H，t)，1.89-1.95(2H，m)，2.59-2.62(2H，m)，2.75-2.77(2H，m)，2.88-2.95(1H，m)，3.48-3.52(4H，m)，4.27(2H，q)，5.77-5.78(1H，d)，7.54(1H，d).MS：m/z?297(MH+).

Be prepared as follows 5-(1,4-Diazesuberane-1-yl) thiophene-2-carboxylic acid ethyl ester as raw material:

Under 25 ℃, nitrogen atmosphere earlier with acid chloride (II) (52.1mg; 0.23mmol), subsequently with potassium tert.-butoxide (624mg, 6.49mmol) add to 5-bromothiophene-2-ethyl formate of stirring (1090mg, 4.64mmol), high piperazine (511mg; 5.10mmol) and (racemize)-(-)-2; 2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (289mg, 0.46mmol) solution in toluene (20ml).The suspension-s that obtains was stirred 3 hours down at 110 ℃.Cooled reaction mixture dilutes with MeOH, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH is required product wash-out from post, and the level that will contain required product is divided and is evaporated to driedly, obtains not pure products of brown buttery.Crude product is used 0-5%7N NH through purification by silica gel column chromatography ₃/ MeOH/DCM gradient elution is used 0-3%NH subsequently ₃/ MeOH/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain 5-(4-ethyl piperazidine-1-yl) the thiophene-2-carboxylic acid ethyl ester (195mg, 17%) of yellow oily.

1H NMR (399.9MHz, CDCl ₃) δ 1.33 (3H, t), 1.89-1.95 (2H, m), 2.88 (2H, t), 3.03-3.06 (2H, m), 3.49-3.54 (2H, m), 3.57 (2H, t), 4.27 (2H, q), 5.80 (1H, d), 7.54 (1H, d) NH does not observe .MS:m/z 255 (MH+).

Embodiment 169

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-ethyl-1,4-Diazesuberane-1-yl) pyrazine-2-methane amide

Under 25 ℃ with 1-ethyl-1, the 4-Diazesuberane (205mg, 1.60mmol) add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in DMSO (4.00ml) (310mg, 0.80mmol) in.The solution that obtains was at room temperature stirred 2 hours.Therefore react incomplete, temperature is elevated to 60 ℃, reaction mixture restir 15 minutes.Reaction mixture is with MeOH (5ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains the crude product of orange dry film form.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (228mg, 59%) of white solid.

1H?NMR(399.9MHz，CDCl ₃)δ1.00(3H，t)，1.91-1.97(2H，m)，2.50(2H，q)，2.56(2H，t)，2.72(2H，t)，2.84-2.91(4H，m)，3.69(6H，s)，3.67-3.71(2H，m)，3.79-3.82(2H，m)，6.25(1H，t)，6.29(2H，d)，6.45(1H，s)，7.81(1H，d)，8.83(1H，d)，9.68(1H，s).MS：m/z?480(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0027 μ M

Embodiment 170

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-ethyl-1,4-Diazesuberane-1-yl) BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-ethyl-1,4-Diazesuberane-1-yl) BM use with embodiment 159 in identical method prepare; But raw materials used is 4-(4-ethyl-1; 4-Diazesuberane-1-yl) ethyl benzoate (0.502g, 1.4mmol), 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (0.346g; 1.40mmol) and the toluene solution of 2M trimethylaluminium (1.750ml, 3.50mmol).Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain jelly, and this jelly and DCM/ ether grind after fixing, obtain the title compound (0.171g, 25.6%) of white solid.

1H?NMR(399.9MHz，DMSO-d ₆)δ1.00(3H，t)，1.89(2H，d)，2.53(2H，d)，2.73(4H，s)，2.87(4H，s)，3.49-3.54(2H，m)，3.54-3.58(2H，m)，3.73(6H，s)，6.33(1H，t)，6.42(3H，d)，6.73(2H，d)，7.87(2H，d)，10.17(1H，s)，12.04(1H，s).MS：m/z?478(MH+)(ESI+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00071 μ M

Be prepared as follows 4-(4-ethyl-1,4-Diazesuberane-1-yl) ethyl benzoate as raw material:

Following at 20 ℃ with sodium cyanoborohydride (0.393g; 6.25mmol) processing 4-(1; 4-Diazesuberane-1-yl) ethyl benzoate (0.621g; 2.5mmol), acetaldehyde (0.701ml, 12.50mmol) and acetate (0.286ml, 5.00mmol) solution in THF (30ml) and methyl alcohol (3ml).The solution that obtains was stirred 18 hours down at 60 ℃.With reaction mixture cooling, add additional quantity acetaldehyde (2.146ml, 38mmol) with triacetyl oxygen base Peng Qinghuana (1.060g, 5.00mmol).Reaction mixture was at room temperature stirred 18 hours.Filter reaction mixture also is evaporated to dried.Resistates is dissolved in 2N HCl (5ml) and methyl alcohol (20ml).The solution of crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains 4-(4-ethyl-1,4-Diazesuberane-1-yl) ethyl benzoate (0.526g, 76%).

1H?NMR(399.9MHz，CDCl ₃)δ1.07(3H，t)，1.36(3H，t)，1.90-2.05(2H，m)，2.52-2.61(2H，m)，2.70-2.77(2H，m)，3.54(2H，t)，3.57(2H，t)，4.29-4.34(2H，m)，6.63-6.67(2H，m)，7.86-7.90(2H，m).MS：m/z?277(MH+).

Be used as 5-[2-(3, the 5-Dimethoxyphenyl) the ethyl]-2H-pyrazoles-3-amine of raw material according to the method preparation of embodiment 2.

Embodiment 171

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-ethyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (1.25ml; 2.50mmol) drop to 2-(the 4-ethyl-1 that is stirring; 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (265mg; 1.00mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(248mg is 1.00mmol) in the suspension-s in toluene (5.01ml) for 2H-pyrazoles-3-amine.The solution that obtains was stirred 18 hours down at 60 ℃.The quencher in methyl alcohol (50ml) of cooled reaction mixture is handled with HCl (the 2M aqueous solution, to pH be 7 or lower), carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The level branch that contains required product still comprises impurity, and therefore it is concentrated into dry doubling comes purifying through crystallization from MeCN, obtains the title compound (104mg, 22%) of Off-white solid form.

1H NMR (399.9MHz, DMSO-d6) δ 0.99 (3H, t), 1.82-1.87 (2H, m), 2.48 (2H, q, the part covered by the DMSO peak), 2.52-2.57 (2H; M, part is covered by the DMSO peak), 2.71 (2H, m), 2.87 (4H, s), 3.72 (6H, s); 3.82 (2H, t), 3.87 (2H, t), 6.33 (1H, t), 6.42 (2H, d); 6.44 (1H, s), 8.88 (2H, s), 10.56 (1H, s), 12.13 (1H, s) .MS:m/z 480 (MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0092 μ M

Be prepared as follows 2-(4-ethyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with 2-chloropyrimide-5-methyl-formiate (200mg; 1.16mmol) solution in methylene dichloride (4.00ml) adds to the 1-ethyl-1 that is stirring; 4-Diazesuberane (149mg; 1.16mmol) and N-ethyl-N-propane-propane-(0.902ml is 5.22mmol) in the solution in methylene dichloride (4.00ml) for 2-amine for the 2-base.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is evaporated to dry doubling is dissolved in MeOH (20ml) again, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 2-(4-ethyl-1, the 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (268mg, 87%) of oyster white oily matter form with required product wash-out and be evaporated to driedly from post, and this oily matter leaves standstill post crystallization.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ0.98(3H，t)，1.81-1.87(2H，m)，2.45-2.50(2H，m)，2.55(2H，m)，2.70-2.72(2H，m)，3.81(3H，s)，3.82(2H，q)，3.86-3.89(2H，m)，8.79(2H，s).MS：m/z?265(MH+).

