CN115385902A - Benzimidazole compound and preparation method and application thereof - Google Patents

Benzimidazole compound and preparation method and application thereof Download PDF

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CN115385902A
CN115385902A CN202210950943.5A CN202210950943A CN115385902A CN 115385902 A CN115385902 A CN 115385902A CN 202210950943 A CN202210950943 A CN 202210950943A CN 115385902 A CN115385902 A CN 115385902A
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cyclopentylethyl
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邱净英
邹月庭
李淑琼
杨丽华
谷小珂
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Xuzhou Medical University
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Abstract

The invention discloses a benzimidazole compound and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry and pharmacotherapy. The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof has good anti-HBV activity, has strong inhibition effect on lamivudine and entecavir resistant HepG2A64 cells (mutation site: rtLl80M + rtM204V + rtTl 84L), and can be applied to preparation of anti-HBV drugs.
Figure DDA0003789110320000011

Description

Benzimidazole compound and preparation method and application thereof
Technical Field
The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a benzimidazole compound. The compounds can be used for preparing medicines with anti-Hepatitis B Virus (HBV) effect. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Hepatitis B is an infectious disease caused by Hepatitis B Virus (HBV) in a chronic carrier state. The chronic hepatitis B has poor prognosis and can be developed into cirrhosis and primary liver cancer, which seriously harms the health of human beings. Currently, anti-HBV drugs used clinically mainly include immunomodulator interferon and HBV DNA polymerase/reverse transcriptase inhibitor nucleoside analogs.
The immunomodulator mainly takes interferon-alpha (INF-alpha) and pegylated interferon-alpha (pegylated interferon-alpha) as main materials, and enhances the resistance of an immune system to viruses by promoting immune cells to express cytokines, enhancing the activities of macrophages and natural killer cells (NK cells) and the like; in addition, interferons can bind directly to viruses, preventing assembly of viral particles. The interferon has the defects of low continuous response rate, multiple side effects and the like.
The nucleotide (acid) analogues comprise lamivudine (lamivudine), entecavir (entecavir), telbivudine (telbivudine), tenofovir (tenofovir), adefovir dipivoxil (adefovir dipivoxil), and the antiviral action mechanism is that after the nucleotide (acid) analogues are phosphorylated, the nucleotide chain of the virus can be incorporated, and the continuous synthesis of the nucleic acid is stopped; and can inhibit the activity of DNA polymerase and reverse transcriptase, thereby inhibiting viral replication. The nucleoside analogue has the target of HBV DNA polymerase/reverse transcriptase, only affects ccc DNA circulation and cannot completely remove ccc DNA, so the phenomenon of relapse is easy to recur after drug withdrawal. In addition, the replication process of HBV has a reverse transcription link, and the reverse transcriptase lacks the function of correction and repair due to the lack of endonuclease, so that HBV is easy to generate drug-resistant variation in the replication process.
In summary, although there are many anti-HBV drugs in clinical practice, the existing drugs still cannot meet the requirements of treatment due to the complexity of the etiology of hepatitis b, the "rebound" caused by the drugs not being able to completely eliminate the virus, "the drug resistance of the virus, and the toxic and side effects of the drugs.
In recent years, pharmaceutical workers at home and abroad break through the life cycle of HBV, expect to effectively play an anti-HBV role by activating the immune response of an organism and solve the problems of rebound and drug resistance of the existing anti-HBV drugs.
Disclosure of Invention
The invention aims to provide a benzimidazole compound based on the prior art, and pharmacological experiments prove that the compound has good anti-HBV activity and has stronger inhibiting effect on lamivudine and entecavir resistant HepG2A64 cells (mutation site: rtLl80M + rtM204V + rtTl 84L).
Another object of the present invention is to provide a process for the preparation of the above compound.
Another object of the present invention is to provide a pharmaceutical use of the above compound.
The technical scheme of the invention is as follows:
the invention relates to a compound with a structure shown as a general formula I, isomers, pharmaceutically acceptable salts thereof,
Figure BDA0003789110300000021
wherein, the first and the second end of the pipe are connected with each other,
R 1 represents hydrogen, halogen, C 1 -C 6 Alkyl, cyano, trifluoromethyl, hydroxy, amino, ester, nitro, C 1 -C 6 Alkoxy or C 1 -C 6 An alkylamino group;
R 2 represents cyclopentane, cyclohexane, phenyl or a substituted phenyl group, which may be optionally mono-or polysubstituted with: cyano, trifluoromethyl, hydroxy, amino, ester, nitro, halogen,C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkylamino alkoxy, substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 An alkylamino group;
said substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 The substituents in alkylamino are: morpholine, piperazine, pyrrole, piperidine, substituted piperazine or substituted piperidine;
the substituent in the substituted piperazine or substituted piperidine is as follows: hydroxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, piperidinyl or carboxy;
x represents-CO-, -NH-CO-, -CO-NH-, a covalent bond, -NH-, an S atom, -S (= O) 2 -、-NH(SO 2 ) -or an O atom;
R 3 represents morpholine, piperidine, imidazole, pyrrole, pyrazole, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino, substituted phenylamino, pyrimidine, pyridine or substituted phenyl, which substituted phenyl or substituted phenylamino may optionally be mono-or polysubstituted by the following substituents: cyano, trifluoromethyl, hydroxy, amino, ester, nitro, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkylamino alkoxy, substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 An alkylamino group;
said substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 Substituents in alkylamino are: morpholine, piperazine, pyrrole, piperidine, substituted piperazine or substituted piperidine;
the substituent in the substituted piperazine or the substituted piperidine is as follows: hydroxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, piperidinyl, or carboxy;
R 4 represents hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl phenyl, C 1 -C 6 An alkoxyphenyl or halophenyl group;
n represents an integer of 1 to 6;
m represents an integer of 1 to 6.
In a preferred embodiment, R 1 Represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, cyano, methoxy or ethoxy.
In a more preferred embodiment, R 1 Represents hydrogen.
In a preferred embodiment, R 2 Represents cyclopentane, cyclohexane, phenyl or a substituted phenyl group, which may be optionally mono-or polysubstituted with: cyano, trifluoromethyl, hydroxy, amino, nitro or halogen.
In a more preferred embodiment, R 2 Represents cyclopentane, cyclohexane or phenyl.
In a preferred embodiment, R 3 Represents morpholine, piperidine, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino, substituted phenylamino or substituted phenyl which may optionally be mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, hydroxy, amino, nitro, halogen, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 An alkylamino group.
In a more preferred embodiment, R 3 Represents morpholine, piperidine, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino or substituted phenyl which may be optionally mono-or polysubstituted with: cyano, trifluoromethyl, hydroxy, amino, nitro, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy or ethoxy.
In a particularly preferred embodiment, R 3 Represents morpholine, piperidine, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino or substituted phenyl which may be optionally mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy or ethoxy.
In a preferred embodiment of the present invention,R 4 represents hydrogen, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group.
In a more preferred embodiment, R 4 Represents hydrogen, methyl or ethyl. Particularly preferably, R 4 Represents hydrogen.
In a preferred embodiment of the method, the first and second containers are, X represents-CO-, -NH-CO-, -CO-NH-or a covalent bond.
In a more preferred embodiment, X represents-CO-, -NH-CO-or a covalent bond.
In a preferred embodiment, n represents an integer from 1 to 3. Particularly preferably, n represents 2.
In a preferred embodiment, m represents an integer of 2 to 5. For example, m represents 2, 3,4 or 5.
Further, the compound of formula I is preferably selected from the following compounds:
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-morpholin-1-one (7 A3);
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (piperidin-1-yl) propan-1-one (7 A4);
n-cyclohexyl-3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propanamide (7A 6);
n-cyclopentyl-3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propanamide (7 A7);
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (o-tolyl) propylamine (7 a 10);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 1);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) cyclopentanecarboxamide (7B 2);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-methylbenzamide (7B 4);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-methylbenzamide (7B 5);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-methylbenzamide (7B 6);
2-chloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 7);
3-chloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 8);
4-chloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 9);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2- (trifluoromethyl) benzamide (7B 10);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3- (trifluoromethyl) benzamide (7B 11);
3-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 12);
4-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 13);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4- (trifluoromethyl) benzamide (7B 14);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-iodobenzamide (7B 15);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-iodobenzamide (7B 16);
2-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 17);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-iodobenzamide (7B 18)
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-fluorobenzamide (7B 19);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-fluorobenzamide (7B 20);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-fluorobenzamide (7B 21);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-methoxybenzamide (7B 22);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-methoxybenzamide (7B 23);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-methoxybenzamide (7B 24);
3-cyano-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 25);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-ethoxybenzamide (7B 26);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-ethoxybenzamide (7B 27);
2, 4-dichloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 28);
3, 4-dichloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 29);
3, 5-dichloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 30);
4-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-fluorobenzamide (7B 33);
3, 5-dibromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 34);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3, 4-difluorobenzamide (7B 35);
n- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-ethylbenzamide (7B 40);
4- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) butan-1-one (7C 2);
6- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) hexan-1-one (7C 3);
5- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) pentan-1-one (7C 4);
3- (5- (5-phenethyl-1, 2, 4-oxadiazol-3-yl) -1H-benzo [ D ] imidazol-1-yl) -1- (pyrrolidin-1-yl) propan-1-one (7D 1);
3- (5- (5- (2-cyclohexylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ D ] imidazol-1-yl) -1- (pyrrolidin-1-yl) propan-1-one (7D 2);
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-methyl-1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) propan-1-one (7E 1)
5- (2-cyclopentylethyl) -3- (1- (3- (pyrrolidin-1-yl) propyl) -1H-benzo [ d ] imidazol-5-yl) -1,2, 4-oxadiazole (7F 1);
5- (2-cyclopentylethyl) -3- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-benzo [ d ] imidazol-5-yl) -1,2, 4-oxadiazole (7F 2);
4- (3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propyl) morpholine (7F 3);
n- (3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propyl) -2-methoxybenzamide (7G 1);
n- (4- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) butyl) -2-methoxybenzamide (7G 2);
n- (5- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) pentyl) -2-methoxybenzamide (7G 3);
n- (3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propyl) -4-methoxybenzamide (7G 4);
n- (4- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) butyl) -4-methoxybenzamide (7G 5);
n- (5- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) pentyl) -4-methoxybenzamide (7G 6).
The structural formulae of the above-mentioned compounds are shown below:
Figure BDA0003789110300000051
Figure BDA0003789110300000061
Figure BDA0003789110300000071
Figure BDA0003789110300000081
Figure BDA0003789110300000091
Figure BDA0003789110300000101
the invention discloses a preparation method of a compound shown in a general formula I,
a) When X represents a covalent bond, the synthetic route is as follows:
Figure BDA0003789110300000102
the specific preparation method of the route comprises the following steps: the method comprises the following steps of (1) adding 4-chloro-3-nitrobenzonitrile and derivatives thereof with hydroxylamine hydrochloride to obtain an intermediate product 1, condensing the intermediate product 1 with substituted acid, directly heating, dehydrating and cyclizing to obtain an intermediate product 2, carrying out nucleophilic substitution on the intermediate product 2 and various substituted amines to obtain an intermediate product 3, reducing the intermediate product 3 with stannous chloride to obtain an intermediate product 4, and continuously cyclizing the intermediate product 4 with various substituted acids to obtain a target compound, wherein the specific synthetic route is as follows:
Figure BDA0003789110300000111
b) When X represents-NH-CO-, the synthetic route is as follows:
Figure BDA0003789110300000112
the specific preparation method of the route comprises the following steps: the method comprises the following steps of (1) adding 4-chloro-3-nitrobenzonitrile and derivatives thereof with hydroxylamine hydrochloride to obtain an intermediate product 1, condensing the intermediate product 1 with substituted acid, then directly heating, dehydrating and cyclizing to obtain an intermediate product 2, carrying out nucleophilic substitution on the intermediate product 2 and various amine compounds to obtain an intermediate product 5, condensing the intermediate product 5 with various substituted acyl chlorides to obtain an intermediate product 6, reducing the intermediate product 6 with stannous chloride to obtain an intermediate product 7, and cyclizing the intermediate product 7 with various substituted acids to obtain a target compound, wherein the specific synthetic route is as follows:
Figure BDA0003789110300000121
c) When X represents-CO-, the synthetic route is as follows:
Figure BDA0003789110300000122
the specific preparation method of the route comprises the following steps: the method comprises the following steps of performing addition reaction on 4-chloro-3-nitrobenzonitrile and derivatives thereof and hydroxylamine hydrochloride to obtain an intermediate product 1, condensing the intermediate product 1 and substituted acid, directly heating, dehydrating and cyclizing to obtain an intermediate product 2, performing nucleophilic substitution on the intermediate product 2 and various amino-substituted ethyl esters to obtain an intermediate product 8, hydrolyzing the intermediate product 8 and sodium hydroxide to obtain an intermediate product 9, performing condensation reaction on the intermediate product 9 to obtain an intermediate product 10, reducing the intermediate product 10 by stannous chloride to obtain an intermediate product 11, and cyclizing the intermediate product 11 and various substituted acids to obtain a target compound, wherein the specific synthetic route is as follows:
Figure BDA0003789110300000131
these intermediates or the target compounds can be purified according to conventional isolation techniques and, if desired, converted into addition salts with pharmaceutically acceptable acids.
