CN105085525A - Isoquinoline sulfonyl derivatives as RHO kinases inhibitor - Google Patents
Isoquinoline sulfonyl derivatives as RHO kinases inhibitor Download PDFInfo
- Publication number
- CN105085525A CN105085525A CN201410174893.1A CN201410174893A CN105085525A CN 105085525 A CN105085525 A CN 105085525A CN 201410174893 A CN201410174893 A CN 201410174893A CN 105085525 A CN105085525 A CN 105085525A
- Authority
- CN
- China
- Prior art keywords
- isoquinoline
- alkylsulfonyl
- butyl ester
- carboxylic acid
- acid tert
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *c1cccc2c1c(*)cnc2* Chemical compound *c1cccc2c1c(*)cnc2* 0.000 description 22
- WZZUXKOQFVNNCG-UHFFFAOYSA-N Bc1cncc2c1c(N=O)ccc2 Chemical compound Bc1cncc2c1c(N=O)ccc2 WZZUXKOQFVNNCG-UHFFFAOYSA-N 0.000 description 1
- XKEYAOJRNJYJMM-UHFFFAOYSA-N C1NC2C1CNC2 Chemical compound C1NC2C1CNC2 XKEYAOJRNJYJMM-UHFFFAOYSA-N 0.000 description 1
- JMWPSCUIQIMVQH-UHFFFAOYSA-N C1NCC2C1CCNC2 Chemical compound C1NCC2C1CCNC2 JMWPSCUIQIMVQH-UHFFFAOYSA-N 0.000 description 1
- MZFUXDMVFNWDLZ-UHFFFAOYSA-N C=NC1C2(CC2)CN(CS(c2cccc3cnccc23)(=O)=O)C1 Chemical compound C=NC1C2(CC2)CN(CS(c2cccc3cnccc23)(=O)=O)C1 MZFUXDMVFNWDLZ-UHFFFAOYSA-N 0.000 description 1
- UHEJMGGBYBFBMF-UHFFFAOYSA-N CCN1CC2NCCC2C1 Chemical compound CCN1CC2NCCC2C1 UHEJMGGBYBFBMF-UHFFFAOYSA-N 0.000 description 1
- HAYCMTZHXBJAEM-UHFFFAOYSA-N Cc1cccc2c1c(Cl)cnc2 Chemical compound Cc1cccc2c1c(Cl)cnc2 HAYCMTZHXBJAEM-UHFFFAOYSA-N 0.000 description 1
- VBTBUCYRQSUCCE-UHFFFAOYSA-N NC1C2(CC2)CNC1 Chemical compound NC1C2(CC2)CNC1 VBTBUCYRQSUCCE-UHFFFAOYSA-N 0.000 description 1
- PUGQKSQYMWHNKV-UHFFFAOYSA-N O=S(C1=CCCc2c1c(Cl)cnc2)(N(CC1)CC2C1NCCC2)=O Chemical compound O=S(C1=CCCc2c1c(Cl)cnc2)(N(CC1)CC2C1NCCC2)=O PUGQKSQYMWHNKV-UHFFFAOYSA-N 0.000 description 1
- DXZZYJCDKMORHU-TXEJJXNPSA-N O=S(c1cccc2cncc(Cl)c12)(N1C[C@H](CNC2)[C@H]2C1)=O Chemical compound O=S(c1cccc2cncc(Cl)c12)(N1C[C@H](CNC2)[C@H]2C1)=O DXZZYJCDKMORHU-TXEJJXNPSA-N 0.000 description 1
- KRIKTHADBQPUEL-CBUCPLPXSA-N O=S(c1cccc2cncc(Cl)c12)(N1C[C@H](CNC2)[C@H]2C1)=[U] Chemical compound O=S(c1cccc2cncc(Cl)c12)(N1C[C@H](CNC2)[C@H]2C1)=[U] KRIKTHADBQPUEL-CBUCPLPXSA-N 0.000 description 1
- NOVCMMVHWVHKFW-UHFFFAOYSA-N O=Sc1cccc2c1ccnc2 Chemical compound O=Sc1cccc2c1ccnc2 NOVCMMVHWVHKFW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of isoquinoline sulfonyl derivatives as a RHO kinases inhibitor and a pharmaceutical composition of the derivatives, and relates to pharmaceutical application of the derivatives. Concretely, the invention relates to compositions shown as a formula (I) or pharmaceutically acceptable salts.
Description
Technical field
The present invention relates to a class as the isoquinoline 99.9 sulfonyl derivative of RHO kinase inhibitor and pharmaceutical composition thereof, and relate to its pharmaceutical applications.Particularly, the present invention relates to compound or its pharmacy acceptable salt shown in formula (I).
Background technology
Fasudil is a kind of newtype drug with extensive pharmacological action; for RHO kinase inhibitor; by increasing the active vasodilation of Myosin light chain phosphatase; reduce the tension force of endotheliocyte; improve cerebral tissue microcirculation, do not produce and increase the weight of robber's blood of brain, simultaneously can antagonism inflammatory factor; neuroprotective anti-apoptotic, promotes neurotization.This result shows that Fasudil Hydrochloride is to the recovery promoting neural function, alleviates clinical symptom, and reducing disability rate has certain curative effect.Therefore for basic unit due to by economic condition restriction and to disease cognitive degree; extreme early thromboembolism treatment can not realize; but for reducing the further progress of disease; in therapeutic time window, rebuild blood circulation seem most important; and Fasudil Hydrochloride has remarkable neuroprotective to ischemic cerebrovascular disease and therapeutic action; be worth the use in clinical especially basic unit, reduce disability rate, improve the quality of living.
WO2004106325 discloses a compounds, belongs to the prodrug of fasudil, and its general structure is such as formula shown in (B-I):
Although there is above-claimed cpd in prior art to can be used as RHO kinase inhibitor, they activity, solvability, pharmacokinetics, druggability etc. in have much room for improvement.
Summary of the invention
The object of the present invention is to provide compound or its pharmacy acceptable salt shown in formula (I),
It is characterized in that,
R
1, X is separately selected from H, F, Cl, Br, I, CN, OH, NH
2, C
1 ?3alkyl, C
1 ?3alkyl oxy, C
1 ?3alkylamino, two C
1 ?3alkylamino, described C
1 ?3alkyl is optionally by R
01replaced, R
01be selected from F, Cl, Br, I, OH, NH
2, R
01number be 1,2 or 3;
R
2be selected from
W, W ' be separately selected from N (R
w1), C (R
w2) (R
w3) or singly-bound;
L, Z are separately selected from singly-bound or C (R
z1) (R
z2);
P, P ' be selected from (CH respectively
2)
q1; Q, Q ' be selected from (CH respectively
2)
q2;
Q
1, q
2separately be selected from 0,1,2,3 or 4;
R
3a, R
3b, R
3, R
w1, R
w2, R
w3, R
z1, R
z2separately be selected from H, F, Cl, Br, I, CN, OH, NH
2, C
1 ?3alkyl, C
1 ?3alkyl oxy, C
1 ?3alkylamino, two C
1 ?3alkylamino, described C
1 ?3alkyl is optionally by R
01replaced.
In a scheme of the present invention, R
3a, R
3b, R
3, R
w1, R
w2, R
w3be selected from halo, hydroxyl generation and/or amine for methyl, ethyl or propyl group;
R
01be selected from F, Cl, Br, I, OH, NH
2, R
01number be 1,2 or 3.
In a scheme of the present invention, described R
1be selected from H, F, Cl, Br, I, methyl, difluoromethyl, trifluoromethyl, methoxyl group; X is selected from H or OH.
In a scheme of the present invention, described structural unit
be selected from:
In a scheme of the present invention, described R
2be selected from
wherein in A, B one be singly-bound, another is methylene radical; R4 is selected from H, F, Cl, Br, I, CN, OH, NH
2, C
1 ?3alkyl, C
1 ?3alkyl oxy, C
1 ?3alkylamino, two C
1 ?3alkylamino, described C
1 ?3alkyl is optionally by R
01replaced, R
01be selected from F, Cl, Br, I, OH, NH
2, R
01number be 1,2 or 3; Preferably, R4 is selected from NH2, ethylamino;
In a scheme of the present invention, R4 is selected from
In a scheme of the present invention, above-claimed cpd or its pharmacy acceptable salt, described R
2be selected from
or
wherein, in D, E, one is singly-bound, and another is methylene radical;
G is selected from (CH
2)
g; T is selected from (CH
2)
t; G, t are separately selected from 0,1,2,3 or 4; R
3bas claim 1 define;
In a scheme of the present invention, g be 1,2,3 or 4, t be 0 or 1;
In a scheme of the present invention, R
3bbe selected from NH
2;
In a scheme of the present invention, R
2be selected from
In a scheme of the present invention, above-mentioned R
2be selected from
wherein, Y is selected from (CH
2)
y; M is selected from (CH
2)
m; Y is selected from 0,1,2 or 3; M is selected from 0 or 1;
In a scheme of the present invention, R
2be selected from
In a scheme of the present invention, above-mentioned R
2be selected from
in a scheme of the present invention, above-claimed cpd or its pharmacy acceptable salt are selected from:
Another object of the present invention is to provide a kind of pharmaceutical composition, and it contains the above-claimed cpd or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
Another object of the present invention is to provide above-claimed cpd or its pharmacy acceptable salt or aforementioned pharmaceutical compositions to treat the application in the medicine of the relevant various illness that vasoconstriction causes in preparation, and wherein said relevant various illnesss comprise cerebral vasospasm, stenocardia, glaucoma, hypertension, fibrosis caused by cerebral embolism, cerebral ischemia, brain injury, vertebrobasilar insufficiency, subarachnoid hemorrhage.
Here adopted term " pharmaceutically acceptable ", for those compounds, material, composition and/or formulation, they are within the scope of reliable medical judgment, be applicable to use with the contact tissue of human and animal, and there is no too much toxicity, pungency, anaphylaxis or other problem or complication, match with rational interests/Hazard ratio.
Term " pharmacy acceptable salt " refers to the salt of the compounds of this invention, prepared by the have compound of specified substituent and the acid of relative nontoxic or alkali that are found by the present invention.When containing relatively acid functional group in compound of the present invention, can by obtaining base addition salt by the mode that the alkali of q.s contacts with the neutral form of this compounds in pure solution or suitable inert solvent.Pharmaceutically acceptable base addition salt comprises sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.When containing the functional group of alkalescence relatively in compound of the present invention, can by obtaining acid salt by the mode that the acid of q.s contacts with the neutral form of this compounds in pure solution or suitable inert solvent.The example of pharmaceutically acceptable acid salt comprises inorganic acid salt, and described mineral acid comprises such as hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphoric acid one hydrogen root, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid HI, phosphorous acid etc.; And organic acid salt, described organic acid comprises acid as similar in acetic acid, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, FUMARIC ACID TECH GRADE, lactic acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, tosic acid, citric acid, tartrate and methylsulfonic acid etc.; Also comprise the salt of amino acid (as arginine etc.), and if the organic acid salt such as glucuronic acid are (see Bergeetal., " PharmaceuticalSalts ", JournalofPharmaceuticalScience66:1 ?19 (1977)).Some specific compound of the present invention contains alkalescence and acid functional group, thus can be converted into arbitrary alkali or acid salt.
Preferably, make salt and alkali or acid contact in a usual manner, then be separated parent compound, thus the neutral form of raw compounds again.The difference of the form of the parent fo salt various with it of compound is some physical properties, such as, different solubility in polar solvent.
" pharmacy acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein, by modifying described parent compound with sour salify or with the mode of alkali salify.The example of pharmacy acceptable salt includes but not limited to: base ratio is as the basic metal or organic salt etc. of the mineral acid of amine or organic acid salt, acid group such as carboxylic acid.Pharmacy acceptable salt comprises conventional avirulent salt or the quaternary ammonium salt of parent compound, the salt that such as nontoxic mineral acid or organic acid are formed.Conventional avirulent salt includes but not limited to that those are derived from mineral acid and organic acid salt, described mineral acid or organic acid be selected from 2 ?acetoxy-benzoic acid, 2 ?ethylenehydrinsulfonic acid, acetic acid, xitix, Phenylsulfonic acid, phenylformic acid, bicarbonate radical, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, glyconic acid, L-glutamic acid, oxyacetic acid, Hydrogen bromide, hydrochloric acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, toxilic acid, oxysuccinic acid, amygdalic acid, methanesulfonic, nitric acid, oxalic acid, pamoic acid, pantothenic acid, toluylic acid, phosphoric acid, poly galacturonic, propionic acid, Whitfield's ointment, stearic acid, sub-acetic acid, succsinic acid, thionamic acid, Sulphanilic Acid, sulfuric acid, tannin, tartrate and tosic acid.
Pharmacy acceptable salt of the present invention can be synthesized by conventional chemical processes by the parent compound containing acid group or base.Generally, the preparation method of such salt is: in water or organic solvent or both mixtures, and these compounds via free acid or alkali form are prepared with stoichiometric suitable alkali or acid-respons.Usually, the non-aqueous media such as preferred ether, ethyl acetate, ethanol, Virahol or acetonitrile.
Except the form of salt, also there is prodrug forms in compound provided by the present invention.Easily there is chemical transformation in physiological conditions thus change into compound of the present invention in the prodrug of compound described herein.In addition, prodrug can be switched to compound of the present invention by chemistry or biochemical method in environment in vivo.
Some compound of the present invention can exist with nonsolvated forms or solvation form, comprises hydrate forms.Generally speaking, solvation form is suitable with non-solvated form, is included within scope of the present invention.Some compound of the present invention can exist with polycrystalline or amorphous form.
Some compound of the present invention can have unsymmetrical carbon (optical center) or double bond.Racemic modification, diastereomer, geometrical isomer and single isomer all comprise within the scope of the present invention.
Herein the compound of raceme, ambiscalemicandscalemic or enantiomer-pure graphic interpretation from Maehr, J.Chem.Ed.1985,62:114 ?120.1985,62:114 ?120.Except as otherwise noted, the absolute configuration of a Stereocenter is represented with webge groove and dotted line key.When compound described herein contains olefinic double bond or other geometry asymmetric center, unless otherwise prescribed, they comprise E, Z geometrical isomer.Similarly, all tautomeric forms include within the scope of the present invention.
Specific geometry or stereoisomer form can be there is in compound of the present invention.The present invention imagines this all compounds, comprise cis and trans-isomer(ide), (?) ?and (+) ?to enantiomorph, (R) ?and (S) ?enantiomorph, diastereomer, (D) ?isomer, (L) ?isomer, and racemic mixture and other mixtures, the such as mixture of enantiomer or diastereomer enrichment, all these mixtures all belong within scope of the present invention.Other unsymmetrical carbon can be there is in the substituting groups such as alkyl.All these isomer and their mixture, include within the scope of the present invention.
The chiral synthesize that can pass through or chiral reagent or other routine techniquess prepare optically active (R) ?and (S) ?isomer and D and L isomer.If expect a kind of enantiomorph of the present invention's compound, can be prepared by asymmetric synthesis or the derivatization with chiral auxiliary(reagent), wherein gained non-enantiomer mixture is separated, and auxiliary group split to provide pure needed for enantiomer.Or, when containing basic functionality (as amino) or acidic functionality (as carboxyl) in molecule, the salt of diastereomer is formed with suitable optically active acid or alkali, then carry out diastereomer fractionation by Steppecd crystallization known in the field or chromatography, then reclaim and obtain pure enantiomorph.In addition, enantiomer is separated normally by using chromatography to complete with diastereomer, and described chromatography adopts chiral stationary phase, and optionally combine with chemical derivatization (such as generating carbaminate by amine).
Compound of the present invention can comprise the atom isotope of unnatural proportions on the atom of one or more this compound of formation.Such as, using radiation compound isotopically labelled, such as tritium (
3h) ， Dian ?125 (
125i) or C ?14 (
14c).The conversion of all isotopics of compound of the present invention, no matter whether radioactivity, all comprises within the scope of the present invention.
Term " pharmaceutically acceptable carrier " refers to the biological activity that can send significant quantity active substance of the present invention, not interferon activity material and any preparation had no side effect to host or patient or the representational carrier of mounting medium comprise water, oil, vegetables and mineral substance, cream base, lotion base, ointment base etc.These matrix comprise suspension agent, tackifier, transdermal enhancer etc.Their preparation by the technician in cosmetic field or part drug field known.About other information of carrier, can with reference to Remington:TheScienceandPracticeofPharmacy, 21stEd., Lippincott, Williams & Wilkins (2005), the content of the document is incorporated to herein by way of reference.
Term " vehicle " typically refers to carrier, thinner and/or medium required for preparation drug composition effective.
For medicine or pharmacologically active agents, term " significant quantity " or " treatment significant quantity " refer to nontoxic but enough consumptions of the medicine that can produce a desired effect or medicament.For the oral dosage form in the present invention, in composition a kind of " significant quantity " of active substance refer to in said composition during another kind of active substance coupling in order to the required consumption that produces a desired effect.The determination of significant quantity varies with each individual, and depend on age and the generalized case of acceptor, also depend on concrete active substance, significant quantity suitable in case can be determined according to routine test by those skilled in the art.
Term " activeconstituents ", " therapeutical agent ", " active substance " or " promoting agent " refers to a kind of chemical entities, and it can disorderly, the disease of therapeutic goal or illness effectively.
Term " is substituted " any one or more hydrogen atoms referred in specific atoms and is substituted with a substituent, and comprises the variant of heavy hydrogen and hydrogen, as long as the valence state of specific atoms is normal and after replacing compound is stable.When substituting group is ketone group (namely=O), mean that two hydrogen atoms are substituted.Ketone replacement can not occur on aromatic base.Term " is optionally substituted " and refers to and can be substituted, and also can not be substituted, and unless otherwise prescribed, substituent kind and number can be arbitrary on the basis that chemically can realize.
When any variable (such as R) occurs once in the composition or structure of compound, its definition is at each occurrence all independently.Therefore, such as, if group by 0 ?2 R replace, then described group can optionally at the most replace by two R, and the R in often kind of situation has independently option.In addition, the combination of substituting group and/or its variant to be only only when such combination can produce stable compound and to be allowed to.
Can be cross connected to two atomic time on a ring when a substituent key, this substituting group can with the arbitrary atom phase bonding on this ring.Do not indicate in cited substituting group its by which atom be connected to chemical structure of general formula comprise but the compound specifically do not mentioned time, this substituting group can pass through its any atom phase bonding.The combination of substituting group and/or its variant is only only when such combination can produce stable compound and is allowed to.
Alkyl and assorted alkyl radicals (comprise be commonly called alkylidene group, alkenyl, sub-assorted alkyl, assorted thiazolinyl,
Those groups of alkynyl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group and heterocycloalkenyl) substituting group be commonly referred to as " alkyl substituent ", they can be selected from but be not limited to one or more: in following groups ?R ’, ?OR ' ,=O ,=NR ' ,=N ?OR ’, ?NR ' R ”, ?SR ', halogen, ?SiR ' R " R " ', OC (O) R ’, ?C (O) R ’, ?CO
2r ’, ?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 " SO
2r ’, ?CN, – NO
2, ?N
3, ?CH (Ph)
2with fluoro (C
1?C
4) alkyl, substituent number 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 ' ' ' ' ' preferably hydrogen, substituted or unsubstituted assorted alkyl, substituted or unsubstituted aryl (such as by 1 ~ 3 aryl substituted with halogen), substituted or unsubstituted alkyl, alkoxyl group, thio alkoxy group or aralkyl independently of one another.When compound of the present invention comprises more than one R group, such as, each R group is selected independently, as when there is more than one R', R ", R " ', R ' ' ' ' and R ' ' ' ' ' group time these groups each.As R' and R " when being attached to same nitrogen-atoms, they can with this nitrogen-atoms in conjunction with formation 5 ?, 6 ?or 7 ?ring.Li Ru ， ?NR'R " be intended to include but are not limited to 1 ?pyrrolidyl and 4 ?morpholinyl.According to above-mentioned about in substituent discussion, it will be understood by those skilled in the art that the group that term " alkyl " is intended to comprise carbon atom bonding and forms in non-hydrogen group, as haloalkyl, (example is as ?CF
3, ?CH
2cF
3) and acyl group (Li Ru ?C (O) CH
3, ?C (O) CF
3, ?C (O) CH
2oCH
3deng).
Similar to substituting group described in alkyl radicals, aryl and heteroaryl substituent are generally referred to as " aryl substituent ", be selected from Li Ru ?R ', ?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 " SO
2r ’, ?CN, – NO
2, ?N
3, ?CH (Ph)
2, fluorine (C
1?C
4) alkoxyl group and fluorine (C
1?C
4) alkyl etc., substituent quantity is open between valent sum on 0 to aromatic nucleus, wherein R ', R ", R " ', R " " and R " " ' preferred from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted assorted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl independently.When compound of the present invention comprises more than one R group, such as, each R group is selected independently, as existence more than one R ', R ", R " ', R " " and R " " ' group time these groups each.
