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CN109535200A - A kind of phosphoramidate prodrug, pharmaceutical composition and its application of nucleoside analog - Google Patents

A kind of phosphoramidate prodrug, pharmaceutical composition and its application of nucleoside analog Download PDF

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Publication number
CN109535200A
CN109535200A CN201710857431.3A CN201710857431A CN109535200A CN 109535200 A CN109535200 A CN 109535200A CN 201710857431 A CN201710857431 A CN 201710857431A CN 109535200 A CN109535200 A CN 109535200A
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methyl
acid
white solid
added
substituted
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Inventor
周星露
刘兴国
胡苗
董晓武
黄文海
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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HANGZHOU HERTZ PHARMACEUTICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of phosphoramidate prodrug of nucleoside analog or its stereoisomers or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate, in the application that preparation is independent or is used in combination in the drug of prevention or treatment hepatitis type B virus (HBV) and/or human immunodeficiency virus (HIV) infection with other drugs.Compound Anti-HBV effect of the present invention and fumaric acid tenofovir Chinese mugwort draw phenol amine (TAF) quite, also have both effect of anti hepatic fibrosis, can assist the therapeutic effect for improving sufferer, and safety is good, has important clinical meaning.

Description

A kind of phosphoramidate prodrug, pharmaceutical composition and its application of nucleoside analog
Technical field
The invention belongs to the antiviral field of medical chemistry, it is related to a kind of nucleoside analog phosphoramidate prodrug, pharmaceutical composition Object and its application in the drug for preventing or treating hepatitis type B virus and/or HIV infection.
Background technique
Virus B hepatitis be by caused by hepatitis type B virus (hepatitis B virus, hereinafter referred to as HBV), Using liver as target organ and infectious disease that a variety of organ injuries can be caused, that main menses are propagated.It is hepatitis b virus infected to be One of maximum infectious diseases is threatened in the world, and global 2,000,000,000 people infected HBV, and there are about 400,000,000 Patients with Chronic HBV Infection.China Belong to the high Endemic Area of HBV infection, according to statistics, there are about 1,200,000,000 hepatitis B virus surface antigens (HBsAg) carrier, hepatitis B is total in China Infection rate is up to 60%, and hepatopathy caused by HBV infection and complication not only cause to seriously affect to patient health, return it is personal and Country brings heavy financial burden.Currently, clinically for the therapeutic agent of hepatitis B based on nucleoside compound, Including Lamivudine, Aldoforwe ester, Entecavir, tenofovir dipivoxil etc., can by influence virus nucleic acid chains, The synthesis of hepatitis B is influenced to suppress the duplication of virus, but so that the surface antigen of HBV is turned out cloudy, so ucleosides Drug needs to take for a long time, easily causes kidney injury and bone-loss, and influences the quality of life even life security of sufferer.
Tenofovir (Tenofovir, PMPA, TFV) is a kind of novel nucleoside acids reverse transcriptase inhibitor, can be effectively right Resist a variety of viruses, for treating disease of viral infection, especially HBV and HIV, but the highly acid of TFV and highly polar causes It is difficult to so bioavilability is poor, and also have certain toxicity to sclerotin through cell membrane.
Structure of modification usually is carried out using phosphate portion of the principle of pro-drug to TFV, to improve its physicochemical property or internal medicine For kinetic property, oral administration biaavailability is improved.Wherein tenofovir dipivoxil (Tenofovir disoproxil Fumarate, TDF) be Ji Leadd B.V, the U.S. exploitation TFV dibasic acid esters prodrug fumarate, it is beautiful in 2001 and 2008 Food and medicine Surveillance Authority, state (FDA) approval is used for the first-line treatment of HIV and HBV infection.The Cell permeable of TDF and oral Bioavilability increases compared with TFV, but is easy to be hydrolyzed to TFV in blood plasma, and may to the patient of renal function defect Cause renal toxicity.Therefore, the said firm develops tenofovir Chinese mugwort again and draws half fumaric acid of phenol amine (Tenofovir alafenamide Fumarate, TAF), two compound Genvoya and Odefsey of TAF are used for HIV by FDA approval respectively at 2015 and 2016 The first-line treatment of infection, and TAF is then used for the treatment of HBV in approval in 2016.The plasma stability of TAF is better than TDF, blood plasma The TFV concentration ratio TDF low 90% of middle metabolism.In addition, the prodrug strategies that TAF takes dramatically increase its hepatic targeting, so TAF Quantity have dropped 10 times compared with TDF, have very high Anti-HBV activity and HIV activity while improve safety, make its kidney damage The side effect of wound and bone-loss is remarkably decreased, and clinically drug resistance incidence is extremely low, and can take for a long time.But TAF is turning Still there is a small amount of hydrolysis during fortune in blood plasma, clinically there is still a need for its plasma stability is further improved, improves drug in group Concentration in knitting, and then the side effects such as clinical dosage, injury of kidney and bone-loss for reducing drug, preferably play treatment HBV With the clinical effectiveness of HIV.
Times Si Fuwei (Besifovir) also belongs to antiviral nucleoside analogs, is currently in the clinical III phase, disease-resistant Cytotoxic activity is strong, and effect and entecavir grace are quite also not easy drug resistance, and have remarkable result, while kidney to the drug resistant patient of Lamivudine Toxicity is remarkably decreased compared with TDF, therefore Besifovir is expected to antiviral (the especially HBV or HIV) drug as a new generation.But The drug is as TDF, and phosphodiester group metabolism is very fast, and hepatic targeting is poor.In addition to this, Besifovir there is also Consume the side effect of body L-carnitine, it is therefore necessary to which the new prodrug for developing Besifovir keeps it from the advantages such as drug resistance On the basis of, its antiviral activity and hepatic targeting are further enhanced, its side effect is reduced.
On the other hand, clinically liver fibrosis caused by the hepar damnification of hepatitis B sufferer so that caused by cirrhosis, liver failure Exhaust and the problems such as liver cancer it is equally very urgent, according to statistics, about 3% patient with chronic HBV's development is liver fibrosis or liver every year Hardening, there are about 250,000 people to die of cirrhosis related with hepatitis B and liver cancer every year.For this clinical problem, lack all the time Effective means.Therefore, the nucleoside medicine with Liver targeting effect is treating HBV simultaneously, also has both anti-fibrosis effect, into And improve the liver fibrosis of sufferer or delay the process of cirrhosis, there is important clinical meaning.
Summary of the invention
The present invention provides phosphoramidate prodrug, pharmaceutical composition and its applications of a kind of nucleoside analog.
Inventor is by Rational drug design and structure optimization, in conjunction with actual clinical demand, takes charge of with tenofovir or again Fu Wei is that structural unit carries out structure optimization, ends with reference to fumaric acid tenofovir and draws the Liver targeting strategy of phenol amine (TAF), and combines Anti-fibrosis Rapid screening techniques are successfully realized the goal in research of Liver targeting and difunctionalization, discovery during structure optimization The phosphoramidate prodrug of the nucleoside analog of brand news a series of.These compounds resist compared with TAF, Besifovir HBV activity quite, also has both effect of anti hepatic fibrosis, can assist the therapeutic effect for improving sufferer, and safety is good, has important Clinical meaning.
The present invention relates to a kind of phosphoramidate prodrug of nucleoside analog or its stereoisomer or its stereoisomer are mixed Object or its pharmaceutically acceptable salt or solvate are closed, there is general formula I:
Wherein:
(1)R1、R1' it is respectively and independently selected from H, NH2Or OH, and at least one is NH2；
(2)R2、R3It is independently selected from H ,-CH3、-CH2CH3、-CH2CH2CH3、CH(CH3)2Or R2、R3With connected carbon atom shape At C3-7Naphthenic base；
(3)R4Selected from H, C1-6Alkyl, C3-6Naphthenic base, C3-6Oxacycloalkyl, C3-6Alkoxyalkyl, or replace or non-take The C in generation6-10Aryl, 6 to 10 unit's heteroaryls or benzyl；
(4) X is selected from O, NH or S；
(5)Y1、Y2、Y3、Y4It is independently selected from CR5Or N；
(6)R5It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、- CF2H, cyano, nitro, hydroxyl, amino, Methanesulfomide, sulfonamide or substituted or non-substituted urea or substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls；
(7)Z1、Z2、Z3、Z4It is independently selected from CR6Or N, wherein Z1、Z2、Z3、Z4At most having one is N；Z1And Z2Can individually at Ring A, ring A are 5 to 7 substituted or non-substituted member rings；
(8)R6It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、- CF2H, cyano, nitro, hydroxyl, amino, substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls；
(9) Q is selected from O or S.
Further, the present invention relates to a kind of phosphoramidate prodrugs or its stereoisomer or its stereoisomer to mix Object or its pharmaceutically acceptable salt or solvate, the structure with general formula II and II ':
Wherein, R2、R3、R4、X、Y1、Y2、Y3、Y4、Z1、Z2、Z3、Z4, Q substituent group define it is fixed with the substituent group in general formula I Justice is identical.
Further, the present invention relates to a kind of phosphoramidate prodrugs or its stereoisomer or its stereoisomer to mix Object or its pharmaceutically acceptable salt or solvate, the structure with general formula III and III ':
Wherein:
(1)R2、R3、R4, X substituent group define defined with the substituent group in general formula I it is identical；
(2)Y1、Y3、Y4It is independently selected from C, CH or N；
(3)R5It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、- CF2H, cyano, nitro, hydroxyl, amino, Methanesulfomide, sulfonamide or substituted or non-substituted urea or substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls, wherein n is substituent group number, n 1,2,3 or 4；Work as Y1、Y3、Y4In one or more When for C, at least one R5Replace at the C；
(4)Z1、Z2、Z3、Z4And the substituent group of Q define defined with the substituent group in general formula I it is identical.