The invention also provides a pharmaceutical composition which takes the compound, the isomer or the pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient and is assisted by pharmaceutically acceptable auxiliary materials. In the composition, the active ingredient can also comprise other anti-HBV drugs or nucleoside anti-HBV drugs besides the compound, the isomer or the pharmaceutically acceptable salt thereof, such as lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir, and can also be combined with interferon and the like.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"alkyl" means a saturated aliphatic group of 1 to 20 carbon atoms, including straight and branched chain groups (a numerical range referred to in this application, e.g., "1 to 20", refers to the group, in this case alkyl, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups containing 1 to 4 carbon atoms are referred to as lower alkyl groups. When the lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"trifluoromethyl" means-CF 3 A group.
"amino" means-NH 2 A group.
"hydroxy" means an-OH group.
"cyano" means a-CN group.
"nitro" means-NO 2 A group.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
"alkylamino" denotes-NH- (alkyl), -N (alkyl) 2 Wherein the alkyl group herein may be a substituted or unsubstituted alkyl group. Representative examples include, but are not limited to, methylamino, ethylamino, dimethylamino, and the like.
"Alkylaminoalkoxy" refers to an alkoxy group in which at least one hydrogen is substituted by an alkylamino group, such as dimethylaminomethoxy, dimethylaminoethoxy, methylaminoethoxy, and the like.
"ester group" means a-C (O) O-alkyl group.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) Salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid and the like, or with organic acids including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, benzoic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid and the like.
(2) The acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, or a salt formed by coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, quinine, etc.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
By adopting the technical scheme of the invention, the advantages are as follows:
the benzimidazole compound provided by the invention has better anti-HBV activity. Researches show that the compounds not only have better anti-HBV activity, can effectively inhibit the replication of HBV DNA, but also have stronger inhibiting effect on lamivudine and entecavir resistant HepG2A64 cells (mutation site: rtLl80M + rtM204V + rtTl 84L). The quinazolinone compound, the isomer thereof or the pharmaceutically acceptable salt thereof provided by the invention can be applied to the preparation of anti-HBV drugs, and has excellent potential application prospects.
Drawings
Figure 1 is the inhibitory effect of compounds 7B11, 7B14, ETV, LAM on HepG2a64 HBV DNA, { P } <0.001; in the figure, 7B11, 7B14, ETV and LAM are shown in order from the left to the right.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-morpholinopropan-1-one (7A 3)
Dissolving (3.6mmol, 250.2mg) hydroxylamine hydrochloride with ethanol (6 mL), adding triethylamine (4.4mmol, 611.5 mu L) to dissociate at 60 ℃ for half an hour, heating to 85 ℃, adding 4-chloro-3-nitrobenzonitrile (2mmol, 365.12mg) to stir for reaction, concentrating under reduced pressure after 3 hours to remove a large amount of ethanol, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain (E) -4-chloro-N' -hydroxy-3-nitrobenzimidazole; dissolving N, N '-carbonyldiimidazole (1.87mmol, 302.94mg) in N, N-dimethylformamide, adding 3-cyclopentylpropionic acid (1.87mmol, 266.6. Mu.L) and triethylamine (3.74mmol, 519.8. Mu.L), stirring at room temperature for 1 hour, adding (E) -4-chloro-N' -hydroxy-3-nitrobenzimidazole (1.87mmol, 403.7mg), heating to 35 ℃, stirring for 3 hours, heating again to 110 ℃, stirring for reaction, stopping heating after three hours, naturally cooling to room temperature, extracting with ethyl acetate, washing with saturated salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3- (4-chloro-3-nitrophenyl) -5- (2-cyclopentylethyl) -1,2, 4-oxadiazole. Dissolving 3- (4-chloro-3-nitrophenyl) -5- (2-cyclopentylethyl) -1,2, 4-oxadiazole (2mmol, 642mg) in N, N-dimethylformamide, adding anhydrous potassium carbonate (6 mmol, 828mg), potassium iodide (0.5 mmol, 83mg) and ethyl 3-aminopropionate (4 mmol,468.6 mg), stirring at 60 ℃ for reaction, monitoring by TLC, stopping heating after three hours, naturally cooling to room temperature, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain ethyl 3- (4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-nitrophenyl) aminopropionate. Ethyl 3- (4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-nitrophenyl) aminopropionate (2mmol, 804.38mg) was dissolved in N, N-dimethylformamide, and after adding a sodium hydroxide solution (6 mmol, 240mg) and stirring in an ice-water bath for 3 hours, hydrochloric acid was added to pH =2, followed by suction filtration to give 3- ((4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-nitrophenyl) amino) propanoic acid (1.5 mmol, 561.2385mg). After dissolving 3- ((4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-nitrophenyl) amino) propionic acid (2mmol, 748.318mg) in methylene chloride, N-methylmorpholine (2.4mmol, 311. Mu.L), morpholine (2mmol, 174.24. Mu.L) and isobutyl chloroformate (4.8mmol, 527.7. Mu.L) were added slowly and dropwise, and the reaction mixture was stirred overnight in an ice-water bath, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to 3- ((4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-nitrophenyl) amino) -1-morpholinopropan-1-one (1.8mmol, 797.80mg). Dissolving 3- ((4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazole-3-yl) -2-nitrophenyl) amino) -1-morpholine propane-1-one (1.8mmol, 797.80mg) in ethanol, adding 1mL hydrochloric acid, stirring anhydrous stannous chloride (6 mmol, 1.14g) at 75 ℃ for reaction, stopping heating after three hours, naturally cooling to room temperature, concentrating under reduced pressure to remove a large amount of ethanol, dissolving with ethyl acetate, adding saturated sodium carbonate solution to adjust pH to alkalinity, filtering with diatomite, washing with ethyl acetate, extracting filtrate with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate to obtain 3- ((2-amino-4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) phenyl) amino) -1-morpholinopropan-1-one, dissolving 3- ((2-amino-4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) phenyl) amino) -1-morpholinopropan-1-one with 2mL of 5N hydrochloric acid and 4mL of formic acid, stirring and reacting at 110 deg.C for three hours, stopping heating, adding ammonia water under ice water bath condition to adjust pH =8, extraction with ethyl acetate, washing with saturated brine, and drying over anhydrous sodium sulfate gave a crude compound, which was subjected to silica gel column chromatography (dichloromethane: methanol =50, 1,v/V) to give the title compound.
White powder, yield 19%; m.p.160.6-162.5 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.54(s,1H,CH),8.14(br,1H,Ar-H),8.06(br,1H,Ar-H),7.50(br,1H,Ar-H),4.63(br,2H,CH 2 ),3.59(br,4H,2×CH 2 ),3.48(br,2H,CH 2 ),3.28(br,2H,CH 2 ),2.97(br,2H,CH 2 ),2.85(br,2H,CH 2 ),1.88(br,5H,2×CH 2 ,CH),1.59(br,4H,2×CH 2 ),1.17(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.98,168.52,167.95,145.07,143.67,135.26,122.26,121.28,120.09,109.71,66.51,66.10,45.50,41.93,40.71,39.51,32.75(2C),32.25(2C),25.93,25.03(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 23 H 29 N 5 O 3 ,424.2343,found 424.2337。
example 2
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (piperidin-1-yl) propan-1-one (7A 4)
Morpholine was replaced by piperidine in a similar manner to example 1, and the rest was the same as in example 1.
Yellow powder, yield 15%; m.p.200.3-201.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.54(s,1H,CH),8.12(br,1H,Ar-H),8.06(br,1H,Ar-H),7.50(br,1H,Ar-H),4.62(br,2H,CH 2 ),3.53(br,2H,CH 2 ),3.22(br,2H,CH 2 ),2.97(br,2H,CH 2 ),2.85(br,2H,CH 2 ),1.88(br,5H,2×CH2,CH),1.57(br,8H,4×CH 2 ),1.38(br,2H,CH 2 ),1.17(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.85,168.54,167.32,145.06,143.73,135.32,122.07,121.01,119.96,109.70,46.16,42.69,40.86,39.44,32.80,32.72,32.18(2C),26.02,25.86,25.19,24.97(2C),24.11；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 31 N 5 O 2 ,422.2551,found 422.2535。
example 3
N-cyclohexyl-3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propanamide (7A 6)
Morpholine was replaced by cyclohexylamine in a similar manner to example 1, except as in example 1.
Yellow powder, yield 25%; m.p.236.9-237.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm: 1 H NMR(400MHz,CDCl 3 )δppm:8.52(s,1H,CH),8.07–8.03(m,2H,2×Ar-H),7.50(d,J＝8.4Hz,1H,Ar-H),5.44(d,J＝8.0Hz,1H,NH),4.59(t,J＝6.0Hz,2H,CH 2 ),3.73–3.65(m,1H,CH),2.98(t,J＝8.0Hz,2H,CH 2 ),2.68(t,J＝6.4Hz,2H,CH 2 ),1.92–1.74(m,8H,4×CH 2 ),1.69–1.54(m,7H,3×CH 2 ,CH),1.33–1.15(m,4H,2×CH 2 ),1.00–0.92(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.20,168.70,168.29,144.83,143.44,135.38,122.48,121.48,119.96,110.24,48.68,41.38,39.71(2C),36.86,32.96(2C),32.44(2C),26.13,25.42,25.22(2C),24.85(2C)；ESI-HRMS(TOF):m/z[M-H] + calcd for C 25 H 33 N 5 O 2 ,434.2561,found434.2540。
example 4
N-cyclopentyl-3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propanamide (7A 7)
Morpholine was replaced with cyclopentylamine in a similar manner to example 1, and the procedure was otherwise the same as in example 1.
White powder, yield 18%; m.p.219.2-220.7 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.49(s,1H,CH),8.00(br,1H,Ar-H),7.94(br,1H,Ar-H),7.48(br,1H,Ar-H),5.76(br,1H,NH),4.56(br,2H,CH 2 ),4.12(br,1H,CH),2.96(br,2H,CH 2 ),2.66(br,2H,CH 2 ),1.89(br,7H,3×CH 2 ,CH),1.64–1.52(m,8H,4×CH 2 ),1.18(br,4H,2×CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.17,168.80,168.73,144.80,143.70,135.43,122.42,121.42,120.05,110.17,51.51,41.29,39.70,36.79,32.92(3C),32.44(2C),26.12,25.21(2C),23.65(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 31 N 5 O 2 ,422.2551,found 422.2551。
example 5
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -N- (o-tolyl) propylamine (7A 10)
The same procedure as in example 1 was repeated except that morpholine was replaced with 2-methylaniline in a similar manner to example 1.
