CN105985356A - Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof - Google Patents

Imidazole [2, 1-b] thiazole derivative as well as preparation method and application thereof Download PDF

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CN105985356A
CN105985356A CN201510059344.4A CN201510059344A CN105985356A CN 105985356 A CN105985356 A CN 105985356A CN 201510059344 A CN201510059344 A CN 201510059344A CN 105985356 A CN105985356 A CN 105985356A
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halogen
alkyl
cycloalkyl
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CN105985356B (en
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余洛汀
魏于全
王宁宇
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Sichuan University
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Sichuan University
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Abstract

The invention belongs to the field of chemical pharmaceuticals, and particularly relates to an imidazole [2, 1-b] thiazole derivative as well as a preparation method and an application thereof. The structure of the imidazole [2, 1-b] thiazole derivative is shown by a formula I. The invention also provides a preparation method and an application of the imidazole [2, 1-b] thiazole derivative. The compound provided by the invention has the advantages of having good activity, having no cross tolerance with an NS3/4A inhibitor, an NS5A inhibitor, and nucleoside and non-nucleoside type NS5B inhibitors, and being capable of cooperatively resisting viruses when applied in combination with the NS3/4A inhibitor, the NS5A inhibitor, the nucleoside and non-nucleoside type NS5B inhibitors, and can be used for treating HCV (hepatitis C virus) infected patients independently or in a manner of forming a pharmaceutical composition together with one or more of ribavirin, PEG-interferon-[alpha], the NS3/4A inhibitor, the NS5A inhibitor, and the nucleoside and non-nucleoside type NS5B inhibitors.

Description

Imidazoles [2,1-b] thiazole and its production and use
Technical field
The invention belongs to chemical medicine, be specifically related to imidazoles [2,1-b] thiazole and its production and use.
Background technology
Chronic hepatitis C is a kind of chronic hepatic diseases being caused by HCV (HCV), is the main cause of cirrhosis and liver cancer, is also the first cause of current liver transplant.Show according to the World Health Organization (WHO) investigation of 1999, the people (1.7 hundred million people) that the whole world there are about 3% has infected HCV (J.Viral.Hepat.1999,6:35-47), the infection rate of China is about 3.2% (40,000,000 people) (Lancet Infect.Dis.2005.5:558 67), and number of the infected has the trend increasing year by year.These have infected the crowd of HCV, after the incubation period of 10-20, the people that there are about 80% would develop into chronic hepatitis C, and the people of 20% will be further developed into cirrhosis, the people of 1%-4% is changed into liver cancer (Med.Res.Rev.2007,27:353-73) by finally deteriorating.
The traditional standard scheme of the treatment chronic hepatitis C of FDA approval is use in conjunction PEG-interferon-' alpha ' and Ribavirin, and this therapeutic scheme exists some problems following: 1. efficient low；2. treatment cycle is long, and medical expense is high；3. toxic and side effect is more serious.Between 2011-2014 years, having 4 kinds of direct antiviral drugs acting on virus oneself protein to be ratified the treatment for HCV by FDA, these medicines can be brought up to 70%-90% by original 50% with the treated effect of Ribavirin and interferon use in conjunction.In addition, 2014, also two kinds of direct antiviral drugs combinations are ratified the treatment for HCV infection patient by FDA, and the efficient of both drug regimens all can reach more than 90%.But still there is medicament-resistant mutation and produce very fast in these medicines at present, the problems such as treatment cycle is longer, and medical expense is higher, thus exploitation to have novel chronic hepatitis C medicine very necessary.
The polyprotein of HCV one about 3000 amino acid of forward single stranded RNA genome encoding of a length of 9.6kb, under virus oneself protein and host protein common acts on, this polyprotein is cut into virus structural protein and the non-structural protein of multiple maturation: Core, E1, E2, P7, NS2/3, NS2, NS3, NS4A, NS4B, NS5A, NS5B.Wherein structural proteins Core, E1, E2, P7 is the necessary part of virion, and non-structural protein NS2/3, NS2, NS3, NS4A, NS4B, NS5A, NS5B have important effect to virus replication and assembling.Suppress these structures and non-structural protein, be all possible to the duplication of suppression virus thus reach antiviral effect.
HCV NS4A protein is a kind of 4 transmembrane proteins, and the necessary membranaceous network of virus replication can be induced to be formed when HCV replicates, therefore particularly significant to viral duplication.NS4B parents spiral 4BAH2 can induce the formation (Sci.Transl.Med.2010 of the necessary lipid vesicle of virus replication, 2,15ra6), and its C-stub area can be connected with virus strand RNA, and this connection to the duplication of HCV is necessary (Nat.Biotechnol.2008,26:1019-1027).Any function of interference all can reach the effect suppressing HCV to replicate, therefore NS4B inhibitor be considered as get a good chance of being resistant to hepatitis C medicine (Viruses, 2010,2:2481-2492；Antiviral Res.,2011,90:93-101).
Content of the invention
The invention provides a kind of imidazoles [2,1-b] thiazole, its structure is as shown in formula I:
Wherein, R1、R2It independently is-H, halogen, C1～C8 alkyl, C3～C8 cycloalkyl, C1～C8 alkoxyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the replacement unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
As preferred scheme, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl, C1～C4 alkoxyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
Preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
It is further preferred that R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
Still more preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
Further preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；R4For halogen or C1～C4 alkyl.
Still further preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；R4For halogen.
Optimum, R1、R2It independently is-H ,-Cl, C1～C4 alkyl, cyclopropyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H ,-Cl ,-Br, methyl or methoxy；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；R4For-Cl.
Above-mentioned imidazoles [2,1-b] thiazole, works as R1And R2When forming the replacement saturated carbon ring of 5～8 yuan, its structure is as shown in formula II:
Wherein, R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
As preferred scheme, R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
Preferably, R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
It is further preferred that R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
Still more preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
Further preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
Still further preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen；R5、R6Independent is-H or C1～C4 alkyl；The integer of n=1～4.
Optimum, R3For pentamethylene；R4For-Cl；R5、R6Independent is-H or methyl；N=1 or 2.
Above-mentioned imidazoles [2,1-b] thiazole, works as R1And R2When forming the replacement unsaturated carbocyclic of 5～8 yuan, its structure is as shown in formula III:
Wherein, R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
As preferred scheme, R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
Preferably, R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
It is further preferred that R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
Still more preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
Further preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
Still further preferably, R3For C3～C6 cycloalkyl；R4For halogen；R7For-H halogen, C1～C4 alkyl or C1～C4 alkoxyl.
Optimum, R3For pentamethylene；R4For-Cl；R5、R6Independent is-H ,-Cl, Br or methyl.
Above-mentioned imidazoles [2,1-b] thiazole, its structural formula is:
Present invention also offers the preparation method of above-mentioned imidazoles [2,1-b] thiazole.
Scheme one, the synthetic route of the thiazole of imidazoles [2,1-b] shown in formula I is as follows:
The operating procedure of the thiazole of imidazoles [2,1-b] shown in formula I is:
A, when R1, R2 independently are-H, halogen, C1～C8 alkyl, C3～C8 cycloalkyl or C1～C8 alkoxyl, raw material 1 and bromine reacts in methyl alcohol and are generated α bromo aldehydes or ketones (intermediate 1-1)；Described raw material 1 is 11 with the mol ratio of bromine；Described reaction temperature is 0～20 DEG C, and the reaction time is 0.5h～3h；
B, intermediate 1-1 and thiocarbamide react in ethanol and obtain thiazolamine (intermediate 1-2)；Described intermediate 1-1 is 1 1～1.5 with the mol ratio of thiocarbamide；Described reaction temperature is 80 DEG C～100 DEG C, and the reaction time is 3h～12h；
C, intermediate 1-2 and 3-BrPA ethyl ester back flow reaction in butanone obtain imidazo [2,1-b] thiazole intermediate (intermediate 1-3)；Described intermediate 1-2 is 1 1.5～4 with the mol ratio of 3-BrPA ethyl ester；The described reaction time is 12h～48h；
D, intermediate 1-3 and NBS, NIS or NCS, in DMF, after reacting 3h～12h, obtain intermediate 1-4 under the conditions of 0 DEG C～30 DEG C；There is hydrolysis with lithium hydroxide at 10 DEG C～50 DEG C in intermediate 1-4, obtains intermediate 1-5；Described intermediate 1-3 is 1 1～3 with the mol ratio of NBS, NIS or NCS；Described intermediate 1-4 is 1 5～50 with the mol ratio of lithium hydroxide；The solvent of described hydrolysis is the mixed solvent that volume ratio is water methanol oxolane=1 22；The time of described hydrolysis is 3h～12h；
It e, is suspended in intermediate-5 and intermediate 4 in dichloromethane, in this suspension backward, be sequentially added into HOBT and EDCI, react 3～12h under room temperature, obtain type I compound；Described intermediate 1-5 is 1 0.8～1.2 with the mol ratio of intermediate 4；EDCI, HOBt are 1.5 1.2 1 with the mol ratio of intermediate 1-5；The described reaction time is 3h～12h.
Scheme two, the synthetic route of the thiazole of imidazoles [2,1-b] shown in formula II is as follows:
The operating procedure of the thiazole of imidazoles [2,1-b] shown in formula II is:
A, work as R1And R2When forming the replacement saturated carbon ring of 5～8 yuan, raw material 2 and NBS react generation α bromo cyclic ketones (intermediate 2-1)；Described raw material 2 is 1 1～1.1 with the mol ratio of NBS；The solvent of described reaction is DMSO；Described reaction temperature is 20 DEG C～30 DEG C, and the time of reaction is 0.5h～3h；
B, intermediate 2-1 with thiocarbamide in ethanol, react 3h～12h under the conditions of 80 DEG C～100 DEG C, obtain thiazolamine (intermediate 2-2)；
C, intermediate 2-2 subsequently again with 3-BrPA ethyl ester in butanone back flow reaction obtain imidazo [2,1-b] thiazole intermediate (intermediate 2-3)；Described intermediate 2-2 is 1 1.5～4 with the mol ratio of 3-BrPA ethyl ester；The described reaction time is 12h～48h；
D, intermediate 2-3 and NBS, NIS or NCS, after 0 DEG C～30 DEG C reaction 3h～12h, obtain intermediate 2-4；Then intermediate 2-4 and lithium hydrate react and obtain intermediate 2-5；Described intermediate 1-3 is 1 1～3 with the mol ratio of NBS, NIS or NCS；Described intermediate 2-4 is 1 5～50 with the mol ratio of lithium hydroxide；The solvent of described hydrolysis is the mixed solvent that volume ratio is water methanol oxolane=1 22；The time of described hydrolysis is 3h～12h；
E, intermediate 2-5 are suspended in dichloromethane with intermediate 4 again, are sequentially added into HOBT and EDCI in this suspension backward, react 3～12h, obtain formula II compound under room temperature；Described intermediate 2-5 is 1 0.8～1.2 with the mol ratio of intermediate 4；EDCI, HOBt are 1.5 1.2 1 with the mol ratio of intermediate 2-5；The described reaction time is 3h～12h.
