CN108084172A - Anti- hepatitis C virus compound - Google Patents
Anti- hepatitis C virus compound Download PDFInfo
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- CN108084172A CN108084172A CN201711322088.9A CN201711322088A CN108084172A CN 108084172 A CN108084172 A CN 108084172A CN 201711322088 A CN201711322088 A CN 201711322088A CN 108084172 A CN108084172 A CN 108084172A
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- 0 C[C@@](CCCCN*)C(C[N+]([O-])=O)=O Chemical compound C[C@@](CCCCN*)C(C[N+]([O-])=O)=O 0.000 description 10
- ADGHBKHEEBMQAB-ZDUSSCGKSA-N Brc(cc1)ccc1-c1cnc([C@H]2NCCCCC2)[nH]1 Chemical compound Brc(cc1)ccc1-c1cnc([C@H]2NCCCCC2)[nH]1 ADGHBKHEEBMQAB-ZDUSSCGKSA-N 0.000 description 1
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- 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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- C07D401/14—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 three or more hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a series of thiophene as Hepatitis C Virus (HCV) inhibitor or its variant derivative and combinations thereof, and it is related to it and is preparing the application in treating chronic hcv infection drug.In particular it relates to series compound as NS5A inhibitor and combinations thereof and pharmaceutical applications.
Description
The application is the divisional application of following application:Applying date 2014-02-21;Application number 201410058355.6;Invention
Title:" as the thiophene of hepatitis C virus inhibitor or its variant derivative and its pharmaceutical applications ".
Technical field
The present invention relates to the thiophene as Hepatitis C Virus (HCV) inhibitor or its variant derivative and combinations thereof,
And it is related to it and is preparing the application in treating chronic hcv infection drug.In particular it relates to as NS5A
Series compound of inhibitor and combinations thereof and pharmaceutical applications.
Background technology
HCV is one of main human pathogen, estimates global patients with chronic HCV infection about 1.7 hundred million, is human immunodeficiency
5 times of malicious 1 type number of the infected.Patients with chronic HCV infection can develop into serious progressive hepatopathy, including hepatic sclerosis and liver cell
Cancer.Therefore, chronic HCV infection is global patient's main causes of death due to hepatopathy.
At present, the chronic HCV infection therapy of standard be using alpha-interferon and Ribavirin and ratify over the past two years its
In a drug combination for directly acting on antiviral (DAA) drug.Though curative effect relatively before alpha-interferon and Ribavirin connection
Medicine is shared to significantly improve, but still it is invalid to part patients with chronic HCV infection, and virus can develop immunity to drugs.In addition alpha-interferon
There is apparent side reaction with Ribavirin.Therefore, the drug of effective treatment chronic HCV infection newly is urgent at present required
's.
HCV is single strand positive strand RNA virus.Belong in the individual category of flaviviridae (Flaviviridae family).It is yellow
All members of Viraceae are the envelope virus particles of the genome containing positive chain RNA, which is uninterruptedly opened by single
The translation of reading frame (ORF) is put, encodes all known virus specified proteins.
There are considerable heterogeneities for the nucleotide of HCV genomes and encoded amino acid sequence.Identified to
Few 6 main genotype, a subgenotype more than 50.Distribution of the main genotypes of HCV in the whole world is different, although having carried out big
Research of the genotype to pathogenesis and therapeutic effect is measured, but still does not know the clinical importance of HCV genetic heterogeneities.
HCV rna gene group length is about 9500 nucleotide, has single open reading frame, single about 3000 of coding
The polyprotein of amino acid.In infection cell, the polyprotein is on multiple sites by leukoprotease and virus protease
Cutting generates structure and non-structural (NS) albumen.For HCV, ripe non-structural protein (NS2, NS3, NS4A, NS4B, NS5A
And NS5B) be formed by what two kinds of virus proteases were realized.It is generally acknowledged that the first (NS2) is metalloproteinases,
NS2-NS3 contacts are cut;Second protease is included in the silk in NS3 (also referred to herein as NS3 protease) N-terminal region
Serine protease, it mediates all follow-up cuttings in NS3 downstreams, be in NS3-NS4A cleavage sites it is cis, NS4A-NS4B,
NS4B-NS5A, NS5A-NA5B site are then to be trans.NS4A albumen seems to play the work of NS3 protease cofactors there are many function
With, and NS3 and other rdrp virus components may be assisted to carry out film positioning.NS3 albumen also show nuclear nucleoside triphosphatase and
RNA helicase activity.The function of two albumen of NS4B and NS5A is not fully understood, but plays important work to the duplication of HCV
With.NS4B is a membrane-spanning protein, participates in the formation of viral replication complex.NS5A is a phosphorylated protein, participates in virus
The duplication of RNA and the formation of virion.NS5B (also known as HCV polymerases) is to participate in depending on for HCV geneome RNAs duplication
The RNA polymerase of RNA.
The documents such as WO2013095275, WO2012122716, CN102863428A each report a series of as HCV suppressions
The effect of the compound of preparation, activity, dissolubility etc. is to be improved.
The content of the invention
It is an object of the invention to provide compound or its pharmaceutically acceptable salt shown in formula (I),
Wherein,
E1、E7Separately structural unit shown in representative formula (a),
Wherein,
R1Selected from C=O, C=S, S (=O), S (=O)2、C(R1a)(R1b);
R3Selected from C (R3a)(R3b), C=O, C=S, S (=O), S (=O)2;
R4Selected from two or more, substituted [chain alkylene, heterochain alkyl, the miscellaneous base of chain hydrocarbon, cyclic hydrocarbon radical, heterocycle, ring are miscellaneous
Base];
R2、R5、R1a、R1b、R3a、R3bSeparately selected from H, F, Cl, Br, I, CN or optionally substituted [OH, SH,
NH2、PH2, alkyl, miscellaneous alkyl, the miscellaneous base of hydrocarbon, the miscellaneous base of miscellaneous alkyl];
n1Or n4Separately it is selected from 0 or 1;
n2Selected from 0,1,2,3,4,5 or 6;
n3Selected from 0,1,2,3,4,5 or 6;
n5Selected from 1,2,3 or 4;
Work as n1、n2、n3Or n4For 0 when, corresponding construction unit represents only to play the singly-bound of connection function;
E2、E6Separately it is selected from-C (=O) N (R6a)C(R6b)(R6c)、CH2, singly-bound, O, S, C=O, C=S, S (=
O), S (=O)2Or structural unit shown in formula (b),
R6a、R6b、R6cSeparately it is selected from H, C1-6Alkyl or alkoxy;
W5、W6Separately represent C, N, optionally substituted [CH2、CH、NH、CH2-CH2, CH=CH, 3~6 yuan of alkyl
Or 3~6 yuan of miscellaneous alkyls], C ≡ C, singly-bound, O, S, C=O, C=S, S (=O), S (=O)2;
W7、W8Separately represent H, F, Cl, Br, I, CN ,=O ,=S or optionally substituted [OH, SH, NH2、PH2、
The miscellaneous base of alkyl, miscellaneous alkyl, hydrocarbon, the miscellaneous base of miscellaneous alkyl], optionally W7With W8Between, W7With W7Between, W8With W8Between connect cyclization;
m7、m8Selected from 0,1,2;
E3、E5Separately it is selected from CH2, singly-bound, O, S, C=O, C=S, S (=O), S (=O)2Or shown in formula (c)
Structural unit;
L1Separately selected from C, N, optionally substituted [NH, CH, CH2、CH2-CH2, CH=CH, 3~6 yuan of alkyl or
3~6 yuan of miscellaneous alkyls], C ≡ C, O, S, C=O, C=S, S (=O), S (=O)2Or singly-bound;
L2、L3、L4、L5、L8、L9Separately selected from C, N, optionally substituted [NH, CH, CH2、CH2-CH2, CH=
CH, 3~6 yuan of alkyl or 3~6 yuan of miscellaneous alkyls], C ≡ C, O, S, C=O, C=S, S (=O), S (=O)2;
L6、L7Separately selected from H, F, Cl, Br, I, CN ,=O ,=S or optionally substituted [OH, SH, NH2、PH2、
The miscellaneous base of alkyl, miscellaneous alkyl, hydrocarbon, the miscellaneous base of miscellaneous alkyl];
p1、p6、p7It is separately selected from selected from 0,1,2,3,4,5 or 6;
E4Selected from structural unit shown in formula (d) or (e),
Wherein, Z1、Z2、X1、X2Separately selected from singly-bound, O, S, C=O, C=S, S=O, S (=O)2Or it is optionally taken
[the CH in generation2, NH, PH, alkyl, miscellaneous alkyl, the miscellaneous base of hydrocarbon, the miscellaneous base of miscellaneous alkyl];
Z3、Z4、X3、X4Separately selected from H, F, Cl, Br, I, CN ,=O ,=S or optionally substituted [OH, SH,
NH2、PH2, alkyl, miscellaneous alkyl, the miscellaneous base of hydrocarbon, the miscellaneous base of miscellaneous alkyl], optionally Z3With Z4Between connect cyclization;
q3、q4Separately it is selected from 0,1,2 or 3;
Represent singly-bound or double bond;
--- --- represents singly-bound, double bond or non-bonding, when
In --- --- represent not bonding when the structural unit be not present;
Optionally, the compound or its pharmaceutically acceptable salt include one or more chiral centres.
Preferably, shown in the minor structure unit such as formula (g) of said structure unit (b),
Wherein,
T1aSeparately it is selected from C, N, optionally substituted [CH2-CH2, CH=CH, CH2, CH, NH, 3~6 yuan of alkyl or
3~6 yuan of miscellaneous alkyls], C ≡ C, singly-bound, O, S, C=O, C=S, S (=O), S (=O)2;
T2a、T3a、T4aSeparately it is selected from C, N, optionally substituted [CH2、CH2-CH2, CH=CH, CH, NH, 3~6
First alkyl or 3~6 yuan of miscellaneous alkyls], C ≡ C, O, S, C=O, C=S, S (=O), S (=O)2;
T5aSelected from H, F, Cl, Br, I, CN ,=O ,=S or optionally substituted [OH, SH, NH2、PH2, alkyl, miscellaneous alkyl,
The miscellaneous base of hydrocarbon, the miscellaneous base of miscellaneous alkyl];
m5aSelected from 0,1,2,3,4,5 or 6;
W5a、W6aSeparately represent C, N, optionally substituted [CH2、NH、CH、CH2-CH2, CH=CH, 3~6 yuan of hydrocarbon
Base or 3~6 yuan of miscellaneous alkyls], C ≡ C, singly-bound, O, S, C=O, C=S, S (=O), S (=O)2;
T6a、T7aSeparately selected from O, S, optionally substituted [NH, CH, CH2、CH2-CH2, CH=CH, 3~6 yuan of hydrocarbon
Base or 3~6 yuan of miscellaneous alkyls], C ≡ C, singly-bound, C=O, C=S, S (=O), S (=O)2;
T8aFrom H, F, Cl, Br, I, CN ,=O ,=S or optionally substituted [OH, SH, NH2、PH2, alkyl, miscellaneous alkyl, hydrocarbon
The miscellaneous base of miscellaneous base, miscellaneous alkyl];
m6aSelected from 0,1,2 or 3, work as m6aFor 0 when, corresponding construction unit, which represents, only plays the singly-bound of connection function;
m8aSelected from 0,1,2,3,4,5 or 6;
Represent singly-bound or double bond;
--- --- represents singly-bound, double bond or non-bonding, whenIn --- ---
The structural unit and its accessory structure unit are not present when representing not bonding, T1a、T2aBoth sides --- --- when different be double bond.
Preferably, minor structure unit is selected from shown in above-mentioned formula (g):
Preferably, structural unit shown in above-mentioned formula (c) is selected from:
Preferably, shown in the minor structure unit such as formula (d-1) of structural unit shown in above-mentioned formula (d):
Wherein,
Z1、Z2Separately selected from singly-bound, O, S, C=O, C=S, S=O, S (=O)2Or optionally substituted [CH2、
The miscellaneous base of NH, PH, alkyl, miscellaneous alkyl, hydrocarbon, the miscellaneous base of miscellaneous alkyl];With
Z5、Z6、Z7、Z8Separately it is selected from optionally substituted [CH2-CH2, CH=CH, CH2, CH, NH, 3~6 yuan of hydrocarbon
Base or 3~6 yuan of miscellaneous alkyls], C ≡ C, singly-bound, O, S, C=O, C=S, S (=O), S (=O)2, Z5、Z6、Z7、Z8Cannot four it is same
When be singly-bound.
Preferably, above-mentioned Z1、Z2Separately it is selected from optionally substituted following radicals:
Phenyl,Xenyl, naphthalene, cyclopenta, furyl, 3- pyrrolinyls, pyrrolidinyl, 1,3- oxygen five
Ring group, pyrazolyl, 2- pyrazolinyls, pyrazolidinyl, imidazole radicals, oxazolyl, thiazolyl, 1,2,3- oxazolyls, 1,2,3- triazolyls,
1,2,4- triazolyls, 1,3,4- thiadiazolyl groups, pyridyl group, piperidyl, 1,4- dioxane base, morpholinyl, are rattled away at 4H- pyranoses
Piperazine base, pyrimidine radicals, pyrazinyl, piperazinyl, 1,3,5- trithianes base, cyanuro 1,3,5, benzofuranyl, benzothienyl,
Indyl, benzimidazolyl, benzothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnoline base or quinoxalinyl.
Preferably, the minor structure unit of structural unit is selected from shown in above-mentioned formula (d-1):
Preferably, the minor structure unit of structural unit shown in above-mentioned formula (e) is selected from:
Preferably, above-mentioned R4Selected from two or more substituted 3~10 yuan of ring groups or heterocycle or the miscellaneous base of ring, the miscellaneous original
Son or hetero atom group are selected from N, O, S, S (=O) or S (=O)2。
Preferably, above-mentioned R4Selected from two or more substituted following radicals:
Preferably, above-mentioned R4Selected from two or more substituted following radicals:
It is further preferred that work as R4During selected from above-mentioned group, R1For C=O, R5
For H, n1、n4And n5For 1, n2And n3For 0, R1With R4Form amido bond.
Preferably, minor structure unit is selected from shown in above-mentioned formula (a):
Preferably, above-mentioned R2、R5、R1a、R1b、R3a、R3bSeparately selected from H, F, Cl, Br, I, CN ,=O ,=S, appoint
Select substituted [OH, NH2, alkyl, cycloalkyl, halogenated alkyl, hydroxyl substituted alkyl, alkoxy, alkoxyalkyl, alkylthio group, alkane sulphur
Base alkyl, alkoxy carbonyl group, Heterocyclylcarbonyl, alkoxycarbonyl amido], the heterocycle be selected from furyl, thienyl, pyrrole radicals,
Pyridyl group, pyrimidine radicals, pyrazolyl or imidazole radicals.
Preferably, abovementioned alkyl, halogenated alkyl, hydroxyl substituted alkyl, alkoxy, alkoxyalkyl, alkylthio group, alkylthio group alkane
Moieties carbon atom number is 1,2,3,4,5 or 6 in base, alkoxy carbonyl group and alkoxycarbonyl amido, the cycloalkyl carbon atoms
Number is 3,4,5 or 6.
Preferably, above-mentioned R2、R5、R1a、R1b、R3a、R3bSeparately selected from H, F, Cl, Br, I, CN ,=O ,=S, appoint
Select substituted [OH, NH2, methyl, isopropyl, cyclopropyl, butyl, tertiary butyl, trifluoromethyl, methylol ,-CH (OH) CH3、-
CH2CH2OH、-CH2CH2(OH)、-CH(OH)CH3, methoxyl group, methoxyl methyl ,-CH (CH3)OCH3、-CH2CH2OCH3、 Methyl mercapto, carbethoxyl group,]。
Preferably, the substituent group of above-mentioned substitution be selected from F, Cl, Br, I, CN ,=O ,=S, it is optionally substituted [OH, SH,
NH2、PH2, alkyl, miscellaneous alkyl, the miscellaneous base of hydrocarbon and/or the miscellaneous base of miscellaneous alkyl].
Preferably, the miscellaneous base of above-mentioned alkyl, miscellaneous alkyl, hydrocarbon, the miscellaneous base of miscellaneous alkyl are selected from optionally substituted [C1-12Alkyl, C1-12
Miscellaneous alkyl, C1-12The miscellaneous base of hydrocarbon, C1-12The miscellaneous base C of hydrocarbon1-12Alkyl ,-C1-12OH、-C0-12COOH、-OC1-12COOH、-C1-12CN、-C0- 12CONH2、-C0-12O C1-12、-C0-12CO C1-12、-C0-12COO C1-12、-C0-12O (O=) C C1-12、-C0-12S (=O) C1-12
Or-C0-12S (=O)2C1-12], wherein, above-mentioned group in itself with aromatic rings, hetero-aromatic ring, cycloaliphatic ring, miscellaneous cycloaliphatic ring, aliphatic chain and/
Or the form of miscellaneous aliphatic chain exists, and the aromatic rings, hetero-aromatic ring, cycloaliphatic ring, miscellaneous cycloaliphatic ring, aliphatic chain and/or miscellaneous aliphatic chain
Number, ring member nitrogen atoms and its number, either the connection mode between ring and chain or chain and chain in chemistry can be steady for ring and ring
It is arbitrary on the premise of fixed realization, hetero atom or hetero atom group are separately selected from O, S, N, S (=O) and/or S (=O
)2, hetero atom or hetero atom group number can stablize in chemistry realization on the premise of be arbitrary.
