CN104109165A

CN104109165A - 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-one derivatives, and preparation method and application thereof

Info

Publication number: CN104109165A
Application number: CN201310428690.6A
Authority: CN
Inventors: 魏用刚; 邱关鹏; 卢泳华; 余彦; 雷柏林; 王松; 黄清平; 高秋; 楚洪柱; 祝国智; 罗新峰; 倪丽君; 陈娅姝; 邓炳初
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2013-04-19
Filing date: 2013-09-18
Publication date: 2014-10-22
Also published as: CN105026392A; WO2014169845A2; WO2014169845A3; CN105026392B

Abstract

The invention relates to 4,5-dihydro-pyrazolo[3,4-c]pyrid-2-one derivatives as shown in a general formula (I) which is described in the specification, and a preparation method and application thereof. Each substituent in the general formula (I) is defined in the specification.

Description

4,5-dihydro-pyrazolo [3,4-c] pyridin-2-ones derivative, its preparation method and application

Technical field

The present invention relates to shown in a kind of general formula (I) 4,5-dihydro-pyrazolo [3,4-c] pyridin-2-ones derivative, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt or prodrug, its preparation method and the pharmaceutical composition that contains them and as the purposes of coagulation factor xa inhibitors.

Background technology

At present, cardiovascular disorder is to cause one of mankind's main causes of death, and its a main aspect is thrombosis, and thrombosis is caused blood coagulation and caused by series of complex reaction.Blood coagulation is a kind of protection mechanism of organism, whereby can be very soon and " sealing " vessel wall damaged reliably, therefore can avoid losing blood or being dropped to bottom line.Maintain normal haemostasis effect, hemorrhage and blood coagulation balance, is subject to the regulation and control of a complex mechanism.The restraining effect of not modulated activation blood coagulation system or shortage reactivation process all may cause various diseases and complication, such as phlebothrombosis, deep venous thrombosis, pulmonary infarction, atherosclerosis, acute coronary syndrome, cerebrovascular disease etc.

In blood coagulation, be divided into traditionally endogenous and exogenous system, intrinsic coagulation approach refers to from XII factor activator to forming IV a-PF3Ca ²⁺after mixture, activate the process of the X factor; Exogenous cruor pathway refers to from the VIII factor and is activated into and forms VII a-Ca ²⁺the process of the compound rear activation X factor of-TF.Being activated to scleroproein formation from the X factor, is common coagulation pathway endogenous, external source blood coagulation, activates the blood Xa factor forming here play a crucial role by the X factor.

Xa factor is a member of the serine stretch protein enzyme family of trypsin-like, and it is zymoplasm that serine stretch protein enzyme family activates thrombogen.Xa factor plays an important role in Coagulation pathways, and is positioned at the initial site of scale effect, and a part factor Xa catalysis 1000 molecule zymoplasms form.Therefore, to liken to for other thrombin or downstream zymoplasm as target spot should be the more effective strategy of anticoagulation to Xa factor.

Conventional traditional anticoagulant comprises that warfarin, heparin, acetylsalicylic acid, chlorine are than Gray etc. clinically.The medicine that wherein relates to factor Xa is heparin, be mainly injection type, comprise unfractionated heparin, low molecular weight heparin (LMWH), Fondapari nux etc., easily cause clinically severe haemorrhage and heparin-induced thrombopenia side reaction, need clinical detection.Compared with traditional blood-clotting agent, novel coagulation factor xa inhibitors has the following advantages: oral, and low bleeding risk, high efficiency, without individuality adjustment and monitor patients.At present go on the market or comprised razaxaban, Eliquis, Yi Dushaban, shellfish Qu Shaban, otamixaban, eribaxaban, LY517717, YM150, letaxaban etc. at the medicine grinding.But go on the market at present or also have some shortcomings at the novel coagulation factor xa inhibitors grinding, such as the solubleness of razaxaban and Eliquis is very poor.

WO00039131 has described the serpin that can be used as trypsin-like, the particularly nitrogen-containing hetero bicyclic derivatives of coagulation factor xa inhibitors, wherein X, Y, Z can be nitrogen and carbon, G selects aromatic ring or nitrogen-containing hetero aromatic ring, A is a cyclic group, and B is a basic group or cyclic group.Do not think that specifically describing in this patent is a part of the present invention, its structural formula is as follows:

WO00200655 has described heteroaryl-phenyl Heterobicyclic compounds and derivative thereof, and as the purposes of coagulation factor xa inhibitors, wherein A is that 5-6 unit aryl or heteroaryl, G2 are that phenyl, naphthyl or 5-10 heteroaryl, Q are Heterobicyclic compounds, differ greatly with compound structure of the present invention, its structural formula is as follows:

WO03026652A1, WO03047520, WO03048081, WO03048158, WO03099276, WO2006047528 has described the P4-P-M-M4 lactam derivatives including Eliquis, wherein encircle that P can not exist or be azo-cycle or the heterocycle of 5-7 unit, ring M is carbocyclic ring or the heterocycle of a 3-10 unit, does not think that specifically describing in this patent is a part of the present invention.

WO2004083174 has described P4-P-M-M4 tetrahydropyrimidine and alkylsulfonyl amidino derivatives and as serpin; the particularly application of coagulation factor xa inhibitors; wherein encircle that P can not exist or be azo-cycle or the heterocycle of 5-7 unit; ring M is carbocyclic ring or the heterocycle of a 3-10 unit, does not think that specifically describing in this patent is a part of the present invention.

WO2007137801 has described the coagulation factor xa inhibitors of new Pyrrolidine, tetrahydro-pyrazole pyridine, imidazolidine pyridine and tetrahydrochysene triazolopyridine derivatives, differs greatly with compound structure of the present invention, and dependency structure formula is as follows:

WO2009007028 has described 1-(4-p-methoxy-phenyl)-7-oxo-6[4-(oxo-piperidine-1-yl) phenyl]-4,6,5,7-tetrahydrochysene-(1H)-pyrazolo [3.4, c] pyridine-3-carboxamide derivatives, and as the purposes of coagulation factor xa inhibitors, wherein R ¹, R ²for alkyl, L is substituted amido or ester group, differs greatly with compound structure of the present invention, and dependency structure formula is as follows:

The present invention is on the basis of tetrahydro pyrazolopyridines, design has the compound shown in general formula (I), so that a kind of novel structure to be provided, drug effect is better, bioavailability height and the better coagulation factor xa inhibitors compounds of solvability, can be used for treating venous thrombosis, dvt forms, deep venous thrombosis of lower limbs, thrombophlebitis, cerebral artery thrombosis forms, arterial thrombosis, Coronary thrombosis, pulmonary infarction, cerebral embolism, renal infarction, hepatic vein embolism, portal vein embolization, chronic disseminated intravascular coagulation, four limbs and central capillary blood vessel arterial thrombosis, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, myocardial infarction, arteriosclerosis, local asphyxia is overworked dead, temporary ischemic, external application obstructive arterial disease, apoplexy, the sterility thrombotic endocarditis of companion's arterial thrombosis, the various diseases that the thrombosis such as cerebrovascular disease cause and complication.

Summary of the invention

The present invention relates to the compound shown in a kind of general formula (I), or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

A is selected from C _6-14aryl or 5 to 14 yuan of heteroaryls, described aryl or heteroaryl are optionally further by 0 to 5 R ⁷replace;

B is selected from 3 to 10 yuan of heterocycles, and described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described heterocycle optionally further replaces by 0 to 3 substituting group, and described substituting group is selected from R ^7aor (=O);

X is selected from O or S (=O) _p;

R ¹, R ², R ³and R ⁴be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl ,-(CH ₂) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-OC (=O) NR ⁸r ^8a,-OC (=O) OR ⁸,-OC (=O) R ⁸,-C (=O) OR ⁸,-N (R ^8b) C (=O) NR ⁸r ^8a,-N (R ⁸) C (=O) OR ^8a,-N (R ⁸) C (=O) R ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸, C _3-10carbocyclic ring, 3 to 10 yuan of heterocycles ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group or-NR ⁷r ^7asubstituting group replace;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, R ¹, R ², R ³, R ⁴in any two groups can together with the atom connected with them, form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace;

R ⁵be selected from independently of one another H, F, Cl, Br, I, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, amino, cyano group ,-(CR ⁷r ^7a) _n-C (=O)-NR ⁷r ^7aor-(CR ⁷r ^7a) _nnR ⁷r ^7a;

R ⁶be selected from-C (=O) NR ⁷r ^7a, cyano group, trifluoromethyl ,-(CH ₂) _ns (=O) _pr ⁸,-C (R ⁷r ^7a) R ⁸,-C (R ⁷r ^7a) OR ⁸, C _3-10carbocyclic ring or 3 to 10 yuan of heterocycles, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described carbocyclic ring or heterocycle are independent optionally further by 0 to 4 R separately ⁸replace;

R ⁷and R ^7abe selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl ,-C (=O) OR ⁸,-N (R ⁸) C (=O) R ^8a,-(CR ⁸r ^8a) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸,-(CH ₂) _n-C _3-10carbocyclic ring ,-C (=O)-(3 to 10 yuan of heterocycles) ,-(CH ₂) _n-(3 to 10 yuan of heterocycles) ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described alkyl, alkoxyl group, carbocyclic ring or heterocycle are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-(3 to 10 yuan of heterocycles) ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl ,-C (=O)-C _1-3alkyl, C _3-10the substituting group of carbocyclic ring or 3 to 10 yuan of heterocycles replaces;

As selection, R ⁷and R ^7acan form (=O);

As selection, R ⁷and R ^7acan together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-(3 to 10 yuan of heterocycles) ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl or-C (=O)-C _1-3the substituting group of alkyl replaces;

As selection, as two R ^7awhile being connected on same atom, can together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-3 are to 10 yuan of heterocycles ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl or-C (=O)-C _1-3the substituting group of alkyl replaces;

R ⁸, R ^8aand R ^8bbe selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _3-10carbocyclic ring or 3 to 10 yuan of heterocycles;

As selection, R ⁸and R ^8acan together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-(3 to 10 yuan of heterocycles) ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl or-C (=O)-C _1-3the substituting group of alkyl replaces;

M is selected from 0,1,2 or 3;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

Preferred version of the present invention, A, in each situation, is selected from C _6-10aryl or 5 to 10 yuan of heteroaryls, described aryl or heteroaryl are optionally further by 0 to 5 R ⁷replace; Preferably phenyl or 5 to 6 heteroaryls, described phenyl or heteroaryl are optionally further by 0 to 5 R ⁷replace.

Preferred version of the present invention, A is in each situation, be selected from replacement or unsubstituted phenyl, naphthyl, pyridyl, furyl, thienyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl or imidazolyl, in the time being substituted, select by 1 to 5 R ⁷replace; Preferred that replace or unsubstituted phenyl or pyridyl, in the time being substituted, select by 1 to 5 R ⁷replace; Further preferred replace or unsubstituted phenyl, in the time being substituted, selects by 1 to 5 R ⁷replace; More preferably phenyl or 1 phenyl that F replaces.

Preferred version of the present invention, compound shown in a kind of general formula (I), wherein this compound is selected from the compound shown in general formula (II), or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is selected from O or S (=O) _p;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, R ⁷and R ^7acan form (=O);

M is selected from 0,1,2 or 3;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

Preferred version of the present invention, X, in each situation, is selected from O or S, and preferably X is O.

Preferred version of the present invention, R ⁵in each situation, be selected from independently of one another H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, amino, cyano group, C _1-4alkyl, C _1-4alkoxyl group or-(CH ₂) _n-C (=O)-NH ₂, preferably H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, amino, cyano group, C _1-4alkyl or C _1-4alkoxyl group, further preferred H, F, Cl, trifluoromethyl, hydroxyl, amino, cyano group, C _1-3alkyl or C _1-3alkoxyl group.

Preferred version of the present invention, R ⁵in each situation; be selected from H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, formamyl or aminomethylene; preferably H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-or isopropoxy, further preferred H or F.

Preferred version of the present invention, R ⁶in each situation, be selected from-C (=O) NR ⁷r ^7a, cyano group, trifluoromethyl ,-(CH ₂) _ns (=O) _pr ⁸,-C (R ⁷r ^7a) R ⁸,-C (R ⁷r ^7a) OR ⁸, C _3-5carbocyclic ring or 3 to 5 yuan of heterocycles, wherein said carbocyclic ring or heterocycle are independent optionally further by 0 to 4 R separately ⁸replace, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S;

R ⁶preferably-C (=O) NR ⁷r ^7a, cyano group, trifluoromethyl ,-(CH ₂) _ns (=O) ₂r ⁸,-C (R ⁷r ^7a) R ⁸,-C (R ⁷r ^7a) OR ⁸, C _3-4carbocyclic ring or 3 to 4 yuan of heterocycles, wherein said carbocyclic ring or heterocycle are independent optionally further by 0 to 4 R separately ⁸replace, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S;

R ⁶further preferably-C (=O) NR ⁷r ^7a, cyano group or-(CH ₂) _ns (=O) ₂r ⁸;

Wherein said R ⁷and R ^7aindependently be selected from separately H, C _1-4alkyl ,-(CH ₂) _n-C _3-5carbocyclic ring or-(CH ₂) _n-C _3-5heterocycle, preferably H or C _1-4alkyl; Wherein said R ⁸be selected from H, F, Cl, hydroxyl, cyano group, amino, C _1-4alkyl or C _1-4alkoxyl group.

Preferred version of the present invention, R ⁶in each situation, be selected from formamyl, 2-isopropyl alcohol radical, 1-ring propyl alcohol base, cyano group, trifluoromethyl, 1-fluoro ethyl, ethoxy acetyl, 1-methyl fluoride, 1,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl, preferably formamyl.

Preferred version of the present invention, m, in each situation, is selected from 0 or 1.

Preferred version of the present invention, compound shown in a kind of general formula (I), wherein this compound is selected from the compound shown in general formula (III), or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

R ¹, R ², R ³and R ⁴be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl ,-(CH ₂) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-OC (=O) NR ⁸r ^8a,-OC (=O) OR ⁸,-OC (=O) R ⁸,-C (=O) OR ⁸,-N (R ^8b) C (=O) NR ⁸r ^8a,-N (R ⁸) C (=O) OR ^8a,-N (R ⁸) C (=O) R ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸, C _3-10carbocyclic ring, 3 to 10 yuan of heterocycles ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, B by 0 to 4 _r, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group or-NR ⁷r ^7asubstituting group replace;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, R ¹, R ², R ³, R ⁴in any two groups atom that can be connected with them form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and 3 to 6 rings that form can be optionally further by 0 to 4 R ^7areplace;

As selection, R ⁷and R ^7acan form (=O);

R ⁸, R ^8aand R ^8bbe selected from independently of one another H, F, Cl, B _r, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _3-10carbocyclic ring or 3 to 10 yuan of heterocycles;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

Preferred version of the present invention, B, in each situation, is selected from 3 to 8 yuan of heterocycles, and described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described heterocycle is optionally further replaced by 0 to 3 substituting group, and described substituting group is selected from R ^7aor (=O);

B is 5 to 6 yuan of heterocycles preferably, and described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described heterocycle is optionally further replaced by 0 to 3 substituting group, and described substituting group is selected from R ^7aor (=O);

Wherein said substituent R ^7abe selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl or-(CH ₂) _nnR ⁸r ^8a,

R ^7apreferably H, F, trifluoromethyl, C _1-4alkyl or-(CH ₂) _nn (C _1-4alkyl) (C _1-4alkyl),

R ^7amore preferably H, F, trifluoromethyl, methyl, ethyl, propyl group or sec.-propyl;

As selection, as two R ^7awhile being connected on same atom, can together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4the substituting group of alkoxyl group, hydroxyl, sulfydryl, cyano group or amide group replaces;

As two R ^7awhile being connected on same atom, can together with the atom connected with them, be preferably formed C _3-5the heterocycle of carbocyclic ring or 3 to 5 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, C by 0 to 4 _1-4alkyl, C _1-4the substituting group of alkoxyl group or cyano group replaces;

As two R ^7awhile being connected on same atom, can together with the atom connected with them, more preferably form C _3-4the heterocycle of carbocyclic ring or 3 to 4 yuan, described heterocycle contains 1 to 2 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, C by 0 to 4 _1-2alkyl or C _1-2alkoxy substituent replaces.

Preferred version of the present invention, B, in each situation, is selected from

Wherein E is selected from C=O or S (=O) ₂, preferably C=O;

Ring Q is selected from 4 to 8 rings, its composition except shown in N-E group, also comprise that carbon atom and 0 to 2 are selected from the heteroatoms of N, O or S, wherein this ring can optionally further be replaced by 0 to 3 substituting group, substituting group is independently selected from R separately ^7aor (=O);

Ring Q preferably 5 to 7 rings, its composition except shown in N-E group, also comprise that carbon atom and 0 to 2 are selected from the heteroatoms of N, O or S, wherein this ring can optionally further be replaced by 0 to 3 substituting group, substituting group is independently selected from R separately ^7aor (=O);

Ring Q more preferably 5 to 6 rings, its composition except shown in N-E group, also comprise that carbon atom and 0 to 2 are selected from the heteroatoms of N, O or S, wherein this ring can optionally further be replaced by 0 to 3 substituting group, substituting group is independently selected from R separately ^7aor (=O);

Wherein said R ^7abe selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl or-(CH ₂) _nnR ⁸r ^8a, preferably H, F, trifluoromethyl, C _1-4alkyl or-(CH ₂) nN (C _1-4alkyl) (C _1-4alkyl), further preferred H, F, trifluoromethyl, methyl, ethyl propyl or sec.-propyl;

In the time that two R7a are connected on same atom, can together with the atom connected with them, further be preferably formed C _3-4the heterocycle of carbocyclic ring or 3 to 4 yuan, described heterocycle contains 1 to 2 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, C by 0 to 4 _1-2alkyl, C _1-2alkoxy substituent replaces.

Preferred version of the present invention, B in each situation, be selected from replacement or unsubstituted pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, indyl, benzofuryl, benzimidazolyl-, pyridyl, 2H-pyranyl, 4H-pyranyl, pyridazinyl, pyrimidyl, pyrazinyl, tetrahydrofuran base, Pyrrolidine base, thiazolidine base,

, in the time being substituted, optionally further being replaced by 1 to 3 substituting group, described substituting group is selected from R ^7aor (=O); That preferably replace or unsubstituted pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, indyl, pyridyl, 2H-pyranyl, 4H-pyranyl, pyridazinyl, pyrimidyl, pyrazinyl, tetrahydrofuran base, Pyrrolidine base, thiazolidine base,

, in the time being substituted, optionally further being replaced by 1 to 3 substituting group, described substituting group is selected from R ^7aor (=O).

Preferred version of the present invention, compound shown in a kind of general formula (I), wherein this compound is selected from the compound shown in general formula (IV), or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

Wherein E is selected from C=O or S (=O) ₂;

Ring Q is selected from 4 to 8 rings, its composition except shown in N-E group, also comprise that carbon atom and 0 to 1 are selected from the heteroatoms of N, O or S, wherein this ring can optionally further be replaced by 0 to 3 substituting group, substituting group is independently selected from R separately ^7aor (=O);

As selection, as two R ^7awhile being connected on same atom, can together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4the substituting group of alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group replaces;

R ¹, R ², R ³and R ⁴be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl ,-(CH ₂) nNR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-OC (=O) NR ⁸r ^8a,-OC (=O) OR ⁸,-OC (=O) R ⁸,-C (=O) OR ⁸,-N (R ^8b) C (=O) NR ⁸r ^8a,-N (R ⁸) C (=O) OR ^8a,-N (R ⁸) C (=O) R ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸, C _3-10carbocyclic ring, 3 to 10 yuan of heterocycles ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group or-NR ⁷r ^7asubstituting group replace;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, R ¹, R ², R ³, R ⁴in any two groups can form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace;

R ^7abe selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl ,-C (=O) OR ⁸,-N (R ⁸) C (=O) R ^8a,-(CR ⁸r ^8a) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸,-(CH ₂) _n-C _3-10carbocyclic ring ,-C (=O)-(3 to 10 yuan of heterocycles) ,-(CH ₂) _n-(3 to 10 yuan of heterocycles) ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described alkyl, alkoxyl group, carbocyclic ring or heterocycle are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-(3 to 10 yuan of heterocycles) ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl ,-C (=O)-C _1-3alkyl, C _3-10the substituting group of carbocyclic ring or 3 to 10 yuan of heterocycles replaces;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

Preferred version of the present invention, compound shown in a kind of general formula (IV), wherein E is selected from C=O;

Ring Q preferably 5 to 7 rings, its composition except shown in N-E group, also comprise that carbon atom and 0 to 1 are selected from the heteroatoms of N, O or S, wherein this ring can optionally further be replaced by 0 to 3 substituting group, substituting group is independently selected from R separately ^7aor (=O);

Further preferred 5 to 6 rings of ring Q, its composition except shown in N-E group, also comprise that carbon atom and 0 to 1 are selected from the heteroatoms of N, O or S, wherein this ring can optionally further be replaced by 0 to 3 substituting group, substituting group is independently selected from R separately ^7aor (=O);

Wherein said R ^7abe selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl or-(CH ₂) _nnR ⁸r ^8a, preferably H, F, trifluoromethyl, C _1-4alkyl or-(CH ₂) _nn (C _1-4alkyl) (C _1-4alkyl), further preferred H, F, trifluoromethyl, C _1-4alkyl or-CH ₂-N (C _1-2alkyl) (C _1-2alkyl);

As two R ^7awhile being connected on same atom, can together with the atom connected with them, further be preferably formed C _3-4the heterocycle of carbocyclic ring or 3 to 4 yuan, described heterocycle contains 1 to 2 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, C by 0 to 4 _1-2alkyl or C _1-2alkoxy substituent replaces.

Preferred version of the present invention, R ¹, R ², R ³and R ⁴in each situation, be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl, C _3-8carbocyclic ring, 3 to 8 yuan of heterocycles ,-O-(CH ₂) _n-C _3-8carbocyclic ring or-O-(CH ₂) _n-(3 to 8 yuan of heterocycles);

R ¹, R ², R ³and R ⁴preferred H, F, Cl, Br, I, hydroxyl, cyano group, amino, C independently of one another _1-4alkyl, C _1-4alkoxyl group, C _3-5carbocyclic ring, 3 to 5 yuan of heterocycles ,-O-(CH ₂) _n-C _3-5carbocyclic ring or-O-(CH ₂) _n-(3 to 5 yuan of heterocycles);

R ¹, R ², R ³and R ⁴further preferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C independently of one another _1-4alkyl, C _1-4alkoxyl group, C _3-4carbocyclic ring or-O-C _3-4carbocyclic ring;

R ¹, R ², R ³and R ⁴more preferably H, F, Cl, C independently of one another _1-2alkyl or C _1-2alkoxyl group;

Wherein said alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl or C _1-4the substituting group of alkoxyl group replaces, preferably H, F, Cl, Br, I, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy;

As selection, wherein R ¹and R ²can form (=O);

As selection, wherein R ³and R ⁴can form (=O);

As selection, wherein R ¹, R ², R ³, R ⁴in any two groups can together with the atom connected with them, form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace;

R ¹, R ², R ³, R ⁴in any two groups can together with the atom connected with them, be preferably formed 3 to 4 rings, described 3 to 4 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 4 rings can be optionally further by 0 to 4 R ^7areplace;

R ¹, R ², R ³, R ⁴in any two groups can together with the atom connected with them, further be preferably formed 3 rings, described 3 rings contain 0 to 1 heteroatoms that is selected from N, O or S, and form 3 rings can be optionally further by 0 to 3 R ^7areplace;

Wherein said radicals R ^7abe selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, C _1-4alkyl, C _1-4alkoxyl group, preferably H, F, hydroxyl, cyano group, methyl, ethyl, methoxy or ethoxy.

Preferred version of the present invention, R ¹, R ², R ³and R ⁴in each situation, independently be selected from separately H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, formamyl, N-ethylamino methyl, allyl group, methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrole base, furyl, thienyl, pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base, Pyrrolidine base, cyclobutoxy group, cyclopentyloxy, oxa-cyclobutyl, oxa-cyclobutoxy group, azelidinyl, nitrogen heterocyclic butoxy, oxa-cyclopentyloxy, nitrogen heterocyclic pentyloxy, cyclopropyl methyl oxygen base,-OC (=O) NH (CH ₃) ,-OC (=O) OCH ₃or-NH (C=O) NH (CH ₃), preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxyl group, oxyethyl group or ring propoxy-, further preferred H, F, Cl, methyl, ethyl, methoxy or ethoxy,

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

Preferably, R ¹, R ², R ³, R ⁴in any two groups form together with can the atom connected with them and replace or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl, pyrryl, N-alkyl pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base or Pyrrolidine base;

More preferably, R ¹, R ², R ³, R ⁴in any two groups can together with the atom connected with them, further form cyclopropyl.

Preferred version of the present invention, R ⁷and R ^7ain each situation, be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl ,-C (=O) OR ⁸,-N (R ⁸) C (=O) R ^8a,-(CR ⁸r ^8a) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸,-(CH ₂) _n-C _3-10carbocyclic ring ,-C (=O)-(3 to 10 yuan of heterocycles) ,-(CH ₂) _n-(3 to 10 yuan of heterocycles) ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles),

R ⁷and R ^7apreferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, trifluoromethyl, C independently of one another _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-2alkyl ,-C (=O)-C _1-2alkoxyl group ,-(CH ₂) _nc (=O) NH ₂,-(CH ₂) _nn (C _1-2alkyl) (C _1-2alkyl) ,-(CH ₂) _n-thiazolinyl ,-(CH ₂) _n-alkynyl ,-(CH ₂) _n-C _3-6carbocyclic ring ,-C (=O)-(3 to 6 yuan of heterocycles) ,-(CH ₂) _n-(3 to 6 yuan of heterocycles) ,-O-(CH ₂) _n-C _3-6carbocyclic ring or-O-(CH ₂) _n-(3 to 6 yuan of heterocycles), further preferred H, F, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group or-(CH ₂) _nn (C _1-2alkyl) (C _1-2alkyl), wherein said heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S;

Wherein said alkyl, alkoxyl group, thiazolinyl, alkynyl, carbocyclic ring or heterocycle are optionally further replaced by 0 to 4 substituting group, and substituting group is selected from H, F, Cl, Br, I, C independently of one another _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-(3 to 10 yuan of heterocycles) ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl ,-C (=O)-C _1-3alkyl, C _3-10carbocyclic ring or 3 to 10 yuan of heterocycles, preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino, C _1-4alkyl, C _1-4alkoxyl group, C _3-5carbocyclic ring or 3 to 5 yuan of heterocycles, further preferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino, methyl, ethyl, methoxy or ethoxy;

As selection, wherein R ⁷and R ^7acan form (=O);

As selection, wherein R ⁷and R ^7acan together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, preferably C _3-8the heterocycle of carbocyclic ring or 3 to 8 yuan, more preferably C _3-5the heterocycle of carbocyclic ring or 3 to 5 yuan; Wherein said heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S; Wherein said heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl or amino substituting group replace, preferably H, F, Cl, Br, I, hydroxyl, methyl alkynyl, methyl, ethyl, methoxy or ethoxy;

As selection, as two R ^7awhile being connected on same atom, can together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, preferably C _3-8the heterocycle of carbocyclic ring or 3 to 8 yuan, further preferred C _3-5the heterocycle of carbocyclic ring or 3 to 5 yuan; Wherein said heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S; Wherein said heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl or amino substituting group replace, preferably H, F, Cl, Br, I, hydroxyl, methyl alkynyl, methyl, ethyl, methoxy or ethoxy.