Scheme three, the synthetic route of the thiazole of imidazoles [2,1-b] shown in formula III is as follows:
The operating procedure of the thiazole of imidazoles [2,1-b] shown in formula III is:
A, work as R1And R2When forming the replacement unsaturated carbocyclic of 5～8 yuan, imidazo [2,1-b] thiazole intermediate (intermediate 3-1) will be obtained for 2-amino phenylpropyl alcohol thiazole (raw material 3) and 3-BrPA ethyl ester back flow reaction in butanone；Described raw material 3 is 1 1.5～4 with the mol ratio of 3-BrPA ethyl ester；The time of described reaction is 12h～48h；
B, intermediate 3-1 and NBS, NIS or NCS, after 0 DEG C～30 DEG C reaction 3h～12h, obtain intermediate 3-2；Described intermediate 3-1 is 1 1～3 with the mol ratio of NBS, NIS or NCS；The solvent of described reaction is DMF；
C, intermediate 3-2 hydrolyze in the presence of lithium hydroxide and obtain intermediate 3-3；Intermediate 3-2 is 1 5～50 with the ingredient proportion of lithium hydroxide；The solvent of described hydrolysis is the mixed solvent that volume ratio is water methanol oxolane=1 22；The time of described hydrolysis is 3h～12h；
D, intermediate 3-3 are suspended in dichloromethane with intermediate 4 again, are sequentially added into HOBT and EDCI in this suspension backward, react 3～12h, obtain formula III compound under room temperature；Described intermediate 3-3 is 1 0.8～1.2 with the mol ratio of intermediate 4；EDCI, HOBt are 1.5 1.2 1 with the mol ratio of intermediate 3-3；The described reaction time is 3h～12h.
The syntheti c route of intermediate 4 is as follows:
The operating procedure preparing intermediate 4 is:
A, 4-Nitrobenzenesulfonyl chloride (raw material 4) and glycine react in the NaOH aqueous solution, obtain 2-(4-nitrobenzene sulphonyl Amido) acetamide (intermediate 4-1)；Described raw material 4 is 1 1～1.05 with the mol ratio of glycine；Described NaOH is 1 1.05～1.5 with the mol ratio of raw material 4；The temperature of described reaction is 0 DEG C～30 DEG C, and the reaction time is 2h～4h；
B, intermediate 4-1 again with R3-NH2Reaction, obtains N-and replaces-2-(4-nitrobenzene sulphonyl amido) acetamide (intermediate 4-2)；Described intermediate 4-2 and R3-NH2Mol ratio be 1 0.8～1.2；HATU and DIEA also to be added in described reaction, HATU, DIEA are 1.5 2～3 1 with the mol ratio of intermediate 4-2；The temperature of described reaction is 0 DEG C～30 DEG C, and the reaction time is 6h～24h；
C, intermediate 4-2 and 1,2-Bromofume reacts in the presence of potassium carbonate in DMF, obtains the Piperazinone compounds (intermediate 4-3) of p-nitrophenyl sulfonyl protection；The mol ratio of described intermediate 4-2, glycol dibromide and potassium carbonate is 1 10 10；The temperature of described reaction is 50 DEG C～80 DEG C, and the reaction time is 18h～36h；
D, intermediate 4-3 slough sulfonyl again under the effect of mercapto-propionate and obtain intermediate 4-4；Described intermediate 4-3, mercapto-propionate are 1 2.5 3 with the mol ratio of lithium hydroxide；Described reaction osmium solvent is the solvent that acetonitrile mixes with volume ratio 49:1 with DMSO；The temperature of described reaction is 50 DEG C, and the reaction time is 3h～12h.
Wherein, R1、R2It independently is-H, halogen, C1～C8 alkyl, C3～C8 cycloalkyl, C1～C8 alkoxyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the replacement unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
Above-mentioned imidazoles [2,1-b] thiazole includes their isotopic compound, racemic modification, optical active isomers, polymorphic forms or its mixture.
Present invention also offers imidazoles [2,1-b] the thiazole pharmaceutically acceptable salt shown in formula I～III or hydrate.
Present invention also offers above-mentioned imidazoles [2,1-b] prodrug of thiazole, according to the present invention, prodrug is the derivative of above-claimed cpd, their own is likely to be of more weak activity or even without activity, but upon administration, in physiological conditions (for example by metabolism, solvolysis or other by way of) be converted to corresponding biologically active form.
A kind of pharmaceutical composition, is to be added the complementary composition of pharmaceutically acceptable by imidazoles [2, the 1-b] thiazole shown in formula I～III and salt thereof or hydrate to be prepared from.It is specially the pharmaceutical composition that imidazoles [2,1-b] thiazole shown in I～III and salt thereof or hydrate are formed with one or more in Ribavirin, PEG-interferon-' alpha ', NS3/4A inhibitor, NS5A inhibitor, nucleosides and non-nucleoside NS5B inhibitor.This pharmaceutical composition can be to be incorporated in same one dosage type low temperature or each to take for people with different dosage form.
Wherein NS3/4A inhibitor includes but is not limited to Telaprevir, Boceprevir, Semiprevir, Danoprevir, Asunaprevir, Faldaprevir, Vedroprevir, MK-5172, MK-7009, ACH1625.
NS5A inhibitor includes but is not limited to Daclatasvir, Ombitasvir, Ledipasvir, Samatasvir, ACH3102, GSK2336805, MK8742, PPI-668, GS5816, JNJ-47910382.
NS5B inhibitor includes but is not limited to Sofosbuvir, RG7128, ABT-333, BI207127, GS9669, GS9190, ANNA-595, BMS-791325, TMC-647055, VX-222, ABT-072.
Present invention also offers imidazoles [2,1-b] thiazole shown in above-mentioned formula I～III and salt thereof or the hydrate purposes in preparation treatment hepatitis C medicine.
The compounds of this invention has excellent activity, with NS3/4A inhibitor, NS5A inhibitor, nucleosides and non-nucleoside NS5B inhibitor without cross resistance, and the advantage that during with NS3/4A inhibitor, NS5A inhibitor, nucleosides and non-nucleoside NS5B inhibitor use in conjunction, there is synergistic corrosion virus, can be independent or form pharmaceutical compositions with one or more in Ribavirin, PEG-interferon-' alpha ', NS3/4A inhibitor, NS5A inhibitor, nucleosides and non-nucleoside NS5B inhibitor, for the treatment of HCV infection patient.
Detailed description of the invention
The source of main agents used in the embodiment of the present invention and material is as follows:
Thin-layer chromatography silica gel (GF254) and column chromatography silica gel (60-100 mesh, 200-300 mesh, 300-400 mesh) are purchased from Haiyang Chemical Plant, Qingdao；Deuterated reagent (containing the internal standard TMS) used in nuclear magnetic resonance is that U.S. Cambridge CIL produces import packing product；N,N-dimethylformamide, oxolane and the butanone used in reaction is that the heavily steaming of commercially available AR is processed or 4A molecular sieve drying；Other all chemical synthesis related reagents are the pure or chemical pure of commercially available analysis.
RPMI-1640, DMEM, hyclone, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA), thiazole bromide blue tetrazolium (MTT), dimethyl sulfoxide (DMSO) are Sigma (USA) product；Benzylpenicillin sodium salt, streptomycin sulphate are North China Pharmaceutical Factory's product；15mL and 50mL centrifuge tube is purchased from BD company；1.5mL, 2mL and 4mL centrifuge tube is purchased from Axygen Scientific company；10 μ L, 200 μ L and 1000 μ L rifle heads are purchased from Ronlabs Scientific Instrument company；6 orifice plates, 96 orifice plates and culture dish are purchased from Corning Incorporated；It is pure that other reagent are domestic analysis.
Huh7 Replicate Sub-system uses and contains 10% hyclone, 100U/mL penicillin, the DMEM complete medium of 100 μ g/mL streptomysins, 5%CO2, 37 DEG C cultivate.
NS3/4A inhibitor simeprevir, NS5A inhibitor Daclatasvir, NS5B inhibitor Sofosbuvir and NS4B inhibitor C lemizole in drug combination test all purchases to medicine bright Kant new drug development Co., Ltd.
The implication relating to english abbreviation in the present invention is as shown in table 1.