Further, the present invention relates to a kind of phosphoramidate prodrugs or its stereoisomer or its stereoisomer to mix Object or its pharmaceutically acceptable salt or solvate, the structure with general formula IV and IV ':
Wherein:
(1)R2、R3、R4, X substituent group define defined with the substituent group in general formula I it is identical；
(2)Y1、Y3、Y4、R5, n substituent group definition and general formula III and III ' in substituent group define it is identical；
(3)Z1It is independently selected from C, CH or N；
(4)R6It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、- CF2H, cyano, nitro, hydroxyl, amino, substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls, wherein m is substituent group Number is 1,2,3 or 4；Need to illustrate when, in the technical scheme, R6Also illustrating that can be in Z1Upper substitution.
Further, the present invention relates to a kind of phosphoramidate prodrugs or its stereoisomer or its stereoisomer to mix Object or its pharmaceutically acceptable salt or solvate, the structure with general formula V and V ':
Wherein:
(l)R2、R3、R4, X substituent group define defined with the substituent group in general formula 1 it is identical；
(2)Y1、Y3、Y4、R5, n substituent group definition and general formula III and III ' in substituent group define it is identical；
(3)Z1、R6, m substituent group definition defined with the substituent group in general formula IV and IV ' it is identical.
The present invention relates to a kind of phosphoramidate prodrug or its stereoisomer or its stereoisomer mixture or its pharmacy Upper acceptable salt or solvate, the pharmaceutically acceptable salt have the structure of general formula V and V ':
Wherein:
(l)R2、R3、R4, X substituent group define defined with the substituent group in general formula 1 it is identical；
(2)Y1、Y3、Y4、R5, n substituent group definition and general formula III and III ' in substituent group define it is identical；
(3)Z1、R6, m substituent group definition defined with the substituent group in general formula IV and IV ' it is identical
(4) acid is independently selected from phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, amber Acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, Loprazolam；Acid and nucleoside phosphoramidite ester mole The range of ratio is 0.5 to 2；Here nucleoside phosphoramidite ester refers to the main part in general formula V and V ' in addition to acid.
A kind of phosphoramidate prodrug of the present invention or its stereoisomer or its stereoisomer mixture or its medicine Acceptable salt or solvate on, phosphorus atoms have chirality, and configuration is S- configuration or R- configuration or S- configuration and R- The mixture of configuration；Work as R2、R3When different, also there is chirality with its connected carbon atom, configuration is S- configuration or R- configuration, or The mixture of person S- configuration and R- configuration.
It is further, excellent according to the structure of general formula I, II and II', III and III ', VI and VI ', V and V ', IV and IV ' It is selected as compound in detail below:
And the stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or molten of above compound Object is closed in agent.Preferably, the compound are as follows:
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (5- methyl - 2- oxy picolinate -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 20a-1
Isopropyl ((R)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (5- methyl - 2- oxy picolinate -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 20a-2
Butyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (5- methyl -2- Oxy picolinate -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 20b
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (fluoro- 4- (5- of 2- - 1 (2H)-yl of methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 21a-1
Isopropyl ((R)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (fluoro- 4- (5- of 2- - 1 (2H)-yl of methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 21a-2
Butyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (2- fluoro- 4- (5- first - 1 (2H)-yl of base -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 21b
Cyclohexyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (fluoro- 4- (5- of 2- - 1 (2H)-yl of methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 21c
Benzyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (2- fluoro- 4- (5- first - 1 (2H)-yl of base -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 21d
Tetrahydrofuran -3- base ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (2- Fluoro- 4- (- 1 (2H)-yl of 5- methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 21e
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (fluoro- 4- (5- of 3- - 1 (2H)-yl of methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 22a
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (2- methyl -4- (- 1 (2H)-yl of 5- methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 22b
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (5- methyl - 2- oxy picolinate -1 (2H)-yl) -2- (trifluoromethyl) phenoxy group) phosphoryl)-l-Alanine ester 22c
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (chloro- 4- (5- of 2- - 1 (2H)-yl of methyl -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 22d
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2- oxygen pyrrole Pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 23a
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (4,6- diformazan - 1 (2H)-yl of base -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 23b
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (4,5- diformazan - 1 (2H)-yl of base -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 23c
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2- oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 23d
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 24a
Butyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 24b
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- fluorophenoxy) phosphoryl)-l-Alanine ester 25a
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- chlorophenoxy) phosphoryl)-l-Alanine ester 25b
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) ((5- methyl -2- Oxygen -2H- [1,3'- bipyridyl] -6'- base) oxygen) phosphoryl)-l-Alanine ester 26a
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) ((5- methyl -2- Oxygen -2H- [1,2'- bipyridyl] -5'- base) oxygen) phosphoryl)-l-Alanine ester 26b
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) ((5- methyl -2- Oxy picolinate -1 (2H)-yl) pyrimidine -2-base) oxygen) phosphoryl)-l-Alanine ester 26c
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (oxygen -2 2-, 5,6,7- tetrahydrofuran -1H- cyclopenta [b] pyridine -1- base) phenoxy group) phosphoryl)-l-Alanine ester 27a
Isopropyl ((S)-((((R) -1- (6- amino -9H- purine -9- base) propyl- 2- yl) oxygen) methyl) (4- (2- oxygen quinoline Quinoline -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 27b
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (5- methyl -2- Oxy picolinate -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 28a
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (2- fluoro- 4- (5- first - 1 (2H)-yl of base -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 28b
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2- oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 29a
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (fluoro- 4- (2- of 2- Oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 29b
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (2- methyl -4- (2- Oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 29c
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) ((5- methyl -2- Oxygen -2H- [1,3'- bipyridyl] -6'- base) oxygen) phosphoryl)-l-Alanine ester 30a
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) ((5- methyl -2- Oxygen -2H- [1,2'- bipyridyl] -5'- base) oxygen) phosphoryl)-l-Alanine ester 30b
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 31a-1
Isopropyl ((R)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 31a-2
Isopropyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- fluorophenoxy) phosphoryl)-l-Alanine ester 32a
Cyclohexyl ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- fluorophenoxy) phosphoryl)-l-Alanine ester 32b
Tetrahydrofuran -3- base ((S)-((1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2, - 1 (6H)-yl of 4- dimethyl -6- oxygen pyrimidine) -2- fluorophenoxy) phosphoryl)-l-Alanine ester 32c
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (5- methyl -2- Oxy picolinate -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 33a
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (2- fluoro- 4- (5- first - 1 (2H)-yl of base -2- oxy picolinate) phenoxy group) phosphoryl)-l-Alanine ester 33b
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2- oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 34a
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (fluoro- 4- (2- of 2- Oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 34b
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (2- methyl -4- (2- Oxygen -5- (trifluoromethyl) pyridine -1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 34c
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) ((5- methyl -2- Oxygen -2H- [1,3'- bipyridyl] -6'- base) oxygen) phosphoryl)-l-Alanine ester 35a
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) ((5- methyl -2- Oxygen -2H- [1,2'- bipyridyl] -5'- base) oxygen) phosphoryl)-l-Alanine ester 35b
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) ((5- (5- methyl - 2- oxy picolinate -1 (2H)-yl) pyrimidine -2-base) oxygen) phosphoryl)-l-Alanine ester 35c
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 36a-1
Isopropyl ((R)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 36a-2
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (chloro- 4- (2,4- of 2- - 1 (6H)-yl of dimethyl -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 37a-1
Isopropyl ((R)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (chloro- 4- (2,4- of 2- - 1 (6H)-yl of dimethyl -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 37a-2
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- fluorophenoxy) phosphoryl)-l-Alanine ester 37b
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- methylphenoxy) phosphoryl)-l-Alanine ester 37c
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2,4- diformazan - 1 (6H)-yl of base -6- oxygen pyrimidine) -2- 4-trifluoromethylphenopendant) phosphoryl)-l-Alanine ester 37d
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (chloro- 4- (2,4- of 3- - 1 (6H)-yl of dimethyl -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 37e
Butyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (the chloro- 4- of 2- (2,4- bis- - 1 (6H)-yl of methyl -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 38a
Cyclohexyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (chloro- 4- (2,4- of 2- - 1 (6H)-yl of dimethyl -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 38b
((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (2- is chloro- for tetrahydrofuran -3- base 4- (- 1 (6H)-yl of 2,4- dimethyl -6- oxygen pyrimidine) phenoxy group) phosphoryl)-l-Alanine ester 38c
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (oxygen -2,5 2-, 6,7- tetrahydro -1H- cyclopenta [b] pyridine -1- base) phenoxy group) phosphoryl)-l-Alanine ester 39a
Isopropyl ((S)-((1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup) methyl) (4- (2- oxygen quinoline - 1 (2H)-yl) phenoxy group) phosphoryl)-l-Alanine ester 39b
And the stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or molten of above formula compound Object is closed in agent.