Preferably, above-mentioned substitution is selected from F, Cl, Br, I, CN ,=O ,=S, OH, SH, NH with substituent group2, halogenated or hydroxyl generation
Amine generation or unsubstituted C1-6Alkyl or miscellaneous alkyl or the miscellaneous base of alkane, hetero atom or hetero atom group are separately selected from C1-6Alkane
Generation or unsubstituted-CONH- ,-CO2-、C1-6Alkane generation or unsubstituted-NH- ,-O- ,-S-, C1-6Alkane generation or unsubstituted
- C=NH ,-C=O ,-C=S, S (=O) and/or S (=O)2, the number of substituent group, hetero atom or hetero atom group is in chemistry
It is arbitrary on the premise of realization can be stablized
Preferably, above-mentioned substitution is selected from halogen, OH, SH, NH with substituent group2、PH2, CN ,=O ,=S, CF3、-OCF3、-
OCH3, protecting group and/or leaving group.
In addition, there are following variants for the structure with chiral centre in above-mentioned any one technical solution:Its chiral centre
It is arbitrary on the premise of realization can be stablized in chemistry positioned at other sites and its number;Alternatively, it also has other chiralitys
Center and its number are arbitrary on the premise of can stablizing realization in chemistry;Alternatively, it does not have chiral centre.
Another object of the present invention is to provide a kind of pharmaceutical composition, including the above-claimed cpd of therapeutically effective amount or its
Pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
Another object of the present invention is to above-claimed cpds or its pharmaceutically acceptable salt or aforementioned pharmaceutical compositions to exist
Prepare the application in the drug for the treatment of HCV.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution
It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when containing relatively acid functional group in the compound of the present invention
To pass through the side that the alkali of sufficient amount is used to be contacted with the neutral form of this kind of compound in pure solution or suitable atent solvent
Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt.
It, can be by pure solution or suitable atent solvent when containing relatively alkaline functional group in the compound of the present invention
Acid-addition salts are obtained with the mode that the sour neutral form with this kind of compound of sufficient amount contacts.Pharmaceutically acceptable acid addition
The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus
A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.;And acylate, the organic acid include
As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid,
Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.;Further include amino acid (such as
Arginine etc.) salt and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical
Salts",Journal of Pharmaceutical Science 66:1-19(1977)).Some specificization of the present invention
It closes object and contains alkalescence and acid functional group, so as to be converted into any alkali or acid-addition salts.
Preferably, in a usual manner salt is made to be contacted with alkali or acid, then separates parent compound, thus again in raw compounds
Property form.The forms of the parent fo of compound and its various salt is the difference is that some physical properties, such as in polarity
Different solubility in solvent.
" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein, by with acid into
Salt modifies the parent compound with the mode of alkali into salt.The example of pharmaceutically acceptable salt includes but not limited to:Base
Such as the inorganic acid or acylate of amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt bag
Include the quaternary ammonium salt of conventional avirulent salt or parent compound, such as the salt that nontoxic inorganic acid or organic acid are formed.Often
The avirulent salt of rule includes but not limited to those salt derived from inorganic acid and organic acid, the inorganic acid or organic acid choosing
From Aspirin, 2- ethylenehydrinsulfonic acids, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon
Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, salt
Acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, first
Alkyl sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, Asia
Acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
The pharmaceutically acceptable salt of the present invention can pass through conventional chemical side by the parent compound containing acid group or base
Method synthesizes.Under normal circumstances, the preparation method of such salt is:In the mixture of water or organic solvent or both, via trip
The appropriate alkali or acid of these compounds and stoichiometry from acid or alkali form react to prepare.It is generally preferable that ether, acetic acid
The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.
Except the form of salt, also there are prodrug forms for compound provided by the present invention.Compounds described herein
Chemical change easily occurs in physiological conditions for prodrug so as to change into the compound of the present invention.In addition, pro-drug can be with
The compound of the present invention is switched to by chemistry or biochemical method in environment in vivo.
Some compounds of the present invention can exist with nonsolvated forms or solvation form, including hydrate shape
Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.The present invention's
Some compounds can exist with polycrystalline or amorphous form.
Some compounds of the present invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right
Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.
Unless otherwise prescribed, term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted
Base substitute, the variant including heavy hydrogen and hydrogen, as long as the valence state of specific atoms be it is normal and substitute after compound be stable
's.When substituent group is ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution is not occurred on aromatic radical.Art
Language " optionally substituted " refers to be substituted, and can not also be substituted, and the species of substituent group and number are in chemistry
Can be arbitrary on the basis of can realizing.
Unless otherwise prescribed, when any variable (such as R) occurs in the composition of compound or structure more than once,
Definition at each occurrence is all independent.If thus, for example, a group were substituted by 0-2 R, the base
Group can optionally at most be substituted by two R, and R in each case has independent option.In addition, substituent group and/
Or the combination of its variant stable compound can be only generated in such combination in the case of be just allowed.
Unless otherwise prescribed, two atoms that can be cross connected to when the key of a group or substituent group on a ring
When, this group or substituent group can be mutually bonded with the arbitrary atom on this ring.When cited group or substituent group
In do not indicate its by which atom be connected to chemical structure of general formula include but be not specifically mentioned compound when, it is this
Group or substituent group can be mutually bonded by its any atom.The combination of group or substituent group and/or its variant only exists
Such combination is just allowed in the case of generating stable compound.
Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl etc.) sheet
Body represents straight chain, branch or cricoid hydrocarbon atomic group or its combination, Ke Yishi as a part of of another substituent group
Fully saturated, unit or polynary undersaturated can be monosubstituted, two substitutions or polysubstituted, can include divalent or more
Valency atomic group has carbon atom (such as C of specified quantity1-C10Represent 1 to 10 carbon).The alkyl includes aliphatic group and virtue
Fragrant alkyl, the aliphatic group include chain and ring-type, are specifically including but not limited to alkyl, alkenyl, alkynyl, the aryl radical
The aryl radical of including but not limited to 6-12 members, such as benzene, naphthalene etc..In some embodiments, term " alkyl " represents straight chain
Or the atomic group or combination thereof of branch, can be fully saturated, unit or polynary undersaturated, can include divalent and
Polyad group.The example of saturated hydrocarbons atomic group includes but not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, tertiary fourth
Base, isobutyl group, sec-butyl, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, n-hexyl, positive heptan
The homologue or isomers of the atomic groups such as base, n-octyl.Unsaturated alkyl has one or more double or triple bonds, example bag
Include but be not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene groups, 2- (butadienyl), 2,4- pentadienyls,
The homologue and isomers of 3- (Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1- and 3- propinyls, 3- butynyls and higher level.
Unless otherwise prescribed, the miscellaneous base of the miscellaneous alkyl, heterocycle, hydrocarbon, the miscellaneous base of ring, the miscellaneous base of miscellaneous alkyl, the miscellaneous base of heterocycle are
Refer in special groups containing hetero atom or hetero atom group, hetero atom or hetero atom group include but not limited to N, NH, it is substituted or
Protected NH, O, S, S (=O), S (=O)2, so-called miscellaneous alkyl, heterocycle are to be connected by carbon atom with molecule rest part
Connect, i.e., hetero atom can be located at the group any interior location (except the group be attached to molecule rest part position it
Outside);The miscellaneous base of so-called hydrocarbon, the miscellaneous base of ring are to be connected by hetero atom with molecule rest part, i.e., hetero atom is located at group attachment
In on the position of molecule rest part;The miscellaneous base of so-called miscellaneous alkyl, the miscellaneous base of heterocycle are by hetero atom and molecule rest part phase
Any interior location that connection, wherein hetero atom can be located at the group (is attached to the position of molecule rest part including the group
It puts).
Unless otherwise prescribed, term " miscellaneous alkyl " or its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl
Base etc.) itself or combine straight chain, branch the or cricoid hydrocarbon atomic group for representing stable with another term or it is combined,
It is made of the carbon atom and at least one hetero atom of certain amount.In some embodiments, term " miscellaneous alkyl " or its bottom
Concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl etc.) itself combines the straight chain for representing stable with another term
, the hydrocarbon atomic group or its composition of branch, be made of the carbon atom and at least one hetero atom of certain amount.In a typical case
In embodiment, hetero atom is selected from B, O, N and S, and wherein nitrogen and sulphur atom is optionally aoxidized, and nitrogen heteroatom is optionally by quaternary ammonium
Change.Hetero atom B, O, N and S can be located at any interior location of miscellaneous alkyl (except the alkyl is attached to the position of molecule rest part
Outside putting).Example includes but not limited to-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-
S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3,-CH=CH-O-CH3、-CH2- CH=N-OCH3With-
CH=CH-N (CH3)-CH3.At most two hetero atoms can be continuous, such as-CH2-NH-OCH3。
Unless otherwise prescribed, term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to usual table
It reaches, refers to those alkyl groups for being connected to the rest part of molecule by an oxygen atom, amino or sulphur atom respectively.
Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocycle alkyl ", " the miscellaneous base of cyclic hydrocarbon " or its subordinate concept (such as ring
The miscellaneous base of alkyl, Heterocyclylalkyl, cycloalkanes, cycloalkenyl group, heterocycloalkenyl, the miscellaneous base of cyclenes, cycloalkynyl radical, heterocycle alkynyl, the miscellaneous base of cycloalkyne etc.)
Itself combines " alkyl ", " miscellaneous alkyl " or " the miscellaneous base of hydrocarbon " for representing cyclisation respectively with other terms.The example of cycloalkyl includes
But it is not limited to cyclopenta, cyclohexyl, 1- cyclohexenyl groups, 3- cyclohexenyl groups, suberyl etc..The non-limiting examples of heterocycle include
1- (1,2,5,6- tetrahydro pyridyl), 1- piperidyls, 2- piperidyls, 3- piperidyls, 4- morpholinyls, morpholinyl, tetrahydrofuran-
2- bases, tetrahydrofuran indol-3-yl, thiophane -2- bases, thiophane -3- bases, 1- piperazinyls and 2- piperazinyls.
Unless otherwise prescribed, term " halogenated element " or " halogen " itself or as another substituent group part expression fluorine,
Chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogen
Generation (C1-C4) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyls and 3- bromopropyls etc.
Deng.
Unless otherwise prescribed, term " aryl " represents the aromatics hydrocarbon substituent of how unsaturated, can be monosubstituted, two substitutions
Or it is polysubstituted, it can be monocyclic or polycyclic (preferably 1 to 3 ring), they are fused together or are covalently attached.Term is " miscellaneous
Aryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, hetero atom be selected from B, N, O and
S, wherein nitrogen and sulphur atom are optionally aoxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to point by hetero atom
The rest part of son.The non-limiting example of aryl or heteroaryl includes phenyl, 1- naphthalenes, 2- naphthalenes, 4- xenyls, 1- pyrroles
Cough up base, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyls, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyls, 4- oxazolyls, 2-
Phenyl -4- oxazolyls, 5- oxazolyls, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- thiazolyls, 4- thiazolyls, 5-
Thiazolyl, 2- furyls, 3- furyls, 2- thienyls, 3- thienyls, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidines
Base, 4- pyrimidine radicals, 5- benzothiazolyls, purine radicals, 2- benzimidazolyls, 5- indyls, 1- isoquinolyls, 5- isoquinolyls,
2- quinoxalinyls, 5- quinoxalinyls, 3- quinolyls and 6- quinolyls.The substituent group of any one above-mentioned aryl and heteroaryl ring system
Selected from acceptable substituent group described below.
Unless otherwise prescribed, for simplicity, aryl when being used in combination with other terms (such as aryloxy group, arylthio,
Aralkyl) include aryl as defined above and heteroaryl ring.Therefore, term " aralkyl " is intended to include aryl to be attached to alkyl
Those atomic groups (such as benzyl, phenethyl, pyridylmethyl etc.), including wherein carbon atom (such as methylene) by such as oxygen
Those alkyl that atom replaces, such as phenoxymethyl, 2- pyridine oxygen methyls 3- (1- naphthoxys) propyl etc..
Unless otherwise prescribed, " ring " represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle
Alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.So-called ring includes condensed ring.It is former on ring
The number of son is generally defined as first number of ring, for example, " 5~7 yuan of rings " refer to surround 5~7 atoms of arrangement.Unless otherwise rule
Fixed, which optionally includes 1~3 hetero atom.Therefore, " 5~7 yuan of rings " include such as phenylpyridine and piperidyl;The opposing party
Face, term " 5~7 membered heterocycloalkyl ring " includes pyridyl group and piperidyl, but does not include phenyl.Term " ring " is further included containing extremely
The ring system of a few ring, each " ring " independently conform to above-mentioned definition.
Unless otherwise prescribed, terms used herein " hetero atom " includes the atom beyond carbon (C) and hydrogen (H), such as including
Oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al) and boron (B) etc..
Unless otherwise prescribed, term " leaving group " refers to that substitution reaction can be passed through by another functional group or atom
The functional group or atom that (such as nucleophilic substitution reaction) is substituted.For example, representative leaving group includes triflate;
Chlorine, bromine, iodine;Sulfonate group, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester;Acyloxy, such as
Acetoxyl group, trifluoroacetyl oxygroup etc..
Unless otherwise prescribed, term " protecting group " includes but not limited to " amino protecting group ", " hydroxyl protection base " or " sulfydryl
Protecting group ".Term " amino protecting group " refers to be suitable for the blocking group for preventing side reaction on ammonia nitrogen position.Representative ammonia
Base protecting group includes but not limited to:Formoxyl;Acyl group, such as alkanoyl (such as acetyl group, tribromo-acetyl base or trifluoroacetyl
Base);Alkoxy carbonyl, such as tert-butoxycarbonyl (Boc);Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl
(Fmoc);Aryl methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4'- methoxyphenyls) methyl;Silicyl,
Such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS).Term " hydroxyl protection base " refers to be suitble to
For preventing the protecting group of hydroxyl side reaction.Representative hydroxyl protection base includes but not limited to:Alkyl, such as methyl, ethyl and uncle
Butyl;Acyl group, such as alkanoyl (such as acetyl group);Aryl methyl, such as benzyl (Bn), to methoxy-benzyl (PMB), 9- fluorenyls
Methyl (Fm) and diphenyl methyl (benzhydryl, DPM);Silicyl, such as trimethyl silyl (TMS) and tertiary butyl diformazan
Base silicyl (TBS) etc..
Unless otherwise prescribed, the example of halogenated alkyl includes but are not limited to:Trifluoromethyl, trichloromethyl, pentafluoroethyl group,
With five chloroethyls." alkoxy " represents the abovementioned alkyl with given number carbon atom connected by oxygen bridge.C1-6Alkoxy bag
Include C1、C2、C3、C4、C5And C6Alkoxy.The example of alkoxy includes but not limited to:It is methoxyl group, ethyoxyl, positive propoxy, different
Propoxyl group, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxys." cycloalkyl " includes saturation ring group, such as
Cyclopropyl, cyclobutyl or cyclopenta.3-7 cycloalkyl includes C3、C4、C5、C6And C7Cycloalkyl." alkenyl " includes linear chain or branch chain
There is one or more carbon-to-carbon double bonds, such as vinyl and propylene on the hydrocarbon chain of configuration, the wherein chain on any stabilization site
Base.
Unless otherwise prescribed, term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Unless otherwise prescribed, term " heterocycle " or " heterocycle " mean stable monocyclic or bicyclic or bicyclic heterocycle, they
Can be that saturation, part are undersaturated or undersaturated (aromatics), they include carbon atom and 1,2,3 or 4 independently
Ring hetero atom selected from N, O and S, wherein above-mentioned arbitrary heterocycle can be fused on a phenyl ring formed it is bicyclic.
Unless otherwise prescribed, the example of heterocyclic compound includes but not limited to:Acridinyl, azocine base, benzimidazolyl,
Benzofuranyl, benzo sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzene
And triazolyl, benzo tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyls,
Carboline base, chromanyl, chromene, cinnoline base decahydroquinolyl, 2H, 6H-1,5,2- dithiazine base, dihydrofuran are simultaneously
[2,3-b] tetrahydrofuran base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyls, indoles alkenyl,
It is indolinyl, indolizine base, indyl, 3H- indyls, isatino bases, isobenzofuran-base, pyrans, isoindolyl, different
Indolinyl, isoindolyl, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl,
Naphthyridines base, octahydro isoquinolyl, oxadiazoles base, 1,2,3-oxadiazoles base, 1,2,4- oxadiazoles bases, 1,2,5- oxadiazoles bases, 1,
3,4- oxadiazoles base, oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, azophenlyene, fen
Thiazine, benzo xanthinyl, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone bases, piperonyl, butterfly
Piperidinyl, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyrido miaow
Azoles, pyridothiazole, pyridyl group, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, pyrazolyl, quinazoline
Base, quinolyl, 4H- quinolizines base, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazolium
Base, 6H-1,2,5- thiadiazine bases, 1,2,3- thiadiazolyl groups, 1,2,4- thiadiazolyl groups, 1,2,5- thiadiazolyl groups, 1,3,4- thiophenes two
Oxazolyl, thianthrene group, thiazolyl, isothiazolyl thienyl, thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole
Base, thienyl, triazine radical, 1,2,3- triazolyls, 1,2,4- triazolyls, 1,2,5- triazolyls, 1,3,4- triazolyls and xanthyl.