Be prepared as follows 1-ethyl-1, the 4-Diazesuberane as raw material:

Under 0 ℃, nitrogen atmosphere with lithium aluminum hydride (38.2ml, 38.19mmol) add to 1-(1,4-Diazesuberane-1-yl) ethyl ketone in THF (59.7ml) (1.697g, 11.93mmol) in.The solution that obtains stirred 1 hour at ambient temperature, stirred 1 hour down at 60 ℃ subsequently.In cooled reaction mixture impouring ice (500ml),, carry out the ion exchange chromatography purifying through the SCX post with HCl (the 2M aqueous solution) acidifying.Use 7M NH ₃/ MeOH obtains the 1-ethyl-1 of yellow liquid shape, 4-Diazesuberane (0.610g, 40%) with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl3)δ1.07(3H，t)，1.74-1.80(2H，m)，2.58(2H，q)，2.64-2.70(4H，m)，2.89-2.95(4H，m).

Embodiment 172

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) pyrazine-2-methane amide

Under 25 ℃ with 1-third-2-thiazolinyl-1; 4-Diazesuberane (224mg; 1.60mmol) add to 5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide in DMSO (4.00ml) (310mg, 0.80mmol) in.The solution that obtains was at room temperature stirred 3 hours.Reaction mixture is with MeOH (5ml) dilution, and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains orange buttery crude product.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (271mg, 69%) of yellow solid shape.

1H?NMR(399.9MHz，CDCl ₃)δ1.91-1.97(2H，m)，2.57(2H，t)，2.72(2H，t)，2.84-2.91(4H，m)，3.06(2H，d)，3.70(6H，s)，3.74-3.83(4H，m)，5.07-5.13(2H，m)，5.73-5.83(1H，m)，6.25(1H，t)，6.29(2H，d)，6.43(1H，s)，7.82(1H，d)，8.83(1H，d)，9.64(1H，s).MS：m/z492(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0034 μ M

5-chloro-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide prepares according to the method shown in the middle embodiment 105.

Embodiment 173

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-propane-2-base-1,4-Diazesuberane-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (1.19ml; 2.38mmol) (4-propane-2-basic-1 to drop to the 2-that is stirring; 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (265mg; 0.95mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(235mg is 0.95mmol) in the suspension-s in toluene (4.76ml) for 2H-pyrazoles-3-amine.The solution that obtains was stirred 18 hours down at 60 ℃.In cooled reaction mixture impouring methyl alcohol (50ml), handle with HCl (the 2M aqueous solution, to pH be 7 or lower), carry out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (81mg, 17%) of Off-white solid form.

1H NMR (399.9MHz, DMSO-d6) δ 0.94-0.95 (6H, m), 1.78 (2H, m), 2.51-2.54 (2H, m; Part is covered by the DMSO peak), 2.67-2.74 (3H, m), 2.87 (4H, s), 3.73 (6H, s); 3.82 (4H, t), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H; S), 8.88 (2H, s), 10.55 (1H, s), 12.13 (1H, s) .MS:m/z494 (MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.018 μ M

Be prepared as follows 2-(4-propane-2-base-1,4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with 2-chloropyrimide-5-methyl-formiate (209mg; 1.21mmol) solution in methylene dichloride (4.00ml) adds to the 1-propane-2-base-1 that is stirring; 4-Diazesuberane (172mg; 1.21mmol) and N-ethyl-N-propane-propane-(0.523ml is 3.02mmol) in the solution in methylene dichloride (4.00ml) for 2-amine for the 2-base.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is evaporated to dry doubling is dissolved in MeOH (20ml) again, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 2-(4-propane-2-base-1, the 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (267mg, 79%) of oyster white oily matter form with required product wash-out and be evaporated to driedly from post, and this oily matter leaves standstill post crystallization.It need not to be further purified and can directly use.

1H NMR (399.9MHz, DMSO-d6) δ 0.92-0.94 (6H, m), 1.74-1.80 (2H, m), 2.71 (2H; T), 2.82-2.89 (1H, m), 3.81 (3H, s), 3.80-3.85 (4H; M), 8.78-8.78 (2H, m), 1x (2H m) is covered MS:m/z 279 (MH+) by the DMSO peak.

Be prepared as follows 1-propane-2-base-1, the 4-Diazesuberane as raw material:

With 4-propane-2-base-1, (3.00g, 10.85mmol) (0.289g 2.71mmol) stirred 18 hours in ethanol (54.3ml) 4-Diazesuberane-1-benzyl formate with 10% palladium on carbon under hydrogen atmosphere, normal atmosphere and envrionment temperature.Reaction mixture is through the Celite diatomite filtration, and with ethanol, methyl alcohol and washed with dichloromethane, concentrating under reduced pressure is filtrated, and obtains 1-propane-2-base-1 of yellow liquid form, 4-Diazesuberane (1.54g, 100%).It need not to be further purified and can directly use.

1H?NMR(399.9MHz，CDCl3)δ1.00-1.02(6H，m)，1.69-1.74(2H，m)，1.94(1H，br?s)，2.63-2.68(4H，m)，2.87-2.94(5H，m).

Be prepared as follows 4-propane-2-base-1,4-Diazesuberane-1-benzyl formate as raw material:

At room temperature just triacetyl oxygen base Peng Qinghuana (5.79g, 27.32mmol) join in batches in acetone (5.00ml) 1,4-Diazesuberane-1-benzyl formate (2.56g, 10.93mmol) and acetate (1.251ml, 21.85mmol) in.Under nitrogen atmosphere, the solution that obtains was stirred 18 hours at ambient temperature.Reaction mixture is concentrated and water (200ml) dilution, alkalize with 2M NaOH.With ether (3x100ml) aqueous phase extracted, water (200ml) and saturated brine (200ml) washing successively subsequently.Organic layer filters and evaporation through dried over mgso, obtains required product (3.00g, 99%).It need not to be further purified and can directly use.

1H NMR (399.9MHz, DMSO-d6) δ 0.92-0.95 (6H, m), 1.63-1.69 (2H, m), 2.60 (2H; T), and 2.80-2.88 (1H, m), 3.38-3.45 (4H, m), 5.09 (2H; S), 7.29-7.40 (5H, m), (2H m) is covered MS:m/z 277 (MH+) by solvent peak.

Embodiment 174

5-(4-cyclopropyl-1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide

In 25 ℃ with 1-cyclopropyl-1; 4-Diazesuberane dihydrochloride (205mg; 0.96mmol) [[2-(3 for 5-to add to 5-chloro-N-in DMSO (4.00ml); The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl] pyrazine-2-methane amide (310mg, 0.80mmol) with N-ethyl-N-propane-2-base propane-2-amine (0.48ml, 2.80mmol) in.The solution that obtains was at room temperature stirred 24 hours.Therefore react incomplete, temperature is elevated to 80 ℃, reaction mixture restir 3 hours.Reaction mixture dilutes with MeOH (5ml).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains brown buttery crude product.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (277mg, 70%) of yellow solid shape.

1H?NMR(399.9MHz，CDCl ₃)δ0.32-0.37(2H，m)，0.38-0.43(2H，m)，1.75-1.80(1H，m)，1.86-1.92(2H，m)，2.74(2H，t)，2.83-2.92(6H，m)，3.70(6H，s)，3.70-3.77(4H，m)，6.26(1H，t)，6.29(2H，d)，6.42(1H，s)，7.82(1H，d)，8.83(1H，d)，9.64(1H，s).MS：m/z?492(MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0037 μ M

Embodiment 175

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (1.35ml; 2.70mmol) drop to the 2-(4-third-2-thiazolinyl-1 that is stirring; 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (300mg; 1.09mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(268mg is 1.09mmol) in the suspension-s in toluene (5.43ml) for 2H-pyrazoles-3-amine.The solution that obtains was stirred 18 hours down at 60 ℃.With the quencher and with HCl (the 2M aqueous solution, to pH be 7 or lower) processing in methyl alcohol (50ml) of cooled reaction mixture, carry out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (220mg, 41%) of Off-white solid form.