Two substituting groups on the adjacent atom of aryl or heteroaryl ring can optionally by general formula by – T ?C (O) ?(CRR ') q ?U ? substituting group replaced, wherein T and U Du on the spot Xuan Zi ?NR ?, ?O ?, CRR' ?or singly-bound, q is the integer of 0 to 3.Alternatively, two substituting groups on the adjacent atom of aryl or heteroaryl ring can optionally by general formula by – A (CH2) rB ? substituting group replaced, wherein A and B independently Xuan Zi – CRR ’ ?, ?O ?, ?NR ?, ?S ?, ?S (O) ?, S (O)
2?, ?S (O)
2nR ’ ?or singly-bound, r is the integer of 1 ~ 4.Optionally, a singly-bound on the new ring formed thus can replace with double bond.Alternatively, two substituting groups on the adjacent atom of aryl or heteroaryl ring can optionally by general formula by – A (CH2) rB ? substituting group replaced, wherein s and d independently be selected from 0 ~ 3 integer, X Shi – O ?, ?NR ’, ?S ?, ?S (O) ?, ?S (O)
2?Huo – S (O)
2nR ’ ?.Substituent R, R ', R " and R " ' separately preferred from hydrogen and substituted or unsubstituted (C
1?C
6) alkyl.
Unless otherwise prescribed, term " halo element " or " halogen " itself or represent fluorine, chlorine, bromine or iodine atom as another substituent part.In addition, term " haloalkyl " is intended to comprise single haloalkyl and multi-haloalkyl.Such as, term " halo (C
1?C
4) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2 ?trifluoroethyl, 4 ?chlorobutyl and 3 ?bromopropyl etc.
The example of haloalkyl includes but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl group, and pentachloro-ethyl." alkoxyl group " represents the abovementioned alkyl with given number carbon atom connected by oxo bridge.C
1 ?6alkoxyl group comprises C
1, C
2, C
3, C
4, C
5and C
6alkoxyl group.The example of alkoxyl group includes but not limited to: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, n-pentyloxy and S ?pentyloxy." cycloalkyl " comprises saturated cyclic group, as cyclopropyl, cyclobutyl or cyclopentyl.3 ?7 cycloalkyl comprise C
3, C
4, C
5, C
6and C
7cycloalkyl." alkenyl " comprises the hydrocarbon chain of straight or branched configuration, wherein any on this chain stable site exists one or more carbon ?carbon double bond, such as vinyl and propenyl.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Unless otherwise prescribed, term " is mixed " and is represented heteroatoms or heteroatoms group (namely containing heteroatomic atomic group), comprise atom beyond carbon (C) and hydrogen (H) and containing these heteroatomic atomic groups, such as comprise 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 be substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O)
2n (H)-or-S (=O) N (H)-.
Unless otherwise prescribed, " ring " represents substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring comprises monocycle, connection ring, volution ring or bridged ring.The number of ring atom is generally defined as first number of ring, and such as, " 5 ~ 7 ring " refers to around arrangement 5 ~ 7 atoms.Unless otherwise prescribed, this ring optionally comprises 1 ~ 3 heteroatoms.Therefore, " 5 ~ 7 ring " comprises such as phenylpyridine and piperidyl; On the other hand, term " 5 ~ 7 yuan of heterocycloalkyl rings " comprises pyridyl and piperidyl, but does not comprise phenyl.Term " ring " also comprises the ring system containing at least one ring, and each " ring " wherein meets above-mentioned definition all independently.
Unless otherwise prescribed, term " heterocycle " or " heterocyclic radical " mean stable monocycle, dicyclo or three rings rolled into a ball containing heteroatoms or heteroatoms, they can be saturated, part is undersaturated or undersaturated (aromatics), they comprise carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S, and wherein above-mentioned any heterocycle can be fused on a phenyl ring and form dicyclo.Nitrogen and sulfur heteroatom can optionally oxidized (namely NO and S (O) p).Nitrogen-atoms can be that be substituted or unsubstituted (i.e. N or NR, wherein R other substituting groups of being H or being defined herein).The side base that this heterocycle can be attached to any heteroatoms or carbon atom forms stable structure.If the compound produced is stable, can there is the replacement on carbon potential or nitrogen position in heterocycle as herein described.Assorted ring nitrogen is optionally quaternized.A preferred version is, when the sum of S and O atom in heterocycle is more than 1, these heteroatomss are not adjacent to each other.Another preferred version is, in heterocycle, the sum of S and O atom is no more than 1.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean 5,6,7 yuan of stable monocycles or the aromatic nucleus of dicyclo or 7,8,9 or 10 yuan of bicyclic heterocyclic radicals, and it comprises carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S.Nitrogen-atoms can be that be substituted or unsubstituted (i.e. N or NR, wherein R other substituting groups of being H or being defined herein).Nitrogen and sulfur heteroatom can optionally oxidized (namely NO and S (O) p).It should be noted that the sum of S and O atom on aromatic heterocycle is no more than 1.Bridged ring is also contained in the definition of heterocycle.Bridged ring is formed when one or more atom (i.e. C, O, N or S) connects two non-conterminous carbon atoms or nitrogen-atoms.Preferred bridged ring includes but not limited to: carbon atom, two carbon atoms, nitrogen-atoms, two nitrogen-atoms and a Ge Tan ?nitrogen base.It should be noted that a bridge always converts monocycle to three rings.In bridged ring, the substituting group on ring also can appear on bridge.
The example of heterogeneous ring compound includes but not limited to: acridyl, azocine base, benzimidazolyl-, benzofuryl, benzo sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo tetrazyl, benzisoxa oxazolyl, benzisothiazole base, benzimidazoline base, carbazyl, 4aH ?carbazyl, carbolinyl, chromanyl, chromene, cinnolines base decahydroquinolyl, 2H, 6H ?1,5,2 ?dithiazine base, dihydrofuran is [2,3 ?b] tetrahydrofuran base also, furyl, furazan base, imidazolidyl, imidazolinyl, imidazolyl, 1H ?indazolyl, indoles thiazolinyl, indolinyl, indolizine base, indyl, 3H ?indyl, isatino base, isobenzofuran-base, pyrans, pseudoindoyl, iso-dihydro-indole-group, pseudoindoyl, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydro isoquinolyl, oxadiazoles base, 1,2,3 ?oxadiazoles base, 1,2,4 ?oxadiazoles base, 1,2,5 ?oxadiazoles base, 1,3,4 ?oxadiazoles base, oxazolidinyl, oxazolyl, isoxazolyl, oxindole base, pyrimidyl, phenanthridinyl, phenanthroline base, azophenlyene, thiodiphenylamine, benzo xanthinyl, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4 ?piperidone base, piperonyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, 2H ?pyrryl, pyrryl, pyrazolyl, quinazolyl, quinolyl, 4H ?quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazyl, 6H ?1,2,5 ?thiadiazine base, 1,2,3 ?thiadiazolyl group, 1,2,4 ?thiadiazolyl group, 1,2,5 ?thiadiazolyl group, 1,3,4 ?thiadiazolyl group, thianthrenyl, thiazolyl, isothiazolyl thienyl, thienyl, thieno-oxazolyl, thieno-thiazolyl, Thienoimidazole base, thienyl, triazinyl, 1,2,3 ?triazolyl, 1,2,4 ?triazolyl, 1,2,5 ?triazolyl, 1,3,4 ?triazolyl and xanthenyl.Also comprise condensed ring and spirocyclic compound.
Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, thiazolinyl, alkynyl, phenyl etc.) itself or as another substituent part represent straight chain, side chain or the hydrocarbon atomic group of ring-type or its combination, it can be completely saturated, unit or polynary undersaturated, can be monosubstituted, two replacements or polysubstituted, divalence or polyad group can be comprised, there is the carbon atom of specified quantity (as C
1?C
10represent 1 to 10 carbon)." alkyl " includes but not limited to aliphatic group and aryl radical, and described aliphatic group comprises chain and ring-type, specifically includes but not limited to alkyl, thiazolinyl, alkynyl, described aryl radical include but not limited to 6 ?the aryl radical of 12 yuan, such as benzene, naphthalene etc.In certain embodiments, atomic group that is that term " alkyl " represents straight chain or side chain or their combination, can be completely saturated, unit or polynary undersaturated, can comprise divalence and polyad group.The example of stable hydrocarbon atomic group includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl, isobutyl-, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl, and the homologue of the atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl or isomer.Unsaturated alkyl has one or more double bond or triple bond, the example include but not limited to vinyl, 2 ?propenyl, butenyl, crot(on)yl, 2 ?isopentene group, 2 ?(butadienyl), 2,4 ?pentadienyl, 3 ?(1,4 ?pentadienyl), ethynyl, 1 ?and 3 ?proyl, 3 ?butynyl, and more senior homologue and isomer.
Unless otherwise prescribed, term " assorted alkyl " or its subordinate concept (such as assorted alkyl, assorted thiazolinyl, assorted alkynyl, heteroaryl etc.) itself or combine with another term the straight chain representing stable, side chain the hydrocarbon atomic group of ring-type or its combine, be made up of the carbon atom of certain number and at least one heteroatoms.In certain embodiments, term " assorted alkyl " itself or combine with another term the straight chain representing stable, the hydrocarbon atomic group of side chain or its composition, be made up of the carbon atom of certain number and at least one heteroatoms.In an exemplary embodiment, heteroatoms is selected from B, O, N and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen heteroatom is optionally quaternized.Heteroatoms B, O, N and S can be positioned at any interior location (comprising the position that this alkyl is attached to molecule rest part) of assorted alkyl.Example Bao draw together but Bu Xian Yu ?CH
2?CH
2?O ?CH
3, ?CH
2?CH
2?NH ?CH
3, ?CH
2?CH
2?N (CH
3) ?CH
3, ?CH
2?S ?CH
2?CH
3, ?CH
2?CH
2, ?S (O) ?CH
3, ?CH
2?CH
2?S (O)
2?CH
3, ?CH=CH ?O ?CH
3, ?CH
2?CH=N ?OCH
3he – CH=CH ?N (CH
3) ?CH
3.Two heteroatomss can be continuous print at the most, Li Ru ?CH
2?NH ?OCH
3.
Term " alkoxyl group ", " alkylamino " and " alkylthio " (or thio alkoxy) belong to idiomatic expression, refer to those alkyl groups being connected to the rest part of molecule respectively by Sauerstoffatom, amino or a sulphur atom.
Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocycle alkyl " or its subordinate concept (such as aryl, heteroaryl, cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl etc.) itself or combine " alkyl " that represent cyclisation respectively with other terms, " assorted alkyl ".In addition, with regard to assorted alkyl or heterocycle alkyl (such as assorted alkyl, Heterocyclylalkyl), heteroatoms can occupy the position that this heterocycle is attached to molecule rest part.The example of cycloalkyl include but not limited to cyclopentyl, cyclohexyl, 1 ?cyclohexenyl, 3 ?cyclohexenyl, suberyl etc.The limiting examples of heterocyclic radical comprise 1 ?(1,2,5,6 ?tetrahydro pyridyl), 1 ?piperidyl, 2 ?piperidyl, 3 ?piperidyl, 4 ?morpholinyl, 3 ?morpholinyl, Si hydrogen Fu Nan ?2 ?base, tetrahydrofuran (THF) Yin Duo ?3 ?base, Si hydrogen Sai Fen ?2 ?base, Si hydrogen Sai Fen ?3 ?base, 1 ?piperazinyl and 2 ?piperazinyl.
Unless otherwise prescribed, term " aryl " represents polyunsaturated aromatic hydrocarbon substituting group, can be monosubstituted, two to replace or polysubstituted, it can be monocycle or many rings (preferably 1 to 3 ring), and they condense together or covalently bound.Term " heteroaryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, heteroatoms is selected from B, N, O and S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl is connected to the rest part of molecule by heteroatoms.The non-limiting example of aryl or heteroaryl comprises phenyl, 1 ?naphthyl, 2 ?naphthyl, 4 ?xenyl, 1 ?pyrryl, 2 ?pyrryl, 3 ?pyrryl, 3 ?pyrazolyl, 2 ?imidazolyl, 4 ?imidazolyl, pyrazinyl, 2 ?oxazolyl, 4 ?oxazolyl, 2 ?Ben Ji ?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, 3 ?pyridyl, 4 ?pyridyl, 2 ?pyrimidyl, 4 ?pyrimidyl, 5 ?benzothiazolyl, purine radicals, 2 ?benzimidazolyl-, 5 ?indyl, 1 ?isoquinolyl, 5 ?isoquinolyl, 2 ?quinoxalinyl, 5 ?quinoxalinyl, 3 ?quinolyl and 6 ?quinolyl.The substituting group of any one aryl above-mentioned and heteroaryl ring system is selected from acceptable substituting group hereinafter described.
For simplicity, aryl is comprising aryl as defined above and heteroaryl ring with (such as aryloxy, arylthio, aralkyl) during other term conbined usage.Therefore, term " aralkyl " is intended to comprise those atomic groups (such as benzyl, styroyl, pyridylmethyl etc.) that aryl is attached to alkyl, comprise wherein carbon atom (as methylene radical) by those alkyl that such as Sauerstoffatom replaces, such as phenoxymethyl, 2 ?pyridine oxygen methyl 3 ?(1 ?naphthyloxy) propyl group etc.
Term " leavings group " refer to can by another kind of functional group or atom by substitution reaction (such as nucleophilic substitution reaction) the functional group that replaces or atom.Such as, representational leavings group comprises triflate; Chlorine, bromine, iodine; Sulfonate group, as methanesulfonates, tosylate, brosylate, p-toluenesulfonic esters etc.; Acyloxy, as acetoxyl group, trifluoroacetyl oxygen base etc.
Term " protecting group " includes but not limited to " amino protecting group ", " hydroxyl protecting group " or " sulfhydryl protected base ".Term " amino protecting group " refers to the blocking group being suitable for stoping side reaction on amino nitrogen position.Representational amino protecting group includes but not limited to: formyl radical; Acyl group, such as alkanoyl (as ethanoyl, tribromo-acetyl base or trifluoroacetyl group); Alkoxy carbonyl, as tert-butoxycarbonyl (Boc); Arylmethoxycarbonyl groups, as carbobenzoxy-(Cbz) (Cbz) and 9 ?fluorenylmethyloxycarbonyl (Fmoc); Arylmethyl, as benzyl (Bn), trityl (Tr), 1,1 ?Er ?(4' ?p-methoxy-phenyl) methyl; Silyl, as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc.Term " hydroxyl protecting group " refers to the protecting group being suitable for stoping hydroxyl side reaction.Representative hydroxyl protecting group includes but not limited to: alkyl, as methyl, ethyl and the tertiary butyl; Acyl group, such as alkanoyl (as ethanoyl); Arylmethyl, as benzyl (Bn), to methoxy-benzyl (PMB), 9 ?fluorenyl methyl (Fm) and diphenyl methyl (diphenyl-methyl, DPM); Silyl, as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc.
Compound of the present invention can be prepared by multiple synthetic method well-known to those skilled in the art, comprise and be equal to substitute mode in embodiment, its embodiment formed with the combination of other chemical synthesis process and the art technology enumerated known by personnel below, preferred embodiment include but not limited to embodiments of the invention.
All solvents used in the present invention are commercially available, can use without the need to being further purified.Reaction is generally carried out under inert nitrogen, in anhydrous solvent.Proton magnetic resonance (PMR) data are recorded on BrukerAvanceIII400 (400MHz) spectrometer, and chemical shift represents with (ppm) at tetramethylsilane low field place.Mass spectrum adds the upper mensuration of 6110 (& 1956A) in Agilent 1200 series.LC/MS or ShimadzuMS comprise a DAD:SPD ?M20A (LC) and ShimadzuMicromass2020 detector.The electric spray ion source (ESI) that mass spectrograph operates under being equipped with a plus or minus pattern.
The present invention adopts following initialism: aq represents water; HATU represents O ?7 ?azepine benzotriazole ?1 ?yl) ?N, N, N', N' ?tetramethyl-urea hexafluorophosphate; EDC represent N ?(3 ?dimethylaminopropyl) ?N' ?ethyl-carbodiimide hydrochloride; M ?CPBA represent 3 ?chloroperoxybenzoic acid; Eq represents equivalent, equivalent; CDI represents carbonyl dimidazoles; DCM represents methylene dichloride; PE represents sherwood oil; DIAD represents diisopropyl azo-2-carboxylic acid; DMF represents N, N ?dimethyl formamide; DMSO represents methyl-sulphoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methyl alcohol; CBz represents carbobenzoxy-(Cbz), is a kind of amine protecting group group; It is a kind of amine protecting group group that BOC represents tert-butyl carbonyl; HOAc represents acetic acid; NaCNBH
3represent sodium cyanoborohydride; R.t. room temperature is represented; O/N representative is spent the night; THF represents tetrahydrofuran (THF); Boc
2o represent Er ?di-tert-butyidicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropyl ethyl amine; SOCl
2represent sulfur oxychloride; CS
2represent dithiocarbonic anhydride; TsOH represents tosic acid; NFSI represent N ?Fu ?N ?(benzenesulfonyl) benzsulfamide; NCS represent 1 ?chlorine Bi Ka Wan ?2,5 ?diketone; N ?Bu
4nF represents tetrabutylammonium; IPrOH represent 2 ?propyl alcohol; Mp represents fusing point.
Compound manually or
software is named, and commercial compound adopts supplier's directory name.
Be furnished with ShimadzuSIL ?20A automatic sampler and Japanese Shimadzu DAD:SPD ?the Shimadzu LC20AB system of M20A detector carry out efficient liquid phase chromatographic analysis, adopt XtimateC18 (3 μm of fillers, specification is 2.1x300mm) chromatographic column.0 ?the method of 60AB_6 minute: application linear gradient, wash-out is started with 100%A (A is the aqueous solution of 0.0675%TFA), and terminating wash-out with 60%B (B is the MeCN solution of 0.0625%TFA), whole process is 4.2 minutes, then with 60%B wash-out 1 minute.Chromatographic column reequilibrate is reached 100:0 in 0.8 minute, and total run time is 6 minutes.10 ?the method of 80AB_6 minute: application linear gradient, wash-out is started with 90%A (A is the aqueous solution of 0.0675%TFA), and terminating wash-out with 80%B (B is the acetonitrile solution of 0.0625%TFA), whole process is 4.2 minutes, then with 80%B wash-out 1 minute.Chromatographic column reequilibrate is reached 90:10 in 0.8 minute, and total run time is 6 minutes.Column temperature is 50 DEG C, and flow velocity is 0.8mL/min.Diode-array detector scanning wavelength be 200 ?400nm.
The silica GF254 of Sanpont ?group carries out thin-layer chromatographic analysis (TLC), conventional ultra-violet lamp irradiates and detects spot, also additive method is adopted to inspect spot in some cases, in these cases, (about 1g Vanillin is dissolved in 100mL10%H with iodine (add about 1g iodine in 10g silica gel and thoroughly mix), Vanillin
2sO
4in obtained), triketohydrindene hydrate (buying from Aldrich) or special developer (thoroughly mixing (NH
4)
6mo
7o
244H
2o, 5g (NH
4)
2ce (IV) (NO
3)
6, 450mLH
2the dense H2SO of O and 50mL
4and obtain) launch thin layer plate, inspect compound.Adopt Still, W.C.; Kahn, M.; AndMitra, M.JournalofOrganicChemistry, the similar approach of disclosed technology in 1978,43,2923 ?2925., 40 ?63 μm (the 230 ?400 order) silica gel of Silicycle carries out flash column chromatography.The common solvent of flash column chromatography or thin-layer chromatography is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
Gilson ?281PrepLC322 system adopts the gloomy UV/VIS of gill ?156 detectors be prepared stratographic analysis, the chromatographic column adopted is AgellaVenusilASBPrepC18,5 m, 150x21.2mm; PhenomenexGeminiC18,5 m, 150x30mm; BostonSymmetrixC18,5 m, 150x30mm; Or PhenomenexSynergiC18,4 m, 150x30mm.When flow velocity is about 25mL/min, with the acetonitrile/water eluting compounds of low gradient, wherein contain 0.05%HCl, 0.25%HCOOH or 0.5%NH in water
3h
2o, total run time be 8 ?15 minutes.