Term explanation:
" the C3-7Naphthenic base " refers to the group of the aliphatic hydrocarbon containing saturated cyclic of 3 to 7 carbon atoms, is selected from cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, 2- methylcyclopropyl groups, 2- ethyl cyclopropyl, 2- isopropyl cyclopropyl, 2- butyl cyclopropyl Base, 2- isobutyl cyclopropyl, 2- tert-butyl cyclopropyl, 2- methyl-cyclobutyl, 3- methyl-cyclobutyl, 2- ethylcyclobutyl, 3- second Tetramethylcyclobutyl, 2- propylcyclobutyl, 2- isopropyl tetramethylcyclobutyl, 3- isopropyl tetramethylcyclobutyl, 2,3- dimethylcyclopentyl, 2,4- diformazan Cyclopentyl, 2- methylcyclohexyl etc., preferably cyclopropyl, cyclobutyl, 2- methyl-cyclopropyl, 2- ethyl cyclopropyl；
" the C1-6Alkyl " refers to the linear chain or branched chain saturated fat hydrocarbyl group of 1 to 6 carbon atom, selected from methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, n-pentyl, isopentyl, tertiary pentyl, neopentyl, n-hexyl, isohesyl, Tertiary hexyl, new hexyl, 2- methyl butyl, 3- methyl butyl, 1- ethyl propyl, 2- methyl amyl, 1,3- dimethylbutyl, 2,3- Dimethylbutyl etc., preferably methyl, ethyl, isopropyl or normal-butyl；
" the C3-6Naphthenic base " refers to the group of the aliphatic hydrocarbon containing saturated cyclic of 3 to 6 carbon atoms, is selected from cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, 2- methylcyclopropyl groups, 2- ethyl cyclopropyl, 2- isopropyl cyclopropyl, 2- methyl-cyclobutyl, 3- methyl Cyclobutyl, 2- ethylcyclobutyl, 3- ethylcyclobutyl etc., preferably cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；
" the C3-6Alkoxyalkyl " refers to the group that the alkoxy containing 3 to 6 carbon atoms is connect with alkyl, preferablyDeng；
" the C3-6Oxacycloalkyl " refers to that one of carbon atom is taken by O in the naphthenic base being made of 4 to 7 carbon atoms Generation, preferablyDeng；
" the C1-3Alkoxy " refers to the group connecting containing 1 to 3 carbon atom aliphatic saturated hydrocarbon with oxygen atom, is selected from methoxy Base, ethyoxyl, propoxyl group, isopropoxy etc., preferably methoxy or ethoxy；
" the substituted or non-substituted urea ", substituent group are selected from methyl, N, N- dimethyl, ethyl, N, N- diethyl, isopropyl Base etc.；
" the C6-10Aryl " refers to 6 to 10 yuan of full carbon monocycles or fused polycycle group with conjugated pi electron system, is selected from Phenyl, 1- naphthalene, 2- naphthalene etc.；" 6 to 10 unit's heteroaryl " refers in 6 yuan to 10 yuan of ring containing aerobic, sulphur or nitrogen heteroatom Miscellaneous monocycle with conjugated pi electron system or miscellaneous fused polycycle group, selected from pyridyl group, pyridazinyl, pyrimidine radicals, indyl, Benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolyl, purine radicals etc.；Substituted aryl and substitution Heterocyclic base on substituent group be selected from methyl, halogen ,-CF3、-CF2H, cyano, nitro, hydroxyl, amino or C1-3Alkoxy；
" 5 to 7 member ring " is selected from phenyl, 5-7 unit's heteroaryl, C5-7Carbocylic radical and 5-7 circle heterocyclic ring base, institute The compound stated, wherein the key being represented by solid and broken lines is double bond, preferably But work as Ring A isIt is singly-bound Deng, the key being represented by solid and broken lines；Substituent group Selected from methyl, halogen ,-CF3、-CF2H, cyano, nitro, hydroxyl, amino or C1-3Alkoxy；
" halogen " refers to fluorine, chlorine, bromine or iodine；
" n " is 1,2,3 or 4, preferably 1 or 2 or 3；
" m " is 1,2,3 or 4, preferably 1 or 2.
Term used herein " solvate " refers to by solute (such as: general formula I~compound of Formula IV of the invention) The compound of the varying chemical metering formed with solvent.For the purposes of the present invention, the solvent cannot interfere the biology of solute Learn activity.The example of suitable solvent includes but is not limited to water, methanol, ethyl alcohol and acetic acid.It is preferable to use solvent be pharmacy can Receive solvent.Suitable pharmaceutical acceptable solvents include but is not limited to water, ethyl alcohol and acetic acid.It is highly preferred that solvent for use is water.
The present invention also provides a kind of pharmaceutical compositions, phosphoramidate prodrug of the present invention containing dose therapeutically effective or Its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate.
According to another aspect of the invention, the present invention also provides phosphoramidate prodrug of the present invention or its solid are different Structure body or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate are preparing independent or and other drugs The application in the drug of prevention or treatment disease of viral infection, especially hepatitis type B virus (HBV) and/or people is used in combination Application in the drug of para-immunity defective virus (HIV) infection.
According to another aspect of the invention, the present invention also provides phosphoramidate prodrug of the present invention or its solid are different Structure body or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate or mixture are further controlled with other Treat the drug combination of hepatopathy.
Inventor experiments prove that, the compounds of this invention replicates suppression to the HBV-DNA of HepG2.2.15 cell System activity is suitable with TAF, can be applied to treatment hepatitis type B virus or the disease as caused by hepatitis type B virus.
Inventor experiments prove that, the compounds of this invention can inhibit TGF-β induce human liver microsome proteins The proliferation activity of LX-2 cell, has the function of anti-hepatic fibrosis.Compound provided by the invention be provided simultaneously with treatment hepatitis B and The effect for improving liver fibrosis/delay cirrhosis process, has the application prospect of difunctional drug.
Specific embodiment
Illustrate exploitativeness of the invention below by embodiment, it will be understood by those of skill in the art that according to existing There is the introduction of technology, corresponding technical characteristic is modified or replaced, the scope of protection of present invention is still fallen within.
The preparation of 1. intermediate 1a~1e of embodiment
Operating procedure: step 1: p bromophenol or substituted p bromophenol (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) is dissolved in 15mL dichloromethane solution, 2, the 3- dihydropyran (34.68mmol) of 3.2mL is then added dropwise, room temperature is stirred It after mixing reaction 1 hour, is washed respectively with 5% sodium hydroxide solution, saturated common salt, organic phase is dry, dense with anhydrous sodium sulfate Contract to obtain white solid, is directly used in and reacts in next step.
Step 2: the product (6.87mmol) of previous step, 5- methylpyridone (4.58mmol), anhydrous is added in DMF Potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C and react 5 hours, be cooled to room temperature, after filtering Collect filtrate, subtract and DMF be evaporated off, then ethyl acetate dissolve, be washed with water respectively, saturated common salt washing, it is organic be added to it is anhydrous Sodium sulphate is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid.
Intermediate 1a (R1=H): white solid, yield 54% (three steps),1H NMR(600MHz,CDCl3):δ7.37(dd, J=9Hz, 2.4Hz, 1H), 7.17 (s, 1H), 6.99 (d, J=8.4Hz, 2H), 6.70-6.65 (m, 3H), 2.13 (s, 3H) .ES-MS m/z:201(M+)。
Intermediate 1b (R1=2- fluorine): white solid, yield 50% (three steps),1H NMR(600MHz,d6-DMSO):δ 10.16 (s, 1H), 7.38 (s, 1H), 7.34 (dd, J=9.6Hz, 2.4Hz, 1H), 7.26-7.24 (m, 1H), 7.02-6.99 (m, 2H), 6.38 (d, J=9.6Hz, 1H), 2.02 (s, 3H)19F NMR(564.4MHz,d6-DMSO):δ-135.21(dd,J =11.3Hz, 7.3Hz, 1F) .ES-MS m/z:219 (M+)。
Intermediate 1c (R1=3- fluorine): white solid, yield 30% (three steps),1H NMR(600MHz,d6-DMSO):δ 10.18 (s, 1H), 7.37-7.33 (m, 2H), 7.19 (t, J=9.0Hz, 1H), 6.71-6.67 (m, 2H), 6.39 (d, J= 10.2Hz,1H),2.01(s,3H).19F NMR(564.4MHz,d6-DMSO):δ-119.88–-119.92(m,1F).ES-MS m/z:219(M+)。
Intermediate 1d (R1=2- methyl): white solid, yield 40% (three steps), ES-MS m/z:215 (M+)。
Intermediate 1e (R1=2- trifluoromethyl): white solid, yield 45% (three steps), ES-MS m/z:269 (M+)。
The preparation of 2. intermediate 1f of embodiment
Operating procedure: step 1: the chloro- phenol of the bromo- 2- of 4- (11.56mmol), potassium carbonate (17.34mmol), benzyl chloride (13.87mmol) is added in 15mL DMF, is reacted at room temperature 24 hours, and 200mL ethyl acetate is added in filtering, filtrate, is then divided It is not washed with 5% sodium hydroxide solution, water, saturated common salt, organic anhydrous sodium sulfate that is added to is dry, and concentration obtains yellow Concentrate is directly used in and reacts in next step.
Step 2: product (6.87mmol), the 5- methylpyridone (4.58mmol), carbonic acid of previous step are added in DMF Caesium (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C and react 10 hours, be cooled to room temperature, collect after filtering Filtrate subtracts and DMF is evaporated off, and then ethyl acetate dissolves, and is washed with water respectively, saturated common salt washing, organic to be added to anhydrous slufuric acid Sodium is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: the product (1.52mmol) of previous step is added in the anhydrous DCM of 40mL, ice salt bath is cooled to -10 DEG C, delays It is slow that Boron tribromide (6.08mmol) is added dropwise, it is reacted 1 hour for 0 DEG C after dropwise addition, then room temperature is reacted 1 hour again, is slowly dripped under ice bath Add water 40mL, separatory funnel liquid separation, water layer uses 20mL DCM to extract again, merges organic layer, and 10mL 10%NaHCO is added3It is molten Liquid has white precipitate generation at once, and filtering, filter cake is washed with 20mL DCM, then by filter cake decompressing and extracting.5mL is added in filter cake Methanol is adjusted to pH=6~7 with 10% hydrochloric acid and makes it dissolve, then be added 40mL DCM, respectively washing, saturated common salt washing, Anhydrous sodium sulfate is dry, and organic layer concentration is spin-dried for, after recrystallization white solid intermediate 1f, yield 44% (three steps),1H NMR (600MHz, d6-DMSO): δ 10.48 (s, 1H), 7.38 (s, 2H), 7.34 (dd, J=9.0Hz, 3.0Hz, 1H), 7.14 (dd, J=8.4Hz, 1.8Hz, 1H), 7.02 (d, J=8.4Hz, 1H), 6.37 (d, J=9.0Hz, 1H), 2.01 (s, 3H) .LC- ESI-MS:236[M+H]。
The preparation of 3. intermediate 2a~2c of embodiment
Operating procedure: step 1: p bromophenol (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) are dissolved in 15mL dichloro Then 2, the 3- dihydropyran (34.68mmol) of 3.2mL is added dropwise in dichloromethane, after reaction being stirred at room temperature 1 hour, respectively with 5% Sodium hydroxide solution, saturated common salt washing, organic phase anhydrous sodium sulfate is dry, is concentrated to give white solid, is directly used in down Single step reaction.