1H NMR (399.9MHz, DMSO-d6) δ 1.82-1.88 (2H, m), 2.53-2.57 (2H, m, the part covered by the DMSO peak), 2.71 (2H, t), 2.88 (4H; S), 3.08 (2H, d), 3.73 (6H, s), 3.83 (2H, t), 3.86-3.88 (2H, m); 5.10-5.13 (1H, m), 5.17 (1H, d), 5.77-5.87 (1H, m), 6.33 (1H, t), 6.42 (2H; D), 6.44 (1H, s), 8.89 (2H, s), 10.56 (1H, s), 12.13 (1H, s) .MS:m/z 492 (MH+).

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.007 μ M

Be prepared as follows 2-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with 2-chloropyrimide-5-methyl-formiate (200mg; 1.16mmol) solution in methylene dichloride (4.00ml) adds to the 1-third-2-thiazolinyl-1 that is stirring; 4-Diazesuberane (163mg; 1.16mmol) and N-ethyl-N-propane-propane-(0.501ml is 2.90mmol) in the solution in methylene dichloride (4.00ml) for 2-amine for the 2-base.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is evaporated to dry doubling is dissolved in MeCN (20ml) again, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains oyster white buttery required compound (304mg, 95%) with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ1.81-1.87(2H，m)，2.55(2H，m)，2.70-2.72(2H，m)，3.06-3.09(2H，m)，3.81(3H，s)，3.80-3.89(4H，m)，5.09-5.13(1H，m)，5.13-5.19(1H，m)，5.76-5.86(1H，m)，8.79(2H，d).MS：m/z?277(MH+).

Be prepared as follows 1-third-2-thiazolinyl-1, the 4-Diazesuberane as raw material:

25 ℃ down toward the high piperazinecarboxylic acid tert-butyl esters of 1-(9.73ml, 50mmol) in methylene dichloride (250ml), drip the PS-TBD resin (40g, 100mmol) and 3-bromine third-1-alkene (4.33ml, 50mmol).Mixture was stirred 2 hours.Filtering PS-TBD is evaporated to filtrating dried, is dissolved in MeOH/EtOAc (1: 9) again, with after short silicagel column filter.The filtrating that obtains is evaporated to dried, handles, at room temperature stirred subsequently 1 hour with TFA (20ml).Reaction mixture is evaporated to dry doubling is dissolved in MeOH (50ml) again, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 1-third-2-thiazolinyl-1 of light yellow oily, 4-Diazesuberane (4.07g, 58.0%) with required product wash-out and be evaporated to driedly from post.

1H?NMR(399.902MHz，CDCl3)δ1.70(m，2H)，1.98(s，1H)，2.59(m，4H)，2.85(m，4H)，3.06(m，2H)，5.07(m，2H)，5.81(m，1H)

Embodiment 176

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (1.35ml; 2.70mmol) drop to 2-(the 4-methyl isophthalic acid that is stirring; 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (270mg; 1.08mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(267mg is 1.08mmol) in the suspension-s in toluene (5.39ml) for 2H-pyrazoles-3-amine.The solution that obtains was stirred 18 hours down at 60 ℃.The quencher in methyl alcohol (50ml) of cooled reaction mixture is handled with HCl (the 2M aqueous solution, to pH be 7 or lower), carries out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The level that will contain pure required compound is divided and to be evaporated to driedly, obtains the title compound (136mg, 27%) of Off-white solid form.The level that will contain pure products is not divided and is concentrated, and through from the MeCN crystallization purifying, obtains the title compound (56.0mg, 11%) of beige solid form.

1H NMR (399.9MHz, DMSO-d6) δ 1.86-1.92 (2H, m), 2.27 (3H, s), 2.64 (2H, t); 2.88 (4H, s), 3.73 (6H, s), 3.81 (2H, t); 3.89 (2H, t), 6.33 (1H, t), 6.41-6.45 (3H, m); 8.89 (2H, s), 10.57 (1H, s), 12.13 (1H, s) .2H is covered MS:m/z 466 (MH+) by the DMSO peak.

Average n=1, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0058 μ M

Be prepared as follows 2-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with 2-chloropyrimide-5-methyl-formiate (200mg; 1.16mmol) solution in methylene dichloride (4.00ml) adds to the 1-methyl isophthalic acid that is stirring; 4-Diazesuberane (0.144ml; 1.16mmol) and N-ethyl-N-propane-propane-(0.902ml is 5.22mmol) in the solution in methylene dichloride (4.00ml) for 2-amine for the 2-base.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is evaporated to dry doubling is dissolved in MeOH (20ml) again, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 2-(4-methyl isophthalic acid, the 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (274mg, 94%) of white solid with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H NMR (399.9MHz, DMSO-d6) δ 1.86-1.89 (2H, m), 2.26 (3H, s), 2.49-2.54 (2H; M, the part by the DMSO peak cover 2.62-2.64 (2H, m), 3.81 (3H, s), 3.80-3.84 (2H; M), and 3.89-3.91 (2H, m), 8.79 (2H, d) .MS:m/z 251 (MH+)

Embodiment 177

2-(4-cyclopropyl-1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide

Under 25 ℃ with trimethylaluminium (1.402ml; 2.80mmol) drop to 2-(the 4-cyclopropyl-1 that is stirring; 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (310mg; 1.12mmol) and 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-(277mg is 1.12mmol) in the suspension-s in toluene (5.61ml) for 2H-pyrazoles-3-amine.The solution that obtains was stirred 18 hours down at 60 ℃.With the quencher and with HCl (the 2M aqueous solution, to pH be 7 or lower) processing in methyl alcohol (50ml) of cooled reaction mixture, carry out the ion exchange chromatography purifying through the SCX post.Use 7MNH ₃/ MeOH obtains not pure products with required product wash-out and be evaporated to driedly from post.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (8.00mg, 1%) of Off-white solid form.Some impure levels are divided merge and be concentrated into driedly,, obtain the title compound (51mg, 9%) of Off-white solid form through crystallization purifying from MeCN.

1H NMR (399.9MHz, DMSO-d6) δ 0.31 (2H, m), 0.41-0.44 (2H, m), 1.84-1.89 (3H, m); 2.71 (2H, t), 2.88 (4H, s), 3.73 (6H, s), 3.81-3.87 (4H; M), 6.33 (1H, t), 6.42 (2H, d), 6.44 (1H, s); 8.89 (2H, s), 10.55 (1H, s), 12.14 (1H, s), 2H is covered MS:m/z 492 (MH+) by the DMSO peak

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0073 μ M

Be prepared as follows 2-(4-cyclopropyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate as raw material:

Under 25 ℃ with 2-chloropyrimide-5-methyl-formiate (200mg; 1.16mmol) solution in methylene dichloride (4.00ml) adds to the 1-cyclopropyl-1 that is stirring; 4-Diazesuberane (247mg; 1.16mmol) and N-ethyl-N-propane-propane-(0.902ml is 5.22mmol) in the solution in methylene dichloride (4.00ml) for 2-amine for the 2-base.The solution that obtains stirred 18 hours at ambient temperature.Reaction mixture is evaporated to dry doubling is dissolved in MeOH (20ml) again, crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH obtains 2-(4-cyclopropyl-1, the 4-Diazesuberane-1-yl) pyrimidine-5-methyl-formiate (312mg, 97%) of Off-white solid form with required product wash-out and be evaporated to driedly from post.It need not to be further purified and can directly use.

