CN106946775B - Compound and application thereof in preparation of anti-hepatitis C virus medicine - Google Patents
Compound and application thereof in preparation of anti-hepatitis C virus medicine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The compound provided by the invention has rich functional group diversity and repairability, and the product is relatively easy to separate and purify.
Description
Technical Field
The invention relates to a compound and application thereof in preparing a medicine for resisting hepatitis C virus.
Background
Hepatitis c is caused by infection with the Hepatitis C Virus (HCV), and is transmitted mainly by blood/body fluids, including dirty needles, syringes, and drug abuse. According to the world health organization, 1.7 million people are infected with HCV worldwide. The positive rate of anti-HCV of healthy people in China is 0.7-3.1%, and about 3800 ten thousand people. Due to various factors such as the biological characteristics of viruses, the immune function of a host and the like, the immunity of the organism is often difficult to effectively remove the viruses, so that 80 percent of infected persons finally develop chronic hepatitis C, 60 percent of chronic patients finally develop cirrhosis, and only liver transplantation can be waited, and other 15 to 20 percent of infected persons naturally recover without treatment; from the patient population, men are twice as sick as women, and 55% of new infected people are between 25 and 44 years old. The currently known hepatitis c virus comprises 7 virus genotypes: of these, 60% of patients are type 1, type 2 is mainly concentrated in mediterranean areas, type 3 is common in southern asia and is common in people with intravenous drug, type 4 is mainly in the middle east, types 5, 6 and 7 are rare and only seen in certain countries.
The current standard therapy for HCV infection is a combination of several drugs, including interferon (PEG IFN- α), Ribavirin (RBV), or boceprevir, telaprevir, simeprevir, sofosbuvir, daclatasvir, etc., with treatment times typically up to 48 weeks.
In 2011, the combination of VICTRELIS(boceprevir)800mg TID + ribavirin + α -interferon is widely adopted, the method is suitable for genotype 1 patients who are treated initially or failed in previous treatment, the treatment time is shortened (shortened to 24 weeks or 32 weeks), and the viral load can be continuously reduced;
in 2011, the incivek (telaprevir) therapy of 750mg TID + ribavirin + α -interferon appears, is suitable for patients with genotype 1, primary treatment or ineffectiveness, relapse or partial reaction, obviously shortens the treatment time (12 weeks), and obviously improves the response rate of the medicament;
in 2013, OLYSIO (simeprevir)750mg TID + ribavirin + α -interferon is applicable to a patient with genotype 1, primary treatment or relapse or with cirrhosis, and the treatment time is remarkably shortened (12 weeks);
2013: the preparation method comprises the following steps of (1) once a day, wherein the preparation method comprises the following steps of (1) preparing a sodium lactate dehydrogenase (SOVALDI), (sofosbuvir)400mg, which is suitable for patients with gene 1 and type 3, initial treatment, relapse or liver cirrhosis accompanied, and remarkably shortening the treatment time (12 weeks or 24 weeks);
2014: the therapy time is shortened to be within 8 weeks by using the HARVONI (sofosbuvir + ledipasvir) once a day, and the cure rate is improved to 90%.
The emergence of the medicines plays a great promoting role in curing HCV, but interferon and ribavirin which are still widely adopted at present have obvious side effects, and some patients adopt interferon single-drug therapy. Genotype 1 patients were treated for 48 weeks with three injections of drug per week; the treatment period for patients of genotypes 2 and 3 was 24 weeks, also with 3 injections per week. 50% of patients can eventually be cured, and no HCV virus is detected 6 months after the treatment is over. Among them, sofosbuvir by Gilead is considered as a heavy drug in the HCV field, but its high price (cure cost up to several hundred thousand yuan) makes it not good for all patients; on the other hand, viruses are easy to mutate to generate drug resistance, so that the existing drugs are ineffective.
Therefore, there is still a need for the development of anti-HCV drugs, and the conventional anti-HCV targets include non-structural proteins of HCV (NS3/4A, NS5A, NS5B, etc.), so that there is a need to provide a novel antiviral compound.
Disclosure of Invention
The invention aims to provide a compound and application thereof in preparing antiviral drugs.
The invention firstly provides a compound shown as a formula I,
in formula I, the group X is ═ N-or ═ CH-;
m represents a substituent R1M is 0, 1 or 2, when m is 2, the radical R1May be the same or different;
radical R1is-H, -F, -Cl, -Br, -I, -OH, -OCH2CF3、-OR、-CF3、-CHF2、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-OCHF2、-CH2OH、-CH2OR、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
radical R2is-H, -OH, -OR OR-R, wherein R is alkyl with 1-6 carbon atoms;
radical R3is-H, -OH, -CH2OH、-CH2OR、-C(＝O)OH、-C(＝O)OR、-C(＝O)NHNH2、-C(＝O)NHOH、-C(＝O)NH2、-CF3or-R, wherein R is alkyl with 1-6 carbon atoms;
radical R4is-Q1-Y-Q2or-Q1-Y-Q2-Z-Q3or-Q1-Q2-Z-Q3or-Q1-Y-Q2-Q3The radicals shown are, in each case,
wherein Q1Is an aromatic ring OR heterocyclic ring substituted with 1 OR more substituents-H, -F, -Cl, -Br, -I, -OH, -OR, -CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
wherein Y and Z are each independently selected from the group consisting of-O-, -N (R)5)-、-S-、-S(＝O)-、-S(＝O)2-、-CH2-、-CF2-、-C(＝O)-、-CHF-、-CH2CH2-、-OCH2-、-OCH2CH2-、-OCH2CH2CH2-、-N(R5)CH2CH2-、-N(R5)CH2CH2CH2-、-CH2O-、-N(R5)CH2-、-CH2N(R5)-、-C(＝O)N(R5)-、-N(R5)C(＝O)-、-S(＝O)2N(R5)-、-(R5)NS(＝O)2-、-C(＝O)O-、-O(O＝)C-、-CH2-n(R5)n-、-CH2C(＝O)N(R5)-、-C(＝O)N(R5)CH2-、-CH2C (═ O) O-and-C (═ O) OCH2-；R5is-C (═ O) R or R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the group R is5May be the same or different;
wherein Q2And Q3Are independently selected from aromatic rings OR aromatic heterocycles substituted by 1 OR more substituents-H, -F, -Cl, -Br, -I, -OH, -OR, -CF3、-SF5、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-SCF3、-OCH2CF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-S(＝O)2CF3、-S(＝O)(＝NH)CF3、-S(＝O)(＝NR)CF3、-CH(OH)CF3、-C(OH)RCF3、-CHRCF3、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different.
The compound shown in the formula I provided by the invention is specifically the following compound:
the present invention further provides a process for the preparation of a compound represented by formula I, comprising the following steps (1) to (2) or (1) to (2) to (3):
(1) carrying out Suzuki reaction, Ullmann coupling reaction, aromatic nucleophilic substitution reaction, amide condensation reaction, esterification reaction or substitution reaction on a compound shown in a formula 1 and a compound shown in a formula 2 or a formula 2' to obtain an intermediate 1;
radical R3is-H, -CH2OR、-C(＝O)OR、-CF3or-R, wherein R is alkyl with 1-6 carbon atoms;
group Q1Is an aromatic ring OR heterocyclic ring substituted with 1 OR more substituents-H, -F, -Cl, -Br, -I, -OH, -OR, -CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
the group A being-CH2Br、-B(OR)2、-Br、-Cl、-OH、-SH、-NH2、-C(＝O)OH、-C(＝O)OCl、-CH2C(＝O)OH、-CH2C(＝O)OCl、-CH2OH、-CH2NH2(ii) a B is-CH2Br、-B(OR)2、-Br、-Cl、-OH、-SH、-NH2、-C(＝O)OH、-C(＝O)OCl、-CH2C(＝O)OH、-CH2C(＝O)OCl、-CH2OH or-CH2NH2R is alkyl with 1-6 carbon atoms;
radical R4is-Q1-Y-Q2or-Q1-Y-Q2-Z-Q3or-Q1-Q2-Z-Q3or-Q1-Y-Q2-Q3A group shown;
group Q2And Q3Independently selected from aromatic rings or aromatic heterocycles substituted with 1 or more substituentsThe substituent is-H, -F, -Cl, -Br, -I, -OH, -OR, -SF5、-CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-S(＝O)2CF3、-S(＝O)(＝NH)CF3、-S(＝O)(＝NR)CF3、-CH(OH)CF3、-C(OH)RCF3、-CHRCF3、-OCF3、-SCF3、-OCH2CF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
the groups Y and Z are independently selected from-O-, -N (R)5)-、-S-、-S(＝O)2-、-CH2-、-C(＝O)-、-CH2CH2-、-OCH2-、-CH2O-、-OCH2CH2-、-OCH2CH2CH2-、-N(R5)CH2CH2-、-N(R5)CH2CH2CH2-、-SCH2-、-CH2S-、-S(＝O)CH2-、-CH2(O＝)S-、-N(R5)CH2-、-CH2N(R5)-、-C(＝O)N(R5)-、-N(R5)CO-、-S(＝O)2N(R5)-、-(R5)NS(＝O)2-、-C(＝O)O-、-O(O＝C)-、-CH2-n(R5)n-、-CH2C(＝O)N(R5)-、-C(＝O)N(R5)CH2-、-CH2C (═ O) O-and-C (═ O) OCH2-; n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the group R5May be the same or different; r5is-C (═ O) R or R, wherein R is alkyl with 1-6 carbon atoms;
(2) the intermediate 1 and arylamine shown in the formula 3 are subjected to condensation reaction under the acidic heating condition to obtain an intermediate 2, namely R2A compound of formula I when it is-H;
the group X is ═ N-or ═ CH-;
m represents a substituent R1M is 0, 1 or 2, when m is 2, the radical R1May be the same or different;
radical R1is-H, -F, -Cl, -Br, -I, -OH, -OCH2CF3、-OR、-CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
radical R3Is as defined in formula 1;
radical R4As defined for intermediate 1;
(3) obtaining the compound shown in the formula I through the following steps 1) or 2):
1) under alkaline or acidic conditions, the intermediate 2 undergoes hydrolysis reaction, ammonolysis reaction, hydrazinolysis reaction or hydroxylammonium hydrolysis reaction to obtain a compound shown in formula I;
2) under alkaline or acidic conditions, carrying out oxidation reaction on the intermediate 2, and carrying out alkylation reaction to obtain a compound shown in a formula I;
in the formula I, R1、R3、R4X and m are as defined above;
radical R2is-H, -OH, -OR OR-R, wherein R is alkyl with 1-6 carbon atoms.