SFC analysis is carried out by the Agilent1260InfinitySFC system with Agilent1260 automatic sampler and AgilentDAD:1260 detector.Chromatographic column adopt ChiralcelOD ?H250x4.6mmI.D., 5um or ChiralpakAS ?H250x4.6mmI.D., 5 m or ChiralpakAD ?H250x4.6mmI.D., 5 m.OD ?the chromatographic condition of H_5_40_2.35ML: ChiralcelOD ?H chromatographic column (specification is 250x4.6mmI.D., m filler), moving phase be 40% ethanol (0.05%DEA) ?CO
2; Flow velocity is 2.35mL/min; Determined wavelength is 220nm.AS ?H_3_40_2.35ML chromatographic condition: ChiralpakAS ?H chromatographic column (specification is 250x4.6mmI.D., 5 m fillers); Moving phase be 40% methyl alcohol (0.05%DEA) ?CO
2; Flow velocity is 2.35mL/min, and determined wavelength is 220nm.OD ?H_3_40_2.35M chromatographic condition: ChiralcelOD ?H chromatographic column (specification is 250x4.6mmI.D, 5 m fillers), moving phase be 40% methyl alcohol (0.05%DEA) ?CO
2, flow velocity is 2.35mL/min, and determined wavelength is 220nm.AD ?H_2_50_2.35ML chromatographic condition: ChiralpakAD ?H chromatographic column (specification is 250x4.6mmI.D, 5mm filler), moving phase be 50% methyl alcohol (0.1%MEA) ?CO
2, flow velocity is 2.35mL/min, and determined wavelength is 220nm.
The WatersThar80Pre ?SFC system using GilsonUV detector carries out preparative SFC analysis, the chromatographic column adopted be ChiralcelOD ?H (specification is 250x4.6mmI.D, 5 m fillers) or ChiralpakAD ?H (specification is 250x4.6mmI.D, 5 m fillers).Flow velocity be about 40 ?80mL/min time, with the Yi Chun of low gradient ?carbonic acid gas or Jia Chun ?carbonic acid gas eluting compounds, wherein methyl alcohol or ethanol contain 0.05%NH
3h
2o, 0.05%DEA or 0.1%MEA, total run time be 20 ?30 minutes.
Compared with prior art, the compounds of this invention is efficient, low toxicity, all achieves significantly even unforeseeable progress, be more suitable for pharmacy in activity, transformation period, solubleness and pharmacokinetics etc.
Embodiment
Describe the present invention below by embodiment, but and do not mean that any unfavorable restriction of the present invention.Describe in detail the present invention herein, wherein also disclose its specific embodiment mode, to those skilled in the art, will be apparent carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention.
Embodiment 1
5-((hexahydropyrrolo is [3,2-b] pyrroles-1 (2H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
Slowly joined in the 22mL vitriol oil by isoquinoline 99.9 1a (47.5mL, 405mmol), fully stir into fritter, then join in the oleum of 200mL20%, room temperature places two days.Then to pour in 700g frozen water and hold over night, the suspension liquid obtained filters, and filter cake washes with water twice (100mLx2), dry, and (50g, productive rate: 60%) are directly used in next step reaction to obtain isoquinoline-5-sulfonic acid 1b
1hNMR (400MHz, D
2o): δ 9.66 (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
Under room temperature, isoquinoline-5-sulfonic acid 1b (4.0g, 0.019mol) is joined in the sulfur oxychloride of 25mL, then add the DMF of 0.1mL.Reaction reflux is after two hours, and decompression evaporates unnecessary sulfur oxychloride, the cold washed with dichloromethane (10mLx2) of residue on evaporation.Drying obtains target product isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (3.9g, yellow solid, productive rate: 100%).
MS-ESI calculated value [M+H]
+227 measured values 227.
3rd step
By isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (150mg; 0.330mmol) be dissolved in 2mL methylene dichloride; 0 DEG C of priority adds cis-hexahydropyrrolo also [3 under nitrogen protection; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1d (80mg; 0.38mmol; commercial goods) and N, N-diisopropyl ethyl amine (0.25mL, 1.14mmol).Gained reaction liquid chamber stirs 16 hours until react end in temperature.With methylene dichloride (10mL) and water (10mL) dilution; dichloromethane extraction (10mLx2); merge organic phase anhydrous sodium sulfate drying; filter; filtrate reduced in volume; target compound 4-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3 is obtained with silicagel column (0-100% ethyl acetate/petroleum ether) purifying; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1e (100mg; colorless oil, productive rate: 65%).
MS-ESI calculated value [M+H]
+404, measured value 404.
4th step
By 4-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1e (100mg; 0.250mmol) be dissolved in the ethyl acetate of 5mL; drip the saturated hydrogen chloride solution of 10mL ethyl acetate in 0 DEG C, reaction solution was in room temperature reaction 0.5 hour.The suspension liquid obtained is filtered; filter cake ethyl acetate washing (10mLx2); dry target compound 5-((hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 1 (60mg; white solid, productive rate: 79%).
1HNMR(400MHz,D
2O):δ9.82(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 is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
1-benzyl-1H-pyrroles-2,5-diketone 2a (74.8g, 0.400mol), 2-chloroethyl amine (58g, 0.5mol) and triethylamine (40g, 0.40mmol) are dissolved in the Isosorbide-5-Nitrae-dioxane of 400mL, reflux 16 hours.Reaction terminates rear cool to room temperature, then concentrating under reduced pressure, crude product chromatography silica gel post (0-100% ethyl acetate/petroleum ether) purifying obtains 1-benzyl-3-((2-chloroethyl) is amino) tetramethyleneimine-2,5-diketone 2b (102g, productive rate: 96%).
1HNMR(400MHz,CDCl
3):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 by sodium hydride (7.74g; 358mmol) be dissolved in 700mLN; in dinethylformamide; 1-benzyl-3-((2-chloroethyl) is amino) tetramethyleneimine-2 is added under the condition of 30 DEG C; the 50mLN of 5-diketone 2b (40g, 0.14mol), in dinethylformamide.Reaction solution stirring at room temperature 1 hour, react completely (1L) in falling back, extraction into ethyl acetate (500mL × 3), organic phase anhydrous sodium sulfate drying, filter, filtrate reduced in volume, resistates chromatography silica gel column purification (0-100% methanol/ethyl acetate) obtains 5-benzyl tetrahydro pyrrolo-[3,4-b] pyrroles-4,6 (2H, 5H)-diketone 2c (20g, colourless oil liquid, productive rate: 59%).
1HNMR(400MHz,CDCl
3):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).
3rd step
Under nitrogen protection; 0 DEG C by Lithium Aluminium Hydride (7.19g; 0.18mol) add in the tetrahydrofuran (THF) of 250mL in batches; 5-benzyl tetrahydro pyrrolo-[3 is dripped at 0 DEG C; 4-b] pyrroles-4; the 250mL tetrahydrofuran solution of 6 (2H, 5H)-diketone 2c (20g, 0.086mol).After dropping terminates, reaction system is warming up to backflow 3 hours gradually.Reaction system is cooled to 0 DEG C, then in reaction solution, dropwise drips 7.2mL water successively, 7.2mL15% sodium hydroxide, 21.6mL water.Reaction solution continues stirring 0.5 hour, filters, and concentrates and obtains 5-benzyl octahydro pyrrolo-[3,4-b] pyrroles 2d (16g, colourless oil liquid, productive rate: 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 dichloride of 300mL, add N successively, N-diisopropyl ethyl amine (19g, 148mmol) and tert-Butyl dicarbonate (17.8g, 0.081mol).Stir 4 hours under reacting on room temperature condition, question response terminates rear directly concentrated, resistates chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) obtains 5-benzyl hexahydropyrrolo also [3,4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2e (18g, colorless oil, productive rate: 81%).MS-ESI calculated value [M+H]
+310, measured value 310.
5th step
By 5-benzyl hexahydropyrrolo also [3,4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2e (12g, 39.7mmol) be dissolved in the tetrahydrofuran (THF) of 1L, add dry hydrogen palladous oxide carbon (1.8g, 10%) under argon shield.Stir 16 hours in 3MPa nitrogen atmosphere and under 70 DEG C of conditions.Room temperature is cooled to after reacting completely, reaction system diatomite filtration removing solid catalyst, filtrate is concentrated obtains cis-hexahydropyrrolo also [3,4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (8g, weak yellow liquid, productive rate: 95%).
1HNMR(400MHz,CD
3OD):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 also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (212mg; 1.00mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (250mg; 1.10mmol) obtain 5-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment one compound 1e; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2g, be directly used in next step reaction.
7th step
5-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2g (50.0mg; 0.130mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment one compound 1; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 2 (19mg; white solid, productive rate: 50%).
1HNMR(400MHz,CD
3OD):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-((six hydrogen-1H-pyrrolo-[3,4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9
The first step
Cis-octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 3a (100mg; 0.44mmol; commercial goods) and isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (114mg; 0.500mmol) obtain 6-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro-1H-pyrrolo-[3 smoothly according to the synthetic method of embodiment one compound 1e; 4-b] pyridine-1-carboxylic acid tert-butyl ester 3b, be directly used in next step reaction.
Second step
6-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 3b (80.0mg; 0.190mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment one compound 1; 4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 3 (40mg; white solid, productive rate: 65%).
1HNMR(400MHz,CD
3OD):δ9.35(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 alkylsulfonyl) isoquinoline 99.9
The first step
3-(isoquinoline 99.9-5-base alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 4a (66mg; 0.33mmol; commercial goods) and isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (107mg; 0.400mmol) obtain 3-(isoquinoline 99.9-5-base alkylsulfonyl)-3 according to the synthetic method of embodiment one compound 1e; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 4b (110mg; yellow oily liquid, productive rate: 85%).
MS-ESI calculated value [M+H]
+390, measured value 390.
Second step
3-(isoquinoline 99.9-5-base alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 4b (30mg; 0.77mmol) obtain 5-(3 according to the synthetic method of embodiment one compound 1; 6-diazabicyclo [3.2.0] heptane-3-alkylsulfonyl) isoquinoline 99.9 4 (15mg; yellow solid, productive rate: 67%).
1HNMR(400MHz,D
2O):δ9.74(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-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro-1,6-naphthyridine
The first step
By N-tertiary butyl oxygen ester-4-piperidone 5a (10g, 0.050mol) be dissolved in 250mL toluene, add 1-methylbenzylamine 5b (6.05g, 50.0mmol). back flow reaction 3 hours at reaction system use point water still head 110 DEG C, be cooled to room temperature, then concentrating under reduced pressure obtains 4-((1-styroyl) imino-) piperidines-1-carboxylic acid tert-butyl ester 5c (15.1g, yellow oily liquid, 100%), product does not need purifying directly to carry out next step reaction.
Second step
Under nitrogen atmosphere, in the 100mL tetrahydrofuran solution of Diisopropylamine (7.4g, 0.075mol), slowly drip the hexane solution of n-Butyl Lithium (34.4mL, 0.086mol, 2M) at-10 DEG C.Stirring reaction 20 minutes at this temperature, be cooled to-30 DEG C in this reaction solution, then slowly drip 4-((1-styroyl) imino-) piperidines-1-carboxylic acid tert-butyl ester 5c (15.1g, 100mL tetrahydrofuran solution 0.05mol), reaction 30 minutes is continued at this temperature after dropwising, then-65 DEG C are cooled to, the tetrahydrofuran solution (9.45g, 60.0mmolin50mLTHF) of the bromo-3-chloropropane of 1-is slowly dripped in this reaction solution.Dropping terminates rear reaction system and is progressively warming up to room temperature reaction 2 hours, then back flow reaction 4 hours.Reaction system cool to room temperature, concentrating under reduced pressure, add water (100mL), then with methyl tertiary butyl ether extraction (200mL × 3), merge organic phase, with saturated sodium-chloride water washing (100mL), organic phase anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains 1-(1-styroyl)-1,2,3,4,7,8-six hydrogen-1,6-naphthyridines-6 (5H)-carboxylic acid tert-butyl ester 5d (17g, yellow oily liquid), product is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+343, measured value 343.
3rd step
By 1-(1-styroyl)-1,2,3,4,7,8-six hydrogen-1,6-naphthyridines-6 (5H)-carboxylic acid tert-butyl ester 5d (7g, 0.02mol) is dissolved in 600mL tetrahydrofuran (THF), adds 10% palladium carbon (700mg, 10%), under 3MPa hydrogen pressure in 40 DEG C of stirring reactions 14 hours.After reaction terminates, diatomite filtration removing palladium carbon, filtrate reduced in volume, thick product chromatography silica gel post (0-100% ethyl acetate/petroleum ether) purifying obtains 1-(1-styroyl) octahydro-1,6-naphthyridines-6 (2H)-carboxylic acid tert-butyl ester 5e (2.26g, yellow oil, productive rate: 33%).
MS-ESI calculated value [M+H]
+345, measured value 345.
4th step
1-(1-styroyl) octahydro-1,6-naphthyridines-6 (2H)-carboxylic acid tert-butyl ester 5e (500mg, 1.45mmol) is dissolved in 5mL ethyl acetate, and the saturated hydrogen chloride solution adding 30mL ethyl acetate was in stirred at ambient temperature 1.5 hours.Question response terminates rear concentrating under reduced pressure and obtains 1-(1-styroyl) decahydro-1,6-naphthyridine 5f (296mg, white solid, productive rate: 84%).
MS-ESI calculated value [M+H]
+245, measured value 245.
5th step
By 1-(1-styroyl) decahydro-1; 6-naphthyridine 5f (296mg; 1.21mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (550mg; 2.42mmol) obtain 6-(isoquinoline 99.9-5-alkylsulfonyl)-1-(1-styroyl) decahydro-1 according to the synthetic method of embodiment 1 compound 1e; 6-naphthyridine 5g (96mg; yellow solid, productive rate: 18%).
MS-ESI calculated value [M+H]
+436, measured value 436.
6th step
6-(isoquinoline 99.9-5-base alkylsulfonyl)-1-(1-styroyl) decahydro-1,6-naphthyridine 5g (30mg, 0.069mmol) is dissolved in 1mL trifluoroacetic acid, in 100 DEG C of microwave reactions 1 hour.Question response terminates rear concentrating under reduced pressure, purifies obtain target compound 6-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro-1,6-naphthyridine 5 (7mg, white solid, productive rate: 31%) by preparation high pressure liquid chromatography.
1HNMR(400MHz,CD
3OD):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) alkylsulfonyl) isoquinoline
The first step
By 1H-pyrrolo-[3,2-b] pyridine 6a (2.00g, 16.9mmol) be dissolved in 30mL methylene dichloride, add DMAP (2.06g, 16.9mmol), triethylamine (2.05g, 20.3mmol) and tert-Butyl dicarbonate (4.42g, 20.3mmol), stirred overnight at room temperature.By reaction solution concentrating under reduced pressure after question response terminates, 1H-pyrrolo-[3 is obtained with eluent system (20% ethyl acetate/petroleum ether /) purifying with chromatography silica gel post, 2-b] pyridine-1-carboxylic acid tert-butyl ester 6b (3.5g, white solid, productive rate: 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, adds platinum dioxide (104mg, 0.460mmol), in 50 DEG C of stirring reactions 24 hours under 4MPa hydrogen pressure.Be cooled to room temperature after reaction terminates then to filter, filtrate reduced in volume, obtains octahydro-1H-pyrrolo-[3,2-b] pyridine-1-carboxylic acid tert-butyl ester 6c (1.00g, colourless oil liquid, 96%), does not need purifying directly to carry out next reaction.
MS-ESI calculated value [M+H]
+227, measured value 227.
3rd step
By octahydro-1H-pyrrolo-[3 under nitrogen protection; 2-b] pyridine-1-carboxylic acid tert-butyl ester 6c (1.00g; 4.42mmol) be dissolved in 30mL methylene dichloride; N is added when 0 DEG C; N-diisopropylethylamine (2.4mL; 13.3mmol) with chlorine benzyl carboxylate (1.13g, 6.63mmol), stirred overnight at room temperature.After question response terminates, concentrating under reduced pressure, add water (20mL), then be extracted with ethyl acetate (30mL × 3), merge organic phase, wash with saturated sodium-chloride water solution (30mL), anhydrous sodium sulfate drying, concentrated, crude product chromatography silica gel column purification (10% ethyl acetate/petroleum ether) obtains six hydrogen-1H-pyrrolo-[3,2-b] pyridine-Isosorbide-5-Nitraes (2H)-dicarboxylic acid 4-benzyl ester-1-tert-butyl ester 6d (1.35g, yellow oily liquid, productive rate: 85%).
MS-ESI calculated value [M+H]
+361, measured value 361.
4th step
Six hydrogen-1H-pyrrolo-es [3,2-b] pyridine-1,4 (2H)-dicarboxylic acid 4-benzyl ester-1-tert-butyl ester 6d (1.35g, 3.75mmol) are dissolved in 5mL ethyl acetate, and the saturated hydrogen chloride solution adding 40mL ethyl acetate was in stirred at ambient temperature 45 minutes.After question response terminates, concentrating under reduced pressure obtains six hydrogen-1H-pyrrolo-[3,2-b] pyridine-4 (2H)-benzyl carboxylate 6e (1.0g, white solid, productive rates: 90%).
MS-ESI calculated value [M+H]
+261, measured value 261.
5th step
By six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H)-benzyl carboxylate 6e (132mg; 0.51mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (141; 0.62mmol) obtain 1-(isoquinoline 99.9-5-alkylsulfonyl) six hydrogen-1H-pyrrolo-[3 according to the synthetic method of embodiment 1 compound 1e; 2-b] pyrrole-4 (2H)-benzyl carboxylate 6f (185mg; yellow oil, productive rate: 81%).
MS-ESI calculated value [M+H]
+452, measured value 452.
6th step
By 1-(isoquinoline 99.9-5-alkylsulfonyl) six hydrogen-1H-pyrrolo-[3; 2-b] pyrrole-4 (2H)-benzyl carboxylate 6f (150mg; 0.332mmol) obtain 5-((octahydro-1H-pyrrolo-[3 according to the synthetic method of embodiment one compound 5; 2-b] pyridine-1-base) alkylsulfonyl) isoquinoline 99.9 6 (64mg; white solid, productive rate: 61%).
1HNMR(400MHz,CD
3OD):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 is [3,4-c] pyrroles-2 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
Cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7a (105mg; 0.49mmo; commercial goods) and isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (136mg; 0.600mmol) obtain 5-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1 compound 1e; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7b, be directly used in next step reaction.
Second step
5-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7b (34mg; 0.082mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment one compound 1; 4-c] pyrroles-2 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 7 (15mg; white solid, productive rate: 60%).
1HNMR(400MHz,CD
3OD):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-((six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9
The first step
By 3,4-pyridine dicarboxylic acid 8a (30.0g, 180mmol) to be dissolved in 250mL acetic anhydride then reflux 3-4 hour until reaction solution becomes clarification, then room temperature is cooled to, the remaining acetic anhydride of pressure reducing and steaming obtains thick product 3,4-dicarboxylic anhydride pyridine 8b and is directly used in next step reaction.
Second step
Benzylamine (28.9g, 270mmol) is dropwise added drop-wise in solid 3,4-dicarboxylic anhydride pyridine 8b (the first step crude product) at 0 DEG C, then naturally rises to room temperature and leave standstill 1 hour.Gained thick liquid 4-benzamido group formyl radical niacin 8c is directly used in next step reaction.
3rd step
Be dissolved in carefully in the acetic anhydride of 150mL by thick for previous step product 4-benzamido group formyl radical niacin 8c, gained solution is heated to 110 DEG C of reactions 4 hours until raw material disappears.The acetic anhydride that after being cooled to room temperature, pressure reducing and steaming is left, by residue with water (100mL) and ethyl acetate (100mL) dilution, extraction into ethyl acetate (100mL × 2), organic phase uses saturated sodium bicarbonate aqueous solution (100mL) successively, water (100mL) and saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying, filter, concentrated, thick product silicagel column is separated (30%-50% ethyl acetate/petroleum ether) and obtains white solid 2-benzyl-1H-pyrroles [3, 4-is also] pyridine-1, 3 (2H)-diketone 8d (29.5g, the overall yield of 3 steps 69%).
1HNMR(400MHz,CDCl
3):δ9.17(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-is also] pyridine-1,3 (2H)-diketone 8d (9.60g, 40.3mmol) and wet palladium carbon (2.0g, 20%) add in 300mL methyl alcohol, this reaction solution be placed in the hydrogen system of 3MPa and be heated to 60 DEG C of reactions and spend the night.After reaction terminates, reaction solution is cooled to room temperature, filtered off through Celite palladium carbon, concentrated weak yellow liquid 2-benzyl-1H-pyrrolo-[3,4-c] hexahydropyridine-1,3 (the 2H)-diketone 8e that obtains of gained filtrate is directly used in next step reaction.