1H?NMR(399.9MHz，DMSO-d6)δ0.28-0.31(2H，m)，0.40-0.45(2H，m)，1.80-1.84(2H，m)，1.85-1.89(1H，m)，2.71(2H，m)，2.85-2.88(2H，m)，3.81(3H，s)，3.82-3.88(4H，m)，8.79(2H，s).MS：m/z?277(MH+)

Embodiment 178

N-[5-[2-[3-(methylamino formyl radical) phenyl] ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM

At room temperature with the toluene solution (0.936ml of 2M trimethylaluminium; 1.87mmol) be added drop-wise to 3-(2-(5-amino-1H-pyrazole-3-yl) ethyl)-N-methyl-benzamide (0.183g that is stirring; 0.75mmol) and 4-(4-N-METHYL PIPERAZINE-1-yl) oil of Niobe (0.176g is 0.75mmol) in the suspension-s in toluene (5ml).Subsequently solution was stirred 18 hours down at 60 ℃.With the reaction mixture cooling, in the impouring methyl alcohol (5ml) and with 2N HCl (15ml) acidifying.Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, each pure level divided be evaporated to driedly, obtains oily matter.Crude product is through preparation HPLC purifying, and the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence is as eluent.The branches at different levels that will contain required compound are evaporated to dried, obtain the title compound (0.109g, 32.6%) of white solid.

1H?NMR(399.9MHz，DMSO-d6)δ1.88(3H，s)，2.23(3H，s)，2.45(4H，t)，2.87-3.02(4H，m)，3.40(4H，t)，6.39(1H，s)，6.97(2H，d)，7.37(1H，s)，7.38(2H，t)，7.65-7.67(1H，m)，7.75(1H，s)，7.90(2H，d)，8.36(1H，d)，10.36(1H，s).MS：m/z?447(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0011 μ M

Be prepared as follows 3-(2-(5-amino-1H-pyrazole-3-yl) ethyl)-N-methyl-benzamide as raw material:

(30.0ml 54.00mmol) adds to THF (60ml) and can not be cooled to-78 ℃ with the solution of 1.8M LDA in THF.Dripped acetonitrile (2.82ml 54.00mmol) added 3-(3-(methylamino formyl radical) phenyl) methyl propionate (2.99g, 13.5mmol) solution in THF (10ml) through 15 minutes.The compound that obtains was stirred 10 minutes down at-78 ℃.Reaction mixture is warmed to 5 ℃ and stirred 30 minutes, and (3.70g 54.00mmol) with ethanol (60.0ml), heats reaction mixture 18 hours down at 80 ℃ to add hydrazine hydrogen chloride.With reaction mixture cooling and be evaporated to dried.Resistates is dissolved in methyl alcohol (50ml), and crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is with required product wash-out from post.Branches at different levels are evaporated to dried, obtain oily matter.Crude product is used the 0-10%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain 3-(2-(5-amino-1H-pyrazole-3-yl) the ethyl)-N-methyl-benzamide (0.450g, 13.64%) of yellow oily.

1H NMR (399.9MHz, DMSO-d ₆) δ 2.73-2.79 (4H, m), 2.89 (1H, d), 3.18 (3H, d), 4.09 (1H, d), 5.19 (1H, s), 7.35 (1H, s), 7.35-7.37 (1H, m), 7.63-7.66 (1H, m), 7.72 (1H, s), 8.38 (1H, d)-1H do not observe MS:m/z 245 (MH+).

Be prepared as follows 3-(3-(methylamino formyl radical) phenyl) methyl propionate as raw material:

With (E)-3-[3-(methylamino formyl radical) phenyl] third-2-olefin(e) acid methyl esters (3.77g; 17.20mmol) and 10% palladium on carbon (0.458g, 0.43mmol) solution in the mixture of ethanol (100ml) and DMF (10.00ml) stirred 18 hours under the hydrogen that room temperature, air bag provide.Through Celite diatomite filtration reaction mixture, be evaporated to driedly, obtain 3-(3-(methylamino formyl radical) phenyl) methyl propionate (3.05g, 80%) of white solid.MS：m/z?222(MH+)。

Be prepared as follows (E)-3-[3-(methylamino formyl radical) phenyl] third-2-olefin(e) acid methyl esters as raw material:

(2.9g, 17.77mmol) (8.91g, 26.66mmol) solution in methylene dichloride (85ml) at room temperature stirred 18 hours with 2-triphenylphosphine subunit (phosphoranylidene) methyl acetate with 3-formyl radical-N-methyl-benzamide.Reaction mixture is evaporated to dried.Crude product is used the 0-10%MeOH/DCM gradient elution through purification by silica gel column chromatography.Each pure level divided be evaporated to driedly, obtain not pure products.Through silicagel column chromatography purification once more, with 50-100%EtOAc/ hexane gradient wash-out.Each pure level divided be evaporated to driedly, obtain (E)-3-[3-(methylamino formyl radical) phenyl] third-2-olefin(e) acid methyl esters (3.77g, 97%).

1H?NMR(399.9MHz，CDCl ₃)δ3.02-3.03(3H，m)，3.81(3H，s)，6.34(1H，s)，6.51(1H，s)，7.42-7.48(2H，m)，7.61-7.66(1H，m)，7.67(1H，d)，7.74-7.76(1H，m)，7.93(1H，t).

Be prepared as follows 3-formyl radical-N-methyl-benzamide as raw material:

With the THF solution of 2M methylamine (44mL, 5eq, 87.5mmol) add to 3-acyl radical methyl benzoate in anhydrous THF (65ml) (2.875g, 1 equivalent, 17.5mmol) in.Under nitrogen atmosphere, reaction mixture is cooled off-50 ℃.The toluene solution of slow adding 2M trimethylaluminium through 15 minutes (22ml, 2.5 equivalents, 43.75mmol).Let this reaction mixture slowly be warming up to room temperature and stirred 18 hours.Reaction mixture is with sodium tartrate aqueous solutions of potassium (50ml) quencher of 20%w/v.With also water (50ml), saturated nacl aqueous solution (50ml) washing of ETHYLE ACETATE (2x100ml) extraction,, obtain jelly through dried over mgso and reduction vaporization.Crude product is through purification by silica gel column chromatography, with 0-2.5% methyl alcohol/DCM gradient elution.Merge pure branches at different levels and evaporation, obtain the 3-formyl radical-N-methyl-benzamide (1.6502g, 58%) of pale solid form.

1H?NMR(399.9MHz，DMSO-d ₆)δ2.78-2.85(3H，m)，7.70-7.75(1H，t)，8.05-8.08(1H，m)，8.04-8.09(1H，m)，8.37-8.39(1H，d)，8.63-8.70(1H，s)，10.08(1H，s).MS：m/z?164(MH+).

Embodiment 179

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(4-ethyl piperazidine-1-yl) BM

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.51ml; 3.02mmol) drop to the 5-[(3 in toluene (6.0ml); The 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazoles-3-amine hydrochlorate (345mg, 1.21mmol) and 4-(4-ethyl piperazidine-1-yl) oil of Niobe (300mg, 1.21mmol) in.Under nitrogen atmosphere, the solution that obtains was stirred 19 hours down at 60 ℃.React incomplete, further add trimethylaluminium (0.50ml, 3.02mmol), with solution 60 ℃ of following restir 4 hours.Reaction mixture is added to methyl alcohol (100ml) also to be handled with HCl (the 2N aqueous solution is 7 or lower up to pH).Crude product carries out the ion exchange chromatography purifying through the SCX post.Some products crystallize out from pure branches at different levels, collect through vacuum filtration, obtain the title compound (95mg, 17%) of white solid.Filtrating is evaporated to dried, obtains another sample (115mg, 20%) of the title compound of white solid.Contain the impure level of each of required product and divide the purifying once more through preparation HPLC, the mixture that uses polarity water (containing 1%NH3) and MeCN decrescence obtains title bonded the 3rd sample (27mg, 5%) of white solid as eluent.

1H?NMR(399.9MHz，DMSO-d ₆)δ1.05(3H，t)，2.38(2H，q)，3.75(6H，s)，5.08(2H，s)，5.67(1H，s)，6.45(1H，t)，6.60(2H，d)，7.01(2H，d)，7.86(2H，d).