In the above-mentioned preparation method, in the step (1),
the conditions of the Suzuki reaction are as follows:
the catalyst can be palladium acetate, the reaction temperature can be 100-120 ℃, and the reaction time can be 10-20 hours;
the conditions of the Ullmann coupling reaction are as follows:
the catalyst can be cuprous iodide, the reaction temperature can be 110-130 ℃, and the reaction time can be 10-20 hours;
the conditions for the aromatic nucleophilic substitution reaction are as follows:
the reaction temperature can be 25-70 ℃, and the reaction time can be 5-20 hours;
the conditions for the amide condensation reaction are as follows:
the reaction temperature can be 2 ℃, and the reaction time can be 3-24 hours;
the esterification conditions were as follows:
the reaction temperature can be 2 ℃, and the reaction time can be 3-24 hours;
the conditions for the substitution reaction are as follows:
the reaction temperature can be 25-70 ℃, and the reaction time can be 5-20 hours.
In the above preparation method, in the step (2)1), the condensation reaction may be performed at 130 ℃ for 24 hours;
the condensation reaction is carried out in the presence of trifluoromethanesulfonic acid or p-toluenesulfonic acid.
In the preparation method, in the step (2)2), the hydrolysis reaction and the hydroxylamine hydrolysis reaction can be carried out at 20-25 ℃ for 5-20 hours;
the hydrazinolysis and the aminolysis can be carried out at 70-90 ℃ for 5-20 hours;
in the step (2)3), the oxidation reaction can be carried out at 20-25 ℃ or 85 ℃ for 1-24 h;
the alkylation reaction can be carried out at 25 ℃ for 1-8 h.
The invention also provides another compound shown as a formula II,
in formula II, the group X is ═ N-or ═ CH-;
m represents a substituent R1M is 0, 1 or 2, when m is 2, the radical R1May be the same or different;
radical R1is-H, -F, -Cl, -Br, -I, -OH, -OCH2CF3、-OR、-CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
radical R2' is-H, -C (═ O) NH2-n(R)n、-P(＝O)(OH)2、-P(＝O)(OR)2or-R, wherein R is alkyl with 1-6 carbon atoms or saturated heterocycle containing nitrogen and oxygen atoms;
radical R3is-H, -OH, -CH2OH、-CH2OR、-C(＝O)OH、-C(＝O)OR、-C(＝O)NHNH2、-C(＝O)NHOH、-C(＝O)NH2、-CF3or-R, wherein R is alkyl with 1-6 carbon atoms;
radical R4is-Q1-Y-Q2or-Q1-Y-Q2-Z-Q3or-Q1-Q2-Z-Q3or-Q1-Y-Q2-Q3The radicals shown are, in each case,
wherein Q1Is an aromatic ring OR heterocyclic ring substituted with 1 OR more substituents-H, -F, -Cl, -Br, -I, -OH, -OR, -CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
wherein Y and Z are independently selected from-O-, -N (R)5)-、-S-、-S(＝O)-、-S(＝O)2-、-CH2-、-CF2-、-C(＝O)-、-CHF-、-CH2CH2-、-OCH2-、-CH2O-、-OCH2CH2-、-OCH2CH2CH2-、-N(R5)CH2CH2-、-N(R5)CH2CH2CH2-、-SCH2-、-CH2S-、-S(＝O)CH2-、-CH2(O＝)S-、-N(R5)CH2-、-CH2N(R5)-、-C(＝O)N(R5)-、-N(R5)CO-、-S(＝O)2N(R5)-、-(R5)NS(＝O)2-、-C(＝O)O-、-O(O＝C)-、-CH2-n(R5)n-、-CH2C(＝O)N(R5)-、-C(＝O)N(R5)CH2-、-CH2C (═ O) O-or-C (═ O) OCH2-，R5is-C (═ O) R or R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the group R is5May be the same or different;
wherein Q2And Q3Independently selected from aromatic rings or aromatic heterocycles substituted with 1 or more substituents-H, -F, -Cl, -Br, -I, -OH, -SF5、-OR、-CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-SCF3、-S(＝O)2CF3、-S(＝O)(＝NH)CF3、-S(＝O)(＝NR)CF3、-CH(OH)CF3、-C(OH)RCF3、-CHRCF3、-OCH2CF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different.
The compound shown in the formula II provided by the invention is specifically the following compound:
the invention further provides a preparation method of the compound shown in the formula II, which comprises the following steps:
(1) carrying out Suzuki reaction, Ullmann coupling reaction, aromatic nucleophilic substitution reaction, amide condensation reaction, esterification reaction or substitution reaction on a compound shown in a formula 1 and a compound shown in a formula 2 or a formula 2' to obtain an intermediate 1;
radical R3is-H, -CH2OR、-C(＝O)OR、-CF3or-R, wherein R is alkyl with 1-6 carbon atoms;
group Q1Is an aromatic ring OR heterocyclic ring substituted with 1 OR more substituents-H, -F, -Cl, -Br, -I, -OH, -OR, -CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
the group A being-CH2Br、-B(OR)2、-Br、-Cl、-OH、-SH、-NH2、-C(＝O)OH、-C(＝O)OCl、-CH2C(＝O)OH、-CH2C(＝O)OCl、-CH2OH、-CH2NH2(ii) a B is-CH2Br、-B(OR)2、-Br、-Cl、-OH、-SH、-NH2、-C(＝O)OH、-C(＝O)OCl、-CH2C(＝O)OH、-CH2C(＝O)OCl、-CH2OH or-CH2NH2R is alkyl with 1-6 carbon atoms;
radical R4is-Q1-Y-Q2or-Q1-Y-Q2-Z-Q3Or-Q1-Q2-Z-Q3or-Q1-Y-Q2-Q3A group shown;
group Q2And Q3Independently selected from aromatic rings OR aromatic heterocycles substituted with 1 OR more substituents-H, -F, -Cl, -Br, -I, -OH, -OR, -SF5、-CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-S(＝O)2CF3、-S(＝O)(＝NH)CF3、-S(＝O)(＝NR)CF3、-CH(OH)CF3、-C(OH)RCF3、-CHRCF3、-OCF3、-SCF3、-OCH2CF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
the groups Y and Z are independently selected from-O-, -N (R)5)-、-S-、-S(＝O)2-、-CH2-、-C(＝O)-、-CH2CH2-、-OCH2-、-CH2O-、-OCH2CH2-、-OCH2CH2CH2-、-N(R5)CH2CH2-、-N(R5)CH2CH2CH2-、-SCH2-、-CH2S-、-S(＝O)CH2-、-CH2(O＝)S-、-N(R5)CH2-、-CH2N(R5)-、-C(＝O)N(R5)-、-N(R5)CO-、-S(＝O)2N(R5)-、-(R5)NS(＝O)2-、-C(＝O)O-、-O(O＝C)-、-CH2-n(R5)n-、-CH2C(＝O)N(R5)-、-C(＝O)N(R5)CH2-、-CH2C (═ O) O-or-C (═ O) OCH2-；R5is-C (═ O) R or R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the group R is5May be the same or different;
(2) carrying out condensation reaction on the intermediate 1 and arylamine shown in the formula 3 under an acidic heating condition to obtain an intermediate 2;
the group X is ═ N-or ═ CH-;
m represents a substituent R1M is 0, 1 or 2, when m is 2, the radical R1May be the same or different;
radical R1is-H, -F, -Cl, -Br, -I, -OH, -OCH2CF3、-OR、-CF3、-NH2-n(R)n、-C(＝O)OR、-C(＝O)OH、-OCF3、-CHF2、-CH2OH、-CH2OR、-OCHF2、-NO2、-CN、-S(＝O)2NH2-n(R)nor-R, wherein R is an alkyl group having 1 to 6 carbon atoms, n represents the number of substituents, n is 0, 1 or 2, and when n is 2, the groups R may be the same or different;
radical R3Is as defined in formula 1;
radical R4As defined for intermediate 1;
(3) under the alkaline condition, the intermediate 2 and acyl chloride undergo esterification reaction to obtain a compound shown in a formula II;
in the formula I, R1、R3、R4X and m are as defined above;
radical R2' is-H, -C (═ O) NH2-n(R)n、-P(＝O)(OH)2、-P(＝O)(OR)2or-R, wherein R is alkyl with 1-6 carbon atoms or saturated heterocycle containing nitrogen and oxygen atoms.