The implication of table 1 english abbreviation
The preparation of embodiment 1 4-(5-chlorine imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 1)
(1) synthesis of 2-(4-nitrobenzene sulphonyl amido) acetic acid:
Under ice bath, glycine (10g, 133mmol) is dissolved in the sodium hydroxide solution (140mL, 140mmol) of 1N, is slowly added to 4-Nitrobenzenesulfonyl chloride (29.5g, 133mmol) wherein.After half an hour, reactant liquor is slowly increased to room temperature, the sodium hydroxide solution of addition 1N to pH > 9.React 2 hours, 150mL sodium hydroxide solution (1N) is added in reactant liquor, and it is extracted with ethyl acetate (100mL × 3), being filtered to remove insoluble substance in aqueous phase, the salt acid for adjusting pH of filtrate 6N, to 1, treats that this suspension continues to stir half an hour, filter, filter cake obtains white product 19.73g, productivity 56.88%, ESI-MS [M+H] through vacuum drying after the washing of a small amount of frozen water+(m/z):261.1。
(2) synthesis of N-cyclopenta-2-(4-nitrobenzene sulphonyl amido) acetamide:
After 2-(4-nitrobenzene sulphonyl amido) acetic acid (1.0eq) and cyclopentamine (1.0eq) are dissolved in DMF, it is separately added into diisopropylethylamine (DIEA wherein, 2.0-3.0eq) with HATU (1.5eq), 12h is reacted under room temperature, pale precipitation is separated out after directly adding water in reactant liquor, with cold water washing and vacuum dried obtain corresponding product after filtration, productivity: 73.12%1H NMR(400MHz,DMSO-d6) δ 8.49 (d, J=8.8Hz, 2H), 8.39 (s, 1H), 8.02 (d, J=8.8Hz, 2H), 7.80 (d, J=6.8Hz, 1H), 3.86～3.77 (m, 1H), 3.51 (s, 2H), 1.72～1.27 (m, 8H).ESI-MS[M+Na]+(m/z):350.1。
(3) synthesis of 4-(4-nitrobenzenesulfonyl)-1 cyclopenta-2-piperazinones:
Add potassium carbonate (10.0eq) in the DMF solution of intermediate N cyclopenta-2-(4-nitrobenzene sulphonyl amido) acetamide (1.0eq), stir half an hour at 60 DEG C.Addition 1 in reactant liquor, 2-Bromofume (10.0eq), continues reaction 24h at 60 DEG C, decompression is distilled off solvent, residual solid is suspended in water and stirs half an hour, filters to obtain faint yellow thick product, is suspended in the thick product being filtrated to get in the watery hydrochloric acid of 1N again and stirs half an hour, filter, filter cake washs through cold water, is vacuum dried, and obtains purer midbody product, and this intermediate can be directly used for next step reaction without further purification, productivity: 86.68%1H NMR(400MHz,DMSO-d6) δ 8.43 (d, J=8.4Hz, 2H), 8.08 (d, J=8.4Hz, 2H), 4.66～4.60 (m, 1H), 3.67 (s, 2H), 3.37～3.26 (m, 4H), 1.59～1.39 (m, 8H).ESI-MS[M+H]+(m/z):354.1。
The synthesis of (4) 1 cyclopenta-2-piperazinones:
Lithium hydroxide (3.0eq) is added in acetonitrile/DMSO (V/V=49/1) solution of mercapto-propionate (2.5eq); stir half an hour at 50 DEG C, in this reactant liquor, be slowly added dropwise acetonitrile/DMSO (V/V=49/1) solution of intermediate 4-(4-nitrobenzenesulfonyl)-1 cyclopenta-2-piperazinones (1.0eq).Continuing at and reacting 6 hours at 50 DEG C, remove solvent under reduced pressure, obtain rufous and be dissolved in dichloromethane to brownish black grease, residual oil thing, be filtered to remove insoluble matter, the watery hydrochloric acid of filtrate 1N washs 2 times, merges hydrochloric acid solution, and regulates pH=12 with potassium hydroxide.Extracting 8 times with dichloromethane afterwards, combined dichloromethane layer, anhydrous magnesium sulfate is dried.Remove solvent under reduced pressure and obtain faint yellow oil product, productivity: 70.51%,1H NMR(400MHz,CDCl3) δ 5.03～4.94 (m, 1H), 3.55 (s, 2H), 3.23 (s, 2H), 3.07 (s, 2H), 1.85～1.45 (m, 8H).
(5) synthesis of imidazo [2,1-b] thiazole-6-Ethyl formate:
Dripping ethyl bromide acetone (90%, 1.625g, 7.5mmol) in the tetrahydrofuran solution of thiazolamine (0.500g, 5mmol), filtering the precipitation of generation under room temperature after reacting 8h, filter cake oxolane washs.Subsequently filter cake is dissolved in the ethanol solution of heat and back flow reaction 8h at 80 DEG C, solvent after cooling, is evaporated off, residual solid cold water wash and filters, be vacuum dried after centre body weight 0.375g, productivity 38.27%,1H NMR(400MHz,DMSO-d6) δ 8.42 (s, 1H), 7.95 (d, J=4.5Hz, 1H), 7.45 (d, J=4.5Hz, 1H), 4.27 (q, J=7.1Hz, 2H), 1.29 (t, J=7.1Hz, 3H).
(6) synthesis of 5-chlorine imidazo [2,1-b] thiazole-6-Ethyl formate:
By previous step intermediate imidazo [2,1-b] after thiazole-6-Ethyl formate (1.0eq) is dissolved in DMF (0.2mol/L), it is slowly added to NCS (1.05eq) wherein, 3h is reacted under room temperature, it is added thereto to the distilled water of 2 times of volumes subsequently and continue to stir half an hour at room temperature, filtering the precipitation generating, filter cake cold water washs and is vacuum dried and obtains corresponding chloro intermediate, productivity: 87.14%.
(7) synthesis of 5-chlorine imidazo [2,1-b] thiazole-6-formic acid:
By 5-chlorine imidazo [2,1-b] thiazole-6-Ethyl formate (1.0eq) is added thereto to the lithium hydroxide aqueous solution (5.0eq) of 1N after being dissolved in oxolane/methyl alcohol (V/V=1/1), 3h is reacted under room temperature, remove solvent under reduced pressure, remaining solid is soluble in water and regulates pH=3 with watery hydrochloric acid, filter the precipitation generating and vacuum dried i.e. obtain hydrolysate, productivity: 84.33%.
(8) synthesis of 4-(5-chlorine imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
5-chlorine imidazo [2,1-b] thiazole-6-formic acid (1.0eq) and 1 cyclopenta-2-piperazinones (1.2eq) be suspended in dichloromethane, with this suspension backward is sequentially added into HOBT (1.2eq) and EDCI (1.5eq), react 3-12h under room temperature until TLC detection acid converts completely.Reactant liquor extracts through water, dried over magnesium sulfate after dichloromethane layer unsaturated carbonate potassium solution and saturated aqueous common salt washing.Purified by column chromatography after mixing sample and obtain target product.Net weight: 56mg, yield 64%.1H NMR(400MHz,CDCl3) δ 7.44 (d, J=3.4Hz, 1H), 7.04 (d, J=4.6Hz, 1H), 4.95 (d, J=9.0Hz, 1H), 4.74 (s, 1H), 4.39 (s, 1H), 4.28 (s, 1H), 3.95 (s, 1H), 3.40 (s, 2H), 1.96～1.40 (m, 8H).13C NMR(100MHz,CDCl3)δ165.35,146.51,134.98,120.76,116.54,115.63,54.13,50.92,47.26,40.03,28.04,24.12。MS(ESI)m/z:391.1[M+K]+。
The synthesis of embodiment 2 4-(5-chloro-2-methyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 2)
(1) synthesis of 2-methylimidazole simultaneously [2,1-b] thiazole-6-Ethyl formate:
5-methyl-2-amino thiazole (1.0eq) and ethyl bromide acetone (1.0eq) are warming up to 80 DEG C of back flow reaction 12h after being dissolved in butanone, again drip ethyl bromide acetone (1.0eq) and continue back flow reaction 12h in reactant liquor, solvent is removed under reduced pressure after cooling reactant liquor, residue with ethyl acetate and water extraction, aqueous layer with ethyl acetate back extraction 2 times, combined ethyl acetate layer is simultaneously washed by saturated aqueous common salt, anhydrous magnesium sulfate is dried, silica gel mixed sample rear pillar chromatographic purifying obtains corresponding product, productivity: 16.86%.
(2) synthesis of 5-chloro-2-methyl imidazo [2,1-b] thiazole-6-Ethyl formate:
It is raw material with 2-methylimidazole simultaneously [2,1-b] thiazole-6-Ethyl formate, pass through and the similar synthetic method of embodiment 1 (6), obtain target compound, productivity 84.45%.
(3) synthesis of 5-chloro-2-methyl imidazo [2,1-b] thiazole-6-formic acid:
It is raw material with 5-chloro-2-methyl imidazo [2,1-b] thiazole-6-Ethyl formate, pass through and the similar synthetic method of embodiment 1 (7), obtain target compound, productivity 79.84%.
(4) synthesis of 4-(5-chloro-2-methyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
It is raw material with 5-chloro-2-methyl imidazo [2,1-b] thiazole-6-formic acid, pass through and the similar synthetic method of embodiment 1 (8), obtain target compound, productivity 65%.1H NMR(400MHz,CDCl3) δ 7.20 (s, 1H), 4.87 (s, 1H), 4.62 (s, 1H), 4.33 (s, 1H), 4.15 (s, 1H), 3.87 (s, 1H), 3.33 (s, 2H), 2.43 (s, 3H), 1.79 (s, 2H), 1.72～1.37 (m, 6H).13C NMR(100MHz,CDCl3)δ165.25,161.33,145.49,131.23,108.22,54.21,50.85,47.11,40.24,28.11,24.12,14.30。MS(ESI)m/z:389.2[M+Na]+。
The synthesis of embodiment 3 4-(5-chloro-2-isopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 3)
(1) synthesis of 5-isopropyl thiazole-2-amine:
To isopentyl aldehyde (1.721g at 0 DEG C, dichloromethane/dioxane (V/V=4/1) solution 20mmol) is slowly added dropwise bromine (1.0mL, dichloromethane/dioxane (V/V=4/1,12mL) solution 20mmol).Reactant liquor obtains 2-bromine isopentyl aldehyde intermediate after continuing reaction 2h at 10 DEG C.
2-bromine isopentyl aldehyde intermediate dichloromethane/dioxane solution be slowly added dropwise to thiocarbamide (1.523g, in dichloromethane/dioxane solution (30mL) 20mmol), add ethanol (6mL) and triethylamine (2.424g, 24mmol).Add 100mL distilled water in reactant liquor after reacting 20h under room temperature, and regulate pH=12 with the sodium hydroxide solution of 12N, after stirring 1h under room temperature, reaction mixture dichloromethane and water extract, and dichloromethane layer saturated aqueous common salt washs and is dried through anhydrous magnesium sulfate.5-isopropyl thiazole-2-amine (e41) 1.202g, productivity 42.26% is purified to obtain through column chromatography after silica gel mixed sample.1H NMR(400MHz,CDCl3) δ 6.73 (s, 1H), 4.84 (s, 2H), 2.99 (d, J=6.8Hz, 1H), 1.25 (t, J=8.3Hz, 6H).
