Anti-inflammatory compound, and preparation and use thereof

Abstract

The present invention provides an anti-inflammatory compound, which is a compound having a structure (I) as shown below: ##STR00001## The compound is a target that is important for autoimmune activation, and that has strong inhibitory effect on PDE4 and penetrates the skin easily, and is a new type anti-inflammatory compound that is easily degraded.

Claims

1. An anti-inflammatory compound, which is a compound having a structure shown below: ##STR00299## wherein R.sup.A is hydrogen, alkyl, or aryl, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl, cycloalkyl, aryl, or halogen; R.sup.B is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, alkenyl, or alkynyl, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl, cycloalkyl, heterocycloalkyl, aryl, or halogen, and one or more carbon atom(s) in the groups is/are optionally replaced with sulfur, sulfoxide, sulfone, or sulfonyl; R.sup.C is hydrogen, alkyl, halogen, or alkoxy; R.sup.D1 is hydrogen, oxo, imino, hydroxy, cyano, amino, amido, alkyl, aryl, an ester group, carboxyl, alkenyl, or alkynyl, and in the above groups one or more hydrogen atom(s) attached to carbon/oxygen/nitrogen in the groups is/are optionally substituted with alkyl, cycloalkyl, alkynyl, alkenyl, aryl, halogen, sulfonyl, a sulfoxide group, or an ether group, and one or more carbon atom(s) in the groups is/are replaced optionally with sulfur, sulfoxide, sulfone, or sulfonyl; C.sub.1-R.sup.D1 bond is a single bond or a double bond; R.sup.D2 is hydrogen, cyano, alkyl, cycloalkyl, aryl, or carboxyl, and in the above groups one or more hydrogen atom(s) attached to carbon/oxygen/nitrogen in the group is/are optionally substituted with alkyl, cycloalkyl, alkynyl, alkenyl, aryl, halogen, sulfonyl, or a sulfoxide group; G1 is a single bond, a double bond or a ring, that comprises C.sub.1 and C.sub.2; and R.sup.E is hydrogen, alkyl, or halogen, wherein when R.sup.D1 is aryl, it is unsubstituted aryl, and when R.sup.D2 is aryl, it is unsubstituted aryl.

2. The anti-inflammatory compound according to claim 1, wherein G1 is a three-membered ring having a specific structure shown below: ##STR00300## in which X is carbon.

3. A method for preparing the anti-inflammatory compound according to claim 1, comprising: using a 3-hydroxybenzaldehyde derivative A as a starting material, and substituting the hydrogen in the hydroxyl group of the 3-hydroxybenzaldehyde derivative A with RB to obtain an intermediate product B; reacting the intermediate product B with trimethylsilyl cyanide to obtain an intermediate product C; reducing the intermediate product C to obtain an intermediate product D having an amino group; and reacting the amino group in the intermediate product D with a six-membered oxygen-containing cyclic compound to obtain a type-A target product, wherein the 3-hydroxybenzaldehyde derivative A is a compound having a structure shown below: ##STR00301## the intermediate product B is a compound having a structure shown below: ##STR00302## the intermediate product C is a compound having a structure shown below: ##STR00303## the intermediate product D is a compound having a structure shown below: ##STR00304## and the type-A target product is a compound having a structure shown below: ##STR00305## subjecting the hydroxyl group on the middle bridge of the type-A target product to an addition/substitution reaction to obtain a type-A-1 target product, wherein the type-A-1 target product is a compound having a structure shown below: ##STR00306## in which Rd is alkyl, cycloalkyl, or an ester group, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl, alkynyl, alkenyl, cycloalkyl, aryl, halogen, hydroxy, thio, cyano, or thioalkyl, or oxidizing the hydroxyl group on the middle bridge of the type-A target product to obtain a type-B target product, wherein the type-B target product is a compound having a structure shown below: ##STR00307##

4. The method for preparing an anti-inflammatory compound according to claim 3, comprising: oximating the carbonyl group on the middle bridge of the type-B target product to obtain a type-B-3 target product, wherein the type-B-3 target product is a compound having a structure shown below: ##STR00308## subjecting the hydroxyl group on the oxime of the type-B-3 target product to an addition/substitution reaction to obtain a type-B-4 target product, wherein the type-B-4 target product is a compound having a structure shown below: ##STR00309## in which Rd-1 is alkyl, cycloalkyl, or an ester group, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl, alkynyl, alkenyl, cycloalkyl, aryl, halogen, hydroxy, thio, cyano, or thioalkyl.

5. The method for preparing the anti-inflammatory compound according to claim 3, comprising: removing the hydroxyl group on the middle bridge of the type-A target product to obtain a type-C target product, wherein the type-C target product is a compound having a structure shown below: ##STR00310##

6. The method for preparing the anti-inflammatory compound according to claim 3, comprising: reacting the carbonyl group on the middle bridge of the type-B target product with a halogenating reagent to obtain an intermediate product X1, and replacing the halogen in the intermediate product X1 to obtain a type-C-3 target product, wherein the intermediate product X1 is a compound having a structure shown below: ##STR00311## in which X is halogen; and the type-C-3 target product is a compound having a structure shown below: ##STR00312## in which Rd-2 is aryl, alkyl, cycloalkyl, an ether group, or an ester group, and in the above groups one or more hydrogen atom(s) attached to carbon in the group is/are optionally substituted with alkyl, alkynyl, alkenyl, cycloalkyl, aryl, halogen, hydroxy, thio, cyano, or thioalkyl.

7. A method for preparing the anti-inflammatory compound according to claim 1, comprising: reacting an acetophenone derivative 1 as a starting material with trimethylsilyl cyanide, to obtain an intermediate product 2; reducing the intermediate product 2 to obtain an intermediate product 3; and reacting the amino group in the intermediate product 3 with a six-membered oxygen-containing cyclic compound to obtain a type-A′ target product, wherein the acetophenone derivative 1 is a compound having a structure shown below: ##STR00313## in which Rd′ is hydrogen, alkyl, aryl, alkynyl, or alkenyl, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl, alkynyl, alkenyl, cycloalkyl, aryl, halogen, hydroxy, thio, cyano, or thioalkyl; the intermediate product 2 is a compound having a structure shown below: ##STR00314## the intermediate product 3 is a compound having a structure shown below: ##STR00315## and the type-A′ target product is a compound having a structure shown below: ##STR00316## removing the hydroxyl group on the middle bridge of the type-A′ target product to obtain a type-C′ target product, wherein the type-C′ target product is a compound having a structure shown below: ##STR00317##

8. The method for preparing the anti-inflammatory compound according to claim 3, comprising: reacting the carbonyl group on the middle bridge of the type-B target product with trimethylsilyl cyanide to obtain an intermediate product Y1, and subjecting the intermediate product Y1 to reduction and elimination to obtain a type-C″ target product, wherein the intermediate product Y1 is a compound having a structure shown below: ##STR00318## the type-C″ target product is a compound having a structure shown below: ##STR00319## or reacting a six-membered N-acetonitrile compound Z1 with a benzaldehyde derivative Z2 to obtain a type-C2″ target product, wherein the six-membered N-acetonitrile compound Z1 is a compound having a structure shown below: ##STR00320## the benzaldehyde derivative Z2 is a compound having a structure shown below: ##STR00321## and the type-CT′ target product is a compound having a structure shown below: ##STR00322##

9. A method for preparing an anti-inflammatory compound according to claim 1, comprising: using a cinnamic acid derivative 1 as a starting material, and esterifying the cinnamic acid derivative 1 to obtain an intermediate product 2; forming a ring from the double bond on the intermediate product 2 to obtain an intermediate product 3; hydrolyzing the terminal ester group on the intermediate product 3 to give an intermediate product 4 having a carboxyl group; aminating the terminal carboxyl group of the intermediate product 4 to obtain an intermediate product 5; and reacting the intermediate product 5 with a six-membered oxygen-containing cyclic compound to obtain a type-D target product, wherein the cinnamic acid derivative 1 is a compound having a structure shown below: ##STR00323## the intermediate product 2 is a compound having a structure shown below: ##STR00324## in which Z is alkyl; the intermediate product 3 is a compound having a structure shown below: ##STR00325## the intermediate product 4 is a compound having a structure shown below: ##STR00326## the intermediate product 5 is a compound having a structure shown below: ##STR00327## and the type-D target product is a compound having a structure shown below: ##STR00328##

10. A method of inhibiting PDE4, comprising: administering the anti-inflammatory compound according to claim 1 as a PDE4 inhibitor.

11. A method of treating inflammatory skin diseases, comprising: administering the anti-inflammatory compound according to claim 1.

12. A drug for treating the inflammatory skin diseases, comprising 0.01-10% of the anti-inflammatory compound according to claim 1; and other components selected from a surfactant, a lipid compound, and an auxiliary agent; wherein the amount of the surfactant accounts for 10-30% of the total weight of the drug; the amount of the lipid compound accounts for 50-85% of the total weight of the drug; and the amount of the auxiliary agent accounts for 10-30% of the total weight of the drug.

13. The anti-inflammatory compound according to claim 1, wherein the compound having a structure shown below: ##STR00329## wherein R.sup.A is hydrogen, alkyl comprising from 1 to 6 carbon atoms, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl comprising from 1 to 6 carbon atoms, cycloalkyl which is three-membered, four-membered, five-membered or six-membered cycle, or halogen; R.sup.B is hydrogen, alkyl comprising from 1 to 6 carbon atoms, cycloalkyl which is a three-membered, four-membered, five-membered or six-membered cycle, heterocycloalkyl which is an oxo/thia three-membered, four-membered, five-membered or six-membered cycle, alkenyl comprising from 2 to 4 carbon atoms, or alkynyl comprising from 2 to 4 carbon atoms, and in the above groups one or more hydrogen atom(s) attached to carbon in the groups is/are optionally substituted with alkyl comprising from 1 to 6 carbon atoms, cycloalkyl which is a three-membered, four-membered, five-membered or six-membered cycle, or halogen, and one or more carbon atom(s) in the groups is/are optionally replaced with a sulfur atom, sulfoxide, sulfone, or sulfonyl; R.sup.C is hydrogen; R.sup.D1 is hydrogen, oxo, imino, hydroxy, cyano, alkyl comprising from 1 to 6 carbon atoms, phenyl, an ester group, carboxyl, or alkynyl comprising from 2 to 4 carbon atoms, and in the above groups one or more hydrogen atom(s) attached to carbon/oxygen in the groups is/are optionally substituted with alkyl comprising 1 to 6 carbon atoms, cycloalkyl which is a three-membered, a four-membered, five-membered or six-membered ring, alkynyl comprising from 2 to 4 carbon atoms, alkenyl comprising from 2 to 4 carbon atoms, or phenyl, and one or more carbon atom(s) in the groups is/are optionally replaced with a sulfur atom; C.sub.1-R.sup.D1 bond is a single bond or a double bond; R.sup.D2 is hydrogen or cyano; G1 is a single bond, a double bond or cyclopropane comprising C.sub.1 and C.sub.2; and R.sup.E is alkyl comprising from 1 to 6 carbon atoms or halogen.

14. The anti-inflammatory compound according to claim 1, wherein the compound is selected from the group consisting of: 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6, dimethylpyridin-4(1H)-one; ##STR00330## ##STR00331## 1-(2-(but-2-yn-1-yloxy)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)ethyl)-2,6-dimethylpyridin-4-(1H)-one; 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2, 6-dimethylpyridin-4(1H)-one; 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2, 6-dimethylpyridin-4(1H)-one; 1-(2-(3-ethoxy-4-methoxyphenyl)-2-oxoethyl)-2, 6-dimethylpyridin-4(1H)-one; 1-(2-(3-propoxy-4-methoxyphenyl)-2-oxoethyl)-2, 6-dimethylpyridin-4(1H)-one; 1-(2-(3-isopropoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-n-butoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-iso-butoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-n-pentyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-n-hexyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclopropyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxo)ethyl-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclobutyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclobutylmethoxy-4-methoxyphenyl)-2-oxo)ethyl-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclohexyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-(cyclopent-3-en-1-yloxy)-4-methoxyphenyl)-2-oxoethyl)-2, 6-dimethylpyridin-4(1H)-one; 1-(2-(3-allyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-((3-methylbut-2-en-1-yl)oxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-propargyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-(but-2-yn-1-yloxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-(oxacyclobutan-3-yl-oxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-(tetrahydrofuran-2-yl)oxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-methylsulfinylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-methylsulfonylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-methylthioethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-methylsulfinylethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-methylsulfonylethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methoxylimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylsulfinylmethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylsulfonylmethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)pyridin-4(1H)-one; 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one; 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-chloropyridin-4(1H)-one; 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropyl)-2,6-dimethylpyridin-4(1H)-one; 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)pyridin-4(1H)-one; (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2-methylpyridin-4(1H)-one; (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-propoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-isopropoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-n-butoxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-iso-butoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-neopentyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-cyclopropyloxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-cyclopropylmethoxy-4-methoxyphenethyl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-cyclobutyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-cyclopentyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-(cyclopent-3-en-1-yloxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-allyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-(3-methylbut-2-en-1-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-(prop-2-yn-1-yloxy)-4-methoxy)styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-(but-2-yn-1-yloxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-(oxacyclobutan-3-yl-oxy)-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-(thiacyclobutan-3-yl-oxy)-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E) -1-((3-(tetrahydrofuran-2-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-2-(5-(2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethenyl)-2-methoxyphenoxy)-N-methylacetamide; (E)-1-((3-cyclopropylformyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-5-(2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethenyl)-2-methoxyphenylmethyl sulfonate; (E)-1-(3-methylthiomethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfinylmethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfonylmethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylthioethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfinylethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfonylethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-((1,1,-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; 1-((E)-4-methoxy-3-(((3S)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one; (S,E)-1-(3-((1,1-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one; 1-((E)-4-methoxy-3-(((3R)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one; (R,E)-1-(3-((1,1-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylthiomethoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfinylmethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfonylmethoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylthioethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfinylethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(3-methylsulfonylethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one; (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; ##STR00332## (S,E)-1-(3-(1,1-dioxotetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; 1-((E)-4-difluoromethoxy-3-(((3R)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one; (R,E)-1-(3-(1,1-dioxotetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-methylethenyl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-1-(2-(3-cyclpropylmethoxy-4-methoxyphenyl)pent-1-en-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one; (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyanoethenyl)-2,6-dimethylpyridin-4(1H)-one; (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-acrylamide; (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-N-methylacrylamide; (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-N,N-dimethylacrylamide; (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-N,N-diethylacrylamide; (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-acrylic acid; (Z)-methyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-acrylate; (Z)-ethyl-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)-acrylate; (Z)-1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pent-1-en-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one; (Z)-2-(3,4-dimethoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridine)-1(4H)-y l)acrylonitrile; (E)-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile; (E)-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylamide; and (E)-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridine)-1(4H)-yl)-N,N-dimethylacrylamide.

Description

DESCRIPTION OF THE EMBODIMENTS

Example 1

(1) ##STR00050##

(2) The specific reaction scheme is as shown below:

(3) ##STR00051##

(4) Step A:

(5) At room temperature, 3-hydroxy-4-methoxybenzaldehyde (3.04 g, 20 mmol) was dissolved in acetonitrile (80 mL), and then potassium carbonate (5.52 g, 40 mmol) and bromomethylcyclopropane (4.05 g, 30 mmol) were added in sequence, and heated to 80° C. for 3 hours with stirring under nitrogen atmosphere. After the reaction was completed, a saturated aqueous sodium chloride solution (60 mL) was added, and extracted with dichloromethane (3×100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by column chromatography to obtain 3-cyclopropylmethoxy-4-methoxybenzaldehyde (3.50 g, 85%).

(6) Step B:

(7) 3-cyclopropylmethoxy-4-methoxybenzaldehyde (3.09 g, 15 mmol) was dissolved in dichloromethane (30 mL); and under nitrogen atmosphere, triethyl amine (4.16 mL, 30 mmol) and trimethylsilyl cyanide (3.75 g, 30 mmol) were added, and stirred for 6 hours at room temperature. The reaction solution was concentrated and rotary dried to obtain a crude product of 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile, which was directly used in the next reaction.

(8) Step C:

(9) 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile (4.57 g, 15 mmol) obtained in the above step was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium aluminum hydride (1.14 g, 30 mmol) was added portion-wise in an ice bath, and stirred overnight at room temperature. After the reaction was completed, water (1.2 mL), an aqueous sodium hydroxide solution (1.2 mL, 15%), and water (3.6 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 2-amino-1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanol.

(10) Step D:

(11) 2-amino-1-(3-(cyclopropylmethoxy)-4-methoxyphenyl)ethanol obtained in the above step was dissolved in ethanol (20 mL), and then 2,6-dimethyl-4H-pyran-4-one (1 g, 10.41 mmol) and an aqueous sodium hydroxide solution (2 M, 20 mL) were added, and stirred overnight at 60° C. After the reaction was completed, the reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6, dimethylpyridin-4(1H)-one (2.01 g, yield 58%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.03 (d, J=1.6 Hz, 2H), 6.90 (dd, J=8.0, 1.6 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 6.05 (s, 2H), 5.03 (dd, J=9.6, 3.2 Hz, 1H), 4.03 (dd, J=15.2, 10.0 Hz, 1H), 3.93-3.84 (m, 6H), 2.47 (s, 6H), 1.39-1.26 (m, 1H), 0.69-0.64 (m, 2H), 0.40-0.36 (m, 2H); LC-MS: m/z 344.2 [M+H].sup.+.

Example 2

(12) ##STR00052##

(13) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) acetate

(14) The specific reaction scheme is as shown below:

(15) ##STR00053##

(16) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (343 mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), and then acetyl chloride (118 mg, 1.5 mmol) and triethyl amine (202 mg, 2.0 mmol) were added in sequence, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) acetate (116 mg, yield 30%, pale yellow oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.05-6.96 (m, 5H), 6.12-6.08 (m, 1H), 4.82-4.75 (m, 1H), 4.62-4.56 (m, 1H), 3.86-3.83 (m, 5H), 2.75 (s, 6H), 2.03 (s, 3H) 1.29-1.21 (m, 1H), 0.64-0.60 (m, 2H), 0.37-0.33 (m, 2H); LC-MS: m/z 386.2 [M+H].sup.+.

Example 3

(17) ##STR00054##

(18) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) propionate

(19) The specific reaction scheme is as shown below:

(20) ##STR00055##

(21) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (343 mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), and then propionyl chloride (139 mg, 1.5 mmol) and triethyl amine (202 mg, 2.0 mmol) were added in sequence, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl) ethyl) propionate (140 mg, yield 35%, pale yellow oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.05-6.97 (m, 5H), 6.15-6.12 (m, 1H), 4.82-4.76 (m, 1H), 4.64-4.59 (m, 1H), 3.86-3.83 (m, 5H), 2.77 (s, 6H), 2.38-2.29 (m, 2H), 1.29-1.24 (m, 1H), 1.05-1.01 (m, 3H), 0.64-0.60 (m, 2H), 0.36-0.33 (m, 2H); LC-MS: m/z 399.9 [M+H].sup.+.

Example 4

(22) ##STR00056##

(23) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) cyclopropylcarboxylate

(24) The specific reaction scheme is as shown below:

(25) ##STR00057##

(26) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (343 mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), and then cyclopropanecarbonyl chloride (157 mg, 1.5 mmol) and triethyl amine (202 mg, 2.0 mmol) were added in sequence, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) cyclopropylcarboxylate (103 mg, yield 25%, pale yellow oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.04-7.01 (m, 2H), 6.95 (s, 1H), 6.35 (s, 2H), 6.11-6.06 (m, 1H), 4.56-4.50 (m, 1H), 4.37-4.32 (m, 1H), 3.89-3.81 (m, 5H), 2.53 (s, 6H), 0.92-0.81 (m, 6H), 0.66-0.62 (m, 2H), 0.39-0.36 (m, 2H); LC-MS: m/z 412.2 [M+H].sup.+.