Preferred version of the present invention, R ⁷and R ^7ain each situation, be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methylol, trifluoromethyl, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, ring propoxy-, methoxycarbonyl, ethoxy carbonyl, ethanoyl, formamyl, N-ethylamino methyl, allyl group, methyl alkynyl, cyclopropyl, cyclopropyl methylene radical, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrole base, furyl, thienyl, pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base, Pyrrolidine base, cyclobutoxy group, cyclopentyloxy, oxa-cyclobutyl, oxa-cyclobutoxy group, azelidinyl, nitrogen heterocyclic butoxy, oxa-cyclopentyloxy, nitrogen heterocyclic pentyloxy, nitrogen heterocyclic amyl group methylene radical, morpholinyl carbonyl, cyclopropyl methyl oxygen base or pentamethylene ethyl oxygen base,

R ⁷and R ^7apreferably H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methylol, trifluoromethyl, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, ring propoxy-, methoxycarbonyl, ethoxy carbonyl, ethanoyl, formamyl, N-ethylamino methyl, allyl group, methyl alkynyl, cyclopropyl, cyclopropyl methylene radical, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrole base, furyl, thienyl, pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base, Pyrrolidine base, cyclobutoxy group, cyclopentyloxy, oxa-cyclobutyl, oxa-cyclobutoxy group, azelidinyl, nitrogen heterocyclic butoxy, oxa-cyclopentyloxy, nitrogen heterocyclic pentyloxy, nitrogen heterocyclic amyl group methylene radical, morpholinyl carbonyl, cyclopropyl methyl oxygen base or pentamethylene ethyl oxygen base,

R ⁷and R ^7afurther preferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methylol, trifluoromethyl, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, isopropoxy, methoxycarbonyl, ethoxy carbonyl, ethanoyl, formamyl, allyl group, methyl alkynyl, cyclopropyl, cyclopropyl methylene radical, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrryl, piperidyl, tetrahydrofuran base or Pyrrolidine base;

R ⁷and R ^7afurther preferred H, F, Cl, hydroxyl, sulfydryl, cyano group, amino, methylol, trifluoromethyl, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, isopropoxy, ethanoyl, formamyl, allyl group, methyl alkynyl, cyclopropyl, cyclopropyl methylene radical, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrryl, piperidyl, tetrahydrofuran base or Pyrrolidine base;

As selection, R ⁷and R ^7acan form (=O);

As selection, R ⁷and R ^7acan together with the atom connected with them, form C _3-6the heterocycle of carbocyclic ring or 3 to 6 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, C by 0 to 4 _1-4alkyl, C _1-4the substituting group of alkoxyl group, hydroxyl, amino, sulfydryl, cyano group, amide group or methyl alkynyl replaces;

Preferably, R ⁷and R ^7acan together with the atom connected with them, form replacement or unsubstituted cyclopropane, oxirane, tetramethylene, azetidine, trimethylene oxide, pentamethylene, pyrroles, piperidines, morpholine or imidazolidyl diketone; In the time being substituted, optionally further replaced by 1 to 3 substituting group, substituting group is selected from H, F, Cl, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group, amino or methoxycarbonyl;

More preferably, R ⁷and R ^7acan together with the atom connected with them, form cyclopropane, azetidine, trimethylene oxide, Pyrrolidine, piperidines or morpholine;

As selection, as two R ^7awhile being connected on same atom, can together with the atom connected with them, form C _3-6the heterocycle of carbocyclic ring or 3 to 6 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, C by 0 to 4 _1-4alkyl, C _1-4the substituting group of alkoxyl group, hydroxyl, amino, sulfydryl, cyano group, amide group or methyl alkynyl replaces;

Preferably, two R ^7awhile being connected on same atom, can together with the atom connected with them, form replacement or unsubstituted cyclopropane, oxirane, tetramethylene, azetidine, trimethylene oxide, imidazolidyl diketone, Pyrrolidine, piperidines or morpholine, in the time being substituted, optionally further replaced by 1 to 3 substituting group, substituting group is selected from H, F, Cl, hydroxyl, methyl, ethyl, methoxyl group, oxyethyl group, amino or methoxycarbonyl;

More preferably, two R ^7awhile being connected on same atom, can together with the atom connected with them, form cyclopropane, azetidine, trimethylene oxide, Pyrrolidine, piperidines or morpholine.

Preferred version of the present invention, R ⁸, R ^8aand R ^8bin each situation, be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _3-10carbocyclic ring or 3 to 10 yuan of heterocycles, preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _3-5carbocyclic ring or 3 to 5 yuan of heterocycles, further preferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl or C _1-4alkoxyl group, more preferably H, F or C _1-3alkyl;

As selecting R ⁸and R ^8acan together with the atom connected with them, form C _3-10the heterocycle of carbocyclic ring or 3 to 10 yuan, is preferably formed C _3-8the heterocycle of carbocyclic ring or 3 to 8 yuan, is further preferably formed C _3-4the heterocycle of carbocyclic ring or 3 to 4 yuan; Wherein said heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S; Wherein said heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl or amino substituting group replace, preferably H, F, Cl, Br, I, hydroxyl, methyl alkynyl, methyl, ethyl, methoxy or ethoxy;

Preferred version of the present invention, R ⁸, R ^8aand R ^8bin each situation, be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, cyclopropyl, cyclobutyl, oxa-cyclopropyl, oxa-cyclobutyl or azelidinyl, preferably H, methyl, ethyl and sec.-propyl;

As selection, R ⁸and R ^8acan together with the atom connected with them, form cyclopropane, tetramethylene, oxirane, trimethylene oxide, azetidine, Pyrrolidine, piperidines or morpholine, described heterocycle or carbocyclic ring are optionally further selected from H, F, Cl, methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino, methoxycarbonyl, ethoxy carbonyl, methylol, hydroxyethyl or ethanoyl substituting group by 0 to 4 and replace; R ⁸and R ^8acan together with the atom connected with them, be preferably formed cyclopropane, Pyrrolidine or piperidines.

Preferred version of the present invention, compound or its steric isomer shown in a kind of general formula (I), oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is selected from O or S;

A is selected from phenyl replacement or unsubstituted, in the time being substituted, selects by 1 to 5 R ⁷replace;

B is selected from one of replacement or unsubstituted following structure:

In the time being substituted, optionally further replaced by 1 to 3 substituting group, described substituting group is selected from R ^7aor (=O);

R ¹, R ², R ³and R ⁴independently be selected from separately H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, formamyl, N-ethylamino methyl, allyl group, methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl ,-OC (=O) NH (CH ₃) ,-OC (=O) OCH ₃or-NH (C=O) NH (CH ₃);

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, wherein R ¹, R ², R ³, R ⁴in any two groups can form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl, pyrryl, N-alkyl pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base or Pyrrolidine base;

R ⁵be selected from H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, formamyl or aminomethylene;

R ⁶be selected from-C (=O) NR ⁷r ^7a, cyano group, trifluoromethyl ,-(CH ₂) _ns (=O) ₂r ⁸,-C (R ⁷r ^7a) R ⁸,-C (R ⁷r ^7a) OR ⁸, C _3-4carbocyclic ring or 3 to 4 yuan of heterocycles, described carbocyclic ring or heterocycle are independent optionally further by 0 to 4 R separately ⁸replace, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S;

R ⁷and R ^7abe selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methylol, trifluoromethyl, methyl, ethyl, propyl group, sec.-propyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, isopropoxy, methoxycarbonyl, ethoxy carbonyl, ethanoyl, formamyl, allyl group, methyl alkynyl, cyclopropyl, cyclopropyl methylene radical, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, pyrryl, piperidyl, tetrahydrofuran base or Pyrrolidine base;

As selection, R ⁷and R ^7acan form (=O);

As selection, R ⁷and R ^7acan together with the atom connected with them, form C _3-5the heterocycle of carbocyclic ring or 3 to 5 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S;

As selection, as two R ^7awhile being connected on same atom, can together with the atom connected with them, form C _3-5the heterocycle of carbocyclic ring or 3 to 5 yuan, described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S;

R ⁸be selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, sec.-propyl, methoxyl group, oxyethyl group, isopropoxy, cyclopropyl, cyclobutyl, oxa-cyclopropyl, oxa-cyclobutyl or azelidinyl;

M is selected from 0,1 or 2;

N is selected from 0,1 or 2;

P is selected from 0,1 or 2.

Preferred version of the present invention, compound or its steric isomer shown in a kind of (I), oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is selected from O;

A is selected from phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F, preferably phenyl or the phenyl by 1 F replacement;

B is selected from

, preferably:

R ¹, R ², R ³and R ⁴independently be selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxy or ethoxy, preferably H, methyl, ethyl, methoxy or ethoxy;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, wherein radicals R ¹, R ², R ³, R ⁴in any two can form cyclopropyl;

R ⁵be selected from H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, allyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy or tert.-butoxy, preferably H or F;

R ⁶be selected from formamyl, 2-isopropyl alcohol radical, 1-ring propyl alcohol base, cyano group, trifluoromethyl 1-fluoro ethyl, ethoxy acetyl, 1-methyl fluoride, 1; 1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl, the preferably further preferred formamyl of formamyl, cyano group or trifluoromethyl.

X is O;

A is phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F;

B is selected from one of following structure:

R ¹, R ², R ³, R ⁴independently be selected from separately H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxy or ethoxy;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

R ⁵independently be selected from separately H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-or isopropoxy;

R ⁶be selected from formamyl, 2-isopropyl alcohol radical, 1-ring propyl alcohol base, cyano group, trifluoromethyl, 1-fluoro ethyl, ethoxy acetyl, 1-methyl fluoride, 1,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl;

M is selected from 0,1 or 2;

P is selected from 0,1 or 2.

X is O;

A is phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F;

B is selected from one of following structure:

R ¹, R ², R ³, R ⁴independently be selected from separately H, methyl or ethyl;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, wherein R ¹, R ², R ³, R ⁴in any two groups can form cyclopropyl;

R ⁵independently be selected from separately H, F, Cl, trifluoromethyl, hydroxyl, methyl or ethyl;

R ⁶be selected from formamyl, 2-isopropyl alcohol radical, 1-ring propyl alcohol base, cyano group, trifluoromethyl, 1-fluoro ethyl, ethoxy acetyl, 1-methyl fluoride, 1,1-difluoromethyl, 1-hydroxyethyl or 1-hydroxymethyl.

X is O;

A is phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F;

B is selected from one of following structure:

R ¹, R ², R ³and R ⁴independently be selected from separately H or methyl;

R ⁵independently be selected from separately H, F, Cl or methyl;

R ⁵be selected from H or F; R ⁶for formamyl.

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ², R ³and R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶be selected from formamyl;

M is 1.

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ²independently be selected from separately H or methyl;

R ³, R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶be selected from formamyl or trifluoromethyl;

M is 1.

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ²independently be selected from separately H or methyl;

R ³, R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶be selected from formamyl or trifluoromethyl;

M is 1.

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ², R ³, R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶for formamyl;

M is 1.

Preferred version of the present invention, the present invention relates to compound and is selected from, but be not limited to:

The suitable pharmacy acceptable salt that the present invention relates to compound shown in general formula (I) comprises, but be not limited to hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.

Preferred version of the present invention, shown in a kind of general formula (I), the suitable pharmacy acceptable salt of compound comprises hydrochloride, vitriol, phosphoric acid salt, acetate, maleate, succinate, fumarate, malate, oxalate, tartrate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, fluoroform sulphonate or their combination.

The present invention relates to general formula (I) described compound or its pharmaceutically acceptable eutectic, wherein eutectic formation comprises proline(Pro), phenylalanine, Pyrrolidonecarboxylic acid.

The present invention relates to the compound shown in a kind of general formula (I-b), its steric isomer or its pharmacy acceptable salt, described compound is the intermediate of the synthetic described compound of general formula (I), wherein:

X` is selected from O or S (=O) _p, preferably O;

Z is selected from F, Cl, Br or I;

R ^1`, R ^2`, R ^3`and R ^4`be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl ,-(CH ₂) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-OC (=O) NR ⁸r ^8a,-OC (=O) OR ⁸,-OC (=O) R ⁸,-C (=O) OR ⁸,-N (R ^8b) C (=O) NR ⁸r ^8a,-N (R ⁸) C (=O) OR ^8a,-N (R ⁸) C (=O) R ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸, C _3-10carbocyclic ring, 3 to 10 yuan of heterocycles ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), preferably H or methyl; Described alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group or-NR ⁷r ^7asubstituting group replace;

As selection, R ^1`and R ^2`can form (=O);

As selection, R ^3`and R ^4`can form (=O);

As selection, R ^1`, R ^2`, R ^3`, R ^4`in any two groups can form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace;

R ^5`be selected from independently of one another H, F, Cl, Br, I, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, amino, cyano group ,-(CR ⁷r ^7a) _n-C (=O)-NR ⁷r ^7aor-(CR ⁷r ^7a) _nnR ⁷r ^7a, preferably H or F;

As selection, R ⁷and R ^7acan form (=O);

R ⁹be selected from C _1-12alkyl, described alkyl is optionally further by 0 to 4 R ⁸replace.

M ^`be selected from 0,1,2 or 3;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

Preferred version of the present invention, Z, in each situation, is selected from Cl;

Preferred version of the present invention, R ⁹in each situation, be selected from methyl, ethyl, sec.-propyl, normal-butyl or isobutyl-.

Preferred version of the present invention, R ^1`, R ^2`, R ^3`and R ^4`independently be selected from separately H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, formamyl, N-ethylamino methyl, allyl group, methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrole base, furyl, thienyl, pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base, Pyrrolidine base, cyclobutoxy group, cyclopentyloxy, oxa-cyclobutyl, oxa-cyclobutoxy group, azelidinyl, nitrogen heterocyclic butoxy, oxa-cyclopentyloxy, nitrogen heterocyclic pentyloxy, cyclopropyl methyl oxygen base,-OC (=O) NH (CH ₃) ,-OC (=O) OCH ₃or-NH (C=O) NH (CH ₃),

As selection, R ^1`and R ^2`can form (=O);

As selection, R ^3`and R ^4`can form (=O);

As selection, R ^1`, R ^2`, R ^3`, R ^4`in any two groups can form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace.

Preferred version of the present invention, R ^1`, R ^2`, R ^3`, R ^4`independently be selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxyl group, oxyethyl group or ring propoxy-, preferably H or methyl;

As selection, R ^1`and R ^2`can form (=O);

As selection, R ^3`and R ^4`can form (=O);

As selection, wherein R ^1`, R ^2`, R ^`3and R ^4`in any two can form replace and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyridyl, furyl, thienyl, pyrryl, N-alkyl pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base or Pyrrolidine base, be preferably formed cyclopropyl.

Preferred version of the present invention, R ^1`, R ^2`, R ^3`and R ^4`independently be selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxy or ethoxy, preferably H or methyl, further preferred H;

As selection, R ^1`and R ^2`can form (=O);

As selection, R ^3`and R ^4`can form (=O);

As selection, wherein R1 ^`, R ^2`, R ^3`and R ^4`in any two can form cyclopropyl.

Preferred version of the present invention, R ^5`be selected from H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, formamyl or aminomethylene, preferably H or F.

Preferred version of the present invention, wherein R ^5`be selected from H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-or isopropoxy, preferably H or F.

Preferred version of the present invention, wherein Z is selected from Cl; R ⁹be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl or isobutyl-.

The present invention relates to the compound shown in a kind of general formula (I-a), its steric isomer or its pharmacy acceptable salt, described compound is the intermediate of the synthetic described compound of general formula (I), wherein:

X ^`be selected from O or S (=O) _p, preferably O;

R ^1`, R ^2`, R ^3`and R ^4`be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl ,-(CH ₂) _nnR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-OC (=O) NR ⁸r ^8a,-OC (=O) OR ⁸,-OC (=O) R ⁸,-C (=O) OR ⁸,-N (R ^8b) C (=O) NR ⁸r ^8a,-N (R ⁸) C (=O) OR ^8a,-N (R ⁸) C (=O) R ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸, C _3-10carbocyclic ring, 3 to 10 yuan of heterocycles ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), preferably H or methyl, further preferred H; Described alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group or-NR ⁷r ^7asubstituting group replace;

As selection, R ^1`and R ^2`can form (=O);

As selection, R ^3`and R ^4`can form (=O);

As selection, R ^1`, R ^2`, R ^3`, R ^4`in any two groups can form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace; R ^1`, R ^2`, R ^3`, R ^4`in any two groups be preferably formed cyclopropyl;

R ^5`be selected from independently of one another H, F, Cl, Br, I, trifluoromethyl, C _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, amino, cyano group ,-(CR ⁷r ^7a) _n-C (=O)-NR ⁷r ⁷a or-(CR ⁷r ^7a) _nnR ⁷r ^7a, preferably H or methyl, further preferred H;

R ⁷and R ^7abe selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, C _1-4alkyl, C _1-4alkoxyl group ,-C (=O)-C _1-5alkyl ,-C (=O) OR ⁸,-N (R ⁸) C (=O) R ^8a,-(CR ⁸r ^8a) nNR ⁸r ^8a,-(CH ₂) _nc (=O) NR ⁸r ^8a,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸,-(CH ₂) _n-alkynyl-R ⁸,-(CH ₂) _n-C _3-10carbocyclic ring ,-C (=O)-(3 to 10 yuan of heterocycles) ,-(CH ₂) _n-(3 to 10 yuan of heterocycles) ,-O-(CH ₂) _n-C _3-10carbocyclic ring or-O-(CH ₂) _n-(3 to 10 yuan of heterocycles), described heterocycle contains 1 to 3 heteroatoms that is selected from N, O or S, and described alkyl, alkoxyl group, carbocyclic ring or heterocycle are optionally further selected from H, F, Cl, Br, I, C by 0 to 4 _1-4alkyl, C _1-4alkoxyl group, hydroxyl, sulfydryl, cyano group, amide group, methyl alkynyl, amino ,-C (=O)-(3 to 10 yuan of heterocycles) ,-C (=O) O-C _1-4the C that alkyl, hydroxyl replace _1-3alkyl ,-C (=O)-C _1-3alkyl, C _3-10the substituting group of carbocyclic ring or 3 to 10 yuan of heterocycles replaces;

As selection, R ⁷and R ^7acan form (=O);

M ^`be selected from 0,1,2 or 3;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

Preferred version of the present invention, m ^`in each situation, be selected from 0 or 1.

Preferred version of the present invention, R ^1`, R ^2`, R ^3`and R ^4`in each situation, be selected from independently of one another H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C _1-4alkyl, C _1-4alkoxyl group, C _1-4alkoxyalkyl, C _3-8carbocyclic ring, 3 to 8 yuan of heterocycles ,-O-(CH ₂) _n-C _3-8carbocyclic ring or-O-(CH ₂) _n-(3 to 8 yuan of heterocycles), wherein said heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and wherein said alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl or C _1-4the substituting group of alkoxyl group replaces, preferably H, F, Cl, Br, I, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy, further preferred H or methyl, more preferably H;

R ^1`, R ^2`, R ^3`and R ^4`preferred H, F, Cl, Br, I, hydroxyl, cyano group, amino, C independently of one another _1-4alkyl, C _1-4alkoxyl group, C _3-5carbocyclic ring, 3 to 5 yuan of heterocycles ,-O-(CH ₂) _n-C _3-5carbocyclic ring or-O-(CH ₂) _n-(3 to 5 yuan of heterocycles), wherein said heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and wherein said alkyl, alkoxyl group, carbocyclic ring or heterocycle is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl or C _1-4the substituting group of alkoxyl group replaces, preferably H, F, Cl, Br, I, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy, further preferred H or methyl, more preferably H;

R ^1`, R ^2`, R ^3`and R ^4`further preferred H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C independently of one another _1-4alkyl, C _1-4alkoxyl group, C _3-4carbocyclic ring or-O-C _3-4carbocyclic ring, wherein said alkyl, alkoxyl group or carbocyclic ring is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl or C _1-4the substituting group of alkoxyl group replaces, preferably H, F, Cl, Br, I, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy, further preferred H or methyl, more preferably H;

R ^1`, R ^2`, R ^3`and R ^4`more preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C independently of one another _1-2alkyl, C _1-2alkoxyl group, C _3-4carbocyclic ring or-O-C _3-4carbocyclic ring, wherein said alkyl, alkoxyl group or carbocyclic ring is independent separately is optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4 _1-4alkyl or C _1-4the substituting group of alkoxyl group replaces, preferably H, F, Cl, Br, I, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy, further preferred H or methyl, more preferably H;

As selection, wherein R ^1`and R ^2`can form (=O);

As selection, wherein R ^3`and R ^4`can form (=O);

As selection, wherein R ^1`, R ^2`, R ^3`, R ^4`in any two groups can together with the atom connected with them, form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace; R ^1`, R ^2`, R ^3`, R ^4`in any two groups can together with the atom connected with them, be preferably formed 3 to 4 rings, described 3 to 4 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 4 rings can be optionally further by 0 to 4 R ^7areplace; R ^1`, R ^2`, R ^3`, R ^4`in any two groups can together with the atom connected with them, further be preferably formed 3 rings, be preferably formed cyclopropyl, described 3 rings contain 0 to 1 heteroatoms that is selected from N, O or S, and form 3 rings can be optionally further by 0 to 3 R ^7areplace; Wherein said R ^7abe selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, C _1-4alkyl, C _1-4alkoxyl group, preferably H, F, hydroxyl, cyano group, methyl, ethyl, methoxy or ethoxy.

Preferred version of the present invention, R ^1`, R ^2`, R ^3`and R ^4`in each situation, independently be selected from separately H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, formamyl, N-ethylamino methyl, allyl group, methyl alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, N-methylpyrrole base, furyl, thienyl, pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base, Pyrrolidine base, cyclobutoxy group, cyclopentyloxy, oxa-cyclobutyl, oxa-cyclobutoxy group, azelidinyl, nitrogen heterocyclic butoxy, oxa-cyclopentyloxy, nitrogen heterocyclic pentyloxy, cyclopropyl methyl oxygen base,-OC (=O) NH (CH ₃) ,-OC (=O) OCH ₃or-NH (C=O) NH (CH ₃), preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxyl group, oxyethyl group or ring propoxy-, further preferred H, F, Cl, methyl, ethyl, methoxy or ethoxy, further preferred H or methyl, more preferably H,

As selection, R ^1`and R ^2`can form (=O);

As selection, R ^3`and R ^4`can form (=O);

As selection, R ^1`, R ^2`, R ^3`, R ^4`in any two groups can together with the atom connected with them, form 3 to 6 rings, comprise volution or and ring, described 3 to 6 rings contain 0 to 3 heteroatoms that is selected from N, O or S, and form 3 to 6 rings can be optionally further by 0 to 4 R ^7areplace R ^1`, R ^2`, R ^3`, R ^4`in any two groups preferably can form together with can the atom connected with them and replace and unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, pyridyl, furyl, thienyl, pyrryl, N-alkyl pyrryl, piperidyl, morpholinyl, thio-morpholinyl, tetrahydrofuran base or Pyrrolidine base, R ^1`, R ^2`, R ^3`, R ^4`in any two groups can together with the atom connected with them, further preferably can form cyclopropyl.

Preferred version of the present invention, R ^5`in each situation, be selected from independently of one another H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, amino, cyano group, C _1-4alkyl, C _1-4alkoxyl group ,-(CH ₂) _n-C (=O)-NR ⁷r ^7aor-(CH ₂) _nnR ⁷r ^7a, preferably H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, amino, cyano group, C _1-4alkyl or C _1-4alkoxyl group, more preferably H, F, Cl, trifluoromethyl, hydroxyl, amino, cyano group, C _1-3alkyl or C _1-3alkoxyl group, further preferred H or F;

Preferred version of the present invention, R ^5`in each situation, be selected from independently of one another H, F, Cl, Br, I, trifluoromethyl, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, formamyl or aminomethylene, preferably H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-or isopropoxy, further preferred H or F;

The present invention relates to one and prepare the method for the compound of general formula of the present invention (I), the method comprises:

General formula (I-a) compound reacts with halo acetylacetic ester and obtains general formula (I-b) compound under oxygenant exists, wherein: halo acetylacetic ester includes but not limited to 2-chloro methyl acetoacetate or 2-chloroacetyl acetacetic ester;

General formula (I-b) compound and general formula (I-e) compound are at alkaline condition ShiShimonoseki ring, and under acidic conditions, de-morpholine obtains general formula (I-c) compound;

Or general formula (I-b) compound and general formula (I-f) are at alkaline condition ShiShimonoseki ring, under acidic conditions, de-morpholine makes general formula (I-d) compound;

Under alkaline condition, there is linked reaction and obtain general formula (I-c) compound in general formula (I-d) compound;

General formula (I-c) compound optionally obtains general formula (I) compound by ammonia solution, hydrolysis, transesterify, replacement, oxidation or reduction reaction, wherein:

Z is selected from F, Cl, Br or I;

A, B, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, X, m definition with described in general formula (I) compound definition consistent, R ^1`, R ^2`, R ^3`, R ^4`, R ^5`, R ⁹, X ^`, m ^`definition with described in general formula (I-b) compound definition consistent.

A kind of pharmaceutical composition the present invention relates to, described pharmaceutical composition contains the described compound of at least one general formula of the present invention (I) for the treatment of effective dose, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt or prodrug, and pharmaceutically acceptable carrier or vehicle.

Further, the present invention relates to compound shown in general formula (I), or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt or prodrug, the purposes in the medicine in the disease relevant with serine protease in preparation treatment.

Preferred version of the present invention, wherein the disease relevant with serine protease is selected from thromboembolic disorders.

Preferred version of the present invention, wherein said serine protease is selected from factor Xa.

Preferred version of the present invention, wherein thromboembolic disorders is selected from the relevant thromboembolic disorders of artery cardiovascular thromboembolic disease, vein cardiovascular thromboembolic disease and heart.

Preferred version of the present invention, wherein thromboembolic disorders is selected from venous thrombosis, dvt forms, deep venous thrombosis of lower limbs, thrombophlebitis, cerebral artery thrombosis forms, arterial thrombosis, Coronary thrombosis, pulmonary infarction, cerebral embolism, renal infarction, hepatic vein embolism, portal vein embolization, chronic disseminated intravascular coagulation, four limbs and central capillary blood vessel arterial thrombosis, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, myocardial infarction, arteriosclerosis, local asphyxia is overworked dead, temporary ischemic, external application obstructive arterial disease, apoplexy, the sterility thrombotic endocarditis of companion's arterial thrombosis, cerebrovascular disease.

The invention still further relates to the method for the treatment of thromboembolic disorders.The method comprise give effective dose on patient treatment comprise pharmaceutically pharmaceutical agent of acceptable salt of compound of the present invention or its.Described compound of the present invention can be combined other therapeutical agent Combined Preparation.

The present invention relates to contain pharmaceutically pharmaceutical agent of acceptable salt of compound of the present invention or its, described pharmaceutical agent can be joint product, for example, comprise first and second kinds of therapeutical agents of significant quantity on host's administering therapeutic that needs are treated like this.Wherein the first therapeutical agent is compound of the present invention or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, the second therapeutical agent is selected from the second factor Xa factor inhibitors, at least one reagent in a kind of antithrombotics, a kind of anti-platelet agents, a kind of thrombin inhibitors, a kind of thrombolytic agent and the agent of a kind of scleroproein solvent.

Preferred version of the present invention, wherein said the second therapeutical agent is to be selected from warfarin, unfraction heparin, low molecular weight heparin, synthetic pentasaccharides, water frog element, Ah adding is by class, Ah a can woods, Ibuprofen BP/EP, how propionic acid of methoxy, sulindac, indomethacin, vialidon, Droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, Tirofiban, Eptifibatide, ReoPro melagatran, two sulfuric acid r-hirudins (having another name called: disulfatohirudin), tissue plasminogen activator, the tissue-type plasminogen activator of modifying, anistreplase, at least one reagent in urokinase and streptokinase.

Preferred version of the present invention, wherein said the second therapeutical agent is at least one anti-platelet agents.

Preferred version of the present invention, wherein said anti-platelet agents is acetylsalicylic acid and clopidogrel.

Preferred version of the present invention, wherein said anti-platelet agents is clopidogrel.

Pharmaceutical agent of the present invention is the pharmaceutical agent for the preparation for the treatment of thromboembolic disorders.

The invention still further relates to compound of the present invention or its pharmaceutically acceptable salt for the preparation of with the medicine of described the second therapeutical agent Combined Preparation treatment thromboembolic disorders in purposes.

Unless there is contrary statement, the term using in specification sheets and claims has following implication.

In group of the present invention and compound, related elemental carbon, hydrogen, oxygen, sulphur, nitrogen or halogen includes their isotropic substance situation, and related elemental carbon, hydrogen, oxygen, sulphur or nitrogen is optionally further substituted by the isotropic substance of one or more their correspondences in group of the present invention and compound, wherein the isotropic substance of carbon comprises ¹²c, ¹³c and ¹⁴c, the isotropic substance of hydrogen comprises protium (H), deuterium (D is again heavy hydrogen), tritium (T is again tritium), the isotropic substance of oxygen comprises ¹⁶o, ¹⁷o and ¹⁸o, the isotropic substance of sulphur comprises ³²s, ³³s, ³⁴s and ³⁶s, the isotropic substance of nitrogen comprises ¹⁴n and ¹⁵n, the isotropic substance of fluorine ¹⁹f, the isotropic substance of chlorine comprises ³⁵cl and ³⁷cl, the isotropic substance of bromine comprises ⁷⁹br and ⁸¹br.

Term " alkyl " refers to saturated aliphatic hydrocarbon groups, comprises straight chain and the branched group of 1 to 20 carbon atom.Preferably contain the alkyl of 1 to 10 carbon atom, non-limiting example comprises, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-nonyl, and various branched chain isomers etc.; The low alkyl group that more preferably contains 1 to 4 carbon atom, non-limiting example comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted; in the time being substituted; substituting group is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, heterocycle alkane sulfydryl, S (=O) _pr ⁸, thiazolinyl-R ⁸or alkynyl-R ⁸.

