CN105085525B

CN105085525B - Isoquinolin sulfonyl derivative as RHO kinase inhibitor

Info

Publication number: CN105085525B
Application number: CN201410174893.1A
Authority: CN
Inventors: 吴凌云; 姚元山; 陈兆国; 陈曙辉
Original assignee: NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
Current assignee: Medshine Discovery Inc; China Resources Pharmaceutical Holdings Co Ltd
Priority date: 2014-04-28
Filing date: 2014-04-28
Publication date: 2019-01-04
Anticipated expiration: 2034-04-28
Also published as: CN105085525A

Abstract

The invention discloses a kind of isoquinolin sulfonyl derivatives and its pharmaceutical composition as RHO kinase inhibitor, and are related to its pharmaceutical applications.In particular it relates to compound shown in formula (I) or its pharmaceutically acceptable salt.

Description

Isoquinolin sulfonyl derivative as RHO kinase inhibitor

Technical field

The present invention relates to a kind of isoquinolin sulfonyl derivatives and its pharmaceutical composition as RHO kinase inhibitor, and relate to And its pharmaceutical applications.In particular it relates to compound shown in formula (I) or its pharmaceutically acceptable salt.

Background technique

Fasudil is a kind of newtype drug with extensive pharmacological action, is RHO kinase inhibitor, by increasing flesh ball The activity expansion blood vessel of protein light chain phosphatase, reduces the tension of endothelial cell, improves brain tissue microcirculation, do not generate and aggravate Robber's blood of brain, at the same can antagonism inflammatory factor, protect neural anti-apoptotic, promote nerve regneration.This is the result shows that hydrochloric acid method relaxes ground Recovery of that nervous function is promoted, mitigates clinical symptoms, and reducing disability rate has certain curative effect.Therefore for base due to by The restriction of economic condition and to disease cognitive degree, extreme early thromboembolism treatment can not achieve, but to reduce the further of disease Progress, rebuilding blood circulation in therapeutic time window seems most important, and Fasudic hydrochloride has to ischemic brain blood The significant neuroprotection of pipe disease and therapeutic effect are worth reducing disability rate in the use of clinical especially base, improve life matter Amount.

WO2004106325 discloses a kind of compound, belongs to the prodrug of Fasudil, general structure such as formula (B- I) institute Show:

Although above compound, which exists in the prior art, can be used as RHO kinase inhibitor, they are in activity, dissolution Property, pharmacokinetics, druggability etc. have much room for improvement.

Summary of the invention

The purpose of the present invention is to provide compound shown in formula (I) or its pharmaceutically acceptable salt,

It is characterized in that

R₁, X be separately selected from H, F, Cl, Br, I, CN, OH, NH₂、C_1‐3Alkyl, C_1‐3Alkyl oxy, C_1‐3Alkyl ammonia Base, two C_1‐3Alkyl amino, the C_1‐3Alkyl is optionally by R₀₁It is replaced, R₀₁Selected from F, Cl, Br, I, OH, NH₂, R₀₁Number It is 1,2 or 3；

R₂It is selected from

W, W ' is separately selected from N (R_w1)、C(R_w2)(R_w3) or singly-bound；

L, Z is separately selected from singly-bound or C (R_z1)(R_z2)；

P, P ' is respectively selected from (CH₂)_q1；Q, Q ' is respectively selected from (CH₂)_q2；

q₁、q₂Separately it is selected from 0,1,2,3 or 4；

R_3a、R_3b、R₃、R_w1、R_w2、R_w3、R_z1、R_z2Separately it is selected from H, F, Cl, Br, I, CN, OH, NH₂、C_1‐3Alkyl, C_1‐3Alkyl oxy, C_1‐3Alkyl amino, two C_1‐3Alkyl amino, the C_1‐3Alkyl is optionally by R₀₁It is replaced.

In a scheme of the invention, R_3a、R_3b、R₃、R_w1、R_w2、R_w3Selected from halogenated, hydroxyl generation and/or amine for methyl, ethyl Or propyl；

R₀₁Selected from F, Cl, Br, I, OH, NH₂, R₀₁Number be 1,2 or 3.

In a scheme of the invention, the R₁Selected from H, F, Cl, Br, I, methyl, difluoromethyl, trifluoromethyl, methoxy Base；X is selected from H or OH.

In a scheme of the invention, the structural unitIt is selected from:

In a scheme of the invention, the R₂It is selected fromWherein in A, B one be singly-bound, Another is methylene；R4 is selected from H, F, Cl, Br, I, CN, OH, NH₂、C_1‐3Alkyl, C_1‐3Alkyl oxy, C_1‐3Alkyl amino, two C_1‐3Alkyl amino, the C_1‐3Alkyl is optionally by R₀₁It is replaced, R₀₁Selected from F, Cl, Br, I, OH, NH₂, R₀₁Number be 1,2 Or 3；Preferably, R4 is selected from NH2, ethylamino；

In a scheme of the invention, R4 is selected from

In a scheme of the invention, above compound or its pharmaceutically acceptable salt, the R₂It is selected fromOrWherein, in D, E one be singly-bound, another is methylene；

G is selected from (CH₂)_g；T is selected from (CH₂)_t；G, t is separately selected from 0,1,2,3 or 4；R_3bAs claim 1 is determined Justice；

In a scheme of the invention, g 1,2,3 or 4, t are 0 or 1；

In a scheme of the invention, R_3bSelected from NH₂；

In a scheme of the invention, R₂It is selected from

In a scheme of the invention, above-mentioned R₂It is selected fromWherein, Y is selected from (CH₂)_y；M is selected from (CH₂)_m；Y is selected from 0,1,2 or 3；M is selected from 0 or 1；

In a scheme of the invention, R₂It is selected from

In a scheme of the invention, above-mentioned R₂It is selected from

This In one scheme of invention, above compound or its pharmaceutically acceptable salt are selected from:

It is another object of the present invention to provide a kind of pharmaceutical composition, the above compound containing therapeutically effective amount Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

It is another object of the present invention to provide above compound or its pharmaceutically acceptable salt or said medicine groups The application in the drug of the various illnesss of correlation caused by object treats vessel retraction in preparation is closed, wherein the relevant various illnesss Including cerebral angiospasm caused by cerebral embolism, cerebral ischemia, cerebral injury, vertebrobasilar insufficiency, subarachnoid hemorrhage, the heart Colic pain, glaucoma, hypertension, fibrosis.

Term " pharmaceutically acceptable " adopted here is for those compounds, material, composition and/or agent For type, they contact use within the scope of reliable medical judgment, suitable for the tissue with human and animal, without Excessive toxicity, irritation, allergic reaction or other problems or complication match with reasonable interests/Hazard ratio.

Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group To pass through the side for using the alkali of sufficient amount to contact with the neutral form of this kind of compound in pure solution or suitable atent solvent Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt. It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical Salts",Journal of Pharmaceutical Science66:1‐19(1977)).Certain specific chemical combination of the invention Object contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.

Preferably, it contacts salt with alkali or acid in a usual manner, then separates parent compound, thus again in raw compounds Property form.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as in polarity Different solubility in solvent.

" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein by with acid at Salt modifies the parent compound at the mode of salt with alkali.The example of pharmaceutically acceptable salt includes but is not limited to: base Such as the inorganic acid or acylate of amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt packet The quaternary ammonium salt of conventional avirulent salt or parent compound is included, such as nontoxic inorganic acid or organic acid are formed by salt.Often The avirulent salt of rule includes but is not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid choosing From Aspirin, 2- ethylenehydrinsulfonic acid, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, salt Acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, first Alkyl sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, Asia Acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.

Pharmaceutically acceptable salt of the invention can pass through conventional chemical side by the parent compound containing acid group or base Method synthesis.Under normal circumstances, the preparation method of such salt is: in the mixture of water or organic solvent or both, via trip It reacts from acid or these compounds of alkali form with the alkali appropriate of stoichiometry or acid to prepare.It is generally preferable that ether, acetic acid The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.

In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Compounds described herein Chemical change easily occurs in physiological conditions for prodrug to be converted to the compound of the present invention.In addition, pro-drug can be with The compound of the present invention is switched to by chemistry or biochemical method in environment in vivo.

Certain compounds of the invention can exist with nonsolvated forms or solvation form, including hydrate shape Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.Of the invention Certain compounds can exist with polycrystalline or amorphous form.

Certain compounds of the invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.

The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure herein is come From Maehr, J.Chem.Ed.1985,62:114-120.1985,62:114-120.Unless otherwise indicated, with wedge key and void Line key indicates the absolute configuration of a Stereocenter.When compound described herein contains in olefinic double bond or other geometry asymmetry The heart, unless otherwise prescribed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included in the present invention Within the scope of.

The compound of the present invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of Compound, including cis and trans isomer, (-)-and (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers and its racemic mixture and other mixtures, such as enantiomter or diastereomer richness The mixture of collection, all these mixtures are within the scope of the present invention.May be present in the substituent groups such as alkyl it is other not Symmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.

Can by chiral synthesis or chiral reagent or other routine techniques prepare optically active (R)-and (S)- Isomers and D and L isomers.If expecting a kind of enantiomer of certain compound of the invention, asymmetric syntheses can be passed through Or prepared by the derivatization with chiral auxiliary, wherein gained non-enantiomer mixture is separated, and auxiliary group is split It opens to provide pure required enantiomter.Alternatively, when containing basic functionality (such as amino) or acidic functionality (such as in molecule Carboxyl) when, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then passes through known in the field point One step crystallizing or chromatography carry out diastereoisomer fractionation, and then recycling obtains pure enantiomer.In addition, enantiomter and The separation of diastereoisomer is usually to be completed by using chromatography, and the chromatography uses chiral stationary phase, and optionally Ground combines (such as generating carbaminate by amine) with chemical derivatization.

The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (³H), iodine-125 (¹²⁵I) or C-14 (¹⁴C).This The transformation of all isotopics of the compound of invention, no matter radioactivity whether, be included within the scope of the present invention.

Term " pharmaceutically acceptable carrier " is to refer to deliver effective quantity active material of the present invention, do not interfere active matter The bioactivity of the matter and any preparation having no toxic side effect to host or patient or the representative carrier of mounting medium include Water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush Into agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters about carrier Breath can refer to Remington:The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.

Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.

For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition " effective quantity " refer to when being combined with active material another in the composition for the required dosage that achieves the desired results.Have The determination of effect amount varies with each individual, and age and ordinary circumstance depending on receptor also depend on specific active material, close in case Suitable effective quantity can be determined by those skilled in the art according to routine test.

Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, it can have The therapeutic purpose disorder of effect ground, disease or illness.

Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, including weight The variant of hydrogen and hydrogen, as long as the compound after the valence state of specific atoms is normal and substitution is stable.When substituent group is When ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution does not occur on aromatic radical.Term " is optionally substituted " refer to and can be substituted, can not also be substituted, unless otherwise prescribed, the type and number of substituent group in chemistry can be with It can be arbitrary on the basis of realization.

When any variable (such as R) occurs more than once in the composition of compound or structure, in every case Under definition be all independent.Thus, for example, the group can be optionally if a group is replaced 0-2 R At most replaced two R, and R in each case has independent option.In addition, the group of substituent group and/or its variant Conjunction is only just allowed in the case where such group of credit union generates stable compound.

When the key of a substituent group can be cross connected to two atomic time on a ring, this substituent group can be with this Arbitrary atom on a ring is mutually bonded.When not indicating it is connected to chemical knot by which atom in cited substituent group Include in structure general formula but be not specifically mentioned compound when, this substituent group can be mutually bonded by its any atom.Substituent group And/or the combination of its variant is only just allowed in the case where such group of credit union generates stable compound.

Alkyl and miscellaneous alkyl atomic group (including be commonly known as alkylidene, alkenyl, sub- miscellaneous alkyl, miscellaneous thiazolinyl,

Those of alkynyl, naphthenic base, Heterocyclylalkyl, cycloalkenyl and heterocycloalkenyl group) substituent group be commonly referred to as " alkane Base substituent group ", they can be one or more of selected from but not limited to following groups :-R ' ,-OR ' ,=O ,=NR ' ,=N- OR ' ,-NR ' R " ,-SR ', halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO₂R’、‐CONR’R”、‐OC(O)NR’R”、‐ NR”C(O)R’、NR’C(O)NR”R”’、‐NR”C(O)₂R ' ,-NR " " '-C (NR ' R " R ' ")=NR " ", NR " " C (NR ' R ")= NR’”、‐S(O)R’、‐S(O)₂R’、‐S(O)₂NR’R”、NR”SO₂R’、‐CN、–NO₂、‐N₃、‐CH(Ph)₂With fluoro (C₁‐C₄) alkane The number of base, substituent group is 0~(2m '+1), and wherein m ' is the sum of carbon atom in this kind of atomic group.R',R",R"',R'''' And R ' ' ' ' ' each independently preferred hydrogen, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted aryl (such as By 1~3 aryl substituted with halogen), substituted or unsubstituted alkyl, alkoxy, thio alkoxy group or aralkyl.When When the compound of the present invention includes more than one R group, for example, each R group is independently to be subject to selection, as worked as There are these groups each of when more than one R', R ", R " ', R ' ' ' ' and R ' ' ' ' ' group.When R' and R " be attached to it is same When a nitrogen-atoms, they can form 5-, 6- or 7- member ring in conjunction with the nitrogen-atoms." it is intended to include but not only limit for example,-NR'R In 1- pyrrolidinyl and 4- morpholinyl.According in the above-mentioned discussion about substituent group, it will be understood by those skilled in the art that term " alkyl " is intended to include group that carbon atom bonding is constituted together in non-hydrogen group, such as halogenated alkyl (such as-CF₃、‐CH₂CF₃) and Acyl group (such as-C (O) CH₃、‐C(O)CF₃、‐C(O)CH₂OCH₃Deng).

Similar to substituent group described in alkyl radicals, aryl and heteroaryl substituent are commonly referred to collectively as " aryl substituent ", ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO2R ' ,-CONR ' selected from such as-R ' ,-OR R " ,-OC (O) NR ' R " ,-NR " C (O) R ', NR ' C (O) NR " R " ' ,-NR " C (O) 2R ' ,-NR " " '-C (NR ' R " R ' ")=NR " ", NR " " C (NR ' R ")=NR ' " ,-S (O) R ' ,-S (O)₂R’、‐S(O)₂NR’R”、NR”SO₂R’、‐CN、–NO₂、‐N₃、‐CH(Ph)₂、 Fluorine (C₁‐C₄) alkoxy and fluorine (C₁‐C₄) alkyl etc., the quantity of substituent group be 0 to chemical valence open on aromatic rings sum Between；Wherein R ', R ", R " ', R " " and R " " ' preferably independently be selected from hydrogen, substituted or unsubstituted alkyl, be substituted or not by Substituted miscellaneous alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.When chemical combination of the invention When object includes more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one R ', R ", R " ', R " " and R " " ' group when each of these groups.

Two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-T-C (O)-by general formula Replaced the substituent group of (CRR ') q-U-, wherein T and U is independently selected from-NR- ,-O-, CRR'- or singly-bound, q be 0 to 3 it is whole Number.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula (CH2) replaced the substituent group of r B-, wherein A and B is independent is selected from-CRR '-,-O- ,-NR- ,-S- ,-S (O)-, S (O)₂‐、‐ S(O)₂NR '-or singly-bound, r are 1~4 integers.Optionally, a singly-bound on the new ring being consequently formed could alternatively be double Key.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula (CH2) replaced the substituent group of r B-, wherein s and d is independently selected from 0~3 integer, and X is-O- ,-NR ' ,-S- ,-S (O)‐、‐S(O)₂Or-S (O)₂NR'‐.Substituent R, R ', R " and R " ' preferably separately are selected from hydrogen and are substituted or are not taken (the C in generation₁‐C₆) alkyl.

Unless otherwise prescribed, term " halogenated element " or " halogen " itself or a part as another substituent group indicate fluorine, Chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogen Generation (C₁‐C₄) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyl and 3- bromopropyl etc. Deng.

The example of halogenated alkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls. " alkoxy " represents the abovementioned alkyl with given number carbon atom connected by oxygen bridge.C_1‐6Alkoxy includes C₁、C₂、C₃、 C₄、C₅And C₆Alkoxy.The example of alkoxy includes but is not limited to: methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxy." naphthenic base " includes saturation ring group, such as cyclopropyl, ring Butyl or cyclopenta.3-7 naphthenic base includes C₃、C₄、C₅、C₆And C₇Naphthenic base." alkenyl " includes the hydrocarbon of straight chain or branched chain Wherein there are one or more carbon-to-carbon double bonds, such as vinyl and acrylic on stabilization site any on the chain in chain.

Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.

Unless otherwise prescribed, " miscellaneous " the expression hetero atom of term or hetero atom group (containing heteroatomic atomic group), including Atom other than carbon (C) and hydrogen (H) and contain these heteroatomic atomic groups, for example including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al), boron (B) ,-O- ,-S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (= O) ,-S (=O)₂, and optionally by substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O)₂N (H)-or-S (=O) N (H)-.

Unless otherwise prescribed, " ring " indicates substituted or unsubstituted naphthenic base, Heterocyclylalkyl, cycloalkenyl, heterocycle alkene Base, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring includes monocycle, connection ring, loop coil and ring or bridged ring.It is former on ring The number of son is generally defined as first number of ring, for example, " 5~7 member ring " refers to around 5~7 atoms of arrangement.Unless otherwise rule Fixed, which optionally includes 1~3 hetero atom.Therefore, " 5~7 member ring " includes such as phenylpyridine and piperidyl；Another party Face, term " 5~7 membered heterocycloalkyl ring " includes pyridyl group and piperidyl, but does not include phenyl.Term " ring " further includes containing extremely The ring system of a few ring, each of these " ring " independently conforms to above-mentioned definition.

Unless otherwise prescribed, term " heterocycle " or " heterocycle " mean the stable monocycle rolled into a ball containing hetero atom or hetero atom, Bicyclic or tricyclic, they can be saturation, part it is unsaturated or unsaturated (aromatics), they include carbon atom and 1, 2,3 or 4 ring hetero atoms independently selected from N, O and S, wherein above-mentioned any heterocycle can be fused to formation pair on a phenyl ring Ring.Nitrogen and sulfur heteroatom can optionally be oxidized (i.e. NO and S (O) p).Nitrogen-atoms can be it is substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent groups of defined mistake herein).The heterocycle can be attached to any hetero atom or carbon atom To form stable structure in side group.If generate compound be it is stable, carbon potential can occur for heterocycle as described herein Or the substitution on nitrogen position.Miscellaneous ring nitrogen is optionally quaternized.One preferred embodiment is, when S in heterocycle and O atom When sum is more than 1, these hetero atoms are not adjacent to each other.Another preferred embodiment is that the sum of S and O atom is no more than in heterocycle 1.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean stable 5,6,7 unit monocycles or it is bicyclic or 7,8,9 or The aromatic rings of 10 membered bicyclic heterocycles, it includes carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S.Nitrogen Atom can be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituent groups of defined mistake herein).Nitrogen (i.e. NO and S (O) p) can be optionally oxidized with sulfur heteroatom.It is worth noting that, the sum of S and O atom does not surpass on aromatic heterocycle Cross 1.Bridged ring is also contained in the definition of heterocycle.When one or more atoms (i.e. C, O, N or S) connects two non-conterminous carbon originals Bridged ring is formed when son or nitrogen-atoms.Preferred bridged ring includes but is not limited to: a carbon atom, two carbon atoms, a nitrogen-atoms, Two nitrogen-atoms and a carbon-to-nitrogen base.It is worth noting that, monocycle is always converted into tricyclic by a bridge.In bridged ring, on ring Substituent group can also appear on bridge.

The example of heterocyclic compound includes but is not limited to: acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzene And sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo Tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyl, carboline base, benzo two Hydrogen pyranose, chromene, cinnoline base decahydroquinolyl, 2H, 6H-1,5,2- dithiazine base, dihydrofuran simultaneously [2,3-b] tetrahydrofuran Base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyl, indoles alkenyl, indolinyl, middle nitrogen Indenyl, indyl, 3H- indyl, isatino base, isobenzofuran-base, pyrans, isoindolyl, iso-dihydro-indole-group, different Yin Diindyl base, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridines base, octahydro isoquinoline Quinoline base, 1,2,3- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles base, 1,3,4- oxadiazoles base, is disliked at oxadiazoles base Oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, azophenlyene, phenthazine, benzo xanthine Base, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone base, piperonyl, pteridyl, purine radicals, pyrrole Mutter base, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, Pyridyl group, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, pyrazolyl, quinazolyl, quinolyl, 4H- quinoline Piperazine base, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiophenes Diazine, 1,2,3- thiadiazolyl group, 1,2,4- thiadiazolyl group, 1,2,5- thiadiazolyl group, 1,3,4- thiadiazolyl group, thianthrene group, thiophene Oxazolyl, isothiazolyl thienyl, thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole base, thienyl, triazine Base, 1,2,3- triazolyl, 1,2,4- triazolyl, 1,2,5- triazolyl, 1,3,4- triazolyl and xanthyl.It further include condensed ring and spiral shell Cycle compound.

Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl etc.) sheet Body indicates straight chain, branch or cricoid hydrocarbon atomic group or combinations thereof as a part of of another substituent group, can be Fully saturated, unit or polynary unsaturated, can be it is monosubstituted, two replace or polysubstituted, may include divalent or more Valence atomic group, carbon atom (such as C with specified quantity₁‐C₁₀Indicate 1 to 10 carbon)." alkyl " includes but is not limited to aliphatic hydrocarbon Base and aryl radical, the aliphatic group include chain and ring-type, are specifically including but not limited to alkyl, alkenyl, alkynyl, the virtue Fragrant alkyl includes but is not limited to aryl radical of 6-12 member, such as benzene, naphthalene etc..In some embodiments, term " alkyl " indicates Straight chain or branch atomic group or their combination can be fully saturated, unit or polynary unsaturated, may include Divalent and polyad group.The example of saturated hydrocarbons atomic group includes but is not limited to methyl, ethyl, n-propyl, isopropyl, positive fourth Base, tert-butyl, isobutyl group, sec-butyl, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, just oneself The homologue or isomers of the atomic groups such as base, n-heptyl, n-octyl.Unsaturated alkyl has one or more double or triple bonds, The example includes but is not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene group, 2- (butadienyl), 2,4- Pentadienyl, 3- (Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1- and 3- propinyl, 3- butynyl and more advanced homologue and different Structure body.

Unless otherwise prescribed, term " miscellaneous alkyl " or its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl Base etc.) itself or combine the stable straight chain of expression, branch or cricoid hydrocarbon atomic group with another term or combinations thereof, It is made of the carbon atom and at least one hetero atom of certain amount.In some embodiments, term " miscellaneous alkyl " itself or with Another term joint indicates stable straight chain, branch hydrocarbon atomic group or combinations thereof object, there is the carbon atom and extremely of certain amount Few hetero atom composition.In an exemplary embodiment, hetero atom is selected from B, O, N and S, wherein nitrogen and sulphur atom optionally by Oxidation, nitrogen heteroatom are optionally quaternized.Hetero atom B, O, N and S can be located at miscellaneous alkyl any interior location (including this Alkyl is attached to the position of molecule rest part).Example includes but is not limited to-CH₂‐CH₂‐O‐CH₃、‐CH₂‐CH₂‐NH‐CH₃、‐ CH₂‐CH₂‐N(CH₃)‐CH₃、‐CH₂‐S‐CH₂‐CH₃、‐CH₂‐CH₂、‐S(O)‐CH₃、‐CH₂‐CH₂‐S(O)₂‐CH₃,-CH=CH-O- CH₃、‐CH₂- CH=N-OCH₃With-CH=CH-N (CH₃)‐CH₃.At most two hetero atoms can be continuously, such as-CH₂‐NH‐ OCH₃。

Term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to and leads to respectively It crosses an oxygen atom, amino or sulphur atom and is connected to those of rest part of molecule alkyl group.

Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocyclic hydrocarbyl " or its subordinate concept (such as aryl, heteroaryl, ring Alkyl, Heterocyclylalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl etc.) itself or combine with other terms distinguish table Show " alkyl ", " miscellaneous alkyl " of cyclisation.In addition, for miscellaneous alkyl or heterocyclic hydrocarbyl (such as miscellaneous alkyl, Heterocyclylalkyl), miscellaneous original Son can take up the position that the heterocycle is attached to molecule rest part.The example of naphthenic base includes but is not limited to cyclopenta, hexamethylene Base, 1- cyclohexenyl group, 3- cyclohexenyl group, suberyl etc..The non-limiting example of heterocycle includes 1- (1,2,5,6- tetrahydropyridine Base), 1- piperidyl, 2- piperidyl, 3- piperidyl, 4- morpholinyl, morpholinyl, tetrahydrofuran -2- base, tetrahydrofuran indoles - 3- base, thiophane -2- base, thiophane -3- base, 1- piperazinyl and 2- piperazinyl.

