CN105745212A - Substituted 4, 5-dihydropyrazolo [3, 4-c] pyridine-2-one spirocyclic derivative, and use thereof - Google Patents

Abstract

The present invention relates to a substituted 4, 5-dihydropyrazolo [3, 4-c] pyridine-2-one spirocyclic derivative represented by general formula (I), and use thereof. The definition of each substituent in the compound of general formula (I) is the same as the definition in the description.

Description

The Spirocyclic derivatives of substituted 4,5- dihydro-pyrazolos [3,4-c] pyridin-2-ones and application Technical field

The present invention relates to 4 replaced shown in a kind of logical formula (I), 5- dihydro-pyrazolos [3,4-c] pyridin-2-ones Spirocyclic derivatives, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt or prodrug, its preparation method and the pharmaceutical composition containing them and the purposes as coagulation factor xa inhibitors.

Background technology

At present, angiocardiopathy is to cause the one of the main reasons of human death, and its main aspect is thrombosis, and thrombosis is to be caused blood coagulation by a series of complex reaction and caused.Blood clotting is a kind of protection mechanism of organism, " can quickly and reliably seal " defect of vascular wall whereby, therefore can avoid losing blood or being preferably minimized limit.Normal haemostasis effect is maintained, i.e. bleeding and coagulation homeostasis is regulated and controled by a complex mechanism.Not modulated coagulation system activation or the inhibitory action of shortage activation process may all cause a variety of diseases and complication, such as phlebothrombosis, DVT, pulmonary embolism, atherosclerosis, acute coronary syndrome, cranial vascular disease.

In blood clotting, traditionally it is divided into endogenous and external source sexual system, intrinsic coagulation pathway refers to the process of activate the X factors after from XII factor activators to IV a-PF3Ca2+ compounds of formation；Exogenous cruor pathway, which refers to the process of be activated into from VII factor to be formed after VII a-Ca2+-TF is combined, activates Ⅹ factor.Fibrin is activated to from the X factors to be formed, is endogenous, external source blood coagulation common coagulation pathway, is played a crucial role here by the factors activated blood Xa factors formed of X.

Xa factor is a member of the serine stretch protein enzyme family of trypsin-like, and serine stretch protein enzyme family activation factor is fibrin ferment.Xa factor plays an important role in Coagulation pathways, and positioned at the initial site of enlarge-effect, a molecule factor Xa is catalyzed 1000 molecule fibrin ferments and formed.Therefore, it should be that anticoagulation is more effectively tactful that Xa factor is compared to be used for other clotting factor or downstream fibrin ferment as target spot.

Clinically conventional traditional anticoagulant includes warfarin, heparin, aspirin, chlorine than Gray etc..The medicine for being directed to factor Xa is heparin, predominantly injection type, including unfractionated heparin, low molecular weight heparin (LMWH), Fondaparinux etc., clinically easily cause severe haemorrhage and heparin-induced decrease of platelet side reaction, it is necessary to clinical detection.Compared with traditional blood-clotting agent, new coagulation factor xa inhibitors have advantages below：Orally, low bleeding risk, high efficiency, without individual adjustment and monitoring patient.List at present or included razaxaban, Eliquis, Yi Dushaban, shellfish Qu Shaban, otamixaban, Ai Lishaban (eribaxaban), LY517717, YM150, letaxaban etc. in the medicine ground.But list at present or also have some shortcomings in the new coagulation factor xa inhibitors ground, such as the solubility of razaxaban and Eliquis is very poor.

WO00039131 describe can as trypsin-like serpin, particularly nitrogenous Heterobicyclic derivatives of coagulation factor xa inhibitors, wherein X, Y, Z can be nitrogen and carbon, G selects aromatic ring or nitrogenous hetero-aromatic ring, A is a cyclic group, and B is a basic group or cyclic group.It is not considered as that it is a part of the invention to be specifically described in this patent, its structural formula is as follows：

WO00200655 describes heteroaryl-phenyl Heterobicyclic compounds and its derivative, and it is used as the purposes of coagulation factor xa inhibitors, wherein A is 5-6 members aryl or heteroaryl, G2 are that phenyl, naphthyl or 5-10 heteroaryls, Q are Heterobicyclic compounds, differed greatly with the compound structure of the present invention, its structural formula is as follows：

WO03026652A1, WO03047520, WO03048081, WO03048158, WO03099276, WO2006047528 describes the P4-P-M-M4 lactam derivatives including Eliquis, its middle ring P can be not present or be the azo-cycle or heterocycle of 5-7 members, and ring M is the carbocyclic ring or heterocycle of a 3-10 member, be not considered as that it is a part of the invention to be specifically described in this patent.

WO2004083174 describes P4-P-M-M4 tetrahydropyrimidines and sulfonyl amidino derivatives and its as serpin; the particularly application of coagulation factor xa inhibitors; its middle ring P can be not present or be the azo-cycle or heterocycle of 5-7 members; ring M is the carbocyclic ring or heterocycle of a 3-10 member, is not considered as that it is a part of the invention to be specifically described in this patent.

WO2007137801 describes the coagulation factor xa inhibitors of new nafoxidine, tetrahydro-pyrazole and pyridine, imidazolidine and pyridine and tetrahydrochysene triazolopyridine derivatives, is differed greatly with the compound structure of the present invention, relevant formula is as follows：

WO2009007028 describes 1- (4- methoxyphenyls) -7- oxos -6 [4- (oxo-piperidine -1- bases) phenyl] -4,6,5,7- tetrahydrochysenes-(1H)-pyrazolo [3.4, c] pyridine-3-carboxamide derivatives, and its it is used as the purposes of coagulation factor xa inhibitors, wherein R¹、R²For alkyl, L is substituted amido or ester group, is differed greatly with the compound structure of the present invention, relevant formula is as follows：

The present invention is that on the basis of tetrahydro pyrazolopyridines, design is novel to provide a kind of structure with the compound shown in logical formula (I), drug effect is more preferable, it is safer, toxic side effect is small, bioavilability height and the more preferable coagulation factor xa inhibitors class compound of dissolubility, available for treatment venous thronbosis, dvt is formed, Lower limb deep venous thrombosis, thrombophlebitis, cerebral artery thrombosis are formed, arterial embolism, coronary artery thrombosis is formed, pulmonary embolism, cerebral embolism, renal embolism, vena hepatica embolism, portal vein embolization, chronic disseminated intravascular coagulation, four limbs and central capilary arterial embolism, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, miocardial infarction, arteriosclerosis, ischaemic is overworked dead, temporary ischemic, external application obstructive arterial disease, apoplexy, with the aseptic thrombotic endocarditis of arterial embolism, a variety of diseases and complication caused by the thrombosis such as cranial vascular disease.

The content of the invention

The present invention relates to the compound shown in a kind of logical formula (I), or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

R¹Selected from cyano group, amino ,-(CH₂) n-C (=O) R^1a、C_1-6Alkyl ,-(CH₂)_n- S (=O)_pR^1a、-(CH₂)_n-C_1-6Alkoxy ,-(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C_3-10Carbocyclic ring or-(CH₂)_n-C_3-10Heterocycle, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the alkyl, alkoxy, carbocyclic ring and heterocycle are optionally further selected from H, F, Cl, Br, (=O), amino, hydroxyl, carboxyl, aldehyde radical, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R^1aAnd R^1bIt is independently selected from hydrogen, amino, hydroxyl ,-(CH₂)_n-C_3-10Carbocyclic ring ,-(CH₂)_n-C_3-10Heterocycle, C_1-4Alkoxy or C_1-4Alkyl, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the alkyl, carbocyclic ring and heterocycle are optionally further selected from H, F, Cl, Br, (=O), amino, hydroxyl, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R²Selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Alkoxy；

Ring M is cyclopropyl, and the cyclopropyl is optionally further by 0 to 3 R³Substitution；

R³It is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl ,-(CR^3aR^3b)_nR^3c、C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy are optionally further selected from H, F, Cl, amino, hydroxyl, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R^3a、R^3bAnd R^3cIt is independently selected from H, F, Cl, Br, I, hydroxyl, amino, C_1-4Alkyl, C_1-4Alkoxy ,-C (=O) OR^3dOr-C (=O) NR^3eR^3f；

R^3d、R^3eAnd R^3fIt is independently selected from H or C_1-4Alkyl；

R⁴Selected from H, F, Cl, Br, I, cyano group, trifluoromethyl ,-(CR^4aR^4b)_nOR^4c、-(CR^4aR^4b)_nNR^4cR^4d,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)_pR^4a、-C(R^4aR^4b)R^4c、C_3-10Carbocyclic ring or 3 to 10 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring or heterocycle are each individually optional further by 0 to 4 R^4eSubstitution；

R^4a、R^4b、R^4c、R^4dAnd R^4eIt is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, nitro, cyano group, amino, trifluoromethyl, C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy are 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 substituent of alkoxy is replaced；

Alternatively, R^4aAnd R^4bIt can be formed (=O)；

Alternatively, R^4aAnd R^4b、R^4cAnd R^4d3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring contains 0 to 3 hetero atom for being selected from N, O or S, and the ring 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 substituent of alkoxy is replaced；

Represent ring D existence or non-existences；

In the presence of ring D, ring E is selected from phenyl or 5 to 6 unit's heteroaryls, and the heteroaryl contains 1 to 3 hetero atom for being selected from N, O or S, and the phenyl or heteroaryl are optionally further by 0 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form 5 to 6 yuan of rings together, and 5 to 6 yuan of rings contain 0 to 2 hetero atom for being selected from N, O or S, and 5 to 6 yuan of rings are optionally further by 0 to 5 R⁶Substitution；

When ring D is not present, ring E is selected from phenyl or 5 to 6 unit's heteroaryls, and the heteroaryl contains 1 to 3 hetero atom for being selected from N, O or S, and the phenyl or heteroaryl are optionally further by 0 to 5 R⁵Substitution；

R⁵It is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl, C_1-4Alkyl, C_1-4Alkoxy ,-(CR^5aR^5b)_nNR^5cR^5d、-(CH₂)_nC (=NR^5c)N(R^5aR^5b)、 -(CR^5aR^5b)_n- C (=O) NR^5cR^5d、-(CR^5aR^5b)_nNR^5dC (=O) R^5c、-(CR^5aR^5b)_nOR^5c、-(CH₂)_nC (=O) R^5aOr-(CH₂)_nS (=O)_pR^5a, or these groups are each individually optional substituted, when substituted, are optionally further selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, C by 1 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R^5a、R^5b、R^5cAnd R^5dIt is independently selected from H, F, Cl, Br, I, hydroxyl, amino, C_1-4Alkyl, C_1-4Alkoxy or C_3-6Carbocyclic ring；

Alternatively, R^5aAnd R^5bIt can be formed (=O)；

Alternatively, R^5aAnd R^5b、R^5cAnd R^5d3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring contains 0 to 3 hetero atom for being selected from N, O or S, and the ring is optionally further selected from F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R⁶It is each independently selected from H, F, Cl, hydroxyl, sulfydryl, cyano group, amino, C_1-4Alkyl or C_1-4Alkoxy；

Alternatively, two R⁶It can be formed (=O)；

Alternatively, as two R⁶When being connected on same atom, 3 to 4 yuan of rings can be formed together with the atom that they are connected, the ring contains 0 to 1 hetero atom for being selected from N, O or S；

M is selected from 0,1,2,3 or 4；

N is selected from 0,1,2,3 or 4；

P is selected from 0,1 or 2.

Preferred scheme of the present invention, a kind of compound selected from shown in logical formula (I), wherein：

Ring M is cyclopropyl, the cyclopropyl optionally further by 0,1,2 or 3 R³Substitution；

R³It is each independently selected from H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, isopropoxy ,-C (=O) OCH₃,-C (=O) OCH₂CH₃Or-C (=O) NH₂, wherein it is preferred that being each independently selected from H, F, trifluoromethyl ,-C (=O) OCH₃,-C (=O) OCH₂CH₃Or-C (=O) NH₂。

Preferred scheme of the present invention, it is a kind of selected from logical formula (I) compound, wherein：Ring M is cyclopropyl.

Preferred scheme of the present invention, a kind of compound selected from shown in logical formula (I), wherein：

In the presence of ring D, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals, pyrazinyl, pyridazinyl, pyrimidine radicals or thienyl；It is preferably selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl；Further preferably it is selected from substituted or unsubstituted phenyl；When substituted, optionally by 1,2 or 3 R⁵Substitution；Ring D forms one of substituted or unsubstituted following structure together including two atoms that ring E is attached thereto：

It is wherein preferredFurther preferably

When substituted, optionally by 1,2 or 3 R⁶Substitution；

When ring D is not present, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals, pyrazinyl, pyridazinyl, pyrimidine radicals or thienyl；Wherein preferred substituted or unsubstituted phenyl, pyridine radicals or thienyl；Further preferred substituted or unsubstituted phenyl；When substituted, optionally by 1,2,3,4 or 5 R⁵Substitution.

Preferred scheme of the present invention,Selected from one of following structure：

It is preferred that R⁵It is independently selected from H, F, Cl ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, hydroxyl, amino, cyano group, trifluoromethyl, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or aminomethylene, preferably H, F, Cl ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, amino, cyano group, trifluoromethyl, methyl, methoxyl group or aminomethylene；R⁶It is independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy, preferably H, methyl, ethyl, methoxy or ethoxy；R and t are independently selected from 0,1,2 or 3.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), wherein the compound is selected from the compound shown in logical formula (II), or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

Ring M is cyclopropyl；

R is selected from 0,1,2 or 3；

T is selected from 0,1,2,3,4 or 5.

Preferred scheme of the present invention, compound shown in a kind of logical formula (II), wherein

R¹Selected from one of cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, carbamoyl, methylol, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls or substituted or unsubstituted following structure：

, when substituted, optionally further replaced by 1 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy；

R²Selected from H, F or Cl, preferably H or F；

Ring M is cyclopropyl；

R⁴Selected from cyano group, trifluoromethyl ,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)₂R^4aOr-C (R^4aR^4b)R^4c；

R^4a、R^4bAnd R^4cIt is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, nitro, cyano group, amino, trifluoromethyl, C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy optionally further by 0,1,2,3 or 4 substituents selected from F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy replace；

Alternatively, R^4aAnd R^4bIt can be formed (=O)；

Alternatively, R^4aAnd R^4b3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring is selected from substitution or cyclopropyl, cyclobutyl, cyclopenta, pentylenetetrazole base, isoxazolyl, imidazole radicals, pyridine radicals or the phenyl for substitution, it is preferred that cyclopropyl, pentylenetetrazole base or pyridine radicals, further preferred cyclopropyl, when substituted, optionally by 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy replace；

R⁵It is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl, C_1-4Alkyl, C_1-4Alkoxy ,-(CR^5aR^5b)_nNR^5cR^5d、-(CH₂)_nC (=NR^5c)N(R^5aR^5b) or-(CH₂)_nS (=O)_pR^5a, preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl, C_1-4Alkyl, C_1-4Alkoxy ,-C (=NR^5c)N(R^5aR^5b)、-(CH₂)_nNH-C_1-4Alkyl ,-(CH₂)_nNH₂、-(CH₂)_nS (=O)_p-C_1-4Alkyl or-(CH₂)_nS (=O)_p-NH₂, described alkyl or alkoxy optionally further by 0,1,2,3 or 4 selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, methyl, ethyl, the substituent of methoxy or ethoxy are replaced.

R^5a、R^5b、R^5cAnd R^5dIt is independently selected from H, hydroxyl, C_1-4Alkyl or C_1-4Alkoxy, preferably H, hydroxyl, methyl, ethyl, isopropyl, methoxy or ethoxy；

R⁶It is each independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy, preferably H, methyl, ethyl, methoxy or ethoxy, further preferred H, methyl or ethyl.

Preferred scheme of the present invention, compound shown in a kind of logical formula (II), wherein

R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, methylol, carbamoyl, methoxymethylene, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,One of or substituted or unsubstituted following structure：When substituted, optionally further replaced by 1 to 4 selected from H, F, Cl, (=O), hydroxyl or methyl substituents；

R²Selected from H, F or Cl, preferably H or F；

Ring M is cyclopropyl；

R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, hydroxy methylene, 1- hydroxyethyls, carbamoyl ,-S (=O)₂-CH₃, 1- hydroxycyclopropyls or 2- hydroxyisopropyls, preferably cyano group, trifluoromethyl, carbamoyl or-S (=O)₂-CH₃。

R⁵It is each independently selected from H, F, Cl, hydroxyl, amino, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, trifluoromethyl, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene, preferably H, F, Cl, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene, further preferred H, F, Cl, cyano group, methoxyl group, ethyoxyl or aminomethylene；

R⁶It is each independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy, preferably H, methyl, ethyl, methoxy or ethoxy, further preferred H, methyl or ethyl.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), wherein the compound is selected from the compound shown in logical formula (III), or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

Ring M is cyclopropyl；

R` is selected from 0,1,2,3,4 or 5.

Preferred scheme of the present invention, compound shown in a kind of logical formula (III), wherein

R¹Selected from one of cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, carbamoyl, methylol, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls or substituted or unsubstituted following structure：

, when substituted, optionally further replaced by 1 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy；

R²Selected from H, F or Cl, preferably H or F；

Ring M is cyclopropyl；

R⁴Selected from cyano group, trifluoromethyl ,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)₂R^4aOr-C (R^4aR^4b)R^4c；

R^4a、R^4bAnd R^4cIt is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, nitro, cyano group, amino, trifluoromethyl, C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy optionally further by 0,1,2,3 or 4 substituents selected from F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy replace；

Alternatively, R^4aAnd R^4bIt can be formed (=O)；

Alternatively, R^4aAnd R^4b3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring is selected from substitution or cyclopropyl, cyclobutyl, cyclopenta, pentylenetetrazole base, isoxazolyl, imidazole radicals, pyridine radicals or the phenyl for substitution, it is preferred that cyclopropyl, pentylenetetrazole base or pyridine radicals, further preferred cyclopropyl, when substituted, optionally by 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy replace；

R⁵It is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl, C_1-4 Alkyl, C_1-4Alkoxy ,-(CR^5aR^5b)_nNR^5cR^5d、-(CH₂)_nC (=NR^5c)N(R^5aR^5b) or-(CH₂)_nS (=O)_pR^5a, preferably H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl, C_1-4Alkyl, C_1-4Alkoxy ,-C (=NR^5c)N(R^5aR^5b)、-(CH₂)_nNH-C_1-4Alkyl ,-(CH₂)_nNH₂、-(CH₂)_nS (=O)_p-C_1-4Alkyl or-(CH₂)_nS (=O)_p-NH₂, described alkyl or alkoxy optionally further by 0,1,2,3 or 4 substituents selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, methyl, ethyl, methoxy or ethoxy replace.

R^5a、R^5b、^R5cAnd R^5dIt is independently selected from H, hydroxyl, C_1-4Alkyl or C_1-4Alkoxy, preferably H, hydroxyl, methyl, ethyl, isopropyl, methoxy or ethoxy.

Preferred scheme of the present invention, compound shown in a kind of logical formula (III), wherein

R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, carbamoyl, methylol, methoxymethylene, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,One of or substituted or unsubstituted following structure：When substituted, optionally further replaced by 1 to 4 selected from H, F, Cl, (=O), hydroxyl or methyl substituents；

R²Selected from H, F or Cl, preferably H or F；

Ring M is cyclopropyl；

R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, hydroxy methylene, 1- hydroxyethyls, carbamoyl ,-S (=O)₂-CH₃, 1- hydroxycyclopropyls or 2- hydroxyisopropyls, preferably cyano group, trifluoromethyl, carbamoyl or-S (=O)₂-CH₃。

R⁵It is each independently selected from H, F, Cl, hydroxyl, amino, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, trifluoromethyl, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene, preferably H, F, Cl, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene, further preferred H, F, Cl, cyano group, methoxyl group, ethyoxyl or aminomethylene.

