CN109803967B - Dihydropyrimidine compound and preparation method and application thereof - Google Patents

Dihydropyrimidine compound and preparation method and application thereof Download PDF

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CN109803967B
CN109803967B CN201780053025.XA CN201780053025A CN109803967B CN 109803967 B CN109803967 B CN 109803967B CN 201780053025 A CN201780053025 A CN 201780053025A CN 109803967 B CN109803967 B CN 109803967B
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methyl
fluorophenyl
azaspiro
chloro
carboxylic acid
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CN109803967A (en
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季明哲
白骅
刘礼飞
龚永祥
李译
曹启雄
邓永先
柴健
骆红英
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Zhejiang Hisun Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Abstract

The invention provides a dihydropyrimidine compound shown as formula (I) or a pharmaceutically acceptable salt, a tautomer, an enantiomer or a diastereoisomer thereof, wherein R is1、R2、R3R and A are as defined in the description and claims. The invention also provides a preparation method of the compound shown in the formula (I) and application of the compound in medicines for treating or preventing diseases infected by hepatitis B virus.

Description

Dihydropyrimidine compound and preparation method and application thereof
Technical Field
The invention relates to a dihydropyrimidine compound and application thereof as a medicament. The compounds have the functions of treating and preventing hepatitis B, are particularly used as Hepatitis B Virus (HBV) inhibitors and treat HBV infection by targeting HBV capsid. The invention also relates to a preparation method of the compound.
Background
Hepatitis B is a disease caused by Hepatitis B Virus (HBV), mainly characterized by hepatitis virus infection, and can cause multiple organ damage. Hepatitis B virus, hepatitis B virus for short, is a DNA virus, and belongs to the hepadnavirus family (hepadnavirus). It can cause acute or persistent/progressive chronic diseases. Hepatitis B is prevalent in countries around the world, with over 4 hundred million people suffering from it, particularly in the Asia-Pacific region. A small number of these patients can be converted to cirrhosis or liver cancer. The anti-hepatitis B virus nucleoside (acid) drugs on the market at present comprise lamivudine, telbivudine, entecavir, tenofovir disoproxil, krafft and the like. The disadvantages of this class of drugs are: the treatment course is not fixed, the drug resistance of the virus is easy to occur, and the disease is easy to recur after the drug is stopped. These disadvantages result in patients not being treated radically.
Deres et al reported heteroaromatic substituted dihydropyrimidine (HAP) compounds represented by Bay41-4109, Bay3905493, which act to inhibit HBV replication by preventing normal nucleocapsid formation. Bay41-4109 showed better drug metabolism parameters in clinical studies (Deres K. et al, Science 299(2003), 893-896). The study on the action mechanism shows that the dihydropyrimidine compound substituted by the heteroaromatic ring changes the included angle between dimers forming the nucleocapsid through the action with the 113-143 amino acid residues of the core protein, so that unstable expanded nucleocapsid is formed, and the degradation of the core protein is accelerated (biochem. Pharmacol.66(2003), 2273-2279).
There is still a need for new compounds that are effective against viruses, in particular for use as medicaments for the treatment and/or prevention of hepatitis b.
Disclosure of Invention
The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt or tautomer or enantiomer or diastereomer thereof:
Figure BDA0001980362320000021
wherein:
R1is phenyl, wherein said phenyl is optionally further substituted by one or more groups selected from halogen, C1-6Alkyl is substituted by a substituent;
R2selected from hydrogen or C1-4An alkyl group;
a is a bond, -O-, -S-or-N (R)5)-；
R5Is hydrogen or C1-4An alkyl group;
R3selected from heteroaryl, preferably thiazolyl, oxazolyl, imidazolyl, thienyl, phenyl or pyridyl, which heteroaryl may be further substituted with one or more groups selected from halogen, methylene (═ CH)2) Oxo (═ O), alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, mercapto, amino, aryl, haloalkyl, alkylsulfonyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halogen-substituted aryl or trifluoromethanesulfonylSubstituted with a substituent of the group;
r is a group shown as follows:
Figure BDA0001980362320000022
R6each independently is- (CR)7R7a)m-OH、-(CR7R7a)n-C(＝O)O-R8、-(CR7R7a)n-C(＝O)-NH-S(O)2-R9、-(CR7R7a)n-C(O)-NR10R10a、-(CR7R7a)n-C(＝O)O-(CR7R7a)n-OC(＝O)O-R8、-S(＝O)pOR8、-(CR7R7a)n-S(＝O)pN(R8)2、-(CR7R7a)n-C(＝O)O-(CR7R7a)n-OC(＝O)-R8、-(CR7R7a)n-C(＝O)O-(CR7R7a)n-C(＝O)O-R8、-(CR7R7a)n-N(R8)2Or is- (CR)7R7a)n-C(＝O)N(R8)2；
R7And R7aEach independently hydrogen, halogen, alkyl or haloalkyl, wherein said alkyl, haloalkyl is optionally further substituted with one or more substituents selected from halogen, methylene (═ CH)2) Oxo (═ O), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, mercapto, amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halo-substituted aryl or trifluoromethanesulfonyl, or R7And R7aAnd the carbon atom to which they are attached, form a cycloalkyl group or a heterocyclic group;
R8each independently is hydrogen, hydroxy, alkylAlkoxy, alkyl-S (═ O)p-, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heterocyclyl-S (═ O)p-, heteroaryl-S (═ O)p-, cycloalkyl-S (═ O)p-or aryl-S (═ O)p-, where said alkyl, alkoxy, alkyl-S (═ O)p-, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heterocyclyl-S (═ O)p-, heteroaryl-S (═ O)p-, cycloalkyl-S (═ O)p-or aryl-S (═ O)p-optionally further substituted by one or more groups selected from halogen, methylene (═ CH)2) Oxo (═ O), alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, mercapto, amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halo-substituted aryl, or trifluoromethanesulfonyl;
R9is alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl or arylalkyl;
R10and R10aEach independently hydrogen, haloalkyl, cycloalkyl, alkyl or hydroxyalkyl, or R10And R10aAnd the nitrogen atom to which they are attached form a heterocyclic group;
each m is independently 1, 2, 3, 4;
n is each independently 0, 1, 2, 3, 4;
each p is independently 1 or 2.
In one embodiment of the present invention, R is preferably a sub-structural formula shown below:
Figure BDA0001980362320000041
in one embodiment of the invention, R is preferably selected from:
Figure BDA0001980362320000042
in one embodiment of the invention, R1Preferably from phenyl, said phenyl being optionally further substituted by one or more halogens.
In another embodiment of the invention, R2Preferably methyl or ethyl.
In another embodiment of the present invention, A is preferably-O-.
In another embodiment of the invention, R3Preferably thiazolyl, imidazolyl or pyridyl, wherein said thiazolyl, imidazolyl or pyridyl is optionally further substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, alkylsulfonyl, cycloalkyl.