Unless otherwise prescribed, term " aryl " indicates the aromatics hydrocarbon substituent of how unsaturated, can be monosubstituted, two substitutions Or it is polysubstituted, it can be monocycle or polycyclic (preferably 1 to 3 ring), they are fused together or are covalently attached.Term is " miscellaneous Aryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, hetero atom be selected from B, N, O and S, wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to point by hetero atom The rest part of son.The non-limiting embodiment of aryl or heteroaryl includes phenyl, 1- naphthalene, 2- naphthalene, 4- xenyl, 1- pyrrole Cough up base, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyl, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyl, 4- oxazolyl, 2- Phenyl -4- oxazolyl, 5- oxazolyl, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- thiazolyl, 4- thiazolyl, 5- Thiazolyl, 2- furyl, 3- furyl, 2- thienyl, 3- thienyl, 2- pyridyl group, 3- pyridyl group, 4- pyridyl group, 2- pyrimidine Base, 4- pyrimidine radicals, 5- benzothiazolyl, purine radicals, 2- benzimidazolyl, 5- indyl, 1- isoquinolyl, 5- isoquinolyl, 2- quinoxalinyl, 5- quinoxalinyl, 3- quinolyl and 6- quinolyl.The substituent group of above-mentioned any one aryl and heteroaryl ring system Selected from acceptable substituent group described below.

For simplicity, aryl when being used in combination with other terms (such as aryloxy group, arylthio, aralkyl) includes such as The aryl and heteroaryl ring of upper definition.Therefore, term " aralkyl " is intended to include that aryl is attached to those of alkyl atomic group (example Such as benzyl, phenethyl, pyridylmethyl), including wherein carbon atom (such as methylene) by such as oxygen atom replace that A little alkyl, such as phenoxymethyl, 2- pyridine oxygen methyl 3- (1- naphthoxy) propyl etc..

Term " leaving group " refer to can by another functional group or atom by substitution reaction (such as it is affine replace it is anti- Answer) replaced functional group or atom.For example, representative leaving group includes triflate；Chlorine, bromine, iodine；Sulphonic acid ester Base, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester；Acyloxy, such as acetoxyl group, trifluoro second Acyloxy etc..

Term " protecting group " includes but is not limited to " amino protecting group ", " hydroxyl protection base " or " sulfhydryl protected base ".Term " amino protecting group " refers to suitable for the blocking group for preventing side reaction on ammonia nitrogen position.Representative amino protecting group includes But it is not limited to: formoxyl；Acyl group, such as alkanoyl (such as acetyl group, trichloroacetyl or trifluoroacetyl group)；Alkoxy carbonyl Base, such as tert-butoxycarbonyl (Boc)；Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Aryl Methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4'- methoxyphenyl) methyl；Silicyl, such as trimethyl first silicon Alkyl (TMS) and t-butyldimethylsilyl (TBS) etc..Term " hydroxyl protection base " refers to suitable for prevention hydroxyl The protecting group of side reaction.Representative hydroxyl protection base includes but is not limited to: alkyl, such as methyl, ethyl and tert-butyl；Acyl group, example Such as alkanoyl (such as acetyl group)；Aryl methyl, such as benzyl (Bn), to methoxy-benzyl (PMB), 9- fluorenyl methyl (Fm) and two Phenyl methyl (benzhydryl, DPM)；Silicyl, such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc..

The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including under The combination of specific embodiment that face is enumerated, itself and other chemical synthesis process is formed by embodiment and art technology Equivalent replacement mode known to upper personnel, preferred embodiment include but is not limited to the embodiment of the present invention.

All solvents used in the present invention are commercially available, and can be used without being further purified.Reaction is usually lazy Under property nitrogen, carried out in anhydrous solvent.Proton magnetic resonance (PMR) data are recorded in Bruker Avance III400 (400MHz) On spectroscope, chemical shift is indicated with (ppm) at tetramethylsilane low field.Mass spectrum is in 1200 series of Agilent plus 6110 (& It is measured on 1956A).LC/MS or Shimadzu MS includes a DAD:SPD-M20A (LC) and Shimadzu Micromass2020 detector.Mass spectrograph is equipped with the electric spray ion source (ESI) operated under a positive or negative mode.

The present invention uses following initialisms: aq represents water；HATU represents O-7- azepine benzo triazol-1-yl)-N, N, N', N'- tetramethylurea hexafluorophosphate；EDC represents N- (3- dimethylaminopropyl)-N'- ethyl-carbodiimide hydrochloride；m‐ CPBA represents 3- chloroperoxybenzoic acid；Eq represents equivalent, equivalent；CDI represents carbonyl dimidazoles；DCM represents methylene chloride；PE generation Table petroleum ether；DIAD represents diisopropyl azo-2-carboxylic acid；DMF represents n,N-Dimethylformamide；DMSO represents dimethyl sulfoxide； EtOAc represents ethyl acetate；EtOH represents ethyl alcohol；MeOH represents methanol；CBz represents benzyloxycarbonyl group, is a kind of amine protecting group group； It is a kind of amine protecting group group that BOC, which represents tert-butyl carbonyl,；HOAc represents acetic acid；NaCNBH₃Represent sodium cyanoborohydride；R.t. generation Table room temperature；O/N is represented overnight；THF represents tetrahydrofuran；Boc₂O represents two carbonic ester of di-t-butyl；TFA represents trifluoro second Acid；DIPEA represents diisopropyl ethyl amine；SOCl₂Represent thionyl chloride；CS₂Represent carbon disulfide；TsOH is represented to toluene sulphur Acid；NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide；NCS represents 1- chlorine pyrrolidine-2,5-dione；n‐Bu₄NF represents fluorine Change tetrabutylammonium；IPrOH represents 2- propyl alcohol；Mp represents fusing point.

Compound manually orSoftware name, commercial compound use supplier's directory name.

With the Shimadzu equipped with Shimadzu SIL-20A autosampler and Japanese Shimadzu DAD:SPD-M20A detector LC20AB system carries out efficient liquid phase chromatographic analysis, using Xtimate C18 (3 μm of fillers, specification 2.1x300mm) chromatography Column.0-60AB_6 minutes methods: applying linear gradient, starts to elute with 100%A (aqueous solution that A is 0.0675%TFA), And elution is terminated with 60%B (the MeCN solution that B is 0.0625%TFA), whole process is 4.2 minutes, is then eluted with 60%B 1 minute.Reached 100:0 for chromatographic column rebalancing 0.8 minute, total run time is 6 minutes.10-80AB_6 minutes methods: it answers With linear gradient, start to elute with 90%A (aqueous solution that A is 0.0675%TFA), and (B is 0.0625%TFA's with 80%B Acetonitrile solution) terminate elution, whole process is 4.2 minutes, then with 80%B elution 1 minute.Chromatographic column rebalancing 0.8 is divided Clock reaches 90:10, and total run time is 6 minutes.Column temperature is 50 DEG C, flow velocity 0.8mL/min.Diode array detector scanning Wavelength is 200-400nm.

Thin-layer chromatographic analysis (TLC) is carried out on the silica GF254 of Sanpont-group, commonly uses ultraviolet lamp irradiation inspection Spotting out also inspects spot using other methods in some cases, in these cases, (about 1g is added in 10g silica gel with iodine Iodine is simultaneously thoroughly mixed), vanillic aldehyde (dissolution about 1g vanillic aldehyde in 100mL10%H₂SO₄In be made), ninhydrin (from Aldrich is bought) or special color developing agent (be thoroughly mixed (NH₄)₆Mo₇O₂₄·4H₂O、5g(NH₄)₂Ce(IV)(NO₃)₆、450mL H₂The dense H2SO of O and 50mL₄And be made) expansion lamellae, inspect compound.Using Still, W.C.；Kahn,M.；and Mitra, M.Journal of Organic Chemistry, the similar approach of technology disclosed in 1978,43,2923-2925., Flash column chromatography is carried out on 40-63 μm of (230-400 mesh) silica gel of Silicycle.Flash column chromatography or thin-layer chromatography it is common Solvent is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.

Preparation chromatography point is carried out using the gloomy UV/VIS-156 detector of gill in Gilson-281Prep LC322 system Analysis, used chromatographic column is Agella Venusil ASB Prep C18,5 m, 150x21.2mm；Phenomenex Gemini C18,5 m,150x30mm；Boston Symmetrix C18,5 m,150x30mm；Or Phenomenex Synergi C18,4 m,150x30mm.When flow velocity is about 25mL/min, with the acetonitrile/water eluting compounds of low gradient, Contain 0.05%HCl, 0.25%HCOOH or 0.5%NH in middle water₃·H₂O, total run time are 8-15 minutes.

With with Agilent1260 autosampler and Agilent DAD:1260 detector Agilent1260Infinity SFC system carries out SFC analysis.Chromatographic column uses Chiralcel OD-H250x4.6mm I.D., 5um Chiralpak AS-H250x4.6mm I.D., 5 m Chiralpak AD-H250x4.6mm I.D., 5 m.The chromatographic condition of OD-H_5_40_2.35ML: (specification is 250x4.6mm I.D. to Chiralcel OD-H chromatographic column, and m is filled out Material), mobile phase is 40% ethyl alcohol (0.05%DEA)-CO₂；Flow velocity is 2.35mL/min；Detection wavelength is 220nm.AS‐H_3_ 40_2.35ML chromatographic condition: Chiralpak AS-H chromatographic column (specification is 250x4.6mm I.D., 5m filler)；Mobile phase is 40% methanol (0.05%DEA)-CO₂；Flow velocity is 2.35mL/min, Detection wavelength 220nm.OD-H_3_40_2.35M chromatography Condition: ChiralcelOD-H chromatographic column (specification is 250x4.6mm I.D, 5m filler), mobile phase is 40% methanol (0.05% DEA)‐CO₂, flow velocity 2.35mL/min, Detection wavelength 220nm.AD-H_2_50_2.35ML chromatographic condition: Chiralpak AD-H chromatographic column (specification is 250x4.6mm I.D, 5mm filler), mobile phase is 50% methanol (0.1%MEA)-CO₂, flow velocity is 2.35mL/min, Detection wavelength 220nm.

Preparative SFC analysis, institute are carried out in the Waters Thar80Pre-SFC system using Gilson UV detector The chromatographic column used is Chiralcel OD-H (specification is 250x4.6mm I.D, 5m filler) or Chiralpak AD-H (rule Lattice are 250x4.6mm I.D, 5m filler).When flow velocity is about 40-80mL/min, with ethyl alcohol-carbon dioxide of low gradient or Methanol-carbon dioxide eluting compounds, wherein methanol or ethyl alcohol contain 0.05%NH₃·H₂O, 0.05%DEA or 0.1% MEA, total run time are 20-30 minutes.

Compared with prior art, the compounds of this invention is efficient, less toxic, in activity, half-life period, solubility and pharmacokinetics Etc. achieve significant or even unexpected progress, more suitable for pharmacy.

Specific embodiment

Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention. The present invention is described in detail herein, wherein its specific embodiment mode is also disclosed, to those skilled in the art Speech, carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention will It is obvious.

Embodiment 1

5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-yl) sulfonyl) isoquinolin

The first step

Isoquinolin 1a (47.5mL, 405mmol) is slowly added into the 22mL concentrated sulfuric acid, fritter is sufficiently stirred into, then It is added in the oleum of 200mL20%, is placed at room temperature for two days.It is subsequently poured into 700g ice water and stands overnight, obtain Suspension filtering, filter cake is washed with water twice (100mL x2), dry, obtain isoquinoline-5-sulfonic acid 1b (50g, yield: 60%) it, is directly used in and reacts in next step

¹H NMR(400MHz,D₂O):δ9.66(s,1H),8.94-8.92(m,1H),8.62-8.60(m,2H),8.58- 8.56 (m, 1H), 8.50-8.48 (m, 1H), 7.99-7.95 (m, 1H) .MS-ESI calculated value [M+H]⁺210, measured value 210.

Second step

Isoquinoline-5-sulfonic acid 1b (4.0g, 0.019mol) is added in the thionyl chloride of 25mL at room temperature, is then added The N,N-dimethylformamide of 0.1mL.After reaction is heated to reflux two hours, decompression evaporates extra thionyl chloride, evaporation residue (10mL x2) is washed with cold methylene chloride.Be dried to obtain target product isoquinolin -5- sulfonic acid chloride 1c (3.9g, yellow solid, Yield: 100%).

MS-ESI calculated value [M+H]⁺227 measured values 227.

Third step

Isoquinolin -5- sulfonic acid chloride 1c (150mg, 0.330mmol) is dissolved in 2mL methylene chloride, under nitrogen protection 0 DEG C cis--hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1d (80mg, 0.38mmol, commercially available quotient is successively added Product) and N, N- diisopropyl ethyl amine (0.25mL, 1.14mmol).Gained reacts liquid chamber at temperature stirring 16 hours until reaction is tied Beam.It is diluted with methylene chloride (10mL) and water (10mL), methylene chloride extracts (10mL x2), merges organic phase anhydrous slufuric acid Sodium dries, filters, and filtrate decompression concentration purifies to obtain target compound 4- with silicagel column (0-100% ethyl acetate/petroleum ether) (isoquinolin -5- base sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1e (100mg, colorless oil, Yield: 65%).

MS-ESI calculated value [M+H]⁺404, measured value 404.

4th step

By 4- (isoquinolin -5- base sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1e (100mg, 0.250mmol) is dissolved in the ethyl acetate of 5mL, and the saturation hydrogen chloride solution of 10mL ethyl acetate is added dropwise in 0 DEG C, Reaction solution was in room temperature reaction 0.5 hour.Obtained suspension filtering, filter cake is washed (10mL x2) with ethyl acetate, dry Target compound 5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-yl) sulfonyl) (60mg, white solid produce isoquinolin 1 Rate: 79%).

¹H NMR(400MHz,D₂O): δ 9.82 (s, 1H), 9.10 (d, J=6.8Hz, 1H), 8.84 (d, J=7.6Hz, 1H), 8.77 (d, J=7.6Hz, 1H), 8.68 (d, J=6.8Hz, 1H), 8.15 (t, J=7.6Hz, 1H), 4.55-4.40 (m, 1H),4.35-4.25(m,1H),3.62-3.55(m,1H),3.50-3.45(m,1H),3.39-3.30(m,2H),2.35-2.00 (m,4H).

MS-ESI calculated value [M+H]⁺304, measured value 304.

Embodiment 2

5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) isoquinolin

The first step

By 1- benzyl -1H- pyrrole-2,5-diones 2a (74.8g, 0.400mol), 2-chloroethyl amine (58g, 0.5mol) and three Ethamine (40g, 0.40mmol) is dissolved in Isosorbide-5-Nitrae-dioxane of 400mL, is heated to reflux 16 hours.It is cooled to after reaction Then room temperature is concentrated under reduced pressure, crude product chromatography silica gel column (0-100% ethyl acetate/petroleum ether) purifying obtains 1- benzyl -3- ((2- chloroethyl) amino) pyrrolidine-2,5-dione 2b (102g, yield: 96%).¹H NMR(400MHz,CDCl₃):δ7.40- 7.25(m,5H),4.66(s,2H),3.82-3.77(m,1H),3.67-3.63(m,2H),3.01-2.94(m,3H),2.55- 2.50(m,1H),2.21-2.15(m,1H).

Second step

Under nitrogen protection, 0 DEG C is dissolved in sodium hydride (7.74g, 358mmol) in 700mL n,N-Dimethylformamide, It is added 1- benzyl -3- ((2- chloroethyl) amino) pyrrolidine-2,5-dione 2b's (40g, 0.14mol) under conditions of 30 DEG C In 50mL N,N-dimethylformamide.Reaction solution is stirred at room temperature 1 hour, fully reacting fall back in (1L), ethyl acetate extraction (500mL × 3) are taken, organic phase is dried, filtered with anhydrous sodium sulfate, filtrate decompression concentration, residue chromatography silica gel column purification (0-100% methanol/ethyl acetate) obtain 5- benzyl tetrahydro pyrrolo- [3,4-b] pyrroles -4,6 (2H, 5H)-diketone 2c (20g, Colourless oil liquid, yield: 59%).

¹H NMR(400MHz,CDCl₃):δ7.37-7.28(m,5H),4.65(s,2H),4.13-4.11(m,1H),3.30- 3.27(m,1H),3.07-3.05(m,1H),2.57-2.56(m,1H),2.15-2.05(m,3H).

Third step

Under nitrogen protection, 0 DEG C Lithium Aluminium Hydride (7.19g, 0.18mol) is added portionwise in the tetrahydrofuran of 250mL, 0 5- benzyl tetrahydro pyrrolo- [3,4-b] pyrroles -4,6 (2H, 5H)-diketone 2c (20g, 0.086mol) 250mL tetra- is added dropwise at DEG C Hydrogen tetrahydrofuran solution.After completion of dropwise addition, reaction system is gradually heated to reflux 3 hours.Reaction system is cooled to 0 DEG C, then successively 7.2mL water, 7.2mL15% sodium hydroxide, 21.6mL water is added dropwise in reaction solution dropwise.Reaction solution continues stirring 0.5 hour, mistake Filter, is concentrated to get 5- benzyl octahydro pyrrolo- [3,4-b] pyrroles 2d (16g, colourless oil liquid, yield: 92%).

MS-ESI calculated value [M+H]⁺203, measured value 203.

4th step

5- benzyl octahydro pyrrolo- [3,4-b] pyrroles 2d (15g, 0.074mol) is dissolved in the methylene chloride of 300mL, according to Secondary addition N, N- diisopropyl ethyl amine (19g, 148mmol) and di-tert-butyl dicarbonate (17.8g, 0.081mol).It reacts on It stirs 4 hours under room temperature, to directly be concentrated after reaction, residue chromatography silica gel column purification (0-100% acetic acid second Ester/petroleum ether) obtain 5- benzyl hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2e (18g, colorless oil, Yield: 81%).MS-ESI calculated value [M+H]⁺310, measured value 310.

5th step

By 5- benzyl hexahydropyrrolo, simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2e (12g, 39.7mmol) is dissolved in In the tetrahydrofuran of 1L, argon gas protection is lower to be added dry hydrogen oxidation palladium carbon (1.8g, 10%).In 3MPa nitrogen atmosphere and 70 DEG C of conditions Lower stirring 16 hours.It is cooled to room temperature after fully reacting, reaction system diatomite is filtered to remove solid catalyst, and filtrate is concentrated to give To cis--hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2f (8g, weak yellow liquid, yield: 95%).

¹H NMR(400MHz,CD₃OD):δ4.21-4.17(m,1H),3.51-3.36(m,2H),3.05-2.90(m,3H), 2.89-2.77(m,2H),2.06-2.02(m,1H),1.77-1.71(m,1H),1.48(s,9H).

6th step

Cis--hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2f (212mg, 1.00mmol) and isoquinoline Quinoline -5- sulfonic acid chloride 1c (250mg, 1.10mmol) obtains 5- (isoquinolin -5- base according to the synthetic method of one compound 1e of embodiment Sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2g, it is directly used in and reacts in next step.

7th step

5- (isoquinolin -5- base sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2g (50.0mg, 0.130mmol) 5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-is obtained according to the synthetic method of one compound 1 of embodiment Base) sulfonyl) isoquinolin 2 (19mg, white solid, yield: 50%).

¹H NMR(400MHz,CD₃OD):δ9.39(s,1H),8.68-8.61(m,2H),8.48-8.38(m,2H),7.88- 7.84(m,1H),3.83-3.74(m,1H),3.25-3.12(m,4H),2.82-2.77(m,3H),1.91-1.86(m,1H), 1.60-1.56(m,1H).

MS-ESI calculated value [M+H]⁺304, measured value 304.

Embodiment 3

5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-yl) sulfonyl) isoquinolin

The first step

Cis--octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3a (100mg, 0.44mmol, commercially available quotient Product) and isoquinolin -5- sulfonic acid chloride 1c (114mg, 0.500mmol) smoothly obtained according to the synthetic method of one compound 1e of embodiment 6- (isoquinolin -5- base sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3b is directly used in next step Reaction.

Second step

6- (isoquinolin -5- base sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3b (80.0mg, 0.190mmol) 5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 is obtained according to the synthetic method of one compound 1 of embodiment (2H)-yl) sulfonyl) isoquinolin 3 (40mg, white solid, yield: 65%).

¹H NMR(400MHz,CD₃OD): δ 9.35 (s, 1H), 8.67-8.57 (m, 2H), 8.47 (d, J=7.2Hz, 1H), 8.37 (d, J=8.0Hz, 1H), 7.81 (t, J=8.0Hz, 1H), 3.47-3.38 (m, 3H), 3.34-3.26 (m, 2H), 2.78- 2.71(m,1H),2.55-2.46(m,1H),2.17-2.07(m,1H),1.65-1.30(m,4H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 4

5- (3,6- diaza-bicyclo [3.2.0] heptane -3- base sulfonyl) isoquinolin

The first step

3- (isoquinolin -5- base sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 4a (66mg, 0.33mmol, commercial goods) and isoquinolin -5- sulfonic acid chloride 1c (107mg, 0.400mmol) according to one compound 1e's of embodiment Synthetic method obtains 3- (isoquinolin -5- base sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 4b (110mg, yellow oily liquid, yield: 85%).

MS-ESI calculated value [M+H]⁺390, measured value 390.

Second step

3- (isoquinolin -5- base sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 4b (30mg, 0.77mmol) 5- (3,6- diazabicyclo [3.2.0] heptane -3- sulphonyl is obtained according to the synthetic method of one compound 1 of embodiment Base) isoquinolin 4 (15mg, yellow solid, yield: 67%).

¹H NMR(400MHz,D₂O): δ 9.74 (s, 1H), 9.17 (d, J=7.2Hz, 1H), 8.78 (d, J=7.2Hz, 1H), 8.7 (d, J=8.4Hz, 1H), 8.6 (d, J=8.4Hz, 1H), 8.09 (t, J=7.2Hz, 1H), 4.15-4.05 (m, 1H),4.05-3.95(m,1H),3.75-3.69(m,3H),3.29-3.24(m,1H),2.96-2.93(m,1H),2.80-2.78 (m,1H)。

MS-ESI calculated value [M+H]⁺290, measured value 290.

Embodiment 5

6- (isoquinolin -5- base sulfonyl) decahydro -1,6- benzodiazine

The first step

N- tert-butyl oxygen ester -4- piperidones 5a (10g, 0.050mol) is dissolved in 250mL toluene, 1- methylbenzylamine is added 5b (6.05g, 50.0mmol) reaction system use divides at 110 DEG C of water still head back flow reaction 3 hours, is cooled to room temperature, then Be concentrated under reduced pressure to give 4- ((1- phenethyl) imino group) piperidines -1- carboxylic acid tert-butyl ester 5c (15.1g, yellow oily liquid, 100%), product, which is not required to purify, directly carries out next step reaction.

Second step

Under nitrogen atmosphere, delay at -10 DEG C into the 100mL tetrahydrofuran solution of diisopropylamine (7.4g, 0.075mol) The slow hexane solution that n-BuLi (34.4mL, 0.086mol, 2M) is added dropwise.It is stirred to react at this temperature 20 minutes, it is cooling To -30 DEG C then be slowly added dropwise into the reaction solution 4- ((1- phenethyl) imino group) piperidines -1- carboxylic acid tert-butyl ester 5c (15.1g, 100mL tetrahydrofuran solution 0.05mol), the reaction was continued at this temperature after being added dropwise 30 minutes, is then cooled to -65 DEG C, the tetrahydrofuran solution (9.45g, 60.0mmolin50mL THF) of the bromo- 3- chloropropane of 1- is slowly added dropwise into the reaction solution. Reaction system is gradually warming up to room temperature reaction 2 hours after completion of dropwise addition, is then refluxed for reaction 4 hours.Reaction system is cooled to room Temperature is concentrated under reduced pressure, adds water (100mL), then extracts (200mL × 3) with methyl tertiary butyl ether(MTBE), merges organic phase, with saturation chlorine To change sodium water washing (100mL), organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate decompression is concentrated to get 1- (1- phenethyl) -1, - 6 (5H)-carboxylic acid tert-butyl ester 5d (17g, yellow oily liquid) of 2,3,4,7,8- hexahydro -1,6- naphthyridines, product is direct without further purification Carry out next step reaction.

MS-ESI calculated value [M+H]⁺343, measured value 343.

Third step

By -6 (5H)-carboxylic acid tert-butyl ester 5d of 1- (1- phenethyl) -1,2,3,4,7,8- hexahydro -1,6- naphthyridines (7g, It 0.02mol) is dissolved in 600mL tetrahydrofuran, is added 10% palladium carbon (700mg, 10%), is stirred under 3MPa Hydrogen Vapor Pressure in 40 DEG C Mix reaction 14 hours.After reaction, diatomite is filtered to remove palladium carbon, filtrate decompression concentration, crude product chromatography silica gel column (0- 100% ethyl acetate/petroleum ether) purifying obtain -6 (2H)-carboxylic acid tert-butyl ester 5e of 1- (1- phenethyl) octahydro -1,6- naphthyridines (2.26g, yellow oil, yield: 33%).