In the above-mentioned preparation method, in the step (1),
the conditions of the Suzuki reaction are as follows:
the catalyst can be palladium acetate, the reaction temperature can be 100-120 ℃, and the reaction time can be 10-20 hours;
the conditions of the Ullmann coupling reaction are as follows:
the catalyst can be cuprous iodide, the reaction temperature can be 110-130 ℃, and the reaction time can be 10-20 hours;
the conditions for the aromatic nucleophilic substitution reaction are as follows:
the reaction temperature can be 25-70 ℃, and the reaction time can be 5-20 hours;
the conditions for the amide condensation reaction are as follows:
the reaction temperature can be 2 ℃, and the reaction time can be 3-24 hours;
the esterification conditions were as follows:
the reaction temperature can be 2 ℃, and the reaction time can be 3-24 hours;
the conditions for the substitution reaction are as follows:
the reaction temperature can be 25-70 ℃, and the reaction time can be 5-20 hours.
In the above preparation method, in the step (2), the condensation reaction may be performed at 130 ℃ for 24 hours;
the condensation reaction may be carried out in the presence of trifluoromethanesulfonic acid or p-toluenesulfonic acid.
In the preparation method, in the step (3), the esterification reaction can be carried out at 60-85 ℃ for 3-10 h.
The compound shown in the formula I or the compound shown in the formula II can be used for preparing products for resisting HCV and other virus infections.
The compound shown in the formula I or the compound shown in the formula II can be used for preparing a prodrug or a pharmaceutically acceptable salt for resisting HCV and other virus infection.
The compound shown in the formula I or the compound shown in the formula II can be used for preparing products for resisting HCV and other virus infections by being combined with other antiviral drugs such as interferon (PEG IFN- α), Ribavirin (RBV), boceprevir, telaprevir, simeprevir, sofosbuvir, daclatasvir and the like.
The compound provided by the invention has abundant functional group diversity and modifiability, and the product is relatively easy to separate and purify. The compound provided by the invention has good inhibitory effect on viruses such as HCV and the like. The compounds are compounds obtained by phenotype screening, the antiviral mechanisms of the compounds are very different, and the compounds have extremely strong novelty and innovation in the compound structure in the field of antiviral, and the reports are not found before. In conclusion, the invention has wide development and application prospects.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of Compound 1
Intermediate A1 was taken in a 100ml round bottom flask and 198mg Pd (dppf) was added2DCM, 2g of potassium phosphate and 1.2g of p-trifluoromethylsulfanylphenylboronic acid pinacol ester, 10ml of toluene are added, the reaction is carried out at 100 ℃ for 12h under argon protection, the solvent is dried by spinning, 100ml of water are added, extraction is carried out twice with 20ml of dichloromethane and the reaction is carried out with petroleum ether: passing through a silica gel column with ethyl acetate 30:1 gave 1g of intermediate a3 (colorless liquid) in 64% yield.
Taking 1g of intermediate A3 and 650mg of intermediate A4 in a25 ml round bottom flask, adding 240mg of p-toluenesulfonic acid monohydrate and 10ml of n-butanol, reacting at 130 ℃ for 16h, spin-drying the solvent under reduced pressure, adding water, extracting 2 times with 20ml of ethyl acetate, extracting with ethyl acetate: passage through a silica gel column with 1:1 petroleum ether gave 320mg of compound 1 (white solid) in 24% overall yield.
Characterization data for compound 1 are as follows:
H-NMR(400MHz,d6-DMSO,ppm):1.82(s,3H),4.11(s,2H),6.93(m，1H),7.37–7.46(m,8H),7.65–7.67(m,2H),11.55(s,1H).LC-MS:calcd forC24H18F4NOS[M+H]+:444.10,found 444.18.
example 2 preparation of Compound 2
Compound 2 was obtained by changing a1 to a5 in reference example 1 under the same conditions and following procedures.
Characterization data for compound 2 are as follows:
H-NMR(400MHz,d6-DMSO,ppm):0.93(t,J＝6.96Hz,3H),2.26(q,J＝7.12Hz,2H),4.14(s，1H),6.91(dd,J＝8.12Hz,J＝11.28Hz,1H),7.34(d,J＝8.32Hz,1H),7.45–7.54(m,7H),7.67(d,J＝7.68Hz,2H),11.52(s,1H).LC-MS:calcd for C25H20F4NOS[M+H]+:458.11,found 458.21。
example 3 preparation of Compound 3
600mg of intermediate A1 are taken in a 100ml round-bottom flask, 420mg of potassium carbonate and 600mg of p-trifluoromethylthiophenol are added, 10ml of N, N-dimethylformamide DMF is added, reaction is carried out at 60 ℃ for 3h under the protection of argon, 100ml of water is added, extraction is carried out twice with 20ml of dichloromethane, and the reaction is carried out with petroleum ether: ethyl acetate 20:1 through a silica gel column to give 918mg of intermediate a6 (colorless liquid) in 90% yield.
Compound 3 was obtained by changing A3 to a6 under the same conditions and by referring to the procedure and conditions in example 1.
Characterization data for compound 3 are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.62(s,1H),7.66(m,4H),7.58(d,J＝7.96Hz,2H),7.52(m,1H),7.39(d,J＝8.40Hz,1H),7.20(d,J＝8.56Hz,2H),6.94(dd,J＝11.88Hz,J＝7.96Hz,1H),5.30(s,2H),1.4(s,3H).LC-MS:calcd for C24H18F4NO2S[M+H]+:460.09,found 460.21.
example 4, preparation of Compound 4 and example 5, preparation of Compound 5
5g of intermediate A7 were weighed into a 100ml round bottom flask and 500mg FeCl were added3.6H2O and 10ml pyridine, adding 12ml 70% tert-butyl peroxide aqueous solution, reacting at 85 ℃ for 24h, adding 100ml 2N hydrochloric acid after the reaction is finished, extracting 3 times with 20ml dichloromethane, combining organic phases, adding dichloromethane: passage through a silica gel column afforded 2.6g of intermediate A8 (white solid) in 55% yield.
Weighing 2.6g of intermediate A8 in a50 ml round bottom flask, adding 20ml of anhydrous tetrahydrofuran and 2.2ml of dimethyl carbonate, then adding 608mg of sodium hydride, refluxing at 75 ℃ for about 8 hours, cooling to room temperature, spin-drying the solvent under reduced pressure, dissolving the residue in dichloromethane, washing 2 times with water, washing once with saturated ammonium chloride solution, spin-drying the organic phase under reduced pressure, and washing the residue with petroleum ether: silica gel column chromatography with 10:1 ethyl acetate gave 1.6g of intermediate a9 (intermediate a9 as a light yellow liquid) in 52% yield.
1.6g of intermediate A9 and 1ml of m-chloroaniline are taken in a25 ml round-bottom flask, 1.5ml of acetic acid and 5ml of methanol are added, after 12 hours of reflux cooling to room temperature, 50ml of water are added, extraction with 10ml of dichloromethane is carried out 3 times, the organic phases are combined, and the mixture is purified by means of petroleum ether: passing through a silica gel column with ethyl acetate 10:1 gave 555mg of intermediate a10 (yellow liquid) in 26% yield.
555mg of intermediate A10 is put into a10 ml sealed tube, 3ml of Dowthern A is added as a solvent, reaction is carried out for 30min at 240 ℃, cooling to room temperature is carried out, and petroleum ether is added to precipitate solid. Recrystallization from petroleum ether, dichloromethane and methanol in this order gave 222mg of a mixture of intermediates A11 and A12 (white solid, approximately 2:1 ratio) in 43% yield.
The mixture of A11 and A12 obtained above was taken in a10 ml round bottom flask, 112mg potassium tert-butoxide and 4ml anhydrous THF were added, stirred at room temperature for 30min, then 92uL N, N-dimethylformyl chloride was added, the reaction was continued for 2h, after completion, 20ml saturated brine was added, extraction was performed 3 times with 10ml ethyl acetate, the organic phases were combined, dichloromethane was used: passing petroleum ether-2: 1 through a silica gel column afforded pure mixtures of compounds 23 and 24, which were then separated by semi-preparative HPLC to afford pure 152mg of compound 4 (white solid) and 68mg of compound 5 (white solid), respectively, in 86% overall yield.
Characterization data for compound 4 are as follows:
H-NMR(400MHz,CDCl3,ppm):3.13(s，3H),3.30(s，3H)，7.26(s，1H),7.34(d,J＝8.20Hz,2H),7.51(d,J＝8.84Hz,1H)，7.89–8.00(m,6H),8.20(s，1H),8.26(d,J＝8.16Hz,2H).LC-MS:calcd for C26H19ClF3N2O4[M+H]+:514.09,found 515.25.
characterization data for compound 5 are as follows:
H-NMR(400MHz,CDCl3,ppm):3.11(s，3H),3.26(s，3H)，7.27(d,J＝9.64Hz,2H),7.56–7.65(m,3H),7.71(s，1H)，7.90–7.94(m,3H),8.14(d,J＝7.88Hz,2H),8.28(d,J＝8.24Hz,2H)。LC-MS:calcd for C26H19ClF3N2O4[M+H]+:514.09,found 515.25。
example 6 preparation of Compound 6
Taking 130mg of compound 4 in a 5ml round bottom flask, adding 0.5ml of ethanedithiol and 180uL of boron trifluoride diacetic acid complex, reacting at room temperature for 10h, pouring the reaction solution into a saturated sodium bicarbonate solution, extracting with 20ml of dichloromethane for 2 times, and obtaining an organic phase which is obtained by reacting dichloromethane: passage through a silica gel column with petroleum ether 2:1 gave 132mg of intermediate a13 (yellow liquid) in 89% yield.
56mg NBS and 1ml anhydrous DCM were put into a suitable plastic bottle and 0.2ml HF was added.pyridine, 74mg of intermediate a13 dissolved in DCM under argon protection at-78 ℃ was added to the above solution and the reaction was continued for 2h, after which the reaction was poured into saturated sodium carbonate solution and extracted 2 times with 10ml of dichloromethane, the resulting organic phase was purified with dichloromethane: passing through a silica gel column with petroleum ether at 2:1 gave 52mg of compound 6 (yellow liquid) in 77% yield.