In another embodiment of the invention, R1Preferably 2 halogen-substituted phenyl; r is2Preferably methyl or ethyl; a is preferably-O-; r3Preferably thiazolyl, imidazolyl or pyridyl, wherein said thiazolyl, imidazolyl or pyridyl is optionally further substituted by one or more groups selected from halogen, methylene (═ CH)2) Oxo (═ O), alkyl, alkoxy, cyano, hydroxyl, nitro, alkylamino, mercapto, amino, aryl, haloalkyl, alkylsulfonyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halo-substituted aryl or trifluoromethanesulfonyl; r is preferably a group shown below:
Figure BDA0001980362320000051
R6each independently is- (CR)7R7a)n-C(＝O)O-R8、-(CR7R7a)n-C(＝O)O-(CR7R7a)n-OC(＝O)-R8Or- (CR)7R7a)n-C(＝O)O-(CR7R7a)n-C(＝O)O-R8；
R7And R7aEach independently hydrogen, halogen, alkyl or haloalkyl, wherein said alkyl, haloalkyl is optionally further substituted with one or more substituents selected from halogen, methylene (═ CH)2) Oxo (═ O), alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, mercapto, amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halo-substituted aryl, or trifluoromethanesulfonyl, or R7And R7aAnd the carbon atom to which they are attached, form a cycloalkyl group or a heterocyclic group;
R8each independently is hydrogen, hydroxy, alkyl, alkoxy, alkyl-S (═ O)p-, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heterocyclyl-S (═ O)p-, heteroaryl-S (═ O)p-, cycloalkyl-S (═ O)p-or aryl-S (═ O)p-, where said alkyl, alkoxy, alkyl-S (═ O)p-, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heterocyclyl-S (═ O)p-, heteroaryl-S (═ O)p-, cycloalkyl-S (═ O)p-or aryl-S (═ O)p-optionally further substituted with one or more substituents selected from halogen, methylene (═ CH)2) Oxo (═ O), alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, mercapto, amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halo-substituted aryl, or trifluoromethanesulfonyl;
n is each independently 0, 1, 2, 3, 4, preferably 0;
each p is independently 1 or 2.
More preferably, the compounds of formula (I) according to the invention are selected from:
Figure BDA0001980362320000071
Figure BDA0001980362320000081
Figure BDA0001980362320000091
Figure BDA0001980362320000101
(1)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(2) (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(3)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (morpholine-4-carbonyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(4) (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(5)4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(6)4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- ((S) -5-azaspiro [2.4] heptane-6-carboxylic acid) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(7)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester;
(8)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester;
(9)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(10) (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(11) (S) -5- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(12) (R) -methyl-4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(13) (1R, 3S, 5R) -2- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid;
(14) (1R, 3S, 5R) -2- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid;
(15) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(16) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((1R, 3S, 5R) -3- ((methylsulfonyl) carbamoyl) -2-azabicyclo [3.1.0] hex-2-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(17) (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (1-methyl-1H-imidazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(18) (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(19) (1S, 2S, 5R) -3- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid;
(20) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (hydroxymethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(21) (R) -methyl-4- (2-bromo-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(22) (S) -5- (((R) -6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(23) (1S, 2S, 5R) -3- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid;
(24) (R) -methyl-4- (2-chloro-4-fluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(25) (R) -methyl-4- (2-bromo-4-fluorophenyl) -2- (4-methylthiazol-2-yl) -6- (((S) -6- ((phenylsulfonyl) carbamoyl) -5-azaspiro [2.4] hept-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(26) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (methylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(27) (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- (dimethylaminomethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(28) (S) -5- (((R) -6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(29) (S) - ((isopropoxycarbonyl) oxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester;
(30) (S) - (pivaloyloxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or tautomer or enantiomer or diastereomer thereof.
In a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or tautomer or enantiomer or diastereomer thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases associated with hepatitis b virus infection.
In yet another aspect of the invention, there is provided a process for the preparation of a compound of formula (I). The method comprises the following steps: reacting a compound represented by formula d with an R-H compound or a salt thereof in the presence of a base to obtain a compound represented by formula (I):
Figure BDA0001980362320000141
wherein R is1、R2、R3R and A are as defined above; wherein the base is preferably an organic base, more preferably triethylamine.
Wherein the compound of formula d is prepared by a process comprising:
step (1): reacting the compound shown in the formula a with the compound shown in the formula b to obtain a compound shown in the formula c:
Figure BDA0001980362320000142
step (2): reacting the compound shown in the formula c with a brominating reagent to obtain a compound shown in a formula d:
Figure BDA0001980362320000151
wherein R is1、R2、R3R and A are as defined above; the brominating reagent in the step (2) is preferably N-bromosuccinimide.
Reference will now be made in detail to certain embodiments of the present invention, which are intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. Where one or more of the incorporated documents, patents, and similar materials are different from or contradictory to the present application (including but not limited to defined terms, term applications, described techniques, and the like), the present invention shall control.
The terms used in the present invention have meanings generally accepted in the art, unless otherwise defined, and further, some of the terms used in the present invention are defined as follows:
the term "comprising" is open-ended, i.e. comprising what is meant by the invention, but not excluding other aspects.
The term "patient" as used herein may include humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group. The alkyl group in this application is preferably C1-6Alkyl, meaning a saturated straight or branched alkyl group comprising from 1 to 6 carbon atoms; particularly preferred alkyl groups in this application are C1-4Alkyl, i.e., saturated straight or branched chain alkyl of 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl, and the like.
"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined above. Preferred alkoxy is C1-6Alkoxy, particularly preferred alkoxy is C1-4An alkoxy group. Term C1-6Alkoxy includes methoxy, ethoxy, n-methoxyPropoxy and isopropoxy, and the like.
The term "cycloalkyl" denotes a saturated carbocyclic ring containing 3 to 12 carbon atoms, in particular 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. In particular, "cycloalkyl" is cyclopropyl, cyclopentyl, cyclohexyl.
"haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms. Preferred alkyl or alkoxy groups are as defined above. Examples include, but are not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxysilyl.
"cycloalkylalkyl" means an alkyl group substituted with one or more cycloalkyl groups. Examples include, but are not limited to: cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and the like.
"aryl" means a monocyclic, bicyclic, and tricyclic carbon ring system containing 6 to 14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6 to 10 or 6 to 7 ring atoms.
"heteroaryl" means monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl and quinolyl. Preferably, the heteroaryl group is a ring system of 5 to 10 ring atoms.
"heteroarylalkyl" means that the heteroaryl group is attached to the rest of the molecule through an alkyl group. Examples include, but are not limited to: pyridine-2-ethyl, thiazole-2-methyl, pyrimidine-2-propyl, and the like.
The term "amino" refers to a primary (-NH)2) Secondary (-NH-) or tertiary amino
Figure BDA0001980362320000161
The term "carboxyl" refers to the group-COOH.
The term "halogen" refers to fluorine, chlorine, bromine and iodine. In particular, halogen means fluorine, chlorine or bromine.
The term "cyano" refers to the group-CN.
The term "hydroxy" refers to the group-OH.
The term "sulfonyl" refers to the group-S (O)2-。
The term "carbonyl" refers to the group-C (═ O) -.
The term "C1-6Alkoxycarbonyl "means a radical C1-6alkoxy-C (O) -, wherein "C" is1-6Alkoxy "is as defined above.
The term "aminocarbonyl" refers to the group amino-c (o) -, wherein the "amino" is as defined above.
The term "C1-6Alkylsulfonyl "means a group C1-6alkyl-S (O)2-, wherein said "C" is1-6Alkyl "is as defined above.
The term "aminosulfonyl" refers to the group amino-S (O)2-, wherein said "amino" is as defined above.
The term "heterocyclyl" refers to a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic or tricyclic ring system comprising 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Wherein said heterocyclyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. Preferably, the heterocyclyl is a 3-10, 3-6 ring member, non-aromatic saturated or partially unsaturated monoA cyclic, bicyclic or tricyclic ring system wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
The term "hydroxyalkyl" means that the hydroxyalkyl group is attached to the rest of the molecule through a carbon atom, wherein the alkyl group is as defined above. The hydroxyalkyl group preferably includes a straight or branched alkyl group having 1 to 10 carbon atoms and substituted with one or more hydroxyl groups. More preferred hydroxyalkyl groups are lower hydroxyalkyl groups having 1 to 6 carbon atoms or 1 to 4 carbon atoms and one or more hydroxyl groups, e.g., hydroxymethyl (-CH)2OH), hydroxyethyl (-CH)2CH2OH) and hydroxypropyl (-CH)2CH2CH2OH), and the like.