Example 5

(27) ##STR00058##

(28) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) benzoate

(29) The specific reaction scheme is as shown below:

(30) ##STR00059##

(31) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (343 mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), and then benzoyl chloride (211 mg, 1.5 mmol) and triethyl amine (202 mg, 2.0 mmol) were added in sequence and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl) ethyl) benzoate (94 mg, yield 21%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.04-8.00 (m, 2H), 7.70-7.65 (m, 1H), 7.56-7.51 (m, 2H), 7.22 (dd, J=8.4, 2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.00 (s, 2H), 6.48-6.44 (m, 1H), 5.00-4.93 (m, 1H), 4.81-4.75 (m, 1H), 3.91-3.87 (m, 5H), 2.82 (s, 6H), 2.03 (s, 3H) 1.32-1.25 (m, 1H), 0.66-0.61 (m, 2H), 0.39-0.35 (m, 2H); LC-MS: m/z 448.2 [M+H].sup.+.

Example 6

(32) ##STR00060##

(33) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) crotonate

(34) The specific reaction scheme is as shown below:

(35) ##STR00061##

(36) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (343 mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), and then crotonyl chloride (157 mg, 1.5 mmol) and triethyl amine (202 mg, 2.0 mmol) were added in sequence, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) crotonate (127 mg, yield 31%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.87 (d, J=8.4 Hz, 1H), 6.82 (dd, J=8.4, 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.33 (s, 2H), 5.98-5.89 (m, 1H), 5.86-5.76 (m, 1H), 4.37-4.28 (m, 1H), 4.13-4.04 (m, 1H), 3.88 (s, 3H), 3.84 (d, J=6.8 Hz, 2H), 2.37 (s, 6H), 1.33-1.28 (m, 1H), 0.69-0.64 (m, 2H), 0.39-0.35 (m, 2H); LC-MS: m/z 412.2 [M+H].sup.+.

Example 7

(37) ##STR00062##

(38) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) 3-methylcrotonate

(39) The specific reaction scheme is as shown below:

(40) ##STR00063##

(41) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (343 mg, 1.0 mmol) was dissolved in dichloromethane (8 mL), and then 3-methylcrotonyl chloride (178 mg, 1.5 mmol) and triethyl amine (202 mg, 2.0 mmol) were added in sequence, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl)3-methyl crotonate (137 mg, yield 32%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.87 (d, J=8.4 Hz, 1H), 6.83 (dd, J=8.4, 2.0 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 6.28 (s, 2H), 5.90 (dd, J=9.2, 4.8 Hz, 1H), 4.91 (s, 1H), 4.30 (dd, J=15.2, 9.2 Hz, 1H), 4.05 (dd, J=15.2, 4.8 Hz, 1H), 3.88 (s, 3H), 3.83 (d, J=7.2 Hz, 2H), 3.02 (s, 2H), 2.37 (s, 6H), 1.69 (s, 3H), 1.35-1.27 (m, 1H), 0.69-0.64 (m, 2H), 0.39-0.35 (m, 2H); LC-MS: m/z 426.2 [M+H].sup.+.

Example 8

(42) ##STR00064##

(43) (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethyl) but-2-ynoate

(44) The specific reaction scheme is as shown below:

(45) ##STR00065##

(46) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (197 mg, 0.69 mmol) and 2-butynoic acid (72 mg, 0.86 mmol) were dissolved in dichloromethane (10 mL), and then 4-dimethylaminopyridine (105 mg, 0.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) were added in sequence, and stirred overnight at 30° C. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (1-(3-cyclopropylmethoxy-4methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1 (4H)-yl)ethyl)but-2-ynoate (37 mg, 9%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.88-6.82 (m, 2H), 6.77 (d, J=1.6 Hz, 1H), 6.22 (s, 2H), 5.90 (dd, J=8.4, 5.2 Hz, 1H), 4.31 (dd, J=15.2, 8.4 Hz, 1H), 4.04 (dd, J=15.2, 5.2 Hz, 1H), 3.88 (s, 3H), 3.84 (d, J=7.2 Hz, 2H), 2.33 (s, 6H), 2.01 (s, 3H), 1.32-1.28 (m, 1H), 0.69-0.64 (m, 2H), 0.39-0.35 (m, 2H). LC-MS: m/z 410.4 [M+H].sup.+.

Example 9

(47) ##STR00066##

(48) 1-(2-(but-2-yn-1-yloxy)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)ethyl)-2,26-dimethylpyridin-4-(1H)-one

(49) The specific reaction scheme is as shown below:

(50) ##STR00067##

(51) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromo-2-butyne (40 mg, 0.30 mmol) and cesium carbonate (98 mg, 0.30 mmol) were added and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL).

(52) The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(but-2-yn-1-yloxy)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)ethyl)-2,26-dimethylpyridin-4-(1H)-one (19 mg, yield 32%, pale yellow oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.89 (d, J=7.6 Hz, 1H), 6.84-6.81 (m, 2H), 6.58 (s, 2H), 4.70-4.66 (m, 1H), 4.30-4.24 (m, 1H), 4.14-4.08 (m, 1H), 4.05-4.00 (m, 1H), 3.91-3.86 (m, 5H), 3.82-3.77 (m, 1H), 2.45 (s, 6H), 1.37-1.31 (m, 1H), 1.27 (s, 3H), 0.72-0.66 (m, 2H), 0.42-0.38 (m, 2H); LC-MS: m/z 396.1 [M+H].sup.+.

Example 10

(53) ##STR00068##

(54) 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(55) The specific reaction scheme is as shown below:

(56) ##STR00069##

(57) Step A:

(58) At room temperature, 3-hydroxy-4-methoxybenzaldehyde (1.52 g, 10 mmol) was dissolved in acetonitrile (40 mL), and then potassium carbonate (2.76 g, 20 mmol) and benzyl bromide (2.56 g, 15 mmol) were added in sequence, and heated to 80° C. for 3 hours with stirring under nitrogen atmosphere. After the reaction was completed, a saturated aqueous sodium chloride solution (30 mL) was added, and extracted with dichloromethane (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by column chromatography to obtain 3-benzoxy-4-methoxybenzaldehyde (2.30 g, 95%, white solid).

(59) Step B:

(60) 3-benzoxy-4-methoxybenzaldehyde (2.30 g, 9.5 mmol) was dissolved in dichloromethane (30 mL), and then triethyl amine (1.92 g, 19 mmol) and trimethylsilyl cyanide (2.82 g, 28.5 mmol) were added in sequence in an ice bath and stirred for 16 hours under nitrogen atmosphere at room temperature. After the reaction was completed, direct rotary drying gave 2-(3-benzoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile, which was directly used in the next reaction.

(61) Step C:

(62) 2-(3-benzoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile obtained in the above step was dissolved in anhydrous tetrahydrofuran (40 mL), and lithium aluminum hydride (1.08 g, 28.5 mmol) was added portion-wise in an ice bath and stirred overnight at room temperature. After the reaction was completed, water (1.1 mL), an aqueous sodium hydroxide solution (1.1 mL, 15%), and water (3.3 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 2-amino-1-(3-benzoxy-4-methoxyphenyl)ethanol, which was directly used in the next reaction.

(63) Step D:

(64) 2-Amino-1-(3-benzoxy-4-methoxyphenyl)ethanol obtained in the above step was dissolved in ethanol (60 mL), and then 2,6-dimethyl-4H-pyran-4-one (1.24 g, 10 mmol), sodium hydroxide (800 mg, 20 mmol) and water (10 mL) were added in sequence, heated to 60° C., and stirred overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-benzoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (1.62 g, 45%, white solid). LC-MS m/z 380.2 [M+H].sup.+.

(65) Step E:

(66) 1-(2-(3-benzoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (1.62 g, 4.26 mmol) was dissolved in dichloromethane (30 mL), and then the Dess-Martin Periodinane (2.16 g, 5.11 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was filtered, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by column chromatography to obtain 1-(2-(3-benzoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (1.37 g, yield 85%, white solid). LC-MS m/z 378.2 [M+H].sup.+.

(67) Step F:

(68) The compound 1-(2-(3-benzoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (1.37 g, 3.61 mmol) was dissolved in methanol (50 mL), then Pd/C (137 mg) and triethyl amine (1 mL) were added, and hydrogen was introduced. The system was stirred overnight at room temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (660 mg, yield 64%, gray solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.73 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.04 (s, 2H), 5.97 (s, 2H), 3.98 (s, 3H), 2.51 (s, 6H); LC-MS: m/z 288.2 [M+H].sup.+.

Example 11

(69) ##STR00070##

(70) 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(71) The specific reaction scheme is as shown below:

(72) ##STR00071##

(73) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (28 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then iodomethane (19 mg, 0.13 mmol) and potassium carbonate (21 mg, 0.15 mmol) were added and stirred for 1 hr at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (10 mg, yield 30%, pale yellow oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.05 (s, 2H), 6.02 (s, 2H), 4.07 (s, 3H), 3.96 (s, 3H), 2.52 (s, 6H); LC-MS: m/z 302.1 [M+H].sup.+.

Example 12

(74) ##STR00072##

(75) 1-(2-(3-ethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(76) The specific reaction scheme is as shown below:

(77) ##STR00073##

(78) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (28 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then iodoethane (21 mg, 0.13 mmol) and potassium carbonate (21 mg, 0.15 mmol) were added and stirred for 1 hr at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-ethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (15 mg, yield 48%, pale yellow oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.04 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.02 (s, 2H), 6.91 (d, J=8.0 Hz, 1H), 6.15 (s, 2H), 4.32 (q, J=6.0 Hz, 2H), 3.92 (s, 3H), 2.62 (s, 6H), 1.51 (t, J=6.0 Hz, 1H); LC-MS m/z 316.1 [M+H].sup.+.

Example 13

(79) ##STR00074##

(80) 1-(2-(3-propoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(81) The specific reaction scheme is as shown below:

(82) ##STR00075##

(83) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (20 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromopropane (10 mg, 0.08 mmol) and potassium carbonate (15 mg, 0.11 mmol) were added and stirred for 2 hours at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-propoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (8 mg, yield 34%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.22 (d, J=2.0 Hz, 1H), 7.14 (dd, J=8.4, 2.0 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.38 (s, 2H), 6.02 (s, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.89 (s, 3H), 2.37 (s, 6H), 1.90-1.80 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); LC-MS: m/z 330.2 [M+H].sup.+.

Example 14

(84) ##STR00076##

(85) 1-(2-(3-isopropoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(86) The specific reaction scheme is as shown below:

(87) ##STR00077##

(88) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (35 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromo-isopropane (17 mg, 0.14 mmol) and potassium carbonate (25 mg, 0.18 mmol) were added, and stirred for 2 hours at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL).

(89) The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-isopropoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (10 mg, yield 63%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.02 (dd, J=8.4, 2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.76 (d, J=14.4 Hz, 1H), 6.60 (d, J=14.4 Hz, 1H), 6.30 (s, 2H), 4.69-4.60 (m, 1H), 3.90 (s, 3H), 2.57 (s, 6H), 1.35 (d, J=6.0 Hz, 6H); LC-MS: m/z 330.2 [M+H].sup.+.

Example 15

(90) ##STR00078##

(91) 1-(2(3-n-butoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(92) The specific reaction scheme is as shown below:

(93) ##STR00079##

(94) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromo-isopropane (95 mg, 0.7 mmol) and potassium carbonate (37 mg, 0.7 mmol) were added, and stirred for 2 hours at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-n-butoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (26 mg, yield 42%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.05 (s, 2H), 6.02 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.96 (s, 3H), 2.52 (s, 6H), 1.84-1.77 (m, 2H), 1.58-1.48 (m, 2H), 0.95 (t, J=7.2 Hz, 3H); LC-MS: m/z 344.1 [M+H].sup.+.

Example 16

(95) ##STR00080##

(96) 1-(2-(3-iso-butoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(97) The specific reaction scheme is as shown below:

(98) ##STR00081##

(99) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromo-isobutane (27 mg, 0.2 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added, and stirred for 2 hours at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-iso-butoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 40%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.02 (dd, J=8.4, 2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.76 (d, J=14.4 Hz, 1H), 6.60 (d, J=14.4 Hz, 1H), 6.30 (s, 2H), 3.92 (s, 3H), 3.81 (d, J=6.8 Hz, 2H), 2.27 (s, 6H), 2.25-2.17 (m, 1H), 1.08 (d, J=6.8 Hz, 6H); LC-MS: m/z 344.1 [M+H].sup.+.

Example 17

(100) ##STR00082##

(101) 1-(2-(3-n-pentyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(102) The specific reaction scheme is as shown below:

(103) ##STR00083##

(104) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromopentane (105 mg, 0.7 mmol) and potassium carbonate (97 mg, 0.7 mmol) were added, and stirred for 5 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-n-pentyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 32%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.07 (s, 2H), 6.03 (s, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.96 (s, 3H), 2.53 (s, 6H), 1.86-1.79 (m, 2H), 1.52-1.36 (m, 4H), 0.95 (t, J=7.2 Hz, 3H); LC-MS: m/z 358.1 [M+H].sup.+.

Example 18

(105) ##STR00084##

(106) 1-(2-(3-n-hexyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(107) The specific reaction scheme is as shown below:

(108) ##STR00085##

(109) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromon-hexane (115 mg, 0.7 mmol) and potassium carbonate (97 mg, 0.7 mmol) were added and stirred for 5 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-n-hexyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (43 mg, yield 66%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.08 (s, 2H), 6.04 (s, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.96 (s, 3H), 2.53 (s, 6H), 1.86-1.78 (m, 2H), 1.54-1.46 (m, 2H), 1.40-1.34 (m, 4H), 0.93 (t, J=7.2 Hz, 3H); LC-MS: m/z 372.0 [M+H].sup.+.

Example 19

(110) ##STR00086##

(111) 1-(2-(3-cyclopropyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(112) The specific reaction scheme is as shown below:

(113) ##STR00087##

(114) Step A:

(115) The compound 3-hydroxy-4-methoxybenzaldehyde (1 g, 6.6 mmol), bromo-cyclopropane (2.4 mg, 19.8 mmol), cesium carbonate (6.5 g, 19.8 mmol), and potassium iodide (168 mg, 0.15 mmol) were dissolved in N, N-dimethylformamide (10 mL), stirred for 1 hr in a sealed tube at 180° C. under nitrogen atmosphere, then heated to 220° C., and stirred for another 1 hr. After the reaction was completed, saturated saline (20 mL) was added, and extracted with dichloromethane (3×20 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by column chromatography gave 3-cyclopropyloxy-4-methoxybenzaldehyde (170 mg, yield 13%, pale yellow oil). LC-MS: m/z 193.4 [M+H].sup.+.

(116) Step B:

(117) 3-cyclopropyloxy-4-methoxybenzaldehyde (170 mg, 0.88 mmol) was dissolved in dichloromethane (4 mL); and under nitrogen atmosphere, triethyl amine (356 mg, 3.52 mmol) and trimethylsilyl cyanide (349 mg, 3.52 mmol) were added, and stirred for 6 hours at room temperature. After the reaction was completed, the reaction solution was concentrated and rotary dried to obtain 2-(3-cyclopropyloxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile, which was directly used in the next reaction.

(118) Step C:

(119) 2-(3-cyclopropyloxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile obtained in the above step was dissolved in anhydrous tetrahydrofuran (20 mL), and then lithium aluminum hydride (100 mg, 2.6 mmol) was added portion-wise in an ice bath and stirred overnight at room temperature. After the reaction was completed, water (0.1 mL), an aqueous sodium hydroxide solution (0.1 mL, 15%), and water (0.3 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried to obtain a crude product of 2-amino-1-(3-cyclopropyloxy-4-methoxyphenyl)ethanol (300 mg).

(120) Step D:

(121) 2-Amino-1-(3-(cyclopropyloxy)-4-methoxyphenyl)ethanol obtained in the above step was dissolved in ethanol (5 mL), and then 2,6-dimethyl-4H-pyran-4-one (124 mg, 1 mmol) and aqueous sodium hydroxide solution (2 M, 2 mL) were added, and stirred overnight at 60° C. The reaction was complete as indicated by LCMS. The reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropyloxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 34%, white solid). LC-MS: m/z 330.1 [M+1-1].sup.+.

(122) Step E:

(123) 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (30 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), and stirred for 2 hours at normal temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain 1-(2-(3-cyclopropyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (15 mg, yield 45%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.97 (dd, J=8.4, 2.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.44 (s, 2H), 5.75 (s, 2H), 4.02 (s, 3H), 2.32 (s, 6H), 2.23-2.19 (m, 1H), 0.94-0.90 (m, 4H); LC-MS: m/z 328.1 [M+H].sup.+.

Example 20

(124) ##STR00088##

(125) 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxo)ethyl-2,6-dimethylpyridin-4(1H)-one

(126) The specific reaction scheme is as shown below:

(127) ##STR00089##

(128) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromomethylcyclopropane (27 mg, 0.2 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added, and stirred for 2 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (36 mg, yield 62%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.79 (dd, J=8.4, 2.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 5.99 (s, 2H), 5.62 (s, 2H), 3.90 (s, 3H), 3.53 (d, J=6.8 Hz, 2H), 2.11 (s, 6H), 1.26-1.21 (m, 1H), 0.62-0.56 (m, 2H), 0.36-0.31 (m, 2H); LC-MS: m/z 342.1 [M+H].sup.+.

Example 21

(129) ##STR00090##

(130) The specific reaction scheme is as shown below:

(131) ##STR00091##

(132) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then cyclobutyl bromide (69 mg, 0.51 mmol) and potassium carbonate (71 mg, 0.51 mmol) were added and stirred for 5 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-cyclobutyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (16 mg, yield 26%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.85 (d, J=8.4 Hz, 1H), 7.45 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (s, 2H), 5.99 (s, 2H), 4.79-4.73 (m, 1H), 3.96 (s, 3H), 2.51 (s, 6H), 2.51-2.45 (m, 1H), 2.23-2.13 (m, 1H), 1.91-1.83 (m, 1H), 1.79-1.70 (m, 1H); LC-MS: m/z 342.1 [M+H].sup.+.

Example 22

(133) ##STR00092##

(134) 1-(2-(3-cyclobutylmethoxy-4-methoxyphenyl)-2-oxo)ethyl-2,6-dimethylpyridin-4(1H)-one

(135) The specific reaction scheme is as shown below:

(136) ##STR00093##

(137) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromomethylcyclobutane (76 mg, 0.51 mmol) and potassium carbonate (71 mg, 0.51 mmol) were added, and stirred for 4 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-cyclobutylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (16 mg, yield 24%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.84 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.91 (s, 2H), 5.95 (s, 2H), 4.04 (d, J=6.8 Hz, 2H), 3.95 (s, 3H), 2.84-2.78 (m, 1H), 2.47 (s, 6H), 2.20-2.10 (m, 2H), 2.02-1.86 (m, 4H); LC-MS: m/z 356.2 [M+H].sup.+.

Example 23

(138) ##STR00094##

(139) 1-(2-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(140) The specific reaction scheme is as shown below:

(141) ##STR00095##

(142) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromocyclopentane (76 mg, 0.51 mmol) and potassium carbonate (71 mg, 0.51 mmol) were added, and stirred for 4 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-cyclopentyl-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 33%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.84 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.39 (s, 2H), 5.71 (s, 2H), 4.95-4.91 (m, 1H), 3.96 (s, 3H), 2.31 (s, 6H), 2.01-1.80 (m, 6H), 1.71-1.61 (m, 2H); LC-MS m/z 356.2 [M+H].sup.+.

Example 24

(143) ##STR00096##

(144) 1-(2-(3-cyclohexyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(145) The specific reaction scheme is as shown below:

(146) ##STR00097##

(147) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromocycloohexane (83 mg, 0.51 mmol) and potassium carbonate (71 mg, 0.51 mmol) were added, and stirred for 4 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-cyclohexyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (8 mg, yield 13%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.86 (d, J=8.4 Hz, 1H), 7.63 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.04 (s, 2H), 6.00 (s, 2H), 4.39-4.32 (m, 1H), 3.95 (s, 3H), 2.52 (s, 6H), 2.02-1.93 (m, 2H), 1.86-1.77 (m, 2H), 1.62-1.52 (m, 2H), 1.45-1.28 (m, 4H); LC-MS m/z 370.2 [M+H].sup.+.

