CN108456208A

CN108456208A - Aza toroid compound and its preparation method and application

Info

Publication number: CN108456208A
Application number: CN201710098384.9A
Authority: CN
Inventors: 张建存; 林财; 邹晴安
Original assignee: Guangzhou Henovcom Bioscience Co ltd
Current assignee: Guangzhou Henovcom Bioscience Co ltd
Priority date: 2017-02-22
Filing date: 2017-02-22
Publication date: 2018-08-28
Anticipated expiration: 2037-02-22
Also published as: CN108456208B; WO2018153312A1

Abstract

The invention discloses a kind of aza toroid compounds and its preparation method and application, belong to medicinal chemistry art.The aza toroid compound with Formulas I structure feature of the present invention or its pharmaceutically acceptable salt or stereoisomer or solvate or prodrug, it can be tied with Autotaxin and be incorporated as Autotaxin inhibitor, and then it can be applied to the disease that there is Autotaxin to express increased pathological characteristics for prevention and treatment, such as cancer, fibrotic disease, especially pulmonary fibrosis and liver fibrosis, metabolic disease, myelodysplastic syndrome, angiocardiopathy, autoimmune disease, inflammation, the nervous system disease or pain etc..The series compound is blocked and is interfered in all kinds of key signal circuit upstreams, mitigate or delay the growth and transfer of tumour cell compared with single inhibitor, can occur drug resistance too early to avoid drug, while providing new possibility to the treatment of tumour cell.

Description

Aza toroid compound and its preparation method and application

Technical field

The present invention relates to field of pharmaceutical chemistry technology, more particularly to a kind of aza toroid compound and preparation method thereof And application.

Background technology

Autotaxin (ATX) is used as a kind of unique ectoenzyme, is seven circumscribed nuotide pyrophosphatase/di-phosphate esters A part for enzyme family, also referred to as circumscribed nuotide pyrophosphatase/phosphodiesterase 2, for being catalyzed lysophosphatidyl choline (LPC) hydrolysis generates the lysophosphatidic acid (LPA) with multiple biological activities.The LPA precursors that still phosphatide does not synthesize, Er Qieneng Cause extensive biological effect by various signal transduction paths.LPA is once generated, can be special by six cell surfaces Receptor protein (LPA_1-6), i.e. g protein coupled receptor (GPCR) mediation plays a role.According to endothelial cell differentiation gene (Edg) With ventricle area unnamed gene, LPA_1-6Respectively LPA1/Edg-2/VZG-1, LPA2/Edg-4, LPA3/Edg-7, LPA4/p2y9/ GPR23, LPA5/GPR92 and LPA6/p2Y5, each receptor pass through G_αAlbumen (Gs, Gi, Gq, and G12/13) mediates, into And cause a series of cell signalling cascade effect.Wherein, main access includes phosphatidylinositol diphosphate ester (PIP₂) Hydrolysis, and then cause intracellular calcium ion release and protein kinase C (PKC) activation；Adenyl cyclase (cAMP) is inhibited to believe Number access；Activate Ras-MAPK, MERK, ERK accesses, regulating cell proliferation activity；Activating phosphatase inositol PI3K-AKT accesses are adjusted Control cell survival and apoptosis activity；Finally, the remodeling of activation Rho access regulating cell skeletons, shape change and cell migration activity. Under many pathological conditions, especially in tumour cell, ATX is in high expression status, leads to LPA excessive concentrations.In tumour In cell, LPA concentration can be increased to 10 μm of ol/L, be far above the normal level of 100nmol/L.Excessive LPA increases intravascular The generation of skin growth factor (VEGF) promotes angiogenesis；The expression for reducing cancer suppressorfactor p53, increases the survival of tumour cell And transfer.ATX-LPA signal paths are related to many physiology and pathologic process, important to have with many serious diseases System includes mainly angiocardiopathy, autoimmune disease, cancer, fibrotic disease, inflammation, the nervous system disease, pain Deng.LPA has multi-functional in tumour generation, promotes the growth of tumour cell, angiogenesis, shifts and occur drug resistance. So reducing the concentration level of LPA, be conducive to the treatment and control of tumour.It is corresponding, inhibit the activity of AXT, blocks LPA Constructive ways, be the research hotspot for treating a variety of serious diseases.

ATX was separated from A2058 melanoma cells for the first time in 1992, was referred to as " autocrine dynamic factor ". ATX is the glycoprotein of the secretion of a 125kDa.With deepening continuously to the research of ATX, promote much using it as the new of target spot The appearance of type inhibitor, wherein what research was most concentrated is cancer and fibrotic disease.Fibrotic disease is mainly that idiopathic lung is fine Dimensionization (IPF) and liver fibrosis.IPF is that one kind showing as Diffuse alveolar inflammation and alveolar structure is disorderly, and leads to interstitial lung Fibrosis carries out a kind of fatal disease of sexual development, and prognosis is poor, and the mean survival time is 2 to 5 years.IPF may be with The most close disease of ATX-LPA pathways, because in lung tissue, it is thin that the expression highest of ATX concentrates on bronchiolar epithelium Born of the same parents and pulmonary alveolar macrophage, and these cells can be with juxtaposition fibroblast stove.

Currently, GLPG1690 comes into the phase II clinical trials stage as Autotaxin inhibitor, it to be used for idiopathic The treatment of pulmonary fibrosis；ATX concentration is closely related with liver fibrosis and liver hardness number in serum, is the best finger of predictive hepatocirrhosis One of mark.In addition, ATX is highly expressed in many tumor tissues, including melanoma, non-small cell lung cancer, liver cancer, kidney, Breast cancer, thyroid cancer, oophoroma and Hodgkin lymphoma.LPA/ATX can promote cell to invade during growth of tumour cell It attacks and shifts.So ATX inhibitor, disabling signal conduction path provide one for clinical anticancer and fibrotic disease New way.

Compared with traditional kinase inhibitor, Autotaxin inhibitor inhibit Autotaxin activity while influence it is a plurality of with The relevant signal path such as cell Proliferation, growth and apoptosis generates preferable inhibition, Er Qieyu to some drug-resistant type tumours The fibrosis of multiple organs is closely related, and is the important target of research and development tencel disease medicament.

Invention content

Based on this, the purpose of the present invention is to provide a kind of aza toroid compounds, can be combined simultaneously with Autotaxin As Autotaxin inhibitor.

To achieve the above object, the present invention takes following technical scheme：

Aza toroid compound or its pharmaceutically acceptable salt with Formulas I structure feature or stereoisomer or molten Agent compound or prodrug：

Wherein：

A is selected from：- N- ,-CH-；

R¹It is selected from：Substituted or non-substituted aryl, substituted or non-substituted contains the heteroatomic virtue of one or more O, N, S Heterocycle, containing substituted or non-substituted alkyl, substituted or non-substituted C3-C8 naphthenic base, it is substituted or non-substituted containing there are one or Multiple heteroatomic Heterocyclylalkyls of O, N, S, substituted or non-substituted naphthalene, substituted or non-substituted benzheterocycle；

R²It is selected from：Substituted or non-substituted aryl, substituted or non-substituted contains the heteroatomic virtue of one or more O, N, S Heterocycle, containing substituted or non-substituted alkyl, substituted or non-substituted C3-C8 naphthenic base, it is substituted or non-substituted containing there are one or Multiple heteroatomic Heterocyclylalkyls of O, N, S, substituted or non-substituted naphthalene, substituted or non-substituted benzheterocycle；

Y is selected from：- OC (O)-,-ROC (O)-,-OC (S)-,-NR³C (O)-,-NR³C (S)-,-C (O)-,-C (O) R- ,-S (O)₂, Or do not have

W is selected from：- O- ,-S- ,-NR³C (O)-,-NR⁴,-C (O)-,-C (O) O- ,-C (O) OR- ,-S (O)-,-S (O)₂,- CR⁵R⁶, or do not have；

R is selected from：C1-C3 alkyl, C3-C6 naphthenic base；

R³、R⁴Independently optionally certainly：H, D ,-SR⁷,-S (=O) R⁷,-S (=O)₂R⁷,-S (=O)₂NR⁷R⁸,-C (=O) R⁷,-OC (=O) R⁷,-C (=O) NR⁷R⁸, CO₂R⁸,-NR⁷R⁸, NCONR⁷R⁸, NCO₂R⁷, OCONR⁷R⁸, CSNR⁷R⁸, NCSN R⁷R⁸, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C10 naphthenic base, C6-C10 substituted aralkyls；

R⁵、R⁶Independently optionally certainly：H, D, halogen ,-CF₃,-CN ,-NO₂,-OH ,-OR⁷,-SR⁷,-S (=O) R⁷,-S (= O)₂R⁷,-S (=O)₂NR⁷R⁸,-C (=O) R⁷,-OC (=O) R⁷,-C (=O) NR⁷R⁸, CO₂R⁸,-NR⁷R⁸, NCONR⁷R⁸, NCO₂R⁷, OCONR⁷R⁸, CSNR⁷R⁸, NCSN R⁷R⁸, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C10 naphthenic base, C6-C10 substitution virtues Alkyl；

R⁷、R⁸Independently optionally certainly：H, C1-C6 alkyl, C2-C6 unsaturated alkyls, at least one O, N, S hetero atom substitution C1-C6 alkyl, the C2-C6 unsaturated alkyls of at least one O, N, S hetero atom substitution.

Q is selected from：- O- ,-S- ,-NH- ,-CO- ,-CO2- ,-CO2-, C1-C3 alkyl, or do not have；

M, n, p and q independently optionally from：1,2 or 3.

In wherein some embodiments, selected from such as Formula Il-Formula VIII compound：

R in formula¹、R², Y, A, W it is as described above.

In wherein some embodiments, the Y is selected from：- OC (O)-,-ROC (O)-,-NR³C (O)-,-C (O)-；The W It is selected from：-NR³C (O)-,-C (O)-,-C (O) O- ,-C (O) OR-；Wherein, R is selected from：C1-C3 alkyl；R³It is selected from：H, C1-C6 alkane Base, C3-C6 unsaturated alkyls, C3-C8 naphthenic base.

In wherein some embodiments, the R¹It is selected from：

Wherein：

R¹⁰It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the heteroatomic C1-C6 of at least one O, N, S Miscellaneous alkyl, C2-C6 unsaturated alkyls, C6-C10 substituted aralkyls ,-CF₃, OR¹¹, NR¹¹R¹²,-CN ,-NO₂,-OH ,-CO₂R¹¹,- CONR¹¹R¹²,-SO₂R¹¹；

R¹¹、R¹²Independently optionally certainly：H, C1-C6 alkyl, C2-C6 unsaturated alkyls contain the miscellaneous original of at least one O, N, S The C1-C6 miscellaneous alkyls of son, contain the heteroatomic C2-C6 unsaturations miscellaneous alkyl of at least one O, N, S；

V is selected from：CR¹⁷R¹⁸, (CR¹⁷R¹⁸) r, C3-C6 naphthenic base, or do not have

Wherein, R¹⁷And R¹⁸It can independently optionally certainly：H, D, F, Cl, C1-C6 alkyl and substitution alkyl, and R¹⁷And R¹⁸It can C3-C6 naphthenic base is collectively formed；

R is selected from：1,2 or 3；

The R²It is selected from：

Wherein：

R⁹It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the heteroatomic C1-C6 of at least one O, N, S Replace alkyl, C2-C6 unsaturated alkyls；

Z is selected from：1,2 or 3；

X is selected from：- O- ,-S- ,-NH- ,-CH-；

R¹³It is selected from：H, C1-C6 alkyl, OR¹⁴, NR¹⁶R¹⁵；

R¹⁹It is selected from：H, C1-C6 alkyl, OR¹⁴, C (O) R, C (O) OR；

R¹⁴And R¹⁵And R¹⁶Separately optionally certainly：H, C1-C6 alkyl and substitution C1-C6 alkyl；

R is selected from：C1-C3 alkyl, C3-C6 naphthenic base；

R²⁰It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the heteroatomic C1-C6 of at least one O, N, S Replace alkyl, C2-C6 unsaturated alkyls, C3-C6 naphthenic base, substituted or non-substituted aryl, substituted or non-substituted contains one A or multiple heteroatomic heteroaromatics of O, N, S.