Preferred scheme of the present invention, compound, wherein R shown in a kind of logical formula (I), (II) and (III)⁵It is each independently selected from substituted or unsubstituted H, F, Cl, Br, I ,-C (=NR^5c)N(R^5aR^5b)、-(CH₂)_nS (=O)_pR^5a, hydroxyl, sulfydryl, cyano group, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, cyclopropyl epoxide or aminomethylene；

It is preferred that substituted or unsubstituted H, F, Cl, Br, I ,-C (=NR^5c)N(R^5aR^2b)、-(CH₂)_nS (=O)_pR^5a, hydroxyl Base, sulfydryl, cyano group, amino, trifluoromethyl, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl epoxide or aminomethylene,

Further preferred H, F, Cl ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, amino, trifluoromethyl, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene；

When substituted, optionally by 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, isopropyl, methoxy or ethoxy replace；

R^5a、R^5bAnd R^5cIt is independently selected from H, F, Cl, Br, I, hydroxyl, amino, C_1-4Alkyl or C_1-4Alkoxy, preferably H, F, Cl, Br, I, hydroxyl, amino, methyl, ethyl or isopropyl.

Preferred scheme of the present invention, a kind of logical formula (I) and compound, wherein R shown in (II)⁶It is each independently selected from H, F, Cl, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl or propoxyl group, preferably H, F, Cl, methyl, ethyl, methoxy or ethoxy；

Alternatively, as two R⁶When being connected on same atom, 3 to 4 yuan of rings can be formed together with the atom that they are connected, 3 to 4 yuan of rings contain 0 to 1 hetero atom for being selected from N, O or S, are preferably formed as cyclopropyl；

Alternatively, two R⁶It can be formed (=O).

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：

R¹Selected from cyano group, amino ,-(CH₂) n-C (=O) R^1a、C_1-6Alkyl ,-(CH₂)_n- S (=O)_pR^1a、-(CH₂)_n-C_1-6Alkoxy ,-(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C_3-7Carbocyclic ring or-(CH₂)_n-C_3-7Heterocycle, preferably cyano group, amino ,-(CH₂)_n- C (=O) R^1a、C_1-4Alkyl ,-(CH₂)_n- S (=O)_pR^1a、-(CH₂)_n-C_1-4Alkoxy ,-(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C₃Carbocyclic ring ,-(CH₂)_n-C₄Carbocyclic ring ,-(CH₂)_n-C₅Carbocyclic ring ,-(CH₂)_n-C₆Carbocyclic ring ,-(CH₂)_n-C₃Heterocycle ,-(CH₂)_n-C₄Heterocycle ,-(CH₂)_n-C₅Heterocycle or-(CH₂)_n-C₆Heterocycle, further preferred cyano group, amino, C_1-4Alkyl, C_1-4Alkoxy ,-(CH₂)_n- S (=O)_pR^1a、-(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C₅Carbocyclic ring ,-(CH₂)_n-C₆Carbocyclic ring ,-(CH₂)_n-C₅Heterocycle or-(CH₂)_n-C₆Heterocycle, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the alkyl, alkoxy, carbocyclic ring, heterocycle are optionally further selected from H, F, Cl, (=O), amino, hydroxyl, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

R^1aAnd R^1bIt is independently selected from hydrogen, amino, hydroxyl, C_1-4Alkyl ,-(CH₂)_n-C₃Carbocyclic ring ,-(CH₂)_n-C₄Carbocyclic ring ,-(CH₂)_n-C₅Carbocyclic ring ,-(CH₂)_n-C₆Carbocyclic ring ,-(CH₂)_n-C₃Heterocycle ,-(CH₂)_n-C₄Heterocycle ,-(CH₂)_n-C₅Heterocycle or-(CH₂)_n-C₆Heterocycle, preferably hydrogen, hydroxyl, C_1-4Alkyl ,-(CH₂)_n-C₃Carbocyclic ring or-(CH₂)_n-C₄Carbocyclic ring, further preferred hydrogen, hydroxyl, methyl, ethyl, isopropyl, cyclopropylmethylene or cyclobutyl, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the alkyl, carbocyclic ring and heterocycle are optionally further selected from H, F, Cl, Br, (=O), amino, hydroxyl, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

N is selected from 0,1,2 or 3.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：

R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, methoxyl group, ethyoxyl, methylol, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls ,-(CH₂)_n- C (=O) R^1a、-(CH₂)_n- S (=O)_pR^1a、-(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n-C_3-6Heterocycle, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring and heterocycle are optionally further replaced by 0 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy；

R^1aAnd R^1bIt is independently selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopenta, cyclohexyl, pyrrole radicals, piperidyl, morpholinyl, thio-morpholinyl or cyclopropylmethylene；

N is selected from 0,1,2 or 3.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：R¹Selected from one of cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, methylol, carbamoyl, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls or substituted or unsubstituted following structure：

, when substituted, optionally further replaced by 1 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, methylol, carbamoyl, methoxymethylene, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,One of or substituted or unsubstituted following structure：When substituted, optionally further replaced by 1 to 4 selected from H, F, Cl, (=O), hydroxyl or methyl substituents.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：R²Selected from H, F or Cl, preferably H or F.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：R⁴Selected from cyano group, trifluoromethyl ,-(CR^4aR^4b)_nOR^4c、-(CR^4aR^4b)_nNR^4cR^4d,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)₂R^4aOr-C (R^4aR^4b)R^4c, preferably cyano group, trifluoromethyl ,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)₂R^4aOr-C (R^4aR^4b)R^4c,

R^4a、R^4bAnd R^4cIt is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, nitro, cyano group, amino, trifluoromethyl, C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy optionally further by 0,1,2,3 or 4 substituents selected from F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy replace；R^4a、R^4bAnd R^4cIt is preferred that H, F, hydroxyl, cyano group, amino, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl or isopropoxy；R^4a、R^4bAnd R^4cFurther preferred H, F, hydroxyl, amino, methyl, ethyl, propyl group or isopropyl；

Alternatively, R^4aAnd R^4bIt can be formed (=O)；

Alternatively, R^4aAnd R^4b3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring is selected from substitution or cyclopropyl, cyclobutyl, cyclopenta, pentylenetetrazole base, isoxazolyl, imidazole radicals, pyridine radicals or the phenyl for substitution, preferably cyclopropyl, pentylenetetrazole base or pyridine radicals；Further preferred cyclopropyl.When substituted, optionally by 1,2,3 or 4 substituents selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl or isopropoxy replace；

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), (II) and (III), wherein：R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, hydroxy methylene, 1- hydroxyethyls, carbamoyl ,-S (=O)₂-CH₃, 1- hydroxycyclopropyls or 2- hydroxyisopropyls, preferably cyano group, trifluoromethyl, carbamoyl or-S (=O)₂-CH₃。

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), wherein：

R¹Selected from one of cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, methylol, carbamoyl, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls or substituted or unsubstituted following structure：

, when substituted, optionally further replaced by 1 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy；

R²Selected from H, F or Cl；

Ring M is cyclopropyl；

R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, carbamoyl ,-S (=O)₂CH₃, 1- hydroxyls Ethyl, hydroxymethyl, 1- hydroxycyclopropyls or 2- hydroxyisopropyls；

In the presence of ring D, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl, when substituted, optionally by 1 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form one of substituted or unsubstituted following structure together：When substituted, optionally by 1 to 3 R⁶Substitution；

When ring D is not present, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl, when substituted, optionally by 1 to 5 R⁵Substitution.

R⁵It is each independently selected from H, F, Cl, hydroxyl, amino, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, trifluoromethyl, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene；

R⁶It is each independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy；

Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), wherein：

R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, methylol, carbamoyl, methoxymethylene, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,One of or substituted or unsubstituted following structure：When substituted, optionally further replaced by 1 to 4 selected from H, F, Cl, (=O), hydroxyl or methyl substituents；

R²Selected from H or F；

Ring M is cyclopropyl；

R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, carbamoyl ,-S (=O)₂CH₃, 1- hydroxyethyls, hydroxymethyl, 1- hydroxycyclopropyls or 2- hydroxyisopropyls, preferably cyano group, trifluoromethyl, carbamoyl or-S (=O)₂CH₃；

When ring D is not present, ring E is phenyl, the phenyl optionally further by 0,1,2,3,4 or 5 R⁵Substitution；

In the presence of ring D, ring E is phenyl, the phenyl optionally further by 0,1,2 or 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form substituted or unsubstituted togetherWhen substituted, optionally by 1,2 or 3 R⁶Substitution；

R⁵It is each independently selected from H, F, Cl, hydroxyl, amino, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, trifluoromethyl, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene, preferably H, F, Cl, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene, further preferred H, F, Cl, cyano group, methoxyl group, ethyoxyl or aminomethylene；

R⁶It is each independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy, preferably H, methyl, ethyl, methoxy or ethoxy, further preferred H, methyl or ethyl；

Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.

Preferred scheme of the present invention, compound shown in a kind of logical formula (I), wherein：

R¹Selected from cyano group, methylol, aldehyde radical, carbamoyl, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,

R²Selected from H or F；

Ring M is cyclopropyl；

R⁴Selected from cyano group, trifluoromethyl, carbamoyl or-S (=O)₂CH₃；

When ring D is not present, ring E is phenyl, and the phenyl is optionally further by 0 to 5 R⁵Substitution；

In the presence of ring D, ring E is phenyl, and the phenyl is optionally further by 0 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form substituted or unsubstituted togetherWhen substituted, optionally by 1 to 3 R⁶Substitution；

R⁵It is each independently selected from H, F, Cl, cyano group, methoxyl group or aminomethylene；

R⁶It is each independently selected from H, F, Cl or methyl；

Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.

A kind of preferred scheme of the present invention, compound shown in logical formula (I), wherein compound is selected from：

The compounds of this invention of the present invention or its pharmaceutically acceptable salt, wherein described salt is selected from hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, malate, oxalates, tartrate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, trifluoroacetic acid, fluoroform sulphonate or combinations thereof, preferably maleate, fumarate, trifluoroacetic acid or fluoroform sulphonate.

A kind of pharmaceutical composition of the present invention, described pharmaceutical composition contains at least one the compounds of this invention for the treatment of effective dose, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt or prodrug, and pharmaceutically acceptable carrier or excipient.

Further, the compounds of this invention of the present invention, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt or prodrug, the purposes in the medicine in preparing the treatment disease relevant with serine protease.

The preferred scheme of the present invention, wherein the disease relevant with serine protease is selected from thromboembolic disorders.

The preferred scheme of the present invention, wherein the serine protease is selected from factor Xa.

The preferred scheme of the present invention, wherein thromboembolic disorders are selected from arterial cardiovascular thromboembolic disorders, intravenous cardio thromboembolic disorders and heart related thromboembolic disorders.

The preferred scheme of the present invention, wherein thromboembolic disorders are selected from venous thronbosis, dvt is formed, Lower limb deep venous thrombosis, thrombophlebitis, cerebral artery thrombosis are formed, arterial embolism, coronary artery thrombosis is formed, pulmonary embolism, cerebral embolism, renal embolism, vena hepatica embolism, portal vein embolization, chronic disseminated intravascular coagulation, four limbs and central capilary arterial embolism, atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, miocardial infarction, arteriosclerosis, ischaemic is overworked dead, temporary ischemic, external application obstructive arterial disease, apoplexy, with the aseptic thrombotic endocarditis of arterial embolism, cranial vascular disease.

The invention further relates to treat the method for thromboembolic disorders.This method includes giving the pharmaceutical agent for including compound of the present invention or its pharmaceutically acceptable salt of effective dose in patient's treatment.The described compound of the present invention can combine other therapeutic agent administrations.

The present invention relates to the pharmaceutical agent containing compound of the present invention or its pharmaceutically acceptable salt, the pharmaceutical agent can be joint product, including first and second kinds of therapeutic agents that the host so treated applies the upper effective dose for the treatment of are needed to one.Wherein the first therapeutic agent is the compound or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug of the present invention, and second therapeutic agent be selected from the Two kinds of clotting factor Xa factor inhibitors, at least one of a kind of anti-coagulants, a kind of anti-platelet agents, a kind of thrombin inhibitor, a kind of thrombolytic agent and a kind of fibrin solvent agent reagent.

The present invention preferred scheme, wherein second of therapeutic agent be selected from warfarin, unfraction heparin, low molecule amount liver rope, synthesis pentasaccharides, hirudin, argatroban, aspirin, brufen, methoxy how propionic acid, sulindac, Indomethacin, mefenamic acid, drogelor, Diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, Eptifibatide, Abciximab melagatran, two sulfuric acid hirudins (also known as：Disulfatohirudin), at least one of tissue plasminogen activator, tissue-type plasminogen activator, anistreplase, urokinase and the streptokinase of modification reagent.

The preferred scheme of the present invention, wherein second of therapeutic agent is at least one anti-platelet agents.

The preferred scheme of the present invention, wherein the anti-platelet agents are aspirin and/or clopidogrel.

The preferred scheme of the present invention, wherein the anti-platelet agents are clopidogrels.

Unless there are opposite statement, the term used in the specification and in the claims has following implications.

During the present invention relates to being replaced by multiple substituents, each substituent can be with identical or differ.

During the present invention relates to containing multiple hetero atoms, each hetero atom can be with identical or differ.

Involved elemental carbon, hydrogen, oxygen, sulphur, nitrogen or halogen include their isotope situation in group of the present invention and compound, and involved elemental carbon, hydrogen, oxygen, sulphur or nitrogen is optionally further substituted by their one or more corresponding isotopes in group of the present invention and compound, the isotope of wherein carbon includes¹²C、¹³C and¹⁴C, the isotope of hydrogen includes protium (H), deuterium (D is called heavy hydrogen), tritium (T is called superheavy hydrogen), and the isotope of oxygen includes¹⁶O、¹⁷O and¹⁸O, the isotope of sulphur includes³²S、³³S、³⁴S and³⁶S, the isotope of nitrogen includes¹⁴N and¹⁵N, the isotope of fluorine¹⁹F, the isotope of chlorine includes³⁵Cl and³⁷Cl, the isotope of bromine includes⁷⁹Br and⁸¹Br。

Term " alkyl " refers to the aliphatic hydrocarbon groups of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.The alkyl of 1 to 10 carbon atom is preferably comprised, non-limiting example includes, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, n-nonyl, and its various branched chain isomers etc.；Low alkyl group more preferably containing 1 to 4 carbon atom, non-limiting example includes methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group or tert-butyl group etc..Alkyl can be substituted or unsubstituted; when substituted; substituent is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or heterocycle alkane sulfydryl.

" alkoxy " refers to-O- alkyl, and wherein alkyl is as herein above defined.Alkoxy can be substituted or unsubstituted, and its non-limiting example includes, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy, Amoxy or hexyloxy, preferably with 1 to 12 yuan of alkoxy.When substituted; substituent is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" alkoxyalkyl " refers to the alkyl being connected with alkoxy.Alkoxyalkyl can be substituted or unsubstituted, its non-limiting example includes, methoxy, methoxy ethyl, ethoxyl methyl, ethoxyethyl group, propoxy methyl, Among, i-propoxymethyl, butoxypropyl, t-butoxy ethyl, amoxy ethyl, hexyloxyehtyl, cyclopropyl epoxide methyl, cyclopropyl epoxide ethyl, cyclopropyl epoxide propyl group or cyclohexyloxy methyl；When substituted; substituent is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" alkenyl " refers in the alkyl that the present invention is defined that, comprising at least one carbon-to-carbon double bond, the alkenyl contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, further preferred 2 to 8 carbon atoms.The non-limiting examples of alkenyl include substituted or unsubstituted vinyl, 2- acrylic, 3- cyclobutenyls, 2- cyclobutenyls, 4- pentenyls, 3- pentenyls, 2- hexenyls, 3- hexenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 3- octenyls, 3- nonenyls or 4- decene bases etc., when substituted, substituent is preferably 1 to 5, independently selected from F, Cl, Br, I,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" alkynyl " refers in the alkyl that the present invention is defined that, comprising at least one carbon-to-carbon triple bond, the 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 include substituted or unsubstituted acetenyl, 1- propinyls, 2-propynyl, 1- butynyls, 2- butynyls, 3- butynyls, 4- pentynyls, 3- pentynyls, 2- hexin bases, 3- hexin bases, 3- butynyls, 2- heptynyls, 3- heptynyls, 4- heptynyls, 3- octynyls, 3- n-heptylacetylenes base or 4- decynyls etc., when substituted, substituent is preferably 1 to 5, independently selected from F, Cl, Br, I,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" carbocyclic ring " refers to saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings or it is non-aromatic can be 3 to 8 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, carbocyclic ring can be connected with bridged ring or loop coil, and non-limiting example includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclohexenyl group, suberyl, cyclopentene, ring Hexadiene, cycloheptatriene, phenyl, naphthyl, benzo cyclopenta, two rings [3.2.1] octyl, two rings [5.2.0] nonyl, three rings [5.3.1.1] dodecyl, adamantyl or spiral shell [3.3] heptane base etc..Carbocyclic ring can be substituted; when substituted; substituent is preferably 1 to 5, independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkane sulfydryl, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" heterocycle " refers to substituted or unsubstituted saturation or undersaturated aromatic rings or non-aromatic ring, aromatic rings and non-aromatic ring can be 3 to 8 yuan monocyclic, 4 to 12 membered bicyclics or 10 to 15 membered tricyclic systems, and be made up of at least one hetero atom for being selected from N, O or S, it is preferred that N, S for selectively replacing in 3 to 10 circle heterocycles, the ring of heterocycle can be oxidized to various oxidation state.Heterocycle can be connected on hetero atom or carbon atom.Heterocycle can be connected with bridged ring or loop coil, non-limiting example includes, oxirane, aziridinyl, oxetanylmethoxy, azelidinyl, 1, 3- dioxolanes, 1, 4- dioxolanes, 1, 3- dioxane, azacycloheptyl, pyridine radicals, furyl, thienyl, pyranose, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, piperidyl, piperazine stings base, morpholinyl, thio-morpholinyl, 1, 3- dithiane, dihydrofuran, dihydropyran, the ring of two thiophene penta, tetrahydrofuran, nafoxidine base, imidazolidine, tetrahydro-thiazoles, oxinane, benzimidazole, 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 etc.；When substituted; substituent is preferably 1 to 5, and substituent is independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" amino " refers to-NH₂Can be substituted or unsubstituted; when substituted; substituent is preferably 1 to 3, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, hydroxyl, amino, alkyl amino, alkyl acylamino, Heterocyclylalkyl, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, hydroxy alkyl, carboxylic acid or carboxylate.

" aryl " refers to that substituted or unsubstituted 6 to 14 yuan full carbon are monocyclic or thick and polycyclic moiety, and the polycyclic moiety of the pi-electron system with conjugation, preferably 6 to 10 yuan aromatic rings, its non-limiting example includes phenyl or naphthyl；The aryl can with it is thick and with heteroaryl, heterocyclic radical or cycloalkyl, and the part being connected with precursor structure is aryl, and its non-limiting example includes benzofuran, benzocyclopentane base or benzothiazole etc..When substituted; substituent is preferably 1 to 5, and substituent is independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

" heteroaryl " refers to substituted or unsubstituted 5 to 15 yuan of aromatic rings, and it is selected from N, O or S hetero atom containing 1 to 3, it is preferred that 5 to 10 yuan of aromatic rings, the non-limiting example of heteroaryl includes pyridine radicals, furyl, thienyl, N- alkyl pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, benzofuran, benzimidazole, benzo pyridine or pyrrolopyridine etc..When substituted; substituent is preferably 1 to 5, and substituent is independently selected from F, Cl, Br, I ,=O, alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, sulfydryl, hydroxyl, nitro, cyano group, amino, alkyl acylamino, cycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkyl sulfydryl, hydroxy alkyl, carboxylic acid, carboxylate or Heterocyclylalkyl sulfydryl.

The present invention "=O " be this area ordinary practice usage, refer to double bond be connected oxygen atom, the double bond oxygen atom being for example connected in carbonyl with carbon atom.