Step 2: product (6.87mmol), pyridone or the substituted pyridone of previous step are added in DMF (4.58mmol), Anhydrous potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture is heated to 140 DEG C and reacts 5 hours, cold But to room temperature, filtering and collecting filter liquid subtracts and DMF is evaporated off, and then ethyl acetate dissolves, and is washed with water respectively, saturated common salt washing, Organic anhydrous sodium sulfate that is added to is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid.
Intermediate 2a (R2=H): white solid, yield 55% (three steps), ES-MS m/z:187 (M+)。
Intermediate 2b (R2=4,6- dimethyl): white solid, yield 50% (three steps), ES-MS m/z:215 (M+)。
Intermediate 2c (R2=4,5- dimethyl): white solid, yield 45% (three steps), ES-MS m/z:215 (M+)。
The preparation of 4. intermediate 2d~2f of embodiment
Operating procedure: step 1: para hydroxybenzene boric acid or substituted para hydroxybenzene boric acid (11.56mmol), to toluene sulphur Sour (0.116mmol) is dissolved in 15mL dichloromethane solution, and 2, the 3- dihydropyran (34.68mmol) of 3.2mL, room temperature is then added dropwise It after being stirred to react 1 hour, is washed respectively with saturated sodium carbonate solution, saturated common salt, organic phase is dry with anhydrous sodium sulfate, is concentrated White solid is obtained, is directly used in and reacts in next step.
Step 2: the 5- trifluoromethyl pyridine -2 (1H)-that the product (9.16mmol) of previous step is added in methyl alcohol, replaces Ketone (4.58mmol), Et3N (18.32mmol) and Cu (OAC)2(0.458mmol), after heating reflux reaction 6 hours, reaction solution is dense Methylene chloride dissolution is added after contracting, is washed respectively with 5% sodium hydroxide solution, saturated common salt, organic phase anhydrous sodium sulfate is dry, Concentration is spin-dried for rear column purification and obtains white solid, for reacting in next step.
Step 3: the product (1.75mmol) and anhydrous AlCl of previous step are added in ethanol3(0.35mmol), is heated back After stream reaction 8 hours, reaction solution concentration is spin-dried for rear column purification and obtains white solid.
Intermediate 2d (R1=H), yield 25% (three steps),1H NMR(600MHz,d6-DMSO):δ9.81(s,1H),8.15 (s, 1H), 7.71 (dd, J=9.6Hz, 2.4Hz, 1H), 7.22 (d, J=8.4Hz, 2H), 6.84 (d, J=8.4Hz, 2H), 6.59 (d, J=10.2Hz, 1H)19F NMR(564.4MHz,d6-DMSO):δ-60.46(s,3F).LC-ESI-MS:256[M+ H]。
Intermediate 2e (R1=2- fluorine), yield 22% (three steps), LC-ESI-MS:274 [M+H].
Intermediate 2f (R1=2- methyl), yield 19% (three steps), LC-ESI-MS:270 [M+H].
The preparation of 5. intermediate 3a~3c of embodiment
Operating procedure: step 1: being added in methyl alcohol accordingly to methoxyphenylboronic acid or substituted to methoxybenzene boron Acid (9.16mmol), 2,6- dimethyl pyrimidine -4 (3H) -one (4.58mmol), Et3N (18.32mmol) and Cu (OAC)2 After heating reflux reaction 6 hours, methylene chloride dissolution is added, respectively with 5% hydroxide in (0.458mmol) after reaction solution concentration Sodium solution, saturated common salt washing, organic phase anhydrous sodium sulfate is dry, and concentration is spin-dried for rear column purification and obtains white solid, is used for down Single step reaction.
Step 2: the product (1.52mmol) of previous step is added in the anhydrous DCM of 40mL, ice salt bath is cooled to -10 DEG C, delays It is slow that Boron tribromide (6.08mmol) is added dropwise, it is reacted 2 hours for 0 DEG C after dropwise addition, then room temperature is reacted 2 hours again, is slowly dripped under ice bath Add water 40mL, separatory funnel liquid separation, water layer uses 20mL DCM to extract again, merges organic layer, and 10mL 10%NaHCO is added3It is molten Liquid has white precipitate generation at once, and filtering, filter cake is washed with 20mL DCM, then by filter cake decompressing and extracting.5mL is added in filter cake Methanol is adjusted to pH=6~7 with 10% hydrochloric acid and makes it dissolve, then be added 40mL DCM, respectively washing, saturated common salt washing, Anhydrous sodium sulfate is dry, and organic layer concentration is spin-dried for, and white solid is obtained after recrystallization.
Intermediate 3a (R1=H): white solid, yield 21% (three steps),1H NMR(600MHz,d6-DMSO):δ9.78 (s, 1H), 7.07 (dd, J=6.6Hz, 2.4Hz, 2H), 6.85 (dd, J=6.0Hz, 1.8Hz, 2H), 6.19 (s, 1H), 2.18 (s,3H),2.04(s,3H).ES-MS m/z:216(M+)。
Intermediate 3b (R1=2- fluorine): white solid, yield 23% (three steps), ES-MS m/z:234 (M+)。
Intermediate 3c (R1=2- chlorine): white solid, yield 20% (three steps), ES-MS m/z:250 (M+)。
Intermediate 3d (R1=2- methyl): white solid, yield 18% (three steps), ES-MS m/z:230 (M+)。
Intermediate 3e (R1=2- trifluoromethyl): white solid, yield 22% (three steps), ES-MS m/z:284 (M+)。
Intermediate 3f (R1=3- chlorine): white solid, yield 23% (three steps), ES-MS m/z:250 (M+)。
The preparation of 6. intermediate 4a of embodiment
Operating procedure: step 1: 5- bromine 2- hydroxyl phenol (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) are dissolved in Then 2, the 3- dihydropyran (34.68mmol) of 3.2mL is added dropwise in 15mL dichloromethane solution, after reaction being stirred at room temperature 1 hour, It is washed respectively with 5% sodium hydroxide solution, saturated common salt, organic phase anhydrous sodium sulfate is dry, is concentrated to give white solid, directly It connects for reacting in next step.
Step 2: the product (6.87mmol) of previous step, 5- methylpyridone (4.58mmol), anhydrous is added in DMF Potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C and react 5 hours, be cooled to room temperature, after filtering Collect filtrate, subtract and DMF be evaporated off, then ethyl acetate dissolve, be washed with water respectively, saturated common salt washing, it is organic be added to it is anhydrous Sodium sulphate is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid 4a, yield 40% (three steps), ES-MS m/z:202 (M+)。
The preparation of 7. intermediate 4b of embodiment
Operating procedure: step 1: 6- bromine 3- hydroxyl phenol (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) are dissolved in Then 2, the 3- dihydropyran (34.68mmol) of 3.2mL is added dropwise in 15mL dichloromethane solution, after reaction being stirred at room temperature 1 hour, It is washed respectively with 5% sodium hydroxide solution, saturated common salt, organic phase anhydrous sodium sulfate is dry, is concentrated to give white solid, directly It connects for reacting in next step.
Step 2: the product (6.87mmol) of previous step, 5- methylpyridone (4.58mmol), anhydrous is added in DMF Potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C and react 5 hours, be cooled to room temperature, after filtering Collect filtrate, subtract and DMF be evaporated off, then ethyl acetate dissolve, be washed with water respectively, saturated common salt washing, it is organic be added to it is anhydrous Sodium sulphate is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid 4b, yield 38% (three steps), ES-MS m/z:202 (M+)。
The preparation of 8. intermediate 4c of embodiment
Operating procedure: step 1: 5- bromine 2- hydroxy pyrimidine (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) are dissolved in Then 2, the 3- dihydropyran (34.68mmol) of 3.2mL is added dropwise in 15mL dichloromethane solution, after reaction being stirred at room temperature 1 hour, It is washed respectively with 5% sodium hydroxide solution, saturated common salt, organic phase anhydrous sodium sulfate is dry, is concentrated to give white solid, directly It connects for reacting in next step.
Step 2: the product (6.87mmol) of previous step, 5- methylpyridone (4.58mmol), anhydrous is added in DMF Potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C and react 5 hours, be cooled to room temperature, after filtering Collect filtrate, subtract and DMF be evaporated off, then ethyl acetate dissolve, be washed with water respectively, saturated common salt washing, it is organic be added to it is anhydrous Sodium sulphate is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid 4c, yield 32% (three steps), ES-MS m/z:203 (M+)。
The preparation of 9. intermediate 5a of embodiment
Operating procedure: step 1: p bromophenol (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) are dissolved in 15mL dichloro Then 2, the 3- dihydropyran (34.68mmol) of 3.2mL is added dropwise in dichloromethane, after reaction being stirred at room temperature 1 hour, respectively with 5% Sodium hydroxide solution, saturated common salt washing, organic phase anhydrous sodium sulfate is dry, is concentrated to give white solid, is directly used in down Single step reaction.