5th step
By lithium aluminium hydride (3.06g at nitrogen protection and 0 DEG C; 80.6mmol) join the 2-benzyl-1H-pyrrolo-[3 that stirred in batches; 4-c] hexahydropyridine-1,3 (2H)-diketone 8e (9.84g, 40.3mmol) 120mL tetrahydrofuran solution in.After adding by reaction solution reflux 2 hours until raw material disappear, be cooled to room temperature, then ice-water bath is cooled to 0 DEG C, and order dropwise drips water (3mL), NaOH solution (3mL, 15% aqueous solution), water (9mL) cancellation is reacted, and mixture is warming up to stirring at room temperature 30min, then filters, concentrated pistac 2-benzyl 8 hydrogen-1H-pyrrolo-[3,4-c] the pyridine 8f that obtains of filtrate is directly used in next step reaction.
6th step
At nitrogen protection and 0 DEG C; by tert-Butyl dicarbonate solution (13.06g; 60.45mmol is dissolved in 15mL methylene dichloride) be dropwise added drop-wise to the 2-benzyl 8 hydrogen-1H-pyrrolo-[3 that stirred; 4-c] pyridine 8f (8.70g; 40.3mmol) with in the 100mL dichloromethane solution of diisopropyl ethyl amine (11.4mL, 80.6mmol).Remove after dropwising ice-water bath naturally rise to room temperature by reaction solution and Keep agitation 2 hours until raw material disappear.Add water in reaction system (100mL), dichloromethane extraction (2 × 50mL), merge organic phase and then use water (50mL) and saturated aqueous common salt (50mL) washing successively, anhydrous sodium sulfate drying, filter, concentrate after obtaining thick product and obtain weak yellow liquid 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8g through silicagel column separation (2% ethanol/methylene).
MS-ESI calculated value [M+H]
+317, measured value 317.
7th step
By 2-benzyl six hydrogen-1H-pyrrolo-[3,4-c] tetrahydrofuran solution of 120mL of pyridine-5 (6H)-carboxylic acid tert-butyl ester 8g (1.5g, 4.7mmol) and 300mg dry hydrogen palladous oxide (10%) is placed in the nitrogen atmosphere of 3MPa and is heated to 60 DEG C of reactions 24 hours.Be cooled to room temperature, filtering palladium hydroxide, filtrate concentrates, and is separated (50%-100% ethanol/methylene) obtains six hydrogen-1H-pyrrolo-es [3 through silicagel column, 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (0.5g, productive rate: 50%).
MS-ESI calculated value [M+H]
+227, measured value 227.
8th step
Six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (90mg; 0.40mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (116mg; 0.510mmol) obtain 2-(isoquinoline 99.9-5-base alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1 compound 1e; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8i, be directly used in next step.
9th step
2-(isoquinoline 99.9-5-base alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8i (36mg; 0.85mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1 compound 1; 4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9 8 (17mg; faint yellow solid, productive rate: 63%).
1HNMR(400MHz,CD
3OD):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
By 1H-pyrrolo-[2,3-c] pyridine 9a (1.00g, 8.47mmol) be dissolved in 20mL methylene dichloride, 2mL triethylamine and tert-Butyl dicarbonate solution (2.00g is added when 0 DEG C, 9.17mmol, be dissolved in 10mL methylene dichloride), reaction system rises to stirring at room temperature 16 hours.After question response terminates, concentrating under reduced pressure obtains 1H-pyrrolo-[2,3-c] pyridine-1-carboxylic acid tert-butyl ester 9b, is directly used in next step reaction.
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, adds platinum dioxide (0.3g, 1.3mmol), gained mixture stirring at room temperature 12 hours under 4MPa hydrogen pressure.Reaction terminates rear mistake and filters platinum dioxide, filtrate reduced in volume, crude product obtains octahydro-1H-pyrrolo-[2,3-c] pyridine-1-carboxylic acid tert-butyl ester 9c (600mg, productive rate: 50%) by chromatography silica gel column purification (0-100% ethanol/methylene).
MS-ESI calculated value [M+H]
+227, measured value 227.
3rd step
By octahydro-1H-pyrrolo-[2; 3-c] pyridine-1-carboxylic acid tert-butyl ester 9c (100mg; 0.44mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (120mg; 0.51mmol) obtain 6-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro-1H-pyrrolo-[2 according to the synthetic method of embodiment one compound 1e; 3-c] pyridine-1-carboxylic acid tert-butyl ester 9d crude product, do not need purifying to be directly used in next step.
MS-ESI calculated value [M+H]
+418, measured value 418.
4th step
By 6-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro-1H-pyrrolo-[2; 3-c] pyridine-1-carboxylic acid tert-butyl ester 9d (100mg; 0.24mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [2 according to the synthetic method of embodiment 1 compound 1; 3-c] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 9 (60mg, productive rate: 79%).
1HNMR(400MHz,CD
3OD):δ9.63(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-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4]-7-in heptan amine
The first step
By 5-azaspiro [2.4] heptane-7-base aminocarboxylic acid tert-butyl ester 10a (50mg; 0.25mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (75mg; 0.32mmol) obtain (5-(isoquinoline 99.9-5-base alkylsulfonyl)-5-azaspiro [2.4] heptane-7-base) aminocarboxylic acid tert-butyl ester 10b (95mg according to the synthetic method of embodiment 1 compound 1e; yellow oily liquid, productive rate: 95%).
MS-ESI calculated value [M+H]
+404, measured value 404.
Second step
By (5-(isoquinoline 99.9-5-base alkylsulfonyl)-5-azaspiro [2.4] heptane-7-base) aminocarboxylic acid tert-butyl ester 10b (30mg; 0.074mmol) obtain 5-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4]-7-in heptan amine 10 (10mg according to the synthetic method of embodiment 1 compound 1; yellow solid, productive rate: 44%).
1HNMR(400MHz,D
2O):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-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4]-7-in heptan amine
The first step
By (5-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4] heptane-7-base) aminocarboxylic acid tert-butyl ester 10b (65mg; 0.16mmol; embodiment 10) be dissolved in the anhydrous N of 4mL; in dinethylformamide; under 0 DEG C of nitrogen protection, add sodium hydride (4.6mg, 0.19mmol), reaction solution adds iodoethane (30mg after stirring 10 minutes at 0 DEG C; 0.19mmol), then rise to room temperature and stir 1 hour.Extract by ethyl acetate (30mL × 2) after adding 20mL saturated sodium-chloride water solution after question response terminates; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; crude product purified by silica gel post (0-100% ethyl acetate/petroleum ether) purifying obtains (5-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4] heptane-7-base) aminocarboxylic acid tert-butyl ester 11a (15mg; yellow oily liquid, productive rate: 22%).
MS-ESI calculated value [M+H]
+432, measured value 432.
Second step
By (5-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4] heptane-7-base) aminocarboxylic acid tert-butyl ester 11a (15mg; 0.035mmol) obtain N-ethyl-5-(isoquinoline 99.9-5-alkylsulfonyl)-5-azaspiro [2.4]-7-in heptan amine 11 (10mg according to the synthetic method of embodiment 1 compound 1; yellow solid, productive rate: 87%).
1HNMR(400MHz,D
2O):δ9.50(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-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3,4-b] azepines 12; 2-(isoquinoline 99.9-5-base alkylsulfonyl)
Octahydro pyrrolo-[3,4-c] azepines 12 '
The first step
By cyclonene 12a (5.00g; 52.1mmol) be dissolved in 50mL methylene dichloride; add N-methoxymethyl-N-(trimethyl silane) benzyl amine 12b (7.74g; 34.7mmol) and 0.5mL trifluoroacetic acid, under nitrogen protection reaction solution in stirring at room temperature 12 hours.After question response terminates, reaction solution saturated sodium bicarbonate aqueous solution (20mL) cancellation, methylene dichloride (20mL × 2) extracts, saturated sodium bicarbonate aqueous solution (20mL) washs, merge organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure is that product 2-benzyl six hydrogen-1H-isoindole-4 (2H)-one 12c is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+230, measured value 230.
Second step
By 2-benzyl six hydrogen-1H-isoindole-4 (2H)-one 12c (4.00g; 17.5mmol) be dissolved in 50mL chloroform; sodiumazide (2.28g is added under 0 DEG C of condition; 35.0mmol) with methylsulfonic acid (1.68g; 17.5mmol), under nitrogen protection reaction solution in stirring at room temperature 12 hours.After question response terminates, dilution that reaction system adds water (50mL), methylene dichloride (30mL × 2) extracts, saturated sodium bicarbonate aqueous solution (30mL) washs, merge organic phase anhydrous sodium sulfate drying, concentrated evaporate to dryness is product 7-benzyl octahydro pyrrolo-[3,4-b] azepines-2 (1H)-one 12d1 and 2-benzyl octahydro pyrrolo-[3,4-c] mixture of azepines-4 (2H)-one 12d2, product is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+245, measured value 245.
3rd step
By 7-benzyl octahydro pyrrolo-[3 under nitrogen protection; 4-b] azepines-2 (1H)-one 12d1 and 2-benzyl octahydro pyrrolo-[3; 4-c] mixture (2.80g of azepines-4 (2H)-one 12d2; 11.5mmol) be dissolved in 40mL tetrahydrofuran (THF); tetrahydrochysene lithium aluminium (872mg is added under 0 DEG C of condition; 22.8mmol); reaction system stirs 2 hours under 60 DEG C of conditions; after question response terminates; 1mL water is added, then the aqueous sodium hydroxide solution of 1mL15% and 3mL water under 0 DEG C of condition.Stirring at room temperature 30 minutes, reacting liquid filtering, filtrate extracts by ethyl acetate (20mL × 2), saturated sodium-chloride water solution (30mL) washs, merge organic phase anhydrous sodium sulfate drying, concentrated evaporate to dryness is product 7-benzyl decahydro pyrrolo-[3,4-b] azepines 12e1 and 2-benzyl decahydro pyrrolo-[3,4-c] mixture of azepines 12e2, product is not purified directly carries out next step reaction.
4th step
By 7-benzyl decahydro pyrrolo-[3; 4-b] azepines 12e1 and 2-benzyl decahydro pyrrolo-[3; 4-c] mixture (2.62g of azepines 12e2; 11.4mmol) be dissolved in 40mL tetrahydrofuran (THF); tert-Butyl dicarbonate (3.73g is added under room temperature condition; 17.1mmol) with triethylamine (1.73g, 17.1mmol), stirring at room temperature 2 hours under nitrogen protection.After question response terminates, dilution that reaction system adds water (50mL), ethyl acetate (30mL × 2) extracts, saturated sodium bicarbonate aqueous solution (30mL) washs, organic phase anhydrous sodium sulfate drying, concentrated evaporate to dryness is product 7-benzyl octahydro pyrrolo-[3,4-b] azepines-1 (2H)-carboxylic acid tert-butyl ester 12f1 and 2-benzyl octahydro pyrrolo-[3,4-c] mixture of azepines-5 (1H)-carboxylic acid tert-butyl ester 12f2, be directly used in next step reaction.
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 pyrrolo-[3,4-c] azepines-5 (1H)-carboxylic acid tert-butyl ester 12f2 (1.90g, 5.74mmol) be dissolved in 50mL methyl alcohol, add 100mg to wet palladium carbon, under hydrogen (1atm) condition, reaction solution stirs 2 hours under 50 DEG C of conditions.After question response terminates, reaction solution direct filtration, filtrate reduced in volume obtains octahydro pyrrolo-[3,4-b] azepines-1 (2H)-carboxylic acid tert-butyl ester 12g1 and octahydro pyrrolo-[3,4-c] mixture of azepines-5 (1H)-carboxylic acid tert-butyl ester 12g2, not purifiedly directly carries out next step reaction.
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] mixture (800mg of azepines-5 (1H)-carboxylic acid tert-butyl ester 12g2, 3.33mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (910mg, 4.00mmol) obtain 7-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3 according to the synthetic method of embodiment one compound 1e, 4-b] azepines-1 (2H)-carboxylic acid tert-butyl ester 12h1 and 2-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3, 4-c] mixture of azepines-5 (1H)-carboxylic acid tert-butyl ester 12h2, product is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+432, measured value 432.
7th step
7-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3, 4-b] azepines-1 (2H)-carboxylic acid tert-butyl ester 12h1 and tert-butyl2-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3, 4-c] mixture (1.43g of azepines-5 (1H)-carboxylic acid tert-butyl ester 12h2, 3.30mmol) obtain 7-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3 according to the synthetic method of embodiment one compound 1, 4-b] azepines 12 (284mg, 26%) and 2-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro pyrrolo-[3 productive rate:, 4-c] azepines 12 ' (32mg).
12:
1HNMR(400MHz,CDCl
3):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’:
1HNMR(400MHz,CDCl
3):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-(isoquinoline 99.9-5-base alkylsulfonyl)-4-azaspiro [2.4]-7-in heptan amine
The first step
Under nitrogen protection, Diisopropylamine (41.6g, 0.41mol) is joined in 1.5L tetrahydrofuran (THF), be cooled to-78 DEG C.Dropping n-Butyl Lithium (150mL, 0.375mol) slowly under nitrogen protection condition, dropwises continuation and reacts one hour at this temperature, then drips third rare nitrile (22.78g, 0.34mol).Continue stirring one hour under reaction system uniform temp after adding vinyl cyanide, then drip 2-ethyl bromoacetate 13a (56.8g, 0.34mol).Dropwise rear reaction system little of reacting completely-78 DEG C of continuation reactions one, then in reaction solution, add saturated aqueous ammonium chloride (2.0L) cancellation reaction, extract by ethyl acetate (500mL × 3), merge organic phase washed with water (500mL) and saturated aqueous common salt (500mL) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, resistates chromatography silica gel post (0-100% ethyl acetate/petroleum ether) purifying obtains ethyl 3-cyano group penta-obtusilic acid methyl esters 13b (13.5g, colorless oil, productive rate: 34%).
1HNMR(400MHz,CDCl
3):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
By ethyl 3-cyano group penta-obtusilic acid methyl esters 13b (6g; 39.2mmol) be dissolved in 1L anhydrous diethyl ether; titanium isopropylate (11.76mL is added under nitrogen protection condition; 39.2mmol); then under room temperature condition, ethylmagnesium bromide (21.6mL is slowly dripped; 64.8mmol, 3M tetrahydrofuran solution).Under room temperature, reaction system stirs three and littlely to disappear up to raw material, then drip 36mL shrend to go out reaction, the suspension liquid obtained filters, filtrate reduced in volume, residue chromatography silica gel post (0-100% ethyl acetate/petroleum ether) purifying obtains 7-vinyl-4-azaspiro [2.4] heptane-5-ketone 13c (3.3g, white solid, productive rate: 63%).
1HNMR(400MHz,CDCl
3):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.
3rd step
By 7-vinyl-4-azaspiro [2.4] heptane-5-ketone 13c (1.2g, 8.75mol) be dissolved in 29mL anhydrous acetonitrile and add 4-N successively, N-lutidine (110mg, 0.875mmol), tert-Butyl dicarbonate acetonitrile solution (2.86g, 13.1mmol, 10mL acetonitrile), stirring at room temperature 5 hours.Reaction solution is poured into cancellation in water (25mL) after reaction terminates, extract by ethyl acetate (30mL × 3), merge organic phase, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, resistates chromatography silica gel post (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, productive rate: 55%).
1HNMR(400MHz,CDCl
3):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
By 5-oxo-7-vinyl-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13d (3.4g, 14.3mmol) be dissolved in the mixing solutions of 34mL methyl alcohol and 51mL water, sodium periodate (9.2g is added under room temperature condition, 43mmol) with perosmic anhydride (55mg, 0.22mmol), stirring at room temperature 4 hours.After reacting completely; add water (40mL) dilution; ethyl acetate (40mL × 3) extracts; merge organic phase, anhydrous sodium sulfate drying, filter; filtrate concentrates; resistates chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) obtains 7-formyl radical-5-oxo-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13e (2.6g, brown oil, productive rate: 76%).
MS-ESI calculated value [M+H]
+240, measured value 240.
5th step
By 7-formyl radical-5-oxo-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13e (2.60g; 10.9mmol) be dissolved in the mixing solutions of the 87mL trimethyl carbinol and 87mL tetrahydrofuran (THF); 2-butylene (22.7mL) is added successively under 0 DEG C of condition; Textone (979mg; the 63mL aqueous solution of 10.9mmol) He two hypophosphite monohydrate sodium dihydrogens (3.39g, 21.8mmol).Reaction solution stirring at room temperature 16 hours, react completely, dilute hydrochloric acid regulates potential of hydrogen to be 4 to pH, then ethyl acetate (50mL × 3) extraction, merges organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains 4-(tert-butoxycarbonyl)-5-oxo-4-azaspiro [2.4] heptane-7-carboxylic acid 13f (2g, faint yellow solid, productive rate: 75%).
1HNMR(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) be dissolved in 30mL toluene, N is added at 0 DEG C, N-diisopropyl ethyl amine (1.51g, 11.7mmol) with diphenyl phosphate azide (3.23g, 11.7mmol).Be heated to 90 DEG C and react half an hour, be cooled to room temperature and add benzylalcohol (1.07g, 9.92mmol).Stirring at room temperature 16 hours, to react completely in falling back (40mL) and extracts by ethyl acetate (40mL × 3).Organic phase anhydrous sodium sulfate drying, filter, filtrate reduced in volume, residue chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) obtains 7-(((benzyloxy) carbonyl) is amino)-5-oxo-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13g (1.8g, white solid, productive rate: 56%).
MS-ESI calculated value [M+H]
+361, measured value 361.
7th step
By 7-(((benzyloxy) carbonyl) is amino)-5-oxo-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13g (200mg under nitrogen protection; 0.56mmol) be dissolved in the tetrahydrofuran (THF) of 3mL; dimethyl sulphide solution (the 3.9mL of borine is dripped in 0 DEG C; 11.7mmol; 3M dimethyl sulphide solution), reaction solution is heated to 60 DEG C of reactions one hour.After reacting completely, pour cancellation reaction in frozen water (20mL) into, with ethyl acetate (20mL × 3) extraction, organic phase anhydrous sodium sulfate drying.Filter, filtrate reduced in volume, residue chromatography (0-100% ethyl acetate/petroleum ether) obtains 7-(((benzyloxy) carbonyl) is amino)-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13h (30mg, colourless oil liquid, productive rate: 16%).
MS-ESI calculated value [M+H]
+347, measured value 347.
8th step
By 7-(((benzyloxy) carbonyl) is amino)-4-azaspiro [2.4] heptane-4-carboxylic acid tert-butyl ester 13h (100mg, 0.39mmol) obtain 4-azaspiro [2.4] heptane-7-base aminocarboxylic acid benzyl ester 13i (101mg according to the synthetic method of embodiment five compound 5f, white solid, productive rate: 100%).
MS-ESI calculated value [M+H]
+247, measured value 247.
9th step
By 4-azaspiro [2.4] heptane-7-base aminocarboxylic acid benzyl ester 13i (70mg; 0.27mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (80mg; 0.35mmol) obtain 4-(isoquinoline 99.9-5-base alkylsulfonyl)-4-azaspiro [2.4] heptane-7-base aminocarboxylic acid benzyl ester 13j (80mg according to the synthetic method of embodiment one compound 1e; colourless oil liquid, productive rate: 68%).
MS-ESI calculated value [M+H]
+438, measured value 438.
Tenth step
By 4-(isoquinoline 99.9-5-base alkylsulfonyl)-4-azaspiro [2.4] heptane-7-base aminocarboxylic acid benzyl ester 13j (40mg; 0.098mmol) obtain 4-(isoquinoline 99.9-5-base alkylsulfonyl)-4-azaspiro [2.4]-7-in heptan amine 13 (11mg according to the synthetic method of embodiment five compound 5; yellow solid, productive rate: 50%).
1HNMR(400MHz,CD
3OD):δ9.42(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-(isoquinoline 99.9-5-alkylsulfonyl) decahydro pyrrolo-[3,2-b] azepines
The first step
Hydroresorcinol 14a (5g, 44.6mmol) is dissolved in 10mL tetrahydrofuran (THF), at room temperature adds thanomin (3.27g, 53.5mmol).Gained suspension is poured in the round-bottomed flask that water trap and 90mL toluene are housed, heated overnight at reflux, reaction system is cooled to room temperature, then concentrating under reduced pressure, resistates chromatography silica gel post (15% ethyl acetate/petroleum ether) purifying obtains 3-(2-hydroxy-ethyl is amino)-hexamethylene-2-ketenes 14b (4.30g, yellow solid, productive rate: 62%).
