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CN104650069A - 4-methyl dihydropyrimidine compound and application thereof to drugs - Google Patents

4-methyl dihydropyrimidine compound and application thereof to drugs Download PDF

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Publication number
CN104650069A
CN104650069A CN201410660151.XA CN201410660151A CN104650069A CN 104650069 A CN104650069 A CN 104650069A CN 201410660151 A CN201410660151 A CN 201410660151A CN 104650069 A CN104650069 A CN 104650069A
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independently
compound
alkyl
hydrogen
methyl
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CN104650069B (en
Inventor
刘辛昌
任青云
颜光华
梁金胜
邹致富
涂林锦
单岳峰
雷斗兴
S·戈尔德曼
张英俊
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a 4-methyl dihydropyrimidine compound and an application thereof as a drug, especially a drug used for treating and preventing hepatitis B, and in particular relates to a compound shown in a general formula (I) or general formula (Ia) in the specification or enantiomers, diastereoisomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts of the compound. All the variables are defined in the specification. The invention also relates to an application of the compound shown in the general formula (I) or general formula (Ia) in the specification or the enantiomers, diastereoisomers, tautomers, hydrates, solvates or pharmaceutically acceptable salts of the compound as drugs, especially drugs used for treating and preventing hepatitis B.

Description

4-methyl Dihydropyrimidines and the application in medicine thereof
Technical field
The present invention is specifically related to a kind of 4-methyl Dihydropyrimidines and pharmaceutical composition thereof, relate to described compound further or described pharmaceutical composition is preparing the purposes in medicine, especially for the preparation of the purposes in the medicine preventing, process, treat or alleviate hepatitis B (HBV) to infect.
Background technology
Hepatitis B virus belongs to hepatovirus section.It can cause acute and or continue/progressive chronic disease.Hepatitis B virus also causes other the Clinical signs many in pathomorphism---the especially chronic inflammatory diseases of liver, liver cirrhosis and hepatocellular canceration.In addition, can have a negative impact in advancing of disease process with the co-infection of hepatitis D.
The conventional medicine being licensed for treatment chronic hepatitis treatment is Interferon, rabbit and lamivudine (lamivudine).But Interferon, rabbit only has medium activity, and there is higher toxic side effects; Although lamivudine (lamivudine) has good activity, its resistance over the course for the treatment of amplification is rapid, and the IC of usually have a rebound after stopping treatment effect, lamivudine (3-TC) 50value is 300nM (Science, 299 (2003), 893-896).
Deres etc. report dihydropyridine (HAP) compound replaced with Bay41-4109, Bay39-5493 hetero-aromatic ring that is representative, and this compounds can by the effect stoping the formation of normal nucleocapsid play inhibition HBV replication.Bay41-4109 has showed good drug metabolism parameter (Science, 299 (2003), 893-896) in clinical studies.The research of its mechanism of action is found, the Dihydropyrimidines that hetero-aromatic ring replaces is by the 113-143 amino-acid residue effect with core protein, change the angle between the dimer forming nucleocapsid, cause forming unstable expansion nucleocapsid, accelerate the degraded (Biochem.Pharmacol.66 (2003), 2273-2279) of core protein.
Still the new compound that effectively can be used as antiviral is needed at present, especially as the medicine treating and/or preventing hepatitis B.
Abstract of invention
The present invention relates to a kind of new 4-methyl Dihydropyrimidines and pharmaceutical composition thereof, and described compound or described pharmaceutical composition are preparing the purposes in medicine, described medicine is used for prevent, process, treating or alleviate virus disease, especially the disease that causes of hepatitis B (HBV) infection or hepatitis B infection.
On the one hand, the present invention relates to a kind of compound, its enantiomer for compound shown in the compound shown in formula (I) or (Ia) or formula (I) or (Ia), diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt
Wherein, R 1for C 6-10aryl or C 1-9heteroaryl;
R 3for C 6-10aryl or C 1-9heteroaryl;
A is a key ,-O-,-S-or-N (R 5)-;
Each R 2and R 5be hydrogen or C independently 1-4alkyl;
R is following subformula:
Wherein, Y is-(CR 8r 8a) m-N (R 8)-,-(CR 8r 8a)-O-(CR 8r 8a) 2-,-(CR 8r 8a) m-S (=O) q-or-(CR 7r 6) m-O-;
Q is-(CR 8r 8a) m-;
X is-(CR 8r 8a) n-(CR 8r 9)-(CR 8r 8a) n-,-(CR 8r 9a) n-(CR 8r 8a) m-,-(CR 8r 8a) n-(CR 8r 9)-O-or-(CR 8r 9a) n-(CR 8r 8a) m-O-;
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino or alkyl independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or alkyl independently;
Each R 6be alkyl independently; Or R 6and R 7cycloalkyl or heterocyclic radical is formed together with the carbon atom be attached thereto;
Each R 8and R 8abe hydrogen, cyano group or alkyl independently, or R 8aand R 8cycloalkyl or heterocyclic radical is formed together with the carbon atom be attached thereto;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, halogen, haloalkyl or alkyl independently, or R 10aand R 10form cycloalkyl or heterocyclic radical together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, alkyl, alkoxyl group, hydroxyl, alkyl-S (=O) independently q-, aryl, heteroaryl, cycloalkyl, heterocyclic radical, heterocyclic radical-S (=O) q-, heteroaryl-S (=O) q-, arylalkyl, cycloalkyl-S (=O) q-or aryl-S (=O) q-;
Each n is 1,2,3 or 4 independently;
Each m is 0,1,2,3 or 4 independently;
Each q is 0,1 or 2 independently;
Wherein, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 8a, R 9, R 9a, R 10, R 10aand R 11described in alkoxyl group, alkyl-S (=O) q-, heterocyclic radical-S (=O) q-, heteroaryl-S (=O) q-, cycloalkyl-S (=O) q-, aryl-S (=O) q-, aryl, C 6-10aryl, heteroaryl, C 1-9heteroaryl, alkyl, C 1-4alkyl, cycloalkyl, heterocyclic radical, arylalkyl, haloalkyl, triazolyl and tetrazyl can optionally by hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene radical (=CH 2), monosubstituted or identical or different polysubstituted of alkyl, alkoxyl group, cyano group, aryl, heteroaryl, cycloalkyl, heterocyclic radical ,-COOH, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the haloalkyl aryl, the aryl of halogen substiuted or the trifyl that replace.
In some embodiments, R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino or C independently 1-4alkyl, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or C independently 1-4alkyl;
Each R 6be C independently 1-4alkyl; Or R 6and R 7c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 8and R 8abe hydrogen or C independently 1-4alkyl, or R 8aand R 8c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, C independently 1-4haloalkyl or C 1-4alkyl, or R 10aand R 10c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, hydroxyl, C 1-4alkyl-S (=O) q-, C 6-10aryl, C 1-9heteroaryl, C 3-6cycloalkyl, C 2-9heterocyclic radical, C 2-9heterocyclic radical-S (=O) q-, C 1-9heteroaryl-S (=O) q-, C 6-10aryl C 1-4alkyl, C 3-6cycloalkyl-S (=O) q-or C 6-10aryl-S (=O) q-.
In some embodiments, R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl or propyl group independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen, methyl, ethyl or propyl group independently;
Each R 6be methyl, ethyl or propyl group independently; Or R 6and R 7cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl is formed together with the carbon atom be attached thereto;
Each R 8and R 8abe hydrogen, methyl, ethyl or propyl group independently, or R 8aand R 8cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl is formed together with the carbon atom be attached thereto;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl or propyl group independently, or R 10aand R 10form cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, C 1-4alkyl-S (=O) 2-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrryl, pyrimidyl, pyridazinyl, di azoly, triazolyl, tetrazyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyrazinyl, pyranyl, triazinyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-or phenyl-S (=O) 2-.
In other embodiments, wherein,
R 1for phenyl;
Each R 2and R 5be hydrogen, methyl or ethyl independently;
R 3for pyridyl, oxazolyl, isoxazolyl, thienyl, furyl, thiazolyl or 1-methyl isophthalic acid H-imidazolyl;
A is-O-;
Wherein, R 1, R 2, R 3and R 5described in pyridyl, oxazolyl, isoxazolyl, thienyl, furyl, thiazolyl, 1-methyl isophthalic acid H-imidazolyl, phenyl, methyl and ethyl can optionally by hydrogen, C 1-4monosubstituted or identical or different polysubstituted of alkyl, fluorine, chlorine or bromine.
In some embodiments, the present invention relates to a kind of compound, its enantiomer for compound shown in the compound shown in formula (II) or (IIa) or formula (II) or (IIa), diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt
Wherein, R 2for hydrogen or C 1-4alkyl;
R 3for thiazolyl or 1-methyl isophthalic acid H-imidazolyl;
R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl or propyl group independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or C independently 1-4alkyl;
Each R 6be C independently 1-4alkyl; Or R 6and R 7c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 8and R 8abe hydrogen or C independently 1-4alkyl, or R 8aand R 8c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, C independently 1-4haloalkyl or C 1-4alkyl, or R 10aand R 10c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, hydroxyl, C 1-4alkyl-S (=O) 2-, C 6-10aryl, C 1-9heteroaryl, C 3-6cycloalkyl, C 2-9heterocyclic radical, C 2-9heterocyclic radical-S (=O) 2-, C 1-9heteroaryl-S (=O) 2-, C 6-10aryl C 1-4alkyl, C 3-6cycloalkyl-S (=O) 2-or C 6-10aryl-S (=O) 2-;
Each R 12be hydrogen, fluorine, chlorine or bromine independently;
Each q is 0,1 or 2 independently;
Each n is 1,2,3 or 4 independently;
Each m is 0,1,2,3 or 4 independently.
In other embodiments, R is following subformula:
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl or propyl group independently, or R 10aand R 10form cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, C 1-4alkyl-S (=O) 2-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrryl, pyrimidyl, pyridazinyl, di azoly, triazolyl, tetrazyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyrazinyl, pyranyl, triazinyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-or phenyl-S (=O) 2-.
On the one hand, the present invention relates to a kind of pharmaceutical composition, this pharmaceutical composition contains compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
In some embodiments, pharmaceutical composition of the present invention, it comprises Anti-HBV drugs further.
In other embodiments, pharmaceutical composition of the present invention, wherein, described Anti-HBV drugs is HBV AG14361, immunomodulator or Interferon, rabbit.
In other embodiment, pharmaceutical composition of the present invention, wherein, described Anti-HBV drugs is for being selected from lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, interferon α-1b, interferon alpha, Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin II, mivotilate, nitazoxanide, Peg-IFN alpha-2b α-2a, virazole, Wellferon-A, sizofiran, Euforavac, Puli is near for peace, Phosphazid, Heplisav, Interferon Alpha-2b, at least one in LEVAMISOLE HCL and propagermanium.
On the other hand, the present invention relates to described compound or described pharmaceutical composition is preparing the purposes in medicine, described medicine is used for preventing, process, treat or alleviate disease viral disease.
In some embodiments, purposes of the present invention, wherein, described virus disease refers to the disease that hepatitis B infection or hepatitis B infection cause.
In other embodiments, purposes of the present invention, wherein, described hepatitis B infection causes disease to refer to liver cirrhosis or canceration of hepatic cell.
On the other hand, the present invention relates to described compound or pharmaceutical composition for the preparation of the purposes of medicine preventing, process, treat or alleviate patient's hepatitis B disease, comprise the dose therapeutically effective giving patient compound or pharmaceutical composition of the present invention as described herein.
The present invention relates to prevention on the other hand, processes, treats or alleviate the method for patient HBV illness, and described method comprises the pharmaceutically acceptable effective dose of use compound of the present invention and carries out administration to patient.
The present invention relates to prevention on the other hand, processes, treats or alleviate the method for patient HBV illness, and the pharmaceutically acceptable effective dose that described method comprises the pharmaceutical composition of use containing compound of the present invention carries out administration to patient.
The present invention relates to use one on the other hand and comprises compound of the present invention to produce for prevention, process or treatment patient HBV illness, and alleviates the purposes of the medicine of its severity.
The present invention relates to a kind of pharmaceutical composition comprising compound of the present invention of use on the other hand and produces for prevention, process or treatment patient HBV illness, and alleviates the purposes of the medicine of its severity.
Some of them embodiment is, described organism is Mammals, and other embodiments are, described organism is the mankind.Other embodiments are, described method further comprises the contact of kinases and HBV therapeutical agent.
The present invention relates to a kind of method suppressing HBV infection on the other hand, and the method comprises the dose of exposure that cell and the compounds of this invention or its composition effectively can suppress HBV.Other embodiment is, described method further comprises the contact of cell and HBV agent.
The present invention relates to the treatment to patient HBV disease on the other hand, and the method comprises the dosage that needs of patients effectively treats required the compounds of this invention or its composition administration.Other embodiment is, described method further comprises the administration of HBV.
The present invention relates to a kind of method suppressing patient's HBV infection on the other hand, and the method comprises the dosage that needs of patients effectively treats required the compounds of this invention or its composition administration.Other embodiments are, described method further comprises the administration of HBV treatment.
The present invention relates on the other hand the preparation of compound that formula (I) or formula (Ia) comprise, the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.The content of these aspects and other aspect will do more specifically complete description below.
Circumstantial letter of the present invention
Definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.In combined document, patent and one or more different from the application or conflicting situations of analogous material (including but not limited to defined term, term application, described technology etc.), be as the criterion with the application.
Should recognize further, some feature of the present invention, for clearly visible, be described in multiple independently embodiment, but also can provide in combination in single embodiment.Otherwise various feature of the present invention, for for purpose of brevity, is described in single embodiment, but also can provide separately or with the sub-portfolio be applicable to arbitrarily.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have the implication identical with the usual understanding of those skilled in the art of the invention.The all patents that the present invention relates to and public publication by reference entirety are incorporated to the present invention.
Unless otherwise indicated, following definition used herein should be applied.For purposes of the present invention, chemical element and periodic table of elements CAS version, and " chemistry and physics handbook ", the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can with reference to " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, and " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley & Sons, description in New York:2007, its full content is incorporated to herein by reference.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, particular compound of the present invention, or as example special inside embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that term " optional replacement " can exchange use with term " substituted or non-substituted ".Generally speaking, term " replacement ", represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently.Wherein said substituting group can be, but be not limited to: hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene radical (=CH 2), alkyl, alkoxyl group, cyano group, hydroxyl, sulfydryl, nitro, alkylamino, amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic radical, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl aryl, the aryl of halogen substiuted or the trifyl etc. that replace.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C 1-6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
Except as otherwise noted or in context, have obvious conflict, article used herein " ", " one (kind) " and " described " are intended to comprise " at least one " or " one or more ".Therefore, these articles used herein refer to the article of one or more than one (i.e. at least one) object.Such as, " component " refers to one or more component, more than one component namely may be had to be taken into account in the embodiment of described embodiment and adopt or use.
Term used in the present invention " patient " refers to people's (comprising adult and children) or other animals.In some embodiments, " patient " refers to people.
Term " comprises " for open language, namely comprises the content specified by the present invention, but does not get rid of otherwise content.
Term " steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer etc.
Term " chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.
Term " enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
Term " diastereomer " refers to two or more chiral centre and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.
Term " alkyl " or " alkyl group ", represent containing 1 to 20 carbon atom, the univalent hydrocarbyl group of saturated straight or branched, wherein, described alkyl can independently optionally replace by one or more substituting group described in the invention.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom.In some embodiments, alkyl group contains 1-10 carbon atom; In other embodiments, alkyl group contains 1-8 carbon atom; In other embodiments, alkyl group contains 1-6 carbon atom; In other embodiments, alkyl group contains 1-4 carbon atom; In other embodiments, alkyl group contains 1-3 carbon atom.
The example of alkyl group comprises, but is not limited to: methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), propyl group (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), 2-methyl-propyl or isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), 1-methyl-propyl or sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl etc.
Term " haloalkyl " or " halogenated alkoxy " represent alkyl or alkoxy base replace by one or more identical or different halogen atom, wherein, described alkyl and alkoxyl group have implication as described in the present invention.Such example comprises, but is not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxy etc.
Term " thiazolinyl " represents the straight or branched monovalent hydrocarbon containing 2-12 carbon atom, wherein has a unsaturated site at least, namely has a carbon-to-carbon sp 2double bond, wherein, described alkenyl group can optionally replace by one or more substituting group described in the invention, it comprises " cis " and the location of " trans ", or the location of " E " and " Z ".In some embodiments, alkenyl group comprises 2-8 carbon atom; In other embodiments, alkenyl group comprises 2-6 carbon atom; In other embodiment, alkenyl group comprises 2-4 carbon atom.The example of alkenyl group comprises, but is not limited to: vinyl (-CH=CH 2), allyl group (-CH 2cH=CH 2) etc.
Term " cycloalkyl " expression contains 3-12 carbon atom, nonaromatic saturated or the unsaturated monocycle of part, dicyclo or the three-ring system of unit price or multivalence.Wherein, the described group of naphthene base substituting group that can optionally be described by one or more the present invention replace.In some embodiments, cycloalkyl comprises 3-12 carbon atom; In other embodiments, cycloalkyl comprises 3-8 carbon atom; In other embodiment, cycloalkyl comprises 3-6 carbon atom.The example of group of naphthene base comprises, but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.