At about δ 2.5, the 4H peak is covered by the DMSO peak.At about δ 3.3, the 4H peak is by H ₂O covers at the peak.MS：m/z466(MH+)。

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.00068 μ M

4-(4-ethyl piperazidine-1-yl) oil of Niobe as raw material is prepared as follows:

Under 25 ℃ with the 1-ethyl piperazidine (3.68ml, 29.0mmol) add to 4-fluorophenyl carbamate in DMSO 99.8MIN. (29.0ml) (1.50ml, 11.6mmol) in.The solution that obtains was stirred 18 hours down at 120 ℃.Concentrated reaction mixture is with EtOAc (50ml) and water (20ml) dilution.(the 2N aqueous solution, 20ml), layering is washed with EtOAc (40ml) to add NaOH.Merge the washing of organic layer and water (40ml) and saturated brine (40ml).Organic layer filters and evaporation through dried over mgso, obtains required product (1.960g, 68%).It need not to be further purified and can use.

1H?NMR(399.9MHz，CDCl ₃)δ1.06(3H，t)，2.40(2H，q)，2.52(4H，t)，3.29(4H，t)，3.79(3H，s)，6.78-6.81(2H，m)，7.83-7.86(2H，m).MS：m/z?249(MH+)

Embodiment 180

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-ethyl piperazidine-1-yl) BM

Under 25 ℃ with trimethylaluminium (2M toluene solution; 1.51ml, 3.02mmol) drop to 5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazoles-3-amine (299mg in toluene (6.0ml); 1.21mmol) and 4-(4-ethyl piperazidine-1-yl) oil of Niobe (300mg, 1.21mmol) in.Under nitrogen atmosphere, the suspension-s that obtains was stirred 24 hours down at 60 ℃.Reaction mixture is added to methyl alcohol (100ml) also to be handled with HCl (the 2N aqueous solution is 7 or littler up to pH).Crude product carries out the ion exchange chromatography purifying through the SCX post.Use 7M NH ₃/ MeOH is required product wash-out from post, branches at different levels is evaporated to dried, obtains not pure products.Crude product (contains 7M NH through purification by silica gel column chromatography with 0-5%MeOH ₃)/DCM gradient elution.Each pure level divided be evaporated to driedly, obtain the title compound (288mg, 51%) of Off-white solid form.

1H?NMR(399.9MHz，DMSO-d ₆)δ1.05(3H，t)，2.38(2H，q)，2.50(4H，2.87(4H，s)，3.26-3.29(4H，m)，3.73(6H，s)，6.33(1H，t)，6.42(2H，d)，6.45(1H，s)，6.96(2H，d)，7.90(2H，d)，10.29(1H，s)，12.07(1H，s).MS：m/z?464(MH+).

Average n=2, FGFR kinases analysis-Caliper Echo Dosing, IC ₅₀0.0017 μ M

According to 4-(4-ethyl piperazidine-1-yl) oil of Niobe of the method preparation of describing among the embodiment 179 as raw material.

The mensuration of enzyme

Kinase whose mensuration-the Caliper of FGFR

For confirming the active inhibition of FGFR, use the Caliper technology to carry out kinase assays.

Kinase activity is determined in the micro plate of Greiner 384-hole and carries out, and the total reaction volume in every hole is 12 μ l.The active kinase whose total concn of FGFR1 is 7.2nM in each reacting hole.The substrate that is used for each mensuration is for being with fluorescently-labeled conventional peptide (length is 13 amino acid, on first K, has fluorescently-labeled KKSRGDYMTMQIG).

Before adding assay plate, compound is diluted to a series of concentration with 5% (v/v) DMSO.Being added in reaction buffer respectively in the compound plate [comprises: 50mM MOPS (Sigma, catalog number (Cat.No.) M1254)-pH6.5,0.004%Triton (Sigma, catalog number (Cat.No.) X-100), 2.4mMDTT, 12mM MgCl ₂, 408 μ M ATP] in enzyme (7.2nM [final concentration]) and substrate (3.6 μ M [final concentration]), the result makes that the final concentration of DMSO in reaction mixture is 0.8%.

At room temperature with assay plate incubation 1.5 hours; [comprise: 100mM HEPES-pH7.5,0.033%Brij-35 (Sigma, catalog number (Cat.No.) B4184) through adding damping fluid subsequently; 0.22%Caliper Coating Reagent#3 (Caliper Life Sciences; Catalog number (Cat.No.) 760050), 88mM EDTA, 5%DMSO] reaction is stopped.Use Caliper

LC3000 (it uses microfluid to measure displacement mobile between the FGFR1 tyrosine phosphorylation form of fluorescent mark peptide and this peptide) to stopping the assay plate reading subsequently.

In analysis, measure the compound of a series of concentration.The average data that each concentration and untreated control hole and 100% suppress control wells is used to obtain to suppress/curve of concentration.By these data, can measure the IC50 value or in the inhibition percent value of fixed concentration.

The inhibition per-cent at 1 μ M of explaining in the literary composition is the calculated value based on the fitting of a curve of testing generation.By the graphic representation of match, be that the effect of the compound of 1 μ M is calculated as centesimal inhibition with concentration.IC ₅₀The compound concentration that in this is measured, suppresses FGFR1 kinase activity 50%.

The FGFR inhibition test result of embodiment

Embodiment Active rank

3 A

4 A

5 A

6 A

7 A

8 A

9 A

13 B

14 B

15 A

16 B

17 B

18 B

19 B

20 A

Active: A is less than 0.3 μ M

B is greater than 0.3 μ M and less than 1 μ M

C is greater than 1 μ M and less than 30 μ M

For example embodiment 14 is 612nM.

FGFR kinase assays-Caliper Echo Dosing

Kinase activity is determined in the micro plate of Greiner 384-hole and carries out, and the total reaction volume in every hole is 12 μ l.The active kinase whose ultimate density of FGFR1 is 7.2nM in each reacting hole.Be used for each substrate of measuring for being with fluorescently-labeled conventional peptide (length is 13 amino acid, on first K, has fluorescently-labeled KKSRGDYMTMQIG).

Use Labcyte Echo 550 acoustic control liquor-transferring systems (Labcyte Echo 550acousticdroplet ejection unit) that compound directly is formulated in the assay plate.The DMSO that 120nl contains compound is accepted in each hole, makes that the ultimate density scope of before adding stop bath, measuring compound is 30 μ M to 30pM.Except that compound, each strip has minimum and maximum control wells, and maximum control wells comprises 120nl DMSO and minimum control wells comprises 120nl 10mM star shaped spore native (LC Laboratories, MA 01801, USA catalog number S-9300).In reaction buffer, [comprise: 50mM MOPS (Sigma, catalog number M1254)-pH 6.5,0.004%Triton (Sigma, catalog number X-100), 2.4mM DTT, 12mM MgCl ₂, 408 μ MATP], in the compound plate, add enzyme (7.2nM [final concentration]) and substrate (3.6 μ M [final concentration]) respectively, causing final DMSO concentration in reaction mixture is 1%.

At room temperature with assay plate incubation 1.5 hours; [comprising: 100mM HEPES-pH7.5,0.033%Brij-35 (Sigma, catalog number B4184) through adding damping fluid subsequently; 0.22%Caliper Coating Reagent#3 (Caliper Life Sciences; Catalog number 760050), 88mM EDTA, 5%DMSO] make reaction terminating.Use Caliper

The inhibition per-cent at 1 μ M of explaining in the literary composition is the calculated value based on the fitting of a curve of testing generation.By the graphic representation of match, be that the effect of the compound of 1 μ M is calculated as centesimal inhibition with concentration.IC ₅₀50% of inhibition FGFR1 kinase activity compound concentration in this is measured.Use typical curve match software package Origin ^TMCalculating should value.Surpass once if compound is determined, then IC ₅₀Value is confirmed as geometric mean.