1HNMR(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
By 3-(2-hydroxy-ethyl is amino)-hexamethylene-2-ketenes 14b (3.70g, 23.9mmol) be dissolved in 120mLN, N-dimethylformamide, four triphenyl phosphorus palladium (552mg are added under nitrogen protection and room temperature, 0.48mmol), trimethylammonium bromobenzene (4.76g, 23.9mmol), salt of wormwood (6.60g, 47.8mmol), gained reaction solution is heated to 150 DEG C of backflows 2 hours, be cooled to concentrating under reduced pressure after room temperature, residue with ethyl acetate (100mL) dilutes, saturated sodium-chloride water solution (100mL) washs, anhydrous sodium sulfate drying, filter, concentrated, resistates chromatography silica gel post obtains 1 with eluent system (15% ethyl acetate/petroleum ether) purifying, 5, 6, 7-Tetrahvdro-indole-4-ketone 14c (2.66g, white solid, productive rate: 82%).
MS-ESI calculated value [M+H]
+136, measured value 136.
3rd step
By 1,5,6,7-Tetrahvdro-indole-4-ketone 14c (4.66g, 34.5mmol) be dissolved in 120mL acetonitrile, at room temperature add N, N-diisopropyl ethyl amine (9.3mL, 51.7mmol), tert-Butyl dicarbonate (8.27g, 37.9mmol) and N, N-lutidine (82mg, 0.69mmol).Reaction solution at room temperature stirs and spends the night.Concentrated by reaction solution after completion of the reaction, resistates chromatography silica gel post obtains 4-oxo-4,5 with eluent system (10% ethyl acetate/petroleum ether) purifying, 6,7-Tetrahvdro-indole-1-carboxylic acid tert-butyl ester 14d (7g, white solid, productive rate: 86%)
4th step
Be dissolved in 20mL methyl alcohol by 4-oxo-4,5,6,7-Tetrahvdro-indole-1-carboxylic acid tert-butyl ester 14d (500mg, 2.13mmol), room temperature adds catalytic amount Glacial acetic acid and 50mg platinum dioxide.Reaction system vacuumizes lower replacing hydrogen, stirs 3 hours at 1MPa hydrogen pressure and 50 DEG C.Be cooled to room temperature after completion of the reaction then to filter, filtrate concentrates, resistates chromatography silica gel post obtains 4-hydroxyl octahydro-1H-indoles-1-carboxylic acid tert-butyl ester 14e (400mg, colourless oil liquid, productive rate: 78%) with eluent (50% ethyl acetate/petroleum ether) purifying.
5th step
4-hydroxyl octahydro-1H-indoles-1-carboxylic acid tert-butyl ester 14e (700mg, 2.9mmol) is dissolved in 35mL methylene dichloride, at 0 DEG C, adds Dai Si-Martin's oxygenant (2.46g, 5.80mmol).At room temperature reaction solution stirs 30 minutes.Reaction terminates rear saturated sodium bicarbonate aqueous solution (50mL) cancellation reaction, and methylene dichloride (30mL × 3) extracts.Merge organic phase, wash with saturated sodium-chloride water solution (50mL), anhydrous sodium sulfate drying, filter, concentrate, resistates chromatography silica gel post obtains 4-oxo octahydro-1H-indoles-1-carboxylic acid tert-butyl ester 14f (470mg with eluent (25% ethyl acetate/petroleum ether) purifying, colourless oil liquid, productive rate: 68%).MS-ESI calculated value [M+H – C
4h
8]
+184, measured value 184.
6th step
By 4-oxo octahydro-1H-indoles-1-carboxylic acid tert-butyl ester 14f (470mg, 1.97mmol) be dissolved in 15mL chloroform, at 0 DEG C, add sodiumazide (250mg, 3.85mmol) and methylsulfonic acid (1.51g, 15.8mmol), at 70 DEG C, reaction solution stirring is spent the night.Reaction solution is poured into saturated sodium bicarbonate (20mL) aqueous solution after reaction terminates, aqueous phase ethyl acetate (40mL) is washed, then concentrate under vacuo and obtain octahydro pyrrolo-[3,2-b] azepines-5 (1H)-one 14g is not purified, directly carries out next step reaction.
7th step
By octahydro pyrrolo-[3,2-b] azepines-5 (1H)-one 14g (303mg, 1.97mmol) be dissolved in 15mL water, chloroformic acid benzyl ester (1.69g is added at 0 DEG C, 9.85mmol) with salt of wormwood (150mg, 1.08mmol), then rise to room temperature and stir 4 hours.Reaction terminates the extraction of rear reaction solution ethyl acetate (20mL × 3), saturated sodium-chloride water solution (20mL) washs, with anhydrous sodium sulfate drying, filter, concentrated, purify (1/2 ethyl acetate/petroleum ether) resistates by thin layer chromatography board and obtain 5-oxo octahydro pyrrolo-[3,2-b] azepines-1 (2H)-benzyl carboxylate 14h (130mg, colorless oil, productive rate: 23%).
1HNMR(400MHz,CDCl
3):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
By 5-oxo octahydro pyrrolo-[3,2-b] azepines-1 (2H)-benzyl carboxylate 14h (180mg, 0.63mmol) is dissolved in 5mL tetrahydrofuran (THF), at-78 DEG C, slowly drip borine (0.63mL, 1.86mmol, 3M dimethyl sulphide solution).After dropwising, reaction solution be warming up to 50 DEG C and stir 4 hours, until reaction terminates.With 3mL methyl alcohol cancellation reaction after cooling, obtains octahydro pyrrolo-[3,2-b] azepines-1 (2H)-benzyl carboxylate 14i by concentrated for the mixture of gained, not purifiedly directly carry out a next step.
9th step
By octahydro pyrrolo-[3,2-b] azepines-1 (2H)-benzyl carboxylate 14i (171mg, 0.625mmol) be dissolved in 3mL methylene dichloride, at room temperature add N successively, N diisopropylethylamine (161mg, 1.25mmol), 4-N, N-lutidine (8mg, 0.025mmol) with tert-Butyl dicarbonate (273mg, 1.25mmol), gained reaction solution stirs and spends the night.Question response terminates middle cancellation reaction of falling back, then methylene dichloride (10mL × 3) is used to extract, merge organic phase saturated sodium-chloride water solution (20mL) washing, with anhydrous sodium sulfate drying, filter, concentrate, purify (1/1 ethyl acetate/petroleum ether) resistates by thin layer chromatography board and obtain hexahydropyrrolo also [3,2-b] azepines-1,4 (2H, 5H)-dicarboxylic acid 1-benzyl ester 4-tertiary butyl ester 14j (180mg, colourless oil liquid, productive rate: 77%).
MS-ESI calculated value [M+H – C
4h
8]
+319, measured value 319.
Tenth step
By hexahydropyrrolo also [3; 2-b] azepines-1; 4 (2H; 5H)-dicarboxylic acid 1-benzyl ester 4-tertiary butyl ester 14j (180mg; 0.48mmol) be dissolved in 20mL tetrahydrofuran (THF); under room temperature and nitrogen protection, add the dry palladium carbon of 18mg, under room temperature, reaction solution stirs 2 hours in 1atm nitrogen atmosphere.By reacting liquid filtering after question response terminates, filtrate concentrates, and obtains octahydro pyrrolo-[3,2-b] azepines-4 (2H)-carboxylic acid tert-butyl ester 14k (30mg, colourless oil liquid, productive rate: 26%).
11 step
By octahydro pyrrolo-[3; 2-b] azepines-4 (2H)-carboxylic acid tert-butyl ester 14k (30mg; 0.12mmol) isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (32mg; 0.14mmol) obtain 1-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3 according to the synthetic method of embodiment one compound 1e; 2-b] azepines-4 (2H)-carboxylic acid tert-butyl ester 14l (30mg; colourless oil liquid, productive rate: 56%).
MS-ESI calculated value [M+H]
+432, measured value 432.
12 step
1-(isoquinoline 99.9-5-base alkylsulfonyl) octahydro pyrrolo-[3; 2-b] azepines-4 (2H)-carboxylic acid tert-butyl ester 14l (30mg; 0.07mmol) obtain 1-(isoquinoline 99.9-5-alkylsulfonyl) decahydro pyrrolo-[3 according to the synthetic method of embodiment one compound 1; 2-b] azepines 14 (15mg; white solid, productive rate: 65%).
1HNMR(400MHz,D
2O):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-ESIcalc'd.[M+H]
+332,found332。
Embodiment 15
5-((six hydrogen-1H-pyrrolo-[3,4-c] pyridine-5 (6H)-Ji) alkylsulfonyl) isoquinoline 99.9
The first step
By 5-oxo octahydro pentamethylene also [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 15a (2g, 8.89mmol) be dissolved in 10mL chloroform, then in reaction solution, sodiumazide (1.2g is added successively, 18.4mmol) with methylsulphonic acid (8.5g, 88.9mmol).Gained mixture is stirred 2 hours at 70 DEG C.Room temperature is cooled to after reacting completely, saturated sodium bicarbonate solution is adjusted to pH=7, then methylene dichloride (20mL × 2) extraction, merge organic phase anhydrous sodium sulfate drying, concentrated, obtain yellow oily liquid six hydrogen-1H-pyrrolo-[3,4-c] pyridine-6 (2H)-one 15b.This yellow oil is directly used in next step reaction.
Second step
By six hydrogen-1H-pyrrolo-es [3,4-c] pyridine-6 (2H)-one 15b (1.22g, 8.72mmol) join in the aqueous sodium hydroxide solution of 40mL10% and the mixing solutions of tetrahydrofuran (THF) (v/v=1/1), then tert-Butyl dicarbonate (3.87g, 17.8mmol) is added.After adding, by mixture stirring at room temperature 3 hours until reaction terminate.Reaction mixture ethyl acetate (30mL × 3) is extracted, merge organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product chromatography silica gel column purification (0-10% methanol/ethyl acetate) obtains 6-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester 15c (0.9g, yellow oily liquid, productive rate: 43%).
3rd step
By 6-oxo six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester 15c (600mg, 2.5mmol) be dissolved in 20mL tetrahydrofuran solution, then Lithium Aluminium Hydride (190mg is added at-10 DEG C, 10mL tetrahydrofuran solution 50mmol), after adding by mixture stirring at room temperature 3 hours.Slowly add 0.19mL shrend to go out reaction, drip the aqueous sodium hydroxide solution of 0.19mL15% and the water of 0.51mL subsequently successively.Stir after 30 minutes and mixture is filtered, filtrate reduced in volume, obtain yellow oily liquid six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester 15d and be directly used in next step reaction.
4th step
By six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester 15d (200mg; 0.88mmol; previous step crude product) and isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (280mg; 1.25mmol) obtain 5-(isoquinoline 99.9-5-base alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment one compound 1e; 4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester 15e (80mg; colourless oil liquid, yield: 22%).
MS-ESI calculated value [M+H-56]
+362, measured value 362.
5th step
By 5-(isoquinoline 99.9-5-base alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester 15e (80mg; 0.19mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment one compound 1; 4-c] pyridine-5 (6H)-Ji) alkylsulfonyl) isoquinoline 99.9 15 (51mg; yellow oil, yield: 85%).
1HNMR(400MHz,CD
3OD):δ9.39(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-(six hydrogen-pyrrolo-[3,2-b] pyrroles-1-alkylsulfonyl)-isoquinoline 99.9
The first step
At-5 DEG C, the vitriol oil (69.0mL) solution of saltpetre (7.98g, 79mmol) is added drop-wise in the 55mL concentrated sulfuric acid solution of 4-chlorine isoquinoline 99.9 16a (10.0g, 61mmol).Mixture stirs after 1 hour and rises to stirred overnight at room temperature at 0 DEG C.Reaction solution is slowly joined in 300mL frozen water after question response terminates, pH to 8 is regulated with solid sodium carbonate, and extract by ethyl acetate (200mL × 2), merge organic phase, anhydrous sodium sulfate drying, filter, concentrated filtrate, and obtain 4-chloro-5-nitroisoquinoline 16b (11.2g, white solid, productive rate: 88%) with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether).
MS-ESI calculated value [M+H]
+209, measured value 209.
Second step
At 0 DEG C, tindichloride hydrate (13g, 57.7mmol) is joined in the 34mL concentrated hydrochloric acid solution of 4-chloro-5-nitroisoquinoline 16b (2.00g, 9.62mmol), be heated to 100 DEG C of stirrings and spend the night.Be cooled to then room temperature regulates reaction solution pH to 8 with solid sodium bicarbonate, extract by ethyl acetate (100mL × 2), merge organic phase, with anhydrous sodium sulfate drying, filter, concentrated filtrate, and obtain 4-chlorine isoquinoline 99.9-5-amine 16c (1.57g with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether), yellow solid, productive rate: 92%).MS-ESI calculated value [M+H]
+179, measured value 179.
3rd step
Join in the 14mL concentrated hydrochloric acid solution of 4-chlorine isoquinoline 99.9-5-amine (1.57g, 8.82mmol) by the 2mL aqueous solution of Sodium Nitrite (620mg, 8.82mmol) at-5 DEG C, gained reaction solution continues stirring 1 hour at-5 DEG C.Then poured into rapidly by this reaction solution and added in the saturated sulfurous gas acetum of 30mL of the cuprous chloride aqueous solution (224mg, 2.20mmol, 2mL water), stirring at room temperature generates to bubble-free.Dilute with frozen water (100mL) after reaction terminates, with saturated sodium bicarbonate aqueous solution, the pH of reaction solution is adjusted to 8, then methylene dichloride (100mL × 2) is used to extract, merge organic phase, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtain 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (1.07g, yellow solid, productive rate: 46%).
MS-ESI calculated value [M+H]
+262, measured value 262.
4th step
Cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 1d (30mg; 0.142mmol) with 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (55.6mg; 0.212mmol) obtain 4-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl)-six hydrogen-pyrrolo-[3 according to the synthetic method of embodiment one compound 1e; 2-b] pyrroles-1-carboxylic acid tert-butyl ester 16e (30mg; yellow oily liquid, productive rate: 48%).
MS-ESI calculated value [M+H]
+438, measured value 438.
5th step
By 4-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl)-six hydrogen-pyrrolo-[3; 2-b] pyrroles-1-carboxylic acid tert-butyl ester 16e (30mg; 0.092mmol) obtain the chloro-5-of 4-(six hydrogen-pyrrolo-[3 according to the synthetic method of embodiment one compound 1; 2-b] pyrroles-1-alkylsulfonyl)-isoquinoline 99.9 16 (20mg; white solid, productive rate: 96%).
1HNMR(400MHz,D
2O):δ9.21(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-(six hydrogen-pyrrolo-[3,4-b] pyrroles-5-alkylsulfonyl)-isoquinoline 99.9
The first step
By six hydrogen-pyrrolo-[3; 4-b] pyrroles-1-carboxylate 2f (30mg; 0.142mmol; embodiment 2) and 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (56mg; 0.212mmol) obtain 5-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl)-six hydrogen-pyrrolo-[3 according to the synthetic method of embodiment one compound 1e; 4-b] pyrroles-1-carboxylate 17e (40mg, yellow oily liquid, productive rate: 65%).
MS-ESI calculated value [M+H]
+438, measured value 438.
Second step
5-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl)-six hydrogen-pyrrolo-[3; 4-b] pyrroles-1-carboxylate 17e (45mg; 0.092mmol) obtain the chloro-5-of 4-(six hydrogen-pyrrolo-[3 according to the synthetic method of embodiment one compound 1; 4-b] pyrroles-5-alkylsulfonyl)-isoquinoline 99.9 17 (30mg; white solid, productive rate: 96%).
1HNMR(400MHz,D
2O):δ9.25(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-((six hydrogen-1H-pyrrolo-[3,4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9
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 isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d according to synthetic method 6-(the 4-chlorine isoquinoline 99.9-5-alkylsulfonyl) octahydro-1H-pyrrolo-[3 of compound 1e; 4-b] pyridine-1-carboxylic acid tert-butyl ester 18a (56mg; yellow oil, productive rate: 93%).
MS-ESI calculated value [M+H]
+452, measured value 452.
Second step
6-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 18a (15mg; 0.035mmol) obtain the chloro-5-of 4-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment one compound 1; 4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 18 (10mg; yellow solid, productive rate: 87%).
1HNMR(400MHz,D
2O):δ9.25(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 alkylsulfonyl)-4-chlorine isoquinoline 99.9
The first step
3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 4a (30mg; 0.15mmol) with 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (44mg; 0.17mmol) obtain 3-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl)-3 according to the synthetic method of embodiment one compound 1e; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 19a (25mg; yellow oily liquid, productive rate: 39%).
MS-ESI calculated value [M+Na] 418, measured value 418.
Second step
3-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 19a (25mg; 0.059mmol) obtain 5-(3 according to the synthetic method of embodiment one compound 1; 6-diazabicyclo [3.2.0] heptane-3-base alkylsulfonyl)-4-chlorine isoquinoline 99.9 19 (8mg; white solid, productive rate: 38%).
1HNMR(400MHz,D
2O):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 isoquinoline 99.9-5-base) alkylsulfonyl) decahydro-1,6-naphthyridine
The first step
By 1-(1-styroyl)-1,2,3,4,7,8-six hydrogen-1,6-naphthyridine-6 (5H)-carboxylic acid tert-butyl ester 5e (15g, 0.044mol) be dissolved in 600mL tetrahydrofuran (THF), add 1.5g palladium hydroxide (20% charcoal load), in 80 DEG C of stirring reactions 16 hours in 3MPa nitrogen atmosphere.Be cooled to room temperature to filter, concentrating under reduced pressure filtrate, obtains octahydro-1,6-naphthyridine-6 (2H)-carboxylic acid tert-butyl ester 20a (320mg with chromatography silica gel column purification (50% methanol/ethyl acetate), yellow oily liquid, productive rate: 3%).
MS-ESI calculated value [M+H]
+241, measured value 241
Second step
By octahydro-1,6-naphthyridine-6 (2H)-carboxylic acid tert-butyl ester 20a (320mg, 1.33mmol) be dissolved in 5mL methylene dichloride, N is added when 0 DEG C, N-diisopropyl ethyl amine (516mg, 3.99mmol) with chlorine benzyl carboxylate (340mg, 2.0mmol), stirring at room temperature 1 hour.After reaction terminates, dilution that then concentrating under reduced pressure adds water (20mL), extract by ethyl acetate (30mL × 2), merge organic phase, wash with saturated sodium-chloride water solution (50mL), anhydrous sodium sulfate drying, concentrated, six hydrogen-1 are obtained with preparing silica-gel plate (3/1 petrol ether/ethyl acetate) purifying, 6-naphthyridine-1,6 (2H, 7H)-1-benzyl 6-tertiary butyl dimethyl ester 20b (275mg, yellow oily liquid, productive rate: 86%).
MS-ESI calculated value [M+H]
+375, measured value 375.
3rd step
By six hydrogen-1,6-naphthyridine-1,6 (2H, 7H)-1-benzyl 6-tertiary butyl dimethyl ester 20b (275mg, 0.73mmol) obtain octahydro-1 according to the synthetic method of embodiment one compound 1,6-naphthyridine-1 (2H)-benzyl carboxylate 20c (200mg, white solid, productive rate: 96%).
MS-ESI calculated value [M+H]
+275, measured value 275.
4th step
By octahydro-1; 6-naphthyridine-1 (2H)-benzyl carboxylate 20c (40mg; 0.15mmol) with 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (42mg; 0.16mmol) obtain 6-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl) octahydro-1 according to the synthetic method of embodiment one compound 1e; 6-naphthyridine-1 (2H)-benzyl carboxylate 20d (20mg; yellow oily liquid, productive rate: 27%).
MS-ESI calculated value [M+H]
+501, measured value 501.
5th step
By 6-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl) octahydro-1; 6-naphthyridine-1 (2H)-benzyl carboxylate 20d (20mg; 0.04mmol) obtain 6-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl) decahydro-1 according to the synthetic method of embodiment five compound 5; 6-naphthyridine 20 (10mg; white solid, productive rate: 68%).
1HNMR(400MHz,CD
3OD):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-alkylsulfonyl)-isoquinoline 99.9
The first step
Octahydro-pyrrolo-[3; 2-b] Pyridine-4-carboxylic acid benzyl ester 6e (30mg; 0.12mmol; embodiment six) and 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (45mg; 0.17mmol) obtain 1-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl)-octahydro pyrrolo-[3 according to the synthetic method of embodiment one compound 1e; 2-b] Pyridine-4-carboxylic acid benzyl ester 21a (30mg, yellow oily liquid, productive rate: 36%).
MS-ESI calculated value [M+H]
+486, measured value 486.