(2) synthesis of 4-(5-chloro-2-isopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
With 5-isopropyl thiazole-2-amine as raw material, through 4 reactions similar with synthetic example 2, obtain target compound, four step gross production rates 17.37%.1H NMR(400MHz,CDCl3) δ 7.14 (s, 1H), 4.96 (s, 1H), 4.75 (s, 1H), 4.38 (s, 1H), 4.29 (s, 1H), 3.94 (s, 1H), 3.38 (s, 2H), 3.20～3.04 (m, 1H), 1.86～1.40 (m, 8H), 1.38 (d, J=6.8Hz, 6H).13C NMR(100MHz,CDCl3)δ165.27,161.09,145.64,132.84,130.94,128.85,105.65,54.11,50.91,47.25,40.25,29.31,28.05,24.11,23.47。MS(ESI)m/z:395.1[M+H]+。
The synthesis of embodiment 4 4-(5-chloro-2-isopropyl-3-methylimidazole simultaneously [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 4)
(1) synthesis of 4-methyl-5-isopropyl thiazole-2-amine and 4-isobutyl thiazole-2-amine:
It is slowly added dropwise bromine (1mL, 20mmol) at 0 DEG C in the methanol solution of 4-methylpenta-2-one (2.003g, 20mmol), under room temperature, react 2h.Add distilled water and continue to stir half an hour in reactant liquor.Extracting with water with ether subsequently, the washing of ether layer saturated aqueous common salt and anhydrous magnesium sulfate are dried.Obtaining the bromo-4-methylpenta-2-one of 1-and the mixture of the bromo-4-methylpenta-2-one of 3-after evaporated under reduced pressure solvent, this mixture is directly used in next step reaction without further purification.
By bromo generate mixing intermediate in ethanol with thiocarbamide (1.523g, 20mmol) back flow reaction 6h, after the cooling of question response liquid, evaporated under reduced pressure solvent, residue is soluble in water and regulates pH=12, subsequently with ethyl acetate and water extractive reaction liquid, the washing of ethyl acetate layer saturated aqueous common salt and anhydrous magnesium sulfate are dried, and purify to obtain 4-methyl-5-isopropyl thiazole-2-amine and 4-isobutyl thiazole-2-amine through column chromatography after silica gel mixed sample.
4-methyl-5-isopropyl thiazole-2-amine, 0.384g, productivity 12.29%, ESI-MS [M+H]+(m/z):157.1。
4-isobutyl thiazole-2-amine, 2.563g, productivity 82.02%, ESI-MS [M+H]+(m/z):157.1。
(2) synthesis of 4-(5-chloro-2-isopropyl-3-methylimidazole simultaneously [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
With 4-methyl-5-isopropyl thiazole-2-amine as raw material, through 4 reactions similar with synthetic example 2, obtain target compound, four step gross production rates 4.85%.1H NMR(400MHz,CDCl3) δ 4.87 (s, 1H), 4.51 (s, 1H), 4.30 (s, 1H), 4.14～3.94 (m, 1H), 3.85 (s, 1H), 3.34 (s, 2H), 3.18 (d, J=5.3Hz, 1H), 2.54 (s, 3H), 1.79 (s, 2H), 1.72～1.36 (m, 6H), 1.23 (d, J=13.3Hz, 6H).13C NMR(100MHz,CDCl3)δ165.11,160.47,145.95,136.25,123.10,54.15,50.93,47.19,39.91,30.03,28.11,24.11,23.79,11.95。MS(ESI)m/z:431.2[M+Na]+。
The synthesis of embodiment 5 4-(5-chloro-3-methylimidazole simultaneously [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 5)
With 4-methyl-2-amino thiazole as raw material, through 4 reactions similar with synthetic example 2, obtain target compound, four step gross production rates 15.58%.1H NMR(400MHz,CDCl3) δ 6.52 (s, 1H), 5.32 (s, 1H), 4.89 (d, J=8.0Hz, 1H), 4.56 (s, 1H), 4.31 (s, 1H), 3.87 (s, 1H), 3.33 (s, 2H), 2.61 (s, 3H), 1.80 (s, 2H), 1.70～1.32 (m, 6H).13C NMR(100MHz,CDCl3)δ165.18,160.50,148.07,134.01,130.17,54.19,50.90,47.18,39.99,28.08,24.11,14.51。MS(ESI)m/z:389.2[M+Na]+.
The synthesis of embodiment 6 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 6)
(1) synthesis of 4-cyclopropyl thiazole-2-amine:
Operation is with embodiment 4 (1), after completing with the ring closure reaction of thiocarbamide, evaporated under reduced pressure solvent, residue be dissolved in after distilled water with 10% sodium hydroxide solution regulation pH=12 and continue at room temperature to stir half an hour, filtering the white precipitate generating, filter cake cold water washs, and obtains white powder product 1.900g, productivity 67.86%, MS (ESI) m/z:141.0 [M+H]+。
(2) synthesis of 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
With 4-cyclopropyl thiazole-2-amine as raw material, through 4 reactions similar with synthetic example 2, obtain target compound, four step gross production rates 21.53%.1H NMR(400MHz,CDCl3) δ 6.37 (d, J=1.2Hz, 1H), 4.87 (d, J=7.9Hz, 1H), 4.57 (s, 1H), 4.32 (s, 1H), 4.12 (s, 1H), 3.88 (s, 1H), 3.32 (s, 2H), 2.17 (s, 1H), 1.79 (s, 2H), 1.71～1.48 (m, 4H), 1.49～1.36 (m, 2H), 1.00 (q, J=6.1Hz, 2H), 0.81～0.72 (m, 2H).13C NMR(100MHz,CDCl3)δ165.40,161.99,146.63,135.64,130.92,115.11,109.16,54.19,50.99,47.26,40.09,28.09,24.17,8.68,7.28.MS(ESI)m/z:415.2[M+Na]+。HRMS(ESI)m/z calcd for C18H21ClN4O2S, 393.1147；Found, 393.1165.
The synthesis of embodiment 7 4-(5-chloro-3-isobutyl group imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 7):
With 4-isobutyl thiazole-2-amine as raw material, through 4 reactions similar with synthetic example 2, obtain target compound, four step gross production rates 3.95%.1H NMR(400MHz,CDCl3) δ 6.52 (s, 1H), 4.86 (d, J=7.5Hz, 1H), 4.54 (s, 1H), 4.32 (s, 1H), 4.07 (s, 1H), 3.87 (s, 1H), 3.33 (s, 2H), 2.78 (d, J=4.6Hz, 2H), 2.12～1.40 (m, 9H), 0.96 (d, J=6.2Hz, 6H).13C NMR(100MHz,CDCl3)δ165.15,161.24,145.67,133.54,129.78,114.30,110.78,54.18,50.88,47.17,39.92,36.63,28.08,27.64,24.11,22.02。MS(ESI)m/z:431.3[M+Na]+。
The synthesis of embodiment 8 1-cyclopenta-4-(2,5-bis-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne) piperazine-2-ketone (compound 8)
(1) synthesis of 2,5-bis-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-Ethyl formate:
By chloro-for 5-3-cyclopropyl imidazo [2,1-b] after thiazole-6-Ethyl formate is dissolved in DMF (0.2mol/L), it is slowly added to NBS (1.05eq) wherein, add another part of NCS (1.05eq) after reacting 3-6h under room temperature and continue to react 12h in reactant liquor, it is added thereto to the distilled water of 2 times of volumes subsequently and continue to stir half an hour at room temperature, filter the precipitation generating, filter cake cold water washs and is vacuum dried and obtains target compound, productivity: 69.53%, MS (ESI) m/z:305.0 [M+H]+。
(2) 1-cyclopenta-4-(2,5-bis-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne) piperazine-2-ketone:
With 2,5-bis-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-Ethyl formate is raw material, passes through and synthetic example 2 (3) and the similar two-step reaction of embodiment 2 (4), obtains target compound, two step gross production rates 25.36%.1H NMR(400MHz,CDCl3) δ 5.06 4.72 (m, 1H), 4.53 (s, 1H), 4.31 (s, 1H), 4.07 (d, J=10.0Hz, 1H), 3.87 (s, 1H), 3.28 (s, 2H), 1.95～1.71 (m, 3H), 1.69-1.50 (m, 4H), 1.49～1.32 (m, 2H), 1.18-1.09 (m, 2H), 1.07～0.99 (m, 2H).13C NMR(100MHz,CDCl3)δ165.25,161.37,143.16,134.09,130.90,118.59,115.34,54.19,50.83,47.19,40.01,28.05,24.10,8.72,6.49。MS(ESI)m/z:449.2[M+Na]+。
The synthesis of embodiment 9 1-cyclopenta-4-(2,5-bis-chloro-3-isobutyl group imidazo [2,1-b] thiazole-6-phosphinylidyne) piperazine-2-ketone (compound 9)
(1) synthesis of 2,5-bis-chloro-3-isobutyl group imidazo [2,1-b] thiazole-6-Ethyl formate:
By chloro-for 5-3-isobutyl group imidazo [2,1-b] after thiazole-6-Ethyl formate is dissolved in DMF (0.2mol/L), it is slowly added to NBS (1.05eq) wherein, add another part of NCS (1.05eq) after reacting 3-6h under room temperature and continue to react 12h in reactant liquor, it is added thereto to the distilled water of 2 times of volumes subsequently and continue to stir half an hour at room temperature, filter the precipitation generating, filter cake cold water washs and is vacuum dried and obtains target compound, productivity: 43.11%, MS (ESI) m/z:320.0 [M+H]+。
(2) synthesis of 1-cyclopenta-4-(2,5-bis-chloro-3-isobutyl group imidazo [2,1-b] thiazole-6-phosphinylidyne) piperazine-2-ketone:
With 2,5-bis-chloro-3-isobutyl group imidazo [2,1-b] thiazole-6-Ethyl formate is raw material, passes through and synthetic example 2 (3) and the similar two-step reaction of embodiment 2 (4), obtains target compound, two step gross production rates 26.75%.1H NMR(400MHz,CDCl3) δ 4.96～4.83 (m, 1H), 4.54 (s, 1H), 4.32 (s, 1H), 4.08 (s, 1H), 3.87 (s, 1H), 3.32 (s, 2H), 2.84 (d, J=4.6Hz, 2H), 2.10 (s, 1H), 1.80 (s, 2H), 1.64 (s, 2H), 1.57 (s, 2H), 1.43 (s, 2H), 0.97 (d, J=5.0Hz, 6H).13C NMR(100MHz,CDCl3)δ165.25,161.21,143.87,134.15,130.76,117.21,114.73,54.23,50.89,47.23,40.04,33.34,29.08,28.07,24.11,21.91。MS(ESI)m/z:465.1[M+Na] +。
The synthesis of embodiment 10 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-(trans-4-hydroxy-cyclohexyl) piperazine-2-ketone (compound 10)
(1) trans-4-{ [3-(1-Methylethyl) is silica-based] oxygen } synthesis of ring amine:
By trans to aminocyclohexanol (2.303g, it 20mmol) is dissolved in DMF, it is sequentially added into tri isopropyl chlorosilane (5.794g, 30mmol) and imidazoles (3.401g, 50mmol), it is dried with anhydrous magnesium sulfate after washing through water and saturated aqueous common salt with ethyl acetate and water extractive reaction liquid, organic phase after reacting 12h under room temperature.Obtain white solid 5.233g, productivity 96.37% after reduced pressure concentration.MS(ESI)m/z:272.2[M+H]+。