Example 25

(148) ##STR00098##

(149) 1-(2-(3-(cyclopent-3-en-1-yloxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(150) The specific reaction scheme is as shown below:

(151) ##STR00099##

(152) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (30 mg, 0.11 mmol) was dissolved in acetonitrile (5 mL), and then cyclopent-3-en-1-yl methanesulfonate (68 mg, 0.42 mmol) and potassium carbonate (58 mg, 0.42 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain 1-(2-(3-(cyclopent-3-en-1-yloxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (12 mg, yield 32%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.85 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.18 (s, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.04-5.91 (m, 2H), 5.77 (s, 2H), 5.17-5.11 (m, 1H), 3.96 (s, 3H), 2.95-2.89 (m, 2H), 2.63-2.60 (m, 2H), 2.53 (s, 6H); LC-MS m/z 354.2 [M+H].sup.+.

Example 26

(153) ##STR00100##

(154) 1-(2-(3-allyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(155) The specific reaction scheme is as shown below:

(156) ##STR00101##

(157) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 3-bromopropene (26 mg, 0.21 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-allyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 42%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.83 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.34 (s, 2H), 6.14-6.03 (m, 1H), 5.68 (s, 2H), 5.43 (d, J=17.2 Hz, 1H), 5.27 (d, J=10.4 Hz, 1H), 4.64 (d, J=4.8 Hz, 2H), 3.95 (s, 3H), 2.26 (s, 6H). LC-MS m/z 328.2 [M+H].sup.+.

Example 27

(158) ##STR00102##

(159) 1-(2-(3-((3-methylbut-2-en-1-yl)oxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(160) The specific reaction scheme is as shown below:

(161) ##STR00103##

(162) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromo-3-methyl-2-butene (31 mg, 0.21 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added, and stirred for 1 hr 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-((3-methylbut-2-en-1-yl)oxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 40%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.63 (d, J=8.4 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.32 (s, 2H), 5.51 (d, J=6.8 Hz, 1H), 5.32 (s, 2H), 4.65 (d, J=6.8 Hz, 2H), 3.98 (s, 3H), 2.21 (s, 6H), 1.79 (s, 3H), 1.77 (s, 3H); LC-MS m/z 356.2 [M+H].sup.+.

Example 28

(163) ##STR00104##

(164) 1-(2-(3-propargyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(165) The specific reaction scheme is as shown below:

(166) ##STR00105##

(167) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then propargyl bromide (25 mg, 0.21 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added, and stirred for 4 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-propargyloxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (21 mg, yield 35%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.03 (s, 2H), 5.78 (s, 2H), 4.85 (d, J=2.4 Hz, 2H), 4.00 (s, 3H), 2.56 (t, J=2.4 Hz, 3H), 2.46 (s, 6H); LC-MS: m/z 326.3 [M+H].sup.+.

Example 29

(168) ##STR00106##

(169) 1-(2-(3-(but-2-yn-1-yloxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(170) The specific reaction scheme is as shown below:

(171) ##STR00107##

(172) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromo-2-butyne (83 mg, 0.70 mmol) and potassium carbonate (97 mg, 0.70 mmol) were added, and stirred for 2 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-(but-2-yn-1-yloxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (14 mg, yield 23%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.90 (dd, J=8.4, 2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.09 (s, 2H), 6.03 (s, 2H), 4.78 (q, J=2.4 Hz, 2H), 3.96 (s, 3H), 2.54 (s, 6H), 1.82 (t, J=2.4 Hz, 3H); LC-MS: m/z 340.0 [M+H].sup.+.

Example 30

(173) ##STR00108##

(174) 1-(2-(3-(oxacyclobutan-3-yl-oxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(175) ##STR00109##

(176) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (158 mg, 0.55 mmol), oxacyclobutan-3-ol (81.4 mg, 1.1 mmol) and triphenylphosphine (288 mg, 1.1 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), the reaction solution was cooled in an ice bath, diisopropyl azodicarboxylate (222 mg, 1.1 mmol) was added dropwise over 5 min under nitrogen atmosphere, and then reacted for 24 hours at room temperature. After the reaction was completed, saturated saline (20 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-(oxacyclobutan-3-yl-oxy)-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (45 mg, yield 24%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.84 (dd, J=8.4, 2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.13 (s, 2H), 6.06 (s, 2H), 5.38-5.32 (m, 1H), 5.06-5.02 (m, 2H), 4.78-4.75 (m, 2H), 4.00 (s, 3H), 2.56 (s, 6H); LC-MS: m/z 344.4 [M+H].sup.+.

Example 31

(177) ##STR00110##

(178) 1-(2-(3-(tetrahydrofuran-2-yl)oxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(179) The specific reaction scheme is as shown below:

(180) ##STR00111##

(181) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and then 2,3-dihydrofuran (68 mg, 0.42 mmol) and pyridinium toluene-4-sulphonate (4.6 mg, 0.018 mmol) were added, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain 14243-(tetrahydrofuran-2-yl)oxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (28 mg, yield 44%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.87 (dd, J=8.4, 2.0 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.40 (s, 2H), 5.87 (d, J=4.4 Hz, 1H), 5.70 (s, 2H), 4.07-4.02 (m, 1H), 3.97-3.92 (m, 1H), 3.94 (s, 3H), 2.31-2.11 (m, 4H), 2.29 (s, 6H); LC-MS m/z 358.1 [M+H].sup.+.

Example 32

(182) ##STR00112##

(183) 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(184) ##STR00113##

(185) Step A:

(186) Under nitrogen atmosphere, 3-hydroxy-4-methoxybenzaldehyde (2 g, 13 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then chloromethyl methyl sulfide (1.5 g, 15.6 mmol) and cesium carbonate (6 g, 19.5 mmol) were added and stirred overnight at room temperature under nitrogen atmosphere. After the reaction was completed, saturated saline (40 mL) was added, and extracted with dichloromethane (3×30 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by column chromatography gave 3-methylthiomethoxy-4-methoxybenzaldehyde (1.7 g, yield 61%, yellow oil). LC-MS: m/z 213.1 [M+H].sup.+.

(187) Step B:

(188) 3-methylthiomethoxy-4-methoxybenzaldehyde (1.7 g, 8 mmol) was dissolved in dichloromethane (20 mL); and under nitrogen atmosphere, triethyl amine (1.6 g, 16 mmol) and trimethylsilyl cyanide (1.6 g, 16 mmol) were added, and stirred for 6 hours at room temperature. The reaction solution was concentrated and rotary dried to obtain 2-(3-methylthiomethoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile, which was directly used in the next reaction.

(189) Step C:

(190) 2-(3-Methylthiomethoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile obtained in the above step was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium aluminum hydride (608 mg, 16 mmol) was added portion-wise in an ice bath and stirred overnight at room temperature. After the reaction was completed, water (0.6 mL), an aqueous sodium hydroxide solution (0.6 mL, 15%), and water (1.8 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary dried to obtain a crude product of 2-amino-1-(3-methylthiomethoxy-4-methoxyphenyl)ethanol.

(191) Step D:

(192) 2-Amino-1-(3-(methylthiomethoxy)-4-methoxyphenyl)ethanol obtained in the above step was dissolved in ethanol (10 mL), and then 2,6-dimethyl-4-pyranone (1.24 g, 10 mmol) and an aqueous sodium hydroxide solution (2 M, 10 mL) were added, and stirred overnight at 60° C. The reaction was complete as indicated by LCMS. The reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (1 g, 35%). LC-MS: m/z 350.1 [M+H].sup.+.

(193) Step E:

(194) 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.14 mmol) was dissolved in dimethylsulfoxide (5 mL), and then sulfur trioxide pyridine complex (111 mg, 0.7 mmol) in DMSO (2.5 mL) was slowly added and stirred overnight at normal temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 51%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.67 (dd, J=8.4, 2.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.28 (s, 2H), 5.31 (s, 2H), 5.23 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 2.12 (s, 6H); LC-MS: m/z 348.2 [M+H].sup.+.

Example 33

(195) ##STR00114##

(196) 1-(2-(3-methylsulfoxidemethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(197) The specific reaction scheme is as shown below:

(198) ##STR00115##

(199) Step A:

(200) 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (56 mg, 0.28 mmol) was added and stirred at room temperature for 2 hours. Then, a saturated aqueous sodium sulfite solution (5 mL) was added and stirred for 10 min. The reaction solution was extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by column chromatography gave 1-(2(3-methylsulfoxidemethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (38 mg, yield 36%, white solid). LC-MS: m/z 366.2 [M+H].sup.+.

(201) Step B:

(202) 1-(2(3-methylsulfoxidemethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (38 mg, 0.1 mmol) was dissolved in dichloromethane (10 mL), and then the Dess-Martin Periodinane (85 mg, 0.2 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was filtered, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by reverse-phase HPLC to obtain 1-(2-(3-methylsulfoxidemethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (10 mg, yield 37%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.93 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.4, 2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.26 (s, 2H), 5.25 (s, 2H), 5.23 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 2.12 (s, 6H); LC-MS: m/z 364.2 [M+H].sup.+.

Example 34

(203) ##STR00116##

(204) 1-(2-(3-methylsulfonemethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(205) The specific reaction scheme is as shown below:

(206) ##STR00117##

(207) Step A:

(208) 1-(2-(3-methylthiomethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 0.29 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (176 mg, 0.87 mmol) was added and stirred overnight at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added and stirred for 10 min. The reaction solution was extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by column chromatography gave 1-(2-(3-methylsulfonemethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, yield 55%, white solid). LC-MS: m/z 382.2 [M+H].sup.+.

(209) Step B:

(210) 1-(2-(3-methylsulfonemethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.13 mmol) was dissolved in dichloromethane (10 mL), and then the Dess-Martin Periodinane (110 mg, 0.26 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was filtered, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by reverse-phase HPLC to obtain 1-(2-(3-methylsulfoxidemethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 61%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.84 (dd, J=8.4, 2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.26 (s, 2H), 5.35 (s, 2H), 5.23 (s, 2H), 3.98 (s, 3H), 3.78 (s, 3H), 2.25 (s, 6H); LC-MS: m/z 380.1 [M+H].sup.+.

Example 35

(211) ##STR00118##

(212) 1-(2-(3-methylthioethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(213) The specific reaction scheme is as shown below:

(214) ##STR00119##

(215) The compound 1-(2-(3-hydroxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (287 mg, 1 mmol) was dissolved in N, N-dimethylformamide (5 mL), and then chloroethyl methyl sulfide (166 mg, 1.5 mmol) and potassium carbonate (276 mg, 2 mmol) were added and stirred for 2 hours at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave 1-(2-(3-methylthioethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one 200 mg, yield 55%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.66 (dd, J=8.4, 2.0 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.28 (s, 2H), 5.31 (s, 2H), 4.27 (t, J=6.8 Hz, 2H), 3.98 (s, 3H), 2.95 (t, J=6.8 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 6H); LC-MS: m/z 362.2 [M+H].sup.+.

Example 36

(216) ##STR00120##

(217) 1-(2-(3-methylsulfoxideethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(218) The specific reaction scheme is as shown below:

(219) ##STR00121##

(220) The compound 1-(2-(3-methylthioethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (28 mg, 0.14 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoxideethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 40%, colorless oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.71 (dd, J=8.4, 2.0 Hz, 1H), 7.66 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.26 (s, 2H), 5.32 (s, 2H), 4.57-4.54 (m, 2H), 3.97 (s, 3H), 3.35-3.31 (m, 1H), 3.15-3.09 (m, 1H), 2.75 (s, 3H), 2.18 (s, 6H); LC-MS: m/z 378.2 [M+H].sup.+.

Example 37

(221) ##STR00122##

(222) 1-(2-(3-methylsulfoneethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(223) The specific reaction scheme is as shown below:

(224) ##STR00123##

(225) The compound 1-(2-(3-methylthioethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (71 mg, 0.35 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoneethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 36%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.74 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.26 (s, 2H), 5.30 (s, 2H), 4.53 (t, J=4.2 Hz, 2H), 3.95 (s, 3H), 3.51 (t, J=4.2 Hz, 2H), 3.18 (s, 3H), 2.18 (s, 6H); LC-MS: m/z 394.2 [M+H].sup.+.

Example 38

(226) ##STR00124##

(227) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(228) ##STR00125##

(229) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(230) The specific reaction scheme is as shown below:

(231) ##STR00126##

(232) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (341 mg, 1 mmol) and hydroxylamine hydrochloride (139 mg, 2 mmol) were dissolved in pyridine (10 mL), and refluxed for 24 hours under nitrogen atmosphere. After the reaction was completed, pyridine was rotary dried, and the reaction solution was purified by reverse-phase HPLC to obtain (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (96 mg, yield 27%, white solid) and (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (43 mg, yield 12%, white solid).

(233) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.45 (d, J=2.0 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 2.0 Hz, 1H), 6.48 (s, 2H), 5.00 (s, 2H), 3.92 (s, 3H), 3.89 (d, J=6.8 Hz, 2H), 2.41 (s, 6H), 1.42-1.32 (m, 1H), 0.68-0.62 (m, 2H), 0.40-0.35 (m, 2H); LC-MS: m/z 357.4 [M+H].sup.+.

(234) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.50 (d, J=2.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.93 (dd, J=8.4, 2.0 Hz, 1H), 6.49 (s, 2H), 5.00 (s, 2H), 3.92 (s, 3H), 3.89 (d, J=6.8 Hz, 2H), 2.41 (s, 6H), 1.42-1.32 (m, 1H), 0.68-0.62 (m, 2H), 0.40-0.35 (m, 2H); LC-MS: m/z 357.4 [M+H].sup.+.

Example 39

(235) ##STR00127##

(236) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(237) The specific reaction scheme is as shown below:

(238) ##STR00128##

(239) The compound (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (36 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 60% sodium hydride (12 mg, 0.3 mmol) was added at 0° C., and stirred for half an hour. Then, iodomethane (28.4 mg, 0.2 mmol) was added, and stirred at room temperature for 4 hours. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 55%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.46 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.02 (dd, J=8.4, 2.0 Hz, 1H), 6.52 (s, 2H), 5.02 (s, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (d, J=6.8 Hz, 2H), 2.45 (s, 6H), 1.32-1.23 (m, 1H), 0.70-0.65 (m, 2H), 0.50-0.38 (m, 2H); LC-MS: m/z 371.2 [M+H].sup.+.

Example 40

(240) ##STR00129##

(241) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxymethylimido) ethyl)-2,6-dimethylpyridin-4(1H)-one

(242) The specific reaction scheme is as shown below:

(243) ##STR00130##

(244) The compound (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (36 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 60% sodium hydride (12 mg, 0.3 mmol) was added at 0° C., and stirred for half an hour. Then, iodomethane (28.4 mg, 0.2 mmol) was added, and stirred at room temperature for 4 hours. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (18 mg, yield 49%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.51 (d, J=2.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.4, 2.0 Hz, 1H), 6.46 (s, 2H), 5.00 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 3.88 (d, J=6.8 Hz, 2H), 2.49 (s, 6H), 1.42-1.32 (m, 1H), 0.68-0.62 (m, 2H), 0.40-0.35 (m, 2H); LC-MS: m/z 371.2 [M+H].sup.+.

Example 41

(245) ##STR00131##

(246) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(247) The specific reaction scheme is as shown below:

(248) ##STR00132##

(249) The compound (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (300 mg, 0.84 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then cesium carbonate (548 mg, 1.68 mmol) and chloromethylmethyl sulfide (122 mg, 1.26 mmol) were added, and stirred overnight at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (200 mg, yield 57%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.23 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.96 (s, 2H), 6.35 (s, 2H), 5.18 (s, 2H), 3.91 (s, 2H), 3.85 (d, J=6.8 Hz, 2H), 2.47 (s, 6H), 2.40 (s, 3H), 1.36-1.28 (m, 1H), 0.69-0.64 (m, 2H), 0.35-0.32 (m, 2H); LC-MS: m/z 417.1 [M+H].sup.+.

Example 42

(250) ##STR00133##

(251) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(252) The specific reaction scheme is as shown below:

(253) ##STR00134##

(254) The compound (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(hydroxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (36 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then cesium carbonate (65 mg, 0.2 mmol) and chloromethylmethyl sulfide (15 mg, 0.15 mmol) were added. and stirred overnight at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 48%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.36 (d, J=8.4 Hz, 1H), 7.25 (s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.86 (s, 2H), 6.38 (s, 2H), 5.10 (s, 2H), 3.96 (s, 2H), 3.90 (d, J=6.8 Hz, 2H), 2.47 (s, 6H), 2.40 (s, 3H), 1.36-1.28 (m, 1H), 0.69-0.64 (m, 2H), 0.35-0.32 (m, 2H); LC-MS: m/z 417.1 [M+H].sup.+.

Example 43

(255) ##STR00135##

(256) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylsulfoxidemethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(257) The specific reaction scheme is as shown below:

(258) ##STR00136##

(259) The compound (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (42 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (18 mg, 0.09 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylsulfoxidemethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 46%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.28 (d, J=8.4 Hz, 1H), 7.21 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.90 (s, 2H), 6.36 (s, 2H), 5.15 (s, 2H), 3.94 (s, 2H), 3.88 (d, J=6.8 Hz, 2H), 2.46 (s, 6H), 2.42 (s, 3H), 1.38-1.30 (m, 1H), 0.69-0.65 (m, 2H), 0.38-0.33 (m, 2H); LC-MS: m/z 433.2 [M+H].sup.+.

Example 44

(260) ##STR00137##

(261) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylsulfonemethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one

(262) The specific reaction scheme is as shown below:

(263) ##STR00138##

(264) The compound (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylthiomethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (42 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (61 mg, 0.3 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(methylsulfonemethoxyimido)ethyl)-2,6-dimethylpyridin-4(1H)-one (26 mg, yield 58%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.23 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.96 (s, 2H), 6.35 (s, 2H), 5.18 (s, 2H), 3.91 (s, 2H), 3.85 (d, J=6.8 Hz, 2H), 2.47 (s, 6H), 2.40 (s, 3H), 1.36-1.28 (m, 1H), 0.69-0.64 (m, 2H), 0.35-0.32 (m, 2H); LC-MS: m/z 449.2 [M+H].sup.+.

Example 45

(265) ##STR00139##

(266) 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)pyridin-4(1H)-one

(267) The specific reaction scheme is as shown below:

(268) ##STR00140##

(269) Step A:

(270) 3-cyclopropylmethoxy-4-methoxybenzaldehyde (3.09 g, 15 mmol) was dissolved in dichloromethane (30 mL); and under nitrogen atmosphere, triethyl amine (4.16 mL, 30 mmol) and trimethylsilyl cyanide (3.75 g, 30 mmol) were added, and stirred for 6 hours at room temperature. The reaction solution was concentrated and rotary dried to obtain 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile, which was directly used in the next reaction.

(271) Step B:

(272) The compound 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-trimethylsiloxyacetonitrile (4.57 g, 15 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium aluminum hydride (1.14 g, 30 mmol) was added portion-wise in an ice bath, and stirred overnight at room temperature. After the reaction was completed, water (1.2 mL), an aqueous sodium hydroxide solution (1.2 mL, 15%), and water (3.6 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 2-amino-1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanol.

(273) Step C:

(274) The compound 2-amino-1-(3-(cyclopropylmethoxy)-4-methoxyphenyl)ethanol was dissolved in ethanol (20 mL), and then pyrone (1 g, 10.41 mmol) and aqueous sodium hydroxide solution (2M, 20 mL) were added, and stirred overnight at 60° C. The reaction was complete as indicated by LCMS. The reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (2 g, 63%). LC-MS: m/z 316.2 [M+H].sup.+.

(275) Step D:

(276) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (280 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL); and under nitrogen atmosphere, Dess-Martin Periodinane (746 mg, 1.76 mmol) was added, and stirred for 3 hours at room temperature. After the reaction was completed, the reaction solution was concentrated, rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)pyridin-4(1H)-one (50 mg, yield 18%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.83 (d, J=7.6 Hz, 2H), 7.68 (dd, J=8.4, 1.2 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.47 (d, J=7.6 Hz, 2H), 5.72 (s, 2H), 3.89 (s, 3H), 3.87 (d, J=6.8 Hz, 2H), 1.26-1.21 (m, 1H), 0.62-0.56 (m, 2H), 0.36-0.31 (m, 2H); LC-MS: m/z 314.1 [M+H].sup.+.