" pharmaceutically acceptable salt " refers to the salt of pharmaceutically acceptable non-toxic acid or alkali, including inorganic bronsted lowry acids and bases bronsted lowry, the salt of organic bronsted lowry acids and bases bronsted lowry.Salt derived from inorganic base includes but is not limited to the metal salt of Al, Ca, Li, My, K, Na and Zn formation；Salt derived from organic base includes but is not limited to primary amine, the salt of secondary amine or tertiary amine, including naturally occurring substituted or unsubstituted amine, cyclammonium and deacidite, such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanol amine, monoethanolamine, dimethylethanolamine, DMAE, 2- DEAE diethylaminoethanols, dicyclohexylamine, caffeine, procaine, choline, glycine betaine, Benethamine Penicillin, ethylenediamine, gucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidyl, N-ethylpiperidine base or the organic salt of polyamino resin formation；Salt derived from inorganic acid and organic acid includes but is not limited to sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzene sulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, butanedioic acid, sulfanilic acid, tartaric acid, p-methyl benzenesulfonic acid, malonic acid, 2 hydroxy propanoic acid, oxalic acid, glycolic, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, L-aminobutanedioic acid, cinnamic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, the organic salt of the formation such as ethyl sulfonic acid or trifluoromethanesulfonic acid.

" eutectic " refers to active pharmaceutical ingredient (active pharmaceutical ingredient,) and eutectic formation (cocrystal former API, CCF) the crystal being combined into the presence of hydrogen bond or other non-covalent bonds, wherein API and CCF pure state is the presence of fixed stoichiometric proportion between solid, and each component at room temperature.Eutectic is a kind of multicomponent crystal, both comprising the binary eutectic formed between two kinds of neutral solids, also the multi-element eutectic comprising neutral solid and the formation of salt or solvate." the eutectic formation " includes but is not limited to various pharmaceutically acceptable acid, alkali, non-ionic compound, and its non-limiting example includes alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), proline (Pro), phenylalanine (Phe), tryptophan (Trp), methionine (Met), glycine (Gly), silk ammonia Sour (Ser), threonine (Thr), cysteine (Cys), tyrosine (Tyr), asparagine (Asn), glutamine (Gln), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzene sulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, furancarboxylic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, butanedioic acid, sulfanilic acid, tartaric acid, p-methyl benzenesulfonic acid, malonic acid, 2 hydroxy propanoic acid, oxalic acid, glycolic, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, L-aminobutanedioic acid, cinnamic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, ethyl sulfonic acid or trifluoromethanesulfonic acid, ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanol amine, monoethanolamine, dimethylethanolamine, DMAE, 2- DEAE diethylaminoethanols, dicyclohexylamine, caffeine, procaine, choline, glycine betaine, Benethamine Penicillin, ethylenediamine, gucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidyl, N-ethylpiperidine base.

" stereoisomer " refers to as the isomers produced by the spatially arrangement mode difference of atom in molecule, including cis-trans-isomer, enantiomter and rotamer.

" pharmaceutical composition " represents compound described in one or more texts or its physiology/pharmaceutically acceptable salt or pro-drug and the mixture of other chemical constituents, other components such as physiology/pharmaceutically acceptable carrier and excipient.The purpose of pharmaceutical composition is to promote the administration of compound on organism body.

" prodrug " refers to that the compounds of this invention with bioactivity can be converted into physiological conditions or by solvolysis.The prodrug of the present invention is prepared by modifying the functional group in the compound, operation or be removed in vivo that the modification can be routinely, and obtains parent compound.A hydroxyl, amino or the sulfydryl that prodrug is included in the compounds of this invention are connected to the compound formed on any group, when the prodrug of the compounds of this invention is delivered to mammalian subject, prodrug is isolated and forms free hydroxyl, free amino or free thin base respectively.The example of prodrug includes but is not limited to, the compound that the hydroxyl or amino-functional group in the compounds of this invention are formed with formic acid, acetic acid or benzoic acid.

" optional ", " optional " or " optionally " mean described later ground event or environment can with but need not occur, including the event or environment generation or the occasion not occurred.For example, " aryl is optionally replaced by alkyl " mean alkyl can with but necessarily exist, the explanation include aryl by alkyl-substituted situation and aryl not by alkyl-substituted situation.

" substituted or unsubstituted " refers to the situation that group can be substituted or unsubstituted, if not pointing out in the present invention, group can be substituted, then it represents that the group is unsubstituted situation.

" alternatively " refer to that the scheme after " alternatively " and the scheme before " alternatively " they are coordination, rather than Further selection situation in the case of front.

" substitution " refers to that one or more hydrogen atoms are by the situation of other substituent groups in group, if described group is replaced by hydrogen atom, the group of formation is identical with the group replaced by hydrogen atom.The substituted situation of group, such as amino, C_1-4Alkyl, C_1-4Alkoxy, C_3-6Carbocyclic ring, 3 to 6 circle heterocycles optionally further by 0,1,2,3 or 4 be selected from H, F, Cl, Br, I, hydroxyl, cyano group, amino, C_1-4Alkyl or C_1-4The substituent of alkoxy is replaced, and the group of formation includes but is not limited to methyl, chloromethyl, trichloromethyl, hydroxymethyl ,-CH₂OCH₃、-CH₂SH、-CH₂CH₂CN、-CH₂NH₂、-NHOH、-NHCH₃、-OCH₂Cl、-OCH₂OCH₂CH₃、-OCH₂CH₂NH₂、-OCH₂CH₂SH、-OCH₂CH₂OH, 1- hydroxycyclopropyl, 2- hydroxycyclopropyls, 2- amino cyclopropyl, 4- methylfurans base, 2- hydroxy phenyls, 4- aminophenyls, phenyl.

Embodiment

Technical scheme is described in detail below in conjunction with drawings and Examples, but protection scope of the present invention includes but is not limited to this.

The structure of compound by nuclear magnetic resonance (NMR) or (and) mass spectrum (MS) determines.NMR displacements (δ) are with 10^-6(ppm) unit is provided.NMR measure is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, and measure solvent is deuterated dimethyl sulfoxide (DMSO-d₆), deuterochloroform (CDCl₃), deuterated methanol (CD₃OD), inside it is designated as tetramethylsilane (TMS).

MS measure uses (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

HPLC measure uses Agilent 1260DAD high pressure liquid chromatographs (100 × 4.6mm of Zorbax SB-C18).

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, and the specification that the silica gel plate that thin-layered chromatography (TLC) is used is used is 0.15mm~0.20mm, and the specification that thin-layer chromatography isolates and purifies product use is 0.4mm~0.5mm.

Column chromatography is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.

Oneself initiation material known of the present invention can be used or synthesized according to methods known in the art, or be can purchase in the smooth science and technology of Thailand, pacified the companies such as silent resistance to Jilin Chemical, Shanghai moral, the imperial chemical industry of Chengdu section, splendid remote chemistry science and technology, lark prestige science and technology.

Blanket of nitrogen refers to that reaction bulb connects the nitrogen balloon of an about 1L volume.

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

Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.

Without specified otherwise in embodiment, reaction is carried out under nitrogen atmosphere.

Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature.

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

Et, ethyl；

Me, methyl；

Bn, benzyl；

Bz, benzoyl；

Intermediate 1

1- (4- methoxyphenyls) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 1)

ethyl 1-(4-methoxyphenyl)-7-oxo-spiro[5,6-dihydropyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

The first step：(1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) methanol (1b)

(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol

Under ice bath, to 1,1- cyclopropane dimethanols (10.0g, 97.90mmol) dichloromethane solution (200mL) in, add imidazoles (10.0g, 146.90mmol), tert-butyl chloro-silicane (14.7g is added dropwise, after dichloromethane solution (80mL) 97.90mmol), completion of dropping, room temperature reaction 7 hours is warming up to.Under ice bath, water (100mL) is added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (70mL × 3), merge organic phase, organic phase anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=40:1~10:1) title compound (1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) methanol (1b), colorless oil (8.5g, yield 40%) is obtained.

¹H NMR(300MHz,CDCl₃)δ3.61(s,2H),3.56(s,2H),2.68(s,1H),0.90(s,9H),0.53-0.49(m,2H),0.46-0.44(m,2H),0.06(s,6H)。

Second step：(1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) formaldehyde (1c)

1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropanecarbaldehyde

Under ice bath, to (1- (((fert-butyidimethylsilyl=silylation) epoxide) methyl) cyclopropyl) methanol (1b) (8.5g, in dichloromethane solution (250mL) 39.30mmol), this Martin's oxidant (20.1g is worn in addition, 47.40mmol), rear room temperature stirring reaction is added 5 hours.Under ice bath, saturated sodium bicarbonate solution (70mL) is added into reaction solution, filtering, after filtrate point liquid, organic phase is washed with water (50mL), with anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=40:1) title compound (1- (((tertbutyldimethylsilyl chloride alkyl) epoxide) methyl) cyclopropyl) formaldehyde (1c), light yellow oil (8.3g, yield 99%) is obtained.

¹H NMR(300MHz,CDCl₃)δ8.95(s,1H),3.86(s,2H),1.07-1.00(m,4H),0.82(s,9H),0.02(s,6H)。

MS m/z(ESI)：215.1[M+1].

3rd step：(E) -3- (1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) ethyl acrylate (1d)

(E)-ethyl 3-(1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)acrylate

Under ice bath; to sodium hydride (320mg; in tetrahydrofuran solution (20mL) 13.40mmol); phosphonoacetate (2.76g is added dropwise; 12.40mmol); after completion of dropping; it is warming up to room temperature reaction 20 minutes; (1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) formaldehyde (1c) (2.2g is added dropwise; tetrahydrofuran (10mL) solution 10.3mmol); after completion of dropping, react at room temperature 2 hours.Water (50mL) is added into reaction solution, extracted with ethyl acetate (50mL × 2), merge organic phase, organic phase anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=30:1) title compound (E) -3- (1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) ethyl acrylate (1d) is obtained, colorless oil (1.5g, yield 52%).

¹H NMR(300MHz,CDCl₃)δ6.68(d,1H),5.84(d,1H),4.21(q,2H),3.68(s,2H),1.30(t,3H),0.97-0.94(m,2H),0.88(s,9H),0.79-0.77(m,2H),0.04(s,6H)。

4th step：(E) -3- (1- (methylol) cyclopropyl) acrylate (1e)

(E)-ethyl 3-(1-(hydroxymethyl)cyclopropyl)acrylate

Under ice bath, to (E) -3- (1- (((t-butyldimethylsilyi) epoxide) methyl) cyclopropyl) ethyl acrylate (1d) (27.0g, in tetrahydrofuran (300mL) solution 94.90mmol), hydrochloric acid (330mL is added dropwise, 949mmol), after completion of dropping, react 1 hour.Reaction solution is extracted with ethyl acetate (100mL × 3), merges organic phase, organic phase anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=8:1) title compound (E) -3- (1- (methylol) cyclopropyl) acrylate (1e), colourless liquid (10.0g, yield 63%) are obtained.

¹H NMR(300MHz,CDCl₃)δ6.64(d,1H),5.98(d,1H),4.20(q,2H),3.65(s,2H),1.82(s,1H),1.29(t,3H),0.97-0.86(m,4H)。

MS m/z(ESI)：171.1[M+1].

5th step：(E) -3- (1- (Methanesulfonvloxvmethvl) cyclopropyl) propyl- 2- olefin(e) acids ethyl ester (1f)

ethyl(E)-3-[1-(methylsulfonyloxymethyl)cyclopropyl]prop-2-enoate

(E) -3- (1- (methylol) cyclopropyl) acrylate (1e) (17g is added into reaction bulb, 100mmol), add dichloromethane (100mL), triethylamine (21mL, 279mmol), DMAP (1.244g is added at 0 DEG C, 10mmol), mesyl chloride (9.3mL is added dropwise, dichloromethane (50mL) solution 120mmol), completion of dropping, room temperature reaction 2 hours, 0 DEG C adds saturated sodium bicarbonate (50mL) solution and reaction is quenched, extraction point liquid, aqueous phase continues to be extracted with dichloromethane (100mL × 2), merge organic phase, anhydrous magnesium sulfate is dried, it is concentrated to give crude title compound (E) -3- (1- (Methanesulfonvloxvmethvl) cyclopropyl) propyl- 2- olefin(e) acids ethyl ester (1f), it is directly used in and casts single step reaction.

6th step：(E) -3- (1- (azido methyl) cyclopropyl) propyl- 2- olefin(e) acids ethyl ester (1g)

ethyl(E)-3-[1-(azidomethyl)cyclopropyl]prop-2-enoate

Crude product (E) -3- (1- (Methanesulfonvloxvmethvl) cyclopropyl) propyl- 2- olefin(e) acids ethyl ester (the 1f) (24.80g added into reaction bulb obtained by previous step reaction, 100mmol), add dimethylformamide (100mL), sodium azide (13.10g, 200mmol), room temperature reaction is stayed overnight.0 DEG C adds water (50mL) and reaction is quenched, ethyl acetate (100mL × 3) is extracted, merge organic phase, saturated nacl aqueous solution (50mL × 2) is washed, merge organic phase, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=10:1) title compound is obtained (E) -3- (1- (azido methyl) cyclopropyl) propyl- 2- olefin(e) acids ethyl ester (1g), yellow oil (18.0g, yield 92.3%).

¹H NMR(400MHz,CDCl₃) δ=6.58-6.54 (d, 1H), 5.92-5.88 (d, 1H), 4.21-4.16 (m, 2H), 3.36 (s, 2H), 1.30-1.27 (m, 3H), 1.00-0.94 (m, 4H).

7th step：7- azaspiros [2.5] octyl- 6- ketone (1h)

7-azaspiro[2.5]octan-6-one

(E) -3- (1- (azido methyl) cyclopropyl) propyl- 2- olefin(e) acids ethyl ester (1g) (23.25g is added into reaction bulb, 186mmol), add ethyl acetate (420mL), sodium acid carbonate (31.25g, 372mmol), palladium carbon (2.3g, 10%w/w), room temperature reaction is stayed overnight.Reacting liquid filtering, concentration, residue obtains title compound 7- azaspiros [2.5] octyl- 6- ketone (1h), white solid (9.8g, yield 42%) with silica gel column chromatography separating-purifying (ethyl acetate).

¹H NMR(400MHz,CDCl₃) δ=6.10 (br, 1H), 3.10 (s, 2H), 2.48-2.45 (m, 2H), 1.66-1.62 (m, 2H), 0.52 (s, 4H).

8th step：Chloro- 7- azaspiros [2.5] the octyl- 6- ketone (1i) of 5,5- bis-

5,5-dichloro-7-azaspiro[2.5]octan-6-one

At 0 DEG C, into the chloroformic solution (260mL) of 7- azaspiros [2.5] octyl- 6- ketone (1h) (7.0g, 56.0mmol), phosphorus pentachloride (93.72g, 450mmol) is added, back flow reaction is warming up to 3 hours.Reaction solution is cooled to 0 DEG C, add frozen water and reaction is quenched to bubble-free generation, divide liquid, aqueous phase is extracted with dichloromethane (30mL × 3), merge organic phase, organic phase is dried with anhydrous magnesium sulfate, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:1) title compound 5, chloro- 7- azaspiros [2.5] the octyl- 6- ketone (1i) of 5- bis-, white solid (6.9g, yield 64%) are obtained.

¹H NMR(400MHz,CDCl₃) δ=8.00 (br, 1H), 3.20 (s, 2H), 2.67 (s, 2H), 0.78-0.75 (m, 2H), 0.61-0.58 (m, 2H).

9th step：7- morpholine -5- azaspiros [2.5] octyl- 7- alkene -6- ketone (1j)

7-morpholino-5-azaspiro[2.5]oct-7-en-6-one

Chloro- 7- azaspiros [2.5] the octyl- 6- ketone (1i) (11.6g, 60.1mmol) of 5,5- bis- and morpholine (100 are added into reaction bulb ML), 140 DEG C are warming up to react 2.5 hours.Reaction solution is concentrated under reduced pressure, residue adds water (50mL), ethyl acetate (200mL × 6) is extracted, merge organic phase, organic phase anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petrol ether/ethyl acetate (v/v)=1:1) title compound 7- morpholine -5- azaspiros [2.5] octyl- 7- alkene -6- ketone (1j), faint yellow solid (7.33g, yield 58.6%) are obtained.

¹H NMR(400MHz,CDCl₃) δ=6.52 (br, 1H), 3.82-3.80 (m, 5H), 3.17 (s, 2H), 2.86-2.83 (m, 4H), 0.80-0.69 (m, 4H).

Tenth step：The chloro- 2- of 2- (2- (4- methoxyphenyls) hydrazone group) ethyl acetate (1l)

ethyl 2-chloro-2-[(4-methoxyphenyl)hydrazono]acetate

By 4- aminoanisoles (1k) (24.6g, 0.2mol) it is dissolved in hydrochloric acid (50mL, 0.2mol, in water (100mL) solution 12N), it is cooled to 0 DEG C, it is slowly added dropwise after natrium nitrosum (16.6g, 0.24mol) water (80mL) solution, completion of dropping, 0 DEG C is reacted 30 minutes, sodium acetate (328g, 0.40mol) regulation reaction solution PH=5~6 are added, are kept for 0 DEG C, 2- chloroacetyl acetacetic esters (32.9g is added dropwise, after methanol (80mL) solution 0.2mol), completion of dropping, kept for 0 DEG C react 1 hour.Ethyl acetate (200mL × 2) extraction is added into reaction solution, merge organic phase, organic phase is with saturated common salt water washing (200mL × 1), anhydrous sodium sulfate drying, it is concentrated under reduced pressure, residue silica gel chromatography (ethyl acetate/petroleum ether (v/v)=1：50~1：10) the chloro- 2- of title compound 2- (2- (4- methoxyphenyls) hydrazone group) ethyl acetate (1l), yellow solid (19.5g, yield 19%) is obtained.

¹H NMR(300MHz,CDCl₃)δ8.30(s,1H),7.17(d,2H),6.89(d,2H),4.38(q,2H),3.80(s,3H),1.40(t,3H)。

MS m/z(ESI)：256.9[M+1].

11st step：1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 1)

ethyl 1-(4-methoxyphenyl)-7-oxo-spiro[5,6-dihydropyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 7- morpholine -5- azaspiros [2.5] octyl- 7- alkene -6- ketone (1j) (4.96g, 23.8mmol) it is dissolved in ethyl acetate (150mL), add 2- chloro- 2- (2- (4- methoxyphenyls) hydrazone group) ethyl acetate (1l) (6.717g, 26.2mmol), triethylamine (10mL, 71.4mmol) with KI (0.395g, 2.38mmol), back flow reaction is warming up to stay overnight, reaction solution is cooled to room temperature, hydrochloric acid (60mL is added at 0 DEG C, 4N), normal-temperature reaction 1 hour.Reaction solution ethyl acetate (200mL × 7) is extracted, and merges organic phase, organic phase anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=40:1~3:1) title compound 1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 1), yellow solid (5.8g, yield 71%) are obtained.

¹H NMR(400MHz,CDCl₃):δ=7.46-7.44 (d, 2H), 6.95-6.93 (d, 2H), 5.61 (br, 1H), 4.42-4.36 (m, 2H), 3.84 (s, 3H), 3.37-3.36 (m, 2H), 1.82-1.79 (m, 2H), 1.39-1.38 (m, 3H), 0.90-0.88 (m, 2H).