" alkoxyl group " refer to-O-alkyl, wherein alkyl is as defined above herein.Alkoxyl group can be that replace or unsubstituted, and its non-limiting example comprises, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, pentyloxy or hexyloxy preferably have 1 to 12 yuan of alkoxyl group.In the time being substituted; substituting group is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl, S (=O) _pr ⁸, thiazolinyl-R ⁸or alkynyl-R ⁸.

" alkoxyalkyl " refers to the alkyl being connected with alkoxyl group.Alkoxyalkyl can be that replace or unsubstituted, its non-limiting example comprises, methoxymethyl, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, propoxy-methyl, propoxy-ethyl, isopropoxy methyl, butoxy propyl group, tert.-butoxy ethyl, pentyloxy ethyl, hexyloxy ethyl, ring propoxy-methyl, ring propoxy-ethyl, ring propoxy-propyl group or cyclohexyloxy methyl; In the time being substituted; substituting group is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl, S (=O) _pr ⁸, thiazolinyl-R ⁸or alkynyl-R ⁸.

" thiazolinyl " is in the alkyl that defines of the present invention, comprises at least one carbon-to-carbon double bond, and described thiazolinyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of thiazolinyl comprises and replacing or unsubstituted vinyl, 2-propenyl, 3-butenyl, crotyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonene base or 4-decene base etc., in the time being substituted, substituting group is preferably 1 to 5, independently selected from F, Cl, Br, I,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl, S (=O) _pr ⁸, thiazolinyl-R ⁸or alkynyl-R ⁸.

" alkynyl " is in the alkyl that defines of the present invention, comprises at least one carbon-to-carbon triple bond, and described alkynyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of alkynyl comprises and replacing or unsubstituted ethynyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexin base, 3-hexin base, 3-butynyl, 2-heptyne base, 3-heptyne base, 4-heptyne base, 3-octyne base, 3-n-heptylacetylene base or 4-decynyl etc., in the time being substituted, substituting group is preferably 1 to 5, independently selected from F, Cl, Br, I,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl, S (=O) _pr ⁸, thiazolinyl-R ⁸or alkynyl-R ⁸.

" carbocyclic ring " refers to saturated or undersaturated aromatic nucleus or non-aromatic ring, aromatic nucleus or non-aromatic can be the monocycle of 3 to 8 yuan, 4 to 12 yuan of dicyclos or 10 to 15 yuan of three-loop systems, carbocyclic ring can be connected with bridged ring or volution, non-limiting example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, cyclopentenes, cyclohexadiene, cycloheptatriene, phenyl, naphthyl, benzo ring amyl group, two ring [3.2.1] octyls, two ring [5.2.0] nonyls, three ring [5.3.1.1] dodecyls, adamantyl or spiroheptane base etc.Carbocyclic ring can be substituted; in the time being substituted; substituting group is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkane sulfydryl, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl ,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸or-(CH ₂) _n-alkynyl-R ⁸.

" heterocycle " refers to saturated or undersaturated aromatic nucleus replacement or unsubstituted, non-aromatic ring, aromatic nucleus, non-aromatic ring can be the monocycles of 3 to 8 yuan, 4 to 12 yuan of dicyclos or 10 to 15 yuan of three-loop systems, and the heteroatoms that is selected from N, O or S by least one forms, preferably 3 to 10 yuan of heterocycles, N, S that in the ring of heterocycle, selectivity replaces can be oxidized to various oxidation state.Heterocycle can be connected on heteroatoms or carbon atom.Heterocycle can be connected with bridged ring or volution, non-limiting example comprises, oxyethane, nitrogen heterocyclic propyl group, oxetanyl, azetidinyl, 1, 3-dioxolane, 1, 4-dioxolane, 1, 3-dioxane, nitrogen heterocyclic heptyl, pyridyl, furyl, thienyl, pyranyl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, piperidyl, piperazine is stung base, morpholinyl, thio-morpholinyl, 1, 3-dithiane, dihydrofuran, dihydropyrane, two thiophenes penta encircle, tetrahydrofuran (THF), Pyrrolidine, imidazolidine, thiazolidine, tetrahydropyrans, benzoglyoxaline, benzo pyridine, pyrrolopyridine, coumaran, azabicyclic [3.2.1] octyl, azabicyclic [5.2.0] nonyl, oxatricyclo [5.3.1.1] dodecyl, azaadamantane base, oxa-spiroheptane base,

Deng; In the time being substituted; substituting group is preferably 1 to 5, and substituting group is independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl ,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸or-(CH ₂) _n-alkynyl-R ⁸.

" amino " refer to-NH ₂can be that replace or unsubstituted; in the time being substituted; substituting group is preferably 1 to 3, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, hydroxyl, amino, alkylamino, alkyl acyl amino, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, hydroxyalkyl, carboxylic acid, carboxylicesters ,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸or-(CH ₂) _n-alkynyl-R ⁸.

" aryl " refers to 6 to 14 yuan of full carbon monocycles replacement or unsubstituted or thick and many cyclic groups, has many cyclic groups of the π-electron system of conjugation, preferably 6 to 10 yuan of aromatic nucleus, and its non-limiting example comprises phenyl or naphthyl; Described aryl can be thick and with heteroaryl, heterocyclic radical or cycloalkyl, and the part being connected with precursor structure is aryl, its non-limiting example comprises cumarone, benzocyclopentane base or benzothiazole etc.In the time being substituted; substituting group is preferably 1 to 5, and substituting group is independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl ,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸or-(CH ₂) _n-alkynyl-R ⁸.

" heteroaryl " refers to and replaces or unsubstituted 5 to 15 yuan of aromatic nucleus, and contain 1 to 3 and be selected from N, O or S heteroatoms, preferably 5 to 10 yuan of aromatic nucleus, the non-limiting example of heteroaryl comprise pyridyl, furyl, thienyl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl,, cumarone, benzoglyoxaline, benzo pyridine or pyrrolopyridine etc.In the time being substituted; substituting group is preferably 1 to 5, and substituting group is independently selected from F, Cl, Br, I ,=O, alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acyl amino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkyl sulfydryl, hydroxyalkyl, carboxylic acid, carboxylicesters, Heterocyclylalkyl sulfydryl ,-(CH ₂) _ns (=O) _pr ⁸,-(CH ₂) _n-thiazolinyl-R ⁸or-(CH ₂) _n-alkynyl-R ⁸.

"=O " of the present invention is this area ordinary practice usage, refers to the Sauerstoffatom connected with two keys, such as the two key Sauerstoffatoms that are connected with carbon atom in carbonyl.

" pharmacy acceptable salt " refers to the salt of pharmaceutically acceptable non-toxic acid or alkali, comprises the salt of inorganic bronsted lowry acids and bases bronsted lowry, organic bronsted lowry acids and bases bronsted lowry.Include but not limited to derived from the salt of mineral alkali the metal-salt that Al, Ca, Li, My, K, Na and Zn form, salt derived from organic bases includes but not limited to primary amine, the salt of secondary amine or tertiary amine, comprise naturally occurring replacement or unsubstituted amine, cyclammonium and deacidite, for example ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, thanomin, dimethylethanolamine, DMAE, 2-DEAE diethylaminoethanol, dicyclohexylamine, trimethyl-xanthine, PROCAINE HCL, PHARMA GRADE, choline, trimethyl-glycine, Penicillin G benethamine, quadrol, glucosamine, methylglucosamine, Theobromine, trolamine, Trometamol, purine, piperazine, piperidines, the organic salt that N-ethylpiperidine or versamid 900 form, include but not limited to sulfuric acid derived from mineral acid and organic acid salt, phosphoric acid, nitric acid, Hydrogen bromide, hydrochloric acid, formic acid, acetic acid, propionic acid, Phenylsulfonic acid, phenylformic acid, toluylic acid, Whitfield's ointment, alginic acid, anthranilic acid, dextrocamphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glucuronic acid, L-glutamic acid, oxyacetic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succsinic acid, sulfanilic acid, tartrate, tosic acid, propanedioic acid, 2 hydroxy propanoic acid, oxalic acid, hydroxyethanoic acid, glucuronic acid, galacturonic acid, Citric Acid, Methionin, arginine, Aspartic Acid, styracin, tosic acid, methylsulfonic acid, the organic salt that ethyl sulfonic acid or trifluoromethanesulfonic acid etc. form.

" eutectic " refers to active pharmaceutical ingredient (active pharmaceutical ingredient, and eutectic formation (cocryst al former API), CCF) crystal being combined under the effect of hydrogen bond or other non covalent bonds, wherein the pure state of API and CCF is at room temperature solid, and has fixing stoichiometric ratio between each component.Eutectic is a kind of polycomponent crystal, has both comprised the two component eutectic forming between two kinds of neutral solids, also comprises the polynary eutectic that neutral solid and salt or solvate form.Described " eutectic formation " includes but not limited to various pharmaceutically acceptable acid, alkali, non-ionic compound, its non-limiting example comprises L-Ala (Ala), α-amino-isovaleric acid (Val), leucine (Leu), Isoleucine (Ile), proline(Pro) (Pro), phenylalanine (Phe), tryptophane (Trp), methionine(Met) (Met), glycine (Gly), Serine (Ser), Threonine (Thr), halfcystine (Cys), tyrosine (Tyr), l-asparagine (Asn), glutamine (Gln), Methionin (Lys), arginine (Arg), Histidine (His), aspartic acid (Asp), L-glutamic acid (Glu), Pyrrolidonecarboxylic acid, sulfuric acid, phosphoric acid, nitric acid, Hydrogen bromide, hydrochloric acid, formic acid, acetic acid, propionic acid, Phenylsulfonic acid, phenylformic acid, toluylic acid, Whitfield's ointment, alginic acid, anthranilic acid, dextrocamphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glucuronic acid, L-glutamic acid, oxyacetic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succsinic acid, sulfanilic acid, tartrate, tosic acid, propanedioic acid, 2 hydroxy propanoic acid, oxalic acid, hydroxyethanoic acid, glucuronic acid, galacturonic acid, Citric Acid, Methionin, arginine, Aspartic Acid, styracin, tosic acid, methylsulfonic acid, ethyl sulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, thanomin, dimethylethanolamine, DMAE, 2-DEAE diethylaminoethanol, dicyclohexylamine, trimethyl-xanthine, PROCAINE HCL, PHARMA GRADE, choline, trimethyl-glycine, Penicillin G benethamine, quadrol, glucosamine, methylglucosamine, Theobromine, trolamine, Trometamol, purine, piperazine, piperidines, N-ethylpiperidine.

" steric isomer " refers to by the molecule Atom isomer that spatially arrangement mode difference produces, comprises cis-trans-isomer, enantiomer and conformer.

" pharmaceutical composition " represents the mixture of compound described in one or more texts or its physiology/pharmacy acceptable salt or prodrug and other chemical composition, for example physiology of other component/pharmaceutically acceptable carrier and vehicle.The object of pharmaceutical composition is to promote the administration of compound to organism.

" prodrug " refers to and can under physiological condition or by solvolysis, be converted into and have bioactive the compounds of this invention.Prodrug of the present invention is prepared by the functional group being modified in this compound, the operation that this modification can be routinely or be removed in vivo, and obtain parent compound.Prodrug comprises that hydroxyl, amino or a sulfydryl in the compounds of this invention is connected to the compound forming on any group, in the time that the prodrug of the compounds of this invention is bestowed mammalian subject, prodrug is isolated and is formed respectively free hydroxyl, free amino or free thin base.The example of prodrug includes but not limited to, the compound that the hydroxyl in the compounds of this invention or amino functional group and formic acid, acetic acid or phenylformic acid form.

" optionally " or " optionally " mean describe subsequently ground event or environment can but needn't occur, comprise the occasion that this event or environment occur or do not occur.For example, " aryl is optionally replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that aryl is replaced by alkyl and aryl are not replaced by alkyl.

The synthetic method of the compounds of this invention

Z is selected from F, Cl, Br or I;

Embodiment

Describe below the beneficial effect of implementation process of the present invention and generation by specific embodiment in detail, be intended to help reader to understand better essence of the present invention and feature, not as restriction that can practical range to this case.

The structure of compound by nucleus magnetic resonance (NMR) or (with) mass spectrum (MS) determines.NMR displacement (δ) is with 10 ^-6(ppm) unit provides.The mensuration of NMR is with (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆), deuterochloroform (CDCl ₃), deuterated methanol (CD ₃oD), be inside designated as tetramethylsilane (TMS).

The mensuration of MS is used (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

The mensuration of HPLC is used Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6mm).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.20mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.

It is carrier that column chromatography generally uses Yantai Huanghai Sea silica gel 200～300 order silica gel.

The starting raw material that oneself knows of the present invention can adopt or synthesize according to methods known in the art, maybe can buy in the smooth science and technology of Thailand, pacify the companies such as resistance to Jilin Chemical, Shanghai moral are silent, Chengdu section dragon chemical industry, splendid chemistry science and technology far away, lark prestige science and technology.

Nitrogen atmosphere refers to that reaction flask connects the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.

Hydrogenation vacuumizes conventionally, is filled with hydrogen, repeatable operation 3 times.

In embodiment, without specified otherwise, reaction is carried out under nitrogen atmosphere.

In embodiment, without specified otherwise, solution refers to the aqueous solution.

In embodiment, without specified otherwise, the temperature of reaction is room temperature.

Room temperature is optimum temperature of reaction, is 20 DEG C～30 DEG C.

Et, ethyl;

Me, methyl;

Bn, benzyl;

Bz, benzoyl;

Intermediate 1:3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5,6-dihydropyridine-2 (1H)-one (1f) (reference CN101967145)

3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5，6-dihydropyridin-2(1H)-one(1f)

The first step: 1-(4-nitrophenyl) piperidines-2-ketone 1b

1-(4-nitrophenyl)piperidin-2-one

By 4-N-methyl-p-nitroaniline 1a (11.0g, 0.08mol) be dissolved in tetrahydrofuran (THF) (200mL), be cooled to 0 DEG C, drip 5-Chlorovaleryl Chloride (16mL, tetrahydrofuran (THF) (50mL) solution 0.12mol), dropwise, rise to room temperature reaction 5 hours, be cooled to 0 DEG C, add sodium hydride (content: w/w=60% in batches, 5.8g, 0.24mol), rise to room temperature reaction 12 hours.Reaction solution is cooled to 0 DEG C, slowly add water (60mL), with ethyl acetate (50mL × 3) extraction, merge organic phase, with saturated aqueous common salt (30mL) washing, organic phase anhydrous sodium sulfate drying, filter, concentrated, ethyl acetate/petroleum ether for residue (v/v)=1: 19 recrystallization, obtain 1-(4-nitrophenyl) piperidines-2-ketone 1b (10.0g, productive rate 58%) of yellow solid shape.

The chloro-1-of second step: 3,3-bis-(4-nitrophenyl) piperidines-2-ketone 1c

3，3-dichloro-1-(4-nitrophenyl)piperidin-2-one

1-(4-nitrophenyl) piperidines-2-ketone 1b (6.6g, 0.03mol) is dissolved in chloroform (30mL), in 10 minutes, adds phosphorus pentachloride (18.7g, 0.09mol), be heated to back flow reaction 3 hours.Reaction solution is cooled to room temperature, be poured in frozen water (50mL) separatory, chloroform for water (30mL × 2) extraction, merge organic phase, with saturated aqueous common salt (30mL × 2) washing, organic phase anhydrous sodium sulfate drying, filters, the concentrated compound 3 that obtains deep yellow solid state, the chloro-1-of 3-bis-(4-nitrophenyl) piperidines-2-ketone 1c (8.0g, crude product, not purifying).

The 3rd step: 1-(4-nitrophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1d

3-morpholino-1-(4-nitrophenyl)-5，6-dihydropyridin-2(1H)-one

Chloro-3,3-bis-1-(4-nitrophenyl) piperidines-2-ketone 1c (8.6g, 0.03mol) is dissolved in morpholine solution (30mL, 0.30mol), is warming up to 130 DEG C of reactions 1.5 hours.Reaction solution is cooled to room temperature, add water (50mL), filter, filter cake obtains deep yellow solid with water wash, obtain compound 1-(4-nitrophenyl)-3-morpholine-5 of deep yellow solid state by re-crystallizing in ethyl acetate, 6-dihydropyridine-2 (1H)-one 1d, (6.1g, productive rate 67%).

The 4th step: 1-(4-aminophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1e

1-(4-aminophenyl)-3-morpholino-5，6-dihydropyridin-2(1H)-one

By 1-(4-nitrophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1d (6.1g, 0.02mol) be dissolved in ethanol (60mL), add nine hydrated sodium sulfide (9.6g, 0.04mol) water (20mL) solution, is warming up to 70 DEG C of reactions 2 hours.Reaction solution is cooled to room temperature, concentrated, in residue, add ethyl acetate (50mL), filter, after filtration cakes torrefaction, obtain compound 1-(4-aminophenyl)-3-morpholine-5 of light yellow solid shape, 6-dihydropyridine-2 (1H)-one 1e (3.8g, productive rate 70%).

The 5th step: 1-(4-(2-oxo-piperidine-1-yl) phenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1f

3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5，6-dihydropyridin-2(1H)-one

By 1-(4-aminophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1e (3.8g, 13.90mmol) be dissolved in tetrahydrofuran (THF) (100mL), add triethylamine (4.2g, 41.70mmol), be cooled to 0 DEG C, drip tetrahydrofuran (THF) (10mL) solution of 5-Chlorovaleryl Chloride (3.1g, 19.50mmol), dropwise, rise to 55 DEG C of reactions 2 hours, be then cooled to 0 DEG C, slowly add sodium hydride (content 60%, 1.7g, 41.70mmol), in 20 minutes, add, rise to room temperature reaction and spend the night.Reaction solution is cooled to 0 DEG C, slowly add water (10mL), concentrating under reduced pressure, add water (10mL), suction filtration, ethyl acetate for filter cake (100mL) washing, obtain light yellow solid, filtrate, with methylene dichloride (100mL × 2) extraction, merges organic phase, with anhydrous sodium sulfate drying, filter, concentrated, residue and filter cake merge compound 1-(4-(2-oxo-piperidine-1-yl) phenyl)-3-morpholine-5 that obtain light yellow solid shape, 6-dihydropyridine-2 (1H)-one 1f (3.6g, productive rate 73%).

Intermediate 2:1-(4-iodophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one (2e) (reference CN101967145)

1-(4-iodophenyl)-3-morpholino-5，6-dihydropyridin-2(1H)-one

The chloro-N-of the first step: 5-(4-iodophenyl) valeramide 2b

5-chloro-N-(4-iodophenyl)pentanamide

Triethylamine (10.1g, 0.10mol) is dissolved in tetrahydrofuran (THF) (200mL), adds 4-Iodoaniline 2a (11.00g, 0.05mol).Reaction solution is cooled to 0 DEG C, drips tetrahydrofuran (THF) (50mL) solution of the chloro-valeryl chloride of 5-(11.6g, 0.10mol), rises to room temperature reaction 3 hours after dropwising.Reaction solution is cooled to 0 DEG C, slowly add water (10mL), rise to room temperature, add ethyl acetate (100mL) and water (200mL), separatory, saturated aqueous common salt for organic phase (100mL) washing, with anhydrous sodium sulfate drying, filter, concentrated, obtain the chloro-N-of compound 5-(4-iodophenyl) the valeramide 2b (13.0g, productive rate 77%) of yellow solid shape.

MS?m/z(ESI)：337.9[M+1].

Second step: 1-(4-iodophenyl) piperidines-2-ketone 2c

1-(4-iodophenyl)piperidin-2-one

Chloro-5-N-(4-iodophenyl) valeramide 2b (13.0g, 0.04mol) is dissolved in tetrahydrofuran (THF) (100mL), is cooled to 0 DEG C, slowly add sodium hydride (content: w/w=60%, 3.2g, 0.08mol), rise to room temperature reaction 3 hours.Reaction solution is cooled to 0 DEG C, slowly add water (10mL), add again the saturated common salt aqueous solution (20mL), separatory, organic phase anhydrous sodium sulfate drying, filter, concentrated, ethyl acetate/petroleum ether for residue (v/v)=1: 4 recrystallization, obtains compound 1-(4-iodophenyl) piperidines-2-ketone 2c of light yellow solid shape, (11.0g, productive rate 95%).

¹H?NMR(300MHz，CDCl ₃)δ1.93-1.99(m，4H)，2.55(t，2H)，3.62-3.60(m，2H)，7.02(d，2H)，7.70(d，2H)

MS?m/z(ESI)：302.0[M+1]

The chloro-1-of the 3rd step: 3,3-bis-(4-iodophenyl) piperidines-2-ketone 2d

3，3-dichloro-1-(4-iodophenyl)piperidin-2-one

1-(4-iodophenyl) piperidines-2-ketone 2c (11.0g, 36.50mmol) is dissolved in chloroform (100mL) solution, adds phosphorus pentachloride (22.8g, 110.00mmol), be heated to 65 DEG C of stirring reactions 4 hours.Reaction solution is cooled to room temperature, pour in frozen water, separatory, the saturated common salt aqueous solution (50mL) washing for organic phase, anhydrous sodium sulfate drying, filter the concentrated chloro-1-of compound 3.3-bis-(the 4-iodophenyl)-piperidines-2-ketone 2d (13.0g, productive rate 96%) that obtains red thickness.

MS?m/z(ESI)：369.8[M+1]

The 4th step: 1-(4-iodophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 2e

1-(4-iodophenyl)-3-morpholino-5，6-dihydropyridin-2(1H)-one

Morpholine (21.2g, 243.00mmol) is added in the chloro-1-of 3,3-bis-(4-iodophenyl)-piperidines-2-ketone 2d (16.0g, 43.36mmol), be heated to 130 DEG C of reactions 4 hours.Reaction solution is cooled to 30 DEG C, add ethyl acetate (50mL) and water (50mL), separatory, the saturated common salt aqueous solution (40mL × 3) washing for organic phase, organic phase anhydrous sodium sulfate drying, filter, concentrated, residue obtains compound 1-(4-iodophenyl)-3-morpholine-5 of yellow solid shape with silica gel column chromatography separation (ethyl acetate/normal hexane (v/v)=1: 10～1: 4), 6-dihydropyridine-2 (1H)-one 2e (6.0g, productive rate 65%).

MS?m/z(ESI)：384.9[M+1]

Embodiment 1

1-(2-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 1)

1-(2-methyl-2，3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

One step: 2-methyl-5-nitro-2,3-Dihydrobenzofuranes 1B

2-methyl-5-nitro-2，3-dihydrobenzofuran

By 2-methyl-2.3-Dihydrobenzofuranes 1A (1.0g, 7.50mmol) be dissolved in acetic acid (10mL), under room temperature, add concentrated nitric acid (125mg, 2.0mmol), be warming up to 70 DEG C, add concentrated nitric acid (375mg, 6.00mmol), maintain 70 DEG C of stirring reactions 1 hour.In reaction solution, add water (50mL) and ethyl acetate (50mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL × 2) washing, anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=1: 0～1: 9) obtains compound 2-methyl-5-nitro-2 of brown solid shape, 3-Dihydrobenzofuranes 1B (170mg, productive rate 13%).

¹H?NMR(400MHz，CDCl ₃)δ8.09(dd，1H)，8.06(d，1H)，6.78(d，1H)，5.16-5.07(m，1H)，3.41(dd，1H)，2.89(dd，1H)，1.52(d，3H)。

Second step: 2-methyl-2,3-Dihydrobenzofuranes-5-amine 1C

2-methyl-2，3-dihydrobenzofuran-5-amine

By 2-methyl-5-nitro-2,3-Dihydrobenzofuranes 1B (670mg, 3.74mmol) is dissolved in acetic acid (30mL), adds nine hydrated sodium sulfide (2.7g, water (10mL) solution 11.22mmol), is warming up to 90 DEG C of reactions 3 hours.Concentration of reaction solution, add water (20mL) and ethyl acetate (30mL), separatory, ethyl acetate for water (20mL × 2) extraction, merges organic phase, saturated aqueous common salt for organic phase (20mL × 2) washing, anhydrous sodium sulfate drying, filters, compound 2-methyl-2 of concentrated yellow solid shape, 3-Dihydrobenzofuranes-5-amine 1C (450mg, productive rate 81%).

¹H?NMR(400MHz，CDCl ₃)δ6.56-6.54(m，2H)，6.45-6.42(m，1H)，4.87-4.78(m，1H)，3.36(s，2H)，3.20(dd，1H)，2.72(dd，1H)，1.42(d，3H)。

MS?m/z(ESI)：150.1[M+1]

The chloro-2-of the 3rd step: 2-(2-(2-methyl 1-2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 1D

ethyl?2-chloro-2-(2-(2-methyl-2，3-dihydrobenzofuran-5-yl)hydrazono)acetate

By concentrated hydrochloric acid (1.7mL, water (3.5mL) solution 20.10mmol) joins 2-methyl-2, 3-Dihydrobenzofuranes-5-amine 1C (1.0g, 6.70mmol) in, stirring reaction 15 minutes at 0 DEG C, at 0 DEG C, drip Sodium Nitrite (555mg, water (8mL) solution 8.00mmol), maintain 0 DEG C of stirring reaction 30 minutes, with sodium acetate (1.1g, 13.40mmol) regulate reaction solution pH=5～6, at 0 DEG C, drip 2-chloroacetyl acetacetic ester (1.1g, methyl alcohol (10mL) solution 6.70mmol), within 10 minutes, add, room temperature reaction 1 hour.In reaction solution, add ethyl acetate (50mL) and water (20mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=1: 0～1: 9) obtains the chloro-2-of compound 2-(2-(the 2-methyl 1-2 of yellow solid shape, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 1D (400mg, productive rate 20%).

The 4th step: 1-(2-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 1E

ethyl?1-(2-methyl-2，3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (457mg, 1.28mmol), the chloro-2-of 2-(2-(2-methyl 1-2, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate (400mg, 1.41mmol) be dissolved in ethyl acetate (30mL), add potassiumiodide (22mg, 0.13mmol) and triethylamine (389mg, 3.84mmol), rise to 90 DEG C of back flow reaction 6 hours, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 1.6mL, 6.40mmol), stirring at room temperature reaction 1 hour.In reaction solution, add water (20mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (30mL × 2), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0 for residue, methanol/ethyl acetate (v/v)=1: 19) obtain compound 1-(2-methyl-2 of yellow solid shape, 3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester 1E (230mg, productive rate 35%).

¹H?NMR(400MHz，CDCl ₃)δ7.36-7.34(m，3H)，7.26-7.25(m，3H)，6.73(d，1H)，5.02-4.90(m，1H)，4.56-4.43(m，2H)，4.15-4.10(m，2H)，3.60-3.59(m，2H)，3.32(dd，3H)，2.82(dd，1H)，2.58(d，2H)，1.98-1.87(m，4H)，1.46-1.41(m，6H)。

MS?m/z(ESI)：515.2[M+H]

The 5th step: 1-(2-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 1

By 1-(2-methyl-2,3-dihydropyridine furans-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 1E (230mg, 0.45mmol) is dissolved in DMF (15mL), add methane amide (121mg, 2.68mmol), sodium methylate (49mg, 0.90mmol), rise to 80 DEG C reaction 18 hours.In reaction solution, add ethyl acetate (30mL) and water (30mL), separatory, ethyl acetate for water (30mL × 2) extraction, saturated aqueous common salt for organic phase (30mL × 3) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (methanol/ethyl acetate (v/v)=0: 1～1: 19) obtains compound 1-(2-methyl-2 of white solid, 3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide compound 1 (80mg, productive rate 37%).

Compound 1:

¹H?NMR(400MHz，CDCl ₃)δ7.36-7.31(m，3H)，7.27-7.25(m，3H)，6.84(s，1H)，6.76(d，1H)，5.56(s，1H)，5.03-4.92(m，1H)，4.11(t，2H)，3.60-3.59(m，2H)，3.40-3.31(m，3H)，2.85(dd，1H)，2.56(s，2H)，1.93(m?4H)，1.47(d，3H)。

MS?m/z(ESI)：486.1[M+1]

Embodiment 2

1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide (compound 2)

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxomorpholino)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The chloro-2-of the first step: 2-(2-(2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 2B

ethyl?2-chloro-2-(2-(2，3-dihydrobenzofuran-5-yl)hydrazono)acetate

By 2, 3-Dihydrobenzofuranes-5-amine 2A (2.0g, 14.80mmol) join hydrochloric acid (14.6mL, 3N), be cooled to-5 DEG C, drip Sodium Nitrite (1.2g, 17.80mmol) water (8mL) solution, after dropwising, 0 DEG C of reaction 30 minutes, slowly add sodium acetate (2.1g, 25.6mmol), regulate reaction solution to pH=5～6, at 0～5 DEG C, drip 2-chloroacetyl acetacetic ester (2.4g, methyl alcohol (5mL) solution 14.80mmol), rise to room temperature reaction 2 hours, in reaction solution, add ethyl acetate (20mL), separatory, saturated aqueous common salt for organic phase (30mL) washing, separatory, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, residue with silica gel column chromatography purify (ethyl acetate/petroleum ether (v/v)=1: 99～1: 9) obtain the chloro-2-of the compound 2-(2-(2 of yellow solid shape, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 2B (200mg, productive rate 5%).