Example 46

(277) ##STR00141##

(278) 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one

(279) The specific reaction scheme is as shown below.

(280) ##STR00142##

(281) Step A:

(282) 3-hydroxy-4-methoxyacetophenone (1.66 g, 10 mmol) was dissolved in acetonitrile (30 mL); and under nitrogen atmosphere, potassium carbonate (2.76 g, 20 mmol) and bromomethylcyclopropane (2.0 g, 15 mmol) were added, and stirred for 6 hours at 80° C. The reaction solution was filtered. The filtrate was concentrated, rotary dried, and purified by column chromatography to obtain 1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanone (2.1 g, yield 95%, white solid).

(283) Step B:

(284) The compound 1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanone (2.2 g, 10 mmol) was dissolved in methanol (30 mL), and then N-bromosuccinimide (2.14 g, 12 mmol) and p-toluenesulfonic acid (1.7 g, 10 mmol) were added to the solution and reacted at 65° C. for hours. After the reaction was completed, the reaction solution was concentrated, rotary dried, and purified by column chromatography to obtain 2-bromo-1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanone (800 mg, yield 27%, white solid).

(285) Step C:

(286) The compound 2-bromo-1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanone (185 mg, 1.5 mmol) and 4-methoxy-2methylpyridine (500 mg, 1.67 mmol) were dissolved in acetonitrile (10 mL), and stirred at 80° C. for 48 hours. After the reaction was completed, the reaction solution was concentrated, rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (300 mg, yield 61%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.76 (dd, J=8.4, 2.0 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.42-6.38 (m, 2H), 5.72 (s, 2H), 3.95 (s, 3H), 3.91 (d, J=6.8 Hz, 2H), 2.24 (s, 3H), 1.34-1.24 (m, 1H), 0.66-0.60 (m, 2H), 0.39-0.34 (m, 2H); LC-MS: m/z 328.1 [M+H].sup.+.

Example 47

(287) ##STR00143##

(288) 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-chloropyridin-4(1H)-one

(289) The specific reaction scheme is as shown below:

(290) ##STR00144##

(291) 2-bromo-1-(3-cyclopropylmethoxy-4-methoxyphenyl)ethanone (594 mg, 2 mmol) and 4-methoxy-2chloropyridine (288 mg, 2 mmol) were dissolved in acetonitrile (10 mL), and stirred at 80° C. for 48 hours. After the reaction was completed, the reaction solution was concentrated, rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-chloropyridin-4(1H)-one (117 mg, yield 17%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (d, J=7.6 Hz, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.18 (dd, J=8.0, 2.4 Hz, 1H), 5.77 (s, 2H), 3.89 (s, 3H), 3.87 (d, J=6.8 Hz, 2H), 1.27-1.22 (m, 1H), 0.62-0.56 (m, 2H), 0.36-0.32 (m, 2H); LC-MS: m/z 348.0 [M+H].sup.+.

Example 48

(292) ##STR00145##

(293) 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropyl)-2,6-dimethylpyridin-4(1H)-one

(294) ##STR00146##

(295) Step A:

(296) 3-hydroxy-4-methoxycinnamic acid (194 mg, 1 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromomethylcyclopropane (338 mg, 2.5 mmol) and potassium carbonate (414 mg, 3 mmol) were added. The reaction solution was stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by column chromatography to obtain cyclopropylmethyl 3-cyclopropylmethoxy-4-methoxycinnamate (200 mg, yield 61%, yellow liquid). LC-MS: m/z 303.3 [M+H].sup.+.

(297) Step B:

(298) Under nitrogen atmosphere, dimethylsulfoxide (4 mL), 60% sodium hydride (28.8 mg, 0.36 mmol) and trimethylsulfoxonium iodide (160 mg, 0.36 mmol) were stirred for 20 min at room temperature. A solution (2 mL) of cyclopropylmethyl 3-cyclopropylmethyl-4-methoxycinnamate (200 mg, 0.66 mmol) in tetrahydrofuran was slowly added. After the dropwise addition, the reaction solution was stirred at room temperature for 1 hr, then heated to 50° C. and continuously stirred for 1 hr. After the reaction was completed, the reaction solution was poured into iced water, and extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by column chromatography to obtain cyclopropylmethyl 2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropylcarboxylate (80 mg, yield 56%, white solid). LC-MS: m/z 317.3 [M+H].sup.+.

(299) Step C:

(300) Cyclopropylmethyl 2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropylcarboxylate (80 mg, 0.25 mmol) was dissolved in methanol (2 mL), and then a sodium hydroxide solution (2N, 1 mL) was added, and stirred for 2 hr under reflux. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification gave 2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropylcarboxylic acid (50 mg, yield 76%, white solid).

(301) Step D:

(302) ##STR00147##

(303) 2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropylcarboxylic acid (50 mg, 0.19 mmol) was dissolved in 1,4-dioxane (2 mL), and then triethyl amine (26 mg, 0.26 mmol) and diphenylphosphoryl azide (64 mg, 0.26 mmol) were added. This reaction solution was stirred for 16 hours at room temperature, then heated to 80° C. and stirred for 1 hr. A mixture of 10% hydrochloric acid in 1,4-dioxane was added and continuously stirred at room temperature for 18 hours. After the reaction was completed, the reaction was quenched by adding a sodium hydroxide solution (1 mL, 3N), and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification gave 2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropylamine (12 mg, yield: 25%, yellow oil).

(304) Step E

(305) ##STR00148##

(306) The compound 2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropylamine (60 mg, 0.24 mmol) was dissolved in ethanol (3 mL), and then 2,6-dimethyl-4H-pyran-4-one (45 mg, 0.36 mmol) and sodium hydroxide (20 mg, 0.48 mmol) were added, and stirred overnight at 60° C. The reaction was complete as indicated by LCMS. The reaction solution was rotary dried, and purified to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclopropyl)-2,6-dimethylpyridin-4(1H)-one (10 mg, yield 11%, yellow oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 6.83 (d, J=8.8 Hz, 1H), 6.75-6.58 (m, 2H), 6.18 (s, 2H), 3.76 (d, J=6.8 Hz, 2H), 3.73 (s, 3H), 2.40 (s, 6H), 1.63-1.54 (m, 2H), 1.29-1.12 (m, 2H), 0.54-0.48 (m, 2H), 0.26-0.22 (m, 2H); LC-MS: m/z 340.0 [M+H].sup.+.

Example 49

(307) ##STR00149##

(308) 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one

(309) The specific reaction scheme is as shown below:

(310) ##STR00150##

(311) Step A:

(312) At room temperature, 3-hydroxy-4-difluoromethoxybenzaldehyde (1.88 g, 10.0 mmol) was dissolved in acetonitrile (10 mL), and then potassium carbonate (2.07 g, 15.0 mmol) and bromomethylcyclopropane (1.76 g, 13.0 mmol) were added in sequence, and heated to 80° C. for 3 hours with stirring under nitrogen atmosphere. After the reaction was completed, saturated saline (30 mL) was added, and extracted with ethyl acetate (3×60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by reverse-phase HPLC to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (2.20 g, 91%). LC-MS: m/z 243.2 [M+H].sup.+.

(313) Step B:

(314) The compound 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (2.20 g, 9.1 mmol) was dissolved in dichloromethane (30 mL), and then triethyl amine (1.84 g, 18.2 mmol) and trimethylsilyl cyanide (2.7 g, 27.3 mmol) were added in sequence in an ice bath and stirred for 16 hours under nitrogen atmosphere at room temperature. After the reaction was completed, the reaction solution was directly rotary dried to obtain the product 2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-trimethylsiloxyacetonitrile (3.1 g, 100%), which was directly used in the next reaction.

(315) Step C:

(316) The compound 2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-trimethylsiloxyacetonitrile (3.1 g, 9.1 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and then lithium aluminum hydride (1.04 g, 27.3 mmol) was added portion-wise in an ice bath, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was diluted with anhydrous tetrahydrofuran (200 mL), and extracted with water (1 mL). An aqueous sodium hydroxide solution (3 mL, 1M) and then water (3 mL) were added, stirred for half an hour, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 2-amino-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanol (2.70 g, 100%). LC-MS: m/z 258.1 [M−18+1].sup.+.

(317) Step D:

(318) The compound 2-amino-1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanol (2.70 g, 9.1 mmol) was dissolved in ethanol (30 mL), and then 2,6-dimethyl-4H-pyran-4-one (1.86 g, 15.0 mmol), sodium hydroxide (0.60 g, 15.0 mmol) and water (10 mL) were added in sequence, heated to 60° C., and stirred for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified to obtain 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (2.4 g, 69%). LC-MS: m/z 380.2 [M+H].sup.+.

(319) Step E

(320) The compound 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.13 mmol) was dissolved in dichloromethane (10 mL), and then the Dess-Martin Periodinane (110 mg, 0.26 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was filtered, and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by reverse-phase HPLC to obtain 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (35 mg, yield 72%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.66 (s, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 6.79 (t, J.sub.H-F=74.4 Hz, 1H), 6.45 (s, 2H), 5.50 (s, 2H), 3.99 (d, J=7.2 Hz, 2H), 2.26 (s, 6H) 1.37-1.28 (m, 1H), 0.72-0.66 (m, 2H), 0.43-0.37 (m, 2H); LC-MS: m/z 378.3 [M+H].sup.+.

Example 50

(321) ##STR00151##

(322) (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)pyridin-4(1H)-one

(323) The specific reaction scheme is as shown below:

(324) ##STR00152##

(325) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)pyridin-4(1H)-one (270 mg, 0.86 mmol) and p-toluenesulfonic acid (443 mg, 2.58 mmol) were dissolved in toluene (5 mL), and stirred overnight under reflux. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)pyridin-4(1H)-one (50 mg, yield 20%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.02 (d, J=7.6 Hz, 2H), 7.52 (d, J=14.4 Hz, 1H), 7.10 (s, 1H), 6.97-6.93 (m, 2H), 6.85 (d, J=14.4 Hz, 1H), 6.21 (d, J=7.6 Hz, 2H), 3.83 (d, J=7.2 Hz, 2H), 3.77 (s, 3H), 1.26-1.21 (m, 1H), 0.62-0.56 (m, 2H), 0.36-0.31 (m, 2H); LC-MS: m/z 298.1 [M+H].sup.+.

Example 51

(326) ##STR00153##

(327) (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2-methylpyridin-4(1H)-one

(328) The specific reaction scheme is as shown below:

(329) ##STR00154##

(330) Step A:

(331) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (654 mg, 2 mmol) was dissolved in methanol (10 mL), and then sodium borohydride (114 mg, 3 mmol) was added portion-wise and stirred at room temperature for 3 hours.

(332) After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added, and the reaction solution was filtered, concentrated, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (620 mg, yield 95%, white solid). LC-MS: m/z 330.4 [M+H].sup.+

(333) Step B:

(334) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (620 mg, 1.88 mmol) and p-toluenesulfonic acid (970 mg, 5.64 mmol) were dissolved in toluene (15 mL), and stirred overnight under reflux. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2-methylpyridin-4(1H)-one (520 mg, yield 84%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.32 (d, J=7.2 Hz, 1H), 7.65 (d, J=14.0 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.12 (dd, J=8.4, 1.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.95 (d, J=14.0 Hz, 1H), 6.66-6.62 (m, 2H), 3.86 (d, J=7.2 Hz, 2H), 3.81 (s, 3H), 2.51 (s, 3H), 1.28-1.22 (m, 1H), 0.62-0.57 (m, 2H), 0.36-0.31 (m, 2H); LC-MS: m/z 312.1 [M+H].sup.+.

Example 52

(335) ##STR00155##

(336) (E)-1-(3-hydroxy-4-methoxystyryl)-2-methylpyridin-4(1H)-one

(337) The specific reaction scheme is as shown below:

(338) ##STR00156##

(339) Step A:

(340) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2-methylpyridin-4(1H)-one (5.74 g, 20 mmol) was dissolved in methanol (100 mL), and then sodium borohydride (1.14 g, 30 mmol) was added portion-wise and stirred at room temperature for 3 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added, and the reaction solution was filtered, concentrated, and purified by column chromatography to obtain 1-(2-(3-hydroxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (5.09 g, yield 88%, colorless oil). LC-MS: m/z 290.4 [M+H].sup.+.

(341) Step B:

(342) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2-methylpyridin-4(1H)-one (5.09 g, 17.6 mmol) and p-toluenesulfonic acid (9.08 g, 52.8 mmol) were dissolved in toluene (100 mL), and stirred overnight under reflux. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2-methylpyridin-4(1H)-one (3.05 g, yield 64%, gray solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.34 (s, 1H), 7.16 (s, 2H), 7.05 (d, J=14.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.62 (d, J=14.0 Hz, 1H), 3.92 (s, 2H), 2.48 (s, 6H); LC-MS: m/z 272.1 [M+H].sup.+.

Example 53

(343) ##STR00157##

(344) (E)-1-(3-propoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(345) The specific reaction scheme is as shown below:

(346) ##STR00158##

(347) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromopropane (34.5 mg, 0.28 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 2 hours at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-propoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 44%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.22 (d, J=2.0 Hz, 1H), 7.14 (dd, J=8.4, 2.0 Hz, 1H), 7.09 (d, J=14.2 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.77 (d, J=14.2 Hz, 1H), 6.38 (s, 2H), 4.03 (t, J=6.4 Hz, 2H), 3.89 (s, 3H), 2.37 (s, 6H), 1.90-1.80 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); LC-MS: m/z 314.2 [M+1-1].sup.+.

Example 54

(348) ##STR00159##

(349) (E)-1-(3-isopropoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(350) The specific reaction scheme is as shown below:

(351) ##STR00160##

(352) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromoisopropane (34.5 mg, 0.28 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 2 hours at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-isopropoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (8 mg, yield 14%, colorless oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.26 (d, J=2.0 Hz, 1H), 7.22 (dd, J=8.4, 2.0 Hz, 1H), 7.21 (d, J=14.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 6.89 (d, J=14.4 Hz, 1H), 4.69-4.60 (m, 1H), 3.90 (s, 3H), 2.57 (s, 6H), 1.35 (d, J=6.0 Hz, 6H). LC-MS: m/z 314.2 [M+H].sup.+.

Example 55

(353) ##STR00161##

(354) (E)-1-((3-n-butoxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(355) The specific reaction scheme is as shown below:

(356) ##STR00162##

(357) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then n-butyl bromide (38 mg, 0.28 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 2 hours at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-n-butoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 34%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.57 (s, 2H), 7.27 (d, J=14.4 Hz, 1H), 7.10 (d, J=1.6 Hz, 1H), 7.04-6.98 (m, 2H), 6.95 (d, J=14.4 Hz, 1H), 4.34 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 2.60 (s, 6H), 1.82-1.75 (m, 2H), 1.50-1.40 (m, 2H), 0.96 (t, J=7.2 Hz, 1H); LC-MS: m/z 328.2 [M+H].sup.+.

Example 56

(358) ##STR00163##

(359) (E)-1-(3-iso-butoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(360) The specific reaction scheme is as shown below:

(361) ##STR00164##

(362) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromoisobutane (38 mg, 0.28 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 2 hours at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-iso-butoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 42%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.02 (dd, J=8.4, 2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.76 (d, J=14.4 Hz, 1H), 6.60 (d, J=14.4 Hz, 1H), 6.30 (s, 2H), 3.92 (s, 3H), 3.81 (d, J=6.8 Hz, 2H), 2.27 (s, 6H), 2.24-2.17 (m, 1H), 1.08 (d, J=6.8 Hz, 6H); LC-MS: m/z 328.2 [M+H].sup.+.

Example 57

(363) ##STR00165##

(364) (E)-1-((3-neopentyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(365) The specific reaction scheme is as shown below:

(366) ##STR00166##

(367) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (200 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromo-neopentane (224 mg, 1.48 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 24 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-neopentyloxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 8%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.25 (s, 2H), 7.05-7.00 (m, 2H), 6.97 (d, J=14.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.70 (d, J=14.4 Hz, 1H), 3.91 (s, 3H), 3.68 (s, 2H), 2.54 (s, 6H), 1.08 (s, 9H); LC-MS m/z 342.3 [M+H].sup.+.

Example 58

(368) ##STR00167##

(369) (E)-1-(3-cyclopropyloxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(370) The specific reaction scheme is as shown below:

(371) ##STR00168##

(372) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 0.3 mmol) and p-toluenesulfonic acid (68.4 mg, 0.6 mmol) were dissolved in toluene (5 mL), and then N,N-dimethylformamide (1 mL) was added and stirred overnight under reflux. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-cyclopropyloxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, yield 53%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.15 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.06 (d, J=14.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.85 (d, J=14.4 Hz, 1H), 6.32 (s, 2H), 4.02 (s, 3H), 2.32 (s, 6H), 2.23-2.19 (m, 1H), 0.94-0.90 (m, 4H); LC-MS m/z 312.3 [M+H].sup.+.

Example 59

(373) ##STR00169##

(374) (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(375) The specific reaction scheme is as shown below:

(376) ##STR00170##

(377) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (186 mg, 0.54 mmol) and p-toluenesulfonic acid (140 mg, 0.81 mmol) were dissolved in toluene (5 mL), and then N,N-dimethylformamide (1 mL) was added and stirred overnight under reflux. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-cyclopropylmethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (80 mg, yield 45%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.07 (d, J=14.4 Hz, 1H), 7.11 (s, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.75 (d, J=14.4 Hz, 1H), 6.41 (s, 2H), 3.89 (d, J=7.2 Hz, 2H), 3.87 (s, 3H), 2.36 (s, 6H), 1.33-1.24 (m, 1H), 0.65-0.60 (m, 2H), 0.38-0.34 (m, 2H); LC-MS: m/z 326.1 [M+H].sup.+.

Example 60

(378) ##STR00171##

(379) (E)-1-(3-cyclopropylmethoxy-4-methoxyphenethyl)-2,6-dimethylpyridin-4(1H)-one

(380) The specific reaction scheme is as shown below:

(381) ##STR00172##

(382) The compound (E)-1-(3-cyclopropyloxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (10 mg, 0.03 mmol) was dissolved in ethanol (3 mL), and then Pd/C (50 mg) was added, and stirred for 2 hours under hydrogen atmosphere at room temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-cyclopropylmethoxy-4-methoxyphenethyl)-2,6-dimethylpyridin-4(1H)-one (2.9 mg, yield 30%, colorless oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.11 (s, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.41 (s, 2H), 3.89 (d, J=7.2 Hz, 2H), 3.87 (s, 3H), 2.89-2.83 (m, 2H), 2.83-2.77 (m, 2H), 2.36 (s, 6H), 1.33-1.24 (m, 1H), 0.65-0.60 (m, 2H), 0.38-0.34 (m, 2H); LC-MS: m/z 328.1 [M+H].sup.+.

Example 61

(383) ##STR00173##

(384) (E)-1-(3-cyclobutyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(385) The specific reaction scheme is as shown below:

(386) ##STR00174##

(387) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromocyclobutane (100 mg, 0.74 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and stirred for 4 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-cyclobutyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (18 mg, yield 15%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.13 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (d, J=14.4 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.75 (d, J=14.4 Hz, 1H), 6.36 (s, 2H), 4.78-4.71 (m, 1H), 3.86 (s, 3H), 2.52-2.44 (m, 2H), 2.34 (s, 6H), 2.22-2.12 (m, 2H), 1.89-1.81 (m, 1H), 1.77-1.65 (m, 1H); LC-MS m/z 326.2 [M+1-1].sup.+.

Example 62

(388) ##STR00175##

(389) (E)-1-((3-cyclopentyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(390) The specific reaction scheme is as shown below:

(391) ##STR00176##

(392) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then bromo-cyclopentane (110 mg, 0.74 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and stirred for 4 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-cyclopentyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (25 mg, yield 20%, pale yellow solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.16 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.06 (d, J=14.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.76 (d, J=14.4 Hz, 1H), 6.36 (s, 2H), 3.35-3.83 (m, 1H), 3.86 (s, 3H), 2.52-2.44 (m, 2H), 2.35 (s, 6H), 1.93-1.79 (m, 6H), 1.69-1.58 (m, 2H); LC-MS m/z 340.2 [M+H].sup.+.