In wherein some embodiments, R¹It is selected from：

R²It is selected from：

R⁹It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the heteroatomic C1-C6 of at least one O, N, S Miscellaneous alkyl, C2-C6 unsaturated alkyls；

Z is selected from：1,2 or 3；

R¹⁰It is selected from：H, halogen, C1-C6C1-C6 alkyl, C1-C6 halogenated alkyls are heteroatomic containing at least one O, N, S C1-C6 miscellaneous alkyls, C2-C6 unsaturated alkyls, C6-C10 substituted aralkyls ,-CF₃, OR¹¹, NR¹¹R¹²,-CN ,-NO₂,-OH ,- CO₂R¹¹,-CONR¹¹R¹²,-SO₂R¹¹；

Y is selected from：- OC (O)-,-ROC (O)-,-C (O)-；

A is selected from：- N- ,-CH-；

W is selected from：-NR³C (O)-,-C (O)-,-C (O) O- ,-C (O) OR-；

R³It is selected from：H, D, halogen ,-CF₃,-CN ,-NO₂,-OH, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C10 cycloalkanes Base, C6-C10 substituted aralkyls；

Wherein, R¹⁷And R¹⁸It can independently optionally certainly：H, D, F, Cl, C1-C6 alkyl and substitution alkyl, R¹⁷And R¹⁸It can be with C3-C6 naphthenic base is collectively formed；

R is selected from：1,2 or 3；

R¹⁹It is selected from：H, C1-C6 alkyl, C (O) R；

R is selected from：C1-C3 alkyl, C3-C6 naphthenic base；

In wherein some embodiments, selected from one of following compound：

The invention also discloses the preparation methods of above-mentioned aza toroid compound, and route is synthesized by the following way and is prepared into It arrives：

Step 1：Compound A is reacted with chlorobenzoyl chloride, generates compound B；

Step 2：Compound B is reacted with methylchloroformate and diisobutylamino lithium, generates compound C；

Step 3：Compound C is reacted with lithium aluminium hydride reduction, generates compound D；

Step 4：Compound D is reacted with paratoluensulfonyl chloride, generates compound E；

Step 5：Compound E is reacted with para toluene sulfonamide, generates compound F；

Step 6：Compound F is reacted with palladium carbon and hydrogen, then is reacted with di-tert-butyl dicarbonate, compound G is generated；

Step 7：Compound G is reacted with magnesium chips, generates compound J；

Step 8：By compound E and ortho-nitrophenyl sulfuryl amine reaction, compound H is generated；

Step 9：Compound H is reacted with benzenethiol and cesium carbonate, then is reacted with di-tert-butyl dicarbonate, compound is generated I；

Step 10：Compound I is reacted with palladium carbon and hydrogen, generates compound G；

Step 11：By compound J and compound R 1COOH, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- second Base carbodiimide hydrochloride and triethylamine react generate compound K；

Step 12：Compound K is first reacted with ethanol solution of hydrogen chloride, then with N, N '-carbonyl dimidazoles, R2-OH and three Ethamine reacts, and generates compound L；

Or

Circuit is synthesized by the following way to be prepared：

Step 1：Compound i is reacted with methyltriphenylphosphonium bromide and potassium tert-butoxide, generates compound ii；

Step 2：Compound ii is reacted with copper zincon and trichloro-acetic chloride, generates compound iii；

Step 3：Compound iii is reacted with zinc powder and saturated ammonium chloride solution, generates compound iv；

Step 4：Compound iv is reacted with sodium borohydride, generates compound v；

Step 5：Compound v is reacted with mesyl chloride, generates compound vi；

Step 6：Compound vi is reacted with Sodium azide, generates compound vii；

Step 7：Compound vii is reacted with hydrogen and palladium carbon reagent, generates compound viii；

Step 8：By compound viii and compound R 1COOH, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- Ethyl-carbodiimide hydrochloride and triethylamine react generate compound ix；

Step 9：Compound ix is first reacted with ethanol solution of hydrogen chloride, then with N, N '-carbonyl dimidazoles, R2-OH and three Ethamine reacts, and generates compound x.

Wherein, m, n, p and q independently optionally from：1,2 or 3.

The invention also discloses above-mentioned aza toroid compound or its pharmaceutically acceptable salts or stereoisomer Or solvate or prodrug are in the drug for preparing the disease that there is Autotaxin to express increased pathological characteristics for prevention and treatment In application.

In wherein some embodiments, the disease that increased pathological characteristics are expressed with Autotaxin includes：Cancer Disease, fibrotic disease, especially pulmonary fibrosis and liver fibrosis, metabolic disease, myelodysplastic syndrome, cardiovascular disease Disease, autoimmune disease, inflammation, the nervous system disease or pain.

Include the above-mentioned aza toroid compound as active constituent the invention also discloses a kind of pharmaceutical composition Or its pharmaceutically acceptable salt or stereoisomer or solvate or prodrug, and pharmaceutically acceptable auxiliary material or load Body.

The pharmaceutically acceptable auxiliary material or carrier can be excipient or sustained release agent etc..The pharmaceutical composition can be with Diversified forms, such as tablet, capsule, powder, syrup, solution, suspension and aerosol, and can reside in it is suitable Solid or liquid-carrier or dilution in.The pharmaceutical composition of the present invention can also be stored in disappearing for suitable injection or instillation In malicious utensil.It also may include odorant agent, flavouring agent etc. in the pharmaceutical composition.

Compared with prior art, the invention has the advantages that：

The aza toroid compound with Formulas I structure feature of the present invention is a kind of novel Autotaxin inhibition Agent is designed according to the calmodulin binding domain CaM space and charge property feature of Autotaxin and substrate with hydrophilic head, hydrophobic The novel framework of property tail portion and flexible coupling part, gained compound generally inhibit Autotaxin effect can reach to receive Mole or sub- nanomole rank, so that it is had following advantages：

1, the series compound and target indicate more specific action site, there is more specific reforming direction, to push away Patent medicine process offer into such inhibitor may.

2, it compared with single inhibitor, is blocked and is interfered in all kinds of key signal circuit upstreams, mitigate or delay to swell The growth and transfer of oncocyte, can occur drug resistance too early to avoid drug, at the same to the treatment of tumour cell provide it is new can Energy.

3, fibrotic disease has larger harmfulness for publilc health, and therapeutic scheme is there is an urgent need for optimizing and enriching at present, Research hotspot of the Autotaxin inhibitor as treatment fibrotic disease, to ensureing that publilc health has active influence.

Specific implementation mode

The unfixed substitution in position is indicated by the straight line being directed toward outside ring in ring in general formula of the present invention.

Term " substitution " refers to the hydrogen-based in the group displacement specific structure with specified substituent group.When in any specific structure More than one position can through more than one be selected from designated group substituent group replace when, the substituent group can be in each position phase It is same or different.As used herein, term " substitution " expection includes all permissible substituent groups of organic compound.It is wide one General aspect, the permissible substituent group include the acyclic and cyclic of organic compound, branch and non-branch, carbocyclic ring and heterocycle, Aromatic series and non-aromatic substituent group.The hetero atoms such as nitrogen can have hydrogen substituent group and/or organic compound as described herein Any permissible substituent group, the substituent group meets heteroatomic valence mumber.

Above-mentioned substituent group is preferred：H, D, halogen ,-CF₃,-OCF₃,-CN ,-NO₂,-OH ,-SH, sulfonyl, carbonyl, aldehyde radical, Carboxyl, ester group, amide groups, azido, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C10 naphthenic base, C6-C10 replace aralkyl Base etc.；

Term " alkyl " refers to saturated hydrocarbyl, includes the alkyl of linear chain or branched chain, if C1-C6 alkyl refers to having 1 to 6 The saturated straight chain of carbon atom or the alkyl of branch, the example of wherein straight chain saturated alkyl include but not limited to ethyl, n-propyl etc., The example for being saturated branched alkyl includes but not limited to isopropyl, tertiary butyl etc.；" unsaturated alkyl " refers to alkenyl or alkynyl Alkyl, include the unsaturated alkyl of linear chain or branched chain, wherein the example of unsaturated straight chained alkyl include but not limited to vinyl, The example of acrylic etc., unsaturated side chain alkyl includes but not limited to 2- methylpropenyls etc.；" naphthenic base " refers to having ring-type The alkyl of structure, as C3-C8 cyclic alkyls refer to the saturated or unsaturated alkane with cyclic structure with 3 to 8 carbon atoms The example of base, wherein saturated cyclic alkyls includes but not limited to cyclopropyl, cyclopenta, ethyl substituted cyclohexyl etc., unsaturation ring The example of shape alkyl includes but not limited to cyclopentene etc., preferred C3-C6 ring-type alkane in the present invention.

Term " aryl " represent comprising single or polycyclic (for example, bicyclic or tricyclic) 4n+2 aromatic rings system (for example, Annular orbit shares 6,10 or 14 pi-electrons), and aromatic ring system has 6-14 ring carbon atom and is free of hetero atom (" C6- 14 aryl ").In some embodiments, aryl has 6 ring carbon atoms (for example, phenyl).In some embodiments, fragrant Base has 10 ring carbon atoms (for example, naphthalene)." aryl " further includes aryl loop system as described above, wherein condensed to have one A or multiple carbocyclic rings or heterocyclic group, wherein the group or point that connect are located in aryl rings, and in this case, carbon atom Number only includes the number of the carbon atom of aromatic ring system.

Term " heteroaromatic " represents with 5-6 ring member nitrogen atoms, contains one to four hetero atoms (being selected from N, O, S) and abide by The single ring systems of H ü ckel rules.Example includes but not limited to pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, furan nucleus, thiophene Ring, thiazole ring, oxazole ring, isoxazole rings, isothiazole ring, imidazole ring, pyrazole ring, triazole ring, tetrazole ring etc..

Term " Heterocyclylalkyl " represents cyclic alkyl as herein defined, and wherein main chain further includes one or more miscellaneous originals Son.

Term " benzheterocycle " represents phenyl ring and is connected by 2 carbon atoms with the miscellaneous naphthenic ring of heteroaromatic as defined herein conjunction It connects, the polycyclic system of formation.

Term " aralkyl " represents while having alkyl and heteroaryl structure as herein defined.

Term " solvate " is used for describing the one or more medicines for including the compounds of this invention and stoichiometry in the text The molecular complex of acceptable solvent molecule (such as ethyl alcohol) on.Term " hydrate " is used when the solvent is water.

The present invention includes the free form of general formula compound, also include its pharmaceutically acceptable salt and stereoisomer and Solvate and prodrug.By conventional chemical processes this can be synthesized from containing the compounds of this invention of alkaline part or acidic moiety The pharmaceutically acceptable salt of invention.In general, by ion-exchange chromatography or passing through free alkali and stoichiometric amount or excessive The reaction in the combination of appropriate solvent or multi-solvents of the inorganic or organic acid of required salt form prepares the salt of alkali compounds.Class As, the salt of acid compound is formed by being reacted with appropriate inorganic or organic base.

Therefore, the pharmaceutically acceptable salt of the compounds of this invention includes by alkaline the compounds of this invention and inorganic or have Machine acid reacts the conventional non-toxic salts for the compounds of this invention to be formed.For example, conventional nontoxic salts include from inorganic acid such as hydrochloric acid, The salt of the preparations such as hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, also include from organic acid for example acetic acid, propionic acid, succinic acid, Glycolic, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, flutters acid, maleic acid, hydroxymaleic acid, benzene second at stearic acid Acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzene sulfonic acid, 2 one acetoxyl group, one benzoic acid, fumaric acid, toluenesulfonic acid, methylsulphur The salt of the preparations such as acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid.

If the compounds of this invention is acid, " pharmaceutically acceptable salt " appropriate refers to by pharmaceutically acceptable Nontoxic alkali include salt prepared by inorganic base and organic base.Salt derived from inorganic base includes aluminium salt, ammonium salt, calcium salt, mantoquita, iron Salt, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc..Particularly preferred ammonium salt, calcium salt, magnesium salts, sylvite And sodium salt.Salt derived from pharmaceutically acceptable organic nontoxic alkali, the alkali includes the salt of primary amine, secondary amine and tertiary amine, substituted Amine include naturally occurring substitution amine, cyclic amine and deacidite for example arginine, glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, ethylaminoethanol, ethanol amine, Ethylenediamine, mono- ethyl piperidines of N, gucosamine, Glucosamine, histidine, hydroxycobalamin, isopropylamine, relies mono- ethyl morpholines of N Propylhomoserin, methyl glucose osamine, morpholine, piperazine, piperidines, croak smack one's lips, polyamines resin, procaine, purine, theobromine, triethylamine, three Methylamine, tripropyl amine (TPA), tromethamine etc..

Except known in the literature or in experimental arrangement in addition to the standard method of illustration, the side in following examples can be used Method prepares the compounds of this invention.It, can be to heretofore described compound and synthetic method in conjunction with following synthetic schemes It is better understood.All parameters and remaining explanation in example are all using quality as foundation in addition to another plus explanation.Column If it is silica gel that filler used in chromatography is undeclared.In the following examples, the experimental methods for specific conditions are not specified, usually presses More solito condition, or according to the normal condition proposed by manufacturer.The synthetic schemes, which describes, can be used for preparing the present invention Described in compound method, the method be only for the purpose of illustration illustrative approach description, do not constitute to this The limitation of range possessed by invention.