Yellow powder, yield 21%; m.p.210.2-210.6 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.50(s,1H,CH),8.04–7.99(m,2H,2×Ar-H),7.53–7.50(m,3H,2×Ar-H,NH),7.18–7.05(m,3H,3×Ar-H),4.64(t,J＝6.0Hz,2H,CH 2 ),2.99–2.94(m,4H,2×CH 2 ),2.05(s,3H,CH 3 ),1.91–1.82(m,5H,2×CH 2 ,CH),1.66–1.53(m,4H,2×CH 2 ),1.20–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.20,168.71,167.86,144.88,143.72,135.39,134.91,130.68,130.38,126.78,126.11,124.14,122.56,121.58,120.14,110.16,41.09,39.71,37.06,32.97,32.44(2C),26.12,25.22(2C),17.78；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 29 N 5 O 2 ,444.2394,found 444.2383。
example 6
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 1)
Dissolving (3.6mmol, 250.2mg) hydroxylamine hydrochloride with ethanol (6 mL), adding triethylamine (4.4mmol, 611.5 mu L) to dissociate at 60 ℃ for half an hour, heating to 85 ℃, adding 4-chloro-3-nitrobenzonitrile (2mmol, 365.12mg) to stir for reaction, concentrating under reduced pressure after 3 hours to remove a large amount of ethanol, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain (E) -4-chloro-N' -hydroxy-3-nitrobenzimidazole; dissolving N, N '-carbonyldiimidazole (1.87mmol, 302.94mg) with N, N-dimethylformamide, adding 3-cyclopentylpropionic acid (1.87mmol, 266.6 mu L) and triethylamine (3.74mmol, 519.8 mu L), stirring at room temperature for 1 hour, adding (E) -4-chloro-N' -hydroxy-3-nitrobenzimidazole (1.87mmol, 403.7 mg), heating to 35 ℃, stirring for 3 hours, heating again to 110 ℃, stirring for reaction, stopping heating after three hours, naturally cooling to room temperature, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3- (4-chloro-3-nitrophenyl) -5- (2-cyclopentylethyl) -1,2, 4-oxadiazole. Dissolving 3- (4-chloro-3-nitrophenyl) -5- (2-cyclopentylethyl) -1,2, 4-oxadiazole (2mmol, 642mg) in N, N-dimethylformamide, adding anhydrous potassium carbonate (6mmol, 828mg), potassium iodide (0.5 mmol, 83mg) and ethylenediamine (4mmol, 267. Mu.L) to react at 60 ℃ with stirring, monitoring the reaction by TLC, stopping heating after three hours, naturally cooling to room temperature, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, dissolving the organic phase with dichloromethane after concentrating under reduced pressure, adding triethylamine (4.4mmol, 611.5. Mu.L) and benzoyl chloride (2.2mmol, 253.5. Mu.L), stirring overnight in ice water bath, extracting the reaction solution with dichloromethane, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain N- (2- ((4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazole-3-yl) -2-nitrophenyl) amino) ethyl) benzamide (1.4mmol, 628.89mg), dissolving by ethanol, adding 1mL of hydrochloric acid, stirring anhydrous stannous chloride (6 mmol, 1.14g) at 75 ℃ for reaction, stopping heating after three hours, naturally cooling to room temperature, concentrating under reduced pressure to remove a large amount of ethanol, adding ethyl acetate for dissolution, adding saturated sodium carbonate solution for adjusting pH to alkalinity, filtering by diatomite, washing by ethyl acetate, extracting filtrate by ethyl acetate, washing by saturated saline, drying by anhydrous sodium sulfate, concentrating under reduced pressure to obtain N- (2- ((2-amino-4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazole-3-organic silicon salt Yl) phenyl) amino) ethyl) benzamide. After dissolving N- (2- ((2-amino-4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) phenyl) amino) ethyl) benzamide (2mmol, 838.46mg) in 2mL of 5N hydrochloric acid and 4mL of formic acid, the reaction was stirred at 110 ℃, after three hours, heating was stopped, and after adjusting PH =8 by adding ammonia under ice-water bath conditions, extraction was performed with ethyl acetate, washing was performed with saturated brine, and drying was performed with anhydrous sodium sulfate to obtain a crude compound, which was subjected to silica gel column chromatography (dichloromethane: methanol = 50.
White powder, yield 23%; m.p.215.2-216.7 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.08(br,1H,CH),7.83–7.74(m,4H,NH,3×Ar-H),7.47–7.36(m,5H,5×Ar-H),4.42(br,2H,CH 2 ),3.84(br,2H,CH 2 ),2.93(br,2H,CH 2 ),1.87(br,5H,2×CH 2 ,CH),1.63–1.54(m,4H,2×CH 2 ),1.16(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.99,168.71,168.34,144.12,143.10,135.31,133.97,131.93,128.67(2C),127.31(2C),122.58,121.50,119.37,109.95,44.46,40.26,39.72,32.96,32.46(2C),26.10,25.24(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 27 N 5 O 2 ,430.2238,found 430.2226。
example 7
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) cyclopentaneamide (7B 2)
The benzoyl chloride was changed to cyclopentylchloride in a similar manner to example 6, and the rest was the same as example 6.
White powder, yield 25%; m.p.252.4-254.3 deg.C; 1 HNMR(400MHz,CDCl 3 )δppm:8.39(s,1H,CH),8.00(dd,J＝1.2,8.4Hz,1H,Ar-H),7.82(s,1H,Ar-H),7.47(d,J＝8.4Hz,1H,Ar-H),6.26(t,J＝5.2Hz,1H,NH),4.40(t,J＝5.6Hz,2H,CH 2 ),3.67(dd,J＝6.0,11.6Hz,2H,CH 2 ),2.98(t,J＝7.6Hz,2H,CH 2 ),2.52–2.45(m,1H,CH),1.93–1.55(m,17H,8×CH 2 ,CH),1.22–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.13,177.28,168.59,144.28,143.61,135.64,122.61,121.65,119.94,110.14,45.70,44.39,39.80,39.71,32.97,32.45(2C),30.54(2C),26.11(2C),25.98,25.22(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 31 N 5 O 2 ,422.2551,found 422.2548。
example 8
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-methylbenzamide (7B 4)
The same procedures as in example 6 were repeated except that benzoyl chloride was changed to 2-methylbenzoyl chloride in a similar manner to example 6.
White powder, yield 24%; m.p.224.9-226.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:7.88(br,1H,CH),7.85(d,J＝1.2Hz,1H,Ar-H),7.83(d,J＝1.6Hz,1H,Ar-H),7.42(d,J＝8.8Hz,1H,Ar-H),7.33–7.32(m,1H,Ar-H),7.31–7.30(m,1H,Ar-H),7.21(br,1H,NH),7.20(br,1H,Ar-H),7.16(br,1H,Ar-H),4.38(t,J＝5.2Hz,2H,CH 2 ),3.86(dd,J＝10.8,6.0Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),2.45(s,3H,CH 3 ),1.93–1.84(m,5H,2×CH 2 ,CH),1.71–1.52(m,4H,2×CH 2 ),1.25–1.14(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.91,170.95,168.23,143.92,143.10,136.35,135.72,135.01,131.25,130.30,127.17,125.84,122.49,121.46,119.23,109.79,44.76,39.74,39.60,33.00,32.48(2C),26.13,25.26(2C),20.13；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 29 N 5 O 2 ,444.2394,found 444.2374。
example 9
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-methylbenzamide (7B 5)
The same procedures as in example 6 were repeated except that benzoyl chloride was changed to 3-methylbenzoyl chloride in a similar manner to example 6.
White powder, yield 25%; m.p.205.0-206.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.08(s,1H,CH),7.91–7.88(m,1H,NH),7.84(dd,J＝8.4,1.2Hz,1H,Ar-H),7.61(s,1H,Ar-H),7.54(d,J＝7.6Hz,1H,Ar-H),7.49(br,1H,Ar-H),7.43(d,J＝8.8Hz,1H,Ar-H),7.29(d,J＝7.6Hz,1H,Ar-H),7.24(d,J＝7.2Hz,1H,Ar-H),4.44(t,J＝5.2Hz,2H,CH 2 ),3.86(dd,J＝10.8,5.6Hz,2H,CH 2 ),2.95(t,J＝8.0Hz,2H,CH 2 ),2.32(s,3H,CH 3 ),1.91–1.83(m,5H,2×CH 2 ,CH),1.70–1.53(m,4H,2×CH 2 ),1.20–1.14(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.01,168.85,168.38,144.15,143.16,138.52,135.37,133.85,132.69,128.54,128.06,124.28,122.56,121.47,119.41,110.01,44.53,40.27,39.73,32.97,32.47(2C),26.12,25.25(2C),21.42；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 26 H 29 N 5 O 2 ,466.2213,found 466.2196。
example 10
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-methylbenzamide (7B 6)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that 4-methylbenzoyl chloride was used instead of benzoyl chloride.
Yellow powder, yield 21%; m.p.234.4-235.0 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.20(s,1H,CH),7.89(dd,J＝8.8,1.2Hz,1H,Ar-H),7.67–7.63(m,3H,3×Ar-H),7.53(t,J＝5.2Hz,1H,NH),7.45(d,J＝8.4Hz,1H,Ar-H),7.18(d,2H,J＝8Hz,2×Ar-H),4.47(t,J＝5.2Hz,2H,CH 2 ),3.86(dd,J＝5.2,10.4Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),2.38(s,3H,CH 3 ),1.92–1.83(m,5H,2×CH 2 ,CH),1.70–1.52(m,4H,2×CH 2 ),1.24–1.13(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.05,168.53,168.44,144.27,143.24,142.49,135.43,130.96,129.39(2C),127.24(2C),122.61,121.53,119.57,110.06,44.56,40.27,39.73,32.99,32.47(2C),26.13,25.25(2C),21.59；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 29 N 5 O 2 ,444.2394,found 444.2381。
example 11
2-chloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 7)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 2-chlorobenzoyl chloride, and the rest was the same as in example 6.
White powder, yield 26%; m.p.203.9-204.5 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.23(t,J＝6.0Hz,1H,NH),7.85(s,1H,CH),7.82(dd,J＝8.4,1.2Hz,1H,Ar-H),7.54(dd,J＝7.2,1.6Hz,1H,Ar-H),7.44–7.43(m,1H,Ar-H),7.42–7.41(m,1H,Ar-H),7.40(s,1H,Ar-H),7.36–7.32(m,1H,Ar-H),7.29–7.25(m,1H,Ar-H),4.42(t,J＝4.8Hz,2H,CH 2 ),3.92(dd,J＝10.8,6.0Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),1.93–1.84(m,5H,2×CH 2 ,CH),1.71–1.53(m,4H,2×CH 2 ),1.25–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.91,168.20,167.81,143.99,143.00,135.13,134.93,131.47,130.96,130.35,129.63,127.16,122.51,121.45,119.15,109.83,44.80,39.74,39.70,33.00,32.49(2C),26.13,25.26(2C)；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 25 H 26 ClN 5 O 2 ,486.1667,found 486.1648。
example 12
3-chloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 8)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-chlorobenzoyl chloride in a similar manner to example 6.
White powder, yield 25%; m.p.195.6-197.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.59(br,1H,NH),7.91(s,1H,CH),7.86(t,J＝0.8Hz,1H,Ar-H),7.77(dd,J＝8.4,0.8Hz,1H,Ar-H),7.70(d,J＝8.0Hz,1H,Ar-H),7.45–7.43(m,2H,2×Ar-H),7.38(d,J＝8.8Hz,1H,Ar-H),7.30(t,J＝8.0Hz,1H,Ar-H),4.43(t,J＝4.8Hz,2H,CH 2 ),3.92(dd,J＝5.6,10.0Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.70–1.54(m,4H,2×CH 2 ),1.25–1.17(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.99,168.21,167.32,143.88,142.77,135.69,135.21,134.73,131.90,129.96,127.82,125.59,122.64,121.55,119.03,109.91,44.57,40.32,39.74,32.98,32.48(2C),26.12,25.26(2C)；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 25 H 26 ClN 5 O 2 ,486.1667,found 486.1651。
example 13
4-chloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 9)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 4-chlorobenzoyl chloride in a similar manner to example 6.
Grey powder, yield 19%; m.p.247.9-249.6 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.27(br,1H,NH),7.94(d,J＝9.2Hz,1H,Ar-H),7.73–7.69(m,3H,3×Ar-H),7.47(d,J＝8.4Hz,1H,Ar-H),7.38(d,J＝8.4Hz,2H,2×Ar-H),7.25–7.23(m,1H,CH),4.51(t,J＝9.2Hz,2H,CH 2 ),3.90(dd,J＝5.6,10.8Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.68–1.55(m,4H,2×CH 2 ),1.23–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.05,168.25,167.59,143.84,142.90,138.20,135.38,132.23,128.94(2C),128.88(2C),122.66,121.62,119.23,110.00,44.55,40.45,39.74,32.97,32.48(2C),26.13,25.26(2C)；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 25 H 26 ClN 5 O 2 ,486.1667,found 486.1646。
example 14
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2- (trifluoromethyl) benzamide (7B 10)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 2-trifluoromethylbenzoyl chloride in a similar manner to example 6.
White powder, yield 15%; m.p.209.6-210.4 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.02(t,J＝5.6Hz,1H,NH),7.88(d,J＝1.2Hz,1H,CH),7.82(dd,J＝1.6,8.4Hz,1H,CH),7.74–7.72(m,1H,Ar-H),7.54–7.52(m,2H,2×Ar-H),7.47–7.45(m,1H,Ar-H),7.41(d,J＝8.8Hz,1H,Ar-H),7.36(s,1H,Ar-H),4.38(t,J＝5.2Hz,2H,CH 2 ),3.92(dd,J＝6.0,10.8Hz,2H,CH 2 ),2.97(t,J＝7.6Hz,2H,CH 2 ),1.94–1.85(m,5H,2×CH 2 ,CH),1.68–1.55(m,4H,2×CH 2 ),1.24–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.95,168.72,168.22,143.85,143.12,135.35,134.85,132.10,130.12,128.53,127.47,126.65,126.62,122.55,121.56,119.22,109.79,44.89,39.73,39.52,32.98,32.47(2C),26.09,25.25(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-58.54；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 26 F 3 N 5 O 2 ,498.2111,found 498.2107。
example 15
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3- (trifluoromethyl) benzamide (7B 11)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-trifluoromethylbenzoyl chloride in a similar manner to example 6.