Further include condensed ring and spiro-compound.
Unless otherwise prescribed, the compound of the present invention can pass through a variety of synthetic methods well-known to those skilled in the art
It prepares, the embodiment formed including the specific embodiment that is set forth below, the combination of itself and other chemical synthesis process
And the equivalent substitution mode in art technology known to personnel, preferred embodiment include but not limited to the reality of the present invention
Apply example.
Unless otherwise prescribed, the structure of compound is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography mass spectrometric (LCMS)
's.NMR displacements (δ) are with 10-6(ppm) unit provides.The measure of NMR is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, is measured molten
Agent is deuterated dimethyl sulfoxide (DMSO-d6), deuterochloroform (CDCl3), deuterated methanol (CD3), OD inside it is designated as tetramethylsilane
(TMS)。
Unless otherwise prescribed, the measure of absolute configuration is measured by the conventional method of monocrystalline X-Ray diffraction, instrument
For Bruker APEX-II CCD, emission types for Cu-K a.
Unless otherwise prescribed, the measure liquid phase part of liquid chromatography mass spectrometric LCMS (the Xtimate C18 2.1* of Agilent 1200
30mm chromatographic columns) and mass spectrum part 6110 (ion source of Agilent:ESI).
Unless otherwise prescribed, the measure of HPLC uses Shimadzu LC10AD high pressure liquid chromatographs (Xtimate C18 2.1*
30mm chromatographic columns).
Unless otherwise prescribed, tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin layer
The specification that the silica gel plate that chromatography (TLC) uses uses is 0.15mm~0.2mm, and thin-layer chromatography isolates and purifies the rule of product use
Lattice are 0.4mm~0.5mm.
Unless otherwise prescribed, column chromatography is carrier generally using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Unless otherwise prescribed, known starting material of the invention may be employed or be closed according to methods known in the art
Into or it is commercially available from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, TCI,
Alfa, the companies such as splendid remote chemistry scientific and technological (Accela ChemBio Inc), Beijing coupling.
Unless otherwise prescribed, can be carried out in embodiment without specified otherwise, reaction under argon atmospher or blanket of nitrogen.Argon gas
Atmosphere or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Unless otherwise prescribed, nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume.
Unless otherwise prescribed, pressure hydration reaction is sent out using Parr 3916EKX types hydrogenation instrument and clear indigo plant QL-500 types hydrogen
Raw device or HC2-SS types hydrogenation instrument.Hydrogenation usually vacuumizes, and is filled with hydrogen, operates 3 times repeatedly.
Unless otherwise prescribed, microwave reaction uses 908860 types of CEM Discover-S or Biotage Initiator
60 microwave reactors.
Unless otherwise prescribed, aqueous solution is referred to without specified otherwise, solution in embodiment.
Unless otherwise prescribed, without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C~30 DEG C.
Unless otherwise prescribed, the monitoring of the reaction process in embodiment uses thin-layered chromatography (TLC), used in reaction
The system of solvent has:A:Dichloromethane and methanol system, B:N-hexane and ethyl acetate system, C:Petroleum ether and ethyl acetate
System, D:Acetone, the volume ratio of solvent is different according to the polarity of compound and is adjusted.
Unless otherwise prescribed, the system of eluant, eluent of column chromatography and the solvent of thin-layered chromatography that purifying compound uses
System includes:A:Dichloromethane and methanol system, B:Petroleum ether and ethyl acetate system, C:Dichloromethane and acetone system, it is molten
The volume ratio of agent is different according to the polarity of compound and is adjusted, can also add in the alkalescence such as a small amount of triethylamine and acetic acid or
Acid reagent is adjusted.
The present invention can be specifically described by embodiment below, these embodiments are not meant to any limit to the present invention
System.
Unless otherwise prescribed, all solvents used in the present invention are commercially available, and can be used without being further purified.
Unless otherwise prescribed, the present invention uses following initialisms:Aq represents water;HATU represent O-7- azepines benzotriazole-
1- yls)-N, N, N', N'- tetramethylurea hexafluorophosphates;It is sub- that EDC represents N- (3- dimethylaminopropyls)-N'- ethyls carbon two
Amine hydrochlorate;M-CPBA represents 3- chloroperoxybenzoic acids;Eq represents equivalent, equivalent;CDI represents carbonyl dimidazoles;DCM represents two
Chloromethanes;PE represents petroleum ether;DIAD represents diisopropyl azo-2-carboxylic acid;DMF represents n,N-Dimethylformamide;DMSO generations
Table dimethyl sulfoxide;EtOAc represents ethyl acetate;EtOH represents ethyl alcohol;MeOH represents methanol;CBz represents benzyloxycarbonyl group, is a kind of
Amine protecting group group;It is a kind of amine protecting group group that BOC, which represents tert-butyl carbonyl,;HOAc represents acetic acid;NaCNBH3Represent cyano boron hydrogen
Change sodium;R.t. room temperature is represented;O/N is represented overnight;THF represents tetrahydrofuran;Boc2O represents two carbonic ester of di-t-butyl;TFA
Represent trifluoroacetic acid;DIPEA represents diisopropyl ethyl amine;SOCl2Represent thionyl chloride;CS2Represent carbon disulfide;TsOH generations
Table p-methyl benzenesulfonic acid;NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide;NCS represents 1- chlorine pyrrolidine-2,5-diones;n-
Bu4NF represents tetrabutylammonium;IPrOH represents 2- propyl alcohol;Mp represents fusing point.
Unless otherwise prescribed, compound manually orSoftware is named, and commercial compound uses supplier's mesh
Record title.
Compared with prior art, the compounds of this invention is efficient, less toxic, in activity, half-life period, solubility and pharmacokinetics
Etc. achieve significantly or even unexpected progress, more suitable for pharmacy.
Specific embodiment
Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention.
The present invention is described in detail herein, wherein its specific embodiment mode is also disclosed that, to those skilled in the art
Speech, carrying out various changes and modifications for the specific embodiment of the invention without departing from the spirit and scope of the present invention will
It is obvious.
Reference example 1:Segment BB-1
Synthetic route:
Step 1:The synthesis of compound BB-1-3
It is inner that compound BB-1-1 (1.38g, 5.0mmol) is dissolved in acetonitrile (15mL), add in compound BB-1-2 (1.08g,
5.0mmol), then it is gradually added into DIPEA (0.65g, 5.0mmol).After adding, above-mentioned reaction is stirred at room temperature overnight.With
Solvent is removed under reduced pressure in reaction solution by Rotary Evaporators, and obtained grease is diluted with 30mL water and uses ethyl acetate (20mL × 2)
Extraction, the organic phase merging that 2 times are obtained are dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration removing solvent is marked
Inscribe compound BB-1-3 (2.0g, 9%).LCMS:m/z,314.0(M-100)+
Step 2:The synthesis of compound BB-1-4
Compound BB-1-3 (2.0g, 4.82mmol) is dissolved in toluene (40mL), addition ammonium acetate (5.6g,
72.44mmol), by above-mentioned reaction heated overnight at reflux.Solvent is removed under reduced pressure after reaction solution cooling, obtained grease 60mL
Water dilutes and ethyl acetate (30mL × 2) is used to extract, and the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, will filtered
Obtained filtrate decompression removes solvent and obtains title compound BB-1-4 (1.8g, 95%).
LCMS:m/z,394.1(M+1)+
Step 3:The synthesis of compound BB-1-5
Compound BB-1-4 (1.8g, 4.56mmol) is dissolved in dichloromethane (20mL), above-mentioned solution is cooled to 0
DEG C, gradually be added dropwise trifluoroacetic acid (6mL), be stirred to react at room temperature 5 it is small when.Reaction solution is removed under reduced pressure with Rotary Evaporators molten
Agent, obtained grease neutralize (pH=8) with saturated sodium bicarbonate solution and are extracted with ethyl acetate (20mL × 2), 2 times are obtained
To organic phase merging dried with anhydrous sodium sulfate, by the filtrate decompression being obtained by filtration removing solvent obtain title compound BB-
1-5 (1.1g, 82%).LCMS:m/z,294.0(M+1)+
Step 4:The synthesis of compound BB-1-7
Compound BB-1-5 (588mg, 2.0mmol) is dissolved in dichloromethane (20mL), sequentially adds compound BB-1-6
(382mg, 2.0mmol), HATU (912mg, 2.4mmol) and DIPEA (309.6mg, 2.4mmol), when stirring 2 is small at room temperature.
30mL water is added in, the organic phase obtained after layering washed once with NaCl solution, organic phase is dried with anhydrous sodium sulfate, decompression
Remove solvent concentration liquid and obtain grease, with prepare silica gel plate purifies and separates (eluent, EtOAc/PE, 3/1) obtain it is titled
Close object BB-1-7 (510mg, 55%).
LCMS:m/z,467.1(M+1)+
Step 5:The synthesis of compound BB-1
Compound BB-1-7 (200mg, 0.428mmol) is dissolved in DMF (6mL), sequentially add boron ester BB-1-8 (163mg,
0.642mmol), KOAc (84mg, 0.856mmol) and Pd (dppf) Cl2 (15mg, 0.02mmol).Air is replaced 3 with nitrogen
It is secondary, reaction solution under nitrogen protection, 110 DEG C reaction 3 it is small when.(30mL) is diluted with water after reaction solution cooling, and uses ethyl acetate
(20mL × 2) extract, and the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration is removed
Solvent obtains crude product, and title compound BB-1 is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 3/1) are prepared
(70mg, 32%).
LCMS:m/z,515.3(M+1)+
Reference example 2:Segment BB-2
Synthetic route:
Step 1:The synthesis of compound BB-2-3
Compound BB-2-1 (3.74g, 20mmol) is dissolved in DMF (100mL), sequentially add compound BB-2-2 (4.3g,
20mmol), HATU (8.36g, 22mmol) and DIPEA (3.87g, 30mmol), when stirring 5 is small at room temperature.It is added in reaction solution
200mL water dilutes, and is extracted with ethyl acetate (200mL × 2), and the organic phase obtained after layering washs one with saturation NaCl solution
Secondary, organic phase is dried with anhydrous sodium sulfate, and solvent concentration liquid is removed under reduced pressure and obtains title compound BB-2-3 (6.1g, 79%).
LCMS:m/z,384.1(M+1)+
Step 2:The synthesis of compound BB-2-4
Compound BB-2-3 (6.0g, 15.63mmol) is dissolved in acetic acid (40mL), be added portionwise ammonium acetate (12g,
155.6mmol).By above-mentioned reaction solution be heated to 90 DEG C reaction 3 it is small when.It is diluted after reaction solution cooling with 150mL water and uses 4N
NaOH neutralizes (pH=8), is extracted with ethyl acetate (50mL × 2), and the organic phase merging that 2 times are obtained is done with anhydrous sodium sulfate
It is dry, the filtrate decompression being obtained by filtration removing solvent is obtained into title compound 2-4 (4.5g, 79%).LCMS:m/z,366.1(M+
1)+
Step 3:The synthesis of compound BB-2-5
Compound BB-2-4 (4.5g, 12.28mmol) is dissolved in dichloromethane (45mL), above-mentioned solution is cooled to 0 DEG C, by
Trifluoroacetic acid (9mL) is gradually added dropwise, is stirred to react at room temperature overnight.Solvent is removed under reduced pressure in reaction solution with Rotary Evaporators, is obtained
Grease neutralize (pH=8) with saturated sodium bicarbonate solution and extracted with ethyl acetate (50mL × 2), have what is obtained for 2 times
Machine mutually with anhydrous sodium sulfate dried by merging, and the filtrate decompression being obtained by filtration removing solvent is obtained title compound BB-2-5
(2.5g, 76.5%).LCMS:m/z,266.0(M+1)+
Step 4:The synthesis of compound BB-2
Compound BB-2-5 (532mg, 2.0mmol) is dissolved in dichloromethane (15mL), sequentially adds compound BB-2-6
(385mg, 2.2mmol), HATU (836mg, 2.2mmol) and DIPEA (368mg, 2.9mmol), are stirred overnight at room temperature.It adds in
20mL water washed once the organic phase obtained after layering with saturation NaCl solution, be separated to organic phase that bottom obtains with anhydrous
Sodium sulphate is dried, and the filtrate decompression after filtering is removed solvent concentration liquid obtains grease, (is drenched with silica gel plate purifies and separates are prepared
Lotion, EtOAc/PE, 3/1) obtain title compound BB-2 (200mg, 24%).LCMS:m/z,423.1(M+1)+
Reference example:Segment BB-3
Synthetic route:
Step 1:The synthesis of compound BB-3-2
Compound BB-2-5 (532mg, 2.0mmol) is dissolved in dichloromethane (20mL), sequentially adds compound BB-1-6
(420mg, 2.2mmol), HATU (912mg, 2.4mmol) and DIPEA (388mg, 3.0mmol), are stirred overnight at room temperature.It adds in
30mL water washed once the organic phase obtained after layering with saturation NaCl solution, be separated to organic phase that bottom obtains with anhydrous
Sodium sulphate is dried, and the filtrate decompression after filtering is removed solvent concentration liquid obtains grease, (is drenched with silica gel plate purifies and separates are prepared
Lotion, EtOAc/PE, 3/1) obtain title compound BB-3-2 (750mg, 85%).LCMS:m/z,439.1(M+1)+
Step 2:The synthesis of compound BB-3
Compound BB-3-2 (300mg, 0.68mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (6mL), where sequentially adds duplex Knit-the-brows
Alcohol borate (258mg, 1.02mmol), KOAc (135mg, 1.38mmol) and Pd (dppf) Cl2(30mg,0.04mmol).With
Nitrogen by air replace 3 times, reaction solution under nitrogen protection, 110 DEG C reaction 3 it is small when.It is diluted with water after reaction solution cooling
(20mL), and extracted with ethyl acetate (20mL × 2), the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, will filtered
Obtained filtrate decompression removes solvent and obtains crude product, is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 3/1) are prepared
Title compound BB-3 (235mg, 71%).
LCMS:m/z,487.3(M+1)+
Reference example 4:Segment BB-4
Synthetic route:
Step 1:The synthesis of compound BB-4-2
Compound BB-8 (292mg, 1.0mmol) is dissolved in dichloromethane (6mL), sequentially adds compound BB-4-1
(208mg, 1.1mmol), HATU (456mg, 1.2mmol) and DIPEA (260mg, 2.0mmol), are stirred overnight at room temperature.It adds in
30mL water washed once the organic phase obtained after layering with saturation NaCl solution, and obtained organic phase is done with anhydrous sodium sulfate
It is dry, the filtrate decompression after filtering is removed into solvent concentration liquid and obtains title compound BB-4-2 (320mg, 69%).LCMS:m/z,
463.1(M+1)+
Step 2:The synthesis of compound BB-4
Compound BB-4-2 (320mg, 0.69mmol) is dissolved in DMF (10mL), duplex Knit-the-brows any alcohol borates sequentially added
(262mg, 1.03mmol), KOAc (135mg, 1.38mmol) and Pd (dppf) Cl2(30mg,0.04mmol).With nitrogen by sky
Gas replace 3 times, reaction solution under nitrogen protection, 110 DEG C reaction 3 it is small when.(20mL) is diluted with water after reaction solution cooling, and uses second
Acetoacetic ester (20mL × 2) extracts, and the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, the filtrate being obtained by filtration is subtracted
Pressure removes solvent and obtains crude product, and title compound BB- is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 1/1) are prepared
4 (260mg, 74%).
LCMS:m/z,511.3(M+1)+
Reference example 5:Segment BB-5
Synthetic route:
Step 1:The synthesis of compound BB-5-2
It is inner that compound BB-1-1 (1.38g, 5.0mmol) is dissolved in acetonitrile (15mL), add in compound BB-5-1 (0.95g,
5.0mmol), then it is gradually added into DIPEA (0.65g, 5.0mmol).After adding, above-mentioned reaction is stirred at room temperature overnight.With
Solvent is removed under reduced pressure in reaction solution by Rotary Evaporators, and obtained grease is diluted with 30mL water and uses ethyl acetate (20mL × 2)
Extraction, the organic phase merging that 2 times are obtained are dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration removing solvent is marked
Inscribe compound BB-5-2 (1.8g, 94%).LCMS:m/z,285.0(M-100)+
Step 2:The synthesis of compound BB-5-3
Compound BB-5-2 (1.8g, 4.66mmol) is dissolved in toluene (50mL), addition ammonium acetate (5.39g,
69.91mmol), by above-mentioned reaction heated overnight at reflux.Solvent is removed under reduced pressure after reaction solution cooling, obtained grease 80mL
Water dilutes and ethyl acetate (60mL × 2) is used to extract, and the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, will filtered
Obtained filtrate decompression removes solvent and obtains title compound BB-5-3 (1.6g, 94%).LCMS:m/z,366.1(M+1)+
Step 3:The synthesis of compound BB-5-4
Compound BB-5-3 (1.6g, 4.36mmol) is dissolved in dichloromethane (20mL), above-mentioned solution is cooled to 0
DEG C, gradually be added dropwise trifluoroacetic acid (6mL), be stirred to react at room temperature 5 it is small when.Reaction solution is removed under reduced pressure with Rotary Evaporators molten
Agent, obtained grease neutralize (pH=8) with saturated sodium bicarbonate solution and are extracted with ethyl acetate (20mL × 2), 2 times are obtained
To organic phase merging dried with anhydrous sodium sulfate, by the filtrate decompression being obtained by filtration removing solvent obtain title compound BB-
5-4 (1.0g, 86%).LCMS:m/z,266.0(M+1)+
Step 4:The synthesis of compound BB-5-5
Compound BB-5-4 (532mg, 2.0mmol) is dissolved in dichloromethane (20mL), sequentially adds compound BB-1-6
(382mg, 2.0mmol), HATU (912mg, 2.4mmol) and DIPEA (516mg, 2.4mmol), when stirring 3 is small at room temperature.Add
Enter 30mL water, the organic phase obtained after layering washed once with NaCl solution, organic phase is dried with anhydrous sodium sulfate, and decompression removes
Solvent concentration liquid is gone to obtain grease, title compound is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 3/1) are prepared
Object BB-5-5 (400mg, 46%).