The term "tautomer" refers to structural isomers of organic compounds that are readily interconverted by a chemical reaction called tautomerization. This reaction usually results in a formal migration of hydrogen atoms or protons with a shift of single and adjacent double bonds, for example compounds of the general formula (I)
Figure BDA0001980362320000181
And tautomers thereof
Figure BDA0001980362320000182
The term "chiral" refers to a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
The term "enantiomer" refers to two isomers of a compound that are not superimposable but in mirror image relationship to each other.
The term "diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers typically have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, as described aboveCompounds of the general formula (xxxvi), specific compounds of the invention, or specific examples, subclasses, as in the examples, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When it is not known in a given formula that a position can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, either identically or differently. Wherein the substituents may be, but are not limited to: fluorine, chlorine, bromine, iodine, oxo (═ O), methylene (═ CH)2) Alkyl, alkoxy, cyano, hydroxy, nitro, alkylamino, mercapto, amino, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, trifluoromethyl, trifluoromethoxy, haloalkyl-substituted aryl, halo-substituted aryl, or trifluoromethanesulfonyl, and the like.
Furthermore, the term "pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and which are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by formula (I) may be formed with suitable acids including inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Particularly preferred is hydrochloric acid, phosphoric acid or sulfuric acid.
Detailed Description
The following reactions are generally operated under a positive pressure of nitrogen. The reaction flask is plugged with a suitable rubber plug, and the substrate can be injected by a syringe. Glassware was dried. The column chromatography is performed using a silica gel column. NMR data were determined by Bruker Advance 400 NMR spectrometer, in CDCl3,d6-DMSO or CD3OD is the solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standards. When multiple peaks occur, the following abbreviations are used: s (singlets, singlet), s, s (singlets, singlet), d (doublets ), t (triplets, triplets), br (broadbanding, broad), dd (doublets of doublets, quartets), ddd (doublets of doublets), ddt (doublets of doublets, doublets), ddd (doublets of doublets, doublets), td (triplets of doublets, triplets), brs (broadbanding singlets, broad singlet). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectrometry (MS) data were determined by Agilent 1100 series LC-MS spectrometer. The ESI source was applied to an LC-MS spectrometer.
The purity of the compounds was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm on a Zorbax SB-C18 column, 2.1X30mm,4 μm,10 min, flow rate 0.6ml/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
DCM or CH2Cl2Methylene dichloride
EtOAc or EA ethyl acetate
THF tetrahydrofuran
CH3OH or MeOH methanol
d6-DMSO deuterated dimethyl sulfoxide
CDCl3Deuterated chloroform
CCl4Carbon tetrachloride
Boc tert-butyloxycarbonyl group
PE Petroleum Ether
K2CO3Potassium carbonate
NaHCO3Sodium bicarbonate
Na2SO4Sodium sulfate
KOAc potassium acetate
DIPEA N, N-diisopropyl ethyl
Amines as pesticides
NBS N-bromosuccinimide
c concentration
g
v/v or v: v volume ratio
mol mole of
mmol millimole
mL of
L liter
h hours
t1/2Half life
AUC area under the time curve
Vss steady state apparent distribution capacitance
Product of large quantities
CL or clean clearance
Bioavailability of F, absolute bioavailalability
Dose of Dose
TmaxTime to peak
CmaxMaximum concentration
hr, ng/mL plasma concentration, time
The starting materials and reagents of the present invention are commercially available from Aldrich Chemical Company, Alfa Chemical Company, the national drug agency, Lin' an Qingshan Chemical reagent works, Jiangsu Huada Chemical group and Hangzhou Chemical reagent Co., Ltd. Unless otherwise indicated, commercial starting materials and reagents were used without further purification. All temperatures in the examples described herein are in degrees Celsius (. degree. C.) unless otherwise specified.
Example 1: preparation of methyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000211
Step 1) Synthesis of Compound 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester
Figure BDA0001980362320000221
The compound methyl 2- (2-chloro-4-fluorobenzyl) -3-oxobutanoate (5.3g,20.7mmol), 2-thiazolecarboxamidine hydrochloride (2.6g,15.9mmol) was dissolved in trifluoroethanol (70ml), potassium acetate (3.1g,31.8mmol) was added, nitrogen gas was substituted 3 times, and the reaction was heated under reflux at 80 ℃ overnight. After completion of the reaction, the reaction mixture was cooled, filtered with suction, concentrated, and the residue was purified by column chromatography (n-heptane/ethyl ester (v/v) ═ 9/1) to give 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (4.4g, 76%) as a yellow solid.
MS(ESI,pos.ion)m/z:367[M+H]+；
Step 2) Synthesis of Compound 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester
Figure BDA0001980362320000222
Methyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (500mg,1.37mmol) was dissolved in CCl4(15ml) under anhydrous conditions, NBS (244mg,1.37mmol) was added, and the reaction was carried out at room temperature for 1 h. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (n-heptane/ethyl ester (v/v) ═ 4/1) to give a yellow solid (350mg, 57%).
MS(ESI,pos.ion)m/z:444，446[M+H]+；
Step 3) Synthesis of Compound (S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester
Figure BDA0001980362320000231
The compound (S) -5- (tert-butoxycarbonyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (1.49g,6.18mmol) was dissolved in THF (40ml), CDI (2.2g,13.6mmol) was added, the reaction was stirred at room temperature for 1h, methylsulfonamide (2.35g,24.7mmol), DBU (2.35g,15.5mmol) and heated at 70 ℃ for 5 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was dissolved in DCM (50ml), washed with 1N HCl (50ml × 2) followed by saturated brine (50ml × 2), the organic phase was concentrated, and the residue was purified by column chromatography (DCM/EA (v/v) ═ 4/1) to give (S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (1.57g, 80%) as a white solid.
MS(ESI,pos.ion)m/z:319[M+H]+；
Step 4) Synthesis of Compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride
Figure BDA0001980362320000232
Under ice-bath conditions, HCl gas (3.6g,98.7mmol) was introduced into THF (50ml), and the compound (S) -tert-butyl 6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate (1.57g,4.94mmol) was dissolved in the above solution and the reaction was stirred at room temperature overnight. After completion of the reaction, the reaction solution was concentrated to give (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (0.95g, 88%) as a white solid.
MS(ESI,pos.ion)m/z:219[M+H-HCl]+；
Step 5) Synthesis of Compound methyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000241
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (240mg,0.539mmol) was dissolved in CHCl3(5ml), and the compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (176mg,0.809mmol), triethylamine (436mg,4.31mmol) and heated at 50 ℃ for 5 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 19/1) to give methyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (70mg, 22%) as a yellow solid.
MS(ESI,pos.ion)m/z:583[M+H]+；
1H NMR(400MHz,CDCl3):δppm 8.47(br,1H),7.90(s,1H),7.61(s,s,1H),7.34(m,1H),7.21(m,1H),7.16(m,1H),7.04(m,1H),6.16(s,s,1H),4.34(m,2H),3.69(s,3H),3.14(s,s,3H),2.22(m,2H),1.98(m,1H),1.34(m,2H),0.69(m,4H).
Example 2: preparation of (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000251
Step 1) Synthesis of Compound 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid Ethyl ester
Figure BDA0001980362320000252
Ethyl 2- (2-chloro-4-fluorobenzyl) -3-oxobutanoate (4.2g,15.8mmol), 2-thiazolecarboxamidine hydrochloride (2.0g,12.1mmol) were dissolved in trifluoroethanol (40ml), potassium acetate (2.4g,24.3mmol) was added, nitrogen was substituted 3 times, and the reaction was heated under reflux at 80 ℃ overnight. After completion of the reaction, the reaction mixture was cooled, filtered with suction, concentrated, and the residue was purified by column chromatography (n-heptane/ethyl ester (v/v) ═ 9/1) to give 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester (2.6g, 43%) as a yellow solid.