Term " heterocyclic radical " refers to and comprises 3-12 annular atoms, and the saturated or part undersaturated monocycle of non-aromatic, dicyclo or three-ring system, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Wherein, the described heterocyclyl groups substituting group that can optionally be described by one or more the present invention replace.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxide compound.In some embodiments, heterocyclic radical is C 2-10heterocyclic radical, represents that heterocyclic radical contains 2-10 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heterocyclic radical is C 2-9heterocyclic radical, represents that heterocyclic radical contains 2-9 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heterocyclic radical is C 2-7heterocyclic radical, represents that heterocyclic radical contains 2-7 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heterocyclic radical is C 2-5heterocyclic radical, represents that heterocyclic radical contains 2-5 carbon atom and is selected from the heteroatoms of O, S and N with at least one.The example of heterocyclic radical comprises, but be not limited to: pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro-pyrimidine base, THP trtrahydropyranyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, epoxypropyl, 2-pyrrolinyl, indolinyl, pyrazolinyl, 1,1-dioxidothiomorpholinyl etc.-CH in heterocyclic radical 2-group is included, but are not limited to by the example of-C (=O)-replacement: 2-oxo-pyrrolidine base, 2-piperidone base, 3-morpholine ketone group, 3-thiomorpholine ketone group and oxo tetrahydro-pyrimidine base etc.
Term " cycloheteroalkylalkyl " represents that heterocyclyl groups is connected with molecule rest part by alkyl group, and wherein, heterocyclic radical and alkyl have implication of the present invention.The substituting group that described cycloheteroalkylalkyl can optionally be described by one or more the present invention replace.Such example comprises, but is not limited to: pyrroles-2-methyl, morpholine-4-methyl, pyrrolidinylmethyl, piperidine methyl, piperidinoethyl, morpholine methyl, morpholinyl ethyl etc.
Term " halogen " or " halogen atom " refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.The example of alkoxy base comprises, but is not limited to: methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), isopropoxy (i-PrO, i-propoxy-,-OCH (CH 3) 2), n-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), tert.-butoxy (t-BuO, t-butoxy, 2-methyl-2-propoxy-,-OC (CH 3) 3), 1-pentyloxy (n-pentyloxy ,-OCH 2cH 2cH 2cH 2cH 3), 2-pentyloxy (-OCH (CH 3) CH 2cH 2cH 3), 3-pentyloxy (-OCH (CH 2cH 3) 2), 2-methyl-2-butoxy (-OC (CH 3) 2cH 2cH 3), 3-methyl-2-butoxy (-OCH (CH 3) CH (CH 3) 2), 3-methyl-l-butoxy (-OCH 2cH 2cH (CH 3) 2), 2-methyl-l-butoxy (-OCH 2cH (CH 3) CH 2cH 3) etc.
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the carbocyclic ring system of the monocycle of 6-10 annular atoms, dicyclo and three rings, wherein, at least one member ring systems is aromatic, wherein each member ring systems comprises 3-7 former molecular ring, and has one or more tie point to be connected with the rest part of molecule.The substituting group that described aromatic yl group can optionally be described by one or more the present invention replace.Term " aryl " can exchange with term " aromatic nucleus " and use.The example of aromatic yl group comprises, but is not limited to: phenyl, 2,3-dihydro-1H-indenyls, naphthyl and anthracene etc.
Term " arylalkyl " represents that aromatic yl group is connected with molecule rest part by alkyl group, and wherein, aryl and alkyl have implication of the present invention.The substituting group that described arylalkyl can optionally be described by one or more the present invention replace.Such example comprises, but is not limited to: benzyl, phenylethyl, naphthyl methyl etc.
Term " heteroaryl " represents containing 5-14 annular atoms, or 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms being selected from nitrogen, oxygen, sulphur, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more tie point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.In some embodiments, heteroaryl is C 1-9heteroaryl, represents that heteroaryl contains 1-9 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heteroaryl is C 1-7heteroaryl, represents that heteroaryl contains 1-7 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heteroaryl is C 1-6heteroaryl, represents that heteroaryl contains 1-6 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heteroaryl is C 1-5heteroaryl, represents that heteroaryl contains 1-5 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heteroaryl is C 1-4heteroaryl, represents that heteroaryl contains 1-4 carbon atom and is selected from the heteroatoms of O, S and N with at least one; In other embodiments, heteroaryl is C 1-3heteroaryl, represents that heteroaryl contains 1-3 carbon atom and is selected from the heteroatoms of O, S and N with at least one.Such example comprises, but is not limited to following monocycle: furyl (as 2-furyl and 3-furyl), imidazolyl is (as TMSIM N imidazole base, 1-methyl isophthalic acid H-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), thiazolyl (2-thiazolyl, 4-thiazolyl and 5-thiazolyl), tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyranyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazoles base, 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, pyrazinyl, 1,3,5-triazines base, di azoly, thiadiazolyl group, triazinyl, also comprise following dicyclo, but be never limited to these dicyclos: benzothiazolyl, benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) etc.
Term " heteroarylalkyl " represents that heteroaryl groups is connected with the rest part of molecule by alkyl group, and wherein, alkyl and heteroaryl have implication as described in the present invention.The substituting group that described heteroarylalkyl can optionally be described by one or more the present invention replace.Such example comprises, but is not limited to: pyridine-2-ethyl, thiazole-2-methyl, imidazoles-2-ethyl, pyrimidine-2-propyl group etc.
Term " alkyl-S (=O) q-", " heterocyclic radical-S (=O) q-", " heteroaryl-S (=O) q-", " cycloalkyl-S (=O) q-" and " aryl-S (=O) q-" represent that alkyl, heterocyclic radical, heteroaryl, cycloalkyl and aryl are by sulfinyl (-S (=O)-) or alkylsulfonyl (-S (=O) 2-) be connected with molecule rest part, wherein, q, alkyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl have implication as described in the present invention, and such example comprises, but is not limited to: methylsulfinyl (-S (=O) CH 3), cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-, phenyl-S (=O) 2-, methyl sulphonyl (-S (=O) 2cH 3) etc.
Term " alkylamino " or " alkylamino " comprise " N-alkylamino " and " N, N-dialkyl amido ", wherein amino group separately replace by one or two alkyl group.Wherein, alkyl group has implication as described in the present invention.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, such example comprises, but be not limited to: N-methylamino-, N-ethylamino, isopropylamino, the third amino, tert-butylamino, n-butyl amine base, 1-methylpropylamino, n-pentyl is amino, n-hexyl is amino, N, N-dimethylamino, N, N-diethylin etc.
Term " haloalkyl replace aryl " represent aromatic yl group can replace by one or more identical or different haloalkyl, wherein, haloalkyl and aryl have implication as described in the present invention.Such example comprises, but is not limited to: 2-trifluoromethyl, 3,5-bis-(trifluoromethyl) phenyl, 3-trifluoromethyl, 4-trifluoromethyl, 2,6-bis-(trifluoromethyl) phenyl etc.
Term " aryl of halogen substiuted " represent aromatic yl group can replace by one or more identical or different halogen atom, wherein, halogen and aryl have implication as described in the present invention.Such example comprises, but is not limited to: fluorophenyl, difluorophenyl, trifluorophenyl, chloro-phenyl-, dichlorophenyl, trichlorophenyl, bromophenyl, tribromo phenyl, dibromo phenyl, fluorochlorobenzene base, bromofluorobenzene base, chloro-bromobenzene base etc.
As described in the invention, two tie points are had to be connected with molecule rest part in system, such as, shown in formula f, expression both can be E end also can be that E ' end is connected with molecule rest part, and namely in the rational situation of molecular structure, the mode of connection at two ends can be exchanged.
In addition, it should be noted that, unless otherwise explicitly pointed out, the describing mode that adopts in the whole text in this article " each ... with ... be independently ", " ... with ... be independently of one another " and " ... with ... be separately " can exchange; should be interpreted broadly, it both can refer in different group, did not affect mutually; also can represent in identical group between concrete option expressed between same-sign, did not affect mutually between concrete option expressed between same-sign.Such as, such as formula e, the concrete option of multiple n is unaffected each other, multiple R 9concrete option mutually between unaffected.
As described in the invention, substituting group is drawn a key and is connected to the member ring systems (being shown below) that the ring at center is formed and represents substituting group any commutable position on ring and can replace.Such as, formula a represents any position that may be substituted on ring, shown in b, c, d, e, f, g and h
As described in the invention, double bond connecting the system (shown in k) that wave key to other atom is formed, to represent double bond containing compound be (Z) configuration or (E) configuration, or the mixture of (Z) configuration and (E) configuration.
Unless other aspects show, structural formula described in the invention comprises all isomeric forms (as enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism)): R, S configuration such as containing asymmetric center, (Z), (E) isomer of double bond, and (Z), (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention or its enantiomer, diastereomer, or the mixture of geometrical isomer (or conformer) all belongs to scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into formula (I) or the compound shown in formula (Ia) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
Unless other aspects show, all tautomeric forms of compound of the present invention are included within scope of the present invention.In addition, unless other aspects show, the structural formula of compound described in the invention comprises the enriched isotope of one or more different atom.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by obtaining through oxidation, reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method to drug compound.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
Stereochemical definition Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994.
Any asymmetric atom (such as, carbon etc.) of compound of the present invention can exist with the form of racemize or enantiomorph enrichment, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess in (R)-or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
The stereoisomeric forms in any ratio that compound of the present invention is all, include, but not limited to: diastereomer, enantiomer, atropisomer and their mixture, as racemic mixture, constitutes a part of the present invention.A lot of organic compound all exists with optical active forms, i.e. the plane of their capable Plane of rotation polarized light.When describing optically active compound, prefix D, L or R, S are used for representing the absolute configuration at molecular chiral center.Prefix d, l or (+), (-) are used for the symbol naming compound plane polarized light to rotate, and (-) or l refer to that compound is left-handed, and prefix (+) or d refer to that compound is dextrorotation.The chemical structure of these steric isomers is identical, but their three-dimensional arrangement is different.Specific steric isomer can be enantiomorph, and the mixture of isomer is commonly referred to enantiomeric mixture.The mixture of enantiomers of 50:50 is called as racemic mixture or racemic modification, and this may cause not having stereoselectivity or stereospecificity in chemical reaction process.Term " racemic mixture " and " racemic modification " refer to the mixture of equimolar two enantiomers, lack optical activity.
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (low energy barrier) of different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) comprise by proton shifting carry out mutual conversion, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66:1-19, described in 1977..The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to: react with amino group the inorganic acid salt formed, example hydrochloric acid salt, hydrobromate, phosphoric acid salt, vitriol, perchlorate; Organic acid salt, as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate; Or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise, adipate, malate, 2 hydroxy propanoic acid salt, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate etc.The salt obtained by suitable alkali is comprised, basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or the alkaline-earth metal that can form salt comprise sodium, lithium, potassium, calcium, magnesium etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to: water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid and monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
Time term " blocking group " or " Pg " refer to a substituting group and other reacted with functional groups, be commonly used to block or protection particular functional group functional.Such as; " amino blocking group " refers to that a substituting group is connected with amino group and blocks or protect in compound amino functional, and suitable amido protecting group comprises ethanoyl, trifluoroacetyl group, tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz) and 9-fluorenes Asia methoxycarbonyl (Fmoc).Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; And P.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
In addition, compound disclosed by the invention, comprises their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.
Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 31p, 32p, 35s, 36cl and 125i.
On the other hand, such as, wherein there is radio isotope in the compound that the present invention that compound of the present invention comprises isotopic enrichment defines, as 3h, 14c and 18those compounds of F, or wherein there is non radioactive isotope, as 2h and 13c.The compound of such isotopic enrichment can be used for metabolism research and (uses 14c), reaction kinetics research (uses such as 2h or 3h), detect or imaging technique, as positron emission tomography (PET) or the SPECT (single photon emission computed tomography) (SPECT) comprising medicine or substrate tissue measure of spread, or can be used in the radiotherapy of patient. 18the compound of F enrichment is desirable especially for PET or SPECT research.Use suitable isotope labeling reagent to substitute original used unmarked reagent described by embodiment in the routine techniques that shown in the formula (I) of isotopic enrichment, compound can be familiar with by those skilled in the art or the present invention and preparation process to prepare.
In addition, particularly deuterium is (that is, for higher isotope 2h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent 2o, acetone-d 6, DMSO-d 6those solvates.
The description of the compounds of this invention
The present invention relates to a kind of new 4-methyl Dihydropyrimidines and pharmaceutical composition thereof, and described compound or described pharmaceutical composition are preparing the purposes in medicine, described medicine is used for prevent, process, treating or alleviate virus disease, especially the disease that causes of hepatitis B (HBV) infection or hepatitis B infection.
On the one hand, the present invention relates to a kind of compound, its enantiomer for compound shown in the compound shown in formula (I) or (Ia) or formula (I) or (Ia), diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt
Wherein, R 1for C 6-10aryl or C 1-9heteroaryl;
R 3for C 6-10aryl or C 1-9heteroaryl;
A is a key ,-O-,-S-or-N (R 5)-;
Each R 2and R 5be hydrogen or C independently 1-4alkyl;
R is following subformula:
Wherein, Y is-(CR 8r 8a) m-N (R 8)-,-(CR 8r 8a)-O-(CR 8r 8a) 2-,-(CR 8r 8a) m-S (=O) q-or-(CR 7r 6) m-O-;
Q is-(CR 8r 8a) m-;
X is-(CR 8r 8a) n-(CR 8r 9)-(CR 8r 8a) n-,-(CR 8r 9a) n-(CR 8r 8a) m-,-(CR 8r 8a) n-(CR 8r 9)-O-or-(CR 8r 9a) n-(CR 8r 8a) m-O-;
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino or alkyl independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or alkyl independently;
Each R 6be alkyl independently, or R 6and R 7cycloalkyl or heterocyclic radical is formed together with the carbon atom be attached thereto;
Each R 8and R 8abe hydrogen, cyano group or alkyl independently, or R 8aand R 8cycloalkyl or heterocyclic radical is formed together with the carbon atom be attached thereto;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, halogen, haloalkyl or alkyl independently, or R 10aand R 10form cycloalkyl or heterocyclic radical together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, alkyl, alkoxyl group, hydroxyl, alkyl-S (=O) independently q-, aryl, heteroaryl, cycloalkyl, heterocyclic radical, heterocyclic radical-S (=O) q-, heteroaryl-S (=O) q-, arylalkyl, cycloalkyl-S (=O) q-or aryl-S (=O) q-;
Each n is 1,2,3 or 4 independently;
Each m is 0,1,2,3 or 4 independently;
Each q is 0,1 or 2 independently;
Wherein, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 8a, R 9, R 9a, R 10, R 10aand R 11described in alkoxyl group, alkyl-S (=O) q-, heterocyclic radical-S (=O) q-, heteroaryl-S (=O) q-, cycloalkyl-S (=O) q-, aryl-S (=O) q-, aryl, C 6-10aryl, heteroaryl, C 1-9heteroaryl, alkyl, C 1-4alkyl, cycloalkyl, heterocyclic radical, arylalkyl, haloalkyl, triazolyl and tetrazyl can optionally by hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene radical (=CH 2), monosubstituted or identical or different polysubstituted of alkyl, alkoxyl group, cyano group, aryl, heteroaryl, cycloalkyl, heterocyclic radical ,-COOH, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the haloalkyl aryl, the aryl of halogen substiuted or the trifyl that replace.
In some embodiments, R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino or C independently 1-4alkyl, or as two R 4when being connected to same carbon atom, R 4and R 4together with the carbon atom be attached thereto or form following group :-C (=CH 2)-;
Each R 7be hydrogen or C independently 1-4alkyl;
Each R 6be C independently 1-4alkyl; Or R 6and R 7c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 8and R 8abe hydrogen or C independently 1-4alkyl, or R 8aand R 8c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, C independently 1-4haloalkyl or C 1-4alkyl, or R 10aand R 10c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, hydroxyl, C 1-4alkyl-S (=O) q-, C 6-10aryl, C 1-9heteroaryl, C 3-6cycloalkyl, C 2-9heterocyclic radical, C 2-9heterocyclic radical-S (=O) q-, C 1-9heteroaryl-S (=O) q-, C 6-10aryl C 1-4alkyl, C 3-6cycloalkyl-S (=O) q-or C 6-10aryl-S (=O) q-.
In some embodiments, R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl or propyl group independently, or as two R 4when being connected to same carbon atom, R 4and R 4together with the carbon atom be attached thereto or form following group :-C (=CH 2)-;
Each R 7be hydrogen, methyl, ethyl or propyl group independently;
Each R 6be methyl, ethyl or propyl group independently; Or R 6and R 7cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl is formed together with the carbon atom be attached thereto;
Each R 8and R 8abe hydrogen, methyl, ethyl or propyl group independently, or R 8aand R 8cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl is formed together with the carbon atom be attached thereto;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl or propyl group independently, or R 10aand R 10form cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, C 1-4alkyl-S (=O) 2-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrryl, pyrimidyl, pyridazinyl, di azoly, triazolyl, tetrazyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyrazinyl, pyranyl, triazinyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-or phenyl-S (=O) 2-.
In other embodiments, wherein, R 1for phenyl;
Each R 2and R 5be hydrogen, methyl or ethyl independently;
R 3for pyridyl, oxazolyl, isoxazolyl, thienyl, furyl, thiazolyl or 1-methyl isophthalic acid H-imidazolyl;
A is-O-;
Wherein, R 1, R 2, R 3and R 5described in pyridyl, oxazolyl, isoxazolyl, thienyl, furyl, thiazolyl, 1-methyl isophthalic acid H-imidazolyl, phenyl, methyl and ethyl can optionally by hydrogen, C 1-4monosubstituted or identical or different polysubstituted of alkyl, fluorine, chlorine or bromine.
