# US 11,440,886 B2 · Anti-inflammatory compound, and preparation and use thereof

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- Number: US 11,440,886 B2
- Document ID: US11440886B2
- Status: Granted
- Kind: B2
- Application number: 16/993,289
- Filed: 2020-08-14
- Published: 2020-12-03
- Granted: 2022-09-13
- Earliest claimed: 2018-04-26
- Assignees: E-nitiate Biopharmaceuticals (Hangzhou) Co., Ltd
- Applicants: E-Nitiate Biopharmaceuticals (Hangzhou) Co., Ltd.
- Inventors: Wang Shen; Pengfei Liu; Jinping Zhu; Qiuping Luo; Pingbo Ke; Yufei Liu; Jida Shen
- Web page: https://patentgrep.com/patent/US11440886B2

## CPC

- C07D 213/68: attached in position 4
- A61K 31/4412: having oxo groups directly attached to the heterocyclic ring
- A61K 31/4427: containing further heterocyclic ring systems
- A61K 31/443: containing a five-membered ring with oxygen as a ring hetero atom
- A61K 31/4436: containing a heterocyclic ring having sulfur as a ring hetero atom
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

The present invention provides an anti-inflammatory compound, which is a compound having a structure (I) as shown below: 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

### Claim 1

An anti-inflammatory compound, which is a compound having a structure shown below:
wherein RA 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;
RB 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;
RC is hydrogen, alkyl, halogen, or alkoxy;
RD1 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;
C1-RD1 bond is a single bond or a double bond;
RD2 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 C1 and C2; and
RE is hydrogen, alkyl, or halogen,
wherein when RD1 is aryl, it is unsubstituted aryl, and when RD2 is aryl, it is unsubstituted aryl.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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:
the intermediate product B is a compound having a structure shown below:
the intermediate product C is a compound having a structure shown below:
the intermediate product D is a compound having a structure shown below:
and
the type-A target product is a compound having a structure shown below:
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:
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:

### Claim 4 (depends on 3)

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:
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:
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.

### Claim 5 (depends on 3)

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:

### Claim 6 (depends on 3)

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:
in which X is halogen; and
the type-C-3 target product is a compound having a structure shown below:
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.

### Claim 7 (depends on 1)

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:
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:
the intermediate product 3 is a compound having a structure shown below:
and
the type-A′ target product is a compound having a structure shown below:
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:

### Claim 8 (depends on 3)

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:
the type-C″ target product is a compound having a structure shown below:
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:
the benzaldehyde derivative Z2 is a compound having a structure shown below:
and
the type-CT′ target product is a compound having a structure shown below:

### Claim 9 (depends on 1)

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:
the intermediate product 2 is a compound having a structure shown below:
in which Z is alkyl;
the intermediate product 3 is a compound having a structure shown below:
the intermediate product 4 is a compound having a structure shown below:
the intermediate product 5 is a compound having a structure shown below:
and
the type-D target product is a compound having a structure shown below:

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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

### Claim 12 (depends on 1)

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.

### Claim 13 (depends on 1)

The anti-inflammatory compound according to claim 1, wherein the compound having a structure shown below:
wherein RA 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;
RB 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;
RC is hydrogen;
RD1 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;
C1-RD1 bond is a single bond or a double bond;
RD2 is hydrogen or cyano;
G1 is a single bond, a double bond or cyclopropane comprising C1 and C2; and
RE is alkyl comprising from 1 to 6 carbon atoms or halogen.

### Claim 14 (depends on 1)

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;
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;
(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.