MS(ESI,pos.ion)m/z:381[M+H]+
Step 2) Synthesis of Compound 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid Ethyl ester
Figure BDA0001980362320000261
Ethyl 4- (2-chloro-4-fluorophenyl) -6-methyl-2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (600mg,1.6mmol) was dissolved in CCl4(5ml), NBS (282mg,1.58mmol) was added, and the reaction was carried out at room temperature for 1h under nitrogen. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (n-heptane/ethyl ester (v/v) ═ 1/1) to give ethyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (460mg, 63%) as a yellow solid.
MS(ESI,pos.ion)m/z:458，460[M+H]+
Step 3) Synthesis of Compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride
Figure BDA0001980362320000262
The compound (S) -5- (tert-butoxycarbonyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (5.0g,20.7mmol) was dissolved in 50ml of THF, and the reaction was stirred at room temperature overnight by passing HCl gas (8.5g,232.9mmol) through THF (50ml) in an ice-water bath. After completion of the reaction, the reaction solution was concentrated to give (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (3.5g, 95%) as a white solid.
MS(ESI,pos.ion)m/z:142[M+H-HCl]+
Step 4) Synthesis of Compound (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000271
The compound ethyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (100mg,0.218mmol) was dissolved in 5ml of CHCl3, the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (87mg,0.489mmol), triethylamine (476mg,1.75mmol) were added, and the reaction was heated at 40 ℃ for 5 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (70mg, 62%) as a yellow solid.
MS(ESI,pos.ion)m/z:520[M+H]+
1H NMR(400MHz,MeOD):δppm8.12(m,2H),7.55(m,1H),7.25(m,1H),7.12(m,1H),6.21(s,s,1H),4.05(m,2H),3.84(m,1H),3.52(m,1H),2.90(m,1H),2.48(m,1H),2.19(m,1H),2.00(m,1H),1.28(m,2H),1.14(m,3H),0.72(m,4H).
Example 3: preparation of methyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (morpholine-4-carbonyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000281
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (200mg,0.45mmol) was dissolved in CHCl3(5ml), the compound (S) -morpholine (5-azaspiro [2.4] heptan-6-yl) ethanone hydrochloride (189mg,0.90mmol), triethylamine (365mg,3.6mmol) were added, and the reaction was heated at 45 ℃ for 1 h. After the reaction was completed, the reaction solution was cooled, concentrated, and the residue was separated and purified by thin layer chromatography using EA as a developing agent to give 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (morpholine-4-carbonyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (70mg, 22%) as a yellow solid.
MS(ESI,pos.ion)m/z:575[M+H]+；
1H NMR(400MHz,CDCl3):δppm 10.24(br,1H),7.95(m,1H),7.43(m,2H),7.15(m,1H),6.95(m,1H),6.23(s,s,1H),4.19(m,1H),3.86-3.50(m,12H),2.98-2.70(m,1H),2.22(m,1H),1.93(m,1H),1.52(m,2H),0.69(m,4H).
Example 4: preparation of (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000291
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (70mg,0.157mmol) was dissolved in CHCl3(5ml), the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (42mg,0.236mmol), triethylamine (127mg,1.26mmol) were added, and the reaction was heated at 50 ℃ for 8 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give (6S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (25mg, 32%)
MS(ESI,pos.ion)m/z:506[M+H]+；
1H NMR(400MHz,MeOD):δppm 8.19(m,2H),7.47(m,1H),7.28(m,1H),7.14(m,1H),6.20(s,1H),3.68(s,3H),3.58(m,2H),2.90(m,1H),2.54(m,1H),2.22(m,1H),2.00(m,1H),1.40(m,2H),0.78(m,4H).
Example 5: preparation of methyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000301
The compound methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (150mg,0.32mmol) was dissolved in CHCl3(5ml), and the compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (70mg,0.32mmol), triethylamine (259mg,2.56mmol) and heated at 40 ℃ for 4 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 19/1) to give methyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate (65mg, 33%) as a yellow solid.
MS(ESI,pos.ion)m/z:613[M+H]+；
1H NMR(400MHz,CDCl3):δppm 9.17(m,1H),8.34(m,1H),7.96(m,1H),7.56(m,1H),7.36(m,1H),7.16(m,1H),6.22(s,s,1H),4.12(m,1H),3.70(m,5H),3.24(s,s,3H),2.83(m,1H),2.42(m,1H),2.05(m,1H),1.29(m,2H),0.69(m,4H).
Example 6: preparation of methyl 4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- ((S) -5-azaspiro [2.4] heptane-6-carboxylate) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000311
The compound methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (3, 5-difluoropyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (100mg,0.21mmol) was dissolved in CHCl3(5ml), and the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (49mg,0.27mmol) and triethylamine (170mg,1.68mmol) were added and the reaction stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was cooled, concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give 4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- ((S) -5-azaspiro [2.4] heptane-6-carboxylic acid) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester as a yellow solid (90mg, 80%).
MS(ESI,pos.ion)m/z:536[M+H]+；
1H NMR(400MHz,CDCl3):δppm 11.65(br,1H),8.32(m,1H),7.37(m,1H),7.29(m,1H),7.16(m,2H),6.99(m,1H),6.16(s,s,1H),4.12(m,1H),3.80(m,1H),3.63(s,3H),2.42(m,2H),2.02(m,1H),1.32(m,2H),0.69(m,4H).
Example 7: preparation of ethyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000321
The compound ethyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (100mg,0.22mmol) was dissolved in CHCl3(5ml), and the compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (62mg,0.28mmol), triethylamine (176mg,1.75mmol) and stirred at room temperature for 6 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester as a yellow solid (60mg, 46%).
MS(ESI,pos.ion)m/z:597[M+H]+；
1H NMR(400MHz,CDCl3):δppm 9.17(s,1H),8.51(s,s,1H),7.63(s,s,1H),7.22(m,1H),7.16(m,1H),7.01(m,1H),6.05(s,s,1H),4.14(m,2H),3.67(m,1H),3.48(m,1H),3.16(s,s,3H),2.72(m,1H),2.43(m,1H),2.12(m,1H),1.34(m,2H),1.15(m,3H),0.69(m,4H).
Example 8: preparation of ethyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000331
The compound ethyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (100mg,0.22mmol) was dissolved in CHCl3(5ml), the compound (S) -N- (cyclopropylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (69mg,0.28mmol), triethylamine (176mg,1.75mmol) were added and the reaction stirred at room temperature for 6 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 19/1) to give 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester as a yellow solid (70mg, 51%).
MS(ESI,pos.ion)m/z:623[M+H]+；
1H NMR(400MHz,CDCl3):δppm 9.50(br,1H),8.57(s,s,1H),7.60(s,s,1H),7.27(m,1H),7.14(m,1H),7.03(m,1H),6.07(s,s,1H),4.14(m,2H),3.80-3.12(m,2H),2.80(m,1H),2.43(m,1H),2.20(m,1H),1.32(m,2H),1.21(m,3H),0.95(m,4H),0.71(m,4H).
Example 9: preparation of methyl 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000341
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (100mg,0.23mmol) was dissolved in CHCl3(5ml), and the compound (S) -N-isopropyl-5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (197mg,0.90mmol), triethylamine (365mg,3.6mmol) and heated at 45 ℃ for 1 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was separated and purified by thin layer chromatography using EA as a developing agent to give 4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (30mg, 24%) as a yellow solid.
MS(ESI,pos.ion)m/z:547[M+H]+；
1H NMR(400MHz,CDCl3):δppm 9.24(br,1H),7.95(m,1H),7.43(m,2H),7.15(m,1H),6.95(m,1H),6.23(s,s,1H),4.39(m,1H),4.13-3.95(m,2H),3.75(s,3H),2.98-2.70(m,1H),2.22(m,1H),1.93(m,1H),1.22(m,6H),1.12(m,2H),0.74(m,4H).
Example 10: preparation of (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000351
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(5ml), the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (64mg,0.36mmol), triethylamine (146mg,1.44mmol) were added, and the reaction was heated at 45 ℃ for 5 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was isolated and purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give a yellow solid (20mg, 22%).