In some embodiments, the present invention relates to a kind of compound, its enantiomer for compound shown in the compound shown in formula (II) or (IIa) or formula (II) or (IIa), diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt
Wherein, R 2for hydrogen or C 1-4alkyl;
R 3for thiazolyl or 1-methyl isophthalic acid H-imidazolyl;
R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl or propyl group independently, or as two R 4when being connected to same carbon atom, R 4and R 4together with the carbon atom be attached thereto or form following group :-C (=CH 2)-;
Each R 7be hydrogen or C independently 1-4alkyl;
Each R 6be C independently 1-4alkyl; Or R 6and R 7c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 8and R 8abe hydrogen or C independently 1-4alkyl, or R 8aand R 8c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, C independently 1-4haloalkyl or C 1-4alkyl, or R 10aand R 10c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, hydroxyl, C 1-4alkyl-S (=O) 2-, C 6-10aryl, C 1-9heteroaryl, C 3-6cycloalkyl, C 2-9heterocyclic radical, C 2-9heterocyclic radical-S (=O) 2-, C 1-9heteroaryl-S (=O) 2-, C 6-10aryl C 1-4alkyl, C 3-6cycloalkyl-S (=O) 2-or C 6-10aryl-S (=O) 2-;
Each R 12be hydrogen, fluorine, chlorine or bromine independently;
Each q is 0,1 or 2 independently;
Each n is 1,2,3 or 4 independently;
Each m is 0,1,2,3 or 4 independently.
In other embodiments, R is following subformula:
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl or propyl group independently, or R 10aand R 10form cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, C 1-4alkyl-S (=O) 2-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrryl, pyrimidyl, pyridazinyl, di azoly, triazolyl, tetrazyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyrazinyl, pyranyl, triazinyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-or phenyl-S (=O) 2-.
In other embodiments, compound of the present invention, its comprise following one of them structure or the enantiomer of one of them structure, diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt:
On the one hand, the present invention relates to a kind of pharmaceutical composition, this pharmaceutical composition comprises compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
In some embodiments, pharmaceutical composition of the present invention, it comprises Anti-HBV drugs further.
In some embodiments, pharmaceutical composition of the present invention, wherein, described Anti-HBV drugs is HBV AG14361, immunomodulator or Interferon, rabbit.
In some embodiments, pharmaceutical composition of the present invention, wherein, described Anti-HBV drugs is for being selected from lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, interferon α-1b, interferon alpha, interferon α-2, Intederon Alpha-2a, Interferon Alpha-2b, interferon beta-1a, interleukin II, mivotilate, nitazoxanide, Peg-IFN alpha-2b α-2a, virazole, Wellferon-A, sizofiran, Euforavac, rintatolimod (Puli is near for peace), Phosphazid, Heplisav, at least one in LEVAMISOLE HCL and propagermanium.
On the other hand, the invention still further relates to described compound or described pharmaceutical composition is preparing the purposes in medicine, described medicine is used for preventing, process, treat or alleviate disease viral disease.
In some embodiments, purposes of the present invention, wherein, described virus disease refers to the disease that hepatitis B infection or hepatitis B infection cause.
In other embodiments, purposes of the present invention, wherein, described hepatitis B infection causes disease to refer to liver cirrhosis or canceration of hepatic cell.
On the other hand, the present invention relates to described compound or pharmaceutical composition for the preparation of the purposes of medicine preventing, process, treat or alleviate patient's hepatitis B disease, comprise the dose therapeutically effective giving patient compound or pharmaceutical composition of the present invention as described herein.
The present invention relates to prevention on the other hand, processes, treats or alleviate the method for patient HBV illness, and described method comprises the pharmaceutically acceptable effective dose of use compound of the present invention and carries out administration to patient.
The present invention relates to prevention on the other hand, processes, treats or alleviate the method for patient HBV illness, and the pharmaceutically acceptable effective dose that described method comprises the pharmaceutical composition of use containing compound of the present invention carries out administration to patient.
The present invention relates to a kind of compound of the present invention of use on the other hand and produces for prevention, process or treatment patient HBV illness, and alleviates the purposes of the medicine of its severity.
The present invention relates to a kind of pharmaceutical composition comprising compound of the present invention of use on the other hand and produces for prevention, process or treatment patient HBV illness, and alleviates the purposes of the medicine of its severity.
Some of them embodiment is, described organism is Mammals, and other embodiment is, described organism is the mankind.Other embodiment is, described method further comprises the contact of kinases and HBV therapeutical agent.
The present invention relates to a kind of method suppressing HBV infection on the other hand, and the method comprises the dose of exposure that cell and the compounds of this invention or its composition effectively can suppress HBV.Other embodiment is, described method further comprises the contact of cell and HBV agent.
The present invention relates to the treatment to patient HBV disease on the other hand, and the method comprises the dosage that needs of patients effectively treats required compound of the present invention or its composition administration.Other embodiment is, described method further comprises the administration of HBV.
The present invention relates to a kind of method suppressing patient's HBV infection on the other hand, and the method comprises the dosage that needs of patients effectively treats required compound of the present invention or its composition administration.Other embodiment is, described method further comprises the administration of HBV treatment.
The present invention relates on the other hand the preparation of compound that formula (I) or formula (Ia) comprise, the method for abstraction and purification.
The present invention also comprises the application of compound of the present invention and pharmacy acceptable salt thereof, effectively suppresses HBV infection for the production of pharmaceutical prod, comprises that those are described in the invention.Compound of the present invention is producing the application effectively suppressed in HBV infection medicine.Compound of the present invention is used for alleviating, stop, control or treat the illness of patient's hepatitis B equally for the production of a kind of pharmaceuticals.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises the effective treatment consumption needed for the combination of formula (I) or the compound representated by (Ia) and at least one pharmaceutically acceptable carrier, assistant agent or thinner.
The present invention comprises the disease effectively suppressing HBV infection equally, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises use formula (I) or (Ia) representative compound is treated patient.
Unless other aspects show, all steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and the pharmaceutically acceptable prodrug of compound of the present invention all belongs to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) or (Ia) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I) or (Ia), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxysuccinic acid, 2 hydroxy propanoic acid, Citric Acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, trifluoromethanesulfonic acid etc. or their combination.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide, ammonium, N +(R 14) 4salt and alkaline earth metal hydroxides etc.Suitable salt comprises, but is not limited to: the organic salt obtained from amino acid, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, N +(R 14) 4salt, as R 14h, C 1-4alkyl, C 6-10aryl, C 6-10aryl C 1-4alkyl etc., and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.Also suitable, nontoxic ammonium is comprised, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
The purposes of the pharmaceutical composition of the compounds of this invention, preparation, administration and compound and pharmaceutical composition
The feature of pharmaceutical composition of the present invention comprises the compound of formula (I) or (Ia), the compound listed by the present invention, or the compound of embodiment 1-16, and pharmaceutically acceptable carrier, assistant agent or vehicle.In composition of the present invention, the amount of compound effectively can suppress hepatitis B virus, be applicable to treat or alleviate the HBV virus infection of the especially acute and chronic sustained of the disease that causes of patient's virus, the chronic viral diseases that HBV causes may cause morbid state to become serious, and chronic HBV infection can cause liver cirrhosis and/or canceration of hepatic cell in many cases.
Compound of the present invention is applicable to the treatment of the acute of infectious hepatitis and chronic viral infection, especially hepatitis B virus (HBV) can effectively be suppressed, be applicable to treat or alleviate the HBV virus infection of the especially acute and chronic sustained of the disease that causes of patient's virus, the chronic viral diseases that HBV causes may cause morbid state to become serious, and chronic HBV infection can cause liver cirrhosis and/or canceration of hepatic cell in many cases.
The present invention includes pharmaceutical preparation, except nontoxic, outside carrier suitable in the pharmacopedics of inertia, also containing one or more compounds of the present invention (I) or (Ia) or composition or containing one or more activeconstituentss (I) or (Ia) or composition of the present invention.
Said medicine preparation also can other active pharmaceutical ingredients beyond inclusion compound (I) or (Ia).
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or its residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to: ion-exchanger, aluminium, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, salt, as sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, with other nontoxic proper lubrication agent as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.For simplicity, local anesthetic, sanitas, buffer reagent etc. can directly be dissolved in carrier.
The compounds of this invention pharmaceutical composition, can the any-mode of following aspect grant: oral administration, Aerosol inhalation, per rectum administration, nose administration, topical, vagina administration, parenterai administration as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, in breastbone, or intracranial injection or transfusion, or by a kind of reservoir medication of outer planting.Preferred mode is oral administration, intramuscular injection, to Intraperitoneal medication or intravenous injection.
The compounds of this invention or containing pharmaceutically acceptable composition can be administration in a unit.Form of administration can be liquid dosage form, solid dosage.Liquid dosage form can be true solution class, colloidal type, particulate formulations, mixed suspension form.Other formulations are tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, suppository, lyophilized injectable powder, inclusion compound, implants, patch, liniment etc. such as.
Oral tablet and capsule can contain vehicle as tackiness agent, as syrup, and gum arabic, sorbyl alcohol, tragacanth, or polyvinylpyrrolidone; Weighting agent, as lactose, sucrose, W-Gum, calcium phosphate, sorbyl alcohol, Padil; Lubricant, as Magnesium Stearate, talcum, polyoxyethylene glycol, tripoli; Disintegrating agent, as yam starch; Or acceptable dibutyl phthalate is as bay sodium alkoxide vitriol.Tablet can with method dressing known in pharmacopedics.
Oral liquid can make the suspension of hydrous oil, solution, emulsion, syrup or elixir, also can make dry product, with front make up water or other suitable medium.This liquid preparation can comprise conventional additive, as suspension agent, and sorbyl alcohol, Walsroder MC 20000S, dextrose syrup, gel, Natvosol, carboxymethyl cellulose, aluminium stearate gel, the food oils of hydrogenation, emulsifying agent, as Yelkin TTS, sorb gathers candy list oleate, gum arabic; Or nonaqueous carrier (may edible oil be comprised), as Prunus amygdalus oil, grease as glycerine, ethylene glycol, or ethanol; Sanitas, as methyl p-hydroxybenzoate or propyl ester, Sorbic Acid.As needs can add seasonings or tinting material.
Suppository can comprise conventional suppository base, as cocoa butter or other glyceryl ester.
Offer medicine outward to stomach, liquid forms is made up of the carrier of compound and a kind of sterilization usually.The first-selected water of carrier.According to the difference of selected carrier and drug level, compound had both dissolved in carrier and also can be made into aaerosol solution, first that compound is soluble in water when making injection solution, loaded in sealed bottle or ampoule after filter-sterilized.
When topical application, the compounds of this invention can make suitable ointment, lotion, or the form of creme, wherein activeconstituents suspends or is dissolved in one or more carrier, wherein ointment formulation operable carrier is including, but not limited to mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; Lotion and the spendable carrier of creme include but not limited to: mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, and cetene is fragrant and mellow, 2-Standamul G, benzyl alcohol and water.
Generally speaking, verified advantageously no matter at human body medicine or in veterinary drug, the administration total amount of active compound of the present invention is about 0.5-500mg in every 24 hours, preferred 1-100mg/kg body weight, if properly, single dose administration several times, to reach required effect.About 1-80mg is preferably containing the amount of active compound in single dose, be more preferably 1-50mg/kg body weight, but also can not in accordance with above-mentioned dosage, namely the kind for the treatment of target and body weight, the character of disease and severity, the type of preparation and the administering mode of medicine is depended on, and dosage period or the timed interval.
Also Anti-HBV drugs is comprised in pharmaceutical composition provided by the invention.Wherein Anti-HBV drugs is HBV AG14361, immunomodulator or Interferon, rabbit.
HBV medicine has lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, interferon α-1b, interferon alpha, Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin II, mivotilate, nitazoxanide, Peg-IFN alpha-2b α-2a, virazole, Wellferon-A, sizofiran, Euforavac, rintatolimod, Phosphazid, Heplisav, Interferon Alpha-2b, LEVAMISOLE HCL, propagermanium etc.
The present invention relates on the other hand a kind of compound of the present invention or pharmaceutical composition for the preparation of the purposes of medicine preventing, process, treat or alleviate patient's hepatitis B disease, comprises giving the pharmaceutically acceptable effective dose of patient and carrying out administration to patient.Hepatitis B disease refers to and causes by hepatitis B virus infection or hepatitis B infection the hepatic diseases that causes, comprises acute hepatitis, chronic hepatitis, liver cirrhosis and stem cell cancer.Acute hepatitis b virus infection can be asymptomatic or show as acute hepatitis symptom.Chronic viral infection patient suffers from active disease, can develop into liver cirrhosis and liver cancer.
Anti-HBV drugs can separate administration with the composition comprising compound of the present invention, as a part for many dosage regimens.Or those medicines can be parts for one-pack type, form single composition together with compound of the present invention.If administration is as a part for many dosage regimens, two promoting agents can transmit mutually simultaneously continuously or within for some time, thus obtain destination agent activity.
The change that can produce the compound of one-pack type and the consumption (those comprise a composition as described in the invention) of composition in conjunction with carrier substance is depended on and is cured mainly and special mode of administration.Normally, the amount of composition of the present invention will be no more than composition and comprise the amount of the normal administration as unique promoting agent.On the other hand, the scope of the amount of existing disclosed composition is approximately the 50%-100% of existing composition normal amount, and the reagent comprised is as sole active therapeutical agent.In the composition that those comprise, composition will play synergy with compound of the present invention.
Compound of the present invention demonstrates stronger antivirus action.This compounds has antiviral activity beyond expectation to HBV, is therefore suitable for the various diseases caused for treatment virus, the disease that especially acute and chronic persistent HBV virus infection causes.The chronic viral diseases caused by HBV can cause the syndrome of various different severity, and as everyone knows, chronic hbv-infection can cause liver cirrhosis and/or hepatocellular carcinoma.
The example of the indication of available the compounds of this invention treatment has: treatment can cause the acute of infectious hepatitis and chronic viral infection, such as different in nature hepatites virus infections.Particularly preferably be the treatment of chronic hepatitis-B infection and the treatment of acute hepatitis b virus infection.
The present invention relates to the compounds of this invention and composition thereof the purposes for the preparation for the treatment of and the prophylaxis of viral diseases particularly medicine of hepatitis B.
General synthetic method
Usually, compound of the present invention can be prepared by method described in the invention, and unless there are further instruction, wherein substituent definition is such as formula shown in (I) or (Ia).Synthetic method below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, unless other aspects show, all temperature are decided to be degree Celsius (DEG C).Unless other aspects show, reagent is bought in goods providers as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, all not through being further purified during use; General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Anhydrous tetrahydro furan, dioxane, toluene, ether is through sodium Metal 99.5 backflow drying and obtains.Anhydrous methylene chloride and chloroform are through hydrolith backflow drying and obtain.Ethyl acetate, sherwood oil, normal hexane, N,N-dimethylacetamide and DMF are through the prior Dryly use of anhydrous sodium sulphate.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all through dry.
Chromatographic column uses silicagel column, and silica gel (200-300 order) is purchased from Haiyang Chemical Plant, Qingdao.Spectroscopic data of the nuclear magnetic resonance is measured by Bruker Avance400 nuclear magnetic resonance spectrometer or Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, with CDC1 3, d 6-DMSO, CD 3oD or d 6-acetone is solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), s, s (singlet, singlet, unimodal, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), ddd (doublet of doublet of doublets, doublet in pairs), dt (doublet of triplets, two triplet), ddt (doublet of doublet of triplets, triplet in pairs), dddd (doublet of doublet of doublet of doublets, double doublet in pairs), td (triplet of doublets, three doublets), br.s (broadened singlet, wide unimodal).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6320 being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the serial LC-MS of Agilent 6120 being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1: the condition of gradient elution of Algorithm moving phase
Time (min) A(CH 3CN，0.1％HCOOH) B(H 2O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purity is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
DCM, CH 2cl 2methylene dichloride
CDC1 3deuterochloroform
CCl 4tetracol phenixin
Boc tertbutyloxycarbonyl
(Boc) 2o tert-Butyl dicarbonate
TMSCl trimethylchlorosilane
CuI cuprous iodide
MeLi lithium methide
G gram
Mol mole
Mmol mmole
ML milliliter
L liter
H hour
LiOH.H 2o monohydrate lithium hydroxide, lithium hydroxide monohydrate
DMSO-d 6deuterated dimethyl sulfoxide
PE sherwood oil
EtOAc, EA ethyl acetate
NaHCO 3sodium bicarbonate
NBS N-bromo-succinimide
D 2o heavy water
ML milliliter
DMF dimethyl formamide
Pd/C, Pd-C palladium carbon
CH 3oH, MeOH methyl alcohol
T 1/2transformation period
AUC area under the drug-time curve
Vss apparent steady state distribution volume
CL, clearance clearance rate
F, absolute bioavailability bioavailability
Dose dosage
T maxpeak time
C maxpeak concentration
Hr *the ng/mL Plasma Concentration * time
Synthetic method
Synthetic method 1
Target compound 3b can be prepared by synthetic method 1, wherein R 1, R 2, R 3, A and R have implication as described in the present invention.There is bromo-reaction and obtain compound 2b in compound 1b, compound 2b and RH is obtained by reacting target compound 3b in the basic conditions under the effect of bromide reagent.
Synthetic method 2
Compound 7b can be prepared by synthetic method 2, and wherein, Z is-O-or-S-, R 14for hydrogen or methyl, R 13for hydrogen, methyl, ethyl, propyl group or sec.-propyl, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.There is wittig and be obtained by reacting compound 4b in compound 4-1b and wittig reagent, compound 4b reduction occurs under the effect of reductive agent and is obtained by reacting compound 5b, and compound 5b obtains compound 6b after being hydrolyzed, and compound 6b deprotection obtains compound 7b.
