WO2010069147A1 - Dihydropyrimidine derivatives, compositions thereof and their use - Google Patents

Dihydropyrimidine derivatives, compositions thereof and their use Download PDF

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Publication number
WO2010069147A1
WO2010069147A1 PCT/CN2009/001489 CN2009001489W WO2010069147A1 WO 2010069147 A1 WO2010069147 A1 WO 2010069147A1 CN 2009001489 W CN2009001489 W CN 2009001489W WO 2010069147 A1 WO2010069147 A1 WO 2010069147A1
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group
dihydropyrimidine
methyl
carboxylate
alkyl
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PCT/CN2009/001489
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French (fr)
Chinese (zh)
Inventor
戈尔德曼⋅西格氟里德
卢妍莲
李静
张英俊
符兆林
卢轩
林淘曦
罗忠华
陈燕桂
Original Assignee
张中能
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Publication of WO2010069147A1 publication Critical patent/WO2010069147A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention provides a novel dihydropyrimidine compound, a process for its preparation and its use as a medicament for the preparation of a medicament for the treatment and prevention of viral diseases, in particular as a medicament for the preparation of a medicament for the treatment and prevention of hepatitis B virus infection.
  • the invention further relates to the use of these dihydropyrimidine other antiviral agents, where appropriate, immunomodulatory agents, and compositions containing these compositions for the treatment and prevention of viral hepatitis, especially hepatitis B. Background technique
  • Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis B virus also causes many other clinical signs in pathology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
  • Interferon and lamivudine are conventional drugs approved for the treatment of chronic hepatitis.
  • interferon is only moderately active and has harmful side effects; although lamivudine has good activity as a new drug, its resistance develops rapidly during treatment and stops treatment.
  • the rebound effect is often followed by WO 99/54312, 99/54326, 99/54329 and US 7074784 relating to the use of a dihydropyrimidine for the treatment and prevention of hepatitis virus infection.
  • the patent US7074784 example discloses a 1,4 dihydropyrimidine compound substituted with a 2-position halopyridyl group and a 6-position basic group.
  • Halogenated ring systems are sensitive to nucleophilic materials such as amines such as morpholine. We have found that the replacement of the two substituents with the other heterocyclic compounds gives better activity and better chemical stability against nucleophilic attack than the previously disclosed compounds.
  • Another object of the present invention is to provide a method for preparing dihydropyrimidine compounds.
  • a further object of the present invention is to provide a medicament containing a dihydropyrimidine compound as a medicament for the preparation of a medicament for the treatment and prevention of a viral disease, in particular as a medicament for the preparation of a medicament for the treatment and prevention of hepatitis B virus infection.
  • 1 represents hydrogen, amino, nitro, cyano, F, Cl, Br, 1, hydroxy, trifluoromethyl, trifluoromethoxy or benzyl; or ⁇ -0: 6 thiol, Alkoxy group of C!-Cs, ⁇ oxycarbonyl group of C,-C 6 , alkylamino group of dC 6 , dialkylamino group of -C 6 , amide group of CC 6 , acyloxy group of -C 6 , An acyl group of C 6 , an alkylthio group of dC 6 , an alkylsulfonyl group of C, -C 6 or an alkanoyl group of - or an unsubstituted pyridine group; or a phenyl group, a naphthyl group, a thio group, a pyridyl group, a thienyl group, Oryl, pyrrolidinyl, imidazolyl,
  • R 2 represents hydrogen, amino, nitro, cyano, F, Cl, Br, I , hydroxy, trifluoromethyl, trifluoromethoxy or benzyl; or - (6-alkyl, C, -C 6 Alkoxy, C,-C 6 alkoxycarbonyl, dC 6 alkylamino, C r C 6 dinonylamino, C,-C 6 amide, C,-C 6 acyloxy , an acyl group of d-Ce, an alkylthio group of dC 6 , an alkylsulfinyl group of C,-C 6 or an alkylsulfonyl group of -C 6 ; or a phenyl group, a naphthyl group, containing 1-5 selected from N, S a heteroatom of 5-12 atoms substituted by a hetero atom of O, wherein the heteroaryl group is pyridinyl, quinolyl, pyrimidinyl, fu
  • A represents a key, -0-, -S -, or -NRu -, where! ⁇ is an alkoxycarbonyl group of ⁇ -C 6 , or a linear, branched, or cyclic saturated or unsaturated C 8 hydrocarbon group, wherein the hydrocarbon group optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH-(-alkyl), -N-(d-alkyl) 2 , the same or different heterochain units, and optionally halogen, nitro, cyano, hydroxy, having 6-10 An aryl group of carbon atoms, an aralkyl group having 6 to 10 carbon atoms or a heteroaryl group;
  • R 3 represents an alkoxycarbonyl group of H, or a linear, branched, or cyclic saturated or unsaturated C,-C 8 hydrocarbon group, or the hydrocarbon group thereof optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH- (-alkyl), -N-(d-alkyl) 2 , the same or different hetero chain units, and optionally halogen, nitro, cyano, hydroxy, having An aryl group of 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula 1 12 1
  • R represents hydrogen, amino, methyl, and when R is methyl, R is a substituent other than unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl or imidazolyl; or R represents
  • Z represents a halogen, and when Z is Br and X is -CH 2 -, it cannot be a thiazol-2-yl group and an unsubstituted pyridyl group;
  • 1 20 represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocyclic ring, C,-C 8 fluorenyl group, C r C 8 alkoxy group, -Cs alkylthio group, C r C 8 alkylsulfinyl, -Cs sulfonyl, C r C acyl, nitro, trifluoromethyl 8 or -CO-N (R 20) 2 , wherein R 2 o can be H or An alkyl group of CrC 8 ;
  • R is morpholin-4-yl-methyl, thiazol-2-yl, R 3 is -CH3, when A is 0, R 2 is not 2,4-dichloro-phenyl;
  • the C 1 -C8 alkyl group means a group having 1-8 carbon atoms in a straight or branched chain, wherein the alkyl group may be independently and optionally optionally substituted by one or more substituents described in the present invention. Replace. A straight or branched alkyl group having 1 to 4 carbon atoms is preferred.
  • Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl and n-hexyl, etc. .
  • aryl may be used alone or as a large part of "aralkyl” “aralkyloxy” or “aryloxyalkyl", unless otherwise specified, aryl means a total of 6-10 membered rings.
  • aryl may be used interchangeably with the term “aromatic ring”, as an aromatic ring may include phenyl, naphthyl.
  • the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thieny
  • aralkyl includes aryl substituted alkyl groups.
  • an arylalkyl group refers to a "lower aralkyl” group, i.e., an aryl group attached to a C1-6 alkyl group.
  • the acyl group of Cr represents a linear or branched acyl group having 1-8 carbon atoms, preferably a linear or branched acyl group having 1 to 6 carbon atoms, and particularly preferred acyl groups are acetyl group and propionyl group.
  • the alkenyl group of C 2 -C 4 represents a linear or branched alkenyl group having 2 to 4 carbon atoms, preferably a vinyl group or a propenyl group.
  • the decyloxy group of -Cs represents a linear or branched alkoxy group having 1-8 carbon atoms, preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, more preferably a methoxy group, Oxy or propoxy.
  • the alkylthio group of -C 8 represents a linear or branched alkylthio group having 1 to 8 carbon atoms, preferably a linear or linear alkylthio group having 1 to 6 carbon atoms, more preferably a methylthio group, Ethylthio or propylthio.
  • the alkoxycarbonyl group of C r C 8 represents a straight-chain or branched playk-like carbonyl group having 1-8 carbon atoms, preferably a linear or linear fluorenyloxycarbonyl group having 1 to 4 carbon atoms, more preferably a methoxy group. Carbonyl, ethoxycarbonyl or propoxycarbonyl.
  • C r C 8 hydrocarbon group include the aforementioned C r C alkyl, C r C 8 alkenyl group 8, C 3 -C 8 cycloalkyl, preferably ( ⁇ - (8 alkyl.
  • the cycloalkyl group of C r C 8 represents a cyclopropyl group, a cyclopentyl group, a cyclobutyl group or a cyclohexyl group, preferably a cyclopropyl group.
  • the compound of the present invention includes the formula (1) or its isomer (la) or a mixture thereof.
  • the isomer of formula (I) generally refers to its tautomer or optical isomer.
  • the isomers (1) and (la) can exist in equilibrium with tautomers. If R4 is hydrogen, the isomers (I) and (la) can exist as tautomers:
  • the compounds of the present invention may exist in the form of optical isomers which are in enantiomeric or diastereomeric relationship between the optical isomer forms.
  • the invention relates to these enantiomers or diastereomers and mixtures thereof.
  • the racemate can be resolved into a single component of a stereoisomer by known methods, such as the introduction of other chiral groups in the molecule of the inventive compound to give optically pure enantiomers. body.
  • the compounds of the invention may also be in the form of a salt, the physiologically acceptable salts of which are preferred in the present invention.
  • the physiologically acceptable salt may be a mineral acid salt or an organic acid salt.
  • inorganic acid salts such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or organic carboxylic acids or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, a salt formed from lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalene-disulfuric acid.
  • the physiologically acceptable salt may also be a metal or ammonium salt of a compound of the invention.
  • Particularly preferred are sodium, potassium, magnesium, or calcium salts, and from ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, fine
  • Some of the compounds of the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the present invention includes those stoichiometric solvates, including hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
  • Z represents halogen, when Z is Br and X is -CH r , R, cannot be thiazol-2-yl and unsubstituted pyridyl;
  • Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl, Or NR 14 R I 5 , wherein R l4 and R l5 may be the same or different and represent a fluorenyl group of CC 4 which is optionally substituted by a hydroxy, alkoxycarbonyl group, or R l4 , R l 5 and The N atom bond synthesizes a heterocyclic ring which is: imidazole, triazole, tetrazole or a group represented by the following formula:
  • Y represents CH r , -CH 2 -CH 2 - , - 0, -8, -50-, 80 2 - or NR 16 , wherein R 16 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l 7 or CO-NR 18 R 19 , R l 7 , R 18 > R l 9 may be the same or different and represent H or C 1 -C 8 fluorenyl;
  • R 20 represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocycle , d- the embankment group, C r of the embankment group, dC 4 alkylthio, d- alkyl sulfinyl, C r C 4 alkylsulfonyl, dC 4 acyl,
  • Some of the examples are alkyl, nitro, F, Cl, Br, hydroxy, trifluoromethyl, CrC 4 alkyl, or unsubstituted pyridyl in formula (I) and (la); or phenyl , thiazolyl, pyrimidinyl, thienyl, furanyl, pyrrolidinyl, imidazolyl, thiazinyl; or the same or different substituents wherein the above ring system is selected from the group consisting of up to 3 substitutions: Base, amino, F, Cl, Br, hydroxy, trifluoromethyl, benzyl, -alkyl, d-alkoxy, -alkoxycarbonyl, C amide, dC 4 acyloxy; R 2 represents an amino group, a nitro group, a F, Cl, Br, a hydroxyl group, a trifluoromethyl group, an alkyl group of dC 4 ; or a phenyl group, or
  • Z represents halogen, when Z is Br, and X is -CH r , R is not a thiazol-2-yl group and an unsubstituted pyridyl group.
  • Z represents phenylbenzenesulfonyloxy, decanoyloxy, pyridyl, , Or NR 14 R 15, wherein R 14 and R l 5 identical or different, represent alkyl, said alkyl optionally substituted by hydroxy, C r C 3 alkoxycarbonyl substituent, or R 14, R I 5 and N atom bond to synthesize a heterocyclic ring, which is: imidazole, triazole, tetrazole or a group represented by the following formula:
  • Y represents CH 2 -, -CH 2 -CH 2 -, -0, -S, -SO-, S0 2 - or NR 16 , wherein R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l 7 or CO-NR 18 R 19 , wherein R 17 , R I 8 , R l9 The same or different, representing an alkyl group of ⁇ or -C 4 ; R 20 represents hydrogen, halogen, cyano, azide, amino,
  • Some of the examples are represented by the formula (I) and Ua) ( ⁇ -(: 3 alkyl, or unsubstituted pyridyl; or phenyl, thiazolyl, pyrimidinyl, thienyl, furyl, imidazolyl)
  • the above ring system is the same or different substituents selected from the group consisting of up to 3 substitutions: nitro, amino, F, Cl, Br, trifluoromethyl, -C 3 alkyl;
  • R 2 An alkyl group representing CrC 3 , or a phenyl group, or a C 5 -C 6 heteroaryl group substituted with 1 to 2 hetero atoms selected from N, S, O, which is a pyridyl group or a pyrimidinyl group Or a thienyl group, an oxazolyl group or a thiazolyl group, wherein the above ring system is the same or different substituents selected from the group consisting of up
  • Z represents methyl sulfonyloxy, methylsulfonyloxy, pyridyl, Or a NR 14 R 1
  • Some of the examples are the same or different substituents of the formula U) and (la) which represent a phenyl group, a thienyl group, a furyl group, an imidazolyl group, or a ring system selected from the group consisting of the following groups, up to 2 substitutions.
  • R 2 represents a phenyl group, which is selected from the same or different substituents of the following groups, up to 3 substitutions: F , Cl, Br, trifluoromethyl, C, -C 3 alkyl, the alkyl is substituted by halogen;
  • A represents -0-, -NR u -, wherein R u represents hydrogen or C, -C 4 alkyl group; R.
  • R 3 represents hydrogen, C r C 4 alkyl group;
  • R, R I5 and N atom bond to form a heterocyclic ring which is a group represented by the following formula:
  • Y represents -0, -S, -SO-, SO r or NR I6 , and
  • R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , - CO-0-R,7 or CO-NR l8 R l9 , R 17 , R, 8 , R l9 may be the same or different, represent an alkyl group of H or C!-C),
  • R 20 represents hydrogen, halogen;
  • Base represents hydrogen.
  • R1 in the formulae (I) and (la) represents a thienyl group, a furyl group, an imidazolyl group, and the above ring system is the same or different substituents selected from the group consisting of up to 2 substitutions: F, Cl, ⁇ , - ⁇ : 3 alkyl
  • R 2 represents a phenyl group, the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br, trifluoromethyl
  • A represents -0-, -NH-
  • R 3 represents hydrogen, C'-alkyl
  • R represents -CH 3 , wherein when R is methyl, it cannot be unsubstituted pyridyl, thiazolyl, substituted phenyl , furanyl, thienyl, imidazolyl
  • R represents -XZ, X represents -CH r ;
  • Z represents Br, when Z is Br, and X is -CH r , it cannot
  • Y represents -0, -S, -SO-, SO r or NR I6 , and
  • R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , - CO-0-R l7 or CO-NR 18 R l9 , wherein R l7 , R l8 , R l9 may be the same or different and represent an alkyl group of H or -, and 11 ⁇ 2 represents hydrogen; in the above definition, when R is morpholine 4-yl-methyl, R, is thiazol-2-yl, R 3 is -CH 3 , when A is 0, R 2 is not 2,4-dichloro-phenyl; represents hydrogen.
  • Some of the examples are represented by the formula (1) and (la), wherein the above ring system is the same or different substituents selected from the group consisting of the following groups: up to 2 substitutions: F , CI. Br; R 2 represents a phenyl group, the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br; A represents -0-, -NH-; R 3 represents hydrogen, (: alkyl, R 2 represents 1 -CH 3, wherein when R is methyl, ⁇ is not unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl, imidazolyl; or represents -XZ, X represents -CH r , Z represents Br, when Z is Br, X is -CH 2 -, it cannot be thiazol-2-yl and unsubstituted pyridyl; or Z represents toluenesulfonyloxy, methyls
  • Y represents -0, -S, -SO-, SO r , NR, 6 , and R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l7 or CO-NR 18 R 19 , wherein R 17 , R, 8 , R l9 may be the same or different, represent an alkyl group of H or d-, and R 20 represents hydrogen; in the above definition, R is morpholin-4-yl-methyl, R is thiazol-2-yl, R 3 is -CH 3 , and when A is 0, R 2 is not 2,4-dichloro-phenyl; represents hydrogen.
  • the compound of the formula (I) and (la) of the present invention or a salt or hydrate thereof may also be a specific compound: 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl) -methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester, 4-(2-chloro-4-fluorophenyl)-6-(morpholine-4 -yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2,4-dichlorophenyl)-6- (morpholine- 4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2-bromophenyl)-6-(monooxythio?
  • the compound of the present invention of the formula (I) or (la) can be produced by the following method:
  • R 2 , R 3 , and R have the same meanings as defined above;
  • R, R4 have the same meaning as before, or
  • R, R 2 , R 3 , , X and Z have the same meanings as defined above, and W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyloxy, And a compound represented by the formula (IX) or (III)
  • a compound represented by the formula (Va) can be reacted with a compound of the formula (IX) or (hydrazine) to prepare a corresponding ⁇ -ketocarboxylic acid.
  • the ester (V), which cannot be prepared by this method, is commercially available.
  • W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyloxy.
  • the aldehyde of the formula (II) used as a starting material is known or can be prepared according to known methods described in the literature [see TD Harris and GP Roth, J. Org. Chem., 44, 146 (1979), published in Germany. 2 165260, July 1972, German publication 2401665, July 1974, Mijano et al., Chemical Abstracts 59, (1963), 13929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961), EP Papadopoulos, M. Mardin and Ch.
  • the hydrazine of the formula (V) used as a starting material is known in some cases or can be prepared according to known methods described in the literature [see Houben-Weyl, Organic Chemistry, Vol. 1 1/ 2, 38 pages (1958); RL Shoiner and FW Neumann, Chemical Review 35, 351 (1944)], or may be prepared as described in WO-A-99/54326 and WO-A-99/54329.
  • the compounds (VIII) and (X) can be produced according to the procedure [A] or [B] described in WO-A-99/54326.
  • inert organic solvents are suitable for the eight, B, C and D steps.
  • Preferred among them are alcohols (e.g., methanol, ethanol, isopropanol), ethers (e.g., dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether), carboxylic acids (such as glacial acetic acid). , dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.
  • alcohols e.g., methanol, ethanol, isopropanol
  • ethers e.g., dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether
  • carboxylic acids such as glacial acetic acid.
  • dimethylformamide dimethyl sulfoxide, acetonit
  • the reaction temperature can be varied within a relatively wide range.
  • a temperature between 20 and 150 Torr is usually used, but is preferably at the boiling temperature of the selected solvent.
  • the reaction can be carried out under atmospheric pressure or under high pressure. It is usually carried out under atmospheric pressure.
  • the reaction can be carried out in the presence or absence of an acid or a base; however, it is preferred to carry out the reaction in the presence of a weak acid such as acetic acid or formic acid.
  • a weak acid such as acetic acid or formic acid.
  • the column is a silicon limb.
  • Silica gel 300-400 mesh
  • d6-DMSO CD30D or d6-acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard.
  • TMS 0.25 ppm
  • s sensinglet, unimodal
  • d doublet, doublet
  • t triplet, triplet
  • m multiplet, multiplet
  • br broadened, wide
  • Peak dd (doublet of doublets), dt (doublet of triplets).
  • Coupling constant expressed in Hertz (Hz).
  • MS mass spectrometry
  • Pure compounds are characterized by: Agilent 1 100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C 18, 2.1 x 30 mm, 4 micorn, 10 min, 0.6 mL/min Flow rate, 5 to 95% (0.1% formic acid in CH3CN) in (0.1 % formic acid in H20). Column was operated at 40 0C.
  • HPLC high performance liquid chromatography
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, muscular, Peritoneal machine, intrathecal, heart Intravenous, intrasternal or intracranial injection or input, or by means of an explanted reservoir, preferably oral, intramuscular, intraperitoneal or intravenous.
  • the compound of the present invention or the pharmaceutical composition containing the compound of the present invention can be administered in unit dosage form, and the dosage form can be a liquid dosage form, a solid dosage form, a liquid dosage form, and can be a true solution, a colloid type, a microparticle dosage form, an emulsion dosage form, and a suspension.
  • Dosage form, other dosage forms such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, stickers Agents, tinctures, etc.
  • the pharmaceutical composition of the present invention may further contain a usual carrier, and the pharmaceutically acceptable carrier herein includes, but is not limited to: ion exchanger, alumina, aluminum stearate, lecithin, serum protein such as human serum albumin, buffer. a substance such as phosphate, glycerol, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, etc., the weight content of the carrier in the pharmaceutical composition It may be from 1% to 98%, usually about 80%. For convenience, local anesthetics, preservatives, buffers and the like may be directly
  • Oral tablets and capsules may contain excipients such as binders (eg, sugars, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (eg, lactose, sucrose, corn, starch, calcium phosphate) , sorbitol, glycine), lubricants (such as magnesium stearate, talc, polyethylene glycol, silica), disintegrants (such as potato starch), or acceptable sizing agents (such as sodium lauryl sulfate) Salts, tablets may be prepared by methods well known in the art of pharmacy.
  • binders eg, sugars, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers eg, lactose, sucrose, corn, starch, calcium phosphate
  • sorbitol, glycine e.glycine
  • lubricants such as magnesium stearate
  • Oral can also be prepared as a suspension of water and oil, a solution, an emulsion, a syrup or an elixir. It can also be made into a dry product, supplemented with water or other suitable medium before use.
  • a liquid preparation may contain conventional additives, such as Suspensions (sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils), emulsifiers (eg lecithin, sorbus) Monosaccharide monooleate, gum arabic); or non-aqueous carrier (may contain edible oils), such as almond oil, oils (such as glycerol, ethylene glycol, or ethanol); preservatives (such as methylparaben) Or propyl ester, sorbic acid), if necessary, add flavoring or coloring agents.
  • Suspensions sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxye
  • the suppository can comprise a conventional suppository base such as cocoa butter or other glycerides.
  • liquid dosage forms are usually made from the compound and a sterile carrier.
  • the carrier is preferred water.
  • the compound can be dissolved in the carrier or in a suspension solution. The compound is dissolved in water before being prepared into an injection solution, filtered and sterilized, and then placed in a sealed bottle or ampoule. .
  • the compound of the invention When applied topically to the skin, the compound of the invention may be in the form of a suitable ointment, lotion, or cream, wherein the active ingredient is suspended or dissolved in one or more carriers, wherein the carrier to which the ointment formulation can be applied includes but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams can be used, including but not limited to: mineral oil, sorbitan Stearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the carrier to which the ointment formulation can be applied includes but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water
  • lotions and creams can be
  • the active compound of the formula (1) in the above pharmaceutical preparation should be present in a concentration of from about 0.1 to 99.5 based on the total amount of the mixture. /. Preferably, it is about 0.5 to 95% by weight.
  • One embodiment of the invention relates to a composition
  • a composition comprising: A) at least one of the above-described dihydropyrimidines, B) at least one other antiviral agent different from A.
  • a detailed embodiment of the invention relates to a composition
  • a composition comprising: A) the above-described dihydropyrimidine, B) HBV polymerase inhibitor, and, where appropriate, C) an immunomodulatory agent.
  • Preferred immunomodulators C) include, for example, all interferons such as alpha-, beta- and gamma-interferons, especially a-2a- and a-2b-interferons, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines. .
  • the present invention also relates to such compositions for the treatment and prevention of HBV infection and their use in the treatment of diseases caused by HBV.
  • compositions of the invention are beneficial for the treatment of HBV-induced diseases relative to a single treatment of a single compound
  • the compositions of the present invention are well tolerated, primarily with enhanced antiviral activity, and with respect to the single component of Tox-50, which has a toxicity range of 50% cell survival.
  • the HBV polymerase inhibitor guanidine used to achieve the object of the present invention is Ph. A. Furman et al., Antimicrobial Agents and Chemotherapy Vol. 36 (No. 12 ), 2688 (1992) Those materials revealed in endogenous polymerase experiments, as well as those described below, inhibit the formation of HBV DNA double strands, resulting in a maximum of 50% of the activity values of zero.
  • HBV virions were transferred from the culture suspension to the positive strand of HBV DNA together with the nucleoside 5'-triphosphate.
  • agarose gel electrophoresis a binding product of 3.2 kb DNA in which [ ⁇ - 32 ⁇ ]-deoxynucleoside 5'-triphosphate and virus were present was found, and there was no potential HBV polymerase-inhibiting property. substance.
  • From the cell culture suspension of HepG2.2.15 cells it was precipitated with polyethylene glycol and concentrated to obtain HBV virions.
  • One part by volume of the clarified cell culture suspension was mixed with 1/4 part by volume of an aqueous solution containing 50% by weight of polyethylene glycol 8000 and 0.6 M of sodium chloride.
  • the pellet was centrifuged at 2500 xg for 15 minutes, and the precipitate was resuspended in 2 ml of a buffer containing 0.05 Mtris-HCI M (pH 7.5), and dialyzed against the buffer containing 100 mM potassium chloride. The sample was frozen at -80 'C.
  • Each reaction mixture (100) contains at least 10 5 HBV virions, 50 mM tris-HCI (p.sub.H 7.5).
  • the gel is dried or transferred to the membrane using Southern transfer techniques.
  • An HBV polymerase inhibitor is present if there is a maximum 50% concentration of the control group.
  • Abacavir (-)-( 1 S-cis)-4-[2-amino-6-(cyclopropylamine)-9H-indol-9-yl]-2-yl-cyclopentene - Methanol, cf.
  • a further preferred embodiment of the invention relates to the invention comprising A) the above-mentioned dihydropyrimidines (I) and (la) and B) lamivudine Lamivudine ) composition aboard
  • Another preferred HBV antiviral agent B contains, for example, a phenylacrylamide represented by the following formula
  • R 2 are independently independently a C,-C 4 alkyl group or have a nitrogen atom at their position to form a ring having 5 to 6 atoms containing carbon and/or oxygen.
  • R 3 to R l2 are each independently hydrogen, halogen, -C 4 alkyl, optionally substituted C r C 4 alkoxy, nitro, cyano or trifluoromethyl.
  • R l 3 is hydrogen, C, -C 4 alkyl, dC 7 acyl or aralkyl, and X is halogen or optionally substituted -C 4 alkyl, and salts thereof.
  • AT-61 is a compound
  • Preferred immunomodulators C) include, for example, all interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, especially a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • interfering agents such as ⁇ -, ⁇ - and ⁇ -interferons, especially a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
  • Another preferred embodiment of the invention relates to a composition
  • a composition comprising A) the above-described dihydropyrimidines (1) and (la); B) lamivudine; and, where appropriate, C) interferon.
  • the invention includes the preparation of a medicament comprising, in addition to a non-toxic, pharmaceutically acceptable carrier, one or more compounds (1) or (la) or compositions of the invention or one or more A composition consisting of the active ingredient (1) or (la) or a composition consisting of the composition of the invention.
  • the active ingredients (I) and (la) referred to in the above pharmaceutical preparations have a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, based on the entire mixture.
  • the above pharmaceutical preparation may also contain other active pharmaceutical ingredients other than the compounds (1) and (la).
  • the content ratio of the components A, B and the appropriate C in the composition of the present invention may vary within a wide range of limitations, preferably 5 to 500 mg A/10 to 1000 mg B , especially 10 to 200 mg A/20. Up to 400 mg B,
  • Component C if appropriate, can also be used, its total use, preferably 10 million IU (international unit), more preferably 2-7 million IU (international unit), 3 weeks per week over a period of more than 3 years Times.
  • the compound or composition of the present invention as defined by the above pharmaceutical preparations usually has a concentration by weight of from about 0.1 to 99.5%, preferably from about 0.5 to 95% (relative to the entire mixture).
  • the above pharmaceutical preparation can be carried out by a known conventional method such as mixing the active ingredient with a carrier.
  • the single ingredient contains the active ingredient preferably in a total amount of from about 0.1 to about 80 mg/kg body weight, preferably 0.1 Up to 30mg kg body weight. In any case, depending on the above dosages, especially depending on the weight of the individual and the subject, the type of preparation, the manner in which the medication is taken, and the time or interval at which the medication is administered are necessary.
  • the present invention also relates to the above compounds and compositions for use in the control of diseases.
  • the invention further relates to a medicament comprising at least one of the above compounds or compositions and, where appropriate, one or more other active pharmaceutical ingredients.
  • the invention further relates to the use of the above compounds and compositions for the manufacture of a medicament for the treatment and prevention of the above mentioned diseases, in particular viral diseases, in particular hepatitis B.
  • the compound was synthesized by a method similar to that of Example 1 using methyl acetoacetic acid. Yield: 55% (melting point: ⁇ 52-154 ⁇ ),
  • Example 4 Methyl 6-molyl-4-(4-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • the compound obtained in Example 2 was synthesized in a similar manner to that in Example 3.
  • This compound uses methyl 6-methyl-4-(2-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5 and It is mentioned in WO 9954329) that it is synthesized as a raw material by the method of Example 11.
  • Mp 148-148, 7 ° C
  • This compound uses methyl 6-methyl-4-(2-bromophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-acid ester (in Chinese patent CN 99805170.5 and It is mentioned in WO 9954329) that it is synthesized as a raw material by the method of Example 11.
  • Mp 165, 8-166, 4 ° C
  • This compound uses ethyl 6-methyl-4-(2-bromophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5 and WO 9954329 mentioned) as a raw material by the method of the synthesis of 11.
  • This compound uses 2,2,2-trifluoroethyl-6-methyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine
  • the -5-carboxylate was synthesized as a raw material by the method of Example 11.
  • This compound was synthesized by a method similar to that of Example 16 using trifluoroacetylpiperazine (Tetrahedron Letters Vol. 36, No. 41, p 7357-7369 (1995) as a starting material.
  • the preparation method is as follows:
  • Hydroxylamine hydrochloride 18.0 g (0.26 mol) was dispersed in 120 ml of formic acid. At 80 ° C, 24 g of 1-methyl-1H-imidazole-2-carbaldehyde (0.22 mol) was added dropwise to the system, and the reaction was completed in 40 minutes. The system was stirred at 80 °C for 2 hours, the reaction was stopped, the solvent was evaporated in vacuo, and then recrystallized from 100 ml of anhydrous ethanol to yield 17.1 g (yield: 62%) of pale yellow crystalline product.
  • reaction was quenched, cooled, filtered, and EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • 2- cyanopyridine 10.4 g (100 mmol) was dissolved in 100 ml of anhydrous methanol, and 18.0 g (100 mmol) of a 30% sodium methoxide solution was added thereto, and 13.4 g (250 mmol) of ammonium chloride was added thereto with stirring at room temperature, and the mixture was stirred at room temperature overnight. . Filtration, the filtrate was concentrated to dryness, stirred with 100 ml of acetone, filtered, and the filter cake was washed with an appropriate amount of acetone, and dried to yield a white solid 18.4 g (yield: 117%).
  • Step 2 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • reaction was quenched, cooled, filtered, and evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 3 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Synthesis of ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzaldehyde as a starting material. ) -2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyridine-2) synthesized by a method similar to that of Example 40 was synthesized. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of ethyl-6-bromomethyl-4-(2,4-dichlorophenyl) by a method similar to that of Example 39 using 2,4-dichlorobenzidine as a starting material.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and ethyl 4-(2,4-dichlorophenyl)-2-(pyridine-2-) synthesized by a method similar to that of Example 40. (6-(4-morpholinemethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of methyl-6-bromomethyl-4-(2-bromo-) by a method similar to that of Example 39 using 2-bromo-4-fluorobenzaldehyde and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and methyl 4-(2-au-4-fluorophenyl)-2-(pyridine-2) synthesized by a method similar to that of Example 40 was synthesized. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate. MS (M+H: 489, 491 )
  • Step 1 Synthesis of methyl-6-bromomethyl-4-(2-chloro-) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 The compound prepared in the first step was introduced into the reaction as a starting material, and methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridine-2) was synthesized by a method similar to that of Example 40. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of methyl-6-bromomethyl-4- (2,4-) by a method similar to that of Example 39 using 2,4-dichlorobenzamide and methyl acetoacetate as starting materials.
  • Step 2 The compound prepared in the first step was put into the reaction as a starting material, and methyl 4-(2,4-dichlorophenyl)-2-(pyridine-2-) synthesized by a method similar to that of Example 40 (6-(4-morpholinemethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 1 Synthesis of methyl-6-bromomethyl-4-(2-chloro) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzhydrazide and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 0.172 g (2 mmol) of anhydrous piperazine was dissolved in 15 ml of absolute ethanol, and 0.9 g (2 mmol) was added dropwise at room temperature.
  • the methyl-6-bromomethyl-4-(2) prepared by the step 1.
  • Step 1 Synthesis of ethyl-6-bromomethyl-4-(2,4-dichlorophenyl) by a method similar to that of Example 39 using 2,4-dichlorobenzaldehyde as a starting material.
  • Step 2 The compound prepared in the first step and 1-trifluoroacetylpiperazine were put into the reaction as a starting material, and the ethyl 4-(2,4-dichlorophenyl) group was synthesized by a method similar to that of Example 45. 2-(Pyridin-2-yl)-6-(4-(1-trifluoroacetyl)piperazinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
  • Step 2 Methyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • the acid ester will be 1.0 g of freshly prepared ethyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-
  • Step 2 1.3 g (3.6 mmol) methyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-
  • Step 3 1.12 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-
  • the 5-carboxylate was dissolved in 120 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes.
  • Step 1 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 2- Chloro-4-fluorobenzaldehyde 1.58 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.30 g (10 mmol) of ethyl acetoacetate, pyrimidine-2-carboxamidine hydrochloride 1.59 g (10 mmol), anhydrous Sodium acetate 1. Og (12 mmol) was stirred and stirred at reflux for 18 h. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester
  • Step 3 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 - Carboxylic esters
  • Step 1 Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate 0.85 g (2 mmol) ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved In 80 ml of carbon tetrachloride, heated to 60 ° C, 0.37 g (2.1 mmol) of N-bromosuccinimide was added in batches, kept at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was steamed at room temperature. The solvent was removed to give a pale yellow crude product, 0.58 g.
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
  • Step 1 Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of methyl 4-(2-indol-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5- post-ester
  • Step 2 Preparation of methyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-di- ft pyridine, 1,4--5-carboxylate 2,4-Dichlorobenzaldehyde 0.88 g (5 mmol) was dissolved in 50 ml of absolute ethanol, and 0.58 g (5 mmol) of methyl acetoacetate and benzamidine hydrochloride 0.78 g (5 mmol) were added. Anhydrous sodium acetate 0.50 g (6 mmol) was added and the mixture was warmed to reflux for 18 hours.
  • Step 2 Preparation of methyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-
  • Carboxylic acid ester 1.3 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-
  • Step 1 Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-
  • Carboxylic acid ester 1.5 g of freshly prepared ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-
  • Step 1 Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-
  • Carboxylic acid ester 95 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5
  • Example 64 The above title compound was obtained by a preparation method similar to that of Example 64.
  • Example 64 The above title compound was obtained by a preparation method similar to that of Example 64.
  • Step 1 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
  • Step 1 Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 1 Preparation of ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 2 Preparation of ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
  • Example 77 Prepared by a method similar to that of Example 70 using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
  • Example 78 It was prepared by a method similar to the preparation method of Example 71 using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
  • Example 78 It was prepared by a method similar to the preparation method of Example 71 using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
  • Step 1 Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyrimidine-5-carboxylate
  • Step 3 Preparation of ethyl 4-(2-au-4-fluorophenyl)-2-methyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate B Base 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-methyl-1,4-dihydropyrimidine-5-carboxylate crude 1.3 g dissolved in 50 ml of ethanol, added 0.5 g (5.7 mmol) of morpholine.
  • the antiviral effect of the compounds of the invention on hepatitis B virus is based on the methods described by MA Sells et al, Proc. Natl. Acad. Sci. 84, 10051009 (1987) and BE orba et al., Antiviral Research 19, 5570 (1992).
  • Antiviral testing was performed on %-well microtiter plates. The first column only received medium and HepG2.2.15 cells as a virus control.
  • test compound 50 mM was first dissolved in DMSO and then diluted in HepG2.2.15 medium.
  • the compound according to the invention is typically pipetted 100 times at each test concentration (1st test concentration) to the second test column of the microtiter plate and then in a medium supplemented with 2% by weight fetal calf serum (volume 25). Diluted 2'° times in two steps.
  • Each well of the microtiter plate containing 2% by weight of fetal bovine serum contained 225 ⁇ l of HepG2.2.15 cell suspension (5 x 10 4 cells/ml). 37;, 5% C0 2 (v/v) The test mixture was incubated for 4 days.
  • the surface suspension was then aspirated and discarded, and 225 freshly prepared medium was added to the wells.
  • the compounds according to the invention were each refilled with a 10-fold concentrated solution in volume. The mixture is continued to grow for 4 days.
  • cytotoxic or cytostatic changes induced by substances in HepG2.2.15 cells for example, changes in cell morphology under light microscopy.
  • the changes induced by these substances in HepG2.2.15 cells are evident compared to untreated cells, such as changes in cell lysis, vacuoles, or cell morphology.
  • 50% toxicity (TOX.-50) refers to a morphology of cells that are 50% compared to the corresponding control cells.
  • the tolerance of some of the compounds according to the invention is tested on other host cells, such as HeLa cells, primary human peripheral hematopoietic cells or transformed cell lines such as H-9 cells.
  • the intracellular or extracellular suspension of HepG2.2.15 cells was denatured (1.5 MNaCI/0.5 N NaOH), neutralized (3 M NaCl/0.5 M Tris HCI, pH 7.5), then wash (2xSSC). The DNA was returned to the membrane by incubating the filter at 120 ° C for 2-4 hours.
  • Detection of viral DNA obtained from He P G2.2.15 cells treated on a nylon filter was performed on non-radioactive, digoxin-labeled hepatitis B DNA probes, each under the conditions of digoxin labeling, and purified. Hybrid based on operational confidence.
  • Pre-hybridization and hybridization were carried out in 5xSSC, l x blocking reagent, 0.1% by weight of N-lauroyl sarcosine, 0.02% by weight of SDS and 100 //g of herring sperm DNA.
  • Pre-hybridization was carried out at 60 ° C for 30 minutes and then specifically hybridized with 20 to 40 ng/ml of digoxin-labeled, denatured HBV-DNA (14 hours, 60 ° C). Wash the filter. Detection of HBV-DNA with digoxin antibody
  • the wash filter is hybridized in a closed test (according to the manufacturer's information). Hybridization was carried out using an anti-DIG antibody and alkaline phosphate fermentation for 30 minutes. After the washing step, the substrate of alkaline phosphatase, CSPD, was added with a filter for 5 minutes, then coated with a plastic film, and incubated for another 15 minutes at 37 Torr. Exposing the filter to the X-ray layer reveals the luminescent signal of hepatitis B DNA (culture depends on signal strength: 10 minutes to 2 hours).
  • the intracellular or extracellular Hepatitis B population was reduced by the compound according to the invention by a maximum half-inhibitory concentration (IC 5 Q, 50% inhibitory concentration) corresponding to a concentration of 50% of the untreated sample.
  • IC 5 Q 50% inhibitory concentration
  • the antiviral effect value exhibited by the compound of the present invention is 1 C 50 lower than 1 ⁇ ⁇ , which is unexpected.
  • the compounds of the invention are useful in the treatment of viral-induced diseases, particularly acute and chronic persistent HBV viral infections. Chronic viral diseases caused by HBV may cause morbidity to become severe, and chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinogenesis in many cases.
  • the indicated regions that may be mentioned are, for example, the treatment of acute and chronic viral infections that may result in infectious hepatitis, such as hepatitis B virus infection.
  • the compounds of the invention are especially suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
  • the compound of the present invention shows a strong antiviral effect, wherein some of the compounds 1C 5 () are less than 2 ⁇ , the IC 50 value of some compounds is between 2 nM and 20 nM, and the IC 5 o value of some compounds is between 20 nM and 200 nM.
  • the compounds of the present invention have unexpected antiviral activity against hepatitis B (HBV) and are therefore suitable for the treatment of various diseases caused by viruses, particularly those caused by acute and chronic persistent HBV infection.
  • Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma.
  • Treatment can lead to acute and chronic viral infections of infectious hepatitis, such as hepatitis B virus infection.
  • infectious hepatitis such as hepatitis B virus infection.
  • Particularly preferred are the treatment of chronic hepatitis B infection and the treatment of acute hepatitis B virus infection.
  • the present invention provides a dihydropyrimidine compound represented by the general formula (I) and its isomer (la), a preparation method thereof and use thereof as a medicament for preparing a medicament for treating and preventing a viral disease, In particular, it is used as a preparation for the treatment and prevention of hepatitis B virus infection.
  • the invention further relates to the use of these dihydropyrimidines together with other antiviral agents, where appropriate, immunomodulatory agents, and compositions containing these compositions for the treatment and prevention of viral hepatitis, especially hepatitis B.
  • the invention has industrial applicability.

Abstract

Dihydropyrimidine derivatives, their isomers, enantiomers, salts and hydrates, process for preparation thereof, and pharmaceutical compositions thereof are provided. The said compounds can be used in manufacture of medicaments for treating and preventing viral diseases preferably hepatitis B infection.

Description

二氢嘧啶类化合物、 其组合物及其应用 技术领域  Dihydropyrimidine compound, composition thereof and application thereof
本发明提供了一种新的二氢嘧啶类化合物，其制备方法及其作为制备治疗和预防病毒性 疾病的药物中的应用， 尤其是作为制备治疗和预防乙型肝炎病毒感染药物中的应用。本发明 还涉及这些二氢嘧啶其他抗病毒剂， 适当情况下， 免疫调节剂的组合物， 以及含有这些组合 物用于治疗和预防病毒性肝炎尤其是乙型肝炎的组合物的用途。 背景技术  The present invention provides a novel dihydropyrimidine compound, a process for its preparation and its use as a medicament for the preparation of a medicament for the treatment and prevention of viral diseases, in particular as a medicament for the preparation of a medicament for the treatment and prevention of hepatitis B virus infection. The invention further relates to the use of these dihydropyrimidine other antiviral agents, where appropriate, immunomodulatory agents, and compositions containing these compositions for the treatment and prevention of viral hepatitis, especially hepatitis B. Background technique
乙型肝炎病毒属于肝病毒科。 它可引起急性的和或持续 /渐进的慢性病。 乙型肝炎病毒还 引起病理形态中许多其他的临床病征- -尤其是肝脏的慢性炎症、 肝硬化和肝细胞的癌变。 另 外， 与丁型肝炎的共同感染在疾病的发展过程中会产生不利影响。  Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis B virus also causes many other clinical signs in pathology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
干扰素和拉米夫定 （lamivudine )是批准用于治疗慢性肝炎治疗的常规药物。 然而， 干 扰素只具有中等的活性， 并具有有害的副反应； 虽然拉米夫定 （lamivudine ) 作为一种新的 药物具有良好的活性， 但其在治疗中抗性发展迅速， 并在停止治疗之后常常出现反弹效应， WO 99/54312, 99/54326, 99/54329 和 US 7074784涉及一种二氢嘧啶用于治疗和预防肝炎病 毒感染的药物的用途。 专利 US7074784实施例公开了 2位卤代吡啶基取代和 6位碱性基团 取代的 1，4二氢嘧啶类化合物。 卤代环系对亲核物质如胺类 （例如吗啉） 较为敏感。 我们发 现， 将 2位取代基替换为其他杂环得到的化合物， 与现有公开的化合物比较， 显示出更好的 活性且对亲核物质攻击具有更好的化学稳定性。  Interferon and lamivudine are conventional drugs approved for the treatment of chronic hepatitis. However, interferon is only moderately active and has harmful side effects; although lamivudine has good activity as a new drug, its resistance develops rapidly during treatment and stops treatment. The rebound effect is often followed by WO 99/54312, 99/54326, 99/54329 and US 7074784 relating to the use of a dihydropyrimidine for the treatment and prevention of hepatitis virus infection. The patent US7074784 example discloses a 1,4 dihydropyrimidine compound substituted with a 2-position halopyridyl group and a 6-position basic group. Halogenated ring systems are sensitive to nucleophilic materials such as amines such as morpholine. We have found that the replacement of the two substituents with the other heterocyclic compounds gives better activity and better chemical stability against nucleophilic attack than the previously disclosed compounds.
最近公开的专利 WO2008/009209, WO 2008/086729 和 WO2008/086730 涉及一种新的 2 位杂环取代二氢嘧啶， 但是只描述了 6位为甲基取代的 1 ,4-二氢嘧啶。 本发明的 6位碱性基团 取代的化合物显示出更好的活性以及由于碱性取代基引入显示的其他优点如在低 PH值下水 溶性更好。 发明内容  The recently published patents WO2008/009209, WO 2008/086729 and WO2008/086730 relate to a novel 2-position heterocyclic-substituted dihydropyrimidine, but only the 1, 4-dihydropyrimidine in which the 6-position is a methyl group is described. The 6-substituent substituted compound of the present invention exhibits better activity and other advantages exhibited by the introduction of a basic substituent such as better water solubility at low pH. Summary of the invention
本发明的目的在于提供一种新的二氢嘧啶类化合物。  It is an object of the present invention to provide a novel dihydropyrimidine compound.
本发明的另一目的在于提供一种二氢嘧啶类化合物的制备方法.  Another object of the present invention is to provide a method for preparing dihydropyrimidine compounds.
本发明的再一目的在于提供一种含有二氢嘧啶类化合物的药物组合物。  It is still another object of the present invention to provide a pharmaceutical composition containing a dihydropyrimidine compound.
本发明的还一目的在于提供含有二氢嘧啶类化合物的药物在作为作为制备治疗和预防 病毒性疾病的药物中的应用， 尤其是作为制备治疗和预防乙型肝炎病毒感染药物中的应用。  A further object of the present invention is to provide a medicament containing a dihydropyrimidine compound as a medicament for the preparation of a medicament for the treatment and prevention of a viral disease, in particular as a medicament for the preparation of a medicament for the treatment and prevention of hepatitis B virus infection.