MS-ESI calculated value [M+H]⁺345, measured value 345.

4th step

- 6 (2H)-carboxylic acid tert-butyl ester 5e (500mg, 1.45mmol) of 1- (1- phenethyl) octahydro -1,6- naphthyridines is dissolved in 5mL Ethyl acetate, the saturation hydrogen chloride solution that 30mL ethyl acetate is added stir 1.5 hours at room temperature.To depressurize after reaction It is concentrated to get 1- (1- phenethyl) decahydro -1,6- benzodiazine 5f (296mg, white solid, yield: 84%).

MS-ESI calculated value [M+H]⁺245, measured value 245.

5th step

By 1- (1- phenethyl) decahydro -1,6- benzodiazine 5f (296mg, 1.21mmol) and isoquinolin -5- sulfonic acid chloride 1c (550mg, 2.42mmol) obtains 6- (isoquinolin -5- sulfonyl) -1- (1- benzene according to the synthetic method of 1 compound 1e of embodiment Ethyl) decahydro -1,6- benzodiazine 5g (96mg, yellow solid, yield: 18%).

MS-ESI calculated value [M+H]⁺436, measured value 436.

6th step

By 6- (isoquinolin -5- base sulfonyl) -1- (1- phenethyl) decahydro -1,6- benzodiazine 5g (30mg, 0.069mmol) be dissolved in 1mL trifluoroacetic acid, in 100 DEG C microwave reaction 1 hour.It is high with preparation to be concentrated under reduced pressure after reaction Pressure liquid chromatography purify target compound 6- (isoquinolin -5- base sulfonyl) decahydro -1,6- benzodiazine 5 (7mg, white are solid Body, yield: 31%).

¹H NMR(400MHz,CD₃OD):δ9.41(s,1H),8.66-8.62(m,1H),8.59-8.54(m,1H),8.50- 8.43 (m, 2H), 7.87 (t, J=8.0Hz, 1H), 4.06-3.50 (m, 4H), 3.14-3.00 (m, 3H), 2.24-2.10 (m, 1H),1.99-1.63(m,6H)。

MS-ESI calculated value [M+H]⁺332, measured value 332.

Embodiment 6

5- ((octahydro -1H- pyrrolo- [3,2-b] pyridine -1- base) sulfonyl) isoquinoline

The first step

1H- pyrrolo- [3,2-b] pyridine 6a (2.00g, 16.9mmol) is dissolved in 30mL methylene chloride, 4- diformazan is added Aminopyridine (2.06g, 16.9mmol), triethylamine (2.05g, 20.3mmol) and di-tert-butyl dicarbonate (4.42g, 20.3mmol), it is stirred overnight at room temperature.To which reaction solution is concentrated under reduced pressure after reaction, with chromatography silica gel column with eluant, eluent system (20% ethyl acetate/petroleum ether /) purify 1H- pyrrolo- [3,2-b] pyridine -1- carboxylic acid tert-butyl ester 6b (3.5g, white are solid Body, yield: 95%).

MS-ESI calculated value [M+H]⁺219, measured value 219.

Second step

1H- pyrrolo- [3,2-b] pyridine -1- carboxylic acid tert-butyl ester 6b (1.00g, 4.59mmol) is dissolved in 30mL acetic acid, It is added platinum dioxide (104mg, 0.460mmol), is stirred to react 24 hours under 4MPa Hydrogen Vapor Pressure in 50 DEG C.After reaction It is cooled to room temperature and then filters, filtrate decompression concentration obtains octahydro -1H- pyrrolo- [3,2-b] pyridine -1- carboxylic acid tert-butyl ester 6c (1.00g, colourless oil liquid, 96%), be not required to purify directly carry out next reaction.

MS-ESI calculated value [M+H]⁺227, measured value 227.

Third step

By octahydro -1H- pyrrolo- [3,2-b] pyridine -1- carboxylic acid tert-butyl ester 6c (1.00g, 4.42mmol) under nitrogen protection It is dissolved in 30mL methylene chloride, n,N-diisopropylethylamine (2.4mL, 13.3mmol) and chlorine benzyl carboxylate is added at 0 DEG C (1.13g, 6.63mmol), is stirred overnight at room temperature.To after reaction, be concentrated under reduced pressure, add water (20mL), then use ethyl acetate It extracts (30mL × 3), merges organic phase, washed with saturated sodium-chloride water solution (30mL), anhydrous sodium sulfate is dry, concentration, slightly Product obtains hexahydro -1H- pyrrolo- [3,2-b] pyridine -1,4 with chromatography silica gel column purification (10% ethyl acetate/petroleum ether) (2H)-dicarboxylic acids 4- the benzyl ester -1- tert-butyl ester 6d (1.35g, yellow oily liquid, yield: 85%).

MS-ESI calculated value [M+H]⁺361, measured value 361.

4th step

Hexahydro -1H- pyrrolo- [3,2-b] pyridine -1,4 (2H)-dicarboxylic acids 4- benzyl ester -1- tert-butyl ester 6d (1.35g, It 3.75mmol) is dissolved in 5mL ethyl acetate, the saturation hydrogen chloride solution that 40mL ethyl acetate is added stirs 45 minutes at room temperature. To after reaction, be concentrated under reduced pressure to give hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-benzyl carboxylate 6e (1.0g, white Solid, yield: 90%).

MS-ESI calculated value [M+H]⁺261, measured value 261.

5th step

By hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-benzyl carboxylate 6e (132mg, 0.51mmol) and isoquinolin - 5- sulfonic acid chloride 1c (141,0.62mmol) obtains 1- (isoquinolin -5- sulfonyl) according to the synthetic method of 1 compound 1e of embodiment Hexahydro -1H- pyrrolo- [3,2-b] pyrrole -4 (2H)-benzyl carboxylate 6f (185mg, yellow oil, yield: 81%).

MS-ESI calculated value [M+H]⁺452, measured value 452.

6th step

By 1- (isoquinolin -5- sulfonyl) hexahydro -1H- pyrrolo- [3,2-b] pyrrole -4 (2H)-benzyl carboxylate 6f (150mg, 0.332mmol) 5- ((octahydro -1H- pyrrolo- [3,2-b] pyridine -1- is obtained according to the synthetic method of one compound 5 of embodiment Base) sulfonyl) isoquinolin 6 (64mg, white solid, yield: 61%).

¹H NMR(400MHz,CD₃OD):δ9.42(s,1H),8.69-8.64(m,2H),8.50-8.40(m,2H),7.88 (t, J=8.0Hz, 1H), 3.83-3.79 (m, 1H), 3.72-3.54 (m, 3H), 3.16-3.10 (m, 1H), 2.99-2.93 (m, 1H),2.27-2.23(m,1H),2.10-2.01(m,2H),1.92-1.84(m,1H),1.77-1.69(m,1H),1.64-1.59 (m,1H)。

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 7

5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) sulfonyl) isoquinolin

The first step

Cis--hexahydropyrrolo simultaneously (105mg, 0.49mmo, commercial goods) [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7a 5- (isoquinoline is obtained according to the synthetic method of 1 compound 1e of embodiment with isoquinolin -5- sulfonic acid chloride 1c (136mg, 0.600mmol) Quinoline -5- base sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7b, it is directly used in and reacts in next step.

Second step

5- (isoquinolin -5- base sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7b (34mg, 0.082mmol) 5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-is obtained according to the synthetic method of one compound 1 of embodiment Base) sulfonyl) isoquinolin 7 (15mg, white solid, yield: 60%).

¹H NMR(400MHz,CD₃OD):δ9.40(s,1H),8.70-8.62(m,2H),8.48-8.44(m,2H),7.87 (t, J=8.0Hz, 1H), 3.28-3.14 (m, 4H), 3.13-3.01 (m, 2H), 2.83-2.70 (m, 2H), 2.64-2.52 (m, 2H)。

Embodiment 8

5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-yl) sulfonyl) isoquinolin

The first step

3,4- pyridine dicarboxylic acid 8a (30.0g, 180mmol) is dissolved in 250mL acetic anhydride and then is heated to reflux 3-4 Hour until reaction solution change clarification, then cools to room temperature, decompression boils off remaining acetic anhydride and obtains crude product 3,4- dicarboxylic acids Acid anhydride pyridine 8b is directly used in react in next step.

Second step

Benzylamine (28.9g, 270mmol) is added drop-wise to solid 3,4- dicarboxylic anhydride pyridine 8b dropwise at 0 DEG C, and (first step is thick Product) in, it is then warmed to room temperature naturally and stands 1 hour.Gained thick liquid 4- benzamido group formoxyl niacin 8c is directly used It is reacted in next step.

Third step

Previous step crude product 4- benzamido group formoxyl niacin 8c is carefully dissolved in the acetic anhydride of 150mL, gained Solution is heated to 110 DEG C of reactions 4 hours until raw material disappears.Decompression boils off remaining acetic anhydride after being cooled to room temperature, will be remaining Object water (100mL) and ethyl acetate (100mL) dilution, ethyl acetate extract (100mL × 2), and organic phase successively uses saturated carbon Sour hydrogen sodium water solution (100mL), water (100mL) and saturated salt solution (100mL) washing, anhydrous sodium sulfate dries, filters, dense Contracting, crude product silica gel post separation (30%-50% ethyl acetate/petroleum ether) obtain white solid 2- benzyl -1H- pyrroles [3,4- And] pyridine -1,3 (2H)-diketone 8d (29.5g, the gross production rate of 3 steps 69%).

¹H NMR(400MHz,CDCl₃): δ 9.17 (s, 1H), 9.07 (d, J=4Hz, 1H), 7.76 (d, J=4Hz, 1H), 7.50-7.40(m,2H),7.30-7.36(m,3H),4.88(s,2H)。

4th step

By 2- benzyl -1H- pyrroles [3,4- simultaneously] pyridine -1,3 (2H)-diketone 8d (9.60g, 40.3mmol) and wet palladium carbon (2.0g, 20%) is added in 300mL methanol, this reaction solution is placed in the hydrogen system of 3MPa and is heated to 60 DEG C and was reacted Night.When being after reaction cooled to room temperature reaction solution, filtered off through Celite palladium carbon, gained filtrate is concentrated to get weak yellow liquid 2- Benzyl -1H- pyrrolo- [3,4-c] hexahydropyridine -1,3 (2H)-diketone 8e is directly used in react in next step.

5th step

Lithium aluminium hydride (3.06g, 80.6mmol) is added portionwise to the 2- benzyl-that stirred at nitrogen protection and 0 DEG C In 1H- pyrrolo- [3,4-c] hexahydropyridine -1,3 (2H)-diketone 8e (9.84g, 40.3mmol) 120mL tetrahydrofuran solution. Reaction solution is heated to reflux 2 hours until raw material disappears after addition, is cooled to room temperature, then ice-water bath is cooled to 0 DEG C, suitable Sequence is added dropwise water (3mL) dropwise, NaOH solution (3mL, 15% aqueous solution), water (9mL) quenching reaction, and mixture is warming up to room temperature and stirs 30min is mixed, is then filtered, filtrate is concentrated to get pistac 2- benzyl 8 hydrogen -1H- pyrrolo- [3,4-c] pyridine 8f and is directly used in It reacts in next step.

6th step

At nitrogen protection and 0 DEG C, by di-tert-butyl dicarbonate solution, (13.06g, 60.45mmol are dissolved in 15mL dichloromethane Alkane) it is added drop-wise to 2- benzyl 8 hydrogen -1H- pyrrolo- [3,4-c] the pyridine 8f (8.70g, 40.3mmol) and diisopropyl that stirred dropwise In the 100mL dichloromethane solution of base ethylamine (11.4mL, 80.6mmol).Be added dropwise move back ice-water bath by reaction solution from It is so warmed to room temperature and continues stirring 2 hours until raw material disappears.Into reaction system plus water (100mL), methylene chloride extract (2 × 50mL), merge organic phase and then successively washed with water (50mL) and saturated salt solution (50mL), anhydrous sodium sulfate is dry, mistake Filter, is concentrated to get after crude product and obtains weak yellow liquid 2- benzyl hexahydro -1H- through silica gel post separation (2% ethanol/methylene) Pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8g.

MS-ESI calculated value [M+H]⁺317, measured value 317.

7th step

By 2- benzyl hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8g (1.5g, 4.7mmol) and The tetrahydrofuran solution of the 120mL of 300mg dry hydrogen palladium oxide (10%) is placed in the nitrogen atmosphere of 3MPa and is heated to 60 DEG C of reactions 24 hours.It is cooled to room temperature, filters out palladium dydroxide, filtrate concentration, through silica gel post separation (50%-100% ethanol/methylene) Obtain hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (0.5g, yield: 50%).

MS-ESI calculated value [M+H]⁺227, measured value 227.

8th step

Hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (90mg, 0.40mmol) and isoquinolin - 5- sulfonic acid chloride 1c (116mg, 0.510mmol) obtains 2- (isoquinolin -5- base sulphur according to the synthetic method of 1 compound 1e of embodiment Acyl group) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8i, it is directly used in next step.

9th step

2- (isoquinolin -5- base sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8i (36mg, 0.85mmol) obtains 5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine-according to the synthetic method of 1 compound 1 of embodiment 2 (3H)-yls) sulfonyl) isoquinolin 8 (17mg, faint yellow solid, yield: 63%).

¹H NMR(400MHz,CD₃OD):δ9.42(s,1H),8.69-8.59(m,2H),8.53-8.35(m,3H),7.87 (t, J=8.0Hz, 1H), 3.53-3.46 (m, 2H), 3.44-3.37 (m, 2H), 3.28-3.22 (m, 1H), 3.19-2.95 (m, 3H),2.62-2.44(m,2H),1.92-1.86(m,1H),1.74-1.63(m,1H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 9

The first step

1H- pyrrolo- [2,3-c] pyridine 9a (1.00g, 8.47mmol) is dissolved in 20mL methylene chloride, 0 DEG C of when is added 2mL triethylamine and di-tert-butyl dicarbonate solution (2.00g, 9.17mmol are dissolved in 10mL methylene chloride), reaction system rises to room Temperature stirring 16 hours.To after reaction, be concentrated under reduced pressure to give 1H- pyrrolo- [2,3-c] pyridine -1- carboxylic acid tert-butyl ester 9b, directly It connects for reacting in next step.

Second step

1H- pyrrolo- [2,3-c] pyridine -1- carboxylic acid tert-butyl ester 9b (1.2g, 5.5mmol) is dissolved in 15mL acetic acid, is added Enter platinum dioxide (0.3g, 1.3mmol), gained mixture is stirred at room temperature 12 hours under 4MPa Hydrogen Vapor Pressure.After reaction It is filtered to remove platinum dioxide, filtrate decompression concentration, crude product is obtained by chromatography silica gel column purification (0-100% ethanol/methylene) To octahydro -1H- pyrrolo- [2,3-c] pyridine -1- carboxylic acid tert-butyl ester 9c (600mg, yield: 50%).

MS-ESI calculated value [M+H]⁺227, measured value 227.

Third step

By octahydro -1H- pyrrolo- [2,3-c] pyridine -1- carboxylic acid tert-butyl ester 9c (100mg, 0.44mmol) and isoquinolin -5- Sulfonic acid chloride 1c (120mg, 0.51mmol) obtains 6- (isoquinolin -5- base sulphonyl according to the synthetic method of one compound 1e of embodiment Base) octahydro -1H- pyrrolo- [2,3-c] pyridine -1- carboxylic acid tert-butyl ester 9d crude product, it is not required to purifying and is directly used in next step.

MS-ESI calculated value [M+H]⁺418, measured value 418.

4th step

By 6- (isoquinolin -5- base sulfonyl) octahydro -1H- pyrrolo- [2,3-c] pyridine -1- carboxylic acid tert-butyl ester 9d (100mg, 0.24mmol) obtains 5- ((hexahydro -1H- pyrrolo- [2,3-c] pyrrole according to the synthetic method of 1 compound 1 of embodiment Pyridine -6 (2H)-yl) sulfonyl) isoquinolin 9 (60mg, yield: 79%).

¹H NMR(400MHz,CD₃OD): δ 9.63 (s, 1H), 8.90 (d, J=6.0Hz, 1H), 8.69 (d, J=6.0Hz, 1H), 8.65-8.55 (m, 2H), 8.01 (t, J=7.8Hz, 1H), 4.00-3.90 (m, 1H), 3.84-3.76 (m, 1H), 3.70- 3.65 (m, 1H), 3.51-3.36 (m, 2H), 3.15-2.98 (m, 1H), 2.65-2.60 (m, 1H), 2.31 (brs, 1H), 2.23- 2.05 (m, 1H), 1.96-1.75 (m, 2H), 1.65-1.55 (m, 1H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 10

5- (isoquinolin -5- sulfonyl) -5- azaspiro [2.4] hept- 7- amine

The first step

By 5- azaspiro [2.4] heptane -7- base amino carboxylic acid tert-butyl ester 10a (50mg, 0.25mmol) and isoquinolin -5- sulphur Acyl chlorides 1c (75mg, 0.32mmol) obtains (5- (isoquinolin -5- base sulfonyl)-according to the synthetic method of 1 compound 1e of embodiment 5- azaspiro [2.4] heptane -7- base) the amino carboxylic acid tert-butyl ester 10b (95mg, yellow oily liquid, yield: 95%).

MS-ESI calculated value [M+H]⁺404, measured value 404.

Second step

By (5- (isoquinolin -5- base sulfonyl) -5- azaspiro [2.4] heptane -7- base) amino carboxylic acid tert-butyl ester 10b (30mg, 0.074mmol) obtains 5- (isoquinolin -5- sulfonyl) -5- azaspiro according to the synthetic method of 1 compound 1 of embodiment [2.4] hept- 7- amine 10 (10mg, yellow solid, yield: 44%).

¹H NMR(400MHz,D₂O):δ9.40(s,1H),8.60-8.58(m,2H),8.55-8.45(m,2H),7.88(t, J=8.0Hz, 1H), 3.79-3.69 (m, 3H), 3.43-3.41 (m, 1H), 3.15-3.10 (m, 1H), 0.96-0.89 (m, 1H), 0.85-0.75(m,1H),0.68-0.61(m,1H),0.48-0.42(m,1H)。

MS-ESI calculated value [M+H]⁺304, measured value 304.

Embodiment 11

N- ethyl -5- (isoquinolin -5- sulfonyl) -5- azaspiro [2.4] hept- 7- amine

The first step

By (5- (isoquinolin -5- sulfonyl) -5- azaspiro [2.4] heptane -7- base) amino carboxylic acid tert-butyl ester 10b (65mg, 0.16mmol, embodiment 10) it is dissolved in the anhydrous n,N-Dimethylformamide of 4mL, sodium hydride is added under 0 DEG C of nitrogen protection (4.6mg, 0.19mmol), reaction solution are added iodoethane (30mg, 0.19mmol) after ten minutes in 0 DEG C of stirring, then rise to room Temperature simultaneously stirs 1 hour.It is extracted after 20mL saturated sodium-chloride water solution is added after reaction with ethyl acetate (30mL × 2), Anhydrous sodium sulfate dries, filters, and filtrate decompression concentration, crude product purified by silica gel column (0-100% ethyl acetate/petroleum ether) purifies To (5- (isoquinolin -5- sulfonyl) -5- azaspiro [2.4] heptane -7- base) the amino carboxylic acid tert-butyl ester 11a (15mg, yellow oily Liquid, yield: 22%).

MS-ESI calculated value [M+H]⁺432, measured value 432.

Second step

By (5- (isoquinolin -5- sulfonyl) -5- azaspiro [2.4] heptane -7- base) amino carboxylic acid tert-butyl ester 11a (15mg, 0.035mmol) N- ethyl -5- (isoquinolin -5- sulfonyl) -5- azaspiro is obtained according to the synthetic method of 1 compound 1 of embodiment [2.4] hept- 7- amine 11 (10mg, yellow solid, yield: 87%).

¹H NMR(400MHz,D₂O): δ 9.50 (s, 1H), 8.73 (d, J=6.4Hz, 1H), 8.58-8.48 (m, 3H), 7.92 (d, J=8.0Hz, 1H), 3.85-3.80 (m, 1H), 3.72-3.61 (m, 2H), 3.35-3.30 (m, 1H), 3.10-3.29 (m, 3H) 1.15 (t, J=7.2Hz, 3H), 1.03-0.94 (m, 1H), 0.85-0.75 (m, 1H), 0.62-0.51 (m, 1H), 0.41-0.32(m,1H)。

MS-ESI calculated value [M+H]⁺332, measured value 332.

Embodiment 12

7- (isoquinolin -5- base sulfonyl) octahydro pyrrolo- [3,4-b] azepines 12；2- (isoquinolin -5- base sulfonyl)

Octahydro pyrrolo- [3,4-c] azepines 12 '

The first step

Cyclonene 12a (5.00g, 52.1mmol) is dissolved in 50mL methylene chloride, N- methoxy-N- is added (trimethyl silane) benzyl amine 12b (7.74g, 34.7mmol) and 0.5mL trifluoroacetic acid, reaction solution is in room temperature under nitrogen protection Stirring 12 hours.To after reaction, reaction solution is quenched with saturated sodium bicarbonate aqueous solution (20mL), methylene chloride (20mL × 2) it extracts, saturated sodium bicarbonate aqueous solution (20mL) washing, merges organic phase anhydrous sodium sulfate drying, being concentrated under reduced pressure is to produce - 4 (2H) -one 12c of object 2- benzyl hexahydro -1H- iso-indoles directly carries out next step reaction without further purification.

MS-ESI calculated value [M+H]⁺230, measured value 230.

Second step

- 4 (2H) -one 12c (4.00g, 17.5mmol) of 2- benzyl hexahydro -1H- iso-indoles is dissolved in 50mL chloroform, 0 DEG C Under the conditions of sodium azide (2.28g, 35.0mmol) and methanesulfonic acid (1.68g, 17.5mmol) is added, reaction solution under nitrogen protection It is stirred at room temperature 12 hours.To after reaction, reaction system adds water (50mL) to dilute, and methylene chloride (30mL × 2) extraction is satisfied It is washed with sodium bicarbonate aqueous solution (30mL), merges organic phase anhydrous sodium sulfate drying, concentration is evaporated as product 7- benzyl Octahydro pyrrolo- [3,4-b] azepines -2 (1H) -one 12d1 and 2- benzyl octahydro pyrrolo- [3,4-c] azepines -4 (2H) -one The mixture of 12d2, product directly carry out next step reaction without further purification.

MS-ESI calculated value [M+H]⁺245, measured value 245.

Third step

By 7- benzyl octahydro pyrrolo- [3,4-b] azepines -2 (1H) -one 12d1 and 2- benzyl octahydro pyrrole under nitrogen protection The mixture (2.80g, 11.5mmol) for coughing up simultaneously [3,4-c] azepines -4 (2H) -one 12d2 is dissolved in 40mL tetrahydrofuran, and 0 DEG C Under the conditions of be added tetrahydrochysene lithium aluminium (872mg, 22.8mmol), reaction system stirs 2 hours under the conditions of 60 DEG C, to the end of reacting Afterwards, 1mL water is added under the conditions of 0 DEG C, then the sodium hydrate aqueous solution of 1mL15% and 3mL water.It is stirred at room temperature 30 minutes, reacts Liquid filtering, filtrate are extracted with ethyl acetate (20mL × 2), and saturated sodium-chloride water solution (30mL) washing merges organic phase nothing Aqueous sodium persulfate is dry, and concentration is evaporated as product 7- benzyl decahydro pyrrolo- [3,4-b] azepines 12e1 and 2- benzyl decahydro pyrrole The mixture of simultaneously [3,4-c] azepines 12e2 is coughed up, product directly carries out next step reaction without further purification.

4th step

By 7- benzyl decahydro pyrrolo- [3,4-b] azepines 12e1 and 2- benzyl decahydro pyrrolo- [3,4-c] azepines The mixture (2.62g, 11.4mmol) of 12e2 is dissolved in 40mL tetrahydrofuran, and di-tert-butyl dicarbonate is added under room temperature (3.73g, 17.1mmol) and triethylamine (1.73g, 17.1mmol) is stirred at room temperature 2 hours under nitrogen protection.To the end of reacting Afterwards, reaction system adds water (50mL) to dilute, ethyl acetate (30mL × 2) extraction, saturated sodium bicarbonate aqueous solution (30mL) washing, Organic phase is dry with anhydrous sodium sulfate, and concentration is evaporated as product 7- benzyl octahydro pyrrolo- [3,4-b] azepines -1 (2H)-carboxylic The mixture of tert-butyl acrylate 12f1 and 2- benzyl octahydro pyrrolo- [3,4-c] azepines -5 (1H)-carboxylic acid tert-butyl ester 12f2, directly For reacting in next step.

MS-ESI calculated value [M+H]⁺331, measured value 331.