(2) synthesis of N-(ring amyl-3-alkene-1-base)-2-(4-nitrobenzene sulphonyl amido) acetamide:
By trans-4-{ [3-(1-Methylethyl) is silica-based] oxygen } after ring amine (1.0eq) and 2-(4-nitrobenzene sulphonyl amido) acetic acid (1.0eq) is dissolved in DMF, it is separately added into diisopropylethylamine (DIEA wherein, 2.0eq) with HATU (1.5eq), under room temperature, react 12h.Reactant liquor ethyl acetate and water extraction, aqueous layer with ethyl acetate back extraction 2 times, combined ethyl acetate layer, water and saturated aqueous common salt washing, organic layer obtains product through silica gel column chromatography after being dried through anhydrous magnesium sulfate.Productivity: 53.13%, MS (ESI) m/z:514.1 [M+H]+。
(3) 4-(4-nitrobenzenesulfonyl)-1-trans-synthesis of { 4-[three (1-Methylethyl) siloxy] cyclohexyl }-2-piperazinones:
Add potassium carbonate (10.0eq) in the DMF solution of N-(ring amyl-3-alkene-1-base)-2-(4-nitrobenzene sulphonyl amido) acetamide (1.0eq), stir half an hour at 60 DEG C.Adding 1 in reactant liquor, 2-Bromofume (10.0eq), at 60 DEG C, continuation reaction 24h, removes solvent under reduced pressure, and residual solid is suspended in water and stirs half an hour, filters to obtain faint yellow thick product.Thick product is extracted with water by ethyl acetate further, and ethyl acetate layer washs through water and saturated aqueous common salt and is dried through anhydrous magnesium sulfate, obtains target compound through silica gel column chromatography, productivity: 42.80%.1H NMR(400MHz,DMSO-d6) δ 8.44 (d, J=8.4Hz, 2H), 8.09 (d, J=8.4Hz, 2H), 4.14～4.04 (m, 1H), 3.65 (s, 2H), 3.65-3.55 (m, 1H), 3.32 (d, J=5.0Hz, 2H), 3.26 (d, J=5.0Hz, 2H), 1.86 (d, J=11.3Hz, 2H), 1.57～1.00 (m, 9H), 1.00 (s, 18H).MS(ESI)m/z:540.3[M+H]+。
(4) 1-trans-synthesis of { 4-[three (1-Methylethyl) siloxy] cyclohexyl }-2-piperazinones:
Lithium hydroxide (3.0eq) is added in acetonitrile/DMSO (V/V=49/1) solution of mercapto-propionate (2.5eq); stir half an hour at 50 DEG C, be slowly added dropwise in this reactant liquor intermediate 4-(4-nitrobenzenesulfonyl)-1-trans-acetonitrile/DMSO (V/V=49/1) solution of { 4-[three (1-Methylethyl) siloxy] cyclohexyl }-2-piperazinones (1.0eq).Continue at and react 6 hours at 50 DEG C, remove solvent under reduced pressure, obtain rufous to brownish black grease, residual oil thing is dissolved in dichloromethane, being filtered to remove insoluble matter, filtrate directly obtains faint yellow oil product through silica gel column chromatography, and product becomes transparent solid after standing overnight, productivity: 42.19%, MS (ESI) m/z:355.2 [M+H]+。
(5) synthesis of 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-(trans-4-hydroxy-cyclohexyl) piperazine-2-ketone:
With 1-trans-{ 4-[three (1-Methylethyl) siloxy] cyclohexyl }-2-piperazinones and 5-chloro-3-cyclopropyl imidazo [2, 1-b] thiazole-6-carboxylic acid is raw material, through the operation step similar with synthetic example 2 (4), obtain intermediate 4-(5-chloro-3-cyclopropyl imidazo [2, 1-b] thiazole-6-phosphinylidyne)-1-(trans-4-((three isopropyls are silica-based) oxygen) cyclohexyl) piperazine-2-ketone, this intermediate is dissolved in methanol hydrochloride solution and stirs 1 hour at room temperature, purify through column chromatography after evaporated under reduced pressure solvent and obtain target product, productivity: 39.17%.1H NMR(400MHz,CDCl3) δ 6.46 (s, 1H), 4.63 (s, 1H), 4.43 (s, 2H), 4.16 (s, 1H), 3.94 (s, 1H), 3.58 (s, 1H), 3.38 (s, 2H), 2.24 (s, 1H), 2.06～1.21 (m, 8H), 1.09 (s, 2H), 0.85 (s, 2H).13CNMR(100MHz,CDCl3)δ165.11,161.93,147.92,135.59,129.51,114.49,109.03,69.78,51.66,47.45,44.38,40.27,34.33,27.19,8.65,7.27。MS(ESI)m/z:445.2[M+Na]+。
The synthesis of embodiment 11 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-(ring amyl-3-alkene-1-base) piperazine-2-ketone (compound 11)
(1) synthesis of N-(ring amyl-3-alkene-1-base)-2-(4-nitrobenzene sulphonyl amido) acetamide:
After 2-(4-nitrobenzene sulphonyl amido) acetic acid (1.0eq) is dissolved in DMF with 3-cyclopentamine hydrochloride (1.0eq), it is separately added into diisopropylethylamine (DIEA wherein, 3.0eq) with HATU (1.5eq), 12h is reacted under room temperature, pale precipitation is separated out after backward reactant liquor directly adds water, with cold water washing and vacuum dried obtain corresponding product after filtration, productivity: 78.51%1H NMR(400MHz,DMSO-d6) δ 8.52～8.24 (m, 4H), 8.03 (d, J=8.4Hz, 2H), 5.66 (s, 2H), 4.25～4.03 (m, 1H), 3.52 (d, J=5.9Hz, 2H), 2.55～2.45 (m, 2H), 2.01 (dd, J=15.4,3.5Hz, 2H).MS(ESI)m/z:326.1[M+H]+。
(2) synthesis of 4-(4-nitrobenzenesulfonyl)-1 (ring amyl-3-alkene-1-base)-2-piperazinones:
Add potassium carbonate (10.0eq) in the DMF solution of N-(ring amyl-3-alkene-1-base)-2-(4-nitrobenzene sulphonyl amido) acetamide (1.0eq), stir half an hour at 60 DEG C.1 is added in reactant liquor, 2-Bromofume (10.0eq), continuing reaction 24h at 60 DEG C, removing solvent under reduced pressure, residual solid is suspended in water and stirs half an hour, filter to obtain faint yellow thick product, being suspended in the thick product being filtrated to get in the watery hydrochloric acid of 1N again and stirring half an hour, filter, filter cake washs through cold water, is vacuum dried, obtaining purer midbody product, this intermediate can be directly used for next step reaction without further purification.MS(ESI)m/z:352.1[M+H]+。
The synthesis of (3) 1 (ring amyl-3-alkene-1-base)-2-piperazinones:
Lithium hydroxide (3.0eq) is added in acetonitrile/DMSO (V/V=49/1) solution of mercapto-propionate (2.5eq); stir half an hour at 50 DEG C, in this reactant liquor, be slowly added dropwise acetonitrile/DMSO (V/V=49/1) solution of 4-(4-nitrobenzenesulfonyl)-1 (ring amyl-3-alkene-1-base)-2-piperazinones (1.0eq).Continuing at and reacting 6 hours at 50 DEG C, remove solvent under reduced pressure, obtain rufous and be dissolved in dichloromethane to brownish black grease, residual oil thing, be filtered to remove insoluble matter, the watery hydrochloric acid of filtrate 1N washs 2 times, merges hydrochloric acid solution, and regulates pH=12 with potassium hydroxide.Extracting 8-10 time with dichloromethane afterwards, combined dichloromethane layer, anhydrous magnesium sulfate is dried.Remove solvent under reduced pressure and obtain faint yellow oil product.Productivity: 48.57%, MS (ESI) m/z:165.1 [M-H]-。
(4) synthesis of 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-(ring amyl-3-alkene-1-base) piperazine-2-ketone:
With 1 (ring amyl-3-alkene-1-base)-2-piperazinones and 5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-carboxylic acid is raw material, through the operation step similar with synthetic example 2 (4), obtain target product, productivity: 33%.1H NMR(400MHz,CDCl3) δ 6.48 (s, 1H), 5.75 (s, 2H), 5.45 (s, 1H), 4.62 (d, J=20.5Hz, 1H), 4.39 (s, 1H), 4.17 (s, 1H), 3.93 (s, 1H), 3.33 (s, 2H), 2.78～2.63 (m, 2H), 2.35～2.16 (m, 3H), 1.14～1.01 (m, 2H), 0.94～0.77 (m, 2H).13C NMR(100MHz,CDCl3)δ164.86,161.81,147.87,135.63,129.43,114.37,109.27,50.90,50.51,47.09,40.02,36.37,8.63,7.25。MS(ESI)m/z:413.2[M+Na]+。
The synthesis of embodiment 12 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclohexyl piperazine-2-ketone (compound 12)
(1) synthesis of 1-cyclohexyl piperazine-2-ketone:
With cyclohexylamine as raw material, through the operation step similar with synthetic example 1 (4), obtain target product, three step gross production rates: 33.90%.1H NMR(400MHz,CDCl3) δ 4.46 (dd, J=11.4,3.6Hz, 1H), 3.54 (s, 2H), 3.27～3.18 (m, 2H), 3.10～3.00 (m, 2H), 1.79 (s, 2H), 1.76-1.29 (m, 8H).
(2) synthesis of 4-(5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-phosphinylidyne)-1-cyclohexyl piperazine-2-ketone:
It is raw material with 1-cyclohexyl piperazine-2-ketone and 5-chloro-3-cyclopropyl imidazo [2,1-b] thiazole-6-carboxylic acid, through the operation step similar with synthetic example 2 (4), obtain target product, productivity: 84.71%.MS(ESI)m/z:429.2[M+Na]+。
The synthesis of embodiment 13 4-(3-chloro-6,7-dihydro-5H-cyclopenta [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 13)
(1) synthesis of 5,6-dihydro-4H-cyclopenta [d] thiazole-2-amine:
Method one, 2-chlorine cyclopentanone (2.372g, it is warming up to 80 DEG C, back flow reaction 12h after 20mmol) being dissolved in ethanol (30mL) with thiocarbamide (1.523g, 20mmol), after question response liquid is cooled to room temperature, filter the white precipitate generating, and with cold absolute ethanol washing, after vacuum drying, obtain Off-white product 1.835g, productivity: 51.93%, MS (ESI) m/z:141.0 [M+H]+。
Method two, it is slowly added to NBS (1.05eq) in the DMSO solution of cyclopentanone (1.0eq) under room temperature, react 20 minutes under room temperature, then it is added thereto to the ammonium chloride solution of 10%, stirring is extracted by ethyl acetate and water after half an hour, ethyl acetate washed with water and saturated aqueous common salt washing, anhydrous magnesium sulfate is dried, and obtains pale yellow oil after reduced pressure concentration.