本发明通式（1 )或其同分异构体 (la)所示的化合物或其对映异构体或它们的盐或水合物：  A compound represented by the formula (1) or its isomer (la) of the present invention or an enantiomer thereof or a salt or hydrate thereof:
Figure imgf000002_0001
Figure imgf000002_0001
其中， 1 ,代表氢、 氨基、 硝基、 氰基、 F、 Cl、 Br、 1、 羟基、 三氟甲基、 三氟甲氧基或苄基; 或 <^-0：6的垸基、 C!-Cs的烷氧基、 C,-C6的垸氧羰基、 d-C6的烷基氨基、 -C6的二烷基氨 基、 C C6的酰胺基、 -C6的酰氧基、 -C6的酰基、 d-C6的烷硫基、 C,-C6的烷亚磺酰基 或 - 的烷 酰基； 或未取代吡定基； 或苯基、 萘基、 噻 基、 啶基、 噻吩基、 喃基、 吡咯烷基、 咪唑基、 噻嗪基； 或其中上述环系任选自下述基团的相同或不同取代基单取代或 多取代： 氨基、 硝基、 氰基、 F、 Cl、 Br、 1、 羟基、 三氟甲基、 三氟甲氧基、 苄基、 d-Ce 的烷基， -C6的烷氧基、 CrC6的烷氧羰基、 C C6的烷基氨基、 C C6的二烷基氨基、 C,-C6 的酰胺基、 - 的酰氧基、 CrC6的酰基、 d-C6的烷硫基、 - 的烷亚磺酰基、 C,-C 的. 垸磺酰基； Wherein, 1 represents hydrogen, amino, nitro, cyano, F, Cl, Br, 1, hydroxy, trifluoromethyl, trifluoromethoxy or benzyl; or <^-0: 6 thiol, Alkoxy group of C!-Cs, 垸oxycarbonyl group of C,-C 6 , alkylamino group of dC 6 , dialkylamino group of -C 6 , amide group of CC 6 , acyloxy group of -C 6 , An acyl group of C 6 , an alkylthio group of dC 6 , an alkylsulfonyl group of C, -C 6 or an alkanoyl group of - or an unsubstituted pyridine group; or a phenyl group, a naphthyl group, a thio group, a pyridyl group, a thienyl group, Oryl, pyrrolidinyl, imidazolyl, thiazinyl; or the same or different substituents in which the above ring system is selected from the group consisting of the following or different substituents: amino, nitro, cyano, F, Cl, Br, 1, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, d-Ce Alkyl group, -C 6 alkoxy group, C r C 6 alkoxycarbonyl group, CC 6 alkylamino group, CC 6 dialkylamino group, C, -C 6 amide group, - acyloxy group An acyl group of C r C 6 , an alkylthio group of dC 6 , an alkylsulfinyl group of -, a C.-C. sulfonyl group;
R2代表氢、 氨基、 硝基、 氰基、 F、 Cl、 Br、 I、 羟基、 三氟甲基、 三氟甲氧基或苄基； 或 -( 6的烷基, C,-C6的烷氧基、 C,-C6的烷氧羰基、 d-C6的烷基氨基、 CrC6的二垸基氨基、 C,-C6的酰胺基、 C,-C6的酰氧基、 d-Ce的酰基、 d-C6的烷硫基、 C,-C6的烷亚磺酰基或 -C6 的烷磺酰基； 或苯基、 萘基、 含有 1-5个选自 N、 S、 O的杂原子取代的 5-12个原子的杂芳 基， 其所述杂芳基为吡啶基、 喹啉基、 嘧啶基、 呋喃基、 噻吩基、 唑基、 咪唑基、 噻唑基、 噻嗪基或吡嗪基； 或其中上述环系任选自下述基团的相同或不同取代基单取代或多取代： F、 Cl、 Br、 I、 三氟甲基、 三氟甲氧基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 -C8的烷 氧基、 C8的垸氧羰基、 -Cs的烷硫基、 <^-¾的烷亚磺酰基、 d-C8的垸磺酰基、 C,-C8 的酰基或 -C8的烷基，或其中所述垸基被具有 6-10个碳原子的芳基、 素、或 -S-R^NR^R, 和 -CO-NR8R9和 -D-CH2-RI0所示基团取代， 其中 R5代表任选被卤素取代的苯基， R«、 R7、 ^和 R9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 C 的酰基或 d- 的烷氧羰基、 苯基或羟基取代苯基； D代表 0、 S、 SO或 S02; Rl()代表任选或选择性被选 自下述基团相同或不同取代基单取代或多取代的苯基： 卤素、 硝基、 三氟甲基、 d-C8的烷 基或 C,-C3的烷氧基； R 2 represents hydrogen, amino, nitro, cyano, F, Cl, Br, I , hydroxy, trifluoromethyl, trifluoromethoxy or benzyl; or - (6-alkyl, C, -C 6 Alkoxy, C,-C 6 alkoxycarbonyl, dC 6 alkylamino, C r C 6 dinonylamino, C,-C 6 amide, C,-C 6 acyloxy , an acyl group of d-Ce, an alkylthio group of dC 6 , an alkylsulfinyl group of C,-C 6 or an alkylsulfonyl group of -C 6 ; or a phenyl group, a naphthyl group, containing 1-5 selected from N, S a heteroatom of 5-12 atoms substituted by a hetero atom of O, wherein the heteroaryl group is pyridinyl, quinolyl, pyrimidinyl, furyl, thienyl, oxazolyl, imidazolyl, thiazolyl, thia a pyridyl or pyrazinyl group; or a mono- or poly-substituent wherein the above ring system is selected from the same or different substituents selected from the group consisting of F, Cl, Br, I, trifluoromethyl, trifluoromethoxy, Trifluoromethanesulfonyl, nitro, cyano, carboxy, hydroxy, -C 8 alkoxy, C 8 oxiranylcarbonyl, -Cs alkylthio, <^-3⁄4 alkylsulfinyl, dC 8 the embankment sulfonyl, C, -C -C 8 acyl or alkyl group of 8, wherein said alkyl with or An aryl group having 6 to 10 carbon atoms, prime, or -SR ^ NR ^ R, and -CO-NR 8 R 9 substituents, and the group represented by -D-CH 2 -R I0, wherein R 5 represents optionally a phenyl group substituted by halogen, R«, R 7 , ^ and R 9 are the same or different and each represent hydrogen, naphthyl, hydroxy-substituted phenyl, hydroxy, C acyl or d-alkoxycarbonyl, phenyl or Hydroxy-substituted phenyl; D represents 0, S, SO or S0 2 ; R l() represents a phenyl group which is optionally or selectively mono- or polysubstituted by the same or different substituents selected from the group consisting of halogens and nitrates a group, a trifluoromethyl group, an alkyl group of dC 8 or an alkoxy group of C, -C 3 ;
A代表一个键、 -0-,、 -S -、 或 -NRu -, 其中 ！^是 ^ -C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 C8的烃基，其中所述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 -NH- ( - 烷基） 、 -N- (d- 烷基） 2、 相同或不同杂链单元， 并且可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基或杂芳基； A represents a key, -0-, -S -, or -NRu -, where! ^ is an alkoxycarbonyl group of ^ -C 6 , or a linear, branched, or cyclic saturated or unsaturated C 8 hydrocarbon group, wherein the hydrocarbon group optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH-(-alkyl), -N-(d-alkyl) 2 , the same or different heterochain units, and optionally halogen, nitro, cyano, hydroxy, having 6-10 An aryl group of carbon atoms, an aralkyl group having 6 to 10 carbon atoms or a heteroaryl group;
R3代表 H、 的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 C,-C8的烃基，或其所述 烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 -NH- ( - 烷基）、 -N- (d- 烷基） 2、 相同或不同杂链单元， 并且可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 1121 |3所示基团取代， 其中 Ru和 Rl3相同或不 同， 并分别代表氢、 苄基或 - 的烷基； R 3 represents an alkoxycarbonyl group of H, or a linear, branched, or cyclic saturated or unsaturated C,-C 8 hydrocarbon group, or the hydrocarbon group thereof optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH- (-alkyl), -N-(d-alkyl) 2 , the same or different hetero chain units, and optionally halogen, nitro, cyano, hydroxy, having An aryl group of 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula 1 12 1 |3 , wherein R u and R l3 are the same or different and are respectively An alkyl group representing hydrogen, benzyl or -;
R代表氢、 氨基、 甲基， 当 R为甲基时， R,为除未取代吡啶基、 噻唑基、 取代苯基、 呋喃 基、 噻吩基或咪唑基之外的取代基； 或 R代表式
Figure imgf000003_0001
R represents hydrogen, amino, methyl, and when R is methyl, R is a substituent other than unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl or imidazolyl; or R represents
Figure imgf000003_0001
所示的基团， 或甲酰基、 氰基、 三氟甲基、 - 的环烷基或吡啶基， 或代表 -X-Z, X 代表 -CH2- 、 -CH2-CH2-、 -CH2-CH2-CH2-或 (C=0)-; a group shown, either formyl, cyano, trifluoromethyl, -cycloalkyl or pyridyl, or -XZ, X represents -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or (C=0)-;
Z代表卤素， 当 Z为 Br, X为 -CH2-时， 不能为噻唑 -2-基和未取代吡啶基； Z represents a halogen, and when Z is Br and X is -CH 2 -, it cannot be a thiazol-2-yl group and an unsubstituted pyridyl group;
或 Z代表甲苯磺酰氧基、 甲磺酰氧基、 苯基、 吡啶基、
Figure imgf000003_0002
、 或 NRI4RI5, 其中 Rl4和 R15可以相同或不同， 代表 d-C4的烷基， 所述垸基任选地被羟基、 C!- 的烷氧羰基取代， 或 Rl4, Rl5和 N原子键合成一个杂环， 所述杂环为咪唑、 三唑、 四 唑或下述通式 (ΠΙ)所示的基团：
Figure imgf000003_0003
其中， B代表" (CH2)n- (n=0，l或 2)、 -CF2-、 -CHF- 或 (C=0)-; Y 代表^ CHr、 -CH2-CH2- 、 -0-、 -S -、 -SO- , S02- 或 NRI6 , 其中 Rl6代表氢、 -CO-CH3、 -CO-CF3、 -CO-0-R17 或 -CO-NR18R19 , 其中 R17 , R18, R19可以相同或不同， 代表 H或 C,- C8的烷基； Or Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl,
Figure imgf000003_0002
Or NR I4 R I5 , wherein R l4 and R 15 may be the same or different and represent an alkyl group of dC 4 which is optionally substituted by a hydroxy, C!- alkoxycarbonyl group, or R l4 , R l5 And a N atom bond to synthesize a heterocyclic ring, the heterocyclic ring being an imidazole, a triazole, a tetrazole or a group represented by the following formula (ΠΙ):
Figure imgf000003_0003
Wherein B represents "(CH 2 ) n - (n = 0, l or 2), -CF 2 -, -CHF- or (C = 0)-; Y represents ^ CH r , -CH 2 -CH 2 - , -0-, -S -, -SO- , S0 2 - or NR I6 , wherein R l6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , -CO-0-R 17 or -CO-NR 18 R 19 , wherein R 17 , R 18 , R 19 may be the same or different and represent an alkyl group of H or C, -C 8 ;
1 20代表氢、 卤素、 氰基、 叠氮基、 氨基、 C5-C7的杂环、 C,-C8的垸基、 CrC8的烷氧基、 -Cs的烷硫基、 CrC8的烷亚磺酰基、 -Cs的磺酰基、 CrC8的酰基、 硝基、 三氟甲基、 或 -CO-N(R20)2, 其中 R2o可以是 H或 CrC8的烷基； 1 20 represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocyclic ring, C,-C 8 fluorenyl group, C r C 8 alkoxy group, -Cs alkylthio group, C r C 8 alkylsulfinyl, -Cs sulfonyl, C r C acyl, nitro, trifluoromethyl 8 or -CO-N (R 20) 2 , wherein R 2 o can be H or An alkyl group of CrC 8 ;
在上述定义中, 当 R为吗啉 -4-基-甲基， 为噻唑 -2-基, R3为- CH3 , A为 0时， R2不为 2,4- 二氯-苯基； In the above definition, when R is morpholin-4-yl-methyl, thiazol-2-yl, R 3 is -CH3, when A is 0, R 2 is not 2,4-dichloro-phenyl;
代表氢、 - 的烷基、 CrC4的烯基、 d-Cuj的烷氧羰基、 d-do的酰基或苯甲酰基。 本发明中， C 1 -C8的烷基是指直链或支链含有 1-8个碳原子的基团， 其中烷基可以独立任选 地被一个或多个本发明所描述的取代基所取代。 优选具有 1-4个碳原子的直链或支链烷基。 其中具体的实旄例包括但并不局限于： 甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 异 丁基和叔丁基、 正戊基和正己基等。 Represents hydrogen, an alkyl group, an alkenyl group of C r C 4 , an alkoxycarbonyl group of d-Cuj, an acyl group of d-do or a benzoyl group. In the present invention, the C 1 -C8 alkyl group means a group having 1-8 carbon atoms in a straight or branched chain, wherein the alkyl group may be independently and optionally optionally substituted by one or more substituents described in the present invention. Replace. A straight or branched alkyl group having 1 to 4 carbon atoms is preferred. Specific examples include but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, n-pentyl and n-hexyl, etc. .
术语"芳基"可以单独使用或作为 "芳烷基""芳烷氧基"或"芳氧基烷基"的一大部分， 除非 另外详细说明， 芳基表示共含有 6- 10元环的单环， 双环的碳环体系， 其中， 至少一个环体 系是芳香族的，其中每一个环体系包含 3-7元环，且只有一个附着点与分子的其余部分相连。 术语"芳基"可以和术语"芳香环 "交换使用， 如芳香环可以包括苯基， 萘基。 另外一些实施例 是， 芳杂环包括以下的单环， 但并不限于这些单环： 2-呋喃基， 3-呋喃基， N-咪唑基， 2-咪 唑基， 4-咪唑基， 5-咪唑基， 3-异噁唑基， 4-异噁唑基， 5-异噁唑基， 2-噁唑基， 唑基， 5-噁唑基, N-吡咯基， 2-吡咯基， 3-吡咯基， 2-吡啶基, 3-吡啶基， 4-吡啶基， 2-嘧啶基, 4- 嘧啶基， 5-嘧啶基， 哒嗪基（如 3-哒嗪基）， 2-噻唑基， 4-噻唑基， 5-噻唑基， 四唑基（如 5- 四唑基）， 三唑基（如 2-三唑基和 5-三唑基）， 2-噻吩基， 3-噻吩基， 吡唑基（如 2-吡唑基）， 异噻唑基， 1 , 2, 3-噁二唑基， 1 , 2 , 5-噁二唑基， 1， 2， 4-噁二唑基， 1 , 2， 3-三唑基， 1 , 2 , 3-硫代二唑基， 1 , 3 , 4-硫代二唑基， 1 , 2， 5-硫代二唑基， 吡嗪基， 1 , 3 , 5-三嗪基； 也包括以下的双环， 但绝不限于这些双环： 苯并咪唑基， 苯并呋喃基， 苯并噻吩基， 吲哚基 (如 2-吲哚基）， 嘌呤基， 喹啉基（如 2-喹啉基， 3-喹啉基， 4-喹啉基）， 和异喹啉基（如 1 - 异喹啉基， 3-异喹啉基或 4-异喹啉基)。  The term "aryl" may be used alone or as a large part of "aralkyl" "aralkyloxy" or "aryloxyalkyl", unless otherwise specified, aryl means a total of 6-10 membered rings. A monocyclic, bicyclic, carbocyclic ring system in which at least one ring system is aromatic, wherein each ring system comprises a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", as an aromatic ring may include phenyl, naphthyl. In other embodiments, the aromatic heterocycle includes the following monocyclic rings, but is not limited to these monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (eg 3-pyridazinyl), 2-thiazolyl , 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl , pyrazolyl (eg 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1 , 2 , 3-thiodiazolyl, 1 , 3 , 4-thiodiazolyl, 1, 2, 5-thiodiazolyl, pyrazinyl, 1 , 3 , 5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, anthracene Base (eg 2-indenyl), fluorenyl, quinolinyl (eg 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (eg 1-isoquinolinyl) , 3-isoquinolyl or 4-isoquinolinyl).
术语"芳烷基"包括芳基取代的烷基基团。 其中一些实施例是， 芳垸基基团是指"较低级 的芳烷基"基团， 即芳基基团连接到 C 1-6的烷基基团上。  The term "aralkyl" includes aryl substituted alkyl groups. In some of these embodiments, an arylalkyl group refers to a "lower aralkyl" group, i.e., an aryl group attached to a C1-6 alkyl group.
Cr 的酰基代表具有 1 -8个碳原子的直链或支链的酰基，优选具有 1 -6个碳原子的直链 或支链酰基， 特别优选的酰基是乙酰基和丙酰基。  The acyl group of Cr represents a linear or branched acyl group having 1-8 carbon atoms, preferably a linear or branched acyl group having 1 to 6 carbon atoms, and particularly preferred acyl groups are acetyl group and propionyl group.
C2-C4的链烯基代表具有 2-4个碳原子的直链或支链烯基， 优选为乙烯基、 丙烯基。The alkenyl group of C 2 -C 4 represents a linear or branched alkenyl group having 2 to 4 carbon atoms, preferably a vinyl group or a propenyl group.
-Cs的垸氧基代表具有 1 -8个碳原子的直链或支链烷氧基，优选具有 1 -6个碳原子的直 链或支链烷氧基， 更优选为甲氧基， 乙氧基或丙氧基。 The decyloxy group of -Cs represents a linear or branched alkoxy group having 1-8 carbon atoms, preferably a linear or branched alkoxy group having 1 to 6 carbon atoms, more preferably a methoxy group, Oxy or propoxy.
-C8的烷硫基代表具有 1 -8个碳原子的直链或支链烷硫基，优选具有 1 -6个碳原子的直 链或直链烷硫基， 更优选为甲硫基、 乙硫基或丙硫基。 The alkylthio group of -C 8 represents a linear or branched alkylthio group having 1 to 8 carbon atoms, preferably a linear or linear alkylthio group having 1 to 6 carbon atoms, more preferably a methylthio group, Ethylthio or propylthio.
CrC8的烷氧羰基代表具有 1 -8个碳原子的直链或支链玩样羰基，优选具有 1-4个碳原子 的直链或直链垸氧羰基， 更优选为甲氧基羰基、 乙氧基羰基或丙氧基羰基。 The alkoxycarbonyl group of C r C 8 represents a straight-chain or branched playk-like carbonyl group having 1-8 carbon atoms, preferably a linear or linear fluorenyloxycarbonyl group having 1 to 4 carbon atoms, more preferably a methoxy group. Carbonyl, ethoxycarbonyl or propoxycarbonyl.
CrC8的烃基包括上述 CrC8的烷基、 CrC8的链烯基、 C3-C8的环烷基, 优选为（^-( 8的 烷基。 C r C 8 hydrocarbon group include the aforementioned C r C alkyl, C r C 8 alkenyl group 8, C 3 -C 8 cycloalkyl, preferably (^ - (8 alkyl.
CrC8的环烷基代表环丙基、 环戊基、 环丁基或环己基， 优选环丙基。 The cycloalkyl group of C r C 8 represents a cyclopropyl group, a cyclopentyl group, a cyclobutyl group or a cyclohexyl group, preferably a cyclopropyl group.
本发明化合物包括通式 （1 ) 或其同分异构体 （la ) 或它们的混合物。 其中所述式 （I ) 异构体一般指其互变异构体或光学异构体。 异构体 （1 ) 和 （la ) 可以互变异构体平衡存 在。 如过 R4为氢， 异构体 （I ) 和 （la ) 可以互变异构体平衡存在：
Figure imgf000005_0001
The compound of the present invention includes the formula (1) or its isomer (la) or a mixture thereof. Wherein the isomer of formula (I) generally refers to its tautomer or optical isomer. The isomers (1) and (la) can exist in equilibrium with tautomers. If R4 is hydrogen, the isomers (I) and (la) can exist as tautomers:
Figure imgf000005_0001
本发明化合物可以以光学异构体形式存在， 所述光学异构体形式之间呈对映体或非对 映体关系。 本发明涉及这些对映体或非对映体以及它们的混合物。 像非对映异构体一样， 外 消旋体可以通过已知方法拆分成立体异构体的单一成分，如在发明化合物的分子中引入其他 手性基团得到光学纯的对映异构体。  The compounds of the present invention may exist in the form of optical isomers which are in enantiomeric or diastereomeric relationship between the optical isomer forms. The invention relates to these enantiomers or diastereomers and mixtures thereof. Like diastereomers, the racemate can be resolved into a single component of a stereoisomer by known methods, such as the introduction of other chiral groups in the molecule of the inventive compound to give optically pure enantiomers. body.
本发明的化合物也可以是盐的形式， 其生理上可接受的盐是本发明优选的.  The compounds of the invention may also be in the form of a salt, the physiologically acceptable salts of which are preferred in the present invention.
生理上可接受的盐可以是无机酸盐或者有机酸盐。优选的是无机酸盐，诸如，例如盐酸、 氢溴酸、 磷酸或硫酸等， 或者有机羧酸或磺酸， 例如醋酸、 马来酸、 反丁烯二酸、 苹果酸、 柠檬酸、 酒石酸、 乳酸、 苯甲酸或甲磺酸、 乙磺酸、 苯磺酸、 甲苯磺酸或萘-二硫磺酸等形 成的盐。  The physiologically acceptable salt may be a mineral acid salt or an organic acid salt. Preferred are inorganic acid salts such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or organic carboxylic acids or sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, a salt formed from lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalene-disulfuric acid.
生理上可接受的盐还可以是本发明化合物的金属盐或者铵盐。尤其优选的是钠、钾、镁、 或钙盐， 以及由氨或有机胺， 诸如乙胺， 二 -或三乙胺， 二-或三乙醇胺， 二环己基胺， 二甲 基氨基乙醇， 精氨酸， 赖氨酸， 乙二胺， 或 2-苯乙胺等生成的铵盐。  The physiologically acceptable salt may also be a metal or ammonium salt of a compound of the invention. Particularly preferred are sodium, potassium, magnesium, or calcium salts, and from ammonia or organic amines such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, fine An ammonium salt formed by a cis, a lysine, an ethylenediamine, or a 2-phenylethylamine.
本发明中的一些化合物可能用水或各种有机溶剂结晶或重结晶， 在这种情况下， 可能形 成各种溶剂化物。 本发明包括那些化学计量的溶剂化物， 包括水合物， 也包括在用低压升华 干燥法制备时形成的包含可变量水的化合物。  Some of the compounds of the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed. The present invention includes those stoichiometric solvates, including hydrates, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
其中一些实施例是通式 U ) 和 （la ) 中的 R,代表氨基、 硝基、 F、 Cl、 Br、 羟基、 三 氟甲基、 三氟甲氧基、 苄基、 -C4的烷基、 C C4的垸氧基、 d- 的烷氧羰基、 C'-C4的酰 胺基、 CrC4的酰氧基、 d- 的酰基、 或未取代吡啶基； 或苯基、 噻唑基、 ¾啶基、 噻吩基、 呋喃基、 吡咯垸基、 咪唑基、 噻嗪基； 或其中上述环系任选自下述基团的相同或不同取代基 最高达 3次取代： 氨基、 硝基、 氰基、 F、 Cl、 Br、 I、 羟基、 三氟甲基、 三氟甲氧基、 苄基、 -C4的烷基， -C4的烷氧基、 -( 4的烷氧羰基、 d- 的烷基氨基、 -C4的二烷基氨基、 CrC4的酰胺基、 C,-C4的酰氧基、 C,-C4的酰基、 C,-Q的烷硫基、 C,-C4的垸亚磺酰基、 C,-C4 的烷磺酰基； R2代表氨基、 硝基、 F、 Cl、 Br、 羟基、 三氟甲基、 三氟甲氧基、 苄基、 C,-C4 的烷基， C,-C4的垸氧基、 - 的垸氧羰基、 CrC4的銑胺基、 -C4的酰基、 C,-C4的酰氧 基， 或苯基、 或含有 1-4个选自 N、 S、 0的杂原子取代的 5-12个原子的杂芳基， 所述杂芳 基为吡啶基、 嘧啶基、 呋喃基、 噻吩基、 ^唑基、 咪唑、 噻唑或噻嗪， 或其中上述环系任选 自下述基团的相同或不同取代基， 最高达 3次取代： F、 Cl、 Br、 1、 三氟甲基、 三氟甲氧 基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 d-C6的烷氧基、 CrC6的烷氧羰基、 C,-C6 的烷硫基、 -C6的烷亚磺酰基、 d-C6的烷磺酰基、 CrC6的酰基、 或 CrC6的垸基， 或其 所述烷基被具有 6-10个碳原子的芳基或卤素取代； A代表一个鍵、 -0-,、 -S -、 或 -NRn-， 其中 1^是 14、 d-C6的垸氧羰基、 或直链、 支链、 或环状饱和或不饱和 CrC6的烃基， 或所 述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 - H- ( -C4烷基）、 -N- ( C!-C^烷基） 2、 相同或不同杂链单元， 并且任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基或杂芳基取代； R3代表 H、 -C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 CrCfi的烃基,或所述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 -NH- ( d-C4烷基）、 -N- ( CrC4烷基） 2、 相同或不同杂链单元， 并且可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 -NRI2RI 3 所示基团取代， 其中 Rl2和 Rl 3相同或不同， 并分别代表氢、 苄基或 C,-C6的烷基； R代表 氢、 氨基、 甲基， 其中当 R为甲基时， ^不能是未取代吡啶基、 噻唑基、 取代苯基、 呋喃 基、 噻吩基、 咪唑基； 或 R代表式 Some of these examples are R in the formulae U) and (la), representing amino, nitro, F, Cl, Br, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, -C 4 alkane a decyloxy group of CC 4 , an alkoxycarbonyl group of d-, an amide group of C'-C 4 , an acyloxy group of C r C 4 , an acyl group of d- or an unsubstituted pyridyl group; or a phenyl group or a thiazole a group, a 3⁄4 pyridine group, a thienyl group, a furyl group, a pyrrolidinyl group, an imidazolyl group, a thiazinyl group; or a substituent wherein the above ring system is selected from the group consisting of the same or different substituents up to 3 substitutions: amino group, nitrate , cyano, F, Cl, Br, I, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, -C4 alkyl, -C 4 alkoxy, -( 4 alkoxycarbonyl , d- alkylamino, di- -C 4 alkylamino is, C r C 4, an amide group, C, -C 4 acyloxy group, C, -C 4 acyl group is, C, -Q is alkylthio a sulfinyl group of C, C, -C 4 , an alkylsulfonyl group of C, -C 4 ; R 2 represents an amino group, a nitro group, an F, a Cl, a Br, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group, benzyl, C, -C 4 alkyl group is, C, -C 4 alkoxy embankment, and - the oxygen embankment Group, CrC milling group 4, -C 4 acyl, and C, -C 4 acyloxy group, or a phenyl group, or contain 1-4 heteroatoms selected from N, S, 0 is substituted heteroatom 5-12 a heteroaryl group of an atom, wherein the heteroaryl group is pyridinyl, pyrimidinyl, furyl, thienyl, oxazolyl, imidazole, thiazole or thiazine, or wherein the above ring system is selected from the group consisting of the following groups Or different substituents up to 3 substitutions: F, Cl, Br, 1, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, nitro, cyano, carboxyl, hydroxy, dC 6 alkane alkoxy, C r C 6 alkoxycarbonyl group, C, -C 6 alkylthio, -C 6 alkylsulfinyl group, and alkylsulfonyl group dC 6, C r C 6 acyl group, or a C r C 6 The thiol group, or the alkyl group thereof, is substituted by an aryl group having 6 to 10 carbon atoms or a halogen; A represents a bond, -0-, -S-, or -NR n -, wherein 1^ is 14 a hydrocarbyl carbonyl group of dC 6 or a linear, branched, or cyclic saturated or unsaturated C r C 6 hydrocarbyl group, or the hydrocarbyl group optionally containing 1-2 selected from 0, S, S0 2 , CO , NH, -H-(-C 4 alkyl), -N-( C!-C^alkyl) 2 , The same or different heterochain units, and optionally substituted by halogen, nitro, cyano, hydroxy, aryl having 6-10 carbon atoms, aralkyl or heteroaryl having 6-10 carbon atoms; 3 represents an alkoxycarbonyl group of H, -C 6 , or a linear, branched, or cyclic saturated or unsaturated CrCfi hydrocarbon group, or the hydrocarbon group optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH-(dC 4 alkyl), -N-(CrC 4 alkyl) 2, identical or different heterochain units, and optionally halogen, nitro, cyano, hydroxy, having 6- An aryl group of 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula -NR I2 R I 3 wherein R l2 and R l 3 are the same or different and are respectively Representing hydrogen, benzyl or C,-C 6 alkyl; R represents hydrogen, amino, methyl, wherein when R is methyl, ^ cannot be unsubstituted pyridyl, thiazolyl, substituted phenyl, furan Base, thienyl, imidazolyl; or R represents
H3CO^/ H 3 CO^/
OCH  OCH
所示的基团， 或代表甲酰基、 氰基、 三氟甲基、 环丙基或吡啶基； 或代表 -X-Z, 其中， X代 表 -CH2-、 -CH2-CH2-、 -CH2-CH2-CH2-或 (C=0)-， The group shown, either represents formyl, cyano, trifluoromethyl, cyclopropyl or pyridyl; or represents -XZ, wherein X represents -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - or (C=0)-,
Z代表卤素， 当 Z为 Br， X为 -CHr时， R,不能为噻唑 -2-基和未取代吡啶基； Z represents halogen, when Z is Br and X is -CH r , R, cannot be thiazol-2-yl and unsubstituted pyridyl;
或 Z代表甲苯磺酰氧基、 甲磺酰氧基、 苯基、 吡啶基、
Figure imgf000006_0001
、 或 NR14RI 5， 其中 Rl4和 Rl5可以相同或不同， 代表 C C4的垸基， 所述烷基任选地被羟基、 的烷氧羰基取代， 或 Rl4、 Rl 5和 N原子键合成一个杂环， 所述杂环是： 咪唑、 三唑、 四唑或下述通式所示的基团：
Figure imgf000006_0002
Or Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl,
Figure imgf000006_0001
Or NR 14 R I 5 , wherein R l4 and R l5 may be the same or different and represent a fluorenyl group of CC 4 which is optionally substituted by a hydroxy, alkoxycarbonyl group, or R l4 , R l 5 and The N atom bond synthesizes a heterocyclic ring which is: imidazole, triazole, tetrazole or a group represented by the following formula:
Figure imgf000006_0002
其中， B代表" (CH2)n- (n=0, l 或 2)、 -CFr、 -CHF- 或 (C=0)-; Y 代表 CHr、 -CH2-CH2- 、 -0、 -8、 -50-、 802-或 NR16 ，其中 R16 代表氢、 CO-CH3、 -CO-CF3、 -CO-0-Rl 7或 CO-NR18R19， Rl 7， R18 > Rl 9可以相同或不同， 代表 H或C1-C8的垸基； R20代表氢、 卤素， 氰基， 叠氮基， 氨基， C5-C7的杂环， d- 的垸基、 Cr 的垸氧基、 d-C4的烷硫基、 d- 的烷亚磺酰基、 CrC4的磺酰基、 d-C4的酰基、 硝基、 三氟甲基； 在上述定义中， 当 R为吗啉 -4-基-甲基， Ri为噻唑 -2-基， R3为- CH3, A为 O时， R2不为 2,4-二氯-苯基; 代表氢、 <^-(：4的垸基、 -C5的烷氧羰基、 Cr 的酰基或苯甲酰基。 Wherein B represents "(CH 2 ) n - (n = 0, l or 2), -CF r , -CHF- or (C = 0)-; Y represents CH r , -CH 2 -CH 2 - , - 0, -8, -50-, 80 2 - or NR 16 , wherein R 16 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l 7 or CO-NR 18 R 19 , R l 7 , R 18 > R l 9 may be the same or different and represent H or C 1 -C 8 fluorenyl; R 20 represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocycle , d- the embankment group, C r of the embankment group, dC 4 alkylthio, d- alkyl sulfinyl, C r C 4 alkylsulfonyl, dC 4 acyl, nitro, trifluoromethyl; In the above definition, when R is morpholin-4-yl-methyl, Ri is thiazol-2-yl, R 3 is -CH 3 , and A is O, R 2 is not 2,4-dichloro-benzene. a group representing hydrogen, <^-(: 4 fluorenyl group, -C 5 alkoxycarbonyl group, Cr acyl group or benzoyl group.
其中一些实施例是通式 （I ) 和 （la ) 中的 代表氨基、 硝基、 F、 Cl、 Br、 羟基、 三 氟甲基、 CrC4的烷基， 或未取代吡啶基； 或苯基、 噻唑基、 嘧啶基、 噻吩基、 呋喃基、 吡 咯烷基、 咪唑基、 噻嗪基； 或其中上述环系任选自下述基团的相同或不同取代基， 最高达 3 次取代： 硝基、 氨基、 F、 Cl、 Br, 羟基、 三氟甲基、 苄基、 - 的烷基， d- 的烷氧基、 - 的烷氧羰基、 C 的酰胺基、 d-C4的酰氧基； R2代表氨基、 硝基、 F、 Cl、 Br、 羟 基、 三氟甲基、 d-C4的烷基； 或苯基、 或含有 1 -4个选自 N、 S、 O 的杂原子取代的 5- 12 个原子的杂芳基， 所述杂芳基是吡啶基、 嘧啶基、 噻吩基、 噁唑基、 噻唑基、 噻嗪基； 或其 中上述环系任选自下述基团的相同或不同取代基， 最高达 3次取代： F、 Cl、 Br、 三氟甲基、 硝基、 氰基、 羧基、 羟基、 C,-C4的烷氧基、 C,-C4的垸氧羰基、 CrC4的酰基、 或 C,-C4的 烷基； 或所述烷基被卤素、或具有 6-8个碳原子的芳基取代； A代表一个键、 -0-、或 -NRn -， R H、 d-C4的烷氧羰基, 环丙烷、 C2-C4的链烯基、 CrC4的烷基， 所述垸基任选吡啶基、 氰基、 苯氧基或苄基； R3代表 H、 CrC4的垸氧羰基， 环丙烷基、 C2-C4的链烯基、 ,-< 4的 烷基， 所述烷基任选吡啶基、 氰基、 苯氧基、 苄基或式 -NR12R13所示基团取代， R12和 R13 相同或不同， 并分别代表氢、 苄基或 CrC4的烷基； R代表氢、 氨基、 甲基， 其中当 R为甲 基时， ^不能是未取代吡啶基、 噻唑基、 取代苯基、 呋喃基、 噻吩基、 咪唑基； 或代表式
Figure imgf000006_0003
Some of the examples are alkyl, nitro, F, Cl, Br, hydroxy, trifluoromethyl, CrC 4 alkyl, or unsubstituted pyridyl in formula (I) and (la); or phenyl , thiazolyl, pyrimidinyl, thienyl, furanyl, pyrrolidinyl, imidazolyl, thiazinyl; or the same or different substituents wherein the above ring system is selected from the group consisting of up to 3 substitutions: Base, amino, F, Cl, Br, hydroxy, trifluoromethyl, benzyl, -alkyl, d-alkoxy, -alkoxycarbonyl, C amide, dC 4 acyloxy; R 2 represents an amino group, a nitro group, a F, Cl, Br, a hydroxyl group, a trifluoromethyl group, an alkyl group of dC 4 ; or a phenyl group, or a hetero atom substituted with 1 to 4 selected from N, S, O a 12 atom heteroaryl group, wherein the heteroaryl group is pyridinyl, pyrimidinyl, thienyl, oxazolyl, thiazolyl, thiazinyl; or wherein the above ring system is the same or selected from the group consisting of different substituents, up to 3 substituents: F, Cl, Br, trifluoromethyl, nitro, cyano, carboxy, hydroxy, C, -C 4 alkyl is Group, C, -C 4 embankment oxycarbonyl group, an acyl group CrC 4, or C, and -C 4 alkyl group; and said alkyl or halogen, having 6-8 carbon atoms, or a substituted aryl group; A representatives a bond, -0-, or -NR n -, an alkoxycarbonyl group of RH, dC 4 , a cyclopropane, an alkyl group of C 2 -C 4 , an alkyl group of C r C 4 , optionally a pyridine group a cyano group, a cyano group, a phenoxy group or a benzyl group; R 3 represents an oxime oxycarbonyl group of H, C r C 4 , a cyclopropyl group, an alkenyl group of C 2 -C 4 , an alkyl group of -< 4 , The alkyl group is optionally substituted with a pyridyl group, a cyano group, a phenoxy group, a benzyl group or a group of the formula -NR 12 R 13 , and R 12 and R 13 are the same or different and each represent an alkane of hydrogen, benzyl or CrC 4 R represents hydrogen, amino, methyl, wherein when R is methyl, ^ cannot be unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl, imidazolyl; or
Figure imgf000006_0003
所示的基团， 或代表甲酰基、 氰基、 三氟甲基、 环丙基或吡啶基， 或代表 -X-Z, X代表 -CH2- 或 -CHrCHr, 其中， The group shown, or represents formyl, cyano, trifluoromethyl, cyclopropyl or pyridyl, or represents -XZ, X represents -CH 2 - or -CH r CH r , wherein
Z代表卤素、 当 Z为 Br, X为 -CHr时， R,不能为噻唑 -2-基和未取代吡啶基。 或 Z代表曱苯磺酰氧基、 曱磧酰氧基、 吡啶基、
Figure imgf000007_0001
、 、 或 NR14R15, 其中 R14和 Rl 5相同或不同， 代表 的烷基， 所述烷基任选地被羟基、 CrC3的烷氧羰基 取代， 或 R14,RI 5和 N原子键合成一个杂环， 所述杂环是： 咪唑、 三唑、 四唑或下述通式所 示的基团：
Figure imgf000007_0002
Z represents halogen, when Z is Br, and X is -CH r , R is not a thiazol-2-yl group and an unsubstituted pyridyl group. Or Z represents phenylbenzenesulfonyloxy, decanoyloxy, pyridyl,
Figure imgf000007_0001
, Or NR 14 R 15, wherein R 14 and R l 5 identical or different, represent alkyl, said alkyl optionally substituted by hydroxy, C r C 3 alkoxycarbonyl substituent, or R 14, R I 5 and N atom bond to synthesize a heterocyclic ring, which is: imidazole, triazole, tetrazole or a group represented by the following formula:
Figure imgf000007_0002
其中， B代表 ~<CH2)n- (η=0, 1 )或 (C=0)-; Y 代表 CH2-、 -CH2-CH2-、 -0、 -S、 -SO-, S02- 或 NR16，其中 Rl6代表氢、 CO-CH3、 -CO-CF3、 -CO-0-Rl 7或 CO-NR18R19, 其中 R17, RI 8, Rl9可以相同或不同， 代表 ^^或 - C4的烷基； R20代表氢、 卤素、 氰基、 叠氮基、 氨基、Wherein B represents ~<CH 2 ) n - (η=0, 1 ) or (C=0)-; Y represents CH 2 -, -CH 2 -CH 2 -, -0, -S, -SO-, S0 2 - or NR 16 , wherein R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l 7 or CO-NR 18 R 19 , wherein R 17 , R I 8 , R l9 The same or different, representing an alkyl group of ^^ or -C 4 ; R 20 represents hydrogen, halogen, cyano, azide, amino,
C-C,的烷基、 c,-c2的烷氧基、 c,-c2的烷巯基、 c,-c2的烷亚磺酰基、 c,-c2的磺酰基、 c,-c2 的酰基、《肖基或三氟甲基；在上述定义中，当 R为吗啉 -4-基-甲基， R,为噻唑 -2-基， R3为 -CH3 , A为 0时， R2不为 2,4-二氯-苯基； R4代表氢、 CrC5的垸氧羰基、 d-C5的酰基或苯甲酰基。 CC, alkyl, c, -c 2 alkoxy, c, -c 2 alkanoyl, c, -c 2 alkylsulfinyl, c, -c 2 sulfonyl, c, -c 2 acyl, "Shockey or trifluoromethyl; in the above definitions, when R is morpholin-4-yl - methyl group, R, is 2-yl, R 3 is -CH 3, a is 0 , R 2 is not a 2,4-dichloro - phenyl; R4 represents hydrogen, C r embankment oxycarbonyl group is C 5, dC or benzoyl 5.
其中一些实施例是通式（I ) 和 Ua ) 中的 代表（^-(：3的烷基， 或未取代吡啶基； 或 苯基、 噻唑基、 嘧啶基、 噻吩基、 呋喃基、 咪唑基； 其中上述环系任选自下述基团的相同或 不同取代基， 最高达 3 次取代： 硝基、 氨基、 F、 Cl、 Br, 三氟甲基、 -C3的烷基； R2代 表 CrC3的烷基， 或苯基、 或含有 1 -2个选自 N、 S、 O的杂原子取代的 C5-C6的杂芳基， 所 述杂芳基是吡啶基、 嘧啶基、 噻吩基、 噁唑基或噻唑基， 其中上述环系任选自下述基团的相 同或不同取代基， 最高达 3次取代： F、 Cl、 Br、 三氟甲基、 C!- 的烷基， 所述烷基被卤素 取代； A代表 -0-、 -NRi r,其中 RM代表氢或 d-C4的烷基; R3代表氢、 d-C4的烷基； R代 表氨基或甲基， 其中当 R为甲基时， ！^不能是未取代吡啶基、 噻唑基、 取代苯基、 呋喃基、 噻吩基、 咪唑基； 或代表 -X-Z, X代表 -CHr， Z代表 F、 Cl、 Br、 当 Z为 Br, X为 -CHr时， R,不能为噻唑 -2-基和未取代吡啶基。 Some of the examples are represented by the formula (I) and Ua) (^-(: 3 alkyl, or unsubstituted pyridyl; or phenyl, thiazolyl, pyrimidinyl, thienyl, furyl, imidazolyl) Wherein the above ring system is the same or different substituents selected from the group consisting of up to 3 substitutions: nitro, amino, F, Cl, Br, trifluoromethyl, -C 3 alkyl; R 2 An alkyl group representing CrC 3 , or a phenyl group, or a C 5 -C 6 heteroaryl group substituted with 1 to 2 hetero atoms selected from N, S, O, which is a pyridyl group or a pyrimidinyl group Or a thienyl group, an oxazolyl group or a thiazolyl group, wherein the above ring system is the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br, trifluoromethyl, C!- An alkyl group, the alkyl group being substituted by a halogen; A representing -0-, -NR ir , wherein R M represents hydrogen or an alkyl group of dC 4 ; R 3 represents hydrogen, an alkyl group of dC 4 ; R represents an amino group or a methyl group wherein when R is methyl, ^ is not unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl, imidazolyl;! or represents -XZ, X Representative -CH r, Z Table F, Cl, Br, when Z is Br, X is -CH r, R, is not thiazol-2-yl and unsubstituted pyridyl.
或 Z代表甲笨磺酰氧基、 甲磺酖氧基、 吡啶基、
Figure imgf000007_0003
或 NR14R 1 |4,1 | 5和 N原子键合成一个杂环， 所述杂环是下述通式所示的基团：
Figure imgf000007_0004
Or Z represents methyl sulfonyloxy, methylsulfonyloxy, pyridyl,
Figure imgf000007_0003
Or a NR 14 R 1 |4 , 1 | 5 and N atom bond to synthesize a heterocyclic ring which is a group represented by the following formula:
Figure imgf000007_0004
其中， B代表" CH2-或 (C=0)-; Y代表 CHr、 -0、 -S、 -SO-、 S02-或 NR16, R,6代表氢、 CO-CH3. -CO-CF3、 -CO-0-Rl7或 CO-NRl 8Rl9, R,7, R18, Rl 9可以相同或不同， 代表 11或（：|- (：4的 烷基； R2。代表氢、 卤素、 氰基、 叠氮基、 氨基、 C C2的烷基、 d-C2的烷氧基、 Ci-C2的酰 基、 硝基或三氟甲基； 在上述定义中， 当 R为吗啉 -4-基-甲基， 为噻唑 -2-基， R3为 -CH3, A为 0时， R2不为 2,4-二氯-苯基; R4代表氢、 d- 的酰基。 Wherein B represents "CH 2 - or (C=0)-; Y represents CH r , -0, -S, -SO-, S0 2 - or NR 16 , and R, 6 represents hydrogen, CO-CH 3 . - CO-CF 3 , -CO-0-R l7 or CO-NR l 8 R l9 , R, 7 , R 18 , R l 9 may be the same or different and represent 11 or (: | - (: 4 alkyl; R 2 represents hydrogen, halogen, cyano, azido, amino, CC 2 alkyl, dC 2 alkoxy, Ci-C 2 acyl, nitro or trifluoromethyl; in the above definition, When R is morpholin-4-yl-methyl, thiazol-2-yl, R 3 is -CH 3 , when A is 0, R 2 is not 2,4-dichloro-phenyl; R 4 represents hydrogen, The acyl group of d-.
其中一些实施例是通式 U ) 和 （la ) 中的 代表苯基、 噻吩基、 呋喃基、 咪唑基、 上述环系任选自下述基团的相同或不同取代基， 最高达 2次取代： 三氟甲基、 氨基、 F、 Cl、 C,-C3的烷基， R2代表苯基， 其任选自下述基团的相同或不同取代基， 最髙达 3次取代： F、 Cl、 Br、 三氟甲基、 C,-C3的烷基， 所述烷基被卤素取代； A代表 -0-、 -NRu-，其中 Ru代表 氢或 C,-C4的烷基； R3代表氢、 CrC4的烷基； R代表 -CH3, 其中当 R为甲基时， R1不能是 未取代吡啶基、 噻唑基、 取代苯基、 呋喃基、 噻吩基、 咪唑基； 或 R代表 -Χ-Ζ,Χ代表 -CHr, Z代表 F、 Cl、 Br, 当 Z为 Br, X为 -CH2-时， 不能为噻唑 -2-基和未取代吡啶基； 或 Z代 表甲苯磺酰氧基、 甲磺酰氧基或 NRMRI5, Some of the examples are the same or different substituents of the formula U) and (la) which represent a phenyl group, a thienyl group, a furyl group, an imidazolyl group, or a ring system selected from the group consisting of the following groups, up to 2 substitutions. : a trifluoromethyl, amino, F, Cl, C, -C 3 alkyl group, R 2 represents a phenyl group, which is selected from the same or different substituents of the following groups, up to 3 substitutions: F , Cl, Br, trifluoromethyl, C, -C 3 alkyl, the alkyl is substituted by halogen; A represents -0-, -NR u -, wherein R u represents hydrogen or C, -C 4 alkyl group; R. 3 represents hydrogen, C r C 4 alkyl group; R Representative -CH 3, wherein when R is methyl, R1 is not Unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl, imidazolyl; or R represents -Χ-Ζ, Χ represents -CH r , Z represents F, Cl, Br, when Z is Br, X is -CH 2 -, not thiazol-2-yl and unsubstituted pyridyl; or Z represents toluenesulfonyloxy, methanesulfonyloxy or NR M R I5 ,
R ，RI5和 N原子键合成一个杂环， 所述杂环是下述通式所示的基团：
Figure imgf000008_0001
R, R I5 and N atom bond to form a heterocyclic ring, which is a group represented by the following formula:
Figure imgf000008_0001
其中 B代表^ CH2-或 (C=0)-; Y 代表 -0、 -S 、 -SO-、 SOr或 NRI6, Rl6代表氢、 CO-CH3、 -CO-CF3、 -CO-0-R,7 或 CO-NRl8Rl9， R17, R,8, Rl9可以相同或不同， 代表 H或 C!-C)的 烷基， R20代表氢、 έ素； 在上述定义中， 当 R为吗啉 -4-基-甲基， R,为噻唑 -2-基， R3为- CH3， A为 0时， R2不为 2,4-二氯-苯基； 代表氢。 Wherein B represents ^ CH 2 - or (C=0)-; Y represents -0, -S, -SO-, SO r or NR I6 , and R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , - CO-0-R,7 or CO-NR l8 R l9 , R 17 , R, 8 , R l9 may be the same or different, represent an alkyl group of H or C!-C), R 20 represents hydrogen, halogen; In the above definition, when R is morpholin-4-yl-methyl, R is thiazol-2-yl, R 3 is -CH 3 , and when A is 0, R 2 is not 2,4-dichloro-benzene. Base; represents hydrogen.