5th step

By 7- benzyl octahydro pyrrolo- [3,4-b] azepines -1 (2H)-carboxylic acid tert-butyl ester 12f1 and 2- benzyl octahydro pyrroles And [3,4-c] azepines -5 (1H)-carboxylic acid tert-butyl ester 12f2 (1.90g, 5.74mmol) is dissolved in 50mL methanol, and 100mg is added Wet palladium carbon, reaction solution stirs 2 hours under the conditions of 50 DEG C under the conditions of hydrogen (1atm).To which after reaction, reaction solution is direct Filtering, filtrate decompression are concentrated to give octahydro pyrrolo- [3,4-b] azepines -1 (2H)-carboxylic acid tert-butyl ester 12g1 and octahydro pyrrolo- [3,4-c] azepines -5 (1H)-carboxylic acid tert-butyl ester 12g2 mixture directly carries out next step reaction without further purification.

MS-ESI calculated value [M+H]⁺241, measured value 241.

6th step

Octahydro pyrrolo- [3,4-b] azepines -1 (2H)-carboxylic acid tert-butyl ester 12g1 and octahydro pyrrolo- [3,4-c] a word used for translation heptan Because -5 (1H)-carboxylic acid tert-butyl ester 12g2 mixture (800mg, 3.33mmol) and isoquinolin -5- sulfonic acid chloride 1c (910mg, 4.00mmol) according to the synthetic method of one compound 1e of embodiment obtain 7- (isoquinolin -5- base sulfonyl) octahydro pyrrolo- [3, 4-b] azepines -1 (2H)-carboxylic acid tert-butyl ester 12h1 and 2- (isoquinolin -5- base sulfonyl) octahydro pyrrolo- [3,4-c] a word used for translation heptan Because of the mixture of -5 (1H)-carboxylic acid tert-butyl ester 12h2, product directly carries out next step reaction without further purification.

MS-ESI calculated value [M+H]⁺432, measured value 432.

7th step

7- (isoquinolin -5- base sulfonyl) octahydro pyrrolo- [3,4-b] azepines -1 (2H)-carboxylic acid tert-butyl ester 12h1 and Tert-butyl2- (isoquinolin -5- base sulfonyl) octahydro pyrrolo- [3,4-c] azepines -5 (1H)-carboxylic acid tert-butyl ester 12h2's Mixture (1.43g, 3.30mmol) obtains 7- (isoquinolin -5- base sulfonyl) according to the synthetic method of one compound 1 of embodiment And 2- (isoquinolin -5- base sulfonyl) decahydro pyrrolo- octahydro pyrrolo- [3,4-b] azepines 12 (284mg, yield: 26%) [3,4-c] azepines 12 ' (32mg).

12:¹H NMR(400MHz,CDCl₃):δ9.28(s,1H),8.62(m,1H),8.52(m,1H),8.33(m,1H), 8.17 (d, J=8.0Hz, 1H), 7.66 (t, J=8.0Hz, 1H), 3.79-3.74 (m, 1H), 3.59-3.55 (m, 1H), 3.49- 3.44(m,1H),3.10-3.07(m,1H),2.86-2.77(m,3H),2.43-2.36(m,2H),1.70-1.63(m,3H), 1.37-1.32(m,3H).

12’:¹H NMR(400MHz,CDCl₃):δ9.35(s,1H),8.66(m,1H),8.53(m,1H),8.35(m,1H), 8.18 (d, J=8.0Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 3.72-3.70 (m, 1H), 3.64-3.62 (m, 1H), 3.07- 3.00(m,1H),2.98-2.93(m,3H),2.84(m,1H),1.99(m,1H),1.85-1.83(m,2H),1.70-1.67(m, 3H),1.66-1.51(m,1H),1.16-1.14(m,1H).

Embodiment 13

4- (isoquinolin -5- base sulfonyl) -4- azaspiro [2.4] hept- 7- amine

The first step

Diisopropylamine (41.6g, 0.41mol) is added in 1.5L tetrahydrofuran under nitrogen protection, is cooled to -78 DEG C. Dropwise addition n-BuLi (150mL, 0.375mol) under the conditions of nitrogen protection slowly is added dropwise continuation and reacts at this temperature One hour, acrylonitrile (22.78g, 0.34mol) then is added dropwise.It adds and continues to stir at the identical temperature of reaction system after acrylonitrile One hour, 2- bromoacetate 13a (56.8g, 0.34mol) then is added dropwise.Rear reaction system is added dropwise to continue instead at -78 DEG C Then up to fully reacting saturated aqueous ammonium chloride (2.0L) quenching reaction is added, with acetic acid second in Ying Yi little into reaction solution Ester (500mL × 3) extraction merges organic phase and is washed with water (500mL) and saturated salt solution (500mL), and anhydrous sodium sulfate is dry, Filtering, filtrate decompression concentration, residue chromatography silica gel column (0-100% ethyl acetate/petroleum ether) purifying obtain ethyl 3- cyanogen Base amyl- obtusilic acid methyl esters 13b (13.5g, colorless oil, yield: 34%).¹H NMR(400MHz,CDCl₃):δ5.83-5.71 (m,1H),5.51(m,1H),5.34(m,1H),4.20(m,2H),3.79-3.71(m,1H),2.81-2.73(m,1H),2.69- 2.61(m,1H),1.28(m,3H).

Second step

The amyl- obtusilic acid methyl esters 13b (6g, 39.2mmol) of ethyl 3- cyano is dissolved in 1L anhydrous ether, is protected in nitrogen Tetraisopropyl titanate (11.76mL, 39.2mmol) is added under the conditions of shield, then in ethylmagnesium bromide is slowly added dropwise under room temperature (21.6mL, 64.8mmol, 3M tetrahydrofuran solution).Reaction system is stirred three hours and is disappeared to raw material at room temperature, is then added dropwise 36mL water quenching reaction, obtained suspension filtering, filtrate decompression concentration, residue chromatography silica gel column (0-100% acetic acid second Ester/petroleum ether) purifying obtain 7- vinyl -4- azaspiro [2.4] heptane -5- ketone 13c (3.3g, white solid, yield: 63%).

¹H NMR(400MHz,CDCl₃):δ6.09(brs,1H),5.68-5.60(m,1H),5.08-5.00(m,2H), 3.0-2.96(m,1H),2.70-2.64(m,1H),2.40-2.36(m,1H),0.83-0.75(m,2H),0.65-0.58(m, 2H).

MS-ESI calculated value [M+H]⁺138, measured value 138.

Third step

7- vinyl -4- azaspiro [2.4] heptane -5- ketone 13c (1.2g, 8.75mol) is dissolved in 29mL anhydrous acetonitrile In sequentially add 4-N, N- lutidines (110mg, 0.875mmol), di-tert-butyl dicarbonate acetonitrile solution (2.86g, 13.1mmol, 10mL acetonitrile), it is stirred at room temperature 5 hours.Reaction solution is poured into water (25mL) after reaction and is quenched, acetic acid is used Ethyl ester (30mL × 3) extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, residue chromatography silicon Rubber column gel column (0-100% ethyl acetate/petroleum ether) purifying obtains 5- oxo -7- vinyl -4- azaspiro [2.4] heptane -4- carboxylic acid Tert-butyl ester 13d (1.2g, brown solid, yield: 55%).

¹H NMR(400MHz,CDCl₃):δ5.66-5.57(m,1H),5.13-5.06(m,2H),2.77-2.72(m,2H), 2.48-2.43(m,1H),1.62-1.60(m,1H),1.51(s,9H),1.43-1.41(m,1H),0.67-0.65(m,1H), 0.54-0.51(m,1H).

MS-ESI calculated value [M+H]⁺238, measured value 238.

4th step

5- oxo -7- vinyl -4- azaspiro [2.4] heptane -4- carboxylic acid tert-butyl ester 13d (3.4g, 14.3mmol) is molten Solution is in the mixed solution of 34mL methanol and 51mL water, in addition sodium metaperiodate (9.2g, 43mmol) and four oxygen under room temperature Change osmium (55mg, 0.22mmol), is stirred at room temperature 4 hours.After fully reacting, water (40mL) is added to dilute, ethyl acetate (40mL × 3) Extraction merges organic phase, and anhydrous sodium sulfate dries, filters, filtrate concentration, residue chromatography silica gel column purification (0-100% second Acetoacetic ester/petroleum ether) obtain 7- formoxyl -5- oxo -4- azaspiro [2.4] heptane -4- carboxylic acid tert-butyl ester 13e (2.6g, brown Grease, yield: 76%).

MS-ESI calculated value [M+H]⁺240, measured value 240.

5th step

7- formoxyl -5- oxo -4- azaspiro [2.4] heptane -4- carboxylic acid tert-butyl ester 13e (2.60g, 10.9mmol) is molten Solution sequentially adds 2- butylene (22.7mL) in the mixed solution of the 87mL tert-butyl alcohol and 87mL tetrahydrofuran under the conditions of 0 DEG C, sub- The 63mL aqueous solution of sodium chlorate (979mg, 10.9mmol) and two hypophosphite monohydrate sodium dihydrogens (3.39g, 21.8mmol).React liquid chamber Temperature stirring 16 hours, fully reacting, it is 4 that dilute hydrochloric acid, which adjusts pH value to pH, and then ethyl acetate (50mL × 3) extracts, and merges Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate decompression is concentrated to get 4- (tert-butoxycarbonyl) -5- oxo -4- azaspiro [2.4] heptane -7- carboxylic acid 13f (2g, faint yellow solid, yield: 75%).

¹H NMR(400MHz,DMSO):δ12.76(brs,1H),2.83-2.72(m,2H),2.56-2.55(m,1H), 1.69-1.66(m,1H),1.41(s,9H),1.35-1.33(m,1H),0.79-0.73(m,2H).

MS-ESI calculated value [M+H]⁺256, measured value 256.

6th step

By 4- (tert-butoxycarbonyl) -5- oxo -4- azaspiro [2.4] heptane -7- carboxylic acid 13f (2.31g, 9.02mmol) It is dissolved in 30mL toluene, N, N- diisopropyl ethyl amine (1.51g, 11.7mmol) and nitrine phosphoric acid hexichol is added at 0 DEG C Ester (3.23g, 11.7mmol).90 DEG C of reaction half an hour are heated to, be cooled to room temperature and benzylalcohol (1.07g, 9.92mmol) is added. Be stirred at room temperature 16 hours, fully reacting fall back in (40mL) and with ethyl acetate (40mL × 3) extract.Organic phase is with anhydrous Sodium sulphate dries, filters, and filtrate decompression concentration, residue is obtained with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) (1.8g, white are solid by 7- (((benzyloxy) carbonyl) amino) -5- oxo -4- azaspiro [2.4] heptane -4- carboxylic acid tert-butyl ester 13g Body, yield: 56%).

MS-ESI calculated value [M+H]⁺361, measured value 361.

7th step

By 7- (((benzyloxy) carbonyl) amino) -5- oxo -4- azaspiro [2.4] heptane -4- carboxylic acid uncle under nitrogen protection Butyl ester 13g (200mg, 0.56mmol) is dissolved in the tetrahydrofuran of 3mL, and the dimethyl sulphide solution of borine is added dropwise in 0 DEG C (3.9mL, 11.7mmol, 3M dimethyl sulphide solution), reaction solution are heated to 60 DEG C and react one hour.After fully reacting, ice is poured into Quenching reaction in water (20mL) is extracted with ethyl acetate (20mL × 3), and organic phase is dry with anhydrous sodium sulfate.Filtering, filtrate subtract Pressure concentration, residue obtain 7- (((benzyloxy) carbonyl) amino) -4- with chromatography (0-100% ethyl acetate/petroleum ether) Azaspiro [2.4] heptane -4- carboxylic acid tert-butyl ester 13h (30mg, colourless oil liquid, yield: 16%).

MS-ESI calculated value [M+H]⁺347, measured value 347.

8th step

By 7- (((benzyloxy) carbonyl) amino) -4- azaspiro [2.4] heptane -4- carboxylic acid tert-butyl ester 13h (100mg, 0.39mmol) 4- azaspiro [2.4] heptane -7- base amino carboxylic acid benzyl ester is obtained according to the synthetic method of five compound 5f of embodiment 13i (101mg, white solid, yield: 100%).

MS-ESI calculated value [M+H]⁺247, measured value 247.

9th step

By 4- azaspiro [2.4] heptane -7- base amino carboxylic acid benzyl ester 13i (70mg, 0.27mmol) and isoquinolin -5- sulphonyl Chlorine 1c (80mg, 0.35mmol) obtains 4- (isoquinolin -5- base sulfonyl) -4- according to the synthetic method of one compound 1e of embodiment Azaspiro [2.4] heptane -7- base amino carboxylic acid benzyl ester 13j (80mg, colourless oil liquid, yield: 68%).

MS-ESI calculated value [M+H]⁺438, measured value 438.

Tenth step

By 4- (isoquinolin -5- base sulfonyl) -4- azaspiro [2.4] heptane -7- base amino carboxylic acid benzyl ester 13j (40mg, 0.098mmol) 4- (isoquinolin -5- base sulfonyl) -4- azaspiro is obtained according to the synthetic method of five compound 5 of embodiment [2.4] hept- 7- amine 13 (11mg, yellow solid, yield: 50%).

¹H NMR(400MHz,CD₃OD): δ 9.42 (s, 1H), 8.65 (d, J=6.4Hz, 1H), 8.54 (d, J=8.0Hz, 1H), 8.47 (d, J=8.0Hz, 1H), 8.38 (d, J=6.4Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 4.16-4.12 (m, 1H),3.67-3.64(m,1H),3.41-3.38(m,1H),2.53-2.51(m,1H),2.09-2.07(m,1H),1.24-1.21 (m,1H),1.15-1.13(m,1H),0.80-0.73(m,2H).

MS-ESI calculated value [M+H]⁺304, measured value 304.

Embodiment 14

1- (isoquinolin -5- sulfonyl) decahydro pyrrolo- [3,2-b] azepines

The first step

By 1, hydroresorcinol 14a (5g, 44.6mmol) is dissolved in 10mL tetrahydrofuran, and ethanol amine is added at room temperature (3.27g,53.5mmol).Gained suspension is poured into the round-bottomed flask equipped with water segregator and 90mL toluene, was heated to reflux Night, reaction system are cooled to room temperature, and are then concentrated under reduced pressure, and residue is pure with chromatography silica gel column (15% ethyl acetate/petroleum ether) Change obtains 3- (2- hydroxy-ethyl amino)-hexamethylene -2- ketenes 14b (4.30g, yellow solid, yield: 62%).

¹H NMR(400MHz,DMSO-d6):δ4.80(s,1H),3.47-3.57(m,2H),3.14-3.22(m,2H), 3.05-2.95(m,1H),2.27-2.35(m,2H),2.09-2.03(m,1H),1.68-1.82(m,2H).

Second step

3- (2- hydroxy-ethyl amino)-hexamethylene -2- ketenes 14b (3.70g, 23.9mmol) is dissolved in 120mL N, N diformazan Base formamide, is added four triphenyl phosphorus palladiums (552mg, 0.48mmol) in nitrogen protection and at room temperature, trimethyl bromobenzene (4.76g, 23.9mmol), potassium carbonate (6.60g, 47.8mmol), gained reaction solution are heated to 150 DEG C of 2 hours of reflux, are cooled to room temperature After be concentrated under reduced pressure, residue with ethyl acetate (100mL) dilute, saturated sodium-chloride water solution (100mL) washing, anhydrous sodium sulfate It drying, filtering, is concentrated, residue chromatography silica gel column obtains 1 with eluant, eluent system (15% ethyl acetate/petroleum ether) purifying, 5,6,7- Tetrahvdro-indole -4- ketone 14c (2.66g, white solid, yields: 82%).

MS-ESI calculated value [M+H]⁺136, measured value 136.

Third step

1,5,6,7- Tetrahvdro-indole -4- ketone 14c (4.66g, 34.5mmol) is dissolved in 120mL acetonitrile, at room temperature plus Enter N, N- diisopropyl ethyl amine (9.3mL, 51.7mmol), di-tert-butyl dicarbonate (8.27g, 37.9mmol) and N, N- diformazan Yl pyridines (82mg, 0.69mmol).Reaction solution is stirred at room temperature overnight.Reaction solution is concentrated after completion of the reaction, residue is used Chromatography silica gel column obtains 4- oxo -4,5,6,7- Tetrahvdro-indole-with eluant, eluent system (10% ethyl acetate/petroleum ether) purifying 1- carboxylic acid tert-butyl ester 14d (7g, white solid, yield: 86%)

4th step

4- oxo -4,5,6,7- Tetrahvdro-indole -1- carboxylic acid tert-butyl ester 14d (500mg, 2.13mmol) is dissolved in 20mL first In alcohol, catalytic amount glacial acetic acid and 50mg platinum dioxide is added in room temperature.Reaction system vacuumizes lower replacing hydrogen, in 1MPa hydrogen pressure 3 hours are stirred at power and 50 DEG C.It is cooled to room temperature and then filters after completion of the reaction, filtrate concentration, residue chromatography silica gel Column obtains 4- hydroxyl octahydro -1H- indoles -1- carboxylic acid tert-butyl ester 14e with eluant, eluent (50% ethyl acetate/petroleum ether) purifying (400mg, colourless oil liquid, yield: 78%).

5th step

4- hydroxyl octahydro -1H- indoles -1- carboxylic acid tert-butyl ester 14e (700mg, 2.9mmol) is dissolved in 35mL methylene chloride, Dai Si-Martin's oxidant (2.46g, 5.80mmol) is added at 0 DEG C.Reaction solution stirs 30 minutes at room temperature.Reaction terminates Saturated sodium bicarbonate aqueous solution (50mL) quenching reaction, methylene chloride (30mL × 3) extraction are used afterwards.Merge organic phase, with saturation Sodium-chloride water solution (50mL) washing, anhydrous sodium sulfate are dried, filtered, are concentrated, and residue is with chromatography silica gel column with eluant, eluent (25% ethyl acetate/petroleum ether) purifying obtains 4- oxo octahydro -1H- indoles -1- carboxylic acid tert-butyl ester 14f (470mg, colorless oil Shape liquid, yield: 68%).MS-ESI calculated value [M+H-C₄H₈]⁺184, measured value 184.

6th step

4- oxo octahydro -1H- indoles -1- carboxylic acid tert-butyl ester 14f (470mg, 1.97mmol) is dissolved in 15mL chloroform, 0 DEG C Lower addition sodium azide (250mg, 3.85mmol) and methanesulfonic acid (1.51g, 15.8mmol), reaction solution is stirred at 70 DEG C Night.Reaction solution is poured into saturated sodium bicarbonate (20mL) aqueous solution after reaction, water phase is washed with ethyl acetate (40mL), so After be concentrated under vacuum to obtain octahydro pyrrolo- [3,2-b] (1H) -one of azepines -5 14g without further purification, directly carry out in next step Reaction.

7th step

Octahydro pyrrolo- [3,2-b] (1H) the -one 14g of azepines -5 (303mg, 1.97mmol) is dissolved in 15mL water, 0 Benzyl chloroformate (1.69g, 9.85mmol) and potassium carbonate (150mg, 1.08mmol) are added at DEG C, is then warmed to room temperature and stirs 4 hours.Reaction solution is extracted with ethyl acetate (20mL × 3) after reaction, and saturated sodium-chloride water solution (20mL) washing is used Anhydrous sodium sulfate dries, filters, and concentration purifies (1/2 ethyl acetate/petroleum ether) residue with thin layer chromatography board and obtains 5- oxo Octahydro pyrrolo- [3,2-b] azepines -1 (2H)-benzyl carboxylate 14h (130mg, colorless oil, yield: 23%).

¹H NMR(400MHz,CDCl₃):δ7.40-7.30(m,5H),5.80(s,1H),5.20-5.06(m,2H),4.08- 4.00(m,1H),3.70-3.55(m,1H),3.47-3.30(m,3H),3.22-3.11(m,1H),2.51-1.37(m,6H)

8th step

5- oxo octahydro pyrrolo- [3,2-b] azepines -1 (2H)-benzyl carboxylate 14h (180mg, 0.63mmol) is dissolved in Borine (0.63mL, 1.86mmol, 3M dimethyl sulphide solution) is slowly added dropwise in 5mL tetrahydrofuran at -78 DEG C.After being added dropwise Reaction solution is warming up to 50 DEG C and is stirred 4 hours, until reaction terminates.3mL methanol quenching reaction is used after cooling, it will be resulting Mixture is concentrated to get octahydro pyrrolo- [3,2-b] azepines -1 (2H)-benzyl carboxylate 14i, directly carries out without further purification Step reaction.

9th step

Octahydro pyrrolo- [3,2-b] azepines -1 (2H)-benzyl carboxylate 14i (171mg, 0.625mmol) is dissolved in 3mL bis- In chloromethanes, N, N diisopropylethylamine (161mg, 1.25mmol), 4-N, N- lutidines are sequentially added at room temperature (8mg, 0.025mmol) and di-tert-butyl dicarbonate (273mg, 1.25mmol), gained reaction solution are stirred overnight.To the end of reacting Middle quenching reaction of falling back merges organic phase saturated sodium-chloride water solution then with methylene chloride (10mL × 3) extraction (20mL) washing, dried, filtered, be concentrated with anhydrous sodium sulfate, with thin layer chromatography board purify (1/1 ethyl acetate/petroleum ether) it is residual Excess obtains hexahydropyrrolo simultaneously [3,2-b] azepines -1,4 (2H, 5H)-dicarboxylic acids 1- benzyl ester 4- tertiary butyl ester 14j (180mg, nothing Color oily liquids, yield: 77%).

MS-ESI calculated value [M+H-C₄H₈]⁺319, measured value 319.

Tenth step

By hexahydropyrrolo simultaneously [3,2-b] azepines -1,4 (2H, 5H)-dicarboxylic acids 1- benzyl ester 4- tertiary butyl ester 14j (180mg, It 0.48mmol) is dissolved in 20mL tetrahydrofuran, under room temperature and nitrogen protection, 18mg is added and does palladium carbon, reaction solution exists at room temperature 2 hours are stirred in 1atm nitrogen atmosphere.To after reaction filter reaction solution, filtrate concentration obtains octahydro pyrrolo- [3,2- B] azepines -4 (2H)-carboxylic acid tert-butyl ester 14k (30mg, colourless oil liquid, yield: 26%).

11st step

By octahydro pyrrolo- [3,2-b] azepines -4 (2H)-carboxylic acid tert-butyl ester 14k (30mg, 0.12mmol) isoquinolin -5- Sulfonic acid chloride 1c (32mg, 0.14mmol) obtains 1- (isoquinolin -5- base sulphonyl according to the synthetic method of one compound 1e of embodiment Base) octahydro pyrrolo- [3,2-b] azepines -4 (2H)-carboxylic acid tert-butyl ester 14l (30mg, colourless oil liquid, yield: 56%).

MS-ESI calculated value [M+H]⁺432, measured value 432.

12nd step

1- (isoquinolin -5- base sulfonyl) octahydro pyrrolo- [3,2-b] azepines -4 (2H)-carboxylic acid tert-butyl ester 14l (30mg, 0.07mmol) obtains 1- (isoquinolin -5- sulfonyl) decahydro pyrrolo- according to the synthetic method of one compound 1 of embodiment [3,2-b] azepines 14 (15mg, white solid, yield: 65%).

¹H NMR(400MHz,D₂O):δ9.81-9.73(m,1H),9.11-9.04(m,1H),8.84-8.76(m,1H), 8.74-8.70(m,1H),8.69-8.65(m,1H),8.15-8.07(m,1H),4.05-3.95(m,1H),3.57-3.53(m, 1H),3.50-3.40(m,1H),3.45-3.38(m,1H),3.34-3.23(m,1H),3.35-3.25(m,1H),2.95-2.90 (m,1H),2.70-2.57(m,1H),2.17-2.07(m,1H),2.03-1.90(m,3H),1.78-1.65(m,2H).

MS-ESI calc'd.[M+H]⁺332,found332。

Embodiment 15

5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-yl) sulfonyl) isoquinolin

The first step

By 5- oxo octahydro pentamethylene, simultaneously [c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 15a (2g, 8.89mmol) is dissolved in 10mL In chloroform, then sequentially added into reaction solution sodium azide (1.2g, 18.4mmol) and methane sulfonic acid (8.5g, 88.9mmol).Gained mixture is stirred 2 hours at 70 DEG C.It is cooled to room temperature after fully reacting, saturated sodium bicarbonate solution It is adjusted to pH=7, then methylene chloride (20mL × 2) extracts, and merges organic phase anhydrous sodium sulfate drying, and concentration obtains Huang Color oily liquids hexahydro -1H- pyrrolo- [3,4-c] (2H) -one of pyridine -6 15b.The yellow oil is directly used in anti-in next step It answers.