Kinase whose mensuration-the ELISA of FGFR

For confirming the active inhibition of FGFR, use ELISA (enzyme-linked immunosorbent assay) technology to carry out kinase assays.

Kinase activity be determined at 384-hole polypropylene board (Matrix, catalog number 4311.Matrix is the part of Thermo Fisher Scientific, 22Friars Drive, and Hudson, New Hampshire 03051 carries out in USA), and each hole TV is 40 μ l.Each hole applies (Sigma, catalog number P3899) with 2 μ g polyEAY base materials and keeps spending the night under 4 ℃.This plate once and with 100 μ l50mM HEPES (pH7.4) washs once with 100 μ l PBS washing before adding kinase assays reagent subsequently.Reaction contains His ₆The FGFR kinases zone of-mark (FGFR kinases zone (amino acid 458-765, C488A, C584S) N-end and His ₆-mark merges and the TEV cleavage site is pressed following sequence encoding: [MHHHHHHEFKGSTSLYKKAGSSENLYFQGA].The most last L-Ala shows the beginning of FGFR protein sequence.According to Mohammadi etc., Cell, the 86th volume, 577-587 (1996) expresses and purifying gained protein.Each kinase reaction comprises 0.1ng His ₆The FGFR kinases zone of-mark, 50mM HEPES (pH 7.4), 0.1mM Na ₃VO ₄, 0.1mM DTT, 0.05% (v/v) Triton X100,20mM MgCl ₂, 160 μ M ATP.Be added in the test mixture of the different concns among 5% (v/v) DMSO respectively, finally being measured DMSO concentration is 1.25% (v/v).At room temperature the plate washing is made reaction terminating three times with kinase reaction incubation 45 minutes and through add 0.05%Tween with 100 μ l PBS.The 4G10-HRP antibody (Upstate Biotechnology, the UBI 16-105 that add 10000 times of dilutions that 40 μ l prepare subsequently in each plate in 0.5% (w/v) BSA/PBS.Upstate is the part of Millipore Corporation, 290Concord Road, Billerca MA 01821 USA) and at room temperature with plate incubation 1 hour.After this, add the antibody-solutions that 0.05%Tween repeated washing plate is removed all traces with 100 μ l PBS subsequently.Add 40 μ l, 50 μ g/ml3 in each plate, 3 ', 5,5 '-TMB (Sigma, catalog number T2885), contain the 0.05M phosphate-citrate salts damping fluid of 0.03% sodium perborate and at room temperature with plate incubation 12 minutes.Through adding 20 μ l 2M H ₂SO ₄Coupling reaction is stopped and being in Spectrafluor Plus at 450nm (Tecan Trading AG reads plate on Switzerland).In analysis, measure the compound of a series of concentration.The average data that each concentration and untreated control hole and 100% suppress control wells is used to obtain to suppress/curve of concentration.By these data, can measure the IC50 value or in the inhibition percent value of fixed concentration.

The inhibition per-cent at 1 μ M of explaining in the literary composition is the calculated value based on the fitting of a curve of testing generation.By the graphic representation of match, be that the effect of the compound of 1 μ M is calculated as centesimal inhibition with concentration.IC ₅₀50% of inhibition FGFR1 kinase activity compound concentration in this is measured.

The FGFR inhibition test result of embodiment

Embodiment Active type

1 A

3 A

4 A

5 A

6 A

7 A

8 A

9 A

10 A

11 A

12 A

13 B

14 B

15 A

16 B

17 B

18 B

19 A

20 A

Active: A is less than 0.3 μ M

B is greater than 0.3 μ M and less than 1 μ M

C is greater than 1 μ M and less than 30 μ M

For example embodiment 14 is 732nM.

Raji cell assay Raji

The Erk phosphorylation of cell pErk-factors stimulated growth

These are used to the ability that the evaluation test compound suppresses factors stimulated growth cell signaling in the mammal cell line with other mensuration.This obtains through the amount of measuring the Erk phosphorylation that receptor tyrosine kinase is regulated in the cell after the compound treatment.

Routinely NIH 3T3 (ECACC, 93061524) cell is passaged in the DMEM that adds 10% foetal calf serum (FCS) (Gibco BRL, 41966), 1%L-Stimulina (Gibco BRL, 25030) and converges rate and be no more than 80%.For measuring, in 96 orifice plates (Costar, 3904) with NIH 3T3 ' s with 1x10 ⁴Individual cells/well is seeded in the DMEM that adds 10% foetal calf serum, the 1%L-Stimulina (Costar, 3904) and at 37 ℃ of (+5%CO ₂) under, in the incubator of humidification incubation.In case cell adheres to (usually after incubation 4-5 hour) fully substratum is removed from each hole and carefully washed with the warm serum free medium of 100 μ l.Add subsequently that 90 μ l add the serum-free DMEM of 1%L-Stimulina in each hole and plate is reentered into 37 ℃ of (+5%CO of humidification ₂) incubator in.Second day, add 10 μ l compounds (using the DMEM of serum-free) in the plate and plate is reentered into 37 ℃ of (+5%CO of humidification by the dilution of the 10mM storing solution in DMSO ₂) in the incubator 1 hour.(Sigma F0291) stimulated NIH 3T3 cell 20 minutes at 37 ℃ of following bFGF with final concentration 3ng/ml subsequently.After stimulation, cell is through adding the fixing and incubation 20 minutes at room temperature of formaldehyde (final concentration 4%v/v).Remove stationary liquid subsequently and, at room temperature changed cell thoroughly 10 minutes subsequently through adding 50 μ l/ hole 0.1%triton/PBS/A with 100 μ l phosphate buffer salt (PBS/A) washed cells twice.Subsequently removing liquid and with 100 μ l/ hole PBS/A washed cells more than twice, add subsequently 50 μ l/ holes anti--phospho p44/42 antibody (Cell Signalling Technology, 9106), the PBS/A that usefulness adds 10%FCS is diluted to 1/500.Anti--phospho p44/42 antibody recognition Erk is in the phosphorylation of 202 threonine residues and 204 tyrosine residuess.At the room temperature incubation after 2 hours, remove antibody-solutions and with the hole with 100 μ l/ hole PBS/A washed twice.Adding adds 50 μ l/ holes, 1/250 goat anti-mouse alexafluor 488 2 anti-(the Molecular Probes of 10%FCS dilution with PBS/A; A11001) and 1/10000 Hoescht (Molecular Probes is H-3570) and at room temperature with plate lucifuge incubation 1 hour.Finally, plate stays final washing lotion with 100 μ l/ hole PBS/A washing three times in the hole before the shrouding.Use Arrayscan (Cellomics) to read plate at 350nm and 488nm place.The average fluorescent strength value (meanaverage intensity fluorescence values) that suppresses control wells for each test compound concentration, untreated control hole and 100% is used to determination test compound I C ₅₀Value.IC ₅₀Value is for suppressing the test compound concentration of 50% phosphorylation.

FGFR inhibition test result for embodiment

Embodiment Active type

1 B

2 A

7 C

8 A

9 B

10 A

11 A

18 B

Active: A is less than 0.3 μ M

B is greater than 0.3 μ M and less than 1 μ M

C is greater than 1 μ M and less than 30 μ M

For example embodiment 14 is 877nM.