其中一些实施例是通式 （I) 和 （la) 中的 R1代表噻吩基、 呋喃基、 咪唑基， 上述环 系任选自下述基团的相同或不同取代基， 最高达 2次取代： F、 Cl、 < ,-<：3的烷基， R2代表 苯基， 任选自下述基团的相同或不同取代基， 最高达 3 次取代： F、 Cl、 Br, 三氟甲基； A 代表 -0-、 -NH-; R3代表氢、 C'- 的烷基； R代表 -CH3, 其中当 R为甲基时， 不能是未 取代吡啶基、 噻唑基、 取代苯基、 呋喃基、 噻吩基、 咪唑基； 或 R代表 -X-Z, X代表 -CHr; Z代表 Br, 当 Z为 Br, X为 -CHr时， 不能为噻唑 -2-基和未取代吡啶基； 或 Z代表甲苯 磺酰氧基、 甲磺酰氧基或 1 14115,1 14，1 |5和 N原子键合成一个杂环， 所述杂环是下述通式 所示的基团：
Figure imgf000008_0002
Some of the examples are that R1 in the formulae (I) and (la) represents a thienyl group, a furyl group, an imidazolyl group, and the above ring system is the same or different substituents selected from the group consisting of up to 2 substitutions: F, Cl, <, -<: 3 alkyl, R 2 represents a phenyl group, the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br, trifluoromethyl A represents -0-, -NH-; R 3 represents hydrogen, C'-alkyl; R represents -CH 3 , wherein when R is methyl, it cannot be unsubstituted pyridyl, thiazolyl, substituted phenyl , furanyl, thienyl, imidazolyl; or R represents -XZ, X represents -CH r ; Z represents Br, when Z is Br, and X is -CH r , it cannot be thiazol-2-yl and unsubstituted pyridyl Or Z represents a toluenesulfonyloxy group, a methanesulfonyloxy group or a 1 14 1 15 , 1 14 , 1 |5 and N atom bond to form a heterocyclic ring, which is a group represented by the following formula: :
Figure imgf000008_0002
其中， B代表 ~CHr或 (C=0)-; Y 代表 -0、 -S、 -SO-, SOr或 NRI6, Rl6代表氢、 CO-CH3、 -CO-CF3、 -CO-0-Rl7或 CO-NR18Rl9, 其中 Rl7, Rl8, Rl9可以相同或不同， 代表 H或 - 的烷基， 1½代表氢； 在上述定义中， 当 R为吗啉 -4-基-甲基， R,为噻唑 -2-基， R3为 -CH3, A为 0时， R2不为 2,4-二氯-苯基； 代表氢。 Wherein B represents ~CH r or (C=0)-; Y represents -0, -S, -SO-, SO r or NR I6 , and R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , - CO-0-R l7 or CO-NR 18 R l9 , wherein R l7 , R l8 , R l9 may be the same or different and represent an alkyl group of H or -, and 11⁄2 represents hydrogen; in the above definition, when R is morpholine 4-yl-methyl, R, is thiazol-2-yl, R 3 is -CH 3 , when A is 0, R 2 is not 2,4-dichloro-phenyl; represents hydrogen.
其中一些实施例是通式 （1) 和 （la) 中的 代表噻吩基、 呋喃基、 咪唑基， 上述环 系任选自下述基团的相同或不同取代基， 最高达 2次取代： F、 CI. Br; R2代表苯基， 任选 自下述基团的相同或不同取代基， 最高达 3 次取代： F、 Cl、 Br; A代表 -0-、 -NH-; R3代 表氢、 （：1 2的烷基， R代表 -CH3, 其中当 R为甲基时， ^不能是未取代吡啶基、 噻唑基、 取代苯基、 呋喃基、 噻吩基、 咪唑基； 或代表 -X-Z，X代表 -CHr， Z代表 Br, 当 Z为 Br， X 为 -CH2-时， 不能为噻唑 -2-基和未取代吡啶基； 或 Z代表甲苯磺酰氧基、 甲磺酰氧基、 或 NRI4R,5, RI4，RI5 和 N 原子键合成一个杂环， 其所述杂环是下述通式所示的基团：
Figure imgf000008_0003
Some of the examples are represented by the formula (1) and (la), wherein the above ring system is the same or different substituents selected from the group consisting of the following groups: up to 2 substitutions: F , CI. Br; R 2 represents a phenyl group, the same or different substituents selected from the group consisting of up to 3 substitutions: F, Cl, Br; A represents -0-, -NH-; R 3 represents hydrogen, (: alkyl, R 2 represents 1 -CH 3, wherein when R is methyl, ^ is not unsubstituted pyridyl, thiazolyl, substituted phenyl, furyl, thienyl, imidazolyl; or represents -XZ, X represents -CH r , Z represents Br, when Z is Br, X is -CH 2 -, it cannot be thiazol-2-yl and unsubstituted pyridyl; or Z represents toluenesulfonyloxy, methylsulfonate An acyloxy group, or an NR I4 R, 5 , R I4 , R I5 and N atom bond to form a heterocyclic ring, the heterocyclic ring being a group represented by the following formula:
Figure imgf000008_0003
其中 B代表 ~CH2-或 (C=0)-; Y 代表 -0、 -S、 -SO-、 SOr、 NR,6, Rl6代表氢、 CO-CH3、 -CO-CF3、 -CO-0-Rl7或 CO-NR18R19, 其中 R17, R,8, Rl9可以相同或不同， 代表 H或 d- 的烷基， R20代表氢； 在上述定义中， 当 R为吗啉 -4-基-甲基， R,为噻唑 -2-基， R3为 -CH3， A为 0时， R2不为 2,4-二氯-苯基； 代表氢。 Wherein B represents ~CH 2 - or (C=0)-; Y represents -0, -S, -SO-, SO r , NR, 6 , and R l6 represents hydrogen, CO-CH 3 , -CO-CF 3 , -CO-0-R l7 or CO-NR 18 R 19 , wherein R 17 , R, 8 , R l9 may be the same or different, represent an alkyl group of H or d-, and R 20 represents hydrogen; in the above definition, R is morpholin-4-yl-methyl, R is thiazol-2-yl, R 3 is -CH 3 , and when A is 0, R 2 is not 2,4-dichloro-phenyl; represents hydrogen.
本发明通式 （I) 和 （la) 化合物或其盐或水合物还可以为下述具体的化合物： 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-甲酸甲酯、 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-甲酸乙酯、 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-甲酸乙酯、 4- (2-溴苯基) -6- (一氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-甲酸甲酯、 4- (2-溴苯基) -6- (一氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-甲酸乙酯、 4- ( 2-溴苯基） -6- (二氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基 ) -1,4-二氢嘧啶 -5-甲酸甲酯、The compound of the formula (I) and (la) of the present invention or a salt or hydrate thereof may also be a specific compound: 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl) -methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester, 4-(2-chloro-4-fluorophenyl)-6-(morpholine-4 -yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2,4-dichlorophenyl)-6- (morpholine- 4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2-bromophenyl)-6-(monooxythio? Phenyl-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester, 4-(2-bromophenyl)-6-(monooxysulfide Methylmorpholine-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate, 4-(2-Bromophenyl)-6-(dioxothiomorpholin-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester,
4- ( 2-溴苯基） -6- (二氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-甲酸乙酯、4-(2-Bromophenyl)-6-(dioxothiomorpholin-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester,
4- ( 2-氯苯基 ) -6- (一氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-甲酸甲酯、4-(2-Chlorophenyl)-6-(monooxathiomorpholin-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester,
4- (2-氯苯基) -6- (一氧硫代 啉 -4-基-甲基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-甲酸乙酯、4-(2-Chlorophenyl)-6-(monooxythioxo-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester ,
4- ( 2-氯苯基 ) -6- (二氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基 ) -1,4-二氢嘧啶 -5-甲酸甲酯、4-(2-Chlorophenyl)-6-(dioxothiomorpholin-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester,
4- ( 2-氯苯基） -6- (二氧硫代吗啉 -4-基-甲基） -2- (噻唑 -2-基 ) -1,4-二氢嘧啶 -5-甲酸乙酯、 乙基 4- (2-溴 -4-氟苯基) -6- (3-氧-哌嗪 -1-基-甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸 酯、 4-(2-Chlorophenyl)-6-(dioxothiomorpholin-4-yl-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid Ester, ethyl 4-(2-bromo-4-fluorophenyl)-6-(3-oxo-piperazin-1-yl-methyl)-2-(thiazol-2-yl)-1,4- Dihydropyrimidine-5-carboxylate,
乙基 4- (2-溴 -4-氟苯基) -6- ((4- (2, 2, 2-三氟乙酰基) 哌嗪 -1-基) 甲基） -2- (噻唑 -2- 基） -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazin-1-yl)methyl)-2-(thiazole- 2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-氯苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
乙基 4- (2-氯苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 甲基 4- (2-溴苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate methyl 4- (2-bromophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
乙基 4- (2-溴苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
2,2,2-三氟乙基- 4- (2-溴 -4-氟苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧 酸酯  2,2,2-Trifluoroethyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4- Dihydropyrimidine-5-carboxylate
乙基 6- ((4- (二甲基氨基甲酰基) 哌嗪小基） -4- (2-溴 -4-氟苯基） -2- (噻唑 -2 基） -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 6-((4-(dimethylcarbamoyl)piperazine) -4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-di Hydropyrimidine-5-carboxylate,
乙基 6- ( ( 4- (二乙基氨基甲酰基) 哌嗪小基） -4- (2-溴 -4-氟苯基) -2- (噻唑 -2 基） -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 6-((4-(diethylcarbamoyl)piperazine)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4- Hydropyrimidine-5-carboxylate,
乙基 4- (2-氯 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 乙基 4- (2-澳 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 乙基 4- (2-溴 -4-氟苯基） -6-溴甲基 -2- (氮甲基咪唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基) -6-溴甲基 -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 -Carboxylic acid ethyl 4-(2-A-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-di Hydropyrimidine-5-carboxylate ethyl 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-(nitromethylimidazol-2-yl)-1,4-dihydropyrimidine -5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate Acid ester,
乙基 4- (2-溴 -4-氟苯基） -6- (4-吗啉甲基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基） -6-甲基 -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(4-morpholinomethyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate Methyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-溴 -4-氟苯基) -6-溴甲基 -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-溴 -4-氟苯基） -6- (4-吗啉甲基) -2- (嘧啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、Methyl 4-(2-bromo-4-fluorophenyl)-6-(4-morpholinomethyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate ,
4- (2-溴 -4-氟苯基) -6-甲基 -2- (呋喃 -2-基) -1,4-二氢嘧啶 -5-乙酸乙酯、 4-(2-Bromo-4-fluorophenyl)-6-methyl-2-(furan-2-yl)-1,4-dihydropyrimidine-5-ethyl acetate,
4- (2-溴 -4-氟苯基) -6-溴甲基 -2- (呋喃 -2-基） -1,4-二氢嘧啶 -5-乙酸乙酯、  4-(2-Bromo-4-fluorophenyl)-6-bromomethyl-2-(furan-2-yl)-1,4-dihydropyrimidine-5-ethyl acetate
4- (2-溴 -4-氟苯基) -6- (4-吗啉甲基） -2- (呋喃 -2-基) -1,4-二氢嘧啶 -5-乙酸乙酯、 甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基甲基) -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基） -6- (吗啉 -4-基甲基） -2- (吡啶 -2-基) -1，4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基甲基) -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基） -6- (吗啉 -4-基甲基) -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基） -6- (哌嗪 -卜基甲基） -2- (吡啶 -2-基） -1，4-二氢嘧啶 -5-後酸酯、 乙基 4- (2,4-二氯苯基) -6- (哌嗪小基甲基） -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基) -6- (哌嗪 -卜基甲基） -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基） -6- ((4- (2, 2, 2-三氟乙酰基） 哌嗪小基） 甲基） -2- (噻唑 -2- 基） -1,4-二氢嘧啶 -5-羧酸酯、 4-(2-Bromo-4-fluorophenyl)-6-(4-morpholinemethyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5-ethyl acetate, A 4-(2-Chloro-4-fluorophenyl)-6-(morpholin-4-ylmethyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid Ester, methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-ylmethyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5- Carboxylic acid ester, ethyl 4- (2-chloro-4-fluorophenyl)-6-(morpholin-4-ylmethyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine -5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-ylmethyl)-2-(pyridin-2-yl)-1,4-di Hydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-6-(piperazine-buylmethyl)-2-(pyridin-2-yl)-1,4 -dihydropyrimidin-5-postate, ethyl 4-(2,4-dichlorophenyl)-6-(piperazinylmethyl)-2-(pyridin-2-yl)-1,4 -dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-6-(piperazine-buylmethyl)-2-(pyridin-2-yl)-1 , 4-dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazine) Methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5- Esters,
乙基 4- (2,4-二氯苯基） -6- ((4- (2, 2, 2-三氟乙酰基） 哌嗪小基） 甲基） -2- (噻唑 -2-基） -1，4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2,4-dichlorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazine)-methyl)-2-(thiazol-2-yl) ) -1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-溴 -4-氟苯基） -6- ((4-乙酰基)哌嗪-卜基） 甲基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2-bromo-4-fluorophenyl)-6-((4-acetyl)piperazine-buyl)methyl)-2-(thiazol-2-yl)-1,4-di Hydropyrimidine-5-carboxylate,
乙基 4- (2,4-二氯苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 甲基 4- ( 2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- ( 2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基） -1，4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基) -2- (卜甲基咪唑 -2-基） -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (噻吩 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (噻吩 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (呋喃 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (呋喃 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (吡咯烷基 -2-基） -1,4-二氢嘧啶 -5-羧酸 酯、 Ethyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic acid methyl 4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinyl)-1,4-dihydro Pyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1 , 4-dihydropyrimidine-5-carboxylate, methyl 4-(2,4-dichlorophenyl)-2-(b-methylimidazol-2-yl)-6-(4-morpholinylmethyl)- 1,4-Dihydropyrimidine-5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrimidine-2- -1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2- ( Pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl) -2-(Thien-2-yl)-1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl -methyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-6- (morpholine- 4-yl-methyl)-2-(thiophen-2-yl)- 1,4-Dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(furan-2 -yl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2- ( Furan-2-yl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl) -2-(pyrrolidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (吡咯烷基 -2-基） -1,4-二氢嘧啶 -5-後酸 酯、 Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrolidin-2-yl)-1,4-dihydropyrimidine- 5- post-ester,
乙基 4- ( 2,4-二氯苯基 ) -6- (吗啉 -4-基 -甲基 ) -2- (吡咯烷基 -2-基 ) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- ( 2-溴 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- ( 1,1-二氧噻嗪 -2-基) -1,4-二氢嘧啶 -5- 羧酸酯、 Ethyl 4-( 2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrolidin-2-yl)-1,4-dihydropyrimidine-5 -carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(1,1-dioxythiazin-2-yl -1,4-dihydropyrimidine-5-carboxylate,
乙基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (4H- ( 1'卜二氧） -1,4-噻嗪 -2-基) -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(4H-(1'-dioxa)-1,4-thiazine- 2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (4H- ( 1，1-二氧) -1,4-噻嗪 -2-基） -1,4-二 氢嘧啶 -5-羧酸酯、 Methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(4H-(1,1-dioxy)-1,4-thiazine- 2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (6H-1,2-噻嗪 -3-基） -1,4-二氢嘧啶 -5-羧酸 酯、 Methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4- Dihydropyrimidine-5-carboxylate,
甲基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基) -2- (6H-1,2-噻嗪 -3-基） -1,4-二氢嘧啶 -5-羧 酸酯、 Methyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4 -dihydropyrimidine-5-carboxylate,
甲基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基) -2- (6H-1，2-噻嗪 -3-基) -1,4-二氢嘧啶 -5-羧 酸酯、 Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4 -dihydropyrimidine-5-carboxylate,
乙基 4- ( 2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (6H-1,2-噻嗪 -3-基） -1,4-二氢嘧啶 -5-羧酸 酯、 Ethyl 4-( 2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4- Dihydropyrimidine-5-carboxylate,
乙基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (6H-1，2-噻嗪 -3-基) -1,4-二氢嘧啶 -5-羧 酸酯、 Ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4 -dihydropyrimidine-5-carboxylate,
乙基 4- (2-溴 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (6H-1,2-噻嗪 -3-基) -1,4-二氢嘧啶 -5-羧 酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4 -dihydropyrimidine-5-carboxylate,
乙基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2-苯基 -1，4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2-苯基 -1，4-二氢 啶-5-羧酸酯、 乙基 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2-苯基 -1，4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2-苯基 -1,4-二氢嘧 '啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基） -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (萘基 -6-基） -1，4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基） -2- (萘基 -6-基） -1，4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- ( 2-氯苯基 ) -6- (( 2-甲基吗啉 -4-基 ) 甲基） -2- (噻唑 -2-基 ) -1，4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2，4-二氯苯基) -6- (( 3-甲基吗啉 -4-基) 甲基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5- 羧酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate, B 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-phenyl-1,4-dihydropyridine-5-carboxylate, ethyl 4-(2,4-Dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate, methyl 4- (2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate, methyl 4-( 2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-phenyl-1,4-dihydropyridinium-5-carboxylate, methyl 4- (2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2 -Bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-dihydropyrimidine-5-carboxylate, Ethyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-dihydropyrimidine-5 -carboxylate, ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-di Hydropyrimidine-5-carboxylate, methyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)- 1,4-Dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl- 6-yl)-1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2- (naphthyl-6-yl)-1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2-chlorophenyl)-6-((2-methylmorpholin-4-yl) Methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2,4-dichlorophenyl)-6- ((3-A) Methylmorpholin-4-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4-苯基 -6- ((吡啶 -4-基) 甲基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-phenyl-6-((pyridin-4-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2,4-二氯苯基） -6- ((吡啶 -4-基） 甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基) -6-丁基 -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2,4-dichlorophenyl)-6-((pyridin-4-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Acid ester, methyl 4-(2-bromo-4-fluorophenyl)-6-butyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-溴 -4-氟苯基) -6- ((二乙基氨基) 甲基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸 酯、 Methyl 4-(2-bromo-4-fluorophenyl)-6-((diethylamino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate Acid ester,
N- ( 4-氟苯基 ) -4- ( 2-溴 -4-氟苯基 ) -6- (吗啉 -4-基甲基） -2- (吡嗪 -2-基 ) -1,4-二氢嘧啶 -5- 甲酰氨、  N-(4-fluorophenyl)-4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-ylmethyl)-2-(pyrazin-2-yl)-1, 4-dihydropyrimidine-5-formylamide,
4- ( 2-溴 -4-氟苯基 ) -6- (吗啉 -4-基甲基 ) -N- ((哌啶 -4-基 ) 甲基 ) -2- (吡嗪 -2-基 ) -1,4-二 氢嘧啶 -5-甲酰氨。  4-(2-Bromo-4-fluorophenyl)-6-(morpholin-4-ylmethyl)-N-((piperidin-4-yl)methyl)-2-(pyrazine-2- Base) -1,4-dihydropyrimidine-5-formylamide.
本发明化合物通式 （I) 或 （la)可通过下述方法制备：  The compound of the present invention of the formula (I) or (la) can be produced by the following method:
A. 首先将甲醛类化合物 （IV) 与通式 （V) 所示的 β-酮酯在加入或不加入碱或酸， 在 惰性有机溶剂存在下进行反应转化成通式 （VI) 所示的化合物： A. First, the formaldehyde compound (IV) and the β-ketoester represented by the formula (V) are reacted in the presence of an inert organic solvent with or without the addition of a base or an acid to form a compound represented by the formula (VI). Compound:
Figure imgf000011_0001
Figure imgf000011_0001
V V
VIVI
Figure imgf000011_0002
Figure imgf000011_0002
其中 R2 、 R3、 和 R的含义如前所述； Wherein R 2 , R 3 , and R have the same meanings as defined above;
然后， 将后者与通式 （VII) 所示的脒或者其盐， 在加入或不加入碱或酸， 在惰性有机 溶剂的情况下， 进行反应：
Figure imgf000011_0003
Then, the latter is reacted with a hydrazine of the formula (VII) or a salt thereof, with or without the addition of a base or an acid, in the presence of an inert organic solvent:
Figure imgf000011_0003
其中 R,、 R4含义如前所述， 或  Where R, R4 have the same meaning as before, or
B. 将通式 （V) 所示化合物同醛（IV)和脒 （VII) 或它们的盐在加入或不加入碱 或酸， 在惰性有机溶剂的情况下， 进行一步反应， 或  B. reacting a compound of the formula (V) with an aldehyde (IV) and hydrazine (VII) or a salt thereof in a one-step reaction with or without adding a base or an acid, in the case of an inert organic solvent, or
C. 当通式 （1 ) 或 （la) 中的 R是 -X-Z的形式， 将通式 （VIII)或 （Villa)所示化合 物
Figure imgf000012_0001
C. When R in the formula (1) or (la) is in the form of -XZ, a compound represented by the formula (VIII) or (Villa)
Figure imgf000012_0001
其中 R,、 R2、 R3 、 、 X和 Z含义如前所述， W是亲核取代基团， 诸如氯化物， 溴化物， 碘化物， 甲磺酰氧基或甲苯磺酰氧基， 与通式 （IX)或 （III)所示化合物
Figure imgf000012_0002
Wherein R, R 2 , R 3 , , X and Z have the same meanings as defined above, and W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyloxy, And a compound represented by the formula (IX) or (III)
Figure imgf000012_0002
其中 Rl4、 Rl5、 R2。含义如前所述， 在加入或不加入碱， 在惰性溶剂的条件下进行反应， D. 将通式 （IV)所示的醛与通式 （XII)所示的化合物， 以及通式 （VII)所示的脒在 加碱或不加碱的条件下进行反应， 在惰性溶剂中进行反应， Where R l4 , R l5 , R 2 . The meaning is as described above, the reaction is carried out in the presence of an inert solvent with or without the addition of a base, D. The aldehyde represented by the formula (IV) and the compound of the formula (XII), and the formula (VII) The hydrazine shown is reacted with or without a base, and the reaction is carried out in an inert solvent.
0  0
R3-A-C-C=C-R R 3 -ACC=CR
0 H 1 0 H 1
ΝΗ2 ( χιι) ΝΗ 2 ( χιι)
其中 13和1 含义如前所述。 Wherein 1 3 and 1 mean the foregoing.
为制备本发明的通式 （1)或 （la)所示化合物， 可将通式 （Va)所示的化合物与通式 化合物 （IX)或 （ΙΙΓ)反应来制备相应的 β-酮羧酸酯 （V), 不能通过此方法制备得到的， 可通过商业途径获得。  To prepare a compound of the formula (1) or (la) of the present invention, a compound represented by the formula (Va) can be reacted with a compound of the formula (IX) or (hydrazine) to prepare a corresponding β-ketocarboxylic acid. The ester (V), which cannot be prepared by this method, is commercially available.
0 0  0 0
w、  w,
X 'Α ( Va)  X 'Α ( Va)
其中 A、 R3 含义如前所述， W是亲核取代基团， 诸如氯化物， 溴化物， 碘化物， 甲磺 銑氧基或甲苯磺酰氧基。 Wherein A and R 3 have the same meanings as defined above, and W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyloxy.
本发明的方法可用下列反应方案举例说明:  The method of the invention can be illustrated by the following reaction scheme:
[A]  [A]
Figure imgf000012_0003
Figure imgf000012_0003
[B] [B]
Figure imgf000013_0001
Figure imgf000013_0001
Figure imgf000013_0002
Figure imgf000013_0002
用作起始物质的通式（ II)的醛是已知的， 或者可以按照文献中记载的已知方法制备 〔参 见 T. D. Harris和 G. P. Roth, 有机化学杂志， 44, 146 ( 1979 ), 德国公开 2 165260, July 1972,德国公开 2401665, July 1974, Mijano等人，化学文摘 59,(1963 ), 13929 c, E. Adler 和 H. -D. Becker, Chem. Scand. 15, 849(1961), E. P. Papadopoulos, M. Mardin 和 Ch. Issidoridis, 有机化学会志， 78, 2543 (1956)1 用作起始原料的 β-酮羧酸酯（III )是公知的， 或者是能够从文献公布的已知方法中类推 制得的 [如, D. Borrmann, "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" , in "Methoden der organ ischen Chemie" ( Houben-Weyl ), vol. VII/4, 230 ff ( 1968 ); Y. Oikawa, . Sugano und O. Yonemitsu, J. Org. Chem. 43 , 2087 ( 1978 ) ]。 The aldehyde of the formula (II) used as a starting material is known or can be prepared according to known methods described in the literature [see TD Harris and GP Roth, J. Org. Chem., 44, 146 (1979), published in Germany. 2 165260, July 1972, German publication 2401665, July 1974, Mijano et al., Chemical Abstracts 59, (1963), 13929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961), EP Papadopoulos, M. Mardin and Ch. Issidoridis, Journal of Organic Chemistry, 78, 2543 (1956)1 The β-ketocarboxylate (III) used as a starting material is well known or can be analogized from known methods published in the literature [e.g., D. Borrmann, "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen" , in "Methoden der organ ischen Chemie" ( Houben-Weyl ), vol. VII/4, 230 ff ( 1968 ); Y. Oikawa, . Sugano und O. Yonemitsu, J. Org. Chem. 43 , 2087 ( 1978)].
用作起始物质的通式化合物 （V ) 的脒在某些情况下是已知的， 或者可以按照文献中 记载的已知方法制备〔参见 Houben— Weyl , 有机化学方法， Vol. 1 1/2, 38页起（ 1958 ); R. L. Shoiner和 F. W. Neumann, 化学评论 35， 351 (1944)〕， 或可根据 WO-A-99/54326 和 WO-A-99/54329 的描述来制备.  The hydrazine of the formula (V) used as a starting material is known in some cases or can be prepared according to known methods described in the literature [see Houben-Weyl, Organic Chemistry, Vol. 1 1/ 2, 38 pages (1958); RL Shoiner and FW Neumann, Chemical Review 35, 351 (1944)], or may be prepared as described in WO-A-99/54326 and WO-A-99/54329.
化合物 （VII ) 或 （VII ) 可通过商业途径获得  Compound (VII) or (VII) is commercially available
化合物 ( VIII ) 和 ( X ) 可根据 WO-A-99/54326中描述的步骤 [A]或 [B ]制得。  The compounds (VIII) and (X) can be produced according to the procedure [A] or [B] described in WO-A-99/54326.
所有的惰性有机溶剂都适用于八、 B、 C和 D步骤。 其中优选的包括醇（如甲醇、 乙醇、 异丙醇）， 醚（如二恶烷、 二乙醚、 四氢呋喃、 乙二醇单甲醚， 乙二醇二甲醚）， 羧酸（诸如 冰醋酸）、 二甲基甲酰胺、 二甲基亚砜、 乙腈、 吡啶和六甲基磷酰三胺。  All inert organic solvents are suitable for the eight, B, C and D steps. Preferred among them are alcohols (e.g., methanol, ethanol, isopropanol), ethers (e.g., dioxane, diethyl ether, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether), carboxylic acids (such as glacial acetic acid). , dimethylformamide, dimethyl sulfoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.
反应温度可以在相当宽的范围内变化。 通常使用 20- 150Ό之间的温度， 但优选的是在所 选溶剂的沸点温度。  The reaction temperature can be varied within a relatively wide range. A temperature between 20 and 150 Torr is usually used, but is preferably at the boiling temperature of the selected solvent.
反应可以在大气压下进行， 也可以在高压下进行。 通常在大气压下进行。  The reaction can be carried out under atmospheric pressure or under high pressure. It is usually carried out under atmospheric pressure.
反应可以在加入或者不加入酸或者碱的环境下进行； 但是， 在弱酸诸如醋酸或者蚁酸等 的存在下进行反应是较好的。  The reaction can be carried out in the presence or absence of an acid or a base; however, it is preferred to carry out the reaction in the presence of a weak acid such as acetic acid or formic acid.
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发 明的其他化合物， 且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。 例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方 法完成， 如适当的保护干扰基团， 通过利用其他已知的试剂除了本发明所描述的， 或将反应 条件做一些常规的修改。 另外， 本发明所公开的反应或已知的反应条件也公认地适用于本发 明其他化合物的制备。  Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare a number of other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by modifications by those skilled in the art, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or The reaction conditions are subject to some conventional modifications. Additionally, the reactions or known reaction conditions disclosed herein are also recognized as being suitable for the preparation of other compounds of the invention.
下面所描述的实施例， 除非其他方面表明所有的温度定为摄氏度。 试剂购买于商品供应 都没有经过进一步纯化， 除非其他方面表明。 一般的试剂从汕头西陇化工厂， 广东光华化学 试剂厂， 广州化学试剂厂， 天津好寓宇化学品有限公司， 青岛腾龙化学试剂有限公司， 和青 岛海洋化工厂购买得到。  The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. Reagent purchases were not further purified unless otherwise indicated. The general reagents were purchased from Shantou Xiqiao Chemical Plant, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.
色谱柱是使用硅肢柱。硅胶（300-400目）购于青岛海洋化工厂。核磁共振光谱以 CDC 13, d6-DMSO， CD30D或 d6-丙酮为溶剂 (报导以 ppm为单位 ), 用 TMS (0 ppm) 或氯仿 (7.25 ppm)作为参照标准。 当出现多重峰的时候， 将使用下面的縮写： s (singlet, 单峰), d (doublet, 双峰）， t (triplet, 三重峰）， m (multiplet, 多重峰）， br (broadened, 宽峰）， dd (doublet of doublets, 四重峰)， dt (doublet of triplets, 双三重峰)。 偶合常数， 用赫兹 (Hz)表示。  The column is a silicon limb. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy was performed on CDC 13, d6-DMSO, CD30D or d6-acetone (reported in ppm) using TMS (0 ppm) or chloroform (7.25 ppm) as a reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet, unimodal), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide) Peak), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).
低分辨率质谱（MS )数据的条件是： Agilent 1200 Series LC S (Zorbax SB-C 18, 2.1 x 30 mm, 4 micorn, 10 min, 0.6 mL/min flow rate, 5 to 95% (0.1 % formic acid in CH3CN) in (0.1% formic acid in H20) with UV detection at 210/254 nm and a low resonance electrospray mode (ESI).  The conditions for low resolution mass spectrometry (MS) data are: Agilent 1200 Series LC S (Zorbax SB-C 18, 2.1 x 30 mm, 4 micorn, 10 min, 0.6 mL/min flow rate, 5 to 95% (0.1 % formic) Acid in CH3CN) in (0.1% formic acid in H20) with UV detection at 210/254 nm and a low resonance electrospray mode (ESI).
纯的化合物的表征方式为： Agilent 1 100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C 18, 2.1 x 30 mm, 4 micorn, 10 min, 0.6 mL/min flow rate, 5 to 95% (0.1% formic acid in CH3CN) in (0.1 % formic acid in H20). Column was operated at 40 0C.  Pure compounds are characterized by: Agilent 1 100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C 18, 2.1 x 30 mm, 4 micorn, 10 min, 0.6 mL/min Flow rate, 5 to 95% (0.1% formic acid in CH3CN) in (0.1 % formic acid in H20). Column was operated at 40 0C.
本发明化合物的药物组合物， 可以以下方面的任意方式施与： 口服、 喷雾吸入、 直肠给 药、 鼻腔给药、 阴道给药、 局部给药、 非肠道给药如皮下、 静脉、 肌肉、 腹膜机、 鞘内、 心 室内、 胸骨内或颅内注射或输入、 或借助一种外植的储器用药， 其中优选口服、 肌注、 腹膜 内或静脉内用药方式。 The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, muscular, Peritoneal machine, intrathecal, heart Intravenous, intrasternal or intracranial injection or input, or by means of an explanted reservoir, preferably oral, intramuscular, intraperitoneal or intravenous.
本发明化合物或含有本发明化合物的药物组合物可以单位计量形式给药，给药剂型可以 是液体剂型、 固体剂型、 液体剂型， 可以是真溶液类、 胶体类、 微粒剂型、 乳剂剂型、 混悬 剂型、 其他剂型， 如片剂、 胶囊、 滴丸、 气雾剂、 丸剂、 粉剂、 溶液剂、 混悬剂、 乳剂、 颗 粒剂、 栓剂、 冻干粉针剂、 包合物、 埋植剂、 贴剂、 搽剂等。  The compound of the present invention or the pharmaceutical composition containing the compound of the present invention can be administered in unit dosage form, and the dosage form can be a liquid dosage form, a solid dosage form, a liquid dosage form, and can be a true solution, a colloid type, a microparticle dosage form, an emulsion dosage form, and a suspension. Dosage form, other dosage forms, such as tablets, capsules, pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powders, inclusions, implants, stickers Agents, tinctures, etc.
本发明的药物组合物中还可以含有常用的载体， 这里所述可药用载体包括但不局限于： 离子交换剂、 氧化铝、 硬脂酸铝、 卵磷脂、 血清蛋白如人血清蛋白， 缓冲物质如磷酸盐、 甘 油、 山梨酸、 山梨酸钾、 饱和植物脂肪酸的部分甘油酯混合物， 水、 盐或电解质， 如硫酸鱼 精蛋白、 磷酸氢二钠、 磷酸氢钾、 氯化钠、 锌盐、 胶态氧化硅、 三硅酸镁、 聚乙烯吡咯烷酮、 纤维素物质、 聚乙二醇、 羧甲基纤维素钠、 聚丙烯酸酯、 蜂蜡、 羊毛酯等， 载体在药物组合 物中的重量含量可以是 1%-98%， 通常大约占到 80%, 为方便起见， 局部麻醉剂， 防腐剂， 缓冲剂等可直接溶于载体中。  The pharmaceutical composition of the present invention may further contain a usual carrier, and the pharmaceutically acceptable carrier herein includes, but is not limited to: ion exchanger, alumina, aluminum stearate, lecithin, serum protein such as human serum albumin, buffer. a substance such as phosphate, glycerol, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts , colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, etc., the weight content of the carrier in the pharmaceutical composition It may be from 1% to 98%, usually about 80%. For convenience, local anesthetics, preservatives, buffers and the like may be directly dissolved in the carrier.
口服片剂和胶囊剂可以含有赋形剂， 如粘合剂 （如糖剂， 阿拉伯胶， 山梨醇， 黄芪胶， 或聚乙烯吡咯烷酮）， 填充剂 （如乳糖、 蔗糖、 玉米、 淀粉、 磷酸钙、 山梨醇、 氨基乙酸）， 润滑剂 （如硬脂酸镁、 滑石、 聚乙二醇、 硅土）， 崩解剂 （如马铃薯淀粉）， 或可接受的增润 剂 （如月桂醇钠硫酸盐）， 片剂可以用制药学上公知的方法制备。  Oral tablets and capsules may contain excipients such as binders (eg, sugars, gum arabic, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (eg, lactose, sucrose, corn, starch, calcium phosphate) , sorbitol, glycine), lubricants (such as magnesium stearate, talc, polyethylene glycol, silica), disintegrants (such as potato starch), or acceptable sizing agents (such as sodium lauryl sulfate) Salts, tablets may be prepared by methods well known in the art of pharmacy.
口服也可以制成水和油的悬浮液， 溶液， 乳浊液， 糖浆或酊剂， 也可以制成干品， 使用 前补充水或其他适合的媒质， 这种液体制剂可以包含常规的添加剂， 如悬浮液（山梨醇， 纤 维素甲醚， 葡萄糖糖浆， 凝胶， 羟乙基纤维素， 羧甲基纤维素， 硬脂酸铝凝胶， 氢化的食用 油脂）， 乳化剂 （如卵磷脂， 山梨聚糖单油酸盐， 阿拉伯胶）； 或非水载体（可能包含可食用 油）， 如杏仁油， 油脂 （如甘油， 乙二醇， 或乙醇）； 防腐剂 （如对羟基苯甲酸甲酯或丙酯， 山梨酸）， 如需要可添加调味剂或着色剂。  Oral can also be prepared as a suspension of water and oil, a solution, an emulsion, a syrup or an elixir. It can also be made into a dry product, supplemented with water or other suitable medium before use. Such a liquid preparation may contain conventional additives, such as Suspensions (sorbitol, cellulose methyl ether, glucose syrup, gel, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils), emulsifiers (eg lecithin, sorbus) Monosaccharide monooleate, gum arabic); or non-aqueous carrier (may contain edible oils), such as almond oil, oils (such as glycerol, ethylene glycol, or ethanol); preservatives (such as methylparaben) Or propyl ester, sorbic acid), if necessary, add flavoring or coloring agents.
栓剂可包含常规的栓剂基质， 如可可黄油或其他甘油酯。  The suppository can comprise a conventional suppository base such as cocoa butter or other glycerides.
对胃外投药， 液态剂型通常由化合物和一种消毒的载体制成。 载体首选水。 依照所选载 体和药物溶度的不同， 化合物既可以溶于载体中， 也可以制成悬浮溶液， 在制成注射用溶液 时先将化合物溶于水中， 过滤消毒后装入封口瓶或安瓿中。  For parenteral administration, liquid dosage forms are usually made from the compound and a sterile carrier. The carrier is preferred water. Depending on the selected carrier and the solubility of the drug, the compound can be dissolved in the carrier or in a suspension solution. The compound is dissolved in water before being prepared into an injection solution, filtered and sterilized, and then placed in a sealed bottle or ampoule. .
当皮肤局部施用时， 本发明化合物可以制成适当的软膏， 洗剂， 或霜剂的形式， 其中活 性成分悬浮或溶解于一种或多种的载体中， 其中软膏制剂可以施用的载体包括但不局限于： 矿物油， 液体凡士林， 白凡士林， 丙二醇， 聚氧化乙烯， 聚氧化丙烯， 乳化蜡和水； 洗剂和 霜剂可使用的载体包括但不限于： 矿物油， 脱水山梨糖醇单硬脂酸酯， 吐温 60 , 十六烷酯 蜡， 十六碳烯芳醇， 2-辛基十二烷醇， 苄醇和水.  When applied topically to the skin, the compound of the invention may be in the form of a suitable ointment, lotion, or cream, wherein the active ingredient is suspended or dissolved in one or more carriers, wherein the carrier to which the ointment formulation can be applied includes but Not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams can be used, including but not limited to: mineral oil, sorbitan Stearate, Tween 60, cetyl ester wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
在上述药物制剂中通式（1 )的活性化合物的存在浓度应为该混合物总量的约 0.1~99.5。/。， 优选约 0.5~95% (重量）。  The active compound of the formula (1) in the above pharmaceutical preparation should be present in a concentration of from about 0.1 to 99.5 based on the total amount of the mixture. /. Preferably, it is about 0.5 to 95% by weight.
本发明的一种实施方案涉及含有： A )至少一种上述的二氢嘧啶， B)至少一种与 A不同 的其他抗病毒剂的组合物。  One embodiment of the invention relates to a composition comprising: A) at least one of the above-described dihydropyrimidines, B) at least one other antiviral agent different from A.
本发明的一个详细的实施方案涉及含有： A ) 上述二氢嘧啶， B ) HBV聚合酶抑制剂， 和合适的情况下， C ) 免疫调节剂的组合物。  A detailed embodiment of the invention relates to a composition comprising: A) the above-described dihydropyrimidine, B) HBV polymerase inhibitor, and, where appropriate, C) an immunomodulatory agent.
优选的免疫调节剂 C) 包括，例如，所有的干扰素诸如 α-, β- 和 γ-干扰素，尤其是 a-2a- 和 a-2b-干扰素， 白细胞介素诸如白细胞介素 -2 , 多肽诸如胸腺素 -a- 1 和胸腺托南 ( thymoctonan ), 咪唑喹啉衍生物诸如 ⑧左咪唑， 免疫球蛋白和治疗疫苗。 .  Preferred immunomodulators C) include, for example, all interferons such as alpha-, beta- and gamma-interferons, especially a-2a- and a-2b-interferons, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines. .
因此， 本发明还涉及用于治疗和预防 HBV感染的这些组合物及其在治疗 HBV 引发的 疾病上的用途。  Accordingly, the present invention also relates to such compositions for the treatment and prevention of HBV infection and their use in the treatment of diseases caused by HBV.
相对于单一化合物的单一治疗， 本发明的组合物的使用对治疗 HBV引发的疾病是有益 的， 主要是增进的抗病毒活性， 以及相对于单个成分的 Tox-50 (有 50%的细胞存活的毒性 范围） 来说， 本发明的组合物具有良好的耐受性。 The use of the compositions of the invention is beneficial for the treatment of HBV-induced diseases relative to a single treatment of a single compound The compositions of the present invention are well tolerated, primarily with enhanced antiviral activity, and with respect to the single component of Tox-50, which has a toxicity range of 50% cell survival.
用于实现本发明目的的 HBV聚合酶抑制剂 Β为 Ph. A. Furman 等在 《抗微生物制剂与 化疗方法》 ( Antimicrobial Agents and Chemotherapy ) Vol.36 ( No. 12 ), 2688 ( 1992 ) 中 的内生聚合酶实验中揭示的那些物质， 以及那些在下文中描述的， 抑制 HBVDNA双链的形 成， 从而导致最大 50%活性值为零的那些物质。  The HBV polymerase inhibitor guanidine used to achieve the object of the present invention is Ph. A. Furman et al., Antimicrobial Agents and Chemotherapy Vol. 36 (No. 12 ), 2688 (1992) Those materials revealed in endogenous polymerase experiments, as well as those described below, inhibit the formation of HBV DNA double strands, resulting in a maximum of 50% of the activity values of zero.
在试管中， 将 HBV 毒粒与核苷 5'-三磷酸盐一起从培养悬浮物中移至 HBV DNA正链 上。通过使用琼酯糖凝胶电泳,发现其中存在有 [α-32Ρ]-脱氧核苷 5'-三磷酸盐和病毒的 3.2kb DNA的结合产品， 不存在具有潜在 HBV聚合酶 -抑制性质的物质。 从 HepG2.2.15 细胞的 细胞培养悬浮物中， 用聚乙二醇沉淀、 浓缩得到 HBV毒粒。 将 1体积份的澄清细胞培养悬 浮物与 1 /4体积份的含有 50% (重量）聚乙二醇 8000 和 0.6M氯化钠的水溶液混合。 2500 x g离心沉淀 15分钟， 沉淀物用 2ml含有0.05 Mtris-HCI M(pH7.5)的缓冲液再悬浮， 用含 有 lOOmM 氯化钾的该缓冲液透析。 样品在 -80 'C时冷冻。 每个反应混合物（100 ） 含有至 少 105 HBV 毒粒、 50mMtris-HCI(p.sub.H 7.5). 300 mM 氯化钾、 50 m 氯化镁、 0.1%® Nonident P-40 (非离子型洗涤剂， Boehringer Mannheim)、 10 μΜ dATP, 10 μΜ dGTP , 10 μΜ dTTP; 10〃Ci [32P]dCTP (3000 Ci/mmol; 最终浓度为 33nM) and 1 μΜ 三磷酸形式的 聚合酶潜在抑制剂。 样品在 37 'C下培养一个小时， 然后加入 50 mM EDTA中止反应。 加 入 10% 重量 /体积 SDS 溶液 （每 90 ml水含有 10 gSDS)到最终浓度为 1% (体积) (基于溶液 总体积)， 加入蛋白酶 K至最终浓度为 lmg/ml。 然后在 37'C培育 1 小时， 用等体积的苯酴 /氯仿 /异戊醇（体积比为 25:24:1 ) 溶液提取， DNA从含有乙醇的水相中沉淀出来。 DNA 小球在 10 凝胶缓冲液（1升水中含有 10.8 g tris、 5.5 g 硼酸和 0.75g EDTA(=TBE buffer)) 中在悬浮， 并用琼脂糖凝胶电泳分离。 将其中的凝胶干燥或者采用 Southern 转移技术将其 中的核酸转到膜上。 形成一定数量的标记 DNA双链进行对照检测 (=空白或有惰性对照物进 行 ndo-pol 反应）。 如果存在对照组的最大 50%浓度则存在 HBV聚合酶抑制剂。 In a test tube, HBV virions were transferred from the culture suspension to the positive strand of HBV DNA together with the nucleoside 5'-triphosphate. By using agarose gel electrophoresis, a binding product of 3.2 kb DNA in which [α- 32 Ρ]-deoxynucleoside 5'-triphosphate and virus were present was found, and there was no potential HBV polymerase-inhibiting property. substance. From the cell culture suspension of HepG2.2.15 cells, it was precipitated with polyethylene glycol and concentrated to obtain HBV virions. One part by volume of the clarified cell culture suspension was mixed with 1/4 part by volume of an aqueous solution containing 50% by weight of polyethylene glycol 8000 and 0.6 M of sodium chloride. The pellet was centrifuged at 2500 xg for 15 minutes, and the precipitate was resuspended in 2 ml of a buffer containing 0.05 Mtris-HCI M (pH 7.5), and dialyzed against the buffer containing 100 mM potassium chloride. The sample was frozen at -80 'C. Each reaction mixture (100) contains at least 10 5 HBV virions, 50 mM tris-HCI (p.sub.H 7.5). 300 mM potassium chloride, 50 m magnesium chloride, 0.1%® Nonident P-40 (non-ionic detergent) , Boehringer Mannheim), 10 μΜ dATP, 10 μΜ dGTP , 10 μΜ dTTP; 10〃Ci [ 32 P]dCTP (3000 Ci/mmol; final concentration 33 nM) and a potential inhibitor of polymerase in the form of 1 μΜ triphosphate. The samples were incubated at 37 'C for one hour and then stopped by the addition of 50 mM EDTA. Add 10% w/v SDS solution (10 g SDS per 90 ml water) to a final concentration of 1% by volume (based on the total volume of the solution) and add proteinase K to a final concentration of 1 mg/ml. It was then incubated at 37 ° C for 1 hour, extracted with an equal volume of phenylhydrazine/chloroform/isoamyl alcohol (25:24:1 by volume) solution, and the DNA was precipitated from the aqueous phase containing ethanol. The DNA pellets were suspended in 10 gel buffer (10.8 g tris, 5.5 g boric acid, and 0.75 g EDTA (= TBE buffer) in 1 liter of water and separated by agarose gel electrophoresis. The gel is dried or transferred to the membrane using Southern transfer techniques. A number of labeled DNA duplexes are formed for control (= blank or with an inert control for the ndo-pol reaction). An HBV polymerase inhibitor is present if there is a maximum 50% concentration of the control group.
优选的 HBV聚合酶抑制剂 B) 包括，例如， 31^=拉米夫定（lamivudine)=4-氨基-卜 [(2R- 顺式) -2- (羟甲基) -1.3-氧硫茂 -5-基- ]-嘧啶 -2(1H)-酮 cf. EP-B 382526 (=U.S. Pat. No.5, 047, 407) 和 WO 91/11186 (=U.S. Pat. No.5, 204, 466);  Preferred HBV polymerase inhibitors B) include, for example, 31^=lamivudine=4-amino-bu[(2R-cis)-2-(hydroxymethyl)-1.3-oxosulfur -5-yl-]-pyrimidine-2(1H)-one cf. EP-B 382526 (=US Pat. No. 5, 047, 407) and WO 91/11186 (=US Pat. No. 5, 204, 466);
阿德福韦酯 （ Adefovir dipivoxil ) =9-[2- [双 (特戊酰羟甲氧基)膦酰甲氧基]乙基]腺嘌呤， cf. EP-B 481214 (=U.S. Pat. Nos.5, 663, 159 和 5, 792, 756), U.S. Pat. Nos.4, 724, 233 和 4, 808, 716;  Adefovir dipivoxil =9-[2- [bis(pivaloyloxymethoxy)phosphonomethoxy]ethyl]adenine, cf. EP-B 481214 (=US Pat. Nos .5, 663, 159 and 5, 792, 756), US Pat. Nos. 4, 724, 233 and 4, 808, 716;
BMS 200475=[ 1 S-( 1..alpha. , 3..alpha.， 4..beta.)]-2-氨基- 1.9-二氢 -9-[4-羟基— 3- (羟甲基) -2-亚 甲基-环戊基 ]-6H-嘌呤 -6-酮， cf. EP-B 481754 (=U.S. Pat. Nos.5， 206, 244 和 5, 340, 816), WO 98/09964 和 99/41275;  BMS 200475=[ 1 S-( 1..alpha. , 3..alpha., 4..beta.)]-2-Amino- 1.9-Dihydro-9-[4-hydroxy-3-(hydroxymethyl) -2-Methylene-cyclopentyl]-6H-indol-6-one, cf. EP-B 481754 (=US Pat. Nos. 5, 206, 244 and 5, 340, 816), WO 98/ 09964 and 99/41275;
阿巴卡韦（ Abacavir )=(-)-( 1 S-顺式 )-4-[2-氨基 -6- (环丙胺) -9H-嘌呤 -9-基] -2-基- 环戊烯 -卜 甲醇， cf. EP-B 349242 (=U.S. Pat. No.5, 049, 671) 和 EP-B 434450 (=U.S. Pat. No.5, 034, 394);  Abacavir = (-)-( 1 S-cis)-4-[2-amino-6-(cyclopropylamine)-9H-indol-9-yl]-2-yl-cyclopentene - Methanol, cf. EP-B 349242 (=US Pat. No. 5, 049, 671) and EP-B 434450 (=US Pat. No. 5, 034, 394);
FTC=(2R-顺式) -4-氨基 -5-氟 - 1 -[2-(羟甲基 )- 1.3-氧硫茂 -5-基] -嘧啶 -2( 1 H)-酮， cf. WO 92/14743 (=U.S. Pat. Nos.5, 204, 466; 5, 210, 085; 5, 539, 116; 5, 700, 937; 5,728,575; 5， 814， 639; 5, 827, 727; 5, 852, 027; 5, 892, 025; 5, 914, 331; 5, 914, 400) 和 WO 92/18517。 p-L-FDDC=5-(6-氨基 -2-氟 -9H-嘌呤 -9-基) -四氢 -2-呋喃甲醇， cf. WO 94/27616 (=U.S. Pat. Nos. 5, 627, 160; 5, 561,120; 5, 631,239 和 5, 830, 881); L-FMAU=卜 (2-脱氧 -2- 氟 -.beta.-L-阿拉伯呋喃糖) -5-甲基 -嘧啶 e- -2.4( 1 H , 3H)-二酮， cf. WO 99/05157, WO 99/05158 和 U.S. Pat. No.5， 753, 789。 FTC=(2R-cis)-4-amino- 5 -fluoro-1-[2-(hydroxymethyl)-1.3-oxothio-5-yl]-pyrimidine-2( 1 H)-one, cf WO 92/14743 (=US Pat. Nos. 5, 204, 466; 5, 210, 085; 5, 539, 116; 5, 700, 937; 5,728,575; 5, 814, 639; 5, 827, 727; 5, 852, 027; 5, 892, 025; 5, 914, 331; 5, 914, 400) and WO 92/18517. pL-FDDC=5-(6-Amino-2-fluoro-9H-fluoren-9-yl)-tetrahydro-2-furanmethanol, cf. WO 94/27616 (=US Pat. Nos. 5, 627, 160 5, 561,120; 5, 631, 239 and 5, 830, 881); L-FMAU = Bu (2-deoxy-2-fluoro-.beta.-L-arabinofuranosyl) -5-methyl-pyrimidine e- - 2.4( 1 H , 3H)-dione, cf. WO 99/05157, WO 99/05158 and US Pat. No. 5, 753, 789.