MS(ESI,pos.ion)m/z:[M+H]+＝520；
1H NMR(400MHz,CDCl3):δppm 11.33(br,1H),7.64(s,1H),7.33(m,1H),7.31(m,1H),7.03(m,1H),6.17(s,1H),5.16(m,1H),4.58(m,1H),3.79(s,3H),3.52(m,1H),2.46(s,3H),2.19(m,1H),2.00(m,1H),1.28(m,2H),0.84(m,4H).
Example 11: preparation of (S) -5- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000361
The compound methyl 6- (bromomethyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(15ml), and the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (48mg,0.27mmol), triethylamine (146mg,1.44mmol) and heated at 45 ℃ for 1 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA: MeOH ═ 9:1) to give (S) -5- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (10mg, 11%) as a yellow solid.
MS(ESI,pos.ion)m/z:[M+H]+＝506；
1H NMR(400MHz,CD3OD):δppm 8.17(m,2H),7.37(m,1H),7.29(m,2H),6.31(s,1H),4.56(m,1H),3.87(m,1H),3.69(s,3H),3.52(m,1H),2.90(m,1H),2.51(m,1H),1.28(m,2H),0.79(m,4H)。
Example 12: preparation of methyl (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000371
The compound methyl 6- (bromomethyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(15ml), and the compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (92mg,0.36mmol), triethylamine (146mg,1.44mmol) and heated at 45 ℃ for 1 h. After completion of the reaction, the reaction solution was cooled, concentrated, and the residue was purified by thin layer chromatography (EA: MeOH ═ 9:1) to give (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (30mg, 29%) as a yellow solid.
MS(ESI,pos.ion)m/z:[M+H]+＝583；
1H NMR(400MHz,CDCl3):δppm 9.46(br,1H),7.99(m,1H),7.64(m,1H),7.26(m,1H),7.15(m，2H),6.34(s,1H),4.88(m,1H),3.80(m,1H),3.63(s,3H),3.02(s,3H),2.76(m,1H)，2.41(m,1H),2.23(m,1H),1.24(m,2H),0.79(m,4H).
Example 13: preparation of (1R, 3S, 5R) -2- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid
Figure BDA0001980362320000381
The compound methyl 6- (bromomethyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(5ml), the compound (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid hydrochloride (44mg,0.27mmol) and triethylamine (146mg,1.44mmol) were added, and the reaction was stirred at 45 ℃ for 5 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give (1R, 3S, 5R) -2- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid (15mg, 17%) as a yellow solid.
MS(ESI,pos.ion)m/z:[M+H]+＝492；
1H NMR(400MHz,CDCl3):δppm 8.15(br,1H),7.90(m,1H),7.83(m,1H),7.51(m,1H),7.38(m,2H),7.23(m,1H),6.27(s,1H),3.65(s,3H),3.44(m,1H),2.55(m,1H),2.22(m,1H),1.78(m,2H),0.91(m,1H),0.78(m,2H).
Example 14: preparation of (1R, 3S, 5R) -2- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid
Figure BDA0001980362320000391
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(5ml), the compound (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid hydrochloride (59mg,0.36mmol), triethylamine (146mg,1.44mmol) and stirred at 45 ℃ for 5 h. After completion of the reaction, it was cooled, the reaction was concentrated, and the residue was isolated and purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give a yellow solid a (10mg, 11%).
MS(ESI,pos.ion)m/z:[M+H]+＝506；
1H NMR(400MHz,CD3OD):δppm 7.59(s,1H),7.51(m,1H),7.25(m,1H),7.10(m,1H),6.14(s,1H),3.79(m,1H),3.64(s,3H),3.36(m,1H),2.61(s,3H),2.55(m,1H),2.22(m,1H),1.78(m,2H),0.91(m,1H)0.78(m,2H).
Example 15: preparation of methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000401
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(5ml), the compound (S) -N-isopropyl-5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (197mg,0.90mmol), triethylamine (365mg,3.6mmol) were added and the reaction was heated at 45 ℃ for 1 h. After the reaction was completed, the reaction solution was cooled, concentrated, and the residue was separated and purified by thin layer chromatography using EA as a developing agent to give (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester as a yellow solid (20mg, 24%).
MS(ESI,pos.ion)m/z:561[M+H]+；
1H NMR(400MHz,CDCl3):δppm 9.20(br,1H),8.02(br,1H),7.43(s,1H),7.15(m,1H),6.95(m,2H),6.12(s,1H),4.39(m,1H),4.13-3.95(m,2H),3.75(s,3H),2.98-2.70(m,1H),2.47(s,3H),2.22(m,1H),1.93(m,1H),1.22(m,6H),1.12(m,2H),0.74(m,4H).
Example 16: preparation of methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((1R, 3S, 5R) -3- ((methylsulfonyl) carbamoyl) -2-azabicyclo [3.1.0] hex-2-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000411
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (180mg,0.41mmol) was dissolved in CHCl3(10ml), the compound (1R, 3S, 5R) -N- (methylsulfonyl) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride (195mg,0.81mmol), triethylamine (332mg,3.28mmol) and the mixture was added and the reaction was stirred at 45 ℃ for 5 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was separated and purified by thin layer chromatography using EA as a developing solvent to give (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((1R, 3S, 5R) -3- ((methylsulfonyl) carbamoyl) -2-azabicyclo [3.1.0] hexan-2-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (37mg, 16%) as a yellow solid.
MS(ESI,pos.ion)m/z:568[M+H]+＝569；
1H NMR(400MHz,CDCl3):δppm 9.70(br,1H),8.22(m,1H),7.73(m,1H),7.34(m,2H),7.02(m,1H),6.11(s,1H),4.64(m,1H),3.66(s,3H),3.22(m,1H),3.05(s,3H),2.48(m,2H),1.43(m,2H),0.96(m,1H),0.87(m,1H),0.50(m,1H).
EXAMPLE 17 preparation of (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (1-methyl-1H-imidazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000421
Figure BDA0001980362320000431
The compound methyl 6- (bromomethyl) -4- (2-chloro-4-fluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(5ml), the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (140mg,0.64mmol), triethylamine (200mg,1.98mmol) were added, and the reaction was heated at 45 ℃ for 5H. After completion of the reaction, it was cooled, the reaction was concentrated, and the residue was isolated and purified by thin layer chromatography (EA: MeOH ═ 9:1) to give a yellow solid (20mg, 18%).
MS(ESI,pos.ion)m/z:[M+H]+＝503；
1H NMR(400MHz,CD3OD):δppm 7.49(m,1H),7.42(m,1H),7.37(m,1H),7.28(m,1H),7.11(m,1H),6.20(s,1H),4.22(m,1H),3.90(s,3H),3.79(m,1H),3.74(s,3H),3.56(m,1H),2.55(m,1H),2.22(m,1H),1.28(m,2H),0.88(m,4H).
Example 18: preparation of methyl (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000441
The compound methyl 6- (bromomethyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (80mg,0.18mmol) was dissolved in CHCl3(15ml), and the compound (S) -N- (cyclopropylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (96mg,0.36mmol), triethylamine (146mg,1.44mmol) were added and the reaction was heated at 45 ℃ for 1 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA: MeOH ═ 9:1) to give (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (15mg, 15%) as a yellow solid.
MS(ESI,pos.ion)m/z:[M+H]+＝609；
1H NMR(400MHz,CDCl3):δppm 9.57(br,1H),8.22(m,1H),7.54(m,1H),7.24(m,1H),7.14(m,2H),
6.32(s,1H),4.84(m,1H),3.81(m,1H),3.77(s,3H)3.12(m,1H),2.80(m,1H),2.43(m,1H),2.20(m,1H),1.76(m,1H),1.32(m,2H),0.97(m,4H),0.79(m,4H).
Example 19: preparation of (1S, 2S, 5R) -3- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid.