Second step

Hexahydro -1H- pyrrolo- [3,4-c] (2H) the -one 15b of pyridine -6 (1.22g, 8.72mmol) is added to 40mL10% Sodium hydrate aqueous solution and tetrahydrofuran mixed solution in (v/v=1/1), di-tert-butyl dicarbonate is then added (3.87g, 17.8mmol).After adding, mixture is stirred at room temperature 3 hours until reaction terminates.By reaction mixture second Acetoacetic ester (30mL × 3) extraction merges organic phase anhydrous sodium sulfate drying, is concentrated under reduced pressure, crude product is pure with chromatography silica gel column Change (0-10% methanol/ethyl acetate) and obtains 6- oxo hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-carboxylic acid tert-butyl ester 15c (0.9g, yellow oily liquid, yield: 43%).

Third step

By 6- oxo hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-carboxylic acid tert-butyl ester 15c (600mg, 2.5mmol) It is dissolved in 20mL tetrahydrofuran solution, it is then molten in the 10mL tetrahydrofuran of -10 DEG C of addition Lithium Aluminium Hydrides (190mg, 50mmol) Mixture is stirred at room temperature 3 hours after adding for liquid.It is slowly added to 0.19mL water quenching reaction, is then successively added dropwise The sodium hydrate aqueous solution of 0.19mL15% and the water of 0.51mL.Stirring filtered mixture after 30 minutes, filtrate decompression concentration, Yellow oily liquid hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-carboxylic acid tert-butyl ester 15d is obtained to be directly used in next step instead It answers.

4th step

By hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-carboxylic acid tert-butyl ester 15d (200mg, 0.88mmol, previous step Crude product) and isoquinolin -5- sulfonic acid chloride 1c (280mg, 1.25mmol) obtained according to the synthetic method of one compound 1e of embodiment 5- (isoquinolin -5- base sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-carboxylic acid tert-butyl ester 15e (80mg, it is colourless Oily liquids, yield: 22%).

MS-ESI calculated value [M+H-56]⁺362, measured value 362.

5th step

By 5- (isoquinolin -5- base sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-carboxylic acid tert-butyl ester 15e (80mg, 0.19mmol) obtains 5- ((hexahydro -1H- pyrrolo- [3,4-c] pyrrole according to the synthetic method of one compound 1 of embodiment Pyridine -5 (6H)-yl) sulfonyl) isoquinolin 15 (51mg, yellow oil, yield: 85%).¹H NMR(400MHz,CD₃OD):δ 9.39 (s, 1H), 8.62 (d, J=8.0Hz, 1H), 8.55 (d, J=8.0Hz, 1H), 8.52-8.39 (m, 3H), 7.85 (t, J= 8.0Hz,1H),3.70-3.58(m,2H),3.41-3.34(m,1H),3.21-3.04(m,4H),2.80-2.75(m,1H), 2.57-2.48(m,1H),2.42-2.32(m,1H),1.85-1.77(m,1H),1.61-1.51(m,1H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 16

The chloro- 5- of 4- (hexahydro-pyrrolo- [3,2-b] pyrroles -1- sulfonyl)-isoquinolin

The first step

The concentrated sulfuric acid (69.0mL) solution of potassium nitrate (7.98g, 79mmol) is added drop-wise to 4- chlorine isoquinolin 16a at -5 DEG C In the 55mL concentrated sulfuric acid solution of (10.0g, 61mmol).Mixture is warmed to room temperature after stirring 1 hour at 0 DEG C and is stirred overnight.To Reaction solution is slowly added into 300mL ice water after reaction, adjusts pH to 8 with solid sodium carbonate, and use ethyl acetate (200mL × 2) extraction, merges organic phase, and anhydrous sodium sulfate dries, filters, and is concentrated filtrate, and with chromatography silica gel column purification (0- 100% ethyl acetate/petroleum ether) obtain 4- chloro- 5- nitroisoquinoline 16b (11.2g, white solid, yield: 88%).

MS-ESI calculated value [M+H]⁺209, measured value 209.

Second step

Stannous chloride hydrate (13g, 57.7mmol) is added to the chloro- 5- nitroisoquinoline 16b of 4- at 0 DEG C In the 34mL concentrated hydrochloric acid solution of (2.00g, 9.62mmol), it is heated to 100 DEG C and is stirred overnight.It is cooled to room temperature and then uses solid carbon Sour hydrogen sodium adjusts the pH to 8 of reaction solution, is extracted with ethyl acetate (100mL × 2), merges organic phase, dry with anhydrous sodium sulfate, Filtering is concentrated filtrate, and obtains 4- chlorine isoquinolin -5- amine with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) 16c (1.57g, yellow solid, yield: 92%).MS-ESI calculated value [M+H]⁺179, measured value 179.

Third step

The 2mL aqueous solution of sodium nitrite (620mg, 8.82mmol) is added to 4- chlorine isoquinolin -5- amine at -5 DEG C In the 14mL concentrated hydrochloric acid solution of (1.57g, 8.82mmol), gained reaction solution continues stirring 1 hour at -5 DEG C.Then this is anti- Answering liquid to pour into rapidly has added the 30mL of stannous chloride aqueous solution (224mg, 2.20mmol, 2mL water) to be saturated sulfur dioxide vinegar In acid solution, it is stirred at room temperature to bubble-free and generates.Water (100mL) dilution on the rocks after reaction, it is molten with saturated sodium bicarbonate water The pH of reaction solution is adjusted to 8 by liquid, is then extracted with methylene chloride (100mL × 2), and organic phase is merged, dry with anhydrous sodium sulfate, Filtering is concentrated filtrate, obtains 4- chlorine isoquinolin -5- sulfonic acid chloride 16d (1.07g, yellow solid, yield: 46%).

MS-ESI calculated value [M+H]⁺262, measured value 262.

4th step

Simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 1d (30mg, 0.142mmol) and 4- chlorine are different for cis--hexahydropyrrolo Quinoline -5- sulfonic acid chloride 16d (55.6mg, 0.212mmol) according to the synthetic method of one compound 1e of embodiment obtains 4-, and (4- chlorine is different Quinoline -5- sulfonyl)-hexahydro-pyrrolo- [3,2-b] pyrroles's -1- carboxylic acid tert-butyl ester 16e (30mg, yellow oily liquid, yield: 48%).

MS-ESI calculated value [M+H]⁺438, measured value 438.

5th step

By 4- (4- chlorine isoquinolin -5- sulfonyl)-hexahydro-pyrrolo- [3,2-b] pyrroles's -1- carboxylic acid tert-butyl ester 16e (30mg, 0.092mmol) obtains the chloro- 5- of 4- (hexahydro-pyrrolo- [3,2-b] pyrrole according to the synthetic method of one compound 1 of embodiment Cough up -1- sulfonyl)-isoquinolin 16 (20mg, white solid, yield: 96%).

¹H NMR(400MHz,D₂O): δ 9.21 (s, 1H), 8.63 (s, 1H), 8.40-8.30 (m, 2H), 7.80 (t, J= 8.0Hz,1H),4.77(s,1H),4.53-4.50(m,1H),3.71-3.66(m,1H),3.35-3.31(m,2H),3.47- 3.44(m,1H),2.54-2.44(m,1H),2.28-2.23(m,1H),2.16-2.11(m,2H).

MS-ESI calculated value [M+H]⁺338, measured value 338.

Embodiment 17

The chloro- 5- of 4- (hexahydro-pyrrolo- [3,4-b] pyrroles -5- sulfonyl)-isoquinolin

The first step

By hexahydro-pyrrolo- [3,4-b] pyrroles -1- carboxylate 2f (30mg, 0.142mmol, embodiment 2) and 4- Chlorine isoquinolin -5- sulfonic acid chloride 16d (56mg, 0.212mmol) obtains 5- (4- chlorine according to the synthetic method of one compound 1e of embodiment Isoquinolin -5- sulfonyl)-hexahydro-pyrrolo- [3,4-b] pyrroles -1- carboxylate 17e (40mg, yellow oily liquid, Yield: 65%).

MS-ESI calculated value [M+H]⁺438, measured value 438.

Second step

5- (4- chlorine isoquinolin -5- sulfonyl)-hexahydro-pyrrolo- [3,4-b] pyrroles -1- carboxylate 17e (45mg, 0.092mmol) obtains the chloro- 5- of 4- (hexahydro-pyrrolo- [3,4-b] pyrrole according to the synthetic method of one compound 1 of embodiment Cough up -5- sulfonyl)-isoquinolin 17 (30mg, white solid, yield: 96%).

¹H NMR(400MHz,D₂O): δ 9.25 (s, 1H), 8.64 (s, 1H), 8.45-8.35 (m, 2H), 7.81 (t, J= 8.0Hz,1H),4.43-4.39(m,1H),3.80-3.75(m,2H),3.65-3.60(m,1H),3.47-3.44(m,1H), 3.37-3.23(m,3H),2.27-2.17(m,1H),1.96-1.89(m,1H).

MS-ESI calculated value [M+H]⁺338, measured value 338.

Embodiment 18

The chloro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-yl) sulfonyl) isoquinolin

The first step

By octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3a (30mg, 0.13mmol, embodiment 3) and 4- Chlorine isoquinolin -5- sulfonic acid chloride 16d according to compound 1e synthetic method 6- (4- chlorine isoquinolin -5- sulfonyl) octahydro -1H- pyrroles And [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 18a (56mg, yellow oil, yield: 93%).

MS-ESI calculated value [M+H]⁺452, measured value 452.

Second step

6- (4- chlorine isoquinolin -5- sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 18a (15mg, 0.035mmol) obtains the chloro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4- according to the synthetic method of one compound 1 of embodiment B] pyridine -6 (2H)-yl) sulfonyl) isoquinolin 18 (10mg, yellow solid, yield: 87%).¹H NMR(400MHz,D₂O):δ 9.25 (s, 1H), 8.63-8.61 (s, 1H), 8.39-8.36 (m, 1H), 8.26-8.24 (m, 1H), 7.80 (t, J=8.0Hz, 1H), 3.98-3.97 (m, 1H), 3.85-3.76 (m, 2H), 3.51 (t, J=10.0Hz, 2H), 3.33-3.31 (m, 1H), 3.04-2.99(m,2H),1.87-1.74(m,4H).

MS-ESI calculated value [M+H]⁺352, measured value 352.

Embodiment 19

5- (3,6- diazabicyclo [3.2.0] heptane -3- base sulfonyl) -4- chlorine isoquinolin

The first step

3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 4a (30mg, 0.15mmol) and 4- chlorine isoquinolin - 5- sulfonic acid chloride 16d (44mg, 0.17mmol) obtains 3- ((4- chlorine isoquinolin -5- according to the synthetic method of one compound 1e of embodiment Base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 19a (25mg, yellow oily liquid, yield: 39%).

MS-ESI calculated value [M+Na] 418, measured value 418.

Second step

3- ((4- chlorine isoquinolin -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 19a (25mg, 0.059mmol) obtains 5- (3,6- diazabicyclo [3.2.0] heptan according to the synthetic method of one compound 1 of embodiment Alkane -3- base sulfonyl) -4- chlorine isoquinolin 19 (8mg, white solid, yield: 38%).¹H NMR(400MHz,D₂O):δ9.27 (s, 1H), 8.70 (brs, 1H), 8.49-8.43 (m, 2H), 7.85 (t, J=8.0Hz, 1H), 5.06-5.01 (m, 1H), 4.26- 4.21(m,1H),4.10-4.07(m,1H),3.83-3.91(m,2H),3.69-3.64(m,1H),3.61-3.54(m,1H), 3.52-3.48(m,1H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 20

6- ((4- chlorine isoquinolin -5- base) sulfonyl) decahydro -1,6- benzodiazine

The first step

By -6 (5H)-carboxylic acid tert-butyl ester 5e of 1- (1- phenethyl) -1,2,3,4,7,8- hexahydro -1,6- benzodiazine (15g, It 0.044mol) is dissolved in 600mL tetrahydrofuran, is added 1.5g palladium dydroxide (load of 20% charcoal), in 80 in 3MPa nitrogen atmosphere It DEG C is stirred to react 16 hours.It is cooled to room temperature filtering, filtrate is concentrated under reduced pressure, with chromatography silica gel column purification (50% methanol/acetic acid second Ester) obtain octahydro -1,6- benzodiazine -6 (2H)-carboxylic acid tert-butyl ester 20a (320mg, yellow oily liquid, yield: 3%).

MS-ESI calculated value [M+H]⁺241, measured value 241

Second step

- 6 (2H)-carboxylic acid tert-butyl ester 20a (320mg, 1.33mmol) of octahydro -1,6- benzodiazine is dissolved in 5mL dichloromethane In alkane, N, N- diisopropyl ethyl amine (516mg, 3.99mmol) and chlorine benzyl carboxylate (340mg, 2.0mmol) is added in 0 DEG C of when, It is stirred at room temperature 1 hour.After reaction, it is concentrated under reduced pressure then plus water (20mL) dilutes, extracted with ethyl acetate (30mL × 2), Merge organic phase, wash with saturated sodium-chloride water solution (50mL), anhydrous sodium sulfate is dry, is concentrated, with preparing silica gel plate (3/1 Petrol ether/ethyl acetate) purifying obtain hexahydro -1,6- benzodiazine -1,6 (2H, 7H) -1- benzyl 6- tert-butyl dimethyl ester 20b (275mg, yellow oily liquid, yield: 86%).

MS-ESI calculated value [M+H]⁺375, measured value 375.

Third step

By hexahydro -1,6- benzodiazine -1,6 (2H, 7H) -1- benzyl 6- tert-butyl dimethyl ester 20b (275mg, 0.73mmol) -1 (2H)-benzyl carboxylate 20c of octahydro -1,6- benzodiazine is obtained according to the synthetic method of one compound 1 of embodiment (200mg, white solid, yield: 96%).

MS-ESI calculated value [M+H]⁺275, measured value 275.

4th step

By octahydro -1,6- benzodiazine -1 (2H)-benzyl carboxylate 20c (40mg, 0.15mmol) and 4- chlorine isoquinolin -5- sulphur Acyl chlorides 16d (42mg, 0.16mmol) obtains 6- ((4- chlorine isoquinolin -5- base) according to the synthetic method of one compound 1e of embodiment Sulfonyl) octahydro -1,6- benzodiazine -1 (2H)-benzyl carboxylate 20d (20mg, yellow oily liquid, yield: 27%).

MS-ESI calculated value [M+H]⁺501, measured value 501.

5th step

By -1 (2H)-benzyl carboxylate 20d of 6- ((4- chlorine isoquinolin -5- base) sulfonyl) octahydro -1,6- benzodiazine (20mg, 0.04mmol) obtains 6- ((4- chlorine isoquinolin -5- base) sulfonyl) ten according to the synthetic method of five compound 5 of embodiment Hydrogen -1,6- benzodiazine 20 (10mg, white solid, yield: 68%).

¹H NMR(400MHz,CD₃OD):δ9.30(s,1H),8.72(s,1H),8.49-8.34(m,2H),7.90-7.85 (m,1H),4.04-3.68(m,3H),3.54-3.40(m,1H),3.27-3.03(m,3H),2.34-2.18(m,1H),2.13- 1.88(m,3H),1.87-1.60(m,3H)。

MS-ESI calculated value [M+H]⁺366, measured value 366.

Embodiment 21

The chloro- 5- of 4- (octahydro-pyrrolo- [3,2-b] pyridine -1- sulfonyl)-isoquinolin

The first step

Octahydro-pyrrolo- [3,2-b] Pyridine-4-carboxylic acid benzyl ester 6e (30mg, 0.12mmol, embodiment six) and 4- chlorine isoquinoline Quinoline -5- sulfonic acid chloride 16d (45mg, 0.17mmol) obtains 1- (4- chlorine isoquinolin-according to the synthetic method of one compound 1e of embodiment 5- sulfonyl)-octahydro pyrrolo- [3,2-b] Pyridine-4-carboxylic acid benzyl ester 21a (30mg, yellow oily liquid, yield: 36%).

MS-ESI calculated value [M+H]⁺486, measured value 486.

Second step

By 1- (4- chlorine isoquinolin -5- sulfonyl)-octahydro pyrrolo- [3,2-b] Pyridine-4-carboxylic acid benzyl ester 21a (30mg, 0.062mmol) the chloro- 5- of 4- (octahydro-pyrrolo- [3,2-b] pyridine -1- is obtained according to the synthetic method of five compound 5 of embodiment Sulfonyl)-isoquinolin 21 (15mg, white solid, yield: 71%).

¹H NMR(400MHz,D₂O): δ 9.33 (s, 1H), 8.78 (s, 1H), 8.55-8.50 (m, 2H), 7.91 (t, J= 8.0Hz,1H),4.64(s,1H),4.18-4.13(m,1H),4.03-3.98(m,1H),3.80-3.75(m,2H),3.17- 3.04(m,1H),2.41-2.36(m,2H),1.97-1.80(m,3H),1.58-1.55(m,1H).

MS-ESI calculated value [M+H]⁺352, measured value 352.

Embodiment 22

The chloro- 5- of 4- (hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-sulfonyl) isoquinolin

The first step

Simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7a (30mg, 0.14mmol) and 4- chlorine are different for cis--hexahydropyrrolo Quinoline -5- sulfonic acid chloride 16d (131mg, 0.58mmol) obtains 5- (4- chlorine isoquinoline according to the synthetic method of one compound 1e of embodiment Quinoline -5- sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 22a (50mg, yellow oily liquid, yield: 81%).

MS-ESI calculated value [M+H]⁺438, measured value 438.

Second step

By 5- (4- chlorine isoquinolin -5- sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 22a (50mg, 0.11mmol) obtains the chloro- 5- of 4- (hexahydropyrrolo simultaneously [3,4-c] pyrrole according to the synthetic method of one compound 1 of embodiment Cough up -2 (1H)-sulfonyls) isoquinolin 22 (35mg, yellow solid, yield: 91%).

¹H NMR(400MHz,D₂O): δ 9.23-9.21 (m, 1H), 8.64 (s, 1H), 8.78 (d, J=8.0Hz, 1H), 8.43-8.38(m,2H),3.61-3.54(m,4H),3.45-3.40(m,2H),3.21-3.19(m,2H),3.05-3.00(m, 2H)。

MS-ESI calculated value [M+H]⁺338, measured value 338.

Embodiment 23

The chloro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-yl) sulfonyl) isoquinolin

The first step

Hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (35mg, 0.16mmol) and 4- chlorine is different Quinoline -5- sulfonic acid chloride 16d (45mg, 0.17mmol) obtains 2- ((4- chlorine isoquinolin -5- base) according to the synthetic method of compound 1e Sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 23a (15mg, yellow oily liquid, yield: 21%).

MS-ESI calculated value [M+Na] 474, measured value 474.

Second step

2- ((4- chlorine isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 23a (15mg, 0.033mmol) obtains the chloro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-c] pyrrole according to the synthetic method of compound 1 Pyridine -2 (3H)-yl) sulfonyl) isoquinolin 23 (10mg, white solid, yield: 86%).

¹H NMR(400MHz,D₂O):δ9.28(s,1H),8.70-8.68(m,1H),8.45-8.41(m,2H),7.85(t, J=8.0Hz, 1H), 3.70-3.60 (m, 2H), 3.52-3.47 (m, 2H), 3.41-3.36 (m, 1H), 3.25-3.14 (m, 3H), 2.89-2.75(m,2H),2.08-2.02(m,1H),1.90-1.82(m,1H)。

MS-ESI calculated value [M+H]⁺352, measured value 352.

Embodiment 24

The fluoro- 5- of 4- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) isoquinolin

The first step

The 144mL tetrahydrofuran solution of 4- bromo-isoquinoline 24a (20g, 96.6mmol) is added drop-wise to just under the conditions of -65 DEG C In the 760mL tetrahydrofuran solution of butyl lithium (133mL, 332.5mmol, 2.5M tetrahydrofuran solution), -65 DEG C after being added dropwise The reaction was continued 30 minutes.Then -65 DEG C in 1 hour into reaction solution be added two benzsulfamide of N- fluorine (66.68g, 216mL tetrahydrofuran solution 211.7mmol) continues stirring 1 hour, is then slowly increased to room temperature after being added dropwise.Wait react After, saturated aqueous ammonium chloride (300mL) is slowly added into reaction solution, and is extracted with ethyl acetate (300mL × 3) It takes, organic phase is washed with saturated sodium-chloride water solution (300mL), and dry, concentration is evaporated, and with chromatography silica gel column purification (0- 100% ethyl acetate/petroleum ether) obtain 4- fluorine isoquinolin 24b (8.5g, Red oil, yield: 60%).

Second step

4- fluorine isoquinolin 24b (8.5g, 57.8mmol) is closed referring to 16 compound 4-chloro -5- nitroisoquinoline 16b of embodiment 4- fluoro- 5- nitroisoquinoline 24c (7.2g, yellow oily liquid, yield: 64.8%) are obtained at method.

Third step

The fluoro- 5- nitroisoquinoline 24c (7.2g, 37.5mmol) of 4- is referring to 16 compound 4-chloro isoquinolin -5- amine of embodiment 16c synthetic method obtains 4- fluorine isoquinolin -5- amine 24d (5.5g, yellow solid, yield: 90%).

4th step

4- fluorine isoquinolin -5- amine 24d (5.5g, 33.95mmol) is according to 16 compound 4-chloro isoquinolin -5- sulphonyl of embodiment The synthetic method of chlorine 16d obtains 4- fluorine isoquinolin -5- sulfonic acid chloride 24e (4.5g, white solid, yield: 54%).

¹H NMR(400MHz,CDCl₃):δ9.32-9.20(m,1H),8.79-8.67(m,2H),8.48-8.37(m,1H), 7.85 (t, J=8.0Hz, 1H)

5th step

Hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1d (30mg, 0.14mmol and 4- fluorine isoquinolin -5- Sulfonic acid chloride 24e (35mg, 0.14mmol) according to one compound 4- of embodiment (isoquinolin -5- base sulfonyl) hexahydropyrrolo simultaneously [3, 2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1e synthetic method obtains 4- ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydropyrrolo And [3,2-b pyrroles -1 (2H)-carboxylic acid tert-butyl ester 24f (56mg, yellow oily liquid, yield: 94%).

MS-ESI calculated value [M+Na] 444, measured value 444.

6th step

4- ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,2-b pyrroles -1 (2H)-carboxylic acid tert-butyl ester 24f (56mg, 0.13mmol obtain the fluoro- 5- of 4- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-according to the synthetic method of embodiment one Base) sulfonyl) isoquinolin 24 (20mg, white solid, yield: 42%).

¹H NMR(400MHz,D₂O): δ 9.24 (s, 1H), 8.56-8.46 (m, 3H), 7.88 (t, J=8.0Hz, 1H), 4.47(m,1H),3.68(m,1H),3.53-3.43(m,1H),3.37-3.24(m,3H),2.45-2.31(m,1H),2.23- 2.08(m,3H).

MS-ESI calculated value [M+H]⁺322, measured value 322.

Embodiment 25

The first step

Cis--hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2f (55mg, 0.24mmol, embodiment two) 4- fluorine isoquinolin -5- sulfonic acid chloride 24e (50mg, 0.2mmol, embodiment 24) obtains 5- ((4- according to the synthetic method of embodiment one Fluorine isoquinolin -5- base) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 25a (55mg, yellow solid, yield: 58%).

MS-ESI calculated value [M+H-56]⁺366, measured value 366.

Second step

5- ((4- fluorine isoquinolin -5- base) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 25a (50mg, 0.085mmol) the fluoro- 5- of 4- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) is obtained according to the synthetic method of embodiment one Sulfonyl) isoquinolin 25 (30mg, white solid, 78%).

¹H NMR(400MHz,D₂O): δ 9.26 (s, 1H), 8.60-8.49 (m, 3H), 7.89 (t, J=7.2Hz, 1H), 4.41 (t, J=6.4Hz, 1H), 36.76-3.25 (m, 7H), 2.26-2.20 (m, 1H), 1.92-1.87 (m, 1H)

MS-ESI calculated value [M+H]⁺322, measured value 322.

Embodiment 26

The fluoro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-yl) sulfonyl) isoquinolin

The first step

Fluoro- isoquinolin -5- sulfonic acid chloride the 24e of 4- (45mg, 0.2mmol, embodiment 24) and cis--octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3a (50mg, 0.22mmol, embodiment three) is obtained according to the synthetic method of embodiment one 6- ((4- fluorine isoquinolin -5- base) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 26a (50mg, nothing Color oily liquids, yield: 52%).

Second step

6- ((4- fluorine isoquinolin -5- base) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 26a (50mg, 0.11mmol) obtains the fluoro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 according to the synthetic method of embodiment one (2H)-yl) sulfonyl) isoquinolin 26 (20mg, white powder solid, yield: 42%).¹H NMR(400MHz,CD₃OD):δ 9.46(s,1H),8.75-8.67(m,1H),8.65-8.56(m,2H),8.05-7.96(m,1H),4.02-3.96(m,1H), 3.95-3.88(m,1H),3.79-3.70(m,2H),3.55-3.50(m,1H),3.36-3.31(m,2H),3.12-3.03(m, 1H),2.94-2.84(m,1H),1.97-1.88(m,1H),1.86-1.76(m,2H).