本发明进一步优选的实施方案涉及含有 A ) 上述二氢嘧啶 （I)和 (la)及 B) 拉米夫定 lamivudine ) 的组合物„ A further preferred embodiment of the invention relates to the invention comprising A) the above-mentioned dihydropyrimidines (I) and (la) and B) lamivudine Lamivudine ) composition „
另一个优选的 HBV 抗病毒剂 B含有， 例如， 下述分子式所示的苯基丙烯酰胺  Another preferred HBV antiviral agent B contains, for example, a phenylacrylamide represented by the following formula
Figure imgf000017_0001
Figure imgf000017_0001
其中， 和 R2 , 分别独立为， C,-C4 的烷基或者， 在他们所在的位置上带有一个氮 原子， 形成具有 5到 6个原子含有碳和 /或氧的环。 R3 到 Rl2 , 分别独立为， 氢、 卤素、 - C4的烷基、 任意取代 Cr C4的烷氧基、 硝基， 氰基或三氟甲基。 Rl 3是氢， C,-C4的烷 基， d-C7的酰基或芳烷基， 以及 X 是卤素或任意取代的 -C4的烷基， 及其盐。 Wherein, and R 2 are independently independently a C,-C 4 alkyl group or have a nitrogen atom at their position to form a ring having 5 to 6 atoms containing carbon and/or oxygen. R 3 to R l2 are each independently hydrogen, halogen, -C 4 alkyl, optionally substituted C r C 4 alkoxy, nitro, cyano or trifluoromethyl. R l 3 is hydrogen, C, -C 4 alkyl, dC 7 acyl or aralkyl, and X is halogen or optionally substituted -C 4 alkyl, and salts thereof.
这些苯基丙烯酰胺及其制备方法已在 WO 98/33501 中公开， 这里提及是为了公开的目 的。 AT-61 是化合物  These phenylacrylamides and their preparation are disclosed in WO 98/33501, which is hereby incorporated by reference. AT-61 is a compound
Figure imgf000017_0002
Figure imgf000017_0002
优选的免疫调节剂 C) 包括例如，所有的干扰如， α-, β-和 γ-干扰素，尤其还可以是 a-2a- 和 a-2b-干扰， 白细胞介素如白细胞介素 -2 , 多肽如胸腺素 -a-1 和胸腺托南 （ thymoctonan ), 咪唑喹啉衍生物如⑧左咪唑， 免疫球蛋白和治疗疫苗。  Preferred immunomodulators C) include, for example, all interfering agents such as α-, β- and γ-interferons, especially a-2a- and a-2b-interfering, interleukins such as interleukin-2 , polypeptides such as thymosin-a-1 and thymoctonan, imidazoquinoline derivatives such as 8 levamisole, immunoglobulins and therapeutic vaccines.
本发明的另一个优选的实施方式涉及含有 A) 上述二氢嘧啶 （1) 和 （la); B) 拉米夫定 ( lamivudine ); 以及合适的情况下 C) 干扰素的组合物。  Another preferred embodiment of the invention relates to a composition comprising A) the above-described dihydropyrimidines (1) and (la); B) lamivudine; and, where appropriate, C) interferon.
本发明包括药物的制备， 除了无毒， 情性的制药学上合适的载体之外， 还含有一种或 多种本发明的化合物 （1) 或 (la) 或组合物或由一种或多种活性成分 (1) 或 （la)组成的组合物 或由者本发明的组合物组成的组合物。  The invention includes the preparation of a medicament comprising, in addition to a non-toxic, pharmaceutically acceptable carrier, one or more compounds (1) or (la) or compositions of the invention or one or more A composition consisting of the active ingredient (1) or (la) or a composition consisting of the composition of the invention.
上述药物制备中所指的活性成分 (I) 和 （la) , 浓度约为 0.1 至 99.5% (重量）， 优选约 为 0.5 至 95% (重量）， 其中含量是相对于整个混合物。  The active ingredients (I) and (la) referred to in the above pharmaceutical preparations have a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, based on the entire mixture.
上述药物制备也可以包含化合物 （1) 和 （la)以外的其他活性药物成分。  The above pharmaceutical preparation may also contain other active pharmaceutical ingredients other than the compounds (1) and (la).
本发明的组合物中组分 A、 B和合适的 C 的含量比例可以在较宽的限制范围内变化， 优选 5至 500 mg A/10 至 1000 mg B , 尤其是 10至 200 mg A/20至 400 mg B,  The content ratio of the components A, B and the appropriate C in the composition of the present invention may vary within a wide range of limitations, preferably 5 to 500 mg A/10 to 1000 mg B , especially 10 to 200 mg A/20. Up to 400 mg B,
组分 C , 适当的时候也可使用， 其总使用量， 优选 卜 10百万 I.U. (国际单位)， 更优选 2-7百万 I.U. (国际单位)， 在超过一年的时期内每周 3次。  Component C, if appropriate, can also be used, its total use, preferably 10 million IU (international unit), more preferably 2-7 million IU (international unit), 3 weeks per week over a period of more than 3 years Times.
上述药物制备所指的本发明的化合物或组合物重量百分浓度通常为约 0.1 - 99.5%,优选 约 0.5-95% (相对于整个混合物）。  The compound or composition of the present invention as defined by the above pharmaceutical preparations usually has a concentration by weight of from about 0.1 to 99.5%, preferably from about 0.5 to 95% (relative to the entire mixture).
上述药物制备可以通过公知的常规方法实现， 例如将活性成分和载体混合。  The above pharmaceutical preparation can be carried out by a known conventional method such as mixing the active ingredient with a carrier.
无论是在人体还是在兽医学上每 24小时服用总剂量为约 0.05至约 500mg kg 体重， 优 选 0.1 至 100mg/kg 体重的活性成分已经被普遍证明是有益的， 合适的单剂的多次服用， 可 以达到理想的效果。 单剂含有的活性成分优选在总量约 0.1 至约 80mg/kg 体重， 优选 0.1 至 30mg kg 体重。 无论如何， 根据上述剂量尤其是根据个人和治疗对象的体重， 药物制作 的类型， 药物服用的方式以及药物服用的时间或间隔有所偏移是必要的。 It has been generally proven to be beneficial to take a total dose of from about 0.05 to about 500 mg kg body weight, preferably from 0.1 to 100 mg/kg body weight, every 24 hours, both human and veterinary, for a single dose of a suitable single dose. , can achieve the desired effect. The single ingredient contains the active ingredient preferably in a total amount of from about 0.1 to about 80 mg/kg body weight, preferably 0.1 Up to 30mg kg body weight. In any case, depending on the above dosages, especially depending on the weight of the individual and the subject, the type of preparation, the manner in which the medication is taken, and the time or interval at which the medication is administered are necessary.
因此， 本发明还涉及用于控制疾病的上述化合物和组合物。  Accordingly, the present invention also relates to the above compounds and compositions for use in the control of diseases.
本发明还涉及至少含有一种上述化合物或组合物和适当的情况下，一种或几种其他活性 药物成分的药物。  The invention further relates to a medicament comprising at least one of the above compounds or compositions and, where appropriate, one or more other active pharmaceutical ingredients.
本发明还涉及，用于制备治疗和预防上述疾病尤其是病毒性疾病特别是乙型肝炎的药物 的上述化合物和组合物的用途。  The invention further relates to the use of the above compounds and compositions for the manufacture of a medicament for the treatment and prevention of the above mentioned diseases, in particular viral diseases, in particular hepatitis B.
具体实施方式 Detailed ways
下面的具体实施例是本发明的优选实施方案， 其不应理解为对本发明构成任何限制。 除特别指明的外， 下述实施例中的百分数均是重量百分数。 混合溶液中溶剂的比例均指 体积比。  The following specific examples are preferred embodiments of the invention and are not to be construed as limiting the invention in any way. Unless otherwise indicated, the percentages in the following examples are by weight. The proportion of the solvent in the mixed solution refers to the volume ratio.
实施例 1 Example 1
乙基 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000018_0001
Figure imgf000018_0001
10.0 g (49.3 mmol) of 2-氯 -4-氟苯甲醛， 8.2 g (63.1 mmol) 乙基乙酰乙酸， 10.3 g (63.1 mmol) 2-脒基-噻唑盐酸盐和 6.2 g (75.7 mmol) 醋酸钠溶解或悬浮于 500 ml 乙醇中回流下沸 腾 16小时。 冷却至室温， 抽气过滤， 水洗残渣去除无机盐。 得产品 12.8 g (53.4%), 熔点: 162- Ι 64Ό ,  10.0 g (49.3 mmol) of 2-chloro-4-fluorobenzaldehyde, 8.2 g (63.1 mmol) ethyl acetoacetate, 10.3 g (63.1 mmol) 2-mercapto-thiazole hydrochloride and 6.2 g (75.7 mmol) Sodium acetate was dissolved or suspended in 500 ml of ethanol and boiled under reflux for 16 hours. Cool to room temperature, filter with air, and wash the residue to remove inorganic salts. Product 12.8 g (53.4%), melting point: 162- Ι 64Ό,
实施例 2 Example 2
甲基 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) -6-甲基 - 1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
该化合物釆用甲基乙酰乙酸通过类似实施例 1 的方法合成得到 产率： 55% (熔点: Ι 52-154Ό),  The compound was synthesized by a method similar to that of Example 1 using methyl acetoacetic acid. Yield: 55% (melting point: Ι 52-154 Ό),
实施例 3 Example 3
乙基 6-氯甲基 - 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) -1 ,4-二氢嘧啶 -5-羧酸酯 Ethyl 6-chloromethyl-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000018_0002
Figure imgf000018_0002
将 4.0 g (8.72 mmol) 实施例 1制得的乙基 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) -6-甲基 -1 ,4- 二氢嘧啶 -5-羧酸酯加入到 80 ml 四氯化碳中， 氩气氛围下加热至 50 'C , 得到澄清溶液。 在此 温度， 加入 1.73 g (9.61 mmol) N-溴琥珀酰亚胺， 保持在该温度混合 10分钟。 立刻冷却， 室 温下抽气过滤， 减压浓缩。 根据 HPLC检验产品纯度高于 90%, 并作为下一步的原材料。  4.0 g (8.72 mmol) of ethyl 4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydrogen prepared in Example 1. The pyrimidine-5-carboxylate was added to 80 ml of carbon tetrachloride and heated to 50 ° C under an argon atmosphere to obtain a clear solution. At this temperature, 1.73 g (9.61 mmol) of N-bromosuccinimide was added and kept at this temperature for 10 minutes. Cool immediately, filter at room temperature, and concentrate under reduced pressure. The purity of the product was checked by HPLC to be higher than 90% and used as a raw material for the next step.
Ri ).70 (石油醚 /乙酸乙酯 =8:2)  Ri ).70 (petroleum ether / ethyl acetate = 8:2)
实施例 4 甲基 6-漠甲基- 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) - 1，4-二氢嘧啶 -5-羧酸酯 该化合物釆用实施例 2制得的化合物按照类似实施例 3的方法合成制得。 R =0.70 油醚 /乙酸乙酯 =8:2) 。 Example 4 Methyl 6-molyl-4-(4-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate The compound obtained in Example 2 was synthesized in a similar manner to that in Example 3. R =0.70 oil ether / ethyl acetate = 8:2).
实施例 5 Example 5
乙基 4- (2-澳 -4-氟苯基) -2- (噻唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-A-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000019_0001
Figure imgf000019_0001
将 lO.Og ( 49.3 mmol ) 的 2-溴 -4-氟苯甲醛， 6.4 g ( 49.3 mmol ) 乙基乙酰乙酸， 8.1 g ( 49.3 mmol ) 2-脒基-噻唑盐酸盐和 4.8 g ( 58.5 mmol ) 醋酸钠溶解或悬浮于 400 ml 乙醇 中并且沸腾回流 16小时。 冷却至室温， 抽气过滤， 水洗残渣去除无机盐。 得 10.8g (51.6%) 的产物。 熔点： 163-165°C。 实施例 6  10% bromo-4-fluorobenzaldehyde, 6.4 g (49.3 mmol) ethyl acetoacetate, 8.1 g (49.3 mmol) 2-mercapto-thiazole hydrochloride and 4.8 g (58.5) Methyl acetate was dissolved or suspended in 400 ml of ethanol and boiled under reflux for 16 hours. Cool to room temperature, filter with air, and wash the residue to remove inorganic salts. Obtained 10.8 g (51.6%) of the product. Melting point: 163-165 ° C. Example 6
甲基 4- (2-溴 -4-氟苯基) -2- (噻唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
该化合物采用乙酰乙酸甲酯通过类似实施例 5 的方法合成得到. 产率： 53% (熔点: 155-157Γ ) 实施例 7  This compound was synthesized by a method similar to that of Example 5 using methyl acetoacetate. Yield: 53% (melting point: 155-157 Γ) Example 7
乙基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000019_0002
Figure imgf000019_0002
5.0 g ( 11.8 mmol) 实施例 5制得的乙基 4- ( 2-溴 -4-氟苯基) -2- (噻唑 -2-基） -6- 甲基 -1,4-二氢嘧啶 -5-羧酸酯加入到 100 ml 四氯化碳中， 氩气氛围下加热至 50'C , 得到澄清 溶液。 在此温度下， 加入 2.33g ( 13.0 mmol) N-溴琥珀酰亚胺， 保持在该温度混合 10分 钟。 立刻冷却， 室温下抽气过滤， 减压浓缩。 根据 HPLC检测产物纯度髙于 90%, 并作为 下一步的原材料。 5.0 g (11. 8 mmol) of ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine prepared in Example 5. The -5-carboxylate was added to 100 ml of carbon tetrachloride and heated to 50 ° C under an argon atmosphere to obtain a clear solution. At this temperature, 2.33 g (13.0 mmol) of N-bromosuccinimide was added and kept at this temperature for 10 minutes. Cool immediately, filter at room temperature, and concentrate under reduced pressure. The purity of the product was determined to be 90% by HPLC and used as the next raw material.
f=0.69 (石油醚 /乙酸乙酯 =8:2) ' 实施例 8 甲基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 f = 0.69 (petroleum ether / ethyl acetate = 8:2) 'Example 8 Methyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
该化合物采用实施例 6制得的化合物按照类似实施例 7的方法合成制得。  This compound was synthesized by the same procedure as in Example 7 using the compound obtained in Example 6.
Rf^0.69 (石油醚 /乙酸乙酯 =8:2)  Rf^0.69 (petroleum ether / ethyl acetate = 8:2)
实施例 9 乙基 4-(2,4-二氯苯基 ）-2- (噻唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Example 9 Ethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000020_0001
Figure imgf000020_0001
10.0 g (57.1 mmol)of2, 4-二氯苯甲醛， 7.4 g (57.1 mmol) 乙基乙酰乙酸， 9.3g(57.1 mmol)2-脒基-噻唑盐酸盐和 5.7g(69.5mmol) 醋酸钠溶解或悬浮于 500ml乙醇中沸腾回流 16小时。 冷却至室温， 抽气过滤， 水洗残渣去除无机盐。 得产物 11.8 g (52.5%) 熔点： 164- 166。（：。  10.0 g (57.1 mmol) of 2, 4-dichlorobenzaldehyde, 7.4 g (57.1 mmol) ethyl acetoacetate, 9.3 g (57.1 mmol) 2-mercapto-thiazole hydrochloride and 5.7 g (69.5 mmol) sodium acetate Dissolved or suspended in 500 ml of ethanol and refluxed for 16 hours. Cool to room temperature, filter with air, and wash the residue to remove inorganic salts. Yield 11.8 g (52.5%) Melting point: 164-166. (:.
实施例 10 乙基 6-溴甲基 4-(2,4-二氯苯基 ）-2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Example 10 Ethyl 6-bromomethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000020_0002
Figure imgf000020_0002
将实施例 9制得的 8.0 g (20.2 mmol) 乙基 4-(2,4-二氯苯基 ）-2- (噻唑 -2-基) -6-甲基 -1,4- 二氢嘧啶 -5-羧酸酯加入到 140ml四氯化碳中， 氩气氛围下加热至 50。C, 得到澄清溶液。 在 此温度， 加入 4.36 g (24.2 mmol) N-溴琥珀酰亚胺， 保持在该温度混合 10分钟。 立刻冷却， 室温下抽气过滤， 减压浓缩。 HPLC 检测产物纯度高于 90%, 并作为下一步的原料。  8.0 g (20.2 mmol) of ethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-methyl-1,4-dihydropyrimidine prepared in Example 9. The -5-carboxylate was added to 140 ml of carbon tetrachloride and heated to 50 under an argon atmosphere. C, a clear solution is obtained. At this temperature, 4.36 g (24.2 mmol) of N-bromosuccinimide was added and kept at this temperature for 10 minutes. Cool immediately, filter at room temperature, and concentrate under reduced pressure. The purity of the product was determined by HPLC to be higher than 90% and used as a starting material for the next step.
RfK).68(石油醚 /乙酸乙酯 =8:2) RfK).68 (petroleum ether / ethyl acetate = 8:2)
实施例 11 Example 11
甲基 4- (2-氯苯基） -2- (噻唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000021_0001
Figure imgf000021_0001
将 3.48g甲基 6-甲基 -4- (2-氯苯基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 （在中国专利 CN 99805170.5中提到）和 1.78gNBS加入 90mL四氯化碳中, 在氮气保护下， 加热至回流， 30分钟后冷却。 过滤， 滤液在真空下蒸去四氯化碳溶剂得到的残渣与 4.5g吗啉加入 25mL 乙醇中， 在 50摄氏度下搅拌 24小时。 蒸干溶剂， 用 50mL纯水洗涤， 并用乙酸乙酯萃取。 合并有机层， 并蒸干， 用甲醇重结晶得到产物。 产率： l.lg。 熔点： 182-182.7'C。 3.48 g of methyl 6-methyl-4-(2-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5) It was mentioned) and 1.78 g of NBS was added to 90 mL of carbon tetrachloride, heated to reflux under nitrogen atmosphere, and cooled after 30 minutes. After filtration, the residue obtained by distilling off the carbon tetrachloride solvent under vacuum and 4.5 g of morpholine were added to 25 mL of ethanol, and stirred at 50 ° C for 24 hours. The solvent was evaporated to dryness, washed with 50 ml of purified The organic layers were combined, evaporated to dryness and then crystall Yield: l.lg. Melting point: 182-182.7'C.
实施例 12 Example 12
乙基 4- (2-氯苯基） -2- (噻唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000021_0002
Figure imgf000021_0002
该化合物用甲基 6-甲基 -4- (2-氯苯基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 （在中 国专利 CN 99805170.5和 WO 9954329中提到） 做为原料通过实施例 11 的方法合成制得。 Mp: 148-148,7°C  This compound uses methyl 6-methyl-4-(2-chlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5 and It is mentioned in WO 9954329) that it is synthesized as a raw material by the method of Example 11. Mp: 148-148, 7 ° C
实施例 13 甲基 4- (2-澳苯基） -2- (噻唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Example 13 Methyl 4-(2-Anophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000021_0003
Figure imgf000021_0003
该化合物用甲基 6-甲基 -4- (2-溴苯基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-幾酸酯 （在中 国专利 CN 99805170.5和 WO 9954329中提到）做为原料通过实施例 11的方法合成制得。 Mp: 165,8-166,4°C  This compound uses methyl 6-methyl-4-(2-bromophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-acid ester (in Chinese patent CN 99805170.5 and It is mentioned in WO 9954329) that it is synthesized as a raw material by the method of Example 11. Mp: 165, 8-166, 4 ° C
实施例 14 Example 14
乙基 4- (2-溴苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000022_0001
Ethyl 4-(2-bromophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000022_0001
该化合物用乙基 6-甲基 -4- (2-溴苯基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯（在中国专 利 CN 99805170.5和 WO 9954329中提到） 做为原料通过实施例 11的方法合成制得. This compound uses ethyl 6-methyl-4-(2-bromophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (in Chinese patent CN 99805170.5 and WO 9954329 mentioned) as a raw material by the method of the synthesis of 11.
Mp: 128，卜 129,4°C Mp: 128, Bu 129, 4 ° C
实施例 15 Example 15
2,2,2-三氟乙基- 4- (2-溴 -4-氟苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-幾 酸酯  2,2,2-Trifluoroethyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4- Dihydropyrimidin-5-acid ester
Figure imgf000022_0002
Figure imgf000022_0002
该化合物用 2,2,2-三氟乙基 -6-甲基 -4- (2-溴 -4-氟苯基) -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯做为原料通过实施例 11 的方法合成制得。  This compound uses 2,2,2-trifluoroethyl-6-methyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine The -5-carboxylate was synthesized as a raw material by the method of Example 11.
Rf:0.24 (流动相: 石油醚 /乙酸乙酯 =3: 1 )  Rf: 0.24 (mobile phase: petroleum ether / ethyl acetate = 3: 1)
0.43 (流动相： 石油醚 /乙酸乙酯 =3: 2)  0.43 (mobile phase: petroleum ether / ethyl acetate = 3: 2)
实施例 16 Example 16
乙基 4- (2-溴 -4-氟苯基) -6- (3-氧-哌嗪小基-甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸 酯 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(3-oxo-piperazine-based-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine- 5-carboxylate
Figure imgf000022_0003
Figure imgf000022_0003
将 200mg 2-酮哌嗪 （文献: Patron, Andrew P.; Pervin, Azra.US Patent No. 113,211. (2002) page 28 pp.)溶于 ImL乙醇， 并加入 200mg实施例 7制备的乙基 6-溴甲基 -4- ( 2-溴 -4-氟苯 基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯中。 室温下撹拌 30分钟后， 将乙醇溶剂在真空 下蒸干。 残渣用乙酸乙酯和水洗涤， 粗产物用乙酸乙酯萃取。 合并有机层， 并干燥， 蒸干溶 剂后在甲醇里重结晶， 得到产物。 产率： 100mg。 熔点： 172.1-173.0Ό。 实施例 17 200 mg of 2-ketopiperazine (Document: Patron, Andrew P.; Pervin, Azra. US Patent No. 113, 211. (2002) page 28 pp.) was dissolved in 1 mL of ethanol, and 200 mg of ethyl 6 prepared in Example 7 was added. -Bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate. After stirring at room temperature for 30 minutes, the ethanol solvent was evaporated to dryness under vacuum. The residue was washed with ethyl acetate and water and then evaporated The organic layers were combined, dried and evaporated to dryness crystall Yield: 100 mg. Melting point: 172.1-173.0 Ό. Example 17
乙基 4- (2-溴 -4-氟苯基） -6- ((4- (2, 2， 2-三氟乙酰基） 哌嗪小基） 甲基） -2- (噻唑 -2- 基） -1，4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazinyl)methyl)-2-(thiazole- 2 - -1,4-dihydropyrimidine-5-carboxylate,
Figure imgf000023_0001
Figure imgf000023_0001
该化合物用三氟乙酰基哌嗪 (Tetrahedron Letters Vol.36, No.41, p 7357 -7369 (1995) 做为起始原料通过类似于实施例 16的方法合成制得。  This compound was synthesized by a method similar to that of Example 16 using trifluoroacetylpiperazine (Tetrahedron Letters Vol. 36, No. 41, p 7357-7369 (1995) as a starting material.
mp: 152,8-153.3°C  Mp: 152, 8-153.3 °C
实施例 18 Example 18
乙基 6- ( ( 4- (二甲基氨基甲酰基) 哌嗪 -1-基) -4- (2-溴 -4-氟苯基） -2- (噻唑 -2 基） -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 6-((4-(dimethylcarbamoyl)piperazin-1-yl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4 - dihydropyrimidine-5-carboxylate,
Figure imgf000023_0002
Figure imgf000023_0002
该化合物用 N, N-二甲基哌嗪 -1-甲酰氨做为起始原料通过类似于买施例 16的方法合成 制得' Rf: 0.11 (石油醚 /乙酸乙酯 =3:1)  The compound was synthesized using N,N-dimethylpiperazine-1-carboxamide as a starting material by a method similar to that of the method of Example 16 to obtain 'Rf: 0.11 (petroleum ether/ethyl acetate = 3:1) )
实施例 19 Example 19
乙基 6- ((4- (二乙基氨基甲酰基） 哌嗪小基） -4- (2-溴 -4-氟苯基） -2- (噻唑 -2 基） -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 6-((4-(diethylcarbamoyl)piperazine) -4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4- Hydropyrimidine-5-carboxylate,
Figure imgf000023_0003
该化合物用 N, N-二乙基哌嗪 -1-甲酰氨做为起始原料通过类似于实施例 16的方法合成 制得。 Rf:0.11 (石油醚 /乙酸乙酯 =3:1)
Figure imgf000023_0003
This compound was synthesized by a method similar to that of Example 16 using N,N-diethylpiperazine-1-carboxamide as a starting material. Rf: 0.11 (petroleum ether / ethyl acetate = 3:1)
实施例 20 Example 20
I-甲基 -1H-咪唑 -2-甲脒盐酸盐
Figure imgf000024_0001
I-methyl-1H-imidazole-2-carboxamidine hydrochloride
Figure imgf000024_0001
制备方法如下： The preparation method is as follows:
步骤一： 制备卜甲基 -1H-咪唑 -2-甲醛 Step 1: Preparation of methyl-1H-imidazole-2-formaldehyde
于 -30°C下， 卜甲基 -1H-咪唑 18.38 g ( 16.8 ml，0.225 mol )投入 300 ml 无水四氢呋喃中， 搅 拌下滴加 2.5M的正丁基锂正己垸溶液 102 ml ( 0.2475mol ), 一小时加完。 滴加完毕维持搅 拌 3小时， 在半小时内滴加 20ml无水 DMF (0.2475 mol )。 当 DMF滴加完毕， 缓慢升高温 度至 -10°C反应 2小时， 自然升温至室温搅拌过夜。 向反应体系内滴加 500ml 的 1N盐酸溶 液淬灭反应， 水层经 4x200ml 乙酸乙酯萃取， 合并乙酸乙酯层， 无水硫酸钠干燥， 减压蒸 除溶剂， 得棕色油状产物 12.0g (收率 48.4%)。 MS (M+H: 111 ) At -30 ° C, p-methyl-1H-imidazole 18.38 g ( 16.8 ml, 0.225 mol) was placed in 300 ml of anhydrous tetrahydrofuran, and 2.5 M of n-butyllithium hexanyl solution 102 ml (0.2475 mol) was added dropwise with stirring. Add one hour. After the dropwise addition was completed, stirring was continued for 3 hours, and 20 ml of anhydrous DMF (0.2475 mol) was added dropwise over half an hour. When the DMF was added dropwise, the temperature was slowly raised to -10 ° C for 2 hours, and the temperature was naturally raised to room temperature and stirred overnight. The reaction was quenched by the addition of 500 ml of 1N aqueous hydrochloric acid, and the mixture was evaporated. The rate is 48.4%). MS (M+H: 111)
'HNMR (CDCIJ) δ: 4.02 (s, 3H, -CH3), 7.12 (s, 1H, =N-C//), 7.27 (s, 1H, -N-C/ ), 9.82 (s, 1H, -CHO). 'HNMR (CDCIJ) δ: 4.02 (s, 3H, -CH 3 ), 7.12 (s, 1H, =NC//), 7.27 (s, 1H, -NC/ ), 9.82 (s, 1H, -CHO) .
步骤二： 制备卜甲基 -1H-咪唑 -2-甲肟 Step 2: Preparation of methyl-1H-imidazole-2-carboxamidine
盐酸羟胺 18.0 g (0.26 mol)分散于 120 ml 甲酸中， 80'C下， 向该体系中滴加 24g 1-甲基 -1H-咪唑 -2-甲醛（0.22 mol )，40分钟加完， 反应体系在 80Ό下持续搅拌 2小时， 停止反应， 真空蒸除溶剂， 用无水乙醇 100 ml重结晶， 收得浅黄色结晶产物 17.1g (收率 62%)。  Hydroxylamine hydrochloride 18.0 g (0.26 mol) was dispersed in 120 ml of formic acid. At 80 ° C, 24 g of 1-methyl-1H-imidazole-2-carbaldehyde (0.22 mol) was added dropwise to the system, and the reaction was completed in 40 minutes. The system was stirred at 80 °C for 2 hours, the reaction was stopped, the solvent was evaporated in vacuo, and then recrystallized from 100 ml of anhydrous ethanol to yield 17.1 g (yield: 62%) of pale yellow crystalline product.
MS ( M+H: 126 )  MS ( M+H: 126 )
步骤三： 制备 1-甲基 -1H-咪唑 -2-甲氰 Step 3: Preparation of 1-methyl-1H-imidazole-2-cyanide
卜甲基 -1H-咪唑 -2-甲肟 10.00 g (0.08 mol) 溶于 20 ml 无水 DMF中， 快速加入乙酸酐 129.6 g ( 1.27 mol ), 加热升温至 120°C搅拌反应 2.5小时。 减压蒸除乙酸酐及溶剂， 残余 物加入 100ml无水乙醇分散， 过滤回收 1-甲基 -1H-咪唑 -2-甲肟， 滤液浓缩蒸除溶剂， 得到 棕色油状产物 7.2g (收率 84%)。 MS ( M+H: 108)  1 methyl-1H-imidazole-2-carboxamidine 10.00 g (0.08 mol) was dissolved in 20 ml of anhydrous DMF, and 129.6 g (1.27 mol) of acetic anhydride was quickly added thereto, and the mixture was heated to 120 ° C and stirred for 2.5 hours. The acetic anhydride and the solvent were evaporated under reduced pressure, and the residue was evaporated and evaporated, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, %). MS ( M+H: 108)
步骤四： 制备卜甲基 -IH-咪唑 -2-甲脒盐酸盐 Step 4: Preparation of methyl-IH-imidazole-2-carboxamidine hydrochloride
于一 30 ml封管中， 投入卜甲基 -1H-咪唑 -2-甲氰 1.7g ( 16mmol )，无水甲醇 20ml, 55% 含量氢化钠 0.76g(17 mmol), 室温搅拌 2.5小时， 加入氯化铵 0.85g ( 16 mmol ) ,密封后升温 至 90'C反应 2.5小时。 停止反应， 冷却， 过滤， 滤饼用 3x10ml 甲醇洗涤， 合并滤液真空浓 缩蒸除溶剂， 残余棕色固体经四氢呋喃重结晶， 收得灰色固体 1.2 g (收率 47%)。  In a 30 ml sealed tube, 1.7 g (16 mmol) of p-methyl-1H-imidazole-2-carbonitrile, 20 ml of anhydrous methanol, and 0.76 g (17 mmol) of sodium hydride in 55%, stirred at room temperature for 2.5 hours, and added with chlorination. The ammonium was 0.85 g (16 mmol), and after cooling, the temperature was raised to 90 ° C for 2.5 hours. The reaction was quenched, cooled, filtered, and EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
MS ( M+H: 125 ) 实施例 21  MS (M+H: 125) Example 21
乙基 4- (2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000025_0001
Ethyl 4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000025_0001
2-溴 -4-氟苯甲醛 1.02g(5mmol)溶于 50 ml无水乙醇中， 加入乙酰乙酸乙酯 0.65 g ( 5 mmol), 卜甲基 -1H-咪唑 -2-甲脒盐酸盐 0.8 g (5 mmol), 无水乙酸钠 0.50g ( 6 mmol ), 升温 至回流撹拌 18小时。 停止反应， 降温， 过滤， 滤液真空浓缩至干得粗品， 粗品经一硅胶柱 分离纯化， 收得浅黄色固体 0.387 g (收率 18.4%)。 MS ( M+H: 421, 423 ) 实施例 22  2-bromo-4-fluorobenzaldehyde 1.02 g (5 mmol) was dissolved in 50 ml of absolute ethanol, ethyl acetoacetate 0.65 g (5 mmol), and methyl-1H-imidazole-2-carboxamidine hydrochloride 0.8 g (5 mmol), anhydrous sodium acetate 0.50 g (6 mmol), warmed to reflux and stirred for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was evaporated to dryness. MS (M+H: 421, 423) Example 22
乙基 6-溴甲基 -4- (2-溴 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazolyl-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000025_0002
Figure imgf000025_0002
乙基 4- ( 2-溴 -4-氟苯基 ) -2- ( 1-甲基咪唑 -2-基 ) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 0.387 g (0.92 mmol)溶解于 40 ml 四氯化碳中， 加热至 60°C下， 分批投入 0.172 g (0.97 mmol) N-溴 代琥珀酰亚胺， 维持 60°C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固 体粗品 0.77 g。 MS ( M+H: 499, 501, 503 ) 实施例 23  Ethyl 4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 0.387 g (0.92 mmol) dissolved in 40 ml of carbon tetrachloride, heated to 60 ° C, 0.172 g (0.97 mmol) N-bromosuccinimide was added in portions, stirred at 60 ° C for 30 minutes, cooled, filtered The solvent was evaporated under reduced pressure at room temperature to give a crude yellow solid (yield: 0.77 g). MS (M+H: 499, 501, 503) Example 23
乙基 4- (2-溴斗氟苯基） -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromofluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinyl)-1,4-dihydropyrimidine-5-carboxylate Acid ester
Figure imgf000025_0003
Figure imgf000025_0003
将 0.77g新制备的乙基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -1,4-二氢 嘧啶 -5-羧酸酯溶解到 70 ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空 蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.136g。  0.77 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-1,4-dihydropyrimidine The -5-carboxylate was dissolved in 70 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0>
Rf:0.42 (流动相： 石油醚 /乙酸乙酯 =1: 1 ) MS (M+H: 506, 508)  Rf: 0.42 (mobile phase: petroleum ether / ethyl acetate = 1 : 1 ) MS (M+H: 506, 508)
'HN R(CDC )5: 1.13 (t, 3H), 2.61 (m, 4H)， 3.84 (m, 4H), 3.88 (d, IH), 3.96 (s, 3H), 'HN R(CDC )5: 1.13 (t, 3H), 2.61 (m, 4H), 3.84 (m, 4H), 3.88 (d, IH), 3.96 (s, 3H),
4.00-4.01 (m, 3H), 6.16 (s, 1H)， 6.91 (s, IH), 6.94 (m, IH), 7.01 (s, IH), 7.19 (q, IH), 7.33 (dd, IH), 9.70 (s, IH). 实施例 24 4.00-4.01 (m, 3H), 6.16 (s, 1H), 6.91 (s, IH), 6.94 (m, IH), 7.01 (s, IH), 7.19 (q, IH), 7.33 (dd, IH) , 9.70 (s, IH). Example 24
乙基 4- ( 2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6-甲基 -1，4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazolyl-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000026_0001
Figure imgf000026_0001
2-氯 -4-氟苯甲醛 0.317 g (2 mmol) 溶于 25 ml无水乙醇中， 加入乙酰乙酸乙酯 0.260 g (5 mmol), 1-甲基 -1H-咪唑 -2-甲脒盐酸盐 0.321 g (2 mmol), 无水乙酸钠 0.20g ( 2.4 mmol ), 升温至回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液真空浓缩至干得粗品， 粗品经一硅 胶柱分离纯化， 收得浅黄色固体 0.124 g (收率 16.4%)。 2-Chloro-4-fluorobenzaldehyde 0.317 g (2 mmol) dissolved in 25 ml of absolute ethanol, added ethyl acetoacetate 0.260 g (5 mmol), 1-methyl-1H-imidazole-2-carboxamidine salt The acid salt was 0.321 g (2 mmol), anhydrous sodium acetate (0.20 g, 2.4 mmol). The reaction was quenched, cooled, filtered, and the filtrate was concentrated in vacuo to dryness. The crude material was isolated and purified on a silica gel column to yield 0.124 g (yield 16.4%).
MS ( M+H: 379 )  MS ( M+H: 379 )
实施例 25.: Example 25.
乙基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazolyl-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000026_0002
乙基 4- ( 2-氯 -4-氟苯基 ) -2- ( 1-甲基咪唑 -2-基 ) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 124 mg (0.33 mmol)溶解于 15 ml 四氯化碳中， 加热至 60'C下， 分批投入 62 mg (0.35 mmol) N-溴代 琥珀酰亚胺， 维持 60°C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体 粗品 87mg。 MS ( M+H: 455,457 )
Figure imgf000026_0002
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 124 mg (0.33 mmol) dissolved in 15 ml of carbon tetrachloride, heated to 60 ° C, 62 mg (0.35 mmol) of N-bromosuccinimide was added in portions, stirred at 60 ° C for 30 minutes, cooled, filtered The filtrate was evaporated to dryness <RTI ID=0.0> MS ( M+H: 455,457 )
实施例 26 Example 26
乙基 4- (2-氯 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 -carboxylate
Figure imgf000026_0003
Figure imgf000026_0003
将 87 mg新制备的乙基 -6-澳甲基 -4- (2-氯 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基) -1,4-二氢 嘧啶 -5-羧酸酯溶解到 8 ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空 蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 10mg。 MS ( M+H: 462 )  87 mg of freshly prepared ethyl-6-methyl-4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-1,4-dihydropyrimidine The -5-carboxylate was dissolved in 8 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 462 )
'HN R(CDCI3)5: 1.13 (t, 3H), 2.60 (m, 4H)， 3.82 (m, 4H), 3.87 (d, 1H), 3.94 (s, 3H), 4.00-4.10 (m, 3H), 6.20 (s, 1 H), 6.87 (dd, 1 H), 6.91 (s, 1 H), 7.01 (s, 1H), 7.13 (dd, 1 H), 7.21 (dd, 1H), 9.69 (s, 1H). 'HN R(CDCI 3 )5: 1.13 (t, 3H), 2.60 (m, 4H), 3.82 (m, 4H), 3.87 (d, 1H), 3.94 (s, 3H), 4.00-4.10 (m, 3H), 6.20 (s, 1 H), 6.87 (dd, 1 H), 6.91 (s, 1 H), 7.01 (s, 1H), 7.13 (dd, 1 H), 7.21 (dd, 1H), 9.69 (s, 1H).
实施例 27 Example 27
乙基 4- (2,4-二氯苯基） -2- ( 1-甲基咪唑 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000027_0001
Ethyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000027_0001
2,4-二氯苯甲醛0.350§(2 0101)溶于251^1无水乙醇中， 加入乙酰乙酸乙酯 0.260 g ( 5 mmol), 卜甲基 -1H-咪唑 -2-甲脒盐酸盐 0.321 g (2 mmol), 无水乙酸钠 0.20g ( 2.4 mmol ), 升 温至回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液真空浓缩至干得粗品， 粗品经一硅胶 柱分离纯化， 收得浅黄色固体 0.062 g (收率 7.9%)。 MS ( M+H: 393, 395 )  2,4-Dichlorobenzaldehyde 0.350§(2 0101) was dissolved in 251^1 absolute ethanol, adding ethyl acetoacetate 0.260 g (5 mmol), and methyl-1H-imidazole-2-carboxamidine hydrochloride 0.321 g (2 mmol), anhydrous sodium acetate 0.20 g (2.4 mmol). The reaction was quenched, the mixture was cooled, filtered, and the filtrate was concentrated in vacuo to dryness. The crude product was purified by silica gel column to yield 0.062 g (yield: 7.9%). MS ( M+H: 393, 395 )
实施例 28 Example 28
乙基 6-溴甲基 -4- (2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazolyl-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000027_0002
Figure imgf000027_0002
乙基 4- (2,4-二氯苯基） -2- ( 1-甲基咪唑 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 62 mg (0.158 mmol)溶解于 10 ml 四氯化碳中， 加热至 60°C下， 分批投入 30 mg (0.166 mmol) N-溴 代琥珀酰亚胺， 维持 60Ό搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固 体粗品 56mg。 MS ( M+H: 471, 473, 475 )  Ethyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 62 mg ( 0.158 mmol) dissolved in 10 ml of carbon tetrachloride, heated to 60 ° C, 30 mg (0.166 mmol) N-bromosuccinimide was added in batches, kept at 60 Torr for 30 minutes, cooled, filtered, and the filtrate was at room temperature. The solvent was evaporated in vacuo to give a pale yellow solid. MS ( M+H: 471, 473, 475 )
实施例 29 Example 29
乙基 4- (2,4-二氯苯基) -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
Figure imgf000027_0003
Figure imgf000027_0003
将 56 mg新制备的乙基 -6-溴甲基 -4- (2,4-二氯苯基） -2- ( 1-甲基咪唑 -2-基） -1,4-二氢嘧 啶 -5-羧酸酯溶解到 5 ml 乙醇中， 同 3倍量的吗啉混合， 室温下撹拌 30 分钟。 室温真空蒸 除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 3mg。 MS (M+H: 478, 480)  56 mg of freshly prepared ethyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-1,4-dihydropyrimidine- The 5-carboxylate was dissolved in 5 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS (M+H: 478, 480)
'HNMR(CDC13)5: 1.13 (t, 3H), 2.60 (m, 4H), 3.82 (m, 4H), 3.87 (d, IH), 3.94 (s, 3H), 4.00-4.10 (m, 3H), 6.20 (s, IH), 6.91 (s, IH), 7.01 (s, IH), 7.16 (d, 2H), 7.40 (s, IH), 9.70 (s, IH). 实施例 30 'HNMR(CDC1 3 )5: 1.13 (t, 3H), 2.60 (m, 4H), 3.82 (m, 4H), 3.87 (d, IH), 3.94 (s, 3H), 4.00-4.10 (m, 3H) ), 6.20 (s, IH), 6.91 (s, IH), 7.01 (s, IH), 7.16 (d, 2H), 7.40 (s, IH), 9.70 (s, IH). Example 30
甲基 4- (2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000028_0001
Methyl 4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000028_0001
2-溴 -4-氟苯甲醛 0.406 g (2 mmol) 溶于 25 ml无水乙醇中， 加入乙酰乙酸甲酯 0.232 g (2 mmol), 卜甲基 -1H-咪唑 -2-甲脒盐酸盐 0.321 g (2 mmol), 无水乙酸钠 0.20g ( 2.4 mmol ), 升温至回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液真空浓缩至干得粗品， 粗品经一硅 胶柱分离纯化， 收得浅黄色固体 0.245 g (收率 30.1%)。 MS ( M+H: 407, 409)  2-bromo-4-fluorobenzaldehyde 0.406 g (2 mmol) dissolved in 25 ml of absolute ethanol, added methyl acetoacetate 0.232 g (2 mmol), benzyl-1H-imidazole-2-carboxamidine hydrochloride 0.321 g (2 mmol), anhydrous sodium acetate 0.20 g (2.4 mmol). The reaction was quenched, cooled, filtered, and the filtrate was concentrated in vacuo to dryness. The crude material was purified by silica gel column to yield 0.245 g (yield 30.1%). MS ( M+H: 407, 409)
实施例 31 Example 31
甲基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazolyl-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000028_0002
甲基 4- ( 2-溴 -4-氟苯基） -2- (卜甲基咪唑 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 245 mg (0.602 mmol)溶解于 25 ml 四氯化碳中， 加热至 60°C下， 分批投入 112 mg (0.632 mmol) N- 溴代琥珀酰亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色 固体粗品 208 mg, 粗品直接用于下步反应。 MS (M+H: 485, 487, 489 )
Figure imgf000028_0002
Methyl 4-(2-bromo-4-fluorophenyl)-2-(b-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 245 mg (0.602 mmol Dissolve in 25 ml of carbon tetrachloride, heat to 60 ° C, add 112 mg (0.632 mmol) of N-bromosuccinimide in batches, maintain 60 ° C for 30 minutes, cool down, filter, filtrate room temperature The solvent was evaporated in vacuo to give EtOAc EtOAc EtOAc. MS (M+H: 485, 487, 489)
实施例 32 Example 32
甲基 4- (2-溴 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 -carboxylate
Figure imgf000028_0003
Figure imgf000028_0003
将 208 mg新制备的甲基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -1,4-二氢 嘧啶 -5-羧酸酯溶解到 25 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空 蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 30 mg。 MS ( M+H: 492, 494) 208 mg of freshly prepared methyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-1,4-dihydropyrimidine The -5-carboxylate was dissolved in 25 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 492, 494)
'HNMR(CDCI3)5: 2.61 (m, 4H), 3.60 (s, 3H), 3.83 (m, 4H)， 3.87 (d, IH), 3.96 (s， 3H), 4.05 (d, J= 17.2Hz, IH), 6.14 (s, IH), 6.91 (d, IH), 6.95 (dd, IH), 7.01 (d, IH), 7.17 (q, IH), 7.33 (dd, 1H),9.74 (s, IH). 'HNMR(CDCI 3 )5: 2.61 (m, 4H), 3.60 (s, 3H), 3.83 (m, 4H), 3.87 (d, IH), 3.96 (s, 3H), 4.05 (d, J= 17.2 Hz, IH), 6.14 (s, IH), 6.91 (d, IH), 6.95 (dd, IH), 7.01 (d, IH), 7.17 (q, IH), 7.33 (dd, 1H), 9.74 (s , IH).