The characterization data are as follows:
H-NMR(400MHz,CDCl3,ppm):3.10(s，3H),3.26(s，3H)，7.26(d,J＝8.40Hz,2H),7.47(d,J＝8.84Hz,1H),7.57(d,J＝9.00Hz,2H)，7.62(d,J＝8.12Hz,2H),7.86(s，1H),7.92(d,J＝8.88Hz,1H),8.15-8.19(m,3H).LC-MS:calcd for C26H19ClF5N2O3[M+H]+:536.09,found 537.22。
example 7 preparation of Compound 7
26mg of Compound 6 was placed in a10 ml round bottom flask, 20. mu.l of hydrazine monohydrate and 2ml of methanol were added thereto, and the mixture was reacted at room temperature for 12 hours, followed by concentration to precipitate a solid, whereby 18mg of Compound 7 (white solid) was obtained in 82% yield.
The characterization data are as follows:
H-NMR(400MHz,d6-DMSO,ppm):6.40(s,1H),7.36(d,J＝7.52Hz,1H),7.52(d,J＝7.24Hz,2H),7.73–7.76(m,5H)，7.95(d,J＝5.76Hz,2H),8.09(d,J＝8.00Hz,1H),11.82(s,1H)。LC-MS:calcd for C23H14ClF5NO2[M+H]+:466.06,found 466.16。
example 8 preparation of Compound 8
Referring to the steps and conditions during example 4, intermediate a11 was changed to compound 1 and N, N-dimethylcarbonyl chloride was changed to 4-morpholinecarbonyl chloride to give compound 8.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):7.92(d,J＝7.76Hz,1H),7.59–7.54(m,5H),7.31–7.27(m,4H),7.17(t,J＝9.00Hz,1H),4.08(s,2H),3.82–3.55(m,8H),2.32(s,3H).LC-MS:calcd for C29H25F4N2O3S[M+H]+:557.14,found 557.16.
example 9 preparation of Compound 9
By referring to the procedure and conditions during example 1, p-trifluoromethylsulfanylphenylboronic acid pinacol ester was changed to p-trifluoromethylphenylboronic acid to obtain compound 9.
The characterization data are as follows:
H-NMR(400MHz,d6-DMSO,ppm):1.82(s,3H),4.07(s,2H),6.92(dd,J＝8.00Hz,J＝11.84Hz,1H),7.30(d,J＝8.12Hz,1H),7.36–7.55(m,8H),11.55(s,1H)。LC-MS:calcd forC24H18F4NO2[M+H]+:428.12,found 428.28。
example 10 preparation of Compound 10
Referring to the procedures and conditions during example 4, intermediate a11 was changed to compound 9 and N, N-dimethylcarbonyl chloride was changed to 4-morpholinecarbonyl chloride to provide compound 10.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):7.92(d,J＝8.40Hz,1H),7.57–7.53(m,3H),7.30(d,J＝7.76Hz,2H),7.24(d,J＝8.84Hz,2H),7.19–7.14(m,3H),5.05(s,2H),7.39–3.53(m,8H),2.32(s,3H).LC-MS:calcd for C29H25F4N2O4[M+H]+:541.17,found 541.21.
example 11 preparation of Compound 11
By referring to the procedure and conditions during example 1, the p-trifluoromethylsulfanylphenylboronic acid pinacol ester was changed to p-trifluoroethoxyphenylboronic acid pinacol ester to obtain compound 11.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):11.78(s,1H),7.81(d,J＝8.28Hz,1H),7.46–7.43(m,1H),7.22(d,J＝7.56Hz,2H),7.00(d,J＝8.08Hz,2H),6.92(d,J＝7.48Hz,2H),6.78(d,J＝7.84Hz,2H),4.26(q,J＝7.96Hz,2H),3.79(s,2H),1.76(s,3H).LC-MS:calcdforC25H20F4NO2[M+H]+:442.14,found 442.22.
example 12 preparation of Compound 12
Intermediate a4 was exchanged for intermediate a14, following the procedures and conditions described in the example 11 procedure, affording compound 12.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.26(d,J＝8.16Hz,1H),7.57–7.50(m,2H),7.37(d,J＝8.04Hz,2H),7.33–7.29(m,3H),7.14(d,J＝8.48Hz,2H),6.88(d,J＝8.52Hz,2H),4.37(q,J＝8.32Hz,2H),3.98(s,2H),2.02(s,3H).LC-MS:calcd forC25H21F3NO2[M+H]+:424.14,found 424.15.
example 13 preparation of Compound 13
Taking 700mg of intermediate A14 and 650mg of intermediate A15 into a25 ml round bottom flask, adding 200mg of p-toluenesulfonic acid monohydrate and 10ml of n-butanol, reacting at 130 ℃ for 16h, spin-drying the solvent under reduced pressure, adding water, extracting 2 times with 20ml of ethyl acetate, extracting with ethyl acetate: passage through a silica gel column with 1:1 petroleum ether gave 215mg of compound 13 (white solid) in 21% overall yield.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.24(d,J＝8.04Hz,1H),7.57–7.51(m,1H),7.44(d,J＝8.28Hz,1H),7.30–7.27(m,5H),2.82–2.85(m,1H),2.42(s,3H),1.30(d,J＝6.96Hz,6H).LC-MS:calcd for C19H20NO[M+H]+:278.15,found 278.17.
example 14 preparation of Compound 14
In a 5ml round bottom flask, 47mg of compound 12 was placed, 70uL methyl iodide, 50mg potassium carbonate and 1ml DMF were added and reacted at room temperature for 5 hours, 50ml water was added, and the organic phase was extracted with 20ml dichloromethane, followed by petroleum ether: ethyl acetate ═ 1: passing through a silica gel column to give 39mg of the product as a white solid in 73% yield.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.24(d,J＝8.04Hz,1H),7.57–7.51(m,1H),7.44(d,J＝8.28Hz,1H),7.30–7.27(m,5H),2.82–2.85(m,1H),2.42(s,3H),1.30(d,J＝6.96Hz,6H).LC-MS:calcd for C19H20NO[M+H]+:278.15,found 278.17.
example 15 preparation of Compound 15
Taking 71mg of compound 12, putting the compound in a10 ml round bottom flask, adding 28mg of potassium tert-butoxide and 3ml of anhydrous THF, adding 40uL of ethyl chloroformate under the protection of argon, reacting at room temperature for 2 hours, adding 50ml of saturated ammonium chloride solution, extracting with 40ml of dichloromethane to obtain an organic phase, and adding petroleum ether: ethyl acetate 5:1 was passed through a silica gel column to give 75mg of intermediate a 16.
Taking the intermediate A16 obtained in the previous step, adding 38mg of m-chloroperoxybenzoic acid methyl ester and 2ml of dichloromethane into a10 ml round bottom flask, reacting for 10 hours at room temperature, adding 40ml of water, extracting with 30ml of dichloromethane to obtain an organic phase, and then adding petroleum ether: passing through a silica gel column with ethyl acetate 1:1 gave 71mg of intermediate a 17.
The intermediate A17 obtained above was taken in a10 ml round bottom flask, 80mg potassium hydroxide and 3ml 95% methanol were added, reacted at room temperature for 5 hours, methanol was removed under reduced pressure, 5ml2N hydrochloric acid was added to give a white solid and collected by filtration to give 45mg, 74% yield.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.31(s,1H),8.19(d,J＝7.76Hz,1H),7.79–7.71(m,2H),7.39–7.33(m,5H),7.27(d,J＝8.48Hz,2H),7.01(d,J＝8.56Hz,2H),4.72(q,J＝8.88Hz,2H),4.00(s,2H),1.75(s,3H).LC-MS:calcd for C25H21F3NO3[M+H]+:440.14,found440.27.
example 16 preparation of Compound 16
Referring to the procedures and conditions during example 11, a1 was changed to a18 to afford compound a 16.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):10.14(s,1H),7.44–7.40(m,2H),7.27(d,J＝7.96Hz,2H),7.10(d,J＝8.52Hz,2H),7.06(d,J＝7.88Hz,2H),6.85(d,J＝8.56Hz,2H),6.78–6.73(m,1H),4.31(q,J＝8.16Hz,2H),3.87(s,2H),2.72(m,1H),1.25(d,J＝6.84Hz,6H).LC-MS:calcd for C27H24F4NO2[M+H]+:470.17,found 470.24.
example 17 preparation of Compound 17
Referring to the procedures and conditions during example 1, a1 was changed to a5 and a2 was changed to a19 to provide compound a 17.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):11.53(s,1H),7.74(d,J＝7.72Hz,1H),7.43(dd,J＝13.24Hz,J＝8.04Hz,H),7.23(d,J＝8.04Hz,2H),7.18(t,J＝7.80Hz,1H),6.95(d,J＝7.84Hz,2H),6.80–6.72(m,4H),4.26(q,J＝8.16Hz,2H),3.83(s,2H),2.67(q,J＝7.16Hz,2H),0.92(t,J＝7.16Hz,3H).LC-MS:calcd for C26H22F4NO2[M+H]+:456.15,found 456.34.
example 18 preparation of Compound 18
Referring to the steps and conditions during example 1, exchange a1 for a5, a2 for a19, and a4 for a14 gave compound a 18.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):9.87(s,1H),8.19(d,J＝8.08Hz,1H),7.61–7.52(m,2H),7.32(d,J＝7.96Hz,2H),7.26–7.20(m,2H),7.15(d,J＝7.76Hz,2H),6.86(d,J＝7.48Hz,1H),6.76–6.74(m,H),4.27(q,J＝8.12Hz,2H),3.93(s,2H),2.41(q,J＝7.24Hz,2H),1,01(t,J＝7.24Hz,3H).LC-MS:calcd for C26H23F3NO2[M+H]+:438.16,found 438.34.