Second step
By 1-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl)-octahydro pyrrolo-[3; 2-b] Pyridine-4-carboxylic acid benzyl ester 21a (30mg; 0.062mmol) obtain the chloro-5-of 4-(octahydro-pyrrolo-[3 according to the synthetic method of embodiment five compound 5; 2-b] pyridine-1-alkylsulfonyl)-isoquinoline 99.9 21 (15mg; white solid, productive rate: 71%).
1HNMR(400MHz,D
2O):δ9.33(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 is [3,4-c] pyrroles-2 (1H)-alkylsulfonyl also) isoquinoline 99.9
The first step
Cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7a (30mg; 0.14mmol) with 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (131mg; 0.58mmol) obtain 5-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment one compound 1e; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 22a (50mg; yellow oily liquid, productive rate: 81%).
MS-ESI calculated value [M+H]
+438, measured value 438.
Second step
By 5-(4-chlorine isoquinoline 99.9-5-alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 22a (50mg; 0.11mmol) obtain the chloro-5-of 4-(hexahydropyrrolo also [3 according to the synthetic method of embodiment one compound 1; 4-c] pyrroles-2 (1H)-alkylsulfonyl) isoquinoline 99.9 22 (35mg; yellow solid, productive rate: 91%).
1HNMR(400MHz,D
2O):δ9.23-9.21(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-((six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9
The first step
By six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (35mg; 0.16mmol) with 4-chlorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d (45mg; 0.17mmol) obtain 2-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of compound 1e; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 23a (15mg; yellow oily liquid, productive rate: 21%).
MS-ESI calculated value [M+Na] 474, measured value 474.
Second step
2-((4-chlorine isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 23a (15mg; 0.033mmol) obtain the chloro-5-of 4-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of compound 1; 4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9 23 (10mg; white solid, productive rate: 86%).
1HNMR(400MHz,D
2O):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 is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
By 4-bromo-isoquinoline 24a (20g under-65 DEG C of conditions, 144mL tetrahydrofuran solution 96.6mmol) is added drop-wise to n-Butyl Lithium (133mL, 332.5mmol, 2.5M tetrahydrofuran solution) 760mL tetrahydrofuran solution in, after dropwising ,-65 DEG C are continued reactions 30 minutes.Then-65 DEG C added the 216mL tetrahydrofuran solution of N-fluorine two benzsulfamide (66.68g, 211.7mmol) in 1 hour in reaction solution, dropwised rear continuation stirring 1 hour, then slowly rose to room temperature.After question response terminates, saturated aqueous ammonium chloride (300mL) is slowly joined in reaction solution, and extract by ethyl acetate (300mL × 3), organic phase saturated sodium-chloride water solution (300mL) washs, drying, concentrated evaporate to dryness, and obtain 4-fluorine isoquinoline 99.9 24b (8.5g with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether), Red oil, productive rate: 60%).
Second step
4-fluorine isoquinoline 99.9 24b (8.5g, 57.8mmol) obtains 4-fluoro-5-nitroisoquinoline 24c (7.2g, yellow oily liquid, productive rate: 64.8%) with reference to embodiment 16 compound 4-chloro-5-nitroisoquinoline 16b synthetic method.
3rd step
4-fluoro-5-nitroisoquinoline 24c (7.2g, 37.5mmol) obtains 4-fluorine isoquinoline 99.9-5-amine 24d (5.5g, yellow solid, productive rate: 90%) with reference to embodiment 16 compound 4-chloro isoquinoline 99.9-5-amine 16c synthetic method.
4th step
4-fluorine isoquinoline 99.9-5-amine 24d (5.5g, 33.95mmol) obtains 4-fluorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 24e (4.5g, white solid, productive rate: 54%) according to the synthetic method of embodiment 16 compound 4-chloro isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d.
1HNMR(400MHz,CDCl
3):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 also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1d (30mg; 0.14mmol and 4-fluorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 24e (35mg; 0.14mmol) according to embodiment one compound 4-(isoquinoline 99.9-5-base alkylsulfonyl) hexahydropyrrolo also [3; 2-b] synthetic method of pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1e obtains 4-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 2-b pyrroles-1 (2H)-carboxylic acid tert-butyl ester 24f (56mg; yellow oily liquid, productive rate: 94%).
MS-ESI calculated value [M+Na] 444, measured value 444.
6th step
4-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 2-b pyrroles-1 (2H)-carboxylic acid tert-butyl ester 24f (56mg; 0.13mmol obtains the fluoro-5-of 4-((hexahydropyrrolo also [3 according to the synthetic method of embodiment one; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 24 (20mg; white solid, productive rate: 42%).
1HNMR(400MHz,D
2O):δ9.24(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 fluoro-5-of 4-((hexahydropyrrolo is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
Cis-hexahydropyrrolo also [3,4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (55mg, 0.24mmol, embodiment two) 4-fluorine isoquinoline 99.9-5-SULPHURYL CHLORIDE 24e (50mg, 0.2mmol, embodiment 24) obtain 5-((4-fluorine isoquinoline 99.9-5-base) hexahydropyrrolo also [3,4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 25a (55mg according to the synthetic method of embodiment one, yellow solid, yield: 58%).
MS-ESI calculated value [M+H-56]
+366, measured value 366.
Second step
5-((4-fluorine isoquinoline 99.9-5-base) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 25a (50mg; 0.085mmol) obtain the fluoro-5-of 4-((hexahydropyrrolo also [3 according to the synthetic method of embodiment one; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 25 (30mg; white solid, 78%).
1HNMR(400MHz,D
2O):δ9.26(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-((six hydrogen-1H-pyrrolo-[3,4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9
The first step
The fluoro-isoquinoline 99.9 of 4--5-SULPHURYL CHLORIDE 24e (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) obtain 6-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) octahydro-1H-pyrrolo-[3,4-b] pyridine-1-carboxylic acid tert-butyl ester 26a (50mg according to the synthetic method of embodiment one; colourless oil liquid, productive rate: 52%).
Second step
6-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 26a (50mg; 0.11mmol) obtain the fluoro-5-of 4-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment one; 4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 26 (20mg; white powder solid, productive rate: 42%).
1HNMR(400MHz,CD
3OD):δ9.46(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 alkylsulfonyl)-4-fluorine isoquinoline 99.9
The first step
3-(isoquinoline 99.9-5-base alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 4a (30mg; 0.15mmol) with the fluoro-isoquinoline 99.9 of 4--5-SULPHURYL CHLORIDE 24e (41mg; 0.17mmol; embodiment 24) obtain 3-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl)-3 according to the synthetic method of embodiment one; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 27a (52mg; yellow oily liquid, productive rate: 84%).
MS-ESI calculated value [M+Na]
+430, measured value 430.
Second step
3-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 27a (52mg; 0.13mmol) obtain 5-(3 according to the synthetic method of embodiment one; 6-diazabicyclo [3.2.0] heptane-3-base alkylsulfonyl)-4-fluorine isoquinoline 99.9 27 (20mg; white solid, productive rate: 44%).
1HNMR(400MHz,D
2O):δ9.42(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) alkylsulfonyl) isoquinoline 99.9
The first step
Six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H)-benzyl carboxylate 6e (50mg; 0.17mmol; embodiment six) and the fluoro-isoquinoline 99.9 of 4--5-SULPHURYL CHLORIDE 24e (50mg; 0.2mmol; embodiment 24) obtain 1-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment one; 2-c] pyridine-5 (6H)-benzyl carboxylate 28a (72mg; yellow oily liquid, productive rate: 91%).
MS-ESI calculated value [M+Na]
+492, measured value 492.
Second step
1-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 2-c] pyridine-5 (6H)-benzyl carboxylate 28a (72mg; 0.15mmol) according to embodiment five compound 6-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro-1; the synthetic method of 6-naphthyridine 5 obtains the fluoro-5-of 4-((octahydro-1H-pyrrolo-[3; 2-c] pyridine-1-base) alkylsulfonyl) isoquinoline 99.9 28 (25mg; white solid, productive rate: 49%).
1HNMR(400MHz,CD
3OD):δ9.28(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 is [3,4-c] pyrroles-2 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
Cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7a (30mg; 0.14mmol; embodiment seven) and the fluoro-isoquinoline 99.9 of 4--5-SULPHURYL CHLORIDE 24e (35mg; 0.14mmol) obtain 5-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment one; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 29a (55mg; yellow oily liquid, productive rate: 92%).
MS-ESI calculated value [M+Na]
+444, measured value 444.
Second step
5-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 29a (55mg; 0.13mmol) obtain the fluoro-5-of 4-((hexahydropyrrolo also [3 according to the synthetic method of embodiment one; 4-c] pyrroles-2 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 29 (26mg; white solid, productive rate: 55%).
1HNMR(400MHz,D
2O):δ9.26(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-((six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9
The first step
Six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (30mg; 0.13mmol; embodiment eight) and the fluoro-isoquinoline 99.9 of 4--5-SULPHURYL CHLORIDE 24e (33mg; 0.13mmol; embodiment 24) obtain 2-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 30a (17mg; yellow oily liquid, productive rate: 29%).
MS-ESI calculated value [M+H]
+436, measured value 436.
Second step
2-((4-fluorine isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 30a (17mg; 0.039mmol) obtain the fluoro-5-of 4-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9 30 (6mg; white solid, productive rate: 46%).
1HNMR(400MHz,D
2O):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 is [3,2-b] pyrroles-1 (2H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
By 4-bromo-isoquinoline 24a (2.0g; 9.6mmol) be dissolved in the 30mL tetrahydrofuran (THF) heavily steamed; and be cooled to-65 DEG C by dry ice acetone bath, slowly drip n-Butyl Lithium (4.0mL, 10mmol under nitrogen protection; 2.5M tetrahydrofuran solution); after dropwising ,-65 DEG C of stir abouts 0.5 hour. then dropwise add DMF (730mg at-65 DEG C; 10mmol), reaction continues to stir 1 hour at this temperature.Saturated aqueous solution (100mL) the cancellation reaction of ammonium chloride is added after question response terminates, extract by ethyl acetate (50mL × 3), merge organic layer saturated sodium-chloride water solution (100mL) to wash, anhydrous sodium sulfate drying, concentrating under reduced pressure, crude product obtains isoquinoline 99.9-4-formaldehyde 31a (550mg, yellow solid, productive rate: 36%) by chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether).
1HNMR(400MHz,CDCl
3):δ10.41(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+H
3o]
+176, measured value 176.
Second step
By isoquinoline 99.9-4-formaldehyde 31a (100mg; 0.63mmol) be dissolved in dry 5mL methylene dichloride, under nitrogen protection, dropwise add diethylin sulfur trifluoride (1.1g, 6.3mmol) in 0 DEG C; after dropwising, rise to room temperature and continue that reaction 5 is little disappears up to raw material.Reaction mixture is slowly added drop-wise in 30mL frozen water, and slowly add saturated sodium bicarbonate aqueous solution, until the pH of mixed solution is 8-9, then use methylene dichloride (20mL × 3) to extract, merge organic phase, anhydrous sodium sulfate drying, filters, concentrating under reduced pressure, crude product is by chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether), obtain 4-difluoromethyl isoquinoline 99.9 31b (80mg, yellow oily liquid, productive rate: 70%).
1HNMR(400MHz,CDCl
3):δ9.36(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.
3rd step
4-difluoromethyl isoquinoline 99.9 31b (1.3g, 7.2mmol) obtains 4-(difluoromethyl)-5-nitroisoquinoline 31c (1.16g, yellow solid, productive rate: 71%) with reference to the method for embodiment 16.
1HNMR(400MHz,CD
3OD):δ9.60(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
By 4-(difluoromethyl)-5-nitroisoquinoline 31c (100mg; 0.45mmol) be dissolved in 30mL dehydrated alcohol; add the hydrazine hydrate (22mg of 10% wet palladium carbon 30mg and 85% under nitrogen protection; 0.45mmol) mixture is refluxed 1 hour at 90 DEG C, then reaction solution be cooled to room temperature and filter.Filtrate concentrated, crude product obtains 4-(difluoromethyl) isoquinoline 99.9-5-amine 31d (62mg, yellow solid, productive rate: 78.5%) by chromatography silica gel column purification (30% ethyl acetate/petroleum ether).
1HNMR(400MHz,CDCl
3):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) isoquinoline 99.9-5-amine 31d (230mg, 1.18mmol) obtain 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (130mg according to the synthetic method of embodiment 16 compound 4-chloro isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d, yellow solid, yield: 39%).
MS-ESI calculated value [M+H]
+278, measured value 278.
6th step
Cis-hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1d (37mg; 0.24mmol; embodiment 1) and 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (68mg; 0.24mmol) obtain 4-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 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) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 31f (50mg; 0.11mmol) obtain 4-(difluoromethyl)-5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 2-b] pyrroles-1 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 31 (25mg; white solid, 53%).
1HNMR(400MHz,D
2O):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 is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
Cis-hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (37mg; 0.24mmol; embodiment 2) and 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (68mg; 0.24mmol; embodiment 31) obtain 5-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-c] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 32a (45mg; yellow solid, productive rate: 41%).
MS-ESI calculated value [M+H]
+454, measured value 454.
Second step
5-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 32a (45mg; 0.1mmol) obtain 4-(difluoromethyl)-5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 32 (25mg; white solid, productive rate: 60%).
1HNMR(400MHz,D
2O):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-((six hydrogen-1H-pyrrolo-[3,4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9
Cis-octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 3a (30mg; 0.18mmol; embodiment 3) and 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (50mg; 0.18mmol; embodiment 31) obtain 6-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) octahydro-1H-pyrrolo-[3 according to the synthetic method of embodiment 1; 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) isoquinoline 99.9-5-base) alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 33a (40mg; 0.085mmol) obtain 4-(difluoromethyl)-5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-b] pyridine-6 (2H)-Ji) alkylsulfonyl) isoquinoline 99.9 33 (10mg; white solid, 27%).
1HNMR(400MHz,D
2O):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 alkylsulfonyl)-4-(difluoromethyl) isoquinoline 99.9
The first step
3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 4a (30mg; 0.18mmol; embodiment 4) and 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (50mg; 0.18mmol; embodiment 31) obtain 3-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl)-3 according to the synthetic method of embodiment 1; 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) isoquinoline 99.9-5-base) alkylsulfonyl)-3,6-diazabicyclos [3.2.0] heptane-6-carboxylic acid tert-butyl ester 34a (40mg, 0.085mmol) obtain according to the synthetic method of embodiment 1
5-(3,6-diazabicyclo [3.2.0] heptane-3-base alkylsulfonyl)-4-(difluoromethyl) isoquinoline 99.9 34 (10mg, white solid, 26%).
1HNMR(400MHz,D
2O):δ9.60(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 is [3,4-c] pyrroles-2 (1H)-Ji also) alkylsulfonyl) isoquinoline 99.9
The first step
Cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7a (37mg; 0.24mmol; embodiment 7) and 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (68mg; 0.24mmol; embodiment 31) obtain 5-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 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) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 35a (52mg; 0.11mmol) obtain 4-(difluoromethyl)-5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-c] pyrroles-2 (1H)-Ji) alkylsulfonyl) isoquinoline 99.9 35 (25mg; white solid, 51%).
1HNMR(400MHz,D
2O):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
Six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (56mg; 0.25mmol; embodiment 8) and 4-(difluoromethyl) isoquinoline 99.9-5-SULPHURYL CHLORIDE 31e (75mg; 0.27mmol; embodiment 31) obtain 2-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 36a (45mg; pale yellowish oil liquid, productive rate: 45%).
MS-ESI calculated value [M+Na]
+490, measured value 490.
Second step
2-((4-(difluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 36a (45mg; 0.096mmol) obtain 4-(difluoromethyl)-5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-2 (3H)-Ji) alkylsulfonyl) isoquinoline 99.9 36 (30mg; white solid, productive rate: 86%).
1HNMR(400MHz,CD
3OD):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 is [3,2-b] pyrroles-1 (2H)-Ji also) alkylsulfonyl)-4-methylisoquinolinium
The first step
To 4-bromo-isoquinoline 24a (15.0g, 72.5mmol) under nitrogen protection, methyl-boron-dihydroxide (8.8g, 146mmol), K
3pO
4(62.0
gthree (dibenzalacetone) two palladium (6.6g is added in 350mL toluene solution 292mmol), 7.2mmol) with dicyclohexyl (2', 6'-dimethoxy-[1,1'-biphenyl]-2-base) phosphine (5.9g, 14.3mmol), gained mixture reflux 20 hours.After question response terminates, reaction solution is poured into water (300mL), extract by ethyl acetate (100mL × 2), what is organic phase anhydrous sodium sulfate drying also, concentrated, 4-methylisoquinolinium 37a (10.7g is obtained with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether), yellow oily liquid, productive rate: 94%).
Second step
4-methylisoquinolinium 37a (10.0g, 69.9mmol) obtains 4-methyl-5-nitro isoquinoline 99.9 37b (10g, yellow oily liquid, productive rate: 76%) according to the synthetic method of embodiment 16.
3rd step
4-methyl-5-nitro isoquinoline 99.9 37b (9.00g, 47.8mmol) obtains 4-methylisoquinolinium-5-amine 37c (6.0g, yellow solid, productive rate: 71%) according to the synthetic method of embodiment 16.
4th step
4-methylisoquinolinium-5-amine 37c (500mg, 3.16mmol) obtains 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (300mg, green solid, productive rate: 40%) according to the synthetic method of embodiment 16.
1HNMR(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 also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1d (33mg; 0.14mmol) with 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (68mg; 0.28mmol) obtain 4-(4-methylisoquinolinium-5-alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 37e (15mg; yellow oily liquid, productive rate: 25%).
MS-ESI calculated value [M+H]
+418, measured value 418.
6th step
4-(4-methylisoquinolinium-5-alkylsulfonyl) hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 37e (15mg; 0.036mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 2-b] pyrroles-1 (2H)-Ji) alkylsulfonyl)-4-methylisoquinolinium 37 (10mg; yellow solid, productive rate: 67%).
1HNMR(400MHz,D
2O):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 is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl)-4-methylisoquinolinium
The first step
Cis-hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (50mg; 0.24mmol; embodiment 2) and 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (85mg; 0.35mmol; embodiment 37) obtain 5-((4-methylisoquinolinium-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 38a (40mg; colourless oil liquid, productive rate: 40%).
Second step
5-((4-methylisoquinolinium-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 38a (40mg; 0.095mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl)-4-methylisoquinolinium 38 (28mg; white solid, productive rate: 75%).
1HNMR(400MHz,D
2O):δ9.52(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 is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl)-4-methylisoquinolinium-1-alcohol
The first step
To 5-((4-methylisoquinolinium-5-base) alkylsulfonyl) hexahydropyrrolo also [3 under 0 DEG C of condition; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 38a (100mg; m-chloro peroxide benzene carboxylic acid (83mg is added in 5mL dichloromethane solution 0.24mmol); 0.48mmol), stirring at room temperature 2 hours is until reaction terminates.5-((1-(tert-butoxycarbonyl) hexahydropyrrolo also [3 is obtained with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether) after direct solvent evaporated; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl)-4-methylisoquinolinium-2-oxide compound 39a (75mg; yellow oily liquid, productive rate: 73%).
Second step
By 5-((1-(tert-butoxycarbonyl) hexahydropyrrolo also [3; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl)-4-methylisoquinolinium-2-oxide compound 39a (75mg, 0.17mmol) to be dissolved in 1mL diacetyl oxide and to stir 2 hours until reaction terminates at 100 DEG C.Reaction solution concentrating under reduced pressure except adding 6mL tetrahydrofuran (THF) after desolventizing, 2mL water and sodium carbonate (37mg, 0.35mmol) stirring at room temperature 30 minutes.Then methylene dichloride (20mL × 3) extraction; organic phase anhydrous sodium sulfate drying; concentrated; 5-((1-hydroxy-4-methyl isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3 is obtained with chromatography silica gel column purification (0-100% ethyl acetate/petroleum ether); 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 39b (35mg; yellow oily liquid, productive rate: 47%).
3rd step
5-((1-hydroxy-4-methyl isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 39b (35mg; 0.081mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl)-4-methylisoquinolinium-1-alcohol 39 (13mg; white solid, productive rate: 48%).
1HNMR(400MHz,D
2O):δ8.57(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-((six hydrogen-1H-pyrrolo-[3,4-b] pyridine-6 (2H)-Ji) alkylsulfonyl)-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) and 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (106mg; 0.44mmol, embodiment 37) obtain 6-(4-methylisoquinolinium-5-alkylsulfonyl) octahydro-1H-pyrrolo-[3,4-b] pyridine-1 – carboxylic acid tert-butyl ester 40a (30mg according to the synthetic method of embodiment 1; yellow oily liquid, productive rate: 31%).
MS-ESI calculated value [M+H]
+432, measured value 432.