White powder, yield 23%; m.p.212.7-213.6 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.35(t,J＝6.0Hz,1H,NH),8.13(s,1H,CH),8.04–8.00(m,2H,2×Ar-H),7.83(dd,J＝1.2,8.4Hz,1H,Ar-H),7.74(d,J＝8.0Hz,1H,Ar-H),7.52(t,J＝7.6Hz,1H,Ar-H),7.47(s,1H,Ar-H),7.41(d,J＝8.4Hz,1H,Ar-H),4.47(t,J＝5.2Hz,2H,CH 2 ),3.94(dd,J＝6.0,10.8Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.69–1.54(m,4H,2×CH 2 ),1.22–1.17(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.05,168.29,167.12,143.78,143.01,135.38,134.70,130.70,129.27,128.47,128.44,124.56,124.53,122.72,121.68,119.25,109.96,44.53,40.43,39.72,32.96,32.45(2C),26.08,25.24(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-62.61；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 26 F 3 N 5 O 2 ,498.2111,found 498.2099。
example 16
3-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 12)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-bromobenzoyl chloride in a similar manner to example 6.
Grey powder, yield 24%; m.p.210.0-214.0 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.74–8.71(m,1H,NH),8.01(t,J＝2.0Hz,1H,Ar-H),7.89(s,1H,CH),7.76–7.74(m,2H,2×Ar-H),7.59–7.56(m,1H,Ar-H),7.42(s,1H,Ar-H),7.35(d,J＝8.4Hz,1H,Ar-H),7.22(t,J＝8.0Hz,1H,Ar-H),4.41(t,J＝5.2Hz,2H,CH 2 ),3.89(dd,J＝5.6,10.4Hz,2H,CH 2 ),2.95(t,J＝7.6Hz,2H,CH 2 ),1.92–1.83(m,5H,2×CH 2 ,CH),1.71–1.53(m,4H,2×CH 2 ),1.23–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.02,168.25,167.17,143.92,142.78,135.88,135.25,134.82,130.67,130.21,126.03,122.78,122.70,121.64,119.11,109.95,44.57,40.31,39.73,32.97,32.47(2C),26.11,25.25(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 26 BrN 5 O 2 ,508.1343,found 508.1339。
example 17
4-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 13)
The procedure of example 6 was followed in a similar manner to change benzoyl chloride to 4-bromobenzoyl chloride, except that the procedure of example 6 was repeated.
White powder, yield 27%; m.p.229.9-230.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.15–8.13(m,1H,NH),8.02(br,1H,CH),7.84(dd,J＝1.2,8.4Hz,1H,CH),7.72–7.68(m,2H,2×Ar-H),7.53–7.50(m,3H,3×Ar-H),7.41(d,J＝8.8Hz,1H,Ar-H),4.46(t,J＝5.2Hz,2H,CH 2 ),3.89(dd,J＝6.0,10.8Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),1.92–1.83(m,5H,2×CH 2 ,CH),1.68–1.56(m,4H,2×CH 2 ),1.21–1.17(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.04,168.26,167.68,143.81,142.90,135.41,132.70,131.90(2C),129.05(2C),126.70,122.68,121.66,119.24,110.00,44.53,40.44,39.74,32.96,32.47(2C),26.11,25.25(2C)；ESI-HRMS(TOF):m/z[M-H] + calcd for C 25 H 26 BrN 5 O 2 ,506.1197,found 506.1181。
example 18
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4- (trifluoromethyl) benzamide (7B 14)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 4-trifluoromethylbenzoyl chloride, and the procedure was repeated.
White powder, yield 25%; m.p.243.8-246.6 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.33(t,J＝5.6Hz,1H,NH),7.99–7.92(m,3H,3×Ar-H),7.84(dd,J＝1.2,8.4Hz,1H,Ar-H),7.64(d,J＝8.4Hz,2H,2×Ar-H),7.49(s,1H,CH),7.42(d,J＝8.4Hz,1H,Ar-H),4.47(t,J＝5.2Hz,2H,CH 2 ),3.92(dd,J＝6.0,10.8Hz,2H,CH 2 ),2.95(t,J＝7.6Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.69–1.56(m,4H,2×CH 2 ),1.21–1.17(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.07,168.26,167.31,143.75,143.01,137.11,135.44,127.89(2C),125.73,125.70,122.75,121.74,119.31,109.94,44.44,40.55,39.72,32.94,32.45(2C),26.08,25.24(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-62.89；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 26 F 3 N 5 O 2 ,498.2111,found 498.2102。
example 19
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-iodobenzamide (7B 15)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 2-iodobenzoyl chloride, and the procedure of example 6 was repeated.
White powder, yield 25%; m.p.212.3-215.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:7.95–7.84(m,4H,NH,CH,2×Ar-H),7.54(s,1H,Ar-H),7.46(d,J＝8.4Hz,1H,Ar-H),7.36–7.29(m,2H,2×Ar-H),7.10–7.05(m,1H,Ar-H),4.43(t,J＝5.2Hz,2H,CH 2 ),3.91(dd,J＝5.6,10.8Hz,2H,CH 2 ),2.97(t,J＝7.6Hz,2H,CH 2 ),1.94–1.85(m,5H,2×CH 2 ,CH),1.69–1.55(m,4H,2×CH 2 ),1.23–1.18(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:178.55,168.93,166.89,142.73,141.75,140.13,138.72,133.70,130.09,127.06,126.94,121.19,120.17,117.93,108.55,91.55,43.48,38.43,38.39,31.64,31.13(2C),24.76,23.91(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 26 IN 5 O 2 ,556.1204,found 556.1192。
example 20
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-iodobenzamide (7B 16)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 3-iodobenzoyl chloride, and the procedure of example 6 was repeated.
White powder, yield 26%; m.p.209.9-212.0 deg.c; 1 H NMR(400MHz,CDCl 3 )δppm:8.36(t,J＝4.8Hz,1H,NH),8.16(s,1H,CH),8.00(d,J＝8.4Hz,1H,Ar-H),7.82–7.76(m,3H,3×Ar-H),7.50(s,1H,Ar-H),7.38(d,J＝8.4Hz,1H,Ar-H),7.11(t,J＝8.0Hz,1H,Ar-H),4.44(t,J＝4.8Hz,2H,CH 2 ),3.91(m,2H,CH 2 ),2.96(t,J＝7.2Hz,2H,CH 2 ),1.92–1.89(m,5H,2×CH 2 ,CH),1.68–1.56(m,4H,2×CH 2 ),1.26–1.18(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.06,168.34,167.09,144.05,143.01,140.75,136.49,135.96,135.36,130.36,126.70,122.73,121.65,119.27,110.00,94.32,44.62,40.37,39.78,33.02,32.52(2C),26.15,25.30(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 26 IN 5 O 2 ,556.1204,found 556.1188。
example 21
2-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 17)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 2-bromobenzoyl chloride in a similar manner to example 6.
Pink powder, yield 23%; m.p.198.2-199.6 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:7.97–7.94(m,1H,NH),7.91(s,1H,CH),7.85(dd,J＝0.8,8.4Hz,1H,Ar-H),7.60(dd,J＝1.2,8.0Hz,1H,Ar-H),7.52(s,1H,Ar-H),7.46–7.44(m,2H,2×Ar-H),7.32–7.23(m,2H,2×Ar-H),4.43(t,J＝5.2Hz,2H,CH 2 ),3.91(dd,J＝5.6,10.8Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.93–1.84(m,5H,2×CH 2 ,CH),1.69–1.53(m,4H,2×CH 2 ),1.25–1.18(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.98,168.65,168.32,144.15,143.24,137.34,135.10,133.53,131.56,129.39,127.68,122.60,121.57,119.56,119.48,109.92,44.69,39.79,39.73,32.99,32.47(2C),26.12,25.25(2C)；ESI-HRMS(TOF):m/z[M-H] + calcd for C 25 H 26 BrN 5 O 2 ,506.1197,found 506.1170。
example 22
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-iodobenzamide (7B 18)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 4-iodobenzoyl chloride, and the procedure of example 6 was repeated.
White powder, yield 17%; m.p.233.3-235.2 deg.c; 1 H NMR(400MHz,CDCl 3 )δppm:8.08(s,1H,NH),7.85(dd,J＝1.2,8.8Hz,2H,2×Ar-H),7.72(d,J＝4.8Hz,2H,2×Ar-H),7.54(s,1H,CH),7.51(d,J＝8.4Hz,2H,2×Ar-H),7.41(d,J＝8.8Hz,1H,Ar-H),4.45(t,J＝5.6Hz,2H,CH 2 ),3.87(dd,J＝5.6,10.8Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),1.92–1.82(m,5H,2×CH 2 ,CH),1.68–1.53(m,4H,2×CH 2 ),1.21–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.05,168.33,167.81,143.93,143.14,137.91(2C),135.43,133.22,128.92(2C),122.67,121.64,119.45,109.96,99.11,44.46,40.46,39.73,32.97,32.47(2C),26.13,25.25(2C)；ESI-HRMS(TOF):m/z[M-H] + calcd for C 25 H 26 IN 5 O 2 ,554.1058,found 554.1044。
example 23
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-fluorobenzamide (7B 19)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 2-fluorobenzoyl chloride, and the rest was the same as in example 6.
White powder, yield 15%; m.p.218.1-218.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.44(br,1H,NH),8.06–8.00(m,2H,2×Ar-H),7.86(s,1H,CH),7.52–7.43(m,2H,2×Ar-H),7.27–7.23(m,1H,Ar-H),7.08–7.03(m,2H,2×Ar-H),4.50(t,J＝6.0Hz,2H,CH 2 ),3.87(dd,J＝6.0,11.6Hz,2H,CH 2 ),2.95(t,J＝7.6Hz,2H,CH 2 ),1.91–1.80(m,5H,2×CH 2 ,CH),1.65–1.52(m,4H,2×CH 2 ),1.18–1.13(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.11,168.68,164.31,160.63(d, 1 J CF ＝246.8Hz),144.41,139.91,135.60,133.91(d, 3 J CF ＝9.3Hz),131.81,125.02,122.64,121.61,120.53(d, 2 J CF ＝11.5Hz),120.24,116.37(d, 2 J CF ＝24.3Hz),110.00,44.24,40.25,39.71,32.97,32.44(2C),26.11,25.22(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-113.16；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 26 FN 5 O 2 ,448.2143,found 448.2140。
example 24
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-fluorobenzamide (7B 20)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-fluorobenzoyl chloride in a similar manner to example 6.
Yellow powder, yield 19%; m.p.204.9-206.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.12(t,J＝5.6Hz,1H,NH),8.02(s,1H,CH),7.83(dd,J＝1.2,8.4Hz,1H,Ar-H),7.58–7.55(m,2H,2×Ar-H),7.51(s,1H,Ar-H),7.41(d,J＝8.4Hz,1H,Ar-H),7.37–7.32(m,1H,Ar-H),7.21–7.16(m,1H,Ar-H),4.46(t,J＝5.2Hz,2H,CH 2 ),3.89(dd,J＝5.6,10.4Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.69–1.54(m,4H,2×CH 2 ),1.21–1.18(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.02,168.29,167.35,164.00(d, 1 J CF ＝246.5Hz),143.92,143.00,136.18(d, 3 J CF ＝6.8Hz),135.33,130.37(d, 3 J CF ＝7.8Hz),122.88,122.67,119.29,119.05(d, 2 J CF ＝21.2Hz),114.88,114.66,109.92,44.24,40.25,39.71,32.97,32.44(2C),26.11,25.22(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-111.43；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 26 FN 5 O 2 ,448.2143,found 448.2146。
example 25
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-fluorobenzamide (7B 21)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 4-fluorobenzoyl chloride, and the rest was the same as in example 6.
