CN101189236A

CN101189236A - Pyrazolo[1,5-a]pyridine derivatives or pharmaceutically acceptable salts thereof

Info

Publication number: CN101189236A
Application number: CNA2006800195272A
Authority: CN
Inventors: 鹈木元; 松本由之; 松枝洋平; 滨田基子; 小杉知巳; 高桑美香; 牧野弘明; 片冈健一郎; 山越优子
Original assignee: Teijin Pharma Ltd
Current assignee: Teijin Pharma Ltd
Priority date: 2005-04-07
Filing date: 2006-04-07
Publication date: 2008-05-28

Abstract

A pyrazolo[1,5-a]pyridine derivative represented by the formula (I) and a medically acceptable salt thereof have an excellent MAPKAP-K2 inhibitory activity. Therefore, a pharmaceutical comprising the compound as an active ingredient is expected to be useful for the treatment or prevention of a MAPKAP-K2-mediated disorder such as an inflammatory disorder, an autoimmune disease, destructive osteopathy, cancer and/or tumor growth.

Description

Pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt

Technical field

The present invention relates to novel pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, contain they pharmaceutical composition, contain their MAPKAP-K2 (mitogen-activated protein kinase activated protein kinase 2) and their novel intermediates as effective constituent.The invention still further relates to and contain curative or the prophylactic agent of these compounds as neurodegeneration/neurological obstacle (comprising dementia), septicemia, autoimmune disorder, destructive osteopathy, inflammatory bowel, psoriatic, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, emaciation, obesity, vasculogenesis, asthma and/or the chronic obstructive pulmonary disease (COPD) of effective constituent.

Background technology

MAPKAP-K2 (mitogen-activated protein kinase activated protein kinase 2) is a serine/threonine kinase, next-door neighbour's kinase whose downstream action of p38 (Fig. 1) in the MAPK approach that stress reaction is brought out.

This p38 kinase pathways is by relevant extracellular stimulus activation of various stress reactions such as heat, ultraviolet ray, bacteria type lipopolysaccharides and struvite cytokines.The activation of this approach causes transcribing the infiltration influential (Martin-Blanco work, Bioessays22,637-645 page or leaf) with phosphorylation, pair cell division, apoptosis, cytodifferentiation, inflammatory response and the cancer cells of initiation factor.

A lot of protein kinases beyond the p38 kinases activation MAPKAP kinases itself, for example Mnk1/2, PRAK and MSK1 (Fig. 1).This approach is for the discovery particularly important of novel anti-inflammatory disease drug.The kinase whose selective depressant of p38 is for the struvite cytokine of cell model that suppresses chronic inflammatory diseases and animal model effective (work such as Lee, Immunopharmacology47,185-201 (2000)).But the p38 kinases is rejected mouse and is had embryonic death.Proved that also the cell by above-mentioned embryonic induction has a lot of abnormalities in the cell response of basic property.Other strategy relevant with anti-inflammatory agent exploitation has: at the inhibitor of this approach of MAPKAP-K2 level.MAPKAP-K2 is present in the nuclear of irritation cell not, and cell is upset and then transfers in the tenuigenin.Known this kinases makes a lot of nuclear factors; and for example relevant heat shock protein of cytoplasmic protein with cytoprotective; with the 5-lipoxidase phosphorylation (work such as Stokoe relevant with biological protection or inflammation; FEBS Lett.313; 307-313 (1992)); work such as Werz; Proc.Natl.Acad.Sci.USA 97; 5261-5266 (2000)); work such as Heindenreich; J.Biol.Chem.274; 14434-14443 (1999)); work such as Tan; EMBO J.15; 4629-4642 (1996)); the Neufeld work; J.Biol.Chem.275,20239-20242 (2000)).Above-mentioned substrate all contains the amino acid motif (XX-Hyd-XRXXSXX,, Hyd is bulky hydrophobic residue) (work such as Stokoe, Biochem.J.296,843-849 (1993)) of the necessary uniqueness of available phosphorus acidifying that MAPKAP-K2 causes here.

At present, MAPKAP-K2 is the unique p38 kinase substrate that identifies special function.The special effect of MAPKAP-K2 is rejected mouse (MAPKAP-K2 by MAPKAP-K2 in the inflammatory response intermediary ^-/-) phenotype show (Kotlyarov etc. work, Nature Cell Biol.1,94-97 (1999)) strongly.This mouse can survive, and is all normal except that inflammatory response is few especially.The disappearance that has proved MAPKAP-K2 recently can cause the protection (work such as Wang, J.Biol.Chem.277,43968-43972 (2002)) from the special neurocyte of ischemic brain injury.Think that MAPKAP-K2 regulates translation and/or the stability of the mRAN of important struvite cytokine.This may be that described protein combines with the key element of finding in the untranslated zone of these cytokines that is rich in AU because MAPKAP-K2 makes protein phosphorylation.These proteinic evaluations at present just under study for action.

Have report to point out: MAPKAP-K2 has the unusual activity (work such as Isaac A.Manke, Molecular Cell 17,37-48 (2005)) of DNA that reparation is caused by ultraviolet ray.The activity of inhibition MAPKAP-K2 then can't be repaired the damage of DAN according to the type of cancer cells, and dead possibility is arranged.

Above content shows that the MAPKAP-K2 inhibitor is effective for neurodegeneration/neurological obstacle (comprising dementia), septicemia, autoimmune disorder, destructive osteopathy, inflammatory bowel, psoriatic, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, emaciation, obesity, vasculogenesis, asthma and/or chronic obstructive pulmonary disease (COPD).

The MAPKAP-K2 inhibitor is known WO2004/054504, WO2004/054505, WO2004/055015, WO2004/055019, WO2004/058176, WO2004/058762, WO2004/099127, WO2005/009370, WO2005/007092, WO2004/076458, WO2004/081013, but different with compound structure of the present invention.

Pyrazolo [1,5-a] pyridine derivate is known WO2004/026872, WO2005/028445 and WO2005/077948.But these compounds are different with compound structure of the present invention, perhaps for example in WO2005/077948 in the disclosed compound, and concrete R ³Also unexposed for the compound of hydroxyl or amino, R is only disclosed ³Be the compound of methyl, specifically do not disclose compound of the present invention in these documents, and target enzyme is also different.

Summary of the invention

The object of the present invention is to provide novel pyrazolo [1, the 5-a] pyridine derivate or its medically acceptable salt that can be used as the MAPKAP-K2 inhibitor.

The curative or the prophylactic agent of MAPKAP-K2 inhibitor that the present invention also aims to provide novel or novel neurodegeneration/neurological obstacle (comprising dementia), septicemia, autoimmune disorder, destructive osteopathy, inflammatory bowel, psoriatic, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, emaciation, obesity, vasculogenesis, asthma and/or chronic obstructive pulmonary disease (COPD).

The new intermediate of the MAPKAP-K2 inhibitor that the present invention also aims to provide novel.

The inventor has carried out deep research, found that: the novel pyrazole shown in the following formula (I) is [1,5-a] pyridine derivate and the excellent MAPKAP-K2 inhibition activity of pharmaceutically acceptable salt demonstration thereof also, thereby has finished the present invention.

That is, the present invention is as follows:

＜1〉[1, the 5-a] pyridine derivate of the pyrazolo shown in the formula (I) or its medically acceptable salt:

[in the formula (I),

R ¹Expression can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical

R ¹Substituting group be selected from halogen atom, cyano group, nitro, can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical ,-OR ^1a,-SR ^1b,-NR ^1cR ^1d,-C (=O) R ^1e,-S (=O) ₂NR ^1fR ^1g,-C (=O) OR ^1h,-C (=O) NR ¹ⁱR ^1j,-NR ^1kC (=O) R ^1lWith-NR ^1mS (=O) ₂R ¹ⁿMore than one substituting group,

R ^1x(x represents a, b, c, d, e, f, g, h, i, j, k, l, m or n) can be identical or different, represents hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C8 alkyl ^1xThe C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl or can substituted aliphatic Heterocyclylalkyl

R ¹For can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical, and this R ¹On be combined with two above R ¹Substituting group the time, these substituting groups can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring,

R ²The expression hydrogen atom, can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aromatic heterocycle alkyl

R ²Substituting group for be selected from halogen atom, cyano group, nitro, can substituted C1-C8 alkyl ,-OR ^2a,-SR ^2b,-NR ^2cR ^2d,-C (=O) R ^2e,-S (=O) ₂NR ^2fR ^2g,-C (=O) OR ^2h,-C (=O) NR ²ⁱR ^2j,-NR ^2kC (=O) R ^2lWith-NR ^2mS (=O) ₂R ²ⁿMore than one substituting group,

R ^2y(y represents a, b, c, d, e, f, g, h, i, j, k, l, m or n) can be identical or different, represents hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C8 alkyl ^2yThe C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl

R ²For can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical, and this R ²On be combined with two above R ²Substituting group the time, these substituting groups can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring.

R ³Expression can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical,

R ³Substituting group for be selected from halogen atom, cyano group, nitro ,-OR ^3a,-SR ^3b,-NR ^3cR ^3d, can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl and more than one substituting group that can substituted aliphatic heterocyclic radical,

R ^3z(z represents a, b, c or d) can be identical or different, represents hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C8 alkyl ^3zThe C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl

R ¹, R ²And R ³Substituent substituting group when not specifying, be to be selected from halogen atom, hydroxyl, cyano group, nitro, amino, the oxo base, carboxyl, trifluoromethyl, pentafluoroethyl group, trifluoromethoxy, can be by (halogen atom, hydroxyl, cyano group or oxo base) the C1-C8 alkyl that replaces, can be by (methyl, halogen atom, hydroxyl, cyano group or oxo base) the C3-C8 ester ring type alkyl that replaces, can be by (halogen atom, hydroxyl or cyano group) the C1-C8 alkoxyl group that replaces, can be by (methyl, halogen atom, hydroxyl, or cyano group) the C3-C8 ester ring type-oxyl of Qu Daiing, can be by (methyl, halogen atom, hydroxyl or cyano group) the aliphatic heterocyclic radical that replaces, can be by (methyl, halogen atom, hydroxyl or cyano group) the C6-C14 aromatic hydrocarbyl that replaces, and can be by (methyl, halogen atom, hydroxyl or cyano group) the more than one substituting group of the aromatic heterocyclic radical that replaces].

＜2〉[1, the 5-a] pyridine derivate of pyrazolo＜1〉or its medically acceptable salt, wherein, R ¹Expression can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical

R ¹Substituting group for be selected from halogen atom, cyano group, nitro, can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical ,-OR ^1a,-SR ^1b,-NR ^1cR ^1d,-C (=O) R ^1e,-S (=O) ₂NR ^1fR ^1g,-C (=O) OR ^1h,-C (=O) NR ¹ⁱR ^1j,-NR ^1kC (=O) R ^1lWith-NR ^1mS (=O) ₂R ¹ⁿMore than one substituting group,

R ²Substituting group for be selected from halogen atom, cyano group, nitro, can substituted C1-C8 alkyl ,-OR ^2a,-SR ^2b,-NR ^2cR ^2d,-C (=O) R ^2e,-S (=O) ₂NR ^2fR ^2g,-C (=O) OR ^2h,-C (=O) NR ²ⁱR ^2j,-NR ^2kC (=O) R ^2l, and-NR ^2mS (=O) ₂R ²ⁿMore than one substituting group,

R ²For can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical, and this R ²On be combined with two above R ²Substituting group the time, these substituting groups can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring,

R ³Substituting group for be selected from halogen atom, cyano group, nitro ,-OR ^3a,-SR ^3b,-NR ^3cR ^3d, can substituted C1-8 alkyl, can substituted C3-C8 ester ring type alkyl and the more than one substituting group of aliphatic heterocyclic radical,

R ¹, R ²And R ³Substituent substituting group when not specifying, for being selected from halogen atom, hydroxyl, cyano group, nitro, amino, can be by (halogen atom, hydroxyl, cyano group or oxo base) the C1-C8 alkyl that replaces, can be by (methyl, halogen atom, hydroxyl, cyano group or oxo base) the C3-C8 ester ring type alkyl that replaces, can be by (halogen atom, hydroxyl or cyano group) the C1-C8 alkoxyl group that replaces, can be by (methyl, halogen atom, hydroxyl or cyano group) the C3-C8 ester ring type-oxyl that replaces, can be by (methyl, halogen atom, hydroxyl or cyano group) the aliphatic heterocyclic radical that replaces, can be by (methyl, halogen atom, hydroxyl or cyano group) the C6-C14 aromatic hydrocarbyl that replaces, with can be by (methyl, halogen atom, hydroxyl or cyano group) the more than one substituting group of the aromatic heterocyclic radical that replaces.

＜3〉＜1〉or＜2 pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, except the following situation:

R ¹Be C1-C6 alkyl that do not have to replace or replaced by fluorine atom or the C3-C7 ester ring type alkyl that does not have replacement, R ²For do not have to replace or by (halogen atom, hydroxyl or-NR ^2cR ^2d) C1-C6 alkyl that replaces or the C3-C7 ester ring type alkyl (R that does not have replacement ^2cOr R ^2dIndependent separately, can be identical or different, for hydrogen atom, do not have the C1-C6 alkyl that replaces or replaced by fluorine atom or a C3-C7 ester ring type alkyl that does not have replacement), and R ³For there not being the C1-C6 alkyl that replaces;

R ¹Be the phenyl that does not have the C1-C6 alkyl that replaces or do not have replacement or replaced, R by halogen atom ²For do not have to replace or by (halogen atom ,-OH or-NR ^2cR ^2d) C1-C6 alkyl that replaces or the C3-C7 ester ring type alkyl (R that does not have replacement ^2cOr R ^2dIndependent separately, can be identical or different, for hydrogen atom, do not have replace or C1-C6 alkyl that fluorine replaces or do not have the C3-C7 ester ring type alkyl of replacement), and R ³Be C1-C6 alkyl that do not have to replace or replaced by fluorine atom or the C3-C7 ester ring type alkyl that does not have replacement;

R ¹Be quilt (NR ^1cR ^1d,-NR ^1k-CO-R ^1l, or-NR ^1mS (=O) ₂R ¹ⁿ) (C1-C8 alkyl or the C3-C8 ester ring type alkyl) that replace, and R ³Do not replace or OR for having ^3aThe alkyl that replaces.

＜4〉＜1〉or＜2 pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ¹For by (fluorine atom ,-NR ^1cR ^1d,-NR ^1k-CO-R ^1lOr NR ^1mS (=O) ₂R ¹ⁿ) the C1-C8 alkyl that replaces of in addition group, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, the C6 aromatic hydrocarbyl that replaced by the group beyond the halogen atom, can substituted C7-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, quilt (NR ^1cR ^1d,-NR ^1k-CO-R ^1l, or-NR ^1mS (=O) ₂R ¹ⁿ) the C3-C8 ester ring type alkyl that replaces of in addition group or can substituted aliphatic heterocyclic radical,

R ³For by fluorine atom or-OR ^3aThe C1-C8 alkyl that in addition group replaces, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical.

＜5〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜4〉or its medically acceptable salt, wherein, R ¹For can substituted C1-C8 alkyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl or can substituted C3-C8 ester ring type alkyl.

＜6〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜4〉or its medically acceptable salt, wherein, R ¹For can substituted C1-C8 alkyl, can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical.

＜7〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜4〉or its medically acceptable salt, wherein, R ¹For can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical.

＜8〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜4〉or its medically acceptable salt, wherein, R ¹For can substituted phenyl.

＜9〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜4〉or its medically acceptable salt, wherein, R ¹For can substituted aromatic heterocyclic radical.

＜10〉[1, the 5-a] pyridine derivate of pyrazolo＜9〉or its medically acceptable salt, wherein, R ¹Be have phenyl with can the heterocyclic fused structure of substituted monocyclic aromatic, and 7 NH group bonded aromatic heterocyclic radicals of pyrazolo [1, the 5-a] pyridine derivate of this phenyl one side and formula (I).

＜11〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜4〉or its medically acceptable salt, wherein, R ¹Be can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl.

＜12〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group for being selected from fluorine atom; the chlorine atom; cyano group; nitro; can substituted C1-C6 alkyl; can substituted C3-C8 ester ring type alkyl; can substituted C1-C6 alkoxyl group; can substituted C1-C6 alkylthio; can substituted phenyl; can substituted aromatic heterocyclic radical; can substituted C1-C6 acyl group; can substituted C1-C6 acyl amino; can substituted amino-sulfonyl (when this amino-sulfonyl has two alkyl substituents; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted C2-C7 alkoxy carbonyl; can substituted sulfuryl amino; and can substituted formamyl (when this formamyl has two alkyl substituents; they are independent separately; can be identical or different, can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring) more than one substituting group.

＜13〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group for being selected from fluorine atom; the chlorine atom; cyano group; nitro; can substituted C1-C6 alkylthio; can substituted C1-C6 acyl group; can substituted C1-C6 acyl amino; can substituted amino-sulfonyl (when this amino-sulfonyl has two alkyl substituents; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted C2-C7 alkoxy carbonyl; can substituted sulfuryl amino; and can substituted formamyl (when this formamyl has two alkyl substituents; they are independent separately; can be identical or different, can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring) more than one substituting group.

＜14〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group be selected from fluorine atom, chlorine atom, cyano group, nitro, can substituted phenyl and more than one substituting group that can substituted aromatic heterocyclic radical.

＜15〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group be to be selected from a substituting group of can substituted phenyl, can substituted aromatic heterocyclic radical, and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom, cyano group and nitro.

＜16〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group for the C1-C6 alkyl that is selected from fluorine atom, chlorine atom, cyano group, can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace, the more than one substituting group of the C3-C8 ester ring type alkyl that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace and the C1-C6 alkyl that replaced by (can substituted C1-C6 alkoxyl group or can substituted C3-C6 ester ring type-oxyl); C3-C6 ester ring type-oxyl) the more than one substituting group of the C1-C6 alkyl of Qu Daiing; Substituting group that wherein can substituted C1-C6 alkoxyl group is the more than one substituting group that is selected from halogen atom, hydroxyl and cyano group, and substituting group that can substituted C3-C6 ester ring type-oxyl is the more than one substituting group that is selected from methyl, halogen atom, hydroxyl, cyano group and oxo base.

＜17〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group be the C3-C8 ester ring type alkyl that is selected from the C1-C6 alkyl that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace, can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replaces and the more than one substituting group of substituted C1-C6 alkyl, and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom and cyano group; Wherein, the substituting group of substituted C1-C6 alkyl is the C1-C6 alkoxyl group that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace or the C3-C6 ester ring type-oxyl that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl, cyano group and oxo base) and replace.

＜18〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group for being selected from the more than one substituting group of can substituted C1-C6 alkyl (1) and can substituted C1-C6 alkyl (2), and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom, cyano group and methyl; Wherein, substituting group that can substituted C1-C6 alkyl (1) is the more than one substituting group that is selected from carboxyl, oxo base and can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) the C1-C6 alkoxyl group that replaces, and substituting group that can substituted C1-C6 alkyl (2) is the aromatic heterocyclic radical that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl and cyano group) and replace or the aliphatic heterocyclic radical that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl and cyano group) and replace.

＜19〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹The C1-C6 alkyl that replaced for can (being selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) of substituting group.

＜20〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group for being selected from fluorine atom, the chlorine atom, cyano group, can (be selected from halogen atom, the more than one substituting group of hydroxyl and cyano group) the C1-C6 alkoxyl group of Qu Daiing, (this aliphatic series heterocyclic radical can (be selected from methyl to the C1-C6 alkoxyl group that is replaced by aliphatic heterocyclic radical, halogen atom, the more than one substituting group of hydroxyl and cyano group) replaces), and [can (be selected from halogen atom, the more than one substituting group of hydroxyl and cyano group) the C1-C6 alkoxyl group of Qu Daiing or can (be selected from methyl, halogen atom, hydroxyl, the more than one substituting group of cyano group and oxo base) the C3-C6 ester ring type-oxyl of Qu Daiing] the more than one substituting group of the C1-C6 alkoxyl group that replaces.

＜21〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group can substituted C1-C6 alkoxyl group (1) for being selected from, the C1-C6 alkoxyl group (2) that replaced by aliphatic heterocyclic radical and the more than one substituting group of substituted C1-C6 alkoxyl group (3), and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom and cyano group; Wherein, substituting group that can substituted C1-C6 alkoxyl group (1) is the more than one substituting group that is selected from halogen atom, hydroxyl and cyano group; The more than one substituting group that the aliphatic series heterocyclic radical can be selected from methyl, halogen atom, hydroxyl and cyano group replaces; The substituting group of substituted C1-C6 alkoxyl group (3) is the C1-C6 alkoxyl group that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace or the C3-C6 ester ring type-oxyl that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl, cyano group and oxo base) and replace.