Intermediate 2

1- (2,3- Dihydrobenzofuranes -2- bases) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 2)

ethyl 1-(4-(2,3-dihydrobenzofuran-2-yl))-7-oxo-spiro[5,6-dihydropyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

The first step：The chloro- 2- of 2- (2- (2,3- Dihydrobenzofuranes -5- bases) hydrazone group) ethyl acetate (2b)

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

2,3- Dihydrobenzofuranes -5- amine (2a) (2.0g, 14.80mmol) is added in hydrochloric acid (14.6mL, 3N), cooled down To -5 DEG C, natrium nitrosum (1.2g is added dropwise, 17.80mmol) water (8mL) solution, after completion of dropping, reacted 30 minutes at 0 DEG C, it is slowly added to sodium acetate (2.1g, 25.6mmol), reaction solution is adjusted to pH=5~6, at 0~5 DEG C, 2- chloroacetyl acetacetic esters (2.4g is added dropwise, methanol (5mL) solution 14.80mmol), it is warmed to room temperature reaction 2 hours, ethyl acetate (20mL) is added into reaction solution, divide liquid, organic phase is washed with saturated aqueous common salt (30mL), divide liquid, organic phase anhydrous sodium sulfate drying, filtering, it is concentrated under reduced pressure, residue purifies (ethyl acetate/petroleum ether (v/v)=1 with silica gel column chromatography:99~1:9) the chloro- 2- of compound 2- (2- (2,3- Dihydrobenzofuranes -5- bases) hydrazone group) ethyl acetate (2B), yellow solid (200mg, yield 5%) is obtained.

¹H NMR(400MHz,CDCl₃)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 -2- bases) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 2)

ethyl 1-(4-(2,3-dihydrobenzofuran-2-yl))-7-oxo-spiro[5,6-dihydropyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

Weigh 7- morpholine -5- azaspiros [2.5] octyl- 7- alkene -6- ketone (1j) (4.11g, 19.8mmol) it is placed in 250mL round-bottomed flasks, ethyl acetate (100mL) is added into reaction bulb, at room temperature, the chloro- 2- of 2- (2- (2 are sequentially added into reaction bulb, 3- Dihydrobenzofuranes -5- bases) hydrazone group) ethyl acetate (2b) (6.38g, 23.8mmol), triethylamine (8.3mL, 59.4mmol) with KI (0.33g, 1.98mmol), back flow reaction is warming up to stay overnight, it is cooled to 0 DEG C, add hydrochloric acid (60mL, 4N), terminating reaction after reacting at room temperature 1 hour.By reaction solution point liquid, aqueous phase is extracted with ethyl acetate (150mL × 3), merges organic phase, organic phase saturated common salt water washing (150mL), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=5:1~0:1) title compound 1- (2,3- Dihydrobenzofuranes -2- bases) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 2), yellow solid (1.9g, yield 27%).

¹H NMR(400MHz,CDCl₃):δ=7.53-7.51 (m, 1H), 7.26-7.20 (m, 1H), 6.81-6.79 (d, 1H), 5.68-5.54 (br, 1H), 4.65-4.61 (m, 2H), 4.41-4.36 (m, 2H), 3.37-3.35 (m, 2H), 3.27-3.23 (m, 2H), 1.82-1.79 (m, 2H), 1.40-1.37 (m, 3H), 0.90-0.88 (m, 2H).

Intermediate 3

1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formic acid second Ester (intermediate 3)

ethyl 1-(2-fluoro-4-methoxyphenyl)-7-oxo-spiro[5,6-dihydropyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

The first step：The fluoro- 4- aminoanisoles (3b) of 2-

2-fluoro-4-methoxy-aniline

The fluoro- 4- methoxy nitrobenzenes (3a) (0.5g, 2.9mmol) of 2- are dissolved in ethyl acetate (10mL), palladium carbon (50mg) is added, reaction 1 hour is stirred at room temperature.By reacting liquid filtering, filtrate is concentrated to give the fluoro- 4- aminoanisoles (3b) of title compound 2-, brown solid (0.3g, yield 73%).

¹H NMR(400MHz,CDCl3)δ6.75(m,1H),6.65(dd,1H),6.56(m,1H),3.74(s,3H),3.41(br,2H)。

MS m/z(ESI)：142.1[M+1].

Second step：The chloro- 2- of 2- [2- (the fluoro- 4- methoxyphenyls of 2-) hydrazone group] ethyl acetate (3c)

ethyl 2-chloro-2-[2-(2-fluoro-4-methoxy-phenyl)hydrazono]acetate

By fluoro- 4- aminoanisoles (the 3b) (2.0g of 2-, 14.20mmol) it is dissolved in hydrochloric acid (3.4mL, in water (5.8mL) solution 12N), it is cooled to -5 DEG C~0 DEG C, natrium nitrosum (1.2g is added dropwise, 17.00mmol) water (3mL) solution, drop Add after finishing, reacted 30 minutes at 0 DEG C, obtain diazonium salt solution, at 0 DEG C, in the mixed liquor that diazonium salt solution is slowly dropped to 2- chloroacetyl acetacetic esters (1.9mL, 14.2mmol) ethyl acetate (10mL) solution and sodium acetate (2.6g, 32.6mmol) water (5.8mL) solution, after completion of dropping, reaction 1 hour is warmed to room temperature.By reaction solution point liquid, organic phase is washed with saturated aqueous common salt (10mL), anhydrous sodium sulfate drying, add ten times of petroleum ether dilutions, directly purified with silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1~10) obtain the chloro- 2- of title compound 2- [2- (the fluoro- 4- methoxyphenyls of 2-) hydrazone group] ethyl acetate (3c), yellow solid (140mg, yield 3.5%).

¹H NMR(400MHz,CDCl3)δ8.33(s,1H),7.51(t,1H),6.74-6.67(m,2H),4.41(q,2H),3.78(s,3H),1.40(t,3H)。

3rd step：1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 3)

ethyl 1-(2-fluoro-4-methoxyphenyl)-7-oxo-spiro[5,6-dihydropyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

Weigh 7- morpholine -5- azaspiros [2.5] octyl- 7- alkene -6- ketone (1j) (3.22g, 15.5mmol) to be placed in 250mL round-bottomed flasks, ethyl acetate (100mL) is added into reaction bulb.At room temperature, the chloro- 2- of 2- [2- (the fluoro- 4- methoxyphenyls of 2-) hydrazone group] ethyl acetate (3c) (5.19g is sequentially added into reaction bulb, 18.6mmol), triethylamine (6.5mL, 46.5mmol) and KI (0.51g, 1.98mmol), it is warming up to back flow reaction to stay overnight, is cooled to 0 DEG C, hydrochloric acid (60mL is added into reaction bulb, 4N), terminating reaction after reacting at room temperature 1 hour.By reaction solution point liquid, aqueous phase is extracted with ethyl acetate (150mL × 3), merges organic phase, and organic phase is washed with saturated aqueous common salt (150mL), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (petroleum ether:Ethyl acetate (v/v)=5:1~0:1) title compound 1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5 are obtained, 6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 3), yellow solid (1.26g, yield 17%).

¹H NMR(400MHz,CDCl₃):δ=7.42-7.38 (m, 1H), 6.76-6.99 (m, 2H), 5.78-5.64 (br, 1H), 4.43-4.34 (m, 2H), 3.83 (s, 3H), 3.37-3.35 (m, 2H), 1.81-1.78 (m, 2H), 1.41-1.37 (m, 3H), 0.90-0.88 (m, 2H).

Embodiment 1

6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 1)

6-[4-(1-cyclopropyl-2-(N,N-dimethy)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：1- (4- iodophenyls) cyclopropane-carboxylic acid (1B)

1-(4-iodophenyl)cyclopropanecarboxylic acid

By 1- phenylcyclopropanecarboxylic acids (16.5g, 101mmol) it is dissolved in acetic acid (70mL), under nitrogen atmosphere, add iodine (27.94g, 101mmol), sodium iodate (4.98g, 25.25mmol) with the concentrated sulfuric acid (1mL), rise to 70 DEG C and react 42 hours.Reaction solution is cooled down, add water (150mL) and ethyl acetate (150mL), divide liquid, aqueous phase is extracted with ethyl acetate (50mL × 2), merge organic phase, organic phase is washed with hypo solution (100mL × 3), water (100mL × 2), saturated aqueous common salt (100mL × 2) successively, anhydrous sodium sulfate drying, concentration, residue with Ethyl acetate/petroleum ether is recrystallized to give title compound 1- (4- iodophenyls) cyclopropane-carboxylic acid (1B), white solid (19.0g, yield 62%).

¹H NMR(400MHz,CDCl₃)δ10.78(s,1H),7.65-7.60(m,2H),7.11-7.05(m,2H),1.66(dd,2H),1.22(dd,2H)。

LCMS m/z=286.7 [M-1].

Second step：6- [4- (1- carboxycyclopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1C)

Ethyl 6-[4-(1-carboxyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 1) (1.3g, 3.8mmol) it is dissolved in dimethyl sulfoxide (DMSO) (40mL), add 1- (4- iodophenyls) cyclopropane-carboxylic acid (1B) (2.2g, 7.6mmol), potassium carbonate (1.6g, 11.4mmol) with 1,10- phenanthrolines (144mg, 0.8mmol), under nitrogen atmosphere, cuprous iodide (153mg, 0.8mmol) is added, 130 DEG C is risen to and reacts 20 hours.Reaction solution is cooled down to 0 DEG C, add hydrochloric acid (3N) and adjust pH value of solution to 3-4, add dichloromethane (100mL) and water (100mL), divide liquid, organic phase washed with water (30mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=2:3~3:2) title compound 6- [4- (1- carboxycyclopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1C), yellow solid (1.14g, yield 60%).

¹H NMR(400MHz,CDCl₃)δ7.45-7.39(d,2H),7.35-7.30(d,2H),7.23(d,2H),6.92-6.87(d,2H),4.40(q,2H),3.83(s,2H),3.80(s,3H),1.86(dd,2H),1.64(dd,2H),1.40(t,3H),1.20(dd,2H),0.93(dd,2H)。

LCMS m/z=502.3 [M+1].

3rd step:6- [4- (1- methylols cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1D)

Ethyl 6-[4-(1-hydroxymethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- carboxycyclopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1C) (1.14g, 2.3mmol) it is dissolved in tetrahydrofuran (40mL), under nitrogen atmosphere, cooling reaction solution adds borine-tetrahydrofuran (6.8mL to -10 DEG C, 6.8mmol), react at room temperature 5 hours.Methanol (5mL) is added into reaction solution, stirring 15 minutes, reaction is quenched, saturated aqueous common salt (30mL), extraction is added, aqueous phase is extracted with ethyl acetate (20mL), merge organic phase, organic phase is washed with saturated aqueous common salt (30mL × 3), anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=3:7~3:2) To title compound 6- [4- (1- methylols cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1D), yellow solid (0.63g, 56%).

¹H NMR(400MHz,CDCl₃)δ7.46-7.41(d,2H),7.35(d,2H),7.24(d,2H),6.92-6.88(m,2H),4.40(q,2H),3.82(s,2H),3.80(s,3H),3.63(s,2H),1.86(dd,2H),1.41(t,3H),0.93(dd,2H),0.83(m,4H)。

LCMS m/z=488.3 [M+1].

4th step：6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1E)

Ethyl 6-[4-(1-formylcyclopropyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- methylols cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1D) (1.25g, 2.6mmol) add in dichloromethane (30mL), add silica gel (1.5g) and dicyclohexylcarbodiimide (840mg, 3.9mmol), reaction 17 hours is stirred at room temperature.Reaction solution is concentrated, residue silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:4~1:1) title compound 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (1E); white solid (1.0g, yield 80%).

¹H NMR(400MHz,CDCl₃)δ9.19(d,1H),7.49-7.41(m,2H),7.32-7.29(m,4H),6.93-6.88(m,2H),4.41(q,2H),3.85(s,2H),3.80(s,3H),1.87(dd,2H),1.56(dd,2H),1.41(t,3H),1.35(dd,2H),0.94(dd,2H)。

LCMS m/z=486.3 [M+1].

5th step：6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1F)

Ethyl 6-[4-(1-cyclopropyl-2-(N,N-dimethy)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (1E) (500mg; 1.03mmol) it is dissolved in methanol (20mL) and tetrahydrofuran (5mL); add dimethylamine tetrahydrofuran solution (2M/L; 0.8mL; 1.54mmol); 50 DEG C are risen to react 1 hour; add sodium cyanoborohydride (194mg; 3.09mmol), 50 DEG C of stirring reactions 3 hours, 60 DEG C of stirring reactions 16 hours.Reaction solution is cooled down to room temperature, silica gel, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate is added：Petroleum ether (v/v)=7：3~1:0, methanol：Dichloromethane (v/v)=1:9) title compound 6- [4- (1- cyclopropyl -2- (N are obtained, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1F), white solid (450mg, yield 85%).

LCMS m/z=515.3 [M+1].

6th step：6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 1)

6-[4-(1-cyclopropyl-2-(N,N-dimethy)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1F) (450mg, 0.87mmol) it is dissolved in N, in dinethylformamide (15mL), add formamide (394mg, 8.74mmol) with sodium methoxide (188mg, 3.48mmol), 95 DEG C are risen to react 2 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (30mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=7：3~1:0, methanol：Dichloromethane (v/v)=1:9) crude product is obtained, crude product is recrystallized to give title compound 6- [4- (1- cyclopropyl -2- (N with dichloromethane/petroleum ether, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 1), white solid (90mg, yield 21%).

¹H NMR(400MHz,CDCl₃)δ7.43(d,2H),7.33(d,2H),7.22(d,2H),6.97-6.88(m,3H),5.37(s,1H),3.82(s,2H),3.82(s,3H),2.62(s,2H),2.27(s,6H),1.97(dd,2H),0.93-0.86(m,4H),0.80(m,2H)。

LCMS m/z=486.4 [M+1].

Embodiment 2

6- [4- (1- cyclopropyl -2- (3.3- difluoro nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 2)

6-[4-(1-cyclopropyl-2-(3.3-difluoropyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxyphenyl)-7-ox o-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：6- [4- (1- cyclopropyl -2- (3.3- difluoro nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (2B)

Ethyl

6-[4-(1-cyclopropyl-2-(3.3-difluoropyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spir o[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- formaldehyde cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1E) (500mg, 1.03mmol) it is dissolved in methanol (30mL) and tetrahydrofuran (20mL), add triethylamine (521mg, 5.15mmol) with 3,3- difluoro nafoxidine hydrochlorides (444mg, 3.09mmol), 60 DEG C are risen to react 1 hour, sodium cyanoborohydride (194mg, 3.09mmol) is added, 60 DEG C is risen to and reacts 18 hours.Reaction solution is cooled to room temperature, add dichloromethane (50mL) and water (30mL), divide liquid, organic phase washed with water (30mL × 2), saturated sodium bicarbonate (30mL × 2) and saturated aqueous common salt (30mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:4) title compound 6- [4- (1- cyclopropyl -2- (3.3- difluoro nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (2B), white solid (350mg, yield 59%).

¹H NMR(400MHz,CDCl₃)δ7.46-7.40(m,2H),7.29(d,2H),7.20(d,2H),6.93-6.88(m,2H),4.40(q,2H),3.83(s,2H),3.80(s,3H),2.89(t,2H),2.68(s,2H),2.59(s,2H),2.25-2.07(m,2H),1.86(dd,2H),1.40(t,3H),0.94(dd,2H),0.82(m,2H),0.70(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-92.34。

LCMS m/z=577.3 [M+1].

Second step：6- [4- (1- cyclopropyl -2- (3.3- difluoro nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 2)

6-[4-(1-cyclopropyl-2-(3.3-difluoropyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- cyclopropyl -2- (3.3- difluoro nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (2B) (350mg, 0.6mmol) it is dissolved in N, in dinethylformamide (30mL), add formamide (273mg, 6.1mmol) with sodium methoxide (130mg, 2.4mmol), 95 DEG C are risen to react 2 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (50mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:4~3:7) crude product is obtained, crude product is recrystallized to give title compound 6- [4- (1- cyclopropyl -2- (3.3- difluoro nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 with dichloromethane/petroleum ether, 4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 2), white solid (160mg, yield 49%).

¹¹H NMR(400MHz,CDCl₃)δ7.46-7.40(d,2H),7.29(d,2H),7.19(d,2H),6.95-6.90(m,3H),5.40(s,1H),3.83(s,2H),3.81(s,3H),2.89(t,2H),2.68(t,2H),2.59(s,2H),2.22-2.08(m,2H),1.97(dd,2H),0.92(dd,2H),0.82(m,2H),0.70(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-92.31。

LCMS m/z=548.4 [M+1].

Embodiment 3

6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 3)

6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H- pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (3B)

Ethyl

6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-p yrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- formaldehyde cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (1E) (500mg, 1.03mmol) it is dissolved in methanol (30mL) and tetrahydrofuran (10mL), add nafoxidine (220mg, 3.09mmol), 60 DEG C are risen to react 1.5 hours, add sodium cyanoborohydride (194mg, 3.09mmol), 60 DEG C are risen to react 18 hours.Reaction solution is cooled to room temperature, add dichloromethane (50mL) and water (30mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, dichloromethane：Methanol (v/v)=1:19) title compound 6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (3B), white solid (320mg, yield 59%).

LCMS m/z=540.8 [M+1].

Second step：6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 3)

6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H- pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (3B) (320mg, 0.59mmol) it is dissolved in N, in dinethylformamide (20mL), add formamide (266mg, 5.91mmol) with sodium methoxide (127mg, 2.36mmol), 95 DEG C are risen to react 3 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (30mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel column chromatography separating-purifying (ethyl acetate：Petroleum ether (v/v)=1：1, ethyl acetate：Dichloromethane (v/v)=1:1, methanol：Dichloromethane (v/v)=1:19) crude product is obtained, crude product is recrystallized to give title compound 6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 with dichloromethane/petroleum ether, 4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 3), white solid (120mg, yield 40%).

¹H NMR(400MHz,CDCl₃)δ7.45-7.40(d,2H),7.33(d,2H),7.19(d,2H),6.95-6.92(m,3H),5.35(s,1H),3.82(s,2H),3.82(s,3H),2.67(m,2H),2.49(m,4H),1.97(dd,2H),1.70(m,4H),0.91(dd,2H),0.81(m,4H)。

LCMS m/z=511.9 [M+1].

Embodiment 4

6- [4- (1- anocy clopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 4)

6-[4-(1-cyanocyclopropyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：The iodo- 4- of 1- (1- anocy clopropyls) benzene (4B)

1-iodo-4-(1-cyanocyclopropyl)benzene

By 1- (1- anocy clopropyls) benzene (1A) (2.0g, 14mmol) it is dissolved in acetic acid (30mL), under nitrogen atmosphere, add iodine (3.6g, 14mmol), sodium iodate (396mg, 3.5mmol) with the concentrated sulfuric acid (0.5mL), rise to 70 DEG C and react 24 hours.Reaction solution is cooled down, add ethyl acetate (80mL) and hypo solution (50mL), divide liquid, organic phase is washed with hypo solution (50mL), water (30mL × 2) and saturated aqueous common salt (50mL × 2) successively, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:0~9:1) the iodo- 4- of title compound 1- (1- anocy clopropyls) benzene (4B), white solid (2.43g, yield 65%) are obtained.

¹H NMR(400MHz,CDCl₃)δ7.67(d,2H),7.03(d,2H),1.74(dd,2H),1.38(dd,2H)。

Second step：6- [4- (1- anocy clopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (4C)

Ethyl

6-[4-(1-cyanocyclopropyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridi ne-4,1'-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -7- oxos-spiral shell [5,6- dihydro-pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (intermediate 1) (600mg, 1.76mmol) it is dissolved in dimethyl sulfoxide (DMSO) (30mL), add 1- iodo- 4- (1- anocy clopropyls) benzene (4B) (946mg, 3.51mmol), potassium carbonate (730mg, 5.28mmol) with 1,10- phenanthrolines (63mg, 0.35mmol), under nitrogen atmosphere, cuprous iodide (67mg, 0.35mmol) is added, 130 DEG C is risen to and reacts 16 hours.Reaction solution is cooled down to room temperature, add dichloromethane (100mL) and water (50mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:4~3:7) title compound 6- [4- (1- anocy clopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (4C), yellow solid (480mg, yield 56%).

¹H NMR(400MHz,CDCl₃)δ7.45-7.40(m,2H),7.32-7.27(m,4H),6.93-6.88(m,2H),4.41(q,2H),3.82(s,2H),3.80(s,3H),1.88(dd,2H),1.70(dd,2H),1.41(t,3H),1.35(dd, 2H),0.94(dd,2H)。

LCMS m/z=482.8 [M+1].