Synthetic method 3
Compound 13b can be prepared by synthetic method 3, wherein, and R 14for hydrogen or methyl, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 8b obtains compound 9b under oxygenant is as the effect of Dai Si-Martin's oxygenant; there is wittig and be obtained by reacting compound 10b in compound 9b and wittig reagent; reduction is there is and is obtained by reacting compound 11b in compound 10b under the effect of reductive agent; compound 11b obtains compound 12b after being hydrolyzed, and compound 12b deprotection obtains compound 13b.
Synthetic method 4
Compound 17b can be prepared by synthetic method 4, and wherein, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 14b obtains compound 15b under the effect of CuI, MeLi and TMSCl, and compound 15b hydrolysis obtains compound 16b, and compound 16b deprotection obtains compound 17b.
Synthetic method 5
Compound 24b can be prepared by synthetic method 5, wherein, and R 14for hydrogen or methyl, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 18b obtains compound 19b under the effect of reductive agent; compound 19b obtains compound 20b under oxygenant is as the effect of Dai Si-Martin's oxygenant; there is wittig and be obtained by reacting compound 21b in compound 20b and wittig reagent; compound 21b obtains compound 22b under the effect of reductive agent; compound 22b obtains compound 23b after being hydrolyzed, and compound 23b deprotection obtains compound 24b.
Synthetic method 6
Compound 34b can be prepared by synthetic method 6, and wherein, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 25b obtains compound 26b under the effect of trimethyl silicone hydride diazomethane and n-Butyl Lithium, compound 26b obtains compound 27b under the effect of rhodium acetate, compound 27b and DAST is obtained by reacting compound 28b, compound 28b obtains compound 29b under the effect of reductive agent, compound 29b obtains compound 30b under oxygenant is as the effect of Dai Si-Martin's oxygenant, there is wittig and be obtained by reacting compound 31b in compound 30b and wittig reagent, compound 31b obtains compound 32b under the effect of reductive agent, compound 32b obtains compound 33b after being hydrolyzed, compound 33b deprotection obtains compound 34b.
Synthetic method 7
Compound 40b can be prepared by synthetic method 7, and wherein, Z is-O-or-S-, R 14for hydrogen or methyl, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 35b obtains compound 36b under oxygenant is as the effect of Dai Si-Martin's oxygenant; there is wittig and be obtained by reacting compound 37b in compound 36b and wittig reagent; compound 37b obtains compound 38b after being hydrolyzed; there is reduction and be obtained by reacting compound 39b in compound 38b, compound 39b deprotection obtains compound 40b under the effect of reductive agent.
Synthetic method 8
Compound 47b can be prepared by synthetic method 8, and wherein, Z is-O-or-S-, R 14for hydrogen or methyl, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 41b obtains compound 42b under the effect of reductive agent; compound 42b obtains compound 43b under oxygenant is as the effect of Dai Si-Martin's oxygenant; there is wittig and be obtained by reacting compound 44b in compound 43b and wittig reagent; compound 44b obtains compound 45b under the effect of reductive agent; compound 45b obtains compound 46b after being hydrolyzed, and compound 46b deprotection obtains compound 47b.
Synthetic method 9
Compound 51b can be prepared by synthetic method 9, and wherein, Z is-O-or-S-, Pg is amino protecting group, as Boc, Fmoc, Cbz etc.Compound 48b obtains compound 49b under the effect of CuI and MeLi, and compound 49b hydrolysis obtains compound 50b, and compound 50b deprotection obtains compound 51b.
Embodiment
The following examples can the present invention will be further described, but these embodiments should as the restriction to scope of the present invention.
Embodiment 1 compound 3-(4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) morpholine-2-Ji) propionic acid synthesize
Step 1) synthesis of compound 2-(3-methoxyl group-3-oxo third-1-alkene-1-base) morpholine-4 – benzyl formate
By 2-formyl morpholine-4 – benzyl formate (1.5g; 6mmol) with methoxycarbonyl methylene triphenylphosphine (2.01g; 6mmol) be dissolved in DCM (30mL); the lower 25 DEG C of reactions of nitrogen protection 12 hours; concentration of reaction solution; resistates obtains colorless oil (0.88g, 48%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:306.1[M+H] +；
1H NMR(400MHz,CDCl 3):δ7.35-7.29(m,5H),6.82-6.78(m,1H),6.09-6.01(m,1H),5.15-5.10(m,2H),4.20-4.11(q,2H),3.94-3.88(m,2H),3.77-3.65(m,3H),3.60-3.58(m,1H),3.02(br.s,1H),2.74(br.s,1H).
Step 2) compound 3-(4-((benzyloxy) carbonyl) morpholine-2-Ji) acrylic acid synthesis
By 2-(3-methoxyl group-3-oxo third-1-alkene-1-base) morpholine-4-benzyl formate (0.86g, 2.82mmol) be dissolved in anhydrous methanol (4mL), add sodium hydroxide (1.12g, water (2mL) solution 28.2mmol), 25 DEG C are reacted 1 hour, add EtOAc (100mL) and water (50mL), pH to 1-2 is adjusted with concentrated hydrochloric acid at 0 DEG C, layering, colorless oil (0.79g, 96%) is obtained after concentration of organic layers.
MS(ESI,pos.ion)m/z:292.1[M+H] +；
1H NMR(400MHz,CDCl 3):δ7.37-7.19(m,5H),6.82-6.79(m,1H),6.09-6.02(m,1H),5.15-5.08(m,2H),4.10-4.01(m,2H),3.94-3.80(m,2H),3.60-3.55(m,1H),3.02(br.s,1H),2.74(br.s,1H).
Step 3) compound 3-(morpholine-2-Ji) propionic acid synthesize
By 3-(4-((benzyloxy) carbonyl) morpholine-2-Ji) vinylformic acid (0.52g, 1.8mmol), Pd-C (10%, 0.05g) be placed in reaction flask with dehydrated alcohol (4mL), atmosphere of hydrogen 25 DEG C reaction 12 hours, filter, white solid (0.2g, 70%) is obtained after concentrated filtrate.
MS(ESI,pos.ion)m/z:160.1[M+H] +；
1H NMR(400MHz,CDCl 3):δ3.66-3.52(m,3H),2.96-2.69(m,4H),2.33-2.21(m,2H),1.69-1.54(m,2H).
Step 4) synthesis of compound 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate
4-(4-fluorophenyl)-4,6-dimethyl-2-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate (1.7g, 4.92mmol, synthetic method is with reference to WO2013144129A1) is dissolved in CCl 4(40mL), 76 DEG C add NBS (0.96g, 5.41mmol), finish, insulation reaction 30 minutes, cooling, concentration of reaction solution, resistates obtains yellow oil (1.4g, 67%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=8/1).
MS(ESI,pos.ion)m/z:424.1[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ9.24(br,1H),8.02(d,1H),7.98(br.s,1H),7.55-7.35(m,2H),7.16(t,2H),4.52(d,1H),4.37(d,1H),3.49(s,3H),1.90(br.s,3H).
Step 5) compound 3-(4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) morpholine-2-Ji) propionic acid synthesize
6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1 is added successively in reaction flask; 4-dihydro-pyrimidin-5-methyl-formiate (0.47g; 1.1mmol), 2-propionic acid morpholine (0.18g; 1.1mmol), salt of wormwood (0.3g; 2.2mmol) with dehydrated alcohol (10mL); the lower 25 DEG C of reactions of nitrogen protection 12 hours; filter; filtrate concentrates, and resistates is through column chromatographic isolation and purification (DCM/CH 3oH (v/v)=25/1) obtain yellow solid (0.13g, 24%).
MS(ESI,pos.ion)m/z:503.2[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ12.05(br,1H),9.45(d,1H),8.02(d,1H),7.93(d,1H),7.44-7.37(m,2H),7.13-7.09(m,2H),3.84-3.75(m,1H),3.64-3.45(m,3H),3.42(s,3H),2.78-2.64(m,2H),2.48-2.44(m,1H),2.35-2.16(m,3H),2.01-1.92(m,1H),1.80(s,3H),1.66-1.59(m,2H).
Embodiment 2 compound (2R, 3S) the synthesis of-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-formic acid
Step 1) synthesis of compound (2R, 3S)-2-methyl-4-benzyl-5-oxomorpholin-3-benzyl formate
(2R is added successively in reaction flask, 3S)-2-methyl-4-benzyl-5-oxo-3-morpholine formic acid (1.07g, 4.25mmol) (synthetic method is with reference to Helvetica Chimica Acta, 87,2004,90-105), salt of wormwood (1.16g, 8.5mmol), acetonitrile (20mL) and benzyl bromine (0.87g, 5.1mmol), 65 DEG C are reacted 6 hours, filter, and filtrate concentrates, resistates obtains colorless oil (1.23g, 85%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=4/1).
MS(ESI,pos.ion)m/z:340.3[M+H] +；
1H NMR(600MHz,CDCl 3):δ7.42-7.18(m,10H),5.52(d,1H),5.22(q,2H),4.33(q,2H),4.23-4.21(m,1H),3.76-3.74(m,2H),1.23(d,3H).
Step 2) synthesis of compound (2R, 3S)-2-methyl-4-benzyl-3-morpholine benzyl formate
By (2R, 3S)-2-methyl-4-benzyl-5-oxo-3-morpholine benzyl formate (15.7g, 46.1mmol) be dissolved in THF (60mL), at nitrogen protection-10 DEG C, slow dropping borine tetrahydrofuran solution (1mol/L, 69.2mL), drip and finish, be warming up to 25 DEG C of reactions 16 hours, after be cooled to-10 DEG C, drip methyl alcohol to emerge to bubble-free, add water (10mL) subsequently, concentrated, EtOAc (150mL) is added in resistates, use sodium hydroxide solution (2mol/L successively, 50mL × 2) and saturated aqueous common salt (50mL × 2) washing, colorless oil (13g is obtained after organic layer is concentrated, 86.7%).MS(ESI,pos.ion)m/z:326.3[M+H] +；
1H NMR(600MHz,CDCl 3):δ7.33-7.27(m,10H),5.22(s,2H),3.80-3.70(m,4H),3.27(d,1H),2.90(d,1H),2.71(d,1H),2.22-2.18(m,1H),1.15(d,3H).
Step 3) synthesis of compound (2R, 3S)-2-methyl-3-morpholine formic acid
(2R is added successively in reaction flask, 3S)-2-methyl-4-benzyl-3-morpholine benzyl formate (10g, 30.76mmol), anhydrous methanol (100mL) and Pd/C (10%, 1g), the lower 25 DEG C of reactions of atmosphere of hydrogen 12 hours, filter, after filtrate is concentrated, obtain white solid (3.8g, 85%).
MS(ESI,pos.ion)m/z:146.2[M+H] +；
1H NMR(600MHz,D 2O):δ4.01-3.98(m,1H),3.82-3.77(m,1H),3.76-3.72(m,1H),3.37(d,1H),3.27-3.24(m,1H),3.19-3.14(m,1H),1.26(d,3H).
Step 4) compound (2R, 3S) the synthesis of-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-formic acid
6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1 is added successively in reaction flask; 4-dihydro-pyrimidin-5-methyl-formiate (0.47g; 1.1mmol), (2R; 3S)-2-methylmorpholine-3-formic acid (0.16g; 1.1mmol), salt of wormwood (0.3g; 2.2mmol) with dehydrated alcohol (15mL); the lower 25 DEG C of reactions of nitrogen protection 12 hours; filter; filtrate concentrates, and resistates is through column chromatographic isolation and purification (DCM/CH 3oH (v/v)=25/1) obtain yellow solid (0.2g, 37%).
MS(ESI,pos.ion)m/z:489.1[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ13.09(br,1H),9.59(s,1H),8.03(d,1H),7.93(br.s,1H),7.42-7.39(m,2H),7.11(t,2H),3.83(d,1H),3.76-3.64(m,2H),3.57-3.43(m,2H),3.41(d,3H),2.90(d,1H),2.74(t,1H),2.37(q,1H),1.81(d,3H),1.19-1.17(m,3H).
Embodiment 3 compound (3R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) synthesis of thiomorpholine-3-formic acid 1,1-dioxide
6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1 is added successively in reaction flask; 4-dihydro-pyrimidin-5-methyl-formiate (0.61g; 1.45mmol), (R)-thiomorpholine-3-formic acid 1; 1-dioxide (0.43g; 2.4mmol), salt of wormwood (0.4g; 2.9mmol) with dehydrated alcohol (25mL); the lower 40 DEG C of reactions of nitrogen protection 12 hours; filter, after filtrate is concentrated, resistates is through column chromatographic isolation and purification (DCM/CH 3oH (v/v)=25/1) obtain yellow solid (50mg, 6.6%).
MS(ESI,pos.ion)m/z:523.1[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ13.23(br,1H),9.51(s,1H),8.01(d,1H),7.93(br.s,1H),7.51-7.41(m,2H),7.19-7.09(m,2H),4.23-4.14(m,1H),4.05(t,1H),3.83(dd,1H),3.58-3.39(m,6H),3.18-3.03(m,3H),1.78(s,3H).
Embodiment 4 compound 3-((2R)-4, the fluoro-1-of 4-bis-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) pyrrolidin-2-yl) propionic acid synthesize
Step 1) synthesis of compound (S)-2-(3-oxyethyl group-3-oxo third-1-alkene-1-base)-4,4-difluoropyrrolidin-1-t-butyl formates
By (S)-4; the fluoro-2-carbonyl pyrrolidine of 4-bis--1-t-butyl formate (4.84g; 20.57mmol) be dissolved in DCM (120mL); 25 DEG C add ethoxycarbonyl methylene triphenyl phosphine (8.59g; 24.69mmol), insulation reaction 12 hours, concentration of reaction solution; resistates obtains light yellow oil (3.96g, 63%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=3/1).
MS(ESI,pos.ion)m/z:206[M+H-100] +；250[M+H-56] +；
1H NMR(600MHz,CDCl 3):δ6.83(m,1H),5.91(d,1H),4.65(d,1H),4.22(d,2H),3.86(s,1H),3.73(m,1H),2.66(d,1H),2.26(dd,1H),1.45(d,9H),1.31(t,3H).
Step 2) synthesis of compound (R)-2-(3-oxyethyl group-3-oxopropyl)-4,4-difluoropyrrolidin-1-t-butyl formates
(S)-2-(3-oxyethyl group-3-oxo third-1-alkene-1-base)-4 is added in reaction flask, 4-difluoropyrrolidin-1-t-butyl formate (0.5g, 1.8mmol), ethanol (10mL) and Pd/C (10%, 60mg), the lower 25 DEG C of reactions of atmosphere of hydrogen 12 hours, filter, after filtrate is concentrated, obtain colorless oil (0.45g, 89.46%).
1H NMR(600MHz,CDCl 3):δ4.15(dd,2H),3.98-3.82(m,1H),3.77(t,1H),3.62(dd,1H),2.61-2.43(m,1H),2.40-2.26(m,2H),2.19-2.07(m,2H),1.91-1.83(m,1H),1.49(s,9H),1.28(t,3H).
Step 3) compound (R)-3-(1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) propionic acid synthesize
(R)-2-(3-oxyethyl group-3-oxopropyl)-4,4-difluoropyrrolidin-1-t-butyl formate (0.45g, 1.46mmol) are dissolved in ethanol (10mL), add LiOH.H 2water (10mL) solution of O (0.62g, 1.47mmol), 25 DEG C are reacted 2 hours.After reaction terminates, add sodium hydroxide solution (2mol/L, 4mL) with water (10mL), with ether (30mL × 2) extraction, after layering, discard organic layer, the hydrochloric acid of water layer 2mol/L adjusts pH to 4, use DCM (50mL × 2) to extract again, after organic layer is concentrated, obtain light yellow oil (0.25g, 61.1%).
MS(ESI,pos.ion)m/z:180[M+H-100] +；224[M+H-56] +；
1H NMR(600MHz,CDCl 3):δ4.30-4.09(m,1H),4.02-3.78(m,1H),3.69-3.56(m,1H),2.61-2.48(m,1H),2.47-2.35(m,1H),2.22-2.09(m,1H),1.92-1.79(m,1H),1.49(s,9H).
Step 4) synthesis of compound (R)-3-(4,4-difluoropyrrolidin-2-base) propionic salt hydrochlorate
(R)-3-(1-(tertbutyloxycarbonyl)-4 is added in reaction flask, 4-difluoropyrrolidin-2-base) propionic acid (0.25g, 0.90mmol) with Hydrochloride/ethyl acetate (50mL), 25 DEG C are reacted 1 hour, white powder (0.15g, 77.9%) is obtained after concentration of reaction solution.
MS(ESI,pos.ion)m/z:180.1[M+H] +.
Step 5) compound 3-((2R)-4, the fluoro-1-of 4-bis-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) pyrrolidin-2-yl) propionic acid synthesize
6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1 is added successively in reaction flask; 4-dihydro-pyrimidin-5-methyl-formiate (0.3g; 0.7mmol), (R)-3-(4; 4-difluoropyrrolidin-2-base) propionic salt hydrochlorate (0.15g; 0.7mmol)), salt of wormwood (0.19g; 1.4mmol) with dehydrated alcohol (15mL); the lower 40 DEG C of reactions of nitrogen protection 12 hours; filter; filtrate concentrates, and resistates is through column chromatographic isolation and purification (DCM/CH 3oH (v/v)=25/1) obtain yellow solid (0.2g, 55%).
MS(ESI,pos.ion)m/z:523.2[M+H] +；
1H NMR(400MHz,DMSO-d 6):δ12.12(br,1H),9.36(br,1H),8.02(d,1H),7.93(s,1H),7.46(br,2H),7.16-7.11(m,2H),4.05-3.96(m,1H),3.79-3.60(m,3H),3.44(s,3H),3.18-2.88(m,2H),2.35-2.27(m,2H),2.15-1.95(m,2H),1.84(s,3H),1.65-1.55(m,1H).