Example 63

(393) ##STR00177##

(394) (E)-1-(3-(cyclopent-3-en-1-yloxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(395) The specific reaction scheme is as shown below:

(396) ##STR00178##

(397) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (100 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then cyclopent-3-en-1-yl methanesulfonate (110 mg, 0.74 mmol) and cesium carbonate (241 mg, 0.74 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-(cyclopent-3-en-1-yloxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (22 mg, yield 15%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.45 (s, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.02-6.99 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 6.74 (d, J=14.4 Hz, 1H), 5.77 (s, 2H), 5.12-5.05 (m, 1H), 3.90 (s, 3H), 2.89-2.82 (m, 2H), 2.69-2.63 (m, 2H), 2.58 (s, 6H); LC-MS m/z 338.1 [M+H].sup.+.

Example 64

(398) ##STR00179##

(399) (E)-1-(3-allyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(400) The specific reaction scheme is as shown below:

(401) ##STR00180##

(402) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 3-bromopropene (44 mg, 0.36 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 2 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-allyloxy-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (12 mg, yield 20%, pale yellow oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.23 (s, 2H), 7.09-6.92 (m, 4H), 6.73-6.69 (m, 1H), 6.16-6.05 (m, 1H), 5.45 (d, J=17.2 Hz, 1H), 5.34 (d, J=10.4 Hz, 1H), 4.67 (d, J=4.0 Hz, 2H), 3.94 (s, 3H), 2.54 (s, 6H); LC-MS m/z 312.2 [M+H].sup.+.

Example 65

(403) ##STR00181##

(404) (E)-1-((3-(3-methylbut-2-en-1-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(405) The specific reaction scheme is as shown below:

(406) ##STR00182##

(407) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromo-3-methyl-2-butene (55 mg, 0.36 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 1 hr at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-((3-(3-methylbut-2-en-1-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (15 mg, yield 18%, yellow solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.08 (s, 2H), 7.08-7.04 (m, 2H), 6.92-6.90 (m, 1H), 6.91 (d, J=14.4 Hz, 1H), 6.69 (d, J=14.4 Hz, 1H), 5.54 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.92 (s, 3H), 2.51 (s, 6H), 1.80 (s, 3H), 1.72 (s, 3H); LC-MS m/z 340.0 [M+H].sup.+.

Example 66

(408) ##STR00183##

(409) (E)-1-(3-(prop-2-yn-1-yloxy)-4-methoxy)styryl)-2,6-dimethylpyridin-4(1H)-one

(410) The specific reaction scheme is as shown below:

(411) ##STR00184##

(412) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 3-bromo-propyne (44 mg, 0.36 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 3 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-(prop-2-yn-1-yloxy)-4-methoxy)styryl)-2,6-dimethylpyridin-4(1H)-one (10 mg, yield 15%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26-7.14 (m, 3H), 7.13 (s, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.73 (d, J=14.4 Hz, 1H), 4.83 (s, 2H), 3.94 (s, 3H), 2.56 (s, 1H), 2.52 (s, 6H); LC-MS m/z 310.1 [M+H].sup.+.

Example 67

(413) ##STR00185##

(414) (E)-1-(3-(but-2-yn-1-yloxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(415) The specific reaction scheme is as shown below:

(416) ##STR00186##

(417) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.18 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 1-bromo-2-butyne (49 mg, 0.36 mmol) and cesium carbonate (117 mg, 0.36 mmol) were added, and stirred for 1 hr at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-(but-2-yn-1-yloxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (15 mg, yield 25%, yellow solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.17 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.09 (s, 2H), 6.98 (d, J=14.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.74 (d, J=14.4 Hz, 1H), 4.78 (s, 2H), 3.93 (s, 3H), 2.52 (s, 6H), 1.86 (s, 3H); LC-MS m/z 324.1 [M+H].sup.+.

Example 68

(418) ##STR00187##

(419) (E)-1-((3-(oxacyclobutan-3-yl-oxy)-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(420) The specific reaction scheme is as shown below:

(421) ##STR00188##

(422) (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (150 mg, 0.55 mmol), oxacyclobutan-3-ol (81.4 mg, 1.1 mmol) and triphenylphosphine (288 mg, 1.1 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), the reaction solution was cooled in an ice bath, diisopropyl azodicarboxylate (222 mg, 1.1 mmol) was added dropwise over 5 min under nitrogen atmosphere, and then reacted for 24 hours at room temperature. After the reaction was completed, saturated saline (20 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-((3-(oxacyclobutan-3-yl-oxy)-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (40 mg, yield 22%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.15 (d, J=8.4 Hz, 1H), 7.07 (s, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.94 (d, J=13.2 Hz, 1H), 6.70 (s, 1H), 6.69 (d, J=13.2 Hz, 1H), 5.27 (m, 1H), 5.01 (m, 1H), 4.88 (m, 1H), 3.94 (s, 3H), 2.53 (s, 6H); LC-MS: m/z 328.2 [M+H].sup.+.

Example 69

(423) ##STR00189##

(424) (E)-1-((3-(thiacyclobutan-3-yl-oxy)-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(425) The specific reaction scheme is as shown below:

(426) ##STR00190##

(427) (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (150 mg, 0.55 mmol), thiacyclobutan-3-ol (99 mg, 1.1 mmol) and triphenylphosphine (288 mg, 1.1 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL), the reaction solution was cooled in an ice bath, diisopropyl azodicarboxylate (222 mg, 1.1 mmol) was added dropwise over 5 min under nitrogen atmosphere, and then reacted for 24 hours at room temperature. After the reaction was completed, saturated saline (20 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-((3-(thiacyclobutan-3-yl-oxy)-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 16%, pale yellow solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.37 (s, 2H), 7.19 (d, J=14.4 Hz, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.05 (dd, J=8.4, 2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.88 (d, J=14.4 Hz, 1H), 5.77-5.69 (m, 1H), 3.90 (s, 3H), 3.65-3.61 (m, 2H), 3.57-3.53 (m, 2H), 2.66 (s, 6H); LC-MS: m/z 344.2 [M+H].sup.+.

Example 70

(428) ##STR00191##

(429) (E)-1-((3-(tetrahydrofuran-2-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(430) The specific reaction scheme is as shown below:

(431) ##STR00192##

(432) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and then 2,3-dihydrofuran (68 mg, 0.42 mmol) and pyridinium toluene-4-sulphonate (4.6 mg, 0.018 mmol) were added, and stirred for 3 hours at room temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-((3-(tetrahydrofuran-2-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (16 mg, yield 24%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (d, J=2.0 Hz, 1H), 7.26 (s, 2H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.05 (d, J=14.4 Hz, 1H), 6.75 (d, J=14.4 Hz, 1H), 5.82 (d, J=4.4 Hz, 1H), 5.70 (s, 2H), 4.13-4.08 (m, 1H), 4.01-3.95 (m, 1H), 3.90 (s, 3H), 2.35 (s, 6H), 2.24-2.14 (m, 2H), 2.02-1.95 (m, 2H); LC-MS m/z 342.3 [M+H].sup.+.

Example 71

(433) ##STR00193##

(434) (E)-2-(5-(2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethenyl)-2methoxyphenoxy)-N-methylacetamide

(435) The specific reaction scheme is as shown below:

(436) ##STR00194##

(437) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (200 mg, 0.74 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then 2-chloro-N-methylacetamide (119 mg, 1.11 mmol) and potassium carbonate (153 mg, 1.11 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-2-(5-(2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethenyl)-2methoxyphenoxy)-N-methylacetamide (100 mg, yield 40%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.28 (d, J=2.0 Hz, 1H), 7.23 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=14.2 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.76 (d, J=14.2 Hz, 1H), 6.35 (s, 2H), 4.55 (s, 2H), 3.92 (s, 3H), 2.84 (s, 3H), 2.34 (s, 6H); LC-MS m/z 343.1 [M+H].sup.+.

Example 72

(438) ##STR00195##

(439) (E)-1-((3-cyclopropylformyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(440) The specific reaction scheme is as shown below:

(441) ##STR00196##

(442) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and then cyclopropanecarbonyl chloride (27 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol) were added and stirred for 2 hours at room temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-((3-cyclopropylformyloxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 35%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.37 (dd, J=8.4, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.11 (s, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.96 (d, J=14.4 Hz, 1H), 6.72 (d, J=14.4 Hz, 1H), 3.92 (s, 3H), 2.52 (s, 6H), 1.96-1.89 (m, 1H), 1.25-1.21 (m, 2H), 1.12-1.06 (m, 2H); LC-MS: m/z 340.2 [M+1-1].sup.+.

Example 73

(443) ##STR00197##

(444) (E)-5-(2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethenyl)-2-methoxyphenylmethyl sulfonate

(445) The specific reaction scheme is as shown below:

(446) ##STR00198##

(447) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (271 mg, 1.0 mmol) was dissolved in N, N-dimethylformamide (10 mL), and then triethyl amine (202 mg, 2.0 mmol), and methylsulfonyl chloride (172 mg, 1.5 mmol) were added, and stirred overnight at room temperature. After the reaction was completed, saturated saline (20 mL) was added, and extracted with dichloromethane (3×20 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-5-(2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)ethenyl)-2-methoxyphenylmethyl sulfonate (130 mg, yield 40%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.61 (d, J=2.4 Hz, 1H), 7.58 (dd, J=8.8, 2.4 Hz, 1H), 7.28 (d, J=14.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 7.05 (s, 2H), 6.96 (d, J=14.4 Hz, 1H), 3.96 (s, 3H), 2.58 (s, 6H). LC-MS: m/z 350.1 [M+H].sup.+.

Example 74

(448) ##STR00199##

(449) (E)-1-(3-methylthiomethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(450) The specific reaction scheme is as shown below:

(451) ##STR00200##

(452) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (70 mg, 0.26 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then chloromethylmethyl sulfide (50 mg, 0.52 mmol) and cesium carbonate (170 mg, 0.52 mmol) were added, and stirred overnight at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylthiomethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, yield 58%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.31 (d, J=2.0 Hz, 1H), 7.25 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.78 (d, J=14.4 Hz, 1H), 6.77 (s, 2H), 5.03 (s, 2H), 3.90 (s, 3H), 2.36 (s, 6H), 2.26 (s, 3H); LC-MS: m/z 332.5 [M+H].sup.+.

Example 75

(453) ##STR00201##

(454) (E)-1-(3-methylsulfoxidemethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(455) The specific reaction scheme is as shown below:

(456) ##STR00202##

(457) The compound (E)-1-(3-methylthiomethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (28 mg, 0.14 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoxidemethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (36 mg, yield 69%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.41 (d, J=2.0 Hz, 1H), 7.28 (dd, J=8.4, 2.0 Hz, 1H), 7.09 (d, J=14.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.03 (s, 2H), 6.68 (d, J=14.4 Hz, 1H), 5.26 (d, J=11.2 Hz, 1H), 5.11 (d, J=11.2 Hz, 1H), 3.96 (s, 3H), 2.36 (s, 6H), 2.26 (s, 3H); LC-MS: m/z 348.2 [M+H].sup.+.

Example 76

(458) ##STR00203##

(459) (E)-1-(3-methylsulfonemethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(460) The specific reaction scheme is as shown below:

(461) ##STR00204##

(462) The compound (E)-1-(3-methylthiomethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (54 mg, 0.27 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfonemethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (26 mg, yield 79%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.50 (d, J=2.0 Hz, 1H), 7.32 (dd, J=8.4, 2.0 Hz, 1H), 7.11 (d, J=8.4, 1H), 7.10 (d, J=14.0 Hz, 1H), 6.79 (d, J=14.0 Hz, 1H), 6.37 (s, 2H), 5.20 (s, 2H), 3.93 (s, 3H), 3.11 (s, 3H), 2.35 (s, 6H); LC-MS m/z 364.1 [M+H].sup.+.

Example 77

(463) ##STR00205##

(464) (E)-1-(3-methylthioethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(465) The specific reaction scheme is as shown below:

(466) ##STR00206##

(467) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (200 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then chloroethyl methyl sulfide (165 mg, 1.5 mmol) and cesium carbonate (489 mg, 1.5 mmol) were added, and stirred overnight at room temperature. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylthioethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (220 mg, yield 87%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.05 (dd, J=8.4, 2.0 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.77 (d, J=14.4 Hz, 1H), 6.59 (d, J=14.4 Hz, 1H), 6.26 (s, 2H), 4.24 (t, J=7.2 Hz, 2H), 3.91 (s, 3H), 2.96 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 2.24 (s, 3H); LC-MS: m/z 346.5 [M+H].sup.+.

Example 78

(468) ##STR00207##

(469) (E)-1-(3-methylsulfoxideethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(470) The specific reaction scheme is as shown below:

(471) ##STR00208##

(472) The compound (E)-1-(3-methylthioethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (28 mg, 0.14 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoxideethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 53%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.07 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.4, 2.0 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.72 (d, J=14.4 Hz, 1H), 6.51 (d, J=14.4 Hz, 1H), 6.17 (s, 2H), 4.50-4.41 (m, 2H), 3.83 (s, 3H), 3.27-3.20 (m, 1H), 3.07-3.01 (m, 1H), 2.68 (s, 3H), 2.17 (s, 6H); LC-MS: m/z 362.1 [M+H].sup.+.

Example 79

(473) ##STR00209##

(474) (E)-1-(3-methylsulfoneethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(475) The specific reaction scheme is as shown below:

(476) ##STR00210##

(477) The compound (E)-1-(3-methylthioethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, 0.09 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (54 mg, 0.54 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoneethoxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (35 mg, yield 61%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.08 (dd, J=8.4, 2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.78 (d, J=14.4 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 6.31 (s, 2H), 4.50 (t, J=4.2 Hz, 2H), 3.89 (s, 3H), 3.50 (t, J=4.2 Hz, 2H), 3.19 (s, 3H), 2.26 (s, 6H); LC-MS: m/z 378.1 [M+H].sup.+.

Example 80

(478) ##STR00211##

(479) (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(480) The specific reaction scheme is as shown below:

(481) ##STR00212##

(482) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (45 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then tetrahydrothiophen-3-yl methanesulfonate (53 mg, 0.29 mmol) and cesium carbonate (95 mg, 0.29 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (35 mg, yield 65%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.10 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.77 (d, J=14.4 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 6.31 (s, 2H), 5.16-5.13 (m, 1H), 3.90 (s, 3H), 3.18-3.08 (m, 1H), 3.09 (d, J=3.6 Hz, 2H), 2.98-2.93 (m, 1H), 2.49-2.42 (m, 1H), 2.27 (s, 6H), 2.08-1.99 (m, 1H); LC-MS: m/z 358.2 [M+H].sup.+.

Example 81

(483) ##STR00213##

(484) (E)-1-(3-((1,1,-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(485) The specific reaction scheme is as shown below:

(486) ##STR00214##

(487) The compound (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (68 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (116 mg, 0.57 mmol) was added and stirred for 3 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-((1,1,-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (62 mg, yield 86%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.28 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.13 (d, J=14.4 Hz, 1H), 7.10 (s, 2H), 6.97 (d, J=14.4 Hz, 1H), 5.34-5.27 (m, 1H), 3.91 (s, 3H), 3.52-3.44 (m, 1H), 3.41-3.32 (m, 2H), 3.23-3.17 (m, 1H), 2.70-2.61 (m, 1H), 2.58-2.47 (m, 1H), 2.54 (s, 6H); LC-MS: m/z 390.1 [M+H].sup.+.

Example 82

(488) ##STR00215##

(489) (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(490) The specific reaction scheme is as shown below:

(491) ##STR00216##

(492) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (45 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then (R)-tetrahydrothiophen-3-yl methanesulfonate (53 mg, 0.29 mmol) and cesium carbonate (95 mg, 0.29 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 56%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.10 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.77 (d, J=14.4 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 6.31 (s, 2H), 5.16-5.13 (m, 1H), 3.90 (s, 3H), 3.18-3.08 (m, 1H), 3.09 (d, J=3.6 Hz, 2H), 2.98-2.93 (m, 1H), 2.49-2.42 (m, 1H), 2.27 (s, 6H), 2.08-1.99 (m, 1H); LC-MS: m/z 358.1 [M+H].sup.+.

Example 83

(493) ##STR00217##

(494) 1-((E)-4-methoxy-3-(((3S)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one

(495) The specific reaction scheme is as shown below:

(496) ##STR00218##

(497) The compound (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (81 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (41 mg, 0.20 mmol) was added and stirred for 3 hours at 0° C. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave a diastereoisomer of 1-((E)-4-methoxy-3-(((3S)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one show below:

(498) ##STR00219##

(499) (25 mg, yield 29%, pale yellow oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (d, J=1.6 Hz, 1H), 7.12 (dd, J=8.4, 1.6 Hz, 1H), 7.07 (d, J=14.4 Hz, 1H), 7.01 (s, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.68 (d, J=14.4 Hz, 1H), 5.28-5.24 (m, 1H), 3.91 (s, 3H), 3.34-3.14 (m, 4H), 2.93-2.85 (m, 1H), 2.51 (s, 6H), 2.34-2.25 (m, 1H); LC-MS: m/z 374.1 [M+H].sup.+.

(500) ##STR00220##

(501) (20 mg, yield 23%, pale yellow oil)′H NMR (400 MHz, CDCl.sub.3) δ 7.17 (d, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=14.4 Hz, 1H), 7.03 (s, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.71 (d, J=14.4 Hz, 1H), 5.48-5.43 (m, 1H), 3.89 (s, 3H), 3.64 (d, J=15.2 Hz, 1H), 3.21-3.07 (m, 3H), 2.83-2.74 (m, 1H), 2.65-2.59 (m, 1H), 2.51 (s, 6H); LC-MS: m/z 374.1 [M+H].sup.+.

Example 84

(502) ##STR00221##

(503) (S,E)-1-(3-((1,1-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(504) The specific reaction scheme is as shown below:

(505) ##STR00222##

(506) The compound (E)-1(((3-(tetrahydrothiophen-3-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (81 mg, 0.23 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (140 mg, 0.69 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-((1,1,-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (58 mg, yield 66%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.26 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 7.05 (s, 2H), 6.97 (d, J=8.4 Hz, 1H), 6.71 (d, J=14.4 Hz, 1H), 5.32-5.27 (m, 1H), 3.91 (s, 3H), 3.52-3.43 (m, 1H), 3.41-3.31 (m, 2H), 3.22-3.16 (m, 1H), 2.69-2.62 (m, 1H), 2.57-2.47 (m, 1H), 2.52 (s, 6H); LC-MS m/z 390.2 [M+1-1].sup.+.

Example 85

(507) ##STR00223##

(508) (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(509) The specific reaction scheme is as shown below:

(510) ##STR00224##

(511) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (45 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then (S)-tetrahydrothiophen-3-yl methanesulfonate (53 mg, 0.29 mmol) and cesium carbonate (95 mg, 0.29 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 56%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.10 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.77 (d, J=14.4 Hz, 1H), 6.58 (d, J=14.4 Hz, 1H), 6.31 (s, 2H), 5.16-5.13 (m, 1H), 3.90 (s, 3H), 3.18-3.08 (m, 1H), 3.09 (d, J=3.6 Hz, 2H), 2.98-2.93 (m, 1H), 2.49-2.42 (m, 1H), 2.27 (s, 6H), 2.08-1.99 (m, 1H); LC-MS: m/z 358.1 [M+H].sup.+.

Example 86

(512) ##STR00225##

(513) 1-((E)-4-methoxy-3-(((3R)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one

(514) ##STR00226##

(515) The compound (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (57 mg, 0.16 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (29 mg, 0.15 mmol) was added and stirred for 3 hours at 0° C. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave a diastereoisomer of 1-((E)-4-methoxy-3-(((3R)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one shown below:

(516) ##STR00227##

(517) (15 mg, yield 25%, pale yellow oil). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.26 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.4, 2.0 Hz, 1H), 7.12 (d, J=14.4 Hz, 1H), 6.99 (d, J=7.6, 1H), 6.96 (s, 2H), 6.80 (d, J=14.4, 1H), 5.18-5.13 (m, 1H), 3.80 (s, 3H), 3.36-3.25 (m, 2H), 3.09-3.00 (m, 2H), 2.69-2.61 (m, 1H), 2.49 (s, 6H), 2.27-2.19 (m, 1H); LC-MS: m/z 374.1 [M+H].sup.+.