Embodiment 27

5- (3,6- diazabicyclo [3.2.0] heptane -3- base sulfonyl) -4- fluorine isoquinolin

The first step

3- (isoquinolin -5- base sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 4a (30mg, 0.15mmol) and the fluoro- isoquinolin -5- sulfonic acid chloride 24e of 4- (41mg, 0.17mmol, embodiment 24) is according to the synthesis of embodiment one Method obtains 3- ((4- fluorine isoquinolin -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 27a (52mg, yellow oily liquid, yield: 84%).

MS-ESI calculated value [M+Na]⁺430, measured value 430.

Second step

3- ((4- fluorine isoquinolin -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 27a (52mg, 0.13mmol) obtains 5- (3,6- diazabicyclo [3.2.0] heptane -3- base sulphur according to the synthetic method of embodiment one Acyl group) -4- fluorine isoquinolin 27 (20mg, white solid, yield: 44%).

¹H NMR(400MHz,D₂O): δ 9.42 (s, 1H), 8.71 (d, J=8.0Hz, 1H), 8.66 (d, J=4.0Hz, 1H), 8.59 (d, J=8.0Hz, 1H), 7.99 (t, J=8.0Hz, 1H), 4.99-4.95 (m, 1H), 4.22-4.17 (m, 1H), 4.00 (d, J=12.4Hz, 1H), 3.85 (d, J=11.2Hz, 1H), 3.78-3.74 (m, 1H), 3.55-3.48 (m, 2H), 3.38-3.34(m,1H).

MS-ESI calculated value [M+H]⁺308, measured value 308.

Embodiment 28

The fluoro- 5- of 4- ((octahydro -1H- pyrrolo- [3,2-c] pyridine -1- base) sulfonyl) isoquinolin

The first step

Hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-benzyl carboxylate 6e (50mg, 0.17mmol, embodiment six) and Fluoro- isoquinolin -5- sulfonic acid chloride the 24e of 4- (50mg, 0.2mmol, embodiment 24) obtains 1- according to the synthetic method of embodiment one ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,2-c] pyridine -5 (6H)-benzyl carboxylate 28a (72mg, it is yellow Color oily liquids, yield: 91%).

MS-ESI calculated value [M+Na]⁺492, measured value 492.

Second step

1- ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,2-c] pyridine -5 (6H)-benzyl carboxylate 28a (72mg, 0.15mmol) is according to five compound 6- of embodiment (isoquinolin -5- base sulfonyl) decahydro -1,6- benzodiazine 5 Synthetic method obtains the fluoro- 5- of 4- ((octahydro -1H- pyrrolo- [3,2-c] pyridine -1- base) sulfonyl) isoquinolin 28 (25mg, white Solid, yield: 49%).

¹H NMR(400MHz,CD₃OD): δ 9.28 (s, 1H), 8.64 (d, J=8.0Hz, 1H), 8.60 (d, J=4.0Hz, 1H), 8.51 (d, J=8.0Hz, 1H), 7.91 (t, J=8.0Hz, 1H), 4.16-4.11 (m, 1H), 3.89-3.83 (m, 1H), 3.81-3.66(m,2H),3.14-3.06(m,1H),3.04-2.93(m,1H),2.34-2.20(m,2H),2.04-1.98(m, 1H),1.85-1.82(m,1H),1.55-1.50(m,2H)。

MS-ESI calculated value [M+H]⁺336, measured value 336.

Embodiment 29

The fluoro- 5- of 4- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) sulfonyl) isoquinolin

The first step

Cis--hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7a (30mg, 0.14mmol, embodiment seven) According to the synthetic method of embodiment one obtaining 5- with the fluoro- isoquinolin -5- sulfonic acid chloride 24e (35mg, 0.14mmol) of 4-, ((4- fluorine is different Quinoline -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 29a (55mg, yellow oily liquid, Yield: 92%).

MS-ESI calculated value [M+Na]⁺444, measured value 444.

Second step

5- ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 29a (55mg, 0.13mmol) obtains the fluoro- 5- of 4- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 according to the synthetic method of embodiment one (1H)-yl) sulfonyl) isoquinolin 29 (26mg, white solid, yield: 55%).

¹H NMR(400MHz,D₂O): δ 9.26 (brs, 1H), 8.58-8.53 (m, 2H), 8.49 (d, J=8.0Hz, 1H), 7.89 (t, J=8.0Hz, 1H), 3.61-3.56 (m, 2H), 3.54-3.47 (m, 2H), 3.45-3.42 (m, 2H), 3.19-3.14 (m,2H),2.98-2.91(m,2H).

MS-ESI calculated value [M+H]⁺322, measured value 322.

Embodiment 30

The fluoro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-yl) sulfonyl) isoquinolin

The first step

Hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (30mg, 0.13mmol, embodiment eight) 2- is obtained according to the synthetic method of embodiment 1 with the fluoro- isoquinolin -5- sulfonic acid chloride 24e of 4- (33mg, 0.13mmol, embodiment 24) ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 30a (17mg, Yellow oily liquid, yield: 29%).

MS-ESI calculated value [M+H]⁺436, measured value 436.

Second step

2- ((4- fluorine isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 30a (17mg, 0.039mmol) obtains the fluoro- 5- of 4- ((hexahydro -1H- pyrrolo- [3,4-c] pyrrole according to the synthetic method of embodiment 1 Pyridine -2 (3H)-yl) sulfonyl) isoquinolin 30 (6mg, white solid, yield: 46%).¹H NMR(400MHz,D₂O):δ9.33 (s, 1H), 8.59 (d, J=5.6Hz, 1H), 8.53-8.49 (m, 2H), 7.92 (t, J=8.0Hz, 1H), 3.67-3.60 (m, 2H),3.50-3.40(m,2H),3.35-3.30(m,1H),3.20–3.08(m,3H),2.81-2.70(m,2H),2.04-1.95 (m,1H),1.83-1.74(m,1H).

MS-ESI calculated value [M+H]⁺336, measured value 336.

Embodiment 31

4- (difluoromethyl) -5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-yl) sulfonyl) isoquinolin

The first step

4- bromo-isoquinoline 24a (2.0g, 9.6mmol) is dissolved in the 30mL tetrahydrofuran steamed again, and uses dry ice acetone bath - 65 DEG C are cooled to, is slowly added dropwise under nitrogen protection n-BuLi (4.0mL, 10mmol, 2.5M tetrahydrofuran solution), is added dropwise After, then 0.5 hour of -65 DEG C of stir abouts n,N-Dimethylformamide (730mg, 10mmol) is added dropwise at -65 DEG C, Reaction continues to stir 1 hour at this temperature.Saturated aqueous solution (100mL) to which ammonium chloride is added after reaction is quenched instead It answers, is extracted with ethyl acetate (50mL × 3), merge organic layer and washed with saturated sodium-chloride water solution (100mL), anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, crude product obtains isoquinolin -4- first by chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) Aldehyde 31a (550mg, yellow solid, yield: 36%).

¹H NMR(400MHz,CDCl₃): δ 10.41 (s, 1H), 9.45 (s, 1H), 9.22 (d, J=8.4Hz, 1H), 8.96 (s, 1H), 8.10 (d, J=8.4Hz, 1H), 7.96-7.92 (m, 1H), 7.76 (t, J=8.4Hz, 1H)

MS-ESI calculated value [M+H₃O]⁺176, measured value 176.

Second step

Isoquinolin -4- formaldehyde 31a (100mg, 0.63mmol) is dissolved in dry 5mL methylene chloride, under nitrogen protection Diethylin sulfur trifluoride (1.1g, 6.3mmol) is added dropwise in 0 DEG C, after being added dropwise, is warmed to room temperature that the reaction was continued 5 hours It disappears to raw material.Reaction mixture is slowly dropped in 30mL ice water, and is slowly added into saturated sodium bicarbonate aqueous solution, until The pH of mixed liquor is 8-9, is then extracted with methylene chloride (20mL × 3), and organic phase is merged, and anhydrous sodium sulfate dries, filters, subtracts Pressure concentration, crude product obtain 4- difluoromethyl isoquinolin by chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) 31b (80mg, yellow oily liquid, yield: 70%).

¹H NMR(400MHz,CDCl₃): δ 9.36 (s, 1H), 8.66 (s, 1H), 8.21 (d, J=8.4Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.86-7.73 (m, 1H), 7.75-7.65 (m, 1H), 7.07 (t, J=54.4Hz, 1H)

MS-ESI calculated value [M+H]⁺180, measured value 180.

Third step

4- difluoromethyl isoquinolin 31b (1.3g, 7.2mmol) obtains 4- (difluoromethyl)-referring to the method for embodiment 16 5- nitroisoquinoline 31c (1.16g, yellow solid, yield: 71%).

¹H NMR(400MHz,CD₃OD): δ 9.60 (s, 1H), 8.94 (s, 1H), 8.60 (d, J=8.0Hz, 1H), 8.45 (d, J=8.0Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 7.24 (t, J=56.0Hz, 1H)

MS-ESI calculated value [M+H]⁺225, measured value 225.

4th step

4- (difluoromethyl) -5- nitroisoquinoline 31c (100mg, 0.45mmol) is dissolved in 30mL dehydrated alcohol, in nitrogen Mixture is flowed back 1 by the hydrazine hydrate (22mg, 0.45mmol) that 10% wet palladium carbon 30mg and 85% is added under gas shielded at 90 DEG C Hour, then reaction solution is cooled to room temperature and is filtered.Filtrate is concentrated, crude product passes through chromatography silica gel column purification (30% second Acetoacetic ester/petroleum ether) obtain 4- (difluoromethyl) isoquinolin -5- amine 31d (62mg, yellow solid, yield: 78.5%).

¹H NMR(400MHz,CDCl₃):δ9.25(s,1H),8.70(s,1H),7.78-7.64(m,1H),7.54-7.49 (m,2H),7.15-7.10(m,1H).

MS-ESI calculated value [M+H]⁺195, measured value 195.

5th step

4- (difluoromethyl) isoquinolin -5- amine 31d (230mg, 1.18mmol) is according to 16 compound 4-chloro isoquinoline of embodiment The synthetic method of quinoline -5- sulfonic acid chloride 16d obtains 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e, and (130mg, yellow solid are received Rate: 39%).

MS-ESI calculated value [M+H]⁺278, measured value 278.

6th step

Cis--hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1d (37mg, 0.24mmol, embodiment 1) 4- is obtained according to the synthetic method of embodiment 1 with 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e (68mg, 0.24mmol) ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 31f (50mg, yellow solid, yield: 46%).

MS-ESI calculated value [M+H]⁺454, measured value 454.

7th step

4- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid uncle Butyl ester 31f (50mg, 0.11mmol) according to the synthetic method of embodiment 1 obtain 4- (difluoromethyl) -5- ((hexahydropyrrolo simultaneously [3, 2-b] pyrroles -1 (2H)-yl) sulfonyl) isoquinolin 31 (25mg, white solid, 53%).

¹H NMR(400MHz,D₂O):δ9.69(s,1H),9.06(s,1H),8.63-8.60(m,2H),8.21-7.94(m, 2H),4.66-4.48(m,2H),3.64-3.61(m,1H),3.54-3.49(m,1H),3.32-3.28(m,2H),2.44-2.39 (m,1H),2.24-2.22(m,1H),2.07-2.05(m,2H).

MS-ESI calculated value [M+H]⁺354, measured value 354.

Embodiment 32

4- (difluoromethyl) -5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) isoquinolin

Cis--hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2f (37mg, 0.24mmol, embodiment 2) With 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e (68mg, 0.24mmol, embodiment 31) according to the synthetic method of embodiment 1 Obtain 5- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 32a (45mg, yellow solid, yield: 41%).

MS-ESI calculated value [M+H]⁺454, measured value 454.

Second step

5- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -1 (2H)-carboxylic acid uncle Butyl ester 32a (45mg, 0.1mmol) according to the synthetic method of embodiment 1 obtain 4- (difluoromethyl) -5- ((hexahydropyrrolo simultaneously [3, 4-b] pyrroles -5 (1H)-yl) sulfonyl) isoquinolin 32 (25mg, white solid, yield: 60%).

¹H NMR(400MHz,D₂O):δ9.63(s,1H),9.04(s,1H),8.71-8.56(m,2H),8.18-7.92(m, 2H),4.41-4.38(m,1H),3.69-3.67(m,2H),3.53-3.50(m,1H),3.36-3.21(m,4H),2.24-2.18 (m,1H),1.90-1.76(m,1H).

MS-ESI calculated value [M+H]⁺354, measured value 354.

Embodiment 33

4- (difluoromethyl) -5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-yl) sulfonyl) isoquinolin

Cis--octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3a (30mg, 0.18mmol, embodiment 3) With 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e (50mg, 0.18mmol, embodiment 31) according to the synthetic method of embodiment 1 Obtain 6- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 33a (40mg, yellow solid, yield: 47%).MS-ESI calculated value [M+H]⁺468, measured value 468.

Second step

6- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid uncle Butyl ester 33a (40mg, 0.085mmol) obtains 4- (difluoromethyl) -5- ((hexahydro -1H- pyrroles according to the synthetic method of embodiment 1 And [3,4-b] pyridine -6 (2H)-yl) sulfonyl) isoquinolin 33 (10mg, white solid, 27%).

¹H NMR(400MHz,D₂O):δ9.64-9.59(m,1H),9.03(s,1H),8.57-8.47(m,2H),8.21- 7.92 (m, 2H), 3.97 (s, 1H), 3.79-3.74 (m, 2H), 3.64-3.61 (m, 1H), 3.46 (t, J=10.2Hz, 1H), 3.32-3.28(m,1H),3.00-2.92(m,2H),1.84-1.72(m,4H).

MS-ESI calculated value [M+H]⁺368, measured value 368.

Embodiment 34

5- (3,6- diazabicyclo [3.2.0] heptane -3- base sulfonyl) -4- (difluoromethyl) isoquinolin

The first step

3,6- diazabicyclos [3.2.0] heptane -6- carboxylic acid tert-butyl ester 4a (30mg, 0.18mmol, embodiment 4) and 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e (50mg, 0.18mmol, embodiment 31) is obtained according to the synthetic method of embodiment 1 3- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 34a (40mg, yellow solid, yield: 50%).

MS-ESI calculated value [M+H]⁺440, measured value 440.

Second step

3- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid Tert-butyl ester 34a (40mg, 0.085mmol) is obtained according to the synthetic method of embodiment 1

5- (3,6- diazabicyclos [3.2.0] heptane -3- base sulfonyl) -4- (difluoromethyl) isoquinolin 34 (10mg, it is white Color solid, 26%).

¹H NMR(400MHz,D₂O): δ 9.60 (s, 1H), 9.07 (s, 1H), 8.65-8.60 (m, 2H), 8.20 (t, J= 53.2Hz, 1H), 7.94 (t, J=8.0Hz, 1H), 5.00-4.95 (m, 1H), 4.20-4.15 (m, 1H), 4.00-3.95 (m, 1H),3.95-3.70(m,2H),3.54-3.50(m,2H),3.35-3.31(m,1H).

MS-ESI calculated value [M+H]⁺340, measured value 340.

Embodiment 35

4- (difluoromethyl) -5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) sulfonyl) isoquinolin

The first step

Cis--hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7a (37mg, 0.24mmol, embodiment 7) With 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e (68mg, 0.24mmol, embodiment 31) according to the synthetic method of embodiment 1 Obtain 5- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 35a (52mg, yellow solid, yield: 48%).MS-ESI calculated value [M+H]⁺454, measured value 454.

Second step

5- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid uncle Butyl ester 35a (52mg, 0.11mmol) according to the synthetic method of embodiment 1 obtain 4- (difluoromethyl) -5- ((hexahydropyrrolo simultaneously [3, 4-c] pyrroles -2 (1H)-yl) sulfonyl) isoquinolin 35 (25mg, white solid, 51%).

¹H NMR(400MHz,D₂O):δ9.59(s,1H),9.05(s,1H),8.66-8.54(m,2H),8.24-7.91(m, 2H),4.56-4.46(m,4H),3.35-3.31(m,2H),3.20-3.15(m,2H),3.00-2.90(m,2H).

MS-ESI calculated value [M+H]⁺354, measured value 354.

Embodiment 36

The first step

Hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (56mg, 0.25mmol, embodiment 8) and 4- (difluoromethyl) isoquinolin -5- sulfonic acid chloride 31e (75mg, 0.27mmol, embodiment 31) is obtained according to the synthetic method of embodiment 1 To 2- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (the 6H)-tertiary fourth of carboxylic acid Ester 36a (45mg, pale yellowish oil liquid, yield: 45%).

MS-ESI calculated value [M+Na]⁺490, measured value 490.

Second step

2- ((4- (difluoromethyl) isoquinolin -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic Tert-butyl acrylate 36a (45mg, 0.096mmol) obtains 4- (difluoromethyl) -5- ((hexahydro -1H- according to the synthetic method of embodiment 1 Pyrrolo- [3,4-c] pyridine -2 (3H)-yl) sulfonyl) isoquinolin 36 (30mg, white solid, yield: 86%).

¹H NMR(400MHz,CD₃OD):δ9.78(s,1H),9.18(s,1H),8.76-8.73(m,1H),8.71-8.66 (m, 1H), 8.39 (t, J=54.0Hz, 1H), 8.08 (t, J=8.0Hz, 1H), 3.66-3.59 (m, 2H), 3.55-3.48 (m, 2H),3.43-3.36(m,1H),3.27-3.23(m,1H),3.24-3.14(m,2H),2.88-2.70(m,2H),2.13-2.02 (m,1H),1.97-1.85(m,1H).

MS-ESI calculated value [M+H]⁺368, measured value 368.

Embodiment 37

5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-yl) sulfonyl) -4- methylisoquinolinium

The first step

To 4- bromo-isoquinoline 24a (15.0g, 72.5mmol), methyl-boric acid (8.8g, 146mmol), K under nitrogen protection₃PO₄ (62.0_g, 292mmol) 350mL toluene solution in tris(dibenzylideneacetone) dipalladium (6.6g, 7.2mmol) and two rings are added Hexyl (2', 6'- dimethoxy-[1,1'- biphenyl] -2- base) phosphine (5.9g, 14.3mmol), it is small that gained mixture is heated to reflux 20 When.It to which reaction solution is poured into water (300mL) after reaction, is extracted with ethyl acetate (100mL × 2), what and organic phase are used Anhydrous sodium sulfate is dry, and concentration obtains 4- methylisoquinolinium with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) 37a (10.7g, yellow oily liquid, yield: 94%).

Second step

4- methylisoquinolinium 37a (10.0g, 69.9mmol) obtains 4- methyl-according to the synthetic method of embodiment 16 5- nitroisoquinoline 37b (10g, yellow oily liquid, yield: 76%).

Third step

4- methyl-5-nitro isoquinolin 37b (9.00g, 47.8mmol) obtains 4- first according to the synthetic method of embodiment 16 Base isoquinolin -5- amine 37c (6.0g, yellow solid, yield: 71%).

4th step

4- methylisoquinolinium -5- amine 37c (500mg, 3.16mmol) obtains 4- methyl according to the synthetic method of embodiment 16 Isoquinolin -5- sulfonic acid chloride 37d (300mg, green solid, yield: 40%).

¹H NMR(400MHz,DMSO-d6):δ9.78(brs.,1H),8.89-8.90(m,1H),8.55-8.50(m, 2H),8.01-7.88(m,1H),3.34(s,3H).

5th step

Cis--hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1d (33mg, 0.14mmol) and 4- methyl Isoquinolin -5- sulfonic acid chloride 37d (68mg, 0.28mmol) obtains 4- (4- methylisoquinolinium -5- according to the synthetic method of embodiment 1 Sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 37e (15mg, yellow oily liquid, yield: 25%).

MS-ESI calculated value [M+H]⁺418, measured value 418.

6th step

4- (4- methylisoquinolinium -5- sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 37e (15mg, 0.036mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-yl) according to the synthetic method of embodiment 1 Sulfonyl) -4- methylisoquinolinium 37 (10mg, yellow solid, yield: 67%).

¹H NMR(400MHz,D₂O):δ9.58(s,1H),8.64-8.62(m,1H),8.51-8.50(m,2H),8.02(t, ), J=8.0,1H 4.85-4.81 (m, 2H), 4.62-4.59 (m, 1H), 3.79-3.73 (m, 1H), 3.66-3.60 (m, 1H), 3.48-3.40(m,2H),3.06(s,3H),2.64-2.54(m,1H),2.34-2.25(m,2H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 38

5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) -4- methylisoquinolinium

The first step

Cis--hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2f (50mg, 0.24mmol, embodiment 2) 5- is obtained according to the synthetic method of embodiment 1 with 4- methylisoquinolinium -5- sulfonic acid chloride 37d (85mg, 0.35mmol, embodiment 37) ((4- methylisoquinolinium -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 38a (40mg, nothing Color oily liquids, yield: 40%).

Second step

5- ((4- methylisoquinolinium -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 38a (40mg, 0.095mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-according to the synthetic method of embodiment 1 Base) sulfonyl) -4- methylisoquinolinium 38 (28mg, white solid, yield: 75%).

¹H NMR(400MHz,D₂O): δ 9.52 (s, 1H) .8.66-8.42 (m, 3H), 7.96 (t, J=7.8Hz, 1H), 4.46(brs.,1H),3.94-3.80(m,2H),3.75-3.70(m,1H),3.55-3.50(m,1H),3.45-3.26(m, 3H),3.01(brs,3H),2.35-2.22(m,1H),2.00-1.95(m,1H).

Embodiment 39

5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) -4- methylisoquinolinium -1- alcohol

The first step

To 5- ((4- methylisoquinolinium -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 under the conditions of 0 DEG C In the 5mL dichloromethane solution of (2H)-carboxylic acid tert-butyl ester 38a (100mg, 0.24mmol) be added m-chloro peroxide benzene carboxylic acid (83mg, 0.48mmol), it is stirred at room temperature 2 hours until reaction terminates.Chromatography silica gel column purification (0-100% second is used after direct solvent evaporated Acetoacetic ester/petroleum ether) obtain 5- ((1- (tert-butoxycarbonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) - 4- methylisoquinolinium -2- oxide 39a (75mg, yellow oily liquid, yield: 73%).

Second step

By 5- ((1- (tert-butoxycarbonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) -4- methyl is different Quinoline -2- oxide 39a (75mg, 0.17mmol) is dissolved in 1mL acetic anhydride stirs 2 hours until reaction terminates at 100 DEG C. 6mL tetrahydrofuran, 2mL water and sodium carbonate (37mg, 0.35mmol) is added after removing solvent is concentrated under reduced pressure for reaction solution and room temperature is stirred It mixes 30 minutes.Then methylene chloride (20mL × 3) extracts, and organic phase is dry with anhydrous sodium sulfate, and concentration is pure with chromatography silica gel column Change (0-100% ethyl acetate/petroleum ether) obtains 5- ((1- hydroxy-4-methyl isoquinolin -5- base) sulfonyl), and hexahydropyrrolo is simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 39b (35mg, yellow oily liquid, yield: 47%).

Third step

5- ((1- hydroxy-4-methyl isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid Tert-butyl ester 39b (35mg, 0.081mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 according to the synthetic method of embodiment 1 (1H)-yl) sulfonyl) -4- methylisoquinolinium -1- alcohol 39 (13mg, white solid, yield: 48%).

¹H NMR(400MHz,D₂O): δ 8.57 (d, J=7.2Hz, 1H), 8.14 (d, J=7.2Hz, 1H), 7.62-7.57 (m,1H),7.19(brs,1H),3.76(brs,2H),3.44(brs,2H),3.40-3.30(m,3H),2.52(s,3H),2.27 (brs,1H),1.96(brs,2H).

Embodiment 40

5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-yl) sulfonyl) -4- methylisoquinolinium

The first step

Cis--octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3a (50mg, 0.22mmol, embodiment 3) It is obtained with 4- methylisoquinolinium -5- sulfonic acid chloride 37d (106mg, 0.44mmol, embodiment 37) according to the synthetic method of embodiment 1 6- (4- methylisoquinolinium-5- sulfonyl) octahydro-1H- pyrrolo- [3,4-b] pyridine-1-carboxylic acid tert-butyl ester 40a (30mg, yellow Oily liquids, yield: 31%).

MS-ESI calculated value [M+H]⁺432, measured value 432.

Second step

6- (4- methylisoquinolinium-5- sulfonyl) octahydro-1H- pyrrolo- [3,4-b] pyridine-1-carboxylic acid tert-butyl ester 40a (30mg, 0.074mmol) obtains 5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-according to the synthetic method of embodiment 1 Base) sulfonyl) -4- methylisoquinolinium 40 (20mg, white solid, yield: 87%).