Abbreviation paraphrase used is as follows in following embodiment：

TsNH₂	Para toluene sulfonamide
		DCM	Dichloromethane
PPh₃	Triphenylphosphine
		PE	Petroleum ether
EA	Ethyl acetate
		DIPEA	Diisopropyl ethyl amine
EDCI	1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
		DMF	N,N-Dimethylformamide
TEA	Triethylamine
		acetone	Acetone
BzCl	Chlorobenzoyl chloride
		LDA	Diisobutylamino lithium
HOBt	I-hydroxybenzotriazole
		DABCO	Triethylene diamine
iPrOH	Isopropanol

Embodiment 1

Compound 1：3,5- dichloro benzyl 6- (4- sulfamoyls benzoyl) -2,6- diaza spiroheptane -2- first The preparation of tert-butyl acrylate.

It synthesizes, includes the following steps according to Above Transmission Lines：

(1) preparation of 1- benzoyls azetidine -3- carboxylate methyl esters (compound 1-1).

A 250mL single port bottles are taken, azetidine -3- carboxylate methyl esters (10g, 86.9mmol) are added, DCM (100mL) is molten Solution, be added triethylamine (14.5mL, 104.2mmol, 1.2 equivalent), be placed in 0 DEG C, be slowly added to BzCl (11.1mL, 95.6mmol, 1.1 equivalents), it is stirred overnight at room temperature, TLC tracking and monitorings.After completion of the reaction, it is cooled to room temperature, saturation NaHCO is added₃Solution and DCM is extracted, saturated common salt washing, and anhydrous sodium sulfate drying is spin-dried for, crosses column, obtain 18.5g yellow liquid, yield 96.8%.ESI- MS m/z：220.1(M+H)⁺。

(2) preparation of 1- benzoyls azetidine -3,3- dimethyl dicarboxylate (compound 1-2).

Compound 1-1 (10g, 45.6mmol) is placed in 250mL two-mouth bottles, argon gas exchanges, and THF is added, is placed in -78 DEG C, Be slowly added to LDA (34.2mL, 68.4mmol, 1.5 equivalent), stir 2h, be slowly added to methylchloroformate (7.0mL, 91.2mmol, 2 equivalents), -70 DEG C are to slowly warm up to, 1h is stirred.Reaction finishes, and saturated ammonium chloride solution and EA extractions is added, satisfies It is washed with salt, anhydrous sodium sulfate drying is spin-dried for, crosses column.Obtain 9g yellow liquids, yield 71%.ESI-MS m/z：278.1 (M+H)⁺.

(3) preparation of (1- benzyl azetidines -3,3- diyl) dimethanol (compound 1-3).

A 250mL two-mouth bottles are taken, lithium aluminium hydride (4.9g, 130mmol, 4 equivalent) is added, argon gas protection is added anhydrous THF is placed at 0 DEG C, stirs 15min, the THF solution of compound 1-2 (9g, 32.5mmol) is slowly added dropwise, is warmed to room temperature, and is stirred 15min.85 DEG C are placed in, return stirring is overnight.Reaction solution is slowly added dropwise into saturated ammonium chloride solution, is filtered through diatomite, Filtrate layered, water layer are extracted 3 times with EA (100mL), saturated common salt washing.It is primary with the extraction of iPrOH/DCM (20%) solution, satisfy It is washed with salt, merges organic layer, anhydrous sodium sulfate drying, evaporated under reduced pressure obtains 4.5g crude products, and thick yield is 67.2%.Directly For in next step.

(4) (1- benzyl azetidines -3,3- diyl) bis- (methylene) is bis- (4- oluene sulfonic acides esters) (compound 1-4) Preparation.

A 100mL single port bottles are taken, compound 1-3 (4g, 19.3mmol) is added, DCM dissolves, addition TEA (10.7mL, 77mmol, 4 equivalents) and DMAP (catalytic amount), it is slowly added to TsCl (12g, 77mmol, 4 equivalent), is stirred overnight at room temperature.It is added Water and DCM extractions, saturated common salt washing, anhydrous sodium sulfate drying are spin-dried for, cross column (PE：EA=5：1).Yellow liquid 6.5g is obtained, Yield is 65.3%.

(5) preparation of 2- benzyls -6- tosyl -2,6- diaza spiroheptanes (compound 1-5).

Take compound 1-4 (6.5g, 19mmol) to be placed in 250mL single port bottles, be added para toluene sulfonamide (3.9g, 22.8mmol, 1.2 equivalents) and potassium carbonate (6.6g, 47.5mmol, 2.5 equivalent), it is placed in 100 DEG C and heats, be stirred overnight.TLC Display raw material reaction finishes, and DMF is removed with oil pump rotation, and EA and water, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, mistake Column (PE: EA=4: 1).Obtain yellow liquid 4.0g.

(6) preparation of 6- tosyls -2,6- diaza spiroheptane -2- t-butyl formates (compound 1-6).

A 500mL single port bottles are taken, compound 1-5 (9.5g, 27.8mmol) is added and is dissolved in methanol (150mL), formic acid is added The palladium carbon (3g, 2.78mmol, 10mol%) that content is 10% is added in (3mL), and hydrogen exchanges, and is placed in 45 DEG C, stirs 2d.It is cooling To room temperature, diatomite filtering, methanol rinses, and Boc acid anhydrides (6.5mL, 27.7mmol, 1 equivalent) is added, 1.5h is stirred at room temperature, and revolves It is evaporated off solvent, crosses column (PE: EA=2: 1), obtain 7g clear crystals, 72%.

The characterize data of compound 1-6 is：¹H NMR (400MHz, Chloroform-d, δ_ppm)：7.70 (d, J= 8.2,2H), 7.36 (d, J=8.2,2H), 3.84 (s, 4H), 3.83 (s, 4H), 2.45 (s, 3H), 1.38 (s, 9H).

(7) preparation of 2-BOC-2,6- diaza spiro [3.3] heptane oxalate (compound 1-7).

A 500mL single port bottles are taken, compound 1-6 (7g, 20mmol) is added, magnesium chips is added in methanol (200mL) dissolving (3.84g, 0.16mol, 8 equivalent), is stirred at room temperature.Reaction solution gradually becomes the sticky shape of white with the dissolving of magnesium chips, and TLC is aobvious Show that raw material reaction finishes.Revolving removes solvent, and ether (150mL) is added, is stirred at room temperature 1h, diatomite filtering, and filtrate is with anhydrous Sodium sulphate is dried, and the ethanol solution (3mL) of anhydrous oxalic acid (0.89g, 9.9mmol, 0.5 equivalent) is added dropwise, and it is heavy to occur white immediately It forms sediment, is filtered under diminished pressure, obtain 3.2g colorless solids, 82%.

The characterize data of compound 1-7 is：¹H NMR (400MHz, CD₃OD+D₂O, δ_ppm)：4.90 (s, 2H), 4.20 (s, 4H), 4.09 (s, 4H), 1.42 (s, 9H).

(8) 6- (4- sulfamoyls benzoyl) -2,6- diaza spiroheptane -2- t-butyl formates (compound 1- 8) preparation.

Take compound 1-7 (600mg, 2.10mmol), compound 2 (884mg, 4.40mmol, 2.1 equivalent), HOBt DMF and TEA is added in 25mL single port bottles in (852mg, 6.30mmol, 3 equivalent) and EDCI (1208mg, 6.30mmol, 3 equivalent) (0.9mL, 6.30mmol, 3 equivalent).It is stirred overnight at room temperature.TLC tracking and monitorings.EA and saturated salt solution extraction, anhydrous sulphur is added Sour sodium drying, is spin-dried for, crosses column (DCM: acetone=3: 1).Obtain white solid product 1.1g, yield 69%.

The characterize data of compound 1-8 is：¹H NMR (400MHz, Chloroform-d, δ_ppm)：7.99 (d, J= 8.4Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 4.49 (s, 2H), 4.31 (s, 2H), 4.10-4.07 (m, 4H), 1.43 (s, 9H).ESI-MSm/z：382.1(M+H)⁺.

(9) preparation of (2,6- diaza spiroheptane -2- carbonyls) benzsulfamide (compound 1-9).

It takes compound 1-8 (100mg, 0.26mmol) to be placed in 25mL single port bottles, hydrogen chloride methanol solution (1mL), room is added Temperature stirring, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(10) 3,5- dichloro benzyl -6- (4- sulfamoyls benzoyl) -2,6- diaza spiroheptane -2- formic acid The preparation of ester (compound 1).

Take 3,5- dichlorbenzyl alcohols (46mg, 0.26mmol, 1 equivalent), N, N '-carbonyl dimidazoles (51mg, 0.31mmol, 1.2 equivalents), 2h is stirred at room temperature in DMF dissolvings.Compound 1-9 is dissolved in DMF, triethylamine (43 μ L, 0.31mmol, 1.2 are added Equivalent), reaction solution is added, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, and EA and water, saturated common salt is added Washing, anhydrous sodium sulfate drying, crosses column (DCM: acetone=3: 1).Obtain white powder 45mg, as compound 1.

The characterize data of the compound 1 is：¹H NMR (400MHz, CD₃OD and DMSO-d₆, δ_ppm)：7.88 (d, J= 8.4Hz, 2H), 7.71 (d, J=8.0Hz, 2H), 7.36 (s, 1H), 7.27 (s, 2H), 4.96 (s, 2H), 4.40 (s, 2H), 4.20 (s, 2H), 4.08 (brs, 4H)¹³C NMR (125MHz, CD₃OD and DMSO-d₆, δ_ppm)：170.1 157.3, 147.8,142.8,137.9,136.2,129.9,129.1,127.7,127.6,66.2,64.3,60.2,34.7.ESI-MS m/ z：484.1(M+H)⁺, 482.1 (M-H)^-.

Embodiment 2

Compound 2：4- (trifluoromethoxy) benzyls -6- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.3] heptan The preparation of alkane -2- formic acid esters.

Take compound 4- trifluoromethoxies benzyl alcohol (50mg, 0.26mmol, 1 equivalent), N, N '-carbonyl dimidazoles (51mg, 0.31mmol, 1.2 equivalents) in 10mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 1-9 is dissolved in DMF, TEA is added (46 μ L, 0.31mmol, 1.2 equivalent) is added reaction solution, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, adds Enter EA and water, saturated common salt washing, column (DCM: acetone=3: 1) is crossed in anhydrous sodium sulfate drying.White powder 45mg is obtained, i.e., For compound 2.

The characterize data of the compound 2 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.89 (d, J=6.4Hz, 2H), 7.78 (d, J=6.4Hz, 2H), 7.49 (d, J=9.2Hz, 4H), 7.37 (d, J=6.4Hz, 4H), 5.05 (s, 2H), 4.44 (s, 2H), 4.21 (s, 2H), 4.11 (brs, 4H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：168.5,156.3,148.8, 146.9,137.3,137.0,130.5,129.2,126.6,122.0,121.9,120.0,65.7,63.3,59.3, 33.6.ESI-MS m/z：500.1(M+H)⁺, 498.1 (M-H)^-.

Embodiment 3

Compound 3：3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonane -7- The preparation of formic acid esters.

(1) preparation of 1- benzoyl piperidines -4- methyl formates (compound 2-1).

A 100mL single port bottles are taken, are added to methyl formate phenylpiperidines (5.1g, 35.6mmol), DCM (50mL) dissolvings add Enter triethylamine (6mL, 42.7mmo, 11.2 equivalent), be placed in 0 DEG C, is slowly added to BzCl (4.5mL, 39.2mmol, 1.1 equivalent), It is stirred overnight at room temperature, TLC tracking and monitorings.After completion of the reaction, it is cooled to room temperature, saturation NaHCO is added₃Solution and DCM extractions, satisfy It is washed with salt, anhydrous sodium sulfate drying is spin-dried for, crosses column, obtain 8.6g yellow liquid, yield 98%.ESI-MS m/z：248.1 (M+H)⁺。

(2) preparation of 1- benzoyl piperidines -4,4- dicarboxylic acid methyl ester (compound 22).

Compound 2-1 (8.6g, 34.8mmol) is placed in 100mL two-mouth bottles, argon gas exchanges, and THF is added, is placed in -78 DEG C, Be slowly added to LDA (26.1mL, 52.2mmol, 1.5 equivalent), stir 2h, be slowly added to methylchloroformate (5.4mL, 69.6mmol, 2 equivalents), -70 DEG C are to slowly warm up to, 1h is stirred.Reaction finishes, and saturated ammonium chloride solution and EA extractions is added, satisfies It is washed with salt, anhydrous sodium sulfate drying is spin-dried for, crosses column.Obtain 8g yellow liquids, yield 75%.ESI-MS m/z：306.1 (M+H)⁺.

(3) preparation of 1- benzyl piepridines -4,4- dimethyl alcohol (compound 2-3).