LCMS:m/z,439.1(M+1)+
Step 5:The synthesis of compound BB-5
Compound BB-5-5 (400mg, 0.91mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (20mL), where sequentially adds duplex Knit-the-brows
Alcohol borate (345mg, 1.36mmol), KOAc (178mg, 1.82mmol) and Pd (dppf) Cl2(35mg,0.047mmol).With
Nitrogen by air replace 3 times, reaction solution under nitrogen protection, 110 DEG C reaction 3 it is small when.It is diluted with water after reaction solution cooling
(30mL), and extracted with ethyl acetate (20mL × 2), the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, will filtered
Obtained filtrate decompression removes solvent and obtains crude product, is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 2/1) are prepared
Title compound BB-5 (300mg, 68%).
LCMS:m/z,487.3(M+1)+
Reference example 6:Segment BB-6
Synthetic route:
Step 1:The synthesis of compound BB-6-2
It is inner that compound BB-6-1 (4.6g, 20mmol) is dissolved in acetonitrile (70mL), add in compound BB-1-1 (5.56g,
20mmol), then it is gradually added into DIPEA (2.58g, 20mmol).After adding, above-mentioned reaction is stirred at room temperature overnight.With rotation
Turn evaporimeter and solvent is removed under reduced pressure in reaction solution, obtained grease is diluted with 100mL water and ethyl acetate (60mL × 2) is used to extract
It takes, the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration removing solvent is obtained title
Compound BB-6-2 (8.4g, 99%).
LCMS:m/z,326.0(M-100)+
Step 2:The synthesis of compound BB-6-3
Compound BB-6-2 (8.4g, 19.7mmol) is dissolved in toluene (120mL), addition ammonium acetate (22.9g,
297.4mmol), by above-mentioned reaction heated overnight at reflux.Solvent is removed under reduced pressure after reaction solution cooling, obtained grease is used
200mL water dilutes and ethyl acetate (150mL × 2) is used to extract, and the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate,
The filtrate decompression being obtained by filtration removing solvent is obtained into title compound BB-6-3 (7.8g, 98%).
LCMS:m/z,406.0(M+1)+
Step 3:The synthesis of compound BB-6-4
Compound BB-6-3 (7.1g, 17.5mmol) is dissolved in dichloromethane (75mL), above-mentioned solution is cooled to 0
DEG C, gradually be added dropwise trifluoroacetic acid (30mL), be stirred to react at room temperature 4 it is small when.Reaction solution is removed under reduced pressure with Rotary Evaporators molten
Agent, obtained grease neutralizes (pH=8) with saturated sodium bicarbonate solution and is extracted with ethyl acetate (100mL × 2), by 2 times
Obtained organic phase merging is dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration removing solvent is obtained title compound
BB-6-4 (5.0g, 93%).LCMS:m/z,306.0(M+1)+
Step 4:The synthesis of compound BB-6-5
Compound BB-6-4 (305mg, 1.0mmol) is dissolved in dichloromethane (10mL), sequentially adds compound BB-1-6
(191mg, 1.0mmol), HATU (456mg, 1.2mmol) and DIPEA (258mg, 2.0mmol), when stirring 3 is small at room temperature.Add
Enter 15mL water, the organic phase obtained after layering washed once with saturation NaCl solution, organic phase is dried with anhydrous sodium sulfate, is subtracted
Pressure removes solvent concentration liquid and obtains grease, and title is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 3/1) are prepared
Compound BB-6-5 (250mg, 52%).
LCMS:m/z,479.0(M+1)+
Step 5:The synthesis of compound BB-6
Compound BB-6-5 (160mg, 0.33mmol) is dissolved in DMF (4mL), duplex Knit-the-brows any alcohol borates sequentially added
(129mg, 0.51mmol), KOAc (65mg, 0.66mmol) and Pd (dppf) Cl2(12mg,0.016mmol).With nitrogen by sky
Gas replace 3 times, reaction solution under nitrogen protection, 110 DEG C reaction 2 it is small when.(10mL) is diluted with water after reaction solution cooling, and uses second
Acetoacetic ester (10mL) extracts, and obtained organic phase merging is dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration is removed
Solvent obtains crude product, and title compound BB-6 is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 1/1) are prepared
(90mg, 52%).LCMS:m/z,527.2(M+1)+
Reference example 7:Segment BB-7
Synthetic route:
Step 1:The synthesis of compound BB-7-1
Compound BB-6-4 (305mg, 1.0mmol) is dissolved in dichloromethane (10mL), sequentially adds compound BB-2-6
(175mg, 1.0mmol), HATU (456mg, 1.2mmol) and DIPEA (258mg, 2.0mmol), when stirring 3 is small at room temperature.Add
Enter 15mL water, the organic phase obtained after layering washed once with saturation NaCl solution, organic phase is dried with anhydrous sodium sulfate, is subtracted
Pressure removes solvent concentration liquid and obtains grease, and title is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 3/1) are prepared
Compound 7-1 (260mg, 56%).
LCMS:m/z,463.0(M+1)+
Step 2:The synthesis of compound BB-7
Compound BB-7-1 (160mg, 0.33mmol) is dissolved in DMF (4mL), duplex Knit-the-brows any alcohol borates sequentially added
(129mg, 0.49mmol), KOAc (65mg, 0.66mmol) and Pd (dppf) Cl2(12mg,0.016mmol).With nitrogen by sky
Gas replace 3 times, reaction solution under nitrogen protection, 110 DEG C reaction 2 it is small when.(10mL) is diluted with water after reaction solution cooling, and uses second
Acetoacetic ester (10mL) extracts, and obtained organic phase merging is dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration is removed
Solvent obtains crude product, and title compound BB-7 is obtained with silica gel plate purifies and separates (eluent, EtOAc/PE, 1/1) are prepared
(110mg, 62%).
LCMS:m/z,511.2(M+1)+
Reference example 8:Segment BB-8
Synthetic route:
Step 1:The synthesis of compound BB-8-2
It is inner that compound BB-2-2 (2.15g, 10mmol) is dissolved in acetonitrile (40mL), add in compound BB-1-1 (2.78g,
10mmol), then it is gradually added into DIPEA (1.29g, 10mmol).After adding, above-mentioned reaction is stirred at room temperature overnight.With rotation
Turn evaporimeter and solvent is removed under reduced pressure in reaction solution, obtained grease is diluted with 50mL water and ethyl acetate (30mL × 2) is used to extract
It takes, the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, and the filtrate decompression being obtained by filtration removing solvent is obtained title
Compound BB-8-2 (3.9g, 95%).
LCMS:m/z,312.0(M-100)+
Step 2:The synthesis of compound BB-8-3
Compound BB-8-2 (3.9g, 9.47mmol) is dissolved in toluene (70mL), addition ammonium acetate (7.3g,
94.8mmol), by above-mentioned reaction heated overnight at reflux.Solvent is removed under reduced pressure after reaction solution cooling, obtained grease 50mL
Water dilutes and ethyl acetate (40mL × 2) is used to extract, and the organic phase merging that 2 times are obtained is dried with anhydrous sodium sulfate, will filtered
Obtained filtrate decompression removes solvent and obtains title compound BB-8-3 (3.2g, 86%).LCMS:m/z,392.1(M+1)+
Step 3:The synthesis of compound BB-8
Compound BB-8-3 (3.0g, 7.65mmol) is dissolved in dichloromethane (60mL), above-mentioned solution is cooled to 0
DEG C, gradually be added dropwise trifluoroacetic acid (20mL), be stirred to react at room temperature 5 it is small when.Reaction solution is removed under reduced pressure with Rotary Evaporators molten
Agent, obtained grease neutralize (pH=8) with saturated sodium bicarbonate solution and are extracted with ethyl acetate (40mL × 2), 2 times are obtained
To organic phase merging dried with anhydrous sodium sulfate, by the filtrate decompression being obtained by filtration removing solvent obtain title compound BB-8
(2.2g, 99%).LCMS:m/z,292.0(M+1)+
Reference example 9:Segment BB-9
Synthetic route:
Step 1:The synthesis of compound BB-9-2
Compound N-Boc-L- proline (4.30g, 20mmol) and potassium carbonate (3.86g, 27.97mmol) are suspended in second
In nitrile (100ml), compound BB-9-1 (3.31g, 10.75mmol) is added at room temperature.Be stirred at room temperature 4 it is small when, TLC detection reaction
After, obtain target compound BB-9-2 (white solid, 1.26g, yield 14%) after being spin-dried for solvent.Product need not purify,
It directly applies in next step.MS m/z:343.7[M-Boc+H]+.
Step 2:The synthesis of compound BB-9-3
At room temperature, compound BB-9-2 (0.80g, 1.81mmol) is dissolved in toluene (50ml), add in ammonium acetate (7.67g,
99.61mmol).Reflux is warming up under nitrogen protection, is stirred overnight, and TLC detections are cooled to room temperature after completion of the reaction, add in water
Reaction, ethyl acetate (50ml × 3) extraction is quenched in (30ml).Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate subtracts
Pressure removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=3:2 → pure ethyl acetate) obtain target compound
BB-9-3 (white powder, 0.29g, yield 38%).MS m/z:422.0[M+H]+.
Step 3:The synthesis of compound BB-9-4
At room temperature, by compound BB-9-3 (5.00g, 11.84mmol) add in hydrogen chloride/ethyl acetate solution (HCl/EA,
4mol/L, 20mL) in, be stirred at room temperature 2 it is small when.TLC detections are spin-dried for solvent after completion of the reaction, obtain white solid intermediate B B-
9-4.Product directly applies in next step without purifying.
Step 4:The synthesis of compound BB-9-5
At room temperature, by above-mentioned white solid intermediate B B-9-4 (0.242g, 0.67mmol), N-Moc-L- valines (BB-
2-6,0.18g, 0.94mmol), diisopropyl ethyl amine (0.31g, 2.39mmol) is dissolved in DMF (3ml), adds in HATU
(0.39g,1.02mmol).Be stirred at room temperature 3 it is small when, TLC detect after completion of the reaction, add in water (10ml) reaction, acetic acid second is quenched
Ester (50ml × 3) extracts.Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression removes solvent, and residue is through silicon
Plastic column chromatography (petrol ether/ethyl acetate=3:2 → pure ethyl acetate) obtain target compound BB-9-5 (yellow solid,
0.22g, yield 68%).MS m/z:481.0[M+H]+.
Step 5:The synthesis of compound BB-9
At room temperature, by compound BB-9-5 (0.22g, 0.46mmol), duplex pinacol borate (0.14g,
Dioxane (4ml) 0.55mmol) is dissolved in, adds in potassium acetate (0.09g, 0.93mmol) and Pd (dppf) under nitrogen protection
Cl2(0.03g,0.04mmol).120 DEG C of microwave reacts 45 minutes, and TLC detections are cooled to room temperature after completion of the reaction, are filtered, filtrate
After being spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=3:2 → pure ethyl acetate) obtain target compound
BB-9 (0.17g, yield 70%).MS m/z:527.1[M+H]+.
Reference example 10:Segment BB-10
Synthetic route:
Step 1:The synthesis of compound BB-10-2
Compound BB-10-2 can be prepared according to the synthesis step 1~4 of reference example 9 (BB-9).LCMS m/z:479.1[M+
H]+
Step 2:The synthesis of compound BB-10
Compound BB-10 can be prepared according to the synthesis step 5 of reference example 9 (BB-9).LCMS m/z:527.1[M+H]+
Reference example 11:Segment BB-11
Synthetic route:
Step 1:The synthesis of compound BB-11-2
Compound BB-11-2 can be prepared according to the synthesis step 1~4 of reference example 9 (BB-9).MS m/z:465.1[M+H
]+.
Step 2:The synthesis of compound BB-11
Compound BB-11 can be prepared according to the synthesis step 5 of reference example 9 (BB-9).MS m/z:511.3[M+H]+.
Reference example 12:Segment BB-12
Synthetic route:
Step 1:The synthesis of compound BB-12-2
Compound BB-12-2 can be prepared according to the synthesis step 1~4 of reference example 9 (BB-9).LCMS m/z:464.9[M+
H]+
Step 2:The synthesis of compound BB-12
Compound BB-12 can be prepared according to the synthesis step 5 of reference example 9 (BB-9).LCMS m/z:488.0[M+Na]+
Reference example 13:Segment BB-13
Synthetic route:
Step 1:The synthesis of compound BB-13-2
Compound BB-13-2 can be prepared according to the synthesis step 1~4 of reference example 9 (BB-9).MS m/z:485.1[M+H
]+.
Step 2:The synthesis of compound BB-13
Compound BB-13 can be prepared according to the synthesis step 5 of reference example 9 (BB-9).MS m/z:531.2[M+H]+Refer to
Example 14:Segment BB-14
Synthetic route:
Step 1:The synthesis of BB-14
BB-14-1 (600mg, 1.90mmol) is dissolved in ethyl acetate (5mL), adds in hydrogen chloride/ethyl acetate solution
(HCl/EA, 4mol/L, 20mL), be stirred at room temperature 3 it is small when.TLC detections are spin-dried for solvent and obtain among white solid after completion of the reaction
Body (410mg).By above-mentioned white solid intermediate (410mg, 1.63mmol), N-Moc-L- valines (BB-2-6,399mg,
2.09mmol), diisopropyl ethyl amine (735mg, 5.70mmol) is dissolved in DMF (10mL), add in HATU (1.08g,
2.84mmol).It being stirred overnight at room temperature, TLC is detected after completion of the reaction, is added in water (10mL) and is quenched reaction, ethyl acetate (50mL ×
3) extract.Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression removes solvent, and residue is through silica gel column chromatography
(petrol ether/ethyl acetate=1:1 → pure ethyl acetate) obtain target compound BB-14 (white solid, 306mg, yield
43.2%).MS m/z:374.9[M+H]+.
Reference example 15:Segment BB-15
Synthetic route:
Step 1:The synthesis of compound BB-15
Compound BB-15 can be prepared according to the synthesis step 1 of reference example 14 (BB-14).1H NMR(CDCl3,400MHz):δ
6.90(s,1H),5.23-5.22(m,1H),4.58-4.40(m,1H),4.13-3.88(m,4H),3.70(s,3H),3.21-
3.20(m,2H),2.88-2.51(m,2H),2.16-2.07(m,3H),1.97-1.79(m,2H).
Reference example 16:Segment BB-16
Synthetic route:
Step 1:The synthesis of compound BB-16-2
At room temperature, compound BB-16-1 (4.1g, 26.2mmol) is dissolved in tetrahydrofuran (20mL), under nitrogen protection
Add in cis -1,2- cyclohexane dicarboxylic acids acid anhydride (AA_013-1,2.0g, 13.0mmol).Be stirred at room temperature 6 it is small when, TLC detection reaction
After be spin-dried for solvent, obtain target compound BB-16-2 (colorless gum, 3.5g, yield 83.2%).Product is without pure
Change, directly apply in next step.1H NMR(CDCl3,400MHz):δ7.78(s,1H),5.23-5.22(m,1H),3.47(s,
2H),3.06-3.03(m,1H),2.78-2.60(m,2H),2.08(brs,1H),1.86(m,1H),1.65-1.51(m,2H),
1.27-1.23 (m, 4H), 1.20 (d, J=6.4Hz, 6H), 0.80-0.63 (m, 2H), 0.58-0.57 (m, 2H)
Step 2:The synthesis of compound BB-16-3
Compound BB-16-2 (3.5g, 10.79mmol) and potassium carbonate (3.1g, 22.5mmol) are suspended in DMF (25mL)
In, 2,4 '-dibromo acetophenone (BB-1-1,3.1g, 11.2mmol) is added at room temperature.Be stirred at room temperature 2 it is small when, TLC detection reaction
After add in water (20mL) and be quenched reaction, ethyl acetate (50mL × 3) extracts.Merge organic phase, dried with anhydrous sodium sulfate,
Filtering, filtrate decompression remove solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=4:1→1:4) targeted is obtained
Close object BB-16-3 (4.8g, yield 87.8%).MS m/z:530.7[M+Na]+.