＜22〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹Substituting group be the more than one substituting group that is selected from the C1-C6 alkoxyl group (2) of can substituted C1-C6 alkoxyl group (1) and can be replaced by aromatic heterocyclic radical, and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom, cyano group and methyl; Wherein, substituting group that can substituted C1-C6 alkoxyl group (1) is the more than one substituting group that is selected from carboxyl, oxo base and can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) the C1-C6 alkoxyl group (3) that replaces; The more than one substituting group that aromatic heterocyclic radical can be selected from methyl, halogen atom, hydroxyl and cyano group replaces.

＜23〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜11〉or its medically acceptable salt, wherein, R ¹The C1-C6 alkoxyl group that replaced for can (being selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) of substituting group.

＜24〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜23〉or its medically acceptable salt, wherein, R ²For hydrogen atom, can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl or can substituted C3-C8 ester ring type alkyl.

＜25〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜24〉or its medically acceptable salt, wherein, R ²For hydrogen atom, can substituted C1-C6 alkyl, can substituted C2-C6 thiazolinyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C12 phenylalkyl or can substituted C3-C6 ester ring type alkyl.

＜26〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜23〉or its medically acceptable salt, wherein, R ²For hydrogen atom, can substituted C1-C6 alkyl, can substituted C2-C6 thiazolinyl or can substituted C3-C6 ester ring type alkyl.

＜27〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜23〉or its medically acceptable salt, wherein, R ²For can substituted C1-C6 alkyl or can substituted C2-C6 thiazolinyl.

＜28〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜23〉or its medically acceptable salt, wherein, R ²For can substituted C1-C4 alkyl.

＜29〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜23〉or its medically acceptable salt, wherein, R ²Be hydrogen atom.

＜30〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜23〉or its medically acceptable salt, wherein, R ²For can substituted phenyl or can substituted aromatic heterocyclic radical.

＜31〉＜1 〉-＜4 〉,＜24 〉-＜30 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ²Substituting group for being selected from halogen atom; cyano group; nitro; hydroxyl; can substituted amino (when two alkyl substituents are arranged on this amino; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted C1-C6 alkyl; can substituted C1-C6 alkoxyl group; can substituted C1-C6 acyl group; can substituted amino-sulfonyl (when this amino-sulfonyl has two alkyl substituents; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted sulfuryl amino; and can substituted formamyl (when two alkyl substituents are arranged on this formamyl; they are independent separately; can be identical or different, can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring) more than one substituting group.

＜32〉＜1 〉-＜4 〉,＜24 〉-＜30 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ²Substituting group for be selected from halogen atom, cyano group, nitro, hydroxyl, can substituted amino (when two alkyl substituents are arranged on this amino; they are independent separately; can be identical or different; can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C1-C6 acyl group and can substituted formamyl (when two alkyl substituents are arranged on this formamyl; they are independent separately; can be identical or different, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring) more than one substituting group.

＜33〉＜1 〉-＜4 〉,＜24 〉-＜30 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ²Substituting group for be selected from halogen atom, cyano group, nitro, hydroxyl, can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C1-C6 alkyl and more than one substituting group that can substituted C1-C6 alkoxyl group.

＜34〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜33〉or its medically acceptable salt, wherein, R ³For can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical.

＜35〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜33〉or its medically acceptable salt, wherein, R ³For can substituted C3-C8 ester ring type alkyl or can substitutedly have 1-4 nitrogen-atoms as heteroatomic aliphatic heterocyclic radical.

＜36〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜33〉or its medically acceptable salt, wherein, R ³For can substituted C5-C6 ester ring type alkyl or can substituted (piperidyl, pyrrolidyl or six hydrogen azepine  yls).

＜37〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜33〉or its medically acceptable salt, wherein, R ³For can substituted cyclohexyl, can substituted piperidyl or can substituted pyrrolidyl.

＜38〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜33〉or its medically acceptable salt, wherein, R ³For can substituted piperidyl.

＜39〉[1, the 5-a] pyridine derivate of each pyrazolo＜1 〉-＜33〉or its medically acceptable salt, wherein, R ³For can substituted C1-C4 alkyl.

＜40〉＜1 〉-＜4 〉,＜34 〉-＜39 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ³Substituting group for be selected from fluorine atom, hydroxyl, cyano group, can substituted C1-C6 alkyl and can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring) more than one substituting group.

＜41〉＜1 〉-＜4 〉,＜34 〉-＜39 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ³Substituting group for being selected from fluorine atom, hydroxyl, cyano group, can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can be via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound interosculate and form ring), can substituted C5-C6 ester ring type alkyl [substituting group is can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can be via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound interosculate and form ring)], and can substituted (piperazinyl, piperidyl or pyrrolidyl) the more than one substituting group of (substituting group is the C1-C6 alkyl that can be replaced by fluorine atom or hydroxyl).

＜42〉pyrazolo shown in the formula (6) [1,5-a] pyridine derivate or salt:

[in the formula, R ²Definition suc as formula (I)].

＜43〉pyrazolo shown in the formula (7) [1,5-a] pyridine derivate or salt:

[in the formula, R ²Suc as formula the definition of (I), W represents halogen atom].

＜44〉pyrazolo shown in the formula (8) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹And R ²Definition suc as formula (I)].

＜45〉pyrazolo shown in the formula (9) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹And R ²Suc as formula the definition of (I), wherein, P represents amino protecting group].

＜46〉pyrazolo shown in the formula (10) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹And R ²Suc as formula the definition of (I), wherein, Boc represents tert-butoxycarbonyl].

＜47〉pyrazolo shown in the formula (11) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹And R ²Suc as formula the definition of (I), wherein, P represents amino protecting group, and L represents perfluoroalkyl group sulfonyl].

＜48〉pyrazolo shown in the formula (12) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹And R ²Suc as formula the definition of (I), wherein, Boc represents tert-butoxycarbonyl, and Tf represents trifyl].

＜49〉pyrazolo shown in the formula (13) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹, R ²And R ³Suc as formula the definition of (I), wherein, P represents amino protecting group].

＜50〉pyrazolo shown in the formula (14) [1,5-a] pyridine derivate or salt:

[in the formula, R ¹, R ²And R ³Suc as formula the definition of (I), wherein, Boc represents tert-butoxycarbonyl].

＜51〉pyrazolo shown in each formula (8)-(14) [1,5-a] pyridine derivate or salt＜44 〉-＜50 〉, wherein, R ¹Be quilt (NR ^1cR ^1d,-NR ^1k-CO-R ^1l, or-NR ^1mS (=O) ₂R ¹ⁿ) except the compound of (C1-C8 alkyl or the C3-C8 ester ring type alkyl) that replace.

＜52〉pharmaceutical composition, this pharmaceutical composition contain＜1 〉-＜41 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt and pharmacopedics on acceptable carrier.

＜53〉MAPKAP-K2 inhibitor, this inhibitor contain＜1 〉-＜41 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt as effective constituent.

＜54〉curative or the prophylactic agent of neurodegeneration/neurological obstacle (comprising dementia), septicemia, autoimmune disorder, destructive osteopathy, inflammatory bowel, psoriatic, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, emaciation, obesity, vasculogenesis, asthma and/or chronic obstructive pulmonary disease (COPD), this medicine contains＜1 〉-＜41 in each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt as effective constituent.

＜55〉curative＜54〉or prophylactic agent, wherein, autoimmune disorder is rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis,juvenile, arthritic psoriasis, graft versus host disease (GVH disease), diabetes or Crohn disease.

The accompanying drawing summary

Fig. 1 is the explanatory view of p38MAPK cascade.

The best mode that carries out an invention

Compound shown in the formula of the present invention (I) is represented by following definitions respectively.

" C1-C8 alkyl " expression of using in this specification sheets has the straight or branched alkyl of 1-8 carbon atom.Its example has: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, 2-methyl amyl, 4-methyl amyl, 3-hexyl, n-hexyl, n-heptyl, 2-methyl hexyl, 5-methyl hexyl, 2-methyl 2-hexyl, 6-methylheptyl or n-octyl etc., but be not limited to this.The alkyl that preferably has 1-6 carbon atom.The alkyl that more preferably has 1-4 carbon atom for example has methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl etc., but is not limited to this.

" the C2-C8 thiazolinyl " that use in this specification sheets is meant the straight or branched thiazolinyl with 2-8 carbon atom.Vinyl, allyl group, 1-propenyl, crotyl, 3-butenyl, 2-methyl isophthalic acid-propenyl, 4-pentenyl, 5-hexenyl or 4-methyl-3-pentenyl etc. are for example arranged, but be not limited to this.The thiazolinyl that preferably has 2-6 carbon atom.The thiazolinyl that more preferably has 2-4 carbon atom for example has vinyl, allyl group, pseudoallyl, 1-propenyl, crotyl, 1-butylene base or 2-methyl isophthalic acid-propenyl etc., but is not limited to this.

" the C2-C8 alkynyl " that use in this specification sheets is meant the straight or branched alkynyl with 2-8 carbon atom, ethynyl, propargyl, 3-methyl propargyl, ethyl acetylene base, 2-butyne-1-base, pentynyl or hexin base etc. for example arranged, but be not limited to this.The alkynyl that preferably has 2-6 carbon atom.The alkynyl that more preferably has 2-4 carbon atom for example has ethynyl, propargyl, 1-proyl or ethyl acetylene base etc., but is not limited to this.

" the C3-C8 ester ring type hydrocarbon " that uses in this specification sheets is meant can part unsaturated, the ester ring type alkyl with 3-8 carbon atom that also can be saturated.Its example has cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl or ring octyl group etc., but is not limited to this.Be preferably ester ring type alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl etc. for example arranged, but be not limited to this with 3-6 carbon atom.

" the C6-C14 aromatic hydrocarbon " used in this specification sheets be meant contain one the ring or one or more saturated or unsaturated ring condense the aromatic hydrocarbon that forms with 6-14 carbon atom.Phenyl, naphthyl, anthryl, 5-indanyl or 5,6,7 are for example arranged, 8-tetrahydrochysene-2-naphthyl etc., but be not limited to this.The aromatic hydrocarbyl that preferably has 6-10 carbon atom for example has phenyl, naphthyl or 5-indanyl etc., but is not limited to this.More preferably phenyl etc.

" aromatic heterocycle " that uses in this specification sheets is meant to have atom that 1-4 is selected from Sauerstoffatom, sulphur atom and nitrogen-atoms as heteroatoms and heterocycle with aromaticity.The furans of comprising is for example arranged, thiophene, the pyrroles, the  azoles, thiazole, isothiazole, imidazoles, pyrazoles, triazole, thiadiazoles, the  diazole, tetrazolium, pyridine, pyrazine, pyrimidine, pyridazine, cumarone, diphenylene-oxide, thionaphthene, indoles, benzoglyoxaline, benzothiazole, benzoxazol, quinoline, isoquinoline 99.9, quinazoline, quinoxaline, purine, pteridine, fen  piperazine, thiodiphenylamine, acridine, carbazole, cinnolines, dithiazole, indazole, isoindole, different  azoles, naphthyridines, the  thiazole, 2, the 3-naphthyridine, tetrazine, the univalent perssad of thiatriazole or triazine etc., but be not limited to this.Preference such as furans, thiophene, pyrroles,  azoles, thiazole, isothiazole, imidazoles, pyrazoles, triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzothiazole, benzoxazol, thionaphthene, cumarone, indoles, indazole, quinoline, 2,3-naphthyridine, quinoxaline, quinazoline, cinnolines or isoindole etc., but be not limited thereto.More preferably for example furans, thiophene, pyrroles,  azoles, thiazole, imidazoles, pyrazoles, pyridine, pyrimidine, pyrazine, pyridazine, benzothiazole, benzoxazol, thionaphthene, cumarone, indoles, indazole, quinoline, 2,3-naphthyridine, quinoxaline, quinazoline or cinnolines etc., but be not limited thereto.

But " the aliphatic heterocycle " that uses in this specification sheets be meant has 1-4 and is selected from the atom of Sauerstoffatom, sulphur atom and nitrogen-atoms as the unsaturated also saturable aliphatic heterocycle of heteroatoms part.Can contain one or two in the aliphatic series heterocyclic ring-C (=O)-or-C (=S)-.The aliphatic heterocyclic radical that has with (aromatic hydrocarbon or aromatic heterocycle) condensed structure is also included within the aliphatic heterocyclic radical.The piperidines of comprising is for example arranged, tetramethyleneimine, pyrroline, tetrahydrofuran (THF), dihydropyrane, six hydrogen azepine , piperazine, rubane, morpholine, thiomorpholine,  azoles quinoline, two  alkane, pyrans, 2-Pyrrolidone, tetrahydrochysene-3H-pyrazoles-3-ketone, 1,2,3, the 4-tetrahydroisoquinoline, 1,2,3, the 4-tetrahydroquinoline, 4,5,6,7-tetrahydrochysene-1H-pyrazolo [5,4-c] pyridine, 4,5,6, the 7-tetrahydro-1 H-pyrrolo is [2,3-c] pyridine also, 4,5,6, the 7-tetramethylene sulfide is [2,3-c] pyridine also, 4,5,6,7-tetrahydrochysene-2H-pyrrolo-[3,4-c] pyridine, 4,5,6, the 7-tetrahydrofuran (THF) is [3,2-c] pyridine also, 1,2,3,4-tetrahydrochysene [2,7] naphthyridines, 4,5,6,7-thiazolidine also [5,4-c] pyridine or 5,6,7, the 8-tetrahydropyrimidine is the univalent perssad etc. of [4,3-d] pyridine etc. also, but is not limited to this.Preference such as piperidines, tetramethyleneimine, pyrroline, tetrahydrofuran (THF), six hydrogen azepine , piperazine, morpholine,  azoles quinoline, two  alkane, pyrans or 1,2,3,4-tetrahydroisoquinoline etc., but be not limited to this.More preferably refer to as heteroatoms have 1-3 at least one for the heteroatoms of nitrogen-atoms, can the unsaturated aliphatic heterocycle that also can be saturated of part.Its example is: piperidines, tetramethyleneimine, pyrroline, six hydrogen azepine , piperazine, morpholine or  azoles quinoline etc., but be not limited to this.More preferably piperidines, tetramethyleneimine, six hydrogen azepine , piperazine or morpholine etc.

" the aromatic hydrocarbon alkyl " that uses in this specification sheets is the group with aromatic hydrocarbon and alkyl combination.Its example has: benzyl, styroyl, (2-naphthyl) methyl, 3-phenyl propyl, 4-phenyl butyl or 5-(1-naphthyl) amyl group etc., but be not limited to this.Be preferably and have the group that phenyl or naphthyl makes up as aromatic hydrocarbon, with the alkyl with 1-6 carbon atom.More preferably have phenyl as aromatic hydrocarbon, with the group that the alkyl with 1-4 carbon atom makes up, its example has benzyl, styroyl, 3-phenyl propyl or 4-phenyl butyl etc., but is not limited to these.

" the aromatic heterocycle alkyl " that uses in this specification sheets is the group of aromatic heterocycle and alkyl combination.Preferably contain 1-3 group that is selected from the heteroatomic 5-10 unit's monocycle or the two ring-type aromatic heterocycles of Sauerstoffatom, sulphur atom and nitrogen-atoms and has the alkyl combination of 1-4 carbon atom.Preferred example has: 2-furyl methyl, 3-furyl methyl, 2-(2-thienyl) ethyl, 2-(3-thienyl) propyl group, 2-methyl isophthalic acid-(1-pyrryl) propyl group or 1-(2-pyrryl) ethyl etc., but be not limited to this.

" the aliphatic Heterocyclylalkyl " that uses in this specification sheets is the group of aliphatic heterocycle and alkyl combination.But preferably have 1-3 group that is selected from the atom of Sauerstoffatom, sulphur atom and nitrogen-atoms as the alkyl combination of unsaturated also saturable aliphatic heterocycle of heteroatoms part and carbonatoms 1-4.Preferred example is: 3-piperidino methyl, 3-pyrrolidyl methyl, 2-(4-piperidyl) ethyl, 2-(2-tetrahydrofuran base) propyl group, 1-(2-morpholinyl) ethyl, morpholino methyl or 1-(1-pyrrolidone-base) ethyl etc., but be not limited to this.

" C1-C8 alkoxyl group " expression of using in this specification sheets has the straight or branched alkoxyl group of 1-8 carbon atom, its example have methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy or positive heptan oxygen base etc., but be not limited to this.The alkoxyl group that preferably has 1-6 carbon atom more preferably has the alkoxyl group of 1-4 carbon atom, and its example has: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy etc., but be not limited to this.

" the ester ring type-oxyl " that uses in this specification sheets is the group of ester ring type hydrocarbon and the combination of oxygen base.Its example has: cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclopentenyl oxygen base, cyclohexyl oxygen base, cyclohexenyl oxygen base, suberyl oxygen base or ring octyl group oxygen base etc., but be not limited to this.The ester ring type-oxyl that preferably has 3-8 carbon atom.The alkoxyl group that more preferably has 3-6 carbon atom, its example has: cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy, cyclohexyl oxygen base etc., but be not limited to this.

" the C1-C6 alkylthio " that uses in this specification sheets is the group of C1-C6 alkyl and sulfenyl combination.Its example has: methyl sulfenyl, ethyl sulfenyl, n-propyl sulfenyl, sec.-propyl sulfenyl, normal-butyl sulfenyl, sec-butyl sulfenyl, isobutyl-sulfenyl, tertiary butyl sulfenyl, n-pentyl sulfenyl, isopentyl sulfenyl, neo-pentyl sulfenyl, tert-pentyl sulfenyl, 2-methyl amyl sulfenyl, 4-methyl amyl sulfenyl, 3-hexyl sulfenyl, n-hexyl sulfenyl or n-heptyl sulfenyl etc., but be not limited to this.The sulfenyl that preferably has 1-4 carbon atom.The sulfenyl that more preferably has 1-3 carbon atom.Its example has: methyl sulfenyl, ethyl sulfenyl, n-propyl sulfenyl, sec.-propyl sulfenyl etc., but be not limited to this.

" the C1-C6 acyl group " that uses in this specification sheets is meant the alkyl with 1-6 carbon atom or the acyl group of ester ring type hydrocarbon.Preferred example has: ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl or valeryl etc., but be not limited to this.

" the C1-C6 acyl amino " that uses in this specification sheets is C1-C6 acyl group and the amino group that makes up.Preferred example has: acetylamino, propionyl amino, butyryl radicals amino, isobutyryl amino, pentanoyl amino, isovaleryl amino or valeryl amino etc., but be not limited to this.

" the C2-C7 alkoxy carbonyl " that uses in this specification sheets is the group of C1-C6 alkoxyl group and carbonyl combination.Preferred example has: methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl or tert-butoxycarbonyl etc., but be not limited to this.

" the C7-C12 phenylalkyl " that uses in this specification sheets is the group of phenyl and the combination of C1-C6 alkyl.Preferred example has: benzyl, styroyl, 2-phenyl propyl, 3-phenyl propyl or 4-phenyl butyl etc., but be not limited to this.

" the amino protecting group " used in this specification sheets is meant the protecting group (bibliography: Protective Groups in Organic Synthesis, 3 editions, JohnWiley ﹠amp of amino commonly used in this field; Sons Inc.).Preferred example has: tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxy carbonyl, 2; 2; 2-trichlorine ethoxy carbonyl, ethanoyl, trifluoroacetyl group, valeryl, benzoyl, 2; 4; the 6-trimethylbenzoyl, to methoxy-benzyl, 3; 4-dimethoxy-benzyl, the tertiary butyl, methoxymethyl, 2-trimethylsilylethoxymethyl or benzyloxymethyl etc., but be not limited to this.Preferred example has: tert-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, ethoxy carbonyl or 2,2, and alkoxy carbonyls such as 2-trichlorine ethoxy carbonyl, but be not limited to this.Further preferred tertiary butoxy carbonyl.

" perfluoroalkyl group sulfonyl " that uses in this specification sheets is meant the polysubstituted alkyl sulphonyl of fluorine that hydroxyl is transformed to leavings group commonly used in this field.Preferred example has: trifyl or nine fluorine fourth alkylsulfonyls etc., but be not limited to this.More preferably trifyl.

" halogen atom " that uses in this specification sheets is meant fluorine atom, chlorine atom, bromine atoms or iodine atom.Preferred fluorine atom, chlorine atom or bromine atoms, more preferably fluorine atom or chlorine atom.