White powder, yield 27%; m.p.198.8-200.7 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.27(br,1H,NH),7.97(s,1H,CH),7.86–7.80(m,3H,3×Ar-H),7.48–7.39(m,2H,2×Ar-H),7.06–7.02(m,2H,2×Ar-H),4.44(t,J＝5.2Hz,2H,CH 2 ),3.88(dd,J＝5.6,10.4Hz,2H,CH 2 ),2.97–2.93(m,2H,CH 2 ),1.91–1.83(m,
5H,2×CH 2 ,CH),1.61–1.55(m,4H,2×CH 2 ),1.21–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δ
ppm:180.02,168.25,167.62,166.22(d, 1 J CF ＝251.0Hz),143.80,142.88,135.41,130.12,129.88(d, 3 J CF
＝8.8Hz,2C),122.62,121.61,119.17,115.80(d, 2 J CF ＝21.8Hz,2C),110.00,44.57,40.45,39.73,32.95,
32.46(2C),26.06,25.24(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-107.34；ESI-HRMS(TOF):m/z
[M-H] + calcd for C 25 H 26 FN 5 O 2 ,446.1998,found 446.1979。
example 26
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -2-methoxybenzamide (7B 22)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 2-methoxybenzoyl chloride in a similar manner to example 6.
White powder, yield 20%; m.p.176.1-177.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.55(s,1H,CH),8.18(d,J＝7.6Hz,1H,Ar-H),8.02(d,J＝8.4Hz,1H,Ar-H),7.98(s,1H,Ar-H),7.87(br,1H,NH),7.54(d,J＝8.8Hz,1H,Ar-H),7.45(t,J＝7.2Hz,1H,Ar-H),7.09(t,J＝7.6Hz,1H,Ar-H),6.89(d,J＝8.4Hz,1H,Ar-H),4.52(t,J＝5.6Hz,2H,CH 2 ),3.89(dd,J＝5.6,11.2Hz,2H,CH 2 ),3.65(s,3H,CH 3 ),2.97(t,J＝7.6Hz,2H,CH 2 ),1.92–1.86(m,5H,2×CH 2 ,CH),1.65–1.54(m,4H,2×CH 2 ),1.18–1.17(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.17,168.75,166.10,157.53,144.69,144.05,135.72,133.39,132.19,122.55,121.57,121.45,120.71,120.27,111.43,110.27,55.84,44.59,39.87,39.70,32.96,32.44(2C),26.10,25.21(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 29 N 5 O 3 ,460.2343,found 460.2343。
example 27
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-methoxybenzamide (7B 23)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-methoxybenzoyl chloride in a similar manner to example 6.
White powder, yield 21%; m.p.190.3-191.1 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.17(s,1H,CH),7.88(dd,J＝1.2,8.4Hz,1H,Ar-H),7.67(t,J＝8.0Hz,1H,NH),7.59(s,1H,Ar-H),7.44(d,J＝8.4Hz,1H,Ar-H),7.36(br,1H,Ar-H),7.28–7.26(m,2H,2×Ar-H),7.03–7.00(m,1H,Ar-H),4.46(t,J＝5.2Hz,2H,CH 2 ),3.86(dd,J＝6.0,11.2Hz,2H,CH 2 ),3.78(s,3H,CH 3 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.92–1.83(m,5H,2×CH 2 ,CH),1.69–1.54(m,4H,2×CH 2 ),1.21–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm: 13 C NMR(100MHz,CDCl 3 )δppm:180.03,168.44,159.88,144.20,143.35,135.46,135.31,129.71,122.62,121.56,119.62,119.13,118.12,112.57,109.98,55.47,44.46,40.33,39.72,32.96,32.46(2C),26.09,25.24(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 29 N 5 O 3 ,460.2343,found 460.2337。
example 28
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-methoxybenzamide (7B 24)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that 4-methoxybenzoyl chloride was used instead of benzoyl chloride.
White powder, yield 26%; m.p.233.7-235.1 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.37(s,1H,CH),7.96(dd,J＝1.2,8.8Hz,1H,Ar-H),7.80(s,1H,Ar-H),7.68(d,J＝8.8Hz,2H,2×Ar-H),7.49(d,J＝8.0Hz,1H,Ar-H),6.88(d,J＝8.8Hz,2H,2×Ar-H),6.80(t,J＝5.6Hz,1H,NH),4.50(t,J＝5.6Hz,2H,CH 2 ),3.88–3.83(m,5H,CH 2 ,OCH 3 ),2.97(t,J＝8.0Hz,2H,CH 2 ),1.92–1.82(m,5H,2×CH 2 ,CH),1.67–1.54(m,4H,2×CH 2 ),1.20–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.12,168.58,167.90,162.62,144.40,135.62,128.97(2C),125.87,122.69,121.64,119.97,113.97(2C),110.11,55.59,44.56,40.34,39.73,32.98,32.46(2C),26.13,25.24(2C)；ESI-HRMS(TOF):m/z[M-H] - calcd for C 26 H 29 N 5 O 3 ,458.2198,found 458.2187。
example 29
3-cyano-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 25)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-cyanobenzoyl chloride in a similar manner to example 6.
White powder, yield 22%; m.p.226.2-227.1 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.71(t,J＝5.6Hz,1H,NH),8.16(s,1H,Ar-H),8.08(d,J＝8.0Hz,1H,Ar-H),7.90(s,1H,CH),7.79(d,J＝8.8Hz,1H,Ar-H),7.71(d,J＝8.8Hz,1H,Ar-H),7.53–7.47(m,2H,2×Ar-H),7.38(d,J＝8.8Hz,1H,Ar-H),4.47(t,J＝5.2Hz,2H,CH 2 ),3.94(dd,J＝5.6,10.0Hz,2H,CH 2 ),2.96(t,J＝7.2Hz,2H,CH 2 ),1.91–1.85(m,5H,2×CH 2 ,CH),1.68–1.54(m,4H,2×CH 2 ),1.21–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.08,168.18,166.39,143.72,142.81,135.42,135.07,134.91,131.85,131.40,129.59,122.73,121.68,118.97,118.02,112.81,109.99,44.56,40.50,39.72,32.96,32.47(2C),26.10,25.25(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 26 N 6 O 2 ,455.2190,found 455.2175。
example 30
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-ethoxybenzamide (7B 26)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 3-ethoxybenzoyl chloride, and the procedure of example 6 was repeated.
White powder, yield 30%; m.p.158.8-159.7 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.55(s,1H,CH),8.23(dd,J＝1.6,8.0Hz,1H,Ar-H),8.15(t,J＝5.6Hz,1H,NH),8.03–7.96(m,2H,2×Ar-H),7.54(d,J＝8.4Hz,1H,Ar-H),7.45–7.41(m,1H,Ar-H),7.08(t,J＝7.6Hz,1H,Ar-H),6.87(d,J＝8.4Hz,1H,Ar-H),4.52(t,J＝5.6Hz,2H,CH 2 ),3.98–3.87(m,4H,2×CH 2 ),2.98(t,J＝7.2Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.67–1.54(m,4H,2×CH 2 ),1.20–1.15(m,2H,CH 2 ),1.01(t,J＝7.2Hz,3H,CH 3 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.17,168.76,166.24,157.03,144.66,144.08,135.70,133.42,132.22,122.52,121.52,121.34,120.48,120.28,112.40,110.24,64.67,44.58,39.82,39.72,32.98,32.45(2C),26.13,25.22(2C),14.30；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 27 H 31 N 5 O 2 ,496.2319,found 496.2312。
example 31
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-ethoxybenzamide (7B 27)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 4-ethoxybenzoyl chloride, and the procedure of example 6 was repeated.
White powder, yield 26%; m.p.235.3-238.4 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.34(s,1H,CH),7.95(dd,J＝1.2,8.4Hz,1H,Ar-H),7.76(s,1H,Ar-H),7.68(d,2H,J＝8.8Hz,2×Ar-H),7.49(d,J＝8.8Hz,1H,Ar-H),6.95(t,J＝5.2Hz,1H,NH),6.87(d,J＝8.8Hz,2H,2×Ar-H),4.49(t,J＝5.2Hz,2H,CH 2 ),4.06(q,J＝7.2Hz,2H,CH 2 ),3.85(dd,J＝6.0,11.2Hz,2H,CH 2 ),2.97(t,J＝7.6Hz,2H,CH 2 ),1.98–1.83(m,5H,2×CH 2 ,CH),1.67–1.54(m,4H,2×CH 2 ),1.43(t,J＝7.2Hz,3H,CH 3 ),1.20–1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.15,168.53,167.97,162.02,144.35,128.98(2C),125.66,122.78,121.76,119.79,114.39(2C),110.21,63.76,44.62,40.25,39.72,32.99,32.46(2C),26.13,25.24(2C),14.77；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 27 H 31 N 5 O 3 ,496.2319,found 496.2306。
example 32
2, 4-dichloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 28)
The procedure of example 6 was repeated in a similar manner to change benzoyl chloride to 2, 4-dichloro-benzoyl chloride, except that the procedure of example 6 was repeated.
White powder, yield 25%; m.p.229.8-230.4 deg.C; 1 H NMR(400MHz,CDCl 3 )δppm:8.09(t,J＝5.2Hz,1H,NH),7.91(s,1H,CH),7.85(d,J＝8.4Hz,1H,Ar-H),7.50–7.41(m,4H,4×Ar-H),7.26–7.24(m,1H,Ar-H),4.44(t,J＝4.8Hz,2H,CH 2 ),3.91(dd,J＝5.6,10.8Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.93–1.86(m,5H,2×CH 2 ,CH),1.68–1.56(m,4H,2×CH 2 ),1.20–1.18(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:179.99,168.24,166.76,143.86,143.10,136.98,135.11,133.31,131.84,130.75,130.22,127.57,122.60,121.57,119.29,109.88,44.57,39.99,39.73,32.99,32.48(2C),26.12,25.25(2C)；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 25 H 25 Cl 2 N 5 O 2 ,520.1278,found 520.1286。
example 33
3, 4-dichloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 29)
The procedure of example 6 was repeated in a similar manner to change benzoyl chloride to 3, 4-dichloro-benzoyl chloride, except that the procedure of example 6 was repeated.
White powder, yield 18%; m.p.215.2-216.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.47(br,1H,NH),7.98–7.95(m,2H,2×Ar-H),7.81(d,J＝8.8Hz,1H,Ar-H),7.67(dd,J＝2.0,8.4Hz,1H,Ar-H),7.53(s,1H,CH),7.45–7.38(m,2H,2×Ar-H),4.46(t,J＝4.8Hz,2H,CH 2 ),3.92(dd,J＝5.2,10.0Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.69–1.56(m,4H,2×CH 2 ),1.22–1.19(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.05,168.20,166.39,143.72,142.84,136.36,135.36,133.62,133.12,130.69,129.71,126.66,122.72,121.70,119.12,109.93,44.58,40.52,39.74,32.96,32.47(2C),26.11,25.25(2C)；ESI-HRMS(TOF):m/z[M-H] + calcd for C 25 H 25 Cl 2 N 5 O 2 ,496.1313,found 496.1284。
example 34
3, 5-dichloro-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 30)
The procedure of example 6 was repeated in a similar manner to the procedure of example 6 except that benzoyl chloride was changed to 3, 5-dichlorobenzoyl chloride, and the rest was the same as in example 6.
White powder, yield 21%; m.p.222.2-223.1 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.75(br,1H,NH),7.89(br,1H,Ar-H),7.77(br,3H,3×Ar-H),7.54(br,1H,Ar-H),7.43(s,1H,CH),7.36(br,1H,Ar-H),4.45(br,2H,CH 2 ),3.95(br,2H,CH 2 ),2.96(br,2H,CH 2 ),1.90(br,5H,2×CH 2 ,CH),1.67–1.58(m,4H,2×CH 2 ),1.20(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.03,168.16,165.94,143.76,142.70,136.64,135.43,135.20(2C),131.66,126.22(2C),122.73,121.65,118.91,109.86,44.67,40.42,39.75,32.98,32.48(2C),26.12,25.26(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 25 Cl 2 N 5 O 2 ,498.1458,found498.1446。
example 35
4-bromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3-fluorobenzamide (7B 33)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3-fluorobenzoyl chloride in a similar manner to example 6.
White powder, yield 23%; m.p.233.3-233.7 deg.c; 1 H NMR(400MHz,CDCl 3 )δppm:8.85(br,1H,NH),7.78(s,1H,CH),7.76(br,1H,Ar-H),7.70–7.67(m,1H,Ar-H),7.52(d,J＝3.2Hz,1H,Ar-H),7.47(s,1H,Ar-H),7.36(d,J＝8.8Hz,1H,Ar-H),4.44(t,J＝4.8Hz,2H,CH 2 ),3.91(dd,J＝5.2,9.6Hz,2H,CH 2 ),2.96(t,J＝7.6Hz,2H,CH 2 ),1.92–1.84(m,5H,2×CH 2 ,CH),1.69–1.54(m,4H,2×CH 2 ),1.23–1.17(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:δ180.01,168.09,166.60,160.31(d, 1 J CF ＝247.7Hz),143.58,142.57,135.29,135.16(d, 4 J CF ＝3.0Hz),133.81,124.17(d, 4 J CF ＝3.2Hz),122.67,121.64,118.84,116.00(d, 2 J CF ＝23.8Hz),113.47(d, 2 J CF ＝20.7Hz),109.88,44.59,40.59,39.75,32.97,32.48(2C),26.12,25.27(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-105.44；ESI-HRMS(TOF):m/z[M-H] - calcd for C 25 H 25 BrFN 5 O 2 ,524.1103,found 524.0998。
example 36
3, 5-dibromo-N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) benzamide (7B 34)
The same procedures as in example 6 were repeated except for changing benzoyl chloride to 3, 5-dibromobenzoyl chloride in a similar manner to example 6.