example 19 preparation of Compound 19
Referring to the procedures and conditions during example 1, a2 was changed to a20 to afford compound a 19.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.54–7.42(m,7H),7.36(d,J＝8.04Hz,2H),7.30(d,J＝8.48Hz,1H),4.11(s,2H),1.97(s,3H).LC-MS:calcd forC24H18FN2O[M+H]+:369.13,found 369.31.
example 20 preparation of Compound 20
Referring to the procedures and conditions during example 1, a2 was changed to a21 to afford compound a 20.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.49(m,1H),7.39(d,J＝8.08Hz,2H),7.32(d,J＝8.04Hz,2H),7.28(d,J＝8.48Hz,1H),7.24–7.15(m,3H),7.10(d,J＝7.44Hz,1H),6.88(dd,J＝11.88Hz,J＝7.92Hz,1H),4.02(s,2H),1.97(s,3H).LC-MS:calcdfor C23H18ClFNO[M+H]+:378.10,found 378.17.
example 21 preparation of Compound 21
Referring to the procedures and conditions during example 1, a4 was changed to a22 to afford compound a 21.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.67(d,J＝8.40Hz,1H),7.61–7.55(m,3H),7.39(d,J＝7.76Hz,2H),7.33(d,J＝6.92Hz,2H),7.28–7.23(m,3H),4.08(s,2H),1.94(s,3H).LC-MS:calcd for C24H18F3N2O3S[M+H]+:471.09,found 471.16.
example 22 preparation of Compound 22
Referring to the procedures and conditions during example 3, trifluoromethylthiophenol was changed to A23 to give Compound A22.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.64(s,1H),8.31(d,J＝2.00Hz,1H),8.03(dd,J＝8.72Hz,J＝1.88Hz,1H),7.76–7.65(m,3H),7.61(d,J＝8.08Hz,2H),7.57–7.52(m,1H),7.38(d,J＝8.40Hz,1H),6.95(dd,J＝11.96Hz,J＝8.04Hz,1H),5.51(s,2H),1.83(s,3H).LC-MS:calcd for C24H16F4N2O4S[M+H]+:505.08,found 505.14.
example 23 preparation of Compound 23
73mg of compound 22 was placed in a25 ml round bottom flask, 49mg of iron powder and 4ml each of acetic acid, water and acetone were added, and the mixture was refluxed at 80 ℃ for 14 hours, 50ml of water was added, and extraction was performed with 50ml of ethyl acetate to obtain an organic phase, and then the organic phase was extracted with dichloromethane: passing through a silica gel column with methanol 100:3 yielded 53mg of compound 23 (yellow solid, 74% yield).
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.63(d,J＝9.04Hz,2H),7.53–7.50(m,3H),7.30(d,J＝8.40Hz,1H),7.05(s,1H),6.95–6.88(m,3H)),5.26(s,2H),3.31(s,2H),1.98(s,3H).LC-MS:calcd for C24H19F4N2O2S[M+H]+:475.10,found 475.13.
example 24 preparation of Compound 24
Taking 5g of methyl p-aldehyde benzoate in a 100ml round bottom flask, adding 50ml of anhydrous tetrahydrofuran under the protection of argon, then slowly adding 11ml of 3.0M ethyl format reagent under the condition of ice bath, slowly raising the temperature to room temperature, continuing to react for 2 hours, removing the solvent under the condition of reduced pressure, then adding dilute hydrochloric acid until the solid disappears, then extracting with ethyl acetate to obtain an organic phase, and using petroleum ether: silica gel column with 6:1 ethyl acetate afforded intermediate a24 as a white solid, 4.2 g.
2.1g of A24 obtained above was taken in a 100ml round bottom flask, 50ml of dichloromethane was added as solvent, then 5.7g of dessimutan oxidant was added in portions, the solvent was removed under reduced pressure after the reaction was over, and then the mixture was treated with petroleum ether: ethyl acetate 15:1 was passed through a silica gel column to give intermediate a25 as a white solid, 1.7 g.
Referring to the steps and conditions during example 1, intermediate A3 was changed to a25 to afford compound a 26.
300mg of intermediate A26 was placed in a25 ml round bottom flask, 10ml of methanol, 0.2ml of water and 300mg of potassium hydroxide were added, and after 5 hours at room temperature, the solvent was removed under reduced pressure, 4N hydrochloric acid was added, and filtration was carried out to obtain A27 as a white solid.
75mg of intermediate A27, 40uL of m-chloroaniline, 72mg of EDCI,45mg of HOBt,45uL of triethylamine and 10mg of DMAP were taken in a10 ml round-bottomed flask, then 2ml of DMF was added, reaction was carried out at room temperature for 3 hours, then 50ml of water was added, extraction was carried out with 50ml of ethyl acetate to obtain an organic phase, and then dichloromethane was used: passing through a silica gel column with methanol 100:5 gave 57mg of a white solid in 57% yield.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.73(s,1H),10.59(s,1H),8.14(d,J＝7.24Hz,2H),8.01(s,1H),7.74–7.72(m,3H),7.58–7.55(m,1H),7.41(d,J＝5.40Hz,2H),7.18(d,J＝7.08Hz,1H),6.97(m,1H),1.85(s,3H).LC-MS:calcd for C23H17ClFN2O2[M+H]+:407.09,found 407.17.
example 25 preparation of Compound 25
Intermediate a2 was exchanged for a28, following the procedures and conditions described in the example 1 procedure, to provide compound 25.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.67(s,1H),7.83(d,J＝8.60Hz,2H),7.56–7.43(m,7H),7.39(d,J＝8.44Hz,1H),6.93(dd,J＝11.92Hz,J＝7.96Hz,1H),4.14(s,2H),1.83(s,3H).LC-MS:calcd for C23H18F6NOS[M+H]+:470.09,found 470.16.
example 26 preparation of Compound 26
Intermediate a2 was exchanged for a29, following the procedures and conditions described in the example 1 procedure, to afford compound 26.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.55(s,1H),8.10(d,J＝8.24Hz,2H),7.78(d,J＝8.36Hz,2H),7.54–7.50(m,5H),7.36(d,J＝8.44Hz,1H),6.93(dd,J＝11.96Hz,J＝7.88Hz,1H),4.27(s,2H),1.82(s,3H).LC-MS:calcd for C24H18F4NO3S[M+H]+:476.09,found476.19.
example 27 preparation of Compound 27
Referring to the procedures and conditions during example 3, trifluoromethylthiophenol was changed to A30 to give Compound A27.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.63(s,1H),7.69(m,3H),7.58(d,J＝8.24Hz,2H),7.56–7.52(m,2H),7.39(d,J＝8.40Hz,1H),7.27(d,J＝8.40Hz,1H),7.05(t,J＝7.48Hz,1H),6.95(dd,J＝12.00Hz,J＝7.92Hz,1H),5.32(s,2H),4.28(q,J＝6.64Hz,2H),1.84(s,3H),1.29(t,J＝7.08Hz,3H).LC-MS:calcd for C26H23FNO4[M+H]+:432.15,found432.17.
example 28 preparation of Compound 28
Referring to example 24, the procedure and conditions in the preparation of intermediate a27, compound a28 was obtained by replacing a26 with compound 27.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.71(s,1H),7.71–7.67(m,3H),7.58–7.48(m,4H),7.40(d,J＝8.40Hz,1H),7.23(d,J＝8.40Hz,1H),7.03(t,J＝7.48Hz,1H),6.95(dd,J＝12.00Hz,J＝7.96Hz,1H),5.31(s,2H),1.85(s,3H).LC-MS:calcd for C24H19FNO4[M+H]+:404.12,found 404.26.
example 29 preparation of Compound 29
60mg of compound 27 was placed in a10 ml round bottom flask, 200uL of hydrazine hydrate and 5ml of methanol were added, reflux was carried out at 80 ℃ for 12 hours, the solvent was removed under reduced pressure, and the mixture was purified by dichloromethane: passing through a silica gel column with methanol 100:10 gave compound 29 as a white solid 42mg in 70% yield.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.64(s,1H),9.29(s,1H),7.70–7.65(m,3H),7.59–7.52(m,3H),7.46–7.38(m,3H),7.21(d,J＝8.20Hz,1H),7.04(t,J＝7.32Hz,1H),6.95(dd,J＝11.48Hz,J＝8.28Hz,1H),5.37(s,2H),4.55(s,2H),1.84(s,3H).LC-MS:calcdfor C24H21FN3O3[M+H]+:418.15,found 418.27.
example 30 preparation of Compound 30
Referring to the steps and conditions during example 1, a1 was exchanged for intermediate a31 to afford compound a 30.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):8.12(s,1H),7.88(d,J＝8.32Hz,1H),7.65(d,J＝7.60Hz,1H),7.52–7.46(m,3H),7.12–7.08(m,3H),6.80(dd,J＝11.64Hz,J＝8.04Hz,1H),4.16(s,2H),1.98(s,3H).LC-MS:calcd for C24H17F4N2O3S[M+H]+:489.08,found 489.19.
example 31 preparation of Compound 31
600mg of sodium azide, 222mg of tetrabutylammonium iodide and 10ml of dimethyl sulfoxide were added to 1.36g of Compound A1 in a50 ml round-bottomed flask, and after 8 hours at room temperature, 100ml of water and 50ml of methylene chloride were added to separate an organic phase, and the solvent was removed under reduced pressure to obtain 900mg of intermediate A32.