Step 2: product (6.87mmol), the 1,5,6,7- tetrahydro -2H- cyclopenta [b] of previous step are added in DMF Pyridin-2-ones (4.58mmol), Anhydrous potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C of reactions It 5 hours, is cooled to room temperature, filtering and collecting filter liquid, subtracts and DMF is evaporated off, then ethyl acetate dissolves, and is washed with water, is saturated respectively Salt washing, organic anhydrous sodium sulfate that is added to is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid 5a, yield 35% (three steps), ES-MS m/z:227 (M+)。
The preparation of 10. intermediate 5b of embodiment
Operating procedure: step 1: p bromophenol (11.56mmol), p-methyl benzenesulfonic acid (0.116mmol) are dissolved in 15mL dichloro Then 2, the 3- dihydropyran (34.68mmol) of 3.2mL is added dropwise in dichloromethane, after reaction being stirred at room temperature 1 hour, respectively with 5% Sodium hydroxide solution, saturated common salt washing, organic phase anhydrous sodium sulfate is dry, is concentrated to give white solid, is directly used in down Single step reaction.
Step 2: the product (6.87mmol) of previous step, quinoline -2 (1H) -one (4.58mmol), anhydrous is added in DMF Potassium carbonate (5.50mmol) and CuI (0.55mmol), mixture are heated to 140 DEG C and react 5 hours, be cooled to room temperature, after filtering Collect filtrate, subtract and DMF be evaporated off, then ethyl acetate dissolve, be washed with water respectively, saturated common salt washing, it is organic be added to it is anhydrous Sodium sulphate is dry, and concentration obtains white solid, is directly used in and reacts in next step.
Step 3: previous step product (1.75mmol) and p-methyl benzenesulfonic acid (0.03mmol), room are added in 10mL ethyl alcohol Temperature is stirred to react 1 hour, and reaction solution is concentrated into 5mL, and active carbon is then added, and is flowed back 30 minutes, is filtered while hot, after filtrate is cooling Precipitation obtains white solid 5b, yield 32% (three steps), ES-MS m/z:237 (M+)。
The preparation of 11. intermediate 6a~6f of embodiment
Operating procedure: molten by TFV (50.8mmol) and corresponding compound 1 (102mmol) after being dried in vacuo half an hour Triethylamine is added after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes in N-Methyl pyrrolidone (39g) (62.3mmol), reaction after ten minutes, are warming up to 100 DEG C, 1,3- dicyclohexylcarbodiimide are then slowly added dropwise in 6 hours N-Methyl pyrrolidone (16g) solution of (DCC, 82.9mmol) continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, It is added water (30mL), then cooling reaction is filtered to remove solid, washs filter cake with water (15mL) to room temperature.It merging filtrate and washes Liquid adds 30mL water after being concentrated under reduced pressure, and adjusts pH to 11 with 25% sodium hydrate aqueous solution, is filtered with diatomite, filtrate second Acetoacetic ester extraction, water phase concentrated hydrochloric acid tune pH to 3, crude product with methanol washing, mashing, isolated white after filtering after filtering Solid.
Intermediate 6a (R1=H): white solid, yield 62%, LC-ESI-MS:471 [M+H].
Intermediate 6b (R1=2- fluorine): white solid, yield 60%, LC-ESI-MS:489 [M+H].
Intermediate 6c (R1=3- fluorine): white solid, yield 58%, LC-ESI-MS:489 [M+H].
Intermediate 6d (R1=2- methyl): white solid, yield 55%, LC-ESI-MS:485 [M+H].
Intermediate 6e (R1=2- trifluoromethyl): white solid, yield 59%, LC-ESI-MS:539 [M+H].
Intermediate 6f (R1=2- chlorine): white solid, yield 56%, LC-ESI-MS:505 [M+H].
The preparation of 12. intermediate 7a~7d of embodiment
Operating procedure: molten by TFV (50.8mmol) and corresponding compound 2 (102mmol) after being dried in vacuo half an hour Triethylamine is added after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes in N-Methyl pyrrolidone (39g) (62.3mmol), reaction after ten minutes, are warming up to 100 DEG C, 1,3- dicyclohexylcarbodiimide are then slowly added dropwise in 6 hours N-Methyl pyrrolidone (16g) solution of (DCC, 82.9mmol) continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, It is added water (30mL), then cooling reaction is filtered to remove solid, washs filter cake with water (15mL) to room temperature.It merging filtrate and washes Liquid adds 30mL water after being concentrated under reduced pressure, and adjusts pH to 11 with 25% sodium hydrate aqueous solution, is filtered with diatomite, filtrate second Acetoacetic ester extraction, water phase concentrated hydrochloric acid tune pH to 3, crude product with methanol washing, mashing, isolated white after filtering after filtering Solid.
Intermediate 7a (R2=H): white solid, yield 63%, LC-ESI-MS:457 [M+H].
Intermediate 7b (R2=4,6- dimethyl): white solid, yield 60%, LC-ESI-MS:485 [M+H].
Intermediate 7c (R2=4,5- dimethyl): white solid, yield 58%, LC-ESI-MS:485 [M+H].
Intermediate 7d (R2=5- trifluoromethyl): white solid, yield 57%, LC-ESI-MS:525 [M+H].
The preparation of 13. intermediate 8a~8c of embodiment
Operating procedure: molten by TFV (50.8mmol) and corresponding compound 3 (102mmol) after being dried in vacuo half an hour Triethylamine is added after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes in N-Methyl pyrrolidone (39g) (62.3mmol), reaction after ten minutes, are warming up to 100 DEG C, 1,3- dicyclohexylcarbodiimide are then slowly added dropwise in 6 hours N-Methyl pyrrolidone (16g) solution of (DCC, 82.9mmol) continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, It is added water (30mL), then cooling reaction is filtered to remove solid, washs filter cake with water (15mL) to room temperature.It merging filtrate and washes Liquid adds 30mL water after being concentrated under reduced pressure, and adjusts pH to 11 with 25% sodium hydrate aqueous solution, is filtered with diatomite, filtrate second Acetoacetic ester extraction, water phase concentrated hydrochloric acid tune pH to 3, crude product with methanol washing, mashing, isolated white after filtering after filtering Solid.
Intermediate 8a (R1=H): white solid, yield 55%, LC-ESI-MS:486 [M+H].
Intermediate 8b (R1=2- fluorine): white solid, yield 52%, LC-ESI-MS:504 [M+H].
Intermediate 8c (R1=2- chlorine): white solid, yield 49%, LC-ESI-MS:520 [M+H].
The preparation of 14. intermediate 9a~9b of embodiment
Operating procedure: molten by TFV (50.8mmol) and corresponding compound 4 (102mmol) after being dried in vacuo half an hour Triethylamine is added after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes in N-Methyl pyrrolidone (39g) (62.3mmol), reaction after ten minutes, are warming up to 100 DEG C, 1,3- dicyclohexylcarbodiimide are then slowly added dropwise in 6 hours N-Methyl pyrrolidone (16g) solution of (DCC, 82.9mmol) continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, It is added water (30mL), then cooling reaction is filtered to remove solid, washs filter cake with water (15mL) to room temperature.It merging filtrate and washes Liquid adds 30mL water after being concentrated under reduced pressure, and adjusts pH to 11 with 25% sodium hydrate aqueous solution, is filtered with diatomite, filtrate second Acetoacetic ester extraction, water phase concentrated hydrochloric acid tune pH to 3, crude product with methanol washing, mashing, isolated white after filtering after filtering Solid.
Intermediate 9a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 35%, LC-ESI-MS:472 [M+ H]。
Intermediate 9b (Y1=H, Y2=N, Y3=H, Y4=H): white solid, yield 45%, LC-ESI-MS:472 [M+ H]。
Intermediate 9c (Y1=N, Y2=H, Y3=N, Y4=H): white solid, yield 33%, LC-ESI-MS:473 [M+ H]。
The preparation of 15. intermediate 10a of embodiment
Operating procedure: by TFV (50.8mmol) and compound 5a (102mmol) after being dried in vacuo half an hour, it is dissolved in N- Methyl pyrrolidone (39g) is added triethylamine (62.3mmol), instead after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes After ten minutes 100 DEG C should be warming up to, be then slowly added dropwise in 6 hours 1,3- dicyclohexylcarbodiimide (DCC, N-Methyl pyrrolidone (16g) solution 82.9mmol) continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, and water is added (30mL), then cooling reaction is filtered to remove solid, washs filter cake with water (15mL) to room temperature.Merging filtrate and washing lotion decompression 30mL water is added after concentration, is adjusted pH to 11 with 25% sodium hydrate aqueous solution, is filtered with diatomite, filtrate ethyl acetate Extraction, water phase concentrated hydrochloric acid tune pH to 3, crude product with methanol washing, mashing after filtering, isolated white solid after filtering, Yield 52%, LC-ESI-MS:497 [M+H].
The preparation of 16. intermediate 10b of embodiment
Operating procedure: by TFV (50.8mmol) and compound 5b (102mmol) after being dried in vacuo half an hour, it is dissolved in N- Methyl pyrrolidone (39g) is added triethylamine (62.3mmol), instead after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes After ten minutes 100 DEG C should be warming up to, be then slowly added dropwise in 6 hours 1,3- dicyclohexylcarbodiimide (DCC, N-Methyl pyrrolidone (16g) solution 82.9mmol) continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, and water is added (30mL), then cooling reaction is filtered to remove solid, washs filter cake with water (15mL) to room temperature.Merging filtrate and washing lotion decompression 30mL water is added after concentration, is adjusted pH to 11 with 25% sodium hydrate aqueous solution, is filtered with diatomite, filtrate ethyl acetate Extraction, water phase concentrated hydrochloric acid tune pH to 3, crude product with methanol washing, mashing after filtering, isolated white solid after filtering, Yield 54%, LC-ESI-MS:507 [M+H].