Step 3:The synthesis of compound BB-16
At room temperature, compound BB-16-3 (1.50g, 2.96mmol) is dissolved in toluene (200mL), adds in ammonium acetate
(11.88g,154.09mmol).Reflux is warming up under nitrogen protection, is stirred overnight, and TLC detections are cooled to room after completion of the reaction
Temperature adds in water (30mL) and reaction, ethyl acetate (50mL × 3) extraction is quenched.Merge organic phase, dried with anhydrous sodium sulfate, mistake
Filter, filtrate decompression remove solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:3 → pure ethyl acetate) it obtains
Target compound BB-16 (pale yellow powder, 0.95g, yield 66.0%).MS m/z:489.3[M+H]+.
Reference example 17:Segment BB-17
Synthetic route:
Step 1:The synthesis of compound BB-17-2
At room temperature, compound BB-17-1 (5g, 22.3mmol) is dissolved in methanol/water (15mL/15mL) in the mixed solvent,
Add in sodium hydroxide (1.8g, 45mmol).Be stirred at room temperature 2 it is small when, TLC detection after completion of the reaction add in water (30mL), use acetic acid
Ethyl ester (52mL) extracts.Water mutually with 6N salt acid for adjusting pH value to 1~2, collects the solid of precipitation, target compound is obtained after dry
BB-17-2 (white solid, 4.0g, yield 85%).1H NMR(DMSO-d6,400MHz):δ 2.97 (t, J=7.6Hz, 2H),
2.87 (t, J=7.6Hz, 2H), 2.49 (s, 3H), 2.39 (t, J=7.6Hz, 2H)
Step 2:The synthesis of compound BB-17-3
By compound BB-17-2 (5g 23.8mmol), triethylamine (4.8g, 47.6mmol) is dissolved in the tert-butyl alcohol (50mL), adds
Enter DPPA (9.8g, 35.6mmol).Reflux is warming up under nitrogen protection, is stirred overnight, and decompression removes after completion of the reaction for TLC detections
Solvent is removed, dissolves the residue in ethyl acetate (200mL), successively with water (50mL × 3), saturated salt solution (50mL) washing.Have
Machine is mutually dried with anhydrous sodium sulfate, filtering, filtrate decompression remove solvent after obtain target compound BB-17-3 (white solid,
5g, yield 75%).Product directly applies in next step without purifying.1H NMR(CDCl3,400MHz):δ6.91(s,1H),
2.91 (t, J=7.6Hz, 2H), 2.56 (t, J=7.6Hz, 2H), 2.42-2.39 (m, 5H), 1.52 (s, 9H)
Step 3:The synthesis of compound BB-17-4
Compound BB-17-3 (5g, 17.8mmol) is dissolved in ethyl acetate (30mL), it is molten to add in hydrogen chloride/ethyl acetate
Liquid (HCl/EA, 4M, 20mL), be stirred at room temperature 3 it is small when.TLC detections are spin-dried for solvent and obtain target compound BB- after completion of the reaction
17-4 (white solid, 3.6g, yield 93%).Product directly applies in next step without purifying.1H NMR(Methanol-d4
400MHz):δ 3.10-3.06 (m, 2H), 2.68 (t, J=7.6Hz, 2H), 2.59-2.56 (m, 5H)
Step 4:The synthesis of compound BB-17-5
At room temperature, by compound BB-17-4 (2.9g, 13.32mmol), isoamyl nitrite (2.3g, 19.64mmol) is molten
In acetonitrile (20mL), copper bromide (3.3g, 14.8mmol) is added in.Be stirred at room temperature under nitrogen protection 3 it is small when, TLC detection reaction
After add in water (10mL) and be quenched reaction, ethyl acetate (30mL × 4) extracts.Merge organic phase, dried with anhydrous sodium sulfate,
Filtering, filtrate decompression remove solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=20:1→10:1) target is obtained
Compound BB-17-5 (dark brown solid, 1.6g, yield 49%).1H NMR(CDCl3,400MHz):δ 3.05 (t, J=7.2Hz,
2H), 2.58 (t, J=7.2Hz, 2H) 2.5-2.45 (m, 2H), 2.42 (s, 3H)
Step 5:The synthesis of compound BB-17-6
Compound BB-17-5 (1.0g, 4.08mmol) is dissolved in glacial acetic acid (10mL).Dropwise addition bromine (653mg,
Glacial acetic acid (1mL) solution 4.09mmol).It is stirred overnight at room temperature, LCMS detections add in t-butyl methyl ether after completion of the reaction
(100mL), successively with water (30mL × 5), saturated salt solution (30mL) washing.Organic phase is dried with anhydrous sodium sulfate, is filtered, filter
Liquid obtains target compound BB-17-6 (dark brown solid, 1.2g, yield 91%) after solvent is removed under reduced pressure.Product need not purify,
It directly applies in next step.MS m/z:324.6[M+H]+.
Step 6:The synthesis of compound BB-17-7
N-Boc-L- proline (400mg, 1.856mmol) and potassium carbonate (510mg, 3.7mmol) are suspended in DMF
In (5mL), it is stirred at room temperature 10 minutes, then adds in compound BB-17-6 (600mg, 1.85mmol).Be stirred at room temperature 2 it is small when,
TLC detections add in ethyl acetate (100mL) after completion of the reaction, successively with water (20mL × 4), saturated salt solution (30mL) washing.
Organic phase is dried with anhydrous sodium sulfate, and filtering, filtrate decompression removes solvent, and residue is through silica gel column chromatography (petroleum ether/acetic acid second
Ester=20:1→5:1) target compound BB-17-7 (644m g, yield 76%) is obtained.MS m/z:359.9[M-Boc+H]+.
Step 7:The synthesis of compound BB-17-8
At room temperature, compound BB-17-7 (650mg, 1.42mmol) is dissolved in toluene (50mL), add in ammonium acetate (1.1g,
14.3mmol).120 DEG C are warming up under nitrogen protection, is stirred overnight, and TLC detections are cooled to room temperature after completion of the reaction, add in water
Reaction, ethyl acetate (50mL × 3) extraction is quenched in (30mL).Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate subtracts
Pressure removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=5:1→1:1) target compound BB-17-8 is obtained
(pale yellow powder, 349mg, yield 56%).1H NMR(CDCl3,400MHz):δ 6.94 (s, 1H), 4.92 (d, J=5.2Hz,
1H),3.38(S,2H),3.00-2.93(m,1H),2.81-2.76(m,1H),2.60-2.56(m,2H),2.44-2.39(m,
2H),2.14-2.07(m,1H),1.98-1.91(m,1H),1.90-1.56(m,2H),1.46(s,9H).MS m/z:439.9[M
+H]+.
Step 8:The synthesis of compound BB-17-9
Compound BB-17-8 (600mg, 1.37mmol) is dissolved in ethyl acetate (10mL), is cooled to 0 DEG C, chlorination is added dropwise
Hydrogen/ethyl acetate solution (HCl/EA, 4mol/L, 10mL), when stirring 1 is small at 0 DEG C.TLC detections are spin-dried for molten after completion of the reaction
Agent obtains target compound BB-17-9 (yellow solid, 510mg, yield 99.4%).Product directly applies to down without purifying
One step.MS m/z:339.8[M+H]+.
Step 9:The synthesis of compound BB-17
At room temperature, by compound BB-17-9 (573mg, 1.53mmol), N-Moc-L- valines (BB-2-6,323mg,
1.69mmol), diisopropyl ethyl amine (594mg, 4.60mmol) is dissolved in DMF (10mL), add in HATU (746mg,
1.96mmol).It being stirred overnight at room temperature, TLC is detected after completion of the reaction, is added in water (10mL) and is quenched reaction, ethyl acetate (50mL ×
3) extract.Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression removes solvent, and residue is through silica gel column chromatography
(petrol ether/ethyl acetate=1:1 → pure ethyl acetate) obtain target compound BB-17 (yellow solid, 317mg, yield
41.9%).MS m/z:497.1[M+H]+.
Reference example 18~20
Table xx:Using compound BB-17-9 as raw material, according to the synthetic method of step 9 in reference example 17, following table is respectively obtained
In compound BB-18, BB-19, BB-20.
Reference example 21:Segment BB-21
Synthetic route:
Step 1:The synthesis of compound BB-2-6
Valine (100g, 751mmol) is added in sodium hydroxide solution (2mol/L, 535mL).Ice bath is cooled to 5
Below DEG C, methylchloroformate (118.13g, 1.25mmol) is added dropwise, and is stirred overnight at room temperature.TLC is detected after completion of the reaction, ice bath
Less than 5 DEG C are cooled to, concentrated hydrochloric acid is added dropwise and adjusts pH value to 5 or so, collects the solid of precipitation, is washed with water (100mL), after dry
Obtain target compound BB-2-6 (white solid, 141g, yield 98.2%).Product directly applies in next step without purifying
。1H NMR(CDCl3400MHz):δ 5.19 (d, J=8.8Hz, 1H), 4.32 (dd, J=8.8Hz, J=4.4Hz, 1H), 3.71
(s, 3H), 2.26-2.18 (m, 1H), 1.01 (d, J=7.2Hz, 3H), 0.94 (d, J=6.4Hz, 3H)
Step 2:The synthesis of compound BB-21-1
By EDCHCl (26.3g, 136.9mmol), N-Moc-L- valines (BB-2-6,17.6g, 92.05mmol), two
Wopropyl ethyl amine (35.4g, 274.4mmol) is dissolved in anhydrous methylene chloride (500mL), is stirred at room temperature and adds in compound after ten minutes
BB-8 (reference example 8,30g, 102.7mmol), and be stirred overnight at room temperature under nitrogen protection.TLC is detected after completion of the reaction, is added in
Reaction is quenched in water (20mL), and organic phase is 5~6 with 10% salt acid elution to pH value, then uses saturated salt solution (100mL) again
Washing, anhydrous sodium sulfate drying.After filtering, filtrate decompression remove solvent obtain compound BB-21-1 (grey foaming solid,
35g, yield 76%).Product directly applies in next step without purifying.MS m/z:449.0[M+H]+.
Step 3:The synthesis of compound BB-21
At room temperature, by compound BB-21-1 (80g, 178mmol), duplex pinacol borate (90g, 354mmol) is dissolved in
Dioxane (600mL) adds in potassium acetate (35g, 357mmol) and Pd (dppf) Cl under nitrogen protection2(13g,
1.78mmol).Reaction solution is heated to 90 DEG C and is stirred overnight under nitrogen protection.TLC detections are cooled to room temperature after completion of the reaction.
After filtering, filtrate is spin-dried for solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=20:1→8:1) targeted is obtained
Close object BB-21 (gray solid, 70g, yield 80%).MS m/z:519.1[M+Na]+.
Reference example 22:Segment BB-22
Synthetic route:
Step 1:The synthesis of compound BB-22-2
At room temperature, methyl hydrazinocarboxylate (BB-22-1,3g, 33mmol) is dissolved in acetone (30mL), added under nitrogen protection
Enter anhydrous magnesium sulfate (8g, 67mmol), when reaction system is warming up to reflux and small stirring 2.TLC detections are cooled to after completion of the reaction
Room temperature.After filtering, filtrate obtains target compound BB-22-2 (white solid, 3.8g, yield 87.8%) after being spin-dried for solvent.Production
Product directly apply in next step without purifying.1H NMR(CDCl3,400MHz):δ 3.82 (brs, 3H), 2.06 (d, J=
1.6Hz,3H),1.85(s,3H).
Step 2:The synthesis of compound BB-22
At room temperature, compound BB-22-2 (3g, 23.1mmol) is dissolved in ethyl acetate/glacial acetic acid (30mL/3mL) to mix
In solvent, platinum dioxide (0.3g) is added under nitrogen protection.In 50 DEG C and small 50psi hydrogen pressure reaction 12, it is cooled to
Room temperature.After filtering, filtrate obtains target compound BB-22 (colorless oil, 2.9g, yield 95.1%) after being spin-dried for solvent.Production
Product directly apply in next step without purifying.1H NMR(CDCl3,400MHz):δ3.62(s,3H),3.25(brs,1H),1.04
(d, J=6.4Hz, 6H)
Reference example 23:Segment BB-23
Synthetic route:
Step 1:The synthesis of compound BB-23-2
At room temperature, by 3- tosyls tetrahydrofuran (BB-23-1,3g, 12.4mmol), diphenyl methylene glycine methyl ester
(1.49g, 5.88mmol) is dissolved in toluene (30mL), under nitrogen protection slowly be added dropwise LiHMDS (1mol/L in THF,
7.1mL,7.1mmol).100 DEG C are heated under nitrogen protection, are stirred overnight.TLC detections are cooled to room temperature after completion of the reaction,
It adds in water (20mL) and reaction, ethyl acetate (50mL × 3) extraction is quenched.Merge organic phase, dried with anhydrous sodium sulfate.Filtering
Afterwards, filtrate decompression removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=35:1→5:1) targeted is obtained
Close object BB-3-2 (orange-yellow grease, 1.52g, yield 80%).1H NMR(CDCl3,400MHz):δ7.67-7.65(m,2H),
7.48-7.36 (m, 6H), 7.22-7.20 (m, 2H), 4.10 (t, J=7.6Hz, 1H), 3.94-3.92 (m, 1H), 3.79-3.46
(m,5H),3.64-3.46(m,1H),3.05-3.01(m,1H),2.07-2.02(m,1H),1.81-1.61(m,1H).
Step 2:The synthesis of compound BB-23-3
At room temperature, compound BB-23-2 (12.2g, 37.8mmol) is dissolved in tetrahydrofuran (100mL), salt is slowly added dropwise
Sour (2mol/L, 75.5mL, 151mmol), be stirred at room temperature 4 it is small when.TLC detections use petroleum ether after being spin-dried for solvent after completion of the reaction
(50mL × 3) are washed, and sodium hydroxide is added in into system and adjusts pH value to 8~9, is then extracted with ethyl acetate (50mL × 3).
Merge organic phase, dried with anhydrous sodium sulfate.After filtering, filtrate is spin-dried for solvent and obtains target compound BB-23-3 (orange-yellow oils
Shape object, 3.2g, yield 53.4%).1H NMR(CDCl3,400MHz):δ3.90-3.85(m,2H),3.73-3.68(m,5H),
3.37 (dd, J=20.8, J=7.2Hz, 1H), 2.52-2.46 (m, 1H), 1.99-1.96 (m, 1H), 1.78-1.77 (m, 1H)
Step 3:The synthesis of compound BB-23-4
At room temperature, compound BB-23-3 (2.88g, 18.1mmol) is dissolved in dichloromethane (50mL), adds in diisopropyl
Ethylamine (7.0g, 54.3mmol), then be added dropwise methylchloroformate (1.88g, 19.9mmol), and be stirred at room temperature 4 it is small when.
Solvent is removed under reduced pressure in TLC detections after completion of the reaction, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=20:1→2:1)
Obtain target compound BB-23-4 (yellow oil, 2.8g, yield 71.2%).1H NMR(CDCl3,400MHz):δ5.38
(brs,1H),4.42-4.38(m,1H),3.92-3.90(m,2H),3.78(s,3H),3.75-3.68(m,6H),2.71-2.67
(m,1H),2.08-1.81(m,2H).
Step 4:The synthesis of compound BB-23-5
At room temperature, by compound BB-23-4 (3.25g, 15.0mmol) be dissolved in methanol/water (100mL/100mL) mix it is molten
In agent, sodium hydroxide (1.2g, 30.0mmol) is added in.Reaction system is warming up to 75 DEG C, when stirring 3 is small, and TLC detection reactions finish
Afterwards with 2N salt acid for adjusting pH value to 1~2, ethyl acetate (200mL × 2) extraction.Merge organic phase, dried with anhydrous sodium sulfate,
After filtering, filtrate is spin-dried for solvent and obtains target compound BB-23-5 (orange-yellow grease, 2.9g, yield 95.4%).1H NMR
(CDCl3,400MHz):δ 5.60 (dd, J=26.4, J=8.4Hz, 1H), 4.40 (brs, 1H), 3.99-3.89 (m, 2H),
3.79-3.72(m,5H),2.80-2.77(m,1H),2.13-2.07(m,1H),1.92-1.80(m,1H).