¹H?NMR(400MHz，CDCl ₃)δ8.27(s，1H)，7.18(s，1H)，6.91(d，1H)，6.73(d，1H)，4.65-4.54(m，2H)，4.38(q，2H)，3.22(t，2H)，1.40(t，3H)。

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 2C

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-6-(4-iodophenyl)-7-oxo-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carbox-ylate

By 1-(4-iodophenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 2e (2.0g, 5.20mmol) be dissolved in ethyl acetate (20mL), add the chloro-2-of 2-(2-(2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 2B (1.8g, 6.70mmol), triethylamine (1.6g, 15.60mmol) and potassiumiodide (86mg, 0.52mmol), be warming up to back flow reaction and spend the night, be cooled to 0 DEG C, add hydrochloric acid (6.5mL, 26.00mmol), stirring at room temperature reaction 1 hour.In reaction solution, add ethyl acetate (20mL) and water (20mL), separatory, saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 99～3: 7) obtains the compound 1-(2 of reddish-brown solid state, 3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazoles [3, 4-c] pyridine-3-carboxamide 2C (1.2g, productive rate 44%).

¹H?NMR(400MHz，CDCl ₃)δ7.76-7.66(m，2H)，7.36(d，1H)，7.24(d，1H)，7.10(d，2H)，6.77(d，1H)，4.60(t，2H)，4.46(q，2H)，4.13-4.08(m，2H)，3.32(t，2H)，3.22(t，2H)，1.44-1.41(m，3H)。

The 3rd step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 2D

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-6-(4-(3-oxomorpholino)phenyl)-7-oxo-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide 2C (400mg, 0.76mmol), morpholine-3-ketone (84mg, 0.83mmol) and potassiumphosphate (321mg, 1.51mmol) are dissolved in 1.4-dioxane (20mL), under nitrogen atmosphere, add cuprous iodide (14mg, 0.07mmol) and N, N-dimethylcyclohexylamine (11mg, 0.07mmol), heating reflux reaction spends the night.Reaction solution is cooled to room temperature, add water (30mL), extract with methylene dichloride (40mL), saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester 2D (200mg, productive rate 53%).

¹H?NMR(400MHz，DMSO-d ₆)δ7.40(m，5H)，7.26(d，1H)，6.82(d，1H)，4.60(t，2H)，4.34(q，2H)，4.21(s，2H)，4.08(t，2H)，4.02-3.97(m，2H)，3.73(t，2H)，3.24-3.19(m，4?H)，1.33(t，3H)。

The 3rd step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 2

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 2D (200mg, 0.40mmol) is dissolved in DMF (5mL), add methane amide (179mg, 3.98mmol), sodium methylate (43mg, 0.80mmol), rise to 80 DEG C of reactions and spend the night.Reaction solution is cooled to room temperature, add water (30mL), extract with methylene dichloride (30mL), saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=1: 99～1: 19) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo morpholine) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide compound 2 (76mg, productive rate 40%).

¹H?NMR(400MHz，CDCl ₃)δ7.39-7.33(m，4H)，7.28-7.25(m，2H)，6.84(s，1H)，6.80(d，1H)，5.48(s，1H)，4.62(t，2H)，4.34(s，2H)，4.15-4.10(m，2H)，4.04-4.01(m，2H)，3.74-3.72(m，2H)，3.38(t，2H)，3.25(t，2H)。

MS?m/z(ESI)：474.2[M+1]

Embodiment 3

1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo thiomorpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 3)

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo thiomorpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 3A

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 2C (400mg, 0.76mmol), thiomorpholine-3-ketone (97mg, 0.83mmol) and potassiumphosphate (321mg, 1.51mmol) are dissolved in 1.4-dioxane (20mL), under nitrogen atmosphere, add cuprous iodide (14mg, 0.076mmol) and N, N-dimethylcyclohexylamine (11mg, 0.076mmol), heating reflux reaction spends the night.Reaction solution is cooled to 0 DEG C, add water (40mL), extract with methylene dichloride (40mL), saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo thiomorpholine) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester 3A (130mg, productive rate 33%).

¹H?NMR(400MHz，CDCl ₃)δ7.37-7.36(m，3H)，7.26-7.28(m，3H)，6.77(d，1H)，4.60(t，2H)，4.46(q，2H)，4.13(t，2H)，3.95-3.93(m，2H)，3.46(s，2H)，3.32(t，2H)，3.22(t，2H)，3.03-3.00(m，2H)，1.43(t，3H)。

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo thiomorpholine) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 3

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(3-oxothiomorpholino)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridi-ne-3-carboxamide

By 1-(2,3-Dihydrobenzofuranes-5-yl)-7-oxo-6-(4-(3-oxo thiomorpholine) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 3B (130mg, 0.25mmol) is dissolved in DMF (5mL), add methane amide (113mg, 2.50mmol), sodium methylate (27mg, 0.50mmo), rise to 80 DEG C of reactions and spend the night.Reaction solution is cooled to room temperature, add water (30mL), extract with methylene dichloride (30mL), saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0 for residue, ethanol/methylene=1: 99～1: the compound 1-(2 that 19) obtains white solid, 3-Dihydrobenzofuranes-5-yl)-6-(4-(3-oxo thiomorpholine) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide compound 3 (21mg, productive rate 17%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.36(m，3H)，7.26-7.28(m，3H)，6.83(s，1H)，6.80(d，1H)，5.44(s，1H)，4.62(t，2H)，4.12(t，2H)，3.96-3.93(m，2H)，3.46(s，2H)，3.38(t，2H)，3.25(t，2H)，3.01-3.02(m，2H)。

MS?m/z(ESI)：490.1[M+1]

Embodiment 4

1-(2,3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 4)

1-(2，3-Dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridin-e-3-carboxamide

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 4A

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(4-(2-oxo-piperidine-1-yl) phenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1f (220mg, 0.62mmol) be dissolved in ethyl acetate (20mL), add the chloro-2-of 2-(2-(2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 2B (200mg, 0.68mmol), potassiumiodide (10mg, 0.06mmol) and triethylamine (190mg, 1.86mmol), being warming up to back flow reaction spends the night.Reaction solution is cooled to 0 DEG C, add hydrochloric acid (110mg, 3.1mmol), rise to stirring at room temperature 1 hour, wash with saturated aqueous common salt (30mL), separatory, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, residue with silica gel column chromatography purify (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtain the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4, 5, 6, 7-tetrahydrochysene-1H-pyrazoles [3, 4-c] Nicotinicum Acidum ethyl ester 4A (230mg, productive rate 74%).

¹H?NMR(400MHz，CDCl ₃)δ7.33-7.36(m，3H)，7.26(m，3H)，6.76(d，1H)，4.60(t，2H)，4.46(q，2H)，4.12(t，2H)，3.60(m，2H)，3.31(t，2H)，3.22(t，2H)，2.56(m，2H)，1.94(m，4H)，1.43(t，3H)。

The 3rd step: 1-(2,3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide compound 4

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

By 1-(2,3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 4A (300mg, 0.60mmol) is dissolved in DMF (2.5mL), add methane amide (79mg, 1.80mmol) and sodium methylate (32mg, 0.60mmol), rise to 70 DEG C of reactions 5 hours.Concentration of reaction solution, methylene dichloride for residue (2mL) dissolves, with silica gel column chromatography purify (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtain the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide compound 4 (120mg, productive rate 43%).

¹H?NMR(400MHz，CDCl ₃)δ7.36-7.33(m，3H)，7.26-7.25(m，3H)，6.86(s，1H)，6.80(s，1H)，5.72(s，1H)，4.61(t，2H)，4.12(t，2H)，3.60(m，2H)，3.37(t，2H)，3.24(t，2H)，2.57-2.54(m，2H)，1.94-1.93(m，4H)。

MS?m/z(ESI)：472.1[M+1]

Embodiment 5

1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 5)

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 5B

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopyridin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 2C (500mg, 0.94mmol), pyridine-2-alcohol (108mg, 1.14mmol) and potassiumphosphate (400mg, 1.88mmol) are dissolved in 1.4-dioxane (10mL), under nitrogen atmosphere, add cuprous iodide (18mg, 0.094mmol) and N, N-dimethylcyclohexylamine (14mg, 0.094mmol), rising to back flow reaction spends the night.Reaction solution is cooled to 0 DEG C, add methylene dichloride (50mL) and water (50mL), separatory, saturated aqueous common salt for organic phase (50mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester 5B (180mg, productive rate 39%).

¹H?NMR(400MHz，CDCl ₃)δ7.47-7.37(m，6H)，7.30-7.26(m，2H)，6.78(d，1H)，6.70(d，1H)，6.27(t，1H)，4.61(t，2H)，4.49-4.44(m，2H)，4.17(t，2H)，3.35(t，2H)，3.23(t，2H)，1.44(t，3H)。

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1 H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 5

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-oxo pyridine-1-2H-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (180mg, 0.36mmol) is dissolved in DMF (5mL), add methane amide (163mg, 3.63mmol), sodium methylate (39mg, 0.73mmol), be warming up to 80 DEG C reaction 7 hours.Reaction solution is cooled to room temperature, add water (60mL), extract with methylene dichloride (40mL), saturated aqueous common salt for organic phase (60mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～3: 97) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide compound 5 (100mg, productive rate 59%).

¹H?NMR(400MHz，CDCl ₃)δ7.45-7.35(m，6H)，7.32-7.22(m，2H)，6.84(s，1H)，6.81(d，1H)，6.75(d，1H)，6.29(t，1H)，5.44(s，1H)，4.62(t，2H)，4.17(t，2H)，3.41(t，2H)，3.25(t，2H)。

MS?m/z(ESI)：468.1[M+1]

Embodiment 6

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyl-1-methyl-ethyl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridin-7-one (compound 6)

1-(2，3-dihydrobenzofuran-5-yl)-3-(2-hydroxypropan-2-yl)-6-(4-(2-oxopiperidin-1-yl)phenyl)-5，6-dihydro-1H-pyrazolo[3，4-c]pyridin-7(4H)-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyl-1-methyl-ethyl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridin-7-one compound 6

By 1-(2; 3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4; 5; 6; 7-tetrahydrochysene-1H-pyrazoles [3; 4-c] Nicotinicum Acidum ethyl ester 4A (200mg; 0.40mmol) be dissolved in anhydrous tetrahydro furan (15mL), with nitrogen protection, gas displacement three times; be cooled to-20 DEG C; slowly drip methyl-magnesium-bromide (1.0mL, 1.0mmol, 1M); add the rear room temperature that slowly rises to, stirring reaction 4 hours under room temperature.Reaction solution is cooled to 0 DEG C, add water (20mL) cancellation reaction, be extracted with ethyl acetate reaction solution (30mL × 1), organic layer saturated common salt water washing (30mL × 1), anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyl-1-methyl-ethyl)-6-(4-(2-oxo pyridine-1 (2H)-yl) phenyl)-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridin-7-one compound 6 (90mg, productive rate 46%).

¹H?NMR(400MHz，DMSO-d6)δ7.32-7.35(m，2H)，7.25-7.29(m，3H)，7.14(dd，1H)，6.74(d，1H)，5.13(s，1H)，4.54(t，2H)，4.00(t，2H)，3.57(t，2H)，3.17(t，2H)，3.09(t，2H)，2.37(t，2H)，1.82(m，4H)，1.50(s，6H)。

MS?m/z(ESI)：487.2[M+1]

Embodiment 7

1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-nitrile (compound 7)

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carbonitrile

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-nitrile

By 1-(2; 3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4; 5,6,7-tetrahydrochysene-1H-pyrazoles [3; 4-c] pyridine-3-carboxamide compound 4 (100mg; 0.21mmol), pyridine (2.10g, 26.50mmol) is dissolved in methylene dichloride (5mL), under nitrogen protection; gas displacement three times, is then cooled to-20 DEG C.Slowly drip trifluoroacetic anhydride (220mg, 1.05mmol), in one hour, dropwise, stirring reaction one hour at-20 DEG C.In reaction solution, slowly drip water (10mL), rise to room temperature, add methylene dichloride (20mL), separatory, methylene dichloride for water (10mL) extraction, merge organic phase, wash with 5%HCl (30mL), use again saturated aqueous common salt (30mL) washing, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～1: 49) obtains white solid compound 1-(2, 3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazoles [3, 4-c] pyridine-3-nitrile compound 7 (60mg, productive rate 63%).

¹H?NMR(400MHz，CDCl ₃)δ7.32-7.35(m，3H)，7.23-7.28(m，3H)，6.78(d，1H)，4.59(t，2H)，4.13(t，2H)，3.62(m，2H)，3.21(t，2H)，3.14(t，2H)，2.59(m，2H)，1.95(m，4H)。

MS?m/z(ESI)：454.2[M+1]

Embodiment 8

1-(7-fluoro-2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide (compound 8)

1-(7-fluoro-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The bromo-2-of the first step: 1-(2-bromine oxethyl)-3-fluorobenzene 8B

1-bromo-2-(2-bromoethoxy)-3-fluorobenzene

By bromo-2-6-fluorophenol 8A (0.5g, 2.60mmol), glycol dibromide (977mg, 5.20mmol), salt of wormwood (717mg, 5.20mmol) be dissolved in acetonitrile (5mL), be heated to 50 DEG C of stirring reactions 4 hours.Reaction solution is down to room temperature, add water (10mL) cancellation reaction, reaction solution is extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated aqueous common salt (20mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil 100%) obtains the bromo-2-of colorless oil 1-(2-bromine oxethyl)-3-fluorobenzene 8B (340mg, productive rate 44%).

¹H?NMR(400MHz，CDCl ₃)δ7.31-7.34(m，1H)，7.04-7.09(m，1H)，6.91-6.98(m，1H)，4.36(t，2H)，3.65(m，2H)。

Second step: 7-is fluoro-2,3-Dihydrobenzofuranes 8C

7-fluoro-2，3-dihydrobenzofuran

By bromo-1-2-(2-bromine oxethyl)-3-fluorobenzene 8B (340mg, 1.10mmol) be dissolved in anhydrous tetrahydro furan (5mL), be cooled to-78 DEG C, slowly add n-Butyl Lithium (0.75mL, 1.20mmol, 1.6M), after adding, at this temperature, react 2 hours, rise to gradually afterwards room temperature, stirring reaction 1 hour under room temperature.Water (5mL) cancellation reaction, be extracted with ethyl acetate reaction solution (15mL × 2), merge organic phase, wash with saturated aqueous common salt (20mL × 1), anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil 100%) obtains colorless oil 7-fluoro-2,3-Dihydrobenzofuranes 8C (60mg, productive rate 40%).

¹H?NMR(400MHz，CDCl ₃)δ6.96(dd，1H)，6.88-6.92(m，1H)，6.75-6.80(m，1H)，4.64(t，2H)，3.24(t，2H)。

The 3rd step: 5-nitro-7-is fluoro-2,3-Dihydrobenzofuranes 8D

7-fluoro-5-nitro-2，3-dihydrobenzofuran

By fluoro-7-2,3-Dihydrobenzofuranes 8C (2.5g, 18.00mmol) be dissolved in glacial acetic acid (10mL), under room temperature, add concentrated nitric acid (0.4g), stirring reaction 30 minutes, be heated to 70 DEG C, then add concentrated nitric acid (1.4g), at this temperature, react 1 hour.Reaction solution is cooled to 0 DEG C, add water (20mL), be extracted with ethyl acetate reaction solution (50mL × 2), merge organic phase, with saturated aqueous common salt (50mL × 1) washing, anhydrous sodium sulfate drying, concentrated, it is fluoro-2 that silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 100～1: 20) obtains faint yellow solid 5-nitro-7-, 3-Dihydrobenzofuranes 8D (1.3g, productive rate 39%).

The 4th step: 5-amino-7-is fluoro-2,3-Dihydrobenzofuranes 8E

7-fluoro-2，3-dihydrobenzofuran-5-amine

By fluoro-5-nitro-7-2,3-Dihydrobenzofuranes 8D (100mg, 0.50mmol) is dissolved in dehydrated alcohol (5mL), adds nine water cure sodium (240mg, 1.00mmol), is heated to 70 DEG C, stirring reaction 30 minutes.Reaction solution is cooled to room temperature, add water (10mL), be extracted with ethyl acetate reaction solution (20mL × 1), merge organic phase, with saturated aqueous common salt (20mL × 1) washing, anhydrous sodium sulfate drying, concentrated, it is fluoro-2 that silica gel column chromatography separating-purifying for residue (sherwood oil/methylene dichloride (v/v)=1: 1) obtains yellow solid 5-amino-7-, 3-Dihydrobenzofuranes 8E (40mg, productive rate 53%).

¹H?NMR(400MHz，CDCl ₃)δ6.36(m，1H)，6.27(dd，1H)，4.56(t，2H)，3.46(s，2H)，3.14(t，2H)。

MS?m/z(ESI)：154.1[M+H]

The chloro-2-of the 5th step: 2-(2-(7-fluoro-2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 8F

ethyl?2-chloro-2-(2-(7-fluoro-2，3-dihydrobenzofuran-5-yl)hydrazono)acetate

By concentrated hydrochloric acid (1.2mL, water (2.5mL) solution 15.1mmol) joins 5-amino-7-fluoro-2,3-Dihydrobenzofuranes 8E (800mg, 5.20mmol) in, stirring reaction 30 minutes at-5～0 DEG C, water (2mL) solution that drips Sodium Nitrite (431mg, 6.24mmol) at 0 DEG C, maintains 0 DEG C of stirring reaction 30 minutes.In another reaction flask, by sodium acetate (984mg, 12.00mmol) in water-soluble (3mL), ethyl acetate (5mL) solution that adds again 2-chloroacetyl acetacetic ester (85.6mg, 5.20mmol), is cooled to-5 DEG C, drip the reaction solution in first reaction flask, holding temperature, at-5～0 DEG C, adds for 10 minutes, stirring reaction 4 hours at 0 DEG C.In reaction solution, add ethyl acetate (50mL) and water (20mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (30mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=50: 1～10: 1) obtains the chloro-2-of the compound 2-(2-(7-fluoro-2 of yellow solid shape, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 8F (700mg, productive rate 47%).

The 6th step: 1-(7-fluoro-2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 8G

ethyl?1-(7-fluoro-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(4-(2-oxo-piperidine-1-yl) phenyl)-3-morpholine-5,6-dihydropyridine-2 (1H)-one 1f (700mg, 2.00mmol) be dissolved in ethyl acetate (15mL), add the chloro-2-of 2-(2-(5-amino-7-fluoro-2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 8F (574mg, 2.00mmol), potassiumiodide (33mg, 0.20mmol) and triethylamine (607mg, 6.00mmol), being warming up to back flow reaction spends the night.Reaction solution is cooled to 0 DEG C, add 4N hydrochloric acid (2.5mL, 10.00mmol), rise to stirring at normal temperature 1 hour, add water (25mL), be extracted with ethyl acetate reaction solution (25mL × 2), merge organic phase, wash with saturated aqueous common salt (30mL × 1), organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains tawny solid 1-(7-fluoro-2, 3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazoles [3, 4-c] Nicotinicum Acidum ethyl ester 8G (260mg, productive rate 26%).

¹H?NMR(400MHz，CDCl ₃)δ7.34(d，2H)，7.26(d，2H)，7.20(m，1H)，7.16-7.17(m，1H)，4.68(t，2H)，4.45(q，2H)，4.08(t，2H)，3.61(t，2H)，3.30(t，2H)，3.26(t，2H)，2.56(t，2H)，1.94(m，4H)，1.42(t，3H)。

MS?m/z(ESI)：519.2[M+1]

The 7th step: 1-(7-fluoro-2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide compound 8

1-(7-fluoro-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-

pyrazolo[3，4-c]pyridine-3-carboxamide

By 1-(7-fluoro-2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] Nicotinicum Acidum ethyl ester 8G (260mg, 0.50mmol) is dissolved in DMF (5mL), add methane amide (225mg, 5.00mmol) and sodium methylate (108mg, 2.00mmol), be warming up to 70 DEG C of reactions 6 hours.Concentration of reaction solution, methylene dichloride for residue (2mL) dissolves, wash with saturated aqueous common salt (30mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, with silica gel column chromatography purify (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtain the compound 1-(7-fluoro-2 of yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine-3-carboxamide compound 8 (25mg, productive rate 10%).

¹H?NMR(400MHz，CDCl3)δ7.33(d，2H)，7.26(d，2H)，7.14-7.19(m，2H)，6.81(s，1H)，5.48(s，1H)，4.69(t，2H)，4.08(t，2H)，3.61(m，2H)，3.36(t，2H)，3.27(t，2H)，2.56(m，2H)，1.93(m，4H)。

MS?m/z(ESI)：490.2[M+1]

Embodiment 9

1-(the fluoro-Dihydrobenzofuranes-5-of 6-yl)-6-(4-(2-oxo-piperidine-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 9

1-(6-fluoro-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 2-(the fluoro-phenoxy group of the bromo-5-of 2-) ethanol 9B

2-(2-bromo-5-fluorophenoxy)ethanol

With ethanol (150mL) dissolving 2,4-difluoro bromobenzene (15g, 77.7mmol), add N-Methyl pyrrolidone (15mL), divide and add potassium tert.-butoxide (30.54g 272mmol) for four times, then at 100 DEG C of reaction 6h.Reaction finishes, and adds water (200mL), with ethyl acetate (150mL × 3) extraction, merges organic phase, saturated aqueous common salt for organic phase (100mL × 2) washing, and anhydrous sodium sulfate drying, filters, concentrated; Obtain compound 2-(the fluoro-phenoxy group of the bromo-5-of 2-) ethanol 9B (9.0g, productive rate 49%) with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10: 1～3: 1).

The bromo-2-of second step: 1-(2-bromine oxethyl)-4-fluorobenzene 9C

1-bromo-2-(2-bromoethoxy)-4-fluorobenzene

Under ice bath, by 2-(the fluoro-phenoxy group of the bromo-5-of 2-) ethanol 9B (8g, 34mmol) under stirring, be dissolved in methylene dichloride (100mL), add successively carbon tetrabromide (14.1g, 42.5mmol) and triphenylphosphine (11.1g, 42.5mmol), under room temperature, react 2h.Reaction finishes, and concentrating under reduced pressure obtains the bromo-2-of compound 1-(2-bromine oxethyl)-4-fluorobenzene 9C (8.0g, productive rate 79%) with silica gel column chromatography separating-purifying (sherwood oil).

The 3rd step: 6-is fluoro-2,3-Dihydrobenzofuranes 9D

6-fluoro-2，3-dihydrobenzofuran

Under nitrogen protection, in dry ice acetone bath, by bromo-1-2-(2-bromine oxethyl)-4-fluorobenzene 9C (2.72g, 9.1mmol) under stirring, be dissolved in tetrahydrofuran (THF) (20mL), drip the hexane solution of n-Butyl Lithium (1.6M, 6.26mL) ,-78 DEG C of reaction 2h, reaction finishes to drip water (20mL), with ethyl acetate (30mL × 3) extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated; Obtain compound 6-with silica gel column chromatography separating-purifying (sherwood oil) fluoro-2,3-Dihydrobenzofuranes 9D (0.8g, productive rate 63%).

The 4th step: 5-nitro-6-is fluoro-2,3-Dihydrobenzofuranes 9E

6-fluoro-5-nitro-2，3-dihydrobenzofuran

By fluoro-6-2,3-Dihydrobenzofuranes 9D (1.2g, 8.69mmol) be dissolved in acetic acid (5mL), under room temperature, add concentrated nitric acid (150mg, 2.4mmol), be warming up to 70 DEG C, add concentrated nitric acid (450mg, 7.2mmol), maintain 70 DEG C of stirring reactions 1 hour.In reaction solution, add water (20mL) and ethyl acetate (50mL), separatory, ethyl acetate for water (50mL × 3) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL × 2) washing, anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=20: 1～10: 1) obtains the compound 5-nitro-6-fluoro-2 of light yellow solid shape, 3-Dihydrobenzofuranes 9E (700mg, productive rate 44%).

¹H?NMR(400MHz，CDCl ₃)δ7.79(d，1H)，6.63(d，1H)，4.77(t，2H)，3.27(t，2H)。

The 5th step: 6-is fluoro-2,3-Dihydrobenzofuranes-5-amine 9F

6-fluoro-2，3-dihydrobenzofuran-5-amine

By fluoro-6-5-nitro-2,3-Dihydrobenzofuranes 9E (550mg, 3.0mmol) is dissolved in methyl alcohol (20mL), add palladium charcoal (82.5mg, palladium content w/w=10%) under nitrogen atmosphere, substitution gas three times, is being to react 4h under room temperature.Reaction finishes, cross filter solid, concentration of reaction solution, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=5: 1～1: 1) obtains the compound 6-fluoro-2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-amine 9F (460mg, productive rate 100%).

¹H?NMR(400MHz，CDCl ₃)δ6.66(d，1H)，6.51(d，1H)，4.52(t，2H)，3.30(br，2H)，3.10(t，2H)。

The chloro-2-of the 6th step: 2-(2-(6-fluoro-2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 9G

ethyl?2-chloro-2-(2-(6-fluoro-2，3-dihydrobenzofuran-5-yl)hydrazono)acetate

By concentrated hydrochloric acid (0.72mL, water (2mL) solution 8.7mmol) joins 6-fluoro-2, 3-Dihydrobenzofuranes-5-amine 9F (460mg, 3mmol), stirring reaction 15 minutes at 0 DEG C, at 0 DEG C, drip Sodium Nitrite (248mg, water (3mL) solution 3.6mmol), maintain 0 DEG C of stirring reaction 1h, with sodium acetate (566mg, 6.9mmol) regulate reaction solution pH=5～6, at 0 DEG C, drip 2-chloroacetyl acetacetic ester (494mg, ethyl acetate (3mL) solution 3mmol), 10min adds, at 0 DEG C, react 30min, be warmed up to room temperature reaction 1h.In reaction solution, add ethyl acetate (30mL) and water (10mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (20mL), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=10: 1～5: 1) obtains the chloro-2-of the compound 2-(2-(6-fluoro-2 of yellow solid shape, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 9G (200mg, productive rate 23%).

¹H?NMR(400MHz，CDCl ₃)δ8.34(s，1H)，7.43(d，1H)，6.56(d，1H)，4.60(t，2H)，4.39(q，2H)，3.20(t，2H)，1.40(t，3H)。

The 7th step: 1-(the fluoro-Dihydrobenzofuranes-5-of 6-yl)-6-(4-(2-oxo-piperidine-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 9H

Ethyl?1-(6-fluoro-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By chloro-2-2-(2-(6-fluoro-2, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 9G (150mg, 0.52mmol), 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (222mg, 0.62mmol), be dissolved in ethyl acetate (5mL), add potassiumiodide (8.6mg, 0.052mmol) and triethylamine (158mg, 1.56mmol), rising to 90 DEG C of backflows spends the night, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 0.65mL, 2.6mmol), stirring at room temperature reaction 1h.In reaction solution, add water (10mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate) obtains compound 1-(the fluoro-Dihydrobenzofuranes-5-of 6-yl)-6-(4-(2-oxo-piperidine-1-yl) phenyl)-7-oxo-4 of yellow solid shape, 5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 9H (180mg, productive rate 67%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.24(m，5H)，6.57(d，1H)，4.64(t，2H)，4.46(t，2H)，4.13(t，2H)，3.59(m，2H)，3.32(t，2H)，3.19(t，2H)，2.56(m，2H)，1.94(m，4H)，1.43(t，3H)。

The 8th step: 1-(the fluoro-Dihydrobenzofuranes-5-of 6-yl)-6-(4-(2-oxo-piperidine-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 9

1-(the fluoro-Dihydrobenzofuranes-5-of 6-yl)-7-oxo-6-(4-(2-oxo-piperidine-1-yl) phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 9H (180mg, 0.347mmol) be dissolved in N, in dinethylformamide (5mL), add methane amide (124.9mg, 2.8mmol), sodium methylate (54mg, 1.04mmol), being warming up to 80 DEG C of reactions spends the night.Reaction solution is cooled to room temperature, removal of solvent under reduced pressure, then dissolve and add silica gel (1g) to mix sample with methylene dichloride, obtain compound 1-(the fluoro-Dihydrobenzofuranes-5-of 6-yl)-6-(4-(2-oxo-piperidine-1-yl) phenyl)-7-oxo-4 of light yellow solid shape with silica gel column chromatography separating-purifying (ethyl acetate), 5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 9 (95mg, productive rate 56%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.24(m，5H)，6.80(s，1H)，6.60(d，1H)，5.46(s，2H)，4.65(t，2H)，4.12(t，2H)，3.59(m，2H)，3.59(m，2H)，3.37(t，2H)，3.22(t，2H)，2.56(m，2H)，1.93(m，4H)。

Embodiment 10

1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-((dimethyl amido) methyl)-1H-imidazoles-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 10

1-(2，3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-7-oxo-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-((dimethyl amido) methyl)-1H-imidazoles-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 10B

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-7-oxo-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 2B (1.2g, 2.27mmol), 1-(1H-imidazoles-2-yl)-N, N-dimethyl methyl amine (284mg, 2.27mmol) and salt of wormwood (627mg, 4.54mmol) be dissolved in 1.4-dioxane (30mL), under nitrogen atmosphere, add cuprous iodide (86.4mg, 0.45mmol) to rise to 120 DEG C of reaction 2h.Reaction solution is cooled to room temperature, add ethyl acetate (50mL) and water (50mL), separatory, saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～4: 96) obtains the compound 1-(2 of light yellow solid shape, 3-Dihydrobenzofuranes-5-yl)-6-(4-(2-((dimethyl amido) methyl)-1H-imidazoles-1-yl) phenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester 10B (400mg, productive rate 34%).