The R of this specification sheets ^1x, R ^2yAnd R ^3zIn, " the C1-C8 alkyl (is combined with two conduct (R on the nitrogen-atoms ^1x, R ^2y, or R ^3z) the C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring) " example have: 1-pyrrolidyl, 2-methyl isophthalic acid-pyrrolidyl, piperidino, morpholino, thiomorpholine generation or piperazinyl etc., but be not limited to this.Preferred example has: 1-pyrrolidyl, piperidino, morpholino, piperazinyl etc., but be not limited to this.

The R of this specification sheets ¹, R ²And R ³Substituent substituting group in; the example of " the C1-C8 alkyl that can be replaced by the oxo base " in " the C1-C8 alkyl that can be replaced by (halogen atom, hydroxyl or oxo base) " has: ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, 2-oxopropyl, 3-oxo butyl or valeryl etc., but be not limited to this.Preferred example has: ethanoyl, propionyl, isobutyryl, pentanoyl, isovaleryl, valeryl etc., but be not limited to this.

The R of this specification sheets ¹And R ²In, " be can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical, and at (this R ¹Or R ²) on be combined with (R more than two ¹Or R ²) substituting group the time, these substituting groups can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring " example have: chroman, indoline, isochroman, isoindoline, 2H; 3H-benzo [e] 1,4-two  English, 2H-benzo [d] 1,3-dioxole, 2H; 3H; 4H-benzo [e] sulfo-pyrans or 2H, 3H, 4H-benzo [e] 1; 4- piperazine etc., but be not limited thereto.Preferred example has: chroman, indoline, isochroman, isoindoline, 2H, and 3H-benzo [e] 1,4-two  English or 2H-benzo [d] 1,3-dioxole etc., but be not limited to this.

In the above-mentioned definition, " C " of " C1 " etc. expression carbon atom for example, thereafter with the numeral carbonatoms.For example, the scope of " C1-C6 " expression carbonatoms 1-carbonatoms 6.Certainly, among the present invention, the different group of carbonatoms represents to have this group of this carbonatoms.For example, " C1-C6 alkyl " is meant that the carbonatoms of the alkyl of definition in " C1-C8 alkyl " is 1-6.The implication of carbonatoms is understood too in other group.

R ¹Expression can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical.Preferably can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical etc.More preferably can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl etc.Further preferably can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical etc., further preferably can substituted phenyl or can substituted aromatic heterocyclic radical etc.R ¹Can substituted aromatic heterocyclic radical preferably have monocyclic aromatic hydrocarbon with can the heterocyclic fused structure of substituted monocyclic aromatic, and 7 NH groups combination of pyrazolo [1, the 5-a] pyridine derivate of ring one side of this aromatic hydrocarbon and formula (I).Monocyclic aromatic hydrocarbon has phenyl etc.The example of preferred aromatic heterocyclic radical has: benzothiazole-4-base, benzothiazole-5-base, benzothiazole-6-base, benzothiazole-7-base, benzoxazol-4-base, benzoxazol-5-base, benzoxazol-6-base, benzoxazol-7-base, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, benzoglyoxaline-7-base, indazole-4-base, indazole-5-base, indazole-6-base, indazole-7-base, thionaphthene-4-base, thionaphthene-5-base, thionaphthene-6-base, thionaphthene-7-base, indoles-4-base, indoles-5-base, indoles-6-base or indoles-7-base etc., more preferably benzothiazole-5-base, benzothiazole-6-base, benzoxazol-5-base, benzoxazol-6-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base, indazole-5-base, indazole-6-base, thionaphthene-5-base, thionaphthene-6-base, indoles-5-base or indoles-6-base etc.

R ¹Substituting group be selected from halogen atom, cyano group, nitro, can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical ,-OR ^1a,-SR ^1b,-NR ^1cR ^1d,-C (=O) R ^1e,-S (=O) ₂NR ^1fR ^1g,-C (=O) OR ^1h,-C (=O) NR ¹ⁱR ^1j,-NR ^1kC (=O) R ^1lWith-NR ^1mS (=O) ₂R ¹ⁿMore than one substituting group.Be preferably be selected from halogen atom, cyano group, can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical ,-OR ^1a,-NR ^1cR ^1d,-C (=O) R ^1e,-S (=O) ₂NR ^1fR ^1g,-C (=O) OR ^1h,-C (=O) NR ¹ⁱR ^1j,-NR ^1kC (=O) R ^1lWith-NR ^1mS (=O) ₂R ¹ⁿDeng 1-5 substituting group, more preferably be selected from halogen atom, can substituted C1-C6 alkyl, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical ,-OR ^1a,-NR ^1cR ^1d,-S (=O) ₂NR ^1fR ^1g,-C (=O) OR ^1h,-C (=O) NR ¹ⁱR ^1j,-NR ^1kC (=O) R ^1lWith-NR ^1mS (=O) ₂R ¹ⁿDeng 1-4 substituting group.More preferably be selected from halogen atom, can substituted C1-C4 alkyl, can substituted C3-C6 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted phenyl, can substituted aromatic heterocyclic radical ,-OR ^1a,-NR ^1cR ^1d,-S (=O) ₂NR ^1fR ^1g,-C (=O) OR ^1h,-C (=O) NR ¹ⁱR ^1j,-NR ^1kC (=O) R ^1lWith-NR ^1mS (=O) ₂R ¹ⁿDeng 1-3 substituting group.

R ^1x(x represents a, b, c, d, e, f, g, h, i, j, k, l, m or n) can be identical or different, represents hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C8 alkyl ^1xThe C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl or can substituted aliphatic Heterocyclylalkyl.Preferred R ^1xRepresent hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C4 alkyl ^1xThe C1-C4 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted phenyl, can substituted aromatic heterocyclic radical, can substituted C3-C6 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted phenylalkyl, can substituted aromatic heterocycle alkyl or can substituted aliphatic Heterocyclylalkyl.More preferably R ^1xRepresent hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C4 alkyl ^1xThe C1-C4 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted aromatic heterocyclic radical, can substituted aliphatic heterocyclic radical, can substituted aromatic heterocycle alkyl or can substituted aliphatic Heterocyclylalkyl.

R ¹For can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical, and this R ¹On be combined with two above R ¹Substituting group the time, these substituting groups can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring.

R ²The expression hydrogen atom, can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aromatic heterocycle alkyl.Be preferably hydrogen atom, can substituted C1-C6 alkyl, can substituted C2-C6 thiazolinyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical or can substituted C3-C8 ester ring type alkyl etc.More preferably hydrogen atom, can substituted C1-C4 alkyl, can substituted phenyl, can substituted aromatic heterocyclic radical or can substituted C3-C6 ester ring type alkyl etc.Further be preferably hydrogen atom or can substituted C1-C4 alkyl etc.

R ²Substituting group for be selected from halogen atom, cyano group, nitro, can substituted C1-C8 alkyl ,-OR ^2a,-SR ^2b,-NR ^2cR ^2d,-C (=O) R ^2e,-S (=O) ₂NR ^2fR ^2g,-C (=O) OR ^2h,-C (=O) NR ²ⁱR ^2j,-NR ^2kC (=O) R ^2l, and-NR ^1mS (=O) ₂R ¹ⁿMore than one substituting group.Be preferably be selected from halogen atom, cyano group, can substituted C1-C6 alkyl ,-OR ^2a,-NR ^2cR ^2d,-S (=O) ₂NR ^2fR ^2g,-C (=O) OR ^2h,-C (=O) NR ²ⁱR ^2j,-NR ^2kC (=O) R ^2l, and-NR ^1mS (=O) ₂R ¹ⁿDeng 1-5 substituting group.More preferably be selected from halogen atom, can substituted C1-C4 alkyl ,-OR ^2a,-NR ^2cR ^2d,-C (=O) OR ^2h,-C (=O) NR ²ⁱR ^2j, and-NR ^2kC (=O) R ^2lDeng 1-3 substituting group.

R ^2y(y represents a, b, c, d, e, f, g, h, i, j, k, l, m or n) can be identical or different, represents hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C8 alkyl ^2yThe C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl.Preferably represent hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C4 alkyl ^2yThe C1-C4 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted phenyl, can substituted aromatic heterocyclic radical, can substituted C3-C6 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted phenylalkyl or can substituted aromatic heterocycle alkyl etc.More preferably represent hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C4 alkyl ^2yThe C1-C4 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted aromatic heterocyclic radical, can substituted aliphatic heterocyclic radical or can substituted aromatic heterocycle alkyl etc.

R ³Expression can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical.Preferably can substituted C3-C6 ester ring type alkyl or can substituted aliphatic heterocyclic radical etc.The more preferably C3-C8 ester ring type alkyl that is replaced by amino or can substituted aliphatic heterocyclic radical etc., wherein, this amino can have substituting group, and this aliphatic series heterocyclic radical has 1-4 nitrogen-atoms as heteroatoms.

R ³Substituting group for be selected from halogen atom, cyano group, nitro ,-OR ^3a,-SR ^3b,-NR ^3cR ^3d, can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl and more than one substituting group that can substituted aliphatic heterocyclic radical.

R ³For can be substituted during the C1-C8 alkyl, preferred R ³Substituting group for being selected from-OR ^3a,-NR ^3cR ^3d, the C3-C8 ester ring type alkyl (this amino can have substituting group) that can be replaced by amino, 1-3 substituting group that can substituted aliphatic heterocyclic radical.Except that this substituting group, can also be selected from halogen atom, cyano group by 1-5 and substituting group that can substituted C1-C6 alkyl etc. replaces.R ³For can be substituted during the C1-C8 alkyl, preferred R ³Substituting group for being selected from-OR ^3a,-NR ^3cR ^3d, the C5-C6 ester ring type alkyl that can be replaced by amino and aliphatic heterocyclic radical that can the substituted 1-2 of a containing nitrogen-atoms 1-2 substituting group.And, except that this substituting group, can also be selected from fluorine atom, cyano group by 1-4 and substituting group that can substituted C1-C4 alkyl etc. replaces.

R ³For can be substituted during C3-C8 ester ring type alkyl, preferred R ³Substituting group for being selected from-OR ^3a,-NR ^3cR ^3d, the C1-C6 alkyl (this amino can have substituting group) that can be replaced by amino and 1-3 substituting group that can substituted aliphatic heterocyclic radical.And, except that this substituting group, can also be selected from halogen atom, cyano group by 1-5 and substituting group that can substituted C1-C6 alkyl etc. replaces.R ³For can be substituted during C3-C8 ester ring type alkyl, preferred R ³Substituting group for being selected from-OR ^3a,-NR ^3cR ^3d, the C1-C6 alkyl that can be replaced by amino and aliphatic heterocyclic radical that can the substituted 1-2 of a containing nitrogen-atoms 1-2 substituting group.And, except that this substituting group, can also be selected from fluorine atom, cyano group by 1-4 and substituting group that can substituted C1-C4 alkyl etc. replaces.

R ³During for can be substituted aliphatic heterocyclic radical, preferred R ³Substituting group for being selected from-OR ^3a,-NR ^3cR ^3d, halogen atom, cyano group, can substituted C1-C6 alkyl, can substituted C3-C8 ester ring type alkyl and 1-5 substituting group that can substituted aliphatic heterocyclic radical etc.R ³During for can be substituted aliphatic heterocyclic radical, preferred R ³Substituting group for being selected from-OR ^3a,-NR ^3cR ^3d, fluorine atom, cyano group, can substituted C1-C4 alkyl, can substituted C3-C6 ester ring type alkyl and 1-4 substituting group that can substituted aliphatic heterocyclic radical etc.

R ^3z(z represents a, b, c or d) can be identical or different, represents hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C8 alkyl ^3zThe C1-C8 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C3-C8 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl.Preferred R ^3zRepresent hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C4 alkyl ^3zThe C1-C4 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted phenyl, can substituted aromatic heterocyclic radical, can substituted C3-C6 ester ring type alkyl, can substituted aliphatic heterocyclic radical, can substituted phenylalkyl or can substituted aromatic heterocycle alkyl etc.More preferably R ^3zRepresent hydrogen atom, can (be combined with two as R on the nitrogen-atoms by substituted C1-C4 alkyl ^3zThe C1-C4 alkyl time, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted aromatic heterocyclic radical, can substituted aliphatic heterocyclic radical or can substituted aromatic heterocycle alkyl etc.

R ¹, R ²And R ³Substituent substituting group when being not particularly limited, be to be selected from halogen atom, hydroxyl, cyano group, nitro, amino, can (be selected from 1-9 halogen atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C8 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-9 halogen atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C8 ester ring type alkyl of Qu Daiing, can (be selected from 1-9 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C8 alkoxyl group of Qu Daiing, can (be selected from 1-2 methyl, 1-9 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C8 ester ring type-oxyl of Qu Daiing, can (be selected from 1-4 methyl, 1-8 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the aliphatic heterocyclic radical of Qu Daiing, can be by (1-4 methyl, 1-5 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C6-C14 aromatic hydrocarbyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-5 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of the aromatic heterocyclic radical of Qu Daiing.

R ¹Substituent substituting group be preferably and be selected from halogen atom, hydroxyl, amino, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C6 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C8 ester ring type alkyl of Qu Daiing, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C6 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C8 ester ring type-oxyl of Qu Daiing, can (be selected from 1-4 methyl, 1-6 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the aliphatic heterocyclic radical of Qu Daiing, can (be selected from 1-4 methyl, 1-5 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C6-C14 aromatic hydrocarbyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-5 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of aromatic heterocyclic radical of Qu Daiing etc., R ¹Substituent substituting group when containing halogen atom, be preferably 1-8; Only from the substituting group except that halogen atom, select R ¹Substituent substituting group the time then be preferably 1-3.More preferably R ¹Substituent substituting group for being selected from halogen atom, hydroxyl, amino, can (be selected from 1-5 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C4 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C6 ester ring type alkyl of Qu Daiing, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C4 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C6 ester ring type-oxyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-6 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of aliphatic heterocyclic radical of Qu Daiing etc., R ¹Substituent substituting group when containing halogen atom, be preferably 1-6; Only from the substituting group except that halogen atom, select R ¹Substituent substituting group the time then be preferably 1-2.

R ²Substituent substituting group be preferably and be selected from halogen atom, hydroxyl, cyano group, nitro, amino, can (be selected from 1-9 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C6 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-9 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C8 ester ring type alkyl of Qu Daiing, can (be selected from 1-9 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C6 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-9 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C8 ester ring type-oxyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-6 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of aliphatic heterocyclic radical of Qu Daiing etc., R ²Substituent substituting group when containing halogen atom, be preferably 1-8; Only from the substituting group except that halogen atom, select R ²Substituent substituting group the time then be preferably 1-3.More preferably be selected from halogen atom, hydroxyl, cyano group, nitro, amino, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C4 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C6 ester ring type alkyl of Qu Daiing, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C4 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C6 ester ring type-oxyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-6 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of aliphatic heterocyclic radical of Qu Daiing etc., R ²Substituent substituting group when containing halogen atom, be preferably 1-8; Only from the substituting group except that halogen atom, select R ²Substituent substituting group the time then be preferably 1-3.Further be preferably and be selected from 1-5 halogen atom, 1-2 hydroxyl, 1-2 cyano group, 1-2 amino, can (be selected from 1-5 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C4 alkyl of Qu Daiing, can (be selected from 1-5 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C4 alkoxyl group of Qu Daiing, and can (be selected from 1-4 methyl, 1-6 halogen atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of aliphatic heterocyclic radical of Qu Daiing etc., R ²Substituent substituting group when containing halogen atom, be preferably 1-6; Only from the substituting group except that halogen atom, select R ²Substituent substituting group the time then be preferably 1-2.

R ³Substituent substituting group be preferably and be selected from halogen atom, hydroxyl, amino, can (be selected from 1-9 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C6 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-9 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C8 ester ring type alkyl of Qu Daiing, can (be selected from 1-9 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C6 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-9 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C8 ester ring type-oxyl of Qu Daiing, can (be selected from 1-4 methyl, 1-6 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the aliphatic heterocyclic radical of Qu Daiing, can (be selected from 1-2 methyl, 1-5 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C6-C14 aromatic hydrocarbyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-5 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the more than one substituting group of aromatic heterocyclic radical of Qu Daiing etc., R ³Substituent substituting group when containing halogen atom, be preferably 1-8; Only from the substituting group except that halogen atom, select R ³Substituent substituting group the time then be preferably 1-3.More preferably R ³Substituent substituting group for being selected from halogen atom, hydroxyl, amino, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C4 alkyl of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C3-C6 ester ring type alkyl of Qu Daiing, can (be selected from 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C4 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-7 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C3-C6 ester ring type-oxyl of Qu Daiing, can (be selected from 1-4 methyl, 1-6 fluorine atom, more than one substituting group with 1-2 hydroxyl) the aliphatic heterocyclic radical of Qu Daiing, can (be selected from 1-4 methyl, 1-5 fluorine atom, more than one substituting group with 1-2 hydroxyl) phenyl of Qu Daiing, and can (be selected from 1-4 methyl, 1-5 fluorine atom, more than one substituting group with 1-2 hydroxyl) the more than one substituting group of aromatic heterocyclic radical of Qu Daiing etc., R ³Substituent substituting group when containing halogen atom, be preferably 1-8, only by selecting R in the substituting group except that halogen atom ³Substituent substituting group the time then be preferably 1-3.Further preferred R ³Substituent substituting group for being selected from halogen atom, hydroxyl, amino, can (be selected from 1-5 fluorine atom, 1-2 hydroxyl, 1-2 cyano group, more than one substituting group with 1-2 oxo base) the C1-C4 alkyl of Qu Daiing, can (be selected from 1-5 fluorine atom, 1-2 hydroxyl, more than one substituting group with 1-2 cyano group) the C1-C4 alkoxyl group of Qu Daiing, can (be selected from 1-4 methyl, 1-6 fluorine atom, more than one substituting group with 1-2 hydroxyl) the aliphatic heterocyclic radical of Qu Daiing, and can (be selected from 1-4 methyl, 1-5 fluorine atom, more than one substituting group with 1-2 hydroxyl) the more than one substituting group of aromatic heterocyclic radical of Qu Daiing etc., R ³Substituent substituting group when containing halogen atom, be preferably 1-6, only by selecting R in the substituting group except that halogen atom ³Substituent substituting group the time then be preferably 1-2.

Pyrazolo shown in the formula (I) [1,5-a] pyridine derivate can exemplify above-mentioned R ¹-R ³Definition and preferably the combination of these groups and the compound that preferably makes up between these groups etc. as preferred compound.

There is basic group sometimes in compound of the present invention in its molecule.In this case, can be transformed into medically acceptable acid salt as required.Described acid for example has mineral acids such as hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and carbonic acid; Perhaps organic acids such as acetate, citric acid, oxysuccinic acid, oxalic acid, tartrate, lactic acid, toxilic acid, fumaric acid and methylsulfonic acid etc.

There is acidic-group sometimes in compound of the present invention in its molecule.In this case, can be transformed into medically acceptable salt as required.Above-mentioned salt has atoxic cationic salts, for example has and Na ⁺, K ⁺Deng alkalimetal ion, Mg ²⁺, Ca ²⁺Deng alkaline-earth metal ions, Al ³⁺, Zn ²⁺Deng metal ion, perhaps ammonia, triethylamine, quadrol, propylene diamine, tetramethyleneimine, piperidines, piperazine, pyridine, Methionin, choline, thanomin, N, the salt of organic basess such as N-dimethylethanolamine, 4-hydroxy piperidine, glycosamine and N-methylglucosamine.

Compound of the present invention can contain one or more unsymmetrical carbon, and in this case, optically active body and racemic modification are also included among the present invention.When having transconfiguration and cis-configuration in the compound of the present invention, transconfiguration and cis-configuration are also included among the present invention.

The example of compound can exemplify the compound shown in the following Table A shown in the formula of the present invention (I).

Table A

There is for example tautomer of following formula (II) expression in pyrazolo shown in the following formula (I) [1,5-a] pyridine derivate.

(in the formula, R ¹, R ², R ³Definition as following formula (I)).

These tautomers are also included within the scope of the present invention.

Compound of the present invention can be synthetic by following method.In various, R ¹, R ², R ³Definition suc as formula (I).About put down in writing in the chemical formula as the reagent of condition or solvent etc., put down in writing herein just for example.Each substituting group can be protected with suitable protecting group as required, also can carry out deprotection in the suitable stage.Herein or respectively following expression of the abbreviation of substituting group, reagent and solvent in the table.