Step 5:The synthesis of compound BB-23-6
At room temperature, by compound BB-23-5 (550mg, 2.71mmol), BB-8 (400mg, 1.37mmol), diisopropyl
Ethylamine (763mg, 5.91mmol) is dissolved in DMF (10mL), adds in HATU (958mg, 2.52mmol).Be stirred at room temperature 3 it is small when,
Solvent is removed under reduced pressure in TLC detections after completion of the reaction, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=10:1 → pure second
Acetoacetic ester) obtain target compound BB-2-6 (yellow solid, 540mg, yield 82.5%).MS m/z:476.8[M+H]+
Step 6:The synthesis of compound BB-23
Compound BB-23 can be prepared according to the synthesis step 3 of reference example 21 (BB-21).MS m/z:525.0[M+H]+
Reference example 24:Segment BB-24
Synthetic route:
Step 1:The synthesis of compound BB-24-2
Compound BB-24-2 can be prepared according to the synthesis step 5 of reference example 23 (BB-23).MS m/z:492.9[M+H]+
Step 2:The synthesis of compound BB-24
Compound BB-24 can be prepared according to the synthesis step 3 of reference example 21 (BB-21).MS m/z:539.2[M+H]+
Reference example 25:Segment BB-25
Synthetic route:
Step 1:The synthesis of compound BB-25-2
Compound BB-25-1 (18.0g, 77.2mmol) is dissolved in ethyl acetate (50mL), it is molten to add in hydrochloric ethyl acetate
Liquid (4mol/L, 50mL), be stirred at room temperature 2 it is small when, TLC detection solvent is removed under reduced pressure after completion of the reaction, obtain target compound BB-
25-2 (faint yellow, 13.0g, yield 100%).Product directly applies in next step without purifying.1H NMR(400MHz,
DMSO-d6):δ 8.37 (brs, 3H), 3.81-3.88 (m, 2H), 3.23 (s, 3H), 1.20 (d, J=6.4Hz, 3H)
Step 2:The synthesis of compound BB-25-3
Sodium hydroxide (12.2g, 305mmol) is dissolved in 200mL water, is cooled to 0 DEG C, adds in compound BB-25-2
(13.0g,76.6mmol).After it is completely dissolved, methylchloroformate (7.2g, 76.2mmol) is added dropwise.It is added dropwise, room temperature is stirred
It mixes overnight.TLC detections add in 1N salt acid for adjusting pH value to 3 after completion of the reaction, are extracted with ethyl acetate (30mL × 3).It is associated with
Machine phase, with saturated common salt water washing, the drying of organic phase anhydrous sodium sulfate, after filtering, filtrate decompression removes solvent, obtains compound
BB-25-3 (white solid, 8.0g, yield 54.8%).Product directly applies in next step without purifying.1H NMR:
(400MHz, DMSO-d6) δ 12.65 (brs, 1H), 7.02 (d, J=9.0Hz, 1H), 4.04-4.01 (m, 2H), 3.76-3.74
(m,1H),3.51(s,3H),3.81(s,3H),1.96(s,3H).
Step 3:The synthesis of compound BB-25-4
Compound BB-25-4 can be prepared according to the synthesis step 5 of reference example 23 (BB-23).MS m/z:465.0[M+H]+
Step 4:The synthesis of compound BB-25
Compound BB-25 can be prepared according to the synthesis step 3 of reference example 21 (BB-21).MS m/z:513.1[M+H]+
Reference example 26:Segment BB-26
Synthetic route:
Step 1:The synthesis of compound BB-26-2
Compound BB-26-2 can be prepared according to the synthesis step 5 of reference example 23 (BB-23).MS m/z:422.9[M+H]+
Step 2:The synthesis of compound BB-26
Compound BB-26 can be prepared according to the synthesis step 3 of reference example 21 (BB-21).MS m/z:469.2[M+H]+
Reference example 27:Segment BB-27
Synthetic route:
Step 1:The synthesis of compound BB-27-2
At room temperature, N-Moc-L- valines (BB-2-6,10g, 52.3mmol) are dissolved in THF (200ml), are cooled to -30
DEG C, add in triethylamine (11.6g, 114.9mmol) and isobutyl chlorocarbonate (9.36g, 68.1mmol).Reaction 1 is small at -30 DEG C
Shi Hou adds Serine hydrochloride (BB-27-1,10.6g, 68.4mmol), the reaction was continued at -30 DEG C 3 it is small when, then
It is warmed to room temperature, is stirred overnight.TLC detections are spin-dried for solvent after completion of the reaction, and residue is dissolved in ethyl acetate (200mL), uses saturation
Saline solution (50mL × 3) washs.Organic phase is dried with anhydrous sodium sulfate, and after filtering, filtrate obtains target chemical combination after being spin-dried for solvent
Object BB-27-2 (white solid, 12.34g, yield 765.3%).Product directly applies in next step without purifying.MS m/z:
276.8[M+H]+
Step 2:The synthesis of compound BB-27-3
At room temperature, by compound BB-27-2 (20g, 72.39mmol), p-methyl benzenesulfonic acid monohydrate (3.64g,
THF (200mL) 19.14mmol) is dissolved in, adds in 2,2-dimethoxypropane (37.7g, 36.22mmol).Reaction system is warming up to
Reflux is stirred at reflux overnight.TLC detections add in ethyl acetate (400mL) after completion of the reaction, use saturated sodium bicarbonate solution successively
(50mL × 2), saturated salt solution (50mL × 2) washing.Organic phase is dried with anhydrous sodium sulfate, and after filtering, filtrate is spin-dried for solvent
After obtain target compound BB-27-3 (yellow oil, 5.0g, yield 21.8%).Product directly applies to down without purifying
One step.MS m/z:339.1[M+Na]+
Step 3:The synthesis of compound BB-27-4
By compound BB-27-3 (1.8g, 5.69mmol), it is mixed to be added to tetrahydrofuran/butanol/water (36mL/9mL/9mL)
It closes in solution, adds in a hydronium(ion) lithia (478.38mg, 11.39mmol), when stirring 2 is small at 30 DEG C, TLC detection reactions
After with 1N salt acid for adjusting pH value to 3, extracted with ethyl acetate (30mL × 3).Merge organic phase, use saturated salt solution
(20mL) wash, then dried with anhydrous sodium sulfate, after filtering, filtrate is spin-dried for solvent, obtain yellow solid intermediate (1.7g,
Yield 98.8%).By above-mentioned intermediate (1.7g, 5.62mmol), 2,4 '-dibromo acetophenone (BB-1-1,1.99g,
Acetonitrile (60mL) 17.15mmol) is dissolved in, adds in triethylamine (1.49g, 14.7mmol) at room temperature.It is stirred overnight at 50 DEG C,
TLC detections are spin-dried for solvent after completion of the reaction, and residue is dissolved in ethyl acetate (200mL), is washed with saturated salt solution (40mL × 3)
It washs.Organic phase is dried with anhydrous sodium sulfate, and filtering, filtrate decompression removes solvent, and obtaining target compound BB-27-4, (yellow is solid
Body, 2.8g, yield 99.6%).Product directly applies in next step without purifying.MS m/z:500.9[M+H]+
Step 4:The synthesis of compound BB-27-5
Compound BB-27-4 (2.8g, 5.61mmol) is dissolved in dioxane (100mL), add in ammonium acetate (8.64g,
112.2mmol).Reaction system is warming up to 110 DEG C under nitrogen protection, is stirred overnight.TLC detections are cooled to room after completion of the reaction
Temperature, filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:1) target compound is obtained
BB-27-5 (yellow solid, 1.2g, yield 44.4%).MS m/z:481.3[M+H]+
Step 5:The synthesis of compound BB-27
Compound BB-27 can be prepared according to the synthesis step 3 of reference example 21 (BB-21).MS m/z:527.3[M+H]+
Reference example 28:Segment BB-28
Synthetic route:
Step 1:The synthesis of compound BB-28-2
At room temperature, N-Moc-L- valines (BB-2-6,5.0g, 26.15mmol) are dissolved in dichloromethane (60mL), added in
Triethylamine (6.07g, 60.1mmol) and HATU (10.85g, 28.54mmol).It is stirred at room temperature after ten minutes, adds in 4- hydroxyl dried meat
Propylhomoserin methyl formate hydrochloride (BB-28-1,5.19g, 28.54mmol).Be stirred at room temperature 4 it is small when, TLC detect after completion of the reaction,
It adds in saturated sodium bicarbonate solution (30mL) and reaction, liquid separation is quenched, water is mutually extracted with dichloromethane (20mL × 3).Merge organic
Phase is dried with anhydrous sodium sulfate, filtering, after filtrate is spin-dried for solvent, residue through silica gel column chromatography (petrol ether/ethyl acetate=
1:1) target compound BB-28-2 (white solid, 2.0g, yield 23.2%) is obtained.
MS m/z:303.0[M+H]+
Step 2:The synthesis of compound BB-28-3
Compound BB-28-2 (2.0g, 6.62mmol) is dissolved in DCM (50mL), adds in Dess-Martin oxidations at room temperature
Agent (DMP, 5.71g, 13.46mmol), is stirred overnight at room temperature.TLC is detected after completion of the reaction, adds in 5% hypo solution
Reaction is quenched in (50mL), then add in saturated sodium bicarbonate solution (100ml), stirring after ten minutes with dichloromethane (100mL ×
3) extract.Merge organic phase, dried with anhydrous sodium sulfate, filtered, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (stone
Oily ether/ethyl acetate=1:1) target compound BB-28-3 (white solid, 1.0g, yield 50.3%) is obtained.MS m/z:
301.0[M+H]+
Step 3:The synthesis of compound BB-28-4
By compound BB-28-3 (1.0g, 3.33mmol), ethylene glycol (2.68g, 43.28mmol) is dissolved in toluene (75mL),
Add in p-methyl benzenesulfonic acid monohydrate (126.15mg, 660mmol).Reaction system is warming up to reflux under nitrogen protection, stirring
Overnight, TLC detections are cooled to room temperature after completion of the reaction, are added in ethyl acetate (30mL), are used saturated sodium bicarbonate solution successively
(50mL × 3), saturated salt solution (50mL) washing, organic phase is dried with anhydrous sodium sulfate, filtered, residual after filtrate is spin-dried for solvent
Object is stayed through silica gel column chromatography (petrol ether/ethyl acetate=1:1) obtaining target compound BB-28-4, (white solid, 900mg are received
Rate 78.3%).MS m/z:344.9[M+H]+
Step 4:The synthesis of compound BB-28-5
By compound BB-28-4 (900mg, 2.62mmol), tetrahydrofuran/butanol/water (20mL/5mL/5mL) is added to
In mixed solution, a hydronium(ion) lithia (239.82g, 5.71mmol) is added in, is stirred overnight at room temperature, TLC detection reactions finish
Afterwards with 1N salt acid for adjusting pH value to 3, extracted with ethyl acetate (20mL × 3).Merge organic phase, washed with saturated salt solution (20mL)
Wash, then dried with anhydrous sodium sulfate, filtered, filtrate is spin-dried for solvent, obtain target compound BB-28-5 (white solid,
680mg, yield 78.8%).Product directly applies in next step without purifying.MS m/z:352.9[M+Na]+
Step 5:The synthesis of compound BB-28-6
By compound BB-28-5 (680mg, 2.06mmol), 2,4 ' dibromo acetophenones (BB-1-1,685mg, 2.47mmol)
Acetonitrile (30mL) is dissolved in, adds in triethylamine (385.8mg, 3.82mmol) at room temperature.It is stirred overnight at 50 DEG C, TLC detections are anti-
Solvent is spin-dried for after answering, residue is dissolved in ethyl acetate (100mL), is washed with saturated salt solution (20mL × 3).Organic phase is used
Anhydrous sodium sulfate is dried, and filtering, filtrate decompression removes solvent, obtains target compound BB-28-6 (yellow solid, 1.02g, production
Rate 93.9%).Product directly applies in next step without purifying.
MS m/z:528.8[M+H]+
Step 6:The synthesis of compound BB-28-7
Compound BB-28-7 (1.02g, 1.93mmol) is dissolved in dioxane (20mL), add in ammonium acetate (1.6g,
21mmol).Reaction system is warming up to 110 DEG C under nitrogen protection, is stirred overnight, and TLC detections are cooled to room temperature after completion of the reaction,
Filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=1:1) target compound BB- is obtained
28-7 (yellow solid, 650mg, yield 66.3%).MS m/z:508.8[M+H]+
Step 7:The synthesis of compound BB-28
At room temperature, by compound BB-28-6 (100mg, 0.20mmol), duplex pinacol borate (55.05mg,
Dioxane (2mL) 0.22mmol) is dissolved in, adds in potassium acetate (63.74mg, 0.65mmol) and Pd (dppf) under nitrogen protection
Cl2(11mg, 0.02mmol).It is heated to flowing back under nitrogen protection, when stirring 4 is small, TLC detections are cooled to room after completion of the reaction
Temperature, filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=1:1) target compound is obtained
BB-28 (yellow color solid, 45mg, yield 40.6%).MS m/z:555.0[M+H]+
Reference example 29:Segment BB-29
Synthetic route:
Step 1:The synthesis of compound BB-29-2
Sodium hydrogen (1.96g, 48.9mmol) is suspended in tetrahydrofuran (60mL), 0 DEG C is cooled to, drips under nitrogen protection
Add compound BB-29-1 (8.0g, 32.6mmol), be added dropwise at 0 DEG C stirring 2 it is small when, then add in iodomethane at 0 DEG C
(8.0g, 48.9mmol), continue at this temperature stirring 2.5 it is small when, TLC detection after completion of the reaction add in water (10mL) be quenched instead
Should, ethyl acetate (80mL × 3) extraction.Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression removes solvent, residual
Object is stayed through silica gel column chromatography (petrol ether/ethyl acetate=9:1→1:1) obtain target compound BB-29-2 (colorless oil,
5.5g, yield 65.2%).1H NMR(CDCl3,400MHz):δ4.33-4.25(m,1H),3.93-3.89(m,1H),3.70(s,
3H),3.59-3.47(m,2H),3.44(s,3H),2.03-1.98(m,2H),1.43(s,9H).
Step 2:The synthesis of compound BB-29-3
At room temperature, compound BB-29-2 (5.5g, 21.3mmol) is dissolved in methanol/water (30mL/30mL) in the mixed solvent,
Add in sodium hydroxide (1.7g, 42.6mmol).Reaction system is warming up to 60 DEG C, when stirring 8 is small, and TLC detections subtract after completion of the reaction
Pressure removes most of solvent, is cooled to 0 DEG C, 2N salt acid for adjusting pH value is added dropwise to 3~4, ethyl acetate (80mL × 3) extracts.It closes
And organic phase, dried with anhydrous sodium sulfate, filter, filtrate be spin-dried for solvent obtain target compound BB-29-3 (yellow oil,
5.0g, yield 95.8%);Product directly applies in next step without purifying.1H NMR(CDCl3,400MHz):δ4.42-4.14
(m,1H),3.99-3.98(m,1H),3.65-3.53(m,2H),3.33(s,3H).2.31-2.05(m,2H),1.47(s,9H).
Step 3:The synthesis of compound BB-29-4
By compound BB-29-3 (5.0g, 20.3mmol) and 2,4 '-dibromo acetophenone (BB-1-1,6.2g, 22.3mmol)
It is dissolved in DMF (50mL), is slowly added to potassium carbonate (5.6g, 40.6mmol).It is stirred overnight at room temperature, TLC is detected after completion of the reaction
It adds in water (30mL) and reaction, ethyl acetate (100mL × 3) extraction is quenched.Merge organic phase, dried with anhydrous sodium sulfate, filtered,
Filtrate decompression removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=20:1→1:1) target compound is obtained
BB-29-4 (red solid, 3.5g, yield 41.7%).1HNMR(CDCl3,400MHz):δ7.79-7.76(m,2H),7.67-
7.65(m,2H),5.58-5.18(m,2H),4.55-4.50(m,1H),4.16-4.05(m,1H).3.67-3.37(m,2H),
3.36(s,3H),2.50-2.40(m,2H),1.47(s,9H).
Step 4:The synthesis of compound BB-29-5
At room temperature, compound BB-29-4 (3.5g, 7.9mmol) is dissolved in toluene (70mL), add in ammonium acetate (6.1g,
79.1mmol).Reaction system is warming up to 120 DEG C, when stirring 6 is small under nitrogen protection, and TLC detections are cooled to room after completion of the reaction
Temperature adds in ethyl acetate (50mL), is washed with water (30mL × 2).Organic phase is dried with anhydrous sodium sulfate, filtering, filtrate decompression
Solvent is removed, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→1:1) target compound BB-29-5 is obtained
(red oil, 3.0g, yield 88.9%).LC/MS m/z:424.0[M+H]+
Step 5:The synthesis of compound BB-29-6
Compound BB-29-5 (2.0g, 4.7mmol) is dissolved in ethyl acetate (5mL), is cooled to 0 DEG C, add in hydrogen chloride/
Ethyl acetate solution (HCl/EA, 4M, 30mL) and at 0 DEG C stirring 2 it is small when.TLC detections are depressurized at room temperature after completion of the reaction
Solvent is removed, obtains compound BB-29-6 (green solid, 1.69g, yield 99.4%);Product is directly applied to without purifying
In next step.LC/MS m/z:323.9[M+3]+
Step 6:The synthesis of compound BB-29
At room temperature, by compound BB-29-6 (885mg, 2.96mmol), N-Moc-L- valines (BB-2-6,518.2mg,
2.96mmol), diisopropyl ethyl amine (954mg, 7.4mmol) is dissolved in DMF (10mL), adds in HATU (1.41g, 3.7mmol).
Be stirred at room temperature 1 it is small when, TLC is detected after completion of the reaction, is added in water (10mL) and is quenched reaction, ethyl acetate (30mL × 3) extracts.It closes
And organic phase, it is dried, filtered with anhydrous sodium sulfate, filtrate decompression removes solvent, and residue is through silica gel column chromatography (petroleum ether/second
Acetoacetic ester=1:1 → pure ethyl acetate) obtain target compound BB-29 (red oil, 841mg, yield 71.3%).LC/
MS m/z:480.4[M+H]+.501.1[M+Na]+
Reference example 30:Segment BB-30
Synthetic route:
Step 1:The synthesis of compound BB-30
With compound BB-29-6 (885mg, 2.46mmol), compound BB-1-6 (566mg, 2.96mmol), diisopropyl
Ethylamine (954mg, 7.4mmol), HATU (1.41g, 3.7mmol) are raw material, according to the conjunction of reference example 29 (BB-29) step 6
Into method, compound BB-30 (1.1g, yield 90.2%) is obtained.LCMS m/z:496.4[M+H]+.