¹H NMR(400MHz,CDCl₃): δ 9.55 (s, 1H), 8.62 (d, J=8.0Hz, 1H), 8.52-8.44 (m, 2H), 8.00 (t, J=8.0Hz, 1H), 4.06 (s, 1H), 3.97-3.91 (m, 1H), 3.89-3.84 (m, 1H), 3.80-3.75 (m, 1H),3.65-3.60(m,1H),3.40-3.35(m,1H),3.10(s,1H),3.07(s,3H),2.04-1.73(m,5H).

MS-ESI calculated value [M+H]⁺332, measured value 332.

Embodiment 41

The first step

3,6- diaza-bicyclo [3.2.0] heptane 6- carboxylic acid tert-butyl ester 4a (30mg, 0.15mmol, embodiment 4) and 4- methyl Isoquinolin -5- sulfonic acid chloride 37d (73mg, 0.31mmol, embodiment 37) obtains 3- (4- methyl according to the synthetic method of embodiment 1 Isoquinolin -5- sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 41a (45mg, yellow oily liquid, Yield: 74%).

MS-ESI calculated value [M+H]⁺404, measured value 404.

Second step

3- (4- methylisoquinolinium -5- sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 41a (45mg, 0.11mmol) obtains 5- (3,6- diazabicyclos [3.2.0] heptane -3- sulphonyl according to the synthetic method of embodiment 1 Base) -4- methylisoquinolinium 41 (25mg, yellow solid, yield: 74%).

¹H NMR(400MHz,D₂O):δ9.49(s,1H),8.57-8.55(m,1H),8.47-8.46(m,2H),7.94(t, J=8.0Hz, 1H), 4.24-4.16 (m, 3H), 3.90 (d, J=8.0Hz, 1H), 3.82-3.78 (m, 1H), 3.73-3.68 (m, 1H), 3.53 (d, J=8.0Hz, 2H), 3.06 (s, 3H).

MS-ESI calculated value [M+H]⁺304, measured value 304.

Embodiment 42

4- methyl -5- ((octahydro -1H- pyrrolo- [3,2-b] pyridine -1- base) sulfonyl) isoquinolin

The first step

Hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-benzyl carboxylate 6e (30mg, 0.12mmol, embodiment 6) and 4- Methylisoquinolinium -5- sulfonic acid chloride 37d (139mg, 0.58mmol, embodiment 37) obtains 1- (4- according to the synthetic method of embodiment 1 Methylisoquinolinium -5- sulfonyl) hexahydro -1H- pyrrolo- [3,2-b] (2H) benzyl carboxylate of pyridine -4 42a (30mg, yellow liquid, Yield: 56%).

MS-ESI calculated value [M+H]⁺466, measured value 466.

Second step

1- (4- methylisoquinolinium -5- sulfonyl) hexahydro -1H- pyrrolo- [3,2-b] (2H) benzyl carboxylate of pyridine -4 42a (30mg, 0.065mmol) according to 5 compound 6- of embodiment (isoquinolin -5- base sulfonyl) decahydro -1,6- benzodiazine 5 conjunction 4- methyl -5- ((octahydro -1H- pyrrolo- [3,2-b] pyridine -1- base) sulfonyl) isoquinolin 42 (5mg, yellow is obtained at method Solid, yield: 23%).

¹H NMR(400MHz,D₂O): δ 8.98 (s, 1H), 8.30 (s, 1H), 8.24-8.21 (m, 2H), 7.64 (t, J= 8.0,1H),4.16-4.11(m,1H),4.06-4.03(m,1H),3.70-3.65(m,2H),3.15-3.03(m,2H),2.78 (s,3H),2.40-2.34(m,2H),1.80-1.72(m,3H),1.52-1.50(m,1H)。

MS-ESI calculated value [M+H]⁺332, measured value 332.

Embodiment 43

5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) sulfonyl) -4- methylisoquinolinium

The first step

Cis--hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7a (30mg, 0.14mmol, embodiment 7) 5- is obtained according to the synthetic method of embodiment 1 with 4- methylisoquinolinium -5- sulfonic acid chloride 37d (68mg, 0.28mmol, embodiment 37) ((4- methylisoquinolinium -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 43a (28mg, it is yellow Color oily liquids, yield: 48%).

MS-ESI calculated value [M+H]⁺418, measured value 418.

Second step

5- ((4- methylisoquinolinium -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 43a (28mg, 0.067mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-according to the synthetic method of embodiment 1 Base) sulfonyl) -4- methylisoquinolinium 43 (8mg, white solid, yield: 34%).

¹H NMR(400MHz,D₂O): δ 8.99 (brs, 1H), 8.39-8.28 (m, 2H), 8.21 (m, 1H), 7.64 (t, J= 8.0Hz,1H),3.68-3.59(m,4H),3.49-3.47(m,2H),3.30-3.23(m,2H),3.12-3.04(m,2H), 2.84-2.76(brs,3H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Embodiment 44

5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-yl) sulfonyl) -4- methylisoquinolinium

The first step

Hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (30mg, 0.13mmol, embodiment 8) and 4- methylisoquinolinium -5- sulfonic acid chloride 37d (48mg, 0.2mmol, embodiment 37) obtains 2- (4- according to the synthetic method of embodiment 1 Methylisoquinolinium -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c]

Pyridine -5 (6H)-carboxylic acid tert-butyl ester 44a (40mg, colourless oil liquid, yield: 70%).

Second step

2- (4- methylisoquinolinium -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (the 6H)-tertiary fourth of carboxylic acid Ester 44a (40mg, 0.47mmol) obtains 5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 according to the synthetic method of embodiment 1 (3H)-yl) sulfonyl) -4- methylisoquinolinium 44 (15mg, white solid, yield: 40%).

¹H NMR(400MHz,D₂O): δ 9.50 (s, 1H), 8.58 (d, J=8.0Hz, 1H), 8.52-8.44 (m, 2H), 7.96 (t, J=8.0Hz, 1H) 3.70-3.65 (m, 2H), 3.57-3.48 (m, 2H), 3.40-3.35 (m, 1H), 3.26-3.10 (m,3H),3.03(s,3H),2.89-2.73(m,2H),2.08-1.97(m,1H),1.89-1.77(m,1H).

Embodiment 45

6- ((4- methylisoquinolinium -5- base) sulfonyl) decahydro -1,6- benzodiazine

The first step

Octahydro -1,6- benzodiazine -1 (2H)-benzyl carboxylate 20c (30mg, 0.11mmol, embodiment 20) 4- methyl isoquinoline Quinoline -5- sulfonic acid chloride 37d (40mg, 0.16mmol, embodiment 37) obtains 6- ((4- methyl isoquinoline according to the synthetic method of embodiment 1 Quinoline -5- base) sulfonyl) octahydro -1,6- benzodiazine -1 (2H)-carboxylic acid tert-butyl ester 45a (40mg, colourless oil liquid, yield: 76%).

Second step

- 1 (2H)-carboxylic acid tert-butyl ester 45a of 6- ((4- methylisoquinolinium -5- base) sulfonyl) octahydro -1,6- benzodiazine (40mg, 0.084mmol) according to 5 compound 6- of embodiment (isoquinolin -5- base sulfonyl) decahydro -1,6- benzodiazine 5 conjunction At method obtain 6- ((4- methylisoquinolinium -5- base) sulfonyl) decahydro -1,6- benzodiazine 45 (12mg, white solid, Yield: 41%).

¹H NMR(400MHz,D₂O):δ9.03(brs,1H),8.36-8.30(m,2H),8.21(brs,1H),7.65 (brs,1H),3.98-3.74(m,2H),3.60-3.55(m,1H),3.45-3.40(m,1H),3.34-2.88(m,4H),2.80 (brs,3H),2.35-2.02(m,2H),1.96-1.70(m,4H),1.59(brs,1H).

Embodiment 46

5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 (1H)-yl) sulfonyl) -4- (trifluoromethyl) isoquinolin

The first step

By 4- bromo-isoquinoline 24a (10g, 48.3mmol) according to the fluoro- 5- nitroisoquinoline 24c's of 24 compound 4- of embodiment Synthetic method obtains the bromo- 5- nitroisoquinoline 46a of 4- (8.5g, yellow solid, yield 85%), and product directly carries out without further purification It reacts in next step.

Second step

The bromo- 5- nitroisoquinoline 46a (1.00g, 3.95mmol) of 4- is dissolved in 40mL1- methyl pyrrolidone, nitrogen protection Under sequentially add potassium fluoride (459mg, 7.90mmol), trifluoromethyl trimethylsilane (2.80g, 19.7mmol) and cuprous iodide (1.13g, 5.93mmol), 100 DEG C of gained mixture are stirred 8 hours, are cooled to room temperature after reaction, and 300mL acetic acid is added Ethyl ester dilution, is filtered to remove solid impurity.Filtrate is successively washed with water (20mL), saturated sodium-chloride water solution (20mL), with nothing Aqueous sodium persulfate dries, filters, and filtrate decompression concentration obtains 5- nitro-with chromatography silica gel column purification (30% ethyl acetate/petroleum ether) 4- trifluoromethyl isoquinolin 46b (500mg, yellow solid, yield: 52%).

¹H NMR (400MHz, DMSO-d6): δ 9.82 (s, 1H), 9.20 (s, 1H), 8.71 (d, J=7.2Hz, 1H), 8.57 (d, J=7.2Hz, 1H), 8.05-8.01 (m, 1H)

MS-ESI calculated value [M+H]⁺243, measured value 243.

Third step

5- nitro -4- trifluoromethyl isoquinolin 46b (1.00g, 4.15mmol) is according to 31 compound 4- (difluoro first of embodiment Base) isoquinolin -5- amine 31d synthetic method obtain 4- trifluoromethyl isoquinolin -5- amine 46c (523mg, yellow solid, yield: 59%).

¹H NMR (400MHz, DMSO): δ 9.41 (s, 1H), 8.76 (s, 1H), 7.61-7.55 (m, 2H), 7.10-7.05 (m,1H),5.45(s,2H).

MS-ESI calculated value [M+H]⁺213, measured value 213.

4th step

4- trifluoromethyl isoquinolin -5- amine 46c (300mg, 1.41mmol) is according to 16 compound 4-chloro isoquinolin of embodiment - The synthetic method of 5- sulfonic acid chloride 16d obtain 4- Trifluoromethylquinocarboxylic -5- sulfonic acid chloride 46d (74mg, light yellow solid, yield: 18%).

¹H NMR (400MHz, DMSO-d6): δ 9.53 (s, 1H), 8.89 (s, 1H), 8.60 (d, J=8.0Hz, 1H), 8.27 (d, J=8.0Hz, 1H), 7.81-7.77 (m, 1H)

5th step

4- trifluoromethyl isoquinolin -5- sulfonic acid chloride 46d (45m_g, 0.15mmol) and cis--hexahydropyrrolo simultaneously [3,4-b] pyrrole It coughs up -1 (2H)-carboxylic acid tert-butyl ester 2f (32mg, 0.15mmol, embodiment 2) and obtains 5- ((4- according to the synthetic method of embodiment 1 (trifluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 46e (30mg, Yellow solid, yield: 42%).

MS-ESI calculated value [M+H]⁺472, measured value 472.

6th step

5- ((4- (trifluoromethyl) isoquinolin -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid uncle Butyl ester 46e (30mg, 0.063mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,4-b] pyrroles -5 according to the synthetic method of embodiment 1 (1H)-yl) sulfonyl) -4- (trifluoromethyl) isoquinolin 46 (14mg, white solid, yield: 60%).

¹H NMR(400MHz,CD₃OD):δ9.62(s,1H),9.04(s,1H),8.58-8.55(m,2H),8.0-7.98 (m,1H),4.35-4.30(m,1H),3.75-3.70(m,1H),3.46-3.35(m,3H),3.27-3.12(m,3H),2.28- 2.23(m,1H),1.99-1.93(m,1H).

MS-ESI calculated value [M+H]⁺372, measured value 372.

Embodiment 47

5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-yl) sulfonyl) -4- methoxyisoquinoliae

The first step

The bromo- 5- nitroisoquinoline 46a of 4- (3.00g, 11.8mmol, embodiment 46) is different according to 16 compound 4-chloro of embodiment The synthetic method of quinoline -5- amine 16c obtains 4- bromo-isoquinoline -5- amine 47a (1.9g, light yellow solid, yield: 73%).

¹H NMR (400MHz, DMSO): δ 9.03 (s, 1H), 8.42 (s, 1H), 7.46-7.42 (m, 1H), 7.36 (d, J= 7.2Hz, 1H), 7.06 (d, J=7.2Hz, 1H), 6.17 (s, 2H)

Second step

By 4- bromo-isoquinoline -5- amine 47a (1.90g, 8.52mmol) according to 16 compound 4-chloro isoquinolin -5- sulphur of embodiment The synthetic method of acyl chlorides 16d obtains 4- bromo-isoquinoline -5- sulfonic acid chloride 47b (500mg, light yellow solid, yield: 20%).

¹H NMR (400MHz, DMSO): δ 9.57 (s, 1H), 8.91 (s, 1H), 8.40 (d, J=7.2Hz, 1H), 8.39 (d, J=7.2Hz, 1H), 7.86-7.82 (m, 1H)

Third step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (57mg, 0.19mmol) and cis--hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 1d (40mg, 0.19mmol, embodiment 1) obtains 4- ((4- bromine isoquinoline according to the synthetic method of embodiment 1 Quinoline -5- base) sulfonyl) simultaneously (62mg, yellow solid produce [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl acrylate 47c hexahydropyrrolo Rate: 68%).

¹H NMR(400MHz,CDCl₃): δ 9.23 (s, 1H), 9.02 (s, 1H), 8.37 (d, J=7.2Hz, 1H), 8.22 (d, J=7.2Hz, 1H), 7.73-7.69 (m, 1H), 4.67-4.47 (m, 2H), 3.81-3.63 (m, 2H), 3.50-3.37 (m, 3H),2.39-2.21(m,2H),2.05-1.93(m,1H),1.45(s,9H).

MS-ESI calculated value [M+H]⁺482, measured value 482.

4th step

4- ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl acrylate 47c (62mg, 0.13mmol) is dissolved in 1mL anhydrous methanol, and pyridine (0.2mg, 0.003mmol) is sequentially added under nitrogen protection, Sodium methoxide (300mg, 1.28mmol) and CuI (12mg, 0.064mmol).Gained mixture stirs 3 hours at 100 DEG C, is cooled to Room temperature is added the dilution of 30mL ethyl acetate, is filtered to remove solid impurity, filtrate successively use saturated aqueous ammonium chloride (20mL), Water (20mL), saturated sodium-chloride water solution (20mL) washing, are dried, filtered with anhydrous sodium sulfate, and thin layer is used in filtrate decompression concentration Silica gel chromatographic plate (100% ethyl acetate) purifies to obtain 4- ((4- methoxyisoquinoliae -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,2- B] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 47d (33mg, white solid, yield: 60%).

MS-ESI calculated value [M+H]⁺434, measured value 434.

5th step

4- ((4- methoxyisoquinoliae -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 47d (33mg, 0.063mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,2-b] pyrroles -1 (2H)-according to the synthetic method of embodiment 1 Base) sulfonyl) -4- methoxyisoquinoliae 47 (26mg, white solid, yield: 83%).¹H NMR(400MHz,D₂O):δ9.31 (s, 1H), 8.61 (d, J=7.6Hz, 1H), 8.50 (d, J=7.6Hz, 1H), 8.34 (s, 1H), 8.05-8.01 (m, 1H), 4.81-4.75(m,1H),4.58-4.57(m,1H),4.16(s,3H),3.80-3.70(m,1H),3.67-3.64(m,1H), 3.41-3.38(m,2H),2.53-2.50(m,1H),2.35-2.34(m,1H),2.25-2.21(m,2H).

MS-ESI calculated value [M+H]⁺334, measured value 334.

Embodiment 48

5- ((hexahydropyrrolo simultaneously [3,2-c] pyrroles -5 (1H)-yl) sulfonyl) -4- methoxyisoquinoliae

The first step

Cis--hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 2f (76mg, 0.36mmol, embodiment 2) 5- is obtained according to the synthetic method of embodiment 1 with 4- bromo-isoquinoline -5- sulfonic acid chloride 47b (94mg, 0.30mmol, embodiment 47) ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 48a (120mg, white Solid, yield 81%)

Second step

5- ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 48a (120mg, 0.250mmol) obtains 5- ((4- methoxyisoquinoliae -5- base) sulfonyl) six according to the synthetic method of embodiment 47 Hydrogen pyrrolo- [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 48b (86mg, white solid, yield: 80%).

MS-ESI calculated value [M+H]⁺434, measured value 434.

Third step

5- ((4- methoxyisoquinoliae -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-b] pyrroles -1 (2H)-carboxylic acid tert-butyl ester 48b (86mg, 0.2mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,2-c] pyrroles -5 (1H)-yl) according to the synthetic method of embodiment 1 Sulfonyl) -4- methoxyisoquinoliae 48 (25mg, white solid, yield: 38%).¹H NMR(400MHz,D₂O):δ9.28(s, 1H),8.56-8.53(m,2H),8.28(s,1H),8.00-7.96(m,1H),4.39-4.36(m,1H),4.10(s,3H), 3.84-3.81(m,1H),3.75-3.74(m,1H),3.62-3.60(m,1H),3.55-3.54(m,1H),3.31-3.27(m, 3H),2.28-2.22(m,1H),1.95-1.92(m,1H).

MS-ESI calculated value [M+H]⁺334, measured value 334.

Embodiment 49

5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-yl) sulfonyl) -4- methoxyisoquinoliae

The first step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (54mg, 0.18mmol, embodiment 47) and cis--octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 3a (40mg, 0.18mmol) according to the synthetic method of embodiment 1 obtains 6-, and ((4- bromine is different Quinoline -5- base) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 49a (receive by 80mg, white solid Rate: 91%).

¹H NMR(400MHz,CDCl3):δ9.21(s,1H),8.99(s,1H),8.34-8.32(m,1H),8.20-8.18 (m,1H),7.72-7.68(m,1H),4.01-3.98(m,1H),3.56-3.51(m,2H),3.48-3.41(m,2H),2.80- 2.75(m,1H),2.28-2.24(m,1H),1.83-1.77(m,2H),1.60-1.57(m,3H),1.43(s,9H).

MS-ESI calculated value [M+H]⁺496, measured value 496.

Second step

6- ((4- bromo-isoquinoline -5- base) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 49a (80mg, 0.16mmol) obtains 6- ((4- methoxyisoquinoliae -5- base) sulfonyl) octahydro-according to the synthetic method of embodiment 47 1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 49b (46mg, white solid, yield: 64%).

MS-ESI calculated value [M+H]⁺448, measured value 448.

Third step

6- ((the iso- 5- yl of 4- methoxyl group) sulfonyl) octahydro -1H- pyrrolo- [3,4-b] pyridine -1- carboxylic acid tert-butyl ester 49b (46mg, 0.1mmol) obtains 5- ((hexahydro -1H- pyrrolo- [3,4-b] pyridine -6 (2H)-according to the synthetic method of embodiment 1 Base) sulfonyl) -4- methoxyisoquinoliae 49 (20mg, white solid, yield: 56%).

¹H NMR:(400MHz,D₂O):δ9.21(s,1H),8.51-8.50(m,1H),8.36-8.34(m,1H),8.29 (s,1H),7.95-7.91(m,1H),4.08(s,3H),3.96-3.94(m,1H),3.83-3.79(m,2H),3.67-3.65 (m,1H),3.54-3.49(m,1H),3.31-3.28(m,1H),3.01-2.93(m,2H),1.90-1.65(m,4H).

MS-ESI calculated value [M+H]⁺348, measured value 348.

Embodiment 50

5- (3,6- diazabicyclo [3.2.0] heptane -3- base sulfonyl) -4- methoxyisoquinoliae

The first step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (57mg, 0.19mmol, embodiment 47) and 3,6- diazabicyclo [3.2.0] Heptane -6- carboxylic acid tert-butyl ester 4a (40mg, 0.12mmol, embodiment 4) according to the synthetic method of embodiment 1 obtains 3-, and ((4- bromine is different Quinoline -5- base) sulfonyl) (82mg, yellow solid produce -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 50a Rate: 87%).

¹H NMR(400MHz,CDCl₃): δ 9.22 (s, 1H), 9.02 (s, 1H), 8.69 (d, J=7.6Hz, 1H), 8.23 (d, J=7.6Hz, 1H), 7.73-7.69 (m, 1H), 4.78-4.76 (m, 1H), 4.10-3.92 (m, 2H), 3.75-3.56 (m, 2H), 3.44-3.12 (m, 3H), 1.39 (s, 9H) .MS-ESI calculated values [M+H]⁺468, measured value 468.

Second step

3- ((4- bromo-isoquinoline -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 50a (82mg, 0.18mmol) obtains 3- ((4- methoxyl group isoxazole -5- base) sulfonyl) -3,6- bis- according to the synthetic method of embodiment 47 Azabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 50b (30mg, white solid, yield 42%).

MS-ESI calculated value [M+H]⁺420, measured value 420.

Third step

3- ((4- methoxyl group isoxazole -5- base) sulfonyl) -3,6- diazabicyclo [3.2.0] heptane -6- carboxylic acid tert-butyl ester 50b (30mg, 0.071mmol) obtains 5- (3,6- diazabicyclos [3.2.0] heptane -3- base according to the synthetic method of embodiment 1 Sulfonyl) -4- methoxyisoquinoliae 50 (20mg, white solid, yield 86%).

¹H NMR(400MHz,D₂O):δ9.32(s,1H),8.62-8.57(m,2H),8.33(s,1H),8.03-7.99(m, 1H), 5.01 (t, J=6.0Hz, 1H), 4.28-4.23 (m, 1H), 4.17 (s, 3H), 4.11 (d, J=13.6Hz, 1H), 3.96 (d, J=13.6Hz, 1H), 3.84-3.79 (m, 1H), 3.62-3.52 (m, 2H), 3.46-3.42 (m, 1H)

MS-ESI calculated value [M+H]⁺320, measured value 320.

Embodiment 51

4- methoxyl group -5- ((octahydro -1H- pyrrolo- [3,2-b] pyridine -1- base) sulfonyl) isoquinolin

The first step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (59mg, 0.19mol, embodiment 47) and hexahydro -1H- pyrrolo- [3,2-b] Pyridine -4 (2H)-benzyl carboxylate 6e (50mg, 19mmol, embodiment 6) according to the synthetic method of embodiment 1 obtains 1-, and ((4- bromine is different Quinoline -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-carboxylic acid tert-butyl ester 51a (90mg, white solid, Yield: 88%).

¹H NMR(400MHz,CDCl₃):δ9.21(s,1H),8.99(s,1H),8.20-8.18(m,2H),7.77-7.70 (m,1H),7.38(brs,5H),5.18(s,2H),4.07-4.05(m,1H),3.89-3.86(m,1H),3.68-3.63(m, 3H),3.45-3.43(m,1H),2.87-2.84(m,1H),2.24-2.16(m,3H),1.69-1.65(m,1H),1.40-1.34 (m,1H).

MS-ESI calculated value [M+H]⁺530, measured value 530.

Second step

1- ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-carboxylic acid tert-butyl ester 51a (90mg, 0.17mmol) obtains 1- ((4- methoxyisoquinoliae -5- base) sulfonyl) six according to the synthetic method of embodiment 47 Hydrogen -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-carboxylate methyl ester 51b (30mg, white solid, yield: 44%).

MS-ESI calculated value [M+H]⁺406, measured value 406.

Third step

To 1- ((4- methoxyisoquinoliae -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,2-b] pyridine -4 (2H)-carboxylic acid The 25% of 0.1m L is added in the 2mL methanol solution of methyl esters 51b (30mg, 0.074mmol) and sodium methoxide (40mg, 0.74mmol) NaOH aqueous solution.By mixture under nitrogen atmosphere microwave heating to 90 DEG C 2 hours.It, will to be cooled to room temperature after reaction Mixture is diluted with ethyl acetate (50mL), and is washed with saturated sodium-chloride water solution (50mL), organic phase anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, residue obtains compound 4- methoxyl group-with thin layer chromatography (50% methanol/ethyl acetate) is prepared 5- ((octahydro -1H- pyrrolo- [3,2-b] pyridine -1- base) sulfonyl) isoquinolin 51 (20mg, white solid, yield: 78%).

¹H NMR(400MHz,CD₃OD):δ9.01(s,1H),8.51-8.49(m,1H),8.40-8.38(m,1H),8.36 (s,1H),7.86-7.82(m,1H),4.15(s,3H),4.14-4.12(m,1H),3.93-3.92(m,1H),3.80-3.76 (m,2H),3.13-3.11(m,1H),3.02-3.00(m,1H),2.34-2.28(m,2H),1.99-1.89(m,2H),1.65- 1.54(m,2H).

MS-ESI calculated value [M+H]⁺348, measured value 348.