3rd step：6- [4- (1- anocy clopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 4)

6-[4-(1-cyanocyclopropyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

6- [4- (1- anocy clopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are added in vexed tank, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (4C) (480mg, 1.0mmol), methanol (15mL) and 25% ammoniacal liquor (1.4g, 10.0mmol), 100 DEG C are warming up to react 36 hours.Reaction solution is cooled down to room temperature, add dichloromethane (80mL) and water (30mL), divide liquid, organic phase washed with water (30mL) and saturated aqueous common salt (30mL) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:4~2:3) title compound 6- [4- (1- anocy clopropyls) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 4), white solid (120mg, yield 26%)

¹H NMR(400MHz,CDCl₃)δ7.43(d,2H),7.30(m,4H),6.93(m,3H),5.42(s,1H),3.82(s,5H),1.99(dd,2H),1.70(dd,2H),1.35(dd,2H),0.92(dd,2H)。

LCMS m/z=453.9 [M+1].

Embodiment 5

6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 5)

6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：6- [4- (1- carboxycyclopropyls) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5B)

Ethyl 6-[4-(1-carboxycyclopropyl)phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

1- (2 is added into DMSO (100mL); 3- Dihydrobenzofuranes -2- bases) -7- oxos-spiral shell [5; 6- dihydro-pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (intermediate 2) (1.9g; 5.4mmol); add 1- (4- iodophenyls) cyclopropane-carboxylic acid (1B) (3.1g, 10.8mmol), potassium carbonate (2.3g, 16.2mmol) and 1; 10- phenanthrolines (198mg; 1.1mmol), under nitrogen protection, cuprous iodide (206mg is added; 1.1mmol), 130 DEG C are warming up to react 20 hours.Reaction solution is cooled to 0 DEG C, add HCl (4N) and adjust pH value of solution to 3~4, add dichloromethane (150mL) and water (100mL), divide liquid, organic phase washed with water (100mL × 2) and saturated aqueous common salt (100mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=3:7~1:1) title compound 6- [4- (1- carboxycyclopropyls) phenyl] -1- (2 is obtained, 3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5B), yellow solid (1.7g, yield 65%).

¹H NMR(400MHz,CDCl₃)δ7.37-7.30(m,3H),7.26-7.19(m,3H),6.75(d,1H),4.58(t,2H),4.43(q,2H),3.82(s,2H),3.21(t,2H),1.86(dd,2H),1.64(dd,2H),1.43-1.38(m,3H),1.20(dd,2H),0.93(dd,2H)。

LCMS m/z=513.8 [M+1].

Second step：6- [4- (1- methylols cyclopropyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5C)

Ethyl 6-[4-(1-hydroxymethylcyclopropyl)phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- carboxycyclopropyls) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5B) (1.7g, 3.3mmol) it is dissolved in tetrahydrofuran (80mL), is cooled to -10 DEG C, adds tetrahydrofuran borine (10mL, 9.9mmol), react at room temperature 16 hours.Methanol (10mL) is added into reaction solution, stirring 15 minutes, add ethyl acetate (30mL) and water (10mL), divide liquid, aqueous phase is extracted with ethyl acetate (50mL), merges organic phase, organic phase is washed with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=3:7~3:2) title compound 6- [4- (1- methylols cyclopropyl) phenyl] -1- (2 is obtained, 3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5C), yellow solid (1.25g, yield 78%).

¹H NMR(400MHz,CDCl₃)δ7.39-7.31(m,3H),7.26-7.20(m,3H),6.75(d,1H),4.58(t,2H),4.40(q,2H),3.81(s,2H),3.64(d,2H),3.21(t,2H),1.86(dd,2H),1.43-1.38(m,3H),0.92(dd,2H),0.83(m,4H)。

LCMS m/z=499.8 [M+1].

3rd step：6- [4- (1- formyls cyclopropyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5D)

Ethyl 6-[4-(1-formylcyclopropyl)phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- methylols cyclopropyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5C) (1.25g, 2.5mmol) it is dissolved in dichloromethane (30mL), the complex salt (809mg, 308mmol) and silica gel (2g) of pyridine and CrO3 in hydrochloric acid solution are added, is reacted at room temperature 5 hours.Reaction solution is concentrated, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~1:1) title compound 6- [4- (1- formyls cyclopropyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrroles are obtained Azoles simultaneously [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5D), white solid (1.1g, yield 88%).

¹H NMR(400MHz,CDCl₃)δ9.20(s,1H),7.38-7.27(m,5H),7.22(dd,1H),6.76(d,1H),4.59(t,2H),4.40(q,2H),3.84(s,2H),3.21(t,2H),1.87(dd,2H),1.56(dd,2H),1.41(t,3H),1.35(dd,2H),0.97-0.91(dd,2H)。

LCMS m/z=497.8 [M+1].

4th step：6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5E)

Ethyl 6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (2; 3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (5D) are dissolved in methanol (30mL) and tetrahydrofuran (10mL); add dimethylamine tetrahydrofuran solution (2M; 1.7mL; 3.3mmol); 60 DEG C are warming up to react 2 hours; add sodium cyanoborohydride (276mg; 4.4mmol), 60 DEG C are reacted 16 hours.Silica gel is added into reaction solution, is concentrated, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:9) title compound 6- [4- (1- cyclopropyl -2- (N are obtained, N- dimethylaminos) ethyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5E), yellow solid (476mg, yield 82%).

LCMS m/z=526.9 [M+1].

5th step：6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 5)

6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- cyclopropyl -2- (N, N- dimethylamino) ethyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos - Spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (5E) (476mg, 0.9mmol) it is dissolved in N, in dinethylformamide (30mL), formamide (407mg, 9mmol) and sodium methoxide (194mg are added, 3.6mmol), 95 DEG C are risen to react 2 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (30mL), divide liquid, organic phase washed with water (50mL × 3) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:20~1:9) title compound 6- [4- (1- cyclopropyl -2- (N are obtained, N- dimethylaminos) ethyl) phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 5), white solid (60mg, yield 13%).

¹H NMR(400MHz,CDCl₃)δ7.32(m,3H),7.21(m,3H),6.90(s,1H),6.78(d,1H),5.33(s,1H),4.60(t,2H),3.82(s,2H),3.23(t,2H),2.50(s,2H),2.22(s,6H),1.96(dd,2H),0.90(dd,2H),0.84(m,2H),0.73(m,2H)。

LCMS m/z=497.9 [M+1].

Embodiment 6

6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 6)

6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：6- [4- (1- carboxycyclopropyls) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (6B)

6-[4-(1-carboxycyclopropyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5; 6- dihydro-pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (intermediate 3) (1.3g; 3.6mmol) it is dissolved in DMSO (30mL); add 1- (4- iodophenyls) cyclopropane-carboxylic acid (1B) (2.1g; 7.2mmol), potassium carbonate (1.5g; 10.8mmol) with 1,10- phenanthrolines (126mg, 0.7mmol); under nitrogen protection; cuprous iodide (137mg, 0.7mmol) is added, 130 DEG C is warming up to and reacts 18 hours.Reaction solution is cooled to 0 DEG C, add HCl (4N) and adjust pH value of solution to 3~4, add dichloromethane (80mL) and water (40mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=3:7~3:2) title compound 6- [4- (1- carboxycyclopropyls) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- formamides (6B), yellow solid (1.1g, yield 61%).

¹H NMR(400MHz,CDCl₃)δ7.42-7.37(m,1H),7.32(d,2H),7.23(d,2H),6.72(dd,1H),6.67(dd,1H),4.43(q,2H),3.87–3.80(m,2H),3.79(s,3H),1.84(m,2H),1.64(dd,2H),1.43-1.38(m,3H),1.19(m,2H),0.93(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-119.60。

LCMS m/z=519.8 [M+1].

Second step：6- [4- (1- methylols cyclopropyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (6C)

6-[4-(1-hydroxymethylcyclopropyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- carboxycyclopropyls) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (6B) (1.1g, 2.1mmol) it is dissolved in tetrahydrofuran (40mL), it is cooled to -0 DEG C, tetrahydrofuran borine (6.4mL, 6.4mmol) is added, is reacted at room temperature 16 hours.Methanol (5mL) is added into reaction solution, Stirring 20 minutes, adds ethyl acetate (10mL) and water (50mL), point liquid, organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:4~1:1) title compound 6- [4- (1- methylols cyclopropyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- formamides (6C), yellow solid (830mg, yield 83%).

¹H NMR(400MHz,CDCl₃)δ7.42(m,1H),7.35(d,2H),7.23(d,2H),6.73(dd,1H),6.68(dd,1H),4.43(q,2H),3.82(m,2H),3.79(s,3H),3.63(d,2H),1.86(m,2H),1.42(t,3H),0.93(m,2H),0.83(m,4H)。

¹⁹F NMR(376MHz,CDCl₃)δ-119.59。

LCMS m/z=505.9 [M+1].

3rd step：6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (6D)

6-[4-(1-formylcyclopropyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- methylols cyclopropyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (6C) (830mg, 1.65mmol) it is dissolved in dichloromethane (30mL), add the complex salt (531mg of pyridine and CrO3 in hydrochloric acid solution, 246mmol) with silica gel (1g), react at room temperature 3 hours.Reaction solution is concentrated, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~1:1) title compound 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropane] -3- formamides (6D); yellow solid (660mg, yield 80%).

¹H NMR(400MHz,CDCl₃)δ9.20(d,1H),7.41(t,1H),7.31-7.29(m,4H),6.73(dd,1H),6.68(dd,1H),4.41(q,2H),3.85(m,2H),3.79(s,3H),1.87(m,2H),1.55(dd,2H),1.44-1.38(m,3H),1.35(m,2H),0.94(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-119.60。

LCMS m/z=503.9 [M+1].

4th step：6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (6E)

Ethyl 6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-1-(4-methoxy-2-fluoro)- 7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- formamides (6D) (660mg; 1.31mmol) it is dissolved in methanol (30mL) and tetrahydrofuran (10mL); add dimethylamine tetrahydrofuran solution (2M; 2.0mL; 3.93mmol); 55 DEG C are warming up to react 2 hours; add sodium cyanoborohydride (329mg; 5.24mmol), 55 DEG C are reacted 16 hours.Silica gel is added into reaction solution, is concentrated, separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:9) title compound 6- [4- (1- cyclopropyl -2- (N are obtained, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (6E), yellow solid (600mg, yield 86%).

LCMS m/z=532.8 [M+1].

5th step：6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 6)

6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- cyclopropyl -2- (N, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (6E) (600mg, 1.13mmol) it is dissolved in N, in dinethylformamide (30mL), add formamide (507mg, 11.27mmol) with sodium methoxide (244mg, 4.52mmol), 95 DEG C are risen to react 2 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (50mL), divide liquid, organic phase washed with water (50mL × 3) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:20~1:9) title compound 6- [4- (1- cyclopropyl -2- (N are obtained, N- dimethylaminos) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 6), white solid (50mg, yield 9%).

¹H NMR(400MHz,CDCl₃)δ7.43-7.28(m,3H),7.20(d,2H),6.88(s,1H),6.72(m,2H), 5.46(s,1H),3.80(s,5H),2.49(s,2H),2.20(s,6H),1.95(m,2H),0.90(m,2H),0.83(m,2H),0.71(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-119.72。

LCMS m/z=503.9 [M+H].

Embodiment 7

6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 7)

6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

The first step：6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (7B)

Ethyl 6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (2; 3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (5D) (500mg; 1.0mmol) it is dissolved in methanol (30mL) and tetrahydrofuran (10mL); add nafoxidine (214mg; 3.0mmol); 55 DEG C are warming up to react 2 hours; add sodium cyanoborohydride (251mg; 4.0mmol), 55 DEG C are reacted 16 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (50mL), divide liquid, organic phase washed with water (50mL × 3) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)= 2:3~3:2, methanol：Dichloromethane (v/v)=1:20) title compound 6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (7B), yellow solid (378mg, yield 68%).

LCMS m/z=552.8 [M+1].

Second step：6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 7)

6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-1-(4-methoxy-2-fluoro)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1'-cyclopropane]-3-carboxamide

By 6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -3- Ethyl formates (7B) (378mg, 0.68mmol) it is dissolved in N, in dinethylformamide (30mL), add formamide (308mg, 6.84mmol) with sodium methoxide (147mg, 2.72mmol), 95 DEG C are risen to react 2 hours.Reaction solution is cooled to room temperature, add dichloromethane (80mL) and water (50mL), divide liquid, organic phase washed with water (50mL × 3) and saturated aqueous common salt (50mL × 2) washing, anhydrous sodium sulfate drying, concentrated residues thing silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:20~1:9) title compound 6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl] -1- (4- methoxyl group -2- fluorophenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -3- formamides (compound 7), white solid (20mg, yield 6%).

¹H NMR(400MHz,CDCl₃)δ7.33(m,3H),7.21(m,3H),6.90(s,1H),6.79(d,1H),5.35(s,1H),4.60(t,2H),3.82(s,2H),3.23(t,2H),2.65(s,2H),2.48(m,4H),1.96(m,2H),1.69(m,4H),0.91(m,2H),0.79(m,4H)。

LCMS m/z=523.8 [M+1].

Embodiment 8

1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- cyclopropyl -2- (N, N- dimethyl) amino-ethyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 8)

1-(4-methoxyphenyl)-6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

The first step：The bromo- 2- of fluoro- 2- of 1,1,1- tri- (2- (4- methoxyphenyls) hydrazone group) ethane (8B)

1,1,1-trifluoro-2-bromo-2-(2-(4-methoxyphenyl)hydrazono)ethane

By 4- methoxyphenyl hydrazine hydrochlorides (30.0g, 172mmol) it is dissolved in ethanol (250mL), add 1- methoxyl groups 2,2,2- trifluoropropanols (21mL, 223mmol), 85 DEG C are warming up to react 18 hours, reaction solution is cooled to room temperature, concentration removes ethanol, DMF (150mL) is added into residue, it is cold to go to 0 DEG C, add N-bromosuccinimide (31.0g, 172mmol), add within 5 minutes, be warmed to room temperature reaction 4 hours.Water (400mL) and ethyl acetate (400mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (150mL × 2), merge organic phase, organic phase washed with water (300mL × 3), saturated aqueous common salt (300mL × 2) washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=0:1~1:19) the fluoro- bromo- 2- of 2- of title compound 1,1,1- tri- (2- (4- methoxyphenyls) hydrazone group) ethane (1B), black liquor (19.0g, yield 37%) is obtained.

Second step：1- (4- methoxyphenyls) -3- trifluoromethyls-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (8C)

1-(4-methoxyphenyl)-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 7- morpholine -5- azaspiros [2.5] octyl- 7- alkene -6- ketone (1j) (7.3g, 35.0mmol) it is dissolved in ethyl acetate (100mL), add 1,1, the bromo- 2- of fluoro- 2- of 1- tri- (2- (4- methoxyphenyls) hydrazone group) ethane (1B) (10.4g, 35.0mmol), triethylamine (10.6g, 105.0mmol) with KI (581mg, 3.5mmol), it is warming up to 90 DEG C to react 24 hours, cools down reaction solution, adds hydrochloric acid (4N, 44mL), 60 DEG C are reacted 4 hours.Water (100mL) and ethyl acetate (100mL) are added into reaction solution, divide liquid, aqueous phase is extracted with ethyl acetate (30mL × 2), merge organic phase, organic phase is washed with saturated aqueous common salt (100mL × 2), anhydrous sodium sulfate drying, is concentrated under reduced pressure, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~2:3) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (8C), yellow solid (380mg, yield 3%) are obtained.

¹H NMR(400MHz,CDCl₃)δ7.48-7.42(d,2H),6.98-6.93(d,2H),5.79(s,1H),3.85(s,3H),3.37(s,2H),1.32(dd,2H),0.97(dd,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.64。

LCMS m/z=337.9 [M+1].

3rd step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carboxycyclopropyls) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (8D)

1-(4-methoxyphenyl)-6-[4-(1-carboxycyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (8C) (390mg; 1.16mmol) it is dissolved in DMSO (30mL); add 1- (4- iodophenyls) cyclopropane-carboxylic acid (1B) (668mg; 2.32mmol), potassium carbonate (481mg; 3.48mmol) with 1; 10- phenanthrolines (42mg; 0.23mmol), under nitrogen protection, cuprous iodide (44mg is added; 0.23mmol), 130 DEG C are warming up to react 18 hours.Reaction solution cooling is added into dichloromethane (80mL) and water (30mL), add hydrochloric acid (4N) and adjust pH value of solution to 3~4, divide liquid, organic phase washed with water (40mL × 2) and saturated aqueous common salt (40mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~1:1) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carboxycyclopropyls) phenyl]-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -7- ketone (8D), yellow solid (440mg, yield 76%).

¹H NMR(400MHz,CDCl₃)δ7.43(d,2H),7.34(d,2H),7.23(d,2H),6.91(d,2H),3.85(s,2H),3.80(s,3H),1.65(dd,2H),1.38(m,2H),1.20(dd,2H),1.01(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.70。

LCMS m/z=497.8 [M+1].

4th step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (8E)

1-(4-methoxyphenyl)-6-[4-(1-hydroxymethylcyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carboxycyclopropyls) phenyl]-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (8D) (440mg; 0.88mmol) it is dissolved in tetrahydrofuran (30mL); under nitrogen protection, -0 DEG C is cooled to, tetrahydrofuran borine (2.7mL is added; 2.65mmol), react at room temperature 16 hours.Methanol (5mL) is added into reaction solution, stirring 20 minutes, add ethyl acetate (10mL) and water (30mL), divide liquid, aqueous phase is extracted with ethyl acetate (20mL), merges organic phase, organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~1:1) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -7- ketone (8E), white solid (370mg, yield 87%).

¹H NMR(400MHz,CDCl₃)δ7.43(d,2H),7.37(d,2H),7.23(dm,2H),6.92(d,2H),3.84(s,2H),3.81(s,3H),3.64(s,2H),1.38(dd,2H),1.01(dd,2H),0.84(m,4H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.70。

LCMS m/z=483.8 [M+1].

5th step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- formyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (8F)

1-(4-methoxyphenyl)-6-[4-(1-formylcyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyrrole Pyridine -4,1`- cyclopropane] -7- ketone (8E) (370mg, 0.77mmol) it is dissolved in dichloromethane (30mL), add the complex salt (330mg of pyridine and CrO3 in hydrochloric acid solution, 1.53mmol) with silica gel (1g), react at room temperature 4 hours.Reaction solution is concentrated, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~2:3) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- formyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (8F); white solid (30mg, yield 81%).

¹H NMR(400MHz,CDCl₃)δ9.17(s,1H),7.44(d,2H),7.32–7.27(m,4H),6.94-6.89(m,2H),3.87(s,2H),3.81(s,3H),1.56(dd,2H),1.39(dd,2H),1.36(dd,2H),1.03(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.69。

LCMS m/z=481.8 [M+1].

6th step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- cyclopropyl -2- (N, N- dimethyl) amino-ethyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 8)

1-(4-methoxyphenyl)-6-[4-(1-cyclopropyl-2-(N,N-dimethylamino)ethyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- formyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (8F) (150mg; 0.31mmol) it is dissolved in methanol (20mL) and tetrahydrofuran (5mL); add dimethylamine tetrahydrofuran solution (2N; 0.3mL; 0.62mmol); 55 DEG C are warming up to react 1 hour; add sodium cyanoborohydride (58mg; 0.93mmol), 55 DEG C are reacted 18 hours.Silica gel is added into reaction solution, is concentrated, with silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:9) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- cyclopropyl -2- (N are obtained, N- dimethyl) amino-ethyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 8), yellow solid (100mg, yield 63%).

¹H NMR(400MHz,CDCl₃)δ7.43(d,2H),7.35(d,2H),7.28(d,2H),6.91(d,2H),3.91(s,2H),3.81(s,3H),2.92(s,2H),2.50(s,6H),1.35(dd,2H),1.11(dd,2H),1.02(dd,2H),0.88(dd,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.92。

LCMS m/z=510.9 [M+1].