Embodiment 5 compound 3-((2S)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) morpholine-2-Ji) propionic acid synthesize
Step 1) synthesis of compound (R)-2-formyl morpholine-4-t-butyl formate
By (R)-2-(methylol) morpholine-4-t-butyl formate (2.17g, 10mmol) be dissolved in DCM (44mL), 0 DEG C adds Dai Si-Martin's oxygenant (5.1g, 12mmol), finish, insulation reaction 2 hours, add saturated sodium bicarbonate solution (40mL), after layering, organic layer uses saturated sodium bicarbonate solution (40mL) and saturated aqueous common salt (40mL) washing successively, anhydrous sodium sulfate drying, obtains colorless oil (1.81g, 84%) after concentration of organic layers.
MS(ESI,pos.ion)m/z:160.2[M+H-56] +.
Step 2) synthesis of compound (S)-2-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-t-butyl formate
By (R)-2-formyl morpholine-4-t-butyl formate (1.81g; 8.4mmol), DCM (40mL) and (triphenylphosphine alkene) ethyl acetate (2.93g; 8.4mmol) implement to obtain colorless oil (1.94g, 81%) by the method described in embodiment 4 step 1.
MS(ESI,pos.ion)m/z:186.1[M+H-100] +.
Step 3) synthesis of compound (S)-2-(3-oxyethyl group-3-oxopropyl) morpholine-4-t-butyl formate
By (S)-2-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-t-butyl formate (1.94g, 6.8mmol), dehydrated alcohol (40mL) and Pd-C (10%, 0.2g) implement to obtain colorless oil (1.78g, 91%) by the method described in embodiment 4 step 2.
MS(ESI,pos.ion)m/z:232.1[M+H-56] +.
Step 4) compound (S)-3-(4-(tertbutyloxycarbonyl) morpholine-2-Ji) propionic acid synthesize
By (S)-2-(3-oxyethyl group-3-oxopropyl) morpholine-4-t-butyl formate (1.78g, 6.2mmol), dehydrated alcohol (10mL), LiOH.H 2o (2.6g, 62mmol) and water (10mL) are implemented to obtain colorless oil (1.59g, 99%) by the method described in embodiment 4 step 3.
MS(ESI,pos.ion)m/z:160.2[M+H-100] +.
Step 5) synthesis of compound (S)-3-(morpholine-2-Ji) propionic salt hydrochlorate
By (S)-3-(4-(tertbutyloxycarbonyl) morpholine-2-Ji) propionic acid (1.59g, 6.1mmol) with Hydrochloride/ethyl acetate (4mol/L, 15mL), 25o reacts 4 hours, filter, obtain white solid (0.94g, 79%).
MS(ESI,pos.ion)m/z:160.1[M+H] +；
1H NMR(400MHz,D 2O):δ4.10-4.02(m,1H),3.80-3.74(m,2H),3.32-3.25(m,2H),3.10(td,1H),2.89(t,1H), 2.47-2.43(m,2H),1.88-1.70(m,2H).
Step 6) compound 3-((2S)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) morpholine-2-Ji) propionic acid synthesize
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (0.78g, 0.18mmol), (S)-3-(morpholine-2-Ji) propionic salt hydrochlorate (36mg, 0.18mmol), salt of wormwood (56mg, 0.36mmol) implement to obtain yellow oil (31mg, 33%) by the method described in embodiment 1 step 5 with ethanol (2mL).
MS(ESI,pos.ion)m/z:503.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ9.38(s,1H),7.85(d,1H),7.55-7.46(m,1H),7.42(dd,2H),7.08-6.93(m,2H),3.90(d,1H),3.69(dt,4H),3.46(s,3H),2.72(d,2H),2.53-2.37(m,3H),2.12(ddd,2H),1.90(s,3H),1.83-1.71(m,2H).
Embodiment 6 compound 3-((3R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-3-base) propionic acid synthesize
Step 1) synthesis of compound (S)-3-formyl morpholine-4-t-butyl formate
By (R)-3-(methylol) morpholine-4-t-butyl formate (1.47g, 6.77mmol) be dissolved in DCM (30mL), 0 DEG C adds Dai Si-Martin's oxygenant (3.44g, 8.12mmol), insulation reaction 1 hour, add saturated sodium bicarbonate solution (30mL), continue stirring 30 minutes, layering, organic layer uses saturated sodium bicarbonate solution (30mL × 3) and saturated aqueous common salt (30mL) washing successively, anhydrous sodium sulfate drying, filters, and filtrate is directly used in next step reaction.
Step 2) synthesis of compound (R)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-t-butyl formate
By (S)-3-formyl morpholine-4-t-butyl formate (1.46g; 6.77mmol) be dissolved in DCM (40mL); 25 DEG C add (triphenylphosphine alkene) ethyl acetate (2.36g; 6.77mmol); insulation reaction 12 hours, filters, after filtrate is concentrated; resistates obtains colorless oil (1.05g, 54%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:186.1[M+H-100] +；
1H NMR(400MHz,CDCl 3):δ6.69(dd,1H),5.89(dd,1H),4.56(s,1H),4.20-4.12(m,2H),3.94-3.82(m,2H),3.77-3.65(m,2H),353-3.43(m,1H),3.27-3.10(m,1H),1.41(s,9H),1.29-1.23(m,3H).
Step 3) synthesis of compound (R)-3-(3-oxyethyl group-3-oxopropyl) morpholine-4-t-butyl formate
(R)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-t-butyl formate (1.05g is added successively in reaction flask, 3.68mmol), dehydrated alcohol (20mL) and Pd-C (10%, 0.2g), atmosphere of hydrogen 30 DEG C reaction 12 hours, filter, filtrate concentrates, and obtains colorless oil (0.96g, 91%).
MS(ESI,pos.ion)m/z:188.1[M+H-100] +；
1H NMR(400MHz,CDCl 3):δ4.12(q,2H),3.98(s,1H),3.84-3.69(m,3H),3.56(dd,1H),3.42(td,1H),3.12(t,1H),2.37-2.27(m,2H),2.25-2.15(m,1H),1.92-1.83(m,1H),1.45(s,9H),1.25(t,3H).
Step 4) compound (R)-3-(4-(tertbutyloxycarbonyl) morpholine-3-base) propionic acid synthesize
(R)-3-(3-oxyethyl group-3-oxopropyl) morpholine-4-t-butyl formate (0.96g, 3.34mmol) is dissolved in dehydrated alcohol (10mL), adds LiOH.H 2o (1.4g, water (10mL) solution 33.4mmol), 25 DEG C are reacted 30 minutes, add EtOAc (150mL) and water (50mL), and ice bath cools, pH to 5-6 is adjusted with concentrated hydrochloric acid, layering, organic layer saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying, colorless oil (0.85g, 98%) is obtained after concentration of organic layers.
MS(ESI,pos.ion)m/z:160.1[M+H-100] +；
1H NMR(400MHz,CDCl 3):δ8.08(br,1H),4.03(br,1H),3.88-3.72(m,3H),3.58(dd,1H),3.44(td,1H),3.13(t,1H),2.43-2.29(m,2H),2.27-2.20(m,1H),1.94-1.83(m,1H),1.46(s,9H).
Step 5) synthesis of compound (R)-3-(morpholine-3-base) propionic salt hydrochlorate
(R)-3-(4-(tertbutyloxycarbonyl) morpholine-3-base) propionic acid (0.9g is added successively in reaction flask, 3.47mmol) with Hydrochloride/ethyl acetate (4mol/L, 15mL), 25 DEG C are reacted 4 hours, filter, obtain white solid (0.53g, 78%).
MS(ESI,pos.ion)m/z:160.1[M+H] +；
1H NMR(400MHz,D 2O):δ4.04-3.96(m,2H),3.75-3.68(m,1H),3.52(dd,1H),3.40-3.35(m,1H),3.34-3.29(m,1H),3.22-3.15(m,1H),2.47(t,2H),1.83(ddd,2H).
Step 6) compound 3-((3R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-3-base) propionic acid synthesize
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (184mg, 0.43mmol), (R)-3-(morpholine-3-base) propionic salt hydrochlorate (85mg, 0.43mmol), salt of wormwood (119mg, 0.87mmol) implement to obtain yellow oil (39mg, 18%) by the method described in embodiment 1 step 5 with ethanol (5mL).
MS(ESI,pos.ion)m/z:503.8[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ8.09-8.06(m,1H),7.75-7.67(m,1H),7.56-7.49(m,1H),7.34-7.23(m,1H),7.25-7.12(m,2H),3.85-3.81(m,1H),3.80-3.75(m,2H),3.70-3.61(m,2H),3.59-3.54(m,1H),3.42(d,3H),2.90(s,1H),2.64(t,1H),2.54-2.40(m,3H),2.31-2.25(m,1H),2.10-2.02(m,1H),1.97-1.91(m,1H),1.80(s,3H).
Embodiment 7 compound 3-((3S)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-3-base) propionic acid synthesize
Step 1) synthesis of compound (R)-3-formyl morpholine-4-t-butyl formate
By (S)-3-(methylol) morpholine-4-t-butyl formate (2.17g, 10mmol) be dissolved in DCM (44mL), 0 DEG C adds Dai Si-Martin's oxygenant (5.1g, 12mmol), insulation reaction 1 hour, add saturated sodium bicarbonate solution (40mL), continue stirring 30 minutes, layering, organic layer uses saturated sodium bicarbonate solution (40mL × 3) and saturated aqueous common salt (40mL) washing successively, anhydrous sodium sulfate drying, concentration of organic layers, obtain micro-yellow oil (1.72g, 80%).
Step 2) synthesis of compound (S)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-t-butyl formate
By (R)-3-formyl morpholine-4-t-butyl formate (1.72g; 8mmol) be dissolved in DCM (40mL); 25 DEG C add (triphenylphosphine alkene) ethyl acetate (2.78g; 8mmol); insulation reaction 12 hours, filters, concentrated filtrate; resistates obtains colorless oil (1.78g, 78%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=10/1).
MS(ESI,pos.ion)m/z:186.2[M+H-100] +.
Step 3) synthesis of compound (S)-3-(3-oxyethyl group-3-oxopropyl) morpholine-4-t-butyl formate
(S)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-t-butyl formate (1.78g is added successively in reaction flask, 6.2mmol), dehydrated alcohol (40mL) and Pd-C (10%, 0.2g), the lower 30 DEG C of reactions of atmosphere of hydrogen 12 hours, filter, concentrated filtrate obtains colorless oil (1.66g, 93%).
MS(ESI,pos.ion)m/z:188.1[M+H-100] +.
Step 4) compound (S)-3-(4-(tertbutyloxycarbonyl) morpholine-3-base) propionic acid synthesize
(S)-3-(3-oxyethyl group-3-oxopropyl) morpholine-4-t-butyl formate (1.66g, 5.8mmol) is dissolved in dehydrated alcohol (10mL), adds LiOH.H 2o (2.43g, water (10mL) solution 58mmol), 25 DEG C are reacted 30 minutes, add EtOAc (150mL) and water (50mL), and ice bath cools, pH to 5-6 is adjusted with concentrated hydrochloric acid, layering, organic layer saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying, colorless oil (1.44g, 96%) is obtained after concentration of organic layers.
MS(ESI,pos.ion)m/z:160.1[M+H-100] +.
Step 5) synthesis of compound (S)-3-(morpholine-3-base) propionic salt hydrochlorate
(S)-3-(4-(tertbutyloxycarbonyl) morpholine-3-base) propionic acid (1.44g is added successively in reaction flask, 5.55mmol) with Hydrochloride/ethyl acetate (4mol/L, 15mL), 25 DEG C are reacted 4 hours, filter, obtain white solid (0.92g, 85%).
MS(ESI,pos.ion)m/z:160.3[M+H] +.
Step 6) compound 3-((3S)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-3-base) propionic acid synthesize
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (184mg, 0.43mmol), (S)-3-(morpholine-3-base) propionic salt hydrochlorate (85mg, 0.43mmol), salt of wormwood (119mg, 0.87mmol) implement to obtain yellow oil (35mg, 15%) by the method described in embodiment 1 step 5 with ethanol (5mL).
MS(ESI,pos.ion)m/z:503.2[M+H] +；
1H NMR(400MHz,CDCl 3):δ7.85(d,1H),7.45(d,1H),7.43-7.36(m,2H),6.97(t,2H),3.88-3.84(m,1H),3.85-3.79(m,2H),3.70-3.62(m,2H),3.58-3.56(m,1H),3.46(2s,3H),2.91(s,1H),2.66(t,1H),2.55-2.39(m,3H),2.38-2.28(m,1H),2.13-2.02(m,1H),1.98-1.91(m,1H),1.88(s,3H).
Embodiment 8 compound 3-((2R, 3R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-base) propionic acid synthesize
Step 1) synthesis of compound (2S, 3R)-2-(benzylamine)-3-hydroxybutyrate
L-threonine (16.7g is added successively in reaction flask, 140mmol), sodium hydroxide solution (2mol/L, 70mL, 140mmol) and phenyl aldehyde (14.56g, 137mmol), 25 DEG C are reacted 1 hour, be cooled to 0 DEG C, add sodium borohydride (3g, 80mmol) in batches, finish, be warming up to 25 DEG C of reactions 12 hours.After reaction terminates, with DCM (30mL × 3) extraction, after layering, discard organic layer.At 10 DEG C, after the pH to 2 with concentrated hydrochloric acid water transfer layer, 5 DEG C of stirring and crystallizing 4 hours, filter, obtain white solid (19.5g, 68%).
MS(ESI,pos.ion)m/z:210.1[M+H] +.
Step 2) synthesis of compound (2R, 3S)-4-benzyl-2-methyl-5-oxomorpholin-3-formic acid
(2S is added successively in reaction flask, 3R)-2-(benzylamine)-3-hydroxybutyrate (21.4g, 102.4mmol), tetrahydrofuran (THF) (110mL) and salt of wormwood (42.5g, water (70mL) solution 307.2mmol), at 0 DEG C, slow dropping chloroacetyl chloride (17.8g, 157.7mmol), drip and finish, 0 DEG C of reaction is after 3 hours, drip sodium hydroxide (16.4g, water (40mL) solution 409.6mmol), drip and finish, 5 DEG C are reacted 4 hours, after being warming up to 25 DEG C, reaction solution PE (50mL × 2) extracts, after layering, water layer is cooled to 15 DEG C, slow dropping concentrated hydrochloric acid adjusts pH to separating out a large amount of solid, 10 DEG C are stirred 12 hours, filter, after filter cake washes with water, obtain white solid (18.1g, 71%).
MS(ESI,pos.ion)m/z:250.1[M+H] +.
Step 3) synthesis of compound ((2R, 3R)-4-benzyl-2-methylmorpholine-3-base) methyl alcohol
Under 0 DEG C of nitrogen protection, by 70% red aluminium toluene solution (153mL, 549mmol) slowly instill (2R, 3S)-4-benzyl-2-methyl-5-oxomorpholin-3-formic acid (26.5g, in toluene (237mL) solution 106mmol), drip and finish, 25 DEG C are reacted 12 hours, be cooled to 10 DEG C, drip ethanol (43mL), with sodium hydroxide solution (2mol/L, 50mL × 3) washing, after layering, discard water layer, organic layer hydrochloric acid (2mol/L, 100mL × 2) extraction, after layering, discard organic layer, EtOAc (300mL) is added in water layer, pH to 7-8 is adjusted with sodium hydroxide solution (2mol/L), after layering, organic over anhydrous dried over sodium sulfate, faint yellow solid (12.2g is obtained after concentrated, 52%).
MS(ESI,pos.ion)m/z:222.1[M+H] +.
Step 4) synthesis of compound (2R, 3R)-3-(methylol)-2-methylmorpholine-4-t-butyl formate
((2R, 3R)-4-benzyl-2-methylmorpholine-3-base) methyl alcohol (9.5g, 43mmol), MeOH (100mL), Pd/C (0.95g, 10%) and (Boc) is added successively in reaction flask 2o (10g, 46mmol), atmosphere of hydrogen 25 DEG C reaction 24 hours, filter, after filtrate is concentrated, resistates obtains pale yellow oil (8.5g, 85%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:132.2[M+H-100] +.
Step 5) synthesis of compound (2R, 3S)-3-formyl radical-2-methylmorpholine-4-t-butyl formate
(2R is added successively in reaction flask, 3R)-3-(methylol)-2-methylmorpholine-4-t-butyl formate (8.5g, 36.7mmol) with DCM (170mL), 0 DEG C adds Dai Si-Martin's oxygenant (18.7g, 44mmol), insulation reaction 3 hours, adds saturated NaHCO 3solution (170mL), stir 30 minutes, after layering, organic layer uses saturated NaHCO successively 3solution (85mL × 2) and saturated aqueous common salt (85mL × 2) washing, anhydrous sodium sulfate drying, obtains colorless oil (5.8g, 69%) after organic layer is concentrated.
Step 6) synthesis of compound (2R, 3R)-3-(3-oxyethyl group-3-oxo third-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate
(2R is added in reaction flask; 3S)-3-formyl radical-2-methylmorpholine-4-t-butyl formate (1.3g; 5.6mmol) with DCM (40mL); 0 DEG C adds ethoxycarbonyl methylene triphenyl phosphine (1.95g; 5.6mmol), 25 DEG C are reacted 12 hours, concentration of reaction solution; resistates obtains colorless oil (0.73g, 41%) through column chromatographic isolation and purification (EtOAc/PE (v/v)=1/16).
MS(ESI,Pos.ion)m/z:200.2[M+H-100] +；
1H NMR(600MHz,CDCl 3):δ6.96(dd,1H),5.89(dd,1H),4.21-4.04(m,2H),4.04-3.90(m,1H),3.90-3.79(m,1H),3.79-3.22(m,4H),1.44(s,9H),1.40(s,3H),1.26(m,3H).