A 250mL two-mouth bottles are taken, lithium aluminium hydride (4g, 105mmol, 4 equivalent) is added, anhydrous THF is added in argon gas protection, It is placed at 0 DEG C, stirs 15min, the THF solution of compound 2-2 (8g, 26.2mmol) is slowly added dropwise, is warmed to room temperature, stir 15min.85 DEG C are placed in, return stirring is overnight.Reaction solution is slowly added dropwise into saturated ammonium chloride solution, is filtered through diatomite, Filtrate layered, water layer are extracted 3 times with EA (100mL), saturated common salt washing.It is primary with the extraction of iPrOH/DCM (20%) solution, satisfy It is washed with salt, merges organic layer, anhydrous sodium sulfate drying, evaporated under reduced pressure obtains 4g crude products, and thick yield is 65.6%.Directly For in next step.

(4) system of (1- benzyl piepridines -4,4- diyl) bis- (methylene) bis- (4- oluene sulfonic acides esters) (compound 2-4) It is standby.

A 100mL single port bottles are taken, compound 2-3 (4g, 17mmol) is added, DCM dissolves, addition TEA (9.4mL, 68mmol, 4 equivalents) and DMAP (catalytic amount), it is slowly added to TsCl (13g, 68mmol, 4 equivalent), is stirred overnight at room temperature.It is added Water and DCM extractions, saturated common salt washing, anhydrous sodium sulfate drying are spin-dried for, cross column (PE: EA=5: 1).Obtain yellow liquid 6g, production Rate is 64%.

(5) system of 7- benzyls -2- ((2- nitrobenzophenones) sulfonyl) -2,7- diaza spiros [3.5] nonane (compound 2-5) It is standby.

Take compound 2-4 (6g, 11mmol) to be placed in 250mL single port bottles, be added para toluene sulfonamide (2.4g, 13.82mmol, 1.2 equivalents) and potassium carbonate (3.8g, 27.5mmol, 2.5 equivalent), it is placed in 100 DEG C and heats, be stirred overnight. TLC shows that raw material reaction finishes, and DMF is removed with oil pump rotation, and EA and water, saturated common salt washing, anhydrous sodium sulfate drying, rotation is added It is dry, cross column (PE: EA=4: 1).Obtain yellow liquid 4.0g.

(6) preparation of 7- benzyls -2,7- diaza spiro [3.5] nonane -2- t-butyl formates (compound 2-6).

Take compound 2-5 (3.77g, 9.9mmol) in 100mL single port bottles, methanol dissolving is added containing 10% palladium carbon (1.05g, 0.99mmol, 10mol%), hydrogen exchange, and are placed in 45 DEG C, stir 2h.TLC shows that raw material reaction finishes, and is cooled to Room temperature, diatomite filtering, methanol rinse, and filtrate is directly added into Boc acid anhydrides (2.31mL, 9.9mmol, 1 equivalent), was stirred at room temperature Night.EA and water extraction, saturated common salt washing is added, anhydrous sodium sulfate drying is spin-dried for, crosses column (PE: EA=2: 1).It is yellow to obtain 2.6g Color liquid.

The preparation of (7) 2,7- diaza spiro [3.5] nonane -7- t-butyl formate hydrochlorides (compound 2-7).

Take compound 2-6 (2.0g, 5.3mmol) in 50mL single port bottles, methanol dissolving, magnesium chips is added, and (polishing removes surface Oxide layer is cut into tiny piece) (1.02g, 42.4mmol, 8 equivalent), it is stirred at room temperature, magnesium chips gradually dissolves, and it is gentle to generate heat Body, reaction solution become the sticky shape of white, TLC tracking and monitorings.After completion of the reaction, it is spin-dried for, ether dissolution is added, anhydrous sodium sulfate is added 1h, diatomite filtering are stirred, filtrate is added dropwise the methanol solution of hydrogen chloride, white precipitate is precipitated immediately, is filtered under diminished pressure under stiring, Obtain white solid 1.0g, yield 72%.

(8) 2- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonane -7- t-butyl formates (compound 2- 8) preparation

2,7- diaza spiros [3.5] nonane -7- t-butyl formates hydrochloride (300mg, 1.14mmol) is taken, to sulfonamide phenyl Formic acid (230mg, 1.14mmol, 1 equivalent), HOBt (462mg, 3.42mmol, 3 equivalent) and EDCI (656mg, 3.42mmol, 3 Equivalent) in 50mL single port bottles, DMF and TEA (1.3mL, 8.56mmol, 8 equivalent) is added.It is stirred at room temperature.TLC tracking and monitorings.Rotation DMF is removed, EA and water extraction is added, saturated common salt washing is dry, is spin-dried for, crosses column (DCM: acetone=3: 1).Obtain white solid Product 410mg, yield 88%.ESI-MS m/z：410.1(M+H)⁺, 408.1 (M-H)^-.

(9) preparation of (2,7 diaza spiros [3.5] nonane -2- carbonyls) benzsulfamide (compound 2-9)

Compound 2-8 (150mg, 0.37mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(10) 3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonane -7- formic acid The preparation of ester (compound 3)

Take 3,5- dichlorbenzyl alcohols (65mg, 0.37mmol, 1 equivalent), N, N '-carbonyl dimidazoles (72mg, 0.44mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 2-9 is dissolved in DMF, addition triethylamine (61 μ L, 0.44mmol, 1.2 equivalents), it is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, and EA is added And saturated sodium bicarbonate solution, saturated common salt washing, anhydrous sodium sulfate drying are spin-dried for, cross column (DCM: acetone=2.5: 1). Obtain white powder 50mg, as compound 3.

The characterize data of the compound 3 is：¹H NMR (400MHz, CD₃OD, δ_ppm)：8.19 (d, J=8.4Hz, 2H), 7.85 (d, J=8.0Hz, 2H), 7.42 (s, 1H), 7.36 (s, 2H), 5.12 (s, 2H), 4.14 (s, 2H), 4.00 (s, 2H), 3.53 (brs, 4H), 1.85 (t, J=5.6Hz, 4H)¹³C NMR (125MHz, CD₃OD and DMSO-d₆, δ_ppm)：168.3 154.1,145.4,140.5,135.6,134.0,127.6,126.8,125.3,64.4,61.6,57.5,40.1,33.7, 33.2.ESI-MS m/z：512.1(M+H)⁺, 510.1 (M-H)⁺.

Embodiment 4

Compound 4：4- (trifluoromethoxy) benzyls -2- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonyl The preparation of alkane -7- formic acid esters.

Take 4- trifluoromethoxies benzyl alcohol (71mg, 0.37mmol, 1 equivalent), N, N '-carbonyl dimidazoles (72mg, 0.44mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.By compound 2-9 (115mg, 0.37mmol) It is dissolved in DMF, triethylamine (61 μ L, 0.44mmol, 1.2 equivalent) is added, be added, be stirred at room temperature.TLC tracking and monitorings.Oil pump revolves Most of solvent is removed, EA and saturated sodium bicarbonate solution, saturated common salt washing is added, anhydrous sodium sulfate drying is spin-dried for, crosses column (DCM: acetone=2.5: 1).Obtain white powder 30mg, as compound 4.

The characterize data of the compound 4 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.89 (d, J=7.6Hz, 2H), 7.82 (d, J=7.6Hz, 2H), 7.48 (s, 4H), 7.37 (d, J=8.0Hz, 2H), 5.09 (s, 2H), 4.03 (s, 2H), 3.79 (s, 2H), 3.40 (brs, 4H), 1.70 (s, 4H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：168.7,155.2,148.7, 146.8,137.4,137.1,130.3,129.2,126.6,121.9,66.2,62.9,59.0,41.5,36.2,34.6.ESI- MS m/z：528.1(M+H)⁺, 526.1 (M-H)^-.

Embodiment 5

Compound 5：3,5- dichloro benzyl -7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonane -2- The preparation of formic acid esters.

(1) 2- (3,5- dichloro benzyl) -2,7- diaza spiros [3.5] nonane -2- formic acid ester group -7- t-butyl formates (are changed Close object 2-10) preparation.

Take 3,5- dichlorbenzyl alcohols (77mg, 0.44mmol, 1.1 equivalent), N, N '-carbonyl dimidazoles (77mg, 0.48mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 2-7 (105mg, 0.4mmol) is molten In DMF, triethylamine (64 μ L, 0.48mmol, 1.2 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings. Most of solvent is removed in oil pump rotation, and EA and saturated sodium bicarbonate solution, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, Cross column (PE: EA=2: 1).Obtain white powder 150mg, yield 87.7%.

The preparation of (2) 3,5- dichloro benzyl -2,7- diaza spiro [3.5] nonane -2- formic acid esters (compound 2-11).

Compound 2-10 (172mg, 0.4mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) 3,5- dichloro benzyl -7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonane -2- formic acid esters The preparation of (compound 5).

Compound 2-11 is taken, to sulfonamide benzoic acid (96mg, 0.48mmol, 1.2 equivalent), HOBt (162mg, 1.2mmol, 3 equivalents) and EDCI (230mg, 1.2mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (0.44mL, 3.2mmol, 8 equivalents).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, and saturated common salt washing is anhydrous Sodium sulphate is dried, and is spin-dried for, and column (DCM: acetone=2.5: 1) is crossed.Obtain micro-yellow powder 50mg, as compound 5.

The characterize data of the compound 5 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (d, J=6.4Hz, 2H), 7.56 (d, J=6.4Hz, 4H), 7.44 (d, J=14Hz, 4H), 5.03 (s, 2H), 3.75 (t, J=30.8Hz, 6H), 3.19 (s, 2H), 1.77 (d, J=36.8Hz, 4H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：167.8,155.4,144.6, 141.2,139.4,134.0,127.4,127.1,126.6,126.1,125.8,64.1,33.9.ESI-MS m/z：512.1(M+ H)⁺, 510.1 (M-H)⁺.

Embodiment 6

Compound 6：(4- (trifluoromethoxy) benzyl) -7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] The preparation of nonane -2- formic acid esters.

(1) (4- (trifluoromethoxy) benzyl) -2,7- diaza spiros [3.5] nonane -2- formic acid ester group -7- tert-butyl esters (are changed Close object 2-12) preparation.

Take 4- trifluoromethoxies benzyl alcohol (85mg, 0.44mmol, 1.1 equivalent), and N, N '-carbonyl dimidazoles (77mg, 0.48 Mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 2-7 (105mg, 0.4mmol) is dissolved in In DMF, triethylamine (64 μ L, 0.48mmol, 1.2 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings.Oil Most of solvent is removed in pump rotation, EA and saturated sodium bicarbonate solution is added, saturated common salt washing is dry, is spin-dried for, crosses column (PE: EA= 2∶1).Obtain white powder 130mg, yield 73%.

(2) (4- (trifluoromethoxy) benzyl) -2,7- diaza spiros [3.5] nonane -2- formic acid esters (compound 2-13) It prepares.

Compound 2-12 (178mg, 0.4mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) (4- (trifluoromethoxy) benzyl) -7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [3.5] nonane - The preparation of 2- formic acid esters (compound 6).

Compound 2-13 is taken, to sulfonamide benzoic acid (96mg, 0.48mmol, 1.2 equivalent), HOBt (162mg, 1.2mmol, 3 equivalents) and EDCI (230mg, 1.2mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (0.44mL, 3.2mmol, 8 equivalents).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, and saturated common salt washing is anhydrous Sodium sulphate is dried, and is spin-dried for, and column (DCM: acetone=2.5: 1) is crossed.Obtain micro-yellow powder 50mg, as compound 6.

The characterize data of the compound 6 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (d, J=6.4Hz, 2H), 7.56 (d, J=6.4Hz, 2H), 7.49 (d, J=6.4Hz, 2H), 7.44 (s, 2H), 7.37 (d, J=6.0Hz, 2H), 5.06 (s, 2H), 3.67 (d, J=34.8Hz, 6H), 3.18 (s, 2H), 1.77 (d, J=36.0Hz, 4H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：167.8,155.7,147.8,144.6,139.4,136.4,129.5,127.1,125.8,121.0, 64.7,33.9,26.3.ESI-MS m/z：528.1(M+H)⁺, 526.1 (M-H)^-.

Embodiment 7

Compound 7：3,5 dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonane -6- first The preparation of acid esters.

(1) preparation of 1- benzoyl piperidines -3- methyl formates (compound 3-1).

A 100mL single port bottles are taken, methyl formate phenylpiperidines (5.1g, 35.6mmol) between addition, DCM (50mL) dissolving add Enter triethylamine (6mL, 42.7mmo, 11.2 equivalent), be placed in 0 DEG C, is slowly added to BzCl (4.5mL, 39.2mmol, 1.1 equivalent), It is stirred overnight at room temperature, TLC tracking and monitorings.After completion of the reaction, it is cooled to room temperature, saturation NaHCO is added₃Solution and DCM extractions, satisfy It is washed with salt, anhydrous sodium sulfate drying is spin-dried for, crosses column, obtain 8.6g yellow liquid, yield 98%.ESI-MS m/z：248.1 (M+H)⁺。

(2) preparation of 1- benzoyl piperidines -3,3- dicarboxylic acid methyl ester (compound 3-2).