实施例 33 Example 33
甲基 4- (2-氯 -4-氟苯基) -2- ( I-甲基咪唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000029_0001
Methyl 4-(2-chloro-4-fluorophenyl)-2-(I-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000029_0001
2-氯 -4-氟苯甲醛 0.285 g ( 1.80 mmol)溶于 25 ml无水乙醇中， 加入乙酰乙酸甲酯 0.209 g ( 1.80 mmol), 卜甲基 -1H-咪唑 -2-甲脒盐酸盐 0.289 g (1.8 mmol), 无水乙酸钠 0.180g (2.2 mmol), 升温至回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液真空浓缩至干得粗品， 粗 品经一硅胶柱分离纯化， 收得浅黄色固体 0.260 g (收率 39.8%)。 MS ( M+H: 363, 365 ) 实施例 34  2-Chloro-4-fluorobenzaldehyde 0.285 g ( 1.80 mmol) was dissolved in 25 ml of absolute ethanol, and methyl acetoacetate 0.209 g ( 1.80 mmol) was added, and methyl-1H-imidazole-2-carboxamidine hydrochloride 0.289 was added. g (1.8 mmol), anhydrous sodium acetate 0.180 g (2.2 mmol). The reaction was stopped, the mixture was cooled, filtered, and the filtrate was concentrated in vacuo to dryness. The crude product was purified by silica gel column to yield 0.260 g (yield 39.8%). MS (M+H: 363, 365) Example 34
甲基 6-溴甲基 -4- (2-氯 -4-氟苯基) -2- ( 甲基咪唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(methylimidazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000029_0002
Figure imgf000029_0002
甲基 4- ( 2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 260 mg (0.717 mmol)溶解于 15 ml 四氯化碳中， 加热至 60°C下， 分批投入 134 mg (0.753 mmol) N- 溴代琥珀酰亚胺， 维持 6CTC搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色 固体粗品 280 mg。 MS ( M+H: 441, 443 )  Methyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 260 mg (0.717 mmol) dissolved in 15 ml of carbon tetrachloride, heated to 60 ° C, 134 mg (0.753 mmol) of N-bromosuccinimide was added in portions, stirring at 6 CTC for 30 minutes, cooling, filtration, filtrate The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 441, 443 )
实施例 35 Example 35
甲基 4- (2-氯 -4-氟苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 -carboxylate
Figure imgf000029_0003
Figure imgf000029_0003
将 280 mg新制备的甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -1,4-二氢 嘧啶 -5-羧酸酯溶解到 30 ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空 蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 46mg„ MS ( M+H: 448, 450 ) 280 mg of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-1,4-dihydropyrimidine The -5-carboxylate was dissolved in 30 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0></RTI>
'HNMR(CDCI3)S: 2.61 (m, 4H), 3.60 (s, 3H), 3.83 (m, 4H), 3.87 (d, IH), 3.94 (s, 3H), 4.04 (d, J= 16.8Hz, IH), 6.18 (s， IH), 6.88 (td, IH), 6.90 (d， 1H)， 7.00 (d， IH), 7.13 (dd, IH), 7.18 (q, IH), 9.74 (s, IH). 'HNMR(CDCI 3 )S: 2.61 (m, 4H), 3.60 (s, 3H), 3.83 (m, 4H), 3.87 (d, IH), 3.94 (s, 3H), 4.04 (d, J= 16.8 Hz, IH), 6.18 (s, IH), 6.88 (td, IH), 6.90 (d, 1H), 7.00 (d, IH), 7.13 (dd, IH), 7.18 (q, IH), 9.74 (s , IH).
实施例 36 Example 36
甲基 4- (2,4-二氯苯基) -2- ( 1-甲基咪唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000030_0001
Methyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000030_0001
2,4-二氯苯甲醛 0.315g ( 1.8 mmol) 溶于 25 ml无水乙醇中， 加入乙酰乙酸甲酯 0.209 g ( 1.8 mmol), 卜甲基 -1H-咪唑 -2-甲脒盐酸盐 0.289 g (1.8 mmol), 无水乙酸钠 0.18 g (2.2 mmol), 升温至回流撹拌 18小时。 停止反应， 降温， 过滤， 滤液真空浓缩至干得粗品， 粗 品经一硅胶柱分离纯化， 收得浅黄色固体 0.153g (收率 22.4%)。 MS ( M+H: 379, 381 ) 实施例 37  2,4-Dichlorobenzaldehyde 0.315 g (1.8 mmol) dissolved in 25 ml of absolute ethanol, added with methyl acetoacetate 0.209 g (1.8 mmol), and methyl-1H-imidazol-2-carboxamidine hydrochloride 0.289 g (1.8 mmol), anhydrous sodium acetate 0.18 g (2.2 mmol), warmed to reflux and stirred for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was evaporated. MS (M+H: 379, 381) Example 37
甲基 6-溴甲基 -4- (2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazolyl-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000030_0002
Figure imgf000030_0002
甲基 4- (2,4-二氯苯基) -2- ( 1-甲基咪唑 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 153 mg (0.403 mmol)溶解于 15 ml 四氯化碳中， 加热至 60°C下， 分批投入 75 mg (0.423 mmol) N-溴 代琥珀酰亚胺， 维持 60°C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固 体粗品 250 mg。 MS ( M+H: 457, 459, 461 )  Methyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 153 mg ( 0.403 mmol) dissolved in 15 ml of carbon tetrachloride, heated to 60 ° C, and 75 mg (0.423 mmol) of N-bromosuccinimide was added in portions, stirred at 60 ° C for 30 minutes, cooled, filtered, The solvent was evaporated to dryness <RTI ID=0.0> MS ( M+H: 457, 459, 461 )
实施例 38 Example 38
甲基 4- (2,4-二氯苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
Figure imgf000030_0003
Figure imgf000030_0003
将 250 mg新制备的甲基 -6-溴甲基 -4- (2,4-二氯苯基) -2- (卜甲基咪唑 -2-基) -1,4-二氢 嘧啶 -5-羧酸酯溶解到 25 ml乙醇中， 同 3倍量的吗啉混合， 室温下撹拌 30 分钟。 室温真空 蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 24 mg。 MS ( M+H: 464, 466) 250 mg of freshly prepared methyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-(b-methylimidazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate The acid ester was dissolved in 25 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 464, 466)
'HNMR(CDC13)6: 2.61 (m, 4H), 3.60 (s, 3H), 3.83 (m, 4H), 3.86 (d, 1H), 3.94 (s, 3H), 4.04 (d, J=17.2Hz, lH),6.17(s, 1H),6.91 (s, 1H), 7.00 (d, 1H)， 7.14 (s， 2H), 7.40 (t, 1H),9.74 (s, 1H). 实施例 39 'HNMR(CDC1 3 )6: 2.61 (m, 4H), 3.60 (s, 3H), 3.83 (m, 4H), 3.86 (d, 1H), 3.94 (s, 3H), 4.04 (d, J=17.2) Hz, lH), 6.17 (s, 1H), 6.91 (s, 1H), 7.00 (d, 1H), 7.14 (s, 2H), 7.40 (t, 1H), 9.74 (s, 1H). Example 39
乙基 6-溴甲基 -4- (2-溴 -4-氟苯基) -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000031_0001
Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000031_0001
上述标题化合物通过以下方式制备得到： The above title compound was prepared in the following manner:
步骤一： 吡啶 -2-甲脒盐酸盐 Step 1: Pyridine-2-carboxamidine hydrochloride
2-氰基吡啶 10.4 g (100 mmol)溶于 100 ml无水甲醇， 加入 30% 甲醇钠溶液 18.0 g (100 mmol), 室温搅拌下加入氯化铵 13.4 g ( 250 mmol ), 维持室温搅拌过夜。 过滤， 滤液浓缩 至干， 加入 100 ml丙酮搅散， 过滤， 适量丙酮洗涤滤饼， 抽干， 收得白色固体 18.4 g (收 率 117%)。  2- cyanopyridine 10.4 g (100 mmol) was dissolved in 100 ml of anhydrous methanol, and 18.0 g (100 mmol) of a 30% sodium methoxide solution was added thereto, and 13.4 g (250 mmol) of ammonium chloride was added thereto with stirring at room temperature, and the mixture was stirred at room temperature overnight. . Filtration, the filtrate was concentrated to dryness, stirred with 100 ml of acetone, filtered, and the filter cake was washed with an appropriate amount of acetone, and dried to yield a white solid 18.4 g (yield: 117%).
步骤二: 乙基 4- (2-溴 -4-氟苯基) -2- (吡啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-溴 -4-氟苯甲醛 2.03 g ( 10 mmol )溶于 100 ml无水乙醇中, 加入 1.30 g ( 10 mmol ) 乙 酰乙酸乙酯， 吡啶 -2-甲脒盐酸盐 1.57 g (10 mmol), 无水乙酸钠 l.Og ( 12 mmol ), 升温至回 流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 得浅黄色粘稠固体 5.7 g， 粗品于 10:1石油醚 /乙酸乙酯中重结晶， 收得浅黄色固体 2.40 g (收率 57.4%)。  2-Bromo-4-fluorobenzaldehyde 2.03 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.30 g (10 mmol) of ethyl acetoacetate, pyridine-2-carboxamidine hydrochloride 1.57 g (10 mmol) Anhydrous sodium acetate 1.0 g (12 mmol) was stirred and stirred at reflux for 18 h. The reaction was quenched, cooled, filtered, and evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
MS (M+H: 418, 420)  MS (M+H: 418, 420)
步骤三： 乙基 6-溴甲基 -4- (2-溴 -4-氟苯基) -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Step 3: Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.84 g (2 mmol)乙基 4- (2-溴 -4-氟苯基） -2- (吡啶 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 100 ml 四氯化碳中， 加热至 60Ό下， 分批投入 0.37 g (2.1 mmol) N-溴代琥珀酰亚 胺， 维持 60Ό搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体粗品 1.4g。  0.84 g (2 mmol) ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolved in 100 ml of carbon tetrachloride, heated to 60 Torr, 0.37 g (2.1 mmol) of N-bromosuccinimide was added in portions, stirred at 60 Torr for 30 minutes, cooled, filtered, and the solvent was evaporated under vacuum at room temperature. A pale yellow solid crude product was obtained.
MS ( M+H: 496, 498, 500)  MS ( M+H: 496, 498, 500)
实施例 40 Example 40
乙基 4- (2-溴 -4-氟苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯  Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000031_0002
Figure imgf000031_0002
将 1.4 g实施例 39新制备的乙基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (吡啶 -2-基） -1,4-二 氢嘧啶 -5-羧酸酯溶解到 150 ml 乙醇中， 同 5倍量的吗啉混合， 室温下搅拌 30 分钟。 室温 真空蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.62g。 MS ( M+H: 503, 505 ) 1.4 g of the freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine- The 5-carboxylate was dissolved in 150 ml of ethanol, mixed with 5 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 503, 505 )
'HNMR(D SO-d6)5: 1.14 (t, 3H), 2.63 (m, 4H), 3.84 (m, 4H), 3.88 (d, J=18Hz, 1H)， 4.00-4.11 (m, 3H), 6.25 (s, 1 H), 6.94 (td, 1 H), 7.28-7.38 (m, 3H), 7.74 (t, 1 H), 8.18 (d, 1H), 8.58 (d, 1H), 10.25 (s, 1H). 'HNMR(D SO-d6)5: 1.14 (t, 3H), 2.63 (m, 4H), 3.84 (m, 4H), 3.88 (d, J=18Hz, 1H), 4.00-4.11 (m, 3H) , 6.25 (s, 1 H), 6.94 (td, 1 H), 7.28-7.38 (m, 3H), 7.74 (t, 1 H), 8.18 (d, 1H), 8.58 (d, 1H), 10.25 ( s, 1H).
实施例 41 Example 41
乙基 4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000032_0001
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000032_0001
步骤一： 用 2-氯 -4-氟苯甲醛做为起始原料通过类似于实施例 39的方法合成制得乙基 -6- 溴甲基 -4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯。  Step 1: Synthesis of ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzaldehyde as a starting material. ) -2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS (M+H: 452, 454 )  MS (M+H: 452, 454)
步骤二： 将步骤一制备的化合为作为起始原料投入反应，通过类似于实施例 40的方法合 成制的乙基 4- ( 2-氯 -4-氟苯基 ) -2- (吡啶 -2-基 ) -6- (4-吗啉甲基 ) -1,4-二氢嘧啶 -5-羧酸酯。  Step 2: The compound prepared in the first step was put into the reaction as a starting material, and ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyridine-2) synthesized by a method similar to that of Example 40 was synthesized. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
MS (M+H: 459)  MS (M+H: 459)
'HNMR(DMSO-d6)8: 1.06 (t, 3H), 2.54 (m, 4H)， 3.70 (m, 4H), 3.88 (d， J=17.2Hz, IH), 3.96 (m, 3H), 6.12 (s， IH), 7.15 (td， J,=8.4Hz, J2=2.4Hz, IH), 7.40 (td, J,=8Hz, J2=2.4Hz, IH), 7.56 (dd, IH), 7.91 (td, IH), 8.05 (d, 1H)， 8.68 (d, 1H)， 10.23 (s， IH). 'HNMR (DMSO-d6) 8: 1.06 (t, 3H), 2.54 (m, 4H), 3.70 (m, 4H), 3.88 (d, J = 17.2 Hz, IH), 3.96 (m, 3H), 6.12 (s, IH), 7.15 (td, J, = 8.4 Hz, J 2 = 2.4 Hz, IH), 7.40 (td, J, = 8 Hz, J 2 = 2.4 Hz, IH), 7.56 (dd, IH), 7.91 (td, IH), 8.05 (d, 1H), 8.68 (d, 1H), 10.23 (s, IH).
实施例 42 Example 42
乙基 4- (2，4-二氯苯基） -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2,4-dichlorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000032_0002
Figure imgf000032_0002
步骤一： 用 2,4-二氯苯甲鹺做为起始原料通过类似于实施例 39的方法合成制得乙基 -6- 溴甲基 -4- (2,4-二氯苯基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯。  Step 1: Synthesis of ethyl-6-bromomethyl-4-(2,4-dichlorophenyl) by a method similar to that of Example 39 using 2,4-dichlorobenzidine as a starting material. -2-(Pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS ( M+H: 468, 470, 472 )  MS ( M+H: 468, 470, 472 )
步骤二： 将步骤一制备的化合为作为起始原料投入反应，通过类似于实施例 40的方法合 成制的乙基 4- (2,4-二氯苯基） -2- (吡啶 -2-基） -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯。  Step 2: The compound prepared in the first step was put into the reaction as a starting material, and ethyl 4-(2,4-dichlorophenyl)-2-(pyridine-2-) synthesized by a method similar to that of Example 40. (6-(4-morpholinemethyl)-1,4-dihydropyrimidine-5-carboxylate.
MS (M+H: 475, 477 )  MS (M+H: 475, 477 )
'HN R(DMSO-d6)8: 1.14 (t， 3H), 2.64 (m, 4H), 3.85 (m, 5H)， 4.00-4.11 (m, 3H), 6.27 (s, IH), 7.15 (d, IH), 7.26 (d, 1H)， 7.37-7.40 (m, 2H), 7.74 (t, IH), 8.18 (d， IH), 8.58 (d, IH), 10.25 (s, IH).  'HN R(DMSO-d6)8: 1.14 (t, 3H), 2.64 (m, 4H), 3.85 (m, 5H), 4.00-4.11 (m, 3H), 6.27 (s, IH), 7.15 (d , IH), 7.26 (d, 1H), 7.37-7.40 (m, 2H), 7.74 (t, IH), 8.18 (d, IH), 8.58 (d, IH), 10.25 (s, IH).
实施例 43 Example 43
甲基 4- (2-溴 -4-氟苯基） -2- (吡啶 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000032_0003
步骤一： 用 2-溴 -4-氟苯甲醛和乙酰乙酸甲酯做为起始原料通过类似于实施例 39的方 法合成制得甲基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯。
Figure imgf000032_0003
Step 1: Synthesis of methyl-6-bromomethyl-4-(2-bromo-) by a method similar to that of Example 39 using 2-bromo-4-fluorobenzaldehyde and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS ( M+H: 482, 484, 486 )  MS ( M+H: 482, 484, 486 )
步骤二： 将步骤一制备的化合为作为起始原料投入反应,通过类似于实施例 40的方法 合成制的甲基 4- ( 2-澳 -4-氟苯基） -2- (吡啶 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸 酯。 MS (M+H: 489, 491 )  Step 2: The compound prepared in the first step was put into the reaction as a starting material, and methyl 4-(2-au-4-fluorophenyl)-2-(pyridine-2) synthesized by a method similar to that of Example 40 was synthesized. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate. MS (M+H: 489, 491 )
'HNMR(CDCI3)S: 2.63 (m， 4H), 3.61 (s, 3H), 3.84 (m, 4H), 3.87 (d, 1H),4.08 (d， 1H)， 6.23 (s, IH), 6.92 (t, IH), 7.26 (t, IH), 7.35 (m, 2H), 7.74 (t， 1H)， 8.18 (d， 1H)， 8.56 (d, 1H)， 10.27 (s, IH). 'HNMR(CDCI 3 )S: 2.63 (m, 4H), 3.61 (s, 3H), 3.84 (m, 4H), 3.87 (d, 1H), 4.08 (d, 1H), 6.23 (s, IH), 6.92 (t, IH), 7.26 (t, IH), 7.35 (m, 2H), 7.74 (t, 1H), 8.18 (d, 1H), 8.56 (d, 1H), 10.27 (s, IH).
实施例 44 Example 44
甲基 4- (2-氯 -4-氟苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000033_0001
Figure imgf000033_0001
步骤一： 用 2-氯 -4-氟苯甲醛和乙酰乙酸甲酯做为起始原料通过类似于实施例 39的方法合成 制得甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯。 Step 1: Synthesis of methyl-6-bromomethyl-4-(2-chloro-) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS (M+H: 438, 440)  MS (M+H: 438, 440)
步骤二： 将步骤一制备的化合为作为起始原料投入反应,通过类似于实施例 40 的方法合成 制的甲基 4- (2-氯 -4-氟苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯。 Step 2: The compound prepared in the first step was introduced into the reaction as a starting material, and methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridine-2) was synthesized by a method similar to that of Example 40. -yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
MS (M+H: 445 )  MS (M+H: 445)
'HN R(CDC13)5: 2.63 (m, 4H)， 3.61 (s， 3H), 3.84 (m, 4H), 3.87 (d, 1H),4.07 (d, IH), 6.26 (s; IH), 6.88 (t, IH), 7.13 (d， IH), 7.28 (d, IH), 7.36 (t, 1H)， 7.74 (t, IH), 8.18 (d, IH), 8.57 (d, IH), 10.27 (s, IH). 'HN R(CDC1 3 )5: 2.63 (m, 4H), 3.61 (s, 3H), 3.84 (m, 4H), 3.87 (d, 1H), 4.07 (d, IH), 6.26 (s ; IH) , 6.88 (t, IH), 7.13 (d, IH), 7.28 (d, IH), 7.36 (t, 1H), 7.74 (t, IH), 8.18 (d, IH), 8.57 (d, IH), 10.27 (s, IH).
实施例 44 Example 44
甲基 4- (2,4-二氯苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2,4-dichlorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000033_0002
Figure imgf000033_0002
步骤一： 用 2，4-二氯苯甲鹾和乙酰乙酸甲酯做为起始原料通过类似于实施例 39的方法合成 制得甲基 -6-溴甲基 -4- (2，4-二氯苯基) -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯。 Step 1: Synthesis of methyl-6-bromomethyl-4- (2,4-) by a method similar to that of Example 39 using 2,4-dichlorobenzamide and methyl acetoacetate as starting materials. Dichlorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS ( M+H: 454, 456, 458 )  MS ( M+H: 454, 456, 458 )
步骤二： 将步骤一制备的化合为作为起始原料投入反应,通过类似于实施例 40的方法合成制 的甲基 4- (2,4-二氯苯基） -2- (吡啶 -2-基） -6- (4-吗啉甲基） -1，4-二氢嘧啶 -5-羧酸酯。 Step 2: The compound prepared in the first step was put into the reaction as a starting material, and methyl 4-(2,4-dichlorophenyl)-2-(pyridine-2-) synthesized by a method similar to that of Example 40 (6-(4-morpholinemethyl)-1,4-dihydropyrimidine-5-carboxylate.
MS ( M+H: 461, 463 ) MS ( M+H: 461, 463 )
'HNMR(CDC13)5: 2.63 (m, 4H)， 3.60 (s, 3H), 3.80 (m, 4H), 3.87 (d, 1H),4.07 (d, IH), 6.26 (s, IH), 7.15 (d, IH), 7.24 (d, IH), 7.36 (t, IH), 7.39(d, IH), 7.74 (t, IH), 8.17 (d, IH), 8.57 (d, IH), 10.29 (s, IH). 实施例 4S 'HNMR(CDC1 3 )5: 2.63 (m, 4H), 3.60 (s, 3H), 3.80 (m, 4H), 3.87 (d, 1H), 4.07 (d, IH), 6.26 (s, IH), 7.15 (d, IH), 7.24 (d, IH), 7.36 (t, IH), 7.39 (d, IH), 7.74 (t, IH), 8.17 (d, IH), 8.57 (d, IH), 10.29 (s, IH). Example 4S
甲基 4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基） -6-哌嗪甲基 -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-piperazinylmethyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000034_0001
Figure imgf000034_0001
步骤一： 用 2-氯 -4-氟苯甲鹾和乙酰乙酸甲酯做为起始原料通过类似于实施例 39的方法 合成制得甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯。  Step 1: Synthesis of methyl-6-bromomethyl-4-(2-chloro) by a method similar to that of Example 39 using 2-chloro-4-fluorobenzhydrazide and methyl acetoacetate as starting materials. 4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS ( M+H: 438, 440)  MS ( M+H: 438, 440)
步骤二：无水哌嗪 0.172 g ( 2 mmol )溶解于 15 ml无水乙醇中，室温下滴加 0.9g{ 2mmol ) 通过步骤一新制备的甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5- 羧酸酯的 10ml乙醇溶液， 室温反应 lh, TLC检测澳化物点消失， 加入 1.5g ( 10.8 mmol ) 无水碳酸钾搅拌 15分钟， 过滤， 滤液室温真空浓缩至干， 经一硅胶柱分离， 乙酸乙酯 /乙醇 洗脱， 收得纯化产物 23mg„  Step 2: 0.172 g (2 mmol) of anhydrous piperazine was dissolved in 15 ml of absolute ethanol, and 0.9 g (2 mmol) was added dropwise at room temperature. The methyl-6-bromomethyl-4-(2) prepared by the step 1. -Chloro-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate in 10 ml of ethanol, reacted at room temperature for 1 h, TLC detected the disappearance of the azide point, added 1.5 g (10. 8 mmol) of anhydrous potassium carbonate was stirred for 15 minutes, filtered, and the filtrate was concentrated to dryness in vacuo.
MS ( M+H: 444， 446)  MS ( M+H: 444, 446)
'HN R(CDCI3)5: 2.16 (s, IH), 2.61 (m, 4H), 3.05 (m, 4H), 3.61 (s, 3H), 3.86 (d, IH), 4.05 (d， IH), 4.85 (br, IH), 6.28 (s, IH), 6.90 (td, IH), 7.14 (dd, IH), 7.30 (dd, IH), 7.36 (m， IH), 7.74 (t, IH), 8.20 (d, IH), 8.59 (d, IH), 10.34 (s, IH). 'HN R(CDCI 3 )5: 2.16 (s, IH), 2.61 (m, 4H), 3.05 (m, 4H), 3.61 (s, 3H), 3.86 (d, IH), 4.05 (d, IH) , 4.85 (br, IH), 6.28 (s, IH), 6.90 (td, IH), 7.14 (dd, IH), 7.30 (dd, IH), 7.36 (m, IH), 7.74 (t, IH), 8.20 (d, IH), 8.59 (d, IH), 10.34 (s, IH).
实施例 46 Example 46
乙基 4- (2-溴 -4-氟苯基） -2- (吡啶 -2-基) -6-哌嗪甲基 -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-piperazinylmethyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000034_0002
Figure imgf000034_0002
将 2.1g (4.2 mmol)实施例 39 新制备的乙基 -6-溴甲基 -4- ( 2-溴 -4-氟苯基） -2- (吡啶 -2- 基） -1,4-二氢嘧啶 -5-羧酸酯溶解到 200 ml乙醇中， 加入等摩尔量的无水哌嗪， 室温下搅拌 30 分钟„ 室温真空蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.12g。  2.1 g (4.2 mmol) of the newly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-1,4- The dihydropyrimidine-5-carboxylate was dissolved in 200 ml of ethanol, and an equimolar amount of anhydrous piperazine was added thereto. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo. The product was 0.12 g.
MS (M+H: 502, 504 ) HNMR(5 )  MS (M+H: 502, 504) HNMR(5)
实施例 47 Example 47
甲基 4- (2-氯 -4-氟苯基） -6- ((4- (2, 2, 2-三氟乙酰基） 哌嗪 -1-基） 甲基） -2- (噻唑 -2- 基） -1,4-二氯嘧啶 -5-羧酸酯
Figure imgf000035_0001
Methyl 4-(2-chloro-4-fluorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazin-1-yl)methyl)-2-(thiazole- 2-yl)-1,4-dichloropyrimidine-5-carboxylate
Figure imgf000035_0001
0.439g ( 1 mmol) 类似于实施例 39的制备方法新制备的甲基 -6-溴甲基 -4- ( 2-氯 -4-氟苯 基） -2- (吡啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯的 40 ml乙醇溶液， 加入 1-三氟乙酰哌嗪 0.364 g(2 mmol), 室温反应 0.5h,滤液室温真空浓缩至干，经一硅胶柱分离， 收得纯化产物 43 mg。  0.439 g (1 mmol) of methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-prepared analogously to the preparation of Example 39 A solution of 1,4-dihydropyrimidine-5-carboxylate in 40 ml of ethanol, added 1-trifluoroacetylpiperazine 0.364 g (2 mmol), reacted at room temperature for 0.5 h, and the filtrate was concentrated in vacuo to dryness. After isolation, the purified product was obtained in 43 mg.
MS ( +H: 540, 542)  MS ( +H: 540, 542)
'HNMR(CDC13)5: 2.71 (t, 4H), 3.62 (t, 4H), 3.93 (d, 1H), 4.18(d, 1H), 6.29 (s, 1H), 6.91 (td, 1H), 7.16 (dd, 1H)， 7.29 (t, 1H).7.40 (m, 1H), 7.77 (td, 1H), 8.21 (d, 1H), 8.57 (d， 1H).10.14 (s, IH). 'HNMR(CDC1 3 )5: 2.71 (t, 4H), 3.62 (t, 4H), 3.93 (d, 1H), 4.18 (d, 1H), 6.29 (s, 1H), 6.91 (td, 1H), 7.16 (dd, 1H), 7.29 (t, 1H).7.40 (m, 1H), 7.77 (td, 1H), 8.21 (d, 1H), 8.57 (d, 1H).10.14 (s, IH).
实施例 48 Example 48
乙基 4- (2,4-二氯苯基） -6- ((4- (2, 2, 2-三氟乙酰基） 哌嗪小基） 甲基） -2- (噻唑 -2- 基） -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2,4-dichlorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazine)-methyl)-2-(thiazol-2-yl) -1,4-dihydropyrimidine-5-carboxylate,
Figure imgf000035_0002
Figure imgf000035_0002
步骤一： 用 2,4-二氯苯甲醛做为起始原料通过类似于实施例 39的方法合成制得乙基 -6- 溴甲基 -4- (2，4-二氯苯基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯。  Step 1: Synthesis of ethyl-6-bromomethyl-4-(2,4-dichlorophenyl) by a method similar to that of Example 39 using 2,4-dichlorobenzaldehyde as a starting material. 2-(Pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate.
MS ( M+H: 468, 470, 472 )  MS ( M+H: 468, 470, 472 )
步骤二： 将步骤一制备的化合物和 1-三氟乙酰哌嗪作为起始原料投入反应，通过类似于 实施例 45的方法合成制得乙基 4- (2,4-二氯苯基） -2- (吡啶 -2-基） -6- (4- ( 1-三氟乙酰基） 哌嗪甲基） -1,4-二氢嘧啶 -5-羧酸酯。  Step 2: The compound prepared in the first step and 1-trifluoroacetylpiperazine were put into the reaction as a starting material, and the ethyl 4-(2,4-dichlorophenyl) group was synthesized by a method similar to that of Example 45. 2-(Pyridin-2-yl)-6-(4-(1-trifluoroacetyl)piperazinylmethyl)-1,4-dihydropyrimidine-5-carboxylate.
实施例 49 Example 49
甲基 4- (2-溴 -4-氟苯基） -6- ((4-乙酰基)哌嗪 -1-基) 甲基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-bromo-4-fluorophenyl)-6-((4-acetyl)piperazin-1-yl)methyl)-2-(thiazol-2-yl)-1,4- Dihydropyrimidine-5-carboxylate
Figure imgf000035_0003
0.80g ( 1.65 mmol) 通过类似于实施例 39的制备方法新制备的甲基 -6-溴甲基 -4- ( 2-溴 -4-氟苯基）-2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯的 80 ml乙醇溶液，加入 1-乙酰哌嗪 0.423 g(3.3 mmol), 室温反应 0.5h, 滤液室温真空浓缩至干， 经一硅胶柱分离， 正己垸 /乙酸乙酯 洗脱， 收得纯化产物 350 mg。 MS ( M+H: 530, 532 )
Figure imgf000035_0003
0.80 g ( 1.65 mmol) methyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl) freshly prepared by a preparation method similar to that of Example 39 - 1,4-dihydropyrimidine-5-carboxylate in 80 ml of ethanol, adding 1-acetylpiperazine 0.423 g (3.3 mmol), reacted at room temperature for 0.5 h, and the filtrate was concentrated to dryness in vacuo and separated on silica gel column. The product was eluted with n-hexane/ethyl acetate to give the purified product 350 mg. MS ( M+H: 530, 532 )
'HNMR(CDC13)S: 2.13 (s, 3H), 2.61 (m, 4H), 3.60 (s, 3H), 3.80 (m， 4H), 3.91 (d, 1H),4.13 (d, 1H), 6.25 (s, 1H), 6.94 (td, 1H), 7.30 (m, 2H), 7.36 (dd, 1H)， 7.74 (td, 1H), 8.18 (d， 1H), 8.55 (d, 1H)， 10.25 (s, 1H). 'HNMR(CDC1 3 )S: 2.13 (s, 3H), 2.61 (m, 4H), 3.60 (s, 3H), 3.80 (m, 4H), 3.91 (d, 1H), 4.13 (d, 1H), 6.25 (s, 1H), 6.94 (td, 1H), 7.30 (m, 2H), 7.36 (dd, 1H), 7.74 (td, 1H), 8.18 (d, 1H), 8.55 (d, 1H), 10.25 (s, 1H).
实施例 50; Example 50;
甲基 4- (2-溴 -4-氟苯基） -2. (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4- (2-bromo-4-fluorophenyl)-2. (pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000036_0001
Figure imgf000036_0001
步骤一： 嘧啶 -2-甲脒盐酸盐 Step 1: Pyrimidine-2-carboxamidine hydrochloride
2-氰基嘧啶 6.0 g (57 mmol ) 溶于 60 ml无水甲醇， 加入 30% 甲醇钠溶液 10.3 g (57 mmol), 室温撹拌下加入氯化铵 7.65 g ( 143 mmol), 维持室温撹拌过夜。 过滤， 滤液浓缩 至干， 加入 60 ml丙酮搅散。 过滤， 适量丙酮洗涤滤饼， 抽干， 收得白色固体 7.9 g (收率 87.4 % )。  2-cyanopyrimidine 6.0 g (57 mmol) dissolved in 60 ml of anhydrous methanol, added with 30% sodium methoxide solution 10.3 g (57 mmol), and added with ammonium chloride 7.65 g ( 143 mmol) at room temperature, and kept at room temperature overnight. . After filtration, the filtrate was concentrated to dryness and then stirred with 60 ml of acetone. After filtration, the acetone cake was washed with an appropriate amount of acetone, and dried to yield a white solid 7.9 g (yield: 87.4%).
步骤二: 甲基 4- (2-溴 -4-氟苯基） -2- (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Methyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-溴 -4-氟苯甲醛 2.03 g ( 10 mmol )溶于 100 ml无水乙醇中， 加入 1.16 g ( 10 mmol) 乙 酰乙酸甲酯， 嘧啶 -2-甲脒盐酸盐 1.59 g (10 mmol), 无水乙酸钠 l.Og ( 12 mmol ), 升温至回 流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱纯化， 收得浅黄 色固体产物 1.61g (收率 39.8%)。 MS (M+H: 405, 407)  2-bromo-4-fluorobenzaldehyde 2.03 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.16 g (10 mmol) of methyl acetoacetate, pyrimidine-2-carboxamidine hydrochloride 1.59 g (10 mmol) was added. Anhydrous sodium acetate 1.0 g (12 mmol) was stirred and stirred at reflux for 18 h. The reaction was stopped, the mixture was cooled, filtered, and the filtrate was evaporated to dryness. The crude product was purified on silica gel column to yield 1.61 g (yield 39.8%). MS (M+H: 405, 407)
实施例 51 Example 51
甲基 6-溴甲基 -4- (2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000036_0002
Figure imgf000036_0002
0.81 g(2 mmol)甲基 4- ( 2-溴 -4-氟苯基） -2- (嘧啶 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸 醋 (实施例 50的方法制备得到)溶解于 80ml 四氯化碳中， 加热至 60°C下， 分批投入 0.374 g (2.1 mmol) N-溴代琥珀酰亚胺， 维持 60Ό搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶 剂， 得浅黄色粗产物 0.75g。 MS ( M+H: 482, 484, 486)  0.81 g (2 mmol) methyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxy vinegar (Prepared by the method of Example 50) dissolved in 80 ml of carbon tetrachloride, heated to 60 ° C, and 0.374 g (2.1 mmol) of N-bromosuccinimide was added in portions, and stirred for 60 minutes at 60 Torr, and the temperature was lowered. The mixture was filtered, and the solvent was evaporated from vacuo. MS ( M+H: 482, 484, 486)
实施例 52: Example 52
甲基 4- (2-溴 -4-氟苯基） -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000037_0001
Methyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000037_0001
将 0.75 g新制备的甲基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (嘧啶 -2-基） -1,4-二氢嘧啶 -5- 羧酸酯溶解到 80ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶 剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.184g。 MS (M+H: 490, 492)  0.75 g of freshly prepared methyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate The acid ester was dissolved in 80 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0></RTI> MS (M+H: 490, 492)
'HNMR(CDC13)5: 2.64 (t, 4H), 3.61 (s, 3H), 3.82-3.86 (m, 5H), 4.04 (d, J=17.6Hz, 1H), 6.34 (s, 1H)， 6.93 (td， 1H), 7.28 (dd, 1H), 7.35 (q， 1H), 7.41 (t, 1H), 8.87 (d, 2H), 10.17 (s, 1H). 实施例 53 'HNMR(CDC1 3 )5: 2.64 (t, 4H), 3.61 (s, 3H), 3.82-3.86 (m, 5H), 4.04 (d, J=17.6Hz, 1H), 6.34 (s, 1H), 6.93 (td, 1H), 7.28 (dd, 1H), 7.35 (q, 1H), 7.41 (t, 1H), 8.87 (d, 2H), 10.17 (s, 1H). Example 53
乙基 4- (2,4-二氯苯基） -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000037_0002
Figure imgf000037_0002
步骤一: 制备乙基 4- (2,4-二氯苯基) -2- (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2,4-二氯苯甲醛 1.75 g ( lOmmol) 溶于 100 ml无水乙醇中， 加入 1.30 g ( lOmmol ) 乙 酰乙酸乙酯， 嘧啶 -2-甲脒盐酸盐 1.59 g (lOmmol), 无水乙酸钠 l.Og ( 12 mmol ), 升温至回 流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱纯化， 收得浅黄 色固体产物 1.84g (收率 47.0%)。 MS ( M+H: 391, 393 )  2,4-dichlorobenzaldehyde 1.75 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.30 g (10 mmol) of ethyl acetoacetate, pyrimidine-2-carboxamidine hydrochloride 1.59 g (10 mmol), anhydrous Sodium acetate 1.0 g (12 mmol) was stirred and stirred at reflux for 18 h. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. The crude material was purified on silica gel column to yield 1.84 g (yield 47.0%). MS ( M+H: 391, 393 )
步骤二： 制备乙基 6-溴甲基 -4- (2,4-二氯苯基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯Step 2: Preparation of ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.90 g (2.3 mmol)乙基 4- (2,4-二氯苯基） -2- (嘧啶 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 90ml 四氯化碳中， 加热至 60。C下， 分批投入 0.427 g (2.4 mmol) N-溴代琥珀酰亚 胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗产物 1.0g。 0.90 g (2.3 mmol) of ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Heat to 60 in 90 ml of carbon tetrachloride. Under C, 0.427 g (2.4 mmol) of N-bromosuccinimide was added in portions, and the mixture was stirred at 60 ° C for 30 minutes, cooled, filtered, and the solvent was evaporated from vacuo.
MS ( M+H: 469, 471, 473 )  MS ( M+H: 469, 471, 473 )
步骤三：乙基 4- (2,4-二氯苯基) -2- (嘧啶 -2-基） -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 将 1.0 g 新制备的乙基 -6-溴甲基 -4- (2,4-二氯苯基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5- 羧酸酯溶解到 100 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除 溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.30g。 MS (M+H: 476, 478 ) Step 3: Ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate The acid ester will be 1.0 g of freshly prepared ethyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5- The carboxylic acid ester was dissolved in 100 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS (M+H: 476, 478 )
'HNMR(CDC13)5: 1.14 (t, 3H)， 2.63 (t， 4H), 3.82 (t， 4H)， 3.85 (d, 1H), 4.05 (m， 3H), 6.36 (s, 1 H), 7.14 (dd, 1H), 7.33 (d, 1 H), 7.36 (d, 1 H), 7.40 (t, 1 H), 8.87 (d, 2H), 10.13 (s, 1 H). 'HNMR(CDC1 3 )5: 1.14 (t, 3H), 2.63 (t, 4H), 3.82 (t, 4H), 3.85 (d, 1H), 4.05 (m, 3H), 6.36 (s, 1 H) , 7.14 (dd, 1H), 7.33 (d, 1 H), 7.36 (d, 1 H), 7.40 (t, 1 H), 8.87 (d, 2H), 10.13 (s, 1 H).
实施例 54 Example 54
甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (嘧啶 -2-基） -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000038_0001
Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5- Carboxylic ester
Figure imgf000038_0001
步骤一：2-氯 -4-氟苯甲鹺 1.58 g( lOmmol )溶于 100 ml无水乙醇中，加入 1.16 g( lOmmol) 乙酰乙酸甲酯， 嘧啶 -2-甲脒盐酸盐 1.59g(10mmol), 无水乙酸钠 l.Og ( 12 mmol ), 升温至 回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱纯化， 收得浅 黄色固体产物甲基 4- ( 2-氯 -4-氟苯基 ) -2- (嘧啶 -2-基 ) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 1.3g (收率 36.0%)。 MS (M+H: 361, 363 )  Step 1: 2-chloro-4-fluorobenzamide 1.58 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.16 g (10 mmol) of methyl acetoacetate and pyrimidine-2-carboxamidine hydrochloride 1.59 g ( 10 mmol), anhydrous sodium acetate 1.0 g (12 mmol). The reaction was quenched, cooled, filtered, and the filtrate was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjj -6-Methyl-1,4-dihydropyrimidine-5-carboxylate 1.3 g (yield 36.0%). MS (M+H: 361, 363 )
步骤二: 1.3 g (3.6 mmol)甲基 4- ( 2-氯 -4-氟苯基) -2- (嘧啶 -2-基) -6-甲基 -1，4-二氢嘧啶 -5- 羧酸酯溶解于 130ml 四氯化碳中， 加热至 60'C下， 分批投入 0.68 g (3.8 mmol) N-溴代琥珀 酰亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗产物甲 基 6-溴甲基 -4- (2-氯 -4-氟苯基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 1.12 g。 Step 2: 1.3 g (3.6 mmol) methyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5- The carboxylic acid ester was dissolved in 130 ml of carbon tetrachloride, heated to 60 ° C, and 0.68 g (3.8 mmol) of N-bromosuccinimide was added in portions. The mixture was stirred at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was filtered. The solvent was evaporated in vacuo <RTI ID=0.0> -5-carboxylate 1.12 g.
MS ( M+H: 439, 441 )  MS ( M+H: 439, 441 )
步骤三: 将 1.12 g新制备的甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基) -2- (嘧啶 -2-基) -1,4-二 氢嘧啶 -5-羧酸酯溶解到 120 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温 真空蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.320g。 MS (M+H: 446, 448 ) Step 3: 1.12 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine- The 5-carboxylate was dissolved in 120 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS (M+H: 446, 448)
'HNMR(CDCI3)5: 2.63 (t, 4H), 3.61 (s, 3H), 3.82-3.86 (m, 5H)， 4.04 (d, J=17.2Hz, 1H), 6.35 (s, 1H), 6.88 (td, 1H), 7.09 (dd, 1H), 7.35(q, 1H), 7.40 (t, 1H), 8.87 (d, 2H), 10.17 (s, 1H). 实施例 55 'HNMR(CDCI 3 )5: 2.63 (t, 4H), 3.61 (s, 3H), 3.82-3.86 (m, 5H), 4.04 (d, J=17.2Hz, 1H), 6.35 (s, 1H), 6.88 (td, 1H), 7.09 (dd, 1H), 7.35(q, 1H), 7.40 (t, 1H), 8.87 (d, 2H), 10.17 (s, 1H). Example 55
乙基 4- (2-氯 -4-氟苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000038_0002
Figure imgf000038_0002
步骤一： 制备乙基 4- (2-氯 -4-氟苯基） -2- (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 2-氯 -4-氟苯甲醛 1.58 g ( lOmmol) 溶于 100 ml无水乙醇中， 加入 1.30 g ( lOmmol) 乙 酰乙酸乙酯， 嘧啶 -2-甲脒盐酸盐 l.59g(10mmol), 无水乙酸钠 1.Og ( 12 mmol ), 升温至回 流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱纯化， 收得浅黄 色固体产物 1.26g (收率 33.6%). MS ( M+H: 375, 377 ) Step 1: Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 2- Chloro-4-fluorobenzaldehyde 1.58 g (10 mmol) was dissolved in 100 ml of absolute ethanol, and 1.30 g (10 mmol) of ethyl acetoacetate, pyrimidine-2-carboxamidine hydrochloride 1.59 g (10 mmol), anhydrous Sodium acetate 1. Og (12 mmol) was stirred and stirred at reflux for 18 h. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
步骤二： 制备乙基 6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (嘧啶 -2-基） -1,4-二氢嘧啶 -5-羧酸 酯  Step 2: Preparation of ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ester
0.80 g (2.1 mmol)乙基 4- ( 2-氯 -4-氟苯基） -2- (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧 酸酯溶解于 80 ml 四氯化碳中， 加热至 60°C下， 分批投入 0.39 g (2.2 mmol) N-溴代琥珀酰 亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗产物 0.63 g' MS ( M+H: 453, 455 )  0.80 g (2.1 mmol) ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolved in 80 ml of carbon tetrachloride, heated to 60 ° C, 0.39 g (2.2 mmol) N-bromosuccinimide was added in batches, kept at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was vacuumed at room temperature. The solvent was evaporated to give a pale yellow crude product: 0.63 g. MS (M+H: 453, 455)
步骤三： 制备乙基 4- (2-氯 -4-氟苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5- 羧酸酯 Step 3: Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5 - Carboxylic esters
将 0.63 g新制备的乙基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (嘧啶 -2-基） -1,4-二氧嘧啶 -5- 羧酸酯溶解到 60ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶 剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.130g。 MS (M+H: 460, 462) 0.63 g of freshly prepared ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dioxopyrimidine-5- The carboxylic acid ester was dissolved in 60 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS (M+H: 460, 462)
'HNMR(DMSO-d6)5: 1.08 (t, 3H), 2.55 (m, 4H)， 3.69 (m, 4H)， 3.87(d, J=16.8Hz, IH), 3.86-4.00 (m, 3H), 6.17 (s， 1H)， 7.16 (td, 1H)， 7.39 (m, IH), 7.64 (t, IH), 8.96 (d, 2H), 10.14 (s, IH).  'HNMR(DMSO-d6)5: 1.08 (t, 3H), 2.55 (m, 4H), 3.69 (m, 4H), 3.87 (d, J = 16.8Hz, IH), 3.86-4.00 (m, 3H) , 6.17 (s, 1H), 7.16 (td, 1H), 7.39 (m, IH), 7.64 (t, IH), 8.96 (d, 2H), 10.14 (s, IH).
实施例 56 Example 56
乙基 4- (2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1，4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000039_0001
Figure imgf000039_0001
步骤一： 制备乙基 4- (2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯Step 1: Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-溴氯 -4-氟苯甲醛 1.02g (5mmol) 溶于 50 ml无水乙醇中， 加入 0.65 g ( 5 mmol ) 乙 酰乙酸乙酯， 嘧啶 -2-甲脒盐酸盐 0.80g(5mmoi), 无水乙酸纳 0.50g ( 6 mmol )， 升温至回流 搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱纯化， 收得浅黄色 固体产物 0.85 g (收率 40.5%)。 MS ( M+H: 419, 421 ) 2-bromochloro-4-fluorobenzaldehyde 1.02g (5mmol) dissolved in 50 ml of absolute ethanol, added 0.65 g (5 mmol) ethyl acetoacetate, pyrimidine-2-carboxamidine hydrochloride 0.80 g (5mmoi) 0.50 g (6 mmol) of anhydrous sodium acetate was added and the mixture was warmed to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. The crude material was purified on silica gel column to yield a pale yellow solid product of 0.85 g (yield 40.5%). MS ( M+H: 419, 421 )
步骤二： 制备乙基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 0.85 g (2 mmol)乙基 4- ( 2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 80 ml 四氯化碳中， 加热至 60°C下， 分批投入 0.37 g (2.1 mmol) N-溴代琥珀酰亚 胺， 维持 60 'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗产物 0.58 g。 Step 2: Preparation of ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate 0.85 g (2 mmol) ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved In 80 ml of carbon tetrachloride, heated to 60 ° C, 0.37 g (2.1 mmol) of N-bromosuccinimide was added in batches, kept at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was steamed at room temperature. The solvent was removed to give a pale yellow crude product, 0.58 g.
MS ( M+H: 497, 499， 501 )  MS ( M+H: 497, 499, 501 )
步骤三： 乙基 4- (2-溴 -4-氟苯基） -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸 酯 Step 3: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
将 0.58 g新制备的乙基 -6-溴甲基 -4- (2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -1，4-二氢嘧啶 -5- 羧酸酯溶解到 60ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶 剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.10g„ MS (M+H: 504, 506 )  0.58 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-1,4-dihydropyrimidine-5-carboxylate The acid ester was dissolved in 60 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>
'HNMR(DMSO-d6)5: 1.08 (t, 3H)， 2.55 (m, 4H), 3.70 (m, 4H), 3.86-4.00 (m, 4H), 6.15 (s, IH), 7.20 (td, IH), 7.39(dd, IH), 7.55 (dd, IH), 7.66 (t, IH), 8.96 (d, 2H), 10.14 (s, IH).  'HNMR(DMSO-d6)5: 1.08 (t, 3H), 2.55 (m, 4H), 3.70 (m, 4H), 3.86-4.00 (m, 4H), 6.15 (s, IH), 7.20 (td, IH), 7.39 (dd, IH), 7.55 (dd, IH), 7.66 (t, IH), 8.96 (d, 2H), 10.14 (s, IH).