White powder, yield 24%; m.p.222.6-223.1 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.57(br,1H,NH),7.98(s,1H,CH),7.93(br,2H,2×Ar-H),7.81(br,1H,Ar-H),7.73(br,1H,Ar-H),7.63(br,1H,Ar-H),7.39(br,1H,Ar-H),4.46(br,2H,CH 2 ),3.94(br,2H,CH 2 ),2.97(br,2H,CH 2 ),1.90(br,5H,2×CH 2 ,CH),1.67–1.57(m,4H,2×CH 2 ),1.20(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.08,168.17,165.71,143.87,142.58,136.64,137.15,136.98,129.49(2C),123.28,122.81,121.74,118.98,109.96,44.68,40.39,39.75,33.00,32.48(2C),26.14,25.26(2C)；ESI-HRMS(TOF):m/z[M-H] - calcd for C 25 H 25 Br 2 N 5 O 2 ,584.0302,found 584.0312。
example 37
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -3, 4-difluorobenzamide (7B 35)
The procedure of example 6 was repeated in a similar manner to that of example 6 except that benzoyl chloride was changed to 3, 4-difluorobenzoyl chloride, and the rest was the same as in example 6.
Yellow powder, yield 19%; m.p.221.2-222.4 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.62(t,J＝5.6Hz,1H,NH),7.80-7.74(m,3H,3×Ar-H),7.63-7.60(m,1H,Ar-H),7.46(s,1H,CH),7.36(d,J＝8.4Hz,1H,Ar-H),7.16-7.10(m,1H,Ar-H),4.44(t,J＝4.8Hz,2H,CH 2 ),3.90(dd,J＝5.6,10.0Hz,2H,CH 2 ),2.94(t,J＝7.6Hz,2H,CH 2 ),1.19-1.83(m,5H,2×CH 2 ,CH),1.67-1.55(m,4H,2×CH 2 ),1.21-1.16(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.00,168.12,166.53,154.08(dd,J CF ＝12.6,246.2Hz),151.49(dd,J CF ＝6.8,236.2Hz),143.53,142.70,135.36,130.99(t,J CF ＝3.9Hz),124.09(q,J CF ＝3.3Hz),122.65,121.66,118.94,117.59(d,J CF ＝35Hz),117.42,109.87,44.54,40.64,39.74,32.95,32.46(2C),26.08,25.25(2C)； 19 F NMR(376MHz,CDCl 3 )δppm:-131.91,-135.87；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 25 F 2 N 5 O 2 ,466.2049,found 466.2049。
example 38
N- (2- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethyl) -4-ethylbenzamide (7B 40)
The procedure of example 6 was repeated in a similar manner to change benzoyl chloride to 4-ethylbenzoyl chloride, except that the procedure of example 6 was repeated.
White powder, yield 27%; m.p.211.4-211.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.12(s,1H,CH),7.84(dd,J＝1.6,8.8Hz,1H,Ar-H),7.74–7.68(m,3H,NH,2×Ar-H),7.51(s,1H,Ar-H),7.42(d,J＝8.4Hz,1H,Ar-H),7.19(d,J＝8.0Hz,2H,2×Ar-H),4.43(t,J＝5.6Hz,2H,CH 2 ),3.84(dd,J＝5.6,10.8Hz,2H,CH 2 ),2.95(t,J＝7.6Hz,2H,CH 2 ),2.65(q,J＝7.6Hz,2H,CH 2 ),1.91–1.82(m,5H,2×CH 2 ,CH),1.66–1.54(m,4H,2×CH 2 ),1.23–1.15(m,5H,CH 2 ,CH 3 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.00,168.58,168.44,148.63,144.21,143.32,135.43,131.29,128.17(2C),127.38(2C),122.56,121.46,119.53,109.98,44.53,40.26,39.73,32.97,32.46(2C),28.86,26.11,25.24(2C),15.35；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 31 N 5 O 2 ,458.2551,found 458.2530。
example 39
4- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) butan-1-one (7C 2)
The procedure of example 1 was repeated in a similar manner to that of example 1 except that ethyl 3-aminopropionate was replaced with methyl 4-aminobutyrate.
White powder, yield 16%; m.p.132.2-132.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(d,J＝0.8Hz,1H,CH),8.03(dd,J＝8.4,1.6Hz,1H,Ar-H),7.98(s,1H,Ar-H),7.54(d,J＝8.4Hz,1H,Ar-H),4.38(t,J＝6.4Hz,2H,CH 2 )3.47(t,J＝6.8Hz,2H,CH 2 ),3.19(t,J＝6.4Hz,2H,CH 2 ),2.97(t,J＝8.0Hz,2H,CH 2 ),2.27–2.17(m,4H,2×CH 2 ),1.92–1.80(m,9H,4×CH 2 ,CH),1.68–1.50(m,4H,2×CH 2 ),1.21–1.10(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.11,169.70,168.82,144.50,143.93,135.91,122.34,121.28,120.19,110.43,46.54,45.84,44.33,39.71,32.99,32.44(2C),30.27,26.11(2C),25.22(2C),24.89,24.43；ESI-HRMS(TOF):m/z[M+Na] + calcd for C 24 H 31 N 5 O 2 ,444.2370,found 444.2355。
example 40
6- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) hexan-1-one (7C 3)
In a similar manner to example 1, ethyl 3-aminopropionate was replaced with methyl 6-aminocaproate, and the rest was the same as in example 1.
White powder, yield 15%; m.p.111.4-112.3 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(br,1H,NH),8.06–8.02(m,2H,2×Ar-H),7.48(d,J＝8.4Hz,1H,Ar-H),4.23(t,J＝7.2Hz,2H,CH 2 )3.45(t,J＝6.8Hz,2H,CH 2 ),3.34(t,J＝6.8Hz,2H,CH 2 ),2.99–2.95(m,2H,CH 2 ),2.23(t,J＝7.2Hz,2H,CH 2 ),1.98–1.80(m,11H,5×CH 2 ,CH),1.72–1.53(m,6H,3×CH 2 ),1.42–1.34(m,2H,CH 2 ),1.19–1.14(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.13,171.15,168.77,144.37,143.57,135.69,122.42,121.43,120.07,110.30,46.65,45.75,45.20,39.70,34.30,32.98,32.44(2C),29.80,26.62,26.15(2C),25.22(2C),24.45,24.15；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 35 N 5 O 2 ,450.2864,found 450.2861。
EXAMPLE 41
5- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) pentan-1-one (7C 4)
The procedure of example 1 was repeated in a similar manner to that of example 1 except that methyl 5-aminopentanoate was used instead of ethyl 3-aminopropionate.
White powder, yield 10%; m.p.143.3-144.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(s,1H,CH),8.05–8.01(m,2H,2×Ar-H),7.49(d,J＝8.8Hz,1H,Ar-H),4.25(t,J＝7.2Hz,2H,CH 2 )3.45(t,J＝6.8Hz,2H,CH 2 ),3.32(t,J＝6.8Hz,2H,CH 2 ),2.97(t,J＝7.6Hz,2H,CH 2 ),2.27(t,J＝7.2Hz,2H,CH 2 ),2.00–1.80(m,11H,5×CH 2 ,CH),1.75–1.52(m,6H,3×CH 2 ),1.19–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.11,170.58,168.81,144.32,143.84,135.74,122.36,121.32,120.19,110.28,46.61,45.77,45.45,39.70,33.85,32.98,32.44(2C),29.73,26.14(2C),25.22(2C),24.43,22.09；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 33 N 5 O 2 ,436.2707,found 436.2672。
example 42
3- (5- (5-phenethyl-1, 2, 4-oxadiazol-3-yl) -1H-benzo [ D ] imidazol-1-yl) -1- (pyrrolidin-1-yl) propan-1-one (7D 1)
The procedure of example 1 was repeated in a similar manner to that of example 1 except that 3-cyclopentylpropionic acid was changed to 3-phenylpropionic acid, and the operation was repeated as in example 1.
White powder, yield 19%; m.p.196.5.3-197.4 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.54(d,J＝0.8Hz,1H,Ar-H),8.15(s,1H,CH),8.06(dd,J＝8.4,1.6Hz,1H,Ar-H),7.52(d,J＝8.4Hz,1H,Ar-H),7.34–7.23(m,4H,4×Ar-H),4.63(t,J＝6.4Hz,2H,CH 2 ),3.43(t,J＝6.4Hz,2H,CH 2 ),3.30–3.17(m,6H,3×CH 2 ),2.79(t,J＝6.4Hz,2H,CH 2 ),1.87–1.78(m,4H,2×CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:178.95,168.86,167.82,145.30,143.91,139.60,135.58,128.78(2C),128.42(2C),126.76,122.37,121.27,120.32,109.98,46.56,45.95,40.81,34.77,32.71,28.65,25.98,24.32；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 25 N 5 O 2 ,416.2081,found 416.2081。
example 43
3- (5- (5- (2-cyclohexylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ D ] imidazol-1-yl) -1- (pyrrolidin-1-yl) propan-1-one (7D 2)
The procedure of example 1 was repeated in a similar manner to that of example 1 except that 3-cyclopentylpropionic acid was changed to 3-cyclohexylpropionic acid.
White powder, yield 12%; m.p.192.6-193.0 deg.c; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(s,1H,CH),8.13(s,1H,Ar-H),8.04(d,J＝8.4Hz,1H,Ar-H),7.51(d,J＝8.4Hz,1H,Ar-H),4.62(t,J＝6.0Hz,2H,CH 2 )3.42(t,J＝6.8Hz,2H,CH 2 ),3.17(t,J＝6.4Hz,2H,CH 2 ),2.97(t,J＝8.0Hz,2H,CH 2 ),2.78(t,J＝6.4Hz,2H,CH 2 ),1.85–1.71(m,11H,5×CH 2 ,CH),1.38–1.16(m,4H,2×CH 2 ),1.01–0.92(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.31,168.79,167.85,145.31,143.91,135.53,122.36,121.34,120.26,109.95,46.56,45.95,40.80,37.22,34.76,34.13,32.93(2C),26.54,26.24(2C),25.98,24.37(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 31 N 5 O 2 ,422.2551,found 422.2529。
example 44
3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-methyl-1H-benzo [ d ] imidazol-1-yl) -1- (pyrrolidin-1-yl) propan-1-one (7E 1)
The procedure of example 1 was repeated in a similar manner to the procedure of example 1 except that formic acid was changed to acetic acid, and the rest was the same as in example 1.