The preparation of embodiment 17. intermediate 11a and 11b
Operating procedure: by 1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 1 (102mmol) is dissolved in N-Methyl pyrrolidone (39g), under nitrogen protection after being dried in vacuo half an hour It after being warming up to 85 DEG C of reactions 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then 6 N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in hour, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 11a (R1=H) (intermediate used is intermediate 1a): white solid, yield 50% (three steps), LC- ESI-MS:483[M+H]。
Intermediate 11b (R1=2- fluorine) (intermediate used is intermediate 1b): white solid, yield 47% (three steps), LC-ESI-MS:501[M+H]。
The preparation of 18. intermediate 12a~12c of embodiment
Operating procedure:
By 1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and corresponding chemical combination Object 2 (2d or 2e or 2f) (102mmol) is dissolved in N-Methyl pyrrolidone (39g), in nitrogen protection after being dried in vacuo half an hour Under be warming up to 85 DEG C reaction 30 minutes after, be added triethylamine (62.3mmol), reaction after ten minutes, be warming up to 100 DEG C, then exist N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in 6 hours, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 12a (R1=H): white solid, yield 45% (three steps), LC-ESI-MS:537 [M+H].
Intermediate 12b (R1=2- fluorine): white solid, yield 42% (three steps), LC-ESI-MS:555 [M+H].
Intermediate 12c (R1=2- methyl): white solid, yield 39% (three steps), LC-ESI-MS:551 [M+H].
The preparation of embodiment 19. intermediate 13a and 13b
Operating procedure: by 1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 4 (102mmol) is dissolved in N-Methyl pyrrolidone (39g), under nitrogen protection after being dried in vacuo half an hour It after being warming up to 85 DEG C of reactions 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then 6 N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in hour, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 13a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 33%, LC-ESI-MS:484 [M+ H]。
Intermediate 13b (Y1=H, Y2=N, Y3=H, Y4=H): white solid, yield 42%, LC-ESI-MS:484 [M+ H]。
The preparation of embodiment 20. intermediate 14a and 14b
Operating procedure: by 1- ((6- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 3 (102mmol) is dissolved in N-Methyl pyrrolidone (39g), under nitrogen protection after being dried in vacuo half an hour It after being warming up to 85 DEG C of reactions 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then 6 N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in hour, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 14a (R1=H) (use intermediate for intermediate 3a): white solid, yield 58%, LC-ESI-MS: 498[M+H]。
Intermediate 14b (R1=2- fluorine) (use intermediate for intermediate 3b): white solid, yield 55%, LC-ESI- MS:516[M+H]。
The preparation of embodiment 21. intermediate 15a and 15b
Operating procedure: by 1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 1 (102mmol) is dissolved in N-Methyl pyrrolidone (39g), under nitrogen protection after being dried in vacuo half an hour It after being warming up to 85 DEG C of reactions 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then 6 N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in hour, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 15a (R1=H): white solid, yield 49% (three steps), LC-ESI-MS:483 [M+H].
Intermediate 15b (R1=2- fluorine): white solid, yield 45% (three steps), LC-ESI-MS:501 [M+H].
The preparation of 22. intermediate 16a~16c of embodiment
Operating procedure: by 1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 2 (2d or 2e or 2f) (102mmol) is dissolved in N-Methyl pyrrolidone (39g) after being dried in vacuo half an hour, It after being warming up to 85 DEG C of reactions under nitrogen protection 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, the N-Methyl pyrrolidone of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is then slowly added dropwise in 6 hours (16g) solution continues heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room Temperature is filtered to remove solid, washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, and use 25% sodium hydrate aqueous solution adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH To 3, crude product with methanol is washed, is beaten, isolated white solid after filtering after filtering.
Intermediate 16a (R1=H): white solid, yield 45% (three steps), LC-ESI-MS:537 [M+H].
Intermediate 16b (R1=2- fluorine): white solid, yield 43% (three steps), LC-ESI-MS:555 [M+H].
Intermediate 16c (R1=2- methyl): white solid, yield 37% (three steps), LC-ESI-MS:551 [M+H].
The preparation of 23. intermediate 17a~17c of embodiment
Operating procedure: by 1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 4 (102mmol) is dissolved in N-Methyl pyrrolidone (39g), under nitrogen protection after being dried in vacuo half an hour It after being warming up to 85 DEG C of reactions 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then 6 N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in hour, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 17a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 32%, LC-ESI-MS:484 [M+ H]。
Intermediate 17b (Y1=H, Y2=N, Y3=H, Y4=H): white solid, yield 40%, LC-ESI-MS:484 [M+ H]。
Intermediate 17c (Y1=N, Y2=H, Y3=N, Y4=H): white solid, yield 30%, LC-ESI-MS:485 [M+ H]。
The preparation of embodiment 24. intermediate 18a and 18b
Operating procedure: by 1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Corresponding compound 3 (102mmol) is dissolved in N-Methyl pyrrolidone (39g), under nitrogen protection after being dried in vacuo half an hour It after being warming up to 85 DEG C of reactions 30 minutes, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then 6 N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is slowly added dropwise in hour, after Continuous heating reaction 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), then cooling reaction to room temperature, is filtered to remove solid Body washs filter cake with water (15mL).Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, water-soluble with 25% sodium hydroxide Liquid adjusts pH to 11, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product after filtering It washed, be beaten with methanol, isolated white solid after filtering.
Intermediate 18a (R1=H): white solid, yield 56%, LC-ESI-MS:498 [M+H].
Intermediate 18b (R1=2- fluorine): white solid, yield 53%, LC-ESI-MS:516 [M+H].
Intermediate 18c (R1=2- chlorine): white solid, yield 50% (three steps), LC-ESI-MS:532 [M+H].
Intermediate 18d (R1=2- methyl): white solid, yield 48% (three steps), LC-ESI-MS:512 [M+H].
Intermediate 18e (R1=2- trifluoromethyl): white solid, yield 45% (three steps), LC-ESI-MS:566 [M+H].
Intermediate 18f (R1=3- chlorine): white solid, yield 52% (three steps), LC-ESI-MS:532 [M+H].
The preparation of 25. intermediate 19a of embodiment
Operating procedure: by 1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Compound 5a (102mmol) is dissolved in N-Methyl pyrrolidone (39g), heats up under nitrogen protection after being dried in vacuo half an hour It after being reacted 30 minutes to 85 DEG C, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then at 6 hours N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is inside slowly added dropwise, continues to add Thermal response 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), and then cooling reaction to room temperature, is filtered to remove solid, uses Water (15mL) washs filter cake.Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, with 25% sodium hydrate aqueous solution tune PH to 11 is saved, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product first after filtering Alcohol washing, mashing, isolated white solid after filtering, yield 50%, LC-ESI-MS:509 [M+H].
The preparation of 26. intermediate 19b of embodiment
Operating procedure: by 1- ((2- amino -9H- purine -9- base) methyl) cyclopropyl oxygroup methyl acid phosphate (50.8mmol) and Compound 5b (102mmol) is dissolved in N-Methyl pyrrolidone (39g), heats up under nitrogen protection after being dried in vacuo half an hour It after being reacted 30 minutes to 85 DEG C, is added triethylamine (62.3mmol), reaction after ten minutes, is warming up to 100 DEG C, then at 6 hours N-Methyl pyrrolidone (16g) solution of 1,3- dicyclohexylcarbodiimide (DCC, 82.9mmol) is inside slowly added dropwise, continues to add Thermal response 16 hours.Reaction solution is cooled to 45 DEG C, is added water (30mL), and then cooling reaction to room temperature, is filtered to remove solid, uses Water (15mL) washs filter cake.Merging filtrate and washing lotion add 30mL water after being concentrated under reduced pressure, with 25% sodium hydrate aqueous solution tune PH to 11 is saved, is filtered with diatomite, filtrate is extracted with ethyl acetate, water phase concentrated hydrochloric acid tune pH to 3, crude product first after filtering Alcohol washing, mashing, isolated white solid after filtering, yield 52%, LC-ESI-MS:519 [M+H].
The preparation of embodiment 27. target compound 20a-1 and 20a-2
Operating procedure: (1) compound 6a (9.3mmol) and 10mL acetonitrile are mixed, adds thionyl chloride (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, obtains compound 20a.
(2) step 1 gained compound 20a (is prepared into column: ChiralpakAS-H through HPLC preparative separation；Mobile phase: A: N-hexane, B: ethyl alcohol), obtain chipal compounds 20a-1 and 20a-2.
Target compound 20a-1: white solid, yield 24%, LC-ESI-MS:584 [M+H].
Target compound 20a-2: white solid, yield 24%, LC-ESI-MS:584 [M+H].
The preparation of 28. target compound 20b of embodiment
Operating procedure: compound 6a (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL tri- of (L)-alanine butyl ester (18.6mmol) are separately added into Ethamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous sodium sulfate Dry, reduced pressure, gained concentrate pass through column chromatographic purifying, and method of the gained compound Jing Guo 27 step 2 of embodiment carries out HPLC preparative separation obtains compound 20b, yield 23%, LC-ESI-MS:598 [M+H].
The preparation of embodiment 29. target compound 21a-1 and 21a-2
Operating procedure: compound 6b (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, compound 21a is obtained, by the side of 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains chipal compounds 21a-1 and 21a-2.
Target compound 21a-1: white solid, yield 25%, LC-ESI-MS:602 [M+H].
Target compound 21a-2: white solid, yield 25%, LC-ESI-MS:602 [M+H].
The preparation of 30. target compound 21b~21e of embodiment
Operating procedure: compound 6b (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, Be subsequently cooled to -20 DEG C, be separately added into corresponding (L)-alanine ester (18.6mmol) methylene chloride (15mL) solution and 2.4mL triethylamine, is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer is by anhydrous Sodium sulphate is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, side of the gained compound Jing Guo 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 21b (R3=normal-butyl): white solid, yield 24%, LC-ESI-MS:616 [M+H].
Target compound 21c (R3=cyclohexyl): white solid, yield 23%, LC-ESI-MS:642 [M+H].
Target compound 21d (R3=benzyl): white solid, total recovery 22%, LC-ESI-MS:650 [M+H].
Target compound 21e (R3=tetrahydrofuran -3- base): white solid, total recovery 21%, LC-ESI-MS:630 [M+ H]。
The preparation of 31. target compound 22a~22d of embodiment
Operating procedure: corresponding compound 6 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through embodiment 27 rapid 2 Method carry out HPLC preparative separation, obtain corresponding chipal compounds.