实施例 57 Example 57
乙基 4- (2-溴 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000039_0002
Figure imgf000039_0002
步骤一： 制备乙基 4- (2-溴 -4-氟苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-溴 -4-氟苯甲酸 1.02g (5 mmol) 溶于 50ml无水乙醇中， 加入 0.65 g ( 5 mmol ) 乙酰 乙酸乙酯， 苯甲脒盐酸盐 0.79 g (5 mmol), 无水乙酸钠 0.62 g ( 7.5 mmol ), 升温至回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓縮至干， 残余物加入 50 ml 1N盐酸酸化， 3><40 ml 甲基叔丁基醚洗涤， 水层加 20%氢氧化纳调 pH至 10- 12, 经 3x40 ml乙酸乙酯萃取， 无水 硫酸钠干燥， 乙酸乙酯溶液浓缩至干， 收得浅黄色固体 0.91 g (收率 43.6%)。 1.02 g (5 mmol) of 2-bromo-4-fluorobenzoic acid was dissolved in 50 ml of absolute ethanol, and 0.65 g (5 mmol) of ethyl acetoacetate, benzamidine hydrochloride 0.79 g (5 mmol), anhydrous Sodium acetate 0.62 g (7.5 mmol) was warmed to reflux for 18 h. Stop the reaction, cool down, filter, concentrate the filtrate to dryness, add the residue to 50 ml of 1N hydrochloric acid, 3><40 ml methyl t-butyl ether, and add 20% sodium hydroxide to adjust the pH to 10-12. Extracted with 3x40 ml of ethyl acetate, anhydrous The mixture was dried over sodium sulfate and evaporated to drynessiel
MS (M+H: 417, 419)  MS (M+H: 417, 419)
步骤二： 制备乙基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Preparation of ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
0.21 g (0.5 mmol)乙基 4- ( 2-溴 -4-氟苯基） -2-苯基 -6-甲基 -1，4-二氢嘧啶 -5-羧酸酯溶解 于 20ml 四氯化碳中， 加热至 60Ό下， 分批投入 0.094 g ( 0.53 mmol ) N-溴代琥珀酰亚胺， 维持 60°C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗品 0.27g.  0.21 g (0.5 mmol) of ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved in 20 ml of tetrachloro In the carbon, heat to 60 Torr, and add 0.094 g (0.53 mmol) of N-bromosuccinimide in batches, stir at 60 ° C for 30 minutes, cool down, filter, and evaporate the solvent at room temperature under vacuum to obtain a pale yellow crude product. 0.27g.
MS (M+H: 495, 497, 499 )  MS (M+H: 495, 497, 499)
步骤三： 乙基 4- (2-溴 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Step 3: Ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
将 0.27 g新制备的乙基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯溶 解到 25ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗品 经一硅胶柱纯化， 收得浅黄色固体产物 7mg。 MS ( M+H: 502, 504)  Dissolve 0.27 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate to 25 ml In ethanol, mix with 3 times the amount of morpholine and stir at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 502, 504)
'HNMR(DMSO-d6)5: 1.07 (t, 3H), 2.57 (m, 4H), 3.66 (m, 4H), 3.80 (d, J=15.2Hz, IH), 3.90-4.00 (m, 3H), 6.01 (s, IH), 7.21 (t， IH), 7.35 (t, IH), 7.45-7.55 (m, 4H), 7.73 (d, 2H), 9.29 (s, IH).  'HNMR(DMSO-d6)5: 1.07 (t, 3H), 2.57 (m, 4H), 3.66 (m, 4H), 3.80 (d, J = 15.2 Hz, IH), 3.90-4.00 (m, 3H) , 6.01 (s, IH), 7.21 (t, IH), 7.35 (t, IH), 7.45-7.55 (m, 4H), 7.73 (d, 2H), 9.29 (s, IH).
实施例 58 Example 58
乙基 4- (2-氯 -4-氟苯基） -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000040_0001
Figure imgf000040_0001
步骤一 ： 制备乙基 4- (2-氯 -4-氟苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-氯 -4-氟苯甲醛 0.61 g ( 3.83 mmol ) 溶于 40 ml无水乙醇中， 加入 0.50 g ( 3.83 mmol ) 乙酰乙酸乙酯， 苯甲脒盐酸盐 0.60 g (3.83 mmol), 无水乙酸纳 0.47 g ( 5.75 mmol )， 升温至 回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓縮至干， 残余物加入 40 ml 1N盐酸酸化， 3x30 ml基叔丁基醚洗涤，水层加 20%氢氧化钠调 pH至 10- 12， 经 3><30ml 乙酸乙酯萃取， 无水硫酸钠干燥， 乙酸乙酯溶液浓缩至干， 收得浅黄色固体 0.66 g (收率 46.2%)。  2-Chloro-4-fluorobenzaldehyde 0.61 g ( 3.83 mmol) dissolved in 40 ml of absolute ethanol, 0.50 g ( 3.83 mmol) of ethyl acetoacetate, benzamidine hydrochloride 0.60 g (3.83 mmol), none The aqueous sodium acetate was 0.47 g (5.75 mmol), and the mixture was heated to reflux for 18 hours. Stop the reaction, cool down, filter, concentrate the filtrate to dryness, add the residue to 40 ml of 1N hydrochloric acid, wash with 3×30 ml of tert-butyl ether, add 20% sodium hydroxide to adjust the pH to 10-12, after 3>< The mixture was extracted with EtOAc (EtOAc)EtOAc.
MS (M+H: 373, 375 )  MS (M+H: 373, 375 )
步骤二： 乙基 6-溴甲基 -4- (2-氯 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
0.66 g ( 1.77 mmol)乙基 4- ( 2-氯 -4-氟苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯溶解 于 20 ml 四氯化碳中， 加热至 60Ό下， 分批投入 0.331 g ( 1.86 mmol ) N-溴代琥珀酰亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗品 0.70g。  0.66 g ( 1.77 mmol) of ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved in 20 ml of four In the carbon chloride, heated to 60 ,, 0.331 g ( 1.86 mmol) of N-bromosuccinimide was added in batches, stirred at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was evaporated under vacuum at room temperature to give a pale yellow. The crude product is 0.70g.
MS (M+H: 451， 453 )  MS (M+H: 451, 453)
步骤三： 乙基 4- (2-氯 -4-氟苯基） -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Step 3: Ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
将 0.70 g新制备的乙基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯溶 解到 70ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗品 经一硅胶柱纯化， 收得浅黄色固体产物 40 mg。 MS (M+H: 458, 460 )  0.70 g of freshly prepared ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate was dissolved in 70 ml In ethanol, mix with 3 times the amount of morpholine and stir at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS (M+H: 458, 460 )
'HNMR(D SO-d6)5: 1.13 (t, 3H), 2.65 (m, 4H), 3.79 (m， 4H)， 3.88 (d， J=17.2Hz, IH), 4.01-4.06 (m， 3H), 6.22 (s, IH), 6.90 (td, IH), 7.12 (dd， 1H)， 7.26-7.30 (m, IH), 7.40-7.47 (m, 3H), 7.68 (d,2H), 9.42 (s, IH).  'HNMR(D SO-d6)5: 1.13 (t, 3H), 2.65 (m, 4H), 3.79 (m, 4H), 3.88 (d, J=17.2Hz, IH), 4.01-4.06 (m, 3H ), 6.22 (s, IH), 6.90 (td, IH), 7.12 (dd, 1H), 7.26-7.30 (m, IH), 7.40-7.47 (m, 3H), 7.68 (d, 2H), 9.42 ( s, IH).
实施例 59 Example 59
乙基 4- (2,4-二氯苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000041_0001
Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000041_0001
步骤一： 乙基 4- (2,4-二氯苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2,4-二氯苯甲醛 0.88 g (5 mmol) 溶于 50 ml无水乙醇中， 加入 0.65 g (5 mmol ) 乙酰 乙酸乙酯， 苯甲脒盐酸盐 0.78 g (5 mmol), 无水乙酸钠 0.62 g ( 7.5 mmol ), 升温至回流搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 残余物加入 50ml lN盐酸酸化， 3x40 ml 甲基叔丁基醚洗涤， 水层加 20%氢氧化钠调 pH至 10- 12, 经 3x40 ml乙酸乙酯萃取， 无水 硫酸钠干燥， 乙酸乙酯溶液浓缩至干， 收得浅黄色固体 1.02 g (收率 52.4%)。  2,4-Dichlorobenzaldehyde 0.88 g (5 mmol) dissolved in 50 ml of absolute ethanol, added 0.65 g (5 mmol) of ethyl acetoacetate, benzamidine hydrochloride 0.78 g (5 mmol), anhydrous Sodium acetate 0.62 g (7.5 mmol) was warmed to reflux for 18 h. Stop the reaction, cool down, filter, concentrate the filtrate to dryness, add the residue to 50 ml of 1N hydrochloric acid acidification, wash with 3x40 ml of methyl tert-butyl ether, add 20% sodium hydroxide to adjust the pH to 10-12, 3x40 ml of acetic acid The ester was extracted, dried over anhydrous sodium sulfate, and evaporated to ethyl ether.
MS ( +H: 389, 391 )  MS ( +H: 389, 391 )
步骤二： 乙基 6-溴甲基 -4- (2,4-二氯苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
1.02 g (2.62 mmol)乙基 4- (2,4-二氯苯基) -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯溶解 于 100ml 四氯化碳中， 加热至 60Ό下， 分批投入 0.49 g ( 2.75 mmol ) N-澳代琥珀酰亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗品 1.20g。  1.02 g (2.62 mmol) of ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved in 100 ml of tetrachlorin In carbon, heat to 60 ,, 0.49 g ( 2.75 mmol) N-A succinimide was added in batches, and stirred at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was evaporated under vacuum at room temperature to obtain a pale yellow crude product 1.20 g.
MS (M+H: 467, 469, 471 )  MS (M+H: 467, 469, 471 )
步骤三： 乙基 4- (2,4-二氯苯基) -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Step 3: Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
将 1.20 g新制备的乙基 -6-溴甲基 -4- (2,4-二氯苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯溶 解到 120 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗 品经一硅胶柱纯化， 收得浅黄色固体产物 80 mg。  Dissolve 1.20 g of freshly prepared ethyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate to 120 ml In ethanol, mix with 3 times the amount of morpholine and stir at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0>
MS ( M+H: 474， 476)  MS ( M+H: 474, 476)
'HNMR(DMSO-d6)5: 1.14 (t, 3H), 2.65 (m, 4H 3.80 (m, 4H), 3.88 (d, J=17.2Hz, IH), 4.02-4.08 (m, 3H), 6.22 (s， 1H 7.14 (dd, IH), 7.23 (t, IH), 7.40-7.47 (m, 4H), 7.69 (d, 2H 9.42 (s, IH).  'HNMR (DMSO-d6) 5: 1.14 (t, 3H), 2.65 (m, 4H 3.80 (m, 4H), 3.88 (d, J = 17.2 Hz, IH), 4.02-4.08 (m, 3H), 6.22 (s, 1H 7.14 (dd, IH), 7.23 (t, IH), 7.40-7.47 (m, 4H), 7.69 (d, 2H 9.42 (s, IH).
实施例 60 Example 60
甲基 4- (2-溴 -4-氟苯基） -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000041_0002
步骤一： 制备甲基 4- (2-漠 -4-氟苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-後酸酯
Figure imgf000041_0002
Step 1: Preparation of methyl 4-(2-indol-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5- post-ester
2-溴 -4-氟苯甲醛 2.03 g ( 10 mmol) 溶于 50 ml无水乙醇中， 加入 1.16 g ( 10 mmol ) 乙 酰乙酸甲酯， 苯甲脒盐酸盐 1.57g(10mmol), 无水乙酸钠 1.0 g ( 12 mmol ), 升温至回流撹 拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 残余物加入 100 ml 1N盐酸酸化， 3>80 ml甲基叔丁基醚洗涤， 水层加 20%氢氧化钠调 pH至 10- 12, 经 3><80 ml乙酸乙酯萃取， 无水硫酸钠干燥， 乙酸乙酯溶液浓缩至干， 收得浅黄色固体 2.3g (收率 57.0%)。  2-bromo-4-fluorobenzaldehyde 2.03 g (10 mmol) dissolved in 50 ml of absolute ethanol, 1.16 g (10 mmol) of methyl acetoacetate, benzamidine hydrochloride 1.57 g (10 mmol), anhydrous Sodium acetate 1.0 g (12 mmol) was warmed to reflux and stirred for 18 hours. Stop the reaction, cool down, filter, concentrate the filtrate to dryness, add the residue to 100 ml of 1N hydrochloric acid, 3>80 ml of methyl t-butyl ether, and add 20% sodium hydroxide to adjust the pH to 10-12. &lt;80 ml of ethyl acetate was extracted, dried over anhydrous sodium sulfate, and ethyl acetate was evaporated to dryness.
MS ( M+H: 403, 405 )  MS ( M+H: 403, 405 )
步骤二： 制备甲基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Preparation of methyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
2.02g (5mmol)¥ 4- ( 2-溴 -4-氟苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯溶解于 200ml 四氯化碳中， 加热至 60'C下， 分批投入 0.935 g ( 5.25 mmol ) N-溴代琥珀酰亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗品 2.5g。 2.02g (5mmol) ¥ 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate was dissolved in In 200 ml of carbon tetrachloride, heated to 60 ° C, 0.935 g ( 5.25 mmol ) of N-bromosuccinimide was added in batches, stirred at 60 ° C for 30 minutes, cooled, filtered, and the solvent was evaporated under vacuum at room temperature. , light yellow crude 2.5g.
MS ( M+H: 481, 483, 485 )  MS ( M+H: 481, 483, 485 )
步骤三： 甲基 4- (2-溴 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Step 3: Methyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
将 2.5 g新制备的甲基 -6-溴甲基 -4- ( 2-溴 -4-氟苯基）-2-苯基 -1，4-二氢嘧啶 -5-羧酸酯溶解 到 250 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗品 经一硅胶柱纯化， 收得浅黄色固体产物 0.186g. MS ( M+H: 488, 490)  Dissolve 2.5 g of freshly prepared methyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate to 250 Mix with 3 times the amount of morpholine in ml ethanol and stir at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0></RTI>
'HNMR(5 )  'HNMR(5)
实施例 61 Example 61
甲基 4- (2-氯 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000042_0001
Figure imgf000042_0001
步骤一： 制备甲基 4- (2-氯 -4-氟苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-氯 -4-氟苯甲醛 0.8g (5 mmol)溶于 50 ml无水乙醇中， 力口入 0.58 g ( 5 mmol ) 乙酰乙 酸甲酯， 苯甲脒盐酸盐 0.78 g (5 mmol), 无水乙酸钠 0.50 g ( 6 mmol ), 升温至回流撹拌 18 小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 残余物加入 50 ml IN盐酸酸化， 3x40 ml 甲基叔丁基醚洗涤， 水层加 20%氢氧化钠调 pH至 10- 12, 经 3x40ml 乙酸乙酯萃取， 无水 硫酸钠干燥， 乙酸乙酯溶液浓缩至干， 收得浅黄色固体 1.03 g (收率 57.4%)。  2-Chloro-4-fluorobenzaldehyde 0.8g (5 mmol) was dissolved in 50 ml of absolute ethanol, and 0.58 g (5 mmol) of methyl acetoacetate and benzamidine hydrochloride 0.78 g (5 mmol) were added. , anhydrous sodium acetate 0.50 g (6 mmol), warmed to reflux and stirred for 18 hours. Stop the reaction, cool down, filter, concentrate the filtrate to dryness, add the residue to 50 ml IN hydrochloric acid, wash with 3×40 ml methyl t-butyl ether, add 20% sodium hydroxide to adjust the pH to 10-12, 3x40ml acetic acid The ester was extracted, dried over anhydrous sodium sulfate and evaporated to ethyl ether.
MS (M+H: 359, 361 )  MS (M+H: 359, 361 )
步骤二： 制备甲基 6-溴甲基 -4- (2-氯 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Preparation of methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
0.71 g (2 mmol)甲基 4- ( 2-氯 -4-氟苯基) -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯溶解于 70 ml 四氯化碳中， 加热至 6CTC下， 分批投入 0.37 g ( 2.1 mmol ) N-溴代琥珀酰亚胺， 维 持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗品 0.45g„  0.71 g (2 mmol) of methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved in 70 ml of four In the carbon chloride, heated to 6CTC, 0.37 g (2.1 mmol) N-bromosuccinimide was added in batches, stirred at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was evaporated under vacuum at room temperature to give a pale yellow. Crude 0.45g
MS (M+H: 437, 439 )  MS (M+H: 437, 439)
步骤三: 制备甲基 4- (2-氯 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 将 0.45 g新制备的甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯溶 解到 60ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗品 经一硅胶柱纯化， 收得浅黄色固体产物 30 mg。 MS ( M+H: 444, 446) Step 3: Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate 0.45 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate dissolved in 60 ml of ethanol The mixture was mixed with 3 times the amount of morpholine and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 444, 446)
'HNMR(DMSO-d6 )δ: 2.69(m, 4H), 3.60(s, 3H), 3.81(m, 4H), 3.90(d, 1H), 4.05(d, 1H), 6.2 l(s, 1H), 6.90(t， 1H), 7.13(d, 1H), 7.28(m， 1H)， 7.43(m, 3H), 7.7 l(d, 2H). 'HNMR (DMSO-d 6 ) δ: 2.69 (m, 4H), 3.60 (s, 3H), 3.81 (m, 4H), 3.90 (d, 1H), 4.05 (d, 1H), 6.2 l (s, 1H), 6.90(t, 1H), 7.13(d, 1H), 7.28(m, 1H), 7.43(m, 3H), 7.7 l(d, 2H).
实施例 62: Example 62
甲基 4- (2,4-二氯苯基） -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000042_0002
Figure imgf000042_0002
步骤一： 制备甲基 4- (2，4-二氯苯基） -2-苯基 -6-甲基 -1,4-二 ft嘧、定 -5-羧酸酯 2,4-二氯苯甲醛 0.88 g (5 mmol) 溶于 50 ml无水乙醇中， 力口入 0.58 g ( 5 mmol ) 乙酰 乙酸甲酯， 苯甲脒盐酸盐 0.78 g (5 mmol), 无水乙酸钠 0.50 g ( 6 mmol ), 升温至回流搅拌 18小时。停止反应， 降温， 过滤， 滤液浓缩至干， 残余物 1.5§加入5011111N盐酸酸化， 3x40 ml甲基叔丁基醚洗涤， 水层加 20%氢氧化钠调 pH至 10- 12， 经 3><40 ml 乙酸乙酯萃取， 无水硫酸钠干燥， 乙酸乙酯溶液浓缩至干， 收得浅黄色固体 l.Og (收率 53.3%)。 Step 1: Preparation of methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-di- ft pyridine, 1,4--5-carboxylate 2,4-Dichlorobenzaldehyde 0.88 g (5 mmol) was dissolved in 50 ml of absolute ethanol, and 0.58 g (5 mmol) of methyl acetoacetate and benzamidine hydrochloride 0.78 g (5 mmol) were added. Anhydrous sodium acetate 0.50 g (6 mmol) was added and the mixture was warmed to reflux for 18 hours. Stop the reaction, cool down, filter, concentrate the filtrate to dryness, residue 1.5 § Add 501 1 111N hydrochloric acid acidification, wash with 3x40 ml methyl t-butyl ether, add 20% sodium hydroxide to adjust the pH to 10-12, 3 &lt; 40 ml of ethyl acetate, dried over anhydrous sodium sulfate, and ethyl acetate.
MS (M+H: 375, 377 )  MS (M+H: 375, 377 )
步骤二: 制备甲基 6-溴甲基 -4- (2，4-二氯苯基) -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Preparation of methyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate
0.70 g ( 1.87 mmol)甲基 4- (2,4-二氯苯基） -2-苯基 -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯溶解 于 70 ml 四氯化碳中， 加热至 60Ό下， 分批投入 0.35 g ( 1.96 mmol ) N-溴代琥珀酰亚胺， 维持 60Ό搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色粗品 0.84g。  0.70 g ( 1.87 mmol) of methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved in 70 ml of tetrachloro In the carbon, heat to 60 ,, 0.35 g ( 1.96 mmol) of N-bromosuccinimide was added in batches, stirred for 60 minutes for 30 minutes, cooled, filtered, and the solvent was evaporated under vacuum at room temperature to give a pale yellow crude product: 0.84 g. .
MS ( M+H: 453, 455， 457 )  MS ( M+H: 453, 455, 457 )
步骤三： 制备甲基 4- (2，4-二氯苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 将 0.84 g新制备的甲基 -6-溴甲基 -4- (2,4-二氯苯基） -2-苯基 -1,4-二氢嘧啶 -5-羧酸酯溶 解到 80ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗品 经一硅胶柱纯化， 收得浅黄色固体产物 70mg。 MS ( M+H: 460， 462) Step 3: Preparation of methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate will be 0.84 g freshly prepared methyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-phenyl-1,4-dihydropyrimidine-5-carboxylate is dissolved in 80 ml of ethanol, Mix with 3 times the amount of morpholine and stir at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 460, 462)
'HNMR(CDCI3)6: 2.65 (t, 4H)， 3.60 (s, 3H), 3.79 (t, 4H), 3.87 (d, J=17.6Hz, IH), 4.03 (d, J=17.6Hz, IH), 6.20 (s, IH), 7.15 (dd, IH), 7.22 (d， IH), 7.40-7.47 (m, 4H), 7.68 (m, 2H), 8.90 (s, IH). 'HNMR(CDCI 3 )6: 2.65 (t, 4H), 3.60 (s, 3H), 3.79 (t, 4H), 3.87 (d, J=17.6Hz, IH), 4.03 (d, J=17.6Hz, IH), 6.20 (s, IH), 7.15 (dd, IH), 7.22 (d, IH), 7.40-7.47 (m, 4H), 7.68 (m, 2H), 8.90 (s, IH).
实施例 63 Example 63
萘 -2-甲脒盐酸盐
Figure imgf000043_0001
Naphthalene-2-carboxamidine hydrochloride
Figure imgf000043_0001
2-氰基萘 9.0 g (58.8 mmol) 溶于 90 ml氯化氢甲醇 （4.5N) 中， 室温下搅拌过夜。 反 应液真空浓缩至干， 残余浅黄色固体 12g, 加入 120 ml 17%氨的甲醇溶液， 于 50'C下， 氨 气氛搅拌 3h。 降温， 真空浓缩蒸除溶剂， 残余物经丙酮洗涤， 抽干， 得淡黄色固体粉末 6g。 固体加入 5体积氯化氢甲醇 （4.5N) 溶液室温下撹拌酸化 0.5h。 蒸除溶剂甲醇， 加入 30ml 丙酮搅散， 过滤， 真空干燥， 得浅黄色固体产物 5.5g (收率 45.3%)„  2-cyanophthalene 9.0 g (58.8 mmol) was dissolved in 90 ml of hydrogen chloride in methanol (4.5 N) and stirred at room temperature overnight. The reaction solution was concentrated to dryness in vacuo to give a pale yellow solid, 12 g, which was then added to 120 ml of 17% ammonia in methanol and stirred at 50 ° C for 3 h. The mixture was cooled, and the solvent was evaporated, evaporated, evaporated, evaporated. The solid was added with 5 volumes of hydrogen chloride in methanol (4.5 N) and the solution was acidified at room temperature for 0.5 h. The solvent methanol was distilled off, stirred with 30 ml of acetone, filtered and dried in vacuo to give pale yellow solid product 5.5 g (yield 45.3%).
实施例 64 Example 64
乙基 4- (2-溴 -4-氟苯基） -2- (萘 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000043_0002
Figure imgf000043_0002
步骤一： 乙基 4- (2-溴 -4-氟苯基） -2- (萘 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-溴 -4-氟苯甲醛 4.06 g (20 mmol)溶于 200 ml无水乙醇中, 加 2.60 g ( 20 mmol ) 乙酰 乙酸乙酯， 萘 -2-甲脒盐酸盐 4.13 g (20 mmol), 无水乙酸钠 2.0g ( 24 mmol ), 升温至回流搅 拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 得浅黄色固体 7.4g， 粗品经一硅胶柱 分离纯化， 收得浅黄色固体 3.60g (收率 38.5%)。 MS (M+H: 467, 469)  2-bromo-4-fluorobenzaldehyde 4.06 g (20 mmol) dissolved in 200 ml absolute ethanol, 2.60 g (20 mmol) ethyl acetoacetate, naphthalene-2-carboxamidine hydrochloride 4.13 g (20 mmol Anhydrous sodium acetate 2.0 g (24 mmol) was heated to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was evaporated to dryness to crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (M+H: 467, 469)
步骤二： 乙基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (萘 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.93 g (2 mmol)乙基 4- ( 2-溴 -4-氟苯基) -2- (萘 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 溶解于 100 ml 四氯化碳中，加热至 60°C下，分批投入 0.37 g (2.1 mmol) N-溴代琥珀酰亚胺， 维持 60Ό搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体粗品 1.3g0.93 g (2 mmol) ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolve in 100 ml of carbon tetrachloride, heat to 60 ° C, and add 0.37 g (2.1 mmol) of N-bromosuccinimide in batches, stir for 60 minutes for 30 minutes, cool down, filter, and vacuum the filtrate at room temperature. Solvent, light yellow solid crude 1.3g
MS (M+H: 545, 547, 549 ) MS (M+H: 545, 547, 549 )
步骤三： 乙基 4- (2-溴 -4-氟苯基) -2- (萘 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 将 1.3 g新制备的乙基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (萘 -2-基） -1,4-二氢嘧啶 -5-羧 酸酯溶解到 130 ml 乙醇中， 同 3倍量的吗啉混合， 室温下撹拌 30 分钟。 室温真空蒸除溶 剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.165g MS (M+H: 552, 554 ) Step 3: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic acid ester 1.3 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine- The 5-carboxylate was dissolved in 130 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0></RTI>
'HNMR(CDCI3)5: 1.16 (t, 3H), 2.70 (t, 4H), 3.85 (t, 4H), 3.93 (d, J= 17.2Hz, IH), 4.10 (m, 3H), 6.28 (s, IH), 6.97 (td, 1H)， 7.33 (m, 2H), 7.54 (t, 2H), 7.88 (m, 4H), 8.14 (s, IH), 9.40 (s, IH). 'HNMR(CDCI 3 ) 5: 1.16 (t, 3H), 2.70 (t, 4H), 3.85 (t, 4H), 3.93 (d, J = 17.2Hz, IH), 4.10 (m, 3H), 6.28 ( s, IH), 6.97 (td, 1H), 7.33 (m, 2H), 7.54 (t, 2H), 7.88 (m, 4H), 8.14 (s, IH), 9.40 (s, IH).
实施例 65 Example 65
乙基 4- (2-氯 -4-氟苯基) -2- (萘 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000044_0001
Figure imgf000044_0001
步骤一： 制备乙基 4- (2-氯 -4-氟苯基） -2- (萘 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-氯 -4-氟苯甲醛 2.38 g ( 15 mmol )溶于 150 ml无水乙醇中， 加 1.95 g ( 15 mmol ) 乙酰 乙酸乙酯， 萘 -2-甲脒盐酸盐 3.10 g (15 mmol), 无水乙酸钠 1.48 g ( 18 mmol ), 升温至回流 搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 得浅黄色固体 5.8g, 粗品经一硅胶 柱分离纯化， 收得浅黄色固体 3.61 g (收率 56.9%)。 MS (M+H: 423, 425 )  2-chloro-4-fluorobenzaldehyde 2.38 g (15 mmol) dissolved in 150 ml absolute ethanol, 1.95 g (15 mmol) ethyl acetoacetate, naphthalene-2-carboxamidine hydrochloride 3.10 g (15 mmol ), anhydrous sodium acetate 1.48 g (18 mmol), and warmed to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was evaporated to dryness, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (M+H: 423, 425 )
步骤二： 乙基 6-溴甲基 -4- (2-氯 -4-氟苯基) -2- (萘 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Ethyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.98 g (2.32 ol)乙基 4- (2-氯 -4-氟苯基) -2- (萘 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 100ml 四氯化碳中， 加热至 60'C, 分批投入 0.434 g (2.44 mmol) N-溴代琥珀酰亚 胺， 维持 6(TC搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体粗品 1.5 g 0.98 g (2.32 ol) ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolved in 100ml of carbon tetrachloride, heated to 60'C, and added 0.434 g (2.44 mmol) of N-bromosuccinimide in batches, maintained at 6 (TC stirred for 30 minutes, cooled, filtered, and the filtrate was evaporated under vacuum at room temperature. Solvent, light yellow solid crude 1.5 g
MS (M+H: 501, 503 ) MS (M+H: 501, 503)
步骤三： 乙基 4- ( 2-氯 -4-氟苯基） -2- (萘 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 将 1.5 g新制备的乙基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (萘 -2-基) -1,4-二氢嘧啶 -5-羧 酸酯溶解到 150 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶 剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 0.22g MS (M+H: 508 510) Step 3: Ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic acid ester 1.5 g of freshly prepared ethyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine- The 5-carboxylate was dissolved in 150 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0></RTI>
'HNMR(CDC13)5: 1.18 (t, 3H), 2.70 (t, 4H), 3.85 (t, 4H), 3.92 (d, J=17.2Hz, IH), 4.10 (m, 3H), 6.30 (s IH), 6.86-7.00 (m, 2H), 7.16(dd, IH), 7.35 (q, IH), 7.55 (t, 2H)， 7.88 (m, 4H), 8.14 (s, IH), 9.06 (s, IH). 'HNMR(CDC1 3 )5: 1.18 (t, 3H), 2.70 (t, 4H), 3.85 (t, 4H), 3.92 (d, J = 17.2 Hz, IH), 4.10 (m, 3H), 6.30 ( s IH), 6.86-7.00 (m, 2H), 7.16(dd, IH), 7.35 (q, IH), 7.55 (t, 2H), 7.88 (m, 4H), 8.14 (s, IH), 9.06 ( s, IH).
实施例 66 Example 66
甲基 4- (2-氯 -4-氟苯基) -2- (萘 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000044_0002
步骤一： 制备甲基 4- ( 2-氯 -4-氟苯基） -2- (萘 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000044_0002
Step 1: Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-氯 -4-氟苯甲醛 0.38g (2.4mmol)溶于 30 ml无水乙醇中， 加 0.28 g ( 2.4 mmol ) 乙酰 乙酸甲酯， 萘 -2-甲脒盐酸盐 0.50 g (2.4 mmol), 无水乙酸钠 0.24 g ( 2.9 mmol )， 升温至回流 搅拌 18小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱分离纯化， 收得浅 黄色固体 91 mg (收率 9.3%)。 MS ( M+H: 409, 411 )  2-Chloro-4-fluorobenzaldehyde 0.38g (2.4mmol) was dissolved in 30 ml of absolute ethanol, adding 0.28 g (2.4 mmol) of methyl acetoacetate, naphthalene-2-carboxamidine hydrochloride 0.50 g (2.4 mmol) ), anhydrous sodium acetate 0.24 g (2.9 mmol), and warmed to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. The crude material was purified on silica gel column to yield pale yellow solid 91 mg (yield 9.3%). MS ( M+H: 409, 411 )
步骤二: 甲基 6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (萘 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Methyl 6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
91 mg (0.22 mmol)甲基 4- ( 2-氯 -4-氟苯基） -2- (萘 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 10ml 四氯化碳中， 加热至 60Ό下， 分批投入 41 mg (0.23 mmol) N-溴代琥珀酰亚 胺，维持 60'C搅拌 30分钟， 降温，过滤，滤液室温真空蒸去溶剂，得浅黄色残余固体 95 mg。  91 mg (0.22 mmol) methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolved in 10 ml of carbon tetrachloride, heated to 60 Torr, 41 mg (0.23 mmol) of N-bromosuccinimide was added in portions, stirred at 60 ° C for 30 minutes, cooled, filtered, and the solvent was evaporated under vacuum at room temperature. , pale yellow residual solid 95 mg.
MS ( M+H: 487, 489)  MS ( M+H: 487, 489)
步骤三： 甲基 4- ( 2-氯 -4-氟苯基） -2- (萘 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 将 95g新制备的甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (萘 -2-基） -1,4-二氢嘧啶 -5-羧酸 酯溶解到 10ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体 2mg。 MS ( M+H: 494, 496) Step 3: Methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic acid ester 95 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-1,4-dihydropyrimidine-5 The -carboxylic acid ester was dissolved in 10 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo <RTI ID=0.0> MS ( M+H: 494, 496)
实施例 67 Example 67
乙基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-dihydropyrimidine-5- Carboxylic ester
Figure imgf000045_0001
Figure imgf000045_0001
上述标题化合物通过类似于实施例 64的制备方法制得。 The above title compound was obtained by a preparation method similar to that of Example 64.
实施例 68 Example 68
甲基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (萘基 -6-基） -1,4-二氢嘧啶 -5-羧酸酯 Methyl 4- (2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-dihydropyrimidine-5 -carboxylate
Figure imgf000045_0002
Figure imgf000045_0002
上述标题化合物通过类似于实施例 64的制备方法制得 实施例 69 The above title compound was obtained by a preparation method similar to that of Example 64.
甲基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基) -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000046_0001
Methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-dihydropyrimidine-5- Carboxylic ester
Figure imgf000046_0001
上述标题化合物通过类似于买施例 64的制备方法制得 实施例 70 The above title compound was obtained by a preparation method similar to that of the preparation of Example 64.
乙基 4- (2-溴 -4-氟苯基) -2- (噻吩 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000046_0002
Figure imgf000046_0002
步骤一: 乙基 4- (2-溴 -4-氟苯基) -2- (噻吩 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-溴 -4-氟苯甲醛 1.01 g (5 mmol) 溶于 50ml无水乙醇中， 力 P 0.65 g ( 5 mmol ) 乙酰乙 酸乙酯， 噻吩 -2-甲脒盐酸盐 0.81 g (5 mmol), 无水乙酸钠 0.50g ( 6 mmol ), 升温至回流搅拌 18 小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱分离纯化， 收得浅黄色 固体 1.40 g (收率 65.8%)。 MS ( M+H: 425, 427 )  2-bromo-4-fluorobenzaldehyde 1.01 g (5 mmol) in 50 ml absolute ethanol, force P 0.65 g (5 mmol) ethyl acetoacetate, thiophene-2-carboxamidine hydrochloride 0.81 g (5 mmol ), anhydrous sodium acetate 0.50 g (6 mmol), and warmed to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. The crude material was purified on silica gel column to yield 1.40 g (yield 65.8%). MS ( M+H: 425, 427 )
步骤二： 乙基 6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Ethyl 6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.84 g(l I)乙基 4- (2-溴 -4-氟苯基） -2- (噻吩 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 80 ml 四氯化碳中,加热至 60'C,分批投入 0.374 g (2.1 mmol) N-溴代琥珀酰亚胺， 维持 60Ό搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体粗品 1.06 g。  0.84 g (l I) ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolve in 80 ml of carbon tetrachloride, heat to 60 ° C, and add 0.374 g (2.1 mmol) of N-bromosuccinimide in batches, stir for 60 minutes for 30 minutes, cool down, filter, and evaporate the solvent at room temperature under vacuum. , a pale yellow solid crude product 1.06 g.
MS (M+H: 501, 503, 505 )  MS (M+H: 501, 503, 505)
步骤三： 乙基 4- (2-溴 -4-氟苯基） -2- (噻吩 -2-基） -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸 酯 Step 3: Ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
将 1.06 g新制备的乙基 -6-溴甲基 -4- (2-溴 -4-氟苯基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5- 幾酸酯溶解到 100 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟， 室温真空蒸除 溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 77mg。 MS ( M+H: 508, 510 )  1.06 g of freshly prepared ethyl-6-bromomethyl-4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidin-5- The acid ester was dissolved in 100 ml of ethanol, and mixed with 3 times the amount of morpholine. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo. MS ( M+H: 508, 510 )
'HNMR(CDC13)6: 1.12 (t, 3H), 2.66 (t, 4H), 3.82 (t， 4H), 3.87 (d, 1H), 4.06 (m, 3H), 6.15 (s, 1H)， 6.95 (t， 1H 7.07 (t, 1H), 7.27 (m, 1H), 7.33 (m, 2H), 7.41 (d， 1H), 8.87 (s, 1H). 'HNMR(CDC1 3 )6: 1.12 (t, 3H), 2.66 (t, 4H), 3.82 (t, 4H), 3.87 (d, 1H), 4.06 (m, 3H), 6.15 (s, 1H), 6.95 (t, 1H 7.07 (t, 1H), 7.27 (m, 1H), 7.33 (m, 2H), 7.41 (d, 1H), 8.87 (s, 1H).
实施例 71 Example 71
甲基 4- (2-氯 -4-氟苯基) -2- (噻吩 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000047_0001
Methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000047_0001
步骤一： 制备甲基 4- (2-氯 -4-氟苯基） -2- (噻吩 -2-基） -6-甲基 -1，4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2-氯 -4-氟苯甲醛 0.80 g ( 5 mmol ) 溶于 50 ml无水乙醇中， 加 0.58 g ( 5 mmol ) 乙酰乙 酸甲酯， 噻吩 -2-甲脒盐酸盐 0.81 g (5 mmol), 无水乙酸钠 0.50g ( 6 mmol ), 升温至回流搅拌 18 小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱分离纯化， 收得浅黄色 固体 1.05 g (收率 57.6%)。 MS ( M+H: 365, 367)  2-chloro-4-fluorobenzaldehyde 0.80 g (5 mmol) dissolved in 50 ml absolute ethanol, added 0.58 g (5 mmol) methyl acetoacetate, thiophene-2-carboxamidine hydrochloride 0.81 g (5 mmol ), anhydrous sodium acetate 0.50 g (6 mmol), and warmed to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. The crude material was purified on silica gel column to yield 1.05 g (yield 57.6%). MS ( M+H: 365, 367)
步骤二： 甲基 6-澳甲基 -4- (2-氯 -4-氟苯基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5-羧酸酯 Step 2: Methyl 6-O-methyl-4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.365 g (1 mmol)甲基 4- ( 2-氯 -4-氟苯基 ) -2- (噻吩 -2-基 ) -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 40 ml 四氯化碳中， 加热至 60°C下， 分批投入 0.187 g (1.05 mmol) N-溴代琥珀酰 亚胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体粗品 0.39 g。 MS (M+H: 443, 445 )  0.365 g (1 mmol) methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Dissolved in 40 ml of carbon tetrachloride, heated to 60 ° C, 0.175 g (1.05 mmol) N-bromosuccinimide was added in batches, kept at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was vacuumed at room temperature. The solvent was evaporated to give a pale yellow solid (0.39 g). MS (M+H: 443, 445)
步骤三： 甲基 4- (2-氯 -4-氟苯基） -2- (噻吩 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸 酯 Step 3: Methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic ester
将 0.39 g新制备的甲基 -6-溴甲基 -4- (2-氯 -4-氟苯基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5- 羧酸酯溶解到 40 ml乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除溶 剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 8mg。 MS ( M+H: 450, 452)  0.39 g of freshly prepared methyl-6-bromomethyl-4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate The acid ester was dissolved in 40 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. The solvent was evaporated in vacuo at rt. MS ( M+H: 450, 452)
实施例 72 Example 72
乙基 4- (2，4-二氯苯基） -2- (噻吩 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000047_0002
Figure imgf000047_0002
步骤一： 制备乙基 4- (2,4-二氯苯基) -2- (噻吩 -2-基) -6-甲基 -1,4-二氢嘧啶 -5-羧酸酯 Step 1: Preparation of ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate
2,4-二氯苯甲醛 0.88 g (5 mmol) 溶于 50 ml无水乙醇中， 力口 0.65 g ( 5 mmol ) 乙酰乙 酸乙酯 > 噻吩 -2-甲脒盐酸盐 0.81 g(5 mmol), 无水乙酸钠 0.50g ( 6 mmol ), 升温至回流搅拌 18 小时。 停止反应， 降温， 过滤， 滤液浓缩至干， 粗品经一硅胶柱分离纯化， 收得浅黄色 固体 1.13 g (收率 56.9%)。 MS ( M+H: 397, 399)  2,4-Dichlorobenzaldehyde 0.88 g (5 mmol) dissolved in 50 ml of absolute ethanol, force 0.65 g (5 mmol) ethyl acetoacetate> thiophene-2-carboxamidine hydrochloride 0.81 g (5 mmol ), anhydrous sodium acetate 0.50 g (6 mmol), and warmed to reflux for 18 hours. The reaction was quenched, cooled, filtered, and the filtrate was concentrated to dryness. The crude material was purified on silica gel column to yield 1.13 g (yield 56.9%). MS ( M+H: 397, 399)
步骤二： 制备乙基 6-溴甲基 -4- (2,4-二氯苯基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5-羧酸酯Step 2: Preparation of ethyl 6-bromomethyl-4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylate
0.791 g (2 mmol)乙基 4- (2,4-二氯苯基） -2- (噻吩 -2-基） -6-甲基 -1,4-二氢嘧啶 -5-羧酸 酯溶解于 80ml 四氯化碳中， 加热至 60°C下， 分批投入 0.374 g (2.1 mmol) N-溴代琥珀酰亚 胺， 维持 60'C搅拌 30分钟， 降温， 过滤， 滤液室温真空蒸去溶剂， 得浅黄色固体粗品 0.99 g。 MS ( M+H: 473, 475, 477) 0.791 g (2 mmol) of ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate dissolved In 80 ml of carbon tetrachloride, heated to 60 ° C, 0.374 g (2.1 mmol) of N-bromosuccinimide was added in portions, stirred at 60 ° C for 30 minutes, cooled, filtered, and the filtrate was evaporated under vacuum at room temperature. The solvent was obtained as a pale yellow solid 0.99 g. MS ( M+H: 473, 475, 477)
步骤三: 乙基 4- (2,4-二氯苯基) -2- (噻吩 -2-基) -6- (4-吗啉甲基) -1，4-二氢嘧啶 -5-羧酸 酯 Step 3: Ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate Acid ester
将 0.99 g新制备的乙基 -6-溴甲基 -4- (2,4-二氯苯基） -2- (噻吩 -2-基） -1,4-二氢嘧啶 -5- 羧酸酯溶解到 100 ml 乙醇中， 同 3倍量的吗啉混合， 室温下搅拌 30 分钟。 室温真空蒸除 溶剂， 粗品经一硅胶柱纯化， 收得浅黄色固体产物 40mg„ MS (M+H: 480, 482 )0.99 g of freshly prepared ethyl-6-bromomethyl-4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid The ester was dissolved in 100 ml of ethanol, mixed with 3 times the amount of morpholine, and stirred at room temperature for 30 minutes. Vacuum evaporation at room temperature Solvent, crude product was purified on a silica gel column to yield 40 mg of y.
'HNMR(CDC13)S: 1.15 (t, 3H), 2.65 (t, 4H), 3.82 (t, 4H), 3.85 (d, 1H), 4.05 (m, 3H), 6.17 (s: 1H)， 7.08 (t, 1H)， 7.16 (d， 1H), 7.24 (d, 1H), 7.35 (d, 1H), 7.40 (m, 2H), 8.89 (s, 1H). 'HNMR(CDC1 3 )S: 1.15 (t, 3H), 2.65 (t, 4H), 3.82 (t, 4H), 3.85 (d, 1H), 4.05 (m, 3H), 6.17 (s: 1H), 7.08 (t, 1H), 7.16 (d, 1H), 7.24 (d, 1H), 7.35 (d, 1H), 7.40 (m, 2H), 8.89 (s, 1H).
实施例 73 Example 73
乙基 4- (2-溴 -4-氟苯基) -6- (4-吗啉甲基) -2- (呋喃 -2-基) -1,4-二氢嘧啶 -5-羧酸酯 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(4-morpholinomethyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000048_0001
Figure imgf000048_0001
通过类似于实施例 70的制备方法， 用呋喃 -2-甲脒盐酸盐为起始原料制备得到。  Prepared by a method similar to that of Example 70, using furan-2-carboxamidine hydrochloride as a starting material.
实施例 74 Example 74
甲基 4- ( 2-氯 -4-氟苯基 ) -6- (吗啉 -4-基-甲基） -2- (呋喃 -2-基 ) -1,4-二氢嘧啶 -5-羧酸酷 Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5- Carboxylic acid
Figure imgf000048_0002
Figure imgf000048_0002
通过类似于实施例 71 的制备方法， 用呋喃 -2-甲脒盐酸盐为起始原料制备得到。  Prepared by a method similar to that of Example 71 using furan-2-carboxamidine hydrochloride as a starting material.
实施例 75 Example 75
乙基 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (呋喃 -2-基） -1,4-二氢嘧啶 -5-酸酸酯 Ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5-acid Acid ester
Figure imgf000048_0003
Figure imgf000048_0003
通过类似于实施例 72的制备方法， 用呋喃 -2-甲脒盐酸盐为起始原料制备得到  Prepared by a preparation method similar to that of Example 72 using furan-2-carboxamidine hydrochloride as a starting material.
实施例 76 Example 76
乙基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (吡咯烷基 -2-基） -1,4-二氢嘧啶 -5-羧酸
Figure imgf000049_0001
Ethyl 4- (2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrolidin-2-yl)-1,4-dihydropyrimidine- 5-carboxylic acid
Figure imgf000049_0001
通过类似于实施例 70的制备方法， 用吡咯烷 -2-甲脒盐酸盐为起始原料制备得到。 实施例 77  Prepared by a method similar to that of Example 70 using pyrrolidine-2-carboxamidine hydrochloride as a starting material. Example 77
甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基） -2- (吡咯烷基 -2-基） -1,4-二氢嘧啶 -5-羧酸 酯 Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrolidin-2-yl)-1,4-dihydropyrimidine- 5-carboxylate
Figure imgf000049_0002
Figure imgf000049_0002
通过类似于实施例 71的制备方法' 用吡咯烷 -2-甲脒盐酸盐为起始原料制备得到。 实施例 78  It was prepared by a method similar to the preparation method of Example 71 using pyrrolidine-2-carboxamidine hydrochloride as a starting material. Example 78
乙基 4- ( 2,4-二氯苯基 ) -6- (吗啉 -4-基-甲基） -2- (吡咯垸基 -2-基 -1,4-二氢嘧啶 -5-羧酸醋  Ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrole-2-yl-1,4-dihydropyrimidine-5- Carboxy vinegar
Figure imgf000049_0003
Figure imgf000049_0003
通过类似于实施例 72的制备方法， 用吡咯烷 -2-甲脒盐酸盐为起始原料制备得到 实施例 79  Prepared by a method similar to that of Example 72, using pyrrolidine-2-carboxamidine hydrochloride as a starting material.