Compound 3-1 (8.6g, 34.8mmol) is placed in 100mL two-mouth bottles, argon gas exchanges, and THF is added, is placed in -78 DEG C, Be slowly added to LDA (26.1mL, 52.2mmol, 1.5 equivalent), stir 2h, be slowly added to methylchloroformate (5.4mL, 69.6mmol, 2 equivalents), -70 DEG C are to slowly warm up to, 1h is stirred.Reaction finishes, and saturated ammonium chloride solution and EA extractions is added, satisfies It is washed with salt, anhydrous sodium sulfate drying is spin-dried for, crosses column.Obtain 8g yellow liquids, yield 75%.ESI-MS m/z：306.1 (M+H)⁺.

(3) preparation of 1- benzyl piepridines -3,3- dimethyl alcohol (compound 3-3).

(4) system of (1- benzyl piepridines -3,3- diyl) bis- (methylene) bis- (4- oluene sulfonic acides esters) (compound 3-4) It is standby.

(5) system of 6- benzyls -2- ((2- nitrobenzophenones) sulfonyl) -2,6- diaza spiros [3.5] nonane (compound 3-5) It is standby.

Take compound 3-4 (6g, 11mmol) to be placed in 250mL single port bottles, be added 2- nitro -4- toluenesulfonamides (2.3g, 13.82mmol, 1.2 equivalents) and potassium carbonate (3.8g, 27.5mmol, 2.5 equivalent), it is placed in 100 DEG C and heats, be stirred overnight. TLC shows that raw material reaction finishes, and DMF is removed with oil pump rotation, and EA and water, saturated common salt washing, anhydrous sodium sulfate drying, rotation is added It is dry, cross column (PE: EA=4: 1).Obtain yellow liquid 3.65g, as product.

(6) preparation of 6- benzyls -2,6- diaza spiro [3.5] nonane -2- t-butyl formates (compound 3-6).

Take compound 3-5 (3.65g, 9.9mmol) in 100mL single port bottles, acetonitrile dissolves, addition benzenethiol (1.03mL, 10.1mmol, 1.02 equivalents) and cesium carbonate (4.8g, 14.9mmol, 1.5 equivalent), it is stirred at room temperature.TLC shows that raw material has reacted Finish, is directly added into Boc acid anhydrides (0.7mL, 3mmol, 1 equivalent), is stirred overnight at room temperature.EA and water extraction, saturated salt solution is added It washes, anhydrous sodium sulfate drying is spin-dried for, crosses column (PE: EA=2: 1).Obtain 2.6g yellow liquids.

The preparation of (7) 2,6- diaza spiro [3.5] nonane -6- t-butyl formate hydrochlorides (compound 3-7).

Take compound 3-6 (1.6g, 5.1mmol) in 50mL single port bottles, methanol dissolving is added containing 10% palladium carbon (0.54g, 0.51mmol, 10mol%), hydrogen exchange, and are placed in 45 DEG C, stir 2h.It is cooled to room temperature, diatomite filtering, methanol It rinses, is spin-dried for.Obtain colorless oil.

(8) 2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonane -6- t-butyl formates (compound 3- 8) preparation.

Compound 3-7 (300mg, 1.33mmol) is taken, to sulfonamide benzoic acid (294mg, 1.46mmol, 1.1 equivalent), HOBt (539mg, 3.99mmol, 3 equivalent) and EDCI (765mg, 3.99mmol, 3 equivalent) in 50mL single port bottles, be added DMF and TEA (0.74mL, 5.32mmol, 4 equivalent).It is stirred overnight at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, satisfies It is washed with salt, it is dry, it is spin-dried for, crosses column (DCM: acetone=3: 1).Obtain white solid 450mg, yield 83%.

(9) preparation of (2,6- diaza spiros [3.5] nonane -2- carbonyls) benzsulfamide (compound 3-9).

Compound 3-8 (120mg, 0.3mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(10) 3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonane -6- formic acid The preparation of ester (compound 7).

Take 3,5- dichlorbenzyl alcohols (53mg, 0.3mmol, 1 equivalent), N, N '-carbonyl dimidazoles (58mg, 0.36mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 3-9 is dissolved in DMF, addition triethylamine (55 μ L, 0.36mmol, 1.2 equivalents), it is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, is added EA and saturated sodium bicarbonate solution, saturated common salt washing, anhydrous sodium sulfate drying are spin-dried for, mistake column (DCM: acetone=2.5: 1).Obtain white powder 25mg, as compound 7.

The characterize data of the compound 7 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (d, J=8.4Hz, 2H), 7.82 (d, J=8.4Hz, 2H), 7.55 (s, 1H), 7.49 (s, 2H), 7.43 (d, J=5.2Hz, 2H), 5.06 (s, 2H), 4.32 (d, J=6.8Hz, 1H), 4.21 (d, J=5.6Hz, 1H), 4.06 (t, J=7.2Hz, 1H), 3.99 (d, J=5.6Hz, 1H), 3.62-3.48 (m, 2H), 2.11 (t, J=8.0Hz, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：155.5 144.7, 141.1,139.3,134.0,127.4,127.2,126.6,126.2,125.8,64.2,34.9,33.1.ESI-MS m/z： 512.1(M+H)⁺, 510.1 (M-H)^-.

Embodiment 8

Compound 8：4- (trifluoromethoxy) benzyls -6- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonyl The preparation of alkane -2- formic acid esters.

Take 4- trifluoromethoxies benzyl alcohol (58mg, 0.3mmol, 1 equivalent), N, N '-carbonyl dimidazoles (58mg, 0.36mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 3-9 (93mg, 0.3mmol) is molten In DMF, triethylamine (55 μ L, 0.36mmol, 1.2 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings. Most of solvent is removed in oil pump rotation, and EA and saturated sodium bicarbonate solution, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, Cross column (DCM: iPrOH=10: 1).Obtain white powder 25mg, as compound 8.

The characterize data of the compound 8 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (d, J=8.4Hz, 2H), 7.82 (d, J=8.4Hz, 2H), 7.55 (s, 1H), 7.49 (s, 2H), 7.43 (d, J=5.2Hz, 2H), 5.06 (s, 2H), 4.32 (d, J=6.8Hz, 1H), 4.21 (d, J=5.6Hz, 1H), 4.06 (t, J=7.2Hz, 1H), 3.99 (d, J=5.6Hz, 1H), 3.62-3.48 (m, 2H), 2.11 (t, J=8.0Hz, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：155.7 147.8, 144.7,139.3,136.3,129.5,127.2,125.9,121.0,64.8,34.9,33.1.ESI-MS m/z：528.1(M+ H)⁺, 526.1 (M-H)^-.

Embodiment 9

Embodiment 9：3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonane -6- The preparation of formic acid esters.

(1) 6- (3,5- dichloro benzyl) -2,6- diaza spiros [3.5] nonane -2- formic acid ester group -7- t-butyl formates (are changed Close object 3-10) preparation.

Take 3,5- dichlorbenzyl alcohols (77mg, 0.44mmol, 1.1 equivalent), N, N '-carbonyl dimidazoles (77mg, 0.48mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 3-7 (90mg, 0.4mmol) is molten In DMF, triethylamine (64 μ L, 0.48mmol, 1.2 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings. Most of solvent is removed in oil pump rotation, and EA and saturated sodium bicarbonate solution, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, Cross column (PE: EA=2: 1).Obtain white powder 140mg, yield 82%.

The preparation of (2) 3,5- dichloro benzyl -2,6- diaza spiro [3.5] nonane -6- formic acid esters (compound 3-11).

Compound 3-10 (129mg, 0.3mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) 3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonane -6- formic acid esters The preparation of (compound 9).

Compound 3-11 is taken, to sulfonamide benzoic acid (72mg, 0.36mmol, 1.2 equivalent), HOBt (122mg, 0.9mmol, 3 equivalents) and EDCI (173mg, 0.9mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (0.33mL, 2.4mmol, 8 equivalents).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, and saturated common salt washing is dry, It is spin-dried for, crosses column (EA: PE=4: 1).Obtain micro-yellow powder 50mg, as compound 9.

The characterize data of the compound 9 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (d, J=6.4Hz, 2H), 7.56 (d, J=6.4Hz, 4H), 7.44 (d, J=14Hz, 4H), 5.03 (s, 2H), 3.75 (t, J=30.8Hz, 6H), 3.19 (s, 2H), 1.77 (d, J=36.8Hz, 4H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：168.1,146.3,144.6, 141.6,136.4,134.4,128.6,127.7,127.0,126.4,126.2,126.0,65.1,61.0,56.9,51.4, 33.2.ESI-MS m/z：512.1(M+H)⁺, 510.1 (M-H)^-.

Embodiment 10

Compound 10：(4- (trifluoromethoxy) benzyl) -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] preparation of nonane -6- formic acid esters.

(1) (4- (trifluoromethoxy) benzyl) -2,6- diaza spiros [3.5] nonane -2- formic acid ester group -6- tert-butyl esters (are changed Close object 3-12) preparation.

Take 4- trifluoromethoxies benzyl alcohol (85mg, 0.44mmol, 1.1 equivalent), N, N '-carbonyl dimidazoles (77mg, 0.48mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 3-7 (105mg, 0.4mmol) is molten In DMF, triethylamine (64 μ L, 0.48mmol, 1.2 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings. Most of solvent is removed in oil pump rotation, and EA and saturated sodium bicarbonate solution, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, It is directly used in next step.

(2) (4- (trifluoromethoxy) benzyl) -2,6- diaza spiros [3.5] nonane -6- formic acid esters (compound 3-13) It prepares.

Compound 3-12 is taken to be placed in 25mL single port bottles, methanol dissolving is added ethanol solution of hydrogen chloride (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) (4- (trifluoromethoxy) benzyl) -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.5] nonane - The preparation of 6- formic acid esters (compound 10).

Compound 3-13 is taken, to sulfonamide benzoic acid (96mE, 0.48mmol, 1.2 equivalent), HOBt (162mg, 1.2mmol, 3 equivalents) and EDCI (230mg, 1.2mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (0.44mL, 3.2mmol, 8 equivalents).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, and saturated common salt washing is anhydrous Sodium sulphate is dried, and is spin-dried for, and column (DCM: acetone=2.5: 1) is crossed.Obtain micro-yellow powder 50mg, as compound 10.

The characterize data of the compound 10 is：¹H NMR (400MHz, DMSO-d₆, 6_ppm)：7.88 (d, J=6.4Hz, 2H), 7.56 (d, J=6.4Hz, 2H), 7.49 (d, J=6.4Hz, 2H), 7.44 (s, 2H), 7.37 (d, J=6.0Hz, 2H), 5.06 (s, 2H), 3.67 (d, J=34.8Hz, 6H), 3.18 (s, 2H), 1.77 (d, J=36.0Hz, 4H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：168.1,148.2,146.3,136.7,136.4,129.8,128.7,126.0,121.3,65.7,61.1, 56.9,51.3,34.8,33.2,26.6.ESI-MS m/z：528.1(M+H)⁺, 526.1 (M-H)^-.

Embodiment 11

Compound 11：3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] octane -6- The preparation of formic acid esters.

(1) the preparation of 2- (methylol) ethyl acrylates (compound 4-1)

Take a 500mL single port bottles, be added paraformaldehyde (20g, 0.66mol, 3 equivalent), ethyl acrylate (22g, 0.22 Mol) and DABCO (24.6g, 0.22mol, 1 equivalent) is dissolved in dioxane/H₂(volume ratio 1: 1) 200mL, is stirred overnight O. Decompression boils off dioxane, and EA and water, liquid separation is added, and water layer EA is extracted 3 times, merges organic layer, saturated common salt washing, anhydrous sulphur The drying of sour sodium, evaporated under reduced pressure mix sample and cross column (PE: EA=4: 1to2: 1) and obtain 11g colourless oil liquids, yield 38.5%.

(2) preparation of 1- benzyls -3- (hydroxymethyl) pyrrolidines -3- Ethyl formates (compound 4-2).

A 500mL single port bottles are taken, N- methoxyl methyls-N- (trimethyl silicane methyl) benzylamine (22g, 0.09mol, 1.13 is added Equivalent) and compound 4-1 (11g, 0.08mol), DCM dissolving, be placed in 0 DEG C, be slowly added dropwise trifluoroacetic acid (1.76g, 16mmol, 20mol%), 1h is stirred at such a temperature, is warming up at 25 DEG C and is continued to stir 12h.TLC tracking and monitorings.1M hydrochloric acid solutions are added, 10min, liquid separation are stirred, EA is washed twice.Water layer is neutralized with saturated sodium bicarbonate solution, is extracted 3 times with EA, and organic layer is eaten with saturation Salt is washed, and anhydrous sodium sulfate drying, evaporated under reduced pressure mixes sample and crosses column (PE: EA=1: 1toDCM: acetone=1: 1), obtains 9g Weak yellow liquid, yield 41%.

(3) preparation of 1- benzyl-pyrroles alkane -3,3- dimethyl alcohol (compound 4-3).