¹H?NMR(400MHz，CDCl ₃)δ7.55-7.53(m，2H)，7.46-7.44(m，2H)，7.37(s，1H)，7.28-7.26(m，1H)，7.12-7.07(m，2H)，6.80-6.77(d，1H)，4.61(t，2H)，4.47(q，2H)，4.19(t，2H)，3.54(m，2H)，3.39-3.36(m，2H)，3.26-3.21(m，2H)，2.37(m，6H)，1.44(t，3H)。

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-((dimethyl amido) methyl)-1H-imidazoles-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 10

1-(2，3-dihydrobenzofuran-5-yl)-6-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)phenyl)-7-oxo-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]5-3-carboxamide

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-(2-((dimethyl amido) methyl)-1H-imidazoles-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (400mg, 0.76mmol) be dissolved in N, in dinethylformamide (10mL), add methane amide (340mg, 7.6mmol), sodium methylate (80mg, 1.52mmol), be warming up to 80 DEG C of reactions and spend the night.Reaction solution is cooled to room temperature, removal of solvent under reduced pressure, then dissolve and add silica gel (1g) to mix sample with methylene dichloride, obtain the compound 1-(2 of light yellow solid shape with silica gel column chromatography separating-purifying (ethanol/methylene (v/v)=0: 1～6: 94), 3-Dihydrobenzofuranes-5-yl)-6-(4-(2-((dimethyl amido) methyl)-1H-imidazoles-1-yl) phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 10 (180mg, productive rate 48%).

¹H?NMR(400MHz，CDCl ₃)δ7.55-7.53(m，2H)，7.46-7.44(m，2H)，7.36(s，1H)，7.28-7.26(m，1H)，7.11-7.07(m，2H)，6.85(s，1H)，6.83-6.81(m，1H)，5.45(s，1H)，4.63(t，2H)，4.18(t，2H)，3.51(s，2H)，3.43(t，2H)，3.26(t，2H)，2.35(m，6H)。

Embodiment 11

1-(3-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 11

1-(3-methyl-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 3-methyl-2,3-Dihydrobenzofuranes 11B

3-methyl-2，3-dihydrobenzofuran

3-methyl cumarone 11A (500mg, 3.78mmol) is dissolved in ethyl acetate (20mL), adds palladium charcoal (50mg, palladium content w/w=10%) under nitrogen atmosphere, substitution gas three times, is being to react 48h under room temperature.Reaction finishes, and crosses filter solid, and concentration of reaction solution, obtains colourless liquid compound 3-methyl-2,3-Dihydrobenzofuranes 11B (450mg, productive rate 89%).

¹H?NMR(400MHz，CDCl ₃)δ7.16-7.10(m，2H)，6.89-6.85(m，1H)，6.80-6.78(m，1H)，4.70-4.66(m，1H)，4.13-4.05(m，1H)，3.50-3.59(m，1H)，1.33(d，3H)。

Second step: 3-methyl-5-nitro-2,3-Dihydrobenzofuranes 11C

3-methyl-5-nitro-2，3-dihydrobenzofuran

By 3-methyl-2,3-Dihydrobenzofuranes 11B (450mg, 3.35mmol) be dissolved in acetic acid (5mL), under room temperature, add concentrated nitric acid (56.5mg, 0.9mmol), be warming up to 70 DEG C, add concentrated nitric acid (169.5mg, 2.69mmol), maintain 70 DEG C of stirring reaction 1h.In reaction solution, add water (100mL) and ethyl acetate (50mL), separatory, saturated aqueous common salt for organic phase (50mL × 2) washing, anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=1: 0～98: 2) obtains compound 3-methyl-5-nitro-2 of light yellow oily, 3-Dihydrobenzofuranes 11C (300mg, productive rate 50%).

¹H?NMR(400MHz，CDCl ₃)δ8.13-8.10(m，1H)，8.06(s，1H)，6.83-6.81(m，1H)，4.88-4.84(m，1H)，4.31-4.24(m，1H)，3.67-3.58(m，1H)，1.40(d，3H)。

The 3rd step: 3-methyl-2,3-Dihydrobenzofuranes-5-amine 11D

3-methyl-2，3-dihydrobenzofuran-5-amine

By 3-methyl-5-nitro-2,3-Dihydrobenzofuranes 11C (2.5g, 14mmol) is dissolved in ethanol (50mL), adds nine hydrated sodium sulfide (8.4g, water (50mL) solution 35mmol), is warming up to 90 DEG C of reactions 3 hours.Concentration of reaction solution, add water (50mL) and ethyl acetate (80mL), separatory, ethyl acetate for water (40mL × 2) extraction, merges organic phase, saturated aqueous common salt for organic phase (40mL × 2) washing, anhydrous sodium sulfate drying, filters, compound 3-methyl-2 of concentrated yellow solid shape, 3-Dihydrobenzofuranes-5-amine 11D (1.1g, productive rate 52%).

¹H?NMR(400MHz，CDCl ₃)δ6.83-6.60(m，2H)，6.55-6.52(m，1H)，4.65-4.61(m，1H)，4.03-3.99(m，1H)，3.50-3.44(m，1H)，1.29(d，3H)。

The chloro-2-of the 4th step: 2-(2-(3-methyl-2,3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 11E

ethyl?2-chloro-2-(2-(3-methyl-2，3-dihydrobenzofuran-5-yl)hydrazono)acetate

By concentrated hydrochloric acid (0.96mL, water (2mL) solution 11.66mmol) joins 3-methyl-2, 3-Dihydrobenzofuranes-5-amine 11D (0.6g, 4.02mmol) in, stirring reaction 15 minutes at 0 DEG C, at 0 DEG C, drip Sodium Nitrite (333mg, water (2mL) solution 4.82mmol), maintain 0 DEG C of stirring reaction 1.5h, with sodium acetate (758mg, 9.25mmol) regulate reaction solution pH=5～6, at 0 DEG C, drip 2-chloroacetyl acetacetic ester (661mg, ethyl acetate (4mL) solution 4.02mmol), 10min adds, room temperature reaction 1h.In reaction solution, add ethyl acetate (30mL) and water (20mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=1: 0～9: 1) obtains the chloro-2-of compound 2-(2-(3-methyl-2 of yellow oily, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 11E (660mg, productive rate 58%).

¹H?NMR(400MHz，CDCl ₃)δ8.28(s，1H)，7.11(s，1H)，6.94-6.91(m，1H)，6.77-6.72(m，1H)，4.73-4.67(m，1H)，4.38(q，2H)，4.11-4.07(m，1H)，3.59-3.50(m，1H)，1.40(t，3H)，1.35(d，3H)。

The 5th step: 1-(3-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 11F

Ethyl?1-(3-methyl-2，3-dihydrobenzofuran-5-yl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4，5，6，7-tetrahydro-1H-pyrazolo[3，4-c]pyridine-3-carboxylate

By 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (600mg, 1.69mmol), the chloro-2-of 2-(2-(3-methyl-2, 3-Dihydrobenzofuranes-5-yl) hydrazone group) ethyl acetate 11E (573mg, 2.03mmol) be dissolved in ethyl acetate (20mL), add potassiumiodide (28mg, 0.169mmol) and triethylamine (513mg, 5.07mmol), rising to 90 DEG C of back flow reaction spends the night, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 2.1mL, 8.45mmol), stirring at room temperature reaction 1h.In reaction solution, add water (30mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (30mL × 2), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 99～1: 0) obtains compound 1-(3-methyl-2 of yellow solid shape, 3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester 11F (380mg, productive rate 44%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.33(m，2H)，7.28-7.24(m，5H)，6.76(d，1H)，4.73-4.69(m，1H)，4.76(q，2H)，4.14-4.07(m，3H)，3.60-3.54(m，2H)，3.33-3.30(m，2H)，2.56(m，2H)，1.94-1.93(m，4H)，1.43(t，3H)，1.32(d，3H)。

The 6th step: 1-(3-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide compound 11

By 1-(3-methyl-2,3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester 11F (380mg, 0.74mmol) is dissolved in DMF (10mL), add methane amide (332mg, 7.4mmol), sodium methylate (80mg, 1.48mmol), rise to 80 DEG C of reactions and spend the night.In reaction solution, add water (50mL), ethyl acetate for water (50mL × 2) extraction, saturated aqueous common salt for organic phase (50mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～2: 98) obtains compound 1-(3-methyl-2 of light yellow solid shape, 3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide compound 11 (150mg, productive rate 42%).

¹H?NMR(400MHz，CDCl ₃)δ7.36-7.25(m，6H)，6.85(s，1H)，6.79(d，1H)，5.46(s，1H)，4.75-4.71(m，1H)，4.15-4.08(m，3H)，3.61(m，3H)，3.39-3.36(m，2H)，2.57(m，2H)，1.94(m?4H)，1.34(d，3H)。

Embodiment 12

1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-methyl-3-oxo-morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 12)

1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 2-methylmorpholine-3-ketone (12B)

2-methylmorpholin-3-one

By 2-monoethanolamine (10.0g, 73.5mmol) be dissolved in 1, in 4-dioxane (100mL), add sodium (1.7g, 73.5mmol), be warming up to 110 DEG C of reactions 7 hours, slowly add 2-chloropropionate (10.0g, 73.5mmol), continue back flow reaction 3 hours.Reacting liquid filtering is removed to precipitation, concentrated, in residue, add water (100mL), extract by ethyl acetate (100mL × 2), extract with methylene dichloride (100mL × 2), merge organic phase, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methylene chloride/methanol (v/v)=70: 1) obtains title compound 2-methylmorpholine-3-ketone (12B), white solid (4.3g, productive rate 51%).

¹H?NMR(400MHz，CDCl ₃)δ7.05(s，1H)，4.23-4.17(m，1H)，3.99-3.96(m，1H)，3.78-3.70(m，1H)，3.59-3.52(m，1H)，3.32-3.27(m，1H)，1.46(dd，3H)。

MS?m/z(ESI)：116.2[M+1]

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-methyl-3-oxo-morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (12C)

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (2C) (2.0g, productive rate 3.6mmol) be dissolved in 1,2-dioxane (30mL), add 2-methylmorpholine-3-ketone (12B) (815mg, 7.2mmol), potassiumphosphate (1.5g, 7.2mmol), copper(I) iodide (100mg) and trans-(1R, 2R)-N, N '-dimethyl-1,2-ring pentamethylene diamine (100mg), is warming up to 80 DEG C of reactions 10 hours.Reaction solution is cooled to room temperature, add water (30mL), extract by ethyl acetate (50mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate) obtains title compound 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-methyl-3-oxo-morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (12C), white solid (1.2g, productive rate 65%).

¹H?NMR(400MHz，CDCl ₃)δ7.31-7.22(m，5H)，7.19(dd，1H)，6.69(d，1H)，4.52(t，2H)，4.38(q，2H)，4.30(q，1H)，4.05(m，2H)，3.88(m，2H)，3.46(m，2H)，3.25(t，2H)，3.15(t，2H)，1.47(d，3H)，1.36(t，3H)。

MS?m/z(ESI)：517.3[M+1]

The 3rd step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-methyl-3-oxo-morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 12)

1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-methyl-3-oxo-morpholin-4-yl)phenyl]-7-oxo-4，5-dihydro?pyrazolo[3，4-c]pyridine-3-carboxamide

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-(2-methyl-3-oxo-morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (12C) (100mg, 0.19mmol) is dissolved in DMF (20mL), add methane amide (1.0mg, 23mmol), sodium methylate (502mg, 9.3mmol), be warming up to 80 DEG C reaction 3 hours.Reaction solution is cooled to room temperature, add water (10mL), concentrated, in residue, add water (20mL), extract with methylene dichloride (30mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methylene chloride/methanol (v/v)=100: 1) obtains title compound 1-(2, 3-Dihydrobenzofuranes-5-yl)-6-[4-(2-methyl-3-oxo-morpholine-4-yl) phenyl]-7-oxo-4, 5-dihydro-pyrazolo [3, 4-c] pyridine-3-carboxamide (compound 12), white solid (400mg, productive rate 36%).

¹H?NMR(400MHz，CDCl ₃)δ7.42-7.30(m，5H)，7.30-7.22(m，1H)，6.84(s，1H)，6.79(d，1H)，5.56(s，1H)，4.61(t，2H)，4.37(q，1H)，4.15-4.04(m，3H)，4.00-3.86(m，2H)，3.59-3.50(m，1H)，3.38(t，2H)，3.24(t，2H)，1.54(d，3H)。MS?m/z(ESI)：488.3[M+1]

Embodiment 13

1-(2,2-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 13) also

1-(2，2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

Bromo-1 (2-hydroxy phenyl) ethyl ketone (1B) of the first step: 2-

2-bromo-1-(2-hydroxyphenyl)ethanone

2-acetyl phenol (10.0g, 13.4mmol) and cupric bromide (27.9g, 124.9mmol) are dissolved in chloroform (60mL), add ethyl acetate (40mL), be warming up to 90 DEG C of reactions 8 hours.Reaction solution is cooled to room temperature, use diatomite suction filtration, in filtrate, add methylene dichloride (100mL) and water (100mL), separatory, methylene dichloride for water (50mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (100mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil) obtains bromo-1 (2-hydroxy phenyl) ethyl ketone (1B) of title compound 2-, brown solid, do not calculate productive rate, be directly used in next step.

¹H?NMR(400MHz，CDCl ₃)δ11.73(s，1H)，7.75(dd，1H)，7.53(dd，1H)，7.02(d，1H)，6.94(t，1H)，4.45(s，2H)。

Second step: cumarone-3 ketone (13C)

benzofuran-3-one

Bromo-2-1 (2-hydroxy phenyl) ethyl ketone (1B) (1.0g, 4.7mmol) is joined in methyl alcohol (40mL), add sodium acetate (1.2g, 14.1mmol), stirring at room temperature reaction 3 hours.In reaction solution, add ethyl acetate (30mL) and saturated aqueous common salt (50mL), separatory, ethyl acetate for water (30mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL × 3) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=1: 0～98: 2) obtains title compound cumarone-3 ketone (13C), light yellow solid (240mg, productive rate 38%).

¹H?NMR(400MHz，CDCl ₃)δ7.68(d，1H)，7.65-7.58(m，1H)，7.15(d，1H)，7.10(t，1H)，4.63(s，2H)。

The 3rd step: 2,2-dimethyl benzofuran-3-ketone (13D)

2，2-dimethylbenzofuran-3-one

By cumarone-3 ketone (13C) (134mg, 1.0mmol) be dissolved in tetrahydrofuran (THF) (15mL) solution, anhydrous and oxygen-free processing, is cooled to-30 DEG C, add sodium hydride (100mg, 60%, 2.5mmol), stirring reaction 20 minutes, drip potassiumiodide (710mg, 5.0mmol), maintain 0 DEG C of reaction 1 hour, room temperature reaction 2 hours.In reaction solution, add saturated sodium bicarbonate (20mL) solution, add water (10mL) and ethyl acetate (50mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (30mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=1: 0～98: 2) obtains title compound 2,2-dimethyl benzofuran-3-ketone (13D), yellow oil (70mg, productive rate 43%).

¹H?NMR(400MHz，CDCl ₃)δ7.67(d，1H)，7.65-7.59(m，1H)，7.08(dd，2H)，1.47(s，6H)。

The 4th step: 2,2-methyl-3H-cumarone-3-alcohol (13E)

2，2-dimethyl-3H-benzofuran-3-ol

2,2-dimethyl benzofuran-3-ketone (13D) (1.0g, 6.2mmol) is dissolved in methyl alcohol (40mL), is cooled to 0 DEG C, add sodium borohydride (1.2g, 30.8mmol), stirring at room temperature reaction 2 hours.In reaction solution, add water (30mL) and ethyl acetate (30mL), separatory, ethyl acetate for water (30mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (30mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=1: 0～9: 1) obtains title compound 2,2-methyl-3H-cumarone-3-alcohol (1E), white solid (400mg, productive rate 40%).

¹H?NMR(400MHz，CDCl ₃)δ7.40(d，1H)，7.26-7.22(m，1H)，6.91(t，1H)，6.79(d，1H)，4.75(s，1H)，1.69(s，1H)，1.49(s，3H)，1.35(s，3H)。

The 5th step: 2,2-dimethyl-3H-cumarone (13F)

2，2-dimethyl-3H-benzofuran

By 2,2-methyl-3H-cumarone-3-alcohol (1E) (82mg, 0.5mmol) and triethyl silicane (70mg; 0.6mmol) be dissolved in anhydrous methylene chloride (15mL); under nitrogen protection, cooling reaction solution, to-78 DEG C, drips BF ₃.Et ₂o (85mg, 0.6mmol), stirring at room temperature reaction 3 hours.In reaction solution, add saturated sodium bicarbonate (10mL) solution, stir 10 minutes, add methylene dichloride (10mL), separatory, methylene dichloride for water (10mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (10mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate: sherwood oil (v/v)=2: 8) obtains title compound 2,2-dimethyl-3H-cumarone (1F), anhydrous liq (10mg, productive rate 14%).

¹H?NMR(400MHz，CDCl ₃)δ7.11(dd，2H)，6.82(dd，1H)，6.73(d，1H)，3.01(s，2H)，1.48(s，6H)。

The 6th step: 2,2-dimethyl-5-nitro-3H-cumarone (13G)

2，2-dimethyl-5-nitro-3H-benzofuran

By 2,2-dimethyl-3H-cumarone (1F) (2.0g, 13.4mmol) be dissolved in acetic acid (40mL), under room temperature, add concentrated nitric acid (0.4mL, 4mmol), be warming up to 70 DEG C, add concentrated nitric acid (1.4mL, 12mmol), be warming up to 70 DEG C of reactions 1 hour.Reaction liquid cooling is gone to room temperature, add saturated aqueous common salt (50mL) and ethyl acetate (50mL), separatory, ethyl acetate for water (50mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated, residue is prepared plate preparation (ethyl acetate: sherwood oil (v/v)=1: 9) and is obtained title compound 2,2-dimethyl-5-nitro-3H-cumarone (13G), light yellow solid with former, directly drop into next step reaction, do not calculate productive rate.

¹H?NMR(400MHz，CDCl ₃)δ8.10(dd，1H)，8.07-8.04(m，1H)，6.75(d，1H)，3.08(s，2H)，1.53(s，6H)。

The 7th step: 2,2-dimethyl-5-amino-3H-cumarone (13H)

2，2-dimethyl-3H-benzofuran-5-amine

By 2,2-dimethyl-5-nitro-3H-cumarone (13G) (2.6g, 13.4mmol) be dissolved in dehydrated alcohol (40mL), add nine water cure sodium (9.7g, water (20mL) solution 40.2mmol), is warming up to 90 DEG C of reactions 2 hours.Reaction solution is concentrated, in residue, add saturated aqueous common salt (20mL) and ethyl acetate (50mL), separatory, ethyl acetate for water (30mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (20mL × 3) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate: sherwood oil (v/v)=1: 9～3: 7) obtains title compound 2,2-dimethyl-5-amino-3H-cumarone (13H), brown color solid (730mg, productive rate 34%).

¹H?NMR(400MHz，CDCl ₃)δ6.53(m，3H)，2.93(s，2H)，1.44(s，6H)。MS?m/z(ESI)：164.1[M+1]

The chloro-2[(2 of the 8th step: 2-, 2-dimethyl-3H-cumarone-5-yl) hydrazone group] ethyl acetate (13I)

ethyl?2-chloro-2-[(2，2-dimethyl-3H-benzofuran-5-yl)hydrazono]acetate

In first reaction flask by 2,2-dimethyl-5-amino-3H-cumarone (13H) (630mg, 4.0mmol) add in the mixing solutions of concentrated hydrochloric acid (1mL) and water (2mL), cooling reaction solution is to-5 DEG C-0 DEG C, drip Sodium Nitrite (331mg, water (4mL) solution 4.80mmol), maintains 0 DEG C of stirring reaction 1 hour.In another reaction flask, by sodium acetate (755mg, 9.20mmol) in water-soluble (5mL), add again 2-chloroacetyl acetacetic ester (658mg, ethyl acetate (10mL) solution 4.00mmol), is cooled to 0 DEG C, drips the reaction solution in first reaction flask, stirring reaction 1 hour at 0 DEG C, stirring at room temperature reaction 1 hour.By reaction solution separatory, ethyl acetate for water (15mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (20mL × 2), organic phase anhydrous sodium sulfate drying, concentrated, residue obtains the chloro-2[(2 of title compound 2-with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1: 0～9: 1), 2-dimethyl-3H-cumarone-5-yl) hydrazone group] ethyl acetate (13I), dark oil thing (500mg, productive rate 42%).

The 9th step: 1-(2,2-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (13J) also

ethyl?1-(2，2-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By chloro-2-2[(2, 2-dimethyl-3H-cumarone-5-yl) hydrazone group] ethyl acetate (13I) (500, 1.70mmol), 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (400mg, 1.10mmol), be dissolved in ethyl acetate (50mL), add potassiumiodide (18mg, 0.11mmol) and triethylamine (334mg, 3.30mmol), rise to 90 DEG C of reactions 24 hours, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 1.4mL, 5.50mmol), stirring at room temperature reaction 1h.In reaction solution, add water (20mL), separatory, ethyl acetate for water (15mL × 2) extraction, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated, residue obtains title compound 1-(2 with silica gel column chromatography separating-purifying (ethyl acetate: sherwood oil (v/v)=2: 8～1: 0), 2-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (13J) also, gray solid (100mg, productive rate 17%).

¹H?NMR(400MHz，CDCl ₃)δ7.33(m，3H)，7.26(m，3H)，6.70(d，1H)，4.45(q，2H)，4.11(t，2H)，3.59(t，2H)，3.31(t，2H)，3.01(s，2H)，2.55(t，2H)，1.98-1.88(m，4H)，1.46(s，6H)，1.42(t，3H)。MS?m/z(ESI)：529.4[M+1]

The tenth step: 1-(2,2-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 13) also

1-(2,2-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (13J) (100mg, 0.19mmol) is dissolved in DMF (10mL), add methane amide (51mg, 1.14mmol), sodium methylate (31mg, 0.57mmol), be warming up to 80 DEG C reaction 16 hours.Reaction solution is cooled to room temperature, removal of solvent under reduced pressure, in residue, add methylene dichloride (20mL) and water (20mL), separatory, methylene dichloride for water (10mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (20mL × 3) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methyl alcohol/petrol ether/ethyl acetate (v/v)=0: 5: 5～5: 0: 95) obtains title compound 1-(2, 2-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (compound 13) (60mg, productive rate 63%).

¹H?NMR(400MHz，CDCl ₃)δ7.38-7.28(m，3H)，7.26(m，3H)，6.82(s，1H)，6.73(d，1H)，5.45(s，1H)，4.11(t，2H)，3.60(m，2H)，3.37(t，2H)，3.04(s，2H)，2.56(t，2H)，1.97-1.88(m，4H)，1.47(s，6H)。

MS?m/z(ESI)：500.5[M+1]

Embodiment 14 and embodiment 15

By 1-(2-methyl-2, 3-dihydropyridine furans-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] pyridine-3-carboxamide (compound 1) carries out chiral separation, adopt HPLC method, with chiral column, chiral isomer is separated and obtains two isomeric compound 1-1 (compound 1 isomer 1 with Preparation equipment, embodiment 14) (ee > 99%, and compound 1-2 (compound 1 isomer 2 RT:12.563min), embodiment 15) (ee > 99%, RT:14.795min) (chiral separation condition: chromatographic column: ChiralCN OD (4.6mm × 250mm, 5 μ m), testing tool: SSI Series III, detect wavelength: 210nm, sample size: 20 μ l, moving phase: ethanol, column oven/DEG C: normal temperature, flow velocity: 0.7mL.min ^-1).

Compound 1-1

¹H?NMR(400MHz，CDCl ₃)δ7.39-7.29(m，3H)，7.26(d，3H)，6.84(s，1H)，6.76(d，1H)，5.50(s，1H)，5.03-4.91(m，1H)，4.11(t，2H)，3.60(s，2H)，3.45-3.25(m，3H)，2.85(dd，1H)，2.56(s，2H)，1.94(s，4H)，1.47(d，3H)。

LCMS?m/z＝486.2[M+H]

Compound 1-2

¹H?NMR(400MHz，CDCl ₃)δ7.33(t，3H)，7.25(d，3H)，6.85(s，1H)，6.76(d，1H)，5.56(s，1H)，5.05-4.89(m，1H)，4.11(t，2H)，3.59(d，2H)，3.43-3.29(m，3H)，2.85(dd，1H)，2.56(d，2H)，1.99-1.82(m，4H)，1.47(d，3H)。

LCMS?m/z＝486.2[M+H]

Embodiment 16

1-(3,3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 16) also

1-(3，3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The bromo-2-of the first step: 1-(2-methyl allyloxy) benzene (16B)

1-bromo-2-(2-methylallyloxy)benzene

By 2-bromopropylene (20.2g, 0.15mol) and 2-bromophenol (17.3g, 0.1mol), be dissolved in acetone (200mL), add salt of wormwood (34g, 0.25mol), back flow reaction is spent the night.By reacting liquid filtering, filter cake washs by ethyl acetate, merging filtrate, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (sherwood oil) obtains the bromo-2-of title compound 1-(2-methyl allyloxy) benzene (16B), colorless oil (20g, productive rate 88%).

¹H?NMR(400MHz，CDCl ₃)δ7.54(dd，1H)，7.23-7.21(m，1H)，6.89-6.81(m，2H)，5.16(s，1H)，?5.01(s，1H)，4.49(s，2H)，1.86(s，3H)。

Second step: 3,3-dimethyl-3H-cumarone (16C)

3，3-dimethyl-3H-benzofuran

By bromo-1-2-(2-methyl allyloxy) benzene (16B) (25g, 0.11mol) be dissolved in toluene (300mL), add tri-tert stannane (48g, 0.165mol) and Diisopropyl azodicarboxylate (2.5g), under nitrogen atmosphere, be warming up to 110 DEG C of reactions and spend the night.Reaction solution is cooled to normal temperature, add 10% to fluoridize first solution (300mL), vigorous stirring 3 hours, separatory, saturated aqueous common salt for organic phase (200mL) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil) obtains title compound 3,3-dimethyl-3H-cumarone (16C), light yellow oil (1.4g, productive rate 9%).

¹H?NMR(400MHz，CDCl ₃)δ7.10-7.06(m，2H)，6.90-6.86(m，1H)，6.79(d，1H)，4.18(m，2H)，1.34(s，6H)。

The 3rd step: 3,3-dimethyl-5-nitro-3H-cumarone (16D)

3，3-dimethyl-5-nitro-3H-benzofuran

By 3,3-dimethyl-3H-cumarone (16C) (1.4g, 9.44mmol) be dissolved in acetic acid (20mL), add nitric acid (68%, 0.24g, 2.6mmol), be warming up to 70 DEG C, drip nitric acid (68%, 0.72g, 0.78mmol), stirring reaction 2 hours.Reaction solution is cooled to normal temperature, add water (100mL) and ethyl acetate (50mL), separatory, saturated aqueous common salt for organic layer (50mL) washing, anhydrous sodium sulfate drying, concentrated, column chromatography separating-purifying for residue (ethyl acetate: sherwood oil (v/v)=0: 1～1: 9) obtains title compound 3,3-dimethyl-5-nitro-3H-cumarone (16D), light yellow solid (0.7g, productive rate 39%).