Taking the intermediate A32 obtained above, putting 1.6g of triphenylphosphine, 10ml of tetrahydrofuran and 0.5ml of water into a50 ml round bottom flask, reacting for 1 hour at 60 ℃, removing the solvent under reduced pressure, adding water and extracting with 50ml of ethyl acetate to obtain an organic phase, and then adding dichloromethane: silica gel column with methanol 100:10 gave 750mg of intermediate a 33.
Referring to the procedures and conditions in example 24, a27 and m-chloroaniline were changed to a33 and p-trifluoromethylthiobenzoic acid to give intermediate a 34.
Referring to the steps and conditions during example 1, A3 was exchanged for intermediate a34 to afford compound a 31.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.58(s,1H),9.37(t,J＝5.88Hz,1H),8.03(d,J＝8.20Hz,2H),7.84(d,J＝8.12Hz,2H),7.56–7.50(m,5H),7.38(d,J＝8.44Hz,1H),6.93(dd,J＝12.00Hz,J＝7.92Hz,1H),4.59(d,J＝5.92Hz,2H),1.83(s,3H).LC-MS:calcd forC25H19F4N2O2S[M+H]+:487.10,found 487.27.
example 32 preparation of Compound 32
Referring to the steps and conditions during example 1, A3 was exchanged for intermediate a35 to afford compound a 32.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.04(s,1H),7.62(d,J＝7.92Hz,1H),7.56–7.46(m,4H),7.32(d,J＝8.44Hz,1H),7.25(d,J＝7.92Hz,2H),6.92(dd,J＝11.88Hz,J＝8.00Hz,1H),4.50(s,2H),3.81(s,3H),1.98(s,3H).LC-MS:calcd forC26H20F4NO3S[M+H]+:502.10,found 502.18.
example 33 preparation of Compound 33
Compound 27 was changed to compound 32 with reference to the procedures and conditions during the procedure of example 28 to give compound 33.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.11(s,1H),7.61–7.49(m,4H),7.43(d,J＝7.84Hz,1H),7.33(d,J＝8.44Hz,1H),7.28(d,J＝7.72Hz,2H),4.56(s,2H),2.01(s,3H).LC-MS:calcd for C25H16F4NO3S[M-H]-:486.09,found 486.07.
example 34 preparation of Compound 34
Referring to the procedure and conditions in example 24, intermediate a27 and m-chloroaniline were changed to compound 33 and dimethylamine hydrochloride and the amount of triethylamine was doubled to give compound 34.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.60–7.47(m,5H),7.28–7.27(m,4H),6.91(dd,J＝11.74Hz,J＝8.12Hz,1H),4,65(s,2H),2.92(s,3H),2.42(s,3H),1.97(s,3H).LC-MS:calcd for C27H23F4N2O2S[M+H]+:515.13,found 515.26.
example 35 preparation of Compound 35
Referring to the procedures and conditions in example 31, A1 and p-trifluoromethylthiobenzoic acid were changed to A36 and m-trifluoromethylbenzoic acid to obtain Compound 35.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.87(d,J＝7.84Hz,1H),7.80(s,1H),7.72(d,J＝1.64Hz,1H),7.56–7.48(m,3H),7.44–7.40(m,2H),7.32(dd,J＝11.96Hz,J＝7.92Hz,1H),4.70(s,2H),1.96(s,3H).LC-MS:calcd for C25H18BrF4N2O3[M+H]+:549.04,found 549.25.
example 36 preparation of Compound 36
74mg of compound 35 was put in a10 ml sealed tube, and 2ml of ammonia water, 10mg of cuprous oxide and 2ml of dimethyl sulfoxide were added, and after reacting at 90 ℃ for 1 hour, 100ml of water was added and extracted with 50ml of ethyl acetate to obtain an organic phase, which was then separated with dichloromethane: passing through a silica gel column with methanol 100:10 gave compound 36 as a white solid 44mg in 68% yield.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.82(d,J＝7.80Hz,1H),7.56(s,1H),7.52–7.43(m,2H),7.37(d,J＝8.20Hz,1H),7.33(d,J＝8.48Hz,1H),7.27(d,J＝7.72Hz,1H),6.87(dd,J＝11.92Hz,J＝7.92Hz,1H),6.81(s,1H),6.72(d,J＝7.64Hz,1H),4.54(s,2H),1.96(s,3H).LC-MS:calcd for C25H20F4N3O3[M+H]+:486.14,found 486.13.
example 37 preparation of Compound 37
Referring to the procedure and conditions in example 34, dimethylamine hydrochloride was changed to monomethylamine hydrochloride to give compound 37.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.55–7.47(m,5H),7.39(d,J＝7.76Hz,1H),7.28–7.26(m,2H),6.90(dd,J＝11.76Hz,J＝8.12Hz,1H),4.26(s,2H),2.80(s,3H),1.96(s,3H).LC-MS:calcd for C26H21F4N2O2S[M+H]+:501.12,found 501.14.
example 38 preparation of Compound 38
Referring to the procedure and conditions in example 1, a4 was changed to a37 to afford compound 38.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.85(d,J＝8.36Hz,1H),7.57–7.28(m,10H),4.08(s,2H),2.12(s,3H).LC-MS:calcd for C24H18F4NOS[M+H]+:444.10,found 444.21.
example 39 preparation of Compound 39
Referring to the procedure and conditions in example 1, a4 was changed to a38 to afford compound 39.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.28(d,J＝8.76Hz,J＝6.36Hz,1H),7.57(d,J＝7.88Hz,2H),7.42(d,J＝7.84Hz,2H),7.36(d,J＝7.92Hz,2H),7.29(d,J＝7.88Hz,2H),7.18(d,J＝9.56Hz,1H),7.06(t,J＝7.56Hz,1H),4.10(s,2H),2.01(s,3H).LC-MS:calcd for C24H18F4NOS[M+H]+:444.10,found 444.21.
example 40 preparation of Compound 40
Referring to the procedure and conditions in example 1, a4 was changed to a39 to afford compound 40.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):8.36(s,1H),8.13(d,J＝8.08Hz,1H),7.60(d,J＝7.56Hz,2H),7.44(d,J＝7.48Hz,2H),7.35–7.21(m,6H),4.08(s,2H),2.07(s,3H).LC-MS:calcd for C24H18F4NOS[M+H]+:444.10,found 444.21.
example 41 preparation of Compound 41
Referring to the procedure and conditions in example 1, a4 was changed to a40 to afford compound 41.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):8.03(d,J＝7.96Hz,2H),7.52–7.47(m,3H),7.43(d,J＝7.80Hz,2H),7.36(d,J＝7.68Hz,2H),7.30(d,J＝8.40Hz,1H),6.89(dd,J＝11.72Hz,J＝8.16Hz,1H),4.19(s,2H),1.97(s,3H).LC-MS:calcd forC24H19F4N2O2S[M+H]+:475.10,found 475.26.
example 42 preparation of Compound 42
Referring to the procedure and conditions in example 1, a4 was changed to a41 to afford compound 42.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):11.77(s,1H),7.88(d,J＝7.80Hz,2H),7.76(d,J＝8.28Hz,1H),7.46(dd,J＝12.72Hz,J＝7.52Hz,1H),7.30(m,4H),6.97(d,J＝7.56Hz,2H),6.78(dd,J＝11.20Hz,J＝8.08Hz,1H),3.97(s,3H),3.05(s,3H),1.82(s,3H).LC-MS:calcdfor C25H21F4N2O2S[M+H]+:489.12,found 489.21.
example 43 preparation of Compound 43
Referring to the procedure and conditions in example 1, a4 was changed to a42 to afford compound 43.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.51(d,J＝7.84Hz,2H),7.46–7.42(m,1H),7.36–7.29(m,5H),7.19(d,J＝7.80Hz,2H),6.89–6.83(m,1H),4.00(s,2H),1.95(s,3H),1.71(s,3H).LC-MS:calcd for C26H22F4NO2[M+H]+:456.15,found 456.22.
example 44 preparation of Compound 44
Referring to the procedure and conditions in example 1, a4 was changed to a43 to afford compound 44.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.47(dd,J＝13.12Hz,J＝7.84Hz,1H),7.39(d,J＝7.56Hz,2H),7.34–7.29(m,3H),7.20(d,J＝7.84Hz,2H),7.03(d,J＝7.92Hz,2H),6.89(dd,J＝11.52Hz,J＝8.28Hz,1H),6.59(t J＝74.12Hz,1H),4.03(s,2H),1.97(s,3H).LC-MS:calcd for C24H19F3NO2[M+H]+:410.13,found 410.36.
example 45 preparation of Compound 45
Referring to the procedure and conditions in example 1, a4 was changed to a44 to afford compound 45.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.48–7.33(m,6H),7.30(d,J＝7.96Hz,2H),7.20(d,J＝7.88Hz,2H),4.96(q,J＝6.92Hz,1H),4.01(s,2H),1.94(s,3H).LC-MS:calcd for C25H20F4NO2[M+H]+:441.14,found 441.21.
example 46 preparation of Compound 46
Referring to the procedure and conditions in example 1, a4 was changed to a45 to afford compound 46.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):11.54(s,1H),7.77(d,J＝8.44Hz,1H),7.48–7.42(m,1H),7.26(d,J＝8.08Hz,2H),7.03(d,J＝8.16Hz,2H),6.99(d,J＝8.44Hz,2H),6.80(dd,J＝11.64Hz,J＝7.96Hz,1H),3.83(s,2H),1.82(s,2H),1.29(s,9H).LC-MS:calcd forC27H27FNO[M+H]+:400.20,found 400.23.