Me: methyl

Et: ethyl

Boc: tert-butoxycarbonyl

DMAP:4-N, the N-dimethyl aminopyridine

THF: tetrahydrofuran (THF)

DHP: dihydropyrane

THP: THP trtrahydropyranyl

Ph: phenyl

TFA: trifluoroacetic acid

Tf: trifyl

1) compound 1- 4Synthetic

Formula 1- 4Shown in compound be known compound, therefore can be synthetic according to methods known in the art.For example can be synthetic by above-mentioned steps.Compound 3Can be synthetic with reference to " R.G.Jones, M.J.Mann, J.Am.Chem.Soc.1953,75,4048-4052 page or leaf ", compound 4Can be synthetic with reference to " R.G.Jones, J.Am.Chem.Soc.1949,71,3994-4000 page or leaf ".

2) by compound 4The compound of synthesis type (6)

In the presence of suitable alkali (for example sodium ethylate), in suitable organic solvent (for example ethanol), 0 ℃ to the temperature range of solvent reflux, make compound 4With a replacement diester malonate reaction, obtain the compound of formula (6).

3) by the compound of the compounds accepted way of doing sth (7) of formula (6)

At suitable alkali (N for example, accelerine) under existence or the non-existence, in suitable organic solvent (for example acetonitrile) or under the condition of no solvent, in 0 ℃-140 ℃ temperature range, make the reaction of the compound of formula (6) and suitable halogenating agent (for example Phosphorus Oxychloride), carry out halogenation, then at suitable organic solvent (for example 1,4-two  alkane) in, at 0 ℃ to the temperature range of solvent reflux, be hydrolyzed by the aqueous solution (for example aqueous sodium hydroxide solution) that contains suitable alkali, obtain the compound of formula (7).

4) by the compound of the compounds accepted way of doing sth (8) of formula (7)

The existence of suitable alkali (for example pyridine) or non-in the presence of, in suitable organic solvent (for example 2-propyl alcohol) or under the condition of no solvent, in 0 ℃-140 ℃ temperature range, make the compound and the R of formula (7) ¹NH ₂The sulfonamide derivatives of expression reacts, and obtains the compound of formula (8).

5) by the compound of the compounds accepted way of doing sth (9) of formula (8)

The existence of suitable alkali (for example triethylamine) or non-in the presence of, at suitable catalyzer (4-N for example, the N-dimethyl aminopyridine) under existence or the non-existence, at suitable organic solvent (for example 1,4-two  alkane) in, at 0 ℃ to the temperature range of solvent reflux, the compound that makes formula (7) and suitable activatory Pization agent are (when P is Boc, be tert-Butyl dicarbonate) reaction, then in appropriate solvent (for example 1,4-two  alkane), add suitable containing or the alkali free aqueous solution (for example aqueous sodium hydroxide solution), be hydrolyzed to the temperature range of solvent reflux at 0 ℃, obtain the compound of formula (9).

6) by the compound of the compounds accepted way of doing sth (11) of formula (9)

In suitable organic solvent (for example pyridine), in the presence of suitable alkali (for example triethylamine), in 0 ℃-50 ℃ temperature range, the compound that makes formula (9) and suitable activatory Lization agent are (when L is Tf, be trifluoromethanesulfonic acid agent (for example trifluoromethanesulfanhydride anhydride)) reaction, but the compound of synthesis type (11).

7) by the compound of the compounds accepted way of doing sth (13) of formula (11)

In suitable organic solvent (for example tetrahydrofuran (THF)) or under the condition of no solvent, the existence of suitable alkali (for example triethylamine) or non-in the presence of, to the temperature range of solvent reflux, make the compound and the R of formula (11) in room temperature ³NH ₂Represented sulfonamide derivatives reacts, and obtains the compound of formula (13).

Method with reference to (Journal of Organic Chemistry, 2005,70,1957-1960) record, at suitable organic solvent (for example 1,4-two  alkane, N, dinethylformamide) in, in the presence of suitable alkali (for example triethylamine), 0 ℃ to the temperature range of solvent reflux, make the compound of formula (9) and activator (for example bromine three (pyrrolidyl)  hexafluorophosphate or benzotriazole-1-base oxygen base three (pyrrolidyl)  hexafluorophosphate) and R ³NH ₂The sulfonamide derivatives of expression reacts, and can obtain the compound of formula (13).

8) by the compound of the compounds accepted way of doing sth (14) of formula (13)

In suitable organic solvent (for example methylene dichloride) or under the condition of no solvent; at 0 ℃ to the temperature range of solvent reflux; make the compound of formula (13) and suitable deprotecting regent (when P is Boc, being strong acid (for example trifluoroacetic acid)) reaction, obtain the compound of formula (14).

Pyrazolo [1,5-a] pyridine derivate shown in formula (5)-Shi (10), (13) and (14) is also same with following formula (II), has tautomer.

The R of pyrazolo [1, the 5-a] pyridine derivate of expression such as formula (5)-(14) ¹-R ³Preferred group R in pyrazolo [1, the 5-a] pyridine derivate of above-mentioned these final compound-Shi (I) expression is arranged ¹-R ³Preferred group.These R ¹-R ³Definition and the combination of these preferred group and these preferred group between the compound that makes up etc. can be used as the preferred compound of represented pyrazolo [1,5-a] pyridine derivate such as formula (5)-(14).

Contain compound of the present invention or medically acceptable salt and use the carrier that in common preparationization, uses or vehicle, other additive preparation as the preparation of effective constituent.Carrier that preparation is used or excipient can be solid or liquid, and lactose, Magnesium Stearate, starch, talcum powder, gelatin, agar, pectin, Sudan Gum-arabic, sweet oil, sesame oil, theobroma oil, ethylene glycol etc. or other carrier or excipient commonly used are for example arranged.Administering mode can be oral administrations such as tablet, pill, capsule, granule, powder and liquid preparation, perhaps injection such as intravenous injection, intramuscular injection, suppository, the any-mode of non-oral administration such as transdermal.

MAPKAP-K2 inhibitor of the present invention disease applicatory has neurodegeneration/neurological obstacle (comprising dementia), septicemia, autoimmune disease, destructive osteopathy, inflammatory bowel, psoriatic, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, emaciation, obesity, vasculogenesis, asthma and/or chronic obstructive pulmonary disease (COPD) etc.

Autoimmune disorder specifically has rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis,juvenile, arthritic psoriasis, graft versus host disease (GVH disease), diabetes or Crohn disease.

And different, being grown up usually, everyone is 1-500mg/ days to the dosage of compound of the present invention according to kind, route of administration, patient's age and the sex of disease and the degree of disease etc.

Embodiment

Following according to specific embodiment explanation the present invention.But the present invention is not limited to these embodiment.

Among the following embodiment, each compound with compound number corresponding to the compound that is exemplified as preferred concrete example in the above-mentioned Table A with compound number.The structure of isolating novel cpd is by using ¹H-NMR and/or possess mass analysis, other suitable analytical procedure that list four utmost point devices in electronic spraying source carry out and confirm.

¹H-NMR composes (400MHz, DMSO-d ₆Or CDCl ₃) provide its chemical shift (δ: ppm) and coupling constant (J:Hz).Following content is represented in following abbreviation respectively.S=is unimodal, d=is bimodal, t=three peaks, q=four peaks, wide unimodal, the m=multimodal of brs=.The result of mass analysis provides with M ⁺+ H, be the additional proton (H of molecular mass (M) of compound ⁺) the measured value of value observation." HPLC retention time " be illustrated in HPLC under the following analysis condition analyze in the retention time (unit: minute) of compound.

HPLC (high performance liquid chromatography) condition

Mensuration system: Hewlett-Packard 1100HPLC

Post: Cadenza CD-C18 (Imtakt) 100mm * 4.6mm (internal diameter)

Solvent: A:H ₂O/ acetonitrile=95/5

0.05％TFA

B:H ₂O/ acetonitrile=5/95

0.05％TFA

Flow velocity: 1.0ml/ minute

Gradient:

0-1 minute, solvent B:10% solvent orange 2 A: 90%

1-13 minute, solvent B:10% → 70% solvent orange 2 A: 90% → 30%

13-14 minute, solvent B:70% → 100% solvent orange 2 A: 30% → 0%

14-16 minute, solvent B:100% solvent orange 2 A: 0%

16-19 minute, solvent B:100% → 0% solvent orange 2 A: 0% → 90%

[embodiment 1]

5,7-dihydroxyl-6-methylpyrazole is synthesizing of [1,5-a] pyridine-4-nitrile (5) also

With 2.14g according to the acetonitrile of synthetic 2-(pyrazole-3-yl) shown in the such scheme (S1) (4)Be dissolved in the 40ml dewatered ethanol, add the 3.78ml methyl-malonic ester and stir.In this solution, add the 3.40g sodium ethylate, under the reflux condition, stirred 3 days then.Reaction soln is returned back to room temperature, add 100ml water then and dilute, add 6mol/L hydrochloric acid,, obtain the crude product that generates pH regulator to 2.With the saturated common salt water washing of gained crude product, drying under reduced pressure obtains the 3.06g title compound then (5)With the preparation HPLC purifying of a part wherein, measure NMR.

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：10.37(br s，1H)，8.22(d，J＝3.2Hz，1H)，6.42(d，J＝3.2Hz，1H)，1.99(s，3H).

ESI/MS：190.0(M ⁺+H，C ₉H ₇N ₃O ₂)

HPLC retention time: 4.58 minutes

Below, the compound of embodiment 2-embodiment 8 uses corresponding raw material and reagent synthetic according to the method for embodiment 1.

[embodiment 2]

5,7-dihydroxyl-6-(2-propenyl) pyrazolo [1,5-a] pyridine-4-nitrile (6)

ESI/MS：216.2(M ⁺+H，C ₁₁H ₉N ₃O ₂).

HPLC retention time: 4.84 minutes

[embodiment 3]

5,7-dihydroxyl-6-phenylpyrazole is [1,5-a] pyridine-4-nitrile (7) also

ESI/MS：252.2(M ⁺+H，C ₁₄H ₉N ₃O ₂).

[embodiment 4]

5,7-dihydroxyl pyrazolo [1,5-a] pyridine-4-nitrile (8)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：11.41(brs，1H)，8.19(d，J＝2.8Hz，1H)，6.41(d，J＝2.8Hz，1H)，5.55(s，1H).

ESI/M S：176.3(M ⁺+H，C ₈H ₅N ₃O ₂).

[embodiment 5]

5,7-dihydroxyl-6-ethyl pyrazolo [1,5-a] pyridine-4-nitrile (9)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm) ：8.24(dd，J＝3.2Hz，0.8Hz，1H)，6.42(dd，J＝3.2Hz，0.8Hz，1H)，2.56(q，J＝7.6H，2H)，1.00(t，J＝7.6H，3H).

ESI/M S：204.0(M ⁺+H，C ₁₀H ₉N ₃O ₂).

[embodiment 6]

5,7-dihydroxyl-6-propyl group pyrazolo [1,5-a] pyridine-4-nitrile (10)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.22(d，J＝4.0Hz，1H)，6.41(d，J＝4.0Hz，1H)，2.54-2.48(m，2H)，1.42(m，J＝7.5Hz，7.3Hz，2H).0.87(t，J＝7.3H，3H).

ESI/MS：218.1(M ⁺+H，C ₁₁H ₁₁N ₃O ₂).

[embodiment 7]

5,7-dihydroxyl-6-(methylethyl) pyrazolo [1,5-a] pyridine-4-nitrile (11)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.23(d，J＝3.2Hz，1H)，6.40(d，J＝3.2Hz，1H)，3.16(m，J＝7.0Hz，1H)，1.42(d，J＝7.0Hz，6H).

ESI/MS：218.1(M ⁺+H，C ₁₁H ₁₁N ₃O ₂).

[embodiment 8]

5,7-dihydroxyl-6-cyclopropyl pyrazolo [1,5-a] pyridine-4-nitrile (12)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm) ：8.17(brs，1H)，6.37(brs，1H)，1.54-1.50(m，1H)，0.83-0.80(m，2H)，0.72-0.68(m，2H).

ESI/MS：216.1(M ⁺+H，C ₁₁H ₉N ₃O ₂).

[embodiment 9]

7-chloro-5-hydroxyl-6-methylpyrazole is synthesizing of [1,5-a] pyridine-4-nitrile (13) also

To 378mg 5,7-dihydroxyl-6-methylpyrazole is [1,5-a] pyridine-4-nitrile also (5)Crude product in add 380 μ l N, accelerine is suspended in the 20ml Phosphorus Oxychloride then, stirs 3 hours under the reflux condition.Reaction soln is cooled to room temperature, then excessive Phosphorus Oxychloride decompression is heated up in a steamer.Resistates is diluted with ethyl acetate and water, and layering is extracted organic layer with saturated sodium bicarbonate aqueous solution is counter, merge with water layer, and be 10 with the 2mol/l aqueous sodium hydroxide solution with pH regulator then, stirred 4 days.Is 2 with 1mol/l hydrochloric acid with pH regulator, uses ethyl acetate extraction three times.The organic layer that merges is used mixed aqueous solution (5: the 1) washing of saturated aqueous common salt and 1mol/l hydrochloric acid.With this organic layer dried over sodium sulfate, decompression is heated up in a steamer and is desolvated then, obtain the 211mg title compound ( 13).With the preparation HPLC purifying of a part wherein, measure NMR.

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.04(d，J＝2.2Hz，1H)，6.53(d，J＝2.2Hz，1H)，2.29(s，3H).ESI/M

S：208.0(M ⁺+H，C ₉H ₆ClN ₃O).

HPLC retention time: 8.07 minutes

Below, the compound of embodiment 10-embodiment 16 uses corresponding raw material and reagent synthetic according to the method for embodiment 9.

[embodiment 10]

7-chloro-5-hydroxyl-6-(2-propenyl) pyrazolo [1,5-a] pyridine-4-nitrile (14)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.05(d，J＝2.2Hz，1H)，6.62(d，J＝2.2Hz，1H)，5.93(m，1H)，5.21-5.15(m，2H)，3.64(dt，J＝6.2Hz，1.5Hz，2H).

ESI/MS：234.3(M ⁺+H，C ₁₁H ₈ClN ₃O).

[embodiment 11]

7-chloro-5-hydroxyl-6-phenylpyrazole is [1,5-a] pyridine-4-nitrile (15) also

ESI/MS：270.1(M ⁺+H，C ₁₄H ₈ClN ₃O).

[embodiment 12]

7-chloro-5-hydroxypyrazoles is [1,5-a] pyridine-4-nitrile (16) also

(400MHz，DMSO-d ₆)δ(ppm)：8.12(d，J＝2.0Hz，1H)，6.86(s，1H)，6.60(d，J＝2.0Hz，1H).

ESI/MS：194.1(M ⁺+H，C ₈H ₄ClN ₃O).

[embodiment 13]

7-chloro-5-hydroxyl-6-ethyl pyrazolo [15-a] pyridine-4-nitrile (17)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.06(dd，J＝1.7Hz，1.7Hz，1H)，6.55(dd，J＝1.7Hz，1.7Hz，1H)，2.77(q，J＝7.6Hz，2H)，1.10(t，J＝7.6Hz，3H).

ESI/MS：222.0(M ⁺+H，C ₁₀H ₈ClN ₃O).

[embodiment 14]

7-chloro-5-hydroxyl-6-propyl group pyrazolo [1,5-a] pyridine-4-nitrile (18)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.06(d，J＝2.2Hz，1H)，6.54(d，J＝2.2Hz，1H)，2.74(t，J＝7.8Hz，2H)，1.53(m，J＝7.8Hz，7.6Hz，2H)，0.94(t，J＝7.6Hz，3H).

ESI/MS：236.1(M ⁺+H，C ₁₁H ₁₀ClN ₃O).

[embodiment 15]

7-chloro-5-hydroxyl-6-(methylethyl) pyrazolo [1,5-a] pyridine-4-nitrile (19)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.04(d，J＝2.2Hz，1H)，6.58(d，J＝2.2Hz，1H)，3.69(m，J＝7.1Hz，1H)，1.43(d，J＝7.1Hz，6H).

ESI/MS：236.2(M ⁺+H，C ₁₁H ₁₀ClN ₃O).

[embodiment 16]

7-chloro-5-hydroxyl-6-cyclopropyl pyrazolo [1,5-a] pyridine-4-nitrile (20)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.05(d，J＝2.2Hz，1H)，6.64(d，J＝2.2Hz，1H)，1.78(tt，J＝8.0Hz，3.6Hz，1H)，1.35-1.31(m，2H)，1.35-1.31(m，2H).

ESI/MS：234.0(M ⁺+H，C ₁₁H ₈ClN ₃O).

[embodiment 17]

The 7-[(4-ethoxyl phenenyl) amino]-5-hydroxyl-6-methyl-pyrazolo [1,5-a] pyridine-4-nitrile (21) Synthetic

With 9.25mg 7-chloro-5-hydroxyl-6-methyl-pyrazolo [1,5-a] pyridine-4-nitrile ( 13) crude product be dissolved in the 2.2ml 2-propyl alcohol, add 289 μ l p-phenetidines, under the condition of reflux, stirred 3 days then.Reaction soln is cooled to room temperature, dilutes with ethyl acetate then.With of mixed aqueous solution (1: the 1) washing of this solution with saturated aqueous common salt and 1mol/L hydrochloric acid, then, use dried over sodium sulfate with saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (9: 1) washing, decompression is heated up in a steamer and is desolvated.With resistates by silica gel column chromatography (hexane/ethyl acetate=1/1) purifying, obtain the 77.8mg title compound ( 21) (yield 56%).

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.09(brs，1H)，7.91(d，J＝2.2Hz，1H)，7.04(d，J＝8.9Hz，2H)，6.88(d，J＝8.9Hz，2H)，6.48(d，J＝2.2Hz，1H)，5.30(brs，1H)，4.04(q，J＝7.0Hz，2H)，1.78(s，3H)，1.43(t，J＝7.0Hz，3H).

ESI/MS：309.1(M ⁺+H，C ₁₇H ₁₆N ₄O ₂).

HPLC retention time: 13.14 minutes

Below, the compound of embodiment 18-embodiment 21 uses corresponding raw material and reagent synthetic according to the method for embodiment 17.

[embodiment 18]

The 7-[(4-ethoxyl phenenyl) amino]-5-hydroxyl-6-(2-propenyl) pyrazolo [1,5-a] pyridine-4-nitrile (22)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.09(s，1H)，7.91(d，J＝2.0Hz，1H)，7.11(d，J＝8.8Hz，2H)，6.87(d，J＝8.8Hz，2H)，6.49(d，J＝2.0Hz，1H)，5.72-5.60(m，1H)，5.04(dq，J＝10.1Hz，1.5Hz，1H)，4.93(dq，J＝17.1Hz，1.5Hz，1H)，4.04(q，J＝7.0Hz，2H)，3.09(dt，J＝5.8Hz，1.6Hz，2H)，1.43(t，J＝7.0Hz，3H).

ESI/MS：335.4(M ⁺+H，C ₁₉H ₁₈N ₄O ₂).

[embodiment 19]

5-hydroxyl-7-{[4-(2-methoxy ethoxy) phenyl] amino }-6-methylpyrazole [1,5-a] pyrrole also Pyridine-4-nitrile (23)

ESI/M S：339.1(M ⁺+H，C ₁₈H ₁₈N ₄O ₃).

[embodiment 20]

5-hydroxyl-6-methyl-7-[(2-methylbenzothiazole-6-yl) amino] pyrazolo [1,5-a] pyridine-4-nitrile (24)

ESI/MS：336.0(M ⁺+H，C ₁₇H ₁₃N ₅OS).

[embodiment 21]

7-(benzothiazole-6-base is amino)-5-hydroxyl-6-methylpyrazole is [1,5-a] pyridine-4-nitrile (25) also

ESI/MS：322.1(M ⁺+H，C ₁₆H ₁₁N ₅OS).

[embodiment 22]

Tert.-butoxy-N-(4-cyano group-5-hydroxyl-6-methylpyrazole is [1,5-a] pyridine-7-yl also)-N-(4-ethoxy The base phenyl) methane amide (26) is synthetic

With 195mg 7-(4-ethoxyl phenenyl amino)-5-hydroxyl-6-methylpyrazole also [1,5-a] pyridine-4-nitrile ( 21) be dissolved in 6.3ml 1, in the 4-two  alkane, add 346mg tert-Butyl dicarbonate and 19mg 4-N, the N-dimethyl aminopyridine at room temperature stirred 1 hour.In this solution, add 1.3ml 0.5mol/l aqueous sodium hydroxide solution, at room temperature stirred 3 hours.Reaction soln is diluted with ethyl acetate, with mixed aqueous solution (1: the 1) washing of saturated aqueous common salt and saturated aqueous ammonium chloride, use dried over sodium sulfate then, decompression is heated up in a steamer and is desolvated.With resistates by silica gel column chromatography (hexane/ethyl acetate=1/1) purifying, obtain the 242mg title compound ( 26) (yield 93%).