乙基 4- (2-澳 -4-氟苯基） -2-甲基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯  Ethyl 4-(2-A-4-fluorophenyl)-2-methyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate
Figure imgf000049_0004
步骤一：制备乙基 4- (2-溴 -4-氟苯基） -2,6-二甲基 -1,4-二氢嘧啶 -5-羧酸酯
Figure imgf000049_0004
Step 1: Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyrimidine-5-carboxylate
2-溴 -4-氟苯甲醛 6.09 g (30mmol), 乙酰乙酸乙酯 4.30 g (33mmol), 盐酸乙脒 2.85 g (30mmol)溶于 600 ml无水乙醇中， 加入无水乙酸钠 2.95 g (36mmol), 加热回流反应过夜。 过滤， 滤液真空浓缩， 残余物加 80ml IN盐酸酸化， 用 2 50ml甲基叔丁基醚醚洗涤， 水 层用 20%氢氧化钠调 pH10~12, 析出白色沉淀， 沉淀经 3 50ml 乙酸乙酯萃取， 浓缩乙酸 乙酯溶液至干， 得浅黄色油状产物 2.2 g (收率 20.6%)。 MS ( M+H: 355, 357) 步骤二：制备乙基 4- (2-溴 -4-氟苯基） -6-溴甲基 -2-甲基 -1,4-二氢 啶-5-羧酸酯 2-bromo-4-fluorobenzaldehyde 6.09 g (30 mmol), ethyl acetoacetate 4.30 g (33 mmol), acetonitrile hydrochloride 2.85 g (30 mmol) dissolved in 600 ml of absolute ethanol, and anhydrous sodium acetate 2.95 g ( 36 mmol), heated to reflux overnight. Filtration, the filtrate was concentrated in vacuo, and the residue was crystallised with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc. After extraction, the ethyl acetate solution was concentrated to dryness to give a crude product (yield: 20.6%). MS (M+H: 355, 357) Step 2: Preparation of ethyl 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-methyl-1,4-dihydropyridine-5 -carboxylate
乙基 4- ( 2-溴 -4-氟苯基 ) -2,6-二甲基 -1,4-二氢嘧啶 -5-羧酸酯 0.710 g ( 2 mmol )投入 70 ml 四氯化碳中， 升温至 60'C全溶。 降温至 55'C， 0.5小时内分批投入 0.374 g ( 2.1 mmol ) N-溴琥珀酰亚胺， 投毕维持 55°C搅拌 0.5 小时。 降温， 过滤， 滤液室温浓缩至干， 得浅黄 色固体粗品 1.3g。 MS (M+H: 435, 433, 437 )  Ethyl 4-(2-bromo-4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyrimidine-5-carboxylate 0.710 g (2 mmol) charged with 70 ml of carbon tetrachloride In the middle, the temperature is raised to 60'C. The temperature was lowered to 55 ° C, 0.374 g (2.1 mmol) of N-bromosuccinimide was added in batches over 0.5 hours, and the mixture was stirred at 55 ° C for 0.5 hour. The temperature was lowered, filtered, and the filtrate was concentrated to dryness to dryness to give a pale yellow solid. MS (M+H: 435, 433, 437)
步骤三： 制备乙基 4- (2-澳 -4-氟苯基） -2-甲基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 乙基 4- ( 2-溴 -4-氟苯基）-6-溴甲基 -2-甲基 -1,4-二氢嘧啶 -5-羧酸酯粗品 1.3 g溶于 50 ml 乙醇中， 加入 0.5 g (5.7 mmol)吗啉， 室温搅拌反应 lh后， 真空蒸除溶剂， 残余物用 20ml 二氯甲烷溶解， 2 x 20 ml水洗涤， 有机层真空浓缩至干， 得浅黄色固体粗品 0.8g。 粗品经 柱层析分离纯化， 收得浅黄色固体产物 70mg。 MS ( M+H: 440, 442) Step 3: Preparation of ethyl 4-(2-au-4-fluorophenyl)-2-methyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate B Base 4-(2-bromo-4-fluorophenyl)-6-bromomethyl-2-methyl-1,4-dihydropyrimidine-5-carboxylate crude 1.3 g dissolved in 50 ml of ethanol, added 0.5 g (5.7 mmol) of morpholine. After stirring for 1 h at rt, EtOAcqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH . The crude product was purified by column chromatography to yield 70 mg of pale yellow solid. MS ( M+H: 440, 442)
'HNMR(CDC13)6: 1.01(t, 3H), 1.85(s, 3H), 2.48 (m, 4H), 3.60 (s, 3H), 3.64 (m， 4H), 3.70 (dd, 2H), 3.90 (q, 2H), 5.76 (s, 1H), 7.19-7.27 (m, 2H), 7.49 (d, 1H), 8.83 (s, 1H). 'HNMR(CDC1 3 )6: 1.01(t, 3H), 1.85(s, 3H), 2.48 (m, 4H), 3.60 (s, 3H), 3.64 (m, 4H), 3.70 (dd, 2H), 3.90 (q, 2H), 5.76 (s, 1H), 7.19-7.27 (m, 2H), 7.49 (d, 1H), 8.83 (s, 1H).
生物活性测试说明 Biological activity test description
本发明的化合物对乙型肝炎病毒的抗病毒作用通过 M. A. Sells 等描述的方法基础上进 行研究， Proc. Natl. Acad. Sci.84, 10051009 (1987) and B. E. orba et al., Antiviral Research 19, 5570(1992)。  The antiviral effect of the compounds of the invention on hepatitis B virus is based on the methods described by MA Sells et al, Proc. Natl. Acad. Sci. 84, 10051009 (1987) and BE orba et al., Antiviral Research 19, 5570 (1992).
抗病毒测试在 ％-孔微量滴定板上进行。 第一直列只接受培养基和 HepG2.2.15 细胞， 作为病毒对照。  Antiviral testing was performed on %-well microtiter plates. The first column only received medium and HepG2.2.15 cells as a virus control.
测试化合物的储备液 (50mM)是先溶解在 DMSO中， 然后在 HepG2.2.15 培养基中稀释 制得。根据本发明的化合物通常每次用移液管移取 100 测试浓度 (1st 测试浓度） 到微量 滴定板的第二测试列， 然后在加入 2% 重量胎牛血清 （体积 25 ） 的培养基中分两步稀释 2'° 倍。  A stock solution of the test compound (50 mM) was first dissolved in DMSO and then diluted in HepG2.2.15 medium. The compound according to the invention is typically pipetted 100 times at each test concentration (1st test concentration) to the second test column of the microtiter plate and then in a medium supplemented with 2% by weight fetal calf serum (volume 25). Diluted 2'° times in two steps.
微量滴定板的每个加入了 2% 重量胎牛血清的培养基的孔中都含有 225 μ\ HepG2.2.15 细胞悬浮液 (5 x 104cells/ml)。 37 ；、 5% C02 (v/v) 培养测试混合物 4天。 Each well of the microtiter plate containing 2% by weight of fetal bovine serum contained 225 μl of HepG2.2.15 cell suspension (5 x 10 4 cells/ml). 37;, 5% C0 2 (v/v) The test mixture was incubated for 4 days.
然后将表面悬浮物吸出丟弃， 向孔中加入 225 新制备的培养基。 根据本发明的化合 物是每个都在 体积中重新加入了 10-fold 浓缩溶液。 混合物继续培养 4天，  The surface suspension was then aspirated and discarded, and 225 freshly prepared medium was added to the wells. The compounds according to the invention were each refilled with a 10-fold concentrated solution in volume. The mixture is continued to grow for 4 days.
在收集悬浮物测试抗病毒效果之前， 先在光学显微镜下或者通过生物化学检测方法 (例 如 Alamar Blue stain or Trypan Blue stain) 检测 HepG2.2.15细胞细胞毒素的改变。  Changes in cytotoxicity of HepG2.2.15 cells were examined under light microscopy or by biochemical assays (eg, Alamar Blue stain or Trypan Blue stain) prior to collecting the antiviral effects of the suspension.
收集表面悬浮物和 /或细胞并用抽真空的方法在 96-孔斑点室上覆盖一层尼龙膜（根据制 造商的信息）。  Surface suspensions and/or cells were collected and a 96-well spot chamber was covered with a nylon membrane (according to the manufacturer's information) by vacuuming.
细胞毒素的测定 Determination of cytotoxin
检测 HepG2.2.15 细胞中物质引发的细胞毒素或抑制细胞的改变， 例如， 在光学显微镜 下细胞形态的改变。 HepG2.2.15 细胞的这些物质引发的改变与未处理过的细胞相比起来是 明显的， 例如， 细胞溶解， 液泡或者细胞形态的改变。 50% 毒性 （TOX.-50)指的是相较于对 应的对照细胞 50% 的细胞表现出一种形态。  Detection of cytotoxic or cytostatic changes induced by substances in HepG2.2.15 cells, for example, changes in cell morphology under light microscopy. The changes induced by these substances in HepG2.2.15 cells are evident compared to untreated cells, such as changes in cell lysis, vacuoles, or cell morphology. 50% toxicity (TOX.-50) refers to a morphology of cells that are 50% compared to the corresponding control cells.
根据本发明一些化合物的耐受性在其他的宿主细胞如， HeLa 细胞， primary 人外周造 血细胞或转化细胞系如 H-9 细胞上进行测试。  The tolerance of some of the compounds according to the invention is tested on other host cells, such as HeLa cells, primary human peripheral hematopoietic cells or transformed cell lines such as H-9 cells.
在本发明的化合物浓度 > 10 /M 是没有检测到细胞毒素的改变。  No change in cytotoxin was detected at concentrations of the compounds of the invention > 10 /M.
抗病毒作用的检测  Antiviral detection
在将表面悬浮物或溶解的细胞转移到点装置（如上述）的尼龙膜上之后， 将 HepG2.2.15 细胞的胞内或胞外悬浮物变性（1.5 MNaCI/0.5NNaOH), 中和 (3 M NaCl/0.5 M Tris HCI, pH 7.5) , 然后水洗 (2xSSC)。 通过在 120'C下培养过滤器 2-4小时， 使 DNA回到膜上。 After the surface suspension or dissolved cells were transferred to a nylon membrane of a spot device (as described above), the intracellular or extracellular suspension of HepG2.2.15 cells was denatured (1.5 MNaCI/0.5 N NaOH), neutralized (3 M NaCl/0.5 M Tris HCI, pH 7.5), then wash (2xSSC). The DNA was returned to the membrane by incubating the filter at 120 ° C for 2-4 hours.
DNA 杂化  DNA hybridization
从尼龙过滤器上处理过的 HePG2.2.15 细胞中得到的病毒 DNA的检测在非放射性， 地 高辛标记的乙型肝炎 DNA探针， 每个均用地高辛标记条件下进行， 纯化并且根据操作信心 进行杂化。 Detection of viral DNA obtained from He P G2.2.15 cells treated on a nylon filter was performed on non-radioactive, digoxin-labeled hepatitis B DNA probes, each under the conditions of digoxin labeling, and purified. Hybrid based on operational confidence.
预杂化和杂化在 5xSSC , l x 封闭试剂， 0.1% (重量） N-月桂酰肌氨酸， 0.02% (重 量） SDS 和 100 //g 青鱼精子 DNA中进行。 预杂化在 60°C进行 30 分钟， 然后与 20 至 40 ng/ml地高辛标记过的， 变性的 HBV - DNA (14小时， 60。C)进行特定杂化。 洗涤过滤器。 用地高辛抗体检测 HBV-DNA  Pre-hybridization and hybridization were carried out in 5xSSC, l x blocking reagent, 0.1% by weight of N-lauroyl sarcosine, 0.02% by weight of SDS and 100 //g of herring sperm DNA. Pre-hybridization was carried out at 60 ° C for 30 minutes and then specifically hybridized with 20 to 40 ng/ml of digoxin-labeled, denatured HBV-DNA (14 hours, 60 ° C). Wash the filter. Detection of HBV-DNA with digoxin antibody
按照造制造商的信息进行地高辛 -标记 DNA的免疫检测：  Perform immunodetection of digoxin-labeled DNA according to the manufacturer's information:
洗涤过滤器在封闭试中杂化 （依照制造商的信息)。杂化使用抗 -DIG抗体和碱性磷酸酵， 进行 30分钟。 在洗涤步骤之后， 加入碱性磷酸酶的底物， CSPD, 带着过滤器培养 5 分钟， 然后包上塑料膜， 37Ό再培养 15 分钟。将过滤器曝光在 X射线层下， 可看见乙型肝炎 DNA 的发光信号 (培养取决于信号强度： 10 分钟至 2小时)。  The wash filter is hybridized in a closed test (according to the manufacturer's information). Hybridization was carried out using an anti-DIG antibody and alkaline phosphate fermentation for 30 minutes. After the washing step, the substrate of alkaline phosphatase, CSPD, was added with a filter for 5 minutes, then coated with a plastic film, and incubated for another 15 minutes at 37 Torr. Exposing the filter to the X-ray layer reveals the luminescent signal of hepatitis B DNA (culture depends on signal strength: 10 minutes to 2 hours).
胞内或胞外乙型肝炎群被根据本发明的化合物降低相当于未处理的样本 50 %的浓度下 测试最大半抑制浓度 （IC5Q, 50% 抑制浓度） 。 The intracellular or extracellular Hepatitis B population was reduced by the compound according to the invention by a maximum half-inhibitory concentration (IC 5 Q, 50% inhibitory concentration) corresponding to a concentration of 50% of the untreated sample.
本发明的化合物中表现出的抗病毒作用值为 1C50低于 1 ηΜ,这是没有预料到的。因此， 本发明的化合物适用于病毒引发的疾病的治疗， 尤其是急性和慢性持续的 HBV病毒感染。 HBV 引发的慢性病毒病可能导致病态变得严重， 慢性乙型肝炎病毒感染在许多情况下可导 致肝硬化和 /或肝细胞癌变。 The antiviral effect value exhibited by the compound of the present invention is 1 C 50 lower than 1 η Μ, which is unexpected. Thus, the compounds of the invention are useful in the treatment of viral-induced diseases, particularly acute and chronic persistent HBV viral infections. Chronic viral diseases caused by HBV may cause morbidity to become severe, and chronic hepatitis B virus infection can lead to cirrhosis and/or hepatocellular carcinogenesis in many cases.
对本发明的化合物来说， 可能被提及的指示区域是， 例如： 可能导致传染性肝炎的急性 和慢性病毒感染的治疗，例如乙肝病毒感染。本发明的化合物尤其适合治疗慢性乙肝感染和 急性和慢性乙肝病毒感染。  For the compounds of the present invention, the indicated regions that may be mentioned are, for example, the treatment of acute and chronic viral infections that may result in infectious hepatitis, such as hepatitis B virus infection. The compounds of the invention are especially suitable for the treatment of chronic hepatitis B infection and acute and chronic hepatitis B virus infection.
本发明的化合物显示出较强的抗病毒作用， 其中部分化合物 1C5()小于 2ηΜ, 部分化合物 IC50值介 2nM与 20nM之间， 部分化合物的 IC5o值介 20nM与 200nM之间. 由于本发明化 合物对乙型肝炎 （HBV ) 具有出乎预料的抗病毒活性， 因此适于用来治疗病毒引起的各种 疾病， 尤其是急性和慢性持久性 HBV病毒感染引起的疾病。 有 HBV 引起的慢性病毒性疾 病可以导致各种不同严重程度的综合症状， 众所周知， 慢性乙型肝炎病毒感染可导致肝硬化 和肝细胞癌。 The compound of the present invention shows a strong antiviral effect, wherein some of the compounds 1C 5 () are less than 2ηΜ, the IC 50 value of some compounds is between 2 nM and 20 nM, and the IC 5 o value of some compounds is between 20 nM and 200 nM. The compounds of the present invention have unexpected antiviral activity against hepatitis B (HBV) and are therefore suitable for the treatment of various diseases caused by viruses, particularly those caused by acute and chronic persistent HBV infection. Chronic viral diseases caused by HBV can lead to a variety of syndromes of varying severity. It is well known that chronic hepatitis B virus infection can lead to cirrhosis and hepatocellular carcinoma.
可用本发明化合物治疗的适应症有：  Indications that can be treated with the compounds of the invention are:
治疗可导致感染性肝炎的急性和慢性病毒感染的， 例如乙型肝炎病毒感染。 特别优选的 是慢性乙型肝炎感染的治疗和急性乙型肝炎病毒感染的治疗。  Treatment can lead to acute and chronic viral infections of infectious hepatitis, such as hepatitis B virus infection. Particularly preferred are the treatment of chronic hepatitis B infection and the treatment of acute hepatitis B virus infection.
试验例:  Test example:
对本发明的化合物进行活性测定， 测试方法如前所述， 结果如下:  The activity of the compound of the present invention was measured. The test method was as described above, and the results were as follows:
Figure imgf000051_0001
虽然， 上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述， 但在本发明 基础上， 可以对之作一些修改或改进， 这对本领域技术人员而言是显而易见的。 因此， 在不 偏离本发明精神的基础上所做的这些修改或改进， 均属于本发明要求保护的范围。
Figure imgf000051_0001
Although the present invention has been described in detail above with reference to the preferred embodiments of the present invention, it will be apparent to those skilled in the art. Therefore, such modifications or improvements made without departing from the spirit of the invention are intended to be within the scope of the invention.
工业实用性 Industrial applicability
本发明提供了一种如通式 （ I ) 及其同分异构体 (la)所示的二氢嘧啶类化合物， 其制备 方法及其作为制备治疗和预防病毒性疾病的药物中的应用，尤其是作为制备治疗和预防乙型 肝炎病毒感染药物中的应用。 本发明还涉及这些二氢嘧啶同其他抗病毒剂， 适当情况下， 免 疫调节剂的组合物，以及含有这些组合物用于治疗和预防病毒性肝炎尤其是乙型肝炎的组合 物的用途。 本发明具有工业实用性。  The present invention provides a dihydropyrimidine compound represented by the general formula (I) and its isomer (la), a preparation method thereof and use thereof as a medicament for preparing a medicament for treating and preventing a viral disease, In particular, it is used as a preparation for the treatment and prevention of hepatitis B virus infection. The invention further relates to the use of these dihydropyrimidines together with other antiviral agents, where appropriate, immunomodulatory agents, and compositions containing these compositions for the treatment and prevention of viral hepatitis, especially hepatitis B. The invention has industrial applicability.

Claims

权 利 要 求 书 通式 （I ) 及其同分异构体 (la)所示的化合物或其对映异构体或它们的盐或水合物: Claims The compounds of the formula (I) and its isomer (la) or their enantiomers or their salts or hydrates are:
Figure imgf000053_0001
其中， 代表 d-Cs的垸基， 或未取代的吡啶基、 苯基、 萘基、 噻唑基、 嘧啶基、 噻吩基、 呋喃基、 吡咯基、 吡咯烷基、 咪唑基、 噻嗪基、 吡嗪基， 或其中上述环系任选被选自下述基 团的相同或不同取代基单取代或多取代： 氨基、 硝基、 氰基、 F、 Cl、 Br、 I、 羟基、 三氟甲 基、 三氟甲氧基、 苄基、 CrC6的烷基， d-C6的烷氧基、 C,-C6的烷氧羰基、 C6的烷基氨 基、 CrC6的二烷基氨基、 CrC6的酰胺基、 CrC6的酰氧基、 d-Ce的酰基、 C,-C6的烷硫基、 -C6的烷亚磺酰基、 d-C^的烷磺酰基;
Figure imgf000053_0001
Wherein, an alkyl group representing d-Cs, or an unsubstituted pyridyl group, a phenyl group, a naphthyl group, a thiazolyl group, a pyrimidinyl group, a thienyl group, a furyl group, a pyrrolyl group, a pyrrolidinyl group, an imidazolyl group, a thiazinyl group, a pyridyl group a pyridyl group, or wherein the above ring system is optionally mono- or polysubstituted with the same or different substituents selected from the group consisting of amino, nitro, cyano, F, Cl, Br, I, hydroxy, trifluoromethyl group, a trifluoromethoxy group, a benzyl group, C r C 6 alkyl, dC 6 alkoxy group, C, -C 6 alkoxycarbonyl group, a C6 alkylamino group, C r C 6 dialkyl amino, C r C 6 amide, C r C 6 acyloxy, d-Ce acyl, C, -C 6 alkylthio is, -C 6 alkylsulfinyl group, dC ^ alkylsulfonyl group ;
R2代表苯基、 萘基、 含有 1-5个选自 N、 S、 0的杂原子的 5-12个原子的杂芳基， 其所述杂 芳基为吡啶基、 喹啉基、 嘧啶基、 呋喃基、 噻吩基、 噁唑基、 咪唑基、 噻唑基、 噻嗪基或吡 嗪基； 或其中上述环系任选被选自下述基团的相同或不同取代基单取代或多取代： F、 Cl、 Br、 1、 三氟甲基、 三氟甲氧基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 C8的烷氧基、 Cr 的垸氧羰基、 - 的垸硫基、 - 的垸亚磺酰基、 d-C8的烷磺酰基、 CrC8的酰基 或 <^-0：8的烷基， 或其中所述烷基被具有 6-10个碳原子的芳基、 卤素、 或 -S-R5、 NR6R7 、 -CO-NR8R9、 -D-CH2-RI()所示基团取代， 其中 R5代表任选被卤素取代的苯基， 、 R7、 R8 和 1 9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 - 的酰基、 CrC8的垸 氧羰基、 苯基； D代表 0、 S、 SO或 S02; R,0代表选择性被选自下述基团的相同或不同取 代基单取代或多取代的苯基： 卤素、 硝基、 三氟甲基、 C,-C8的烷基或 CrC8的烷氧基； A代表一个键、 -0-、 -S -、 或 -NRM-， 其中 1„是 d-C6的烷氧羰基、 或直链、 支链、 或 环状饱和或不饱和（：,-：8的烃基， 或其中所述烃基任选含有 1-2个选自 0、 S、 S02、 CO, NH、 -NH- ( d-C4烷基） 、 -N- ( -C4烷基） 2、 相同或不同杂链单元， 并且上述烃基或含 有杂链单元的烃基任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10 个碳原子的芳垸基或杂芳基取代； R 2 represents a phenyl group, a naphthyl group, a heteroaryl group having 5 to 5 atoms of 1 to 5 hetero atoms selected from N, S, 0, and the heteroaryl group is a pyridyl group, a quinolyl group, a pyrimidine group. Or a furyl group, a thienyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a thiazolyl group or a pyrazinyl group; or wherein the above ring system is optionally monosubstituted or polysubstituted with the same or different substituents selected from the group consisting of Substitution: F, Cl, Br, 1, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, nitro, cyano, carboxy, hydroxy, C 8 alkoxy, C r垸 oxycarbonyl , - anthracenylthio, - fluorenesulfinyl, dC 8 alkylsulfonyl, C r C 8 acyl or <^-0: 8 alkyl, or wherein the alkyl is 6-10 Substituting a aryl group of a carbon atom, a halogen, or a group represented by -SR 5 , NR6R 7 , -CO-NR 8 R 9 , -D-CH 2 -R I() , wherein R 5 represents an optionally substituted by halogen Phenyl, R 7 , R 8 and 1 9 are the same or different and represent hydrogen, naphthyl, hydroxy-substituted phenyl, hydroxy, -acyl, C r C 8 fluorenyloxy, phenyl; D represents 0 , S, SO or S0 2 ; R, 0 represents a phenyl group which is optionally mono- or polysubstituted by the same or different substituents selected from the group consisting of halogen, nitro, trifluoromethyl, C, -C 8 alkyl or C r C 8 Alkoxy; A represents a bond, -0-, -S-, or -NR M -, where 1 „ is an alkoxycarbonyl group of dC 6 , or a linear, branched, or cyclic saturated or unsaturated (: a hydrocarbon group of -: 8 or wherein the hydrocarbon group optionally contains 1-2 selected from the group consisting of 0, S, S0 2 , CO, NH, -NH-( dC 4 alkyl), -N- ( -C 4 alkane yl) 2, identical or different hetero chain members, and said hydrocarbon group or a hydrocarbon group optionally containing heteroatoms chain units is halogen, nitro, cyano, hydroxy, an aryl group having 6-10 carbon atoms, 6-10 Substituting an aryl or heteroaryl group of a carbon atom;
R3代表 H、 C,-C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 - 的烃基， 或其中 所述烃基任选含有 1-2个选自 0、 S、 S02、 CO. 亂 -NH- ( CrC4烷基）、 -N- ( d-C4烷基） 2 - 相同或不同杂链单元， 并且上述烃基或含有杂链单元的烃基任选被卤素、 硝基， 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 ->^121 13所示 基团取代， 其中 Rl2和 Rl3相同或不同， 并分别代表氢、 苄基或 d-C6的烷基； R 3 represents an alkoxycarbonyl group of H, C, -C 6 , or a linear, branched, or cyclic saturated or unsaturated hydrocarbon group, or wherein the hydrocarbon group optionally contains 1-2 selected from 0, S , S0 2 , CO. chaotic-NH-(C r C 4 alkyl), -N-( dC 4 alkyl) 2 - same or different hetero chain units, and the above hydrocarbon group or hydrocarbon group containing a hetero chain unit is optionally a halogen, a nitro group, a cyano group, a hydroxyl group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula -> 12 1 13 , Wherein R l2 and R l3 are the same or different and each represent an alkyl group of hydrogen, benzyl or dC 6 ;
H3CO H 3 CO
R代表 0CH3、 甲酰基、 氰基、 三氟甲基、 C3-C4的环烷基或吡啶基， 或代表 -X-Z, 其 中 X代表 -CH2- 、 -CHrCHr、 -CH2-CH2-CH2-^(C=0)-; Z 代表甲苯磺酰氧基、 甲磺酰氧基、 苯基、 吡啶基、 z '0 、
Figure imgf000054_0001
或R represents 0CH3 , formyl, cyano, trifluoromethyl, C 3 -C 4 cycloalkyl or pyridyl, or represents -XZ, wherein X represents -CH 2 -, -CH r CH r , -CH 2 -CH 2 -CH 2 -^(C=0)-; Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl, z '0,
Figure imgf000054_0001
or
NR,4R,5, 其中 R14和 R15相同或不同， 代表 (^-(^的垸基， 或所述烷基任选地被羟基、 CrC3 的烷氧羰基取代， 或 R,4 , Rl 5和 N原子键合成一个杂环， 所述杂环为咪唑、 三唑、 四唑或 下述通式 (111)所示的基团:
Figure imgf000054_0002
NR, 4 R,5, wherein R 14 and R 15 are the same or different and represent a thiol group of (^-(^, or the alkyl group is optionally substituted by alkoxycarbonyl group of a hydroxyl group, C r C 3 , or R , 4, R 5 and N atomic bonds to synthesize a heterocyclic ring, the heterocyclic ring being an imidazole, a triazole, a tetrazole or a group represented by the following formula (111):
Figure imgf000054_0002
其中， B代表 ~(CH2)n- (n=0，l或 2)、 -CFr、 -CHF- 或 (OO)-; Y 代表 ~CH2-、 -CH2-CH2- 、 -0-、 -S -、 -SO- , SOr 或 NRI6 , 其中 Rl6代表氢、 -CO-CH3、 -CO-CF3、 -CO-0-R,7 或 -CO-NRl 8R19， 其中 R17, R|8, Rl9相同或不同， 代表 H或 C,- C8的烷基; Wherein B represents ~(CH 2 ) n - (n=0, l or 2), -CF r , -CHF- or (OO)-; Y represents ~CH 2 -, -CH 2 -CH 2 - , - 0-, -S -, -SO-, SO r or NR I6 , wherein R l6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , -CO-0-R, 7 or -CO-NR l 8 R 19 , wherein R 17 , R | 8 , R l9 are the same or different and represent an alkyl group of H or C, -C 8 ;
R20代表氢、 卤素、 氰基、 叠氮基、 氨基、 CrC7的杂环、 的烷基、 d-C8的烷氧基、 C,-C8的烷硫基、 d- 的烷亚磺酰基、 -C8的磺酰基、 d-Cs的酰基、 硝基、 三氟甲基、 或 -CO-N(R21)2, 其中 R2 I是 ^！或。,.^垸基； R 20 represents hydrogen, halogen, cyano, azide, amino, heterocycle of C r C 7 , alkyl, dC 8 alkoxy, C, -C 8 alkylthio, d- alkane Sulfonyl, -C 8 sulfonyl, d-Cs acyl, nitro, trifluoromethyl, or -CO-N(R 21 ) 2 , wherein R 2 I is ^! or. ,.^垸基;
R4代表氫， 的烷基、 C2-C4的烯基、 C,-C10的烷氧羰基、 -do的酰基或 d-do苯甲酰 基。 Alkyl R4 represents hydrogen, a, C 2 -C 4 alkenyl group, C, -C 10 alkoxycarbonyl group, an acyl or -DO d-do benzoyl.
2. 如权利要求 1 所述的化合物， 其特征在于， R,代表 C,-C6的烷基， 或苯基、 萘基、 嘧啶 基、 噻吩基、 呋喃基、 吡咯基、 吡咯烷基、 咪唑基、 噻嗪基、 吡嗪基， 或其中上述环系任选 被选自下述基团的相同或不同取代基单取代或多取代： 氨基、 硝基、 氰基、 F、 Cl、 Br、 I、 羟基、 三氟甲基、 三氟甲氧基、 苄基、 C6的烷基， d-C6的烷氧基、 d- 的烷氧羰基、 的烷基氨基、 C,-C6的二烷基氨基、 C,-C6的酰胺基、 C,-C6的輓氧基、 CrC6的酰基、 CrC6的烷硫基、 (^-(：6的烷亚磺酰基、 Ci- 的烷磺酰基； The compound according to claim 1, wherein R represents an alkyl group of C, -C 6 or a phenyl group, a naphthyl group, a pyrimidinyl group, a thienyl group, a furyl group, a pyrrolyl group, a pyrrolidinyl group, Imidazolyl, thiazinyl, pyrazinyl, or wherein the above ring system is optionally mono- or polysubstituted with the same or different substituents selected from the group consisting of amino, nitro, cyano, F, Cl, Br , I, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, C6 alkyl, dC 6 alkoxy, d-alkoxycarbonyl, alkylamino, C, -C 6 Alkylamino, C,-C 6 amide group, C,-C 6 oxyl group, C r C 6 acyl group, C r C 6 alkylthio group, (^-(: 6 alkylsulfinyl group) , an alkylsulfonyl group of Ci-;
R2代表苯基、 萘基、 含有 1 -5个选自 N、 S、 0的杂原子的 5-12个原子的杂芳基， 其所述杂 芳基为吡啶基、 喹啉基、 嘧啶基、 呋喃基、 噻吩基、 n ;唑基、 咪唑基、 噻唑基、 噻嗪基或吡 嗪基； 或其中上述环系任选被选自下述基团的相同或不同取代基单取代或多取代： F、 Cl、 Br, 1、 三氟甲基、 三氣甲氧基、 三氣甲橫酰基、 硝基、 氰基、 幾基、 经基、 C :8的烷氧基、 CrCs的烷氧羰基、 Ci-C8的烷硫基、 -C8的烷亚磺酰基、 CrC8的烷磺酰基、 -(：8的酰基、 或 Ci-C8的垸基， 或其中所述烷基被具有 6-10个碳原子的芳基、 卤素、 或 -S-R5、 NR6R7和 -CO-NR8R9和 -D-CH2-R10所示基团取代， 其中 R5代表任选被卤素取代的苯基， 、 R7、 R8 和 R9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 - 的酰基或 -C8的烷 氧羰基、 苯基； D代表 0、 S、 SO或 S02; Rl()代表选择性被选自下述基团相同或不同取代 基单取代或多取代的苯基： 卤素、 硝基、 三氟甲基、 <^-(：8的烷基或 C,-C8的垸氧基； A代表一个键、 -0-,、 -S -、 或 -NRH-， 其中 1^是 1 、 -C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 C'- 的烃基， 或其中所述烃基任选含有 1 -2个选自 0、 S、 S02、 CO、 NH , -NH- ( d- 烷基） 、 -N- ( d- 烷基） 2、 相同或不同杂链单元， 并且上述烃基或含 有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6- 10 个碳原子的芳烷基或杂芳基取代； R 2 represents a phenyl group, a naphthyl group, a heteroaryl group having 1 to 5 atoms of 5 to 12 atoms selected from N, S, 0, and the heteroaryl group is a pyridyl group, a quinolyl group, a pyrimidine group. group, a furyl group, a thienyl group, n; oxazolyl, imidazolyl, thiazolyl, thiazine or pyrazinyl; or wherein said ring system is optionally substituted by identical or different substituents selected from the following groups substituted with mono or Multi-substitution: F, Cl, Br, 1, trifluoromethyl, tri-methoxy, tri-triyl, nitro, cyano, alkyl, thiol, C: 8 alkoxy, CrC s Alkoxycarbonyl, an alkylthio group of Ci-C 8 , an alkylsulfinyl group of -C 8 , an alkylsulfonyl group of CrC 8 , an acyl group of -8 : or an alkyl group of Ci-C 8 , or The alkyl group is substituted with an aryl group having 6 to 10 carbon atoms, a halogen, or a group represented by -SR 5 , NR 6 R 7 and -CO-NR 8 R 9 and -D-CH 2 -R 10 , wherein R 5 represents a phenyl group optionally substituted by halogen, and R 7 , R 8 and R 9 are the same or different and each represent hydrogen, naphthyl, hydroxy-substituted phenyl, hydroxy, -acyl or -C 8 alkoxycarbonyl; , phenyl; D represents 0, S, SO or S0 2 ; R l() represents a phenyl group which is optionally mono- or polysubstituted by the same or different substituents selected from the group consisting of halogen, nitro, trifluoromethyl, <^-(: 8 alkyl or C, a C 8 methoxy group; A represents a bond, -0-, -S -, or -NR H -, wherein 1 ^ is a 1, -C 6 alkoxycarbonyl group, or a straight chain, a branched chain, or a cyclic saturated or unsaturated C'-hydrocarbyl group, or wherein the hydrocarbyl group optionally contains 1 - 2 selected from the group consisting of 0, S, S0 2 , CO, NH, -NH-(d-alkyl), -N- (d-alkyl) 2 , the same or different hetero chain units, and the above hydrocarbon group or a hydrocarbon group containing a hetero chain unit may be optionally halogen, nitro, cyano, hydroxy, aryl having 6 to 10 carbon atoms, An aralkyl or heteroaryl group having 6 to 10 carbon atoms;
R3代表 H、 - 的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 C,-C8的烃基， 或其中 所述烃基任选含有卜 2个选自 0、 S、 S02、 CO、 NH、 -NH- ( <：1-(：4烷基）、 -N- ( C「C4烷基） 2、 相同或不同杂链单元， 并且上述烃基或含有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 -NRI 2RI 3所示 基团取代， 其中 Rl 2和 R13相同或不同， 并分别代表氢、 苄基或 C,-C6的烷基； H3CO. R 3 represents H, - alkoxycarbonyl, or a linear, branched, or cyclic saturated or unsaturated C, -C 8 hydrocarbyl group, or wherein the hydrocarbyl group optionally contains 2 selected from 0, S, S0 2 , CO, NH, -NH- ( <: 1-(: 4 alkyl), -N- ( C "C 4 alkyl) 2 , the same or different hetero chain units, and the above hydrocarbon group or hetero chain unit The hydrocarbyl group may be optionally halogen, nitro, cyano, hydroxy, aryl having 6-10 carbon atoms, aralkyl having 6-10 carbon atoms, heteroaryl or formula -NR I 2 R I Substituted by a group of 3 , wherein R 2 2 and R 13 are the same or different and each represent hydrogen, benzyl or C,-C 6 alkyl; H 3 CO.
R代表 QGH3、 甲酰基、 氰基、 CrC4的环垸基或吡啶基， 或代表 -X-Z, X代表 -CH: -CH2-CH2-、 -CH2-CH2-CH2-或 (C=0)-; R represents QGH3 , formyl, cyano, cyclopropyl or pyridyl of C r C 4 , or represents -XZ, X represents -CH: -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - Or (C=0)-;
Z代表甲苯磺酰氧基、甲磺酰氧基、苯基、吡啶基、
Figure imgf000055_0001
、 、 、或 -NRMR，5, 其中 R14和 Rl 5相同或不同， 代表 的烷基， 所述烷基任选地被羟基、 C.- 的烷氧羰基 取代， 或 RI4,R15和 N原子键合成一个杂环， 所述杂环为咪唑、 三唑、 四唑或下述通式 (III) 所示的基团：
Figure imgf000055_0002
Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl,
Figure imgf000055_0001
, , or -NR M R, 5 , wherein R 14 and R l 5 are the same or different, represent an alkyl group, the alkyl group optionally substituted by a hydroxyl group, a C.-alkyloxycarbonyl group, or R I4 , The R 15 and N atom bonds form a heterocyclic ring which is an imidazole, a triazole, a tetrazole or a group represented by the following formula (III):
Figure imgf000055_0002
其中， B代表 ~(CH2)n- (n=0, l或 2)、 -CF2-、 -CHF- 或 (C=0)-; Y 代表^ CH2-、 -CH2-CH2- 、 -0-、 -S -、 -SO- , S02- 或 NR16 , 其中 Rl6代表氢、 -CO-CH3、 -CO-CF3、 -CO-0-R,7 或 - CO-NRl8Rl9， 其中 R17， R,8 - R19相同或不同, 代表 H或 C,- C8的烷基； Wherein B represents ~(CH 2 ) n - (n=0, l or 2), -CF 2 -, -CHF- or (C=0)-; Y represents ^ CH 2 -, -CH 2 -CH 2 - , -0-, -S -, -SO- , S0 2 - or NR 16 , wherein R l6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , -CO-0-R, 7 or - CO -NR l8 R l9 , wherein R 17 , R, 8 - R 19 are the same or different and represent an alkyl group of H or C, -C 8 ;
R2o代表氢、 卤素、 氰基、 叠氮基、 氨基、 C5-C7的杂环、 -Cs的烷基、 d-Cs的烷氧基、 -C8的烷硫基、 CrC8的烷亚磺酰基、 C8的磺酰基、 C,-C8的酰基、 硝基、 三氟甲基、 或 -CO-N(R2l)2, 其中 R2I是 H或 d- 烷基； R 2 o represents hydrogen, halogen, cyano, azide, amino, C 5 -C 7 heterocyclic ring, -Cs alkyl group, d-Cs alkoxy group, -C 8 alkylthio group, C r C 8 alkylsulfinyl, C 8 sulfonyl, C,-C 8 acyl, nitro, trifluoromethyl, or -CO-N(R 2l ) 2 , wherein R 2I is H or d-alkane base;
代表氣、 CrC4的垸基、 C2-C4的烯基、 d- o的烷氧羰基、 -do的酰基或 CrC10苯甲酰 基。 Representative gas, C r C alkyl with 4, C 2 -C 4 alkenyl group, d- o alkoxycarbonyl group, -do acyl or C r C 10 benzoyl.
3. 如权利要求 2所述的化合物， 其特征在于， 代表 - 的垸基、 或苯基、 萘基、 噻 吩基、 呋喃基、 吡咯基、 吡咯烷基、 咪唑基、 噻嗪基， 或其中上述环系任选被选自下述基团 的相同或不同取代基单取代或多取代： 氨基、 硝基、 氰基、 F、 CI, Br. 1. 羟基、 三氟甲基、 三氟甲氧基、 苄基、 ^-^的烷基， d-C6的烷氧基、 CrC6的烷氧羰基、 d-C6的烷基氨基、 -^的二烷基氨基、 C,-C6的酰胺基、 -C6的酰氧基、 OC6的酰基、 的烷硫基、 C,-C6 的烷亚磺酰基、 的烷磺酰基； The compound according to claim 2, which represents - an indenyl group, or a phenyl group, a naphthyl group, a thienyl group, a furyl group, a pyrrolyl group, a pyrrolidinyl group, an imidazolyl group, a thiazinyl group, or The above ring system is optionally mono- or polysubstituted with the same or different substituents selected from the group consisting of amino, nitro, cyano, F, CI, Br. 1. hydroxy, trifluoromethyl, trifluoromethyl Oxyl, benzyl, ^-^alkyl, dC 6 alkoxy, C r C 6 alkoxycarbonyl, dC 6 alkylamino, -^dialkylamino, C, -C 6 An amide group, an acyloxy group of -C 6 , an acyl group of OC 6 , an alkylthio group, an alkylsulfonyl group of C,-C 6 , an alkylsulfonyl group;
R2代表苯基、 萘基、 或含有 1-5个选自 N、 S、 0的杂原子的 5-12个原子的杂芳基， 其所述 杂芳基为吡啶基、 喹啉基、 嘧啶基、 呋喃基、 噻吩基、 Bjg唑基、 咪唑基、 噻唑基、 噻嗪基或 吡嗪基； 或其中上述环系任选自下述基团的相同或不同取代基单取代或多取代： R 2 represents a phenyl group, a naphthyl group, or a heteroaryl group having 5 to 5 atoms of 1 to 5 hetero atoms selected from N, S, 0, wherein the heteroaryl group is a pyridyl group, a quinolyl group, Pyrimidinyl, furyl, thienyl, Bjgzolyl, imidazolyl, thiazolyl, thiazinyl or pyrazinyl; or monosubstituted or polysubstituted wherein the above ring system is selected from the same or different substituents selected from the group consisting of :
F、 CI , Br、 1、 三氟甲基、 三氟甲氧基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 C,-C8 的烷氧基、 -Cs的烷氧羰基、 d- 的烷硫基、 d- 的烷亚磺酰基， CrC8的烷磺酰基、 C!- 的酰基、或 d-C8的烷基，或其中所述烷基被具有 6-10个碳原子的芳基、 素、或 -S-R5、 1 «1 7和-( 0^1 81 9和 -D-CHrR^jf示基团取代， 其中 R5代表任选被卤素取代的苯基， 、 R7、 1 8和 1 9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 d-Cs的酰基或 ，-^ 的烷氧羰基、 苯基； D代表 0、 S、 SO或 S02; R1()代表选择性被选自下述基团相同或不同 取代基单取代或多取代的苯基： 卤素、 硝基、 三氟甲基、 -( 8的烷基或 C,-C8的烷氧基； A代表一个键、 -0-,、 -S -、 或 -NRu-， 其中 1^是 11、 -C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 C,-C8的烃基， 或其中所述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 H . -NH- ( C,- 垸基） 、 -N- ( CrC4烷基） 2、 相同或不同杂链单元， 并且上述烃基或含 有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10 个碳原子的芳烷基或杂芳基取代； F, CI, Br, 1, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyl, nitro, cyano, carboxyl, hydroxy, C, -C 8 alkoxy, -Cs alkoxy a carbonyl group, an alkylthio group of d-, an alkylsulfinyl group of d-, an alkylsulfonyl group of C r C 8 , an acyl group of C!-, or an alkyl group of dC 8 , or wherein the alkyl group is 6-10 One carbon atom of aryl, aryl, or -SR 5 , 1 «1 7 and -( 0^1 8 1 9 and -D-CHrR^jf are substituted, wherein R 5 represents benzene optionally substituted by halogen The radicals, R 7 , 1 8 and 1 9 are the same or different and each represent hydrogen, naphthyl, hydroxy-substituted phenyl, hydroxy, d-Cs acyl or, -^ alkoxycarbonyl, phenyl; D represents 0 , S, SO or S0 2 ; R 1 () represents a phenyl group which is optionally mono- or polysubstituted by the same or different substituents selected from the group consisting of halogen, nitro, trifluoromethyl, -( 8 Alkyl or C,-C 8 alkoxy; A represents a bond, -0-, -S -, or -NR u -, wherein 1^ is 11, a C 6 alkoxycarbonyl, or a straight chain , branched, or cyclic saturated or unsaturated C, a hydrocarbyl group of -C 8 , or wherein the hydrocarbyl group optionally contains 1-2 One selected from the group consisting of 0, S, S0 2 , CO, H. -NH- (C,-fluorenyl), -N-(C r C 4 alkyl) 2 , the same or different hetero chain units, and the above hydrocarbon group or The hydrocarbon group having a hetero chain unit may be optionally substituted by a halogen, a nitro group, a cyano group, a hydroxyl group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms or a heteroaryl group;
R3代表 H、 CrC6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 CrC8的烃基， 或其中 所述烃基任选含有 1-2个选自 0、 S、 S02、 C0、 NH、 -NH- ( CrC4烷基）、 -N- ( CrC4烷基） 2、 相同或不同杂链单元， 并且上述烃基或含有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6- 10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 -NRI2RI3所示 基团取代， 其中 1 |2和1 |3相同或不同， 并分别代表氢、 苄基或 - 的烷基； R 3 represents an alkoxycarbonyl group of H, C r C 6 , or a linear, branched, or cyclic saturated or unsaturated C r C 8 hydrocarbon group, or wherein the hydrocarbon group optionally contains 1-2 selected from 0 , S, S0 2 , C0, NH, -NH- (C r C 4 alkyl), -N- (C r C 4 alkyl) 2, the same or different hetero chain units, and the above hydrocarbon group or hetero chain unit The hydrocarbyl group may be optionally halogen, nitro, cyano, hydroxy, aryl having 6-10 carbon atoms, aralkyl having 6-10 carbon atoms, heteroaryl or formula -NR I2 R I3 a group substituted, wherein 1 | 2 and 1 | 3 are the same or different and each represents an alkyl group of hydrogen, benzyl or -;
R代表
Figure imgf000056_0001
、 甲酰基、 氰基、 C3-C4的环烷基或吡啶基， 或代表 -X-Z, X代表 -CH2- 、 -CH2-CH2- - -CH2-CH2-CH2-或 (C=0)-; R stands for
Figure imgf000056_0001
, formyl, cyano, C 3 -C 4 cycloalkyl or pyridyl, or -XZ, X represents -CH 2 -, -CH2-CH2- -CH 2 -CH 2 -CH 2 - or C=0)-;
Z 代表甲苯磺酰氧基、 甲磺酰氧基、 苯基、 吡啶基、
Figure imgf000056_0002
、 或 R14Ri5, 其中 和 Rl5相同或不同， 代表 C,-C4的烷基， 所述烷基任选地被羟基、 C,-C3 的烷氧羰基取代， 或 RI4,RI 5和 N原子键合成一个杂环， 所述杂环为咪唑、 三唑、 四唑或下 述通式 (III)所示的基团：
Figure imgf000056_0003
Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl,
Figure imgf000056_0002
Or R 14 Ri5, and R l5 wherein the same or different, represent a C, -C 4 alkyl, said alkyl optionally substituted by hydroxy, C, -C 3 alkoxycarbonyl substituent, or R I4, R The I 5 and N atom bonds form a heterocyclic ring which is an imidazole, a triazole, a tetrazole or a group represented by the following formula (III):
Figure imgf000056_0003
其中， B代表" (CH2)n- (n=0，l或 2)、 -CFr、 -CHF- 或 (C=0)-; Y 代表 ~CH2-、 -CH2-CH2- 、 -0-、 -S -、 -SO-、 S02- 或 NRI6 , 其中 Rl6代表氢、 -CO-CHj - -CO-CF3 > -CO-0-R,7 或 -CO-NR|8R|9 , 其中 Rl7, R18, Rl9相同或不同， 代表 H或 Cr C8的烷基; Wherein B represents "(CH 2 ) n - (n = 0, l or 2), -CF r , -CHF- or (C = 0)-; Y represents ~CH 2 -, -CH 2 -CH 2 - , -0-, -S -, -SO-, S0 2 - or NR I6 , where R l6 represents hydrogen, -CO-CHj - -CO-CF3 > -CO-0-R, 7 or -CO-NR| 8 R| 9 , wherein R l7 , R 18 , and R l9 are the same or different and represent an alkyl group of H or C r C 8 ;
1½>代表氢、 卤素、 氰基、 叠氮基、 氨基、 c5-c7的杂环、 crc8的烷基、 crc8的烷氧基、 - 的烷硫基、 CrC8的烷亚磺酰基、 -C8的磺酰基、 d- 的酰基、 硝基、 三氟甲基、 或 -CO-N(R21)2. 其中 R21是 H或 d-C8烷基； 11⁄2> represents hydrogen, halogen, cyano, azido, amino, c 5 -c 7 heterocycle, c r c 8 alkyl, c r c 8 alkoxy, -alkylthio, C r An alkylsulfinyl group of C 8 , a sulfonyl group of -C 8 , an acyl group of d-, a nitro group, a trifluoromethyl group, or a -CO-N(R 21 ) 2 . wherein R 21 is H or dC 8 alkyl;
代表氢、 - 的烷基、 C2-C4的烯基、 do的烷氧羰基、 Crdo的酰基或 d-d。苯甲酰 基。 Represents hydrogen, -alkyl, C 2 -C 4 alkenyl, do alkoxycarbonyl, Crdo ac or dd. Benzoyl.