A 100mL two-mouth bottles are taken, lithium aluminium hydride (3.03g, 79.8mmol, 3 equivalent) is added, argon gas protection is added anhydrous THF is placed at 0 DEG C, stirs 15min, the THF solution of compound 4-2 (7g, 26.6mmol) is slowly added dropwise, is warmed to room temperature, and is stirred 1h.Reaction solution is slowly added dropwise into saturated ammonium chloride solution, is filtered through diatomite, filtrate layered, water layer is extracted with EA (100mL) It takes 3 times, saturated common salt washing.Primary with the extraction of iPrOH/DCM (20%) solution, saturated common salt washing merges organic layer, anhydrous Sodium sulphate is dried, and evaporated under reduced pressure obtains 5g crude products.It is directly used in next step.

(4) system of (1- benzyl-pyrrole alkane -3,3- diyl) bis- (methylene) bis- (4- oluene sulfonic acides esters) (compound 4-4) It is standby.

A 100mL single port bottles are taken, compound 4-3 (2g, 9mmol) is added, DCM dissolves, addition TEA (5mL, 36.2mmol, 4 equivalents) and DMAP (catalytic amount), it is slowly added to TsCl (6.9g, 36.2mmol, 4 equivalent), is stirred overnight at room temperature.Be added water and DCM is extracted, saturated common salt washing, and anhydrous sodium sulfate drying is spin-dried for, crosses column (PE: EA=5: 1).Obtain yellowish solid 4g, yield It is 85%.

(5) preparation of 6- benzyls -2- tosyls -2,6- diaza spiro [3.4] octane (compound 4-5).

Take compound 4-4 (3.4g, 6.5mmol) to be placed in 100mL single port bottles, be added para toluene sulfonamide (1.34g, 7.8mmol, 1.2 equivalents) and potassium carbonate (2.24g, 16.25mmol, 2.5 equivalent), it is placed in 100 DEG C and heats, be stirred overnight. TLC shows that raw material reaction finishes, and DMF is removed with oil pump rotation, and EA and water, saturated common salt washing, anhydrous sodium sulfate drying, rotation is added It is dry, cross column.Obtain yellow liquid 2g.

(6) preparation of 2- tosyls -2,6- diaza spiro [3.4] octane -6- t-butyl formates (compound 4-6).

Take compound 4-5 (2g, 5.6mmol) in 50mL single port bottles, formic acid (catalytic amount) is added, and addition contains in methanol dissolving 10% palladium carbon (596mg, 0.56mmol, 10mol%), hydrogen exchange, and are placed in 45 DEG C, stir 1d.It is cooled to room temperature, diatomite Filtering, methanol rinse, and Boc acid anhydrides (1.29mL, 5.6mmol, 1 equivalent) is added, 1.5h is stirred at room temperature, is spin-dried for, and cross column (PE: EA =2: 1).Obtain 1.2g yellow liquids.

The preparation of (7) 2,6- diaza spiro [3.4] octane -6- t-butyl formate oxalates (compound 4-7).

Take compound 4-6 (1.2g, 3.3mmol) in 50mL single port bottles, methanol dissolving, magnesium chips is added, and (polishing removes surface Oxide layer is cut into tiny piece) (634mg, 26.4mmol, 8 equivalent), it is stirred at room temperature, magnesium chips gradually dissolves, and it is gentle to generate heat Body, reaction solution become the sticky shape of white, TLC tracking and monitorings.After completion of the reaction, it is spin-dried for, ether dissolution is added, anhydrous sodium sulfate is added 1h, diatomite filtering are stirred, filtrate is added dropwise the ethanol solution of anhydrous oxalic acid, white precipitate is precipitated immediately, depressurized under stiring Filter, obtains white solid 500mg, as product.

The characterize data of compound 4-7 is：¹H NMR (400MHz, D₂O, δ_ppm)：4.09 (d, J=8.0Hz, 2H), 4.02 (d, J=8.4Hz, 2H), 3.35 (d, J=17.2Hz, 2H), 3.31 (d, J=19.2Hz, 2H), 2.17 (t, J= 5.6Hz, 2H), 1.38 (s, 9H)

(8) 2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] octane -6- t-butyl formates (compound 4- 8) preparation.

Compound 4-7 (250mg, 0.51mmol) is taken, to sulfonamide benzoic acid (203mg, 1.01mmol, 2 equivalent), HOBt DMF and TEA is added in 50mL single port bottles in (409mg, 3.03mmol, 6 equivalent) and EDCI (581mg, 3.03mmol, 6 equivalent) (1.95mL, 12.84mmol, 12 equivalent).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction, saturation food is added Salt is washed, dry, is spin-dried for, and column (DCM: acetone=3: 1) is crossed.Obtain white solid product 323mg, yield 80%.

(9) preparation of 4- (2,6- diaza spiros [3.4] octane -2- carbonyls) benzsulfamide (compound 4-9).

Compound 4-8 (150mg, 0.38mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(10) 3,5- dichloro benzyl -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] octane -6- formic acid The preparation of ester (compound 11).

Take 3,5- dichlorbenzyl alcohols (67mg, 0.38mmol, 1 equivalent), N, N '-carbonyl dimidazoles (74mg, 0.46mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 4-9 is dissolved in DMF, addition triethylamine (63 μ L, 0.46mmol, 1.2 equivalents), it is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, and EA is added And saturated sodium bicarbonate solution, saturated common salt washing is dry, is spin-dried for, crosses column (DCM: acetone=2.5: 1).Obtain white powder 50mg, as compound 11.

The characterize data of the compound 11 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (d, J=8.4Hz, 2H), 7.82 (d, J=8.4Hz, 2H), 7.55 (s, 1H), 7.49 (s, 2H), 7.43 (d, J=5.2Hz, 2H), 5.06 (s, 2H), 4.32 (d, J=6.8Hz, 1H), 4.21 (d, J=5.6Hz, 1H), 4.06 (t, J=7.2Hz, 1H), 3.99 (d, J=5.6Hz, 1H), 3.62-3.48 (m, 2H), 2.11 (t, J=8.0Hz, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：167.7 153.5, 145.9,141.4,141.3,136.1,128.3,127.3,126.1,125.6,64.4,64.3,61.8,57.2,54.9, 54.8,54.4,44.8,44.3,35.3,34.5.ESI-MS m/z：498.1(M+H)⁺, 496.1 (M-H)^-.

Embodiment 12

Compound 12：4- (trifluoromethoxy) benzyls -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] The preparation of octane -6- formic acid esters.

Take 4- trifluoromethoxies benzyl alcohol (73mg, 0.38mmol, 1 equivalent), N, N '-carbonyl dimidazoles (74mg, 0.46mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound (112mg, 0.38mmol) is dissolved in In DMF, triethylamine (63 μ L, 0.46mmol, 1.2 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings.Oil Most of solvent is removed in pump rotation, and EA and saturated sodium bicarbonate solution, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, mistake Column (DCM: acetone=2.5: 1).Obtain white powder 50mg, as compound 12.

The characterize data of the compound 12 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.89 (d, J=6.4Hz, 2H), 7.82 (d, J=5.2Hz, 2H), 7.52 (t, J=6.4Hz, 4H), 7.37 (d, J=6.4Hz, 2H), 5.09 (s, 2H), 4.31 (d, J=5.6Hz, 1H), 4.21 (d, J=5.2Hz, 1H), 4.05 (d, J=8.0Hz, 1H), 3.99 (d, J=8.0Hz, 1H), 3.60-3.50 (m, 2H), 2.11 (dd, J=4.8,4.8Hz, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：167.5 153.5,147.6,145.8,136.4,136.3,135.9,129.2,128.2,125.5,120.9,120.8,118.9,64.8, 64.7,61.6,57.0,54.8,54.3,44.6,44.1,35.1,34.3.ESI-MS m/z：514.4(M+H)⁺, 512.4 (M- H)^-.

Embodiment 13

Compound 13：3,5- dichloro benzyl -6- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] octane -2- The preparation of formic acid esters.

(1) 2- (3,5- dichloro benzyl) -2,6- diaza spiros [3.4] nonane -2- formic acid ester group -6- t-butyl formates (are changed Close object 4-10) preparation.

Take 3,5- dichlorbenzyl alcohols (77mg, 0.44mmol, 2.2 equivalent), N, N '-carbonyl dimidazoles (77mg, 0.48mmol, 2.4 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 4-7 (105mg, 0.2mmol) is molten In DMF, triethylamine (64 μ L, 0.48mmol, 2.4 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings. Most of solvent is removed in oil pump rotation, and EA and saturated sodium bicarbonate solution, saturated common salt washing is added, and anhydrous sodium sulfate drying is spin-dried for, It is directly used in next step.

The preparation of (2) 3,5- dichloro benzyl -2,6- diaza spiro [3.4] octane -2- formic acid esters (compound 4-11).

Compound 4-10 is taken to be placed in 25mL single port bottles, methanol dissolving is added ethanol solution of hydrogen chloride (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) 3,5- dichloro benzyl -6- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] octane -2- formic acid esters The preparation of (compound 13).

Compound 4-11 is taken, to sulfonamide benzoic acid (96mg, 0.48mmol, 1.2 equivalent), HOBt (162mg, 1.2mmol, 3 equivalents) and EDCI (230mg, 1.2mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (0.44mL, 3.2mmol, 8 equivalents).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, and saturated common salt washing is anhydrous Sodium sulphate is dried, and is spin-dried for, and column (DCM: acetone=2.5: 1) is crossed.Obtain micro-yellow powder 50mg, as compound 13.

The characterize data of the compound 13 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.88 (t, J=1.2Hz, 2H), 7.70,7.69 (dd, J=3.2,3.2Hz, 2H), 7.57 (t, J=5.2Hz, 1H), 7.47 (d, J=3.6Hz, 2H), 7.43 (d, J=6.4Hz, 1H), 7.38 (s, 1H), 5.05 (d, J=20.0Hz, 2H), 3.93-3.78 (m, 4H), 3.67 (s, 1H), 3.56 (s, 1H), 3.54 (t, J=5.6Hz, 1H), 3.42 (t, J=5.2Hz, 1H), 2.13-2.06 (m, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：167.1,167.1,155.3,145.0,145.0,141.2,139.8,139.6,134.0,134.0, 127.7,127.6,127.4,127.3,126.1,126.0,125.6,125.5,64.2,64.1,57.0,54.8,47.4, 44.6,40.2,38.7,35.9,33.8.ESI-MSm/z：498.1(M+H)⁺, 496.1 (M-H)^-.

Embodiment 14

Compound 14：(4- (trifluoromethoxy) benzyl) -6- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] preparation of nonane -2- formic acid esters.

(1) (4- (trifluoromethoxy) benzyl) -2,6- diaza spiros [3.4] nonane -2- formic acid ester group -6- tert-butyl esters (are changed Close object 4-12) preparation.

Take 4- trifluoromethoxies benzyl alcohol (85mg, 0.44mmol, 2.2 equivalent), N, N '-carbonyl dimidazoles (77mg, 0.48mmol, 2.4 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 4-7 (105mg, 0.2mmol) is molten In DMF, triethylamine (64 μ L, 0.48mmol, 2.4 equivalent) is added, is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings. Most of solvent is removed in oil pump rotation, EA and saturated sodium bicarbonate solution is added, saturated common salt washing is dry, is spin-dried for, is directly used in down One step.

(2) (4- (trifluoromethoxy) benzyl) -2,6- diaza spiros [3.4] nonane -6- formic acid esters (compound 4-13) It prepares.

Compound 4-12 is taken to be placed in 25mL single port bottles, methanol dissolving is added ethanol solution of hydrogen chloride (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) (4- (trifluoromethoxy) benzyl) -6- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] nonane - The preparation of 2- formic acid esters (compound 14).

Compound 4-13 is taken, to sulfonamide benzoic acid (96mg, 0.48mmol, 1.2 equivalent), HOBt (162mg, 1.2mmol, 3 equivalents) and EDCI (230mg, 1.2mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (0.44mL, 3.2mmol, 8 equivalents).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction is added, and saturated common salt washing is anhydrous Sodium sulphate is dried, and is spin-dried for, and column (DCM: acetone=2.5: 1) is crossed.Obtain micro-yellow powder 50mg, as compound 14.

The characterize data of the compound 14 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.87 (d, J=6.0Hz, 2H), 7.70 (d, J=6.0Hz, 2H), 7.51-7.45 (m, 4H), 7.38-7.33 (m, 2H), 5.08 (d, J=20.0Hz, 2H), 3.85-3.67 (m, 4H), 3.59 (s, 1H), 3.56 (s, 1H), 3.53 (t, J=5.6Hz, 1H), 3.43,3.41 (dd, J= 4.8,5.2Hz, 1H), 2.13-2.05 (m, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：167.1,155.6,155.5, 147.8,145.0,145.0,139.8,139.6,136.4,129.5,129.4,127.7,127.6,125.6,121.0, 120.9,119.0,64.8,64.7,64.7,57.0,54.8,47.4,44.6,40.2,38.6,35.9,33.9.ESI-MS m/ z：514.4(M+H)⁺, 512.4 (M-H)^-.