Second step
6-(4-methylisoquinolinium-5-alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1 – carboxylic acid tert-butyl ester 40a (30mg; 0.074mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-b] pyridine-6 (2H)-Ji) alkylsulfonyl)-4-methylisoquinolinium 40 (20mg; white solid, productive rate: 87%).
1HNMR(400MHz,CDCl
3):δ9.55(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-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (73mg; 0.31mmol, embodiment 37) obtain 3-(4-methylisoquinolinium-5-alkylsulfonyl)-3,6-diazabicyclos [3.2.0] heptane-6-carboxylic acid tert-butyl ester 41a (45mg according to the synthetic method of embodiment 1; yellow oily liquid, productive rate: 74%).
MS-ESI calculated value [M+H]
+404, measured value 404.
Second step
3-(4-methylisoquinolinium-5-alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 41a (45mg; 0.11mmol) obtain 5-(3 according to the synthetic method of embodiment 1; 6-diazabicyclo [3.2.0] heptane-3-alkylsulfonyl)-4-methylisoquinolinium 41 (25mg; yellow solid, productive rate: 74%).
1HNMR(400MHz,D
2O):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) alkylsulfonyl) isoquinoline 99.9
The first step
Six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H)-benzyl carboxylate 6e (30mg; 0.12mmol; embodiment 6) and 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (139mg; 0.58mmol, embodiment 37) obtain 1-(4-methylisoquinolinium-5-alkylsulfonyl) six hydrogen-1H-pyrrolo-[3,2-b] pyridine-4 (2H) benzyl carboxylate 42a (30mg according to the synthetic method of embodiment 1; yellow liquid, productive rate: 56%).
MS-ESI calculated value [M+H]
+466, measured value 466.
Second step
1-(4-methylisoquinolinium-5-alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H) benzyl carboxylate 42a (30mg; 0.065mmol) according to embodiment 5 compound 6-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro-1; the synthetic method of 6-naphthyridine 5 obtains 4-methyl-5-((octahydro-1H-pyrrolo-[3; 2-b] pyridine-1-base) alkylsulfonyl) isoquinoline 99.9 42 (5mg; yellow solid, productive rate: 23%).
1HNMR(400MHz,D
2O):δ8.98(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 is [3,4-c] pyrroles-2 (1H)-Ji also) alkylsulfonyl)-4-methylisoquinolinium
The first step
Cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7a (30mg; 0.14mmol; embodiment 7) and 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (68mg; 0.28mmol; embodiment 37) obtain 5-((4-methylisoquinolinium-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 43a (28mg; yellow oily liquid, productive rate: 48%).
MS-ESI calculated value [M+H]
+418, measured value 418.
Second step
5-((4-methylisoquinolinium-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 43a (28mg; 0.067mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-c] pyrroles-2 (1H)-Ji) alkylsulfonyl)-4-methylisoquinolinium 43 (8mg; white solid, productive rate: 34%).
1HNMR(400MHz,D
2O):δ8.99(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-((six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-Ji) alkylsulfonyl)-4-methylisoquinolinium
The first step
Six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (30mg; 0.13mmol; embodiment 8) and 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (48mg; 0.2mmol; embodiment 37) obtain 2-(4-methylisoquinolinium-5-base) alkylsulfonyl according to the synthetic method of embodiment 1) six hydrogen-1H-pyrrolo-es [3,4-c]
Pyridine-5 (6H)-carboxylic acid tert-butyl ester 44a (40mg, colourless oil liquid, productive rate: 70%).
Second step
2-(4-methylisoquinolinium-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 44a (40mg; 0.47mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-2 (3H)-Ji) alkylsulfonyl)-4-methylisoquinolinium 44 (15mg; white solid, productive rate: 40%).
1HNMR(400MHz,D
2O):δ9.50(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) alkylsulfonyl) decahydro-1,6-naphthyridine
The first step
Octahydro-1; 6-naphthyridine-1 (2H)-benzyl carboxylate 20c (30mg; 0.11mmol; embodiment 20) 4-methylisoquinolinium-5-SULPHURYL CHLORIDE 37d (40mg; 0.16mmol, embodiment 37) obtain 6-((4-methylisoquinolinium-5-base) alkylsulfonyl) octahydro-1,6-naphthyridine-1 (2H)-carboxylic acid tert-butyl ester 45a (40mg according to the synthetic method of embodiment 1; colourless oil liquid, productive rate: 76%).
Second step
6-((4-methylisoquinolinium-5-base) alkylsulfonyl) octahydro-1; 6-naphthyridine-1 (2H)-carboxylic acid tert-butyl ester 45a (40mg; 0.084mmol) according to embodiment 5 compound 6-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro-1; the synthetic method of 6-naphthyridine 5 obtains 6-((4-methylisoquinolinium-5-base) alkylsulfonyl) decahydro-1; 6-naphthyridine 45 (12mg; white solid, productive rate: 41%).
1HNMR(400MHz,D
2O):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 is [3,4-b] pyrroles-5 (1H)-Ji also) alkylsulfonyl)-4-(trifluoromethyl) isoquinoline 99.9
The first step
By 4-bromo-isoquinoline 24a (10g, 48.3mmol) obtain 4-bromo-5-nitroisoquinoline 46a (8.5g according to the synthetic method of embodiment 24 compound 4-fluoro-5-nitroisoquinoline 24c, yellow solid, productive rate 85%), product is not purified directly carries out next step reaction.
Second step
By bromo-for 4-5-nitroisoquinoline 46a (1.00g; 3.95mmol) be dissolved in 40mL1-methyl-2-pyrrolidone; Potassium monofluoride (459mg is added successively under nitrogen protection; 7.90mmol), trifluoromethyl trimethylsilane (2.80g, 19.7mmol) and cuprous iodide (1.13g, 5.93mmol); 100 DEG C, gained mixture stirs 8 hours; be cooled to room temperature after reaction terminates, add 300mL diluted ethyl acetate, solids removed by filtration impurity.Filtrate uses water (20mL), saturated sodium-chloride water solution (20mL) to wash successively, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, 5-nitro-4-trifluoromethyl isoquinoline 99.9 46b (500mg is obtained with chromatography silica gel column purification (30% ethyl acetate/petroleum ether), yellow solid, productive rate: 52%).
1HNMR(400MHz，DMSO-d6):δ9.82(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.
3rd step
5-nitro-4-trifluoromethyl isoquinoline 99.9 46b (1.00g, 4.15mmol) obtain 4-trifluoromethyl isoquinoline 99.9-5-amine 46c (523mg according to the synthetic method of embodiment 31 compound 4-(difluoromethyl) isoquinoline 99.9-5-amine 31d, yellow solid, productive rate: 59%).
1HNMR(400MHz，DMSO):δ9.41(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 isoquinoline 99.9-5-amine 46c (300mg, 1.41mmol) obtain 4-Trifluoromethylquinocarboxylic-5-SULPHURYL CHLORIDE 46d (74mg according to the synthetic method of embodiment 16 compound 4-chloro isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d, light yellow solid, productive rate: 18%).
1HNMR(400MHz,DMSO-d6):δ9.53(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 isoquinoline 99.9-5-SULPHURYL CHLORIDE 46d (45m
g0.15mmol) and cis-hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (32mg; 0.15mmol; embodiment 2) obtain 5-((4-(trifluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 46e (30mg, yellow solid, productive rate: 42%).
MS-ESI calculated value [M+H]
+472, measured value 472.
6th step
5-((4-(trifluoromethyl) isoquinoline 99.9-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 46e (30mg; 0.063mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-5 (1H)-Ji) alkylsulfonyl)-4-(trifluoromethyl) isoquinoline 99.9 46 (14mg; white solid, productive rate: 60%).
1HNMR(400MHz,CD
3OD):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 is [3,2-b] pyrroles-1 (2H)-Ji also) alkylsulfonyl)-4-methoxyisoquinoliae
The first step
4-bromo-5-nitroisoquinoline 46a (3.00g, 11.8mmol, embodiment 46) obtain 4-bromo-isoquinoline-5-amine 47a (1.9g, light yellow solid, productive rate: 73%) according to the synthetic method of embodiment 16 compound 4-chloro isoquinoline 99.9-5-amine 16c.
1HNMR(400MHz,DMSO):δ9.03(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) obtain 4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (500mg according to the synthetic method of embodiment 16 compound 4-chloro isoquinoline 99.9-5-SULPHURYL CHLORIDE 16d, light yellow solid, productive rate: 20%).
1HNMR(400MHz,DMSO):δ9.57(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).
3rd step
4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (57mg; 0.19mmol) and cis-hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 1d (40mg; 0.19mmol; embodiment 1) obtain 4-((4-bromo-isoquinoline-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl acrylate 47c (62mg; yellow solid, productive rate: 68%).
1HNMR(400MHz,CDCl
3):δ9.23(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) alkylsulfonyl) hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl acrylate 47c (62mg; 0.13mmol) be dissolved in 1mL anhydrous methanol; pyridine (0.2mg is added successively under nitrogen protection; 0.003mmol); sodium methylate (300mg, 1.28mmol) and CuI (12mg, 0.064mmol).Gained mixture stirs 3 hours at 100 DEG C, be cooled to room temperature, add 30mL diluted ethyl acetate, solids removed by filtration impurity, filtrate uses saturated aqueous ammonium chloride (20mL) successively, water (20mL), saturated sodium-chloride water solution (20mL) washs, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, 4-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) hexahydropyrrolo also [3 is obtained with thin-layer chromatography silica-gel plate (100% ethyl acetate) purifying, 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 47d (33mg, white solid, productive rate: 60%).
MS-ESI calculated value [M+H]
+434, measured value 434.
5th step
4-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 2-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 47d (33mg; 0.063mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 2-b] pyrroles-1 (2H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae 47 (26mg; white solid, productive rate: 83%).
1HNMR(400MHz,D
2O):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 is [3,2-c] pyrroles-5 (1H)-Ji also) alkylsulfonyl)-4-methoxyisoquinoliae
The first step
Cis-hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 2f (76mg; 0.36mmol; embodiment 2) and 4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (94mg; 0.30mmol; embodiment 47) obtain 5-((4-bromo-isoquinoline-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 48a (120mg; white solid, productive rate 81%)
Second step
5-((4-bromo-isoquinoline-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 48a (120mg; 0.250mmol) obtain 5-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 47; 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.
3rd step
5-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-b] pyrroles-1 (2H)-carboxylic acid tert-butyl ester 48b (86mg; 0.2mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 2-c] pyrroles-5 (1H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae 48 (25mg; white solid, yield: 38%).
1HNMR(400MHz,D
2O):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-((six hydrogen-1H-pyrrolo-[3,4-b] pyridine-6 (2H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae
The first step
4-bromo-isoquinoline-5-SULPHURYL 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) obtain 6-((4-bromo-isoquinoline-5-base) alkylsulfonyl) octahydro-1H-pyrrolo-[3,4-b] pyridine-1-carboxylic acid tert-butyl ester 49a (80mg according to the synthetic method of embodiment 1; white solid, yield: 91%).
1HNMR(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) alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 49a (80mg; 0.16mmol) obtain 6-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) octahydro-1H-pyrrolo-[3 according to the synthetic method of embodiment 47; 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.
3rd step
6-((the iso-5-yl of 4-methoxyl group) alkylsulfonyl) octahydro-1H-pyrrolo-[3; 4-b] pyridine-1-carboxylic acid tert-butyl ester 49b (46mg; 0.1mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-b] pyridine-6 (2H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae 49 (20mg; white solid, yield: 56%).
1HNMR:(400MHz,D
2O):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 alkylsulfonyl)-4-methoxyisoquinoliae
The first step
4-bromo-isoquinoline-5-SULPHURYL 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) obtain 3-((4-bromo-isoquinoline-5-base) alkylsulfonyl)-3,6-diazabicyclos [3.2.0] heptane-6-carboxylic acid tert-butyl ester 50a (82mg according to the synthetic method of embodiment 1; yellow solid, productive rate: 87%).
1hNMR (400MHz, CDCl
3): 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 value [M+H]
+468, measured value 468.
Second step
3-((4-bromo-isoquinoline-5-base) alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 50a (82mg; 0.18mmol) obtain 3-((the different azoles of 4-methoxyl group-5-base) alkylsulfonyl)-3 according to the synthetic method of embodiment 47; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 50b (30mg; white solid, productive rate 42%).
MS-ESI calculated value [M+H]
+420, measured value 420.
3rd step
3-((the different azoles of 4-methoxyl group-5-base) alkylsulfonyl)-3; 6-diazabicyclo [3.2.0] heptane-6-carboxylic acid tert-butyl ester 50b (30mg; 0.071mmol) obtain 5-(3 according to the synthetic method of embodiment 1; 6-diazabicyclo [3.2.0] heptane-3-base alkylsulfonyl)-4-methoxyisoquinoliae 50 (20mg; white solid, productive rate 86%).
1HNMR(400MHz,D
2O):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) alkylsulfonyl) isoquinoline 99.9
The first step
4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (59mg; 0.19mol; embodiment 47) and six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H)-benzyl carboxylate 6e (50mg; 19mmol; embodiment 6) obtain 1-((4-bromo-isoquinoline-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 2-b] pyridine-4 (2H)-carboxylic acid tert-butyl ester 51a (90mg; white solid, yield: 88%).
1HNMR(400MHz,CDCl
3):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) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H)-carboxylic acid tert-butyl ester 51a (90mg; 0.17mmol) obtain 1-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 47; 2-b] pyridine-4 (2H)-carboxylate methyl ester 51b (30mg; white solid, yield: 44%).
MS-ESI calculated value [M+H]
+406, measured value 406.
3rd step
To 1-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 2-b] pyridine-4 (2H)-carboxylate methyl ester 51b (30mg; 0.074mmol) and in the 2mL methanol solution of sodium methylate (40mg, 0.74mmol) add the 25%NaOH aqueous solution of 0.1mL.By mixture microwave heating to 90 DEG C 2 hours under nitrogen atmosphere.Room temperature is cooled to after question response terminates; mixture ethyl acetate (50mL) is diluted; and wash with saturated sodium-chloride water solution (50mL); organic phase anhydrous sodium sulfate drying; concentrating under reduced pressure; resistates Preparative TLC chromatogram purification (50% methanol/ethyl acetate) obtains compound 4-methoxyl group-5-((octahydro-1H-pyrrolo-[3; 2-b] pyridine-1-base) alkylsulfonyl) isoquinoline 99.9 51 (20mg; white solid, yield: 78%).
1HNMR(400MHz,CD
3OD):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 is [3,4-c] pyrroles-2 (1H)-Ji also) alkylsulfonyl)-4-methoxyisoquinoliae
The first step
4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (58mg; 0.19mmol; embodiment 47) and cis-hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 7a (40mg; 0.19mmol; embodiment 7) obtain 5-((4-bromo-isoquinoline-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 52a (80mg; white solid, yield: 88%).
1HNMR(400MHz,CDCl
3):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) alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 52a (80mg; 0.17mmol) obtain 5-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) hexahydropyrrolo also [3 according to the synthetic method of embodiment 47; 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.
3rd step
5-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) hexahydropyrrolo also [3; 4-c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 52b (45mg; 0.1mmol) obtain 5-((hexahydropyrrolo also [3 according to the synthetic method of embodiment 1; 4-c] pyrroles-2 (1H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae 52 (20mg; white solid, yield: 58%).
1HNMR(400MHz,D
2O):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-((six hydrogen-1H-pyrrolo-[3,4-c] pyridine-2 (3H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae
The first step
4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (54mg; 0.17mmol; embodiment 47) and six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 8h (40mg; 0.17mmol; embodiment 8) obtain 2-((4-bromo-isoquinoline-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 53a (40mg; yellow solid, productive rate: 46%).
MS-ESI calculated value [M+H]
+496, measured value 496.
Second step
2-((4-bromo-isoquinoline-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 53a (40mg; 0.081mmol) obtain 2-((the different azoles of 4-methoxyl group-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 47; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 53b (20mg; white solid, productive rate: 55%).
MS-ESI calculated value [M+H]
+448, measured value 448.
3rd step
2-((the different azoles of 4-methoxyl group-5-base) alkylsulfonyl) six hydrogen-1H-pyrrolo-es [3; 4-c] pyridine-5 (6H)-carboxylic acid tert-butyl ester 53b (20mg; 0.044mmol) obtain 5-((six hydrogen-1H-pyrrolo-es [3 according to the synthetic method of embodiment 1; 4-c] pyridine-2 (3H)-Ji) alkylsulfonyl)-4-methoxyisoquinoliae 53 (14mg; white solid, productive rate: 77%).
1HNMR(400MHz，D
2O):δ9.26(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) alkylsulfonyl) decahydro-1,6-naphthyridine 55
The first step
4-bromo-isoquinoline-5-SULPHURYL CHLORIDE 47b (49mg; 0.16mmol; embodiment 47) and octahydro-1; 6-naphthyridine-1 (2H)-benzyl carboxylate 20c (50mg; 0.16mmol, embodiment 20) obtain 6-((4-bromo-isoquinoline-5-base) alkylsulfonyl) octahydro-1,6-naphthyridine-1 (2H)-benzyl carboxylate 54a (46mg according to the synthetic method of embodiment 1; yellow solid, productive rate: 53%).
1HNMR(400MHz,CDCl
3):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) alkylsulfonyl) octahydro-1; 6-naphthyridine-1 (2H)-benzyl carboxylate 54a (46mg; 0.084mmol) obtain 6-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) octahydro-1 according to the synthetic method of embodiment 47; 6-naphthyridine-1 (2H)-benzyl carboxylate 55b (20mg; white solid, productive rate: 47%).
MS-ESI calculated value [M+H]
+496, measured value 496.
3rd step
6-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) octahydro-1; 6-naphthyridine-1 (2H)-benzyl carboxylate 55b (20mg; 0.04mmol) according to embodiment 5 compound 6-(isoquinoline 99.9-5-base alkylsulfonyl) decahydro-1; the synthetic method of 6-naphthyridine 5 obtains 6-((4-methoxyisoquinoliae-5-base) alkylsulfonyl) decahydro-1; 6-naphthyridine 55 (3mg; white solid, productive rate: 21%).
1hNMR (400MHz, CD
3oD): δ 8.97 (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-(isoquinoline 99.9-5-base alkylsulfonyl)-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) with N-benzyl-1-methoxyl group-N-((trimethyl silicon based) methyl) methylamine 55b (1.09g; the 0.6mL dichloromethane solution of trifluoroacetic acid (520mg, 4.59mmol) is added dropwise in 15mL dichloromethane solution 4.59mmol).
Gained mixture is warming up to 25 DEG C to stir 4 hours, then use 50mL dchloromethane, and wash with unsaturated carbonate aqueous solutions of potassium (50mLx2) and saturated sodium-chloride water solution (50mLx1), organic phase anhydrous sodium sulfate drying, filter, concentrating under reduced pressure.Resistates Preparative TLC chromatoplate purifying (50% ethyl acetate/petroleum ether) obtains 2-benzyl six hydrogen pyrans also [4,3-c] pyrroles-4 (6H)-one 55c (533mg, colourless oil liquid, yield: 75%).
1HNMR(400MHz,CDCl
3):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 2-benzyl six hydrogen pyrans also [4 at 0 DEG C, 3-c] pyrroles-4 (6H)-one 55c (9.00g, pass into the hydrogen bromide of fresh preparation in 100mL ethanolic soln 38.9mmol), and react 3 hours at this temperature, then stir 24 hours at 25 DEG C.Concentrated by reaction solution after question response terminates, crude product is recrystallization in ethanol, obtains 1-base-4-(2-bromotrifluoromethane) tetramethyleneimine-3-carboxylic acid, ethyl ester 55d (9.0g, white solid, productive rate: 85%).
1HNMR(400MHz,CDCl
3):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.
3rd step
1-benzyl-4-(2-bromotrifluoromethane) tetramethyleneimine-3-carboxylic acid, ethyl ester 55d (1.00g under nitrogen protection; 2.94mmol) be dissolved in 100mL anhydrous tetrahydro furan; lithium hexamethyldisilazide (17.6mL is dripped at-78 DEG C; the tetrahydrofuran solution of 17.6mmol, 1.0M).Then reaction solution be warming up to 20 DEG C and react 18 hours.After question response terminates, reaction solution ethyl acetate (100mL) is diluted, saturated aqueous ammonium chloride (100mLx3), saturated sodium-chloride water solution (100mLx1) is used to wash successively, organic phase anhydrous sodium sulfate drying, filter, filtrate reduced in volume, resistates Preparative TLC chromatoplate purifying (50% ethyl acetate/petroleum ether) obtains 3-benzyl-3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester 55e (130mg, white solid, productive rate: 17%).