White powder, yield 5%; m.p.164.7-165.7 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.38(br,1H,Ar-H),7.96(dd,J＝8.4,1.6Hz,1H,Ar-H),7.40(d,J＝8.4Hz,1H,Ar-H),4.53(t,J＝7.2Hz,2H,CH 2 ),3.40(t,J＝6.4Hz,2H,CH 2 ),3.10(t,J＝6.4Hz,2H,CH 2 ),2.95(t,J＝7.6Hz,2H,CH 2 ),2.74(t,J＝6.8Hz,2H,CH 2 ),2.67(s,3H,CH 3 ),1.91–1.74(m,9H,4×CH 2 ,CH),1.65–1.51(m,4H,2×CH 2 ),1.18–1.13(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.03,168.91,168.01,153.37,142.90,136.85,121.69,121.10,118.84,109.60,46.65,45.97,40.09,39.70,34.28,32.98,32.44(2C),26.12,25.97,25.22(2C),24.32,14.07；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 31 N 5 O 2 ,422.2551,found 422.2547。
example 45
5- (2-Cyclopentanethyl) -3- (1- (3- (pyrrolidin-1-yl) propyl) -1H-benzo [ d ] imidazol-5-yl) -1,2, 4-oxadiazole (7F 1)
Dissolving (3.6mmol, 250.2mg) hydroxylamine hydrochloride with ethanol (6 mL), adding triethylamine (4.4mmol, 611.5 mu L) to dissociate at 60 ℃ for half an hour, heating to 85 ℃, adding 4-chloro-3-nitrobenzonitrile (2mmol, 365.12mg) to stir for reaction, concentrating under reduced pressure after 3 hours to remove a large amount of ethanol, extracting with ethyl acetate, washing with saturated saline solution, drying with anhydrous sodium sulfate, and concentrating the organic phase under reduced pressure to obtain (E) -4-chloro-N' -hydroxy-3-nitrobenzimidazole; will be provided withDissolving N, N '-carbonyldiimidazole (1.87mmol, 302.94mg) in N, N-dimethylformamide, adding 3-cyclopentylpropionic acid (1.87mmol, 266.6. Mu.L) and triethylamine (3.74mmol, 519.8. Mu.L), stirring at room temperature for 1 hour, adding (E) -4-chloro-N' -hydroxy-3-nitrobenzimidazole (1.87mmol, 403.7mg), heating to 35 deg.C, stirring at room temperature for 3 hours, heating to 110 deg.C again, stirring for reaction, stopping heating after three hours, cooling to room temperature naturally, extracting with ethyl acetate, washing with saturated salt water, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 3- (4-chloro-3-nitrophenyl) -5- (2-cyclopentylethyl) -1,2, 4-oxadiazole. Dissolving 3- (4-chloro-3-nitrophenyl) -5- (2-cyclopentylethyl) -1,2, 4-oxadiazole (2mmol, 642mg) in N, N-dimethylformamide, adding anhydrous potassium carbonate (6mmol, 828mg), potassium iodide (0.5mmol, 83mg) and 1- (3-aminopropyl) pyrrolidine (4mmol, 505.80. Mu.L), stirring at 60 ℃ for reaction, monitoring the reaction by TLC, stopping heating after three hours, naturally cooling to room temperature, extracting with ethyl acetate, washing with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -2-nitro-N- (3- (pyrrolidine-1-yl) propyl) aniline, dissolving with ethanol, adding 1mL hydrochloric acid, stirring anhydrous stannous chloride (6 mmol, 1.14g) at 75 deg.C for reaction, stopping heating after three hours, naturally cooling to room temperature, concentrating under reduced pressure to remove a large amount of ethanol, adding ethyl acetate for dissolution, adding saturated sodium carbonate solution to adjust pH to alkalinity, filtering with diatomite, washing with ethyl acetate, extracting the filtrate with ethyl acetate, washing with saturated saline solution, and drying with anhydrous sodium sulfate to obtain 4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -N 1 - (3- (pyrrolidin-1-yl) propyl) benzene-1, 2-diamine. Reacting 4- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -N 1 After dissolving (3- (pyrrolidin-1-yl) propyl) benzene-1, 2-diamine in 2mL of 5N hydrochloric acid and 4mL of formic acid, the reaction was stirred at 110 ℃, heating was stopped after three hours, and after adjusting PH =8 by adding ammonia water under ice-water bath conditions, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate to obtain a crude compound, which was subjected to silica gel column chromatography (dichloromethane: methanol =50, 1V/V) to obtain the title compound.
White powder, yield 8%; m.p.116.7-118.7 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(d,J＝0.8Hz,1H,Ar-H),8.04(dd,J＝8.4,1.2Hz,1H,Ar-H),8.00(s,1H,CH),7.52(d,J＝8.8Hz,1H,Ar-H),4.33(t,J＝6.8Hz,2H,CH 2 ),2.98(t,J＝7.6Hz,2H,CH 2 ),2.50(br,4H,2×CH 2 ),2.43(t,J＝6.8Hz,2H,CH 2 ),2.11–2.04(m,2H,CH 2 ),1.92–1.79(m,9H,4×CH 2 ,CH),1.67–1.53(m,4H,2×CH 2 ),1.20–1.15(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.06,168.88,144.74,144.02,135.92,122.27,121.22,120.23,110.23,54.03(2C),52.42,42.87,39.71,32.99,32.44(2C),28.82,26.12,25.22(2C),23.60(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 31 N 5 O 2 ,394.2601,found 394.2606。
example 46
5- (2-Cyclopentanethyl) -3- (1- (2- (pyrrolidin-1-yl) ethyl) -1H-benzo [ d ] imidazol-5-yl) -1,2, 4-oxadiazole (7F 2)
The procedure of example 38 was repeated in a similar manner to example 38 except that 1- (3-aminopropyl) pyrrolidine was changed to 1- (2-aminoethyl) pyrrolidine.
Grey powder, yield 7%; m.p.161.7-163.8 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.43(d,J＝16.4Hz,1H,Ar-H),8.26(s,1H,CH),8.02(dd,J＝8.4,1.6Hz,1H,Ar-H),7.58(d,J＝8.4Hz,1H,Ar-H),4.72(t,J＝6.8Hz,2H,CH 2 ),3.41(t,J＝6.4Hz,2H,CH 2 ),3.02(br,4H,2×CH 2 ),2.95(t,J＝6.8Hz,2H,CH 2 ),1.97–1.82(m,9H,4×CH 2 ,CH),1.65–1.52(m,4H,2×CH 2 ),1.15–1.13(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.08,168.82,144.76,143.84,135.85,122.28,121.22,120.21,110.07,55.28,54.34(2C),44.59,39.69,32.98,32.44(2C),26.12,25.21(2C),23.64(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 22 H 29 N 5 O,380.2445,found 380.2445。
example 47
4- (3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propyl) morpholine (7F 3)
In a similar manner to example 38, 1- (3-aminopropyl) pyrrolidine was replaced with N- (3-aminopropyl) morpholine and the rest was the same as in example 38.
Grey powder, yield 9%; m.p.114.2-116.1 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(d,J＝0.8Hz,1H,Ar-H),8.04(dd,J＝8.4,1.6Hz,1H,Ar-H),7.99(s,1H,CH),7.52(d,J＝8.4Hz,1H,Ar-H),4.32(t,J＝6.4Hz,2H,CH 2 ),3.72(t,J＝4.4Hz,4H,2×CH 2 ),2.97(t,J＝8.0Hz,2H,CH 2 ),2.39(br,4H,2×CH 2 ),2.27(t,J＝6.4Hz,2H,CH 2 ),2.08–2.02(m,2H,CH 2 ),1.93–1.81(m,5H,2×CH 2 ,CH),1.66–1.50(m,4H,2×CH 2 ),1.20–1.45(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.10,168.83,144.73,144.01,135.87,122.28,121.29,120.29,110.17,67.00(2C),54.66,53.56(2C),42.52,39.70,32.98,32.44(2C),26.26,26.11,25.22(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 23 H 31 N 5 O 2 ,410.2551,found 410.2550。
example 48
N- (3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propyl) -2-methoxybenzamide (7G 1)
The procedure of example 26 was repeated in a similar manner to the procedure of example 26 except that ethylenediamine was changed to 1, 3-propanediamine, and the rest was changed to that of example 26.
Grey powder, yield 21%; m.p.163.1-164.4 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.45(br,1H,CH),8.11–8.08(m,1H,NH),8.00–7.99(m,1H,Ar-H),7.97–7.92(m,2H,2×Ar-H),7.41–7.32(m,2H,2×Ar-H),7.00–6.95(m,1H,Ar-H),6.89–6.85(m,1H,Ar-H),4.27–4.20(m,2H,CH 2 ),3.84–3.81(m,3H,OCH 3 ),3.43–3.38(m,2H,CH 2 ),2.88–2.84(m,2H,CH 2 ),2.16–2.11(m,2H,CH 2 ),1.81–1.75(m,5H,2×CH 2 ,CH),1.55–1.45(m,4H,2×CH 2 ),1.07(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.08,168.71,165.89,157.42,144.53,143.95,135.69,133.07,132.15,122.27,121.33,121.24,121.04,120.08,111.33,110.15,55.98,42.99,39.64,37.00,32.91,32.39(2C),30.11,26.05,25.18(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 31 N 5 O 3 ,474.2500,found 474.2443。
example 49
N- (4- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) butyl) -2-methoxybenzamide (7G 2)
The procedure of example 26 was repeated in a similar manner to that of example 26 except that ethylenediamine was changed to 1, 4-butanediamine, and the like was repeated.
White powder, yield 26%; m.p.149.1-150.2 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.45(s,1H,CH),8.21(br,1H,Ar-H),8.02–8.00(m,2H,2×Ar-H),7.89(br,1H,NH),7.50–7.44(m,2H,2×Ar-H),7.09–7.08(m,1H,Ar-H),6.95(m,1H,Ar-H),4.30–4.28(m,2H,CH 2 ),3.90(s,3H,OCH 3 ),3.52(br,2H,CH 2 ),2.98–2.97(m,2H,CH 2 ),2.00–1.85(m,8H,4×CH 2 ),1.65–1.55(m,5H,2×CH 2 ,CH),1.17(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl3)δppm:180.12,168.81,165.67,157.45,144.42,144.01,135.76,132.97,132.37,122.36,121.48,121.28,120.25,111.34,110.26,56.00,44.93,39.71,38.69,32.99,32.45(2C),27.31,27.23,26.13,25.22(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 28 H 33 N 5 O 3 ,488.2656,found 488.2588。
example 50
N- (5- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) pentyl) -2-methoxybenzamide (7G 3)
The procedure of example 26 was repeated in a similar manner to the procedure of example 26 except that ethylenediamine was changed to 1, 5-pentanediamine, and the rest was changed to that of example 26.
White powder, yield 24%; m.p.157.3-158.4 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.52(br,1H,CH),8.18(dd,J＝2.0,8.0Hz,1H,Ar-H),8.01(dd,J＝1.6,8.4Hz,1H,Ar-H),7.96(s,1H,Ar-H),7.85(t,J＝5.6Hz,1H,NH),7.48–7.40(m,2H,2×Ar-H),7.08–7.04(m,1H,Ar-H),6.93(d,J＝8.4Hz,1H,Ar-H),4.22(t,J＝6.8Hz,2H,CH 2 ),3.87(s,3H,OCH 3 ),3.44(dd,J＝6.8,12.8Hz,2H,CH 2 ),2.96(t,J＝8.0Hz,2H,CH 2 ),2.00–1.80(m,7H,3×CH 2 ,CH),1.66–1.52(m,6H,3×CH 2 ),1.45–1.38(m,2H,CH 2 ),1.18–1.13(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.10,168.80,165.45,157.43,144.30,143.98,135.79,132.82,132.33,122.37,121.46,121.43,121.28,120.22,111.35,110.21,55.98,45.27,39.71,39.34,32.99,32.45(2C),29.60,29.27,26.13,25.22(2C),24.28；ESI-HRMS(TOF):m/z[M+H] + calcd for C 29 H 35 N 5 O 3 ,502.2813,found 502.2743。
example 51
N- (3- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) propyl) -4-methoxybenzamide (7G 4)
The procedure of example 28 was repeated in a similar manner to replace ethylenediamine with 1, 3-propanediamine, except that the procedure of example 28 was repeated.
White powder, yield 25%; m.p.207.9-208.9 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.49(s,1H,CH),8.04–7.99(m,2H,2×Ar-H),7.67(d,J＝8.8Hz,2H,2×Ar-H),7.44(d,J＝8.8Hz,1H,Ar-H),6.87(d,J＝8.8Hz,2H,2×Ar-H),6.55(br,1H,NH),4.29(t,J＝7.2Hz,2H,CH 2 ),3.81(s,3H,OCH 3 ),3.47(dd,J＝6.4,12.8Hz,2H,CH 2 ),2.95(t,J＝7.6Hz,2H,CH 2 ),2.24–2.17(m,2H,CH 2 ),1.90–1.79(m,5H,2×CH 2 ,CH),1.64–1.49(m,4H,2×CH 2 ),1.16–1.12(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.16,168.74,167.59,162.39,144.46,144.00,135.64,128.78(2C),126.31,122.49,121.46,120.26,113.88(2C),110.14,55.50,43.14,39.71,37.40,32.98,32.44(2C),30.29,26.12,25.22(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 31 N 5 O 3 ,474.2500,found 474.2452。
example 52
N- (4- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) butyl) -4-methoxybenzamide (7G 5)
The procedure of example 28 was repeated in a similar manner to that of example 28 except that ethylenediamine was changed to 1, 4-butanediamine.