Embodiment 9

1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 9)

1-(4-methoxyphenyl)-6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

The first step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 9)

1-(4-methoxyphenyl)-6-[4-(1-cyclopropyl-2-(pyrrolidin-1-yl)ethyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- formyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (8F) (150mg; 0.31mmol) it is dissolved in methanol (20mL) and tetrahydrofuran (5mL); add nafoxidine (44mg; 0.62mmol); 60 DEG C are warming up to react 3 hours; add sodium cyanoborohydride (58mg; 0.93mmol), 66 DEG C are reacted 18 hours.Reaction solution is concentrated, dichloromethane (60mL) and water (30mL) are added into residue, divide liquid, organic phase washed with water (30mL × 3), saturated aqueous common salt (30mL) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:1~1:0, methanol：Dichloromethane (v/v)=1:9) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- cyclopropyl -2- (nafoxidine -1- bases) ethyl) phenyl]-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 9), yellow solid (80mg, yield 48%).

¹H NMR(400MHz,CDCl₃)δ7.46-7.41(m,2H),7.33(d,2H),7.17(d,2H),6.94-6.89(m,2H),3.84(s,2H),3.80(s,3H),2.62(s,2H),2.46(m,4H),1.68(m,4H),1.37(t,2H),1.01(t, 2H),0.80-0.75(m,4H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.92。

LCMS m/z=536.9 [M+1].

Embodiment 10

1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carbamyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 10)

1-(4-methoxyphenyl)-6-[4-(1-carbamoylcyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

The first step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carbamyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 10)

1-(4-methoxyphenyl)-6-[4-(1-carbamoylcyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carboxycyclopropyls) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (8D) (100mg, 0.2mmol) it is dissolved in tetrahydrofuran (20mL), add 2- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (153mg, 0.4mmol), N, N- diisopropyl ethyl amines (129mg, 1.0mmol) and ammoniacal liquor (1mL), are reacted at room temperature 3 hours.Ethyl acetate (30mL) and water (20mL) are added into reaction solution, divide liquid, organic phase washed with water (20mL), 10% sodium hydroxide solution (40mL × 2) and saturated aqueous common salt (30mL) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (acetic acid second Ester：Petroleum ether (v/v)=3:7~1:1) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carbamyls cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (compound 10); yellow solid (50mg, yield 50%).

¹H NMR(400MHz,CDCl₃)δ7.43(d,4H),7.30(d,2H),6.93(d,2H),5.46(s,1H),5.33(s,1H),3.86(s,2H),3.81(s,3H),1.42(m,2H),1.03(m,4H),0.89-0.84(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.92。

LCMS m/z=496.8 [M+1].

Embodiment 11

1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 11)

1-(4-methoxyphenyl)-6-[4-(1-hydroxymethylcyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

The first step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 11)

1-(4-methoxyphenyl)-6-[4-(1-hydroxymethylcyclopropyl)phenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (1- carboxycyclopropyls) phenyl]-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (8D) (360mg; 0.72mmol) it is dissolved in tetrahydrofuran (20mL); under nitrogen protection Tetrahydrofuran borine (2.2mL, 2.17mmol) is added, is reacted at room temperature 18 hours.Methanol (5mL) is added into reaction solution, stirring 20 minutes, add ethyl acetate (30mL) and water (20mL), divide liquid, aqueous phase is extracted with ethyl acetate (20mL), merges organic phase, organic phase is washed with saturated aqueous common salt (30mL), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~2:3) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 11), white solid (270mg, yield 78%).

¹H NMR(400MHz,CDCl₃)δ7.44(d,2H),7.36(d,2H),7.23(d,2H),6.91(d,2H),3.84(s,2H),3.81(s,3H),3.63(s,2H),1.38(m,2H),1.01(m,2H),0.83(m,4H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.91。

LCMS m/z=483.8 [M+1].

Embodiment 12

1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- mesyl -1- cyclopropyl) ethylphenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 12)

1-(4-methoxyphenyl)-6-[4-(2-methylsulfonyl-1-cyclopropyl)ethylphenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

The first step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (the bromo- 1- cyclopropyl of 2-) ethylphenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (12B)

1-(4-methoxyphenyl)-6-[4-(2-bromo-1-cyclopropyl)ethylphenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- methylols cyclopropyl) phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 11) (200mg, 0.41mmol) it is dissolved in dichloromethane (20mL), it is cooled to 0 DEG C, add carbon tetrabromide (206mg, 0.62mmol) with triphenylphosphine (163mg, 0.62mmol), maintain to stir 30 minutes at 0 DEG C, be warmed to room temperature reaction 20 hours.Water (20mL) is added into reaction solution, point liquid, organic phase washed with water (20mL) and saturated aqueous common salt (20mL) are washed, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:9~1:5) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (the bromo- 1- cyclopropyl of 2-) ethylphenyl]-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropane] -7- ketone (12B), white solid (170mg, yield 76%).

¹H NMR(400MHz,CDCl₃)δ7.44(d,2H),7.36(d,2H),7.23(d,2H),6.92(d,2H),3.86(s,2H),3.81(s,3H),3.57(s,2H),1.39(dd,2H),1.10(dd,2H),1.02(m,4H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.92。

Second step：1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- mesyl -1- cyclopropyl) ethylphenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (compound 12)

1-(4-methoxyphenyl)-6-[4-(2-methylsulfonyl-1-cyclopropyl)ethylphenyl]-3-(trifluoromethyl)spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-7-one

By 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (the bromo- 1- cyclopropyl of 2-) ethylphenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropane] -7- ketone (12B) (170mg, 0.31mmol) it is dissolved in N, in dinethylformamide (15mL), methanesulfonic sodium (48mg, 0.47mmol) is added, 130 DEG C is warming up to and reacts 2 hours.Reaction solution is cooled down, add dichloromethane (80mL) and water (50mL), divide liquid, organic phase washed with water (50 × 3mL) and saturated aqueous common salt (30mL × 2) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (ethyl acetate：Petroleum ether (v/v)=1:5~2:3) title compound 1- (4- methoxyphenyls) -3- trifluoromethyls -6- [4- (2- mesyl -1- cyclopropyl) ethylphenyl]-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropane] -7- ketone (compound 12); white solid (80mg, yield 47%).

¹H NMR(400MHz,CDCl₃)δ7.44(d,2H),7.42(d,2H),7.27(d,2H),6.92(d,2H),3.84(s,2H),3.81(s,3H),3.29(s,2H),2.48(s,3H),1.39(m,2H),1.11(m,2H),1.06(m,2H),1.01(m,2H)。

¹⁹F NMR(376MHz,CDCl₃)δ-59.93。

LCMS m/z=545.8 [M+1].

Embodiment 13

1- (2; 3- Dihydrobenzofuranes -5- bases) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 13)

1-(2,3-dihydrobenzofuran-5-yl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (13B)

Ethyl 6-[4-[1-(bromomethyl)cyclopropyl]phenyl]-1-(2,3-dihydrobenzofuran-5-yl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- [1- (methylol) cyclopropyl] phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (5C) (1.3g, 2.6mmol) it is dissolved in dichloromethane (30mL), add carbon tetrabromide (1.3g, 3.9mmol), add triphenylphosphine (1.0g, 3.9mmol), react 24 hours at room temperature.Silica gel mixed sample concentration is added into reaction solution, with silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:1) title compound 6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -1- (2 is obtained, 3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (13B), white solid (562mg, yield 40%).

¹H NMR(400MHz,CDCl₃)δ7.33(m,3H),7.22(dd,3H),6.76(d,1H),4.59(t,2H),4.40(q,2H),3.82(s,2H),3.66(s,1H),3.57(s,1H),3.21(t,2H),1.85(m,3H),1.40(t,3H),1.03–0.96(m,3H),0.96–0.91(m,2H)。

Second step：1- (2; 3- Dihydrobenzofuranes -5- bases) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (13C)

Ethyl 1-(2,3-dihydrobenzofuran-5-yl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -1- (2,3- Dihydrobenzofuranes -5- bases) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (13B) (562mg, 1.0mmol) it is dissolved in DMF (15mL), adds methane sulfinic acid sodium (153mg, 1.5mmol), 130 DEG C are reacted 2 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (50mL), divide liquid, organic phase is washed with water (30mL × 2), with saturated common salt water washing (30mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:2) title compound 1- (2 is obtained; 3- Dihydrobenzofuranes -5- bases) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- Ethyl formates (13C); white solid (250mg, yield 45%).

¹H NMR(400MHz,CDCl₃)δ7.42(d,2H),7.29(dd,3H),7.21(dd,1H),6.76(d,1H),4.59(t,2H),4.40(q,2H),3.81(s,2H),3.29(s,2H),3.21(t,2H),2.46(s,3H),1.87(q,2H),1.40(t,3H),1.11(t,2H),1.05(t,2H),0.93(td,2H)。

LCMS m/z=562.3 [M+1].

3rd step：1- (2; 3- Dihydrobenzofuranes -5- bases) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 13)

1-(2,3-dihydrobenzofuran-5-yl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 1- (2; 3- Dihydrobenzofuranes -5- bases) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (13C) (250mg, 0.45mmol) are dissolved in 20mL N; in dinethylformamide; add formamide (200mg, 4.45mmol), sodium methoxide (97mg; 1.8mmol), 95 DEG C are reacted 5 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, title compound 1- (2 is obtained with dichloromethane and petroleum ether mixed solvent crystallization, 3- Dihydrobenzofuranes -5- bases) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3, 4-c] pyridine -4, 1`- cyclopropyl] -3- formamides (compound 13), white solid (150mg, yield 63%).

¹H NMR(400MHz,DMSO)δ7.66(s,1H),7.46–7.31(m,4H),7.24(d,3H),6.79(d,1H),4.59(t,2H),3.82(s,2H),3.55(s,2H),3.21(t,2H),2.63(s,3H),1.69(s,2H),1.07(s,2H),0.93(s,4H)。

LCMS m/z=533.3 [M+1].

Embodiment 14

1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 14)

1-(2-fluoro-4-methoxy-phenyl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (14B)

Ethyl 6-[4-[1-(bromomethyl)cyclopropyl]phenyl]-1-(2-fluoro-4-methoxy-phenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- [1- (methylol) cyclopropyl] phenyl] -1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (6C) (758mg, 1.5mmol) it is dissolved in dichloromethane (30mL), carbon tetrabromide (1.5g, 4.5mmol) is added, triphenylphosphine (1.2g is added, 4.5mmol), react 24 hours at room temperature.Silica gel mixed sample concentration is added, with silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:1) title compound 6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (14B), white solid (500mg, yield 59%).

¹H NMR(400MHz,CDCl₃)δ7.44–7.33(m,3H),7.24(d,2H),6.70(ddd,2H),4.41(q,2H),3.83(s,2H),3.79(s,3H),3.57(s,2H),1.86(s,2H),1.41(t,3H),1.09(t,2H),1.00(t,2H),0.93(t,2H)。

LCMS m/z=568.3 [M+1].

Second step：1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (14C)

Ethyl 1-(2-fluoro-4-methoxy-phenyl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (14B) (500mg, 0.88mmol) it is dissolved in N, in dinethylformamide (15mL), methane sulfinic acid sodium (135mg, 1.3mmol) is added, 130 DEG C are reacted 2 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (50mL), divide liquid, organic phase washed with water (30mL × 2) and saturated aqueous common salt (30mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:2) title compound 1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -6- [4- [1- (mesylmethyl) are obtained Cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (14C), white solid (150mg, yield 30%).

¹H NMR(400MHz,CDCl₃)δ7.45–7.35(m,3H),7.28(s,2H),6.71(ddd,2H),4.41(q,2H),3.80(s,5H),3.28(s,2H),2.46(s,3H),1.87(s,2H),1.41(t,3H),1.10(t,2H),1.05(t,2H),0.94(d,2H)。

LCMS m/z=568.3 [M+1].

3rd step：1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 14)

1-(2-fluoro-4-methoxy-phenyl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- Ethyl formates (14C) (150mg; 0.26mmol) it is dissolved in N; in dinethylformamide (20mL); add formamide (119mg; 2.64mmol); sodium methoxide (56mg; 1.04mmol), 95 DEG C are reacted 5 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase washed with water (50mL × 2) and washed with saturated aqueous common salt (50mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=3:2~2:3) title compound 1- (the fluoro- 4- methoxyl groups-phenyl of 2-) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropyl] -3- formamides (compound 14); white solid (80mg, yield 57%).

¹H NMR(400MHz,CDCl₃)δ7.47–7.33(m,3H),7.27(m,2H),6.88(s,1H),6.80–6.68(m,2H),5.37(s,1H),3.81(s,5H),3.28(s,2H),2.46(s,3H),1.98(s,2H),1.14–1.02(m,4H),0.92(s,2H)。

LCMS m/z=539.3 [M+1].

Embodiment 15

1- (4- methoxyphenyls) -6- [4- [1- (Methyaminomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 15)

1-(4-methoxyphenyl)-6-[4-[1-(methylaminomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：1- (4- methoxyphenyls) -6- [4- [1- (Methyaminomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (15B)

Ethyl 1-(4-methoxyphenyl)-6-[4-[1-(methylaminomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -6- [4- [1- formyls cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- Ethyl formates (1E) (500mg; 1.03mmol) it is dissolved in methanol (30mL) and tetrahydrofuran (10mL); add the methanol solution (2N of methylamine; 1mL; 2.06mmol); add anhydrous zinc chloride (562mg; 4.12mmol), 55 DEG C are reacted 1 hour.Sodium cyanoborohydride (194mg, 3.09mmol) is added, 55 DEG C are reacted 4 hours.Silica gel mixed sample concentration is added, with silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1) title compound 1- (4- methoxyphenyls) -6- [4- [1- (Methyaminomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (15B), white solid (516mg, yield 100%).

LCMS m/z=501.3 [M+1].

Second step：1- (4- methoxyphenyls) -6- [4- [1- (Methyaminomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 15)

1-(4-methoxyphenyl)-6-[4-[1-(methylaminomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 1- (4- methoxyphenyls) -6- [4- [1- (Methyaminomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (15B) (516mg, 1.03mmol) it is dissolved in DMF (20mL), adds formamide (464mg, 10.3mmol), sodium methoxide (223mg, 4.12mmol), 95 DEG C are reacted 16 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=3:2~2:3；Dichloromethane：Methanol (v/v)=49:1~9:1) title compound 1- (4- methoxyphenyls) -6- [4- [1- (Methyaminomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 15), white solid (100mg, yield 21%).

¹H NMR(400MHz,DMSO)δ7.69(s,1H),7.51–7.45(m,2H),7.37(s,1H),7.32–7.26(m,2H),7.24–7.19(m,2H),7.03–6.95(m,2H),3.82(s,2H),3.80(s,3H),2.65(s,2H),2.24(s,3H),1.69(dd,2H),0.94(dd,2H),0.80–0.74(m,2H),0.74–0.67(m,2H)。

LCMS m/z=472.4 [M+1].

Embodiment 16

1- (4- methoxyphenyls) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 16)

1-(4-methoxyphenyl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：1- (4- methoxyphenyls) -6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (16B)

Ethyl 1-(4-methoxyphenyl)-6-[4-[1-(bromomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -6- [4- [1- (methylol) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (1D) (1.5g, 3.1mmol) it is dissolved in dichloromethane (30mL), carbon tetrabromide (3.1g, 9.3mmol) is added, triphenylphosphine (2.4g is added, 9.3mmol), react 18 hours at room temperature.Silica gel mixed sample concentration is added, with silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:1) title compound 1- (4- methoxyphenyls) -6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (16B), white solid (1.5g, yield 88%).

¹H NMR(400MHz,CDCl₃)δ7.45–7.40(m,2H),7.37–7.32(m,2H),7.26–7.22(m,2H),6.93–6.88(m,2H),4.40(q,2H),3.83(s,2H),3.80(s,3H),3.57(s,2H),1.86(q,2H),1.41(t,3H),1.10(t,2H),1.00(t,2H),0.94(dd,2H)。

LCMS m/z=550.2 [M+1].

Second step：1- (4- methoxyphenyls) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (16C)

Ethyl 1-(4-methoxyphenyl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine - 4,1`- cyclopropyl] -3- Ethyl formates (16B) (600mg, 1.09mmol) are dissolved in DMF (15mL), add methane sulfinic acid sodium (167mg, 1.64mmol), and 130 DEG C are reacted 2 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (50mL), divide liquid, organic phase is washed with water (30mL × 2), with saturated common salt water washing (30mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:2) title compound 1- (4- methoxyphenyls) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropyl] -3- Ethyl formates (16C); yellow solid (330mg, yield 55%).

¹H NMR(400MHz,CDCl₃)δ7.42(t,4H),7.27(d,2H),6.93–6.88(m,2H),4.40(q,2H),3.81(s,2H),3.80(s,3H),3.28(s,2H),2.46(s,3H),1.87(q,2H),1.40(t,3H),1.10(t,2H),1.05(t,2H),0.93(dd,2H)。

LCMS m/z=550.3 [M+1].

3rd step：1- (4- methoxyphenyls) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 16)

1-(4-methoxyphenyl)-6-[4-[1-(methylsulfonylmethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 1- (4- methoxyphenyls) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- Ethyl formates (16C) (330mg; 0.6mmol) it is dissolved in DMF (20mL), adds formamide (270mg; 6.0mmol); sodium methoxide (130mg, 2.4mmol), 95 DEG C are reacted 16 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (50mL), divide liquid, organic phase washed with water (40mL × 2) and saturated aqueous common salt (40mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=3:2~2:3) title compound 1- (4- methoxyphenyls) -6- [4- [1- (mesylmethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained; 4-c] pyridine -4; 1`- cyclopropyl] -3- formamides (compound 16); white solid (200mg, yield 64%).

¹H NMR(400MHz,DMSO)δ7.69(s,1H),7.48(d,2H),7.40(d,3H),7.25(d,2H),6.99(d,2H),3.83(s,2H),3.80(s,3H),3.55(s,2H),2.63(s,3H),1.69(s,2H),1.07(s,2H),0.94(s,4H)。

LCMS m/z=521.3 [M+1].

Embodiment 17

1- (4- methoxyphenyls) -6- [4- [1- (amino methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 17)

1-(4-methoxyphenyl)-6-[4-[1-(aminomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：1- (4- methoxyphenyls) -6- [4- [1- (azido-methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (17B)

Ethyl 1-(4-methoxyphenyl)-6-[4-[1-(azidomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -6- [4- [1- (bromomethyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (16B) (200mg, 0.36mmol) it is dissolved in N, in dinethylformamide (10mL), sodium azide (95mg, 1.45mmol) is added, 60 DEG C are reacted 18 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 1) washing, anhydrous sodium sulfate drying, concentration, obtain title compound 1- (4- methoxyphenyls) -6- [4- [1- (azido-methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (17B), yellow liquid (185mg Yield 100%).

¹H NMR(400MHz,CDCl₃)δ7.46–7.40(m,2H),7.36–7.31(m,2H),7.27–7.23(m,2H),6.93–6.88(m,2H),4.40(q,2H),3.83(s,2H),3.80(s,3H),3.37(s,2H),1.86(q,2H),1.40(t,3H),0.94(dd,2H),0.90(d,4H)。

LCMS m/z=513.3 [M+1].

Second step：1- (4- methoxyphenyls) -6- [4- [1- (amino methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (17C)

Ethyl 1-(4-methoxyphenyl)-6-[4-[1-(aminomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 1- (4- methoxyphenyls) -6- [4- [1- (azido-methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3, 4-c] pyridine -4, 1`- cyclopropyl] -3- Ethyl formates (17B) (836mg, 1.63mmol) it is dissolved in methanol (20mL), 0 DEG C adds cobalt chloride (43mg, 0.33mmol), room temperature reaction 30 minutes, 0 DEG C adds sodium borohydride (124mg, 3.26mmol), room temperature reaction 1 hour, 0 DEG C adds water (10mL) and reaction is quenched, add dichloromethane (50mL), suction filtered through kieselguhr, filtrate adds water (50mL), divide liquid, organic phase washed with water (50mL × 2) and saturated aqueous common salt (50mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1~9:1) title compound 1- (4- methoxyphenyls) -6- [4- [1- (amino methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (17C), yellow solid (330mg, yield 55%).