1HNMR(400MHz,CDCl
3):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) He one hydronium(ion) Lithium Oxide 98min (63mg, 1.5mmol) to be dissolved in the mixed solvent of 7mL tetrahydrofuran (THF)/ethanol/water (v/v/v=4/2/1) and to be heated to 40 DEG C and stirs 6 hours.After question response terminates, reaction solution is cooled to 0 DEG C, with 6N hydrochloric acid, reaction solution pH is adjusted to 2, add 30mL saturated sodium-chloride water solution, ethyl acetate and tetrahydrofuran (THF) mixed solvent (v/v=4/1,100mL × 3) extraction, organic phase washed with water (100mL × 2), saturated sodium-chloride water solution washing (100mLx2), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain crude product 3-benzyl-3-azabicyclo [3.2.0] heptane-1-carboxylic acid 55f (30mg, white solid, productive rate: 95%).Product is not purified directly carries out next step reaction.
1HNMR(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-diisopropylethylamine (56mg, 0.43mmol) with diphenyl phosphate azide (65mg, 0.24mmol) be dissolved in the 2mL trimethyl carbinol, gained reaction solution stirs 2 hours at 40 DEG C, then rises to 80 DEG C and stirs 12 hours.After question response terminates, reaction solution is cooled to room temperature, dilute with 50mL saturated sodium-chloride water solution, extraction into ethyl acetate (100mLx3), organic phase washed with water (100mL) and saturated sodium-chloride water solution (100mL) washing, anhydrous sodium sulfate drying, filter, filtrate reduced in volume obtains 3-benzyl-3-azabicyclo [3.2.0] heptane-1-base aminocarboxylic acid tert-butyl ester 55g (20mg, white solid, productive rate: 31%).Product is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+303, measured value 303.
6th step
3-benzyl-3-azabicyclo [3.2.0] heptane-1-base aminocarboxylic acid tert-butyl ester 55g (20mg, 0.066mmol) is dissolved in 5mL tetrahydrofuran (THF), adds Pd (OH) under nitrogen protection
2/ C (5mg, 20%wt).Reaction solution stirs 48 hours until reaction terminates lower 30 DEG C of nitrogen atmosphere (40Psi).After question response liquid is cooled to room temperature, filter, filtrate reduced in volume obtains 3-azabicyclo [3.2.0] heptane-1-base aminocarboxylic acid tert-butyl ester 55h (10mg, white solid, productive rate: 71%).Product is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+213, measured value 213.
7th step
By 3-azabicyclo [3.2.0] heptane-1-base aminocarboxylic acid tert-butyl ester 55h (20mg; 0.094mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (22mg; 0.094mmol) obtain 3-(isoquinoline 99.9-5-base alkylsulfonyl)-3-azabicyclic [3.2.0] heptane-1-aminocarbamic acid 55i (15mg according to the synthetic method of embodiment 1; white solid, productive rate: 40%).Product is not purified directly carries out next step reaction.
MS-ESI calculated value [M+H]
+404, measured value 404.
8th step
3-(isoquinoline 99.9-5-base alkylsulfonyl)-3-azabicyclic [3.2.0] heptane-1-aminocarbamic acid 55i (30mg; 0.074mmol) be dissolved in 3mL anhydrous methylene chloride; drip trifluoroacetic acid (0.5mL is dissolved in the solution of 1mL methylene dichloride) at 0 DEG C, stirred under nitrogen atmosphere 3 hours is until raw material disappears.Reaction solution methylene dichloride (50mL) is diluted; saturated sodium bicarbonate aqueous solution (50mLx3), saturated sodium-chloride water solution (50mL) is used to wash successively; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume preparative HPLC purifying obtains product 3-(isoquinoline 99.9-5-base alkylsulfonyl)-3-azabicyclic [3.2.0] heptane-1-amine 55 (3mg; white solid, productive rate: 13%).1HNMR(400MHz,CD
3OD):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-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-amine
The first step
By 3-azabicyclo [3.1.0] hexane-1-base aminocarboxylic acid tert-butyl ester 56a (50mg; 0.25mmol) with isoquinoline 99.9-5-SULPHURYL CHLORIDE 1c (75mg; 0.25mmol; embodiment 1) obtain (3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-base) aminocarboxylic acid tert-butyl ester 56b (80mg according to the synthetic method of embodiment 1; yellow oily liquid, productive rate: 82%).
MS-ESI calculated value [M+H]
+390, measured value 390.
Second step
(3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-base) aminocarboxylic acid tert-butyl ester 56b (30mg; 0.077mmol) obtain 3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-amine 56 (7mg according to the synthetic method of embodiment 1; yellow solid, productive rate: 29%).
1HNMR(400MHz,D
2O):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-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-amine
The first step
(3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-base) aminocarboxylic acid tert-butyl ester 56b (50mg; 0.13mmol) obtain ethyl (3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-base) t-butyl carbamate 57a (33mg according to the synthetic method of embodiment 11; yellow oily liquid thing, productive rate: 62%).
MS-ESI calculated value [M+H]
+418, measured value 418.
Second step
Ethyl (3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-base) t-butyl carbamate 57a (33mg; 0.079mmol) obtain N-ethyl-3-(isoquinoline 99.9-5-alkylsulfonyl)-3-azabicyclic [3.1.0] hexane-1-amine 57 (10mg according to the synthetic method of embodiment 1; yellow solid, productive rate: 40%).
1HNMR(400MHz,D
2O):δ9.59(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 suppresses IC
50value.
Experiment material:
Measure Slow Red solution: 20mMHepes (pH7.5), 10mMMgCl2,1mMEGTA, 0.02%Brij35,0.02mg/mlBSA, 0.1mMNa3VO4,2mMDTT, 1%DMSO
Experimental implementation:
ROCK protein kinase substrate LongS6Kinasesubstratepeptide will be added in the buffered soln of fresh preparation, concentration 20 μMs. then add 1nMROCK protein kinase, uniform stirring. the serial DMSO diluent using Echo550 to add containing testing compound (starts from 10 μMs, by 3 times of serial dilutions). preincubation 20 minutes under room temperature, adds
33p-ATP (intensity of radioactivity 10 μ Ci/ μ L) initiation reaction, room temperature reaction two hours.Then use P81 ion exchange paper (Whatman#3698-915) to filter, use 0.75% phosphoric acid washing.Filter-Binding method is used to detect intensity of radioactivity.
The protein kinase inhibiting activity of compound is expressed as the remaining protein kinase activity of relative substrate blank (simple DMSO).Prism software package (GraphPadSoftware, SanDiegoCalifornia, USA) is utilized to calculate IC50 value and curve.
Experimental result:
Table 1 protein kinase inhibiting activity test result
| Trial-product (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 μMs; ++ < 1 μM; +++ < 0.1 μM;--N/A
Conclusion: the compounds of this invention has significantly even unexpected protease inhibiting activity.
Claims (9)
1. compound shown in formula (I) or its pharmacy acceptable salt,
It is characterized in that,
R
1, X is separately selected from H, F, Cl, Br, I, CN, OH, NH
2, C
1 ?3alkyl, C
1 ?3alkyl oxy, C
1 ?3alkylamino, two C
1 ?3alkylamino, described C
1 ?3alkyl is optionally by R
01replaced, R
01be selected from F, Cl, Br, I, OH, NH
2, R
01number be 1,2 or 3;
R
2be selected from
W, W ' be separately selected from N (R
w1), C (R
w2) (R
w3) or singly-bound;
L, Z are separately selected from singly-bound or C (R
z1) (R
z2);
P, P ' be selected from (CH respectively
2)
q1; Q, Q ' be selected from (CH respectively
2)
q2;
Q
1, q
2separately be selected from 0,1,2,3 or 4;
R
3a, R
3b, R
3, R
w1, R
w2, R
w3, R
z1, R
z2separately be selected from H, F, Cl, Br, I, CN, OH, NH
2, C
1 ?3alkyl, C
1 ?3alkyl oxy, C
1 ?3alkylamino, two C
1 ?3alkylamino, described C
1?
3alkyl is optionally by R
01replaced; Preferably, R
3a, R
3b, R
3, R
w1, R
w2, R
w3be selected from halo, hydroxyl generation and/or amine for methyl, ethyl or propyl group;
R
01be selected from F, Cl, Br, I, OH, NH
2, R
01number be 1,2 or 3.
2. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that, R
1be selected from H, F, Cl, Br, I, methyl, difluoromethyl, trifluoromethyl, methoxyl group; X is selected from H or OH.
3. compound according to claim 2 or its pharmacy acceptable salt, wherein structural unit
be selected from:
4. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that R2 is selected from
wherein in A, B one be singly-bound, another is methylene radical; R
4be selected from H, F, Cl, Br, I, CN, OH, NH
2, C
1 ?3alkyl, C
1 ?3alkyl oxy, C
1 ?3alkylamino, two C
1 ?3alkylamino, described C
1 ?3alkyl is optionally by R
01replaced, R
01be selected from F, Cl, Br, I, OH, NH
2, R
01number be 1,2 or 3;
Preferably, R
4be selected from NH
2, ethylamino;
Further preferably, R
4be selected from
5. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that, R
2be selected from
or
wherein, in D, E, one is singly-bound, and another is methylene radical; G is selected from (CH
2)
g; T is selected from (CH
2)
t; G, t are separately selected from 0,1,2,3 or 4; R
3bas claim 1 define;
Preferably, g be 1,2,3 or 4, t be 0 or 1;
Preferably, R
3bbe selected from NH
2;
Further preferably, R
2be selected from
6. compound according to claim 1 or its pharmacy acceptable salt, is characterized in that, R
2be selected from
wherein, Y is selected from (CH
2)
y; M is selected from (CH
2)
m; Y is selected from 0,1,2 or 3; M is selected from 0 or 1;
Preferably, R
2be selected from
7. compound according to claim 1 or its pharmacy acceptable salt, it is selected from:
8. a pharmaceutical composition, it contains the compound according to claim 1 ~ 7 any one or its pharmacy acceptable salt and pharmaceutically acceptable carrier for the treatment of significant quantity.
9. the application in the medicine of the relevant various illness that the compound according to claim 1 ~ 7 any one or its pharmacy acceptable salt or pharmaceutical composition according to claim 8 cause in preparation treatment vasoconstriction, wherein said relevant various illnesss comprise cerebral vasospasm, stenocardia, glaucoma, hypertension, fibrosis caused by cerebral embolism, cerebral ischemia, brain injury, vertebrobasilar insufficiency, subarachnoid hemorrhage.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410174893.1A CN105085525B (en) | 2014-04-28 | 2014-04-28 | Isoquinolin sulfonyl derivative as RHO kinase inhibitor |
| EP15786613.8A EP3138843B1 (en) | 2014-04-28 | 2015-04-21 | Isoquinolinesulfonyl derivative as rho kinase inhibitor |
| PCT/CN2015/077045 WO2015165341A1 (en) | 2014-04-28 | 2015-04-21 | Isoquinolinesulfonyl derivative as rho kinase inhibitor |
| JP2016565494A JP6581111B2 (en) | 2014-04-28 | 2015-04-21 | Isoquinoline sulfone derivatives as RHO kinase inhibitors |
| US15/306,965 US9856264B2 (en) | 2014-04-28 | 2015-04-21 | Isoquinolinesulfonyl derivative as RHO kinase inhibitor |
| ES15786613T ES2774923T3 (en) | 2014-04-28 | 2015-04-21 | Isoquinolinsulfonyl derivatives as RHO kinase inhibitors |
| TW104113440A TWI676622B (en) | 2014-04-28 | 2015-04-27 | Isoquinoline sulfonium derivatives as RHO kinase inhibitors |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410174893.1A CN105085525B (en) | 2014-04-28 | 2014-04-28 | Isoquinolin sulfonyl derivative as RHO kinase inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105085525A true CN105085525A (en) | 2015-11-25 |
| CN105085525B CN105085525B (en) | 2019-01-04 |
Family
ID=54566941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410174893.1A Active CN105085525B (en) | 2014-04-28 | 2014-04-28 | Isoquinolin sulfonyl derivative as RHO kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105085525B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107235975A (en) * | 2017-06-29 | 2017-10-10 | 天津药明康德新药开发有限公司 | The synthetic method of 6 benzyl of the tert-butyl group 4 oxygen subunit octahydro 1H pyrrolo-es [3,4 b] picolinic acid ester |
| WO2019015608A1 (en) * | 2017-07-19 | 2019-01-24 | 南京明德新药研发股份有限公司 | Isoquinolinylsulfonyl derivative and use thereof |
| WO2019057121A1 (en) * | 2017-09-25 | 2019-03-28 | 南京明德新药研发股份有限公司 | Crystal form of isoquinolinesulfonyl derivative and preparation method therefor |
| WO2019201296A1 (en) * | 2018-04-18 | 2019-10-24 | 南京明德新药研发有限公司 | Pyrazole compound used as rho kinase inhibitor |
| WO2020253882A1 (en) * | 2019-06-21 | 2020-12-24 | 中山大学中山眼科中心 | Isoquinolinone derivatives serving as rock protein kinase inhibitors and use thereof |
| CN113549063A (en) * | 2020-04-23 | 2021-10-26 | 南京药石科技股份有限公司 | Preparation method of optically isomeric octahydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210521A (en) * | 1996-02-02 | 1999-03-10 | 日本新药株式会社 | Isoquinoline derivatives and drugs |
| WO2007103719A2 (en) * | 2006-03-03 | 2007-09-13 | Incyte Corporation | MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME |
| CN101622243A (en) * | 2007-02-28 | 2010-01-06 | 旭化成制药株式会社 | Sulfonamide derivative |
-
2014
- 2014-04-28 CN CN201410174893.1A patent/CN105085525B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1210521A (en) * | 1996-02-02 | 1999-03-10 | 日本新药株式会社 | Isoquinoline derivatives and drugs |
| WO2007103719A2 (en) * | 2006-03-03 | 2007-09-13 | Incyte Corporation | MODULATORS OF 11-β HYDROXYL STEROID DEHYDROGENASE TYPE 1, PHARMACEUTICAL COMPOSITIONS THEREOF, AND METHODS OF USING THE SAME |
| CN101622243A (en) * | 2007-02-28 | 2010-01-06 | 旭化成制药株式会社 | Sulfonamide derivative |
Non-Patent Citations (3)
| Title |
|---|
| CHARLOTTE E. ALLEN ET AL.: "Synthesis and evaluation of heteroaryl substituted diazaspirocycles as scaffolds to probe the ATP-binding site of protein kinases", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| REGISTRY: "RN: 1493852-50-8, 1218053-59-8", 《STN COLUMBUS》 * |
| TUOPING LUO ET AL.: "STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability", 《PNAS》 * |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107235975B (en) * | 2017-06-29 | 2019-04-30 | 天津药明康德新药开发有限公司 | The synthetic method of tert-butyl 6- benzyl -4- oxygen subunit octahydro -1H- pyrrolo- [3,4-b] picolinic acid ester |
| CN107235975A (en) * | 2017-06-29 | 2017-10-10 | 天津药明康德新药开发有限公司 | The synthetic method of 6 benzyl of the tert-butyl group 4 oxygen subunit octahydro 1H pyrrolo-es [3,4 b] picolinic acid ester |
| AU2018303069B2 (en) * | 2017-07-19 | 2020-10-22 | China Resources Pharmaceutical Holdings Company Limited | Isoquinolinylsulfonyl derivative and use thereof |
| WO2019015608A1 (en) * | 2017-07-19 | 2019-01-24 | 南京明德新药研发股份有限公司 | Isoquinolinylsulfonyl derivative and use thereof |
| CN111065637B (en) * | 2017-07-19 | 2022-02-01 | 华润医药控股有限公司 | Isoquinoline sulfonyl derivative and application thereof |
| US11155559B2 (en) | 2017-07-19 | 2021-10-26 | China Resources Pharmaceutical Holdings Company Limited | Sulfonyl-substituted isoquinolines as inhibitors of RHO kinase and hERG potassium channel activity |
| CN111065637A (en) * | 2017-07-19 | 2020-04-24 | 华润医药控股有限公司 | Isoquinoline sulfonyl derivative and application thereof |
| CN111132983A (en) * | 2017-09-25 | 2020-05-08 | 华润医药控股有限公司 | Crystal form of isoquinoline sulfonyl derivative and preparation method thereof |
| WO2019057121A1 (en) * | 2017-09-25 | 2019-03-28 | 南京明德新药研发股份有限公司 | Crystal form of isoquinolinesulfonyl derivative and preparation method therefor |
| CN111132983B (en) * | 2017-09-25 | 2022-05-17 | 华润医药控股有限公司 | Crystal form of isoquinoline sulfonyl derivative and preparation method thereof |
| WO2019201296A1 (en) * | 2018-04-18 | 2019-10-24 | 南京明德新药研发有限公司 | Pyrazole compound used as rho kinase inhibitor |
| WO2020253882A1 (en) * | 2019-06-21 | 2020-12-24 | 中山大学中山眼科中心 | Isoquinolinone derivatives serving as rock protein kinase inhibitors and use thereof |
| CN113906017A (en) * | 2019-06-21 | 2022-01-07 | 广州润尔眼科生物科技有限公司 | Isoquinolinone derivatives as ROCK protein kinase inhibitors and application thereof |
| CN113549063A (en) * | 2020-04-23 | 2021-10-26 | 南京药石科技股份有限公司 | Preparation method of optically isomeric octahydro-2H-pyrrolo [3,4-c ] pyridine-2-carboxylic acid tert-butyl ester |
| CN113549063B (en) * | 2020-04-23 | 2024-04-05 | 南京药石科技股份有限公司 | Preparation method of optical isomerism octahydro-2H-pyrrolo [3,4-c ] pyridine-2-tert-butyl carboxylate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105085525B (en) | 2019-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111989321B (en) | KRAS G12C inhibitors | |
| CN114615981B (en) | KRAS G12D inhibitors | |
| EP3647311B1 (en) | Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof | |
| CN108699038B (en) | Spirocyclic heptane salicylamides and related compounds as Rock inhibitors | |
| CN104837829B (en) | Inhibitor compound | |
| CN107873031B (en) | Benzoxazinone derivatives and analogs thereof as modulators of TNF activity | |
| EP3421465B1 (en) | Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof | |
| ES2925173T3 (en) | Propionic acids substituted in position 3 as inhibitors of integrin alpha V | |
| TWI676622B (en) | Isoquinoline sulfonium derivatives as RHO kinase inhibitors | |
| CN109153643B (en) | Substituted indole MCL-1 inhibitors | |
| EP2991977B1 (en) | C-linked heterocycloalkyl substituted pyrimidines and their uses | |
| CN105085525A (en) | Isoquinoline sulfonyl derivatives as RHO kinases inhibitor | |
| TW201414737A (en) | Imidazotriazinecarbonitriles useful as kinase inhibitors | |
| CN102918043A (en) | Pyrrolopyrimidine compounds as inhibitors of CDK4/6 | |
| KR101921486B1 (en) | ANALOGS OF 4H-Pyrazolo[1,5-a]benzimidazole compounds AS PARP INHIBITORS | |
| CN104974161A (en) | 4H-pyrazolo[1,5-[alpha]]benzimidazole compound analogue as PARP inhibitor | |
| CN116888108B (en) | Novel EGFR degradation agent | |
| TW201734020A (en) | Inhibitors of bruton's tyrosine kinase and methods of their use | |
| CN111032643A (en) | Quinolinone compounds | |
| AU2017388376A1 (en) | Poly-ADP ribose polymerase (PARP) inhibitors | |
| JP7312171B2 (en) | pyrazolopyridinone compound | |
| CN116096719A (en) | Pyridazinylamino derivatives as ALK5 inhibitors | |
| KR102412045B1 (en) | Hydrazide compound as blood coagulation factor xa inhibitor | |
| CN116332948A (en) | Nitrogen-containing tetracyclic compound, preparation method and medicinal application thereof | |
| CN117693502A (en) | Compounds for inhibiting or degrading ITK, compositions comprising the same, methods of making the same, and methods of using the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 210032 Jiangsu city of Nanjing province Nanjing high tech Development Zone of High Road No. 9 business office building room 218 Patentee after: Nanjing Mingde New Drug Development Co.,Ltd. Address before: 210032 Jiangsu city of Nanjing province Nanjing high tech Development Zone of High Road No. 9 business office building room 218 Patentee before: MEDSHINE DISCOVERY Inc. |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200416 Address after: 100120 building 7, yard 2, Beisanhuan Middle Road, Chaoyang District, Beijing Patentee after: China Resources pharmaceutical Holding Co.,Ltd. Address before: 210032 Jiangsu city of Nanjing province Nanjing high tech Development Zone of High Road No. 9 business office building room 218 Patentee before: Nanjing Mingde New Drug Development Co.,Ltd. |