Target compound 22a (R1=3- fluorine), white solid, yield 23%, LC-ESI-MS:602 [M+H].
Target compound 22b (R1=2- methyl), white solid, yield 20%, LC-ESI-MS:598 [M+H].
Target compound 22c (R1=2- trifluoromethyl), white solid, yield 22%, LC-ESI-MS:652 [M+H].
Target compound 22d (R1=2- chlorine), white solid, yield 21%, LC-ESI-MS:619 [M+H].
The preparation of 32. target compound 23a~23d of embodiment
Operating procedure: corresponding compound 7 (9.3mmol) and 10mL second dried meat are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 23a (R2=H): white solid, yield 24%, LC-ESI-MS:570 [M+H].
Target compound 23b (R2=4,6- dimethyl): white solid, yield 20%, LC-ESI-MS:598 [M+H].
Target compound 23c (R2=4,5- dimethyl): white solid, yield 18%, LC-ESI-MS:598 [M+H].
Target compound 23d (R2=5- trifluoromethyl): white solid, yield 21%, LC-ESI-MS:638 [M+H].
The preparation of embodiment 33. target compound 24a and 24b
Operating procedure: compound 8a (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, Be subsequently cooled to -20 DEG C, be separately added into corresponding (L)-alanine ester (18.6mmol) methylene chloride (15mL) solution and 2.4mL triethylamine, is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer is by anhydrous Sodium sulphate is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, side of the gained compound Jing Guo 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 24a (R3=isopropyl): white solid, yield 23%, LC-ESI-MS:599 [M+H].
Target compound 24b (R3=normal-butyl): white solid, yield 22%, LC-ESI-MS:613 [M+H].
The preparation of embodiment 34. target compound 25a and 25b
Operating procedure: corresponding compound 8 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 25a (R1=2- fluorine), white solid, yield 24%, LC-ESI-MS:617 [M+H].
Target compound 25b (R1=2- chlorine), white solid, yield 21%, LC-ESI-MS:634 [M+H].
The preparation of 35. target compound 26a~26c of embodiment
Operating procedure: corresponding compound 9 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 26a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 17%, LC-ESI-MS:585 [M+H]。
Target compound 26b (Y1=H, Y2=N, Y3=H, Y4=H): white solid, yield 18%, LC-ESI-MS:585 [M+H]。
Target compound 26c (Y1=N, Y2=H, Y3=N, Y4=H): white solid, yield 15%, LC-ESI-MS:586 [M+H]。
The preparation of 36. target compound 27a of embodiment
Operating procedure: compound 10a (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, method of the gained compound Jing Guo 27 step 2 of embodiment into Row HPLC preparative separation obtains chipal compounds 27a, white solid, yield 15%, LC-ESI-MS:610 [M+H].
The preparation of 37. target compound 27b of embodiment
Operating procedure: compound 10b (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, method of the gained compound Jing Guo 27 step 2 of embodiment into Row HPLC preparative separation obtains chipal compounds 27b, white solid, yield 18%, LC-ESI-MS:620 [M+H].
The preparation of embodiment 38. target compound 28a and 28b
Operating procedure: corresponding compound 11 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 28a (R1=H): white solid, yield 24%, LC-ESI-MS:596 [M+H].
Target compound 28b (R1=2- fluorine): white solid, yield 25%, LC-ESI-MS:614 [M+H].
The preparation of 39. target compound 29a~29c of embodiment
Operating procedure: corresponding compound 12 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 29a (R1=H): white solid, yield 23%, LC-ESI-MS:650 [M+H].
Target compound 29b (R1=2- fluorine): white solid, yield 22%, LC-ESI-MS:668 [M+H].
Target compound 29c (R1=2- methyl): white solid, yield 19%, LC-ESI-MS:664 [M+H].
The preparation of embodiment 40. target compound 30a and 30b
Operating procedure: corresponding compound 13 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 30a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 16%, LC-ESI-MS:597 [M+H]。
Target compound 30b (Y1=H, Y2=N, Y3=H, Y4=H): white solid, yield 20%, LC-ESI-MS:597 [M+H]。
The preparation of embodiment 41. target compound 31a-1 and 31a-2
Operating procedure: compound 14a (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, compound 31a is obtained, by the side of 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains chipal compounds 31a-1 and 31a-2.
Target compound 31a-1: white solid, yield 24%, LC-ESI-MS:611 [M+H].
Target compound 31a-2: white solid, yield 24%, LC-ESI-MS:611 [M+H].
The preparation of 42. target compound 32a~32c of embodiment
Operating procedure: compound 14b (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, Be subsequently cooled to -20 DEG C, be separately added into corresponding (L)-alanine ester (18.6mmol) methylene chloride (15mL) solution and 2.4mL triethylamine, is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer is by anhydrous Sodium sulphate is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, side of the gained compound Jing Guo 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 32a (R3=isopropyl): white solid, yield 25%, LC-ESI-MS:629 [M+H].
Target compound 32b (R3=cyclohexyl): white solid, yield 24%, LC-ESI-MS:669 [M+H].
Target compound 32c (R3=tetrahydrofuran -3- base): white solid, total recovery 19%, LC-ESI-MS:657 [M+ H]。
The preparation of embodiment 43. target compound 33a and 33b
Operating procedure: corresponding compound 15 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 33a (R1=H): white solid, yield 23%, LC-ESI-MS:596 [M+H].
Target compound 33b (R1=2- fluorine): white solid, yield 24%, LC-ESI-MS:614 [M+H].
The preparation of 44. target compound 34a~34c of embodiment
Operating procedure: corresponding compound 16 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 34a (R1=H): white solid, yield 24%, LC-ESI-MS:650 [M+H].
Target compound 34b (R1=2- fluorine): white solid, yield 23%, LC-ESI-MS:668 [M+H].
Target compound 34c (R1=2- methyl): white solid, yield 18%, LC-ESI-MS:664 [M+H].
The preparation of 45. target compound 35a~35c of embodiment
Operating procedure: corresponding compound 17 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 35a (Y1=N, Y2=H, Y3=H, Y4=H): white solid, yield 17%, LC-ESI-MS:597 [M+H]。
Target compound 35b (Y1=H, Y2=N, Y3=H, Y4=H): white solid, yield 18%, LC-ESI-MS:597 [M+H]。
Target compound 35c (Y1=N, Y2=H, Y3=N, Y4=H): white solid, yield 16%, LC-ESI-MS:598 [M+H]。
The preparation of embodiment 46. target compound 36a-1 and 36a-2
Operating procedure: compound 18a (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, compound 36a is obtained, by the side of 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains chipal compounds 36a-1 and 36a-2.
Target compound 36a-1: white solid, yield 24%, LC-ESI-MS:611 [M+H].
Target compound 36a-2: white solid, yield 24%, LC-ESI-MS:611 [M+H].
The preparation of embodiment 47. target compound 37a-1 and 37a-2
Operating procedure: compound 18c (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, compound 37a is obtained, by the side of 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains chipal compounds 37a-1 and 37a-2.
Target compound 37a-1: white solid, yield 25%, LC-ESI-MS:646 [M+H].
Target compound 37a-2: white solid, yield 25%, LC-ESI-MS:646 [M+H].
The preparation of 48 target compound 37b~37e of embodiment
Operating procedure: corresponding compound 18 (9.3mmol) and 10mL acetonitrile are mixed, thionyl chloride is added (21.0mmol) is heated to 80 DEG C or so, and 25mL bis- is added after gained residue is cooling in the evaporating solvent under reduced pressure after solution clarification Chloromethanes dissolution, is subsequently cooled to -20 DEG C, is separately added into the methylene chloride (15mL) of (L)-alanine isopropyl ester (18.6mmol) Solution and 2.4mL triethylamine, are to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer warp It crosses anhydrous sodium sulfate drying, be concentrated under reduced pressure, gained concentrate passes through column chromatographic purifying, and gained compound passes through 27 step of embodiment 2 method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 37b (R1=2- fluorine), white solid, yield 25%, LC-ESI-MS:629 [M+H].
Target compound 37c (R1=2- methyl), white solid, yield 22%, LC-ESI-MS:625 [M+H].
Target compound 37d (R1=2- trifluoromethyl), white solid, yield 20%, LC-ESI-MS:679 [M+H].
Target compound 37e (R1=3- chlorine), white solid, yield 20%, LC-ESI-MS:646 [M+H].
The preparation of 49. target compound 38a~38c of embodiment
Operating procedure: compound 18c (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, Be subsequently cooled to -20 DEG C, be separately added into corresponding (L)-alanine ester (18.6mmol) methylene chloride (15mL) solution and 2.4mL triethylamine, is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer is by anhydrous Sodium sulphate is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, side of the gained compound Jing Guo 27 step 2 of embodiment Method carries out HPLC preparative separation, obtains corresponding chipal compounds.
Target compound 38a (R3=normal-butyl): white solid, yield 24%, LC-ESI-MS:660 [M+H].
Target compound 38b (R3=cyclohexyl): white solid, yield 25%, LC-ESI-MS:686 [M+H].
Target compound 38c (R3=tetrahydrofuran -3- base): white solid, total recovery 20%, LC-ESI-MS:674 [M+ H]。
The preparation of 50. target compound 39a of embodiment
Operating procedure: compound 19a (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, method of the gained compound Jing Guo 27 step 2 of embodiment into Row HPLC preparative separation obtains chipal compounds 39a, white solid, yield 16%, LC-ESI-MS:622 [M+H].