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.01(brs，1H)，7.17(d，J＝8.7Hz，2H)，6.85(d，J＝8.7Hz，2H)，6.51(d，J＝2.0Hz，1H)，6.12(brs，1H)，3.96(q，J＝7.0Hz，2H)，2.07(brs，3H)，1.35(s，9H)，1.28(t，J＝7.0Hz，3H).

ESI/MS：409.2(M ⁺+H，C ₂₂H ₂₄N ₄O ₄).

HPLC retention time: 14.54 minutes

Below, the compound of embodiment 23-embodiment 37 uses corresponding raw material and reagent synthetic according to the method for embodiment 22.

[embodiment 23]

Tert.-butoxy-N-[4-cyano group-5-hydroxyl-6-(2-propenyl) pyrazolo [1,5-a] pyridine-7-yl]-N- (4-ethoxyl phenenyl) methane amide (27)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：12.09(brs，1H)，8.07(brs，1H)，7.11(d，J＝8.8Hz，2H)，6.85(d，J＝8.8Hz，2H)，6.54(d，J＝1.7Hz，1H)，5.75-5.55(m，1H)，5.00-4.80(m，2H)，3.96(q，J＝7.2Hz，2H)，3.45-3.30(m，2H)，1.28(t，J＝7.0Hz，3H)，1.15(brs，9H).

ESI/MS：435.3(M ⁺+H，C ₂₄H ₂₆N ₄O ₄).

HPLC retention time: 15.29 minutes

[embodiment 24]

(tert.-butoxy)-N-(4-cyano group-5-hydroxyl-6-methyl (pyrazolo [1,5-a] pyridine-7-yl))-N-[4- (2-methoxy ethoxy) phenyl] methane amide (28)

ESI/MS:383.1 (M ⁺+ H, C ₂₃H ₂₆N ₄O ₅: iso-butylene (C has been removed in observation ₄H ₈: MS 56))

[embodiment 25]

(tert.-butoxy)-N-[4-cyano group-5-hydroxyl-6-methyl (pyrazolo [1,5-a] pyridine-7-yl)]-N-(2- Methylbenzothiazole-6-yl) methane amide (29)

ESI/MS：436.1(M ⁺+H，C ₂₂H ₂₁N ₅O ₃S).

[embodiment 26]

Tert.-butoxy-N-(4-cyano group-5-hydroxyl-6-phenylpyrazole is [1,5-a] pyridine-7-yl also)-N-(4-ethoxy The base phenyl) methane amide (30)

ESI/MS：471.4(M ⁺+H，C ₂₇H ₂₆N ₄O ₄)

[embodiment 27]

Tert.-butoxy-N-(4-cyano group-5-hydroxyl-6-ethyl pyrazolo [1,5-a] pyridine-7-yl)-N-(4-ethoxy The base phenyl) methane amide (31)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.81(d，1.7H，1H)，7.20(d，J＝8.7Hz，2H)6.75(d，J＝8.7Hz，2H)，6.26(d，1.7H，1H)，3.94(q，J＝7.1Hz，2H)，3.14(q，J＝7.3Hz，2H)，1.36(t，J＝7.1Hz，3H)，1.30(t，J＝7.3Hz，3H)，1.26(s，9H)，

ESI/MS：423.2(M ⁺+H，C ₂₃H ₂₆N ₄O ₄).

[embodiment 28]

Tert.-butoxy-N-(4-cyano group-5-hydroxyl-6-propyl group pyrazolo [1,5-a] pyridine-7-yl)-N-(4-ethoxy The base phenyl) methane amide (32)

ESI/MS：437.2(M ⁺+H，C ₂₄H ₂₈N ₄O ₄).

[embodiment 29]

Tert.-butoxy-N-{4-cyano group-5-hydroxyl-6-(methylethyl) pyrazolo [1,5-a] pyridine-7-yl }-N- (4-ethoxyl phenenyl) methane amide (33)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.97(d，1.7H，1H)，7.21(d，J＝8.8Hz，2H)6.79(d，J＝8.8Hz，2H)，6.51(d，1.7H，1H)，3.96(q，J＝7.0Hz，2H)，3.45-3.38(m，1H)，1.37(br，6H)，1.27(brs，9H).

ESI/MS：437.2(M ⁺+H，C ₂₄H ₂₈N ₄O ₄).

[embodiment 30]

Tert.-butoxy-N-(4-cyano group-5-hydroxyl-6-cyclopropyl pyrazolo [1,5-a] pyridine-7-yl)-N-(4-second Oxygen base phenyl) methane amide (34)

ESI/MS：435.2(M ⁺+H，C ₂₄H ₂₆N ₄O ₄)

[embodiment 31]

(tert.-butoxy)-N-(2-chloro-phenyl-)-N-[4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl)] Methane amide (35)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.08(d，J＝2.4Hz，1H)，7.64(dd，J＝8.0，2.4Hz，1H)，7.51(dd，J＝8.0，2.4Hz，1H)，7.32-7.22(m，2H)，6.75(s，1H)，6.68(d，J＝2.4Hz，1H)，1.47(s，9H).

ESI/MS：385.2(M ⁺+H，C ₁₉H ₁₇ClN ₄O ₃).

[embodiment 32]

(tert.-butoxy)-N-[4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl)]-N-(2-methylthio group Phenyl) methane amide (36)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.00(s，1H)，7.48(dd，J＝8.0，1.2Hz，1H)，7.31-7.24(m，2H)，7.04(t d，J＝8.0，1.2Hz，1H)，6.78(s，1H)，6.54(d，J＝2.4Hz，1H)，2.48(s，3H)，1.36(s，9H).

ESI/MS：397.4(M ⁺+H，C ₂₀H ₂₀N ₄O ₃S).

[embodiment 33]

(tert.-butoxy)-N-[4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl)]-N-(2-methoxyl group Phenyl) methane amide (37)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.98(d，1H)，7.37(dd，J＝8.0，1.6Hz，1H)，7.26(t，J＝8Hz，1H)，6.94(d，J＝8.0Hz，1H)，6.84(t，J＝8.0Hz，1H)，6.53(d，J＝2.0Hz，1H)，6.44(s，1H)，3.83(s，3H)，1.35(s，3H).

ESI/MS：381.4(M ⁺+H，C ₂₀H ₂₀N ₄O ₄).

[embodiment 34]

(tert.-butoxy)-N-[4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl)]-N-(2-methylbenzene Base) methane amide (38)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.98(d，J＝2.0Hz，1H)，7.25-7.15(m，3H)，7.07(t，J＝8.0Hz，1H)，6.87(s，1H)，6.52(d，J＝2.0Hz，1H)，6.21(s，1H)，2.28(s，3H)，1.35(s，9H).

ESI/MS：365.6(M ⁺+H，C ₂₀H ₂₀N ₄O ₃).

[embodiment 35]

(tert.-butoxy)-N-[4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl)]-N-(2-methylbenzene And thiazole-6-yl) methane amide (39)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.03(d，J＝2.0Hz1H)，7.45(dt，J＝8.0，2.0Hz，1H)，7.05(ddd，J＝8.0，2.0，1.6Hz，1H)，6.61(d，J＝2.0Hz，1H)，6.47(s，1H)，2.89(s，3H)，1.32(s，9H).

ESI/MS：422.3(M ⁺+H，C ₂₁H ₁₉N ₅O ₃S).

[embodiment 36]

(tert.-butoxy)-N-[4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl)]-N-(4-xenyl) Methane amide (40)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.01(d，J＝2.0Hz1H)，7.52-7.50(m，4H)，7.41-7.35(m，5H)，6.87(s，1H)，6.58(d，J＝2.0Hz，1H)，6.45(s，1H)，1.38(s，9H).

ESI/MS：427.1(M ⁺+H，C ₂₅H ₂₂N ₄O ₃)

[embodiment 37]

N-benzothiazole-6-base (tert.-butoxy)-N-[4-cyano group-5-hydroxyl-6-methyl (pyrazolo [1,5-a] Pyridine-7-yl)] methane amide (41)

ESI/MS：422.3(M ⁺+H，C ₂₁H ₁₉N ₅O ₃S)

[embodiment 38]

Tert.-butoxy-N-[4-cyano group-5-hydroxyl-6-(2-hydroxyethyl) pyrazolo [1,5-a] pyridine-7-yl]- Synthesizing of N-(4-ethoxyl phenenyl) methane amide (42)

With 248mg tert.-butoxy-N-[4-cyano group-5-hydroxyl-6-(2-propenyl) pyrazolo [1,5-a] pyridine-7-base N-(4-ethoxyl phenenyl) methane amide (27) is dissolved in 4.6ml tetrahydrofuran (THF) and the 1.1ml water, add the 611mg sodium periodate, be cooled to 0 ℃ then.In this solution, drip 0.58ml perosmic anhydride (2.5 weight %, 2-methyl-2-propanol solution), at room temperature stirred 2 hours.Reaction soln is diluted with ethyl acetate, add the sodium thiosulfate solution termination reaction then.Separate organic layer,, the organic layer that merges is used mixed aqueous solution (9: the 1) washing of saturated aqueous common salt and saturated aqueous ammonium chloride then with the water layer ethyl acetate extraction.With the organic layer dried over sodium sulfate, decompression is heated up in a steamer and is desolvated then.In resistates, add the 5.7ml dissolve with methanol, add the 21.6mg sodium borohydride, at room temperature stirred 1 hour.Reaction soln is diluted with ethyl acetate, use the saturated common salt water washing then.Use the dried over sodium sulfate organic layer, decompression is heated up in a steamer and is desolvated then.This crude product with silica gel column chromatography (hexane/ethyl acetate=2/1 → 1/2) purifying, is obtained 128mg title compound (42) (yield 51%).

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：10.39(brs，1H)，7.95(brs，1H)，7.12(d，J＝9.0Hz，2H)，6.78(d，J＝9.0Hz，2H)，6.55(brs，1H)，3.96(q，J＝7.0Hz，2H)，3.78(brs，1H)，3.10(brs，1H)，3.04-2.86(m，2H)，1.37(t，J＝7.0Hz，3H)，1.26(brs，9H).

ESI/MS：439.4(M ⁺+H，C ₂₃H ₂₆N ₄O ₅).

[embodiment 39]

Tert.-butoxy-N-{4-cyano group-5-hydroxyl-6-[2-(t-butyldimethylsilyloxy base) ethyl] pyrrole Azoles is [1,5-a] pyridine-7-yl also }-N-(4-ethoxyl phenenyl) methane amide (43) synthetic

With 128mg tert.-butoxy-N-[4-cyano group-5-hydroxyl-6-(2-hydroxyethyl) pyrazolo [1,5-a] pyridine-7-yl]-N-(4-ethoxyl phenenyl) methane amide ( 42) be dissolved in the 2.9ml methylene dichloride, add 110mg TERT-BUTYL DIMETHYL CHLORO SILANE and 50mg imidazoles, at room temperature stirred then 3 hours.In this reaction soln, add 2.9ml methyl alcohol, at room temperature stirred again 15 hours.Reaction soln is diluted with ethyl acetate, wash with saturated sodium-chloride water solution then.Use the dried over sodium sulfate organic layer, decompression is heated up in a steamer and is desolvated, then by silica gel column chromatography (hexane/ethyl acetate=3/1 → 1/1) purifying, obtain the 107.3mg title compound ( 43) (yield 66%).

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：9.96(brs，1H)，7.99(d，J＝1.8Hz，1H)，7.12(d，J＝8.8Hz，2H)，6.79(d，J＝8.8Hz，2H)，6.59(d，J＝1.8Hz，1H)，3.97(m，2H)，3.76(brs，1H)，3.15-2.90(m，3H)，1.38(t，J＝6.9Hz，3H)，1.26(brs，9H)，0.84(s，9H)，0.03(s，3H)，0.01(s，3H).

ESI/MS：553.5(M ⁺+H，C ₂₉H ₄₀N ₄O ₅Si).

[embodiment 40]

7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-the 6-methylpyrazole is also Synthesizing of [1,5-a] pyridine-5-base (trifluoromethyl) sulphonate (44)

With 20.4mg tert.-butoxy-N-(4-cyano group-5-hydroxyl-6-methylpyrazole is [1,5-a] pyridine-7-yl also)-N-(4-ethoxyl phenenyl) methane amide ( 26) be dissolved in 250 μ l pyridines, be cooled to 0 ℃.In this solution, drip 12.6 μ l trifluoromethanesulfanhydride anhydrides, at room temperature stirred 1 hour.Reaction soln is diluted with ethyl acetate, with 1mol/l salt acid elution organic layer.With the organic layer dried over sodium sulfate, decompression is heated up in a steamer and is desolvated then, obtain the 27.0mg title compound ( 44).With the preparation HPLC purifying of a part wherein, measure NMR.

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：8.16(d，J＝2.1Hz，1H)，7.20(d，J＝8.9Hz，2H)，6.94(d，J＝2.1Hz，1H)，6.82(d，J＝8.9Hz，2H)，3.99(q，J＝7.0Hz，2H)，2.33(s，3H)，1.39(t，J＝7.0Hz，3H)，1.29(brs，9H).

ESI/MS：541.2(M ⁺+H，C ₂₃H ₂₃F ₃N ₄O ₆S).

[embodiment 41]

(3S)-3-{7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-methyl pyrrole Also [1,5-a] pyridine-5-base is amino for azoles } piperidine acid tert-butyl ester (45) synthetic

To 108mg 7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-methylpyrazole also [1,5-a] pyridine-5-base (trifluoromethyl) sulphonate ( 44) middle 801mg (the 3S)-3-amino piperidine formic acid that adds Uncle's fourthEster stirred 1 hour down at 100 ℃.Reaction mixture is cooled to room temperature, with the ethyl acetate dilution, organic layer is used successively mixed aqueous solution (1: the 1) washing of mixed aqueous solution (1: 1), saturated sodium-chloride water solution and the saturated sodium bicarbonate aqueous solution of 0.1mol/l aqueous sodium hydroxide solution, saturated sodium-chloride water solution and 1mol/l hydrochloric acid then.With the organic layer dried over sodium sulfate, decompression is heated up in a steamer and is desolvated, then by silica gel column chromatography (hexane/ethyl acetate=7/3) purifying, obtain the 5.9mg title compound ( 45) (yield 5%).

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：7.89(brs，1H)，7.24-7.12(m，2H)，6.90-6.78(m，2H)，6.30(brs，1H)，5.91(brs，1H)，4.21(brs，1H)，3.96(q，J＝7.1Hz，2H)，3.88-3.52(m，2H)，3.40-2.86(m，2H)，2.08(brs，3H)，1.78-1.65(m，2H)，1.50-1.10(m，23H).

ESI/MS：591.2(M ⁺+H，C ₃₂H ₄₂N ₆O ₅).

HPLC retention time: 16.38 minutes

[embodiment 42]

N-{5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(4-xenyl) methane amide (46) synthetic

With 27mg (tert.-butoxy)-N-(4-cyano group-5-hydroxyl (pyrazolo [1,5-a] pyridine-7-yl))-N-(4-xenyl) methane amide (40) is dissolved in 600 μ l 1, in the 4-two  alkane, add 22 μ l triethylamines, 36mg benzotriazole-1-base oxygen base three (pyrrolidyl)  hexafluorophosphate, at room temperature stirred 10 minutes.Add the 145mg anti-form-1, the 4-diamino-cyclohexane at room temperature stirred 4 hours again.Reaction mixture is diluted with ethyl acetate, wash organic layer with the 1mol/L aqueous sodium hydroxide washes.Use the dried over sodium sulfate organic layer, decompression is heated up in a steamer and is desolvated, then by thin-layer silicon plastic column chromatography (ethyl acetate/2mol/l methanolic ammonia solution=5/1) purifying, obtain title compound ( 46).

ESI/MS：523.2(M ⁺+H，C ₃₁H ₃₄N ₆O ₂)

Below, the compound of embodiment 43-embodiment 80 uses corresponding raw material and reagent synthetic according to the method for (embodiment 40 and embodiment 41) or the method for embodiment 42.

[embodiment 43]

(3S)-3-(the 7-[(tert.-butoxy)-N-(4-ethoxyl phenenyl) carbonylamino]-4-cyano group-6-(2-propylene Base) (pyrazolo [1,5-a] pyridine-5-yl) } amino) piperidine acid tert-butyl ester (47)

ESI/MS：617.4(M ⁺+H，C ₃₄H ₄₄N ₆O ₅).

[embodiment 44]

(3R)-and 3-[(7-{ (tert.-butoxy)-N-[4-(2-methoxy ethoxy) phenyl] carbonylamino }-4-cyanogen Base-6-methyl (pyrazolo [1,5-a] pyridine-5-yl)) amino] piperidine acid tert-butyl ester (48)

ESI/MS：621.3(M ⁺+H，C ₃₃H ₄₄N ₆O ₆).

[embodiment 45]

(3S)-and 3-[(7-{ (tert.-butoxy)-N-[4-(2-methoxy ethoxy) phenyl] carbonylamino }-4-cyano group -6-methyl (pyrazolo [1,5-a] pyridine-5-yl)) amino] piperidine acid tert-butyl ester (49)

ESI/MS：607.3(M ⁺+H，C ₃₂H ₄₂N ₆O ₆).

[embodiment 46]

N-{5-[is trans-(4-aminocyclohexyl) amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7- Base) } (tert.-butoxy)-N-[4-(2-methoxy ethoxy) phenyl] methane amide (50)

ESI/MS：535.3(M ⁺+H，C ₂₉H ₃₈N ₆O ₄).

[embodiment 47]

(3S)-3-(the 7-[(tert.-butoxy)-N-(2-methylbenzothiazole-6-yl) carbonylamino]-4-cyano group-6- Methyl (pyrazolo [1,5-a] pyridine-5-yl) } amino) piperidine acid tert-butyl ester (51)

ESI/MS：618.2(M ⁺+H，C ₃₂H ₃₉N ₇O ₄S).

[embodiment 48]

(3S)-3-{ 7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-phenyl pyrazoline Azoles also [1,5-a] pyridine-5-base is amino } piperidine acid tert-butyl ester (52)

ESI/MS：653.5(M ⁺+H，C ₃₇H ₄₄N ₆O ₅).

[embodiment 49]

(3S)-3-{7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-ethyl pyrrole Azoles also [1,5-a] pyridine-5-base is amino } piperidine acid tert-butyl ester (53)

ESI/MS：605.5(M ⁺+H，C ₃₃H ₄₄N ₆O ₅).

[embodiment 50]

N-{5-[is trans-the 4-aminocyclohexyl) and amino]-4-cyano group-6-ethyl (pyrazolo [1,5-a] pyridine-7- Base) } (tert.-butoxy)-N-(4-ethoxyl phenenyl) methane amide (54)

ESI/MS：519.5(M ⁺+H，C ₂₉H ₃₈N ₆O ₃).

[embodiment 51]

(3S)-3-{7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-propyl group pyrrole Azoles also [1,5-a] pyridine-5-base is amino } piperidine acid tert-butyl ester (55)

ESI/MS：619.6(M ⁺+H，C ₃₄H ₄₆N ₆O ₅).

[embodiment 52]

N-{ 5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group-6-propyl group (pyrazolo [1,5-a] pyridine-7- Base) } (tert.-butoxy)-N-(4-ethoxyl phenenyl) methane amide (56)

ESI/MS：533.6(M ⁺+H，C ₃₀H ₄₀N ₆O ₃)

[embodiment 53]

(3S)-3-{7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-(methyl second Base) pyrazolo [1,5-a] pyridine-5-base is amino } piperidine acid tert-butyl ester (57)

ESI/MS：619.7(M ⁺+H，C ₃₄H ₄₆N ₆O ₅).

[embodiment 54]

N-{5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group-6-(methylethyl) (pyrazolo [1,5-a] Pyridine-7-yl) } tert.-butoxy))-N-(4-ethoxyl phenenyl) methane amide (58)

ESI/MS：533.5(M ⁺+H，C ₃₀H ₄₀N ₆O ₃).

[embodiment 55]

(3S)-3-{7-[N-tert-butoxycarbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-cyclopropyl Pyrazolo [1,5-a] pyridine-5-base is amino } piperidine acid tert-butyl ester (59)

ESI/MS：617.6(M ⁺+H，C ₃₄H ₄₄N ₆O ₅).

[embodiment 56]

N-{5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group-6-cyclopropyl (pyrazolo [1,5-a] pyridine- The 7-yl) } (tert.-butoxy)-N-(4-ethoxyl phenenyl) methane amide (60)

ESI/MS：531.6(M ⁺+H，C ₃₀H ₃₈N ₆O ₃).

[embodiment 57]

(tert.-butoxy)-N-(2-chloro-phenyl-)-N-[4-cyano group-5-((3S)-3-piperidyl amino) (pyrazolo [1,5-a] pyridine-7-yl)] methane amide (61)

ESI/MS：567.4(M ⁺+H，C ₂₉H ₃₅ClN ₆O ₄).