Embodiment 15

Compound 15：3,5- dichloro benzyl -7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [4.4] octane -2- The preparation of formic acid esters.

(1) 7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [4.4] octane -2- t-butyl formates (compound 5- 1) preparation.

Take 2-BOC-2,7- diaza-spiros [4.4] nonane (400mg, 1.77mmol), to sulfonamide benzoic acid (427mg, 2.12mmol, 1.2 equivalents), HOBt (717mg, 5.31mmol, 3 equivalent) and EDCI (1018mg, 5.31mmol, 3 equivalent) in DMF and TEA (1.96mL, 14.16mmol, 8 equivalent) is added in 25mL single port bottles.It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, EA and water extraction, saturated common salt washing is added, anhydrous sodium sulfate drying is spin-dried for, crosses column (DCM: acetone=2.5: 1).It obtains in vain Color solid product 280mg.

(2) preparation of 4- (2,7- diaza spiros [4.4] octane -2- carbonyls) benzsulfamide (compound 5-2).

Compound 5-1 (120mg, 0.3mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(3) 3,5- dichloro benzyl -7- (4- sulfamoyls benzoyl) -2,7- diaza spiros [4.4] octane -2- formic acid esters The preparation of (compound 15).

Take 3,5- dichlorbenzyl alcohols (53mg, 0.3mmol, 1 equivalent), N, N '-carbonyl dimidazoles (58mg, 0.36mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 5-2 is dissolved in DMF, addition triethylamine (55 μ L, 0.36mmol, 1.2 equivalents), it is added, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, and EA and saturated carbon is added Sour hydrogen sodium solution, saturated common salt washing, anhydrous sodium sulfate drying are spin-dried for, cross column (DCM: acetone=2.5: 1).Obtain white powder Last 45mg, as compound 15.

The characterize data of the compound 15 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.89 (d, J=7.6Hz, 2H), 7.82 (d, J=7.6Hz, 2H), 7.48 (s, 4H), 7.37 (d, J=8.0Hz, 2H), 5.09 (s, 2H), 4.03 (s, 2H), 3.79 (s, 2H), 3.40 (brs, 4H), 1.70 (s, 4H)¹³C NMR (125MHz, DMSO-d6, δ_ppm)：168.7,155.2,148.7, 146.8,137.4,137.1,130.3,129.2,126.6,121.9,66.2,62.9,59.0,41.5,36.2,34.6.ESI- MS m/z：512.1(M+H)⁺, 510.1 (M-H)^-.

Embodiment 16

Compound 16：4- (trifluoromethoxy) benzyls -2- (4- sulfamoyls benzoyl) -2,6- diaza spiros [3.4] The preparation of octane -6- formic acid esters.

Take 4- trifluoromethoxies benzyl alcohol (58mg, 0.3mmol, 1 equivalent), N, N '-carbonyl dimidazoles (58mg, 0.36mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 5-2 is dissolved in DMF, is added three Ethamine (55 μ L, 0.36mmol, 1.2 equivalent) is added, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, is added EA and saturated sodium bicarbonate solution, saturated common salt washing is dry, is spin-dried for, crosses column (DCM: acetone=2.5: 1).Obtain white powder Last 48mg, as compound 16.

The characterize data of the compound 16 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：7.87 (d, J=6.4Hz, 2H), 7.74 (d, J=6.0Hz, 2H), 7.68 (d, J=6.0Hz, 2H), 7.52-7.46 (m, 4H), 7.38 (d, J=6.4Hz, 2H), 5.11 (d, J=23.6Hz, 2H), 3.59-3.22 (m, 8H), 1.93-1.77 (m, 4H)¹³C NMR (125MHz, DMSO-d₆, 6_ppm)：167.1,153.8,153.7,147.8,145.0,139.8,136.6,129.4,129.3,127.7,127.6,125.7, 125.6,121.0,64.9,56.8,54.5,54.2,49.0,47.8,45.1,33.7,32.9,26.3.ESI-MS m/z： 528.1(M+H)⁺, 526.1 (M-H)^-.

Embodiment 17

Compound 17：3,5- dichloro benzyl -2- (4- sulfamoyls benzamido) -7- azaspiros [3.5] nonane -7- first The preparation of acid esters.

(1) preparation of 4- methylenepiperidines -1- t-butyl formates (compound 6-1).

At 0 DEG C, to addition methyltriphenylphosphonium bromide (14.7g, 40.5mmol, 1.35 equivalent) and uncle in ether (90mL) Butanol potassium (4.38g, 39mmol, 1.3 equivalent), is stirred at room temperature 2 hours after adding.Reaction solution is cooled with an ice bath, by 4- oxo piperazines Pyridine -1- t-butyl formates (5.98g, 30mmol) are dissolved in ether (30mL) and are added drop-wise in above-mentioned reaction solution, and room temperature reaction is overnight. Filtering, is spin-dried for, and column chromatography purifying (petroleum ether: ethyl acetate=50: 1) obtains colourless oil liquid 5.2g, yield：88%.

The characterize data of compound 6-1 is：¹H NMR (400MHz, Chloroform-d, δ_ppm)：4.75 (s, 2H), 3.43 (t, J=5.6Hz, 4H), 2.19 (t, J=5.6Hz, 4H), 1.48 (s, 9H).

The preparation of bis- chloro-2-oxo -7- azepine [3.5] nonane -7- t-butyl formates (compound 6-2) of (2) 1,2-.

Compound 6-1 (1g, 5.07mmol) is dissolved in ether (20mL), copper zincon (4.4g, 34.5mmol), nitrogen is added At 10 DEG C, DME (5mL) solution dissolved with trichloro-acetic chloride (1.84mL, 16.5mmol, 3 equivalent) is added dropwise in gas shielded, continues room Temperature reaction is overnight.Reaction solution is poured slowly into -10 DEG C of saturated salt solution (30mL), diatomite filtering, ethyl acetate (20mL × 3) it extracts, saturated salt solution (30mL × 2) washing is dry, is spin-dried for, column chromatography purifies (petroleum ether: ethyl acetate=15: 1) Obtain brown oil liquid 880mg, yield：56%.It does not purify and directly carries out next step reaction.

(3) preparation of 2- oxos -7- azepine [3.5] nonane -7- t-butyl formates (compound 6-3).

Compound 6-2 (880mg, 2.88mmol) is dissolved in methanol (10mL), be added saturated ammonium chloride solution (10mL) and Zinc powder (1.12g), room temperature reaction is overnight.Filtering, is spin-dried for, adds water (20mL), is extracted with ethyl acetate (20mL × 2), saturation food Brine (20mL x2) washs, and organic layer is dried over anhydrous sodium sulfate, is spin-dried for, column chromatography purifying (petroleum ether: ethyl acetate=8: 1) colorless oil 490mg, yield are obtained：72%.

The characterize data of compound 6-3 is：¹H NMR (400MHz, Chloroform-d, δ_ppm)：3.43 (t, J= 5.6Hz, 4H), 2.84 (s, 4H), 1.72 (t, J=5.6Hz, 4H), 1.49 (s, 9H).

(4) preparation of 2- hydroxyls -7- azepine [3.5] nonane -7- t-butyl formates (compound 6-4).

Compound 6-3 (490mg, 2.05mmol) is dissolved in methanol (10mL), sodium borohydride is added portionwise in ice bath cooling (156mg, 4.10mmol, 2 equivalent) reacts at room temperature 1 hour.It is spin-dried for, adds water (20mL), extracted with ethyl acetate (20mL × 2), Saturated salt solution (20mL x2) washs, and organic layer is dried over anhydrous sodium sulfate, is spin-dried for, and column chromatography purifies (petroleum ether: acetic acid second Ester=3: 1) white solid 450mg, yield are obtained：91%.

The characterize data of compound 6-4 is：¹H NMR (400MHz, Chloroform-d, δ_ppm)：4.35 (m, 1H), 3.33 (m, 4H), 2.30 (m, 2H), 1.70 (m, 3H), 1.53 (m, 4H), 1.47 (m, 9H).

(5) system of 2- ((methyl sulphonyl) oxygroup) -7- azaspiros [3.5] nonane -7- t-butyl formates (compound 6-5) It is standby.

Take compound 6-4 (1g, 4.1mmol) in 50mL single port bottles, DCM dissolves, addition TEA (0.86mL, 6.2mmol, 1.5 equivalent), it is placed at -10 DEG C, MsCl (0.48mL, 6.2mmol, 1.5 equivalent) is added dropwise, is added dropwise, 1h is stirred at room temperature.Add Enter to be saturated NaHCO₃Solution, extraction, saturated common salt washing, anhydrous sodium sulfate drying are spin-dried for, are directly used in next step.

(6) preparation of 2- azidos -7- azaspiro [3.5] nonane -7- t-butyl formates (compound 6-6).

Take compound 6-5 (4.1mmol) in 50mL single port bottles, DMF dissolvings, Sodium azide is added, and (1.1g, 16.4mmol, 4 work as Amount), it is placed at 90 DEG C, is stirred overnight.Most of DMF is removed in oil pump rotation, and EA and water, extraction, saturated common salt washing, anhydrous sulphur is added Sour sodium drying, is spin-dried for, crosses column (PE: EA=8: 1).Obtain colorless oil as product 1.05g.Two step yields are 96%.ESI-MS m/z： 267.1(M+H)⁺, 265.1 (M-H)^-.

(7) preparation of 2- amino -7- azaspiro [3.5] nonane -7- t-butyl formates (compound 6-7).

Take compound 6-6 (1.05g, 4.1mmol) in 50mL single port bottles, the palladium carbon of 10% content is added in methanol dissolving (0.44g, 0.041mmol, 10mol%), hydrogen exchange, and 2h is stirred at room temperature.Diatomite filters, and methanol is removed in rotation, and EA is added and satisfies It is extracted with saline solution, collects organic phase, anhydrous sodium sulfate drying is spin-dried for, is directly used in next step.ESI-MS m/z：241.1(M +H)⁺, 239.1 (M-H)^-.

(8) 2- (4- sulfamoyls benzamido) -7- azaspiros [3.5] nonane -7- t-butyl formates (compound 6-8) Preparation.

Compound 6-7 (350mg, 1.46mmol) is taken, to sulfonamide benzoic acid (352mg, 1.75mmol, 1.2 equivalent), HOBt (591mg, 4.38mmol, 3 equivalent) and EDCI (840mg, 4.38mmol, 3 equivalent) in 25mL single port bottles, be added DMF and TEA (1mL, 7.3mmol, 5 equivalent).It is stirred at room temperature.TLC tracking and monitorings.DMF is removed in rotation, and EA and water extraction, saturated salt solution is added It washes, it is dry, it is spin-dried for, crosses column (DCM: acetone=2.5: 1).Obtain white solid product 400mg.ESI-MS m/z：424.1(M+ H)⁺, 422.1 (M-H)^-.

(9) preparation of N- (7- azaspiros [3.5] nonane -2- bases) -4- sulfamoylbenzamides (compound 6-9).

Compound 6-8 (120mg, 0.28mmol) is taken to be placed in 25mL single port bottles, ethanol solution of hydrogen chloride is added in methanol dissolving (1mL), is stirred at room temperature, TLC tracking and monitorings.Solvent is removed in rotation.It is directly used in next step.

(10) 3,5- dichloro benzyl -2- (4- sulfamoyls benzamido) -7- azaspiros [3.5] nonane -7- formic acid esters The preparation of (compound 17).

Take 3,5- dichlorbenzyl alcohols (53mg, 0.3mmol, 1 equivalent), N, N '-carbonyl dimidazoles (58mg, 0.36mmol, 1.2 equivalents) in 25mL single port bottles, 2h is stirred at room temperature in DMF dissolvings.Compound 6-9 is dissolved in DMF, addition triethylamine (55 μ L, 0.36mmol, 1.2 equivalents), it is added in reaction solution, is stirred at room temperature.TLC tracking and monitorings.Most of solvent is removed in oil pump rotation, and EA is added And saturated sodium bicarbonate solution, saturated common salt washing is dry, is spin-dried for, crosses column (DCM: acetone=2.5: 1).Obtain white powder 40mg, as compound 17.