4.如权利要求 2所述的化合物， 其特征在于， 代表苯基、 萘基、 噻吩基、 呋喃基、 吡 咯基、 吡咯烷基、 咪唑基、 噻嗪基， 或其中上述环系任选被选自下述基团的相同或不同取代 基单取代或多取代： 氨基、 硝基、 氰基、 F、 Cl、 Br、 I、 羟基、 三氟甲基、 三氟甲氧基、 苄 基、 -C6的烷基， C,-C6的烷氧基、 -C6的烷氧羰基、 d-C6的垸基氨基、 d- 的二垸基 氨基、 CrC6的酰胺基、 C,-C6的酰氧基、 （^-(^的酰基、 -Ce的垸硫基、 的烷亚磺酰 基、 C6的烷磺酰基； The compound according to claim 2, which represents a phenyl group, a naphthyl group, a thienyl group, a furyl group, a pyrrolyl group, a pyrrolidinyl group, an imidazolyl group, a thiazinyl group, or wherein the above ring system is optionally Mono- or poly-substituted with the same or different substituents selected from the group consisting of amino, nitro, cyano, F, Cl, Br, I, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, -C 6 alkyl, C,-C 6 alkoxy, -C 6 alkoxycarbonyl, dC 6 decylamino, d-dinonylamino, CrC 6 amide, C,-C 6 acyloxy, (^ - (^ acyl, -Ce the embankment thio, alkyl sulfinyl, C 6 alkylsulfonyl group;
R2代表苯基、 或任选被选自下述基团的相同或不同取代基单取代或多取代的苯基： F、 Cl、 Br、 I、 三氟甲基、 三氟甲氧基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 -C8的烷氧基、 CrC8的烷氧羰基、 C,-C8的烷硫基、 -C8的烷亚磺酰基、 CrC8的烷磺酰基、 CrC8的酰基 或 -(：8的烷基， 或其中所述垸基被具有 6- 10个碳原子的芳基、 卤素、 或 -S-R5、 NR, 7 、 -CO-NR8R9、 -D-CHrRl0所示基团取代， 其中 R5代表任选被卤素取代的苯基， 、 R7、 R8 和 1 9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 （^-(^的酰基、 CrC8的烷 氧羰基、 苯基； D代表 0、 S、 SO或 S02; R1()代表选择性被选自下述基团的相同或不同取 代基单取代或多取代的苯基： 卤素、 硝基、 三氟甲基、 C!- 的烷基或 <^-0：8的烷氧基； A代表、 -0-、 -NR,,-, 其中！^是 的直连或支链垸基； R 2 represents a phenyl group, or a phenyl group which is mono- or polysubstituted by the same or different substituents selected from the group consisting of F, Cl, Br, I, trifluoromethyl, trifluoromethoxy, Trifluoromethanesulfonyl, nitro, cyano, carboxyl, hydroxy, -C 8 alkoxy, C r C 8 alkoxycarbonyl, C,-C 8 alkylthio, -C 8 alkylsulfin acyl, C r C 8 alkylsulfonyl group, C r C 8 acyl group or - (: 8 alkyl, or wherein is alkyl with 6-10 carbon atoms having an aryl group, a halogen, or -SR 5 a group substituted by NR, 7 , -CO-NR 8 R 9 , -D-CH r R l0 , wherein R 5 represents a phenyl group optionally substituted by halogen, and R 7 , R 8 and 1 9 are the same or different, and each represents hydrogen, a naphthyl group, a hydroxy-substituted phenyl, hydroxyl, (^ - (^ acyl, C r C 8 alkoxycarbonyl group, a phenyl group; D representative of 0, S, SO or S0 2; R 1 () represents a phenyl group which is optionally mono- or polysubstituted by the same or different substituents selected from the group consisting of halogen, nitro, trifluoromethyl, C!-alkyl or <^-0: 8 Alkoxy group; A stands for, -0-, -NR,,-, where! ^ is a direct or branched sulfhydryl group;
R3代表 -C4的直连或支链烷基； R 3 represents a straight or branched alkyl group of -C 4 ;
R代表 CrC4的环烷基或吡啶基， 或代表 -X-Z, X代表 -CH2- 、 -CH2-CH2-、 -CH2-CH2-CH: 或 (c=o)-; R represents a cycloalkyl or pyridyl group of C r C 4 or represents -XZ, and X represents -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH: or (c=o)- ;
Z 代表甲苯磺酰氧基、 甲磺酰氧基、 苯基、 吡啶基、
Figure imgf000057_0001
、 或Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl,
Figure imgf000057_0001
, or
NRI4R,5, 其中 Rl4和 Rl5相同或不同， 代表 <^-< 4的烷基， 所述垸基任选地被羟基、 CrC3 的烷氧羰基取代， 或 RI4,RI5和 N原子键合成一个杂环， 所述杂环为咪唑、 三唑、 四唑或下 述通式 (III)所示的基团：
Figure imgf000057_0002
NR I4 R, 5, wherein R l4 and R l5 same or different and represent <^ - <4 alkyl, optionally substituted alkyl with the hydroxyl group, C r C 3 alkoxycarbonyl substituent, or R I4, The R I5 and the N atom bond form a heterocyclic ring which is an imidazole, a triazole, a tetrazole or a group represented by the following formula (III):
Figure imgf000057_0002
其中， B代表 ~ CH2)„-(n=0,l或 2)、 -CF2-、 -CHF- 或 (C=0)-; Y 代表 ~CH2-、 -CH2-CH2- 、 -0-、 -S -、 -SO-、 S02- 或 NRI6 , 其中 Rl6代表氢、 -CO-CH3、 -CO-CF3、 -CO-0-R,7 或 -CO-NR,gR|9, 其中 Rl7, R,8. Rl9相同或不同， 代表 H或 C「 C8的烷基； Wherein B represents ~CH 2 )„-(n=0,l or 2), -CF 2 -, -CHF- or (C=0)-; Y represents ~CH 2 -, -CH 2 -CH 2 - , -0-, -S -, -SO-, S0 2 - or NR I6 , wherein R l6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , -CO-0-R, 7 or -CO- NR,gR| 9 , wherein R l7 , R, 8 . R l9 are the same or different and represent an alkyl group of H or C "C 8 ;
R2o代表氢、 卤素、 氰基、 叠氮基、 氨基、 C5-C7的杂环、 d-C8的烷基、 -C8的烷氧基、 -Cs的垸硫基、 CrCs的烷亚磺酰基、 d-C8的磺酰基、 <^-<：8的酰基、 硝基、 三氟甲基、 或 -CO-N(R2,)2, 其中 R21是！！或^-^烷基； R 2 o represents hydrogen, halogen, cyano, azido, amino, C 5 -C 7 heterocycle, dC 8 alkyl, -C 8 alkoxy, -Cs thiol, C r C An alkylsulfinyl group of s , a sulfonyl group of dC 8 , an acyl group of <^-<: 8 , a nitro group, a trifluoromethyl group, or -CO-N(R 2 ,) 2 , wherein R 21 is! ! Or ^-^alkyl;
R4代表氢、 CRC4的烷基、 （：2-(：4的烯基、 d-do的烷氧羰基、 -CHJ的酰基或 -(：1()苯甲酰 基。 R4 represents hydrogen, an alkyl group of C R C 4 , (: 2 - (: 4 alkenyl group, d-do alkoxycarbonyl group, -CHJ acyl group or -(: 1 () benzoyl group ) .
5. 如权利要求 2所述的化合物， 其特征在于， 代表咪唑基、 或任选被选自下述基团 的相同或不同取代基单取代或多取代咪唑基： 氨基、 硝基、 氰基、 F、 CI, Br、 、 羟基、 三 氟甲基、 三氟甲氧基、 苄基、 C6的烷基， C,-C6的垸氧基、 - 的烷氧羰基、 C,-C6的烷 基氨基、 <^-(：6的二烷基氨基、 的酰胺基、 d-C6的酰氧基、 d- 的酰基、 C,-C6的烷 硫基、 C'- 的烷亚磺酰基、 - 的烷磺酰基； The compound according to claim 2, which is a mono- or poly-substituted imidazolyl group which represents an imidazolyl group or is optionally selected from the group consisting of the following groups: amino group, nitro group, cyano group , F, CI, Br, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, C6 alkyl, C, -C 6 decyloxy, - alkoxycarbonyl, C, -C 6 Alkylamino, <^-(: 6 dialkylamino, amide, dC 6 acyloxy, d- acyl, C, -C 6 alkylthio, C'-alkyl sulfin Acyl, -alkylsulfonyl;
R2代表苯基、 或任选被选自下述基团的相同或不同取代基单取代或多取代的苯基： F、 Cl、 Br, 1、 三氟甲基、 三氟甲氧基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 C 的垸氧基、 -C8的垸氧羰基、 C 的烷硫基、 <^ ：8的烷亚磺酰基、 d-C8的垸磺酰基、 -Cs的酰基 或 ^-^的烷基， 或其中所述烷基被具有 6-10个碳原子的芳基、 卤素、 或 -S-R5、 R6R7 、 -CO-NR8R9、 -D-CH2-R10所示基团取代， 其中 R5代表任选被卤素取代的苯基， 、 R7、 R8 和 R9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 - 的酰基、 d- 的烷 氧羰基、 苯基； D代表 0、 S、 SO或 S02; Rl()代表选择性被选自下述基团的相同或不同取 代基单取代或多取代的苯基： 卤素、 硝基、 三氟甲基、 C,-C8的烷基或 (^-(8的垸氧基； A代表一个键、 -0-、 -S-, 或 -NRM-， 其中 ,是 14、 d- 的烷氧羰基， 或直链、 支链、 或 环状饱和或不饱和（^-( 8的烃基， 或其中所述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 -NH- (C,-C4烷基） 、 -N- (CrC4烷基） 2、 相同或不同杂链单元， 并且上述烃基或含 有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10 个碳原子的芳烷基或杂芳基取代； R 2 represents a phenyl group, or a phenyl group which may be mono- or polysubstituted by the same or different substituents selected from the group consisting of F, Cl, Br, 1, trifluoromethyl, trifluoromethoxy, Trifluoromethanesulfonyl, nitro, cyano, carboxyl, hydroxy, C decyloxy, -C 8 fluorenyloxycarbonyl, C alkylthio, <^: 8 alkylsulfinyl, dC 8 fluorene a sulfonyl group, an acyl group of -Cs or an alkyl group of -, wherein the alkyl group is an aryl group having 6 to 10 carbon atoms, a halogen, or -SR 5 , R6R 7 , -CO-NR 8 R 9 a group substituted with -D-CH 2 -R 10 wherein R 5 represents a phenyl group optionally substituted by halogen, and R 7 , R 8 and R 9 are the same or different and each represent hydrogen, naphthyl, hydroxy Substituted phenyl, hydroxy, acyl group of -, alkoxycarbonyl group of d-, phenyl; D represents 0, S, SO or S0 2 ; R l() represents the same or different substitution of a group selected from the group consisting of: Mono- or poly-substituted phenyl: halogen, nitro, trifluoromethyl, C, -C 8 alkyl or (^-( 8 decyloxy; A represents a bond, -0-, -S -, or -NR M -, wherein is 14, d- alkoxycarbonyl Or a linear, branched, or cyclic saturated or unsaturated (^ - hydrocarbon group (8, wherein the hydrocarbyl or optionally containing 1-2 heteroatoms selected from 0, S, S0 2, CO , NH, -NH - (C,-C 4 alkyl), -N-(C r C 4 alkyl) 2 , the same or different hetero chain units, and the above hydrocarbon group or a hydrocarbon group containing a hetero chain unit may optionally be halogen, nitro, a cyano group, a hydroxyl group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms or a heteroaryl group;
R3代表 H、 d-C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 - 的烃基， 或其中 所述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 -NH- (d-C4烷基）、 -N- iC!-C^烷基） 2、 相同或不同杂链单元， 并且上述烃基或含有杂链单元的烃基可任选被卤素、 硝基、 氰 基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 -NRI2R 所示基团取代， 其中 Rl2和 Rl3相同或不同， 并分别代表氢、 苄基或 Cr 的垸基；R 3 represents an alkoxycarbonyl group of H, dC 6 , or a linear, branched, or cyclic saturated or unsaturated hydrocarbon group, or wherein the hydrocarbon group optionally contains 1-2 selected from 0, S, S0 2 , CO, NH, -NH-(dC 4 alkyl), -N- iC!-C^alkyl) 2 , the same or different hetero chain units, and the above hydrocarbon group or hydrocarbon group containing a hetero chain unit may optionally be halogen Nitro, cyanide a group, a hydroxyl group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula -NR I2 R wherein R l2 and R l3 are the same or Different, and respectively represent hydrogen, benzyl or Cr sulfhydryl groups;
R 代表 C3-C4 的环烷基或吡啶基， 或代表 -X-Z, 其中 X 代表 -CH2- 、 -CHrCHr、 -CHrCHrCHr或 (C=0)-; R represents a C 3 -C 4 cycloalkyl or pyridyl group, or represents -XZ, wherein X represents -CH 2 - , -CH r CH r , -CH r CH r CH r or (C=0)-;
Z 代表甲苯磺酰氧基、 甲磺酰氧基、 苯基、 吡啶基、
Figure imgf000058_0001
、 或Z represents toluenesulfonyloxy, methanesulfonyloxy, phenyl, pyridyl,
Figure imgf000058_0001
, or
NR14Ri5, 其中 Rl4和 R15相同或不同， 代表 - 的烷基， 或所述烷基任选地被羟基、 CrC3 的烷氧羰基取代， 或 RM, R15和 N原子键合成一个杂环， 所述杂环为咪唑、 三唑、 四唑或 下述通式 (III)所示的基团：
Figure imgf000058_0002
NR 14 Ri5, wherein R l4 and R 15 are the same or different and represent an alkyl group, or the alkyl group is optionally substituted by a hydroxyl group, an alkoxycarbonyl group of C r C 3 , or a RM, R 15 and N atom bond A heterocyclic ring is synthesized, which is an imidazole, a triazole, a tetrazole or a group represented by the following formula (III):
Figure imgf000058_0002
其中， B代表 ~(CH2)„-(n=0,l或 2)、 -CFr、 -CHF- 或 (C=0)-; Y 代表" CH2-、 -CH2-CH2- 、 -0-、 -S -、 -SO-、 S02- 或 NR16 , 其中 Rl6代表氢、 -CO-CH3、 -CO-CF3、 -CO-0-R,7 或 -CO-NR18Rl9, 其中 R17, R,8, Rl9相同或不同， 代表 H或 - C8的烷基； Wherein B represents ~(CH 2 )„-(n=0, l or 2), -CF r , -CHF- or (C=0)-; Y represents "CH 2 -, -CH 2 -CH 2 - , -0-, -S -, -SO-, S0 2 - or NR 16 , wherein R l6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , -CO-0-R, 7 or -CO- NR 18 R l9 , wherein R 17 , R, 8 , and R l9 are the same or different and represent an alkyl group of H or -C 8 ;
1½)代表氢、 卤素、 氰基、 叠氮基、 氨基、 C5-C7的杂环、 -C8的烷基、 d-C8的烷氧基、 C,-C8的烷硫基、 d- 的烷亚磺酰基、 d-C8的磺酰基、 d-C8的酰基、 硝基、 三氟甲基、 或 -CO-N(R2,)2, 其中 R2I是 H或 C,-Cg烷基； 11⁄2) represents hydrogen, halogen, cyano, azido, amino, C 5 -C 7 heterocyclic ring, -C 8 alkyl group, dC 8 alkoxy group, C,-C 8 alkylthio group, d - alkyl sulfinyl group, a sulfonyl group 8 dC, dC 8 acyl, nitro, trifluoromethyl, or -CO-N (R 2,) 2, wherein R 2I is H or a C, -Cg alkyl ;
R4代表氢、 - 的烷基、 CrC4的烯基、 Cr o的烷氧羰基、 -C^的酰基或 -( |()苯甲酰 基。 R4 represents hydrogen, an alkyl group of -, an alkenyl group of C r C 4 , an alkoxycarbonyl group of Cr o , an acyl group of -C^ or a -( |() benzoyl group.
6. 如权利要求 2所述的化合物， 其特征在于， 代表嘧啶基、 吡嗪基， 或其中上述环系任 选被选自下述基团的相同或不同取代基单取代或多取代： 氨基、 硝基、 氰基、 F、 Cl、 Br、 1、 羟基、 三氟甲基、 三氟甲氧基、 苄基、 -C6的垸基， 的烷氧基、 -C6的烷氧羰基、 C,-C6的烷基氨基、 -C6的二烷基氨基、 CrC6的酰胺基、 C,-C6的酰氧基、 CrC6的酰基、 CrC6的烷硫基、 -C6的垸亚磺酰基、 CrC6的烷磺酰基； 6. The compound according to claim 2, which represents a pyrimidinyl group, a pyrazinyl group, or a monosubstituted or polysubstituted group wherein the above ring system is optionally selected from the same or different substituents selected from the group consisting of: amino groups , nitro, cyano, F, Cl, Br, 1, hydroxy, trifluoromethyl, trifluoromethoxy, benzyl, -C 6 fluorenyl, alkoxy, -C 6 alkoxycarbonyl , C,-C 6 alkylamino group, -C 6 dialkylamino group, C r C 6 amide group, C,-C 6 acyloxy group, C r C 6 acyl group, C r C 6 An alkylthio group, a -C 6 sulfinyl group, an alkylsulfonyl group of CrC 6 ;
R2代表苯基、 或任选被选自下述基团的相同或不同取代基单取代或多取代的苯基： F、 Cl、 Br、 1、 三氟甲基、 三氟甲氧基、 三氟甲磺酰基、 硝基、 氰基、 羧基、 羟基、 C,-C8的烷氧基、 C,-C8的烷氧羰基、 或 <^-(：8的烷基， 或其中所述烷基被具有 6-10个碳原子的芳基、 卤素、 或 -S-R5、 NR6R7和 -CO-NR8R9和 -D-CHrRl0所示基团取代， 其中 R5代表任选被卤素取代的 苯基， R6、 R7、 R8和 R9相同或不同， 并分别代表氢、 萘基、 羟基取代苯基、 羟基、 CrC8 的酰基或 -C8的烷氧羰基、 苯基； D代表 0、 S、 SO或 S02; R1()代表选择性被选自下述 基团相同或不同取代基单取代或多取代的苯基： ώ素、销基、三數甲基、 C,-C8的烷基或 -0：8 的烷氧基； R 2 represents a phenyl group, or a phenyl group which may be mono- or polysubstituted by the same or different substituents selected from the group consisting of F, Cl, Br, 1, trifluoromethyl, trifluoromethoxy, Trifluoromethanesulfonyl, nitro, cyano, carboxy, hydroxy, C, -C 8 alkoxy, C, -C 8 alkoxycarbonyl, or <^-(: 8 alkyl, or The alkyl group is substituted by an aryl group having 6 to 10 carbon atoms, a halogen, or a group represented by -SR 5 , NR 6 R 7 and -CO-NR 8 R 9 and -D-CH r R l0 , wherein R 5 represents a phenyl group optionally substituted by halogen, and R 6 , R 7 , R 8 and R 9 are the same or different and each represent hydrogen, naphthyl, hydroxy-substituted phenyl, hydroxy, C r C 8 acyl or -C 8 alkoxycarbonyl group, a phenyl group; D representative of 0, S, SO or S0 2; R 1 () is selected from the same selectively on behalf of the following groups or different substituents phenyl mono- or polysubstituted by: ώ Su , a pin group, a trimethyl group, a C, a C 8 alkyl group or a-0: 8 alkoxy group;
A代表一个键、 -0-、 或 -NRu -,  A represents a key, -0-, or -NRu -,
其中！^是！"!、 - 的垸氧羰基， 或直链、 支链、 或环状饱和或不饱和 d-C3的烃基， 或其 中所述烃基任选含有 卜 2个选自 0、 S、 S02、 CO、 NH、 -NH- (C!- 烷基） 、 -N- (C,-C4 烷基） 2、 相同或不同杂链单元， 并且上述烃基或含有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基或杂芳基取代； R3代表 H、 d-C6的烷氧羰基， 或直链、 支链、 或环状饱和或不饱和 CrC8的烃基， 或其中 所述烃基任选含有 1-2个选自 0、 S、 S02、 CO、 NH、 -NH- (CrC4烷基）、 -N- (C,-C4烷基） 2、 相同或不同杂链单元， 并且上述烃基或含有杂链单元的烃基可任选被卤素、 硝基、 氰基、 羟基、 具有 6-10个碳原子的芳基、 具有 6-10个碳原子的芳烷基、 杂芳基或式 -NRI2RI3所示 基团取代， 其中 Rl2和 Rl3相同或不同， 并分别代表氢、 苄基或 C C6的烷基； among them! ^Yes! "!, - a methoxycarbonyl group, or a linear, branched, or cyclic saturated or unsaturated dC 3 hydrocarbon group, or wherein the hydrocarbon group optionally contains 2 selected from 0, S, S0 2 , CO, NH, -NH-(C!-alkyl), -N-(C,-C 4 alkyl) 2 , the same or different hetero chain units, and the above hydrocarbon group or hydrocarbon group containing a hetero chain unit may optionally be halogen, Nitro, cyano, hydroxy, aryl having 6-10 carbon atoms, arylalkyl or heteroaryl having 6-10 carbon atoms; R 3 representing H, dC 6 alkoxycarbonyl, or straight a chain, a branched chain, or a cyclic saturated or unsaturated C r C 8 hydrocarbon group, or wherein the hydrocarbon group optionally contains 1-2 selected from the group consisting of 0, S, S0 2 , CO, NH, -NH- (C r C 4 alkyl), -N-(C,-C 4 alkyl) 2, the same or different hetero chain units, and the above hydrocarbon group or a hydrocarbon group containing a hetero chain unit may optionally be halogen, nitro, cyano, a hydroxy group, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 6 to 10 carbon atoms, a heteroaryl group or a group represented by the formula -NR I2 R I3 wherein R l2 and R l3 are the same or different And representing an alkyl group of hydrogen, benzyl or C C6 , respectively;
R代表 -X-Z, X代表 -CHr 、 -CHrCHr、 -CH2-CHrCHr或 (C=0)-; R represents -XZ, X represents -CH r , -CH r CH r , -CH 2 -CH r CH r or (C=0)-;
Z代表、
Figure imgf000059_0001
、 或 NR14RI5, 其中 Rl4和 R15相同或不同， 代表Z stands for,
Figure imgf000059_0001
, or NR 14 R I5 , where R l4 and R 15 are the same or different, represent
CRC4的烷基， 所述烷基任选地被羟基、 - 的烷氧羰基取代， 或 RI4,R15和 N原子键合成 一个杂环， 所述杂环为咪唑、 三唑、 四唑或下述通式 (111)所示的基团：
Figure imgf000059_0002
An alkyl group of C R C 4 , which is optionally substituted by a hydroxy group, an alkoxycarbonyl group, or a ring of R I4 , R 15 and N to form a hetero ring, which is an imidazole, a triazole, Tetrazole or a group represented by the following formula (111):
Figure imgf000059_0002
其中， B代表 ~<CH2)n-(n=0,l或 2)、 -CFr、 -CHF- 或 (C=0)-; Y 代表" CHr、 -CH2-CH2- 、 -0-、 -S -、 -SO-、 S02- 或 NR16 , 其中 Rl6代表氢、 -CO-CH3、 -CO-CF3、 -CO-0-R,7 或 -CO-NRl8Rl9， 其中 R17, R,8- Rl9相同或不同， 代表 H或 - C8的烷基； Wherein B represents ~<CH 2 ) n -(n=0, l or 2), -CF r , -CHF- or (C=0)-; Y represents "CH r , -CH 2 -CH 2 - , -0-, -S -, -SO-, S0 2 - or NR 16 , wherein R l6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , -CO-0-R, 7 or -CO-NR L8 R l9 , wherein R 17 , R, 8- R l9 are the same or different and represent an alkyl group of H or -C 8 ;
RM代表氡、 卤素、 氰基、 叠氮基、 氨基、 （：5-(：7的杂环、 -(：8的烷基、 C,-C8的烷氧基、 -Cs的烷硫基、 C CS的烷亚磺酰基、 CRC8的磺酰基、 d- 的酰基、 硝基、 三氟甲基、 或 -CO-N(R21)2. 其中 R2I是 H或 d-C8烷基; R M represents anthracene, halogen, cyano, azido, amino, (: 5 - (: 7 heterocyclic, - (: 8 alkyl, C, -C 8 alkoxy, -Cs alkyl sulfide) a C, an alkylsulfinyl group of C CS , a sulfonyl group of C R C 8 , an acyl group of d-, a nitro group, a trifluoromethyl group, or a -CO-N(R 21 ) 2 . wherein R 2I is H or dC 8 alkyl;
代表氢。  Represents hydrogen.
7. 如权利要求 2-6任意一项所述的化合物， 其特征在于， 化合物选自：  The compound according to any one of claims 2 to 6, wherein the compound is selected from the group consisting of:
乙基 4- ( 2-氯 -4-氟苯基） -2- ( 甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- ( 2-溴 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 - (2-溴 -4-氟苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -2- (卜甲基咪唑 -2-基） -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 甲基 4- (2-溴 -4-氟苯基） -2- (卜甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- ( 2-氯 -4-氟苯基） -2- ( 1-甲基咪唑 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基) -2- ( 1-甲基咪唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (嘧啶 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-氯 -4-氟苯基) -2- (嘧啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基） -2- (噻吩 -2-基） -6- (4-吗啉甲基） -1，4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基) -2- (噻吩 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -2- (噻吩 -2-基) -6- (4-吗啉甲基) -1，4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基） -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-chloro-4-fluorophenyl)-2-(methylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate Acid ester, ethyl 4-(2-bromo-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinyl)-1,4-dihydrogen Pyrimidine-5-carboxylate, methyl 4-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinyl)-1,4-di Hydropyrimidine-5-carboxylate, ethyl-(2-bromo-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1,4-di Hydropyrimidine-5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-2-(bmethylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4- Dihydropyrimidine-5-carboxylate methyl 4-(2-bromo-4-fluorophenyl)-2-(bmethylimidazol-2-yl)-6-(4-morpholinylmethyl)-1,4 -dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-2-(1-methylimidazol-2-yl)-6-(4-morpholinylmethyl -1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2,4-dichlorophenyl)-2-(1-methylimidazol-2-yl)-6- (4- Morpholine methyl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-2-(pyrimidin-2-yl)-6- (4- Morpholine methyl) -1,4-di Pyrimidine-5-carboxylate methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrimidin-2-yl)-1,4 -dihydropyrimidine-5-carboxylate, ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyrimidin-2-yl)-6-(4-morpholinylmethyl)-1, 4-dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)-1 , 4-dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)- 1,4-Dihydropyrimidine-5-carboxylate, ethyl 4-(2,4-dichlorophenyl)-2-(thiophen-2-yl)-6-(4-morpholinylmethyl)- 1,4-Dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4- Dihydropyrimidine-5-carboxylate,
乙基 4- (2-氯 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate,
乙基 4- (2,4-二氯苯基) -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- ( 2-溴 -4-氟苯基） -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4- (2-bromo-4-fluorophenyl)-2-phenyl-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-氯 -4-氟苯基) -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2-chloro-4-fluorophenyl)-2-phenyl-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2,4-二氯苯基) -2-苯基 -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基） -2- (萘 -2-基） -6- (4-吗啉甲基） -1，4-二氢嘧啶 -5-羧酸酯、 乙基 4- ( 2-氯 -4-氟苯基) -2- (萘 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (萘基 -6-基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- ( 2-氯 -4-氟苯基) -2- (萘 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (萘基 -6-基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (萘基 -6-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基) -2-甲基 -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯. Methyl 4-(2,4-dichlorophenyl)-2-phenyl-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate, Ethyl 4-(2-bromo-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate Ethyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylic acid Ester, ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4-dihydropyrimidine- 5-carboxylate, methyl 4- (2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl)-1,4 -dihydropyrimidine-5-carboxylate, methyl 4-(2-chloro-4-fluorophenyl)-2-(naphthalen-2-yl)-6-(4-morpholinylmethyl)-1, 4-dihydropyrimidine-5-carboxylate, methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl-6-yl) -1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(naphthyl) -6-yl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-2-methyl-6-(4-morpholinylmethyl ) -1,4-dihydropyrimidine-5-carboxylate.
8. 如权利要求 2-6任意一项所述的化合物， 其特征在于， 化合物选自：  The compound according to any one of claims 2 to 6, wherein the compound is selected from the group consisting of:
乙基 4- (2-溴 -4-氟苯基） -6- (4-吗啉甲基） -2- (呋喃 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基) -6- (吗啉 -4-基-甲基) -2- (呋喃 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (呋喃 -2-基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (吡咯垸基 -2-基） -1,4-二氢嘧啶 -5-羧酸 酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(4-morpholinomethyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5-carboxylate Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(furan-2-yl)-1,4-dihydropyrimidine-5 -carboxylate, ethyl 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(furan-2-yl)-1,4-dihydro Pyrimidine-5-carboxylate, ethyl 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrolidinyl-2-yl)- 1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-氯 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- (吡咯烷基 -2-基） -1,4-二氢嘧啶 -5-羧酸 酯、 Methyl 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(pyrrolidin-2-yl)-1,4-dihydropyrimidine- 5-carboxylate,
乙基 4- ( 2,4-二氯苯基 -6- (吗啉 -4-基 -甲基 -2- 吡咯烷基 -2-基 ) -1,4-二氢嘧啶 -5-羧酸酯、 4- (2-溴 -4-氟苯基） -6- (吗啉 -4-基-甲基） -2- ( 1,1-二氧噻嗪 -2-基） -1,4-二氢嘧啶 -5-甲酸乙 酯、 Ethyl 4-( 2,4-dichlorophenyl-6-(morpholin-4-yl-methyl-2-pyrrolidin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid Ester, 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(1,1-dioxythiazin-2-yl)-1,4 -dihydropyrimidine-5-carboxylic acid ethyl ester,
4- ( 2-氯 -4-氟苯基 -6- 吗啉 -4-基-甲基） -2- ( 4H- ( 1,卜二氧 ) -1，4-噻嗪 -2-基 ) -1，4-二氢嘧 啶 -5-甲酸乙酯、  4-(2-Chloro-4-fluorophenyl-6-morpholin-4-yl-methyl)-2-(4H-(1,dioxy)-1,4-thiazin-2-yl) -1,4-dihydropyrimidine-5-carboxylic acid ethyl ester,
4- (2,4-二氯苯基) -6- (吗啉 -4-基-甲基) -2- (4H- ( 1,卜二氧) -1,4-噻嗪 -2-基) -1,4-二氢嘧 啶 -5-甲酸甲酯、  4-(2,4-Dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(4H-(1,dioxy)-1,4-thiazin-2-yl -1,4-dihydropyrimidine-5-carboxylic acid methyl ester,
4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (6H-1,2-噻嗪 -3-基） -1,4-二氢嘧啶 -5-甲酸甲酯、 4- ( 2-溴 -4-氟苯基 ) -6- (吗啉 -4-基 -甲基 ) -2- ( 6H-1,2-噻嗪 -3-基 ) -1,4-二氢嘧啶 -5-甲鲛甲酯、 4- ( 2-氯 -4-氟苯基 ) -6- (吗啉 -4-基-甲基） -2- ( 6H-1,2-噻嗪 -3-基 ) -1,4-二氢嘧啶 -5-甲酸甲酯、 4- (2,4-二氯苯基） -6- (吗啉 -4-基-甲基） -2- (6H-1，2-噻嗪 -3-基） -1,4-二氢嘧啶 -5-甲酸乙酯、 4- ( 2-氯 -4-氟苯基 ) -6- (吗啉 -4-基-甲基） -2- (6H-1,2-噻嗪 -3-基 ) -1,4-二氢嘧啶 -5-甲酸乙酯、 4- ( 2-溴 -4-氟苯基 ) -6- (吗啉 -4-基-甲基） -2- ( 6H-1,2-噻嗪 -3-基 ) -1,4-二氢嘧啶 -5-甲酸乙酯、 N- ( 4-氟苯基） -4- ( 2-溴 -4-氟苯基 -6- (吗啉 -4-基甲基） -2- (吡嗪 -2-基 -1,4-二氢嘧啶 -5- 甲酰氨、  4-(2,4-Dichlorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4-dihydro Methyl pyrimidine-5-carboxylate, 4-(2-bromo-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3- -1,4-dihydropyrimidine-5-methylammonium methyl ester, 4-(2-chloro-4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H -1,2-thiazin-3-yl)-1,4-dihydropyrimidine-5-carboxylic acid methyl ester, 4-(2,4-dichlorophenyl)-6-(morpholin-4-yl- Methyl)-2-(6H-1,2-thiazin-3-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2-chloro-4-fluorophenyl)-6 - (morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, 4-(2-bromo 4-fluorophenyl)-6-(morpholin-4-yl-methyl)-2-(6H-1,2-thiazin-3-yl)-1,4-dihydropyrimidine-5-carboxylic acid Ethyl ester, N-(4-fluorophenyl)-4-(2-bromo-4-fluorophenyl-6-(morpholin-4-ylmethyl)-2-(pyrazin-2-yl-1 , 4-dihydropyrimidine-5-formylamide,
4- ( 2-溴 -4-氟苯基 -6- 吗啉 -4-基甲基 ) -N- ((哌啶 -4-基 ) 甲基） -2- (吡嗪 -2-基 -1,4-二 氢嘧啶 -5-甲酰氨。  4-(2-Bromo-4-fluorophenyl-6-morpholin-4-ylmethyl)-N-((piperidin-4-yl)methyl)-2-(pyrazin-2-yl- 1,4-Dihydropyrimidine-5-formylamide.
9. 如权利要求 1所述的化合物， 其特征在于，  9. The compound of claim 1 wherein:
R,代表未取代吡啶基， 或噻唑基； R, representing an unsubstituted pyridyl group, or a thiazolyl group;
R2代表 έ素取代的苯基； R 2 represents a halogen substituted phenyl group;
Α代表 -0- ； Α stands for -0- ;
R3代表- CH3 , -CH2-CH3, -CF3; R 3 represents -CH 3 , -CH2-CH3, -CF 3 ;
R代表式 -X-Z, X代表 -CHr 、 -CH2-CHr、 Z通式 (III)所示的基团：
Figure imgf000060_0001
R represents a formula -XZ, and X represents a group represented by -CH r , -CH 2 -CH r , and Z formula (III):
Figure imgf000060_0001
其中' B代表 -CH2 -或 -(C=0)-; Y 代表 -0-、 -NR16-, 其中 R，6代表氢、 -CO-CH3、 -CO-CF3、 或 -CO-NRl8Rl9, 其中 Rl8, Rl9可以相同或不同， 代表 11或 d- 的烷基； R20代表氢、 卤素； Wherein 'B represents -CH 2 - or -(C=0)-; Y represents -0-, -NR 16 -, wherein R, 6 represents hydrogen, -CO-CH 3 , -CO-CF 3 , or -CO -NR l8 R l9 , wherein R l8 , R l9 may be the same or different and represent an alkyl group of 11 or d-; R 20 represents hydrogen, halogen;
R 代表氢； R represents hydrogen;
其中， 上述定义的化合物中不包含以下所述化合物： Wherein, the compound defined above does not include the following compounds:
乙基 - (2-溴 -4-氟苯基） -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基） -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) -6-(4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate, Methyl 4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate , ethyl 4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylic acid Ester,
甲基 4-(2-氯 -4-氟苯基 ）-2- (噻唑 -2-基) -6-(4-吗啉甲基) -1, 4-二氢嘧啶 -5-羧酸酯、 乙基 4-(2，4-二氯苯基 ）-2- (噻唑 -2-基) -6-(4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate , ethyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate ,
甲基 4-(2,4-二氯苯基 ）-2- (噻唑 -2-基) -6-(4-吗啉甲基) -1，4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate,
甲基 4-(2-氯 -4-氟苯基 ）-2- (吡啶 -2-基） -6-(4-吗啉甲基) -1, 4-二氢嘧啶 -5-羧酸酯、 甲基 4-(2-氯 -4-氟苯基 )-2- (吡啶 -2-基) -6- (哌嗪小基甲基） -1, 4-二氢嘧啶 -5-羧酸酯。 Methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate , methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-(piperazinylmethyl)-1,4-dihydropyrimidine-5-carboxylic acid ester.
10 . 根据权利要求 9所述的化合物， 其特征在于， 所述化合物选自：  The compound according to claim 9, wherein the compound is selected from the group consisting of:
乙基 4- (2-溴 -4-氟苯基) -6- (3-氧 -哌嗪小基-甲基） -2- (噻唑 -2-基) -1,4-二氢嘧啶 -5-羧酸 酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-(3-oxo-piperazine-based-methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine- 5-carboxylate,
乙基 4- (2-溴 -4-氟苯基） -6- ((4- (2, 2, 2-三氟乙酰基） 哌嗪-卜基） 甲基） -2- (噻唑 -2- 基） -1,4-二氤嘧啶 -5-羧酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazine-bu)methyl)-2-(thiazole-2 -yl)-1,4-dipyrimidine-5-carboxylate,
甲基 4- (2-氯苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯 、 乙基 4- (2-氯苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 、 乙基 4- (2-溴苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2-chlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4 - (2-Chlorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate, methyl 4-(2 -bromophenyl)-2-(thiazol-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylate, ethyl 4-(2-bromobenzene Benzyl-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate,
2,2,2-三氟乙基- 4- (2-溴 -4-氟苯基) -2- (噻唑 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧 酸酯 、  2,2,2-Trifluoroethyl-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-6-(4-morpholinylmethyl)-1,4- Dihydropyrimidine-5-carboxylate,
乙基 6- ((4- (二甲基氨基甲酰基） 哌嗪- 基） -4- (2-溴 -4-氟苯基) -2- (噻唑 -2 基） -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 6-((4-(dimethylcarbamoyl)piperazine-yl)-4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-di Hydropyrimidine-5-carboxylate,
乙基 6- ((4- (二乙基氨基甲酰基) 哌嗪小基） -4- (2-溴 -4-氟苯基) -2- (噻唑 -2 基） -1,4- 二氢嘧啶 -5-羧酸酯、 Ethyl 6-((4-(diethylcarbamoyl)piperazine) -4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4- Hydropyrimidine-5-carboxylate,
乙基 4- (2-溴 -4-氟苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基） -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基） -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2-氯 -4-氟苯基） -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯、 乙基 4- (2,4-二氯苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基） -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2-溴 -4-氟苯基) -2- (吡啶 -2-基) -6- (4-吗啉甲基) -1,4-二氢嘧啶 -5-羧酸酯 甲基 4- (2-氯 -4-氟苯基) -2- (吡啶 -2-基) -6-哌嗪甲基 -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate , methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinomethyl)-1,4-dihydropyrimidine-5-carboxylic acid Ester, methyl 4-(2,4-dichlorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylic acid Ester, ethyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate Ethyl ester, ethyl 4-(2,4-dichlorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5-carboxylate Acid ester, methyl 4-(2-bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-(4-morpholinylmethyl)-1,4-dihydropyrimidine-5- Carboxylic acid methyl 4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-6-piperazinylmethyl-1,4-dihydropyrimidine-5-carboxylate,
4- (2,4-二氯苯基) -6- (哌嗪 -卜基甲基） -2- (吡啶 -2-基） -1,4-二氢嘧啶 -5-甲酸乙酯、 乙基 4- (2-溴 -4-氟苯基） -2- (吡啶 -2-基) -6-哌嗪甲基 -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- ( 2-氯 -4-氟苯基） -6- ((4- (2， 2, 2-三氟乙酰基） 哌嗪小基） 甲基） -2- (噻唑 -2- 基） -1,4-二氢嘧啶 -5-羧酸酯、  4-(2,4-Dichlorophenyl)-6-(piperazin-buylmethyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester, B 4-(2-Bromo-4-fluorophenyl)-2-(pyridin-2-yl)-6-piperazinylmethyl-1,4-dihydropyrimidine-5-carboxylate, methyl 4- (2-Chloro-4-fluorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazinyl)methyl)-2-(thiazol-2-yl)-1 , 4-dihydropyrimidine-5-carboxylate,
乙基 4- (2,4-二氯苯基） -6- ((4- (2, 2, 2-三氟乙酰基） 哌嗪-卜基） 甲基） -2- (噻唑 -2- 基） -1,4-二氢嘧啶 -5-羧酸酯、 Ethyl 4-(2,4-dichlorophenyl)-6-((4-(2, 2, 2-trifluoroacetyl)piperazin-bu)methyl)-2-(thiazole-2- -1,4-dihydropyrimidine-5-carboxylate,
甲基 4- (2-溴 -4-氟苯基） -6- ((4-乙酰基) 哌嗪小基） 甲基） -2- (噻唑 -2-基） -1,4-二氢嘧啶 -5-羧酸酯、 Methyl 4-(2-bromo-4-fluorophenyl)-6-((4-acetyl)piperazine small)methyl)-2-(thiazol-2-yl)-1,4-dihydro Pyrimidine -5-carboxylate,
甲基 4- ( 2-氯苯基 ) -6- (( 2-甲基吗啉 -4-基 )甲基） -2- (噻唑 -2-基 ) -1,4-二氢嘧啶 -5-羧酸酯、 甲基 4- (2,4-二氯苯基) -6- ((3-甲基吗啉 -4-基) 甲基） -2- (噻唑 -2-基) -1，4-二氢嘧啶 -5- 羧酸酯。 Methyl 4-(2-chlorophenyl)-6-((2-methylmorpholin-4-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5 -carboxylate, methyl 4-(2,4-dichlorophenyl)-6-((3-methylmorpholin-4-yl)methyl)-2-(thiazol-2-yl)-1 , 4-dihydropyrimidine-5-carboxylate.
11. 制备权利要求 1-10所述任意一项化合物的方法， 其特征在于， 包括如下步骤： A. 首先将甲醛类化合物 （IV) 与通式 （V)所示的 (3-嗣酯在加入或不加入碱或酸， 在惰性 有机溶剂存在下进行反应转化成通式 （VI) 所示的化合物：  11. Process for the preparation of a compound according to any one of claims 1 to 10, characterized in that it comprises the following steps: A. First, the formaldehyde compound (IV) and the (3-oxime ester) of the formula (V) are The reaction is converted to the compound of the formula (VI) by adding or not adding a base or an acid in the presence of an inert organic solvent:
R2-CHO IV R 2 -CHO IV
Figure imgf000062_0001
Figure imgf000062_0001
其中 R2 、 R3、 和 R的含义如前所述； Wherein R 2 , R 3 , and R have the same meanings as defined above;
然后， 将后者与通式 （VII) 所示的脒或者其盐 在加入或不加入碱或酸， 在惰性有机溶剂 的情况下， 进行反应：
Figure imgf000062_0002
Then, the latter is reacted with hydrazine or a salt thereof of the formula (VII) with or without the addition of a base or an acid in the presence of an inert organic solvent:
Figure imgf000062_0002
其中 R,、 含义如前所述， 或 Where R, meaning has the same as before, or
B. 将通式 （V) 所示化合物同 （IV)和脒 （VII) 或它们的盐在加入或不加入碱或酸， 在惰性有机溶剂的情况下， 进行一步反应； 或  B. The compound of the formula (V) is reacted with (IV) and ruthenium (VII) or their salts in a one-step reaction with or without the addition of a base or an acid in an inert organic solvent; or
C. 当通式 （I) 或 （la) 中的 R是 -X-Z的形式， 将通式 （VIII) 或 （Villa) 所示化合物  C. When R in the formula (I) or (la) is in the form of -X-Z, the compound of the formula (VIII) or (Villa)
Figure imgf000062_0003
(Villa) 其中 R,、 R2、 R3 、 、 X和 Z 含义如前所述， W 是亲核取代基团， 诸如氯化物， 溴化 物， 碘化物， 甲磺酰氧基或甲苯磺酰氧基， 与通式 （IX) 或 （111) 所示化合物
Figure imgf000062_0003
(Villa) wherein R, R 2 , R 3 , X and Z have the same meanings as defined above, and W is a nucleophilic substituent such as chloride, bromide, iodide, methanesulfonyloxy or toluenesulfonyl Oxy group, with a compound of the formula (IX) or (111)
R20"^ R 20"^
NR14R|5 ( IX) Y' (111) NR 14 R|5 ( IX) Y' (111)
其中 Rl4、 Rl5、 R2。含义如前所述， 在加入或不加入碱， 在惰性溶剂的条件下进行反应， D. 将通式 （IV) 所示的醛与通式 （XII) 所示的化合物， 以及通式 （VII) 所示的脒在加 碱或不加碱的条件下进行反应， 在惰性溶剂中进行反应， Where R l4 , R l5 , R 2 . The meaning is as described above, the reaction is carried out in the presence of an inert solvent with or without the addition of a base, D. The aldehyde represented by the formula (IV) and the compound of the formula (XII), and the formula (VII) The hydrazine shown is reacted with or without a base, and the reaction is carried out in an inert solvent.
0  0
R3-A-C-C=C-R R 3 -ACC=CR
H H
NH2 (XII) 其中 R3和 R含义如前所述。 NH 2 (XII) Wherein R 3 and R have the same meanings as described above.
12、 权利要求 1-10任意一项所述的的化合物用于控制疾病。  12. A compound according to any one of claims 1 to 10 for use in the control of a disease.
13、 一种药物组合物， 所述药物组合物含有至少一种权利要求 1-10所述化合物， 且其 进一步含有一种或多种其它活性药物组分。  13. A pharmaceutical composition comprising at least one compound of claims 1-10, further comprising one or more additional active pharmaceutical ingredients.
14、 一种由下列组分组成的组合物：  14. A composition consisting of the following components:
A) 至少一种如权利要求 1-10任意一项所述的化合物，  A) at least one compound according to any one of claims 1-10,
B) 至少一种不同于 A的 HBV 抗病毒剂， 和适当情况下，  B) at least one HBV antiviral agent different from A, and where appropriate,
C) 至少一种免疫调节剂或一种干扰素。  C) at least one immunomodulator or an interferon.
15、 根据权利要求 14所述的组合物， 其特征在于， 组分 B 是 HBV聚合酶抑制剂， 恩 替卡韦， 阿德福韦酯， 拉米夫定或下述通式所示的化合物及其盐  The composition according to claim 14, wherein component B is an HBV polymerase inhibitor, entecavir, adefovir dipivoxil, lamivudine or a compound represented by the following formula:
Figure imgf000063_0001
Figure imgf000063_0001
其中， 和 R2, 分别独立地为， - 的烷基或者， 与其所在位置上的氮原子一起， 形成具有 5-6个环原子包括碳和 /或氧原子的环， R3至 1 |2分别独立地为氢、 卤素， （^-^的 垸基、 任意取代的 d- 烷氧基、 硝基、 氰基或三氟甲基。 Wherein, and R 2 , independently of the alkyl group of - or together with the nitrogen atom at the position thereof, form a ring having 5 to 6 ring atoms including carbon and/or oxygen atoms, R 3 to 1 |2 Each independently is hydrogen, halogen, fluorenyl, optionally substituted d-alkoxy, nitro, cyano or trifluoromethyl.
16、 根据权利要求 15所述的组合物， 其特征在于， 所述化合物具有如下结构：  The composition according to claim 15, wherein the compound has the following structure:
Figure imgf000063_0002
Figure imgf000063_0002
17. 一种药物组合物， 包含至少一种权利要求 1-10任意一项所述的化合物， 或权利要 求 11-14任意一项所述的药物组合物， 适当时包含一种或多种其他活性物质.  A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 10, or a pharmaceutical composition according to any one of claims 11 to 14, optionally comprising one or more other Active substance.
18. 根据权利要求 1-10任意一项所述的化合物或权利要求 13-17任意一项所述的组合物 在制备治疗和预防病毒性疾病的药物中的应用。  Use of a compound according to any one of claims 1 to 10 or a composition according to any one of claims 13 to 17 for the preparation of a medicament for the treatment and prevention of a viral disease.
19. 根据权利要求 1-10任意一项所述的化合物或权利要求 13-17任意一项所述的组合物 在制备治疗和预防病乙型肝炎感染的药物中的应用。  19. Use of a compound according to any one of claims 1 to 10 or a composition according to any one of claims 13 to 17 for the manufacture of a medicament for the treatment and prevention of hepatitis B infection.
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