Step 7) synthesis of compound (2R, 3R)-3-(3-oxyethyl group-3-oxopropyl)-2-methylmorpholine-4-t-butyl formate
(2R is added in reaction flask, 3R)-3-(3-oxyethyl group-3-oxo third-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate (0.73g, 2.4mmol), EtOAc (35mL) and Pd/C (10%, 0.73g, 6.86mmol), atmosphere of hydrogen 25 DEG C reaction 12 hours, filters, colorless oil (0.7g, 95%) is obtained after filtrate is concentrated.
MS(ESI,pos.ion)m/z:202.2[M+H-100] +.
Step 8) compound 3-((2R, 3R)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-base) propionic acid synthesize
(2R, 3R)-3-(3-oxyethyl group-3-oxopropyl)-2-methylmorpholine-4-t-butyl formate (0.84g, 2.8mmol), ethanol (10mL) and LiOH.H is added in reaction flask 2o (1.2g, water (10mL) solution 28mmol), 25 DEG C are reacted 30 minutes, add EtOAc (15mL) and water (10mL), adjust pH to 5 ~ 6 with concentrated hydrochloric acid, layering for 0 DEG C, organic layer saturated aqueous common salt (50mL × 2) washs, anhydrous sodium sulfate drying, obtains colorless oil (0.62g, 86%) after concentrated.
MS(ESI,pos.ion)m/z:174.2[M+H-100] +；
MS(ESI,Neg.ion)m/z:272.2[M-H] -.
Step 9) synthesis of compound 3-((2R, 3R)-2-methylmorpholine-3-base) propionic salt hydrochlorate
3-((2R is added in reaction flask, 3R)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-base) propionic acid (0.62g, 2.3mmol) with Hydrochloride/ethyl acetate (4mol/L, 10mL), 25 DEG C are reacted 4 hours, and filter, filter cake EtOAc (10mL) washs, obtain pale solid (0.36g, 92%).
MS(ESI,pos.ion)m/z:174.1[M+H] +.
Step 10) compound 3-((2R, 3R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-base) propionic acid synthesize
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (90mg, 0.21mmol), 3-((2R, 3R)-2-methylmorpholine-3-base) propionic salt hydrochlorate (36mg, 0.21mmol), salt of wormwood (59mg, 0.42mmol) implement to obtain yellow oil (28mg, 28%) by the method described in embodiment 1 step 5 with ethanol (2.5mL).
MS(ESI,pos.ion)m/z:517.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ7.87-7.83(m,1H),7.47(d,1H),7.42(dd,2H),6.97(t,2H),4.12-3.99(m,2H),3.83-3.68(m,3H),3.50(s,2H),3.42(s,2H),2.43-2.28(m,5H),2.06-2.01(m,1H),1.88(d,3H),1.42(d,3H).
Embodiment 9 compound 3-((2S, 3S)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-base) propionic acid synthesize
Step 1) synthesis of compound (2R, 3S)-2-(benzylamine)-3-hydroxybutyrate
D-Thr (16.7g, 140mmol), sodium hydroxide solution (2mol/L, 70mL is added successively in reaction flask, 140mmol) with phenyl aldehyde (14.56g, 137mmol), 25 DEG C are reacted 1 hour, are cooled to 0 DEG C, add sodium borohydride (3g in batches, 80mmol), finish, be warming up to 25 DEG C of reactions 12 hours, stopped reaction, with DCM (30mL × 3) extraction, after layering, discard organic layer, water layer is cooled to 5 DEG C, adjust pH to 1-2 with concentrated hydrochloric acid, insulated and stirred crystallization 4 hours, filter, obtain white solid (20.9g, 73%).
MS(ESI,pos.ion)m/z:210.1[M+H] +.
Step 2) synthesis of compound (2S, 3R)-4-benzyl-2-methyl-5-oxomorpholin-3-formic acid
(2R is added successively in reaction flask, 3S)-2-(benzylamine)-3-hydroxybutyrate (21.4g, 102.4mmol), tetrahydrofuran (THF) (110mL) and salt of wormwood (42.5g, water (70mL) solution 307.2mmol), 0 DEG C slowly drips chloroacetyl chloride (17.8g, 157.7mmol), drip and finish, insulation reaction 3 hours, drip sodium hydroxide (16.4g, water (40mL) solution 409.6mmol), drip and finish, be cooled to 3 DEG C of reactions 4 hours, be warming up to 25 DEG C, reaction solution PE (50mL × 2) extracts, water layer is cooled to 15 DEG C, dripping concentrated hydrochloric acid adjusts pH to separate out to a large amount of solid, 10 DEG C are stirred 12 hours, filter, filter cake washes with water, obtain white solid (16.1g, 63%).
MS(ESI,pos.ion)m/z:250.1[M+H] +.
Step 3) synthesis of compound ((2S, 3S)-4-benzyl-2-methylmorpholine-3-base) methyl alcohol
Under 0 DEG C of nitrogen protection, by 70% red aluminium toluene solution (153mL, 549mmol) slowly instill (2S, 3R)-4-benzyl-2-methyl-5-oxomorpholin-3-formic acid (26.5g, in toluene (237mL) solution 106mmol), drip and finish, 25 DEG C are reacted 12 hours, be cooled to 10 DEG C, drip ethanol (43mL), with sodium hydroxide (50mL × 3, 2mol/L) wash, organic layer hydrochloric acid (100mL × 2, 2mol/L) extract, after layering, discard organic layer, water layer adds EtOAc (300mL), pH to 8 is adjusted with sodium hydroxide solution (2mol/L), after layering, organic over anhydrous dried over sodium sulfate, faint yellow solid (9.5g is obtained after concentrated, 40%).
MS(ESI,pos.ion)m/z:222.1[M+H] +.
Step 4) synthesis of compound (2S, 3S)-3-(methylol)-2-methylmorpholine-4-t-butyl formate
((2S, 3S)-4-benzyl-2-methylmorpholine-3-base) methyl alcohol (9.5g, 43mmol), MeOH (100mL), Pd/C (0.95g, 10%) and (Boc) is added successively in reaction flask 2o (10g, 46mmol), atmosphere of hydrogen 25 DEG C reaction 24 hours, filter, concentrated filtrate, resistates obtains pale yellow oil (8.9g, 90%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=2/1).
MS(ESI,pos.ion)m/z:132.2[M+H-100] +.
Step 5) synthesis of compound (2S, 3S)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate
By Dai Si-Martin's oxygenant (19.5g at 0 DEG C, 46mmol) add (2S, 3S)-3-(methylol)-2-methylmorpholine-4-t-butyl formate (8.9g, in DCM (250mL) solution 38mmol), finish, insulation reaction 3 hours, add 2-(triphenylphosphine alkene) ethyl acetate (40g, 115mmol), be warming up to 25 DEG C of reactions 12 hours, add saturated NaHCO 3solution (250mL), stir stratification after 1 hour, organic layer uses saturated NaHCO successively 3solution (150mL × 2) and saturated aqueous common salt (150mL × 2) washing, anhydrous sodium sulfate drying, after concentrated, resistates obtains pale yellow oil (9.5g, 83%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:200.2[M+H-100] +.
Step 6) synthesis of compound (2S, 3S)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate
(2S is added successively in reaction flask, 3S)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate (9.5g, 32mmol), MeOH (200mL) and Pd/C (0.95g, 10%), atmosphere of hydrogen 25 DEG C reaction 12 hours, filter, after filtrate is concentrated, obtain colorless oil (8g, 83%).
MS(ESI,pos.ion)m/z:202.3[M+H-100] +.
Step 7) compound 3-((2S, 3S)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-base)-propionic acid synthesize
(2S, 3S)-3-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate (7.9g, 26.2mmol), ethanol (150mL) and LiOH.H is added successively in reaction flask 2o (4.2g, water (50mL) solution 100mmol), 25 DEG C are reacted 30 minutes, concentration of reaction solution, add EtOAc (300mL) and water (100mL), at 0 DEG C, adjust pH to 4-6, after layering with concentrated hydrochloric acid, organic layer saturated aqueous common salt (100mL × 2) washs, anhydrous sodium sulfate drying, obtains colorless oil (6.5g, 91%) after concentrated.
MS(ESI,pos.ion)m/z:174.2[M+H-100] +.
Step 8) synthesis of compound 3-((2S, 3S)-2-methylmorpholine-3-base) propionic salt hydrochlorate
3-((2S is added successively in reaction flask, 3S)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-base)-propionic acid (1g, 3.7mmol) with Hydrochloride/ethyl acetate (4mol/L, 10mL), 25 DEG C are reacted 4 hours, filter, obtain white solid (0.6g, 77%).
MS(ESI,pos.ion)m/z:174.3[M+H] +；
1H NMR(600MHz,D 2O):δ4.05(dd,1H),3.84-3.79(m,1H),3.74-3.70(m,1H),3.34(d,1H),3.21(td,1H),3.10(td,1H),2.55(t,2H),2.06-2.03(m,1H),1.82-1.76(m,1H),1.26(d,3H).
Step 9) compound 3-((2S, 3S)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-base) propionic acid synthesize
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (283mg, 0.67mmol), 3-((2S, 3S)-2-methylmorpholine-3-base) propionic salt hydrochlorate (140mg, 0.67mmol), salt of wormwood (190mg, 1.36mmol) implement to obtain yellow oil (113mg, 33%) by the method described in embodiment 1 step 5 with ethanol (10mL).
MS(ESI,pos.ion)m/z:517.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ9.22(s,1H),7.86(t,1H),7.44(d,3H),6.98(t,2H),4.15-3.90(m,2H),3.85-3.65(m,3H),3.51(s,2H),3.45(s,2H),2.42-2.21(m,5H),2.08-2.05(m,1H),1.78(d,3H),1.42(d,3H).
The synthesis of embodiment 10 compound 3-((2R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-2-Ji)-2 Methylpropionic acid
Step 1) synthesis of compound (R)-2-(3-oxyethyl group-2-methyl-3-oxopropan-1-alkene-1-base) morpholine-4-benzyl formate
By (S)-2-formyl morpholine-4-benzyl formate (4.99g; 20mmol) be dissolved in DCM (180mL); add ethoxycarbonyl ethylidene triphenylphosphine (7.25g; 20mmol); 25 DEG C are reacted 12 hours, filter, concentrated filtrate; resistates obtains colorless oil (3g, 45%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=15/1).
MS(ESI,pos.ion)m/z:334.3[M+H] +；
1H NMR(400MHz,DMSO-d 6):δ7.38-7.30(m,5H),6.48(d,1H),5.12(s,2H),4.31-4.23(m,1H),4.13(q,2H),3.84-3.79(m,3H),3.52(td,1H),3.02(br,1H),2.83(br,1H),1.83(s,3H),1.22(t,3H).
Step 2) synthesis of compound (R)-3-(4-((benzyloxy) carbonyl) morpholine-2-Ji)-2-methacrylic acid
(R)-2-(3-oxyethyl group-2-methyl-3-oxopropan-1-alkene-1-base) morpholine-4-benzyl formate (2.3g, 6.9mmol) is dissolved in ethanol (46mL), adds LiOH.H 2o (2.89g, water (23mL) solution 69mmol), 25 DEG C are reacted 1 hour, and concentration of reaction solution, adds EtOAc (250mL) in resistates, pH to 4-5 is adjusted with concentrated hydrochloric acid, layering, organic layer saturated aqueous common salt (100mL) washing, anhydrous sodium sulfate drying, colorless oil (2g, 95%) is obtained after concentrated.
MS(ESI,pos.ion)m/z:306.2[M+H] +；
1H NMR(400MHz,CDCl 3):δ8.82(br,1H),7.41-7.33(m,5H),6.74(d,1H),5.19(s,2H),4.33-4.20(m,1H),4.05-3.85(m,3H),3.64-3.58(m,1H),3.20-3.05(m,1H),2.88(br,1H),1.93(s,3H).
Step 3) synthesis of compound 3-((R)-4-((benzyloxy) carbonyl) morpholine-2-Ji)-2 Methylpropionic acid
(R)-3-(4-((benzyloxy) carbonyl) morpholine-2-Ji)-2-methacrylic acid (2g is added successively in reaction flask, 6.6mmol), Pd/C (10%, 200mg) with ethanol (40mL), atmosphere of hydrogen 25 DEG C reaction 12 hours, filter, concentrated filtrate, obtains colorless oil (1.9g, 94%).
MS(ESI,pos.ion)m/z:308.1[M+H] +；
1H NMR(400MHz,CDCl 3):δ8.70(br,1H),7.41-7.33(m,5H),5.17(s,2H),4.07-3.85(m,3H),3.59-3.42(m,2H),3.02(br,1H),2.84-2.67(m,2H),2.03-1.78(m,1H),1.65-1.45(m,1H),1.31-1.22(m,3H).
Step 4) compound 2-methyl-3-((R)-morpholine-2-Ji) propionic acid synthesize
By 3-((R)-4-((benzyloxy) carbonyl) morpholine-2-Ji)-2 Methylpropionic acid (0.7g, 2.3mmol) be dissolved in methyl-phenoxide (14mL), at nitrogen protection 0 DEG C, add aluminum trichloride (anhydrous) (1.84g, 13.8mmol), finish, be warming up to 25 DEG C of reactions 12 hours, ice bath is lowered the temperature, drip water (20mL), add EtOAc (40mL) subsequently, layering, discard organic layer, water layer EtOAc (40mL × 4) extracts, water layer hydrogenation sodium solution (3mol/L) adjusts pH to 7, centrifugal, get supernatant liquor, concentrated supernatant obtains product crude product, white solid (0.4g, 100%).
MS(ESI,pos.ion)m/z:174.3[M+H] +.
Step 5) synthesis of compound 3-((2R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-2-Ji)-2 Methylpropionic acid
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (614mg, 1.45mmol), 2-methyl-3-((R)-morpholine-2-Ji) propionic acid (251mg, 1.45mmol), salt of wormwood (404mg, 2.89mmol) implement to obtain yellow oil (35mg, 5%) by the method described in embodiment 1 step 5 with ethanol (10mL).
MS(ESI,pos.ion)m/z:517.8[M+H] +；
1H NMR(400MHz,CDCl 3):δ9.34(d,1H),7.84(t,1H),7.41(d,3H),6.97(t,2H),3.95-3.84(m,2H),3.76-3.67(m,2H),3.62(t,2H),3.45(d,3H),2.69-2.62(m,3H),2.55-2.48(m,2H),2.43-2.30(m,3H),1.89(s,3H),1.64-1.53(m,2H).
Embodiment 11 compound 3-(2R, 3R) the synthesis of-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-2 Methylpropionic acid
Step 1) synthesis of compound (2R, 3R)-3-(3-methoxyl group-2-methyl-3-oxo third-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate
By (2R; 3S)-3-formyl radical-2-methylmorpholine-4-t-butyl formate (2.29g; 10mmol) be dissolved in DCM (100mL); 0 DEG C adds 2-(triphenylphosphine subunit) methyl propionate (3.48g; 10mmol), 25 DEG C are reacted 12 hours, concentration of reaction solution; resistates obtains colorless oil (1.59g, 53%) through column chromatographic isolation and purification (EtOAc/PE (v/v)=1/16).
MS(ESI,Pos.ion)m/z:200.1[M+H-100] +.
Step 2) synthesis of compound (2R, 3R)-3-(3-methoxyl group-2-methyl-3-oxopropyl)-2-methylmorpholine-4-t-butyl formate
By (2R, 3R)-3-(3-methoxyl group-2-methyl-3-oxopropyl-1-alkene-1-base)-2-methylmorpholine-4-t-butyl formate (1.59g, 5.3mmol) be dissolved in MeOH (50mL), add Pd/C (1.59g, 1.5mmol), atmosphere of hydrogen 25 DEG C reaction 12 hours, filter, concentrated filtrate, obtains colorless oil (1.15g, 72%).
MS(ESI,pos.ion)m/z:202.2[M+H-100] +.
Step 3) synthesis of compound 3-((2R, 3R)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-base)-2 Methylpropionic acid
(2R, 3R)-3-(3-methoxyl group-2-methyl-3-oxopropyl)-2-methylmorpholine-4-t-butyl formate (1.0g, 3.3mmol) is dissolved in ethanol (35mL), adds LiOH.H 2o (1.38g, water (35mL) solution 33mmol), 25 DEG C are reacted 30 minutes, add EtOAc (60mL) and water (30mL), drip concentrated hydrochloric acid at 0 DEG C and adjust pH to 5 ~ 6, layering, organic layer saturated aqueous common salt (100mL × 2) washs, anhydrous sodium sulfate drying, obtains colorless oil (0.9g, 90%) after concentrated.
MS(ESI,pos.ion)m/z:188.1[M+H-100] +.
Step 4) synthesis of compound 3-((2R, 3R)-2-methylmorpholine-3-base)-2 Methylpropionic acid hydrochloride
3-((2R is added in reaction flask, 3R)-4-(tert-butoxycarbonyl)-2-methylmorpholine-3-base)-2 Methylpropionic acid (0.9g, 3mmol) with Hydrochloride/ethyl acetate (4mol/L, 60mL), 25 DEG C are reacted 4 hours, concentration of reaction solution, obtains light brown oily matter (0.51g, 76%).
MS(ESI,Pos.ion)m/z:188.3[M+H] +.
Step 5) compound 3-(2R, 3R) the synthesis of-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-2 Methylpropionic acid
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (283mg, 0.67mmol), 3-((2R, 3R)-2-methylmorpholine-3-base)-2 Methylpropionic acid hydrochloride (170mg, 0.76mmol), salt of wormwood (190mg, 1.36mmol) implement to obtain yellow oil (51mg, 14%) by the method described in embodiment 1 step 5 with ethanol (10mL).