LCMS m/z=487.4 [M+1].

3rd step：1- (4- methoxyphenyls) -6- [4- [1- (amino methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 17)

1-(4-methoxyphenyl)-6-[4-[1-(aminomethyl)cyclopropyl]phenyl]-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 1- (4- methoxyphenyls) -6- [4- [1- (amino methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (17C) (500mg, 1.03mmol) it is dissolved in DMF (20mL), adds formamide (4635mg, 10.3mmol), sodium methoxide (223mg, 4.12mmol), 95 DEG C are reacted 3 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (50mL), divide liquid, organic phase washed with water (40mL × 2) and saturated aqueous common salt (40mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (dichloromethane：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=49:1~9:1) title compound 1- (4- methoxyphenyls) -6- [4- [1- (amino methyl) cyclopropyl] phenyl] -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 17), white solid (230mg, yield 64%).

¹H NMR(400MHz,DMSO)δ7.69(s,1H),7.51–7.46(m,2H),7.38(s,1H),7.32–7.26(m,2H),7.26–7.20(m,2H),7.02–6.96(m,2H),3.83(s,2H),3.80(s,3H),2.72(s,2H),1.97(s,2H),1.69(dd,2H),0.94(dd,2H),0.79(q,2H),0.67(q,2H)。

LCMS m/z=458.3 [M+1].

Embodiment 18

1- (4- methoxyphenyls) -7- oxos -6- [4- [1- (pyrrolidin-1-yl methyl) cyclopropyl] phenyl] spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formonitrile HCNs (compound 18)

1-(4-methoxyphenyl)-7-oxo-6-[4-[1-(pyrrolidin-1-ylmethyl)cyclopropyl]phenyl]spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carbonitrile

By 1- (4- methoxyphenyls) -7- oxos -6- [4- [1- (pyrrolidin-1-yl methyl) cyclopropyl] phenyl]-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- formamides (compound 3) (150mg; 0.3mmol) it is dissolved in dichloromethane (20mL); nitrogen protection is lower to add pyridine (2.9g; 36.54mmol); it is cooled to -20 DEG C; TFAA (308mg is added dropwise; 1.47mmol), it is gradually increased to room temperature reaction 2 hours.Reaction solution adds water (30mL) and dichloromethane (20mL), point liquid, Organic phase uses hydrochloric acid (2N), 5% sodium hydroxide solution (50ml) and saturated aqueous common salt (50ml) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether successively：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1~9:1) title compound 1- (4- methoxyphenyls) -7- oxos -6- [4- [1- (pyrrolidin-1-yl methyl) cyclopropyl] phenyl] spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formonitrile HCNs (compound 18), white solid (60mg, yield 42%).

¹H NMR(400MHz,CDCl₃)δ7.44(m,2H),7.33(m,2H),7.17(m,2H),6.93(m,2H),3.88(s,2H),3.81(s,3H),2.62(s,2H),2.46(s,4H),1.67(s,4H),1.56(s,2H),1.11(s,2H),0.78(d,4H)。

LCMS m/z=494.4 [M+1].

Embodiment 19

6- [4- [1- (dimethylamino methyl) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formonitrile HCNs (compound 19)

6-[4-[1-(dimethylaminomethyl)cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carbonitrile

By 6- [4- [1- (dimethylamino methyl) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- formamides (compound 1) (100mg; 0.2mmol) it is dissolved in dichloromethane (20mL); nitrogen protection is lower to add pyridine (2.0g; 25.2mmol); it is cooled to -20 DEG C; TFAA (216mg is added dropwise; 1.0mmol), it is gradually increased to room temperature reaction 3 hours.Reaction solution adds water (30mL) and dichloromethane (20mL), divide liquid, organic phase uses hydrochloric acid (2N successively, 50mL × 2), 5% sodium hydroxide solution (50mL × 2) and saturated aqueous common salt (50mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1~9:1) title compound 6- [4- [1- (dimethylamino methyl) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] (the change of -3- formonitrile HCNs Compound 19), yellow solid (50mg, yield 53%).

¹H NMR(400MHz,CDCl₃)δ7.45(d,2H),7.32(m,2H),7.18(m,2H),6.92(d,2H),3.88(s,2H),3.81(s,3H),2.47(s,2H),2.20(s,6H),1.56(m,2H),1.10(m,2H),0.83(m,2H),0.71(m,2H)。

LCMS m/z=468.4 [M+1].

Embodiment 20

1- [4- [3- carbamyls -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -6- bases] phenyl] cyclopropanecarboxylic acid (compound 20)

1-[4-[3-carbamoyl-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-6-yl]phenyl]cyclopropanecarboxylic acid

By 1- [4- [3- carbethoxyl groups -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -6- bases] phenyl] cyclopropanecarboxylic acid (1C) (200mg, 0.4mmol) it is dissolved in DMF (20mL), adds formamide (180mg, 4.0mmol), sodium methoxide (86mg, 1.6mmol), 95 DEG C are reacted 18 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (30mL), with 4N salt acid for adjusting pH to 2-3, divide liquid, organic phase washed with water (30mL × 2) and saturated aqueous common salt (30mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=49:1) title compound 1- [4- [3- carbamyls -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -6- bases] phenyl] cyclopropanecarboxylic acid (compound 20), white solid (80mg, yield 42%).

¹H NMR(400MHz,DMSO)δ12.28(s,1H),7.70(s,1H),7.49(d,2H),7.38(s,1H),7.31(d,2H),7.24(d,2H),6.99(d,2H),3.84(s,2H),3.80(s,3H),1.69(d,2H),1.44(d,2H),1.10(d,2H),0.95(s,2H)。

LCMS m/z=473.3 [M+1].

Embodiment 21

6- [4- [1- (methylol) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 21)

6-[4-[1-(hydroxymethyl)cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 6- [4- [1- (methylol) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (1D) (230mg, 0.47mmol) it is dissolved in DMF (20mL), adds formamide (212mg, 4.720mmol), sodium methoxide (102mg, 1.88mmol), 95 DEG C are reacted 18 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (30mL), divide liquid, organic phase washed with water (30mL × 2) and saturated aqueous common salt (30mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue methylene chloride/methanol/petroleum ether crystallization obtains title compound 6- [4- [1- (methylol) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 21), white solid (90mg, yield 42%).

¹H NMR(400MHz,DMSO)δ7.69(s,1H),7.48(d,2H),7.38(s,1H),7.29(d,2H),7.22(d,2H),6.99(d,2H),4.64(s,1H),3.82(s,2H),3.80(s,3H),3.51(d,2H),1.69(s,2H),0.94(s,2H),0.82(s,2H),0.69(s,2H)。

LCMS m/z=459.3 [M+1].

Embodiment 22

6- [4- [1- formaldehyde cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 22)

6-[4-(1-formylcyclopropyl)phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 6- [4- [1- formaldehyde cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (1E) (200mg, 0.41mmol) it is dissolved in DMF (20mL), adds formamide (185mg, 4.1mmol), sodium methoxide (89mg, 1.64mmol), 95 DEG C are reacted 5 hours.Reaction solution is cooled down, add dichloromethane (50mL) and water (30mL), divide liquid, organic phase washed with water (30mL × 2) and saturated aqueous common salt (30mL × 1) washing, anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=7:3~1:1；Ethyl acetate：Dichloromethane (v/v)=1:19) title compound 6- [4- [1- formaldehyde cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 22), white solid (90mg, yield 48%).

¹H NMR(400MHz,CDCl₃)δ9.20(s,1H),7.46–7.41(m,2H),7.29(s,4H),6.96–6.90(m,3H),5.39(s,1H),3.85(s,2H),3.82(s,3H),1.99(q,2H),1.56(q,2H),1.35(q,2H),0.93(q,2H)。

LCMS m/z=457.3 [M+1].

Embodiment 23

1- (4- methoxyphenyls) -7- oxos -6- [4- [1- (pyrrolidin-1-yl methyl) cyclopropyl] phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamide 2,2,2- trifluoroacetates (compound 23)

1-(4-methoxyphenyl)-7-oxo-6-[4-[1-(pyrrolidin-1-ylmethyl)cyclopropyl]phenyl]spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide 2,2,2-trifluoroacetic acid

By 1- (4- methoxyphenyls) -7- oxos -6- [4- [1- (pyrrolidin-1-yl methyl) cyclopropyl] phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 7) (100mg, 0.2mmol) it is dissolved in ethyl acetate (10mL) and dichloromethane (3mL), add trifluoroacetic acid (22mg, 0.2mmol), react at room temperature 24 hours.Reaction solution is concentrated to give title compound 1- (4- methoxyphenyls) -7- oxos -6- [4- [1- (pyrrolidin-1-yl methyl) cyclopropyl] phenyl]-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides 2,2,2- trifluoroacetates (compound 23), white solid (110mg, yield 88%).

¹H NMR(400MHz,DMSO)δ9.26(s,1H),7.71(s,1H),7.47(dd,4H),7.39(s,1H),7.32(d,2H),6.99(d,2H),3.84(s,2H),3.80(s,3H),3.49(d,2H),3.36(dd,2H),2.87(m,2H),1.96–1.85(m,2H),1.78(dd,2H),1.74–1.68(m,2H),1.04(t,2H),0.94(m,4H)。

¹⁹F NMR(376MHz,DMSO)δ-74.63。

LCMS m/z=512.4 [M+1].

Embodiment 24

6- [4- [1- [[(3R) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 24)

6-[4-[1-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：6- [4- [1- [[(3R) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxygen Generation-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (24B)

Ethyl 6-[4-[1-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (1E) (300mg; 0.62mmol) it is dissolved in 20mL methanol and 10mL tetrahydrofurans; add (R) -3- pyrrolidinols (108mg; 1.24mmol); add anhydrous zinc chloride (338mg; 2.48mmol), 55 DEG C are reacted 1 hour.Sodium cyanoborohydride (117mg, 1.86mmol) is added, 55 DEG C are reacted 16 hours.Concentration, reaction solution adds dichloromethane (80mL) and water (50mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1~9:1) title compound 6- [4- [1- [[(3R) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (24B), white solid (250mg, yield 72%).

LCMS m/z=557.4 [M+1].

Second step：6- [4- [1- [[(3R) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 24)

6-[4-[1-[[(3R)-3-hydroxypyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 6- [4- [1- [[(3R) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (24B) (250mg, 0.45mmol) it is dissolved in N, in dinethylformamide (20mL), add formamide (202mg, 4.5mmol), sodium methoxide (87mg, 1.6mmol), 95 DEG C are reacted 4 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1, dichloromethane：Methanol (v/v)= 19:1~9:1) title compound 6- [4- [1- [[(3R) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 24), white solid (140mg, yield 59%).

¹H NMR(400MHz,CDCl₃)δ7.45–7.40(m,2H),7.35(d,2H),7.21(d,2H),6.96–6.88(m,3H),5.33(s,1H),4.24(s,1H),3.82(s,5H),2.88(s,4H),2.44(s,1H),2.23(m,4H),1.98(q,2H),0.92(dd,2H),0.87(m,4H)。

LCMS m/z=528.3 [M+1].

Embodiment 25

6- [4- [1- [[(3S) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 25)

6-[4-[1-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：6- [4- [1- [[(3S) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (25B)

Ethyl 6-[4-[1-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (1E) (300mg, 0.62mmol) are dissolved in methanol (20mL) and tetrahydrofuran (10 ML in), (R) -3- pyrrolidinols (108mg, 1.24mmol) are added, anhydrous zinc chloride (338mg, 2.48mmol) is added, 55 DEG C are reacted 1 hour.Sodium cyanoborohydride (117mg, 1.86mmol) is added, 55 DEG C are reacted 16 hours.Concentration, reaction solution adds dichloromethane (80mL) and water (50mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1~9:1) title compound 6- [4- [1- [[(3S) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (25B), white solid (230mg, yield 67%).

LCMS m/z=557.4 [M+1].

Second step:6- [4- [1- [[(3S) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 25)

6-[4-[1-[[(3S)-3-hydroxypyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 6- [4- [1- [[(3S) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (25B) (230mg, 0.41mmol) it is dissolved in N, in dinethylformamide (20mL), add formamide (185mg, 4.1mmol), sodium methoxide (89mg, 1.8mmol), 95 DEG C are reacted 4 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~0:1；Dichloromethane：Methanol (v/v)=19:1~9:1) title compound 6- [4- [1- [[(3S) -3- hydroxyl pyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 25), white solid (100mg, yield 46%).

¹H NMR(400MHz,CDCl₃)δ7.46–7.40(m,2H),7.35(d,2H),7.22(d,2H),6.96–6.88(m,3H),5.34(s,1H),4.24(s,1H),3.82(s,5H),3.12–2.65(m,4H),2.47(s,1H),2.39–2.02(m,4H),1.98(q,2H),0.92(dd,2H),0.91–0.81(m,4H)。

LCMS m/z=528.4 [M+1].

Embodiment 26

6- [4- [1- (1- hydroxyethyls) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 26)

6-[4-[1-(1-hydroxyethyl)cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 6- [4- [1- formaldehyde cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos - spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropyl] -3- formamides (1E) (46mg; 0.1mmol) it is dissolved in tetrahydrofuran (15mL); -78 DEG C add methyl-magnesium-bromide (2mol/L under nitrogen protection; 0.25mL, 0.5mmol), it is gradually increased to room temperature reaction 4 hours.Reaction solution adds dichloromethane (20mL) and water (20mL), divide liquid, organic phase is washed with water (20mL × 1), with saturated common salt water washing (20mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=4:1~3:2) title compound 6- [4- [1- (1- hydroxyethyls) cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 26), white solid (20mg, yield 20%).

¹H NMR(400MHz,CDCl₃)δ7.43(d,2H),7.35(d,2H),7.23(d,2H),6.93(d,3H),5.34(s,1H),3.83(s,2H),3.82(s,3H),3.36(q,1H),1.98(dd,2H),1.10(d,3H),0.92(dd,2H),0.88–0.82(m,2H),0.78–0.72(m,2H)。

LCMS m/z=473.4 [M+1].

Embodiment 27

6- [4- [1- [[(3R) -3- fluoropyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 27)

6-[4-[1-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

The first step：6- [4- [1- [[(3R) -3- fluoropyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (27B)

Ethyl 6-[4-[1-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxylate

By 6- [4- (1- formyls cyclopropyl) phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3; 4-c] pyridine -4; 1`- cyclopropane] -3- Ethyl formates (1E) (300mg; 0.62mmol) it is dissolved in methanol (20mL) and tetrahydrofuran (10mL); add (R) -3- Fluoropyrrolidine hydrochloride salts (156mg; 1.24mmol); add anhydrous zinc chloride (338mg; 2.48mmol); triethylamine (188mg; 1.86mmol), 55 DEG C are reacted 1 hour.Sodium cyanoborohydride (117mg, 1.86mmol) is added, 55 DEG C are reacted 3 hours.Concentration, reaction solution adds dichloromethane (80mL) and water (50mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 2), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=1:1~3:7) title compound 6- [4- [1- [[(3R) -3- fluoropyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (27B), white solid (230mg, yield 60%).

LCMS m/z=559.3 [M+1].

Second step：6- [4- [1- [[(3R) -3- fluoropyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 27)

6-[4-[1-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclopropyl]phenyl]-1-(4-methoxyphenyl)-7-oxo-spiro[5H-pyrazolo[3,4-c]pyridine-4,1`-cyclopropane]-3-carboxamide

By 6- [4- [1- [[(3R) -3- fluoropyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3,4-c] pyridine -4,1`- cyclopropyl] -3- Ethyl formates (27B) (230mg, 0.41mmol) it is dissolved in N, in dinethylformamide (20mL), add formamide (185mg, 4.1mmol), sodium methoxide (88mg, 1.64mmol), 95 DEG C are reacted 5 hours.Reaction solution is cooled down, add dichloromethane (60mL) and water (60mL), divide liquid, organic phase is washed with water (50mL × 2), with saturated common salt water washing (50mL × 1), anhydrous sodium sulfate drying, concentration, residue silica gel chromatographic column separating-purifying (petroleum ether：Ethyl acetate (v/v)=3:2~1:4) title compound 6- [4- [1- [[(3R) -3- fluoropyrrolidine -1- bases] methyl] cyclopropyl] phenyl] -1- (4- methoxyphenyls) -7- oxos-spiral shell [5H- pyrazolos [3 are obtained, 4-c] pyridine -4,1`- cyclopropyl] -3- formamides (compound 27), white solid (100mg, yield 46%).

¹H NMR(400MHz,DMSO)δ7.69(s,1H),7.50–7.45(m,2H),7.37(s,1H),7.30(t,2H),7.20(d,2H),7.01–6.95(m,2H),5.23–5.01(m,1H),3.81(d,5H),2.84–2.52(m,5H),2.33(dd,1H),2.16–1.93(m,1H),1.86–1.71(m,1H),1.69(dd,2H),0.94(dd,2H),0.78(d,2H),0.73(m,2H)。

¹⁹F NMR(376MHz,DMSO)δ-166.42。

LCMS m/z=530.3 [M+1].

Test case：

Test case 1, the compounds of this invention are to factor Xa vitro enzyme activity inhibition

Following methods can be used to determine the external inhibitory action to people source clotting factor xa activity of the compounds of this invention, be represented with inhibition constant Ki.

Containing 0.05M Tris, 0.15M NaCl, 0.1%PEG-8000 reaction buffer (pH=7.5) are middle to prepare people's source factor Xa (Enzo life science) working solution and chromogenic substrate (sekisui, article No.：222) working solution.Test compound adds dimethyl sulfoxide (DMSO) to be configured to 10mM storing solution, then is diluted to the reaction buffer containing 1%DMSO 0.1-1000nM working solution.30 μ L test compounds working solutions (control group adds 30 μ L reaction buffers) and 150 μ L factor Xa working solutions, the final concentration of 1nM of factor Xa are added in 96 orifice plates, is incubated at room temperature 30 minutes.Then chromogenic substrate working solution 120 μ L, final concentration of 0.2mM are added, starts reaction.With ELIASA (Perkin Elmer, Envision) METHOD FOR CONTINUOUS DETERMINATION 30 minutes at 405nm, measure per minute is once.

Test compound Ki is calculated as follows, as a result as shown in table 1；

Ki=IC₅₀/(1+[S]/Km)

In formula：

IC₅₀- the test compound concentration of substrate hydrolysis rate reduction 50% is caused by SPSS16.0 softwares linear regression calculating.

[S]-concentration of substrate

Km-Michaelis constant, 0.35mM

Table 1：External factor Xa enzyme assay experimental result

Embodiment is numbered	Ki(nM)
		1	0.10
2	0.66
		3	1.72
4	0.85
		5	0.042
6	0.067
		7	0.069
8	0.049
		9	0.099
10	3.20
		11	0.83
12	0.11
		13	0.25
14	0.26
		15	0.30
16	0.27
		17	0.43
18	0.24
		19	0.26
20	0.57
		21	0.2
22	0.15
		24	0.11
25	0.11
		27	0.072

Conclusion：The compounds of this invention has obvious inhibitory action in buffer solution to people source FXa.

Test case 2, external act on human plasma coagulation function determine

20 25-35 one full year of life healthy volunteers (not taking medicine in one week), elbow venipuncture takes a blood sample 20mL in 3.8% sodium citrate anticoagulant tube, and the ratio of anti-coagulants and blood is 1：9,2500 revs/min of 4 DEG C of centrifugation (Beckman, Allegrax-30R) 10 minutes, 4 DEG C of supernatant platelet-rich blood plasma 15000 rev/min is taken to centrifuge 10 minutes, collecting upper strata platelet poor plasma is used for prothrombin time (PT) and activated partial thromboplastin time (aPTT) detection.Preparation of reagents and test are with reference to kit (being purchased from Instrumentation laboratory companies, lot number is respectively N0821168 and N0820966) specification.The compounds of this invention and Eliquis of various concentrations mix to (volume ratio is 1 with platelet poor plasma：9), final compound concentration is 0-20 μM, full automatic blood-coagulation instrument (Instrumentation laboratory, ACL ELITE) test PT, aPTT.Origin fitting binomials calculate compound concentration EC needed for one times of cruor time extending_2×, as a result as shown in table 2.