Cell FGFR1-is based on the inhibition (using phosphoric acid specific one anti-and fluorescence two anti-mensuration) of the FGFR1 IIIc phosphorylation of the transient expression of cell

This mensuration is designed to detect through the antibody staining of the fixed cell that uses the ArrayScan technology for detection inhibition of the FGFR1 phosphorylation of transient expression.(for the description of ArrayScan technology referring to http://www.cellomics.com/content/menu/Arrayscan/)

Routinely the Cos-1 cell is passaged in the DMEM that adds 3% foetal calf serum (FCS) (Gibco BRL, 41966), 1%L-Stimulina (Gibco BRL, 25030) and converges rate 80%.For measuring, collect the Cos-1 cell and be used for cell transfecting converging rate 90-95%.For each 96-orifice plate, add 24 μ lLipofectamine 2000 (lipofectamine, Invitrogen, catalog number 11668-019) and incubation 5 minutes at room temperature in the 809 μ l OptiMEM (Invitrogen, catalog number 11058-021).For each 96 orifice plate, the FGFR1/pcDNA3.1 of 20 μ g, 3 ' FLAG mark (In-house clone 15, MSD 4793) is diluted to TV 833 μ l with OptiMEM.Isopyknic DNA and Lipofectamine 2000 merged (DNA: the ratio of lipid=1: 1.2) and at room temperature incubation is 20 minutes." FLAG-tag " is the mark of purifying/detection, and it comprises aminoacid sequence: N-DYKDDDDK-C." FLAG-tag " cloned at the N of FGFR1 end.This clone is total length, wild type FGFR1 IIIc shaped body.

The Cos-1 cell that uses the Coulter-counter counting to collect also further is diluted to 2.5x10 with 1%FCS/DMEM ⁵Individual cell/ml.For each 96-hole, need the 8.33ml cell.Add complicated transfection solution in the cell solution and with cell with 2.5x10 ⁵Individual cells/well is seeded in the DMEM that adds 1% foetal calf serum in 96 orifice plates (Costar, 3904), the 1%L-Stimulina and at 37 ℃ of (+5%CO ₂) under in the incubator of humidification, be incubated overnight (24 hours).Second day, in plate, add 25 μ l compounds (using the DMEM of serum-free) and plate is placed humidification, 37 ℃ of (+5%CO again by the dilution of the 10mM storing solution in DMSO ₂) in the incubator 1 hour.Use vacuum take-off that substratum is removed from the hole; Make cell fixation and incubation 20 minutes at room temperature through in each hole, adding 50 μ l100% methyl alcohol.Remove stationary liquid and with 200 μ l phosphate buffered saline (PBS)s (PBS/A) washings once subsequently, subsequently at room temperature through adding 50 μ l/ hole 0.1%triton/PBS/A with cell permeabilization 20 minutes with the hole.To change liquid thoroughly subsequently removes; Cell with 200 μ l/ hole PBS/A washing repeatedly; An anti-solution (Cell Signalling Technologies#CS3476 is diluted in the mouse anti-phospho FGFR1 among the PBS/A that contains 10%FCS+0.1%Tween20) that adds 40 μ l 1/1000 subsequently in each hole.

After 1 hour, remove antibody-solutions also once at the room temperature incubation with 200 μ l/ hole PBS/A washing holes.Add 40 μ l, 1/,500 two anti-(A11005 subsequently; Goat anti-mouse 594) solution and 1/10000Hoechst (in the PBS/A that contains 10%FCS+0.1%Tween 20 dilution) together and with plate incubation 1 hour under lucifuge, room temperature.Finally, plate with 200 μ l/ hole PBS/A washing once stays final washing lotion in the hole before the shrouding.Plate is gone up reading at Arrayscan (Cellomics).Be not used to set the scope that 0% and 100% compound suppresses by adding passage 2 (594nm) value that compound (peak) and reference compound (minimum value) hole obtain in the plate.Compound data and these value stdn are measured the dilution range that obtains the test compound that 50% of phosphorylation FGFR1 suppresses.

Cell FGFR1 (ECHO)-based on the inhibition of the FGFR1 IIIc phosphorylation of the transient expression of the use ECHO of cell technology (use phosphoric acid specificity one anti-anti-) with fluorescence two

This mensuration is designed to detect through the antibody staining of the fixed cell that uses the ArrayScan technology for detection inhibition of the FGFR1 phosphorylation of transient expression.

Routinely the Cos-1 cell is passaged in the DMEM that adds 3% foetal calf serum (FCS) (Gibco BRL, 41966), 1%L-Stimulina (Gibco BRL, 25030) and converges rate 80%.For measuring, collect the Cos-1 cell and be used for cell transfecting converging rate 90-95%.For each 96-orifice plate, add 24 μ l Lipofectamine 2000 and incubation 5 minutes at room temperature in the 809 μ l OptiMEM.For each 96 orifice plate, the FGFR1/pcDNA3.1 of 20 μ g, 3 ' FLAG mark (In-house clone15, MSD 4793) is diluted to TV 833 μ l with OptiMEM.Isopyknic DNA and liposome 2000 transfection reagents (Lipofectamine 2000) are merged (DNA: the ratio of lipid=1: 1.2) and at room temperature incubation is 20 minutes.

The Cos-1 cell that uses the Coulter-counter counting to collect also further is diluted to 2.5x10 with 1%FCS/DMEM ⁵Individual cell/ml.For each 96-hole, need the 8.33ml cell.Add the transfection solution formed by various components in the cell solution and with cell with 2.5x10 ⁵Individual cells/well is seeded in the DMEM that adds 1% foetal calf serum in 96 orifice plates (Costar, 3904), the 1%L-Stimulina and at 37 ℃ of (+5%CO ₂) under in the incubator of humidification, be incubated overnight (24 hours).

Second day, in 100%DMSO, obtaining concentration was 10mM with the compound dissolution that derives from dry sample.40 μ l compounds are added in each hole of 384Labcyte plate (Labcyte catalog number P-05525) subangle (comprising positive control (100%DMSO), negative control (10 μ M) and reference compound (250nM)).Subsequently 384 Labcyte plates are transferred to Hydra is diluted in compound in the residue hole of subangle at 1: 100.Use Quadra with the sucking-off on the assay plate of 70 μ l substratum, subsequently plate is transferred on the ECHO 550.Also 384 Labcyte compound plates are transferred on the ECHO 550.The compound of following concentration range is transferred to the assay plate on the ECHO 550: 1) 10 μ M, 2) 3 μ M, 3) 1 μ M, 4) 0.3 μ M, 5) 0.1 μ M, 6) 0.01 μ M.

Patting plate makes compound mix with cell culture medium and is allowed to condition at 37 ℃, 5%CO ₂Following incubation 1 hour.

Use vacuum take-off to remove medium; Make cell fixation and incubation 20 minutes at room temperature through in each hole, adding 50 μ l, 100% methyl alcohol.Remove stationary liquid and once subsequently, subsequently through at room temperature adding 50 μ l/ hole 0.1%triton/PBS/A with cell permeabilization 20 minutes with 200 μ l phosphate buffer salt (PBS/A) washing holes.Removing liquid after cell washs repeatedly with 200 μ l/ hole PBS/A, adds 40 μ l, 1/1,000 1 anti-solution (Cell SignallingTechnologies #CS3476 in each hole subsequently; The mouse anti of in containing the PBS/A of 10%FCS+0.1%Tween20, diluting-phospho FGFR1).

At room temperature incubation is after 1 hour, removes antibody-solutions and with the hole with 200 μ l/ hole PBS/A washing once.Add 40 μ l, 1/,500 two anti-(A11005 subsequently; Goat anti-mouse 594) solution and 1/10000 Hoechst (PBS/A with containing 10%FCS+0.1%Tween 20 dilutes together) and at room temperature with plate incubation 1 hour.Finally, this plate with 200 μ l/ hole PBS/A washing is once stayed final washing lotion in the hole, subsequently plate is sealed.This plate is gone up reading at Arrayscan (Cellomics).Be not used to set the scope that 0% and 100% compound suppresses by adding passage 2 (594nm) value that compound (peak) and reference compound (minimum value) hole obtain in the plate.Compound data and these value stdn are measured the dilution range that obtains the test compound that 50% of phosphorylation FGFR1 suppresses.