[embodiment 58]

N-{5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(2-chloro-phenyl-) methane amide (62)

ESI/MS：481.4(M ⁺+H，C ₂₅H ₂₉ClN ₆O ₂).

[embodiment 59]

(tert.-butoxy)-N-[5-(trans-the 4-[(tert.-butoxy) and carbonylamino] cyclohexyl } amino)-4-cyano group (pyrazolo [1,5-a] pyridine-7-yl)]-N-(2-methylbenzothiazole-6-yl) methane amide (63)

ESI/MS：618.5(M ⁺+H，C ₃₂H ₃₉N ₇O ₄S).

[embodiment 60]

N-{5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(2-p-methoxy-phenyl) methane amide (64)

ESI/MS：477.2(M ⁺+H，C ₂₆H ₃₂N ₆O ₃).

[embodiment 61]

N-{5-[(is trans-the 4-aminocyclohexyl) and amino]-4-cyano group (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(2-methylthio group phenyl) methane amide (65)

ESI/MS：493.3(M ⁺+H，C ₂₆H ₃₂N ₆O ₂S).

[embodiment 62]

(tert.-butoxy)-N-[4-cyano group-5-((3S)-3-piperidyl amino) (pyrazolo [1,5-a] pyridine-7- Base)]-N-(4-xenyl) methane amide (66)

ESI/MS：609.6(M ⁺+H，C ₃₅H ₄₀N ₆O ₄).

[embodiment 63]

N-{5-[(is trans-the 2-aminocyclohexyl) and amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7- Base) } (tert.-butoxy)-N-(4-ethoxyl phenenyl) methane amide (67)

ESI/MS：505.6(M ⁺+H，C ₂₈H ₃₆N ₆O ₃).

[embodiment 64]

(tert.-butoxy)-N-[4-cyano group-6-methyl-5-(4-piperidyl amino) (pyrazolo [1,5-a] pyridine-7- Base)]-N-(4-ethoxyl phenenyl) methane amide (68)

ESI/MS：591.6(M ⁺+H，C ₃₂H ₄₂N ₆O ₅).

[embodiment 65]

The N-{5-[(3-aminocyclohexyl) amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7- Base) } (tert.-butoxy)-N-(4-ethoxyl phenenyl) methane amide (69)

ESI/MS：505.6(M ⁺+H，C ₂₈H ₃₆N ₆O ₃).

[embodiment 66]

The N-{5-[(2-amino-ethyl) amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(4-ethoxyl phenenyl) methane amide (70)

ESI/MS：551.6(M ⁺+H，C ₂₉H ₃₈N ₆O ₅).

[embodiment 67]

The N-{5-[(3-aminopropyl) amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(4-ethoxyl phenenyl) methane amide (71)

ESI/MS：565.5(M ⁺+H，C ₃₀H ₄₀N ₆O ₅).

[embodiment 68]

The amino butyl of N-{5-[(4-) amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(4-ethoxyl phenenyl) methane amide (72)

ESI/MS：579.6(M ⁺+H，C ₃₁H ₄₂N ₆O ₅).

[embodiment 69]

(tert.-butoxy)-N-{4-cyano group-6-methyl-5-[(tetramethyleneimine-3-ylmethyl) amino] (pyrazolo [1,5- A] pyridine-7-yl)-N-(4-ethoxyl phenenyl) methane amide (73)

ESI/MS：591.6(M ⁺+H，C ₃₂H ₄₂N ₆O ₅).

[embodiment 70]

(tert.-butoxy)-N-(4-cyano group-6-methyl-5-{[2-(2-piperidyl) ethyl] amino } { pyrazolo [1,5-a] pyridine-7-yl))-N-(4-ethoxyl phenenyl) methane amide (74)

ESI/MS：619.6(M ⁺+H，C ₃₄H ₄₆N ₆O ₅).

[embodiment 71]

(tert.-butoxy)-N-{4-cyano group-6-methyl-5-[(tetramethyleneimine-2-ylmethyl) amino] (pyrazolo [1,5- A] pyridine-7-yl)-N-(4-ethoxyl phenenyl) methane amide (75)

ESI/MS：591.5(M ⁺+H，C ₃₂H ₄₂N ₆O ₅).

[embodiment 72]

(tert.-butoxy)-N-{4-cyano group-6-methyl-5-[(2-piperidino methyl) amino] (pyrazolo [1,5-a] Pyridine-7-yl) }-N-(4-ethoxyl phenenyl) methane amide (76)

ESI/MS：605.5(M ⁺+H，C ₃₃H ₄₄N ₆O ₅).

[embodiment 73]

(tert.-butoxy)-N-{4-cyano group-5-{[3-(cyclohexyl amino) propyl group] amino }-6-methyl (pyrazolo [1,5-a] pyridine-7-yl) }-N-(4-ethoxyl phenenyl) methane amide (77)

ESI/MS：547.6(M ⁺+H，C ₃₂H ₄₂N ₆O ₃).

[embodiment 74]

(tert.-butoxy)-N-{4-cyano group-6-methyl-5-[(3-piperidino methyl) amino] (pyrazolo [1,5-a] Pyridine-7-yl) }-N-(4-ethoxyl phenenyl) methane amide (78)

ESI/MS：605.7(M ⁺+H，C ₃₃H ₄₄N ₆O ₅).

[embodiment 75]

(tert.-butoxy)-N-{4-cyano group-6-methyl-5-[(2-tetramethyleneimine-2-base ethyl) amino] (pyrazolo [1,5-a] pyridine-7-yl) }-N-(4-ethoxyl phenenyl) methane amide (79)

ESI/MS：605.6(M ⁺+H，C ₃₃H ₄₄N ₆O ₅).

[embodiment 76]

The amino hexyl of N-{5-[(6-) amino]-4-cyano group-6-methyl (pyrazolo [1,5-a] pyridine-7-yl) } (uncle Butoxy)-N-(4-ethoxyl phenenyl) methane amide (80)

ESI/MS：507.6(M ⁺+H，C ₂₈H ₃₈N ₆O ₃).

[embodiment 77]

(tert.-butoxy)-N-{4-cyano group-6-methyl-5-{[2-(1-methylpyrrolidin-2-yl) ethyl] ammonia Base } (pyrazolo [1,5-a] pyridine-7-yl) }-N-(4-ethoxyl phenenyl) methane amide (81)

ESI/MS：519.5(M ⁺+H，C ₂₉H ₃₈N ₆O ₃).

[embodiment 78]

(3S)-3-(7-[N-benzothiazole-6-base (tert.-butoxy) carbonylamino]-4-cyano group-6-methyl (pyrrole Azoles is [1,5-a] pyridine-5-yl also) } amino) piperidine acid tert-butyl ester (82)

ESI/MS：604.5(M ⁺+H，C ₃₁H ₃₇N ₇O ₄S).

[embodiment 79]

(3S)-3-(the 7-[(tert.-butoxy)-N-(2-ethyl benzothiazole-6-yl) carbonylamino]-4-cyano group-6- Methyl (pyrazolo [1,5-a] pyridine-5-yl) } amino) piperidine acid tert-butyl ester (83)

ESI/MS：632.6(M ⁺+H，C ₃₃H ₄₁N ₇O ₄S).

[embodiment 80]

4-(the 7-[(tert.-butoxy)-N-(4-ethoxyl phenenyl) carbonylamino]-4-cyano group-the 6-methylpyrazole is also [1,5-a] pyridine-5-yl } amino)-1,2,3,4-tetrahydroisoquinoline-2-t-butyl formate (84)

ESI/MS：639.5(M ⁺+H，C ₃₆H ₄₂N ₆O ₅).

[embodiment 81]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-methylpyrazole [1,5-a] pyrrole also Synthesizing of pyridine-4-nitrile (85)

With 6.1mg (3S)-3-{7-[N-tert.-butoxy-carbonyl-N-(4-ethoxyl phenenyl) amino]-4-cyano group-6-methyl-pyrazolo [1,5-a] pyridine-5-base is amino } piperidine carboxylic acid Uncle's fourthEster ( 45) crude product be dissolved in 350 μ l methylene dichloride, add 150 μ l trifluoroacetic acids, at room temperature stirred 1 hour.Decompression is heated up in a steamer and is desolvated and trifluoroacetic acid, with preparation HPLC purifying, obtain the 1.81mg title compound ( 85) (yield 24%, trifluoroacetate).

With the gained title compound ( 85) (trifluoroacetate) be dissolved in the methyl alcohol, is carried on the storng-acid cation exchange resin SCX post, uses methanol wash then, with 0.1mol/l ammonia/methanol solution wash-out, decompression is heated up in a steamer and is desolvated then, obtain title compound ( 85) (episome).

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.79(d，J＝2.1Hz，1H)，7.67(s，1H)，6.94(d，J＝8.9Hz，2H)，6.85(d，J＝8.9Hz，2H)，6.38(d，J＝2.1Hz，1H)，5.37(brs，1H)，4.41(brs，1H)，4.02(q，J＝7.0Hz，2H)，3.09(dd，J＝11.6Hz，2.6Hz，1H)，2.93-2.87(m，2H)，2.77(td，J＝15.0Hz，5.4Hz，1H)，2.00-1.50(m，4H)，1.81(s，3H)，1.42(t，J＝7.0Hz，3H).

ESI/MS：391.2(M ⁺+H，C ₂₂H ₂₆N ₆O).

HPLC retention time: 9.34 minutes

Below, the compound of embodiment 82-embodiment 1 29 uses corresponding raw material and reagent synthetic according to the method for embodiment 81.

[embodiment 82]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-(2-propenyl) pyrazolo [1,5- A] pyridine-4-nitrile trifluoroacetate (86)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.76(brs，1H)，8.63(s，1H)，8.59(brs，1H)，7.88(d，J＝2.1Hz，1H)，6.90-6.79(m，4H)，6.30(d，J＝2.1Hz，1H)，5.70(d，J＝9.3Hz，1H)，5.68-5.50(m，1H)，4.97-4.84(m，2H)，4.40-4.28(m，1H)，3.96(q，J＝7.1Hz，2H)，3.40-3.15(m，4H)，2.99-2.86(m，1H)，2.83-2.70(m，1H)，2.20-2.10(m，1H)，1.93-1.82(m，1H)，1.76-1.63(m，1H)，1.62-1.48(m，1H)，1.29(t，J＝7.1Hz，3H).

ESI/MS：417.2(M ⁺+H，C ₂₄H ₂₈N ₆O).

HPLC retention time: 10.17 minutes

[embodiment 83]

5-[(3S)-the 3-piperidyl amino]-7-[4-(2-methoxy ethoxy) phenyl amino]-the 6-methylpyrazole And [1,5-a] pyridine-4-nitrile trifluoroacetate (87)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm) ：8.82(s，1H)，8.79(brs，1H)，8.61(brs，1H)，7.90(d，J＝2.2Hz，1H)，6.90-6.85(m，4H)，6.30(d，J＝2.2Hz，1H)，5.86(d，J＝9.3Hz，1H)，4.31(brs，1H)，4.03(t，J＝4.6Hz，2H)，3.63(t，J＝4.6Hz，2H)，3.40(d，J＝11.0Hz，1H)，3.29(s，3H)，3.23(d，J＝12.0Hz，1H)，3.07-2.99(m，1H)，2.78(d，J＝11.0Hz，1H)，2.17(d，J＝12.0Hz，1H)，1.88(brs，1H)，1.75(s，3H)，1.75-1.60(m，2H).

ESI/MS：421.3(M ⁺+H，C ₂₃H ₂₈N ₆O ₂).

HPLC retention time: 8.17 minutes

[embodiment 84]

5-[(3S)-3-pyrrolidyl amino]-7-[4-(2-methoxy ethoxy) phenyl amino]-6-methyl pyrrole Azoles is [1,5-a] pyridine-4-nitrile trifluoroacetate (88) also

ESI/MS：407.2(M ⁺+H，C ₂₂H ₂₆N ₆O ₂).

HPLC retention time: 8.10 minutes

[embodiment 85]

5-(trans-4-aminocyclohexyl amino)-7-[4-(2-methoxy ethoxy) phenyl amino]-the 6-methyl Pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (89)

ESI/MS：435.3(M ⁺+H，C ₂₄H ₃₀N ₆O ₂).

HPLC retention time: 8.41 minutes

[embodiment 86]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-(2-hydroxyethyl) pyrazolo [1,5-a] pyridine-4-nitrile (90)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：8.32(s，1H)，7.78(d，J＝2.0Hz，1H)，6.82-6.73(m，4H)，6.61(d，J＝8.5Hz，1H)，6.19(d，J＝2.0Hz，1H)，5.23(brs，1H)，4.17-4.08(m，1H)，3.94(q，J＝7.0Hz，2H)，3.40-3.30(m，2H)，3.08-3.01(m，1H)，2.78-2.71(m，1H)，2.67-2.51(m，4H)，2.03-1.94(m，1H)，1.67-1.35(m，3H)，1.28(t，J＝7.0Hz，3H).

ESI/MS：421.3(M ⁺+H，C ₂₃H ₂₈N ₆O ₂).

HPLC retention time: 8.29 minutes

[embodiment 87]

5-[(3S)-the 3-piperidyl amino]-(2-methylbenzothiazole-6-base is amino)-the 6-methylpyrazole is also for 7- [1,5-a] pyridine-4-nitrile (91)

¹H-NMR(400MHz，DMSO-d ₆)δ(ppm)：9.10(s，1H)，7.87(d，J＝2.1Hz，1H)，7.76(d，J＝8.8Hz，1H)，7.35(d，J＝2.4Hz，1H)，7.10(dd，J＝8.8Hz，2.4Hz，1H)，6.29(d，J＝2.1Hz，1H)，5.94(d，J＝9.0Hz，1H)，4.27-4.25(m，1H)，3.18(d，J＝9.0Hz，1H)，2.94(d，J＝12.0Hz，1H)，2.85(dd，J＝12.0Hz，9.0Hz，1H)，2.72(s，3H)，2.69-2.64(m，1H)，2.03(brs，1H)，1.85(s，3H)，1.74-1.54(m，3H).

ESI/MS：418.2(M ⁺+H，C ₂₂H ₂₃N ₇S).

HPLC retention time: 7.80 minutes

[embodiment 88]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino) pyrazolo [1,5-a] pyridine-4-nitrile Trifluoroacetate (92)

ESI/MS：377.2(M ⁺+H，C ₂₁H ₂₄N ₆O).

HPLC retention time: 8.49 minutes

[embodiment 89]

5-[(3S)-the 3-piperidyl amino]-7-(2-chloro-phenyl-amino) pyrazolo [1,5-a] pyridine-4-nitrile trifluoro Acetate (93)

ESI/MS：367.1(M ⁺+H，C ₁₉H ₁₉ClN ₆).

HPLC retention time: 10.91 minutes

[embodiment 90]

5-(trans-4-aminocyclohexyl amino)-7-(2-chloro-phenyl-amino) pyrazolo [1,5-a] pyridine-4-nitrile Trifluoroacetate (94)

ESI/MS：381.2(M ⁺+H，C ₂₀H ₂₁ClN ₆).

HPLC retention time: 8.81 minutes

[embodiment 91]

5-(3-piperidyl amino)-7-(4-ethoxyl phenenyl amino)-6-phenylpyrazole is [1,5-a] pyridine-4-also Nitrile trifluoroacetate (95)

ESI/MS：453.3(M ⁺+H，C ₂₇H ₂₈N ₆O).

HPLC retention time: 9.80 minutes

[embodiment 92]

5-(trans-4-aminocyclohexyl amino)-7-(2-methylbenzothiazole-6-base is amino) pyrazolo [1,5- A] pyridine-4-nitrile trifluoroacetate (96)

ESI/MS：418.2(M ⁺+H，C ₂₂H ₂₃N ₇S).

HPLC retention time: 8.06 minutes

[embodiment 93]

5-(trans-4-aminocyclohexyl amino)-7-(4-xenyl amino) pyrazolo [1,5-a] pyridine-4-nitrile Trifluoroacetate (97)

ESI/MS：423.1(M ⁺+H，C ₂₆H ₂₆N ₆).

HPLC retention time: 10.05 minutes

[embodiment 94]

5-(trans-4-aminocyclohexyl amino)-7-(2-p-methoxy-phenyl amino) pyrazolo [1,5-a] pyridine- 4-nitrile trifluoroacetate (98)

ESI/MS：377.1(M ⁺+H，C ₂₁H ₂₄N ₆O).

HPLC retention time: 8.87 minutes

[embodiment 95]

5-(trans-4-aminocyclohexyl amino)-7-(2-methylthio group phenyl amino) pyrazolo [1,5-a] pyridine- 4-nitrile trifluoroacetate (99)

ESI/MS：390.1(M ⁺+H，C ₂₁H ₂₄N ₆S).

HPLC retention time: 9.12 minutes

[embodiment 96]

5-[(3S)-the 3-piperidyl amino]-7-(4-xenyl amino) pyrazolo [1,5-a] pyridine-4-nitrile trifluoro Acetate (100)

ESI/MS：409.1(M ⁺+H，C ₂₅H ₂₄N ₆).

HPLC retention time: 9.52 minutes

[embodiment 97]

5-[(is trans-the 2-aminocyclohexyl) and amino]-7-[(4-ethoxyl phenenyl amino)]-the 6-methylpyrazole is also [1,5-a] pyridine-4-nitrile trifluoroacetate (101)

ESI/MS：405.2(M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 9.37 minutes

[embodiment 98]

5-[(is trans-the 4-aminocyclohexyl) and amino]-the 7-[(4-ethoxyl phenenyl) amino]-the 6-methylpyrazole is also [1,5-a] pyridine-4-nitrile trifluoroacetate (102)

ESI/MS：405.1(M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 9.94 minutes

[embodiment 99]

7-[(4-ethoxyl phenenyl amino)-6-methyl-5-(4-piperidyl amino) pyrazolo [1,5-a] pyridine-4- Nitrile trifluoroacetate (103)

ESI/MS：391.1(M ⁺+H，C ₂₂H ₂₆N ₆O).

HPLC retention time: 9.49 minutes

[embodiment 100]

The 5-[(3-aminocyclohexyl) amino]-the 7-[(4-ethoxyl phenenyl) amino]-the 6-methylpyrazole also [1,5-a ] pyridine-4-nitrile trifluoroacetate (104)

ESI/MS：405.1(M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 10.04 minutes

[embodiment 101]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-ethyl pyrazolo [1,5-a] pyrrole Pyridine-4-nitrile (105)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.78(d，J＝2.2Hz，1H)，7.51(s，1H)，7.03(d，J＝8.3Hz，2H)，6.84(d，J＝8.3Hz，2H)，6.36(d，J＝2.2Hz，1H)，5.42(brs，1H)，4.50-4.47(m，1H)，4.01(q，J＝7.0Hz，2H)，3.19-3.12(m，1H)，2.96-2.87(m，2H)，2.87-2.78 (m，1H)，2.37(q，J＝7.6Hz，2H)，2.00-1.50(m，4H)，1.41(t，J＝7.0Hz，3H)，0.90(t，J＝7.6Hz，3H).

ESI/MS：405.2(M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 9.20 minutes

[embodiment 102]

The 5-[(2-amino-ethyl) amino]-the 7-[(4-ethoxyl phenenyl) amino]-6-methylpyrazole [1,5-a] pyrrole also Pyridine-4-nitrile trifluoroacetate (106)

ESI/MS：351.1(M ⁺+H，C ₁₉H ₂₂N ₆O).

HPLC retention time: 8.41 minutes

[embodiment 103]

The 5-[(3-aminopropyl) amino]-the 7-[(4-ethoxyl phenenyl) amino]-6-methylpyrazole [1,5-a] pyrrole also Pyridine-4-nitrile trifluoroacetate (107)

ESI/MS：365.1(M ⁺H，C ₂₀H ₂₄N ₆O).

HPLC retention time: 8.60 minutes

[embodiment 104]

The amino butyl of 5-[(4-) amino]-the 7-[(4-ethoxyl phenenyl) amino]-6-methylpyrazole [1,5-a] pyrrole also Pyridine-4-nitrile trifluoroacetate (108)

ESI/MS：379.1(M ⁺+H，C ₂₁H ₂₆N ₆O).

HPLC retention time: 8.88 minutes

[embodiment 105]

5-(trans-4-aminocyclohexyl amino)-7-(4-ethoxyl phenenyl amino)-6-ethyl pyrazolo [1,5- A] pyridine-4-nitrile (109)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.78(d，J＝2.2Hz，1H)，7.53(s，1H)，7.01(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，6.37(d，J＝2.2Hz，1H)，4.32-4.27(m，1H)，4.02(q，J＝7.1Hz，2H)，2.34-2.23(m，4H)，2.23-1.97(m，10H)，1.42(t，J＝7.1Hz，3H)，0.85(t，J＝7.6Hz，3H).