Figure BDA0001980362320000451
The compound methyl 6- (bromomethyl) -4- (2-chloro-3-fluorophenyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (70mg,0.16mmol) was dissolved in CHCl3(5ml), and the compound (1S, 2S, 5R) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid hydrochloride (53mg,0.32mmol), DIPEA (203mg,1.60mmol) and heated at 50 ℃ for 3 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA: MeOH ═ 9:1) to give (1S, 2S, 5R) -3- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (10mg, 13%) as a yellow solid.
MS(ESI,pos.ion)m/z:[M+H]+＝491；
1H NMR(400MHz,CD3OD):δppm 7.96(m,1H),7.82(m,1H),7.34-7.11(m,3H),6.20(s,1H),4.59(m,1H),4.40(m,1H),3.98(m,1H),3.61(s,3H),2.33(m,1H),2.0(m,1H),1.81(m,1H),1.34(m,2H),0.93(m,2H).
Example 20: preparation of methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (hydroxymethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000461
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (330mg,0.74mmol) was dissolved in CHCl3(15ml), the compound (S) -5-azaspiro [2.4] heptan-6-ylmethanol hydrochloride (242mg,1.48mmol), triethylamine (603mg,5.92mmol) were added, and the reaction was stirred at 50 ℃ for 3 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA) to give methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (hydroxymethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (45mg, 12%) as a yellow solid.
MS(ESI,pos.ion)m/z:491[M+H]+；
1H NMR(400MHz,CDCl3):δppm 7.85(m,1H),7.48(s,1H),7.31(m,1H),7.15(m,1H),6.94(m,1H),6.18(s,1H),4.48(m,1H),4.27(m,1H),3.84(m,3H),3.78(s,3H),3.34(m,1H),3.18(m,1H),2.92(m,1H)2.09(m,2H),0.88(m,4H).
Example 21: preparation of methyl (R) -methyl-4- (2-bromo-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000471
The compound methyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (500mg,0.99mmol) was dissolved in CHCl3(25ml), the compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (427mg,1.68mmol) and triethylamine (800mg,8mmol) were added and the reaction stirred at 45 ℃ for 5 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA) to give (R) -methyl-4- (2-bromo-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester as a yellow solid (250mg, 39%).
MS(ESI,pos.ion)m/z:639,641[M+H]+；
1H NMR(400MHz,CDCl3):δppm 7.43(m,3H),7.08(m,1H),6.15(s,1H),4.35(m,1H),4.11(m,1H),3.81(m,1H),3.65(s,3H),3.53(m,1H),3.05(s,3H),2.71(s,3H),2.62(m,2H),2.45(m,1H),1.80(m,1H),0.73(m,4H).
Example 22: preparation of (S) -5- (((R) -6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000481
The compound methyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (500mg,0.99mmol) was dissolved in CHCl3(25ml), the compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (352mg,2mmol) and triethylamine (800mg,8mmol) were added, and the reaction was stirred at 50 ℃ for 5 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 19/1) to give (S) -5- (((R) -6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (120mg, 21%) as a yellow solid.
MS(ESI,pos.ion)m/z:562,564[M+H]+；
1H NMR(400MHz,CDCl3):δppm 7.77(s,1H),7.49(m,2H),7.21(m,1H),6.25(s,1H),3.74(m,2H),3.67(s,3H),3.61(m,2H),2.87(m,1H),2.69(s,3H),2.53(m,1H),2.02(m,2H),0.90-0.64(m,4H).
Example 23: preparation of (1S, 2S, 5R) -3- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid
Figure BDA0001980362320000491
The compound methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (100mg,0.22mmol) was dissolved in CHCl3(8ml), the compound (1S, 2S, 5R) -3-azabicyclo [3.1.0] hexane-2-carboxylate (100mg,0.61mmol) and triethylamine (178mg,1.76mmol) were added, and the reaction was stirred at 50 ℃ for 3 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 19/1) to give (1S, 2S, 5R) -3- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid (10mg, 9%) as a yellow solid.
MS(ESI,pos.ion)m/z:492[M+H]+；
1H NMR(400MHz,CD3OD):δppm 8.17(m,1H),7.25(m,2H),7.12(m,2H),6.25(s,1H),4.63(m,1H),3.98(m,1H),3.61(s,3H),2.33(m,1H),2.0(m,1H),1.81(m,1H),1.34(m,2H),0.93(m,2H).
Example 24: preparation of methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000501
The compound (S) -N- (methylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (36mg,0.12mmol) was dissolved in CHCl3(5ml), and methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (27mg,0.06mmol), triethylamine (49mg,0.48mmol) and heated at 45 ℃ for 5 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA: MeOH ═ 9:1) to give (R) -methyl-4- (2-chloro-4-fluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (8mg, 23.5%) as a yellow solid.
MS(ESI,pos.ion)m/z:580[M+H]+；
1H NMR(400MHz,CDCl3):δppm 7.38(m，1H),7.36(m,2H),7.33(m,2H),6.24(s，1H),4.35(m,1H),4.11(m,1H),3.81(m,1H),3.65(s,3H),3.53(m,1H),3.05(s,3H),2.71(s,3H),2.62(m,2H),2.45(m,1H),1.80(m,1H),0.83(m,4H).
Example 25: preparation of methyl (R) -methyl-4- (2-bromo-4-fluorophenyl) -2- (4-methylthiazol-2-yl) -6- (((S) -6- ((phenylsulfonyl) carbamoyl) -5-azaspiro [2.4] hept-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000511
The compound (S) -N- (phenylsulfonyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (204mg,0.64mmol) was dissolved in CHCl3(10ml), and methyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (200mg,0.40mmol) and triethylamine (324mg,3.2mmol) were added and the mixture was heated at 50 ℃ for 5 h. After the reaction was completed, it was cooled, the reaction solution was concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 19/1) to give (R) -methyl-4- (2-bromo-4-fluorophenyl) -2- (4-methylthiazol-2-yl) -6- (((S) -6- ((phenylsulfonyl) carbamoyl) -5-azaspiro [2.4] hept-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester (90mg, 32%) as a yellow solid.
MS(ESI,pos.ion)m/z:702,704[M+H]+；
1H NMR(400MHz,CDCl3):δppm 8.90(br,1H),7.77(m,2H),7.45(m,1H),7.40(m,2H),7.35(s,1H),7.27(m,2H),6.82(m,1H),6.08(s,1H),4.29(m,1H),4.18(m,1H),3.78(m,1H),3.64(s,3H),3.44(m,1H),2.79(s,3H),2.50(m,1H),2.44(m,1H),2.03(m,2H),0.72(m,4H).
Example 26: preparation of methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (methylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000521
The compound (S) -N- (methyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (380mg,1.99mmol) was dissolved in CHCl3(15ml), and methyl 4- (2-chloro-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (360mg,0.81mmol), N, N-diisopropylethylamine (1.4ml) and heated at 45 ℃ for 1 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA) to give methyl (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (methylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (125mg, 30%) as a yellow solid.
MS(ESI,pos.ion)m/z:518[M+H]+；
1H NMR(400MHz,CDCl3):δppm 9.13(br,1H),7.85(m,1H),7.54(m,2H),7.17(m,1H),6.97(m,1H),6.20(s,1H),4.36(m,1H),4.03(m,1H),3.60(s,3H),2.90-2.70(m,5H),2.45(m,2H),1.92(m,2H),0.64(m,4H).
Example 27: preparation of methyl (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- (dimethylaminomethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate
Figure BDA0001980362320000531
Figure BDA0001980362320000541
The compound (S) -N- (dimethyl) -5-azaspiro [2.4] heptane-6-carboxamide hydrochloride (130mg,0.77mmol) was dissolved in CHCl3(6ml), and methyl 4- (2-chloro-3-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (115mg,0.26mmol) and N, N-diisopropylethylamine (0.45ml) were added and the reaction was heated at 45 ℃ for 1 h. After completion of the reaction, the reaction mixture was cooled, washed, concentrated, and the residue was purified by thin layer chromatography (EA) to give methyl (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- (dimethylaminomethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (42mg, 30%) as a yellow solid.