Reference example 31:Segment BB-31
Synthetic route:
Step 1:The synthesis of compound BB-31-1
Compound BB-2-2 (1.40g, 6.50mmol) and diisopropyl ethyl amine (1.01g, 7.81mmol) are dissolved in second
In nitrile (15mL), 0 DEG C is cooled to, is slowly added to compound AA_108-2 (2.00g, 7.15mmol).Stirring 0.5 is small at 0 DEG C
When, solvent is removed under reduced pressure in TLC detections after completion of the reaction, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:1) obtain
Target compound BB-31-1 (white solid, 1.26g, yield 33%).LC/MS m/z:435.0[M+Na]+.
Step 2:The synthesis of compound BB-31-2
At room temperature, compound BB-31-1 (1.26g, 3.04mmol) is dissolved in toluene (50mL), adds in ammonium acetate
(2.34g,30.39mmol).Reaction system is warming up to reflux under nitrogen protection, is stirred overnight, and TLC detections are cold after completion of the reaction
But to room temperature, ethyl acetate (50mL) is added in, is washed with water (30mL × 2).Organic phase is dried with anhydrous sodium sulfate, is filtered, filter
Solvent is removed under reduced pressure in liquid, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:3 → pure ethyl acetate) obtain targeted
Close object BB-31-2 (white solid, 0.72g, yield 60%).LC/MS m/z:394.8[M+H]+.
Step 3:The synthesis of compound BB-31
Compound BB-31-2 (0.72g, 1.82mmol) is dissolved in ethyl acetate (10mL), is cooled to 0 DEG C, adds in chlorination
Hydrogen/ethyl acetate solution (HCl/EA, 4M, 30mL), be stirred at room temperature 1 it is small when.Decompression removes at room temperature after completion of the reaction for TLC detections
Solvent is removed, obtains white solid;Without purifying, directly apply in next step.
At room temperature, by above-mentioned white solid, compound BB-1-6 (0.52g, 2.73mmol), diisopropyl ethyl amine
(1.06g, 8.19mmol) is dissolved in DMF (4mL), adds in HATU (1.04g, 2.73mmol).Be stirred at room temperature 3 it is small when, TLC detections are anti-
After answering, add in water (10mL) and reaction, ethyl acetate (30mL × 3) extraction is quenched.Merge organic phase, done with anhydrous sodium sulfate
Dry, filtering, filtrate decompression removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:3 → pure ethyl acetate)
Obtain target compound BB-31 (yellow solid, 0.85g, yield 92%).LC/MS m/z:466.0[M+H]+.
Reference example 32:Segment BB-32
Synthetic route:
Step 1:The synthesis of compound BB-32-1
Compound BB-2-2 (1.96g, 9.22mmol) and diisopropyl ethyl amine (1.43g, 11.06mmol) are dissolved in second
In nitrile (15mL), 0 DEG C is cooled to, is slowly added to compound AA_117-2 (3.00g, 10.14mmol).Stirring 1 is small at 0 DEG C
When, solvent is removed under reduced pressure in TLC detections after completion of the reaction, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:1) obtain
Target compound BB-32-1 (brown gum, 3.7g, yield 94.4%).LC/MS m/z:329.8[M-Boc+H]+.
Step 2:The synthesis of compound BB-32-2
With BB-32-1 (3.93g, 9.13mmol), ammonium acetate (7.04g, 91.34mmol) is raw material, according to reference example 31
(BB-31) synthetic method of step 2 obtains compound BB-32-2 (3.0g, yield 85.0%).LCMS m/z:310.0[M-
Boc+H]+.
Step 3:The synthesis of compound BB-32
With compound BB-32-2 (3.0g, 7.31mmol), hydrogen chloride/ethyl acetate solution (HCl/EA, 4M, 100mL),
Compound BB-1-6 (566mg, 2.96mmol), diisopropyl ethyl amine (1.31g, 10.10mmol), HATU (1.65g,
4.33mmol) for raw material, according to the synthetic method of reference example 31 (BB-31) step 3, obtain compound BB-32 (yellow solid,
0.60g, yield 43%).1H NMR(CDCl3,400MHz):δ 7.49 (dd, J=8.0Hz, J=2.8Hz, 1H), 7.34 (d, J=
8.0Hz, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 5.70 (d, J=8.0Hz), 5.31 (m, 1H), 4.58 (m, 1H), 3.73
(m, 2H), 3.70 (s, 3H), 3.27 (s, 3H), 2.85 (m, 1H), 2.22 (m, 1H), 1.44 (m, 1H), 1.19 (d, J=
8.0Hz, 1H), 0.88 (m, 1H) embodiments 1:AL_001
Synthetic route:
Step 1:The synthesis of compound AL_001
At room temperature, by compound BB-17 (40mg, 0.081mmol), BB-21 (44.4mg, 0.090mmol) is dissolved in DMF/
THF/H2O (1.5mL/1.5mL/1.5mL) in the mixed solvent adds in sodium carbonate (17.3mg, 0.163mmol) under nitrogen protection
With Pd (dppf) Cl2(6mg,0.0081mmol).100 DEG C are heated under nitrogen protection, is stirred overnight, and TLC detections have been reacted
Finish postcooling to room temperature, filtering, after filtrate is spin-dried for solvent, residue obtains target compound AL_ through efficient liquid phase preparative separation
001 (yellow solid, 14.3mg, yield 22.4%).MS m/z:785.3[M+H]+.
With reference to the synthetic method of step 1 in AL_001, compound in following table is synthesized:
Embodiment 20:AL_023
Synthetic route:
Step 1:The synthesis of compound AL_023-2
At room temperature, by compound AL_023-1 (1.5g, 5.75mmol), N, O- dimethyl azanol hydrochlorides (613mg,
6.29mmol), diisopropyl ethyl amine (1.5g, 11.63mmol) is dissolved in DMF (10mL), add in HATU (2.4g,
6.32mmol).Be stirred at room temperature 1 it is small when, TLC detect after completion of the reaction, add in water (10mL) reaction, ethyl acetate (50mL is quenched
× 3) extract.Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression removes solvent, and residue is through silica gel column chromatography
(petrol ether/ethyl acetate=9:1→3:2) amide intermediate (yellow solid, 1.65g, yield 94.3%) is obtained.By above-mentioned acyl
Amine intermediate (1.4g, 4.6mmol) is dissolved in tetrahydrofuran (20mL), is cooled to -20 DEG C, and the second of methyl-magnesium-bromide is slowly added dropwise
Ethereal solution (3mol/L, 5mL, 15mmol), drop finish, be stirred at room temperature 1 it is small when, TLC detection after completion of the reaction add in water (10mL) quench
It goes out reaction, ethyl acetate (50mL × 3) extraction.Merging organic phase, anhydrous sodium sulfate drying is filtered, and filtrate decompression removes solvent,
Residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→5:2) obtain target compound AL_023-2 (yellow liquid,
0.9g, yield 75.6%).1H NMR(CDCl3,400MHz):δ3.04(m,2H),2.57(m,2H),2.47(s,3H),1.78-
1.76(m,4H).
Step 2:The synthesis of compound AL_023-3
Compound AA_023-2 (2.5g, 9.65mmol) is dissolved in tetrahydrofuran (100mL), ice bath is cooled to less than 5 DEG C,
Add in phenyltrimethyl-ammonium tribromide (4.3g, 9.65mmol).Be stirred at room temperature 12 it is small when, TLC detection add in water after completion of the reaction
Reaction, ethyl acetate (50mL × 3) extraction is quenched in (10mL).Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate subtracts
Pressure removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→2:1) target compound AL_023- is obtained
3 (yellow liquid, 3.3g, yields 85.3%).MS m/z:338.7[M+H]+.
Step 3:The synthesis of compound AL_023-4
Compound AL_023-3 (3.3g, 9.76mmol) and potassium carbonate (4g, 28.99mmol) are suspended in DMF (20mL)
In, Boc-L- proline (3.1g, 14.41mmol) is added at room temperature.Be stirred at room temperature 1 it is small when, TLC detection add in after completion of the reaction
Reaction, ethyl acetate (50mL × 3) extraction is quenched in water (10mL).Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate
Yellow intermediate is obtained after being spin-dried for solvent.Above-mentioned intermediate is dissolved in toluene (100mL), add in ammonium acetate (3.42g,
44.5mmol).Reflux is warming up under nitrogen protection, and when stirring 12 is small, TLC detections are cooled to room temperature after completion of the reaction, are added in
Reaction, ethyl acetate (100mL × 3) extraction is quenched in water (30mL).Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate
Solvent is removed under reduced pressure, residue is through silica gel column chromatography (petrol ether/ethyl acetate=3:2→1:4) target compound AL_ is obtained
023-4 (pale yellow powder, 2.75g, yield 62.3%).MS m/z:454.0[M+H]+.
Step 4:The synthesis of compound AL_023-5
By compound AL_023-4 (0.25g, 0.553mmol) be added to hydrogen chloride/ethyl acetate solution (HCl/EA,
4mol/L, 5mL) in, be stirred at room temperature 1 it is small when.TLC detections are spin-dried for solvent after completion of the reaction, obtain target compound AL_023-5
(pale solid, 0.190g, yield 88.3%).Product directly applies in next step without purifying.MS m/z:353.8[M+
H]+.
Step 5:The synthesis of compound AL_023-6
By compound AL_023-5 (195mg, 0.502mmol), N-Moc-L- valines (BB-2-6,117mg,
0.612mmol), diisopropyl ethyl amine (143mg, 1.11mmol) is dissolved in DMF (10mL), add in HATU (253mg,
0.661mmol), be stirred at room temperature 1 it is small when.TLC detections add in water (10mL) and reaction, ethyl acetate (30mL are quenched after completion of the reaction
× 3) extract.Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate decompression removes solvent, and residue is through silica gel column chromatography
(petrol ether/ethyl acetate=9:1→1:1) target compound AL_023-6 (pale yellow powder, 225.6mg, yield are obtained
88.3%).MS m/z:511.0[M+H]+.
Step 6:The synthesis of compound AL_023
At room temperature, by compound AL_023-6 (40mg, 0.078mmol), BB-24 (51mg, 0.094mmol) is dissolved in DMF/
THF/H2O (2ml/2mL/2mL) in the mixed solvent adds in sodium carbonate (17mg, 0.157mmol) and Pd under nitrogen protection
(dppf)Cl2(4mg,0.005mmol).100 DEG C, when stirring 8 is small are heated under nitrogen protection, and TLC is detected after completion of the reaction
It is cooled to room temperature, filters, after filtrate is spin-dried for solvent, residue obtains target compound AL_023 through efficient liquid phase preparative separation
(white solid, 24mg, yield 36%).MS m/z:421.5[M/2+H]+.
Embodiment 21:AL_031
Synthetic route:
Step 1:The synthesis of compound AL_031-1
Compound AL_031-1 can be prepared according to step 5 in AL_023.LCMS m/z:526.8[M+H]+
Step 2:The synthesis of compound AL_031
Compound AL_031 can be prepared according to step 6 in AL_023.LCMS m/z:408.5[M/2+H]+
With reference to the synthetic method of step 6 in AL_023, compound in following table is synthesized:
Embodiment 26:AL_029
Synthetic route:
Step 1:The synthesis of compound AL_029
At room temperature, by compound AL_029-1 (100mg, 0.333mmol), BB-21 (364mg, 0.733mmol) is dissolved in
DMF/THF/H2O (1.5mL/1.5mL/1.5mL) in the mixed solvent, under nitrogen protection add in sodium carbonate (141.3mg,
1.33mmol) and Pd (dppf) Cl2(48.8mg,0.067mmol).100 DEG C are heated under nitrogen protection, are stirred overnight, TLC
Detection is cooled to room temperature after completion of the reaction, is filtered, after filtrate is spin-dried for solvent, residue obtains target through efficient liquid phase preparative separation
Compound AL_029 (yellow solid, 14.1mg, yield 4.8%).MS m/z:880.1[M+H]+.
Embodiment 27:AA_239
Synthetic route:
Step 1:The synthesis of compound AA_239-1
By compound AG_075-1 (2g, 5.92mmol), tributyl (1- ethoxy ethylenes base) tin (2.34g,
5.92mmol) with being dissolved in dioxane (20mL), nitrogen protection is lower to add in Pd (dppf) Cl2(870mg, 1.28mmol) and Pd
(PPh3)4(1370mg,1.28mmol).80 DEG C, when stirring 4 is small are warming up under nitrogen protection.TLC detections are cold after completion of the reaction
But arrive room temperature, add in water (8mL), then add in NBS (4.2g, 23.67mmol), be stirred at room temperature 12 it is small when.TLC detections have been reacted
Water (10mL) is added in after finishing, is then extracted with ethyl acetate (50ml × 3), solvent is removed under reduced pressure and obtains alpha-brominated ketone intermediate;
Without purifying, directly apply in next step.Above-mentioned alpha-brominated ketone intermediate and potassium carbonate (1.64g, 11.84mmol) are suspended in
In DMF (20mL), compound AA_192-2 (2.1g, 7.7mmol) is added at room temperature.Be stirred at room temperature 2 it is small when, TLC detection reaction
After add in water (10mL), with ethyl acetate (50mL × 3) extract, anhydrous sodium sulfate drying, filtering, filtrate decompression remove it is molten
Agent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) obtain target compound AA_239-1 (1.1g,
Two step yields 36.3%).LCMS m/z:575.1[M+H]+.
Step 2:The synthesis of compound AA_239-2
At room temperature, compound AA_239-1 (1g, 1.74mmol) is dissolved in toluene (100mL), add in ammonium acetate (1.34g,
17.4mmol).Reflux is warming up under nitrogen protection, and when stirring 12 is small, TLC detections are cooled to room temperature after completion of the reaction, are added in
Ethyl acetate (100mL) is washed with saturated salt solution (30mL × 3).Organic phase is dried with anhydrous sodium sulfate, and filtering, filtrate subtracts
Pressure removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) target compound AA_239- is obtained
2 (white solid, 0.45g, yields 46.3%).LCMS m/z:555.1[M+H]+.
Step 3:The synthesis of compound AA_239-3
At room temperature, by compound AA_239-2 (150mg, 0.27mmol), duplex pinacol borate (345mg,
Dioxane (10mL) 1.37mmol) is dissolved in, adds in potassium acetate (213mg, 2.17mmol) and Pd (dppf) under nitrogen protection
Cl2(40mg,0.054mmol).110 DEG C, when stirring 2 is small are heated under nitrogen protection, and TLC detections are cooled to after completion of the reaction
Room temperature, filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:1→1:4) mesh is obtained
Mark compound AA_239-3 (white solid, 115mg, yield 70.5%).LCMS m/z:601.1[M+H]+.
Step 4:The synthesis of compound AA_239
By compound AA_239-3 (30mg, 0.049mmol), compound BB-14 (23mg, 0.059mmol) is dissolved in tetrahydrochysene
Furans/glycol dimethyl ether/water (2mL/2mL/2mL) in the mixed solvent, under nitrogen protection add in sodium carbonate (11mg,
0.099mmol) and Pd (dppf) Cl2(5mg,0.0098mmol).100 DEG C, when reaction 8 is small are warming up under nitrogen protection, TLC
Detection is cooled to room temperature after completion of the reaction, is filtered, after filtrate is spin-dried for solvent, residue obtains target through efficient liquid phase preparative separation
Compound AA_239 (white solid, 8mg, yield 21.8%).LCMS m/z:384.2[M/2+H]+.
Embodiment 28:AA_238
Synthetic route:
Step 1:The synthesis of compound AA_238-1
By compound AG_075-1 (15g, 44.38mmol), 1,2- dithioglycol (5g, 53.26mmol) is dissolved in chloroform
BF is added dropwise in (10mL)3.Et2O(5.5ml,44.38mmol).Reflux is warming up under nitrogen protection, when stirring 2 is small, TLC detections
It is cooled to room temperature after completion of the reaction, adds in water (10mL) and reaction, chloroform (30mL × 3) extraction is quenched.Merge organic phase, use is anhydrous
Sodium sulphate is dried, and filtering, filtrate decompression removes solvent and obtains thioketal intermediate (white solid, 17.5g, yield 88.3%).
N- N-iodosuccinimides (NIS, 13.6g, 60.36mmol) are dissolved in dichloromethane (50mL), -78 DEG C are cooled to, in nitrogen
Protection is lower to add in pyridine hydrofluoride (3.6g, 36.22mmol).When stirring 1 is small at this temperature, add among above-mentioned thioketal
Dichloromethane (5ml) solution of body (5g, 12.07mmol), continue at -78 DEG C stirring 1 it is small when, TLC detect after completion of the reaction
It adds in water (10mL) and reaction is quenched, extracted with dichloromethane (50mL × 3).Merge organic phase, dried with anhydrous sodium sulfate, mistake
Filter, filtrate decompression remove solvent and obtain target compound AA_238-1 (brown liquid, 3.2g, yield 78.3%).1H NMR
(CDCl3,400MHz):δ7.75(m,2H),7.61(m,2H),7.40(m,2H).