ESI/MS：419.3(M ⁺+H，C ₂₄H ₃₀N ₆O).

HPLC retention time: 9.38 minutes

[embodiment 106]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-(trans-the 4-[(2-methyl-propyl) and amino] cyclohexyl } Amino) pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (110)

ESI/MS：461.2(M ⁺+H，C ₂₇H ₃₆N ₆O).

HPLC retention time: 10.25 minutes

[embodiment 107]

5-[((3S) (3-piperidyl)) amino]-6-methyl-7-(phenyl amino) pyrazolo [1,5-a] pyridine-4-nitrile Trifluoroacetate (111)

ESI/MS：347.1(M ⁺+H，C ₂₀H ₂₂N ₆).

HPLC retention time: 8.48 minutes

[embodiment 108]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[(tetramethyleneimine-3-ylmethyl) amino] pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (112)

ESI/MS：391.1(M ⁺+H，C ₂₂H ₂₆N ₆O).

HPLC retention time: 9.54 minutes

[embodiment 109]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[(2-(2-piperidyl) ethyl) amino] pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (113)

ESI/MS：419.2(M ⁺+H，C ₂₄H ₃₀N ₆O).

HPLC retention time: 10.16 minutes

[embodiment 110]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[(tetramethyleneimine-2-ylmethyl) amino] pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (114)

ESI/MS：391.1(M ⁺+H，C ₂₂H ₂₆N ₆O).

HPLC retention time: 9.49 minutes

[embodiment 111]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-(trans-the 4-[benzylamino] and cyclohexyl } amino) Pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (115)

ESI/MS：495.2(M ⁺+H，C ₃₀H ₃₄N ₆O).

HPLC retention time: 10.44 minutes

[embodiment 112]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-(trans-the 4-[(3-phenyl propyl) and amino] cyclohexyl } Amino) pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (116)

ESI/MS：523.3(M ⁺+H，C ₃₂H ₃₈N ₆O).

HPLC retention time: 11.06 minutes

[embodiment 113]

5-[((3S)-and the 3-piperidyl) amino]-7-(benzothiazole-6-base amino)-6-methylpyrazole also [1,5-a] Pyridine-4-nitrile trifluoroacetate (177)

ESI/MS：404.1(M ⁺+H，C ₂₁H ₂₁N ₇S).

HPLC retention time: 7.02 minutes

[embodiment 114]

5-[((3S)-and the 3-piperidyl) amino]-7-[(2-ethyl benzothiazole-6-yl) amino]-the 6-methylpyrazole And [1,5-a] pyridine-4-nitrile trifluoroacetate (118)

ESI/MS：432.1(M ⁺+H，C ₂₃H ₂₅N ₇S).

HPLC retention time: 8.87 minutes

[embodiment 115]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[(2-piperidino methyl) amino] pyrazolo [1,5-a] Pyridine-4-nitrile trifluoroacetate (119)

ESI/MS：405.1 (M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 9.90 minutes

[embodiment 116]

5-{[3-(cyclohexyl amino) propyl group] amino }-the 7-[(4-ethoxyl phenenyl) amino]-the 6-methylpyrazole is also [1,5-a] pyridine-4-nitrile trifluoroacetate (120)

ESI/MS：447.2(M ⁺+H，C ₂₆H ₃₄N ₆O).

HPLC retention time: 11.25 minutes

[embodiment 117]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-propyl group pyrazolo [1,5-a] pyrrole Pyridine-4-nitrile (121)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.77(d，J＝2.2Hz，1H)，7.51(s，1H)，7.02(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，6.36(d，J＝2.2Hz，1H)，5.58(brs，1H)，4.50-4.47(m，1H)，4.01(q，J＝7.0Hz，2H)，3.08-3.04(m，1H)，2.91-2.84(m，2H)，2.78-2.72(m，1H)，2.28(dd，J＝9.0，6.8Hz，2H)，2.01-1.94(m，1H)，1.89-1.79(m，1H)，1.70-1.60(m，1H)，1.57-1.52(m，1H)，1.42(t，J＝7.0Hz，3H)，1.40-1.30(m，2H)，0.69(t，J＝7.3Hz，3H).

ESI/MS：419.3(M ⁺+H，C ₂₄H ₃₀N ₆O).

HPLC retention time: 10.65 minutes

[embodiment 118]

5-(trans-4-aminocyclohexyl amino)-7-(4-ethoxyl phenenyl amino)-6-propyl group pyrazolo [1,5- A] pyridine-4-nitrile (122)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.78(d，J＝1.7Hz，1H)，7.55(s，1H)，7.01(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，6.38(d，J＝1.7Hz，1H)，4.30-4.01(m，2H)，4.02(q，J＝7.0Hz，2H)，2.72(brs，1H)，2.30-2.17(m，4H)，2.01-1.95(m，2H)，1.64(brs，3H)1.41(t，J＝7.0Hz，3H)，1.40-1.30(m，4H)，0.68(t，J＝7.3Hz，3H).

ESI/MS：433.3(M ⁺+H，C ₂₅H ₃₂N ₆O).

HPLC retention time: 10.95 minutes

[embodiment 119]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-(methylethyl) pyrazolo [1,5-a] pyridine-4-nitrile (123)

¹H-NMR(400MHz，CDCl ₃)δ(ppm)：7.75(d，J＝2.2Hz，1H)，7.30(s，1H)，7.01(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，6.33(d，J＝2.2Hz，1H)，5.58(brs，1H)，4.60-4.50(m，1H)，4.01(q，J＝7.0Hz，2H)，3.40-3.30(m，1H)，3.08-3.02(m，1H)，2.98-2.88(m，2H)，2.79-2.71(m，1H)，2.07-2.03(m，1H)，1.85-1.65(m，1H)，1.60-1.52(m，1H)，1.42(t，J＝7.0Hz，3H)，1.25(d，J＝7.3Hz，3H)，1.18(d，J＝7.3Hz，3H).

ESI/MS：419.3(M ⁺+H，C ₂₄H ₃₀N ₆O).

HPLC retention time: 10.37 minutes

[embodiment 120]

5-(trans-4-aminocyclohexyl amino)-7-(4-ethoxyl phenenyl amino)-6-(methylethyl) pyrazoles And [1,5-a] pyridine-4-nitrile (124)

ESI/MS：433.3(M ⁺+H，C ₂₅H ₃₂N ₆O).

HPLC retention time: 10.72 minutes

[embodiment 121]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-(trans-the 4-[(2-phenylethyl) and amino] cyclohexyl } Amino) pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (125)

ESI/MS：509.2(M ⁺+H，C ₃₁H ₃₆N ₆O).

HPLC retention time: 12.43 minutes

[embodiment 122]

5-(the 4-[(cyclohexyl methyl) and amino] cyclohexyl } amino)-the 7-[(4-ethoxyl phenenyl) amino]-the 6-first Base pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (126)

ESI/MS：501.2(M ⁺+H，C ₃₀H ₄₀N ₆O).

HPLC retention time: 12.65 minutes

[embodiment 123]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[4-(1,2,3, the 4-tetrahydro isoquinolyl) amino] pyrazoles And [1,5-a] pyridine-4-nitrile trifluoroacetate (127)

ESI/MS：439.1(M ⁺+H，C ₂₆H ₂₆N ₆O)

HPLC retention time: 10.81 minutes

[embodiment 124]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[(3-piperidino methyl) amino] pyrazolo [1,5-a] Pyridine-4-nitrile trifluoroacetate (128)

ESI/MS：405.6(M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 10.30 minutes

[embodiment 125]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-[(2-tetramethyleneimine-2-base ethyl) amino] pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (129)

ESI/MS：405.6(M ⁺+H，C ₂₃H ₂₈N ₆O).

HPLC retention time: 7.73 minutes

[embodiment 126]

5-[(3S)-the 3-piperidyl amino]-7-(4-ethoxyl phenenyl amino)-6-cyclopropyl pyrazolo [1,5-a] Pyridine-4-nitrile (130)

ESI/MS：417.2(M ⁺+H，C ₂₄H ₂₈N ₆O).

HPLC retention time: 10.27 minutes

[embodiment 127]

5-(trans-4-aminocyclohexyl amino)-7-(4-ethoxyl phenenyl amino)-6-cyclopropyl pyrazolo [1,5-a] pyridine-4-nitrile (131)

ESI/MS：431.3(M ⁺+H，C ₂₅H ₃₀N ₆O).

HPLC retention time: 10.78 minutes

[embodiment 128]

The amino hexyl of 5-[(6-) amino]-the 7-[(4-ethoxyl phenenyl) amino]-6-methylpyrazole [1,5-a] pyrrole also Pyridine-4-nitrile trifluoroacetate (132)

ESI/MS：407.2(M ⁺+H，C ₂₃H ₃₀N ₆O).

HPLC retention time: 10.49 minutes

[embodiment 129]

The 7-[(4-ethoxyl phenenyl) amino]-6-methyl-5-{[2-(1-methylpyrrolidin-2-yl) ethyl] amino } Pyrazolo [1,5-a] pyridine-4-nitrile trifluoroacetate (133)

ESI/MS：419.2(M ⁺+H，C ₂₄H ₃₀N ₆O).

HPLC retention time: 11.67 minutes

[embodiment 130]

For synthetic compound among the above embodiment, the mass analysis that possesses the ionogenic time-of-flight mass spectrometer of electronic spraying (TOF-MS) by use is confirmed.

About the result of mass analysis, with " M by device shown below and analysis condition observation ⁺+ H " value (obs.Mass: the i.e. additional proton (H of the molecular mass of compound (M) ⁺) measured value), " M ⁺+ H " calculated value (pred.Mass) together, by the actual measurement " M ⁺+ H " the composition formula (Formula) that calculates of value shown in following table B.

Quality analysis apparatus: the LCMS-IT-TOF of Shimadzu Seisakusho Ltd.

LC：Promihence

Post: ZORBZX XDB-C18 (post) 1.8 μ m 2.1mm * 30mm

UV:PDA detects (254nm)

Flow: 0.5ml/ minute

Column temperature: 40 ℃

Detect voltage: 1.60kV

[gradient condition]

Solvent: A:H ₂O/ acetonitrile=95/5

0.05％TFA

B:H ₂O/ acetonitrile=5/95

0.05％TFA

Flow velocity: 0.5ml/ minute

Gradient:

0-0.2 minute, solvent B:5% solvent orange 2 A: 95%

0.2-2.5 minute, solvent B:5% → 100% solvent orange 2 A: 95% → 0%

2.5-3.8 minute, solvent B:100% solvent orange 2 A: 0%

3.8-4.0 minute, solvent B:100% → 5% solvent orange 2 A: 0% → 95%

4.0-4.5 minute, solvent B:5% solvent orange 2 A: 95%

Table B

The compound number of embodiment	obs.Mass	pred.Mass	Formula
The compound number of embodiment	obs.Mass	pred.Mass	Formula		(M ⁺+H)	(M ⁺+H)	(M)
13	208.0278	208.0278	C ₉H ₆ClN ₃O		(M ⁺+H)	(M ⁺+H)	(M)
13	208.0278	208.0278	C ₉H ₆ClN ₃O	21	309.1351	309.1352	C ₁₇H ₁₆N ₄O ₂
26	409.1892	409.1876	C ₂₂H ₂₄N ₄O ₄	21	309.1351	309.1352	C ₁₇H ₁₆N ₄O ₂
26	409.1892	409.1876	C ₂₂H ₂₄N ₄O ₄	27	435.2012	435.2032	C ₂₄H ₂₆N ₄O ₄
45	591.3299	591.3295	C ₃₂H ₄₂N ₆O ₅	27	435.2012	435.2032	C ₂₄H ₂₆N ₄O ₄
45	591.3299	591.3295	C ₃₂H ₄₂N ₆O ₅	85	391.2288	391.2246	C ₂₂H ₂₆N ₆O
86	417.2428	417.2403	C ₂₄H ₂₈N ₆O	85	391.2288	391.2246	C ₂₂H ₂₆N ₆O
86	417.2428	417.2403	C ₂₄H ₂₈N ₆O	87	421.2357	421.2352	C ₂₃H ₂₈N ₆O ₂
88	407.2214	407.2195	C ₂₂H ₂₆N ₆O ₂	87	421.2357	421.2352	C ₂₃H ₂₈N ₆O ₂
88	407.2214	407.2195	C ₂₂H ₂₆N ₆O ₂	89	435.2531	435.2508	C ₂₄H ₃₀N ₆O ₂
90	421.2367	421.2352	C ₂₃H ₂₈N ₆O ₂	89	435.2531	435.2508	C ₂₄H ₃₀N ₆O ₂
90	421.2367	421.2352	C ₂₃H ₂₈N ₆O ₂	91	418.1827	418.1814	C ₂₂H ₂₃N ₇S

The compound number of embodiment	obs.Mass	pred.Mass	Formula
The compound number of embodiment	obs.Mass	pred.Mass	Formula		(M ⁺+H)	(M ⁺+H)	(M)
92	377.2078	377.2090	C ₂₁H ₂₄N ₆O		(M ⁺+H)	(M ⁺+H)	(M)
92	377.2078	377.2090	C ₂₁H ₂₄N ₆O	93	367.1457	367.1438	C ₁₉H ₁₉ClN ₆
94	381.1612	381.1594	C ₂₀H ₂₁ClN ₆	93	367.1457	367.1438	C ₁₉H ₁₉ClN ₆
94	381.1612	381.1594	C ₂₀H ₂₁ClN ₆	95	453.2427	453.2403	C ₂₇H ₂₈N ₆O
96	418.1834	418.1814	C ₂₂H ₂₃N ₇S	95	453.2427	453.2403	C ₂₇H ₂₈N ₆O
96	418.1834	418.1814	C ₂₂H ₂₃N ₇S	97	423.2320	423.2297	C ₂₆H ₂₆N ₆
98	377.2109	377.2090	C ₂₁H ₂₄N ₆O	97	423.2320	423.2297	C ₂₆H ₂₆N ₆
98	377.2109	377.2090	C ₂₁H ₂₄N ₆O	99	393.1862	393.1861	C ₂₁H ₂₄N ₆S
100	409.2125	409.2141	C ₂₅H ₂₄N ₆	99	393.1862	393.1861	C ₂₁H ₂₄N ₆S
100	409.2125	409.2141	C ₂₅H ₂₄N ₆	101	405.2431	405.2403	C ₂₃H ₂₈N ₆O
102	405.2450	405.2403	C ₂₃H ₂₈N ₆O	101	405.2431	405.2403	C ₂₃H ₂₈N ₆O
102	405.2450	405.2403	C ₂₃H ₂₈N ₆O	103	391.2260	391.2246	C ₂₂H ₂₆N ₆O

The compound number of embodiment	obs.Mass	pred.Mass	Formula
The compound number of embodiment	obs.Mass	pred.Mass	Formula		(M ⁺+H)	(M ⁺+H)	(M)
104	405.2447	405.2403	C ₂₃H ₂₈N ₆O		(M ⁺+H)	(M ⁺+H)	(M)
104	405.2447	405.2403	C ₂₃H ₂₈N ₆O	105	405.2432	405.2403	C ₂₃H ₂₈N ₆O
106	351.1901	351.1933	C ₁₉H ₂₂N ₆O	105	405.2432	405.2403	C ₂₃H ₂₈N ₆O
106	351.1901	351.1933	C ₁₉H ₂₂N ₆O	107	365.2110	365.2090	C ₂₀H ₂₄N ₆O
108	379.2245	379.2246	C ₂₁H ₂₆N ₆O	107	365.2110	365.2090	C ₂₀H ₂₄N ₆O
108	379.2245	379.2246	C ₂₁H ₂₆N ₆O	109	419.2537	419.2559	C ₂₄H ₃₀N ₆O
110	461.3022	461.3029	C ₂₇H ₃₆N ₆O	109	419.2537	419.2559	C ₂₄H ₃₀N ₆O
110	461.3022	461.3029	C ₂₇H ₃₆N ₆O	111	347.1956	347.1984	C ₂₀H ₂₂N ₆
112	391.2223	391.2246	C ₂₂H ₂₆N ₆O	111	347.1956	347.1984	C ₂₀H ₂₂N ₆
112	391.2223	391.2246	C ₂₂H ₂₆N ₆O	113	419.2561	419.2559	C ₂₄H ₃₀N ₆O
114	391.2245	391.2246	C ₂₂H ₂₆N ₆O	113	419.2561	419.2559	C ₂₄H ₃₀N ₆O
114	391.2245	391.2246	C ₂₂H ₂₆N ₆O	115	495.2898	495.2872	C ₃₀H ₃₄N ₆O

The compound number of embodiment	obs.Mass	pred.Mass	Formula
The compound number of embodiment	obs.Mass	pred.Mass	Formula		(M ⁺+H)	(M ⁺+H)	(M)
116	523.3180	523.3185	C ₃₂H ₃₈N ₆O		(M ⁺+H)	(M ⁺+H)	(M)
116	523.3180	523.3185	C ₃₂H ₃₈N ₆O	117	404.1644	404.1657	C ₂₁H ₂₁N ₇S
118	432.1972	432.1970	C ₂₃H ₂₅N ₇S	117	404.1644	404.1657	C ₂₁H ₂₁N ₇S
118	432.1972	432.1970	C ₂₃H ₂₅N ₇S	119	405.2418	405.2403	C ₂₃H ₂₈N ₆O
120	447.2912	447.2872	C ₂₆H ₃₄N ₆O	119	405.2418	405.2403	C ₂₃H ₂₈N ₆O
120	447.2912	447.2872	C ₂₆H ₃₄N ₆O	121	419.2559	419.2559	C ₂₄H ₃₀N ₆O
122	433.2709	433.2716	C ₂₅H ₃₂N ₆O	121	419.2559	419.2559	C ₂₄H ₃₀N ₆O
122	433.2709	433.2716	C ₂₅H ₃₂N ₆O	123	419.2569	419.2559	C ₂₄H ₃₀N ₆O
124	433.2737	433.2716	C ₂₅H ₃₂N ₆O	123	419.2569	419.2559	C ₂₄H ₃₀N ₆O
124	433.2737	433.2716	C ₂₅H ₃₂N ₆O	125	509.3063	509.3029	C ₃₁H ₃₆N ₆O
126	501.3338	501.3342	C ₃₀H ₄₀N ₆O	125	509.3063	509.3029	C ₃₁H ₃₆N ₆O
126	501.3338	501.3342	C ₃₀H ₄₀N ₆O	128	405.2407	405.2403	C ₂₃H ₂₈N ₆O

The compound number of embodiment	obs.Mass	pred.Mass	Formula
The compound number of embodiment	obs.Mass	pred.Mass	Formula		(M ⁺+H)	(M ⁺+H)	(M)
129	405.2408	405.2403	C ₂₃H ₂₈N ₆O		(M ⁺+H)	(M ⁺+H)	(M)
129	405.2408	405.2403	C ₂₃H ₂₈N ₆O	130	417.2416	417.2403	C ₂₄H ₂₈N ₆O
131	431.2572	431.2559	C ₂₅H ₃₀N ₆O	130	417.2416	417.2403	C ₂₄H ₂₈N ₆O
131	431.2572	431.2559	C ₂₅H ₃₀N ₆O	132	407.2558	407.2559	C ₂₃H ₃₀N ₆O
133	419.2568	419.2559	C ₂₄H ₃₀N ₆O	132	407.2558	407.2559	C ₂₃H ₃₀N ₆O

[embodiment 131]

Be used to measure the conventional determining method that the MAPKAP-K2 enzymic activity suppresses

(preparation of compound solution)

In DMSO, making its concentration is 20mmol/l with compound dissolution, preserves down at-20 ℃.Should preserve solution and dilute successively, prepare the solution of 200 times of concentration of required scope with DMSO.Be 1: 20 with its dilute with water again, prepare 10 times of concentration solution of required scope, use 5 each solution of μ l in per 50 μ l reaction.By the serial dilution of whole compounds, keeping final DMSO concentration is 0.5%.Under ultimate density scope 100 μ mol/l to 0.03 μ mol/l, carry out the routine test of compound, but also can test with lower concentration according to its activity.