MS(ESI,pos.ion)m/z:531.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ7.89(d,1H),7.52-7.36(m,3H),6.99(t,2H),4.13-4.03(m,1H),4.01-3.89(m,2H),3.78-3.71(m,1H),3.69-3.64(m,1H),3.63-3.59(m,1H),3.57-3.50(m,1H),3.50-3.41(m,3H),3.38(d,1H),3.28-3.17(m,1H),2.83-2.62(m,2H),2.60-2.44(m,3H),2.40-2.20(m,2H),1.93-1.84(dd,3H).
The synthesis of embodiment 12 compound 5-((2R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-2-Ji) valeric acid
Step 1) synthesis of compound (R)-3-(morpholine-2-Ji) ethyl propionate
(R)-2-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base) morpholine-4-benzyl formate (3.4g is added successively in reaction flask, 10.65mmol), Pd/C (10%, 340mg) with ethanol (60mL), atmosphere of hydrogen 25 DEG C reaction 12 hours, filter, colorless oil (1.9g, 95.5%) is obtained after filtrate is concentrated.
MS(ESI,pos.ion)m/z:188.2[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ4.05(q,2H),3.70-3.67(m,2H),3.38(td,1H),3.75(d,1H),2.66-2.57(m,2H),2.37-2.27(m,3H),1.63-1.52(m,2H),1.18(t,3H).
Step 2) synthesis of compound (R)-2-(3-oxyethyl group-3 oxopropyl) morpholine-4-t-butyl formate
(R)-3-(morpholine-2-Ji) ethyl propionate (1.83g, 9.77mmol), (Boc) is added successively in reaction flask 2o (2.56g, 11.73mmol) with ethanol (40mL), 25 DEG C add triethylamine (1.48g, 14.66mmol), insulation reaction 12 hours, concentration of reaction solution, in resistates, add EtOAc (200mL), organic layer uses 1% hydrochloric acid (100mL × 2) and saturated aqueous common salt (100mL) washing successively, anhydrous sodium sulfate drying, micro-yellow oily matter (2.8g, 100%) is obtained after concentrated.
MS(ESI,pos.ion)m/z:232.3[M+H-56] +；
1H NMR(400MHz,DMSO-d 6):δ4.05(q,2H),3.80-3.67(m,3H),3.36-3.23(m,2H),2.83(br,1H),2.53(br,1H),2.43-2.30(m,2H),1.73-1.56(m,2H),1.40(s,9H),1.18(t,3H).
Step 3) synthesis of compound (R)-2-(3-hydroxypropyl) morpholine-4-t-butyl formate
Tetrahydrochysene lithium aluminium (0.43g is added successively in reaction flask, 11.34mmol), 0 DEG C adds anhydrous tetrahydro furan (40mL), drip (R)-2-(3-oxyethyl group-3 oxopropyl) morpholine-4-t-butyl formate (2.7g, anhydrous tetrahydro furan (20mL) solution 9.45mmol), drip and finish, insulation reaction 1 hour, add water (0.5mL) successively, sodium hydroxide solution (10%, 1mL) with water (1.5mL), continue stirring 30 minutes, add EtOAc (300mL), organic layer saturated aqueous common salt (150mL × 3) washs, anhydrous sodium sulfate drying, after filtrate is concentrated, resistates obtains colorless oil (1.34g through column chromatographic isolation and purification (PE/EtOAc (v/v)=2/1), 58%).
MS(ESI,pos.ion)m/z:190.2[M+H-56] +；
1H NMR(400MHz,CDCl 3):δ3.93-3.82(m,3H),3.71-3.62(m,2H),3.53(td,1H),3.41-3.35(m,1H),2.93(td,1H),2.65(dd,1H),2.12(s,1H),1.75-1.68(m,2H),1.64-1.52(m,2H),1.48(s,9H).
Step 4) synthesis of compound (R)-2-(3-oxopropyl) morpholine-4-t-butyl formate
(R)-2-(3-hydroxypropyl) morpholine-4-t-butyl formate (1.34g is added successively in reaction flask, 5.5mmol) with DCM (50mL), 0 DEG C adds Dai Si-Martin's oxygenant (2.8g, 6.6mmol), insulation reaction 1 hour, adds saturated NaHCO 3solution (50mL) cancellation is reacted, and continue stirring after 20 minutes, layering, organic layer uses saturated NaHCO successively 3solution (50mL × 2) and saturated sodium-chloride water (50mL) washing, anhydrous sodium sulfate drying, after concentrated, resistates is directly used in next step reaction.
Step 5) synthesis of compound (R)-2-(5-oxyethyl group-5-oxopentyl-3-alkene-1-base) morpholine-4-t-butyl formate
By (R)-2-(3-oxopropyl) morpholine-4-t-butyl formate (0.93g, 3.83mmol) be dissolved in DCM (50mL), 25 DEG C add (triphenylphosphine alkene) ethyl acetate (1.33g, 3.83mmol), insulation reaction 12 hours, filters, after filtrate is concentrated, resistates obtains colorless oil (0.86g, 72%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=6/1).
MS(ESI,pos.ion)m/z:214.3[M+H-100] +；
1H NMR(400MHz,CDCl 3):δ6.99-6.91(m,1H),5.87-5.81(m,1H),4.19(q,2H),3.90-3.80(m,3H),3.48(td,1H),3.37-3.31(m,1H),2.95-2.75(m,1H),2.59(t,1H),2.42-2.22(m,2H),1.69-1.58(m,2H),1.46(s,9H),1.29(t,3H).
Step 6) synthesis of compound (R)-2-(5-oxyethyl group-5-oxopentyl) morpholine-4-t-butyl formate
(R)-2-(5-oxyethyl group-5-oxopentyl-3-alkene-1-base) morpholine-4-t-butyl formate (0.86g is added successively in reaction flask, 2.74mmol), Pd/C (10%, 172mg) with ethanol (30mL), atmosphere of hydrogen 25 DEG C reaction 12 hours, filter, colorless oil (0.75g, 100%) is obtained after filtrate is concentrated.
MS(ESI,pos.ion)m/z:216.3[M+H-100] +；
1H NMR(400MHz,CDCl 3):δ4.12(q,2H),3.88-3.78(m,3H),3.48(td,1H),3.35-3.27(m,1H),2.90(td,1H),2.56(t,1H),2.29(t,2H),1.69-1.59(m,2H),1.54-1.48(m,2H),1.46(s,9H),1.43-1.31(m,2H),1.25(t,3H).
Step 7) synthesis of compound (R)-5-(4-(tertbutyloxycarbonyl) morpholine-2-Ji) valeric acid
(R)-2-(5-oxyethyl group-5-oxopentyl) morpholine-4-t-butyl formate (0.75g, 2.38mmol), ethanol (7.5mL) and LiOH.H is added successively in reaction flask 2o (1g, water (7.5mL) solution 23.8mmol), 25 DEG C are reacted 1 hour, in reaction solution, add EtOAc (180mL) and water (50mL), adjust pH to 6-7, after layering with concentrated hydrochloric acid, organic layer saturated aqueous common salt (100mL × 2) washs, anhydrous sodium sulfate drying, obtains colorless oil (0.5g, 74%) after concentrated.
MS(ESI,neg.ion)m/z:286.2[M-H] -；
1H NMR(400MHz,CDCl 3):δ9.04(br,1H),3.95-3.75(m,3H),3.50(td,1H),3.38-3.30(m,1H),2.93(td,1H),2.58(t,1H),2.36(t,2H),1.73-1.63(m,2H),1.58-1.49(m,2H),1.47(s,9H),1.44-1.34(m,2H).
Step 8) synthesis of compound (R)-5-(morpholine-2-Ji) valerate hydrochlorate
(R)-5-(4-(tertbutyloxycarbonyl) morpholine-2-Ji) valeric acid (0.5g is added successively in reaction flask, 1.74mmol), EtOAc (1mL) and Hydrochloride/ethyl acetate (4mol/L, 8mL), 25 DEG C are reacted 3 hours, filter, wash with a small amount of EtOAc, 25 DEG C of vacuum-drying 6 hours, obtain white solid (0.31g, 80%).
MS(ESI,pos.ion)m/z:188.2[M+H] +；
1H NMR(400MHz,D 2O):δ4.03(dd,1H),3.81-3.71(m,2H),3.27(t,2H),3.10(td,1H),2.85(t,1H),2.32(t,2H),1.59-1.45(m,4H),1.44-1.27(m,2H).
Step 9) synthesis of compound 5-((2R)-4-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-morpholine-2-Ji) valeric acid
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (283mg, 0.67mmol), (R)-5-(morpholine-2-Ji) valerate hydrochlorate (150mg, 0.67mmol), salt of wormwood (190mg, 1.36mmol) implement to obtain yellow oil (81mg, 23%) by the method described in embodiment 1 step 5 with ethanol (10mL).
MS(ESI,pos.ion)m/z:531.3[M+H] +；
1H NMR(400MHz,CDCl 3):δ9.44(s,1H),7.88(d,1H),7.48-7.41(m,3H),6.99(t,2H),3.92(d,1H),3.75(dd,1H),3.71-3.56(m,3H),3.49(s,3H),2.72(s,2H),2.48-2.31(m,3H),2.17-2.06(m,1H),1.92(s,3H),1.75-1.63(m,2H),1.60-1.50(m,2H),1.49-1.39(m,2H).
Embodiment 13 compound 3-((2S)-4, the fluoro-1-of 4-bis-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) pyrrolidin-2-yl) propionic acid synthesize
Step 1) synthesis of compound (R)-4,4-bis-fluoro-2-carbonyl pyrrolidine-1-t-butyl formate
By (R)-4, the fluoro-2-of 4-bis-(methylol) pyrroles-1-t-butyl formate (10g, 42.2mmol), DCM (200mL) and Dai Si-Martin's oxygenant (21.5g, 50.6mmol) implement to obtain light yellow oil (4.8g, 48%) by the method described in embodiment 5 step 1.
MS(ESI,pos.ion)m/z:180.1[M+H-56] +.
Step 2) synthesis of compound (R)-2-(3-oxyethyl group-3-oxopropyl-1-alkene-1-base)-4,4-difluoropyrrolidin-1-t-butyl formates
By (R)-4; the fluoro-2-carbonyl pyrrolidine of 4-bis--1-t-butyl formate (4.84g; 20.57mmol), DCM (120mL) and ethoxycarbonyl methylene triphenyl phosphine (8.59g; 24.69mmol) implement to obtain light yellow oil (3.83g, 61%) by the method described in embodiment 4 step 1.MS(ESI,pos.ion)m/z:206.0[M+H-100] +.
Step 3) synthesis of compound (S)-2-(3-oxyethyl group-3-oxopropyl)-4,4-difluoropyrrolidin-1-t-butyl formates
By (R)-2-(3-oxyethyl group-3-oxo third-1-alkene-1-base)-4,4-difluoropyrrolidin-1-t-butyl formate (3.8g, 12.4mmol), MeOH (80mL) and Pd/C (10%, 0.38g) implement to obtain colorless oil (3.3g, 86%) by method described in embodiment 4 step 2.
MS(ESI,pos.ion)m/z:208.1[M+H-100] +.
Step 4) compound (S)-3-(1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) propionic acid synthesize
By (S)-2-(3-oxyethyl group-3-oxopropyl)-4,4-difluoropyrrolidin-1-t-butyl formate (3.2g, 10.4mmol), ethanol (32mL) and LiOH.H 2water (32mL) solution of O (2.2g, 52.1mmol) is implemented to obtain light brown oil thing (2.53g, 87%) by the method described in embodiment 4 step 3.
MS(ESI,pos.ion)m/z:224.1[M+H-56] +.
Step 5) synthesis of compound (S)-3-(4,4-difluoropyrrolidin-2-base) propionic salt hydrochlorate
By (S)-3-(1-(tertbutyloxycarbonyl)-4,4-difluoropyrrolidin-2-base) propionic acid (2.5g, 9mmol) with Hydrochloride/ethyl acetate (4mol/L, 50mL) implement to obtain white powder (1.6g, 83%) by method described in embodiment 4 step 4.
MS(ESI,pos.ion)m/z:180.2[M+H] +；
1H NMR(600MHz,D 2O):δ4.00-3.94(m,1H),3.82(dd,1H),3.72(dd,1H),2.83-2.76(m,1H),2.57-2.47(m,2H),2.39-2.32(m,1H),2.16-2.03(m,2H).
Step 6) compound 3-((2S)-4, the fluoro-1-of 4-bis-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) pyrrolidin-2-yl) propionic acid synthesize
By 6-(brooethyl)-4-(4-fluorophenyl)-4-methyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (614mg, 1.45mmol), (2S)-4,4-difluoro-pyrrolidin-2-base) propionic salt hydrochlorate (312mg, 1.45mmol), salt of wormwood (808mg, 5.80mmol) implement to obtain yellow oil (48mg, 6%) by the method described in embodiment 1 step 5 with ethanol (20mL).
MS(ESI,pos.ion)m/z:523.8[M+H] +；
1H NMR(400MHz,CDCl 3):δ9.09(d,1H),7.84(t,1H),7.49-7.33(m,3H),7.01-6.95(m,2H),3.59(d,1H),3.50(s,1H),3.39(s,2H),3.22-3.20(m,1H),3.18-3.04(m,2H),2.55-2.43(m,1H),2.38-2.22(m,3H),1.85(s,3H),1.77-1.66(m,1H).
The synthesis of embodiment 14 compound (3S)-4-((6-(the bromo-4-fluorophenyl of 2-)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) morpholine-3-carboxylic acid hydrochloride
Step 1) synthesis of compound 2-(2-bromo-4-fluorine benzal base)-3-oxobutyrate
The bromo-4-fluorobenzaldehyde of 2-(30.0g is added in reaction flask, 147.8mmol), methyl acetoacetate (19.22g, 147.8mmol), piperidines (1.01g, 11.82mmol), acetic acid (768.9mg, 11.82mmol) with ethanol (120mL), 30 DEG C are reacted 12 hours, concentration of reaction solution, resistates obtains light yellow liquid (29.7g, 66.7%) through column chromatographic isolation and purification (PE/EtOAc (v/v)=20/1).
MS(ESI,pos.ion)m/z:301.0[M+H] +.
Step 2) synthesis of compound 2-ethanoyl-3-(bromo-4 fluorophenyls of 2-)-methyl-butyrate
CuI (16.2g is added in reaction flask, 85mmol) with anhydrous tetrahydro furan (200mL), at nitrogen protection 0 DEG C, diethyl ether solution (the 1.6mol/L of slow dropping lithium methide, 53.2mL, 85mmol), insulation reaction was cooled to-78 DEG C after 1 hour, drip 2-(2-bromo-4-fluorine benzal base)-3-oxobutyrate (10.0g, anhydrous tetrahydro furan (50mL) 34.0mmol), drip and finish, insulation reaction 1 hour, add saturated ammonium chloride solution (50mL), EtOAc (100mL × 2) extracts, organic layer saturated aqueous common salt (50mL × 2) washs, anhydrous sodium sulfate drying, after concentrated, resistates obtains light yellow oil (7.98g through column chromatographic isolation and purification (PE/EtOAc (v/v)=20/1), 73.9%).
MS(ESI,neg.ion)m/z:315.0[M-H] -.
Step 3) compound 2-ethanoyl-3-(the bromo-4-fluorophenyl of 2-)-2-butylene acid methyl esters synthesis
By 2-ethanoyl-3-(bromo-4 fluorophenyls of 2-)-methyl-butyrate (14.0g, 44.2mmol) be dissolved in anhydrous tetrahydro furan (200mL), sodium hydride (60% is added under nitrogen protection, 2.65g, 66.3mmol), 25 DEG C drip tetraphenylphosphonium chloride selenium (12.7g, tetrahydrofuran (THF) (50mL) solution 66.3mmol), drip and finish, insulation reaction 1 hour, add the mixed solvent (150mL of PE/ ether, v/v=1/1), use saturated sodium bicarbonate solution (60 mL) and saturated aqueous common salt (50mL) washing successively, concentration of organic layers, add DCM (150mL), H 2o 2solution (30%, 14mL), 25 DEG C are reacted 2 hours, add DCM (100mL), organic phase uses saturated sodium bicarbonate solution (60mL) and saturated aqueous common salt (60mL) washing successively, anhydrous sodium sulfate drying, after concentration of organic layers, resistates obtains light yellow liquid (10.0g, 71%) through column chromatographic isolation and purification (EtOAc/ normal hexane (v/v)=1/20).
MS(ESI,pos.ion)m/z:315.00[M+H] +.
Step 4) synthesis of compound 4-(bromo-4 fluorophenyls of 2-)-4,6-dimethyl-2-(thiazol-2-yl)-Isosorbide-5-Nitraes-dihydro-pyrimidin-5-methyl-formiate
By 2-thiazole amitraz hydrochloride (10.4g, 63.6mmol) with sodium bicarbonate (10.7g, 127.2mmol) be dissolved in N-Methyl pyrrolidone (200mL), be warming up to 120 DEG C, drip 2-ethanoyl-3-(the bromo-4-fluorophenyl of 2-)-2-butylene acid methyl esters (10.0g, N-Methyl pyrrolidone (10mL) solution 31.8mmol), insulation reaction 5 hours, be cooled to 30 DEG C, add water (300mL), EtOAc (600mL) extracts, after organic layer is concentrated, resistates obtains yellow solid (1.28g through column chromatographic isolation and purification (EtOAc/ normal hexane (v/v)=1/3), 10.0%).
MS(ESI,pos.ion)m/z:424.0[M+H] +.