Table 2：The compounds of this invention is to the blood coagulation resisting function of human plasma (with PT EC_2×With aPTT EC_2×Represent)

Embodiment is numbered	PT EC<sub>2×</sub>(μM)	aPTT EC<sub>2×</sub>(μM)
			1	0.4	0.9
5	0.4	0.8
			6	0.4	0.9
7	0.4	1.0
			8	3.1	3.9
9	2.8	4.1
			13	2.1	5.2
14	3.7	5.0
			15	0.7	1.7
16	2.4	5.1
			17	0.9	1.7
18	1.3	5.6
			19	1.0	2.1
21	3.4	6.3
			22	2.0	4
24	0.4	1.8
			25	0.6	1.6

Conclusion：The compounds of this invention has obvious blood coagulation resisting function to human plasma in vitro.

Test case 3, Pharmacokinetic Evaluation

Male SD rat (is purchased from Shanghai Slac Experimental Animal Co., Ltd., credit number：SCXK (SH) 2007000546318) 180-220g, fasting feedwater stay overnight, 3 Oral Administration in Rats gavages 5mg/kg, 3 rat intravenous injection 0.5mg/kg.Oral administration group, before administration and upon administration 15,30 and 45 minutes and 1,2,4,8, blood samplings in 12 and 24 hours；Intravenously administrable group, before administration and upon administration 5,15 and 30 minutes and 1,2,4,8, blood samplings in 12 and 24 hours.4 DEG C of blood sample 3500 rev/min is centrifuged 10 minutes, collects blood plasma, in -40 DEG C of preservations.Take each μ L of time point rat plasma 20, after the μ L of acetonitrile solution 200 mixing for adding containing the internal standard, vortex mixed 5 minutes, 3700 revs/min centrifuge 15 minutes, the μ L of supernatant 80 are taken to be mixed with 80 μ L water, the μ L of mixed liquor 10 are taken to carry out LC-MS/MS (Anjelen Sci. ＆ Tech. Inc, API4000) analyses.Main pharmacokinetic parameter is analyzed with the non-compartment model of the softwares of WinNonlin 6.3, as a result as shown in table 3.

Table 3：Pharmacokinetic parameter result

Claims (32)

1. A kind of compound shown in logical formula (I), or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

   R¹Selected from cyano group, amino ,-(CH₂)_n- C (=O) R^1a、-(CH₂)_n- S (=O)_pR^1a、C_1-6Alkyl ,-(CH₂)_n-C_1-6Alkoxy ,-(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C_3-10Carbocyclic ring or-(CH₂)_n-C_3-10Heterocycle, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the alkyl, alkoxy, carbocyclic ring and heterocycle are optionally further selected from H, F, Cl, Br, (=O), amino, hydroxyl, carboxyl, aldehyde radical, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

   R^1aAnd R^1bIt is independently selected from hydrogen, amino, hydroxyl ,-(CH₂)_n-C_3-10Carbocyclic ring ,-(CH₂)_n-C_3-10Heterocycle, C_1-4Alkoxy or C_1-4Alkyl, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the alkyl, carbocyclic ring and heterocycle are optionally further selected from H, F, Cl, Br, (=O), amino, hydroxyl, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

   R²Selected from H, F, Cl, Br, I, C_1-4Alkyl or C_1-4Alkoxy；

   Ring M is cyclopropyl, and the cyclopropyl is optionally further by 0 to 3 R³Substitution；

   R³It is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl ,-(CR^3aR^3b)_nR^3c、C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy are optionally further selected from H, F, Cl, amino, hydroxyl, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

   R^3a、R^3bAnd R^3cIt is independently selected from H, F, Cl, Br, I, hydroxyl, amino, C_1-4Alkyl, C_1-4Alkoxy ,-C (=O) OR^3dOr-C (=O) NR^3eR^3f；

   R^3d、R^3eAnd R^3fIt is independently selected from H or C_1-4Alkyl；

   R⁴Selected from H, F, Cl, Br, I, cyano group, trifluoromethyl ,-(CR^4aR^4b)_nOR^4c、-(CR^4aR^4b)_nNR^4cR^4d,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)_pR^4a、-C(R^4aR^4b)R^4c、C_3-10Carbocyclic ring or 3 to 10 circle heterocycles, the heterocycle contain 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring or heterocycle are each individually optional further by 0 to 4 R^4eSubstitution；

   R^4a、R^4b、R^4c、R^4dAnd R^4eBe each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, nitro, Cyano group, amino, trifluoromethyl, C_1-4Alkyl or C_1-4Alkoxy, the amino, alkyl or alkoxy are 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 substituent of alkoxy is replaced；

   Alternatively, R^4aAnd R^4bIt can be formed (=O)；

   Alternatively, R^4aAnd R^4b、R^4cAnd R^4d3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring contains 0 to 3 hetero atom for being selected from N, O or S, and the ring 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 substituent of alkoxy is replaced；

   Represent ring D existence or non-existences；

   In the presence of ring D, ring E is selected from phenyl or 5 to 6 unit's heteroaryls, and the heteroaryl contains 1 to 3 hetero atom for being selected from N, O or S, and the phenyl or heteroaryl are optionally further by 0 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form 5 to 6 yuan of rings together, and 5 to 6 yuan of rings contain 0 to 2 hetero atom for being selected from N, O or S, and 5 to 6 yuan of rings are optionally further by 0 to 5 R⁶Substitution；

   When ring D is not present, ring E is selected from phenyl or 5 to 6 unit's heteroaryls, and the heteroaryl contains 1 to 3 hetero atom for being selected from N, O or S, and the phenyl or heteroaryl are optionally further by 0 to 5 R⁵Substitution；

   R⁵It is each independently selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, amino, cyano group, trifluoromethyl, C_1-4Alkyl, C_1-4Alkoxy ,-(CR^5aR^5b)_nNR^5cR^5d、-(CH₂)_nC (=NR^5c)N(R^5aR^5b)、-(CR^5aR^5b)_n- C (=O) NR^5cR^5d、-(CR^5aR^5b)_nNR^5dC (=O) R^5c、-(CR^5aR^5b)_nOR^5c、-(CH₂)_nC (=O) R^5aOr-(CH₂)_nS (=O)_pR^5a, or these groups are each individually optional substituted, when substituted, are optionally selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 1 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

   R^5a、R^5b、R^5cAnd R^5dIt is independently selected from H, F, Cl, Br, I, hydroxyl, amino, C_1-4Alkyl, C_1-4Alkoxy or C_3-6Carbocyclic ring；

   Alternatively, R^5aAnd R^5bIt can be formed (=O)；

   Alternatively, R^5aAnd R^5b、R^5cAnd R^5d3 to 6 yuan of rings can be formed together with the atom that they are connected, the ring contains 0 to 3 hetero atom for being selected from N, O or S, and the ring is optionally further selected from F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, C by 0 to 4_1-4Alkyl or C_1-4The substituent of alkoxy is replaced；

   R⁶It is each independently selected from H, F, Cl, hydroxyl, sulfydryl, cyano group, amino, C_1-4Alkyl or C_1-4Alkoxy；

   Alternatively, two R⁶It can be formed (=O)；

   Alternatively, as two R⁶When being connected on same atom, one 3 can be formed together with the atom that they are connected To 4 yuan of rings, the ring contains 0 to 1 hetero atom for being selected from N, O or S；

   M is selected from 0,1,2,3 or 4；

   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 stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

   Ring M is cyclopropyl, and the cyclopropyl is optionally further by 0 to 3 R³Substitution；

   R³It is each independently selected from H, F, Cl, trifluoromethyl, hydroxyl, amino, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl, isopropoxy ,-C (=O) OCH₃,-C (=O) OCH₂CH₃Or-C (=O) NH₂。
3. Compound according to claim 2, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：Ring M is cyclopropyl.
4. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

   In the presence of ring D, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals, pyrazinyl, pyridazinyl, pyrimidine radicals or thienyl, when substituted, optionally by 1 to 3 R⁵Substitution；Ring D forms one of substituted or unsubstituted following structure together including two atoms that ring E is attached thereto：

   When substituted, optionally by 1 to 3 R⁶Substitution；

   When ring D is not present, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals, pyrazinyl, pyridazinyl, pyrimidine radicals or thienyl, when substituted, optionally by 1 to 5 R⁵Substitution.
5. Compound according to claim 4, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

   In the presence of ring D, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl, when substituted, optionally by 1 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form one of substituted or unsubstituted following structure together：When substituted, optionally by 1 to 3 R⁶Substitution；

   When ring D is not present, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl, when substituted, optionally by 1 to 5 R⁵Substitution.
6. Compound according to claim 5, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

   In the presence of ring D, ring E is selected from substituted or unsubstituted phenyl, when substituted, optionally by 1 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form substituted or unsubstituted togetherWhen substituted, optionally by 1 to 3 R⁶Substitution；

   When ring D is not present, ring E is selected from substituted or unsubstituted phenyl, when substituted, optionally by 1 to 5 R⁵Substitution.
7. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein the compound is selected from the compound shown in logical formula (II), wherein：

   Ring M is cyclopropyl；

   R is selected from 0,1,2 or 3；

   T is selected from 0,1,2,3,4 or 5.
8. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein the compound is selected from the compound shown in logical formula (III), wherein：

   Ring M is cyclopropyl；

   R` is selected from 0,1,2,3,4 or 5.
9. Compound according to claim 1,7 or 8 any one, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein R⁵It is each independently selected from substituted or unsubstituted H, F, Cl, Br, I ,-C (=NR^5c)N(R^5aR^5b)、-(CH₂)_nS (=O)_pR^5a, hydroxyl, sulfydryl, cyano group, amino, hydroxymethyl, trifluoromethyl, methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, cyclopropyl epoxide or aminomethylene, when substituted, optionally replaced by 1 to 4 substituent selected from H, F, Cl, Br, I, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, isopropyl, methoxy or ethoxy；

   R^5a、R^5bAnd R^5cIt is independently selected from H, F, Cl, Br, I, hydroxyl, amino, C_1-4Alkyl or C_1-4Alkoxy.
10. Compound according to claim 9, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein R⁵It is each independently selected from H, F, Cl ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, amino, trifluoromethyl, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene.
11. Compound according to claim 1 or 7, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein R⁶It is each independently selected from H, F, Cl, hydroxyl, sulfydryl, cyano group, amino, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl or propoxyl group；

    Alternatively, as two R⁶When being connected on same atom, 3 to 4 yuan of rings can be formed together with the atom that they are connected, 3 to 4 yuan of rings contain 0 to 1 hetero atom for being selected from N, O or S；

    Alternatively, two R⁶It can be formed (=O).
12. Compound according to claim 11, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein R⁶It is independently selected from H, F, Cl, methyl, ethyl, methoxy or ethoxy；

    Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.
13. Compound according to claim 1,7 or 8, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

    R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, methoxyl group, ethyoxyl, methylol, methoxymethylene, ethoxymeyhylene, 1- hydroxyethyls ,-(CH₂)_n- C (=O) R^1a、-(CH₂)_n- S (=O)_pR^1a、 -(CH₂)_n-NR^1aR^1b、-(CH₂)_n-C_3-6Carbocyclic ring or-(CH₂)_n-C_3-6Heterocycle, the heterocycle contains 1 to 4 hetero atom for being selected from N, O or S, and the carbocyclic ring and heterocycle are optionally further replaced by 0 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy；

    R^1aAnd R^1bIt is independently selected from hydrogen, amino, methyl, ethyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopenta, cyclohexyl, pyrrole radicals, piperidyl, morpholinyl, thio-morpholinyl or cyclopropylmethylene；

    N is selected from 0,1,2 or 3.
14. Compound according to claim 13, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

    R¹Selected from one of cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, methylol, carbamoyl, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls or substituted or unsubstituted following structure：When substituted, optionally further replaced by 1 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy.
15. Compound according to claim 1,7 or 8, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

    R²Selected from H, F or Cl.
16. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein R⁴Selected from cyano group, trifluoromethyl ,-C (=O) NR^4aR^4b、-(CH₂)_nS (=O)₂R^4aOr-C (R^4aR^4b)R^4c；

    R^4a、R^4bAnd R^4cIt is each independently selected from H, F, hydroxyl, cyano group, amino, methyl, ethyl, propyl group, isopropyl, methoxyl group, ethyoxyl or isopropoxy；

    Alternatively, R^4aAnd R^4bIt can be formed (=O)；

    Alternatively, R^4aAnd R^4bCyclopropyl can be formed together with the atom that they are connected.
17. Compound according to claim 16, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, hydroxy methylene, 1- hydroxyethyls, carbamoyl ,-S (=O)₂-CH₃, 1- hydroxycyclopropyls or 2- hydroxyisopropyls.
18. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

    R¹Selected from one of cyano group, amino, carboxyl, aldehyde radical, methyl, ethyl, methylol, carbamoyl, methoxymethylene, ethoxymeyhylene, mesyl methylene, 1- hydroxyethyls or substituted or unsubstituted following structure：When substituted, optionally further replaced by 1 to 4 substituent selected from H, F, Cl, (=O), amino, hydroxyl, carboxyl, aldehyde radical, methyl, ethyl, isopropyl, methoxy or ethoxy；

    R²Selected from H, F or Cl；

    Ring M is cyclopropyl；

    R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, carbamoyl ,-S (=O)₂CH₃, 1- hydroxyethyls, hydroxymethyl, 1- hydroxycyclopropyls or 2- hydroxyisopropyls；

    In the presence of ring D, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl, when substituted, optionally by 1 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form one of substituted or unsubstituted following structure together：When substituted, optionally by 1 to 3 R⁶Substitution；

    When ring D is not present, ring E is selected from substituted or unsubstituted phenyl, pyridine radicals or thienyl, when substituted, optionally by 1 to 5 R⁵Substitution.

    R⁵It is each independently selected from H, F, Cl, hydroxyl, amino, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, trifluoromethyl, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene；

    R⁶It is each independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy；

    Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.
19. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

    R¹Selected from cyano group, amino, carboxyl, aldehyde radical, methyl, methylol, carbamoyl, methoxymethylene, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,One of or substituted or unsubstituted following structure：When substituted, optionally further by 1 to 4 are replaced selected from H, F, Cl, (=O), hydroxyl or methyl substituents；

    R²Selected from H or F；

    Ring M is cyclopropyl；

    R⁴Selected from cyano group, a methyl fluoride, difluoromethyl, trifluoromethyl, carbamoyl ,-S (=O)₂CH₃, 1- hydroxyethyls, hydroxymethyl, 1- hydroxycyclopropyls or 2- hydroxyisopropyls；

    When ring D is not present, ring E is phenyl, and the phenyl is optionally further by 0 to 5 R⁵Substitution；

    In the presence of ring D, ring E is phenyl, and the phenyl is optionally further by 0 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form substituted or unsubstituted togetherWhen substituted, optionally by 1 to 3 R⁶Substitution；

    R⁵It is each independently selected from H, F, Cl, hydroxyl, amino, cyano group ,-C (=NH) NH₂,-S (=O)₂NH₂,-S (=O)₂CH₃, trifluoromethyl, methyl, ethyl, isopropyl, normal-butyl, isobutyl group, methoxyl group, ethyoxyl, isopropoxy, cyclopropyl epoxide or aminomethylene；

    R⁶It is each independently selected from H, F, Cl, hydroxyl, cyano group, amino, methyl, ethyl, methoxy or ethoxy；

    Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.
20. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein：

    R¹Selected from cyano group, methylol, aldehyde radical, carbamoyl, mesyl methylene, methylamino methylene, aminomethylene, 1- hydroxyethyls,

    R²Selected from H or F；

    Ring M is cyclopropyl；

    R⁴Selected from cyano group, trifluoromethyl, carbamoyl or-S (=O)₂CH₃；

    When ring D is not present, ring E is phenyl, and the phenyl is optionally further by 0 to 5 R⁵Substitution；

    In the presence of ring D, ring E is phenyl, and the phenyl is optionally further by 0 to 3 R⁵Substitution；Ring D, including two atoms that ring E is attached thereto form substituted or unsubstituted togetherWhen substituted, optionally by 1 to 3 R⁶Substitution；

    R⁵It is each independently selected from H, F, Cl, cyano group, methoxyl group or aminomethylene；

    R⁶It is each independently selected from H, F, Cl or methyl；

    Alternatively, as two R⁶When being connected on same atom, cyclopropyl can be formed together with the atom that they are connected.
21. Compound according to claim 1, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, wherein compound are selected from：
22. Compound, its stereoisomer according to any one of claim 1~21 or its pharmaceutically acceptable salt, wherein described salt is selected from hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, malate, oxalates, tartrate, benzoate, cinnamate, tosilate, benzene sulfonate, mesylate, trifluoroacetic acid, fluoroform sulphonate or combinations thereof.
23. A kind of pharmaceutical composition, described pharmaceutical composition contains the compound according to any one in claim 1~22 or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, and pharmaceutically acceptable carrier or excipient for the treatment of effective dose.
24. The purposes of compound or its stereoisomer, oxynitrides, hydrate, solvate, metabolite in claim 1~22 described in any one, pharmaceutically acceptable salt, eutectic or prodrug in the medicine in preparing the treatment disease relevant with serine protease.
25. Purposes according to claim 24, wherein the disease relevant with serine protease is selected from thromboembolic disorders.
26. Purposes according to claim 24-25, wherein the serine protease is selected from factor Xa.
27. Purposes according to claim 26, wherein thromboembolic disorders are selected from arterial cardiovascular thromboembolic disorders, intravenous cardio thromboembolic disorders and heart related thromboembolic disorders.
28. Purposes according to claim 27, wherein described thromboembolic disorders are selected from venous thronbosis, dvt formation, thrombophlebitis, cerebral artery thrombosis formation, arterial embolism, coronary artery thrombosis formation, pulmonary embolism, renal embolism, cerebral embolism, overworked dead, the temporary ischemic of atherosclerosis, acute coronary syndrome, unstable angina, acute coronary syndrome, miocardial infarction, arteriosclerosis, ischaemic, external application obstructive arterial disease, apoplexy or cranial vascular disease.
29. Containing the compound described in any one in claim 1~22, or its stereoisomer, oxynitrides, hydrate, solvate, metabolite, the wherein pharmaceutical agent of pharmaceutically acceptable salt, eutectic or prodrug, institute Stating pharmaceutical agent includes：The first therapeutic agent and second of therapeutic agent of effective dose in treatment, wherein described first therapeutic agent is compound described in any one in claim 1~22, or its stereoisomer, oxynitrides, hydrate, solvate, pharmaceutically metabolite, acceptable salt, eutectic or prodrug, the second therapeutic agent is selected from least one of second Xa factor inhibitor, anti-coagulants, anti-platelet agents, thrombin inhibitor, thrombolytic agent and fibrinolytic agent reagent.
30. Pharmaceutical agent according to claim 29, wherein described second of therapeutic agent is to be selected from warfarin, unfraction heparin, low molecule amount liver rope, the pentasaccharides of synthesis, hirudin, argatroban, aspirin, brufen, methoxy how propionic acid, sulindac, Indomethacin, mefenamic acid, drogelor, Diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, Eptifibatide, Abciximab melagatran, two sulfuric acid hirudins, tissue plasminogen activator, the tissue-type plasminogen activator of modification, anistreplase, at least one of urokinase and streptokinase reagent.
31. Pharmaceutical agent described in claim 30, wherein second of therapeutic agent is at least one anti-platelet agents.
32. Pharmaceutical agent described in claim 31, wherein the anti-platelet agents are aspirin and/or clopidogrel.