¹H?NMR(400MHz，CDCl ₃)δ8.11(dd，1H)，8.00(d，1H)，6.83(d，1H)，4.40(s，2H)，1.40(s，6H)。

The 4th step: 3,3-dimethyl-5-amino-3H-cumarone (16E)

3，3-dimethyl-3H-benzofuran-5-amine

3,3-dimethyl-5-nitro-3H-cumarone (16D) (0.7g, 3.6mmol) is dissolved in methyl alcohol (20mL), adds palladium carbon (20mg), under atmosphere of hydrogen, react and spend the night.By reaction solution iodine diatomite filtration, filtrate is concentrated obtains title compound 3,3-dimethyl-5-amino-3H-cumarone (16E), light brown solid (0.56g, productive rate 95%).

¹H?NMR(400MHz，CDCl ₃)δ6.62-6.59(m，1H)，6.51-6.48(m，2H)，4.16(s，2H)，3.60(br，2H)，1.30(s，6H)。

The chloro-2-[(3 of the 5th step: 2-, 3-dimethyl-3H-cumarone-5-yl) hydrazone group] ethyl acetate (16F)

By 3, 3-dimethyl-5-amino-3H-cumarone (16E) (0.56g, 3.43mmol) join in water (1.4mL) solution of concentrated hydrochloric acid (0.82mL), be cooled to 0～-5 DEG C, drip Sodium Nitrite (284mg, 4.12mmol) water (0.7mL) solution, after dropwising, 0 DEG C of reaction 60 minutes, this diazonium salt solution is added drop-wise to the 2-chloroacetyl acetacetic ester (565mg that is cooled to 0 DEG C, ethyl acetate (2.7mL) solution and sodium acetate (647mg 3.43mmol), in the aqueous solution (1.4mL) mixing solutions 7.89mmol), after dropwising, maintain 0 DEG C of reaction 30 minutes, rise to room temperature reaction 3 hours.In reaction solution, add ethyl acetate (20mL) and saturated aqueous common salt (30mL), separatory, organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, residue with silica gel column chromatography purify (ethyl acetate/petroleum ether (v/v)=0: 1～1: 9) obtain the chloro-2-[(3 of title compound 2-, 3-dimethyl-3H-cumarone-5-yl) hydrazone group] ethyl acetate (16F), light yellow oil (300mg, productive rate 30%).

The 6th step: 1-(3,3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (16G) also

ethyl?1-(3，3-dimethyl-3H-benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By chloro-2-2-[(3, 3-dimethyl-3H-cumarone-5-yl) hydrazone group] ethyl acetate (16F) (300, 1.0mmol), 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (500mg, 1.41mmol), potassiumiodide (23.4mg, 0.14mmol) and triethylamine (428mg, 4.23mmol), be dissolved in ethyl acetate (50mL), rising to 80 DEG C of reactions spends the night, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 1.8mL, 7.05mmol), stirring at room temperature reaction 1h.In reaction solution, add saturated aqueous common salt (30mL), separatory, organic phase anhydrous sodium sulfate drying, filter, concentrated, residue obtains title compound 1-(3 with silica gel column chromatography separating-purifying (ethyl acetate: sherwood oil (v/v)=1: 1～1: 0), 3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (16G), light yellow solid (210mg, productive rate 28%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.33(m，2H)，7.29-7.22(m，4H)，6.75(d，1H)，4.49-4.41(m，?2H)，4.26(s，2H)，4.12(t，2H)，3.60-3.56(m，2H)，3.31(t，2H)，2.57-2.55(m，2H)，1.95-1.93(m，4H)，1.46-1.42(m，3H)，1.35(s，6H)。

The 7th step: 1-(3,3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 16) also

1-(3,3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (16G) (210mg, 0.4mmol) is dissolved in DMF (5mL), add methane amide (180mg, 4mmol), sodium methylate (43.2mg, 0.8mmol), be warming up to 80 DEG C of reactions and spend the night.Reaction solution is cooled to room temperature, add water (50mL), separatory, ethyl acetate for water (50mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～1: 19) obtains title compound 1-(3, 3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (compound 16), white solid (70mg, productive rate 36%).

¹H?NMR(400MHz，CDCl ₃)δ7.35(m，2H)，7.27-725(m，4H)，6.86(s，1H)，6.79(d，1H)，5.46(s，1H)，4.29(s，2H)，4.11(t，2H)，3.61(m，2H)，3.37(t，2H)，2.57(m，2H)，1.94(m，4H)，1.37(s，6H)。

Embodiment 17

1-(cumarone-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 17) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(cumarone-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (17B) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-(5-trifluoromethyl-2-oxo-pyridin-2-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (2C) (2.0g, 3.78mmol) is dissolved in 1,2-dioxane (50mL), add 5-5-flumethiazine-2-ketone (1.2g, 7.56mmol), potassiumphosphate (1.6g, 7.56mmol), copper(I) iodide (100mg) and trans-(1R, 2R)-N, N '-dimethyl-1,2-ring pentamethylene diamine (100mg), under nitrogen atmosphere, is warming up to 80 DEG C of reactions 10 hours.Reaction solution is cooled to room temperature, add water (50mL), extract by ethyl acetate (50mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate) obtains title compound 1-(cumarone-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (17B), white solid (1.0g, productive rate 48%).

Second step: 1-(cumarone-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 17) also

1-(cumarone-5-yl)-6-[4-(5-trifluoromethyl-2-oxo-pyridine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (17B) (950mg, 1.68mmol) be dissolved in N, in dinethylformamide (10mL), add methane amide (757mg, 16.8mmol), sodium methylate (364mg, 6.72mmol), be warming up to 80 DEG C of reactions 3 hours.Reaction solution is cooled to room temperature, add water (50mL), separatory, ethyl acetate for water (50mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～1: 19) obtains title compound 1-(3, 3-dimethyl-3H-cumarone-5-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (compound 16), white solid (200mg, productive rate 22%).

¹H?NMR(400MHz，CDCl ₃)δ7.63(s，1H)，7.44-7.42(m，3H)，7.34-7.29(m，3H)，7.28(m，1H)，6.85(s，1H)，6.80(d，1H)，6.72(d，1H)，5.50(s，1H)，4.62(t，2H)，4.17(t，2H)，3.42(t，2H)，3.26(t，2H)。

Embodiment 18

1-(the fluoro-cumarone-5-of 4-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 18) also

1-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The bromo-1-of the first step: 2-(2-bromine oxethyl)-3-fluorobenzene (18B)

2-bromo-1-(2-bromoethoxy)-3-fluorobenzene

Fluoro-3-2-bromophenol (10.0g, 0.05mol) is added in acetonitrile (100mL) solution, add salt of wormwood (15.2g, 0.11mol) He 1,2-ethylene dibromide (19.7g, 0.11mol), rises to 50 DEG C of reactions 32 hours.By reaction solution suction filtration, ethyl acetate for filter cake (20mL × 3) washing, merging filtrate, add water (50mL), separatory, ethyl acetate for water (50mL) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil) obtains the bromo-1-of title compound 2-(2-bromine oxethyl)-3-fluorobenzene (18B), anhydrous liq (9.0g, productive rate 60%).

¹H?NMR(400MHz，CDCl ₃)δ7.25(m，1H)，6.82(m，1H)，6.78(m，1H)，4.35(t，2H)，3.68(t，2H)。

Second step: 4-fluorine cumarone (18C)

4-fluorobenzofuran

By bromo-2-1-(2-bromine oxethyl)-3-fluorobenzene (18B) (4g, 13.4mmol) be dissolved in tetrahydrofuran solution (20mL), be cooled to-78 DEG C, under nitrogen atmosphere, drip butyllithium (9.2mL, 14.7mmol), maintain-78 DEG C of reactions 2 hours.At-78 DEG C, in reaction solution, add water (10mL) cancellation reaction, separatory, ethyl acetate for water (10mL × 3) extraction, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil) obtains title compound 4-fluorine cumarone (18C), anhydrous liq (1.4g, productive rate 76%).

The 3rd step: 4-fluoro-5-bromine cumarone (18D)

4-fluoro-5-bromobenzofuran

4-fluorine cumarone (18C) (3.4g, 24.6mmol) is dissolved in acetonitrile (30mL) solution, is cooled to 0 DEG C, add N-bromo-succinimide (4.8g, 27.1mmol), keep 0 DEG C of reaction 30 minutes, then rise to room temperature reaction 2 hours.Reaction solution is concentrated, and silica gel column chromatography separating-purifying for residue (sherwood oil) obtains the fluoro-5-bromine of title compound 4-cumarone (18D), light yellow solid (5.2g, productive rate 97%).

¹H?NMR(400MHz，CDCl ₃)δ7.26-7.24(m，1H)，6.49(d，1H)，4.64(t，2H)，3.28(t，2H)。

The 4th step: the 4-amino cumarone of fluoro-5-(18E)

4-fluoro-5-aminobenzofuran

Fluoro-4-5-bromine cumarone (18D) (5.2g, 24mmol) is dissolved in ammoniacal liquor (4.08g, 240mmol), adds copper (1.82g, 28.9mmol), in tube sealing, rise to 100 DEG C of reactions and spend the night.By reacting liquid filtering, obtain the solid 4-amino cumarone of fluoro-5-(18E), filtrate is concentrated, anhydrous sodium sulfate drying, residue obtains the title compound 4-amino cumarone of fluoro-5-(18E) with silica gel column chromatography separating-purifying (sherwood oil: ethyl acetate (v/v)=10: 1～5: 1), light yellow solid (amounting to 1.6g, productive rate 44%).

¹H?NMR(400MHz，CDCl ₃)δ6.62(t，1H)，6.42(d，1H)，4.56(t，2H)，3.86(br，2H)，3.22(t，2H)。

The chloro-2-of the 5th step: 2-(2-(4-fluorine cumarone-5-yl) hydrazone group) ethyl acetate (18F)

ethyl?2-chloro-2-(2-(4-fluorobenzofuran-5-yl)hydrazono)acetate

In first reaction flask, add amino cumarone (the 18E) (500mg of the fluoro-5-of 4-, 3.26mmol), water (10mL) and concentrated hydrochloric acid (0.79mL, 9.45mmol), cooling reaction solution is to-5 DEG C-0 DEG C, drip water (5mL) solution of Sodium Nitrite (269.9mg, 3.91mmol), maintain 0 DEG C of stirring reaction half an hour; In another reaction flask, add 2-chloroacetyl acetacetic ester (536.6mg, 3.26mmol), sodium acetate (615mg, 7.50mmol), water (5mL) and ethyl acetate (5mL), be cooled to 0 DEG C, drip the reaction solution in first reaction flask, stirring reaction 2 hours at 0 DEG C.In reaction solution, add ethyl acetate (10mL), separatory, ethyl acetate for water (10mL × 2) extraction, merge organic phase, with anhydrous sodium sulfate drying, concentrated, residue obtains the chloro-2-of title compound 2-(2-(4-fluorine cumarone-5-yl) hydrazone group) ethyl acetate (18F) with silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10: 1～5: 1), light yellow oil (600mg, productive rate 64%).

The 6th step: 1-(the fluoro-cumarone-5-of 4-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (18G) also

Ethyl?1-(4-fluorobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By chloro-2-2-(2-(4-fluorine cumarone-5-yl) hydrazone group) ethyl acetate (18F) (600, 2.1mmol) be dissolved in ethyl acetate (30mL), add 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (892.6mg, 2.52mmol), potassiumiodide (34.9mg, 0.21mmol) and triethylamine (637.5mg, 6.3mmol), under nitrogen atmosphere, be warming up to backflow, react 20 hours, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 20mL), stirring at room temperature reaction 2h.By reaction solution separatory, organic phase anhydrous sodium sulfate drying, filter, concentrated, residue obtains title compound 1-(the fluoro-cumarone-5-of 4-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl with silica gel column chromatography separating-purifying (ethyl acetate)]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (18G) also, light yellow solid (180mg, productive rate 15%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.33(m，2H)，7.25-7.23(m，3H)，6.61(d，1H)，4.65(t，2H)，4.46(q，2H)，4.13(t，2H)，3.60(m，2H)，3.29(m，4H)，2.57(m，2H)，1.94(m，4H)，1.43(m，3H)。

The 7th step: 1-(the fluoro-cumarone-5-of 4-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 18) also

By 1-(the fluoro-cumarone-5-of 4-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (18G) (180mg, 0.347mmol) be dissolved in DMF (5mL), add methane amide (125mg, 2.78mmol), sodium methylate (56.3mg, 1.04mmol), under nitrogen atmosphere, be warming up to 80 DEG C of reactions 6 hours.Reaction solution is concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate) obtains title compound 1-(the fluoro-cumarone-5-of 4-yl)-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (compound 18), white solid (80mg, productive rate 47%).

¹H?NMR(400MHz，CDCl ₃)δ7.36-7.33(m，2H)，7.25-7.20(m，3H)，6.81(br，1H)，6.64(d，1H)，5.44(br，1H)，4.67(t，2H)，4.12(t，2H)，3.60(m，2H)，3.40-3.26(m，4H)，2.59(m，2H)，1.94(m，4H)。

Embodiment 19

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(methylol)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 19)

1-(2，3-dihydrobenzofuran-5-yl)-3-(hydroxymethyl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(methylol)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 19)

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-piperidine-1-yl) phenyl]-4, 5, 6, 7-tetrahydrochysene-1H-pyrazoles [3, 4-c] Nicotinicum Acidum ethyl ester (4B) (2g, 4mmol) be suspended in anhydrous methanol (20mL), add sodium borohydride (2.57g in batches, 68mmol), complete post-heating to 40 DEG C reaction 3h, ice bath is cooling, drip saturated ammonium chloride (100mL), use successively ethyl acetate (50mL), methylene dichloride (20mL × 2) extraction, merge organic layer, saturated sodium-chloride for organic phase (20mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue obtains title compound 1-(2 with silica gel column chromatography separating-purifying (ethyl acetate), 3-Dihydrobenzofuranes-5-yl)-3-(methylol)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (compound 19), light yellow solid (1.2g, productive rate 66%)

¹H?NMR(400MHz，CDCl ₃)δ7.33-7.35(m，3H)，7.26-7.21(m，3H)，6.77(d，1H)，4.79(s，2H)，4.59(t，2H)，4.15-4.08(m，2H)，3.59-3.60(m，2H)，3.22(t，2H)，3.05(t，2H)，2.56-2.58(m，2H)，2.05(m，1H)，1.98-1.89(m，4H)。

LC-MS：[M+1]459.3

Embodiment 20

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 20)

1-(2，3-dihydrobenzofuran-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridine-3-aldehyde (20B)

1-(2，3-dihydrobenzofuran-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carbaldehyde

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-3-(methylol)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (1g, 2.18mmol) be dissolved in dry methylene dichloride (20mL), under nitrogen protection, ice bath is cooled to 0 DEG C, add Dai Si-Martin oxygenant (1.02g, 2.40mmol), 0 DEG C of reaction 2h, add saturated sodium bicarbonate (10mL), separatory, methylene dichloride for water layer (20mL × 2) extraction, merge organic layer, diatomite filtration, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains crude product silica gel column chromatography separating-purifying (ethyl acetate) and obtains title compound 1-(2, 3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridine-3-aldehyde (20B), white solid (600mg, productive rate 60%).

¹H?NMR(400MHz，CDCl ₃)δ10.13(s，1H)，7.40-7.39(m，1H)，7.36-7.24(m，5H)，6.81(d，1H)，4.62(t，2H)，4.13(t，2H)，3.60-3.58(m，2H)，3.33(t，2H)，3.25(t，2H)，2.57-2.54(m，2H)，1.99-1.88(m，4H)。

LC-MS：[M+1]457.1

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 20)

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridine-3-aldehyde (4g, 8.76mmol) be dissolved in dry methylene dichloride (150mL), under nitrogen protection, be cooled to-40 DEG C by dry ice acetone, slowly drip methyl-magnesium-bromide (the tetrahydrofuran solution 10.5mL of 1N, 10.5mmol), drip off the rear room temperature reaction 2h that is naturally warming up to, add saturated ammonium chloride solution (10mL), separatory, methylene dichloride for water layer (50mL × 2) extraction, merge organic layer, saturated sodium-chloride (30mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue obtains title compound 1-(2 with silica gel column chromatography separating-purifying (ethyl acetate), 3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (compound 20), light yellow solid (2.8g, productive rate 68%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.33(m，3H)，7.26-7.19(m，3H)，6.76(d，1H)，5.09(q，1H)，4.58(t，2H)，4.10(t，2H)，3.60(m，2H)，3.22(t，2H)，3.15-3.04(m，2H)，2.56(m，2H)，1.94-1.93(m，5H)，1.63(d，3H)。

LC-MS：[M+1]473.1

Embodiment 21

1-(cumarone-5-yl) the fluoro-4-of-6-[3-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide also

1-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(the fluoro-4-nitrophenyl of 2-) piperidines-2-ketone (21B)

1-(2-fluoro-4-nitrophenyl)piperidin-2-one

By piperidines-one (4.4g, 0.11mol) be dissolved in N-Methyl pyrrolidone (300mL), be cooled to 0 DEG C, add sodium cyanide (9.9g, 0.1mol), stirring reaction half an hour in batches, drip 3,4-difluoro nitrobenzene (15.9g, 0.1mol), rises to normal-temperature reaction and spends the night.In reaction solution, slowly add water (300mL) and ethyl acetate (500mL), separatory, saturated aqueous common salt for organic layer (300mL) washing, anhydrous sodium sulfate drying, concentrated, residue with silica gel column chromatography separating-purifying (ethyl acetate: sherwood oil (v/v)=1: 9～1: 3) to title compound 1-(the fluoro-4-nitrophenyl of 2-) piperidines-2-ketone (21B), light yellow solid (4.5g, productive rate 19%).

¹H?NMR(400MHz，CDCl ₃)δ8.10-8.03(m，2H)，7.52-7.48(m，1H)，3.65(t，2H)，2.62-2.59(m，2H)，2.05-1.96(m，4H)。

Second step: 1-(the fluoro-4-aminophenyl of 2-) piperidines-2-ketone (21C)

1-(2-fluoro-4-aminophenyl)piperidin-2-one

By 1-(the fluoro-4-nitrophenyl of 2-) piperidines-2-ketone (21B) (3.5g, 14.7mmol) be dissolved in ethanol (30mL), add nine water cure sodium (12.6g, 36.7mmol), be warming up to 80 DEG C, react 1 hour.Reaction solution is cooled to normal temperature, add water (100mL) and ethyl acetate (50mL), separatory, saturated aqueous common salt for organic layer (50mL) washing, anhydrous sodium sulfate drying, concentrated, residue with silica gel column chromatography separating-purifying (ethyl acetate: sherwood oil (v/v)=1: 99～2: 3) to title compound 1-(the fluoro-4-aminophenyl of 2-) piperidines-2-ketone (21C), light yellow solid (1.1g, productive rate 37%).

¹H?NMR(400MHz，CDCl ₃)δ6.97(t，1H)，6.44(d，2H)，3.53(m，2H)，2.54(m，2H)，1.93-1.92(m，4H)。

The 3rd step: 1-(the fluoro-4-iodophenyl of 2-) piperidines-2-ketone (21D)

1-(2-fluoro-4-iodophenyl)piperidin-2-one

By 1-(the fluoro-4-aminophenyl of 2-) piperidines-2-ketone (21C) (1.1g, 5.28mmol) be dissolved in hydrochloric acid (1.32mL, in water (3mL) solution 15.84mmol), be cooled to 0～-5 DEG C, drip Sodium Nitrite (546mg, water (3mL) solution 7.92mmol), keep 0 DEG C of stirring reaction half an hour, add potassiumiodide (4.38g, water (15mL) solution 26.40mmol), rises to normal-temperature reaction 1 hour.In reaction solution, add water (50mL) and ethyl acetate (50mL), separatory, organic layer is used 10% sodium hydroxide molten (50mL), saturated aqueous common salt (50mL) washing successively, anhydrous sodium sulfate drying, concentrated, residue with silica gel column chromatography separating-purifying (ethyl acetate: sherwood oil (v/v)=1: 99～1: 9) to title compound 1-(the fluoro-4-iodophenyl of 2-) piperidines-2-ketone (21D), dark-coloured solid (1.1g, productive rate 66%).

¹H?NMR(400MHz，CDCl ₃)δ7.52-7.50(m，2H)，6.99(t，1H)，3.58-3.55(m，2H)，2.56(m，2H)，1.96-1.95(m，4H)。

The 4th step: 1-(cumarone-5-yl) the fluoro-4-of-6-[3-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (21E) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[3-fluoro-4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydro?pyrazolo[3，4-c]pyridine-3-carboxylate

At microwave reaction wherein, by 1-(2, 3-dihydropyridine furans-5-yl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester (3f) (960mg, 3mmol) be dissolved in 1.4-dioxane (20mL), add 1-(the fluoro-4-iodophenyl of 2-) piperidines-2-ketone (21D) (935mg, 3mmol) and potassiumphosphate (1.3g, 6mmol), nitrogen bubble, add cuprous iodide (57mg, 0.3mmol) and N, N-dimethylcyclohexylamine (43.5mg, 0.3mmol), be heated to 150 DEG C, microwave reaction 6 hours.Reaction solution is cooled to normal temperature, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains compound 1-(cumarone-5-yl) the fluoro-4-of-6-[3-(2-oxo-piperidine-1-yl) phenyl of light yellow solid shape]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (21E) (300mg, productive rate 19%).

¹H?NMR(400MHz，CDCl ₃)δ7.36(s，1H)，7.20-7.13(m，4H)，6.78(d，1H)，4.61(t，2H)，4.46(q，2H)，4.12(t，2H)，3.55(m，2H)，3.32(t，2H)，3.23(t，2H)，2.57(m，2H)，1.95(m，4H)，1.45-1.41(m，3H)。

The 5th step: 1-(cumarone-5-yl) the fluoro-4-of-6-[3-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 21) also

By 1-(cumarone-5-yl) the fluoro-4-of-6-[3-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (21E) (300mg, 0.578mmol) be dissolved in N, in dinethylformamide (10mL), add methane amide (260mg, 5.78mmol), sodium methylate (62mg, 1.156mmol), being warming up to 90 DEG C of reactions spends the night.Reaction solution is cooled to 0 DEG C, add water (50mL), extract by ethyl acetate (50mL × 2), merge organic phase, saturated aqueous common salt for organic phase (100mL) washing, anhydrous sodium sulfate drying, concentrated, residue obtains title compound 1-(cumarone-5-yl) the fluoro-4-of-6-[3-(2-oxo-piperidine-1-yl) phenyl with dichloromethane/ethyl acetate recrystallization]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (compound 21) (70mg, productive rate 25%).

¹H?NMR(400MHz，CDCl ₃)δ7.34(s，1H)，7.24-7.19(m，4H)，6.82-6.80(m，2H)，5.44(s，1H)，4.62(t，2H)，4.11(t，2H)，3.54(m，2H)，3.38(t，2H)，3.25(t，2H)，2.57(m，2H)，1.95(m，4H)。

Embodiment 22

1-(cumarone-5-yl)-6-[4-((2R)-2-methyl-5-oxo morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 22) also

1-(benzofuran-5-yl)-7-oxo-6-[4-((2R)-2-methyl-5-oxo-morpholin-4-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: N-(2S-2-hydroxypropyl)-2-bromoacetamide (22B)

N-(2S-2-hydroxypropyl)-2-bromoacetamide

By 2S-2-hydroxyl propylamine (6.8g, 90.5mmol) be dissolved in ethyl acetate (100mL), add sodium bicarbonate (11.4g, 136mmol) and water (10mL), be cooled to 0 DEG C, drip bromoacetyl bromide (20.2g, 99.6mmol), room temperature reaction 3 hours.Ethyl acetate for reaction solution (100mL × 4) is extracted, merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=3: 2) obtains title compound N-(2S-2-hydroxypropyl)-2-bromoacetamide (22B), yellow solid (5.0g, productive rate 28%).

Second step: (2R)-2-methyl-morpholine-5-ketone (22C)

(2R)-2-methyl-morpholin-5-one

By N-(2S-2-hydroxypropyl)-2-bromoacetamide (22B) (5.2g, 26.53mmol) be dissolved in the trimethyl carbinol (200mL), add potassium tert.-butoxide (7.4g, 66.31mmol), under room temperature, react 2 hours.In reaction solution, add water (10mL), concentrate and remove most of solvent, add water (50mL), extract by ethyl acetate (100mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=1: 2) obtains title compound (2R)-2-methyl-morpholine-5-ketone (22C), white solid (700mg, productive rate 23%).

¹H?NMR(400MHz，CDCl ₃)δ6.97(s，1H)，4.21(dd，2H)，3.90-3.77(m，1H)，3.32-3.20(m，2H)，1.27(t，3H)。

The 3rd step: 1-(cumarone-5-yl)-6-[4-((2R)-2-methyl-5-oxo morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (22D) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-((2R)-2-methyl-5-oxo-morpholin-4-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-dihydropyridine furans-5-yl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (3f) (10.0g, 30.6mmol) be dissolved in 1.4-dioxane (500mL), add (2R)-2-methyl-morpholine-5-ketone (22C) (720mg, 6.25mmol), cuprous iodide (100mg) and potassiumphosphate (2.65mg, 12.6mmol) and N, N-dimethylcyclohexylamine (100mg), under nitrogen atmosphere, room temperature to 110 DEG C, reacts 10 hours.Reaction solution is cooled to normal temperature, add water (50mL), wash with methylene dichloride (50mL × 2), merge organic phase, with anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate) obtains title compound 1-(cumarone-5-yl)-6-[4-((2R)-2-methyl-5-oxo morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (22D), white powder (0.6g, productive rate 18%)

¹H?NMR(400MHz，CDCl ₃)δ7.31-7.27(m，5H)，7.18-7.21(m，1H)，6.70(d，1H)，4.53(t，2H)，4.38(q，2H)，4.27(dd，2H)，4.05(t，2H)，3.99(m，1H)，3.56(m，1H)，3.40(dd，1H)，3.25(t，2H)，3.15(t，2H)，1.36(t，3H)，1.25(d，3H)。

MS?m/z(ESI)：517.2[M+1]

The 4th step: 1-(cumarone-5-yl)-6-[4-((2R)-2-methyl-5-oxo morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 22) also

By 1-(cumarone-5-yl)-6-[4-((2R)-2-methyl-5-oxo morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (22D) (600mg, 1.16mmol) be dissolved in N, in dinethylformamide (10mL), add methane amide (522mg, 11.6mmol), sodium methylate (251mg, 4.65mmol), be warming up to 80 DEG C of reactions 3 hours.In reaction solution, add water (15mL), extract with methylene dichloride (20mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, residue silica gel column chromatography separating-purifying (methylene dichloride: methyl alcohol (v/v)=80: 1) obtains title compound 1-(cumarone-5-yl)-6-[4-((2R)-2-methyl-5-oxo morpholine-4-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (compound 22), white solid (200mg, productive rate 35%).

¹H?NMR(400MHz，CDCl ₃)δ7.38-7.32(m，5H)，7.26(m，1H)，6.84(s，1H)，6.79(d，1H)，5.50(s，1H)，4.62(t，2H)，4.36(dd，2H)，4.11(t，2H)，4.05(m，1H)，3.63(m，1H)，3.47(dd，1H)，3.38(t，2H)，3.25(t，2H)，1.32(d，3H)。

MS?m/z(ESI)：488.1[M+1]

Embodiment 23

1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholine-4-yl] phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 23)

1-(2，3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The bromo-N-[(2R of the first step: 2-)-2-hydroxypropyl] ethanamide (23B)

2-bromo-N-[(2R)-2-hydroxypropyl]acetamide

By 2R-2-hydroxyl propylamine (10g, 0.133mol) be dissolved in ethyl acetate (500mL), add sodium bicarbonate (16.7g, water (300mL) solution 0.2mol), be cooled to 0 DEG C and drip bromoacetyl bromide (29.6g, 0.146mol), drip off rear 0 DEG C of reaction 3h.By reaction solution separatory, ethyl acetate for water layer (200mL × 2) extraction, merge organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate (v/v)=1: 1-3: 7) obtain the bromo-N-[(2R of title compound 2-)-2-hydroxypropyl] ethanamide (23B), white solid (22B) (2.0g, productive rate 8%).

¹H?NMR(400MHz，CDCl ₃)δ6.91(br，1H)，3.92-3.88(m，1H)，3.84(s，2H)，3.44-3.38(m，1H)，?3.13-3.05(m，1H)，2.48(br，1H)，1.15(d，3H)。

LC-MS：[M+1]198.1.