Step 5) synthesis of compound 4-(bromo-4 fluorophenyls of 2-)-6-(brooethyl)-4-methyl-2-(thiazol-2-yl)-Isosorbide-5-Nitrae-dihydro-pyrimidin-5-methyl-formiate
By 4-(bromo-4 fluorophenyls of 2-)-4,6-dimethyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (0.5g, 1.18mmol) be dissolved in DCM (30mL), 40 DEG C add NBS (0.23g, 1.3mmol), insulation reaction 30 minutes, concentration of reaction solution obtains yellow oil (0.3g, 50%).
Step 6) synthesis of compound (3S)-4-((6-(the bromo-4-fluorophenyl of 2-)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) morpholine-3-formic acid
4-(bromo-4 fluorophenyls of 2-)-6-(brooethyl)-4-methyl-2-(thiazol-2-yl)-1 is added in reaction flask, 4-dihydro-pyrimidin-5-methyl-formiate (0.24g, 0.47mmol), (S)-3-morpholine formic acid (61.6mg, 0.47mmol), salt of wormwood (129.9mg, 0.94mmol) implement to obtain yellow oil (25mg, 9.1%) by the method described in embodiment 1 step 5 with dehydrated alcohol (20mL).
MS(ESI,pos.ion)m/z:552.05[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ8.14(d,2H),7.69(dd,1H),7.56(d,1H),7.29(td,1H),4.17(s,3H),4.03(d,4H),3.83(s,3H),3.34(d,3H),2.02(d,3H).
Embodiment 15 compound (2S)-1-((6-(the bromo-4-fluorophenyl of 2-)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base)-methyl) synthesis of-4,4-difluoropyrrolidin-2-formic acid
4-(bromo-4 fluorophenyls of 2-)-4-methyl-6-brooethyl-2-(thiazol-2-yl)-1 is added successively in reaction flask, 4-dihydro-pyrimidin-5-methyl-formiate (0.6g, 1.18mmol), (S)-4,4-difluoropyrrolidin-2-carboxylic acid hydrochloride (0.22g, 1.18mmol), salt of wormwood (0.33g, 2.36mmol) implement to obtain yellow solid (0.17g, 24.3%) by the method described in embodiment 1 step 5 with dehydrated alcohol (20mL).
MS(ESI,pos.ion)m/z:573.05[M+H] +；
1H NMR(400MHz,DMSO-d 6):δ8.03(d,2H),7.68(s,1H),7.51(s,1H),7.27(s,1H),4.20-3.83(m,3H),3.78 (d,1H),3.46(d,1H),3.32(s,2H),3.16(d,1H),2.76(s,1H),2.46-2.35(m,1H),2.05-1.85(m,3H).
Embodiment 16 compound (2R, 3S) the synthesis of-4-((6-(the bromo-4-fluorophenyl of 2-)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl)-2-methylmorpholine-3-formic acid
By 4-(the bromo-4-fluorophenyl of 2-)-4-methyl-6-brooethyl-2-(thiazol-2-yl)-1,4-dihydro-pyrimidin-5-methyl-formiate (0.6g, 1.18mmol), (2R, 3S)-2-methylmorpholine-3-formic acid (0.17g, 1.18mmol), salt of wormwood (325.7mg, 2.36mmol) implement to obtain yellow solid (0.1g, 15%) by the method described in embodiment 1 step 5 with dehydrated alcohol (20mL).
MS(ESI,pos.ion)m/z:567.1[M+H] +；
1H NMR(600MHz,DMSO-d 6):δ8.03(d,2H),7.68(s,1H),7.51(s,1H),7.27(s,1H),4.20-3.83(m,3H),3.78(d,1H),3.46(d,1H),3.32(s,2H),3.16(d,1H),2.76(s,1H),2.46-2.35(m,1H),2.05-1.85(m,3H).
Embodiment 17: carry out external Anti-HBV activity drug activity determination experiment with HBV HepG2.2.15 cell strain
1, experimental technique:
QPCR detects cell culture fluid viral DNA content computerized compound to the concentration (EC of HIV suppression one half 50), specific experiment method is as follows:
Inoculation HepG2.2.15 cell is to 96 porocyte culture plates (40,000 cells/well), (the highest final concentration of compound is 16.4 μMs, 3 times of gradient dilutions within second day, to add the cell culture fluid process cell of different concns testing compound, 9 dilution point, duplicate hole).Within 5th day, change the nutrient solution containing medicine to be measured, within the 8th day, collect culture supernatant and the DNA extracted in supernatant.
Viral DNA extracts: with reference to QIAamp 96DNA Blood Kit (QIAGEN 51161).
Quantitative PCR: according to PCR system configuration reaction mixture, mixed solution is added 96 hole PCR Sptting plates (quantitatively special); (standard substance template maximum concentration is 1 × 10 to add the standard substance template of having diluted in proportion 7copy number/μ l, 9 times of dilutions, 7 points, minimum concentration is 10 copy numbers/μ l); Add sample form; With shrouding film, 96 orifice plates are sealed up; Quantitative PCR apparatus is run according to setting program.
Compound calculates hbv replication inhibition percentage: %Inh.=[1-adds compound treatment HBV DNA amount/DMSO control treatment HBV DNA and measures] × 100.
Computerized compound is to the EC of hbv replication 50value: application GraphPad Prism 5 analysis software, selects " four parameter logistic equation " thus calculates EC 50value.
2, experimental result: in table 2
Table 2: compound is at the Anti-HBV effect of HBV HepG2.2.15 cell strain
Embodiment EC 50(μmol) Embodiment EC 50(μmol)
Embodiment 1 0.4 Embodiment 7 0.09
Embodiment 2 0.3996 Embodiment 9 0.12
Embodiment 4 0.8 Embodiment 10 0.45
Embodiment 5 1.0 Embodiment 12 0.6
Embodiment 6 0.9 Embodiment 13 0.4
3, conclusion:
Compound of the present invention demonstrates the effect of stronger resisting HBV virus.This compounds has antiviral activity beyond expectation to HBV, is therefore applicable to the various diseases for the treatment of because HBV virus infection causes.
Embodiment 18: the PK determination experiment of test compounds in ICR Mice Body
1, experimental technique:
ICR its mouse oral gavage gives 10mg/kg or the test compounds through tail vein injection 2mg/kg.
After administration, temporally point (0.083,0.25,0.5,1,2,4,6,8 and 24 hour) orbital vein blood sampling, is collected in and adds EDTA-K 2anticoagulant tube in.Plasma sample, after liquid-liquid extraction, on triple quadrupole bar tandom mass spectrometer, carries out quantitative analysis in multiple reaction ion monitoring (MRM) mode.The non-compartment model method of WinNonlin 6.3 software is adopted to calculate pharmacokinetic parameters.
2, experimental result: in table 3:
Table 3: the PK data of compound in ICR Mice Body
Note: Roche-11-(2S)-4, the fluoro-1-of 4-bis-((6-(4-fluorophenyl)-5-(methoxycarbonyl)-6-methyl-2-(thiazol-2-yl)-3,6-dihydro-pyrimidin-4-base) methyl) pyrroles-2-formic acid (specifically synthesizing see patent WO2013144129A1); N/A-expression does not carry out correlation detection; AUC lastthe AUC of-0-24h; AUC iNFthe AUC of-0-infinite time;
Table 3 result shows: after the administration of ICR mouse stomach, and embodiment 1 is rapid at mouse body absorption, and the peak time in blood plasma is 0.083 hour, the AUC of embodiment 1 lastfor 1430hr*ng/mL exposed amount is better, apparently higher than Roche-11, illustrate that the absorption of compound in Mice Body is good.After intravenously administrable, the clearance rate of embodiment 1 is 4.68L/h/Kg, and apparent steady state distribution volume is 0.41L/kg.With the AUC of embodiment lastcalculate, the absolute bioavailability that mouse stomach gives 10mg/kg embodiment 1 is respectively 67.14%, and bioavailability is better, higher than 31% of Roche-11.
Although above with general explanation, embodiment and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.

Claims (14)

1. a compound, its enantiomer for compound shown in the compound shown in formula (I) or (Ia) or formula (I) or (Ia), diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt
Wherein, R 1for C 6-10aryl or C 1-9heteroaryl;
R 3for C 6-10aryl or C 1-9heteroaryl;
A is a key ,-O-,-S-or-N (R 5)-;
Each R 2and R 5be hydrogen or C independently 1-4alkyl;
R is following subformula:
Wherein, be-(CR 8r 8a) m-N (R 8)-,-(CR 8r 8a)-O-(CR 8r 8a) 2-,-(CR 8r 8a) m-S (=O) q-or-(CR 7r 6) m-O-;
Q is-(CR 8r 8a) m-;
X is-(CR 8r 8a) n-(CR 8r 9)-(CR 8r 8a) n-,-(CR 8r 9a) n-(CR 8r 8a) m-,-(CR 8r 8a) n-(CR 8r 9)-O-or-(CR 8r 9a) n-(CR 8r 8a) m-O-;
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino or alkyl independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or alkyl independently;
Each R 6be alkyl independently; Or R 6and R 7cycloalkyl or heterocyclic radical is formed together with the carbon atom be attached thereto;
Each R 8and R 8abe hydrogen, cyano group or alkyl independently, or R 8aand R 8cycloalkyl or heterocyclic radical is formed together with the carbon atom be attached thereto;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, halogen, haloalkyl or alkyl independently, or R 10aand R 10form cycloalkyl or heterocyclic radical together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, alkyl, alkoxyl group, hydroxyl, alkyl-S (=O) independently q-, aryl, heteroaryl, cycloalkyl, heterocyclic radical, heterocyclic radical-S (=O) q-, heteroaryl-S (=O) q-, arylalkyl, cycloalkyl-S (=O) q-or aryl-S (=O) q-;
Each n is 1,2,3 or 4 independently;
Each m is 0,1,2,3 or 4 independently;
Each q is 0,1 or 2 independently;
Wherein, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 8a, R 9, R 9a, R 10, R 10aand R 11described in alkoxyl group, alkyl-S (=O) q-, heterocyclic radical-S (=O) q-, heteroaryl-S (=O) q-, cycloalkyl-S (=O) q-, aryl-S (=O) q-, aryl, C 6-10aryl, heteroaryl, C 1-9heteroaryl, alkyl, C 1-4alkyl, cycloalkyl, heterocyclic radical, arylalkyl, haloalkyl, triazolyl and tetrazyl can optionally by hydrogen, fluorine, chlorine, bromine, iodine, oxo (=O), methylene radical (=CH 2), monosubstituted or identical or different polysubstituted of alkyl, alkoxyl group, cyano group, aryl, heteroaryl, cycloalkyl, heterocyclic radical ,-COOH, hydroxyl, nitro, alkylamino, amino, trifluoromethyl, trifluoromethoxy, the haloalkyl aryl, the aryl of halogen substiuted or the trifyl that replace.
2. compound according to claim 1, wherein,
R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino or C independently 1-4alkyl, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or C independently 1-4alkyl;
Each R 6be C independently 1-4alkyl; Or R 6and R 7c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 8and R 8abe hydrogen or C independently 1-4alkyl, or R 8aand R 8c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, C independently 1-4haloalkyl or C 1-4alkyl, or R 10aand R 10c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, hydroxyl, C 1-4alkyl-S (=O) q-, C 6-10aryl, C 1-9heteroaryl, C 3-6cycloalkyl, C 2-9heterocyclic radical, C 2-9heterocyclic radical-S (=O) q-, C 1-9heteroaryl-S (=O) q-, C 6-10aryl C 1-4alkyl, C 3-6cycloalkyl-S (=O) q-or C 6-10aryl-S (=O) q-.
3. according to the compound shown in claim 2, wherein,
R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl or propyl group independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen, methyl, ethyl or propyl group independently;
Each R 6be methyl, ethyl or propyl group independently; Or R 6and R 7cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl is formed together with the carbon atom be attached thereto;
Each R 8and R 8abe hydrogen, methyl, ethyl or propyl group independently, or R 8aand R 8cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl is formed together with the carbon atom be attached thereto;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl or propyl group independently, or R 10aand R 10form cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, C 1-4alkyl-S (=O) 2-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrryl, pyrimidyl, pyridazinyl, di azoly, triazolyl, tetrazyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyrazinyl, pyranyl, triazinyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-or phenyl-S (=O) 2-.
4. compound according to claim 1, wherein,
R 1for phenyl;
Each R 2and R 5be hydrogen, methyl or ethyl independently;
R 3for pyridyl, oxazolyl, isoxazolyl, thienyl, furyl, thiazolyl or 1-methyl isophthalic acid H-imidazolyl;
A is-O-;
Wherein, R 1, R 2, R 3and R 5described in pyridyl, oxazolyl, isoxazolyl, thienyl, furyl, thiazolyl, 1-methyl isophthalic acid H-imidazolyl, phenyl, methyl and ethyl can optionally by hydrogen, C 1-4monosubstituted or identical or different polysubstituted of alkyl, fluorine, chlorine or bromine.
5. compound according to claim 1, its enantiomer for compound shown in the compound shown in formula (II) or (IIa) or formula (II) or (IIa), diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt
Wherein, R 2for hydrogen or C 1-4alkyl;
R 3for thiazolyl or 1-methyl isophthalic acid H-imidazolyl;
R is following subformula:
Each R 4be hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl or propyl group independently, or as two R 4when being connected to same carbon atom, R 4and R 4following group is formed :-C (=CH together with the carbon atom be attached thereto 2)-;
Each R 7be hydrogen or C independently 1-4alkyl;
Each R 6be C independently 1-4alkyl; Or R 6and R 7c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 8and R 8abe hydrogen or C independently 1-4alkyl, or R 8aand R 8c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical;
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, C independently 1-4haloalkyl or C 1-4alkyl, or R 10aand R 10c is formed together with the carbon atom be attached thereto 3-6cycloalkyl or C 2-9heterocyclic radical, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, hydroxyl, C 1-4alkyl-S (=O) 2-, C 6-10aryl, C 1-9heteroaryl, C 3-6cycloalkyl, C 2-9heterocyclic radical, C 2-9heterocyclic radical-S (=O) 2-, C 1-9heteroaryl-S (=O) 2-, C 6-10aryl C 1-4alkyl, C 3-6cycloalkyl-S (=O) 2-or C 6-10aryl-S (=O) 2-;
Each R 12be hydrogen, fluorine, chlorine or bromine independently;
Each q is 0,1 or 2 independently;
Each n is 1,2,3 or 4 independently;
Each m is 0,1,2,3 or 4 independently.
6. compound according to claim 1 or 5, wherein,
R is following subformula:
Each R 9be-(CR independently 10r 10a) m-OH, triazolyl, tetrazyl ,-(CR 10r 10a) m-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) m-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) m-C (=O) N (R 11) 2;
Each R 9abe triazolyl ,-(CR independently 10r 10a) n-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-R 11,-(CR 10r 10a) m-S (=O) qn (R 11) 2,-(CR 10r 10a) m-N (R 11) 2,-S (=O) qoR 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O) O-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-OC (=O)-R 11,-(CR 10r 10a) n-C (=O) O-(CR 10r 10a) m-C (=O) O-R 11or-(CR 10r 10a) n-C (=O) N (R 11) 2;
Each R 10and R 10abe hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, ethyl or propyl group independently, or R 10aand R 10form cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl together with the carbon atom be attached thereto, or form following group :-C (=O)-;
Each R 11be hydrogen, C independently 1-4alkyl, C 1-4alkoxyl group, C 1-4alkyl-S (=O) 2-, phenyl, pyridyl, thiazolyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrryl, pyrimidyl, pyridazinyl, di azoly, triazolyl, tetrazyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl group, pyrazinyl, pyranyl, triazinyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclopropyl-S (=O) 2-, cyclobutyl-S (=O) 2-, cyclopentyl-S (=O) 2-, cyclohexyl-S (=O) 2-, naphthyl-S (=O) 2-or phenyl-S (=O) 2-.
7. compound according to claim 1, its comprise following one of them structure or the enantiomer of one of them structure, diastereomer, tautomer, hydrate, solvate, prodrug, steric isomer, oxynitride or pharmacy acceptable salt:
8. a pharmaceutical composition, it comprises the compound described in any one of claim 1-7, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
9. pharmaceutical composition according to claim 8, it comprises Anti-HBV drugs further.
10. pharmaceutical composition according to claim 9, wherein, described Anti-HBV drugs is HBV AG14361, immunomodulator or Interferon, rabbit.
11. pharmaceutical compositions according to claim 9, wherein, described Anti-HBV drugs is for being selected from lamivudine, Telbivudine, tenofovir disoproxil, Entecavir, adefovir ester, Alfaferone, Alloferon, celmoleukin, Clevudine, emtricitabine, Fa Puluowei, Interferon, rabbit, Bao Ganling CP, Recomvinated Interferon α-2a, interferon α-1b, interferon alpha, Intederon Alpha-2a, interferon beta-1a, interferon α-2, interleukin II, mivotilate, nitazoxanide, Peg-IFN alpha-2b α-2a, virazole, Wellferon-A, sizofiran, Euforavac, Puli is near for peace, Phosphazid, Heplisav, Interferon Alpha-2b, at least one in LEVAMISOLE HCL and propagermanium.
Described in compound described in 12. any one of claim 1-7 or any one of claim 8-11, pharmaceutical composition is preparing the purposes in medicine, and described medicine is used for preventing, process, treat or alleviate disease viral disease.
13. purposes according to claim 12, wherein, described virus disease refers to the disease that hepatitis B infection or hepatitis B infection cause.
14. purposes according to claim 13, wherein, described hepatitis B infection causes disease to refer to liver cirrhosis or canceration of hepatic cell.
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