After this pale yellow oil and thiocarbamide (1.0eq) are dissolved in ethanol, it is warming up to 80 DEG C of back flow reaction 12h, reduced pressure concentration after the cooling of question response liquid, residual oil thing regulates pH=12 with the sodium hydroxide solution of 10% after being dissolved in water, then extracting with water with ethyl acetate, ethyl acetate washed with water and saturated aqueous common salt washing, anhydrous magnesium sulfate is dried, silica gel mixed sample rear pillar chromatographic purifying obtains 5,6-dihydro-4H-cyclopenta [d] thiazole-2-amine.Productivity: 25.16%, MS (ESI) m/z:141.0 [M+H]+。
(2) synthesis of 4-(3-chloro-6,7-dihydro-5H-cyclopenta [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
With 5,6-dihydro-4H-cyclopenta [d] thiazole-2-amine is raw material, through the four-step reaction similar with synthetic example 2, obtains target compound, four step gross production rates 12.84%.1H NMR(400MHz,CDCl3) δ 4.97 (s, 1H), 4.74 (s, 1H), 4.38 (s, 1H), 4.27 (s, 1H), 3.93 (s, 1H), 3.38 (s, 2H), 3.11 (s, 2H), 2.92 (t, J=6.8Hz, 2H), 2.63～2.51 (m, 2H), 1.95～1.45 (m, 8H).13C NMR(100MHz,CDCl3)δ165.31,161.03,145.79,133.01, 127.49,125.33,54.10,50.87,47.20,40.04,33.09,28.06,26.34,25.72,24.13。MS(ESI)m/z:415.2[M+Na]+。
The synthesis of embodiment 14 4-(3-chloro-5,6,7,8-tetrahydro benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 14)
(1) synthesis of 4,5,6,7-tetrahydro benzo [d] thiazole-2-amine:
It is slowly added to NBS (1.05eq) in the DMSO solution of cyclohexanone (1.0eq) under room temperature, react 20 minutes under room temperature, then it is added thereto to the ammonium chloride solution of 10%, stirring is extracted by ethyl acetate and water after half an hour, ethyl acetate washed with water and saturated aqueous common salt washing, anhydrous magnesium sulfate is dried, and obtains pale yellow oil after reduced pressure concentration.
After this pale yellow oil and thiocarbamide (1.0eq) are dissolved in ethanol, it is warming up to 80 DEG C of back flow reaction 12h, reduced pressure concentration after the cooling of question response liquid, residual oil thing regulates pH=12 with the sodium hydroxide solution of 10% after being dissolved in water, then extract with water with ethyl acetate, ethyl acetate washed with water and saturated aqueous common salt washing, anhydrous magnesium sulfate is dried, silica gel mixed sample rear pillar chromatographic purifying obtains 4,5,6,7-tetrahydro benzos [d] thiazole-2-amine, productivity 74.68%, MS (ESI) m/z:155.1 [M+H]+。
(2) synthesis of 4-(3-chloro-5,6,7,8-tetrahydro benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
With 4,5,6,7-tetrahydro benzos [d] thiazole-2-amine is raw material, through the four-step reaction similar with synthetic example 2, obtains target compound, four step gross production rates 10.89%.1H NMR(400MHz,CDCl3) δ 4.95 (s, 1H), 4.66 (s, 1H), 4.38 (s, 1H), 4.20 (s, 1H), 3.94 (s, 1H), 3.40 (s, 2H), 3.06 (s, 2H), 2.72 (s, 2H), 2.03～1.77 (m, 6H), 1.77～1.56 (m, 4H), 1.56～1.42 (m, 2H).13C NMR(100MHz,CDCl3)δ165.29,161.34,145.14,133.14,127.20,125.19,117.78,54.12,50.94,47.23,40.00,28.05,24.71,24.11,23.34,22.31,21.61。MS(ESI)m/z:429.1[M+Na]+。
The synthesis of embodiment 15 4-(3-chloro-6,7,8,9-tetrahydrochysene-4H-cycloheptatriene [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 15)
With cycloheptanone as raw material, react through five steps similar with synthetic example 14, obtain target compound, five step gross production rates 1.91%.1H NMR(400MHz,CDCl3) δ 4.93 (s, 1H), 4.68 (s, 1H), 4.39 (s, 1H), 4.22 (s, 1H), 3.97 (s, 1H), 3.42 (s, 2H), 3.13 (t, J=7.1Hz, 2H), 2.79 (t, J=7.1Hz, 2H), 2.03～1.57 (m, 12H), 1.55～1.40 (m, 2H).13C NMR(100MHz,CDCl3)δ165.31,161.17,145.43,132.94,127.27,125.24,54.11,50.92,47.25,40.02,29.33,28.97,28.43,28.05,26.51,24.12,19.79。MS(ESI)m/z:421.2[M+H]+。
The synthesis of embodiment 16 4-(3-chloro-7-methyl-5,6,7,8-tetrahydro benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 16)
With 4-methyl cyclohexanone as raw material, react through five steps similar with synthetic example 14, obtain target compound, five step gross production rates 7.47%.1H NMR(400MHz,CDCl3) δ 4.96 (s, 1H), 4.64 (s, 1H), 4.38 (s, 1H), 4.16 (s, 1H), 3.93 (s, 1H), 3.41 (s, 2H), 3.22 (d, J=15.1Hz, 1H), 2.98 (s, 1H), 2.77 (d, J=13.9Hz, 1H), 2.44～2.30 (m, 1H), 2.05 (d, J=9.1Hz, 2H), 1.86 (s, 2H), 1.78～1.41 (m, 7H), 1.14 (d, J=6.2Hz, 3H).13C NMR(100MHz,CDCl3)δ165.20,160.91,146.21,132.62,127.04,125.16,54.13,50.90,47.21,39.90,32.46,29.57,28.92,28.06,24.11,22.99,20.87。MS(ESI)m/z:443.2[M+Na]+。
The synthesis of embodiment 17 4-(3-chloro-7,7-dimethyl-5,6,7,8-tetrahydro benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 17)
With 4,4-dimethylcyclohexanon is raw material, reacts through five steps similar with synthetic example 14, obtains target compound, five step gross production rates 7.28%.1H NMR(400MHz,CDCl3) δ 4.87 (s, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 4.09 (d, J=17.9Hz, 1H), 3.86 (s, 1H), 3.33 (s, 2H), 2.98 (s, 2H), 2.42 (s, 2H), 1.78 (s, 2H), 1.71～1.48 (m, 6H), 1.49～1.31 (m, 2H), 1.03 (s, 6H).13C NMR(100MHz,CDCl3)δ165.28,160.89,145.19,133.28,125.91,124.51,54.10,50.89,47.19,40.23,38.00,34.44,30.61,28.05,27.54,24.11,21.09。MS(ESI)m/z:457.2[M+Na]+。
The synthesis of the chloro-2-of embodiment 18 3-(4-cyclopenta-3-oxypiperazin-1-phosphinylidyne)-6,7-dihydrobenzo [d] imidazo [2,1-b] thiazole-8 (5H)-one (compound 18)
With 1, hydroresorcinol is raw material, reacts through five steps similar with synthetic example 14, obtains target compound, five step gross production rates 0.59%.1H NMR(400MHz,CDCl3) δ 5.30 (s, 1H), 4.96 (s, 1H), 4.62～4.14 (m, 2H), 4.01～3.58 (m, 1H), 3.43 (s, 2H), 2.68 (t, J=6.4Hz, 2H), 2.29 (s, 2H), 1.97～1.40 (m, 10H).13CNMR(100MHz,CDCl3)δ191.42,166.37,161.57,144.48,125.38,122.13,54.10,50.86,47.27,40.14,37.16,28.16,24.12,22.19,21.96。MS(ESI)m/z:419.5[M–H]-；MS(ESI)m/z:421.3[M+H]+。
The synthesis of embodiment 19 4-(3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 19)
(1) synthesis of benzo [d] imidazo [2,1-b] thiazole-2-Ethyl formate:
2-aminobenzothiazole (1.0eq) and ethyl bromide acetone (2.0eq) back flow reaction 12h in butanone, reduced pressure concentration reactant liquor after reactant liquor cooling, residual solid or grease ethyl acetate extract with water, it is dried through saturated aqueous common salt washing and anhydrous magnesium sulfate, rear silica gel mixed sample rear pillar chromatographic purifying obtains benzo [d] imidazo [2,1-b] thiazole-2-Ethyl formate.Productivity: 52.47%, MS (ESI) m/z:247.1 [M+H]+。
(2) synthesis of 3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-Ethyl formate:
By intermediate benzo [d] imidazo [2,1-b] after thiazole-2-Ethyl formate (1.0eq) is dissolved in DMF (0.2mol/L), it is slowly added to NCS (1.05eq) wherein, 3h is reacted under room temperature, it is added thereto to the distilled water of 2 times of volumes subsequently and continue to stir half an hour at room temperature, filter the precipitation generating, filter cake cold water washs and is vacuum dried and obtains 3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-Ethyl formate, productivity: 81.23%, MS (ESI) m/z:281.0 [M+H]+。
(3) synthesis of 3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-formic acid:
Intermediate 3-chlorobenzene simultaneously [d] imidazo [2,1-b] the hydrolysis operation of thiazole-2-Ethyl formate is with the synthesis of embodiment 1 (7), after reaction completes, reduced pressure concentration reactant liquor, residual solid suspend with water in and regulate pH=3, filtering after continuing to stir half an hour, the washing of filter cake cold water is vacuum dried and to obtain corresponding hydrolysate, productivity: 79.44%.