(518) ##STR00228##

(519) (10 mg, yield 17%, pale yellow oil).sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.33 (d, J=2.0 Hz, 1H), 7.30 (dd, J=8.4, 2.0 Hz, 1H), 7.26 (d, J=14.4 Hz, 1H), 7.10 (d, J=7.6, 1H), 7.09 (s, 2H), 6.93 (d, J=14.4, 1H), 5.52-5.49 (m, 1H), 3.89 (s, 3H), 3.76-3.71 (m, 1H), 3.30-3.22 (m, 2H), 3.76-3.71 (m, 1H), 2.77-2.67 (m, 1H), 2.65-2.63 (m, 1H), 2.61 (s, 6H); LC-MS: m/z 374.1 [M+H].sup.+.

Example 87

(520) ##STR00229##

(521) (R,E)-1-(3-((1,1-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(522) The specific reaction scheme is as shown below:

(523) ##STR00230##

(524) The compound (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (49 mg, 0.24 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-((1,1,-dioxotetrahydrothiophen-3-yl)oxy)-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (12 mg, yield 40%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.23 (s, 1H), 7.22 (dd, J=8.4, 2.0 Hz, 1H), 7.12 (d, J=14.4 Hz, 1H), 7.10 (dd, J=8.4, 2.0 Hz, 1H), 6.96 (s, 2H), 6.81 (d, J=14.4, 1H), 5.20-5.16 (m, 1H), 3.80 (s, 3H), 3.38-3.28 (m, 2H), 3.25-3.24 (m, 1H), 3.13-3.07 (m, 1H), 2.49 (s, 6H), 2.47-2.34 (m, 2H); LC-MS: m/z 390.0 [M+H].sup.+.

Example 88

(525) ##STR00231##

(526) (E)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)styryl)-2,6-dimethylpyridin-4(1H)-one

(527) The specific reaction scheme is as shown below:

(528) ##STR00232##

(529) Step A:

(530) The compound 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (80 mg, 0.21 mmol) was dissolved in trichloromethane (10 mL), and heated to 80° C. Then thionyl chloride (0.5 mL) was added and stirred at 80° C. for 15 min. After the reaction was completed, the reaction solution was directly rotary dried to obtain a crude product of 1-(2-chloro-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethyl)-2,6-dimethylpyridin-4(1H)-one (85 mg, 100%). LC-MS: m/z 398.2 [M+H].sup.+.

(531) Step B:

(532) The compound 1-(2-chloro-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethyl)-2,6-dimethylpyridin-4(1H)-one (85 mg, 0.21 mmol) was dissolved in ethanol (10 mL), and then sodium hydroxide (64 mg, 1.60 mmol) and water (2 mL) were added in sequence, heated to 100° C., and stirred for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified to obtain (E)-1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)styryl)-2,6-dimethylpyridin-4(1H)-one (20 mg, 26%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.41 (d, J=2.0 Hz, 1H), 7.34 (d, J=14.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.4, 2.0 Hz, 1H), 7.12 (t, J.sub.H-F=74.4 Hz, 1H), 6.91 (d, J=14.4 Hz, 1H), 6.49 (s, 2H), 3.95 (d, J=7.2 Hz, 2H), 2.34 (s, 6H), 1.31-1.21 (m, 1H), 0.62-0.57 (m, 2H), 0.37-0.33 (m, 2H); LC-MS: m/z 362.2 [M+H].sup.+.

Example 89

(533) ##STR00233##

(534) (E)-1-(3-methoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(535) The specific reaction scheme is as shown below:

(536) ##STR00234##

(537) Step A:

(538) At room temperature, 3-hydroxy-4-difluoromethoxybenzaldehyde (2.36 g, 12.5 mmol) was dissolved in acetonitrile (40 mL), and then potassium carbonate (3.46 g, 25.1 mmol) and benzyl bromide (2.79 g, 16.3 mmol) were added in sequence, and heated to 80° C. for 3 hours with stirring under nitrogen atmosphere. After the reaction was completed, a saturated aqueous sodium chloride solution (30 mL) was added, and extracted with dichloromethane (3×120 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified by column chromatography to obtain 3-benzoxy-4-difluoromethoxybenzaldehyde (3.30 g, 95%).

(539) Step B:

(540) 3-benzoxy-4-difluoromethoxybenzaldehyde (3.30 g, 11.9 mmol) was dissolved in dichloromethane (30 mL), and then triethyl amine (2.40 g, 23.7 mmol) and trimethylsilyl cyanide (3.53 g, 35.6 mmol) were added in sequence in an ice bath and stirred for 16 hours under nitrogen atmosphere at room temperature. After the reaction was completed, the reaction solution was directly rotary dried to obtain 2-(3-benzoxy-4-difluoromethoxyphenyl)-2-trimethylsiloxyacetonitrile, which was directly used in the next reaction.

(541) Step C:

(542) The compound 2-(3-benzoxy-4-difluoromethoxyphenyl)-2-trimethylsiloxyacetonitrile (4.47 g, 11.9 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), and then lithium aluminum hydride (1.35 g, 35.6 mmol) was added portion-wise in an ice bath, and stirred overnight at room temperature. After the reaction was completed, the reaction was diluted with anhydrous tetrahydrofuran (200 mL), and then water (1.35 mL), an aqueous sodium hydroxide solution (1.35 mL, 15%), and water (4.05 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 2-amino-1-(3-benzoxy-4-difluoromethoxyphenyl)ethanol, which was directly used in the next reaction.

(543) Step D:

(544) The compound 2-amino-1-(3-benzoxy-4-difluoromethoxyphenyl)ethanol (3.67 g, 11.9 mmol) was dissolved in ethanol (60 mL), and then 2,6-dimethyl-4H-pyran-4-one (2.19 g, 17.7 mmol), sodium hydroxide (708 mg, 17.7 mmol) and water (10 mL) were added in sequence, heated to 60° C., and stirred for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-benzoxy-4-difluoromethoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (2.3 g, 47%). LC-MS m/z 416.2 [M+H].sup.+.

(545) Step E:

(546) The compound 1-(2-(3-benzoxy-4-difluoromethoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (2.3 g, 5.3 mmol) was dissolved in trichloromethane (80 mL), and then heated to 90° C. Thionyl chloride (3 mL) was added and stirred at 90° C. for 15 min. After the reaction was completed, the reaction solution was directly rotary dried to obtain a crude product of 1-(2-(3-benzoxy-4-difluoromethoxyphenyl)-2-chloroethyl)-2,6-dimethylpyridin-4(1H)-one (2.15 g, 93%). LC-MS m/z 434.2 [M+H].sup.+.

(547) Step F:

(548) The compound 1-(2-(3-benzoxy-4-difluoromethoxyphenyl)-2-chloroethyl)-2,6-dimethylpyridin-4(1H)-one (2.15 g, 5.0 mmol) was dissolved in ethanol (40 mL), and then sodium hydroxide (1.2 g, 30 mmol) and water (15 mL) were added in sequence, heated to 90° C., and stirred for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified to obtain (E)-1-(3-benzoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (1.5 g, 75%). LC-MS: m/z 398.2 [M+H].sup.+.

(549) Step G:

(550) The compound (E)-1-(3-benzoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (400 mg, 1.0 mmol) was dissolved in anhydrous dichloromethane (100 mL), and titanium tetrachloride (1 M, 2 mL, 2.0 mmol) was slowly added dropwise in an ice bath, and stirred overnight at room temperature. After the reaction was completed, the reaction solution was rotary dried, and purified to obtain (E)-1-(3-hydroxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 16%). LC-MS: m/z 308.2 [M+H].sup.+.

(551) Step H:

(552) The compound (E)-1-(3-hydroxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.16 mmol) was dissolved in acetonitrile (5 mL), and then iodomethane (30 mg, 0.21 mmol) and potassium carbonate (90 mg, 0.65 mmol) were added, and stirred for 2 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-methoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (38 mg, yield 71%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.21 (d, J=8.0 Hz, 1H), 7.08-7.05 (m, 2H), 6.96 (d, J=14.0 Hz, 1H), 6.69 (d, J=14.0 Hz, 1H), 6.59 (t, J.sub.H-F=74.8 Hz, 1H), 6.41 (s, 2H), 3.95 (s, 3H), 2.31 (s, 6H); LC-MS: m/z 322.2 [M+H].sup.+.

Example 90

(553) ##STR00235##

(554) (E)-1-(3-methylthiomethoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(555) The specific reaction scheme is as shown below:

(556) ##STR00236##

(557) The compound (E)-1-(3-hydroxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (35 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then chloromethylmethyl sulfide (22 mg, 0.23 mmol) and cesium carbonate (150 mg, 0.46 mmol) were added, and stirred for 1 hr at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylthiomethoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 71%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.24-7.22 (m, 2H), 7.16 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=14.4 Hz, 1H), 6.77 (s, 2H), 6.76 (d, J=14.4 Hz, 1H), 6.59 (t, J.sub.H-F=74.0 Hz, 1H), 5.29 (s, 2H), 2.41 (s, 6H), 2.29 (s, 3H); LC-MS: m/z 368.4 [M+H].sup.+.

Example 91

(558) ##STR00237##

(559) (E)-1-(3-methylsulfoxidemethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(560) The specific reaction scheme is as shown below:

(561) ##STR00238##

(562) The compound (E)-1-(3-methylthiomethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (78 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (39 mg, 0.19 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoxidemethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (64 mg, yield 78%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.72 (s, 1H), 7.27 (d, J=14.8 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.03 (s, 2H), 6.80 (d, J=14.8 Hz, 1H), 6.64 (t, J.sub.H-F=73.6 Hz, 1H), 5.26 (d, J=11.2 Hz, 1H), 5.11 (d, J=11.2 Hz, 1H), 2.77 (s, 3H), 2.52 (s, 6H); LC-MS: m/z 384.0 [M+H].sup.+.

Example 92

(563) ##STR00239##

(564) (E)-1-(3-methylsulfonemethoxy-4-difluoromethoxy-styryl)-2,6-dimethylpyridin-4(1H)-one

(565) The specific reaction scheme is as shown below:

(566) ##STR00240##

(567) The compound (E)-1-(3-methylthiomethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (78 mg, 0.21 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (128 mg, 0.63 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfonemethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (35 mg, yield 41%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.56 (d, J=2.0 Hz, 1H), 7.27 (d, J=8.4, 2.0 Hz, 1H), 7.26 (d, J=14.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 6.91 (d, J=14.4 Hz, 1H), 6.79 (t, J.sub.H-F=73.6 Hz, 1H), 5.23 (s, 2H), 3.01 (s, 3H), 2.49 (s, 6H); LC-MS: m/z 399.9 [M+H].sup.+.

Example 93

(568) ##STR00241##

(569) (E)-1-(3-methylthioethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(570) The specific reaction scheme is as shown below:

(571) ##STR00242##

(572) At room temperature, (E)-1-(4-(difluoromethoxy)-3-hydroxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then potassium carbonate (34 mg, 0.24 mmol) and chloroethyl methyl sulfide (36 mg, 0.33 mmol) were added in sequence, and heated to 80° C. for 16 hours with stirring under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(3-methylthioethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (8 mg, 14%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.18 (d, J=8.4 Hz, 1H), 7.06-6.99 (m, 2H), 6.84 (d, J=14.0 Hz, 1H), 6.59 (t, J=14.0 Hz, 1H), 6.58 (d, J.sub.H-F=75.2 Hz, 1H), 6.19 (s, 2H), 4.20 (t, J=6.4 Hz, 2H), 2.87 (t, J=6.4 Hz, 2H), 2.19 (s, 6H), 2.16 (s, 3H); LC-MS: m/z 382.2 [M+H].sup.+.

Example 94

(573) ##STR00243##

(574) (E)-1-(3-methylsulfoxideethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(575) The specific reaction scheme is as shown below:

(576) ##STR00244##

(577) The compound (E)-1-(3-methylthioethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (55 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (27 mg, 0.13 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoxideethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (16 mg, yield 28%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (s, 1H), 7.26 (d, J=14.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 6.79 (d, J=14.4 Hz, 1H), 6.58 (t, J.sub.H-F=74.0 Hz, 1H), 4.60 (t, J=8.8 Hz, 1H), 3.33-3.26 (m, 1H), 3.16-3.10 (m, 1H), 2.75 (s, 3H), 2.51 (s, 6H); LC-MS: m/z 398.0 [M+H].sup.+.

Example 95

(578) ##STR00245##

(579) (E)-1-(3-methylsulfoneethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(580) The specific reaction scheme is as shown below:

(581) ##STR00246##

(582) The compound (E)-1-(3-methylthioethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (55 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and then m-chloroperoxybenzoic acid (85 mg, 0.42 mmol) was added and stirred for 2 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-methylsulfoneethoxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (33 mg, yield 75%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.45 (s, 1H), 7.36 (d, J=14.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.04 (s, 2H), 7.00 (d, J=14.4 Hz, 1H), 6.58 (t, J.sub.H-F=74.4 Hz, 1H), 4.55 (t, J=5.2 Hz, 1H), 3.66 (t, J=5.2 Hz, 1H), 3.15 (s, 3H), 2.59 (s, 6H); LC-MS: m/z 414.0 [M+H].sup.+.

Example 96

(583) ##STR00247##

(584) (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one

(585) The specific reaction scheme is as shown below:

(586) ##STR00248##

(587) The compound (E)-1-(3-hydroxy-4-methoxystyryl)-2,6-dimethylpyridin-4(1H)-one (42 mg, 0.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then tetrahydrothiophen-3-yl methanesulfonate (53 mg, 0.29 mmol) and cesium carbonate (95 mg, 0.29 mmol) were added, and stirred for 1 hr at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 54%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.41 (d, J=2.0 Hz, 1H), 7.27 (d, J=14.4 Hz, 1H), 7.26 (dd, J=8.4, 2.0 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.91 (d, J=14.4 Hz, 1H), 6.79 (t, J.sub.H-F=75.0 Hz, 1H), 6.65 (s, 2H), 5.36-5.32 (m, 1H), 3.16 (dd, J=12.0, 4.4 Hz, 1H), 3.11-3.02 (m, 2H), 2.99-2.94 (m, 1H), 2.49-2.41 (m, 1H), 2.45 (s, 6H), 2.10-2.01 (m, 1H); LC-MS: m/z 394.2 [M+H].sup.+.

Example 97

(588) ##STR00249##

(589) (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(590) The specific reaction scheme is as shown below:

(591) ##STR00250##

(592) The compound (E)-1-(3-hydroxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (50 mg, 0.15 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then (R)-tetrahydrothiophen-3-yl methanesulfonate (53 mg, 0.29 mmol) and cesium carbonate (95 mg, 0.29 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (S,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (10 mg, yield 17%, pale yellow solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.23 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4, 2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.87 (d, J=14.4 Hz, 1H), 6.77 (d, J=14.4 Hz, 1H), 6.64 (d, J=14.4 Hz, 1H), 6.61 (t, J.sub.H-F=74.8 Hz, 1H), 6.29 (s, 2H), 5.21-5.16 (m, 1H), 3.16-3.09 (m, 3H), 3.03-2.97 (m, 1H), 2.52-2.47 (m, 1H), 2.26 (s, 6H), 2.11-2.02 (m, 1H); LC-MS: m/z 394.2 [M+H].sup.+.

Example 98

(593) ##STR00251##

(594) The specific reaction scheme is as shown below:

(595) ##STR00252##

(596) The compound (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (103 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (48 mg, 0.24 mmol) was added and stirred for 2 hours at 0° C. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave a diastereoisomer of 1-((E)-4-difluoromethoxy-3-(((3S)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one shown below:

(597) ##STR00253##

(598) (42 mg, yield 39%, pale yellow oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.48 (s, 1H), 7.37 (d, J=14.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H), 6.94 (s, 2H), 6.81 (d, J=14.4 Hz, 1H), 6.80 (t, J.sub.H-F=72.4 Hz, 1H), 5.46-5.38 (m, 1H), 3.46-3.38 (m, 1H), 3.33-3.17 (m, 3H), 2.94-2.85 (m, 1H), 2.54 (s, 6H), 2.41-2.32 (m, 1H); LC-MS: m/z 410.1 [M+H].sup.+.

(599) ##STR00254##

(600) (30 mg, yield 28%, pale yellow oil). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.35 (s, 1H), 7.30 (d, J=14.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.16 (dd, J=8.4, 1.2 Hz, 1H), 6.95 (s, 2H), 6.82 (d, J=14.4 Hz, 1H), 6.48 (t, J.sub.H-F=73.6 Hz, 1H), 5.58-5.53 (m, 1H), 3.60 (d, J=15.2 Hz, 1H), 3.17 (dd, J=15.2, 4.8 Hz, 1H), 3.11-3.07 (m, 2H), 2.90-2.80 (m, 1H), 2.65-2.61 (m, 1H), 2.51 (s, 6H); LC-MS: m/z 410.1 [M+H].sup.+.

Example 99

(601) ##STR00255##

(602) (S,E)-1-(3-(1,1-dioxotetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(603) The specific reaction scheme is as shown below:

(604) ##STR00256##

(605) The compound (E)-1-((3-(tetrahydrothiophen-3-yl)oxy-4-methoxy)-styryl)-2,6-dimethylpyridin-4(1H)-one (55 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (85 mg, 0.42 mmol) was added and stirred for 3 hours at room temperature. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (S,E)-1-(3-(1,1-dioxotetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (52 mg, yield 86%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44 (s, 1H), 7.36 (d, J=14.0, Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.96 (s, 2H), 6.81 (d, J=14.0 Hz, 1H), 6.60 (t, J.sub.H-F=73.6 Hz, 1H), 5.45-5.40 (m, 1H), 3.50-3.35 (m, 3H), 3.27-2.21 (m, 1H), 2.70-2.58 (m, 2H), 2.53 (s, 6H); LC-MS m/z 426.0 [M+H].sup.+.

Example 100

(606) ##STR00257##

(607) (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(608) The specific reaction scheme is as shown below:

(609) ##STR00258##

(610) The compound (E)-1-(3-hydroxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (200 mg, 0.58 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then (S)-tetrahydrothiophen-3-yl methanesulfonate (212 mg, 1.16 mmol) and cesium carbonate (758 mg, 2.3 mmol) were added, and stirred overnight at 80° C. under nitrogen atmosphere. After the reaction was completed, saturated saline (20 mL) was added, and extracted with dichloromethane (3×20 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (30 mg, yield 13%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.23 (d, J=8.4 Hz, 1H), 7.11 (dd, J=8.4 2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.89 (d, J=14.4 Hz, 1H), 6.65 (d, J=14 Hz, 1H), 6.60 (m, J=14.4 Hz, 1H), 6.63 (t, J=74.8 Hz, 1H), 6.31 (s, 2H), 5.21-5.16 (m, 1H), 3.16-3.09 (m, 3H), 3.03-2.97 (m, 1H), 2.52-2.47 (m, 1H), 2.26 (s, 6H), 2.11-2.02 (m, 1H); LC-MS m/z 394.0 [M+H].sup.+.

Example 101

(611) ##STR00259##

(612) 1-((E)-4-difluoromethoxy-3-(((3R)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one

(613) The specific reaction scheme is as shown below:

(614) ##STR00260##

(615) The compound (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (55 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (26 mg, 0.13 mmol) was added and stirred for 3 hours at 0° C. Then, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave a diastereoisomer of 1-((E)-4-difluoromethoxy-3-(((3R)-1-oxotetrahydrothiophen-3-yl)oxy)styryl)-2,6-dimethylpyridin-4(1H)-one shown below:

(616) ##STR00261##

(617) (20 mg, yield 35%, pale yellow oil). .sup.1H NMR (400 MHz, CD.sub.3Cl) δ 7.50 (s, 1H), 7.20 (d, J=12.8 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.95 (s, 2H), 6.82 (s, 1H), 6.80 (m, J=76.4 Hz, 1H), 5.43 (m, 1H), 3.44-3.38 (m, 2H), 3.29-3.16 (m, 2H), 2.92-2.89 (m, 1H), 2.54 (s, 6H), 2.41-2.33 (m, 1H); LC-MS: m/z 410.0 [M+H].sup.+.