(MAPKAP-K2 enzyme assay)

In the 5%DMSO solution of 5 μ l test-compounds, add 25 μ l peptide substrates solution, add 60 μ mol/l peptide substrates, 20 μ mol/l ATP, 60mmol/l Tris damping fluid (pH7.5), 0.2mmol/l EGTA, 0.2% beta-mercaptoethanol, 20mmol/l magnesium acetate, 0.1 μ Ci[γ-33P then] ATP (specific activity is about 110TBq/mmol), add 20 μ l MAPKAP-K2 enzyme solution again, initiation reaction [10mU recombinant human MAPKAP-K2,50mmol/l Tris damping fluid (pH7.5), 0.1mmol/l EGTA, 0.1% beta-mercaptoethanol, 0.1%BSA].At room temperature reacted 30 minutes, and added the 200mmol/l phosphoric acid of 50 μ l then, termination reaction, the reaction mixture with 90 μ l is adsorbed on the multi-screen PH plate (Millipore) again, uses the 100mmol/l phosphoric acid washing.With the plate drying, add the MicroScint-O (Perkin-Elmer) of 30 μ l then, measure count per minute by scintillometer again, determine to suppress active.Peptide substrate is Lys-Lys-Leu-Asn-Arg-Thr-Leu-Ser-Val-Ala.

(note)

Contrast %=(X-B)/(Tot-B) * 100

Suppress %=100-contrast %

The count per minute in X=test-compound hole

B=does not contain the count per minute in the hole of enzyme

Tot=only with the DMSO solvent, do not contain the count per minute (MAPKAP-K2 suppresses active calculating) in the hole of test-compound

IC ₅₀Compound concentration when value=50% suppresses

Each compound to the validity of MAPKAP-K2 shown in following table C.

(in the activity intensity in the table, ++ ++ be IC ₅₀Value＜0.2 μ mol/l, +++be 0.2≤IC ₅₀Value＜1 μ mol/l, ++ be 1 μ mol/l≤IC ₅₀Value＜10 μ mol/l ,+be 10 μ mol/l≤IC ₅₀Value＜100 μ mol/l)

Table C

The compound number of embodiment	Activity intensity	The compound number of embodiment	Activity intensity
The compound number of embodiment	Activity intensity	The compound number of embodiment	Activity intensity	85	++++	110	++++
86	++++	111	++++	85	++++	110	++++
86	++++	111	++++	87	++++	112	++
88	+++	113	+	87	++++	112	++
88	+++	113	+	89	++++	114	++
90	++++	115	+++	89	++++	114	++

The compound number of embodiment	Activity intensity	The compound number of embodiment	Activity intensity
The compound number of embodiment	Activity intensity	The compound number of embodiment	Activity intensity	91	++++	116	+++
92	+++	117	++++	91	++++	116	+++
92	+++	117	++++	93	+++	118	++++
94	+++	119	++	93	+++	118	++++
94	+++	119	++	95	+++	120	++
96	+++	121	++++	95	+++	120	++
96	+++	121	++++	97	++++	122	++++
98	+++	123	++++	97	++++	122	++++
98	+++	123	++++	99	++	124	++++
100	+++	125	+++	99	++	124	++++
100	+++	125	+++	101	+	126	+++
102	++++	127	++	101	+	126	+++
102	++++	127	++	103	+++	128	++
104	++	129	++	103	+++	128	++
104	++	129	++	105	++++	130	+++
106	+++	131	++++	105	++++	130	+++
106	+++	131	++++	107	+++	132	+
108	+++	133	+	107	+++	132	+
108	+++	133	+	109	++++

Industrial applicability

Compound of the present invention can be used as MAPKAP-K2 inhibitor or its intermediate.

The compound of the application of the invention can provide novel MAPKAP-K2 inhibitor or curative or the preventive medicine of neurodegeneration/neurology obstacle (comprising dementia), inflammatory disorder, septicemia, autoimmune disease, destructive osteopathy, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, cachexia, obesity, Angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD) as active ingredient.

Claims

1. [1, the 5-a] pyridine derivate of the pyrazolo shown in the formula (I) or its medically acceptable salt:

In the formula (I),

R ¹, R ²And R ³Substituent substituting group when not specifying, be to be selected from halogen atom, hydroxyl, cyano group, nitro, amino, the oxo base, carboxyl, trifluoromethyl, pentafluoroethyl group, trifluoromethoxy, can be by (halogen atom, hydroxyl, cyano group or oxo base) the C1-C8 alkyl that replaces, can be by (methyl, halogen atom, hydroxyl, cyano group or oxo base) the C3-C8 ester ring type alkyl that replaces, can be by (halogen atom, hydroxyl or cyano group) the C1-C8 alkoxyl group that replaces, can be by (methyl, halogen atom, hydroxyl, or cyano group) the C3-C8 ester ring type-oxyl of Qu Daiing, can be by (methyl, halogen atom, hydroxyl or cyano group) the aliphatic heterocyclic radical that replaces, can be by (methyl, halogen atom, hydroxyl or cyano group) the C6-C14 aromatic hydrocarbyl that replaces, and can be by (methyl, halogen atom, hydroxyl or cyano group) the more than one substituting group of the aromatic heterocyclic radical that replaces.

2. the pyrazolo of claim 1 [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ¹Expression can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical

3. claim 1 or 2 pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, except the following situation:

R ¹Be the phenyl that does not have the C1-C6 alkyl that replaces or do not have replacement or replaced, R by halogen atom ²For do not have to replace or by (halogen atom ,-OH or-NR ^2cR ^2d) C1-C6 alkyl that replaces or the C3-C7 ester ring type alkyl (R that does not have replacement ^2cOr R ^2dIndependent separately, can be identical or different, for hydrogen atom, do not have replace C1-C6 alkyl that fluorine replaces or do not have the C3-C7 ester ring type alkyl of replacement), and R ³Be C1-C6 alkyl that do not have to replace or replaced by fluorine atom or the C3-C7 ester ring type alkyl that does not have replacement;

4. claim 1 or 2 pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ¹For by (fluorine atom ,-NR ^1cR ^1d,-NR ^1k-CO-R ^1lOr NR ^1mS (=O) ₂R ¹ⁿ) the C1-C8 alkyl that replaces of in addition group, can substituted C2-C8 thiazolinyl, can substituted C2-C8 alkynyl, the C6 aromatic hydrocarbyl that replaced by the group beyond the halogen atom, can substituted C7-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl, quilt (NR ^1cR ^1d,-NR ^1k-CO-R ^1l, or-NR ^1mS (=O) ₂R ¹ⁿ) the C3-C8 ester ring type alkyl that replaces of in addition group or can substituted aliphatic heterocyclic radical,

R ³For by fluorine atom or-OR ^3aThe C1-C8 alkyl that in addition group replaces, substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical.

5. each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt among the claim 1-4, wherein, R ¹For can substituted C1-C8 alkyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl or can substituted C3-C8 ester ring type alkyl.

6. each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt among the claim 1-4, wherein, R ¹For can substituted C1-C8 alkyl, can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical.

7. each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt among the claim 1-4, wherein, R ¹For can substituted C6-C14 aromatic hydrocarbyl or can substituted aromatic heterocyclic radical.

8. each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt among the claim 1-4, wherein, R ¹For can substituted phenyl.

9. each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt among the claim 1-4, wherein, R ¹For can substituted aromatic heterocyclic radical.

10. the pyrazolo of claim 9 [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ¹Be have phenyl with can the heterocyclic fused structure of substituted monocyclic aromatic, and 7 NH group bonded aromatic heterocyclic radicals of pyrazolo [1, the 5-a] pyridine derivate of this phenyl one side and formula (I).

11. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-4 or its medically acceptable salt, wherein, R ¹Be can substituted C7-C16 aromatic hydrocarbon alkyl or can substituted aromatic heterocycle alkyl.

12. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group for being selected from fluorine atom; the chlorine atom; cyano group; nitro; can substituted C1-C6 alkyl; can substituted C3-C8 ester ring type alkyl; can substituted C1-C6 alkoxyl group; can substituted C1-C6 alkylthio; can substituted phenyl; can substituted aromatic heterocyclic radical; can substituted C1-C6 acyl group; can substituted C1-C6 acyl amino; can substituted amino-sulfonyl (when this amino-sulfonyl has two alkyl substituents; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted C2-C7 alkoxy carbonyl; can substituted sulfuryl amino; and can substituted formamyl (when this formamyl has two alkyl substituents; they are independent separately; can be identical or different, can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring) more than one substituting group.

13. appoint among the claim 1-11-pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt, wherein, R ¹Substituting group for being selected from fluorine atom; the chlorine atom; cyano group; nitro; can substituted C1-C6 alkylthio; can substituted C1-C6 acyl group; can substituted C1-C6 acyl amino; can substituted amino-sulfonyl (when this amino-sulfonyl has two alkyl substituents; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted C2-C7 alkoxy carbonyl; can substituted sulfuryl amino; and can substituted formamyl (when this formamyl has two alkyl substituents; they are independent separately; can be identical or different, can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring) more than one substituting group.

14. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group be selected from fluorine atom, chlorine atom, cyano group, nitro, can substituted phenyl and more than one substituting group that can substituted aromatic heterocyclic radical.

15. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group be to be selected from a substituting group of can substituted phenyl, can substituted aromatic heterocyclic radical, and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom, cyano group and nitro.

16. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group for the C1-C6 alkyl that is selected from fluorine atom, chlorine atom, cyano group, can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace, the more than one substituting group of the C3-C8 ester ring type alkyl that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace and the C1-C6 alkyl that replaced by (can substituted C1-C6 alkoxyl group or can substituted C3-C6 ester ring type-oxyl); Substituting group that wherein can substituted C1-C6 alkoxyl group is the more than one substituting group that is selected from halogen atom, hydroxyl and cyano group, and substituting group that can substituted C3-C6 ester ring type-oxyl is the more than one substituting group that is selected from methyl, halogen atom, hydroxyl, cyano group and oxo base.

17. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group be the C3-C8 ester ring type alkyl that is selected from the C1-C6 alkyl that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace, can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replaces and the more than one substituting group of substituted C1-C6 alkyl, and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom and cyano group; Wherein, the substituting group of substituted C1-C6 alkyl is the C1-C6 alkoxyl group that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace or the C3-C6 ester ring type-oxyl that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl, cyano group and oxo base) and replace.

18. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group for being selected from the more than one substituting group of can substituted C1-C6 alkyl (1) and can substituted C1-C6 alkyl (2), and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom, cyano group and methyl; Wherein, substituting group that can substituted C1-C6 alkyl (1) is the more than one substituting group that is selected from carboxyl, oxo base and can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) the C1-C6 alkoxyl group that replaces, and substituting group that can substituted C1-C6 alkyl (2) is the aromatic heterocyclic radical that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl and cyano group) and replace or the aliphatic heterocyclic radical that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl and cyano group) and replace.

19. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹The C1-C6 alkyl that replaced for can (being selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) of substituting group.

20. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group for being selected from fluorine atom, the chlorine atom, cyano group, can (be selected from halogen atom, the more than one substituting group of hydroxyl and cyano group) the C1-C6 alkoxyl group of Qu Daiing, (this aliphatic series heterocyclic radical can (be selected from methyl to the C1-C6 alkoxyl group that is replaced by aliphatic heterocyclic radical, halogen atom, the more than one substituting group of hydroxyl and cyano group) replaces), and [can (be selected from halogen atom, the more than one substituting group of hydroxyl and cyano group) the C1-C6 alkoxyl group of Qu Daiing or can (be selected from methyl, halogen atom, hydroxyl, the more than one substituting group of cyano group and oxo base) the C3-C6 ester ring type-oxyl of Qu Daiing] the more than one substituting group of the C1-C6 alkoxyl group that replaces.

21. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group can substituted C1-C6 alkoxyl group (1) for being selected from, the C1-C6 alkoxyl group (2) that replaced by aliphatic heterocyclic radical and the more than one substituting group of substituted C1-C6 alkoxyl group (3), and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom and cyano group; Wherein, substituting group that can substituted C1-C6 alkoxyl group (1) is the more than one substituting group that is selected from halogen atom, hydroxyl and cyano group; The more than one substituting group that the aliphatic series heterocyclic radical can be selected from methyl, halogen atom, hydroxyl and cyano group replaces; The substituting group of substituted C1-C6 alkoxyl group (3) is the C1-C6 alkoxyl group that can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) and replace or the C3-C6 ester ring type-oxyl that can (be selected from the more than one substituting group of methyl, halogen atom, hydroxyl, cyano group and oxo base) and replace.

22. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹Substituting group be the more than one substituting group that is selected from the C1-C6 alkoxyl group (2) of can substituted C1-C6 alkoxyl group (1) and can be replaced by aromatic heterocyclic radical, and can contain the more than one substituting group that is selected from fluorine atom, chlorine atom, cyano group and methyl; Wherein, substituting group that can substituted C1-C6 alkoxyl group (1) is the more than one substituting group that is selected from carboxyl, oxo base and can (be selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) the C1-C6 alkoxyl group (3) that replaces; The more than one substituting group that aromatic heterocyclic radical can be selected from methyl, halogen atom, hydroxyl and cyano group replaces.

23. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-11 or its medically acceptable salt, wherein, R ¹The C1-C6 alkoxyl group that replaced for can (being selected from the more than one substituting group of halogen atom, hydroxyl and cyano group) of substituting group.

24. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²For hydrogen atom, can substituted C1-C8 alkyl, can substituted C2-C8 thiazolinyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C16 aromatic hydrocarbon alkyl, can substituted aromatic heterocycle alkyl or can substituted C3-C8 ester ring type alkyl.

25. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²For hydrogen atom, can substituted C1-C6 alkyl, can substituted C2-C6 thiazolinyl, can substituted C6-C14 aromatic hydrocarbyl, can substituted aromatic heterocyclic radical, can substituted C7-C12 phenylalkyl or can substituted C3-C6 ester ring type alkyl.

26. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²For hydrogen atom, can substituted C1-C6 alkyl, can substituted C2-C6 thiazolinyl or can substituted C3-C6 ester ring type alkyl.

27. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²For can substituted C1-C6 alkyl or can substituted C2-C6 thiazolinyl.

28. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²For can substituted C1-C4 alkyl.

29. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²Be hydrogen atom.

30. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-23 or its medically acceptable salt, wherein, R ²For can substituted phenyl or can substituted aromatic heterocyclic radical.

31. [1, the 5-a] pyridine derivate of each pyrazolo among claim 1-4, the 24-30 or its medically acceptable salt, wherein, R ²Substituting group for being selected from halogen atom; cyano group; nitro; hydroxyl; can substituted amino (when two alkyl substituents are arranged on this amino; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted C1-C6 alkyl; can substituted C1-C6 alkoxyl group; can substituted C1-C6 acyl group; can substituted amino-sulfonyl (when this amino-sulfonyl has two alkyl substituents; they are independent separately; can be identical or different; can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring); can substituted sulfuryl amino; and can substituted formamyl (when two alkyl substituents are arranged on this formamyl; they are independent separately; can be identical or different, can be via Sauerstoffatom; nitrogen-atoms; sulphur atom or singly-bound interosculate and form ring) more than one substituting group.

32. [1, the 5-a] pyridine derivate of each pyrazolo among claim 1-4, the 24-30 or its medically acceptable salt, wherein, R ²Substituting group for be selected from halogen atom, cyano group, nitro, hydroxyl, can substituted amino (when two alkyl substituents are arranged on this amino; they are independent separately; can be identical or different; can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C1-C6 acyl group and can substituted formamyl (when two alkyl substituents are arranged on this formamyl; they are independent separately; can be identical or different, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring) more than one substituting group.

33. [1, the 5-a] pyridine derivate of each pyrazolo among claim 1-4, the 24-30 or its medically acceptable salt, wherein, R ²Substituting group for be selected from halogen atom, cyano group, nitro, hydroxyl, can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring), can substituted C1-C6 alkyl and more than one substituting group that can substituted C1-C6 alkoxyl group.

34. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-33 or its medically acceptable salt, wherein, R ³For can substituted C1-C8 alkyl, can substituted C3-C8 ester ring type alkyl or can substituted aliphatic heterocyclic radical.

35. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-33 or its medically acceptable salt, wherein, R ³For can substituted C3-C8 ester ring type alkyl or can substitutedly have 1-4 nitrogen-atoms as heteroatomic aliphatic heterocyclic radical.

36. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-33 or its medically acceptable salt, wherein, R ³For can substituted C5-C6 ester ring type alkyl or can substituted (piperidyl, pyrrolidyl or six hydrogen azepine  yls).

37. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-33 or its medically acceptable salt, wherein, R ³For can substituted cyclohexyl, can substituted piperidyl or can substituted pyrrolidyl.

38. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-33 or its medically acceptable salt, wherein, R ³For can substituted piperidyl.

39. [1, the 5-a] pyridine derivate of each pyrazolo among the claim 1-33 or its medically acceptable salt, wherein, R ³For can substituted C1-C4 alkyl.

40. [1, the 5-a] pyridine derivate of each pyrazolo among claim 1-4, the 34-39 or its medically acceptable salt, wherein, R ³Substituting group for be selected from fluorine atom, hydroxyl, cyano group, can substituted C1-C6 alkyl and can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can interosculate via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound and form ring) more than one substituting group.

41. [1, the 5-a] pyridine derivate of each pyrazolo among claim 1-4, the 34-39 or its medically acceptable salt, wherein, R ³Substituting group for being selected from fluorine atom, hydroxyl, cyano group, can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can be via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound interosculate and form ring), can substituted C5-C6 ester ring type alkyl [substituting group is can substituted amino (when two alkyl substituents are arranged on this amino, they are independent separately, can be identical or different, can be via Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound interosculate and form ring)], and can substituted (piperazinyl, piperidyl or pyrrolidyl) the more than one substituting group of (substituting group is the C1-C6 alkyl that can be replaced by fluorine atom or hydroxyl).

42. the pyrazolo shown in the formula (6) [1,5-a] pyridine derivate or salt:

In the formula, R ²Definition suc as formula (I).

43. the pyrazolo shown in the formula (7) [1,5-a] pyridine derivate or salt:

In the formula, R ²Suc as formula the definition of (I), W represents halogen atom.

44. the pyrazolo shown in the formula (8) [1,5-a] pyridine derivate or salt:

In the formula, R ¹And R ²Definition suc as formula (I).

45. the pyrazolo shown in the formula (9) [1,5-a] pyridine derivate or salt:

In the formula, R ¹And R ²Suc as formula the definition of (I), wherein, P represents amino protecting group.

46. the pyrazolo shown in the formula (10) [1,5-a] pyridine derivate or salt:

In the formula, R ¹And R ²Suc as formula the definition of (I), wherein, Boc represents tert-butoxycarbonyl.

47. the pyrazolo shown in the formula (11) [1,5-a] pyridine derivate or salt:

In the formula, R ¹And R ²Suc as formula the definition of (I), wherein, P represents amino protecting group, and L represents perfluoroalkyl group sulfonyl.

48. the pyrazolo shown in the formula (12) [1,5-a] pyridine derivate or salt:

In the formula, R ¹And R ²Suc as formula the definition of (I), wherein, Boc represents tert-butoxycarbonyl, and Tf represents trifyl.

49. the pyrazolo shown in the formula (13) [1,5-a] pyridine derivate or salt:

In the formula, R ¹, R ²And R ³Suc as formula the definition of (I), wherein, P represents amino protecting group.

50. the pyrazolo shown in the formula (14) [1,5-a] pyridine derivate or salt:

In the formula, R ¹, R ²And R ³Suc as formula the definition of (I), wherein, Boc represents tert-butoxycarbonyl.

51. the pyrazolo shown in each formula (8)-(14) [1,5-a] pyridine derivate or salt among the claim 44-50, wherein, R ¹Be quilt (NR ^1cR ^1d,-NR ^1k-CO-R ^1l, or-NR ^1mS (=O) ₂R ¹ⁿ) except the compound of (C1-C8 alkyl or the C3-C8 ester ring type alkyl) that replace.

52. pharmaceutical composition, this pharmaceutical composition contain among the claim 1-41 each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt and pharmacopedics on acceptable carrier.

53.MAPKAP-K2 inhibitor, this inhibitor contain among the claim 1-41 each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt as effective constituent.

54. the curative or the prophylactic agent of neurodegeneration/neurological obstacle (comprising dementia), septicemia, autoimmune disorder, destructive osteopathy, inflammatory bowel, psoriatic, diabetes, cancer, ischemia-reperfusion obstacle, vascularization sexual dysfunction, emaciation, obesity, vasculogenesis, asthma and/or chronic obstructive pulmonary disease (COPD), this medicine contain among the claim 1-41 each pyrazolo [1,5-a] pyridine derivate or its medically acceptable salt as effective constituent.

55. the curative of claim 54 or prophylactic agent, wherein, autoimmune disorder is rheumatoid arthritis, ankylosing spondylitis, rheumatoid arthritis,juvenile, arthritic psoriasis, graft versus host disease (GVH disease), diabetes or Crohn disease.