(4) synthesis of 4-(3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone:
With 1-cyclopentyl-based piperazine-2-ketone (81mg, 0.48mmol) with 3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-formic acid (101mg, it 0.40mmol) is raw material, through the operation step similar with synthetic example 2 (4), obtain target product 70mg, productivity: 43%.1H NMR(400MHz,CDCl3) δ 8.29 (d, J=7.6Hz, 1H), 7.73 (d, J=7.8Hz, 1H), 7.54～7.40 (m, 2H), 5.09～4.86 (m, 1H), 4.75 (s, 1H), 4.41 (s, 1H), 4.26 (s, 1H), 3.96 (s, 1H), 3.39 (d, J=15.4Hz, 2H), 1.95～1.45 (m, 8H).13C NMR(100MHz,CDCl3)δ166.33,161.34,145.95,135.02,131.99,130.41,126.47,126.17,124.36,114.26,54.18,50.93,47.30,40.15,28.06,24.13。MS(ESI)m/z:403.1[M+H]+。
The synthesis of embodiment 20 4-(3-chloro-7-methoxyl group benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 20)
With 2-amino-6-methoxybenzothiazole as raw material, through the four-step reaction similar with synthetic example 19, obtain target compound, four step gross production rates 18.42%.1H NMR(400MHz,CDCl3) δ 8.19 (s, 1H), 7.25 (s, 1H), 7.05 (d, J=8.2Hz, 1H), 4.98 (s, 1H), 4.77 (s, 1H), 4.42 (s, 1H), 4.28 (s, 1H), 3.97 (s, 1H), 3.91 (s, 3H), 3.42 (s, 2H), 1.89 (s, 2H), 1.72～1.44 (m, 6H).13C NMR(100MHz,CDCl3)δ165.37,160.82,158.07,131.89,126.59,125.88,119.66,114.97,113.74,108.66,55.99,54.15,50.91,47.47,40.05,28.08,24.13。MS(ESI)m/z:455.2[M+Na]+。
The synthesis of embodiment 21 1-cyclopenta-4-(3,7-dichloro benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne) piperazine-2-ketone (compound 21)
With 2-amino-6-chloro benzothiazole as raw material, through the four-step reaction similar with synthetic example 19, obtain target compound, four step gross production rates 23.43%.1H NMR(400MHz,CDCl3) δ 8.24 (d, J=7.6Hz, 1H), 7.68 (s, 1H), 7.41 (d, J=7.9Hz, 1H), 4.87 (s, 1H), 4.66 (d, J=14.6Hz, 1H), 4.34 (s, 1H), 4.15 (d, J=18.6Hz, 1H), 3.89 (s, 1H), 3.35 (s, 2H), 1.80 (s, 2H), 1.72～1.50 (m, 4H), 1.46 (d, J=14.8Hz, 2H).13C NMR(100MHz,CDCl3)δ165.34,160.97,145.09,134.98,132.10,130.42,127.02,126.80,124.19,115.13,114.98,54.33,50.82,47.27,40.07,28.08,24.12。MS(ESI)m/z:437.3[M+H]+。
The synthesis of embodiment 22 4-(7-bromo-3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 22)
With 2-amino-6-bromo benzothiazole as raw material, through the four-step reaction similar with synthetic example 19, obtain target compound, four step gross production rates 17.40%.1H NMR(400MHz,CDCl3) δ 8.09 (d, J=7.4Hz, 1H), 7.82 (s, 1H), 7.55 (d, J=8.3Hz, 1H), 4.88 (s, 1H), 4.67 (s, 1H), 4.34 (s, 1H), 4.18 (s, 1H), 3.89 (s, 1H), 3.34 (s, 2H), 1.81 (s, 2H), 1.71～1.50 (m, 4H), 1.44 (s, 2H).13C NMR(100MHz,CDCl3)δ165.29,161.02,144.89,135.14,130.87,129.77,127.00,124.51,119.32,115.27,54.25,50.88,47.29,40.09,28.09,24.13。MS(ESI)m/z:481.2[M+H]+。
The synthesis of embodiment 23 4-(3-chloro-7-methyl benzo [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-cyclopentyl-based piperazine-2-ketone (compound 23)
With 2-amino-6-methylbenzothiazole as raw material, through the four-step reaction similar with synthetic example 19, obtain target compound, four step gross production rates 10.36%.1H NMR(400MHz,CDCl3) δ 8.09 (d, J=8.0Hz, 1H), 7.48 (s, 1H), 7.24 (d, J=8.3Hz, 1H), 4.89 (s, 1H), 4.67 (s, 1H), 4.34 (s, 1H), 4.17 (s, 1H), 3.89 (s, 1H), 3.35 (s 2H), 2.42 (s, 3H), 1.80 (s, 2H), 1.72～1.35 (m, 6H).13C NMR(100MHz,CDCl3)δ165.31,160.93,145.09,136.84,134.09,130.4,129.75,127.64,124.46,113.96,54.22,50.85,47.26,40.08,28.08,24.13,21.45。MS(ESI)m/z:439.1[M+Na]+。
The synthesis of embodiment 24 4-(3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-(trans-4-hydroxy-cyclohexyl) piperazine-2-ketone (compound 24)
With 3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-formic acid (76mg, 0.30mmol)-{ 4-[three (1-Methylethyl) siloxy] cyclohexyl }-2-piperazinones (128mg trans with 1-, it 0.36mmol) is raw material, pass through and the similar reaction of synthetic example 19 (4), obtain target compound 112mg, productivity 86%.1H NMR(400MHz,DMSO-d6) δ 8.28 (d, J=8.0Hz, 1H), 8.12 (d, J=7.8Hz, 1H), 7.60 (t, J=7.6Hz, 1H), 7.53 (t, J=7.5Hz, 1H), 4.54 (s, 2H), 4.16 (s, 2H), 4.06 (s, 1H), 3.80 (s, 1H), 3.34 (s, 3H), 1.87 (d, J=10.7Hz, 2H), 1.54 (s, 4H), 1.24 (d, J=7.8Hz, 2H).13C NMR(100MHz,DMSO-d6)δ164.01,160.06,145.12,134.99,131.48,129.71,126.77,126.19,125.27,113.76,68.02,51.33,46.51,43.88,40.97,34.34,26.65。MS(ESI)m/z:433.1[M+H]+。
The synthesis of embodiment 25 4-(3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-phosphinylidyne)-1-(ring amyl-3-alkene-1-base) piperazine-2-ketone (compound 25)
With 3-chlorobenzene simultaneously [d] imidazo [2,1-b] thiazole-2-formic acid (50mg, 0.20mmol) He 1 (ring amyl-3-alkene-1-base)-2-piperazinones (40mg, it 0.24mmol) is raw material, pass through and the similar reaction of synthetic example 19 (4), obtain target compound 29mg, productivity 36%.1H NMR(400MHz,CDCl3) δ 8.32 (d, J=7.8Hz, 1H), 7.76 (d, J=7.7Hz, 1H), 7.56～7.42 (m, 2H), 5.77 (s, 2H), 5.49 (s, 1H), 4.78 (s, 1H), 4.43 (s, 1H), 4.26 (s, 1H), 3.96 (s, 1H), 3.36 (s, 2H), 2.84～2.65 (m, 2H), 2.31 (dd, J=15.6,3.6Hz, 2H).13C NMR(100MHz,CDCl3)δ164.84,160.23,145.05,135.03,131.96,130.48,129.45,126.51,126.23,124.39,114.30,50.91,50.52,47.25,40.09,36.40。MS(ESI)m/z:423.1[M+Na]+。
Embodiment 26 Compound ira vitro anti-HCV activity is tested
HCV Replicon luciferase Assay (detection of Hepatitis C virus replicon luciferase) is to utilize fluorescein enzyme process test compound anti-HCV activity.Its principle is the Replicate Sub-system that in vitro can infect merging the sub-gene group of the HCV NS3-NS5 encoding gene containing genotype 1b with luciferase encoding gene and being formed, after infecting Huh7.0 cell by electroporation technology, this Replicate Sub-system can replicate in intracellular, may thereby determine that HCV replicon activity by uciferase activity in test cell.
Test method is as follows:
Carry out 10 concentration point of 1:2 serial dilution, duplicate hole to the compounds of this invention, add in 96 orifice plates.It is suspended in stable HCV genotype 1b replicon cell in the nutrient solution containing 10%FBS, with in the density kind of 8000 cells in every hole to 96 orifice plates containing compound.Cell is at 5%CO2, cultivate 3 days under the conditions of 37 DEG C.Fluorescein enzymatic assays compound anti-hepatitis C virus replicon inhibitory activity, is calculated the medium effective concentration EC of compound by matched curve50。
HCV Replicon MTT Assay (Hepatitis C virus replicon system cells toxicity detection) is compound of reaction poisonous effect to Huh7.0 cell under variable concentrations by MTT method test number of viable cells.MTT is the hydrionic weld of a kind of acceptance, may act on the respiratory chain in living cells mitochondria, tetrazolium ring opening under the effect of succinate dehydrogenase and cromoci, generate blue first a ceremonial jade-ladle, used in libation crystallization, the growing amount of first a ceremonial jade-ladle, used in libation crystallization is only directly proportional to number of viable cells, the first a ceremonial jade-ladle, used in libation crystallization generating is dissolved in dimethyl sulfoxide (DMSO), utilizes ELIASA to measure the optical density OD value at 570nm, can reflect number of viable cells.
Test method is as follows:
Adjusting cell concentration with complete culture solution is 2 × 104/ mL, is inoculated in 96 orifice plates, every hole 200 μ L, overnight incubation, processes cell with the above-claimed cpd of various dose respectively, set isopyknic solvent control group simultaneously next day, and DMSO concentration is 0.1% (the DMSO cell proliferation of 0.1% is without impact).Each group sets 3 multiple holes, 37 DEG C, 5%CO2Cultivate.After cultivating 48 and 72 hours, take 1 culture plate, every hole adds 5mg/mL MTT reagent 20 μ L, continue to cultivate 2h, abandoning supernatant, then adding DMSO 150 μ L, vibration mixes 15min, measure absorbance (A) value (A value is directly proportional to viable count) with ELIASA (λ=570nm), take its mean value.Cell proliferation inhibition rate (%)=(solvent control group A570-experimental group A570)/solvent control group A570× 100%.Calculated the CC of compound by the inhibiting rate matched curve under variable concentrations50。
Table 2 lists the EC of part of compounds in the present invention50And CC50。
The medium effective concentration EC50 of table 2 compound on gene type 1b replicon and the half growth inhibitory concentration to Huh7
From Table 2, it can be seen that the embodiment of the present invention has good inhibitory activity, the medium effective concentration (EC of major part embodiment to HCV genotype 1b replicon50) it is in sub-micromolar to nanomolar range, and each embodiment does not demonstrates obvious cytotoxicity to Replicate Sub-system.Show that the compounds of this invention has a higher security, potential become a kind of excellent anti-hepatitis medicine.