example 47 preparation of Compound 47
Referring to the procedure and conditions in example 1, a4 was changed to a46 to afford compound 47.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.50–7.46(m,1H),7.39(d,J＝8.08Hz,2H),7.33(d,J＝8.04Hz,2H),7.09(d,J＝8.56Hz,1H),7.25(d,J＝8.36Hz,2H),7.16(d,J＝8.32Hz,2H),6.91(dd,J＝11.80Hz,J＝7.96Hz,1H),4.03(s,2H),1.97(s,3H).LC-MS:calcd for C23H18FNO[M+H]+:378.10,found 378.19.
example 48 preparation of Compound 48
Referring to the procedure and conditions in example 1, a4 was changed to a47 to afford compound 48.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.45–7.42(m,1H),7.33(d,J＝8.04Hz,2H),7.28(d,J＝7.88Hz,2H),7.09(d,J＝8.44Hz,2H),6.89–6.80(m,3H),3.95(m,2H),3.76(s,3H),1.95(s,3H).LC-MS:calcd for C24H21FNO2[M+H]+:374.15,found 374.23.
example 49 preparation of Compound 49
Taking 250mg of compound 32 in a50 ml round bottom flask, adding 450mg of lithium chloride, 5ml of methanol and 20ml of tetrahydrofuran at room temperature, then adding 400mg of sodium borohydride in portions, refluxing for 12 hours at 70 ℃, adding 2N hydrochloric acid, and extracting with ethyl acetate to obtain an organic phase, adding dichloromethane: passing through a silica gel column with methanol 100:5 gave compound 49,120mg as a white solid in 51% yield.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.58–7.56(m 3H),7.51–7.47(m,1H),7.36(dd,J＝7.80Hz,J＝1.72Hz,1H),7.31(d,J＝7.28Hz,2H),7.26(d,J＝8.12Hz,2H),4.66(s,2H),2.00(s,3H).LC-MS:calcd for C25H20F4NO2S[M+H]+:474.11,found474.21.
example 50 preparation of Compound 50
Weighing 2g of 2-bromo-5-acetylpyridine, 2.1g of p-trifluoroacetylaminophenol, 380mg of cuprous iodide, 492mg of 2-pyridinecarboxylic acid and 4.3g of tripotassium phosphate in a 100ml round-bottom flask under the protection of argon, adding 20ml of DMSO as a solvent, reacting at 110 ℃ for about 10 hours, cooling to room temperature, adding 100ml of water, extracting with 20ml of ethyl acetate for 3 times, decompressing the obtained organic phase, spin-drying the solvent, and using petroleum ether as a residue: ethyl acetate 5:1 (vol/vol) was passed through a silica gel column to give 2.1g of intermediate a48 (intermediate a48 as a white solid) in 65% yield.
Referring to the procedures and conditions in example 1, A3 and a4 were changed to a48 and a14 to obtain compound 48.
The characterization data are as follows:
H-NMR(400MHz,MeOD,ppm):6.57(s,1H),7.18(d,J＝8.68Hz,1H),7.23(d,J＝8.88Hz,2H)，7.51(m,1H)，7.53(t,J＝7.76Hz,1H),7.76(m，3H),8.26(m,2H),8.58(d,J＝2.08Hz,1H).LC-MS:calcd forC22H15F3N3O3[M+H]+:426.10,found 426.24.
example 51 preparation of Compound 51
Weighing 400mg of 2-bromo-4-propionylpyridine and 451mg of p-trifluoroacetylphenol into a25 ml round-bottom flask, adding 276mg of potassium carbonate and 10ml of anhydrous DMF, reacting at 130 ℃ for 5 hours under the protection of argon, cooling to room temperature, adding 100ml of water, extracting with 20ml of dichloromethane for three times, combining organic phases, washing with water and saturated common salt in sequence, carrying out reduced pressure spin-drying on the organic phases, and reacting with petroleum ether: passing through a silica gel column with ethyl acetate 6:1 gave 228mg of intermediate a49 (white solid) in 34% yield.
Referring to the procedure and conditions in example 1, A3 and a4 were changed to a49 and a14 to obtain compound 51.
The characterization data are as follows:
H-NMR(400MHz,d6-DMSO,ppm):1.93(s,3H),7.22–7.30(m,4H),7.60(m,2H),7.77(d,J＝8.72Hz,2H),8.08(dd,J＝1.68Hz,J＝8.44Hz,1H),8.13(d,J＝8.08Hz,1H),8.37(s,1H),11.37(b,1H),11.71(s,1H).LC-MS:calcd for C23H17F3N3O3[M+H]+:440.11,found440.21.
example 52 preparation of Compound 52
Weighing 400mg of 2-bromo-4-propionyl pyridine and 427mg of p-trifluoromethylthiophenol into a25 ml round-bottom flask, adding 276mg of potassium carbonate and 10ml of anhydrous DMF, reacting at 130 ℃ for 5 hours under the protection of argon, cooling to room temperature, adding 100ml of water, extracting with 20ml of dichloromethane for three times, combining organic phases, washing with water and saturated common salt in sequence, carrying out reduced-pressure spin-drying on the organic phases, and carrying out petroleum ether: passing through a silica gel column with ethyl acetate 8:1 gave 600mg of intermediate a50 (white solid) in 92% yield.
Referring to the procedure and conditions in example 1, A3 and a4 were changed to a50 and a14 to obtain compound 52. The characterization data are as follows:
H-NMR(400MHz,d6-DMSO,ppm):1.92(s,3H),7.29–7.38(m,4H),7.57-7.62(m,2H),7.80(d,J＝8.20Hz,2H),8.13(d,J＝8.00Hz,2H),8.40(s,1H),11.70(s,1H).LC-MS:calcdfor C22H16F3N2O2S[M+H]+:429.09,found 429.18.
example 53 preparation of Compound 53
1.5g of p-hydroxyacetone and A51 were put in a 100ml round-bottom flask, and 1.4g of potassium carbonate, 500mg of sodium iodide and 50ml of acetone were added, refluxed at 60 ℃ for 7 hours, and filtered to remove solids to obtain a filtrate. Then using petroleum ether: ethyl acetate 1:1 was gradually increased to dichloromethane: methanol: triethylamine 100:5:1, on silica gel column afforded 1.1g of intermediate a52 in 43% yield.
Referring to the procedure and conditions in example 1, A3 was changed to a52 to afford compound 53.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3,ppm):7.70(d,J＝8.36Hz,1H),7.40(dd,J＝13.12Hz,J＝7.96Hz,1H),7.23(d,J＝8.36Hz,1H),6.80(dd,J＝11.68Hz,J＝8.08Hz,1H),6.68(d,J＝8.24Hz,2H),4.05(t,J＝5.26Hz,2H),2.84(t,J＝5.26Hz,2H),2.60(m,4H),1.84(s,3H),1.66–1.63(m,4H),1.49–1.47(m,2H).LC-MS:calcd for C23H26FN2O2[M+H]+:381.19,found431.32.
example 54 preparation of Compound 54
Referring to the procedures and conditions in example 53, a51 was changed to a52 to provide compound 54.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.55–7.49(m,1H),7.43(d,J＝8.64Hz,2H),7.35(d,J＝8.48Hz,1H),7.06(d,J＝8.64Hz,2H),6.93(dd,J＝11.88Hz,J＝7.72Hz,1H),4.13(t,J＝6.12Hz,3H),3.75(t,J＝4.56Hz,4H),2.61(t,J＝7.44Hz,2H),2.55(m,4H),2.07–2.02(m,5H).LC-MS:calcd for C23H26FN2O3[M+H]+:397.18,found397.25.
example 55 preparation of Compound 55
Reference to preparation of a50 gave a 53;
500mg of A53 was put in a 100ml sealed tube, and 560mg of potassium carbonate, 664mg of potassium iodide and 500ul of 1, 4-dibromobutane were added thereto, and the mixture was heated at 90 ℃ for 10 hours, and then the solid was removed by filtration to obtain a filtrate. Then using petroleum ether: passage through a silica gel column with ethyl acetate 20:1 gave 400mg of intermediate a54 in 65% yield.
Referring to the procedure and conditions in example 1, A3 was changed to a54 to afford compound 55.
The characterization data are as follows:
1H-NMR(400MHz,d6-DMSO,ppm):11.61(s,1H),7.61–7.53(m,2H),7.38(d,J＝8.24,1H),7.27(d,J＝8.08,1H),7.00–6.91(m,4H),6.57(d,J＝7.92,2H),3.21(m,4H),1.94(m,4H),1.85(s,3H),.LC-MS:calcd for C26H23F2N2O2[M+H]+:433.16,found 433.18.
example 56 preparation of Compound 56
Reference to preparation of a54 gave a 56;
referring to the procedure and conditions in example 1, A3 was changed to a55 to afford compound 56.
The characterization data are as follows:
1H-NMR(400MHz,CDCl3:d4-MeOD＝0.2:0.3,ppm):7.47(m,1H),7.31(m,2H),7.14(d,J＝8.16Hz,1H),7.69–6.86(m,6H),3.08(m,4H),2.95(s,3H),1.72(m,4H),1.56(m,2H).LC-MS:calcd for C27H25F2N2O2[M+H]+:447.19,found 447.16.
EXAMPLE 57 antiviral Activity of Compounds of the invention
The compound prepared above was selected for antiviral activity testing.
The materials and instruments used are shown in tables 1 and 2, respectively.
Materials used in Table 1
TABLE 2 instruments used
The test procedure was as follows:
1. the experimental method comprises the following steps:
1) cell culture:
(1) the frozen Huh7.5.1 cells are taken out of liquid nitrogen and immediately placed into a37 ℃ water bath for thawing, and 15mL of DMEM + 10% FBS + 1% PS culture medium is added into a centrifuge tube until the cells are molten. Centrifuging at 800g for 5min, discarding supernatant, adding 13mL of the above suspension cells, packaging into T75 culture flask at 37 deg.C with 5% CO2The culture was carried out for 24 hours.