MS(ESI,pos.ion)m/z:533[M+H]+；
1H NMR(400MHz,CDCl3):δppm 7.88(m,1H),7.40(m，1H),7.21(m,1H),7.03(m,1H),6.99(m,1H),6.26(s,1H),4.44(m,1H),3.96(m,1H),3.82(m,1H),3.62(s,3H),3.07(s,3H),3.01(s,3H),2.69(m,1H),2.25(m,1H),1.94(m,2H),0.62(m,4H).
Example 28: preparation of (S) -5- (((R) -6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
Figure BDA0001980362320000551
The compound (S) -5-azaspiro [2.4] heptane-6-carboxylic acid hydrochloride (360mg,2.03mmol) was dissolved in CHCl3(20ml), and methyl 4- (2-bromo-4-fluorophenyl) -6- (bromomethyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylate (496mg,1.01mmol), triethylamine (816mg,8.08mmol) and heated at 45 ℃ for 8 h. After completion of the reaction, the reaction mixture was cooled, concentrated, and the residue was purified by thin layer chromatography (EA/MeOH (v/v) ═ 9/1) to give (S) -5- (((R) -6- (2-bromo-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (150mg, 22%)
MS(ESI,pos.ion)m/z:548,550[M+H]+；
1H NMR(400MHz,MeOD):δppm 7.96(m,1H),7.86(m,1H),7.55(m,1H),7.50(m,1H),7.20(m,1H),6.15(s,1H),4.59(m，1H),4.48(m，1H),3.73(m，1H),3.64(s,3H),3.46(m,1H),2.69(m,1H),2.14(m,2H),0.84(m,4H).
Example 29: preparation of methyl (S) - ((Isopropoxycarbonyl) oxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylate
Figure BDA0001980362320000561
Compound (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (1.0g,1.9mmol) was dissolved in acetonitrile (10mL), potassium carbonate (1.3g,9.4mmol) and a catalytic amount of sodium iodide were added, and the mixture was replaced with nitrogen 3 times and stirred at room temperature for 30 minutes. Chloromethyl isopropyl carbonate (1.5g, 9.8mmol) was added to the reaction flask and the reaction was warmed to 55 ℃ for 5 hours. After completion of the reaction, the reaction mixture was cooled, filtered, concentrated, and the residue was purified by column chromatography (n-heptane/ethyl ester (v/v) ═ 4/1) to give (S) - ((isopropoxycarbonyl) oxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester (750mg, 60.9%) as a yellow solid.
MS(ESI,pos.ion)m/z:621[M+H]+；
1H NMR(400MHz,DMSO-d6):δppm 9.75(s,1H),8.15(m,1H),7.92(m,1H),7.41(m,2H),7.18(m,1H),6.01(s,1H),5.75(m,1H),5.67(m,1H),4.80(m,1H),4.30(m,1H),4.10(m,1H),3.96(m,1H),3.50(s,3H),2.95(m,1H),2.76(m,1H),2.30(m,1H),1.98(m,1H),1.22(m,6H),0.60(m,4H).
Example 30: preparation of methyl (S) - (pivaloyloxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylate
Figure BDA0001980362320000571
Compound (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid (0.2g,0.39mmol) was dissolved in acetonitrile (2mL), and potassium carbonate (0.269g,1.95mmol) and a catalytic amount of sodium iodide were added, and the mixture was replaced with nitrogen 3 times and stirred at room temperature for 30 minutes. Chloromethyl pivalate (0.298g, 1.98mmol) was added to the reaction flask and the reaction was warmed to 55 ℃ for 5 hours. After completion of the reaction, the reaction mixture was cooled, filtered, concentrated, and the residue was purified by column chromatography (n-heptane/ethyl ester (v/v) ═ 4/1) to give methyl (S) - (pivaloyloxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylate (180mg, 73.4%) as a yellow solid.
MS(ESI,pos.ion)m/z:619[M+H]+；
1H NMR(400MHz,DMSO-d6):δppm 9.84(s,1H),8.00(m,1H),7.94(m,1H),7.43(m,2H),7.20(m,1H),6.03(s,1H),5.82(m,1H),5.64(m,1H),,4.31(m,1H),4.11(m,1H),3.91(m,1H),3.61(s,3H),2.95(m,1H),2.75(m,1H),2.36(m,1H),1.98(m,1H),1.10(s,9H),0.62(m,4H).
Pharmacodynamic test
In vitro anti-HBV pharmacodynamic activity detection experiment by using HBV HepG2.2.15 cell strain
1. The experimental method comprises the following steps:
qPCR is used for detecting the virus DNA content of cell culture solution and calculating the concentration of the compound for inhibiting the virus for half (EC50), and the specific experimental method is as follows:
HepG2.2.15 cells were seeded into 24-well cell culture plates (200,000 cells/well) and cells were treated the next day by adding cell culture medium containing different concentrations of test compound (compound maximum concentration 5. mu.M, 5-fold gradient dilution, 6 dilution points). And replacing the culture solution containing the drug to be detected on the fifth day, collecting the culture supernatant on the eighth day, and centrifuging.
Quantitative PCR: reference is made to the hepatitis B virus nucleic acid quantitative determination kit (PCR-fluorescent probe method). Adding a nucleic acid releasing agent into a PCR reaction tube, and adding a diluted standard template into each tube (the highest concentration of the standard template is 4X107IU/mL, the ten-fold dilution is 4 points, and the lowest concentration is 4X104 IU/mL); adding a sample template; preparing a reaction mixed solution according to a PCR system, and adding the reaction mixed solution into a reaction tube; covering a PCR reaction tube cover; the quantitative PCR instrument was run according to the set program.
Percentage inhibition of HBV replication by compounds was calculated: % inh. ═ 1 total HBV DNA treated with compound/total HBV DNA treated with control X100.
Calculation of the EC of Compounds on HBV replication50The value: EC was calculated using GraphPad Prism5 analytical software using the "four parameter logistic equation50The value is obtained.
2. The experimental results are as follows: see table 1:
table 1: anti-HBV activity of compound in HBV HepG2.2.15 cell strain
Figure BDA0001980362320000591
Activity interval: a (a is more than 0.001 and less than or equal to 0.20 mu mol).
The experimental result shows that the compound has stronger anti-HBV virus effect, thus being applicable to treating various diseases caused by HBV virus infection.
Toxicity test
In vitro toxicity CC Using HepG2 cell line50Detection experiment
1. The experimental method comprises the following steps:
detecting the HepG2 cell viability by using a cell viability detection kit by a luminescence method and calculating the concentration (CC) of the compound for inhibiting half of the HepG2 cell viability50) The specific experimental method is as follows:
HepG2 cells were seeded into 96-well cell culture plates (4,000 cells/well) and cells were treated the next day by adding cell culture media containing different concentrations of test compounds (compounds up to 200. mu.M, 10-fold gradient dilution, 6 dilution points). And detecting the cell viability by using a luminescence cell viability detection kit on the fifth day.
Percentage inhibition of HepG2 cell viability by compound was calculated: % inh. - [ 1-compound treated HepG2 cell viability/control treated HepG2 cell viability ] X100.
CC for calculating viability of compound to HepG2 cells50The value: the CC was calculated using GraphPad Prism5 analytical software and the "four parameter logistic equation50The value is obtained.
2. The experimental results are as follows: see table 2:
table 2: CC of Compounds on HepG2 cells50Value of
Compound (I) CC50(μmol)
Control Compounds 82
Example 1 83
Example 2 120
Example 4 132
Example 7 90
Example 8 110
Example 10 115
Example 19 108
Example 22 70
Example 23 96
Example 28 79
Remarking: the structural formula of the reference compound is shown as the following formula, and the preparation method is disclosed in example 2 of WO 2014037480.