Second step: (6S)-6-methylmorpholine-3-ketone (23C)

(6S)-6-methylmorpholin-3-one

By bromo-2-N-[(2R)-2-hydroxypropyl] ethanamide (2g, 10.2mmol) be dissolved in the trimethyl carbinol (150mL), add potassium tert.-butoxide (2.86g, 25.5mmol), room temperature reaction 2h, add water (50mL), methylene dichloride (100mL) and 4N hydrochloric acid regulate pH=6, separatory, methylene dichloride for water layer (50mL) extraction, merge organic layer, saturated sodium-chloride for organic layer (50mL) washing, anhydrous sodium sulfate drying, title compound (6S)-6-methylmorpholine-3-ketone (23C) of concentrating under reduced pressure, (740mg, productive rate 63%), be directly used in next step.

The 3rd step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholine-4-yl] phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (23D)

ethyl?1-(2，3-dihydrobenzofuran-5-yl)-6-[4-[(2R)-2-methyl-5-oxo-morpholin-4-yl]phenyl]-7-oxo-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester (1.66g, 3.13mmol) be dissolved in 1, in 4-dioxane (15mL), add (6S)-6-methylmorpholine-3-ketone (23C) (740mg, 6.43mmol), potassiumphosphate (1.33g, 6.26mmol), N, N-dimethylcyclohexylamine (44.5mg, 0.313mmol), under nitrogen atmosphere, add cuprous iodide (60mg, 0.313mmol), being heated to 110 DEG C of reactions spends the night.Reaction solution is cooled to room temperature, add water (30mL), extract with methylene dichloride (40mL), saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains title compound 1-(2, 3-Dihydrobenzofuranes-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholine-4-yl] phenyl]-7-oxo-4, 5-dihydro-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester (23D), light yellow solid (890mg, productive rate 55%).

¹H?NMR(400MHz，CDCl ₃)δ7.33-7.23(m，5H)，7.21-7.18(m，1H)，6.69(d，1H)，4.53(t，2H)，4.41-4.38(m，2H)，4.33-4.21(m，2H)，4.02-3.94(m，1H)，3.60-3.51(m，1H)，3.42-3.38(m，1H)，3.25(t，2H)，3.15(t，2H)，1.36(t，3H)，1.25(d，3H)，1.19-1.15(m，2H)。

LC-MS：[M+1]517.3.

The 4th step: 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholine-4-yl] phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] pyridine-3-carboxamide (compound 23)

By 1-(2,3-Dihydrobenzofuranes-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholine-4-yl] phenyl]-7-oxo-4,5-dihydro-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (23D) (880mg, 1.7mmol) is dissolved in DMF (10mL), add methane amide (766mg, 17mmol), sodium methylate (367mg, 6.80mmol), rise to 80 DEG C of reactions and spend the night.N is removed in decompression, dinethylformamide, methylene dichloride for residue (50mL) dissolves, water (100mL) washing, separatory, saturated sodium-chloride for organic layer (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (petrol ether/ethyl acetate=1: 1-0: 1 ethanol/methylene (v/v)=1: 19) obtains title compound 1-(2, 3-Dihydrobenzofuranes-5-yl)-6-[4-[(2S)-2-methyl-5-oxo-morpholine-4-yl] phenyl]-7-oxo-4, 5-dihydro-pyrazolo [3, 4-c] pyridine-3-carboxamide (compound 23), light yellow solid (480mg, productive rate 55%).

¹H?NMR(400MHz，d ₆-DMSO)δ7.71(br，1H)，7.42-7.36(m，6H)，7.29-7.26(m，1H)，6.77(d，1H)，4.59(t，2H)，4.22-4.20(m，2H)，4.08-3.94(m，3H)，3.60-3.52(m，2H)，3.28-3.19(m，4H)，1.25(d，3H)。

LC-MS：[M+1]488.2

Embodiment 24

1-(cumarone-5-yl)-3-trifluoromethyl-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine (compound 24) also

1-(benzofuran-5-yl)-3-trifluoromethyl-7-oxo-6-[4-(1，2，3，4-tetrazole-5-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine

The first step: cumarone-5-hydrazonium salt hydrochlorate (24B)

By amino 5-cumarone (5.5g, 40.7mmol) add in the mixture of concentrated hydrochloric acid (10mL) and water (20mL), be cooled to-5～0 DEG C, drip water (10mL) solution of Sodium Nitrite (3.4g, 48.8mmol), maintain 0 DEG C of stirring reaction 1 hour, at 0 DEG C, drip concentrated hydrochloric acid (15mL) solution of tin chloride dihydrate (27.6g, 122.1mmol), within 10 minutes, drip off, maintain 0 DEG C of reaction 2 hours.In reaction solution, add ethyl acetate (100mL), add 10% sodium hydroxide solution to regulate pH=8～9, suction filtration, by filtrate separatory, ethyl acetate for water (50mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic phase (50mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, placement is spent the night, have solid to separate out, filter, dry cake obtains title compound cumarone-5-hydrazonium salt hydrochlorate (24B), gray solid (1.3g, productive rate 17%).

The bromo-2-of second step: 2-(2-(cumarone-5-yl) hydrazone group)-1,1,1-Halothane (24C)

By cumarone-5-hydrazonium salt hydrochlorate (24B) (1.3g, 7.0mmol) and 1-methoxyl group-2,2,2 ,-trifluoroethanol (1.1g, 9.0mmol) is dissolved in ethanol (40mL), be warming up to 85 DEG C of reactions 4 hours, reaction solution is cooling, concentrate away ethanol, in residue, add N, dinethylformamide (20mL), is cooled to 0 DEG C, adds N-bromo-succinimide (1.2g, 7.0mmol), room temperature reaction 2 hours.In reaction solution, add water (100mL) and ethyl acetate (100mL), separatory, ethyl acetate for water (50mL × 2) extraction, merge organic phase, organic phase is water (80mL × 2) successively, saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=1: 0～19: 1) obtains the bromo-2-of title compound 2-(2-(cumarone-5-yl) hydrazone group)-1, 1, 1-Halothane (24C), red-brown solid (700mg, 33%).

¹H?NMR(400MHz，CDCl ₃)δ7.93(s，1H)，7.10-7.06(m，1H)，6.87-6.81(m，1H)，6.72(d，1H)，4.57(t，2H)，3.21(t，2H)。

The 3rd step: 1-(cumarone-5-yl)-3-trifluoromethyl-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine (compound 24) also

By 3-morpholine-1-(4-(2-oxo-piperidine-1-yl) phenyl)-5, 6-dihydropyridine-2 (1H)-one (1f) (391mg, 1.1mmol), the bromo-2-of 2-(2-(cumarone-5-yl) hydrazone group)-1, 1, 1-Halothane (24C) (309mg, 1.0mmol) be dissolved in ethyl acetate (50mL), add potassiumiodide (17mg, 0.1mmol) and triethylamine (304mg, 3.0mmol), rise to 85 DEG C of back flow reaction 16 hours, reaction solution is cooled to 0 DEG C, add hydrochloric acid (4N, 1.25mL, 5.0mmol), stirring at room temperature reaction 1 hour.In reaction solution, add water (30mL), separatory, ethyl acetate for water (20mL × 2) extraction, merge organic phase, wash with saturated aqueous common salt (30mL × 2), anhydrous sodium sulfate drying, filter, concentrated, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains title compound 1-(cumarone-5-yl)-3-trifluoromethyl-6-[4-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine (compound 24) (370mg, productive rate 74%).

¹H?NMR(400MHz，CDCl ₃)δ7.36-7.31(m，3H)，7.28-7.24(m，3H)，6.78(d，1H)，4.60(t，2H)，4.14(t，2H)，3.60(t，2H)，3.23(t，2H)，3.15(t，2H)，2.57(t，2H)，1.96-1.92(m，4H)。

LC-MS：[M+1]497.1

Embodiment 25

1-(cumarone-5-yl)-6-[4-(1,2,3,4-Yetrazol-5-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 25) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(1，2，3，4-tetrazole-5-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(cumarone-5-yl)-6-[4-cyano-phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (25B) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-Cyanophenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-dihydropyridine furans-5-yl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (3f) (10.0g, 30.6mmol) and 4-cyano group-1 iodobenzene (14.0g, 61.1mmol) be dissolved in 1.4-dioxane (100mL), add cuprous iodide (583mg, 3.0mmol) and potassiumphosphate (13.0g, 61.1mmol), under nitrogen atmosphere, add N, N-dimethylcyclohexylamine (427mg, 3.0mmol), be heated to 110 DEG C, react 16 hours.Reaction solution is cooled to normal temperature, add methylene dichloride (100mL), filter, methylene dichloride for filter cake (50mL × 2) washing, merge organic phase, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (methylene dichloride: ethyl acetate (v/v)=1: 0～9: 1) obtains compound 1-(cumarone-5-yl)-6-[4-cyano-phenyl of light yellow solid shape]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (25B) (9.0g, productive rate 69%)

¹H?NMR(400MHz，CDCl ₃)δ7.68-7.63(m，2H)，7.49-7.44(m，2H)，7.36-7.33(m，1H)，7.24(dd，1H)，6.78(d，1H)，4.61(t，2H)，4.46(q，2H)，4.16(t，2H)，3.35(t，2H)，3.23(t，2H)，1.43(t，3H)。

Second step: 1-(cumarone-5-yl)-6-[4-cyano-phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (25C) also

1-(benzofuran-5-yl)-7-oxo-6-[4-Cyanophenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

In tube sealing, add 1-(cumarone-5-yl)-6-[4-cyano-phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (25B) (1.4g, 3.3mmol), add methyl alcohol (8mL) and ammoniacal liquor (25%, 0.56g, 33.0mmol), be warming up to 90 DEG C of reactions 24 hours.Reaction solution is cooled to room temperature, add methylene dichloride (50mL) and water (50mL), separatory, methylene dichloride for water (20mL × 2) extraction, merge organic phase, saturated aqueous common salt for organic layer (30mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate: sherwood oil (v/v)=1: 19～2: 4) obtains title compound 1-(cumarone-5-yl)-6-[4-cyano-phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (25C), white solid (760mg, productive rate 58%).

¹H?NMR(400MHz，CDCl ₃)δ7.65(d，2H)，7.46(d，2H)，7.33(s，1H)，7.24(dd，1H)，6.85(s，1H)，6.81(d，1H)，5.65(s，1H)，4.63(t，2H)，4.15(t，2H)，3.41(t，2H)，3.25(t，2H)。

LCMS?m/z＝400.1[M+1]

The 3rd step: 1-(cumarone-5-yl)-6-[4-(1,2,3,4-Yetrazol-5-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 25) also

In tube sealing, add 1-(cumarone-5-yl)-6-[4-cyano-phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (25C) (300mg, 0.75mmol), sodium azide (73mg, 1.13mmol), triethylamine hydrochloride (156mg, 1.13mmol) and triethylamine (759mg, 7.5mmol), be warming up to 130 DEG C of confined reactions 12 hours.Reaction solution is cooled to room temperature, add methylene dichloride (30mL) and water (30mL), separatory, methylene dichloride for water (10mL) washing, in water, add NaOH solution regulator solution pH=13～14, wash with methylene dichloride (20mL × 2), by water layer concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (methyl alcohol: methylene dichloride (v/v)=1: 19～2: 23) obtains title compound, yellow solid (70mg, productive rate 21%).

¹H?NMR(400MHz，DMSO)δ8.05(d，2H)，7.73(s，1H)，7.60(d，2H)，7.45(d，2H)，7.29(d，1H)，6.82(d，1H)，4.60(t，2H)，4.14(t，2H)，3.21(m，4H)。

LCMS?m/z＝443.1[M+1]

Embodiment 26

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyl cyclopropyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 26)

1-(2，3-dihydrobenzofuran-5-yl)-3-(1-hydroxycyclopropyl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-ethanoyl-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (26B)

3-acetyl-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

By raw material 1-(2; 3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4; 5-dihydro-pyrazolo [3; 4-c] pyridin-7-one (compound 20) (500mg; 1.06mmol) be dissolved in dry methylene chloride (10mL); under nitrogen protection, be cooled to 0 DEG C; add Dai Si-Martin oxygenant (539mg; 1; 27mmol), 0 DEG C is stirred and rises to room temperature reaction after 10 minutes and spend the night.Add saturated sodium bicarbonate (10mL), separatory, methylene dichloride for water layer (20mL × 2) extraction, merge organic layer, saturated sodium-chloride for organic phase (10mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=1: 1-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-ethanoyl-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (26B), white solid (400mg, productive rate 80%).

¹H?NMR(400MHz，CDCl ₃)δ7.53-7.24(m，6H)，6.80(d，1H)，4.61(t，2H)，4.12-4.08(m，2H)，3.60-3.59(m，2H)，3.29(dt，4H)，2.65(s，3H)，2.57-2.54(m，2H)，1.94-1.93(m，4H)。

LC-MS：[M+1]471.1

Second step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-tertiary butyl dimethyl Si base vinyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (26C)

3-[1-[tert-butyl(dimethyl)silyl]oxyvinyl]-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-3-ethanoyl-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (26B) (370mg, 0.79mmol) be dissolved in dry methylene dichloride (10mL), under nitrogen protection, add 2, 6-lutidine (126mg, 1.18mmol), be cooled to 0 DEG C, drip tertiary butyl dimethyl silyl triflate (270mg, 1.02mmol), dripping off the rear room temperature reaction that is naturally warming up to spends the night, ice bath is cooling, drip saturated sodium bicarbonate (5mL), methylene dichloride (10mL × 3) extraction, merge organic layer, saturated sodium-chloride for organic phase (10mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=3: 1-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-(1-tertiary butyl dimethyl Si base vinyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (26C), white solid (370mg, productive rate 80%).

¹H?NMR(400MHz，CDCl ₃)δ7.32-7.02(m，8H)，6.71(dd，1H)，5.00-4.96(m，1H)，4.54-4.49(m，2H)，4.45-3.99(m，1H)，3.53(m，2H)，3.28-3.06(m，4H)，2.50-2.48(m，2H)，1.87-1.86(m，4H)，1.04-0.79(m，9H)，0.17(s，3H)，0.01-0.03(m，3H)。

LC-MS：[M+1]585.3

The 3rd step 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-tertiary butyl dimethyl Si basic ring propyl group)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (26D)

3-[1-[tert-butyl(dimethyl)silyl]oxycyclopropyl]-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-3-(1-tertiary butyl dimethyl Si base vinyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (26C) (100mg, 0.17mmol) be dissolved in dry methylene dichloride (2mL), under nitrogen protection, be cooled to 0 DEG C, add zinc ethyl (the toluene solution 0.17mL of 2N, 0.34mmol), stir and within 10 minutes, add again methylene iodide (91mg, 0.34mmol) after adding, 0 DEG C of stirring rises to room temperature reaction 20 minutes for 5 minutes again, add saturated ammonium chloride (5mL), separatory, methylene dichloride for water layer (5mL × 2) extraction, merge organic layer, saturated sodium-chloride for organic phase (5mL) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=7: 3-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-(1-tertiary butyl dimethyl Si basic ring propyl group)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (26D), white solid (50mg, productive rate 49%).

¹H?NMR(400MHz，CDCl ₃)δ7.34(m，3H)，7.22(m，3H)，6.75(d，1H)，4.57(t，2H)，4.10-4.08(m，2H)，3.61(m，2H)，3.21(t，2H)，3.13(t，2H)，2.62(m，2H)，1.94(m，4H)，1.10-1.06(m，4H)，0.85(s，9H)，0.05(s，6H)。

The 4th step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyl cyclopropyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 26)

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-3-(1-tertiary butyl dimethyl Si basic ring propyl group)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (26D) (45mg, 0.075mmol) be dissolved in the mixed solvent (v/v=1/1 of methylene dichloride and tetrahydrofuran (THF), 2mL), add tetrabutyl ammonium fluoride (196mg, 0.75mmol), room temperature reaction 2h, add water (5mL), methylene dichloride (5mL), separatory, saturated sodium-chloride for organic layer (2mL × 3) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=1: 1-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyl cyclopropyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (compound 26), white solid.

¹H?NMR(400MHz，CDCl ₃)δ7.34-7.30(m，3H)，7.25-7.18(m，3H)，6.75(d，1H)，4.57(t，2H)，4.07(t，2H)，3.59-3.58(m，2H)，3.21(t，2H)，3.12(t，2H)，2.57-2.48(m，3H)，1.97-1.88(m，4H)，1.20(m，4H)。

LC-MS：[M+1]485.1

Embodiment 27

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(difluoromethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 27)

3-(difluoromethyl)-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(difluoromethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 27)

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-7-oxo-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridine-3-aldehyde (500mg, 1.09mmol) be dissolved in dry methylene dichloride (5mL), under nitrogen protection, dry ice-propanone is cooled to-78 DEG C, slowly drip diethylin sulfur trifluoride (DAST) (396mg, 2.19mmol), adding the rear room temperature reaction that is naturally warming up to spends the night, add saturated sodium bicarbonate (10mL), separatory, methylene dichloride for water layer (15mL × 2) extraction, merge organic layer, wash with saturated sodium-chloride (10mL × 2), anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=1: 1-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-(difluoromethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (compound 27), white solid (120mg, productive rate 23%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.33(m，3H)，7.28-7.27(m，1H)，7.25-7.22(m，2H)，6.93-6.66(t，1H)，6.79(s，1H)，4.60(t，2H)，4.13(t，2H)，3.61(m，2H)，3.25-3.16(m，4H)，2.59(m，2H)，1.94(m，4H)。

¹⁹F?NMR(376MHz，CDCl ₃)δ-112.16.

LC-MS：[M+1]479.1

Embodiment 28

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(methyl fluoride)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 28)

3-(fluoromethyl)-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(methyl fluoride)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 28)

3-(gluoromethyl)-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-3-(methylol)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (600mg, 1.3mmol) be dissolved in dry methylene dichloride (10mL), under nitrogen protection, dry ice-propanone is cooled to-78 DEG C, slowly drip diethylin sulfur trifluoride (DAST) (356mg, 1.96mmol),-78 DEG C of reaction 1h after adding, rise to room temperature, add saturated sodium bicarbonate (10mL), separatory, methylene dichloride for water layer (10mL × 2) extraction, merge organic layer, wash with saturated sodium-chloride (10mL), anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=1: 1-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-(methyl fluoride)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (compound 28), white solid (250mg, productive rate 42%).

¹H?NMR(400MHz，CDCl ₃)δ7.37-7.31(m，3H)，7.26-7.25(m，3H)，6.77(d，1H)，5.50(d，2H)，4.59(t，2H)，4.12(t，2H)，3.60-3.59(m，2H)，3.22(t，2H)，3.09(t，2H)，2.57-2.55(m，2H)，1.94-1.93(m，4H)。

⁹F?NMR(376MHz，CDCl ₃)δ-211.24

LC-MS：[M+1]461.1

Embodiment 29

1-(cumarone-5-yl) the fluoro-4-of-6-[2-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 22) also

1-(benzofuran-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: N-(fluoro-4 bromophenyls of 3-)-5-chlorine valeramide (29B)

N-(3-fluoro-4-bromophenyl)-5-chloropentanamide

Fluoro-3-4-bromaniline (5.7g, 0.03mol) is dissolved in methylene dichloride (100mL), adds triethylamine (8.3mL, 0.06mol), be cooled to 0 DEG C, drip 5-Chlorovaleryl Chloride (6mL, 0.045mol), rise to room temperature reaction 3 hours.In reaction solution, add water (200mL), separatory, saturated aqueous common salt for organic phase (100mL) washing, anhydrous sodium sulfate drying, concentrated, obtain title compound N-(fluoro-4 bromophenyls of 3-)-5-chlorine valeramide (29B), light yellow solid (9.2g, productive rate 100%).

¹H?NMR(400MHz，CDCl ₃)δ7.62(dd，1H)，7.47-7.40(m，2H)，7.08(dd，1H)，3.60-3.48(m，2H)，2.45-2.40(m，2H)，1.88(m，2H)，1.28-1.25(m，2H)。

Second step: 1-(fluoro-4 bromophenyls of 3-) piperidines-2-ketone (29C)

1-(3-fluoro-4-bromophenyl)piperidin-2-one

By N-(fluoro-4 bromophenyls of 3-)-5-chlorine valeramide (29B) (9.2g, 0.03mol) be dissolved in tetrahydrofuran (THF) (50mL), be cooled to 0 DEG C, add sodium hydride (2.4g in batches, 0.06mol), rise to normal-temperature reaction 4 hours.Reaction solution is cooled to 0 DEG C, drip water (10mL), add saturated aqueous common salt (100mL), separatory, organic layer is extracted with ethyl acetate (100mL), merge organic phase, saturated aqueous common salt for organic phase (100mL) washing, anhydrous sodium sulfate drying, concentrated, residue obtains title compound 1-(fluoro-4 bromophenyls of 3-) piperidines-2-ketone (29C), light yellow solid (7.3g, productive rate 90%) by 30% recrystallization from ethyl acetate/petroleum ether.

¹H?NMR(400MHz，CDCl ₃)δ7.55(dd，1H)，7.11(dd，1H)，6.98(ddd，1H)，3.65-3.62(m，2H)，2.56(t，2H)，1.99-1.94(m，4H)。

The 3rd step: 1-(cumarone-5-yl) the fluoro-4-of-6-[2-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (22D) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[2-fluoro-4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2,3-dihydropyridine furans-5-yl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (3f) (1.96g, 6mmol) and 1-(fluoro-4 bromophenyls of 3-) piperidines-2-ketone (29C) (1.63g, 6mmol) is dissolved in 1.4-dioxane (50mL), add potassiumphosphate (2.54g, 12mmol), under nitrogen atmosphere, add cuprous iodide (114mg, 0.6mmol) and N, N-dimethylcyclohexylamine (87mg, 0.6mmol), is heated to 110 DEG C of reactions 2 days.Reaction solution is cooled to normal temperature, pad diatomite filtration, filtrate decompression is concentrated, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=0: 1～2: 98) obtains compound 1-(cumarone-5-yl) the fluoro-4-of-6-[2-(2-oxo-piperidine-1-yl) phenyl of light yellow solid shape]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (22D) (140mg, productive rate 5%).

¹H?NMR(400MHz，CDCl ₃)δ7.37-7.32(m，3H)，7.13-7.06(m，2H)，6.77(d，1H)，4.60(t，2H)，4.46(q，2H)，4.03(t，2H)，3.60(m，2H)，3.34(t，2H)，3.22(t，2H)，2.58(m，2H)，1.94(m，4H)，1.43(m，3H)。

The 4th step: 1-(cumarone-5-yl) the fluoro-4-of-6-[2-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 22) also

By 1-(cumarone-5-yl) the fluoro-4-of-6-[2-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (22D) (140mg, 0.27mmol) be dissolved in N, in dinethylformamide (5mL), add methane amide (121mg, 2.7mmol), sodium methylate (29mg, 0.54mmol), being warming up to 90 DEG C of reactions spends the night.Reaction solution is cooled to normal temperature, add water (50mL), extract by ethyl acetate (50mL), merge organic phase, saturated aqueous common salt for organic phase (50mL) washing, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methylene chloride/methanol (v/v)=1: 0～98: 2) obtains title compound 1-(cumarone-5-yl) the fluoro-4-of-6-[2-(2-oxo-piperidine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (compound 22) (50mg, productive rate 38%).

¹H?NMR(400MHz，CDCl ₃)δ7.37-7.29(m，3H)，7.13-7.07(m，2H)，6.84(s，1H)，6.80(d，1H)，5.46(s，1H)，4.62(m，2H)，4.02(t，2H)，3.60(m，2H)，3.40(t，2H)，3.25(t，2H)，2.57(t，2H)，1.95-1.93(m，4H)。

Embodiment 30

1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-fluoro ethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 30)

3-(1-fluoroethyl)-1-(2，3-dihydrobenzofuran-5-yl)-6-[4-(2-oxo-1-piperidyl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridin-7-one

The first step: 1-(2,3-Dihydrobenzofuranes-5-yl)-3-(1-fluoro ethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4,5-dihydro-pyrazolo [3,4-c] pyridin-7-one (compound 30)

By 1-(2, 3-Dihydrobenzofuranes-5-yl)-3-(1-hydroxyethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (600mg, 1.27mmol) be dissolved in dry methylene dichloride (10mL), under nitrogen protection, dry ice-propanone is cooled to-78 DEG C, slowly drip diethylin sulfur trifluoride (DAST) (276mg, 1.52mmol),-78 DEG C of reaction 1h after adding, rise to room temperature, add saturated sodium bicarbonate (5mL), separatory, methylene dichloride for water layer (20mL × 2) extraction, merge organic layer, wash with saturated sodium-chloride (10mL × 2), anhydrous sodium sulfate drying, concentrating under reduced pressure, (the sherwood oil: ethyl acetate (v/v)=1: 1-0: 1) obtain title compound 1-(2 of silica gel column chromatography separating-purifying for residue, 3-Dihydrobenzofuranes-5-yl)-3-(1-fluoro ethyl)-6-[4-(2-oxo-1-piperidines) phenyl]-4, 5-dihydro-pyrazolo [3, 4-c] pyridin-7-one (compound 30), white solid (250mg, productive rate 42%).

¹H?NMR(400MHz，CDCl ₃)δ7.35-7.33(m，3H)，7.26-7.22(m，3H)，6.76(d，1H)，5.82(dq，1H)，4.58(t，2H)，4.18-4.05(m，2H)，3.60(m，2H)，3.22(t，2H)，3.14-3.11(m，2H)，2.56(m，2H)，1.93(m，4H)，1.79(dd，3H)。

¹⁹F?NMR(376MHz，CDCl ₃)δ-169.94

LC-MS：[M+1]475.1

Embodiment 31

1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 5-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 31) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 5-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (31B) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(5-fluoro-2-oxo-pyridin-2-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxyalte

By 1-(2,3-dihydropyridine furans-5-yl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (3f) (1.0g, 1.9mmol) be dissolved in 1.4-dioxane (10mL), add 5-fluorine pyridin-2-ones (236mg, 2.1mmol) and potassiumphosphate (806g, 3.8mmol), cuprous iodide (36mg, 0.19mmol) and N, N-dimethylcyclohexylamine (22mg, 0.19mmol), be heated to 150 DEG C, react 5 hours.Reaction solution is cooled to normal temperature, pour in water (30mL), extract by ethyl acetate (30mL × 2), merge organic phase, saturated aqueous common salt for organic phase (30mL) washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (ethyl acetate/petroleum ether (v/v)=1: 1～1: 0) obtains compound 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of the 5-yl) phenyl of light yellow solid shape]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] Nicotinicum Acidum ethyl ester (31B) (700mg, productive rate 71%).

¹H?NMR(400MHz，CDCl ₃)δ7.50-7.43(m，2H)，7.43-7.34(m，4H)，7.25(m，2H)，6.77(d，1H)，6.64(dd，1H)，4.61(t，2H)，4.46(q，2H)，4.24-4.07(m，2H)，3.35(t，2H)，3.23(t，2H)，1.43(t，3H)。

MS?m/z(ESI)：515.1[M+1]

Second step: HCX-160-190-1

By 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 5-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (31B) (700mg, 1.66mmol) be dissolved in N, in dinethylformamide (10mL), add methane amide (612mg, 13.6mmol), sodium methylate (294mg, 5.44mmol), be warming up to 80 DEG C of reactions 4 hours.Reaction solution is concentrated, in residue, add methylene dichloride (30mL), water (30mL × 2) successively, saturated aqueous common salt (30mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, silica gel column chromatography separating-purifying for residue (methylene dichloride: methyl alcohol (v/v)=50: 1～20: 1) obtains title compound 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 5-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (compound 31) (110mg, productive rate 17%).

¹H?NMR(400MHz，DMSO)δ7.93(dd，1H)，7.68(m，2H)，7.52-7.41(m，6H)，7.30(dd，1H)，6.81(d，1H)，6.52(dd，1H)，4.60(t，2H)，4.09(t，2H)，3.26-3.15(m，4H)。

MS?m/z(ESI)：486.1[M+1]

Embodiment 32

1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 3-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 32) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: HCX-180-38-1

1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 3-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (32B) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-(3-fluoro-2-oxo-pyridin-2-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(2; 3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxygen-4; 5; 6; 7-tetrahydrochysene-1H-pyrazoles [3; 4-c] Nicotinicum Acidum ethyl ester (1.0g, 1.9mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (10mL); under nitrogen protection, add 3-fluorine pyridine-2-alcohol (236mg 2.1mmol); potassiumphosphate (806mg 3.8mmol), cuprous iodide (36mg 0.19mmol), trans-(1R; 2R)-N; N ' dimethyl 1,2-cyclohexane diamine (27mg 0.19mmol), microwave 150 degree reaction 4 hours.After reaction finishes, add 20mL EA, wash 2 times (20mL × 2), saturated common salt water washing 1 time (20mL × 1), anhydrous sodium sulfate drying, concentrating under reduced pressure, silicagel column column chromatography separating-purifying for residue (ethyl acetate: sherwood oil (v/v)=1: 5-1: title compound 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 3-yl) phenyl 2)]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (32B), greyish white solid (0.7g, productive rate 71.4%).