Claims

1. formula (I) compound or its pharmacy acceptable salt:

Wherein

X represents CH ₂Or O;

Y represents CH ₂

R ³Be hydrogen;

-A-(R ¹) _aRepresentative

Group; With

-B-(R ²) _bRepresentative

2. the formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein:

-A-(R ¹) _aRepresentative

Group; With

-B-(R ²) _bRepresentative

3. the formula of claim 1 (I) compound, wherein said compound is selected from:

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-methoxyl group-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-morpholine-4-base-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(4-fluorine piperidines-1-yl) methyl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-fluoro-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-3-methoxyl group-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-3-morpholine-4-base-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-2-methoxyl group-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-ethoxy ethoxy) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(piperidino) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-piperidyl methoxy base) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-piperazine-1-base-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-6-piperazine-1-base-pyridine-3-carboxamide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(dimethylaminomethyl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-hydroxyl-oxethyl) BM,

4-(2-aminopropyl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(3,3-dimethyl--piperidino) methyl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[4-(2-hydroxyethyl) piperazine-1-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(3-fluoro-piperidino) methyl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-morpholine-4-base oxethyl) BM,

4-[2-(4,4-two fluoro-piperidino) oxyethyl group]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(2-morpholine-4-base ethyl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(methyl-(tetrahydrofuran-2-ylmethyl) amino) methyl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-piperidyl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-dimethylamino-BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-5-piperazine-1-base-thiophene-2-carboxamide derivatives,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) pyridine-2-carboxamide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(the 2-dimethyl aminoethyl is amino) BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-methoxyl group-BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-6-piperazine-1-base-pyridine-3-carboxamide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl]-2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl]-3-piperazine-1-base-BM,

4-(1,4-Diazesuberane-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-1H-pyrazole-3-yl] BM,

N-[5-[2-[5-(dimethylaminomethyl)-2-furyl] ethyl]-1H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM,

N-[5-[2-(2, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(3,5-lupetazin-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-iodo-BM,

[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 1H-pyrazole-3-yl]-2-[(3-methyl isophthalic acid; 2- azoles-5-yl) methylamino] BM

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-6-(4-N-METHYL PIPERAZINE-1-yl) pyridazine-3-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-N-METHYL PIPERAZINE-1-carbonyl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-propane-2-base piperazine-1-yl) BM,

4-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM,

4-(4-cyclobutyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM,

4-(4-ethanoyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl] BM,

N-[5-[2-(3-p-methoxy-phenyl) ethyl]-1H-pyrazole-3-yl]-4-(4-methyl sulphonyl piperazine-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(1-methyl-4-piperidyl) BM,

4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM,

4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-[(4-N-METHYL PIPERAZINE-1-yl) methyl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4,5-tri methyl piperazine-1-yl) BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) thiophene-2-carboxamide derivatives,

4-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM,

4-(1-cyclopropyl piperidine-4-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,5-lupetazin-1-yl] BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM,

4-[5-[[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] formamyl] thiophene-2-yl] piperazine-1-t-butyl formate,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(1-methyl piperidine-4-yl) BM,

4-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM,

5-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxamide derivatives,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-N-METHYL PIPERAZINE-1-yl) thiophene-2-carboxamide derivatives,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3,3-lupetazin-1-yl) pyrazine-2-methane amide,

5-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(3,3-lupetazin-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,5-lupetazin-1-yl] pyrazine-2-methane amide,

5-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

5-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

4-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM,

[[2-(3 for 5-for N-; The 5-Dimethoxyphenyl) ethyl]-the 2H-pyrazole-3-yl]-4-(4-methyl-4-oxidation piperazine-4- -1-yl) BM

4-(4-cyclobutyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM,

2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] thiophene-2-carboxamide derivatives,

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] thiophene-2-carboxamide derivatives,

5-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) pyrazine-2-methane amide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,4-lupetazin-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] pyrazine-2-methane amide,

2-(4-cyclopropyl piperazine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

2-(1,3,4,6,7,8,9,9a-octahydro pyrido [2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

5-[(3R, 5S)-4-(cyano methyl)-3,5-lupetazin-1-yl]-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] pyrazine-2-methane amide,

5-[(3R, 5S)-4-(cyano methyl)-3,5-lupetazin-1-yl]-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-2-(3,4-lupetazin-1-yl) pyrimidine-5-methane amide,

2-(4-cyclopropyl piperazine-1-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

2-(3,4,6,7,8,8a-six hydrogen-1H-pyrrolo-[2,1-c] pyrazine-2-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(3,4-lupetazin-1-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-[(3R, 5S)-3,4,5-N-METHYL PIPERAZINE-1-yl] pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[4-(1-hydroxy propane-2-yl) piperazine-1-yl] BM,

N-(3-(3,5-dimethoxy benzyloxy)-1H-pyrazoles-5-yl)-2-((3R, 5S)-3,4,5-tri methyl piperazine-1-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(3,3-lupetazin-1-yl) BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(3,3-lupetazin-1-yl) thiophene-2-carboxamide derivatives,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-(4-ethyl piperazidine-1-yl) thiophene-2-carboxamide derivatives,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) thiophene-2-carboxamide derivatives,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-ethyl-3-N-METHYL PIPERAZINE-1-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(1-third-2-thiazolinyl piperidin-4-yl) BM,

4-(1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(1-Propargyl piperidin-4-yl) BM,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-5-[(3S, 5R)-3,5-lupetazin-1-yl] thiophene-2-carboxamide derivatives,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[1-(2-methoxy ethyl) piperidin-4-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-[(3S)-and 3-propane-2-base piperazine-1-yl] pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-methyl-3-oxo piperazine-1-yl) pyrimidine-5-methane amide,

4-(1,2,3,4,4a, 5,7,7a-octahydro pyrrolo-[3,4-b] pyridine-6-yl)-N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(1-methyl piperidine-4-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(1-methyl-3,6-dihydro-2H-pyridin-4-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,5-lupetazin-1-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,4,5-tri methyl piperazine-1-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-is than azoles-3-yl]-5-(3-dimethylamino tetramethyleneimine-1-yl) pyrazine-2-methane amide,

5-(3-diethylamino tetramethyleneimine-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(1-ethyl piperidine-4-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-[3-(methoxymethyl) piperazine-1-yl] pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(3-methylamino tetramethyleneimine-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(1-methyl piperidine-4-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) BM,

4-(4-cyclopropyl-1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-propane-2-base-1,4-Diazesuberane-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-propane-2-base-1,4-Diazesuberane-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-propane-2-base-1,4-Diazesuberane-1-yl) thiophene-2-carboxamide derivatives,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-ethyl-1,4-Diazesuberane-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-ethyl-1,4-Diazesuberane-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-ethyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-5-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-propane-2-base-1,4-Diazesuberane-1-yl) pyrimidine-5-methane amide,

5-(4-cyclopropyl-1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrazine-2-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-third-2-thiazolinyl-1,4-Diazesuberane-1-yl) pyrimidine-5-methane amide,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-2-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrimidine-5-methane amide,

2-(4-cyclopropyl-1,4-Diazesuberane-1-yl)-N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl] pyrimidine-5-methane amide,

N-[5-[(3, the 5-Dimethoxyphenyl) methoxyl group]-2H-pyrazole-3-yl]-4-(4-ethyl piperazidine-1-yl) BM,

N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-(4-ethyl piperazidine-1-yl) BM,

Reach the wherein pharmacy acceptable salt of any.

4. the formula of claim 1 (I) compound, wherein said compound are N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-2H-pyrazole-3-yl]-4-[(3R, 5S)-3,5-lupetazin-1-yl] BMs.

5. the formula of claim 1 (I) compound, wherein said compound is N-[5-[2-(3, the 5-Dimethoxyphenyl) ethyl]-1H-pyrazole-3-yl]-4-(3,4-lupetazin-1-yl) BM.

6. the formula of claim 1 (I) compound or its pharmacy acceptable salt are used for producing the purposes in the inhibiting medicine of FGFR warm-blooded animal in preparation.