Figure BDA0001980362320000611
Toxicity testThe results show that the compounds of the invention are less toxic. And control Compound (murine LD)50>600 mg) of a compound, e.g., the compound of example 4 (murine LD)50>1000 mg) showed less toxicity than the control compound and better safety.
Pharmacokinetic testing experiment
Pharmacokinetic study of test Compounds in Beagle dogs
1. Experimental method 1:
beagle dogs were injected intravenously via the forelimb with 2mg/kg of test compound.
Blood was collected via jugular vein at time points (0.083, 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours) after administration and collected in anticoagulation tubes with EDTA-K2. Blood samples were centrifuged at 5500rpm for 10min before plasma was obtained. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed on LC-MS/MS in a multiplex reaction ion monitoring (MRM) format. Pharmacokinetic parameters were calculated using a non-compartmental model using winnonlin6.3 software.
2. Data: see table 3:
table 3: pharmacokinetic data of Compounds in Beagle dogs
Figure BDA0001980362320000621
Pharmacokinetic testing experiment
Pharmacokinetic study of test Compounds in Beagle dogs
1. Experimental method 2:
beagle dogs orally took 10mg/kg of test compound.
Blood was collected via jugular vein at time points (0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours) after administration and collected in anticoagulation tubes with EDTA-K2. Blood samples were centrifuged at 5500rpm for 10min before plasma was obtained. Plasma samples were subjected to liquid-liquid extraction and then quantitatively analyzed on LC-MS/MS in a multiplex reaction ion monitoring (MRM) format. Pharmacokinetic parameters were calculated using a non-compartmental model using winnonlin6.3 software.
2. Data: see table 4:
table 4: pharmacokinetic data of Compounds in Beagle dogs
Figure BDA0001980362320000622
The results in tables 3 and 4 show that: most of the indicators of the compound of example 4, such as area under the drug curve (AUC) after IV or PO administration in Beagle dogs, compared to the control compound0-t) Area under the time curve (AUC)0-inf) Bioavailability (F%) Clearance (CL) and steady state performance fractional volume (Vss) were both far better than the area under the drug time curve (AUC) for the control compound0-t) Area under the time curve (AUC)0-inf) Bioavailability (F%) Clearance (CL) and steady state exhibit fractional volume (Vss).
In conclusion, the compound has stronger anti-HBV virus effect; and the compound has more favorable drug-induced test results and good toxicity test results, which makes the compound more likely to be effective and safe drugs. In particular, the compound of example 4 has a moderate clearance rate (4.99mL/kg/min) and a good bioavailability (48%), good toxicity test results (CC)50132 mu mol), which indicates that the compound of the embodiment 4 has very good application prospect in the aspect of resisting HBV virus.

Claims (13)

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof:
Figure FDA0003570550380000011
wherein:
R1is phenyl, wherein said phenyl is optionally further substituted with one or more substituents selected from halogen;
R2is selected from C1-4An alkyl group;
a is-O-or-S-;
R3selected from thiazolyl, imidazolyl or pyridyl, said thiaThe azolyl, imidazolyl or pyridyl group may be further substituted with one or more groups selected from halogen or C1-4Substituted by a substituent of an alkyl group;
r is a group shown as follows:
Figure FDA0003570550380000012
R6each independently is- (CR)7R7a)m-OH、-(CR7R7a)n-C(＝O)-NH-S(O)2-R9、-(CR7R7a)n-C(＝O)-NR10R10a、-(CR7R7a)n-C(＝O)O-(CR7R7a)n-OC(＝O)O-R8、-(CR7R7a)n-C(＝O)O-(CR7R7a)n-OC(＝O)-R8Or- (CR)7R7a)n-C(＝O)N(R8)2；
R7And R7aEach independently is hydrogen or C1-4Alkyl, wherein said C1-4Alkyl is further substituted with one or more substituents selected from ═ O;
R8each independently is hydrogen or C1-4An alkyl group; r9Is C1-4Alkyl radical, C6-10Aryl or C3-6A cycloalkyl group;
R10and R10aEach independently is hydrogen or C1-4Alkyl, or R10And R10aAnd the nitrogen atom to which it is attached, to form a heterocyclic group, wherein the heterocyclic group is a non-aromatic, saturated or partially unsaturated, monocyclic, bicyclic, or tricyclic ring system of 3 to 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms; m is 1;
n is 0 and 1 independently.
2. The compound of claim 1, wherein R2Is methyl or ethyl.
3. The compound of claim 1 or 2, wherein a is-O-.
4. The compound of claim 1 or 2, wherein R is selected from:
Figure FDA0003570550380000021
5. the compound of claim 1, wherein:
R1is 2 halo-substituted phenyl;
R2is methyl or ethyl;
a is-O-.
6. A compound selected from:
Figure FDA0003570550380000031
Figure FDA0003570550380000041
Figure FDA0003570550380000051
Figure FDA0003570550380000061
(1)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(2) (S) -5- ((6- (2-chloro-4-fluorophenyl) -5- (ethoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(3)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (morpholine-4-carbonyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(4) (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(5)4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(6)4- (2-chloro-4-fluorophenyl) -2- (3, 5-fluoropyridin-2-yl) -6- ((S) -5-azaspiro [2.4] heptane-6-carboxylic acid) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(7)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester;
(8)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid ethyl ester;
(9)4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(10) (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (4-methylthiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(11) (S) -5- (((R) -6- (2-chloro-3-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(12) (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(15) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (isopropylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(17) (S) -5- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (1-methyl-1H-imidazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid;
(18) (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- ((cyclopropylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(20) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (hydroxymethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(21) (R) -methyl-4- (2-bromo-4-fluorophenyl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (4-methylthiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(24) (R) -methyl-4- (2-chloro-4-fluorophenyl) -2- (1-methyl-1H-imidazol-2-yl) -6- (((S) -6- ((methylsulfonyl) carbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(25) (R) -methyl-4- (2-bromo-4-fluorophenyl) -2- (4-methylthiazol-2-yl) -6- (((S) -6- ((phenylsulfonyl) carbamoyl) -5-azaspiro [2.4] hept-5-yl) methyl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(26) (R) -methyl-4- (2-chloro-4-fluorophenyl) -6- (((S) -6- (methylcarbamoyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiazol-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(27) (R) -methyl 4- (2-chloro-3-fluorophenyl) -6- (((S) -6- (dimethylaminomethyl) -5-azaspiro [2.4] heptan-5-yl) methyl) -2- (thiapyridin-2-yl) -1, 4-dihydropyrimidine-5-carboxylic acid methyl ester;
(29) (S) - ((isopropoxycarbonyl) oxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester;
(30) (S) - (pivaloyloxy) methyl 5- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) - (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester.
7. A pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6.
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the treatment or prophylaxis of a disease caused by hepatitis b virus infection.
9. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1, which process comprises: reacting a compound represented by formula d with an R-H compound or a salt thereof in the presence of a base to obtain a compound represented by formula (I):
Figure FDA0003570550380000091
wherein R is1、R2、R3R and A are as defined in claim 1.
10. The method of claim 9, wherein the base is an organic base.
11. The production method according to claim 9, wherein the base is triethylamine.
12. The method of claim 9, wherein the compound of formula d is prepared by a method comprising:
step (1): reacting the compound shown in the formula a with the compound shown in the formula b to obtain a compound shown in the formula c:
Figure FDA0003570550380000092
step (2): reacting the compound shown in the formula c with a brominating reagent to obtain a compound shown in a formula d:
Figure FDA0003570550380000093
wherein R is1、R2、R3R and A are as defined in claim 1.
13. The method according to claim 9, wherein the brominating reagent in step (2) is N-bromosuccinimide.
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