(2) Cell liquid change: by the next day, cells grew adherently. If the cell state was good, the medium in the flask was aspirated, washed once with 10mL of DMEM + 10% FBS + 1% PS medium, and then 13mL of DEME + 10% FBS + 1% PS medium was added. 37 ℃ and 5% CO2The culture was carried out for 2 days.
(3) Cell liquid change: on the fourth day, the growth state of the cells was observed, about 70% of the cells were attached to the bottom of the flask, the medium in the flask was aspirated, and after washing once with 10mL of DMEM + 10% FBS + 1% PS medium, 13mL of DEME + 10% FBS + 1% PS medium was added. 37 ℃ and 5% CO2The culture was carried out for 2 days.
(4) Pancreatin digestion of adherent cells: the culture flask was taken out, and the growth state of the cells was observed under an optical microscope. Approximately 90% of the cells were spread out over the bottom of the flask and were a monolayer. The culture broth in the cell culture flask was discarded. A0.25% pancreatin solution was added, the volume depending on the size of the flask, to allow sufficient infiltration of the cells. The culture bottle is placed in an incubator at 37 ℃ for about 1-3 minutes, the cells are visually dropped, and a proper amount of culture solution containing serum is added to stop the reaction. And (5) blowing and beating for dispersion.
(5) Counting by a blood counting plate: the hemocytometer plates and coverslips were washed with 95% ethanol. And (3) putting the cover glass on a counting area of the blood counting chamber, taking 50 mu L of cell sap, and adding 50 mu L of cell sap into the grooves on two sides of the middle platform of the counting chamber along the lower edge of the cover glass, so that the cell sap fills the counting area by utilizing the surface tension of the liquid and no bubbles are generated. Standing for a moment to allow the cells to settle on the counting plate and not drift with the liquid. The number of cells in the grid was observed under an optical microscope.
(6) Cell division: calculating the number of cells counted on the blood counting chamberDilution factor. 100 μ L of diluted cells were added to each well. RD cells were dispensed into 96-well plates (3 × 104/well). 37 ℃ and 5% CO2The culture was carried out for 1 day.
2) And (3) HCV virus culture:
when the cells are attached to the wall by about 90 percent, adding the virus with the final concentration of 100TCID50, blowing the cells to be completely floated after about 48 hours of infection, subpackaging the culture medium containing the virus into a50 mL sterile centrifuge tube, centrifuging at 1000rpm for 5min, and taking the supernatant, namely the amplified virus. The virus was packaged in sterile EP tubes and frozen at-80 ℃.
3) Screening for inhibitors
(1) Cultured huh7.5.1 cells were plated in 96-well plates at 3000 cells per well, and 100 μ l of cells per well were plated to a monolayer of approximately 90% abundance. (first day afternoon the plate was good, next morning use).
(2) To the experimental and cell control groups, 50. mu.l each of 50. mu.M and 2. mu.M inhibitor (diluted with DMEM + 10% FBS + 1% PS medium) was added to each well, and the cells were cultured at 37 ℃ in a 5% CO2 incubator for 6-8h, and 3 parallel experiments were repeated.
(3) To the experimental group, 50 μ l of eGFP-tagged HCV virus (diluted with DMEM + 10% FBS + 1% PS medium) was added to each well. To the virus control group, 50 μ l of EV 71 virus with eGFP tag, DMEM + 10% FBS + 1% PS medium 50 μ l was added; to the cell control group, 50. mu.l of DMEM + 10% FBS + 1% PS medium was added. Culturing at 37 deg.C in 5% CO2 incubator for 48 h.
(4) The 96-well plate was removed and observed under a fluorescence microscope. The results are recorded.
4) CPE Observation
(1) And selecting the drugs with obvious inhibition effect and low cytotoxicity for secondary screening. Inhibitors were diluted with DMEM + 10% FBS + 1% PS in 12 gradients at 100 μ M initial concentration, 3 fold dilution of drug concentration.
(2) Cultured huh7.5.1 cells were plated in 96-well plates at 3000 cells per well, and 100 μ l of cells per well were plated to a monolayer of approximately 90% abundance. (first day afternoon the plate was good, next morning use).
(3) 50. mu.l of the inhibitor diluted in step (1) was added to each well of the experimental group and the cell control group at 37 ℃ in 5% CO2The culture is carried out for 6-8h in an incubator, and 3 groups of parallel tests are repeated.
(4) After 6-8h of inhibitor addition, the 96-well plate was removed from the incubator. To the experimental group, 50 μ l of eGFP-tagged HCV virus (diluted with DMEM + 10% FBS + 1% PS medium) was added to each well. To the virus control group, 50. mu.l of an eGFP-tagged HCV virus, DMEM + 10% FBS + 1% PS medium, 50. mu.l was added; to the cell control group, 50. mu.l of DMEM + 10% FBS + 1% PS medium was added. 96-well plates were incubated at 37 ℃ with 5% CO2Culturing in an incubator for 48 h.
(5) The 96-well plate was removed and observed under a fluorescence microscope. The results are recorded.
5) Detection of inhibitors EC50
(1) Cultured huh7.5.1 cells were plated in 96-well plates at 3000 cells per well, and 100 μ l of cells per well were plated to a monolayer of approximately 90% abundance. (first day afternoon the plate was good, next morning use).
(2) Compounds were diluted with medium containing 5% DMSO and 10% FBS.
(3) The medium in each well of the experimental group was pipetted off the 96-well plate and 50. mu.L of diluted inhibitor was added to each 96-well plate, repeating three wells for each concentration. Three additional wells were used as virus control (no inhibitor added).
(4) The 96-well plate was placed at 37 ℃ in 5% CO2Culturing in an incubator for 6-8 h.
(5) 50. mu.L of HCV virus (containing luciferase reporter gene) at a concentration of 100TCID50JFH-1 was added to each well and carefully mixed. At 37 ℃ with 5% CO2Culturing in an incubator for 48 h.
(6) After 48h, the 96-well plate was removed, the supernatant was aspirated, 100 μ LRenilla-GloTMLuciferase reagent was added to each well, incubated at room temperature in the dark for 3-5 minutes, the liquid in each well was aspirated into a 96-well white plate and counted using Glomax plate reader reading.
Active EC for Compounds prepared in the examples of the invention50As shown in table 3.
TABLE 3 EC for the respective Compounds50
As can be seen from the data in Table 3, the compounds provided by the present invention have a better inhibitory activity against hepatitis C virus.
Claims (3)
1. A compound of the formula I,
in the formula I, m represents a substituent R1M is 0 or 1;
radical R1is-H, -F or-Cl;
radical R2is-H, -OH or-R, wherein R is alkyl with 1-6 carbon atoms;
radical R3is-R, wherein R is alkyl with 1-6 carbon atoms;
radical R4is-Q1-Y-Q2The radicals shown are, in each case,
wherein Q1Is a benzene ring substituted by 1 or more substituents, the substituents being-H, -F, -Br, -NO2、-NH2-C (═ O) OR OR-CH2OH, wherein R is alkyl with 1-6 carbon atoms;
wherein Y is selected from-O-, -CH2-、-CF2-、-CH2O-、-OCH2CH2-or-OCH2CH2CH2-；
Wherein Q2Is a benzene ring substituted with 1 or more substituents-CF3、-OCF3、-OCH2CF3、-NH2-n(R)n、-CN、-SF5、-SCF3、-C(＝O)OR、-C(＝O)OH、-S(＝O)2CF3、S(＝O)(＝NH)CF3、-S(＝O)(＝NR)CF3、-CH(OH)CF3、-OCHF2、-C(OH)RCF3or-R, wherein R is alkyl with 1-6 carbon atoms, n is 0, 1 or 2, and when n is 2, the groups R can be same or different.
2. The compound of claim 1, wherein: the structural formula of the compound is as follows:
3. use of a compound according to claim 1 or 2 for the manufacture of a medicament against hepatitis c virus;
the medicament is a pharmaceutically acceptable salt.
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| CN1829709A (en) * | 2003-08-01 | 2006-09-06 | 健亚生物科技公司 | Bicyclic imidazol derivatives against flaviviridae |
| CN103180310A (en) * | 2010-07-26 | 2013-06-26 | 爱尔兰詹森研发公司 | Hetero-bicyclic derivatives as hcv inhibitors |
| CN103864699A (en) * | 2012-12-11 | 2014-06-18 | 北京大学 | Preparation and application of new non-nucleoside S-DABOs pyrimidone derivatives having both anti-HBV effect and anti-HIV and anti-HCV effects |
| CN104203940A (en) * | 2011-12-28 | 2014-12-10 | 爱尔兰詹森研发公司 | Hetero-bicyclic derivatives as HCV inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1829709A (en) * | 2003-08-01 | 2006-09-06 | 健亚生物科技公司 | Bicyclic imidazol derivatives against flaviviridae |
| CN103180310A (en) * | 2010-07-26 | 2013-06-26 | 爱尔兰詹森研发公司 | Hetero-bicyclic derivatives as hcv inhibitors |
| CN104203940A (en) * | 2011-12-28 | 2014-12-10 | 爱尔兰詹森研发公司 | Hetero-bicyclic derivatives as HCV inhibitors |
| CN103864699A (en) * | 2012-12-11 | 2014-06-18 | 北京大学 | Preparation and application of new non-nucleoside S-DABOs pyrimidone derivatives having both anti-HBV effect and anti-HIV and anti-HCV effects |
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