Grey powder, yield 23%; m.p.192.0-193.7 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.50(br,1H,CH),8.04–7.93(m,2H,2×Ar-H),7.70–7.67(m,2H,2×Ar-H),7.50–7.45(m,1H,Ar-H),6.91–6.86(m,2H,2×Ar-H),6.38(br,1H,NH),4.28–4.23(m,2H,CH 2 ),3.81(br,3H,OCH 3 ),3.49–3.43(m,2H,CH 2 ),2.99–2.93(m,2H,CH 2 ),1.95–1.81(m,7H,3×CH 2 ,CH),1.63–1.52(m,6H,3×CH 2 ),1.16(br,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.14,168.79,167.35,162.28,144.39,143.99,135.73,128.74(2C),126.58,122.42,121.32,120.19,113.84(2C),110.26,55.50,44.86,39.71,38.95,32.98,32.44(2C),27.30,27.17,26.13,25.22(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 28 H 33 N 5 O 3 ,488.2656,found 488.2592。
example 53
N- (5- (5- (5- (2-cyclopentylethyl) -1,2, 4-oxadiazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) pentyl) -4-methoxybenzamide (7G 6)
The procedure of example 28 was repeated in a similar manner to the procedure of example 28 except that ethylenediamine was changed to 1, 5-pentanediamine, and the rest was changed to that of example 28.
White powder, yield 28%; m.p.188.2-189.5 ℃; 1 H NMR(400MHz,CDCl 3 )δppm:8.53(s,1H,CH),8.02(dd,J＝1.2,8.4Hz,1H,Ar-H),7.95(s,1H,Ar-H),7.68(d,J＝8.8Hz,2H,2×Ar-H),7.47(d,J＝8.4Hz,1H,Ar-H),6.89(d,J＝8.8Hz,2H,2×Ar-H),6.24(br,1H,NH),4.20(t,J＝7.2Hz,2H,CH 2 ),3.83(s,3H,OCH 3 ),3.42(dd,J＝6.8,13.2Hz,2H,CH 2 ),2.97(t,J＝7.6Hz,2H,CH 2 ),1.89–1.84(m,7H,3×CH 2 ,CH),1.62–1.52(m,6H,3×CH 2 ),1.42–1.37(m,2H,CH 2 ),1.18–1.14(m,2H,CH 2 )； 13 C NMR(100MHz,CDCl 3 )δppm:180.13,168.79,167.24,162.19,144.32,143.97,135.79,128.69(2C),126.81,122.38,121.29,120.22,113.81(2C),110.22,55.49,45.22,39.70,39.57,32.98,32.44(2C),29.57,29.37,26.12,25.22(2C),24.16；ESI-HRMS(TOF):m/z[M+H] + calcd for C 29 H 35 N 5 O 3 ,502.2813,found 502.2763。
the following are some of the pharmacological tests and results of representative compounds of the invention:
1. anti-HBV DNA Activity
According to the results of the cytotoxicity of the compounds on HepG 2.2.15 (CC) 50 >20 μ M), and medium and low dose groups were set, and a liquid medicine was prepared using DMEM containing 2% fbs, and a positive control group and a virus control group of Lamivudine (LAM) (structure shown below) as anti-HBV drugs, which were added to 96-well cell culture plates at 0.2 mL/well, 3 wells per concentration, respectively. The cells were lysed with 0.5% NP-40 by collecting cell supernatants every 3 days after exchange and on day 6. Extracting total DNA of the cell from the cell lysate by using DNAextraction Soln1.0 extracting solution, and detecting the carrying capacity of the HBV DNA in the cell by using an RT-PCR method. The results of the experiment are shown in tables 1 and 2.
Figure BDA0003789110300000361
Figure BDA0003789110300000362
TABLE 1 inhibitory Activity of the representative Compounds of the invention on HepG 2.2.15 cell HBV DNA replication
Figure BDA0003789110300000363
Figure BDA0003789110300000371
Table 1 shows that the compounds have certain inhibitory activity on HBV DNA replication, wherein the inhibitory rates of the compounds 7G5, 7B8, 7B11, 7B27 and 7B28 at 4 mu M are 81.03%, 82.78%, 84.47%, 83.66% and 81.91%, respectively, and the compounds have better anti-HBV activity. Other compounds of the present application also have similar inhibition rate data and exhibit good inhibitory activity.
TABLE 2 IC of representative compounds of the invention for HepG 2.2.15 cell HBV DNA replication 50
Figure BDA0003789110300000372
Table 2 shows that the compounds have certain inhibitory activity on HBV DNA replication, the compounds 7B11, 7B14, 7B26, 7B35 and 7G1 have good effect, wherein the IC of the compound 7B35 50 The value is optimal, reaches 0.49 mu M and has better anti-HBV activity. Other compounds of the present application also have similar IC' s 50 Data, show good inhibitory activity.
3. Anti-drug-resistant HBV activity
The method comprises the steps of taking lamivudine and entecavir combined drug-resistant cell HepG2A64 (mutation sites: rtLl80M + rtM204V + rtTl 84L) as a test research object, measuring the influence of active compounds 7B11 and 7B14 on the HBV DNA replication of the drug-resistant cell, judging the sensitivity of the three drug-resistant mutation sites to a target compound, and evaluating the anti-drug-resistant HBV activity of the target compound.
According to the results of cytotoxicity of the compound against HepG2A64, 5 different concentrations of the compound were prepared into drug solutions using DMEM containing 2% FBS, and a Lamivudine (LAM) and Entecavir (ETV) positive control group and a virus control group were added to 96-well cell culture plates at 0.6 mL/well in 3 wells per concentration, respectively. Every 3 days the medium was changed, and on day 6 the cell supernatant was collected and the cells lysed with 0.5% NP-40. Extracting total DNA of the cell by using DNA Extraction Soln1.0 extracting solution from the cell lysate, and detecting the carrying capacity of HBV DNA in the cell by using an RT-PCR method. The results of the experiment are shown in FIG. 1.
The experimental results are as follows: the compounds 7B11 and 7B14 can effectively inhibit the replication of HBV DNA of HepG2A64 cells at the concentration of 4 mu M, the inhibition rates are 81.99% and 66.82%, respectively, and the inhibition rates of HepG 2.2.15 cells are 84.43% and 68.75%, respectively, so that the compounds 7B11 and 7B14 are not considered to generate drug resistance. The positive controls lamivudine (lamivudine, LAM) and entecavir (entecavir, ETV) do not have ideal inhibitory effect on drug-resistant virus, and lamivudine (100 μ M) and entecavir (10 μ M) have the inhibitory rates of 17.33% and 22.80% on HBV DNA replication of HepG2a64 cells, respectively (the inhibitory rates of HepG 2.2.15 cells are 90.10% and 98.60%, respectively).
TABLE 3 IC of representative compounds of the invention on HepG2A64 cell HBV DNA replication 50
Figure BDA0003789110300000381
Table 3 shows that the compounds have certain inhibitory activity on HBV DNA replication, wherein the IC of the compound 7B11 50 The value is optimal, reaches 0.44 mu M and has better anti-HBV activity. Other compounds of the present application also have similar IC' s 50 Data, show good inhibitory activity.
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications of the technical solutions described in the foregoing embodiments are still possible, or some technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. A compound, isomer or pharmaceutically acceptable salt thereof shown in formula I,
Figure FDA0003789110290000011
wherein, the first and the second end of the pipe are connected with each other,
R 1 represents hydrogen, halogen, C 1 -C 6 Alkyl, cyano, trifluoromethyl, hydroxy, amino, ester, nitro, C 1 -C 6 Alkoxy or C 1 -C 6 An alkylamino group;
R 2 represents cyclopentane, cyclohexane, phenyl or substituted phenyl, which may beOptionally mono-or polysubstituted with: cyano, trifluoromethyl, hydroxy, amino, ester, nitro, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkylamino alkoxy, substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 An alkylamino group;
said substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 Substituents in alkylamino are: morpholine, piperazine, pyrrole, piperidine, substituted piperazine or substituted piperidine;
the substituent in the substituted piperazine or substituted piperidine is as follows: hydroxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, piperidinyl or carboxy;
x represents-CO-, -NH-CO-, -CO-NH-, a covalent bond, -NH-, an S atom, -S (= O) 2 -、-NH(SO 2 ) -or an O atom;
R 3 represents morpholine, piperidine, imidazole, pyrrole, pyrazole, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino, substituted phenylamino, pyrimidine, pyridine or substituted phenyl, which may optionally be mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, hydroxy, amino, ester, nitro, halogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkoxy radical, C 1 -C 6 Alkylamino radical, C 1 -C 6 Alkylamino alkoxy, substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 An alkylamino group;
said substituted C 1 -C 6 Alkoxy or substituted C 1 -C 6 The substituents in alkylamino are: morpholine, piperazine, pyrrole, piperidine, substituted piperazine or substituted piperidine;
the substituent in the substituted piperazine or substituted piperidine is as follows: hydroxy, hydroxymethyl, hydroxyethyl, phenyl, benzyl, piperidinyl or carboxy;
R 4 represents hydrogen, C 1 -C 6 Alkyl radical, C 1 -C 6 Alkyl phenyl, C 1 -C 6 An alkoxyphenyl or halophenyl group;
n represents an integer of 1 to 6;
m represents an integer of 1 to 6.
2. A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, cyano, methoxy or ethoxy; preferably, R 1 Represents hydrogen.
3. A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Represents cyclopentane, cyclohexane, phenyl or substituted phenyl, which may be optionally mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, hydroxy, amino, nitro or halogen; preferably, R 2 Represents cyclopentane, cyclohexane or phenyl.
4. A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 Represents morpholine, piperidine, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino, substituted phenylamino or substituted phenyl, which may optionally be mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, hydroxy, amino, nitro, halogen, C 1 -C 3 Alkyl radical, C 1 -C 3 Alkoxy radical, C 1 -C 3 An alkylamino group; preferably, R 3 Represents morpholine, piperidine, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino or substituted phenyl which may be optionally mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, hydroxy, amino, nitro, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy or ethoxy; more preferably, R 3 Represents morpholine, piperidine, cyclopentane, cyclopentylamino, cyclohexane, cyclohexylamino, phenyl, phenylamino or substituted phenyl, said substitutionThe phenyl or substituted phenylamino group may be optionally mono-or polysubstituted with the following substituents: cyano, trifluoromethyl, fluoro, chloro, bromo, iodo, methyl, ethyl, methoxy or ethoxy.
5. A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 Represents hydrogen, C 1 -C 3 Alkyl or C 1 -C 3 An alkoxy group; preferably, R 4 Represents hydrogen, methyl or ethyl; more preferably, R 4 Represents hydrogen.
6. A compound, isomer, or pharmaceutically acceptable salt thereof, according to claim 1, wherein, X represents-CO-, -NH-CO-, -CO-NH-, or a covalent bond; preferably, X represents-CO-, -NH-CO-or a covalent bond; n represents an integer of 1 to 3; preferably, n represents 2; m represents an integer of 2 to 5.
7. A compound, isomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein compound is selected from the group consisting of:
Figure FDA0003789110290000021
Figure FDA0003789110290000031
Figure FDA0003789110290000041
Figure FDA0003789110290000051
Figure FDA0003789110290000061
Figure FDA0003789110290000071
8. a process for the preparation of a compound according to claim 1,
a) When X represents a covalent bond, the synthetic route is as follows:
Figure FDA0003789110290000081
b) When X represents-NH-CO-, the synthetic route is as follows:
Figure FDA0003789110290000082
c) When X represents-CO-, the synthetic route is as follows:
Figure FDA0003789110290000091
9. a pharmaceutical composition comprising a compound, isomer or pharmaceutically acceptable salt thereof according to any of claims 1-7 as an active ingredient or as a major active ingredient, in association with a pharmaceutically acceptable carrier.
10. Use of a compound, isomer, or pharmaceutically acceptable salt thereof according to any of claims 1-7 for the manufacture of an anti-HBV medicament.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108947911A (en) * 2018-07-03 2018-12-07 中山大学 A kind of benzimidazoles compound and its synthetic method and application with anti-hepatitis B activity and antibacterial activity
CN109748910A (en) * 2018-12-17 2019-05-14 徐州医科大学 A kind of quianzolinones, preparation method and medical usage
WO2019136147A1 (en) * 2018-01-03 2019-07-11 The Board Of Trustees Of The University Of Illinois Toll-like receptor signaling inhibitors
WO2022087422A1 (en) * 2020-10-22 2022-04-28 Chulalongkorn University Pyrrolidine-3-carboxamide derivatives and related uses

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019136147A1 (en) * 2018-01-03 2019-07-11 The Board Of Trustees Of The University Of Illinois Toll-like receptor signaling inhibitors
CN108947911A (en) * 2018-07-03 2018-12-07 中山大学 A kind of benzimidazoles compound and its synthetic method and application with anti-hepatitis B activity and antibacterial activity
CN109748910A (en) * 2018-12-17 2019-05-14 徐州医科大学 A kind of quianzolinones, preparation method and medical usage
WO2022087422A1 (en) * 2020-10-22 2022-04-28 Chulalongkorn University Pyrrolidine-3-carboxamide derivatives and related uses

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