The preparation of 51. target compound 39b of embodiment
Operating procedure: compound 19b (9.3mmol) and 10mL acetonitrile being mixed, thionyl chloride (21.0mmol) is added, 80 DEG C or so are heated to, the dissolution of 25mL methylene chloride is added in the evaporating solvent under reduced pressure after solution clarification after gained residue is cooling, - 20 DEG C are subsequently cooled to, methylene chloride (15mL) solution and 2.4mL of (L)-alanine isopropyl ester (18.6mmol) are separately added into Triethylamine is to slowly warm up to room temperature.After completion of the reaction, it is washed with 10% sodium dihydrogen phosphate, organic layer passes through anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and gained concentrate passes through column chromatographic purifying, method of the gained compound Jing Guo 27 step 2 of embodiment into Row HPLC preparative separation obtains chipal compounds 39b, white solid, yield 19%, LC-ESI-MS:632 [M+H].
52. effect on hepatitics B virus in vitro screening active ingredients of embodiment
Using HepG2.2.15 cell model, measures the compounds of this invention and HepG2.2.15 cell is secreted into supernatant The anti-hepatitis B activity of the compounds of this invention is evaluated in the influence of HBV-DNA contents level.
1, test method:
(1) by HepG2.2.15 cell inoculation in 96 orifice plates, untested compound, the 4th day replacement culture medium is added in next day And untested compound, in the 8th day collection culture supernatant.
(2) HBV-DNA in supernatant is purified using Qiaphony nucleic acid purifier.
(3) it takes 2 microlitres of supernatants for PCR amplification (real-time fluorescence quantitative PCR), while being arranged HBV-DNA standard sample 4 For doing standard curve.According to corresponding HBV-DNA copy number in resulting culture supernatant is detected, sample is calculated to HBV- The inhibiting rate of DNA replication dna obtains its IC50。
(4) it the influence that HepG2.2.15 cell is grown using mtt assay detection drug: is added to the every hole of tissue culture plate 200 microlitres of MTT (0.5mg/mL) continue to be incubated for 4 hours, abandon supernatant, 150 microlitres of DMSO are added in every hole, using microplate reader (wavelength The OD value for 570nm) measuring each hole calculates CC according to the survival rate of cell50。
1 compound of table secretes into culture supernatant the influence of HBV-DNA contents level to HepG2.2.15
Note: CC50Influence for example pharmaceuticals to the growth of HepG2.2.15 cell, 50% lethasl concentration；
IC50For sample to the inhibition of DNA copy up to 50% when concentration, "+": IC50>0.1μM；" ++ ": 0.1 μM < IC50< 0.01μM；" +++ ": IC50<0.01μM；
SI is that the bioactivity of sample selects coefficient, and value > 2 SI are effective, and are the bigger the better.
2, experiment conclusion: in HepG2.2.15 cells and supernatant level, test to HBV-DNA inhibition of DNA replication activity with Positive control drug TAF activity is quite；In the cell line surveyed, toxicity is not shown.
Influence of 53. compound of embodiment to human liver microsome proteins LX-2 cell Proliferation vigor
1, experimental method: LX-2 cell is inoculated in 96 orifice plates with 3000/hole, then overnight incubation changes no blood into Clear DMEM culture medium after starvation culture 24 hours, changes into containing 2% serum, 10ng/mL TGF-β and 1 μM of untested compound DMEM culture medium is incubated for processing cell, and the DMEM culture medium culture for staying " control " to organize 2% serum (is not added TGF-β and is also not added Untested compound processing), cell viability and density are surveyed with CCK-8 within 72 hours after dosing, obtain corresponding inhibiting rate (%).
The influence for the human liver microsome proteins LX-2 cell Proliferation vigor that 2 compound of table induces TGF-β
Note: inhibiting rate: "-": < 10%；"+": 0~50%；" ++ ": 50%~80%；" +++ ": > 80%.
2, experiment conclusion: the proliferation for the human liver microsome proteins LX-2 cell that test compound can inhibit TGF-β to induce is living Power has the function of anti-hepatic fibrosis, can be used for improving liver fibrosis or delays the process of cirrhosis.

Claims (10)

1. a kind of phosphoramidate prodrug of nucleoside analog, it is characterised in that: have structure shown in general formula I:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate, in which:
R1、R1' it is respectively and independently selected from H, NH2Or OH or OCH3, and at least one is NH2；
R2、R3It is respectively and independently selected from H ,-CH3、-CH2CH3、-CH2CH2CH3、CH(CH3)2Or R2、R3It is formed with connected carbon atom C3-7Naphthenic base；
R4Selected from H, C1-6Alkyl, C3-6Naphthenic base, C3-6Oxacycloalkyl, C3-6Alkoxyalkyl or substituted or non-substituted C6-10 Aryl, 6 to 10 unit's heteroaryls or benzyl；
X is selected from O, NH or S；
Y1、Y2、Y3、Y4It is independently selected from CR5Or N；
R5It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、-CF2H, cyanogen Base, nitro, hydroxyl, amino, Methanesulfomide, sulfonamide or substituted or non-substituted urea or substituted or non-substituted C6-10Virtue Base, 6 to 10 unit's heteroaryls；
Z1、Z2、Z3、Z4It is independently selected from CR6Or N, wherein Z1、Z2、Z3、Z4At most having one is N；Z1And Z2It can independent cyclization A, ring A For 5 to 7 substituted or non-substituted member rings；
R6It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、-CF2H, cyanogen Base, nitro, hydroxyl, amino, substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls；
Q is selected from O or S.
2. the phosphoramidate prodrug of nucleoside analog according to claim 1, it is characterised in that: have general formula II or II ' institute The structure shown:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate.
3. the phosphoramidate prodrug of nucleoside analog according to claim 1, which is characterized in that have general formula III or III ' Shown in structure:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate, in which:
Y1、Y3、Y4It is independently selected from C, CH or N；
R5It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、-CF2H, cyanogen Base, nitro, hydroxyl, amino, Methanesulfomide, sulfonamide or substituted or non-substituted urea or substituted or non-substituted C6-10Virtue Base, 6 to 10 unit's heteroaryls, wherein n is substituent group number, n 1,2,3 or 4；
Work as Y1、Y3、Y4In one or more be C when, at least one R5Replace at the C.
4. the phosphoramidate prodrug of nucleoside analog according to claim 1, which is characterized in that have general formula IV and IV ' institute The structure stated:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate, in which:
Y1、Y3、Y4、R5, n substituent group define defined with the corresponding substituent group in claim 3 it is identical；
Z1It is independently selected from C, CH or N；
R6It is independently selected from hydrogen, C1-6Alkyl, C1-3Alkoxy, C3-6Naphthenic base, C3-6Alkoxyalkyl, halogen ,-CF3、-CF2H, cyanogen Base, nitro, hydroxyl, amino, substituted or non-substituted C6-10Aryl, 6 to 10 unit's heteroaryls；Wherein m is substituent group number, m It is 1,2,3 or 4；
Z1When for C, at least one R6Replace at the C.
5. the phosphoramidate prodrug of nucleoside analog according to claim 1, which is characterized in that have shown in general formula V and V ' Structure:
Or its stereoisomer or its stereoisomer mixture or its pharmaceutically acceptable salt or solvate, in which:
Y1、Y3、Y4、R5, n substituent group define defined with the corresponding substituent group in claim 3 it is identical；
Z1、R6, m substituent group define defined with the corresponding substituent group in claim 4 it is identical.
6. the phosphoramidate prodrug of nucleoside analog according to claim 1, it is characterised in that: the knot with general formula V and V ' Structure:
Or its stereoisomer or its stereoisomer mixture or solvate, in which:
Y1、Y3、Y4、R5Substituent group define defined with the corresponding substituent group in claim 3 it is identical；
Z1、R6, m substituent group define defined with the corresponding substituent group in claim 4 it is identical；
Acid is independently selected from phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, rich horse At least one of acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-methyl benzenesulfonic acid, malic acid, Loprazolam.
7. the phosphoramidate prodrug of any one of -6 nucleoside analogs according to claim 1, it is characterised in that: phosphorus atoms have Chirality, configuration are the mixtures of S- configuration or R- configuration or S- configuration and R- configuration；Work as R2、R3When different, with its company Carbon atom also has chirality, and configuration is the mixture of S- configuration or R- configuration or S- configuration and R- configuration.
8. the phosphoramidate prodrug of nucleoside analog according to claim 1, which is characterized in that have a structure that
9. a kind of pharmaceutical composition, which is characterized in that including the phosphoramidate prodrug as described in any one of claim 1-8 One of or it is a variety of.
10. a kind of phosphoramidate prodrug as described in any one of claim 1-8 is preparing independent or is joining with other drugs It closes using the application in the drug of prevention or treatment hepatitis type B virus and/or HIV infection.
CN201710857431.3A 2017-09-21 2017-09-21 A kind of phosphoramidate prodrug, pharmaceutical composition and its application of nucleoside analog Pending CN109535200A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022194799A1 (en) 2021-03-18 2022-09-22 Merck Patent Gmbh Heteroaromatic compounds for organic electroluminescent devices

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160122374A1 (en) * 2014-10-29 2016-05-05 Gilead Sciences, Inc. Methods for treating filoviridae virus infections
CN106167504A (en) * 2015-11-04 2016-11-30 洛阳聚慧医药科技有限公司 Acyclonucleosides phosphamide D amino acid ester derivative and the preparation of salt thereof and in the application of anti-virus aspect
CN106866737A (en) * 2015-12-11 2017-06-20 南京圣和药业股份有限公司 Phosphonate derivative and its application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160122374A1 (en) * 2014-10-29 2016-05-05 Gilead Sciences, Inc. Methods for treating filoviridae virus infections
CN106167504A (en) * 2015-11-04 2016-11-30 洛阳聚慧医药科技有限公司 Acyclonucleosides phosphamide D amino acid ester derivative and the preparation of salt thereof and in the application of anti-virus aspect
CN106866737A (en) * 2015-12-11 2017-06-20 南京圣和药业股份有限公司 Phosphonate derivative and its application

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022194799A1 (en) 2021-03-18 2022-09-22 Merck Patent Gmbh Heteroaromatic compounds for organic electroluminescent devices

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