¹H?NMR(400MHz，CDCl ₃)δ7.47(d，2H)，7.41(d，2H)，7.37(s，1H)，7.28(d，1H)，7.18(dd，1H)，7.14(dd，1H)，6.78(d，1H)，6.18(dd，1H)，4.61(t，2H)，4.47(q，2H)，4.18(t，2H)，3.35(t，2H)，3.23(t，2H)，1.49-1.39(m，3H)。

MS?m/z(ESI)：515.1[M+1]

Second step: 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 3-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 32) also

By 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 3-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (32B) (0.7g 1.36mmol) is dissolved in N, in dinethylformamide (10mL), add sodium methylate (294mg 5.44mmol), methane amide (612mg 13.6mmol), 80 degree reactions are spent the night.Reaction solution decompression is removed to N, dinethylformamide, add methylene dichloride (30mL) dissolution residual substance, water (30mL × 2) successively, saturated aqueous common salt (30mL × 2) washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue obtains title compound 1-(cumarone-5-yl)-6-[4-(the fluoro-2-oxo-pyridine-1-of 3-yl) phenyl with silicagel column column chromatography separating-purifying (ethyl acetate: sherwood oil (v/v)=1: 5-1 :)]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (compound 32), off-white color solid (0.2g 30.3%).

¹H?NMR(400MHz，CDCl ₃)δ7.47(d，2H)，7.41(d，2H)，7.36(s，1H)，7.31-7.26(m，1H)，7.21-7.15(m，1H)，7.15-7.10(m，1H)，6.82(m，2H)，6.18(m，1H)，5.50(s，1H)，4.62(t，2H)，4.17(t，2H)，3.41(t，2H)，3.25(t，2H)。

MS?m/z(ESI)：486.0[M+1]

Embodiment 33

1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 33) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (33B) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-pyrazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

Under nitrogen atmosphere, by 1-(2,3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] Nicotinicum Acidum ethyl ester (2C) (1.0g, 1.9mmol), pyrazine-2-ketone (0.36g, 3.7mmol), potassiumphosphate (0.8g, 3.7mmol), copper(I) iodide (100mg) and trans-(1R, 2R)-N, N '-dimethyl-1,2-ring pentamethylene diamine (100mg) joins in microwave tube, add 1,2-dioxane (40mL), be warming up to 150 DEG C of reactions 1.5 hours.Reaction solution is cooled to room temperature, add water (20mL), extract by ethyl acetate (20mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methylene dichloride: methyl alcohol (v/v)=25: 1) obtains title compound 1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (33B), yellow solid (0.4g, productive rate 43%).

¹H?NMR(400MHz，DMSO-d ₆)δ8.12(d，1H)，7.66(m，1H)，7.53(m，4H)，7.42-7.40(m，2H)，7.29-7.27(m，1H)，6.81(d，1H)，4.60(t，2H)，4.32(q，2H)，4.13(t，2H)，3.24-3.20(m，4H)，1.33(t，3H)。

MS?m/z(ESI)：498.1[M+1]

Second step: 1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 33) also

1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (33B) (0.4g, 0.8mmol) is dissolved in and in ammonia/methanol solution (10mL), is warming up to 100 DEG C of reactions and spends the night.Reaction solution is cooled to room temperature, extract by ethyl acetate (50mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (ethanol/methylene (v/v)=1: 50) obtains title compound 1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (compound 33), white solid (200mg, productive rate 54%).

¹H?NMR(400MHz，DMSO-d ₆)δ8.12(d，1H)，7.72(s，1H)，7.66(dd，1H)，7.55-7.50(m，4H)，7.43-7.44(m，2H)，7.40(dd，1H)，7.28(dd，1H)，6.81(d，1H)，4.60(t，2H)，4.02(t，2H)，3.22-3.19(m，4H)。

MS?m/z(ESI)：469.0[M+1]

Embodiment 34

1-(cumarone-5-yl)-6-[4-(2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 34) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxo-piperazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 4-tert-butoxycarbonyl-piperazine-2-ketone (34B)

4-tert-butoxycarbonyl-2-oxo-piperazine

Piperazine-2-ketone (1.0g, 1mmol), tert-Butyl dicarbonate (2.3g, 1.1mmol), triethylamine (1.21g, 1.2mmol) are joined in dichloromethane solution (60mL), and room temperature reaction spends the night.Reaction solution water (30mL × 2) is washed, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (sherwood oil: ethyl acetate (v/v)=1: 2) obtains title compound 4-tert-butoxycarbonyl-piperazine-2-ketone (34B), white solid (1.0g, productive rate 50%).

¹H?NMR(400MHz，DMSO-d ₆)δ3.81(s，2H)，3.45(t，2H)，3.17(t，2H)，1.41(s，9H)。

Second step: 1-(cumarone-5-yl)-6-[4-(4-tert-butoxycarbonyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (34C) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-(4-tertbutoxycarbonyl-2-oxo-piperazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

Under nitrogen atmosphere, by 1-(2, 3-Dihydrobenzofuranes-5-yl)-6-(4-iodophenyl)-7-oxo-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-c] Nicotinicum Acidum ethyl ester (2C) (1.0g, 1.9mmol), 4-tert-butoxycarbonyl-piperazine-2-ketone (34B) (0.75g, 3.78mmol), potassiumphosphate (0.8g, 3.78mmol), copper(I) iodide (100mg, 0.19mmol) with trans-(1R, 2R)-N, N '-dimethyl-1, 2-ring pentamethylene diamine (100mg, 0.19mmol) join in microwave tube, add 1, 2-dioxane (40mL), be warming up to 150 DEG C of reactions 1.5 hours.Reaction solution is cooled to room temperature, add water (50mL), extract by ethyl acetate (50mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methylene dichloride: methyl alcohol (v/v)=100: 1) obtains title compound 1-(cumarone-5-yl)-6-[4-(4-tert-butoxycarbonyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (34C), white solid (0.6g, productive rate 53%).

¹H?NMR(400MHz，CDCl ₃)δ7.39-7.30(m，3H)，7.28-7.25(m，3H)，6.76(d，1H)，4.60(t，2H)，4.45(t，2H)，4.25(s，2H)，4.13(q，2H)，3.77(t，2H)，3.68(t，2H)，3.32(t，2H)，3.22(t，2H)，1.50(s，9H)，1.43(t，3H)。

MS?m/z(ESI)：602.2[M+1]

The 3rd step: 1-(cumarone-5-yl)-6-[4-(4-tert-butoxycarbonyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (34D) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(4-tertbutoxycarbonyl-2-oxo-piperazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

By 1-(cumarone-5-yl)-6-[4-(4-tert-butoxycarbonyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] Nicotinicum Acidum ethyl ester (34C) (700mg) is dissolved in N, in dinethylformamide (20mL), add sodium methylate (251mg, 4.65mmol), methane amide (522mg, 11.6mmol), 80 degree reactions 4 hours, cool to room temperature, add 20mL water, with ethyl acetate 50mL extraction three times, anhydrous sodium sulfate drying, concentrated, silica gel column chromatography separating-purifying for residue (methylene dichloride: methyl alcohol (v/v)=100: 1) obtains title compound 1-(cumarone-5-yl)-6-[4-(4-tert-butoxycarbonyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] pyridine-3-carboxamide (34D), yellow solid (0.4g, productive rate 60%).

¹H?NMR(400MHz，DMSO-d ₆)δ7.71(s，1H)，7.42(m，2H)，7.37(m，4H)，7.29-7.26(m，1H)，6.79(d，1H)，4.59(t，2H)，4.07-4.03(m，4H)，3.69(m，4H)，3.22-3.18(m，4H)，1.41(s，9H)。

MS?m/z(ESI)：573.2[M+1]

The 4th step: 1-(cumarone-5-yl)-6-[4-(2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 34) also

By 1-(cumarone-5-yl)-6-[4-(4-tert-butoxycarbonyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (34D) (0.4g, 8.7mmol) be dissolved in trifluoroacetic acid (9.9g) and 20mL methylene dichloride room temperature reaction 5 hours.By concentrated dry to methylene dichloride and trifluoroacetic acid, add 50 ml waters and potash solid, adjust _ph is 9 left and right, with ethyl acetate 50mL extraction three times, anhydrous sodium sulfate drying is concentrated, crude product obtains title compound 1-(cumarone-5-yl)-6-[4-(2-oxo piperazine-1-yl) phenyl with 50mL ethyl alcohol recrystallization]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (compound 34), white solid (0.10g, productive rate: 30%).

¹H?NMR(400MHz，DMSO-d ₆)δ7.71(s，1H)，7.37(m，2H)，7.31(m，4H)，7.26(m，1H)，6.79(d，1H)，4.59(t，2H)，4.05(m，2H)，3.57(t，2H)，3.38(s，2H)，3.18(m，4H)，3.00(t，2H)，2.76(s，1H)。

MS?m/z(ESI)：473.1[M+1]

Embodiment 35

1-(cumarone-5-yl)-6-[4-(4-methyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 35) also

1-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxamide

The first step: 1-(cumarone-5-yl)-6-[4-(2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (35B) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-(2-oxopiperazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

1-(cumarone-5-yl)-6-[4-(2-Oxopyrazine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] Nicotinicum Acidum ethyl ester (33B) (1.4g, 2.8mmol), be dissolved in methylene chloride/methanol mixing solutions (v/v=l: 6, 35mL), add palladium carbon (0.2g), room temperature normal pressure, add hydrogen reaction 4 hours, filter palladium carbon, concentrated solvent, obtain the 1-of compound shown in title (cumarone-5-yl)-6-[4-(2-oxo piperazine-1-yl) phenyl]-7-oxo-4, 5-dihydro-1 h-pyrazole also [3, 4-c] Nicotinicum Acidum ethyl ester (35B), yellow solid (1g, productive rate: 71%).

¹H?NMR(400MHz，DMSO-d ₆)δ7.35(m，1H)，7.33-7.27(m，4H)，7.25(m，1H)，6.81(d，1H)，4.60(t，2H)，4.31(q，2H)，4.07(t，2H)，3.58(t，2H)，3.39(s，2H)，3.17(m，4H)，3.01(t，2H)，1.33(t，3H)。

MS?m/z(ESI)：502.1[M+1]

Second step: 1-(cumarone-5-yl)-6-[4-(4-methyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] Nicotinicum Acidum ethyl ester (35C) also

Ethyl?1-(benzofuran-5-yl)-7-oxo-6-[4-(4-methyl-2-oxopiperazin-1-yl)phenyl]-4，5-dihydropyrazolo[3，4-c]pyridine-3-carboxylate

By 1-(cumarone-5-yl)-6-[4-(2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (35A) (1.0g, 1.98mmol), formalin (37%) (0.32g, 3.98mmol), acetic acid (0.5mL), in the dioxane (10mL) adding, finally add sodium cyanoborohydride (0.25g, 3.9mmol), room temperature reaction 2 hours.In reaction solution, add 50mL water, with methylene dichloride 50mL extraction three times, anhydrous sodium sulfate drying, concentrated, obtain title compound 1-(cumarone-5-yl)-6-[4-(4-methyl-2-oxo piperazine-1-yl) phenyl with residue silica gel column chromatography separating-purifying (methylene dichloride: methyl alcohol (v/v)=25: 1)]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (35C), white solid (1.4g, productive rate 29%)

¹H?NMR(400MHz，DMSO-d ₆)δ7.41-7.36(m，5H)，7.27-7.25(m，1H)，6.81(d，1H)，4.60(t，2H)，4.31(q，2H)，4.08(t，2H)，3.87(t，2H)，3.61(dd，2H)，3.43(t，2H)，3.22-3.19(m，4H)，2.84(s，3H)，1.33(t，3H)。

The 3rd step: 1-(cumarone-5-yl)-6-[4-(4-methyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole is [3,4-c] pyridine-3-carboxamide (compound 35) also

By 1-(cumarone-5-yl)-6-[4-(4-methyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] Nicotinicum Acidum ethyl ester (35C) (0.3g, 0.8mmol) be dissolved in ammonia/methanol solution (10mL), add in autoclave, be warming up to 100 DEG C of reactions and spend the night.Reaction solution is cooled to room temperature, filter, again methyl alcohol for solid (50mL) reflux is washed, cooling, filter, obtain title compound 1-(cumarone-5-yl)-6-[4-(4-methyl-2-oxo piperazine-1-yl) phenyl]-7-oxo-4,5-dihydro-1 h-pyrazole also [3,4-c] pyridine-3-carboxamide (compound 35), white solid (100mg, productive rate 35%).

¹H?NMR(400MHz，DMSO-d ₆)δ7.71(s，1H)，7.43(m，2H)，7.32(m，4H)，7.26(m，1H)，6.80(d，1H)，4.59(t，2H)，4.05(t，2H)，3.63(t，2H)，3.20(m，4H)，3.10(s，2H)，2.71(t，2H)，2.28(s，3H)。

MS?m/z(ESI)：487.1[M+1]

Test case:

Test case 1, compound dissolution degree are measured

(1) preparation of typical curve solution

Take the trial-product being dried after constant weight in right amount in volumetric flask, choose appropriate solvent sample is dissolved to constant volume completely, be made into the typical curve solution of a series of concentration gradients, after membrane filtration with 0.45mm, enter HPLC, record peak area, taking peak area as ordinate zou, the quality of sampling volume contained drug is that X-coordinate carries out linear regression, obtains the typical curve equation of this compound.

(2) preparation of need testing solution and mensuration

Taking appropriate trial-product (general 1～2mg), add appropriate solvent to be measured (general 1～2mL), with the powerful jolting 30 seconds every 5 minutes of vortex vibrator, observe the dissolving situation in 30 minutes, is the saturated solution of sample if do not dissolve; If dissolve, continue to add sample, until no longer dissolve.Then this saturated solution is placed in to water bath, constantly jolting at the temperature requiring, and extracted supernatant liquid in 4,24 hours, after the filter of 0.45mm filters, get subsequent filtrate and enter HPLC mensuration; If 4 hours are consistent with 24 hours measurement results, illustrate that solution has reached balance, measured result is solubility results, if inconsistent, illustrate and does not reach balance, continues to get a mensuration, until balance; If the concentration of need testing solution is too large in mensuration process, exceed standard curve range, need accurately after dilution, to measure again.

(3) calculating of experimental result

By the peak area substitution typical curve equation of the need testing solution of measuring, calculate the concentration (mg/mL) of surveyed saturation balance solution, be solubleness, result is as shown in table 1.

Take the trial-product being dried after constant weight appropriate, the typical curve solution that is made into a series of concentration gradients, filters laggard HPLC, taking peak area as ordinate zou, the quality of sampling volume contained drug is that X-coordinate carries out linear regression, obtains the typical curve equation of this compound.

Preparation trial-product saturated solution is placed in treats testing temperature constant water bath box, constantly jolting, and extracted supernatant liquid in 4,24 hours, filter laggard HPLC and measure; If 4 hours and 24 hours measurement results inconsistent, continue to get a mensuration, until consistent.

By the peak area substitution typical curve equation of the need testing solution of measuring, calculate the concentration (mg/mL) of surveyed saturation balance solution, be solubleness.

Table 1, solubility test experimental result

Conclusion: the solubleness of the compounds of this invention in 37 DEG C/physiological saline is obviously better than control compound Eliquis.

Test case 2, the compounds of this invention are to factor Xa vitro enzyme activity inhibition

Following methods can be used to measure the external restraining effect to people source thrombin xa activity of the compounds of this invention, represents with suppressing constant K i.

Containing 0.05M Tris, 0.15M NaCl, preparation people source factor Xa (Enzo life science) working fluid and chromogenic substrate (sekisui, article No.: 222) working fluid in the reaction buffer (pH=7.5) of 0.1%PEG-8000.Test compounds adds methyl-sulphoxide (DMSO) and is mixed with the storing solution of 10mM, then is diluted to the working fluid of 0.1-1000nM with the reaction buffer that contains 1%DMSO.In 96 orifice plates, add 30 μ L test compounds working fluids (control group adds 30 μ L reaction buffers) and 150 μ L factor Xa working fluids, factor Xa final concentration is 1nM, incubated at room 30 minutes.Then add chromogenic substrate working fluid 120 μ L, final concentration is 0.2mM, starts reaction.By microplate reader (Perkin Elmer, Envision), 405nm place METHOD FOR CONTINUOUS DETERMINATION 30 minutes, per minute was measured once.

Calculate as follows test compounds Ki, result is as shown in table 2:

Ki＝IC ₅₀/(1+[S]/Km)

In examination:

IC ₅₀-calculate and cause the test compounds concentration of substrate hydrolysis rate reduction 50% by the linear regression of SPSS16.0 software.

[S]-concentration of substrate

Km-Michaelis-Menton constant, 0.35mM

Table 2, vitro human source factor Xa restraining effect experimental result

Embodiment numbering	Ki(nM)
		Eliquis	0.31
1	1.10
		2	0.23
3	0.24
		4	0.23
5	0.15

[1253]?

6	7.02
		7	0.98
8	0.45
		9	0.14
10	0.41
		12	0.83
15 (compound 1-2)	0.70
		19	3.12
20	2.91
		21	0.20
22	0.46
		23	1.31
24	0.37
		26	2.01
27	1.12
		28	1.02
29	0.49
		30	0.71
31	0.14
		32	0.13
33	0.12
		34	3.29

Conclusion: the compounds of this invention has certain FXa restraining effect, particularly the compound of embodiment 2～5,9,21～22,31～33 is obviously better than control compound Eliquis to people source FXa restraining effect in damping fluid.

Test case 3, the effect of Rats In Vitro Clinical significant of coagulation function are measured

(a) rat is (purchased from Da Shuo bio tech ltd, Chengdu, credit number: SOXK (river) 2008-24) femoral artery blood sampling, with 3.8% Sodium Citrate anti-freezing, the ratio of antithrombotics and blood is 1: 9,2500 revs/min 4 DEG C centrifugal (Beckman, Allegrax-30R) 10 minutes, upper strata is is rich in thrombocyte blood plasma, get 15000 revs/min 4 DEG C, upper strata centrifugal 10 minutes, upper strata is platelet poor plasma.Prothrombin time (PT), the preparation of activated partial thromboplastin time (aPTT) reagent and test reference reagent box (are all purchased from Saikexide Science & Technology Development Co., Ltd., Beijing, lot number is respectively D1B058-1, D2B061-1) specification sheets.The compounds of this invention of different concns and Eliquis are mixed with platelet poor plasma (volume ratio is 1: 9), compound final concentration is 0-20 μ M, full automatic blood-coagulation instrument (Saikexide Science & Technology Development Co., Ltd., Beijing, SF-8000) test PT, aPTT.Origin matching binomialexpression calculates one times of required compound concentration EC of cruor time extending _{2 ×}, result is as shown in table 3.

Table 3, the compounds of this invention blood coagulation resisting function to rat plasma is (with PT EC _{2 ×}with aPTT EC _{2 ×}represent)

Embodiment numbering	PT?EC _2×(μM)	aPTT?EC _2×(μM)
			Eliquis	3.4	10.1
2	2.5	5.0
			3	2.4	5.0
4	3.0	7.0
			5	1.7	4.0

Conclusion: the compounds of this invention Rats In Vitro blood plasma has obvious blood coagulation resisting function, is better than control compound Eliquis.

(b) 20 25-35 one full year of life healthy volunteers, 20mL is in 3.8% Sodium Citrate anticoagulant tube in elbow venipuncture blood sampling, the ratio of antithrombotics and blood is 1: 9,2500 revs/min of 4 DEG C of centrifugal (Beckman, Allegrax-30R) 10 minutes, get upper strata and be rich in 15000 revs/min 4 DEG C of thrombocyte blood plasma centrifugal 10 minutes, collect upper strata platelet poor plasma for prothrombin time (PT) and activated partial thromboplastin time (aPTT) detection.Reagent preparation and test reference reagent box (be all purchased from Instrumentation laboratory company, lot number is respectively N0821168 and N0820966) specification sheets.The compounds of this invention of different concns and Eliquis are mixed with platelet poor plasma (volume ratio is 1: 9), compound final concentration is 0-20 μ M, full automatic blood-coagulation instrument (Instrumentation laboratory, ACL ELITE) test PT, aPTT.Origin matching binomialexpression calculates one times of required compound concentration EC of cruor time extending _{2 ×}, result is as shown in table 4.

Table 4, the compounds of this invention blood coagulation resisting function to human plasma is (with PT EC _{2 ×}with aPTT EC _{2 ×}represent)

Embodiment numbering	PT?EC _2×(μM)	aPTT?EC _2×(μM)
			Eliquis	1.4	5.3
1	3.5	13.5
			2	1.1	3.3
3	1.3	6.0
			4	1.0	2.6
5	0.67	2.8
			8	1.4	4.6
9	2.3	5.7
			10	1.0	3.3
12	2.2	7.7
			15 (compound 1-2)	6.8	8.1
21	0.9	3.5

[1263]?

22	3.9	14.4
			28	3.3	11.8
29	3.0	11.1
			31	1.4	5.2
32	1.0	3.3
			33	0.9	2.6

Conclusion: the compounds of this invention is external has obvious blood coagulation resisting function to human plasma, particularly the compound of embodiment 2,4,8,10,21,31～33 is obviously better than control compound Eliquis.

Test case 4, Pharmacokinetic Evaluation

Male SD rat is (purchased from Shanghai Slac Experimental Animal Co., Ltd., credit number: SCXK (SH) 2007000546318) 180-220g, fasting feedwater is spent the night, 3 Oral Administration in Rats gavage 5mg/kg, 3 rat intravenous injection 0.5mg/kg.Oral administration group, 15,30 and 45 minutes and blood sampling in 1,2,4,8,12 and 24 hour before administration and after administration; Intravenously administrable group, 5,15 and 30 minutes and blood sampling in 1,2,4,8,12 and 24 hour before administration and after administration.Centrifugal 10 minutes of 3500 revs/min 4 DEG C of blood samples, collect blood plasma, in-40 DEG C of preservations.Get each time point rat plasma 20 μ L, add containing after interior target acetonitrile solution 200 μ L mixing, vortex mixed 5 minutes, 3700 revs/min centrifugal 15 minutes, getting supernatant liquor 80 μ L mixes with 80 μ L water, get mixed liquid 10 μ L and carry out LC-MS/MS (Anjelen Sci. & Tech. Inc, API4000) analysis.The main non-compartment model analysis of WinNonlin 6.3 software for pharmacokinetic parameter, result as shown in Table 5,6.

Table 5 the compounds of this invention oral administration biaavailability experimental result

Embodiment numbering	Administering mode	Bioavailability F (%)
			Eliquis	Oral	10.6
1	Oral	26.2
			4	Oral	18.1
9	Oral	29.3
			10	Oral	19.9
24	Oral	26.2
			29	Oral	28.0

Conclusion: the bioavailability of the compounds of this invention is obviously better than control compound Eliquis.

Table 6 the compounds of this invention Tmax experimental result

Embodiment numbering	Administering mode	Peak time Tmax (h)
			Eliquis	Oral	2.00
1	Oral	0.42
			2	Oral	1.33
3	Oral	1.00
			4	Oral	0.67
8	Oral	0.67
			9	Oral	0.42
10	Oral	1.17
			21	Oral	0.25
22	Oral	1.00
			24	Oral	0.25

Conclusion: the onset time of the compounds of this invention is obviously faster than control compound Eliquis.

Claims

1. the compound shown in general formula (I), or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

B is selected from 3 to 10 yuan of heterocycles, and described heterocycle contains 1 to 4 heteroatoms that is selected from N, O or S, and described heterocycle is optionally further replaced by 0 to 3 substituting group, and described substituting group is selected from R ^7aor (=O);

X is selected from O or S (=O) _p;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, R ⁷and R ^7acan form (=O);

M is selected from 0,1,2 or 3;

N is selected from 0,1,2,3 or 4;

P is selected from 0,1 or 2.

2. compound according to claim 1, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is selected from O or S;

B is selected from one of replacement or unsubstituted following structure:

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

As selection, R ⁷and R ^7acan form (=O);

M is selected from 0,1 or 2;

N is selected from 0,1 or 2;

P is selected from 0,1 or 2.

3. compound according to claim 2, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F;

B is selected from one of following structure:

R ¹, R ², R ³and R ⁴independently be selected from separately H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, cyclopropyl, methoxy or ethoxy;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

M is selected from 0,1 or 2;

P is selected from 0,1 or 2.

4. compound according to claim 3, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F;

B is selected from one of following structure:

R ¹, R ², R ³and R ⁴independently be selected from separately H, methyl or ethyl;

As selection, R ¹and R ²can form (=O);

As selection, R ³and R ⁴can form (=O);

5. compound according to claim 1, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl is optionally further replaced by 0 to 4 F;

B is selected from one of following structure:

R ¹, R ², R ³and R ⁴independently be selected from separately H or methyl;

R ⁵independently be selected from separately H, F, Cl or methyl;

6. compound according to claim 5, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

R ⁵be selected from H or F; R ⁶for formamyl.

7. compound according to claim 5, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ², R ³and R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶for formamyl;

M is 1.

8. compound according to claim 5, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ²independently be selected from separately H or methyl;

R ³, R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶be selected from formamyl or trifluoromethyl;

M is 1.

9. compound according to claim 5, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ²independently be selected from separately H or methyl;

R ³, R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶be selected from formamyl or trifluoromethyl;

M is 1.

10. compound according to claim 5, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein:

X is O;

A is phenyl, and wherein phenyl can further be replaced by 1 F;

B is selected from one of following structure:

R ¹, R ², R ³, R ⁴independently be selected from separately H;

R ⁵independently be selected from separately H or F;

R ⁶for formamyl;

M is 1.

11. according to the compound described in claim 1 or 5, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, and wherein compound is selected from one of following structure:

12. compounds according to claim 11, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein compound is selected from one of following structure:

13. according to the compound described in any one in claim 1～12, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein said salt is selected from hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2 hydroxy propanoic acid salt, oxalate, oxyacetate, salicylate, glucuronate, galacturonic hydrochlorate, citrate, tartrate, aspartate, glutaminate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, esilate, fluoroform sulphonate or their combination.

14. according to the compound described in any one in claim 1～12, or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, wherein eutectic formation comprises proline(Pro), phenylalanine, Pyrrolidonecarboxylic acid.

15. 1 kinds of pharmaceutical compositions, described pharmaceutical composition contain treatment effective dose according to the compound described in any one in claim 1～12 or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, and pharmaceutically acceptable carrier or vehicle.

Compound in 16. claims 1～12 described in any one or its steric isomer, oxynitrides, hydrate, solvate, meta-bolites, pharmaceutically acceptable salt, eutectic or prodrug, the purposes in the medicine of preparation treatment thromboembolic disorders.

17. purposes according to claim 16, wherein said thromboembolic disorders is selected from venous thrombosis, dvt formation, thrombophlebitis, cerebral artery thrombosis formation, arterial thrombosis, Coronary thrombosis, pulmonary infarction, renal infarction, cerebral embolism, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, myocardial infarction, arteriosclerosis, overworked dead, the temporary ischemic of local asphyxia, external application obstructive arterial disease, apoplexy or cerebrovascular disease.

18. contain in claim 1～14 pharmaceutically pharmaceutical agent of acceptable salt of the compound described in any one or its, wherein said pharmaceutical agent comprises: the first therapeutical agent of effective dose and the second therapeutical agent in treatment, wherein said the first therapeutical agent is pharmaceutically acceptable salt form of described compound in any claim in claim 1～14 or its, described the second therapeutical agent is to be selected from the second Xa factor inhibitor, antithrombotics, anti-platelet agents, thrombin inhibitors, at least one reagent in thrombolytic agent and fibrinolytic agent.

19. pharmaceutical agents according to claim 18, wherein said the second therapeutical agent is to be selected from warfarin, acetylsalicylic acid, clopidogrel, unfraction heparin, lower molecular weight liver rope, synthetic pentasaccharides, water frog element, Ah adding is by class, Ah a can woods, Ibuprofen BP/EP, how propionic acid of methoxy, sulindac, indomethacin, vialidon, Droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, Tirofiban, Eptifibatide, ReoPro melagatran, two sulfuric acid r-hirudins (having another name called: disulfatohirudin), tissue plasminogen activator, the tissue-type plasminogen activator of modifying, anistreplase, at least one reagent in urokinase and streptokinase.