Step 2:The synthesis of compound AA_238-2
By compound AA_238-1 (7.48g, 20.77mmol), tributyl (1- ethoxy ethylenes base) tin (7.5g,
It 20.77mmol) is dissolved in dioxane (100mL), nitrogen protection is lower to add in Pd (dppf) Cl2(3g, 4.15mmol) and Pd
(PPh3)4(4.8g,4.15mmol).80 DEG C, when stirring 4 is small are warming up under nitrogen protection.TLC detections cool down after completion of the reaction
To room temperature, add in water (20mL), then add in NBS (15g, 83.07mmol), be stirred at room temperature 12 it is small when.TLC detection reactions finish
Water (10mL) is added in afterwards, is then extracted with ethyl acetate (50ml × 3), and is removed under reduced pressure solvent and obtains alpha-brominated ketone intermediate;Nothing
It needs to purify, directly apply in next step.Above-mentioned alpha-brominated ketone intermediate and potassium carbonate (1.5g, 11.09mmol) are suspended in DMF
In (20mL), compound AA_192-2 (1.98g, 7.21mmol) is added at room temperature.Be stirred at room temperature 2 it is small when, TLC detection has reacted
Water (10mL) is added in after finishing, is extracted with ethyl acetate (50mL × 3), anhydrous sodium sulfate drying, filtering, filtrate decompression removes molten
Agent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) obtain target compound AA_238-2 (1.3g,
Two step yields 46.3%).LCMS m/z:596.8[M+H]+.
Step 3:The synthesis of compound AA_238-3
At room temperature, compound AA_238-2 (2.1g, 4.45mmol) is dissolved in toluene (100mL), adds in ammonium acetate
(3.42g,44.5mmol).Reflux is warming up under nitrogen protection, and when stirring 12 is small, TLC detections are cooled to room after completion of the reaction
Temperature adds in ethyl acetate (100mL), is washed with saturated salt solution (30mL × 3).Organic phase is dried with anhydrous sodium sulfate, filtering,
Filtrate decompression removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) target compound is obtained
AA_238-3 (white solid, 1.3g, yield 62.3%).LCMS m/z:577.1[M+H]+.
Step 4:The synthesis of compound AA_238-4
At room temperature, by compound AA_238-3 (150mg, 0.26mmol), duplex pinacol borate (331mg,
Dioxane (10mL) 1.13mmol) is dissolved in, adds in potassium acetate (205mg, 2.09mmol) and Pd (dppf) under nitrogen protection
Cl2(40mg,0.052mmol).110 DEG C, when stirring 2 is small are heated under nitrogen protection, and TLC detections are cooled to after completion of the reaction
Room temperature, filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→1:4) mesh is obtained
Mark compound AA_238-4 (white solid, 105mg, yield 66%).LCMS m/z:623.3[M+H]+.
Step 5:The synthesis of compound AA_238
Compound AA_238-4 (20mg, 0.032mmol), compound BB-14 (15mg, 0.039mmol) are dissolved in tetrahydrochysene
Furans/glycol dimethyl ether/water (2mL/2mL/2mL) in the mixed solvent, under nitrogen protection add in sodium carbonate (9mg,
0.064mmol) and Pd (dppf) Cl2(5mg,0.0064mmol).100 DEG C, when reaction 8 is small are warming up under nitrogen protection, TLC
Detection is cooled to room temperature after completion of the reaction, is filtered, after filtrate is spin-dried for solvent, residue obtains target through efficient liquid phase preparative separation
Compound AA_238 (white solid, 8.2mg, yield 27.8%).LCMS m/z:395.2[M/2+H]+.
Embodiment 29:AA_241_A and AA_241_B
Synthetic route:
Step 1:The synthesis of compound AA_241-1
Compound AG_075-1 (1g, 2.96mmol) is dissolved in toluene (10mL), 0 DEG C is cooled to, drips under nitrogen protection
Add trimethyl aluminium (5.92ml, 11.83mmol).Be stirred at room temperature 1 it is small when, TLC detections are cooled to 0 DEG C after completion of the reaction, add in water
Reaction, dichloromethane (50mL × 3) extraction is quenched in (10mL).Merge organic phase, dried with anhydrous sodium sulfate, filtered, filtrate rotation
After dry solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) target compound AA_241-1 is obtained
(yellow liquid, 0.82g, yield 82.3%).1H NMR(CDCl3,400MHz):δ7.68(m,2H),7.49(m,4H),1.719
(s,3H).
Step 2:The synthesis of compound AA_241-2
By compound AA_241-1 (1g, 2.84mmol), tributyl (1- ethoxy ethylenes base) tin (1.03g,
It 2.84mmol) is dissolved in dioxane (20mL), nitrogen protection is lower to add in Pd (dppf) Cl2(417mg, 0.57mmol) and Pd
(PPh3)4(657mg,0.57mmol).80 DEG C, when stirring 4 is small are warming up under nitrogen protection.TLC detections cool down after completion of the reaction
To room temperature, add in water (4mL), then add in NBS (2g, 11.36mmol), be stirred at room temperature 12 it is small when.TLC is detected after completion of the reaction
Water (10mL) is added in, is then extracted with ethyl acetate (50ml × 3), is removed under reduced pressure solvent and obtains alpha-brominated ketone intermediate;It need not
Purifying directly applies in next step.Above-mentioned alpha-brominated ketone intermediate and potassium carbonate (0.78g, 5.68mmol) are suspended in DMF
In (20mL), compound AA_192-2 (1.01g, 3.69mmol) is added at room temperature.Be stirred at room temperature 2 it is small when, TLC detection has reacted
Water (10mL) is added in after finishing, is extracted with ethyl acetate (50mL × 3), anhydrous sodium sulfate drying, filtering, filtrate decompression removes molten
Agent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) obtaining target compound AA_241-2, (yellow is solid
Body, 0.65g, two step yields 40.3%).LCMS m/z:591.1[M+H]+.
Step 3:The synthesis of compound AA_241-3
At room temperature, compound AA_241-2 (650mg, 1.11mmol) is dissolved in toluene (100mL), adds in ammonium acetate
(853mg,11.1mmol).Reflux is warming up under nitrogen protection, and when stirring 12 is small, TLC detections are cooled to room after completion of the reaction
Temperature adds in ethyl acetate (100mL), is washed with saturated salt solution (30mL × 3).Organic phase is dried with anhydrous sodium sulfate, filtering,
Filtrate decompression removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→1:4) target compound is obtained
AA_241-3 (white solid, 320mg, yield 52.3%).LCMS m/z:571.1[M+H]+.
Step 4:The synthesis of compound AA_241-4
At room temperature, by compound AA_241-3 (120mg, 0.21mmol), duplex pinacol borate (269mg,
Dioxane (10mL) 1.06mmol) is dissolved in, adds in potassium acetate (166mg, 1.69mmol) and Pd (dppf) under nitrogen protection
Cl2(36mg,0.044mmol).110 DEG C, when stirring 2 is small are heated under nitrogen protection, and TLC detections are cooled to after completion of the reaction
Room temperature, filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=2:1→1:4) mesh is obtained
Mark compound AA_241-4 (white solid, 85mg, yield 66%).LCMS m/z:617.2[M+H]+.
Step 5:The synthesis of compound AA_241_A and AA_241_B
Compound AA_241-4 (70mg, 0.114mmol), compound BB-14 (213mg, 0.568mmol) are dissolved in tetrahydrochysene
Furans/glycol dimethyl ether/water (2mL/2mL/2mL) in the mixed solvent, under nitrogen protection add in sodium carbonate (97mg,
0.911mmol) and Pd (dppf) Cl2(15mg,0.023mmol).100 DEG C, when reaction 8 is small are warming up under nitrogen protection, TLC
Detection is cooled to room temperature after completion of the reaction, is filtered, and after filtrate is spin-dried for solvent, residue is prepared through efficient liquid phase (table 3, method 6)
Isolated target compound AA_241_A (white solid, 7mg) and AA_241_B (white solid, 7mg), yield 17.8%.
AA_241_A:LCMS m/z:384.1[M/2+H]+.AA_241_A:LCMS m/z:384.1[M/2+H]+.
Embodiment 30:AG_075
Synthetic route:
Step 1:The synthesis of compound AG_075
At room temperature, by 2,7-, bis- bromo- 9-Fluorenones (AG_075-1,0.2g, 0.59mmol), duplex pinacol borate
(0.6g, 2.37mmol) is dissolved in dioxane (10mL), adds in potassium acetate (350mg, 3.55mmol) and Pd under nitrogen protection
(dppf)Cl2(100mg,0.12mmol).110 DEG C, when reaction 2 is small are warming up under nitrogen protection, and TLC is detected after completion of the reaction
It is cooled to room temperature, filters, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→1:4)
Obtain white solid (0.198g, yield 77.3%).By above-mentioned white solid (30mg, 0.069mmol), compound BB-14
(78mg, 0.208mmol) is dissolved in tetrahydrofuran/glycol dimethyl ether/water (2mL/2mL/2mL) in the mixed solvent, is protected in nitrogen
Shield is lower to add in sodium carbonate (37mg, 0.35mmol) and Pd (dppf) Cl2(10mg,0.014mmol).It is warming up under nitrogen protection
100 DEG C, when reaction 8 is small, TLC detections are cooled to room temperature after completion of the reaction, are filtered, and after filtrate is spin-dried for solvent, residue is through efficient
Liquid phase (table 3, method 6) preparative separation obtains target compound AG_075 (white solid, 14mg, yield 26.4%).LCMS m/
z 83.4[M/2+H]+.
Embodiment 31:AG_082_A and AG_082_B
Synthetic route:
Step 1:The synthesis of AG_082-2
9,10- dihydro phenanthrenes (AG_082-1,5g, 27.74mmol) are dissolved in dichloromethane (50mL), add in iron powder (78mg,
1.39mmol).0 DEG C is cooled to, bromine (9.8g, 61.03mmol) is added dropwise.Be stirred at room temperature 8 it is small when, TLC detect after completion of the reaction
It adds in water (10mL) and reaction, dichloromethane (50mL × 3) extraction is quenched.Merge organic phase, dried with anhydrous sodium sulfate, filtered,
Filtrate decompression removes solvent, and residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→3:2) target AG_082- is obtained
2 (white solid, 6.2g, yields 65.9%).NMR(CDCl3,400MHz):δ7.59-7.57(m,2H),7.46-7.41(m,
4H),2.88-2.86(m,4H).
Step 2:The synthesis of compound AG_082_A and AG_082_B
At room temperature, by compound AG_082-2 (0.2g, 0.59mmol), duplex pinacol borate (0.6g,
Dioxane (10mL) 2.37mmol) is dissolved in, adds in potassium acetate (350mg, 3.55mmol) and Pd (dppf) under nitrogen protection
Cl2(100mg,0.12mmol).110 DEG C, when reaction 2 is small are warming up under nitrogen protection, and TLC detections are cooled to after completion of the reaction
Room temperature, filtering, after filtrate is spin-dried for solvent, residue is through silica gel column chromatography (petrol ether/ethyl acetate=9:1→1:4) obtain white
Color solid (0.198g, yield 77.34%).By above-mentioned white solid (40mg, 0.093mmol), compound BB-14 (104mg,
Tetrahydrofuran/glycol dimethyl ether/water (2mL/2mL/2mL) in the mixed solvent 0.278mmol) is dissolved in, is added under nitrogen protection
Enter sodium carbonate (59mg, 0.56mmol) and Pd (dppf) Cl2(15mg,0.018mmol).100 DEG C are warming up under nitrogen protection,
React 8 it is small when, TLC detection be cooled to room temperature after completion of the reaction, filter, after filtrate is spin-dried for solvent, residue is through efficient liquid phase system
Standby isolated target compound AG_082_A (white solid, 7mg) and AG_082_B (white solid, 7mg), yield
20.8%.AG_082_A:LCMS m/z:383.4[M/2+H]+.AG_082_B:LCMS m/z:383.4[M/2+H]+.
Experimental example 1:In-vitro evaluation
Experiment purpose:
Surely turn replicon (replicon) raji cell assay Raji HCV-Ab IgG with HCV genotype 1a (HCV-1a) and 1b (HCV-1b)
Close the EC of object50And CC50Value.Genotype 1a replicons source is cloned for H77, contains K1691R, K2040R and S2204I adaptability
Mutation.Genotype 1b replicons source is cloned for Con1, contains E1202G, T1280I and K1846T adaptive mutations.
Background introduction:
HCV 1a (HCV-1a) contain related HCV gene hypotypes to 1b (HCV-1b) genotype subgenomic replicon system
Nonstructural protein gene, G418 resistant genes NEO and luciferase gene so that HCV GAP-associated protein GAPs and luciferase can be thin
Stablize expression in born of the same parents.The height of the levels of replication of HCV replicons can be determined by the expression height for detecting luciferase gene.
Therefore, model of the system as in-vitro screening HCV-Ab IgG compound activity.
Experiment material:
HCV replicon cells system:HCV-1a and HCV-1b cells.
Cell culture fluid:DMEM (Invitrogen, Cat.#11960077) culture solution, add 10% hyclone (FBS,
Sigma, Cat.#12003C) and 1% dual anti-(penicillin 5000IU/mL, streptomysin 10mg/mL, Hyclone, Cat.#
SV30010)。
Pancreatin (Invitrogen, Cat.#25200072).
PBS(Invitrogen,Cat.#10010023)。
Trypan blue (Invitrogen, Cat.#15250061).
Cell Titer-fluor(Promega,Cat.#G6082)。
Bright-Glo(Promega,Cat.#E2650)。
CO2Incubator, Thermo 240I.
Multidrop automatic liquid separation devices, Thermo.
The full-automatic microwell plate pretreatment systems of POD 810Plate Assembler, Labcyte.
Scepter Handheld Automated Cell Counter hand-held automatic cell counters,
Millipore。
Microplate Spectrophotometer microplate spectrophotometers, Molecular Device.
Experimental procedure and method:
A) compound solution is prepared, dilutes and is loaded:
Compound pulvis is dissolved in 100%DMSO.Then to compound with 5 times of dilutions, 6 points, with Echo sound wave liquid reliefs
Equipment (Echo liquid handler) is added in cell plates.Ensure DMSO final concentration of 0.5%.Each compound is done double multiple
Hole.Highest initial concentration is 100,10 or 1nM, and 5 times dilute, 6 points.
B) cell culture (HCV-1a or HCV-1b replicon cells):
1) culture supernatant of cell culture is sopped up, cell is washed with 10mL PBS.
2) preheated pancreatin is added in into washed Tissue Culture Flask, and rotating and culturing bottle makes pancreatin uniform fold blake bottle
Bottom.37 DEG C are put into, 5%CO2It is digested in incubator.
3) each T150 blake bottles 10-15mL culture solution suspension cells draw 0.1mL and dilute 2 times with trypan blue solution
It counts.
4) with culture solution diluting cells to 8 × 104/ mL will be diluted with automatic liquid separation device (Thermo Scientific)
Cell be added to 96 orifice plates (Greiner, Cat.#655090) (100 μ L/ holes, 8000cells/ holes) containing compound.It is placed in
37 DEG C, 5%CO2Incubator culture 3 days.
Cell control well:Compound is not added with, containing only 0.5%DMSO.
5) plus chemical luminous substrate Cell Titer-fluor are to cell hole, with chemiluminescence detection system after being incubated 30 minutes
The Envison (Ex at 405nm and read at 515nm) that unites detects signal.According to light-emitting data analysis of compounds to HCV
The influence of replicon cell activity, and for calculating CC50Value.
6) and then luciferase luminous substrate Bright-Glo is added, temperature is incubated uses chemiluminescence detection system after five minutes
Envison detects (wavelength
>700nm) uciferase activity;According to the HCV-Ab IgG inhibitory activity of luciferase data analysis of compounds and based on
Calculate EC50Value.C) data processing and analysis:
Non linear fit analysis is carried out using GraphPad Prism softwares to suppression percentage (inh ﹪) data to obtain
EC50Or CC50Value.Experimental result is shown in Table 1:
Table 1HCV replicon cells EC50/CC50Test result
Note:EC50Show the activity of the external anti-hepatitis C virus of molecule, EC50Have less than 1uM, that is, representation compound external
Activity.Size according to activity has divided four sections:A (0.001nM~0.1nM);B (0.101nM~1.0nM);C
(1.001nM~10.0nM);D (10.001nM~100nM).CC50Numerical value show molecule in vitro toxicity size, numerical value gets over
Big toxicity is smaller.
Conclusion:The compounds of this invention has excellent external anti-hepatitis C virus activity.
Claims (4)
1. following formula: compound or its pharmaceutically acceptable salt, are selected from:
2. compound according to claim 1 or its pharmaceutically acceptable salt, wherein the structure with chiral centre is deposited
In following variant:It is arbitrary on the premise of its chiral centre is located at other sites and its number can stablize realization in chemistry;
Alternatively, its also there is other chiral centres and its number can stablize realization in chemistry on the premise of be arbitrary;Alternatively, it is not
With chiral centre.
3. a kind of pharmaceutical composition, compound according to claim 1 including therapeutically effective amount or its can pharmaceutically connect
The salt and pharmaceutically acceptable carrier received.
4. compound according to claim 1 or its pharmaceutically acceptable salt or drug according to claim 2
Application of the composition in the drug for preparing treatment HCV.
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CN111732570B (en) * | 2020-07-06 | 2022-11-29 | 湖北工程学院 | Imidazolidinone with antiviral activity, and synthetic method and application thereof |
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