Embodiment 52

5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) sulfonyl) -4- methoxyisoquinoliae

The first step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (58mg, 0.19mmol, embodiment 47) and cis--hexahydropyrrolo simultaneously [3,4- C] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 7a (40mg, 0.19mmol, embodiment 7) according to the synthetic method of embodiment 1 obtains 5- ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 52a (80mg, white Solid, yield: 88%).

¹H NMR(400MHz,CDCl₃):δ9.21(s,1H),9.00(s,1H),8.43-8.41(m,1H),8.22-8.20 (m,1H),7.73-7.69(m,1H),3.76-3.72(m,2H),3.38-3.34(m,4H),3.08-3.03(m,4H),1.61 (s,9H).

MS-ESI calculated value [M+H]⁺482, measured value 482.

Second step

5- ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 52a (80mg, 0.17mmol) obtains 5- ((4- methoxyisoquinoliae -5- base) sulfonyl) hexahydro according to the synthetic method of embodiment 47 Pyrrolo- [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 52b (45mg, white solid, yield: 63%).

MS-ESI calculated value [M+H]⁺434, measured value 434.

Third step

5- ((4- methoxyisoquinoliae -5- base) sulfonyl) hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-carboxylic acid tert-butyl ester 52b (45mg, 0.1mmol) obtains 5- ((hexahydropyrrolo simultaneously [3,4-c] pyrroles -2 (1H)-yl) according to the synthetic method of embodiment 1 Sulfonyl) -4- methoxyisoquinoliae 52 (20mg, white solid, yield: 58%).

¹H NMR(400MHz,D₂O):δ9.22(s,1H),8.53-8.49(m,2H),8.28(s,1H),7.97-7.93(m, 1H),4.10(s,3H),3.64-3.60(m,4H),3.56-3.53(m,2H),3.24-3.22(m,2H),3.08-3.05(m, 2H).

MS-ESI calculated value [M+H]⁺334, measured value 334.

Embodiment 53

5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 (3H)-yl) sulfonyl) -4- methoxyisoquinoliae

The first step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (54mg, 0.17mmol, embodiment 47) and hexahydro -1H- pyrrolo- [3,4-c] Pyridine -5 (6H)-carboxylic acid tert-butyl ester 8h (40mg, 0.17mmol, embodiment 8) obtains 2- ((4- according to the synthetic method of embodiment 1 Bromo-isoquinoline -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 53a (40mg, yellow Solid, yield: 46%).

MS-ESI calculated value [M+H]⁺496, measured value 496.

Second step

2- ((4- bromo-isoquinoline -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 53a (40mg, 0.081mmol) obtains 2- ((4- methoxyl group isoxazole -5- base) sulfonyl) six according to the synthetic method of embodiment 47 Hydrogen -1H- pyrrolo- [3,4-c] pyridine -5 (6H)-carboxylic acid tert-butyl ester 53b (20mg, white solid, yield: 55%).

MS-ESI calculated value [M+H]⁺448, measured value 448.

Third step

2- ((4- methoxyl group isoxazole -5- base) sulfonyl) hexahydro -1H- pyrrolo- [3,4-c] pyridine -5 (the 6H)-tertiary fourth of carboxylic acid Ester 53b (20mg, 0.044mmol) obtains 5- ((hexahydro -1H- pyrrolo- [3,4-c] pyridine -2 according to the synthetic method of embodiment 1 (3H)-yl) sulfonyl) -4- methoxyisoquinoliae 53 (14mg, white solid, yield: 77%).

¹H NMR (400MHz, D₂O): δ 9.26 (s, 1H), 8.57 (d, J=7.2Hz, 1H), 8.46 (d, J=7.2Hz, 1H),8.33(s,1H),8.01-7.97(m,1H),4.15(s,3H),3.72-3.66(m,2H),3.59-3.53(m,2H), 3.42-3.37(m,1H),3.25-3.14(m,3H),2.87-2.77(m,2H),2.10-2.02(m,1H),1.88-1.82(m, 1H).

MS-ESI calculated value [M+H]⁺348, measured value 348.

Embodiment 54

6- ((4- methoxyisoquinoliae -5- base) sulfonyl) decahydro -1,6- benzodiazine 55

The first step

4- bromo-isoquinoline -5- sulfonic acid chloride 47b (49mg, 0.16mmol, embodiment 47) and octahydro -1,6- benzodiazine -1 (2H)-benzyl carboxylate 20c (50mg, 0.16mmol, embodiment 20) obtains 6- ((4- bromine isoquinoline according to the synthetic method of embodiment 1 Quinoline -5- base) sulfonyl) octahydro -1,6- benzodiazine -1 (2H)-benzyl carboxylate 54a (46mg, yellow solid, yield: 53%).

¹H NMR(400MHz,CDCl₃):δ9.22(s,1H),9.01(s,1H),8.34-8.12(m,2H),7.72-7.68 (m,1H),7.37-7.32(m,5H),5.15(s,2H),4.12-3.84(m,2H),3.71-3.49(m,2H),3.26-2.67 (m,2H),2.05-1.67(m,4H),1.54-1.45(m,4H).

MS-ESI calculated value [M+H]⁺544, measured value 544.

Second step

6- ((4- bromo-isoquinoline -5- base) sulfonyl) octahydro -1,6- benzodiazine -1 (2H)-benzyl carboxylate 54a (46mg, 0.084mmol) 6- ((4- methoxyisoquinoliae -5- base) sulfonyl) octahydro -1,6- is obtained according to the synthetic method of embodiment 47 Benzodiazine -1 (2H)-benzyl carboxylate 55b (20mg, white solid, yield: 47%).

MS-ESI calculated value [M+H]⁺496, measured value 496.

Third step

- 1 (2H)-benzyl carboxylate 55b of 6- ((4- methoxyisoquinoliae -5- base) sulfonyl) octahydro -1,6- benzodiazine (20mg, 0.04mmol) according to 5 compound 6- of embodiment (isoquinolin -5- base sulfonyl) decahydro -1,6- benzodiazine 5 synthesis Method obtain 6- ((4- methoxyisoquinoliae -5- base) sulfonyl) decahydro -1,6- benzodiazine 55 (3mg, white solid, yield: 21%).

¹H NMR(400MHz,CD₃OD):δ8.97(s,1H),8.39-8.33(m,2H),8.31(s,1H),7.80-7.76 (m,1H),4.11(s,3H),3.95-3.56(m,2H),3.41-3.35(m,1H),3.20-3.03(m,2H),2.83-2.49 (m, 2H), 1.98-1.84 (m, 1H), 1.80-1.48 (m, 6H) .MS-ESI calculated value [M+H]⁺362, measured value 362.

Embodiment 55

3- (isoquinolin -5- base sulfonyl) -3- azabicyclic [3.2.0] heptane -1- amine

The first step

Under nitrogen protection, -78 DEG C to 5,6- dihydro -2H- pyran-2-one 55a (300mg, 3.06mmol) and N- benzyl -1- It is added dropwise in the 15mL dichloromethane solution of methoxyl group-N- ((trimethyl silicon substrate) methyl) methylamine 55b (1.09g, 4.59mmol) The 0.6mL dichloromethane solution of trifluoroacetic acid (520mg, 4.59mmol).

Gained mixture is warming up to 25 DEG C to stir 4 hours, is then diluted with 50mL methylene chloride, and use saturated potassium carbonate Aqueous solution (50mL x2) and saturated sodium-chloride water solution (50mL x1) washing, organic phase are dried, filtered with anhydrous sodium sulfate, are subtracted Pressure concentration.Residue with preparation thin layer chromatography board purify (50% ethyl acetate/petroleum ether) obtain 2- benzyl hexahydro pyrans simultaneously [4, 3-c] pyrroles -4 (6H) -one 55c (533mg, colourless oil liquid, yield: 75%).

¹H NMR(400MHz,CDCl₃):δ7.26-7.18(m,5H),4.34-4.33(m,2H),4.18-4.15(m,1H), 3.57-3.46(m,2H),2.89-2.85(m,2H),2.77-2.73(m,1H),2.71-2.61(m,1H),2.23-2.19(m, 1H),1.94-1.93(m,1H),1.60-1.59(m,1H).

MS-ESI calculated value [M+H]⁺232, measured value 232.

Second step

To the 100mL of 2- benzyl hexahydro pyrans simultaneously [4,3-c] pyrroles -4 (6H) -one 55c (9.00g, 38.9mmol) at 0 DEG C It is passed through freshly prepared hydrogen bromide in ethanol solution, and reacts 3 hours at this temperature, is then stirred 24 hours at 25 DEG C. To which reaction solution is concentrated after reaction, crude product recrystallizes in ethanol, obtains 1- base -4- (2- bromoethyl) pyrrolidines -3- Carboxylic acid, ethyl ester 55d (9.0g, white solid, yield: 85%).¹H NMR(400MHz,CDCl₃):δ7.69-7.67(m,2H), 7.42-7.41(m,3H),4.41-4.37(m,2H),4.26-4.19(m,2H),3.93-3.88(m,1H),3.72-3.62(m, 1H),3.42-3.39(m,2H),3.33-3.29(m,2H),3.05-2.95(m,1H),2.82-2.79(m,1H),1.92-1.87 (m,2H),1.33-1.27(m,3H).

MS-ESI calculated value [M+H]⁺340, measured value 340.

Third step

1- benzyl -4- (2- bromoethyl) pyrrolidines -3- carboxylic acid, ethyl ester 55d (1.00g, 2.94mmol) is dissolved under nitrogen protection In 100mL anhydrous tetrahydro furan, lithium hexamethyldisilazide (the four of 17.6mL, 17.6mmol, 1.0M are added dropwise at -78 DEG C Hydrogen tetrahydrofuran solution).Then reaction solution is warming up to 20 DEG C and reacted 18 hours.To after reaction by reaction solution ethyl acetate (100mL) dilution, is successively washed with saturated aqueous ammonium chloride (100mL x3), saturated sodium-chloride water solution (100mL x1), Organic phase is dried, filtered with anhydrous sodium sulfate, and filtrate decompression concentration, residue purifies (50% acetic acid with thin layer chromatography board is prepared Ethyl ester/petroleum ether) obtaining 3- benzyl -3- azabicyclo [3.2.0] heptane -1- carboxylic acid, ethyl ester 55e, (130mg, white solid produce Rate: 17%).

1H NMR(400MHz,CDCl₃):δ7.41-7.39(m,2H),7.34-7.31(m,2H),7.26-7.23(m, 1H),4.17-4.12(m,2H),3.71-3.67(m,2H),2.96-2.94(m,2H),2.85-2.82(m,1H),2.45-2.26 (m,3H),2.14-2.09(m,2H),1.77-1.76(m,1H),1.27-1.24(m,3H).

MS-ESI calculated value [M+H]⁺260, measured value 260.

4th step

By 3- benzyl -3- azabicyclo [3.2.0] heptane -1- carboxylic acid, ethyl ester 55e (130mg, 0.5mmol) and a hydronium(ion) Lithia (63mg, 1.5mmol) is dissolved in 7mL tetrahydrofuran/ethanol/water (v/v/v=4/2/1) in the mixed solvent and is heated to 40 DEG C are stirred 6 hours.To which reaction solution is cooled to 0 DEG C after reaction, reaction solution pH is adjusted to 2 with 6N hydrochloric acid, 30mL is added Saturated sodium-chloride water solution, ethyl acetate and tetrahydrofuran mixed solvent (v/v=4/1,100mL × 3) extraction, organic phase is successively (100mL x2) is washed with water (100mL × 2), saturated sodium-chloride water solution, is dried, filtered with anhydrous sodium sulfate, filtrate decompression Concentration, obtains crude product 3- benzyl -3- azabicyclo [3.2.0] heptane -1- carboxylic acid 55f (30mg, white solid, yield: 95%).It produces Object directly carries out next step reaction without further purification.

1H NMR(400MHz,DMSO-d6):δ11.01(brs,1H),7.62-7.47(m,5H),4.45(s,2H), 2.44-2.42(m,7H),2.19-1.92(m,2H).

MS-ESI calculated value [M+H]⁺232, measured value 232.

5th step

By 3- benzyl -3- azabicyclo [3.2.0] heptane -1- carboxylic acid 55f (50mg, 0.22mmol), N, N- diisopropyl Ethamine (56mg, 0.43mmol) and diphenyl phosphate azide (65mg, 0.24mmol) are dissolved in the 2mL tert-butyl alcohol, gained reaction solution It is stirred 2 hours at 40 DEG C, then rises to 80 DEG C and stir 12 hours.To after reaction be cooled to room temperature reaction solution, 50mL is used Saturated sodium-chloride water solution dilution, ethyl acetate extract (100mL x3), organic phase washed with water (100mL) and saturated sodium-chloride Aqueous solution (100mL) washing, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to get 3- benzyl -3- azabicyclo [3.2.0] heptane -1- base the amino carboxylic acid tert-butyl ester 55g (20mg, white solid, yield: 31%).Product without further purification directly into Row reacts in next step.

MS-ESI calculated value [M+H]⁺303, measured value 303.

6th step

By 3- benzyl -3- azabicyclo [3.2.0] heptane -1- base amino carboxylic acid tert-butyl ester 55g (20mg, 0.066mmol) It is dissolved in 5mL tetrahydrofuran, Pd (OH) is added under nitrogen protection₂/ C (5mg, 20%wt).Reaction solution is at nitrogen atmosphere (40Psi) Lower 30 DEG C of stirrings 48 hours until reaction terminates.After reaction solution is cooled to room temperature, filtering, filtrate decompression is concentrated to get 3- azepine Bicyclic [3.2.0] heptane -1- base the amino carboxylic acid tert-butyl ester 55h (10mg, white solid, yield: 71%).Product is straight without further purification Row is tapped into react in next step.

MS-ESI calculated value [M+H]⁺213, measured value 213.

7th step

By 3- azabicyclo [3.2.0] heptane -1- base amino carboxylic acid tert-butyl ester 55h (20mg, 0.094mmol) and isoquinoline Quinoline -5- sulfonic acid chloride 1c (22mg, 0.094mmol) obtains 3- (isoquinolin -5- base sulfonyl)-according to the synthetic method of embodiment 1 3- azabicyclic [3.2.0] heptane -1- aminocarbamic acid 55i (15mg, white solid, yield: 40%).Product is straight without further purification Row is tapped into react in next step.

MS-ESI calculated value [M+H]⁺404, measured value 404.

8th step

3- (isoquinolin -5- base sulfonyl) -3- azabicyclic [3.2.0] heptane -1- aminocarbamic acid 55i (30mg, It 0.074mmol) is dissolved in 3mL anhydrous methylene chloride, trifluoroacetic acid is added dropwise at 0 DEG C, and (0.5mL is dissolved in the molten of 1mL methylene chloride Liquid), stirred under nitrogen atmosphere 3 hours until raw material disappearance.Reaction solution is diluted with methylene chloride (50mL), successively uses saturated carbon Sour hydrogen sodium water solution (50mL x3), saturated sodium-chloride water solution (50mL) washing, are dried, filtered, filtrate subtracts with anhydrous sodium sulfate Pressure concentration purifies to obtain product 3- (isoquinolin -5- base sulfonyl) -3- azabicyclic [3.2.0] heptane -1- amine 55 with HPLC is prepared (3mg, white solid, yield: 13%).1H NMR(400MHz,CD₃OD):δ9.49(s,1H),8.76-8.74(m,1H), 8.70-8.68(m,1H),8.56-8.53(m,2H),7.96-7.92(m,1H),3.84-3.82(m,1H),3.56-3.54(m, 1H),3.15-3.11(m,1H),2.99-2.96(m,1H),2.31-2.21(m,3H),1.65-1.63(m,1H),1.39-1.38 (m,1H).

MS-ESI calculated value [M+H]⁺304, measured value 304.

Embodiment 56

3- (isoquinolin -5- sulfonyl) -3- azabicyclic [3.1.0] hexane -1- amine

The first step

By 3- azabicyclo [3.1.0] hexane -1- base amino carboxylic acid tert-butyl ester 56a (50mg, 0.25mmol) and isoquinolin - 5- sulfonic acid chloride 1c (75mg, 0.25mmol, embodiment 1) obtains (3- (isoquinolin -5- sulphonyl according to the synthetic method of embodiment 1 Base) -3- azabicyclic [3.1.0] hexane -1- base) amino carboxylic acid tert-butyl ester 56b (80mg, yellow oily liquid, yield: 82%).

MS-ESI calculated value [M+H]⁺390, measured value 390.

Second step

(3- (isoquinolin -5- sulfonyl) -3- azabicyclic [3.1.0] hexane -1- base) amino carboxylic acid tert-butyl ester 56b (30mg, 0.077mmol) obtains 3- (isoquinolin -5- sulfonyl) -3- azabicyclic according to the synthetic method of embodiment 1 [3.1.0] hexane -1- amine 56 (7mg, yellow solid, yield: 29%).

¹H NMR(400MHz,D₂O):δ9.70(s,1H),8.90-8.85(m,1H),8.75-8.70(m,1H),8.65- 8.60(m,1H),8.60-8.55(m,1H),8.05-8.00(m,1H),3.82-3.80(m,1H),3.53-3.47(m,1H), 3.45-3.36(m,2H),1.95-1.87(m,1H),1.15-1.13(m,1H),0.83-0.77(m,1H).

MS-ESI calculated value [M+H]⁺290, measured value 290.

Embodiment 57

N- ethyl -3- (isoquinolin -5- sulfonyl) -3- azabicyclic [3.1.0] hexane -1- amine

The first step

(3- (isoquinolin -5- sulfonyl) -3- azabicyclic [3.1.0] hexane -1- base) amino carboxylic acid tert-butyl ester 56b (50mg, 0.13mmol) obtains ethyl (3- (isoquinolin -5- sulfonyl) -3- azabicyclic according to the synthetic method of embodiment 11 [3.1.0] hexane -1- base) t-butyl carbamate 57a (33mg, yellow oily liquid object, yield: 62%).

MS-ESI calculated value [M+H]⁺418, measured value 418.

Second step

Ethyl (3- (isoquinolin -5- sulfonyl) -3- azabicyclic [3.1.0] hexane -1- base) t-butyl carbamate 57a (33mg, 0.079mmol) obtains N- ethyl -3- (isoquinolin -5- sulfonyl) -3- azepine two according to the synthetic method of embodiment 1 Ring [3.1.0] hexane -1- amine 57 (10mg, yellow solid, yield: 40%).

¹H NMR(400MHz,D₂O): δ 9.59 (s, 1H), 8.71 (d, J=6.8Hz, 1H), 8.63-8.54 (m, 3H), 7.96 (d, J=8.0Hz, 1H), 3.88 (d, J=9.2Hz, 1H), 3.54-3.41 (m, 3H), 3.09-2.99 (m, 2H), 2.05- 2.00 (m, 1H), 1.25 (t, J=8.4Hz, 1H), 1.14 (t, J=7.2Hz, 3H), 0.90-0.85 (m, 1H).

MS-ESI calculated value [M+H]⁺318, measured value 318.

Experimental example 1: in-vitro evaluation ROCK protein kinase inhibiting activity

Experiment purpose: the ROCK protein kinase of detection compound inhibits IC₅₀Value.

Experimental material:

Buffer solution: 20mM Hepes (pH7.5), 10mM MgCl2,1mM EGTA, 0.02%Brij35 is measured, 0.02mg/ml BSA, 0.1mM Na3VO4,2mM DTT, 1%DMSO

Experimental implementation:

ROCK protein kinase substrate Long S6Kinase substrate will be added in freshly prepared buffer solution Then 1nM ROCK protein kinase is added in peptide, 20 μM of of concentration, uniform stirring is added using Echo550 contains to be measuredization Precincubation 20 minutes at room temperature serial DMSO dilution (starting from 10 μM, be serially diluted by 3 times) for closing object, are added³³P-ATP (is put Penetrate 10 μ Ci/ μ L of intensity) initiation reaction, it reacts at room temperature two hours.Then P81 ion exchange paper (Whatman#3698- is used 915) it filters, with 0.75% phosphoric acid washing.Activity is detected using Filter-Binding method.

The protein kinase that the protein kinase inhibiting activity of compound is expressed as opposite substrate blank (simple DMSO) remaining is living Property.IC50 value and song are calculated using Prism software package (GraphPad Software, San Diego California, USA) Line.

Experimental result:

1 protein kinase inhibiting activity test result of table

Test sample (compound obtained by each embodiment)	Protein kinase inhibiting activity
		Embodiment 1	++
Embodiment 2	++
		Embodiment 3	++

Embodiment 4	++
		Embodiment 5	++
Embodiment 6	++
		Embodiment 7	++
Embodiment 8	++
		Embodiment 9	+
Embodiment 10	--
		Embodiment 11	--
Embodiment 12/12 '	++/++
		Embodiment 13	+++
Embodiment 14	++
		Embodiment 15	++
Embodiment 16	++
		Embodiment 17	++
Embodiment 18	++
		Embodiment 19	+++
Embodiment 20	++
		Embodiment 21	++
Embodiment 22	++
		Embodiment 23	++
Embodiment 24	+
		Embodiment 25	++
Embodiment 26	++
		Embodiment 27	++
Embodiment 28	++
		Embodiment 29	++
Embodiment 30	++
		Embodiment 31	--
Embodiment 32	--

Embodiment 33	--
		Embodiment 34	--
Embodiment 35	--
		Embodiment 36	--
Embodiment 37	++
		Embodiment 38	+++
Embodiment 39	++
		Embodiment 40	+++
Embodiment 41	+++
		Embodiment 42	+++
Embodiment 43	+++
		Embodiment 44	+++
Embodiment 45	+
		Embodiment 46	--
Embodiment 47	+
		Embodiment 48	+
Embodiment 49	+
		Embodiment 50	+
Embodiment 51	+
		Embodiment 52	+
Embodiment 53	+
		Embodiment 54	+
Embodiment 55	+
		Embodiment 56	++
Embodiment 57	+

Note: 5 μM of+<；++ 1 μM of <；+++ 0.1 μM of <；--N/A

Conclusion: the compounds of this invention has significant or even unexpected protease inhibiting activity.

Claims

1. compound shown in formula (I) or its pharmaceutically acceptable salt,

It is characterized in that

R₁Selected from H, F, Cl, C_1-3Alkyl, C_1-3Alkyl oxy；

X is selected from H, F, Cl, Br, I, CN, OH, NH₂、C_1-3Alkyl, C_1-3Alkyl oxy；

R₂It is selected from

W is selected from N (R_w1) or C (R_w2)(R_w3)；

L is selected from C (R_z1)(R_z2)；

Z is selected from singly-bound or C (R_z1)(R_z2)；

P is selected from (CH₂)_q1；

Q is selected from (CH₂)_q2；

q₁Selected from 0,1,2,3 or 4；

q₂Selected from 2,3 or 4；

R_3a、R_3b、R_w1、R_w2、R_w3、R_z1、R_z2Separately it is selected from H, F, Cl, Br, I, OH, NH₂、C_1-3Alkyl；

2. compound according to claim 1 or its pharmaceutically acceptable salt, characterized in that R₁Selected from H, F, Cl, first Base, methoxyl group；X is selected from H or OH.

3. compound according to claim 2 or its pharmaceutically acceptable salt, wherein structural unitChoosing From:

4. compound according to claim 1 or its pharmaceutically acceptable salt, characterized in that R₂It is selected fromWherein, E is singly-bound, and D is methylene；G is selected from (CH₂)_g；T is selected from (CH₂)_t；g Selected from 0,1,2,3 or 4；T is selected from 2,3 or 4；R_3bAs defined in claim 1.

5. compound according to claim 4 or its pharmaceutically acceptable salt, characterized in that R_3bSelected from NH₂。

6. compound shown in formula (I) or its pharmaceutically acceptable salt,

It is characterized in that

R₁Selected from H, F, Cl, C_1-3Alkyl, C_1-3Alkyl oxy；

R₂It is selected from

7. compound shown in formula (I) or its pharmaceutically acceptable salt,

It is characterized in that

R₁Selected from H, F, Cl, C_1-3Alkyl, C_1-3Alkyl oxy；

R₂It is selected fromWherein, Y is selected from (CH₂)_y；M is selected from (CH₂)_m；Y is selected from 0,1,2 or 3；

M is selected from 0 or 1.

8. compound shown in formula (I) or its pharmaceutically acceptable salt,

It is characterized in that

R₁Selected from H, F, Cl, C_1-3Alkyl, C_1-3Alkyl oxy；

R₂It is selected from

9. following compounds or its pharmaceutically acceptable salt, are selected from:

10. a kind of pharmaceutical composition, compound described in any one according to claim 1~9 containing therapeutically effective amount Or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

11. compound or its pharmaceutically acceptable salt described in any one or according to claim according to claim 1~9 Application in the drug of the various illnesss of correlation caused by pharmaceutical composition described in 10 treats vessel retraction in preparation, wherein described Relevant various illnesss be selected from cerebral embolism, cerebral ischemia, cerebral injury, vertebrobasilar insufficiency, caused by subarachnoid hemorrhage Cerebral angiospasm, angina pectoris, glaucoma, hypertension, fibrosis.