(618) ##STR00262##

(619) (10 mg, yield 17%, pale yellow oil).sup.1H NMR (400 MHz, CD.sub.3Cl) δ 7.34 (s, 1H), 7.30 (d, J=14.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.94 (s, 2H), 6.82 (d, J=14.4 Hz, 1H), 6.48 (t, J=73.6 Hz, 1H), 5.55 (m, 1H), 3.59 (d, J=14.8 Hz, 1H), 3.19-3.14 (m, 1H), 3.11-3.08 (m, 2H), 2.90-2.81 (m, 1H), 2.64-2.61 (m, 1H), 2.54 (s, 6H); LC-MS: m/z 410.0 [M+H].sup.+.

Example 102

(620) ##STR00263##

(621) (R,E)-1-(3-(1,1-dioxotetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one

(622) The specific reaction scheme is as shown below:

(623) ##STR00264##

(624) The compound (R,E)-1-(3-(tetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (40 mg, 0.1 mmol) was dissolved in dichloromethane (5 mL), and then 85% m-chloroperoxybenzoic acid (61 mg, 0.3 mmol) was added and stirred for 2 hours at room temperature. After the reaction was completed, a saturated aqueous sodium sulfite solution (10 mL) was added, stirred for 10 min, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (R,E)-1-(3-(1,1-dioxotetrahydrothiophen-3-yl)oxy-4-difluoromethoxystyryl)-2,6-dimethylpyridin-4(1H)-one (33 mg, yield 75%, white solid). .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.43 (d, J=1.6 Hz, 1H), 7.38 (dd, J=8.4, 2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.06 (s, 2H), 7.01 (d, J=14.4 Hz, 1H), 6.87 (t, J=75.2 Hz, 1H), 5.43-5.39 (m, 1H), 3.56-8.51 (m, 1H), 3.44-3.36 (m, 2H), 3.31-3.25 (m, 1H), 2.66-2.62 (m, 2H), 2.61 (s, 6H); LC-MS: m/z 426.0 [M+H].sup.+.

Example 103

(625) ##STR00265##

(626) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-methylethenyl)-2,6-dimethylpyridin-4(1H)-one

(627) The specific reaction scheme is as shown below:

(628) ##STR00266##

(629) Step A:

(630) 3-Cyclopropylmethoxy-4-methoxyphenylacetophenone (220 mg, 1.0 mmol) was dissolved in acetonitrile (2 mL); and under nitrogen atmosphere, cesium fluoride (76 mg, 0.50 mmol) was added, trimethylsilyl cyanide (149 mg, 1.50 mmol) was slowly added dropwise at 0° C., and stirred for 5 hours. The reaction solution was filtered, and rotary dried to obtain a crude product of 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-trimethylsiloxy-propionitrile. LC-MS: m/z 320.2 [M+H].sup.+.

(631) Step B:

(632) The compound 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-trimethylsiloxy-propionitrile (319 mg, 1.0 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL); and under nitrogen atmosphere, lithium aluminum hydride (96 mg, 2.0 mmol) was slowly added dropwise at 0° C., and the solution was stirred at room temperature for 1 hr. After the reaction was completed, sodium sulfate decahydrate was added to quench the reaction. Then, the reaction solution was filtered, and the filtrate was rotary dried to obtain a crude product of 1-amino-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-2-propanol. LC-MS: m/z 252.2 [M+H].sup.+.

(633) Step C:

(634) The compound 1-amino-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-2-propanol (251 mg, 1.0 mmol) was dissolved in ethanol (3 mL), and then 2,6-dimethyl-4H-pyran-4-one (186 mg, 1.5 mmol) and sodium hydroxide (80 mg, 2.0 mmol) were added, and stirred overnight at 60° C. The reaction was complete as indicated by LCMS. The reaction solution was rotary dried, and purified to obtain 1-(2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-2-hydroxypropyl)-2,6-dimethylpyridin-4(1H)-one (40 mg, yield 11%). LC-MS: m/z 358.0 [M+H].sup.+.

(635) Step D:

(636) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxypropyl)-2,6-dimethylpyridin-4(1H)-one (36 mg, 0.1 mmol) was dissolved in toluene (3 mL), and then p-toluenesulfonic acid (29 mg, 0.15 mmol) was added and stirred overnight at 110° C. The reaction was complete as indicated by TLC. The reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-methylethenyl)-2,6-dimethylpyridin-4(1H)-one (27 mg, yield 80%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.05-7.03 (m, 1H), 6.92-6.90 (m, 2H), 6.68 (s, 2H), 6.10 (s, 1H), 3.92 (s, 3H), 3.88 (d, J=6.8 Hz, 2H), 2.42 (s, 3H), 2.52 (s, 6H), 1.12-1.06 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H); LC-MS: m/z 340.2 [M+H].sup.+.

Example 104

(637) ##STR00267##

(638) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one

(639) ##STR00268##

(640) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one

(641) ##STR00269##

(642) Step A:

(643) Trisphenyl phosphite (1.49 g, 4.80 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), and then triethyl amine (0.53 mg, 5.20 mmol) and the compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)pyridin-2,6-dimethyl-4(1H)-one (1.36 mg, 4.00 mmol) was slowly added to the reaction solution at −60° C. and stirred for 15 min. Then, bromine (0.77 mg, 4.80 mmol) was slowly added to the reaction solution. After the reaction was completed, the reaction was quenched with a saturated aqueous ammonium chloride solution, and the reaction solution was directly rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-bromoethenyl)-2,6-dimethylpyridin-4(1H)-one (708 mg, yield 44%). LC-MS: m/z 403.9 [M+H].sup.+.

(644) Step B:

(645) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-bromoethenyl)-2,6-dimethylpyridin-4(1H)-one (200 mg, 0.50 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL). Under nitrogen atmosphere, palladium acetate (5.5 mg, 5 mol %), sodium carbonate (5 mg, 0.50 mmol) and phenylboronic acid (73.0 mg, 0.60 mmol) were added to the reaction solution, and stirred at 80° C. for 1 hr. After the reaction was completed, a saturated ammonium chloride solution (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. The reaction solution was filtered, rotary dried, and purified by reverse-phase HPLC to obtain (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one (69 mg, yield 34%, white solid) and (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one (30.4 mg, yield 15%, white solid).

(646) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.40 (s, 1H), 8.35 (s, 1H), 8.06-8.04 (m, 2H), 7.68-7.66 (m, 3H), 7.26-7.20 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.33 (m, 1H), 3.85 (d, J=6.8 Hz, 2H), 3.81 (s, 3H), 2.83 (s, 6H), 0.89-0.82 (m, 1H), 0.62-0.58 (m, 2H), 0.34-0.30 (m, 2H); LC-MS: m/z 401.9 [M+H].sup.+.

(647) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-phenylethenyl)-2,6-dimethylpyridin-4(1H)-one: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.50 (s, 1H), 8.39 (s, 1H), 8.12-8.08 (m, 2H), 7.65-7.62 (m, 3H), 7.32 (d, J=8.4 Hz, 1H), 7.10-7.00 (m, 2H), 6.13 (m, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.81 (s, 3H), 2.83 (s, 6H), 0.89-0.82 (m, 1H), 0.62-0.58 (m, 2H), 0.34-0.30 (m, 2H); LC-MS: m/z 401.9 [M+H].sup.+.

Example 105

(648) ##STR00270##

(649) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)pent-1-en-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one

(650) The specific reaction scheme is as shown below:

(651) ##STR00271##

(652) Step A:

(653) 3-(cyclopropylmethoxy)-4-methoxybenzaldehyde (1.03 g, 5 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL); and under nitrogen atmosphere, 1-ethynylmagnesium bromide (0.5 M, 12 mL, 6 mmol) was added dropwise at 0° C., warmed to room temperature, and stirred for 3 hours at room temperature. The reaction was quenched with a saturated aqueous ammonium chloride solution, and extracted with dichloromethane (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 1-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-alkynyl-1-butanol (1.50 g). LC-MS: m/z 228.9 [M−17].sup.+.

(654) Step B:

(655) The compound 1-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-alkynyl-1-butanol (1.50 g, 5 mmol) was dissolved in dichloromethane (20 mL); and Dess-Martin Periodinane (3.18 g, 7.5 mmol) and solid sodium bicarbonate (6.30 g, 75 mmol) were added at 35° C., and stirred for 1 hr. After the reaction was completed, a saturated sodium bicarbonate solution was added, and extracted with dichloromethane (3×30 mL). The organic phases were combined, and dried over anhydrous sodium sulfate, filtered, rotary dried, and purified to obtain a crude product of 1-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-alkynyl-1-butanol, which was directly used in the next reaction. LC-MS: m/z 249.9 [M+H].sup.+.

(656) Step C:

(657) The compound 1-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-alkynyl-1-butanone (336 mg, 1.5 mmol) was dissolved in acetonitrile (5 mL); and under nitrogen atmosphere, cesium fluoride (114 mg, 0.75 mmol) was added, trimethylsilyl cyanide (225 mg, 2.25 mmol) was slowly added dropwise at 0° C., and stirred for 1.5 hours. After the reaction was completed, the reaction solution was filtered, and rotary dried to obtain a crude product of 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(trimethylsiloxy)pent-3-ynyl nitrile. LC-MS: m/z 344.2 [M+H].sup.+.

(658) Step D:

(659) The compound 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(trimethylsiloxy)-3-alkynylpentyl nitrile (413 mg, 1.5 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL); and under nitrogen atmosphere, lithium aluminum hydride (114 mg, 3.0 mmol) was slowly added dropwise at 0° C., and the solution was stirred at room temperature for 1 hr. After the reaction was completed, sodium sulfate decahydrate was added to quench the reaction. The reaction solution was filtered, and the filtrate was rotary dried to obtain a crude product of 1-amino-2-(3-cyclopropylmethoxy)4-methoxyphenyl)-3-alkynyl-2-pentanol. LC-MS: m/z 276.2 [M+H].sup.+.

(660) Step E:

(661) The compound 1-amino-2-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-3-alkynyl-2-pentanol (413 mg, 1.5 mmol) was dissolved in ethanol (5 mL), and then 2,6-dimethylpyran-4-one (279 mg, 2.25 mmol) and sodium hydroxide (120 mg, 3.0 mmol) were added, and stirred overnight at 60° C. The reaction was complete as indicated by LCMS. The reaction solution was rotary dried, and purified to obtain 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxypent-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (20 mg, yield 3%). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.12-7.07 (m, 2H), 6.86 (d, J=8.4 Hz, 1H), 6.20 (s, 1H), 6.10 (s, 1H), 4.22-4.12 (m, 2H), 3.88 (s, 3H), 3.83 (d, J=7.2 Hz, 2H), 2.42 (s, 3H), 2.20 (s, 3H), 1.88 (s, 3H), 1.34-1.28 (m, 1H), 0.67-0.62 (m, 2H), 0.39-0.35 (m, 2H); LC-MS: m/z 381.9 [M+H].sup.+.

(662) Step F:

(663) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxypent-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (20 mg, 0.05 mmol) was dissolved in toluene (3 mL), and then p-toluenesulfonic acid (15 mg, 0.08 mmol) was added and stirred overnight at 60° C. The reaction was complete as indicated by TLC. The reaction solution was rotary dried, and purified to obtain

(664) (Z)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)pent-1-en-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (18 mg, yield 90%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.27 (dd, J=8.4, 2.0 Hz, 1H), 7.16 (J=8.4 Hz, 1H), 6.92-6.90 (m, 2H), 6.31 (s, 2H), 3.92-3.90 (m, 5H), 2.25 (s, 6H), 1.98 (s, 3H), 1.40-1.31 (m, 1H), 0.70-0.65 (m, 2H), 0.41-0.37 (m, 2H). LC-MS: m/z 363.9 [M+H].sup.+.

Example 106

(665) ##STR00272##

(666) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyanoethenyl)-2,6-dimethylpyridin-4(1H)-one

(667) The specific reaction scheme is as shown below:

(668) ##STR00273##

(669) Step A:

(670) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (2.50 g, 7.3 mmol) was dissolved in dichloromethane (50 mL); and Dess-Martin Periodinane (4.80 g, 11.0 mmol) and sodium bicarbonate (9.00 g, 110 mmol) were slowly added at 35° C., and stirred for 1 hr. After the reaction was completed, a saturated sodium bicarbonate solution (50 mL) was added, and extracted with dichloroethane (3×30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification gave 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2, 6-dimethylpyridin-4(1H)-one (1.98 g, yield 80%, white solid). LC-MS: m/z 342.4 [M+H].sup.+.

(671) Step B:

(672) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-oxoethyl)-2,6-dimethylpyridin-4(1H)-one (500 mg, 1.5 mmol) was dissolved in acetonitrile (25 mL); and under nitrogen atmosphere, triethyl amine (456 mg, 4.5 mmol) was added, trimethylsilyl cyanide (600 mg, 6.0 mmol) was slowly added dropwise at 0° C., and stirred for 4 hours. The reaction solution was rotary dried to obtain a crude product of 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyano-2-(trimethylsilyloxy)ethyl)-2,6-dimethylpyridin-4(1H)-one. LC-MS: m/z 441.4 [M+H].sup.+.

(673) Step C:

(674) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyano-2-(trimethylsilyloxy)ethyl)-2,6-dimethylpyridin-4(1H)-one (660 mg, 1.5 mmol) was dissolved in acetonitrile (25 mL), and aqueous hydrochloric acid (3M, 1.5 mL) was added and stirred at 80° C. for 0.5 hours. The reaction was complete as indicated by TLC. The reaction solution was rotary dried to obtain a crude product of 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyano-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one. LC-MS: m/z 369.4 [M+H].sup.+.

(675) Step D:

(676) The compound 1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyano-2-hydroxyethyl)-2,6-dimethylpyridin-4(1H)-one (552 mg, 1.5 mmol) was dissolved in chloroform (25 mL), and then thionyl chloride (1.0 mL) was added and stirred for 0.5 hours at 80° C. The reaction was complete as indicated by TLC. The reaction solution was rotary dried, and purified to obtain (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyanoethenyl)-2,6-dimethylpyridin-4(1H)-one (283 mg, 54%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.44 (s, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.14 (d, J=1.2 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.36 (s, 2H), 3.95-3.92 (m, 5H), 2.30 (s, 6H), 1.38-1.30 (m, 1H), 0.71-0.67 (m, 2H), 0.42-0.38 (m, 2H). LC-MS: m/z 351.4 [M+H].sup.+.

Example 107

(677) ##STR00274##

(678) (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylamide

(679) The specific reaction scheme is as shown below:

(680) ##STR00275##

(681) (E)-1-(2-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-cyanoethenyl)-2,6-dimethylpyridin-4(1H)-one (500 mg, 1.4 mmol) was dissolved in acetonitrile (10 mL), and then potassium hydroxide (10 wt %, 10 mL) was added at room temperature and stirred at 80° C. for 2 hours. The reaction was complete as indicated by TLC. The reaction solution was directly rotary dried, and purified by column chromatography to obtain (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylamide (140 mg, 27%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.73 (s, 1H), 7.56 (s, 1H), 7.13 (s, 1H), 7.04 (s, 2H), 6.99 (s, 1H), 5.96 (s, 2H), 3.85 (d, J=7.2 Hz, 2H), 3.80 (s, 3H), 2.27 (m, 6H), 0.87-0.84 (m, 1H), 0.61-0.56 (m, 2H), 0.35-0.31 (m, 2H); LC-MS: m/z 369.1 [M+H].sup.+.

Example 108

(682) ##STR00276##

(683) (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N-methylacrylamide

(684) The specific reaction scheme is as shown below:

(685) ##STR00277##

(686) The compound (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylamide (30 mg, 0.08 mmol) was dissolved in N, N-dimethylformamide (0.5 mL), and then 60% sodium hydride (16 mg, 0.4 mmol) was added, and stirred at 70° C. for 0.5 hours. Iodomethane (12 mg, 0.08 mmol) was added to the reaction solution, and stirred at 70° C. for another 1 hr. The reaction solution was quenched with a saturated aqueous ammonium chloride solution, and the reaction solution was directly rotary dried, and purified by column chromatography to obtain (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N-methylacrylamide (5 mg, 17%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.04-7.02 (m, 1H), 6.93-6.91 (m, 2H), 6.63 (s, 1H), 6.28 (s, 2H), 6.02 (s, 1H), 3.92 (s, 3H), 3.88 (d, J=6.8 Hz, 2H), 2.81 (t, J=4.8 Hz, 3H), 2.34 (s, 6H), 0.97-0.83 (m, 1H), 0.76-0.62 (m, 2H), 0.40-0.36 (m, 2H); LC-MS: m/z 383.1 [M+H].sup.+.

Example 109

(687) ##STR00278##

(688) (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-dimethylacrylamide

(689) The specific reaction scheme is as shown below:

(690) ##STR00279##

(691) The compound (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylamide (30 mg, 0.08 mmol) was dissolved in N, N-dimethylformamide (0.5 mL), and then 60% sodium hydride (16 mg, 0.4 mmol) was added, and stirred at 70° C. for 0.5 hours. Iodomethane (24 mg, 0.16 mmol) was added to the reaction solution, and stirred at 70° C. for another 1 hr. The reaction was quenched with a saturated aqueous ammonium chloride solution, and the reaction solution was directly rotary dried and purified by column chromatography to obtain (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-dimethylacrylamide (10 mg, 50%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.70-6.97 (m, 1H), 6.93-6.91 (m, 2H), 6.70 (s, 1H), 6.27 (s, 2H), 3.92 (s, 3H), 3.88 (d, J=6.8 Hz, 2H), 2.92 (s, 3H), 2.78 (s, 3H), 2.37 (s, 6H), 1.37-1.29 (m, 1H), 0.69-0.65 (m, 2H), 0.40-0.36 (m, 2H). LC-MS: m/z 397.1 [M+H].sup.+.

Example 110

(692) ##STR00280##

(693) (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-diethylacrylamide

(694) The specific reaction scheme is as shown below:

(695) ##STR00281##

(696) The compound (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylamide (20 mg, 0.06 mmol) was dissolved in N, N-dimethylformamide (0.5 mL), and then 60% sodium hydride (12 mg, 0.3 mmol) was added, and stirred at 70° C. for 0.5 hours. Iodoethane (19 mg, 0.12 mmol) was added to the reaction solution, and stirred at 70° C. for another 1 hr. The reaction was quenched with a saturated aqueous ammonium chloride solution, and the reaction solution was directly rotary dried and purified by column chromatography to obtain (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-diethylacrylamide (6 mg, 30%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.04-7.01 (m, 1H), 6.95-6.91 (m, 2H), 6.72 (s, 1H), 6.41 (s, 2H), 3.92 (s, 3H), 3.88 (d, J=7.2 Hz, 2H), 3.34-3.31 (m, 2H), 3.18 (q, J=6.8 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H), 0.90-0.82 (m, 1H), 0.81 (t, J=7.2 Hz, 3H), 0.69-0.65 (m, 2H), 0.40-0.36 (m, 2H); LC-MS: m/z 425.1 [M+H].sup.+.

Example 111

(697) ##STR00282##

(698) (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylic acid

(699) The specific reaction scheme is as shown below:

(700) ##STR00283##

(701) Step A:

(702) The compound (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-diethylacrylamide (60.0 mg, 0.16 mmol) was dissolved in N,N-dimethylformamide (5 mL). 4-dimethylaminopyridine (4.0 mg, 0.03 mmol) and triethyl amine (36 mg, 0.36 mmol) were added at 35° C., and then di-tert butyl dicarbonate (71 mg, 0.33 mmol) was slowly added to the reaction solution and stirred for 2 hours. After the reaction was completed, the reaction solution was rotary dried to obtain a crude product of (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-di-tert butyloxycarbonylacrylamide. LC-MS: m/z 569.2 [M+H].sup.+.