The test of embodiment 27 compound on gene type 1a replicon activity
The present invention has investigated the inhibitory activity to HCV genotype 1a Strain for the compounds of this invention also further, to investigate whether the inhibitory activity to HCV for the compounds of this invention has broad spectrum activity.
Test method is as follows:
Carry out 10 concentration point of 1:2 serial dilution, duplicate hole to the compounds of this invention, add in 96 orifice plates.It is suspended in stable HCV-1a replicon cell in the nutrient solution containing 10%FBS respectively, with in the density kind of 8000 cells in every hole to 96 orifice plates containing compound.Cell is at 5%CO2, cultivate 3 days under the conditions of 37 DEG C.Fluorescein enzymatic assays compound anti-hepatitis C virus replicon inhibitory activity.Application GraphPad Prism software calculates the EC of compound50。
Table 3 lists representation compound 6 and the EC of two kinds of genotype of 25 couples of HCV (genotype 1a and genotype 1b)50。
Table 3 compound 6 and the inhibitory activity of 25 pairs of genotype 1a and 1b
From table 3 it is observed that the embodiment of the present invention all demonstrates good inhibitory activity to HCV genotype 1a and genotype 1b replicon, therefore the compounds of this invention is applicable to the treatment of Multi-genotype HCV infection.
The inhibitory activity to medicament-resistant mutation strain for embodiment 28 compound is tested
The present invention has investigated the inhibitory activity to many kinds of multidrug resistant disease strains of HCV genotype 1b for the compounds of this invention also further, to investigate whether the compounds of this invention exists cross resistance with the HCV inhibitor reported at present.Test Virus strain includes a kind of NS3/4A inhibitor persister (A156T), 1 kind of NS5A inhibitor persister (Y93H), 5 kinds of NS4B inhibitor persister (H3R, Q26R, H94R, F98C, V105M) and 4 kinds of NS5B inhibitor persister (M423I, P495A, Y448H, S282T)
Test method is as follows:
Carry out 8 concentration point of 1:2 serial dilution, duplicate hole to compound, add in 96 orifice plates.Hepatitis C virus replicon rna is proceeded to Huh7 cell by electric shocking method, enters in 96 orifice plates containing compound cell with the density kind of 10000 cells in every hole subsequently.Cell is at 5%CO2, cultivate 3 days under the conditions of 37 DEG C.Measure uciferase activity.Application GraphPad Prism software calculates the EC of compound50Value.
Table 4 lists representation compound embodiment 6 and the EC to 10 kinds of persisters for the embodiment 2550
Table 4 compound different medicament-resistant mutation strain inhibitory activity to HCV genotype 1b
As can be seen from Table 4, the medicament-resistant mutation being positioned on NS4B gene demonstrates resistance in various degree to the embodiment of the present invention, and the medicament-resistant mutation being positioned on NS3/4A, NS5A and NS5B to the compounds of this invention same sensitivity.Show that the compounds of this invention is probably a kind of NS4B inhibitor, the compounds of this invention also can be with the generation of NS3/4A, NS5A and NS5B use in conjunction suppression medicament-resistant mutation, develop novel hepatitis therapeutic scheme, and the compounds of this invention also potential as medicinal application in the HCV infection person to other drug resistance.
Embodiment 29 compound is studied with other direct antiviral HCV inhibitor drug combinations
HCV is a kind of single strand RNA virus, and its mutation rate is very high.Current clinical research discovery, nearly all direct antiviral drugs for HCV, all there is a certain proportion of persister before administration.And after being administered, due to the effect of medicament selection, the ratio regular meeting of these persisters is greatly increased, so that major part medicine is after individually the taking of short time, the situation of viral rebound occurs.In addition, except the persister of these naturally occurring, after all of direct antiviral drugs individually takes a period of time, all can occur that substantial amounts of acquired resistance suddenlys change.Therefore, by the HAART of several antiviral drugs use in conjunction it is considered to be the fully erased HCV maximally effective means of virus, and the pure oral pharmaceutical compositions of noiseless element also becomes the final goal of CHC treatment.
The present invention has investigated representation compound 6 and NS3/4A inhibitor Simeprevir, NS5A inhibitor Daclatasvir, NS5B inhibitor Sofosbuvir and drug combination situation in extensive concentration range for the NS4B inhibitor C lemizole further, and calculate drug combination index (the Combination Index under each concentration combination, CI) (Pharmacol Rev., 2006,58:621 681).
Table 5～table 8 illustrates compound 6 and NS3/4A inhibitor Simeprevir, NS5A inhibitor Daclatasvir, NS5B inhibitor Sofosbuvir and drug combination situation in extensive concentration range for the NS4B inhibitor C lemizole.Can be seen that from table 5～table 8, compound 6 and NS3/4A inhibitor Simeprevir, NS5A inhibitor Daclatasvir, NS5B inhibitor Sofosbuvir all show when major part concentration combination and add and to synergy, and can show under low concentration combination with NS4B inhibitor C lemizole and add and to synergy.As can be seen here, the drug regimen that the compounds of this invention is formed with NS3/4A inhibitor, NS5A inhibitor, NS5B inhibitor and NS4B inhibitor, has the advantage in treatment when treating HCV infection patient.
Drug combination index (CI) under each concentration combination when table 5 compound 6 and NS3/4A inhibitor Simeprevir use in conjunction
Drug combination index (CI) under each concentration combination when table 6 compound 6 and NS5A inhibitor Daclatasvir use in conjunction
Drug combination index (CI) under each concentration combination when table 7 compound 6 and NS5B inhibitor Sofosbuvir use in conjunction
Drug combination index (CI) under each concentration combination when table 8 compound 6 and NS5B inhibitor C lemizole use in conjunction
CI scope shown in above-mentioned table 5～table 8 is as shown in table 9 with the corresponding relation of drug combination effect.
Table 9
CI scope <0.5 0.5-0.7 0.7-0.9 0.9-1.1 >1.1
Drug combination effect High Collaboration Collaborative Slight collaborative Add and Antagonism

Claims (10)

1. imidazoles [2,1-b] thiazole, its structure is as shown in formula I:
Wherein, R1、R2It independently is-H, halogen, C1～C8 alkyl, C3～C8 cycloalkyl, C1～C8 alkoxyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the replacement unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl.
2. imidazoles according to claim 1 [2,1-b] thiazole, it is characterised in that:
R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl, C1～C4 alkoxyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
Preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
It is further preferred that R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
Still more preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
Further preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；
R4For halogen or C1～C4 alkyl；
Still further preferably, R1、R2It independently is-H, halogen, C1～C4 alkyl, C3～C6 cycloalkyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；
R4For halogen；
Optimum, R1、R2It independently is-H ,-Cl, C1～C4 alkyl, cyclopropyl；Or R1And R2Form the unsaturated cyclic ketones of the replacement saturated carbon ring of 5～8 yuan, the unsaturated carbocyclic of 5～8 yuan or 5～8 yuan；Described replacement saturated carbon ring, the substituent of replacement unsaturated carbocyclic are-H ,-Cl ,-Br, methyl or methoxy；
R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H or hydroxyl；R4For-Cl.
3. imidazoles according to claim 1 [2,1-b] thiazole, it is characterised in that: work as R1And R2When forming the replacement saturated carbon ring of 5～8 yuan, its structure is as shown in formula II:
Wherein, R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4.
4. imidazoles according to claim 3 [2,1-b] thiazole, it is characterised in that:
R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4；
Preferably, R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4；
It is further preferred that R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4；
Still more preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4；
Further preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen；R5、R6Independent is-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；The integer of n=1～4；
Still further preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen；R5、R6Independent is-H or C1～C4 alkyl；The integer of n=1～4；
Optimum, R3For pentamethylene；R4For-Cl；R5、R6Independent is-H or methyl；N=1 or 2.
5. imidazoles according to claim 1 [2,1-b] thiazole, it is characterised in that: work as R1And R2When forming the replacement unsaturated carbocyclic of 5～8 yuan, its structure is as shown in formula III:
Wherein, R3For halogen, C1～C8 alkyl, replace C3～C8 cycloalkyl or C3～C8 cycloalkenyl group；The substituent of described replacement C3～C8 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；
R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；
R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl.
6. imidazoles according to claim 5 [2,1-b] thiazole, it is characterised in that:
R3For halogen, C1～C4 alkyl, replace C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
Preferably, R3For replacing C3～C6 cycloalkyl or C3～C6 cycloalkenyl group；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
It is further preferred that R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H, halogen, hydroxyl or C1～C4 alkyl；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
Still more preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen, cyano group, C1～C4 alkyl, acetenyl or vinyl；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
Further preferably, R3For replacing C3～C6 cycloalkyl；The substituent of described replacement C3～C6 cycloalkyl is-H；R4For halogen；R7For-H, halogen, C1～C4 alkyl or C1～C4 alkoxyl；
Still further preferably, R3For C3～C6 cycloalkyl；R4For halogen；R7For-H halogen, C1～C4 alkyl or C1～C4 alkoxyl；
Optimum, R3For pentamethylene；R4For-Cl；R5、R6Independent is-H ,-Cl, Br or methyl.
7. imidazoles [2,1-b] thiazole, its structural formula is:
8. imidazoles described in claim 1～7 [2,1-b] thiazole pharmaceutically acceptable salt or hydrate.
9. a pharmaceutical composition, is to be added the complementary composition of pharmaceutically acceptable by imidazoles [2, the 1-b] thiazole described in any one of claim 1～7, the salt described in claim 8 or hydrate to be prepared from.
10. the salt described in imidazoles described in claim 1～7 [2,1-b] thiazole, claim 8 or purposes in preparation treatment hepatitis C medicine for the hydrate.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101878210A (en) * 2007-12-06 2010-11-03 泰博特克药品公司 Amide compound as boosters
WO2011060000A1 (en) * 2009-11-12 2011-05-19 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
CN102459281A (en) * 2009-04-13 2012-05-16 百时美施贵宝公司 Hepatitis c virus inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101878210A (en) * 2007-12-06 2010-11-03 泰博特克药品公司 Amide compound as boosters
CN102459281A (en) * 2009-04-13 2012-05-16 百时美施贵宝公司 Hepatitis c virus inhibitors
WO2011060000A1 (en) * 2009-11-12 2011-05-19 Bristol-Myers Squibb Company Hepatitis c virus inhibitors

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