The characterize data of the compound 17 is：¹H NMR (400MHz, DMSO-d₆, δ_ppm)：8.80 (d, J=7.2Hz, 1H), 8.00 (d, J=8.4Hz, 2H), 7.82 (d, J=8.8Hz, 2H), 7.58 (t, J=0.8Hz, 1H), 7.46 (s, 2H), 7.42 (d, J=0.8Hz, 2H), 5.06 (s, 2H), 4.46,4.42 (dd, J=8.0,8.0Hz, 1H), 2.25 (t, J=10.8Hz, 2H), 1.89 (t, J=8.4Hz, 2H), 1.59 (t, J=6.8Hz, 2H), 1.52 (t, J=5.6Hz, 2H)¹³C NMR (125MHz, DMSO-d₆, δ_ppm)：164.4,154.1,146.2,141.4,134.0,127.9,127.4,126.6,126.1, 125.8,125.5,64.6,41.0,40.7,31.8,25.5.ESI-MS m/z：526.1(M+H)⁺, 524.1 (M-H)^-.

Experimental example

(1) the activity screen method of target compound.

Principle：Using lysoPLD enzymatic activitys can by substrate lysophosphatidylcholine (lysophosphatidylcholine, ) and the like LPC it is hydrolyzed.This experiment substrate FS-3 fluoresceins used and fluorescent quenching element mark simultaneously LPC analogs.When ATX acts on the substrate, fluorescein is hydrolyzed and is released, to be detected.

Reagent and instrument：ATX enzymes, substrate FS-3 and its corresponding reagent are purchased from Echelon Biosciences Inc. Company (Salt Lake City, UT, USA), DMSO (Sigma companies).Envision2104 fluor testers (U.S. Perkin Elmer companies), sample injector (Eppendorf companies), microwell plate (corning companies).

Specific experiment step：Configure 10 μM of storing liquid first plus in the deionized water of 2ml to substrate FS-3, while according to Illustrate plus suitable deionized water prepares buffer solution C and D.It includes the enzyme buffer liquid of buffer solution C and D and appropriate ATX enzymes to add 20 μ l Into 384 microwell plates, each hole is then plus the compound of the series concentration gradient of 2.5 μ l is compareed with corresponding, incubation at room temperature 10 Minute, the FS-3 substrates of 2.5 μ l are then added per hole, with microwell plate plate reader into one hour of Mobile state read plate, emits light and swashs Luminous wavelength is respectively 485nM and 528nM.Inhibiting rate of the compound to enzyme reaction is calculated according to fluorescence ratio, is used GraphPad softwares carry out the IC that analysis calculates compound₅₀Value.

The average IC of compound₅₀Value is summarized as：A：IC₅₀＜ 10nM；B：10nM ＜ IC₅₀＜ 50nM；C：IC₅₀＞ 50nM.

The experimental results are shown inthe following table.

Inhibitory activity of 1 target compound of table to Autotaxin

Compound	PF-8380	1	2	3	4	5	6	7	8
										IC₅₀/nM	A	A	A	B	B	B	A	A	C
Compound	9	10	11	12	13	14	15	16	17
										IC₅₀/nM	B	B	A	A	A	A	A	A	B

It can be obtained according to the above results, from the point of view of enzyme activity level, above compound, which has Autotaxin, to be inhibited to make With suppression level occupy several or tens nanomoles, it was demonstrated that target skeleton is suitble to the active pocket of target spot.Wherein, 10 chemical combination The inhibition of object is in the same order of magnitude with control compound PF-8380.

Each technical characteristic of embodiment described above can be combined arbitrarily, to keep description succinct, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, it is all considered to be the range of this specification record.

Several embodiments of the invention above described embodiment only expresses, the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention Range.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.

Claims

1. the aza toroid compound or its pharmaceutically acceptable salt or stereoisomer with Formulas I structure feature or solvent Compound or prodrug：

Wherein：

A is selected from：- N- ,-CH-；

R¹It is selected from：Substituted or non-substituted aryl, substituted or non-substituted contains the heteroatomic heteroaromatic of one or more O, N, S, Containing substituted or non-substituted alkyl, substituted or non-substituted C3-C8 naphthenic base, it is substituted or non-substituted containing one or more O, N, the heteroatomic Heterocyclylalkyls of S, substituted or non-substituted naphthalene, substituted or non-substituted benzheterocycle；

R²It is selected from：Substituted or non-substituted aryl, substituted or non-substituted contains the heteroatomic heteroaromatic of one or more O, N, S, Containing substituted or non-substituted alkyl, substituted or non-substituted C3-C8 naphthenic base, it is substituted or non-substituted containing one or more O, N, the heteroatomic Heterocyclylalkyls of S, substituted or non-substituted naphthalene, substituted or non-substituted benzheterocycle；

R is selected from：C1-C3 alkyl, C3-C6 naphthenic base；

R³、R⁴Independently optionally certainly：H, D ,-SR⁷,-S (=O) R⁷,-S (=O)₂R⁷,-S (=O)₂NR⁷R⁸,-C (=O) R⁷,-OC (=O) R⁷,-C (=O) NR⁷R⁸, CO₂R⁸,-NR⁷R⁸, NCONR⁷R⁸, NCO₂R⁷, OCONR⁷R⁸, CSNR⁷R⁸, NCSNR⁷R⁸, C1-C6 alkane Base, C3-C6 unsaturated alkyls, C3-C10 naphthenic base, C6-C10 substituted aralkyls；

R⁵、R⁶Independently optionally certainly：H, D, halogen ,-CF₃,-CN ,-NO₂,-OH ,-OR⁷,-SR⁷,-S (=O) R⁷,-S (=O)₂R⁷,-S (=O)₂NR⁷R⁸,-C (=O) R⁷,-OC (=O) R⁷,-C (=O) NR⁷R⁸, CO₂R⁸,-NR⁷R⁸, NCONR⁷R⁸, NCO₂R⁷, OCONR⁷R⁸, CSNR⁷R⁸, NCSNR⁷R⁸, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C10 naphthenic base, C6-C10 substitution aralkyls Base；

R⁷、R⁸Independently optionally certainly：H, C1-C6 alkyl, C2-C6 unsaturated alkyls, the C1- of at least one O, N, S hetero atom substitution C6 alkyl, the C2-C6 unsaturated alkyls of at least one O, N, S hetero atom substitution.

Q is selected from：- O- ,-S- ,-NH- ,-CO- ,-CO2-, C1-C3 alkyl or do not have C3-C6 naphthenic base；

M, n, p and q independently optionally from：1,2 or 3.

2. aza toroid compound according to claim 1 or its pharmaceutically acceptable salt or stereoisomer or molten Agent compound or prodrug, which is characterized in that selected from such as Formula Il-Formula VIII compound：

R in formula¹、R², Y, A, W it is as described in claim 1.

3. aza toroid compound according to claim 2 or its pharmaceutically acceptable salt or stereoisomer or molten Agent compound or prodrug, which is characterized in that

The Y is selected from：- OC (O)-,-ROC (O)-,-NR³C (O)-,-C (O)-；

The W is selected from：-NR³C (O)-,-C (O)-,-C (O) O- ,-C (O) OR-；

Wherein, R is selected from：C1-C3 alkyl；

R³It is selected from：H, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C8 naphthenic base.

4. aza toroid compound according to claim 1 or its pharmaceutically acceptable salt or stereoisomer or molten Agent compound or prodrug, which is characterized in that

The R¹It is selected from：

Wherein：

R¹⁰It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the miscellaneous alkane of the heteroatomic C1-C6 of at least one O, N, S Base, C2-C6 unsaturated alkyls, C6-C10 substituted aralkyls ,-CF₃, OR¹¹, NR¹¹R¹²,-CN ,-NO₂,-OH ,-CO₂R¹¹,- CONR¹¹R¹²,-SO₂R¹¹；

R¹¹、R¹²Independently optionally certainly：H, C1-C6 alkyl, C2-C6 unsaturated alkyls are heteroatomic containing at least one O, N, S C1-C6 miscellaneous alkyls contain the heteroatomic C2-C6 unsaturations miscellaneous alkyl of at least one O, N, S；

Wherein, R¹⁷And R¹⁸It can independently optionally certainly：H, D, F, Cl, C1-C6 alkyl and substitution alkyl, and R¹⁷And R¹⁸It can be total to With formation C3-C6 naphthenic base；

R is selected from：1,2 or 3；

The R²It is selected from：

Wherein：

R⁹It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls replace alkane containing the heteroatomic C1-C6 of at least one O, N, S Base, C2-C6 unsaturated alkyls；

Z is selected from：1,2 or 3；

X is selected from：- O- ,-S- ,-NH- ,-CH-；

R¹³It is selected from：H, C1-C6 alkyl, OR¹⁴, NR¹⁶R¹⁵；

R¹⁹It is selected from：H, C1-C6 alkyl, OR¹⁴, C (O) R, C (O) OR；

R is selected from：C1-C3 alkyl, C3-C6 naphthenic base；

R²⁰It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the heteroatomic C1-C6 substitutions of at least one O, N, S Alkyl, C2-C6 unsaturated alkyls, C3-C6 naphthenic base, substituted or non-substituted aryl, it is substituted or non-substituted containing there are one or Multiple heteroatomic heteroaromatics of O, N, S.

5. aza toroid compound according to claim 1 or 2 or its pharmaceutically acceptable salt or stereoisomer Or solvate or prodrug, which is characterized in that

R¹It is selected from：

R²It is selected from：

R⁹It is selected from：H, halogen, C1-C6 alkyl, C1-C6 halogenated alkyls contain the miscellaneous alkane of the heteroatomic C1-C6 of at least one O, N, S Base, C2-C6 unsaturated alkyls；

Z is selected from：1,2 or 3；

R¹⁰It is selected from：H, halogen, C1-C6C1-C6 alkyl, C1-C6 halogenated alkyls contain the heteroatomic C1-C6 of at least one O, N, S Miscellaneous alkyl, C2-C6 unsaturated alkyls, C6-C10 substituted aralkyls ,-CF₃, OR¹¹, NR¹¹R¹²,-CN ,-NO₂,-OH ,-CO₂R¹¹,- CONR¹¹R¹²,-SO₂R¹¹；

Y is selected from：- OC (O)-,-ROC (O)-,-C (O)-；

A is selected from：- N- ,-CH-；

W is selected from：-NR³C (O)-,-C (O)-,-C (O) O- ,-C (O) OR-；

R³It is selected from：H, D, halogen ,-CF₃,-CN ,-NO₂,-OH, C1-C6 alkyl, C3-C6 unsaturated alkyls, C3-C10 naphthenic base, C6-C10 substituted aralkyls；

Wherein, R¹⁷And R¹⁸It can independently optionally certainly：H, D, F, Cl, C1-C6 alkyl and substitution alkyl, R¹⁷And R¹⁸It can be common Form C3-C6 naphthenic base；

R is selected from：1,2 or 3；

R¹⁹It is selected from：H, C1-C6 alkyl, C (O) R；

R is selected from：C1-C3 alkyl, C3-C6 naphthenic base；

6. aza toroid compound according to claim 1 or its pharmaceutically acceptable salt or stereoisomer or molten Agent compound or prodrug, which is characterized in that selected from one of following compound：

7. the preparation method of claim 1-6 any one of them aza toroid compounds, which is characterized in that pass through following conjunction It is prepared at route：

Step 7：Compound G is reacted with magnesium chips, generates compound J；

Step 9：Compound H is reacted with benzenethiol and cesium carbonate, then is reacted with di-tert-butyl dicarbonate, compound I is generated；

Step 11：By compound J and compound R 1COOH, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- ethyl carbon Diimmonium salt hydrochlorate and triethylamine react generate compound K；

Step 12：Compound K is first reacted with ethanol solution of hydrogen chloride, then with N, N '-carbonyl dimidazoles, R2-OH and triethylamine Reaction generates compound L；

Or

Circuit is synthesized by the following way to be prepared：

Step 5：Compound v is reacted with mesyl chloride, generates compound vi；

Step 6：Compound vi is reacted with Sodium azide, generates compound vii；

Step 8：By compound viii and compound R 1COOH, I-hydroxybenzotriazole, 1- (3- dimethylamino-propyls) -3- ethyls Carbodiimide hydrochloride and triethylamine react generate compound ix；

Step 9：Compound ix is first reacted with ethanol solution of hydrogen chloride, then with N, N '-carbonyl dimidazoles, R2-OH and triethylamine Reaction generates compound x.

Wherein, m, n, p and q independently optionally from：1,2 or 3.

8. claim 1-6 any one of them aza toroid compounds or its pharmaceutically acceptable salt or stereoisomer Or solvate or prodrug are in the drug for preparing the disease that there is Autotaxin to express increased pathological characteristics for prevention and treatment In application.

9. application according to claim 9, which is characterized in that described that there is Autotaxin to express increased pathology spy The disease of sign includes：Cancer, fibrotic disease, especially pulmonary fibrosis and liver fibrosis, metabolic disease, myeloproliferative disorder are comprehensive Simulator sickness, angiocardiopathy, autoimmune disease, inflammation, the nervous system disease or pain.

10. a kind of pharmaceutical composition, which is characterized in that include claim 1-7 any one of them nitrogen as active constituent Miscellaneous volution compound or its pharmaceutically acceptable salt or stereoisomer or solvate or prodrug, and pharmaceutically can be with The auxiliary material or carrier of receiving.