(703) Step B:

(704) The compound (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-N,N-di-tert butyloxycarbonylacrylamide (90 mg, 0.16 mmol) was dissolved in methanol (2 mL), and a sodium hydroxide solution (2N, 1 mL) was added to the reaction solution at 35° C. and stirred for 2 hours. After the reaction was completed, water (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified to obtain (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylic acid (23.1 mg, yield 39%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.18-7.16 (d, J=8.0 Hz, 1H), 7.11 (s, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.82 (s, 1H), 3.92 (s, 3H), 3.90 (d, J=6.4 Hz, 2H), 2.6 (s, 6H), 1.33-1.27 (m, 1H), 0.68-0.63 (m, 2H), 0.41-0.35 (m, 2H). LC-MS: m/z 370.1 [M+H].sup.+.

Example 112

(705) ##STR00284##

(706) (Z)-methyl 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylate

(707) The specific reaction scheme is as shown below:

(708) ##STR00285##

(709) The compound (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylic acid (10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL), and one drop of N,N-dimethylformamide was added to the reaction solution. Oxalyl chloride (8 mg, 0.03 mmol) was slowly added to the reaction solution, and stirred for 1 hr. Then, methanol (0.5 mL) was added to the reaction solution. After the reaction was completed, the reaction was quenched with a saturated aqueous ammonium chloride solution, and the reaction solution was directly rotary dried and purified by column chromatography to obtain (Z)-methyl 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylate (3 mg, yield 26%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02 (s, 1H), 7.95 (s, 2H), 7.15 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.94-3.93 (m, 5H), 3.70 (s, 3H), 2.83 (s, 6H), 1.70-1.59 (m, 1H), 0.68-0.63 (m, 2H), 0.40-0.39 (m, 2H); LC-MS: m/z 384.3 [M+H].sup.+.

Example 113

(710) ##STR00286##

(711) (Z)-ethyl 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylate

(712) The specific reaction scheme is as shown below:

(713) ##STR00287##

(714) (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylic acid (10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL), and one drop of N,N-dimethylformamide was added to the reaction solution. Oxalyl chloride (8 mg, 0.03 mmol) was slowly added to the reaction solution, and stirred for 1 hr. Then, ethanol (0.5 mL) was added to the reaction solution. After the reaction was completed, the reaction was quenched with a saturated aqueous ammonium chloride solution, and the reaction solution was directly rotary dried and purified by column chromatography to obtain (Z)-ethyl 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylate (4 mg, yield 34%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.64 (s, 1H), 7.65 (s, 2H), 7.28 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H), 4.00 (d, J=6.8 Hz, 2H), 3.92 (m, 3H), 2.92 (s, 6H), 1.45-1.32 (m, 1H), 1.15 (t, J=14.4 Hz, 3H), 0.67-0.63 (m, 2H), 0.44-0.40 (m, 2H); LC-MS: m/z 398.3 [M+H].sup.+.

Example 114

(715) ##STR00288##

(716) (Z)-1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pent-1-en-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one

(717) The specific reaction scheme is as shown below:

(718) ##STR00289##

(719) Step A:

(720) At room temperature, 4-(difluoromethoxy)-3-hydroxybenzaldehyde (0.964 g, 5.13 mmol) was dissolved in acetonitrile (10 mL), and then potassium carbonate (1.06 g, 7.69 mmol) and bromomethylcyclopropane (0.9 g, 6.67 mmol) were added in sequence, and heated to 80° C. for 3 hours with stirring under nitrogen atmosphere. After the reaction was completed, water (30 mL) was added, and extracted with dichloromethane (3×30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified to obtain 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (1.16 g, yield 93%). LC-MS: m/z 343.2 [M+H].sup.+.

(721) Step B:

(722) The compound 3-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (1.16 g, 4.79 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and then prop-1-yn-1-ylmagnesium bromide (0.5 N, 19.2 mL, 9.6 mmol) was slowly added in an ice bath, and stirred for 16 hours at room temperature under nitrogen atmosphere. After the reaction was completed, the reaction solution was quenched with water (30 mL), and extracted with ethyl acetate (3×60 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, rotary dried, and purified to obtain 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)but-2-yn-1-ol (1.01 g, 74%).

(723) Step C:

(724) The compound 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)but-2-yn-1-ol (1.01 g, 3.58 mmol) was dissolved in dichloromethane (50 mL), and then Dess-Martin periodinane (3.04 g, 7.16 mmol) were added and stirred overnight at room temperature. After the reaction was completed, the reaction solution was filtered, rotary dried, and purified to obtain 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)but-2-yn-1-one (0.96 g, yield 96%).

(725) Step D:

(726) The compound 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)but-2-yn-1-one (0.96 g, 3.43 mmol) was dissolved in dichloromethane (10 mL), and then triethyl amine (0.693 g, 6.86 mmol) and trimethylsilyl cyanide (1.02 g, 10.29 mmol) were added in sequence in an ice bath and stirred for 16 hours under nitrogen atmosphere at room temperature. After the reaction was completed, the reaction solution was directly rotary dried to obtain a crude product of 2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(trimethylsiloxy)pent-3-ynyl nitrile, which was directly used in the next reaction.

(727) Step E:

(728) The compound 2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(trimethylsiloxy)pent-3-ynyl nitrile (1.30 g, 3.43 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL); and then lithium aluminum hydride (0.391 g, 10.29 mmol) was added portion-wise in an ice bath, and stirred overnight at room temperature. After the reaction was completed, water (0.4 mL), a 15% aqueous sodium hydroxide solution (0.4 mL), and water (1.2 mL) were added in sequence, stirred for half an hour, dried over anhydrous sodium sulfate, filtered, and rotary dried to obtain a crude product of 1-amino-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pent-3-yn-2-ol, which was directly used in the next reaction.

(729) Step F:

(730) The compound 1-amino-2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pent-3-yn-2-ol (1.07 g, 3.43 mmol) was dissolved in ethanol (40 mL), and then 2,6-dimethyl-4H-pyran-4-one (0.553 g, 4.46 mmol), sodium hydroxide (206 mg, 5.15 mmol) and water (6 mL) were added in sequence, heated to 60° C., and stirred for 72 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified by column chromatography to obtain 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-hydroxypent-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (120 mg, yield 8%). LC-MS: m/z 418.2 [M+H].sup.+.

(731) Step G:

(732) The compound 1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-hydroxypent-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (120 mg, 0.29 mmol) was dissolved in trichloromethane (10 mL), and heated to 90° C. Then thionyl chloride (0.5 mL) was added and stirred at 90° C. for 15 min. After the reaction was completed, the reaction solution was directly rotary dried to obtain a crude product of 1-(2-chloro-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pent-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one. LC-MS: m/z 436.2 [M+H].sup.+.

(733) Step H:

(734) The compound 1-(2-chloro-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)pent-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (125 mg, 0.29 mmol) was dissolved in ethanol (10 mL), and then sodium hydroxide (72 mg, 1.8 mmol) and water (2 mL) were added in sequence, heated to 90° C., and stirred for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified by reverse-phase HPLC to obtain the product (Z)-1-(2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)pent-1-en-3-yn-1-yl)-2,6-dimethylpyridin-4(1H)-one (2.3 mg, yield 2%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38-7.28 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 7.01 (s, 2H), 6.69 (t, J=75.2 Hz, 1H), 3.97 (d, J=6.4 Hz, 2H), 2.48 (s, 6H), 1.95 (s, 3H), 1.35-1.25 (m, 1H), 0.70-0.65 (m, 2H), 0.42-0.36 (m, 2H); LC-MS: m/z 400.1 [M+H].sup.+.

Example 115

(735) ##STR00290##

(736) (Z)-2-(3,4-dimethoxyphenyl)-3-(2,6dimethyl-4-carbonylpyridine)-1(4H)-yl)acrylonitrile

(737) The specific reaction scheme is as shown below:

(738) ##STR00291##

(739) The compound (Z)-3-(2,6dimethyl-4-carbonylpyridine)-1(4H)-yl)-2-(3-hydroxy4-methoxyphenyl)acrylonitrile (100 mg, 0.34 mmol) was dissolved in acetonitrile (10 mL), and then iodomethane (96 mg, 0.68 mmol) and potassium carbonate (187 mg, 1.35 mmol) were added and stirred for 5 hours at 85° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was rotary dried, and purified by reverse-phase HPLC to obtain (Z)-2-(3,4-dimethoxyphenyl)-3-(2,6dimethyl-4-carbonylpyridine)-1(4H)-yl)acrylonitrile (21 mg, yield 33%, white solid). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.65 (s, 1H), 7.29 (dd, J=8.4, 2.0 Hz, 1H), 7.18 (d, J=2.0 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.51 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 2.37 (s, 6H); LC-MS m/z 311.2 [M+H].sup.+.

Example 116

(740) ##STR00292##

(741) (E)-3-(3-cyclopropylmethoxy-4methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile

(742) ##STR00293##

(743) (Z)-3-(3-cyclopropylmethoxy-4methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile

(744) The specific reaction scheme is as shown below:

(745) ##STR00294##

(746) Step A

(747) 2,6-dimethyl-4H-pyran-4-one (620 mg, 5 mmol) and aminoacetonitrile hydrochloride (463 mg, 6 mmol) were dissolved in pyridine (10 mL), and stirred for 46 hours at 80° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried, and purified by column chromatography to obtain 2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acetonitrile (583 mg, yield 72%, white solid). LC-MS: m/z 163.1 [M+H].sup.+.

(748) Step B

(749) 2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acetonitrile (162 mg, 1 mmol) and 3-cyclopropylmethoxy-4-methoxybenzaldehyde (206 mg, 1 mmol) were dissolved in pyridine (10 mL), and stirred overnight at 100° C. under nitrogen atmosphere. After the reaction was completed, the reaction solution was rotary dried to remove pyridine, and purified by reverse-phase HPLC to obtain (E)-3-(3-cyclopropylmethoxy-4methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile (126 mg, yield 36%, white solid) and (Z)-3-(3-cyclopropylmethoxy-4methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile (20 mg, yield 6%, white solid).

(750) (E)-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.85 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 2.0 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.38 (s, 2H), 3.92 (s, 3H), 3.88 (d, J=6.8 Hz, 2H), 2.22 (s, 6H), 1.26-1.17 (m, 1H), 0.65-0.58 (m, 2H), 0.32-0.26 (m, 2H); LC-MS: m/z 351.2 [M+H].sup.+.

(751) (Z)-3-(3-cyclopropylmethoxy-4methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.58 (s, 1H), 7.23 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.4, 1.6 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 6.09 (s, 2H), 3.80 (s, 3H), 3.53 (d, J=6.8 Hz, 2H), 3.34 (s, 6H), 2.02 (s, 6H), 1.16-1.11 (m, 1H), 0.56-0.52 (m, 2H), 0.27-0.23 (m, 2H); LC-MS: m/z 351.2 [M+H].sup.+.

Example 117

(752) ##STR00295##

(753) (E)-3-(3-propylmethoxy-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylamide

(754) ##STR00296##

(755) (E)-3-(3-cyclopropylmethoxy-4methoxyphenyl)-2(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)acrylonitrile (350 mg, 1 mmol) was dissolved in acetonitrile (10 mL), and then potassium hydroxide (10 wt %, 10 mL) was added at room temperature and stirred at 80° C. for 2 hours. After the reaction was completed, the reaction solution was directly rotary dried, and purified by reverse-phase HPLC to obtain (Z)-2-(3-cyclopropylmethoxy-4-methoxyphenyl)-3-(2,6-dimethyl-4-carbonylpyridin-1(4H)-yl)-acrylamide (247 mg, 67%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.82 (s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.87 (dd, J=8.4, 2.0 Hz, 1H), 6.38 (d, J=2.0 Hz, 1H), 6.14 (s, 2H), 3.80 (s, 3H), 3.51 (d, J=6.8 Hz, 2H), 1.94 (s, 6H), 1.16-1.07 (m, 1H), 0.56-0.51 (m, 2H), 0.27-0.24 (m, 2H); LC-MS: m/z 369.4 [M+H].sup.+.

Example 118

(756) ##STR00297##

(757) (E)-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridine)-1(4H)-yl)-N,N-dimethylacrylamide

(758) The specific reaction scheme is as shown below:

(759) ##STR00298##

(760) The compound (E)-3-(3-(cyclopropylmethoxy)-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridine)-1(4H)acrylamide (37 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), and then 60% sodium hydride (24 mg, 0.6 mmol) was added at 0° C., and stirred for half an hour. Then, iodomethane (43 mg, 0.3 mmol) was added, and stirred at room temperature for 4 hours. After the reaction was completed, saturated saline (10 mL) was added, and extracted with dichloromethane (3×10 mL). The organic phases were combined, and dried over anhydrous sodium sulfate. Filtration, rotary drying, and purification by reverse-phase HPLC gave (E)-3-(3-cyclopropylmethoxy-4-methoxyphenyl)-2-(2,6-dimethyl-4-carbonylpyridine)-1 (4H)-yl)-N, N-dimethylacrylamide (22 mg, yield 55%, white solid). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.28 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.87 (dd, J=8.4, 1.6 Hz, 1H), 6.49 (d, J=1.6 Hz, 1H), 6.09 (s, 2H), 3.80 (s, 3H), 3.53 (d, J=6.8 Hz, 2H), 3.34 (s, 6H), 2.02 (s, 6H), 1.16-1.11 (m, 1H), 0.56-0.52 (m, 2H), 0.27-0.23 (m, 2H); LC-MS: m/z 397.2 [M+H].sup.+.

Example 119

(761) Determination of the inhibition of the compounds on PDE4B1 activity by using cAMP HTRF® assay

(762) The inhibitory effect of the compounds on human PDE4B1 enzyme activity was determined by quantifying the 5′-adenosine monophosphate (5′-AMP) formed from 3′,5′-cyclic adenosine monophosphate (cAMP).

(763) The test compound or water (control) and human recombinant PDE4B1 enzyme (4.8 U) were mixed in a buffer solution (pH 7.4) consisting of 1× Hanks' balanced salt solution (HBSS), 5 mM HEPES, 3 mM MgCl2, and 0.1% BSA and incubated for 10 min. A cAMP enzyme substrate (final concentration 40 nM) was added, and the mixture was incubated at room temperature for 60 min. Then a fluorescent acceptor (Dye2 labeled with cAMP), a fluorescent donor (anti-cAMP antibody labeled with europium cryptate) and a non-specific phosphodiesterase inhibitor IBMX (3-isobutyl-1-methyl xanthine; final concentration 1 mM) were added. After 60 min, the fluorescence transfer related to the amount of remaining cAMP was measured on a microplate reader (Rubystar, BMG) at λex=337 nm, λem=620 nm and λem=665 nm. The enzyme activity is calculated from the ratio of the signals measured at 665 nm and 620 nm. The results are expressed as percent inhibition of the enzyme activity of the control (without PDE4 inhibitor). The enzyme was omitted for measurement of the basic control. The IC50 value (IC50=the concentration that caused the half-maximum inhibition of the specific activity of the control) is derived from dose-response measurements with eight different concentrations (n=2; repeated 2 times)

(764) The experimental results obtained are listed in Table 1.

(765) TABLE-US-00001 Example IC.sub.50 (nM)   1 760   2 125   3 39   4 36   5 5   6 19   7 5.7   8 23   9 25  10 3300  11 44  12 N.A.  13 4.9  14 21  15 33  16 10.3  17 16  18 4.5  19 4.6  20 13  21 4.6  22 20  23 5  24 23  25 11.5  26 39  27 65  28 92  29 93  30 116  31 26  32 13.9  33 830  34 420  35 32  36 1250  37 510  38-1 1090  38-2 71  39 1070  40 6.8  41 1.22  42 8.2  43 4.9  44 30  45 170  46 25  47 7.1  48 420  49 2.9  50 180  51 57  52 N.A.  53 15  54 26  55 54  56 16  57 100  58 5.5  59 5.1  60 1200  61 6.2  62 10.2  63 11.1  64 43  65 520  66 270  67 170  68 27  69 5200  70 8.1  71 1420  72 3900  73 2000  74 38  75 290  76 105  77 26.4  78 36  79 160  80 7  81 1.15  82 7.5  83-1 550  83-2 106  84 230  85 3.8  86-1 310  86-2 81  87 78  88 2.8  89 6.9  90 3.8  91 75  92 94  93 12.9  94 137  95 260  96 2.4  97 3.7  98-1 97  98-2 12.5  99 59 100 1.5 101-1 99 101-2 26 102 50 103 14 104-1 1700 104-2 8400 105 3 106 2.7 107 450 108 760 109 180 110 460 111 6600 112 138 113 170 114 1.6 115 9.9 116-1 460 116-2 35 117 3600 118 320

Example 120

(766) Inhibition of the compounds on proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs)

(767) The effect of the compounds on the release characteristics of TNFa cytokines in frozen human peripheral blood mononuclear cells (PBMCs) was determined.

(768) Fresh human PBMCs were isolated, and suspended in a fresh medium. The PBMC medium (CM) is RPMI1640 containing 10% FBS, 1% PBS, and 2 mM L-glutamine. The cells were plated at a density of 2*10{circumflex over ( )}5 cells/well (100 ul). The test compound was dissolved in DMSO to form a 10 mM sample (DMSO, 100%). The compound was diluted with PBMC medium to the required concentrations. The sample (50 uL) was incubated for 1 hr with cells at 37° C., 5% CO2, after which the inducer (LPS, 1 ug/mL) was added. The inducer+vehicle (LPS+0.05% DMSO) was used as a control in this experiment. The vehicle without inducer was used as a negative control. Crisaborole was used as a positive control. After 24 hours of incubation, the supernatant was extracted and stored at −80° C. The supernatant was thawed and the TNFα level in the supernatant was measured by Luminex4-plex assay.

(769) Result:

(770) Using this experimental method, it is determined that the EC50 of Example 77 is =11 nM, the EC50 of Example 80 is <5 nM; and the EC50 of Example 88 is <5 nM.

Example 121

(771) Test of Inhibition on allergic dermatitis on mouse ear induced by topically administered phorbol ester

(772) The test compounds are used to treat various skin diseases such as itching, redness, dryness, crusting, desquamation, inflammation and discomfort.

(773) The test compound was topically applied to the right ear of the test animal 30 minutes before and 15 minutes after the administration of (12-) phorbol myristate(-13-)acetate (PMA). The dosing volume was 20 ul/ear for a solvent vehicle or 20 mg/ear for a cream.

(774) Male CD-1 mice weighing 24±2 g were used. All animals were maintained in an environment at a controlled temperature (22° C.-23° C.) and humidity (70%-80%), with a 12-h-light and 12-h-dark photoperiod. The animals were raised in the animal room for at least 1 week before they are used for experimental test. The mice were allowed to access food and drinking water freely. Generally, all aspects of this work were carried out in accordance with the guidelines of Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 1996), including animal breeding, experimentation, and handling.

(775) Each group had 5 mice. PMA (4 pg in 20 uL acetone) was applied topically to the front and back surfaces of the right ear of each animal. The vehicle (ethanol:acetone/1:1, 20 μL/ear) or test compound (specified dose in 20 uL of 1:1 acetone:ethanol, for each ear) was applied 30 minutes before and 15 minutes after PMA administration, and crisaborole was administered as a positive control. Then, 6 hours after PMA administration, ear swelling was measured as an indicator of inflammation using a staining micrometer. The percentage of inhibition is calculated according to the following formula: ([IC−IT]/IC)×100%, where IC and IT means the increase in ear thickness (mm) of mice in the control and treatment groups, respectively. 30% or more inhibition is considered to have significant anti-inflammatory activity.

Example 123

(776) Formulation of Topical Preparations.

(777) Compounds of the present invention, such as compound 88, can be administered as a gel, lotion, ointment and solution, and the route of administration includes, but is not limited to, topical administration, instillation, aerosol, transdermal patch, via insertion, or oral administration.

(778) The following is a preparation method of 1% ointment preparation (weight percentage):

(779) 1% compound, 15% PEG400, 0.02% butylated hydroxytoluene, 2% span 80, 10% white wax, and 71.98% white petrolatum were mechanically stirred until an ointment was formed.